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Classifications

Harrison's Part

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Subtypes

5

Acute pericarditis

A first episode, typically over days, self-limited in most patients treated with a non-steroidal anti-inflammatory drug and colchicine. Most cases in the developed world are idiopathic and presumed post-viral.

Recurrent pericarditis

Relapse after a documented symptom-free interval, and the commonest complication of the disease rather than an unusual outcome. This is the mechanistically distinctive subtype, because it behaves like an autoinflammatory disease rather than like a resolving response to an injury, and because it is the population in which interleukin-1 blockade was tested and approved. A minority of these patients carry variants in genes that cause hereditary periodic fever syndromes. No subtype_term is bound here, because this subtype covers recurrence of any cause and is therefore broader than MONDO:0016662, which is bound to the idiopathic subtype below.

Show evidence (1 reference)

PMID:21873705 SUPPORT Human Clinical

"Recurrence is the most common complication of pericarditis, affecting 10% to 50% of patients."

Establishes recurrence as the dominant complication rather than an uncommon one, which is what justifies curating it as a subtype and what makes prevention from the first episode the standard of care rather than a response to relapse.

Idiopathic recurrent pericarditis MONDO:0016662

The recurrent form with no identified cause, which is the population in which the autoinflammatory account was developed and in which the interleukin-1 blockade trials were run. It is bound to its own MONDO identifier because the genetic and therapeutic evidence in this entry is specific to it rather than to recurrence generally.

Constrictive pericarditis MONDO:0006711

Fibrotic, sometimes calcified, non-compliant pericardium that restricts diastolic filling. It is the structural end state, but not always an irreversible one, since a transient form resolves with anti-inflammatory therapy. Risk of progression is strongly aetiology-dependent and is highest after tuberculous and purulent disease.

Tuberculous pericarditis MONDO:0005903

The dominant form in high-burden settings, particularly with HIV co-infection. It is separated as a subtype because its natural history differs from the idiopathic form in the respect that matters most, namely a much higher rate of progression to constriction, and because its treatment is antimicrobial rather than anti-inflammatory.

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Discussions and Knowledge Gaps

3

Is the association between corticosteroid use and recurrence causal, and if so does it act by leaving the innate loop untouched, by prolonging viral persistence, or by selecting patients whose pain is not inflammatory?

OPEN QUESTION OPEN why_do_corticosteroids_make_recurrence_more_likely

Attached to

pathophysiology#Autoinflammatory recurrence loop

The finding is robust enough to have changed guidelines, since corticosteroid use was an independent risk factor for recurrence in multivariable analysis of a randomised trial. Its interpretation is not settled. The mechanistic reading offered by this entry, that suppressing adaptive immunity does nothing to an innate interleukin-1 loop, is consistent with the drug response pattern but is not directly demonstrated. A competing reading is confounding by indication, since sicker patients receive steroids. A third possibility is raised by the observation that corticosteroid dependence in a recurrent-pericarditis cohort was associated with chronic pain, which would mean part of what is treated as steroid-dependent inflammatory disease is a pain syndrome that steroids cannot fix and that no anti-inflammatory endpoint will capture. These have different consequences for how refractory disease should be managed.

Show evidence (2 references)

PMID:16186437 SUPPORT Human Clinical

"After multivariate analysis, corticosteroid use (OR 4.30, 95% CI 1.21 to 15.25; P=0.024) was an independent risk factor for recurrences."

The observation the question is about. The wide confidence interval is itself part of why the effect size, and therefore its interpretation, remains open.

PMID:35658515 SUPPORT Human Clinical

"We also found that corticosteroid dependence in IRP is associated with chronic noninflammatory pain."

Supports the third reading, that some steroid-dependent disease is not inflammatory. Graded PARTIAL because an association cannot establish which way the relationship runs.

What sustains the interleukin-1 loop between relapses, and is there a point at which interleukin-1 blockade can be stopped without the disease returning?

KNOWLEDGE GAP OPEN interleukin_1_blockade_controls_but_does_not_cure

Attached to

pathophysiology#Autoinflammatory recurrence loop pathophysiology#Interleukin-1 release and cytokine amplification

Both randomised trials of interleukin-1 blockade used a withdrawal design, and both showed the disease returning promptly when the drug was stopped. That is what establishes the mechanism, and it is also the problem, because it means the treatment is suppressive rather than curative and patients face indefinite injections. What holds the loop primed between clinically silent intervals is unknown. Candidate explanations include a persistent stimulus in the pericardium, an epigenetically trained innate immune state, and an underlying autoinflammatory genotype in the subset who carry one, but none has been shown to predict who can stop treatment.

Proposed experiments

Biomarker-guided withdrawal of interleukin-1 blockade

exp_biomarker_guided_il1_withdrawal

In patients in sustained remission on interleukin-1 blockade, randomise withdrawal guided by pericardial late gadolinium enhancement and C-reactive protein against fixed-duration continuation, with autoinflammatory-gene genotype as a prespecified stratifier, to test whether residual pericardial inflammation or genotype identifies who can stop.

Show evidence (1 reference)

PMID:27825009 SUPPORT Human Clinical

"Median flare-free survival (time to flare) was 72 (interquartile range, 64-150) days after randomization in the placebo group and was not reached in the anakinra group (P <.001)."

Shows the disease returning within about ten weeks of withdrawal, which is what makes indefinite treatment the current default and defines the gap.

Does constrictive pericarditis produced by autoimmune myocarditis in a cytokine-deficient mouse model the fibrotic organisation that follows tuberculous, purulent, or radiation pericarditis in patients?

HUMAN MODEL MISMATCH OPEN constriction_model_fidelity

Attached to

pathophysiology#Fibrotic organization of the pericardium pathophysiology#Constrictive physiology

The only established animal model of constriction arises from cardiac-myosin-induced autoimmune myocarditis in interferon-gamma-knockout mice. It reproduces the haemodynamics convincingly and, by matching animals for myocarditis severity, it settles that the physiology is pericardial. But the route to it is a route human patients do not take. Human constriction follows chronic granulomatous infection, purulent infection, cardiac surgery, or irradiation, and the absence of interferon-gamma in the model is not incidental, since interferon-gamma is central to the Th1 response that drives tuberculous pericarditis, the commonest cause of constriction worldwide. A model that removes the cytokine most implicated in the dominant human aetiology may be modelling the phenotype rather than the mechanism. This is a fidelity question, not an absence of evidence, which is why it is recorded as a model mismatch rather than a knowledge gap.

Proposed experiments

Infection-driven model of pericardial constriction

exp_infection_driven_constriction_model

Develop and characterise a constriction model driven by intrapericardial mycobacterial antigen or by a purulent infectious challenge in immunocompetent animals, and compare its pericardial transcriptome and fibrotic architecture against both the interferon-gamma knockout model and human pericardiectomy specimens, to determine which model the human lesion resembles.

Show evidence (1 reference)

PMID:15505106 SUPPORT Model Organism

"Cardiac myosin-induced experimental autoimmune myocarditis in interferon (IFN)-gamma-knockout (KO) mice results in increased cardiac inflammation and development of severe grossly detectable pericarditis."

States the route by which constriction is produced in the model, which is the route that differs from human aetiology. Graded PARTIAL because it supports the model existing without addressing its translational validity, which is the open question.

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Pathophysiology

9

Pericardial injury from a heterogeneous trigger

Viral infection, mycobacterial or pyogenic infection, uraemic toxin accumulation, myocardial or surgical injury, irradiation, malignant infiltration, or systemic autoimmune disease injures the pericardial mesothelium. The list is long and the downstream response is not, which is the central structural feature of this disease. Trigger identity determines the probability of progression to constriction and determines what treats the cause, but it barely determines the acute syndrome. Curating one trigger node rather than a separate chain per aetiology reflects that convergence.

pericardial mesothelial cell CL:0000077

pericardium UBERON:0002407

Downstream

Inflammasome activation in pericardial tissue Injured and stressed mesothelial cells and resident macrophages engage innate immune sensing, which is the first shared step of the response.

Inflammasome activation in pericardial tissue

Innate immune sensing assembles the NLRP3 inflammasome in pericardial mesothelial cells and macrophages. This is the convergence point of the module, and it is established in human pericardial tissue rather than inferred from the drug response alone, with inflammasome components more strongly stained in patients with chronic pericarditis than in controls and the same activation reproduced in a mouse model of the disease.

pericardial mesothelial cell CL:0000077 macrophage CL:0000235

NLRP3 inflammasome complex assembly GO:0044546 ↑ INCREASED

pericardium UBERON:0002407

Experimental models

Zymosan A intrapericardial injection mouse model OTHER The model reproduces inflammasome activation in the pericardium and allows blockers to be compared against each other.

Downstream

Interleukin-1 release and cytokine amplification Assembled inflammasome cleaves pro-interleukin-1-beta to its active form and releases it.

Show evidence (2 references)

PMID:33665514 SUPPORT Human Clinical

"Patients with pericarditis presented an intensification of the inflammasome activation compared with control subjects."

Establishes inflammasome activation in human pericardial tissue rather than in a model system, which is what makes this node a curated mechanism rather than an inference from drug response.

PMID:33665514 SUPPORT Model Organism

"An intense activation of the inflammasome in pericarditis was demonstrated both in humans and in mice."

Confirms the same activation in a mouse model, giving the cross-species convergence that supports it as the mechanism rather than an epiphenomenon of chronic tissue.

Interleukin-1 release and cytokine amplification

Active interleukin-1 alpha and beta drive a nuclear-factor-kappa-B-dependent cascade of interleukin-6, tumour necrosis factor, and chemokines. Interleukin-1 also induces its own production, which is the property that turns an injury response into a self-sustaining loop and gives the disease its tendency to recur. This node is the drug target for the two agents that work in refractory disease.

positive regulation of interleukin-1 beta production GO:0032731 ↑ INCREASED positive regulation of canonical NF-kappaB signal transduction GO:0043123 ↑ INCREASED

Downstream

Acute pericardial inflammatory exudate Cytokine signalling raises microvascular permeability and recruits leukocytes into the pericardium.

Autoinflammatory recurrence loop Interleukin-1-driven induction of further interleukin-1 sustains the response beyond the original trigger in susceptible patients.

Show evidence (1 reference)

PMID:33200890 SUPPORT Human Clinical

"Interleukin-1 has been implicated as a mediator of recurrent pericarditis."

States the premise the trial was designed to test, and the trial result recorded on the treatment entry is what converts that premise into support for this node.

Acute pericardial inflammatory exudate

Neutrophils arrive first and are followed by lymphocytes and macrophages, microvascular permeability rises, and fibrin is deposited on the serosal surfaces. Every feature of the acute clinical syndrome comes from this node. The friction rub is the sound of fibrin-roughened layers moving on each other, the pain is irritation of the pain-sensitive parietal layer, the effusion is the permeability change, and the diffuse rather than territorial electrocardiographic change follows from the fact that the inflamed surface wraps the whole heart instead of following a coronary territory.

neutrophil CL:0000775 macrophage CL:0000235

pericardial sac UBERON:0002406

Downstream

Pericardial effusion accumulation Increased permeability and reduced lymphatic clearance let fluid collect in the pericardial space.

Fibrotic organization of the pericardium Persistent or severe inflammation may organise rather than resolve, with the probability depending strongly on the aetiology rather than on the acute severity.

Autoinflammatory recurrence loop

In a substantial minority the inflammation does not settle after the trigger has gone, and the disease relapses after symptom-free intervals. The loop is innate rather than adaptive, and three independent lines of evidence say so. Interleukin-1 blockade suppresses it and withdrawal releases it. A minority of patients carry variants in the genes that cause hereditary periodic fever syndromes, and pericarditis is itself a recognised feature of those syndromes. And corticosteroids, which act mainly on the adaptive arm, make recurrence more likely rather than less. This node is why recurrent pericarditis is curated as its own subtype rather than as repetition of the acute one.

Downstream

Acute pericardial inflammatory exudate Each relapse reproduces the acute inflammatory response without a new external trigger.

Show evidence (3 references)

PMID:33200890 SUPPORT Human Clinical

"During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group."

A randomised-withdrawal design turns the recurrence rate into a direct measurement of how much of the ongoing disease depends on interleukin-1 signalling, which is the claim this node makes.

PMID:35658515 SUPPORT Human Clinical

"Innate immune modulators, colchicine and anti-interleukin-1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP."

States the inference from drug response to mechanism that this node encodes, and names its provenance in the monogenic autoinflammatory diseases the drugs were developed for.

PMID:35658515 SUPPORT Human Clinical

"Pericarditis was observed in all examined monogenic autoinflammatory diseases (0.4%-3.7% of cases)."

Runs the argument in the other direction. Pericarditis occurs in every monogenic interleukin-1-driven syndrome examined, which is what one expects if the pericardium is a characteristic target of an innate inflammatory loop.

Pericardial effusion accumulation

Fluid collects in a space that normally holds a few tens of millilitres. Whether it matters depends on the rate rather than the volume, because the parietal pericardium stretches slowly and a slowly accumulating effusion of a litre may be tolerated while a rapidly accumulating one of two hundred millilitres is not.

pericardial sac UBERON:0002406

Downstream

Cardiac tamponade Tamponade follows only when the intrapericardial pressure rises to the level of cardiac filling pressures, which depends on the rate of accumulation and the compliance of the sac.

Cardiac tamponade

Intrapericardial pressure rises to equal and then exceed cardiac filling pressures, so the chambers cannot fill in diastole and cardiac output falls. The physiology is compressive rather than contractile, which is what it shares with constriction and with the obstructive shock of pulmonary embolism, and it produces the inspiratory fall in systolic pressure known as pulsus paradoxus through exaggerated ventricular interdependence within a fixed total volume.

pericardial sac UBERON:0002406

Fibrotic organization of the pericardium

Rather than resolving, the inflamed pericardium may organise, with fibroblast activation and excessive matrix deposition, sometimes proceeding to calcification. The likelihood is set by the aetiology and not by the noise of the acute episode, being low after idiopathic and viral disease and high after tuberculous and purulent disease. Radiation-associated fibrosis is the least tractable, since it can appear years after exposure and involves the myocardium and valves alongside the pericardium.

fibroblast CL:0000057

pericardium UBERON:0002407

Experimental models

Interferon-gamma knockout mouse constrictive pericarditis model OTHER Pericardial inflammation and fibrosis are the lesion that produces the phenotype in this model.

Downstream

Constrictive physiology A non-compliant pericardial shell sets a fixed limit on total cardiac volume.

Constrictive physiology

A rigid pericardium caps total cardiac volume, so diastolic pressures equalise across chambers, filling stops abruptly in early diastole, and the ventricles compete for a fixed space. The result is a right-heart-failure syndrome with raised venous pressure, ascites, and oedema in a patient whose ventricular contraction is normal, which is the reason it is routinely mistaken for liver or renal disease. It is not necessarily irreversible. A transient form associated with ongoing inflammation resolves with anti-inflammatory therapy, so the choice between drugs and pericardiectomy turns on distinguishing active inflammation from established fibrosis.

pericardium UBERON:0002407

Experimental models

Interferon-gamma knockout mouse constrictive pericarditis model OTHER The model reproduces the constrictive haemodynamic phenotype and attributes it to the pericardial rather than the myocardial disease.

Show evidence (1 reference)

PMID:15505106 SUPPORT Model Organism

"Comparison of IFN-gamma-KO and wild-type mice matched for the severity of myocardial disease further confirmed that pericarditis, and not myocarditis, was responsible for smaller LV volumes, reduced cardiac output, increased cardiac stiffness, and increased peak filling rate adjusted for..."

Attributes the constrictive haemodynamics specifically to the pericardial rather than the myocardial disease by matching for myocarditis severity, which is exactly the confound that makes the attribution hard in patients.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Metabolism 1

Fever HP:0001945

Respiratory 1

Dyspnoea Dyspnea HP:0002094

Constitutional 1

Pericarditic chest pain HP:0100749

Temporal: ACUTE

Other 8

Pericardial friction rub HP:0034788

Pericardial effusion HP:0001698

Widespread ST-segment elevation HP:0012251

PR-segment depression HP:0031594

Cardiac tamponade HP:0033415

Severity: SEVERE

Pulsus paradoxus HP:6000046

Constrictive pericarditis HP:0002563

Course: PROGRESSIVE

Elevated C-reactive protein Elevated circulating C-reactive protein concentration HP:0011227

Show evidence (1 reference)

PMID:35658515 SUPPORT Human Clinical

"IRP frequently manifested with systemic inflammation"

Supports systemic inflammation as a frequent manifestation in an idiopathic recurrent pericarditis cohort. No frequency band is assigned and no proportion is quoted, because the numeric figure in the source is reported for a referral recurrent-disease population rather than for unselected acute pericarditis.

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Genetic Associations

2

MEFV

Gene: MEFV hgnc:6998 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:35658515 SUPPORT Human Clinical

"Rare deleterious MEFV variants were more frequent in IRP than in ancestry-matched controls (allele frequency 9/200 versus 2932/129 200, P=0.040)."

Establishes the enrichment and, in the same sentence, its fragility. Graded PARTIAL deliberately, because nine variant alleles and a p-value of 0.040 support an association worth recording without supporting a confident effect estimate.

TNFRSF1A

Gene: TNFRSF1A hgnc:11916 relationship_type: SUSCEPTIBILITY variant_origin: GERMLINE

Show evidence (1 reference)

PMID:23745996 SUPPORT Human Clinical

"IRAP patients carrying TNFRSF1A gene mutations have been recently described."

Supports the existence of the association qualitatively. Graded PARTIAL because the report is a description of individual patients carrying rare variants and cannot support a frequency or an effect size.

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Medical Actions

9

Non-steroidal anti-inflammatory therapy

Action: Pharmacotherapy NCIT:C15986

Aspirin or ibuprofen at anti-inflammatory doses, the first-line treatment for symptom control and for suppressing the acute inflammatory response. Aspirin is preferred after myocardial infarction, where other non-steroidal agents may interfere with infarct healing.

Mechanism Target:

INHIBITS Acute pericardial inflammatory exudate — Prostaglandin synthesis inhibition reduces the vascular and nociceptive components of the acute inflammatory response.

Colchicine

Action: Pharmacotherapy NCIT:C15986

Agent: colchicine CHEBI:23359

Added to anti-inflammatory therapy from the first episode, and the single best-evidenced intervention in the disease. Its effect is on recurrence rather than on the acute episode alone, which fits a drug acting on the inflammasome-driven loop rather than on the injury that started it. That it improves pericardial inflammation only partially in experimental models, while interleukin-1 blockade improves it substantially, is consistent with its clinical position as an agent that reduces recurrence without abolishing it.

Mechanism Target:

INHIBITS Autoinflammatory recurrence loop — Colchicine suppresses inflammasome-dependent inflammation, which is the loop that drives recurrence rather than the acute injury response.

Show evidence (3 references)

PMID:23992557 SUPPORT Human Clinical

"The primary outcome occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (relative risk reduction in the colchicine group, 0.56; 95% confidence interval, 0.30 to 0.72; number needed to treat, 4; P<0.001)."

The double-blind trial in a first episode, establishing the reduction in incessant or recurrent pericarditis with a number needed to treat of four.

PMID:21873705 SUPPORT Human Clinical

"At 18 months, the recurrence rate was 24% in the colchicine group and 55% in the placebo group"

Extends the benefit to patients who have already relapsed once, which is the population in which the recurrence loop is established rather than hypothetical.

PMID:33665514 SUPPORT Model Organism

"Colchicine partially improved the pericardial inflammation."

Supports the mechanistic account of colchicine as an incomplete inflammasome-directed agent, which is why it reduces rather than abolishes recurrence. Graded PARTIAL because the observation is in the mouse model and describes an incomplete effect.

Corticosteroid therapy

Action: Pharmacotherapy NCIT:C15986

Reserved as second-line, for patients who cannot take or do not respond to non-steroidal agents and colchicine, or whose pericarditis is part of a systemic autoimmune disease. The reason for the reservation is not toxicity alone. Corticosteroid use was an independent risk factor for recurrence in multivariable analysis of a randomised trial, so the intuitive treatment for an inflamed serosa makes the natural history worse. A plausible reading is that suppressing the adaptive arm does not touch the innate loop that drives relapse, and a separate cohort observation that steroid dependence tracks chronic pain suggests some of what appears to be steroid-dependent disease is not inflammatory at all.

Mechanism Target:

INHIBITS Acute pericardial inflammatory exudate — Corticosteroids suppress the acute inflammatory response, which is why they relieve symptoms quickly while leaving the recurrence loop intact.

Show evidence (4 references)

PMID:16186437 REFUTE Human Clinical

"After multivariate analysis, corticosteroid use (OR 4.30, 95% CI 1.21 to 15.25; P=0.024) was an independent risk factor for recurrences."

Refutes first-line corticosteroid use by showing it independently predicts recurrence. Curated as REFUTE against early use rather than against the drug class in the specific indications where it remains appropriate.

PMID:35658515 SUPPORT Human Clinical

"In this cohort of patients with IRP, corticosteroid dependence was common (39/136, 28.7%) and was associated with chronic pain"

Supports the reading that corticosteroid dependence is entangled with chronic pain. Graded PARTIAL because an association in a referral cohort cannot establish the direction of that relationship.

PMID:25178809 SUPPORT Human Clinical

"Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04)."

The result that runs opposite to the COPE finding above. In tuberculous disease adjunctive prednisolone reduced progression to constriction, where in idiopathic disease corticosteroid use independently predicted recurrence. Two opposite effects of one drug class in one clinical syndrome is the strongest curated evidence in this entry that the syndrome carries more than one mechanism. Graded PARTIAL because it is a secondary endpoint in a trial whose primary outcome was null.

+ 1 more reference

Rilonacept

Action: Pharmacotherapy NCIT:C15986

Agent: rilonacept NCIT:C84137

A soluble interleukin-1 receptor fusion protein that traps both interleukin-1 alpha and interleukin-1 beta, given weekly by subcutaneous injection, and the first agent approved specifically for recurrent pericarditis. Its trial design is what makes it mechanistically informative. Patients were brought into remission on drug and then randomised to continue or withdraw, so the recurrence rate on placebo measures how much of the ongoing disease depends on interleukin-1 rather than how much a drug relieves symptoms.

Mechanism Target:

INHIBITS Interleukin-1 release and cytokine amplification — Trapping interleukin-1 alpha and beta interrupts the self-amplifying cytokine loop at the node that sustains it.

Show evidence (2 references)

PMID:33200890 SUPPORT Human Clinical

"During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group."

The randomised-withdrawal result, which is both the efficacy evidence and the mechanistic evidence that the ongoing disease is interleukin-1 dependent.

PMID:33200890 SUPPORT Human Clinical

"During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days."

Records the speed of response, which matters because a mechanism-directed agent acting on the driver should resolve both symptom and inflammatory marker rather than symptom alone.

Anakinra

Action: Pharmacotherapy NCIT:C15986

Agent: anakinra NCIT:C38717

A recombinant interleukin-1 receptor antagonist, tested in the narrowest and most refractory population in this disease, namely patients with at least three previous recurrences who were both colchicine-resistant and corticosteroid-dependent. That these patients responded is the strongest argument that the refractory phenotype is interleukin-1 driven rather than simply severe.

Mechanism Target:

INHIBITS Interleukin-1 release and cytokine amplification — Receptor antagonism blocks signalling by both interleukin-1 alpha and beta at the same node the interleukin-1 trap acts on, by a different molecular route.

Show evidence (2 references)

PMID:27825009 SUPPORT Human Clinical

"Recurrent pericarditis occurred in 9 of 10 patients (90%; incidence rate, 2.06% of patients per year) assigned to placebo and 2 of 11 patients (18.2%; incidence rate, 0.11% of patients per year) assigned to anakinra"

Quantifies the effect in the colchicine-resistant, corticosteroid-dependent population, which is where the interleukin-1 hypothesis makes its riskiest prediction.

PMID:27825009 SUPPORT Human Clinical

"In this preliminary study of patients with recurrent pericarditis with colchicine resistance and corticosteroid dependence, the use of anakinra compared with placebo reduced the risk of recurrence over a median of 14 months. Larger studies are needed to replicate these findings as well as to..."

The authors' own qualification, curated so the entry records that this is a twenty-one patient trial rather than a definitive one. Graded PARTIAL for that reason.

Antitubercular therapy

Action: Antibiotic Therapy NCIT:C15620

Standard multidrug antitubercular treatment, the aetiology-directed therapy for the tuberculous subtype and the only situation in this disease where killing an organism is the treatment. It is assumed as background standard of care in every arm of the trials conducted in this population, which is why the evidence here establishes it as the platform rather than testing it. The same trial's findings on adjunctive prednisolone are curated on the corticosteroid treatment entry, where they belong, since it was the corticosteroid and not the antitubercular therapy that was randomised.

Mechanism Target:

INHIBITS Pericardial injury from a heterogeneous trigger — Eradicating the organism removes the persistent stimulus driving the response, which is possible only where the trigger is an infection that can be killed.

Show evidence (1 reference)

PMID:25178809 SUPPORT Human Clinical

"Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered."

Establishes antitubercular therapy as the background standard of care in this subtype, and simultaneously records that it is not sufficient, which is why adjunctive strategies were tested at all.

Intensified haemodialysis

Action: Hemodialysis NCIT:C15248

Increasing dialysis dose or initiating dialysis, the aetiology-directed treatment for uraemic and dialysis-associated pericarditis. It is the mechanistic counterpart of antitubercular therapy in a non-infectious setting, since both remove the persistent stimulus rather than suppressing the response to it, and it is the reason this aetiology is the one where an anti-inflammatory drug is not the first move.

Mechanism Target:

INHIBITS Pericardial injury from a heterogeneous trigger — Clearing the accumulated uraemic solutes removes the substance injuring the pericardium.

Show evidence (1 reference)

PMID:28873222 SUPPORT Human Clinical

"Uremic pericarditis, the most common manifestation of uremic pericardial disease, is a contemporary problem that calls for intensive hemodialysis, anti-inflammatories, and often, drainage of large inflammatory pericardial effusions."

States intensive haemodialysis as a component of treatment in this aetiology, which is the claim this treatment entry makes.

Pericardiocentesis

Action: Pericardiocentesis NCIT:C52010

Drainage of pericardial fluid, required urgently for tamponade and used diagnostically for undiagnosed large effusions. It relieves the haemodynamic consequence without touching the inflammation that produced it.

Mechanism Target:

INHIBITS Cardiac tamponade — Removing fluid lowers intrapericardial pressure below cardiac filling pressures and restores diastolic filling.

Pericardiectomy

Action: Pericardiectomy NCIT:C51643

Surgical removal of the constricting pericardium, the definitive treatment for fixed constriction. Outcome depends heavily on aetiology, and radiation-associated constriction does worst, with around one in ten dying perioperatively and roughly a third alive at ten years. Those numbers are the argument for distinguishing reversible from fixed constriction before operating rather than after.

Mechanism Target:

INHIBITS Constrictive physiology — Removing the rigid shell lifts the fixed limit on cardiac volume and allows diastolic filling to resume.

Show evidence (2 references)

PMID:34547827 SUPPORT Human Clinical

"The overall operative mortality was 10.1% (n = 10)."

Quantifies the perioperative risk in the radiation-associated group. Graded PARTIAL because it supports the operation being high-risk in this aetiology rather than supporting or refuting the operation in general.

PMID:34547827 SUPPORT Human Clinical

"The overall 1, 5-, and 10-years survival was 73.6%, 53.4%, and 32.1%, respectively."

Records the long-term survival that makes radiation-associated constriction the worst surgical aetiology, which is the aetiology-dependence this entry curates.

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Environmental Factors

3

Mediastinal irradiation

Radiotherapy to the mediastinum, historically for Hodgkin lymphoma and for breast cancer, causes both acute pericarditis and a delayed fibrosing constrictive disease that may appear years to decades later. It is curated separately from the other triggers because its outcome is the worst of any aetiology, with poor long-term survival after pericardiectomy, and because it is iatrogenic and therefore preventable by treatment planning.

Show evidence (1 reference)

PMID:34547827 SUPPORT Human Clinical

"Pericardiectomy for postradiation constrictive pericarditis has been reported to generally have unfavorable outcomes."

A 100-patient cohort of pericardiectomy performed specifically for constrictive pericarditis following mediastinal irradiation establishes mediastinal irradiation as a recognized cause of pericardial disease.

Mechanism Target:

TRIGGERS Pericardial injury from a heterogeneous trigger — Ionising radiation injures the pericardial mesothelium and microvasculature, entering the shared chain at the trigger node.

EXACERBATES Fibrotic organization of the pericardium — Radiation injury biases the pericardium towards fibrotic organisation rather than resolution, which is why constriction is the characteristic late outcome.

Show evidence (1 reference)

PMID:34547827 SUPPORT Human Clinical

"Pericardiectomy performed for radiation-associated constrictive pericarditis has poor long-term outcomes."

Establishes radiation-associated constriction as a distinct and worse entity than constriction from other causes, which is the basis for curating this exposure as acting on the fibrotic node rather than only on the trigger node.

End-stage renal disease and uraemia

Accumulated uraemic solutes inflame the pericardium in advanced renal failure, and an analogous syndrome occurs in patients already on dialysis when dialysis is inadequate. It is the one aetiology whose first-line treatment is neither anti-inflammatory nor antimicrobial but removal of the causative solutes.

Show evidence (1 reference)

PMID:28873222 SUPPORT Human Clinical

"A rising prevalence of end-stage renal disease (ESRD) has led to a rise in ESRD-related pericardial syndromes, calling for a better understanding of its pathophysiology, diagnoses, and management."

Establishes end-stage renal disease and its associated uraemia as a recognized cause of pericardial syndromes, including pericarditis.

Mechanism Target:

TRIGGERS Pericardial injury from a heterogeneous trigger — Uraemic solute accumulation injures the pericardium directly, entering the shared chain at the trigger node.

Show evidence (1 reference)

PMID:28873222 SUPPORT Human Clinical

"Uremic pericarditis, the most common manifestation of uremic pericardial disease, is a contemporary problem that calls for intensive hemodialysis, anti-inflammatories, and often, drainage of large inflammatory pericardial effusions."

Identifies uraemia as a distinct pericarditis aetiology and records that intensified dialysis is part of its treatment, which is the observation supporting a solute-driven trigger.

Cardiac injury and surgery

Myocardial infarction, cardiac surgery, catheter procedures, device implantation, and chest trauma all produce a delayed pericarditis grouped as post-cardiac injury syndrome. The latency between the injury and the syndrome is the clue to its immune-mediated character, and it includes the entity long known as Dressler syndrome.

Show evidence (1 reference)

PMID:38559602 SUPPORT Human Clinical

"All these conditions give rise to PCIS due to an inciting cardiac injury to pericardial or pleural mesothelial cells, leading to subsequent inflammation syndromes ranging from uncomplicated pericarditis to massive pleural effusion."

Establishes that myocardial infarction, cardiac surgery, catheter procedures, device implantation, and chest trauma converge on a shared cardiac-injury trigger that causes pericarditis.

Mechanism Target:

TRIGGERS Pericardial injury from a heterogeneous trigger — Mechanical or ischaemic injury to the heart exposes the pericardium to injured tissue and initiates the shared response after a latent period.

Show evidence (1 reference)

PMID:38559602 SUPPORT Human Clinical

"Post-cardiac injury syndrome (PCIS) is an umbrella term used for the post-pericardiotomy syndrome, post-myocardial infarction (MI) related pericarditis (Dressler syndrome), and post-traumatic pericarditis"

Establishes that these distinct injuries are grouped as one syndrome, which is the clinical expression of the etiological convergence this entry models with a single trigger node.

🔬

Biochemical Markers

2

C-reactive protein

Cardiac troponin

🔬

Diagnosis

3

Clinical diagnosis from pain, rub, electrocardiogram, and effusion

The diagnosis is made when at least two of four features are present, namely characteristic pericarditic chest pain, a friction rub, widespread ST-segment elevation or PR-segment depression, and a new or worsening pericardial effusion. No single feature is required, which reflects that each is intermittent or absent in a substantial fraction of cases.

C-reactive protein guided treatment and activity decisions

The acute-phase response is used to time the taper of anti-inflammatory therapy and the return to exercise, rather than only to support the diagnosis. This is unusual among cardiovascular diseases and follows from inflammation being the disease rather than a marker of it.

Cardiac magnetic resonance to distinguish reversible from fixed constriction

Pericardial late gadolinium enhancement identifies ongoing pericardial inflammation, which is what separates the transient constriction that resolves on anti-inflammatory therapy from fixed fibrocalcific disease requiring surgery. Given the operative mortality of pericardiectomy this distinction is the highest-stakes decision in the disease.

📈

Progression

4

Acute episode

Days to a few weeks. Most idiopathic and viral disease resolves with a non-steroidal anti-inflammatory drug and colchicine.

Recurrence

Relapse after a symptom-free interval, the commonest complication. Its frequency is the reason colchicine is given from the first episode rather than after a first relapse.

Show evidence (1 reference)

PMID:21873705 SUPPORT Human Clinical

"Recurrence is the most common complication of pericarditis, affecting 10% to 50% of patients."

States the frequency and the position of recurrence as the dominant complication of the disease.

Refractory recurrent disease

A subgroup becomes colchicine-resistant and corticosteroid-dependent, with substantial morbidity from both the disease and its treatment. This is the population in which interleukin-1 blockade was tested, and in which corticosteroid dependence was found to track chronic pain as well as inflammation.

Constriction

Fibrotic organisation restricting diastolic filling, developing over months to years. Risk is aetiology-dependent, low after idiopathic and viral disease and much higher after tuberculous and purulent pericarditis. Radiation-associated constriction may appear years to decades after exposure and carries the worst surgical outcome.

📊

Prevalence

1

Worldwide

Unknown Unknown

No population occurrence figure is recorded, because no reference cited in this entry reports one. Pericarditis is common as a proportion of emergency presentations with chest pain, and tuberculous pericarditis dominates in high-burden settings, but quantifying either would require sources this entry does not cite.

🔀

Differential Diagnoses

4

Conditions with similar clinical presentations that must be differentiated from Pericarditis:

ST-elevation myocardial infarction

Overlapping Features Shares chest pain and ST-segment elevation. The distinction is geometric. Pericarditis inflames a surface that wraps the whole heart and produces widespread concave elevation without reciprocal depression, whereas infarction follows one coronary territory. Getting it wrong in the direction of infarction leads to unnecessary catheterisation, and in the other direction to a missed occlusion.

Restrictive cardiomyopathy

Overlapping Features Shares the physiology of impaired diastolic filling with preserved contraction and is the hardest differential in constriction. The distinction matters absolutely, because pericardiectomy treats one and does nothing for the other, and it turns on ventricular interdependence, which is present when a rigid shell forces the ventricles to share a fixed volume and absent when the myocardium itself is stiff.

Pulmonary embolism

Overlapping Features Shares pleuritic chest pain, breathlessness, and, in the tamponade case, obstructive shock with raised venous pressure and a clear chest. Both impair ventricular filling rather than contraction.

Myocarditis

Overlapping Features Not so much a differential as an overlapping process, since the same inflammation extends into the subepicardial myocardium in a substantial minority and raises troponin. The overlap matters because myocardial involvement changes exercise advice and arrhythmia risk.

🧫

Experimental Models

2

Interferon-gamma knockout mouse constrictive pericarditis model OTHER

Cardiac myosin-induced experimental autoimmune myocarditis in interferon-gamma-deficient mice, which develop grossly visible pericarditis with pericardial inflammation and fibrosis and a haemodynamic phenotype reproducing human constriction, including the square-root sign on pressure tracing. Its value is that it solves an attribution problem. Because the model also produces myocarditis, the authors matched animals for myocardial disease severity and showed the constrictive haemodynamics tracked the pericardial disease and not the myocardial disease, which is the confound that makes restrictive and constrictive physiology hard to separate in patients. Its limitation is that constriction arises here from an autoimmune myocarditis protocol in a cytokine-deficient animal, which is not how human constriction arises.

Organism

house mouse NCBITaxon:10090

Publication

PMID:15505106

Pathograph links

Constrictive physiology The model reproduces the constrictive haemodynamic phenotype and attributes it to the pericardial rather than the myocardial disease.

Fibrotic organization of the pericardium Pericardial inflammation and fibrosis are the lesion that produces the phenotype in this model.

Show evidence (2 references)

PMID:15505106 SUPPORT Model Organism

"Constrictive pericarditis represents a serious hemodynamic syndrome that may lead to heart failure. Studies of its pathophysiological mechanisms have been impeded by the lack of an animal model."

States the gap this model was built to fill, which is also the reason mechanistic understanding of constriction lags behind that of the acute disease.

PMID:15505106 SUPPORT Model Organism

"This phenotype was not associated with the severity of myocarditis but correlated with the presence of grossly detectable adhesive pericarditis present only in the KO group and characterized by increased pericardial inflammation and fibrosis."

The dissociation from myocarditis severity, which is what makes the model informative about pericardial rather than myocardial mechanism.

Zymosan A intrapericardial injection mouse model OTHER

Intrapericardial injection of zymosan A, producing pericardial inflammation with inflammasome activation matching that seen in human pericardial tissue. It was used to test inflammasome blockers against colchicine, and it is the source of the observation that colchicine improves pericardial inflammation only partially where interleukin-1 directed agents improve it substantially.

Organism

house mouse NCBITaxon:10090

Publication

PMID:33665514

Pathograph links

Inflammasome activation in pericardial tissue The model reproduces inflammasome activation in the pericardium and allows blockers to be compared against each other.

Show evidence (2 references)

PMID:33665514 SUPPORT Model Organism

"A mouse model of pericarditis was developed through the intrapericardial injection of zymosan A."

Describes the model and its route of induction.

PMID:33665514 SUPPORT Model Organism

"Among inflammasome blockers, NLRP3 inflammasome inhibitor, anakinra, and interleukin-1 trap were found to significantly improve pericardial alterations."

Provides the preclinical counterpart of the two clinical trials curated on the treatment entries, testing the same pathway from the opposite direction.

{ }

Source YAML

click to show

name: Pericarditis
creation_date: "2026-08-10T03:40:00Z"
category: Complex
disease_term:
  preferred_term: pericarditis
  term:
    id: MONDO:0005904
    label: pericarditis
description: >
  Inflammation of the pericardium, the fibroserous sac enclosing the heart. Two facts organise
  the entry. The first is that the pericardium has a narrow repertoire. Viral infection,
  tuberculosis, uraemia, cardiac surgery, myocardial infarction, radiotherapy, malignancy, and
  systemic autoimmune disease all converge on the same inflammatory response, which is why the
  clinical syndrome is nearly identical across causes and why the largest aetiological category
  in the developed world is idiopathic. The second is that the engine of recurrence is
  autoinflammatory rather than autoimmune. It runs on the innate immune system, on the NLRP3
  inflammasome and interleukin-1, not on adaptive immunity, and the demonstration is therapeutic
  rather than merely correlative. Withdrawing an interleukin-1 trap from patients in remission
  returned three-quarters of them to relapse within weeks while those who stayed on drug did not
  relapse. The same logic explains the trap that runs the other way. Corticosteroids, which
  suppress the adaptive arm and are the intuitive treatment for an inflamed serosa, are an
  independent risk factor for recurrence.
parents:
- pericardium disorder
- inflammatory disease

classifications:
  harrisons_chapter:
  - classification_value: CARDIOVASCULAR
    notes: >-
      Curated as cardiovascular because the affected structure and the haemodynamic consequences
      are cardiac. Its mechanism belongs to innate immunology, and the recurrent form is treated
      with drugs developed for hereditary periodic fever syndromes, so an immunological
      classification captures the biology better than the anatomy does.

has_subtypes:
- name: Acute pericarditis
  display_name: Acute pericarditis
  description: >
    A first episode, typically over days, self-limited in most patients treated with a
    non-steroidal anti-inflammatory drug and colchicine. Most cases in the developed world are
    idiopathic and presumed post-viral.
- name: Recurrent pericarditis
  display_name: Recurrent pericarditis
  description: >
    Relapse after a documented symptom-free interval, and the commonest complication of the
    disease rather than an unusual outcome. This is the mechanistically distinctive subtype,
    because it behaves like an autoinflammatory disease rather than like a resolving response to
    an injury, and because it is the population in which interleukin-1 blockade was tested and
    approved. A minority of these patients carry variants in genes that cause hereditary periodic
    fever syndromes. No subtype_term is bound here, because this subtype covers recurrence of any
    cause and is therefore broader than MONDO:0016662, which is bound to the idiopathic subtype
    below.
  evidence:
  - reference: PMID:21873705
    reference_title: "Colchicine for recurrent pericarditis (CORP): a randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrence is the most common complication of pericarditis, affecting 10% to 50% of patients."
    explanation: >-
      Establishes recurrence as the dominant complication rather than an uncommon one, which is
      what justifies curating it as a subtype and what makes prevention from the first episode
      the standard of care rather than a response to relapse.
- name: Recurrent pericarditis idiopathic
  display_name: Idiopathic recurrent pericarditis
  subtype_term:
    preferred_term: idiopathic recurrent pericarditis
    term:
      id: MONDO:0016662
      label: idiopathic recurrent pericarditis
  description: >
    The recurrent form with no identified cause, which is the population in which the
    autoinflammatory account was developed and in which the interleukin-1 blockade trials were
    run. It is bound to its own MONDO identifier because the genetic and therapeutic evidence in
    this entry is specific to it rather than to recurrence generally.
- name: Constrictive pericarditis
  display_name: Constrictive pericarditis
  subtype_term:
    preferred_term: constrictive pericarditis
    term:
      id: MONDO:0006711
      label: constrictive pericarditis
  description: >
    Fibrotic, sometimes calcified, non-compliant pericardium that restricts diastolic filling.
    It is the structural end state, but not always an irreversible one, since a transient form
    resolves with anti-inflammatory therapy. Risk of progression is strongly aetiology-dependent
    and is highest after tuberculous and purulent disease.
- name: Tuberculous pericarditis
  display_name: Tuberculous pericarditis
  subtype_term:
    preferred_term: pericardial tuberculosis
    term:
      id: MONDO:0005903
      label: pericardial tuberculosis
  description: >
    The dominant form in high-burden settings, particularly with HIV co-infection. It is
    separated as a subtype because its natural history differs from the idiopathic form in the
    respect that matters most, namely a much higher rate of progression to constriction, and
    because its treatment is antimicrobial rather than anti-inflammatory.

pathophysiology:
- name: Pericardial injury from a heterogeneous trigger
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Tissue Injury"
  description: >
    Viral infection, mycobacterial or pyogenic infection, uraemic toxin accumulation, myocardial
    or surgical injury, irradiation, malignant infiltration, or systemic autoimmune disease
    injures the pericardial mesothelium. The list is long and the downstream response is not,
    which is the central structural feature of this disease. Trigger identity determines the
    probability of progression to constriction and determines what treats the cause, but it
    barely determines the acute syndrome. Curating one trigger node rather than a separate
    chain per aetiology reflects that convergence.
  cell_types:
  - preferred_term: pericardial mesothelial cell
    term:
      id: CL:0000077
      label: mesothelial cell
  locations:
  - preferred_term: pericardium
    term:
      id: UBERON:0002407
      label: pericardium
  downstream:
  - target: Inflammasome activation in pericardial tissue
    causal_link_type: DIRECT
    description: >
      Injured and stressed mesothelial cells and resident macrophages engage innate immune
      sensing, which is the first shared step of the response.

- name: Inflammasome activation in pericardial tissue
  biological_scale: CELLULAR
  description: >
    Innate immune sensing assembles the NLRP3 inflammasome in pericardial mesothelial cells and
    macrophages. This is the convergence point of the module, and it is established in human
    pericardial tissue rather than inferred from the drug response alone, with inflammasome
    components more strongly stained in patients with chronic pericarditis than in controls and
    the same activation reproduced in a mouse model of the disease.
  cell_types:
  - preferred_term: pericardial mesothelial cell
    term:
      id: CL:0000077
      label: mesothelial cell
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  biological_processes:
  - preferred_term: NLRP3 inflammasome complex assembly
    term:
      id: GO:0044546
      label: NLRP3 inflammasome complex assembly
    modifier: INCREASED
  locations:
  - preferred_term: pericardium
    term:
      id: UBERON:0002407
      label: pericardium
  evidence:
  - reference: PMID:33665514
    reference_title: "The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Patients with pericarditis presented an intensification of the inflammasome activation compared with control subjects."
    explanation: >-
      Establishes inflammasome activation in human pericardial tissue rather than in a model
      system, which is what makes this node a curated mechanism rather than an inference from
      drug response.
  - reference: PMID:33665514
    reference_title: "The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "An intense activation of the inflammasome in pericarditis was demonstrated both in humans and in mice."
    explanation: >-
      Confirms the same activation in a mouse model, giving the cross-species convergence that
      supports it as the mechanism rather than an epiphenomenon of chronic tissue.
  downstream:
  - target: Interleukin-1 release and cytokine amplification
    causal_link_type: DIRECT
    description: >
      Assembled inflammasome cleaves pro-interleukin-1-beta to its active form and releases it.

- name: Interleukin-1 release and cytokine amplification
  biological_scale: MOLECULAR
  description: >
    Active interleukin-1 alpha and beta drive a nuclear-factor-kappa-B-dependent cascade of
    interleukin-6, tumour necrosis factor, and chemokines. Interleukin-1 also induces its own
    production, which is the property that turns an injury response into a self-sustaining loop
    and gives the disease its tendency to recur. This node is the drug target for the two agents
    that work in refractory disease.
  biological_processes:
  - preferred_term: positive regulation of interleukin-1 beta production
    term:
      id: GO:0032731
      label: positive regulation of interleukin-1 beta production
    modifier: INCREASED
  - preferred_term: positive regulation of canonical NF-kappaB signal transduction
    term:
      id: GO:0043123
      label: positive regulation of canonical NF-kappaB signal transduction
    modifier: INCREASED
  evidence:
  - reference: PMID:33200890
    reference_title: "Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Interleukin-1 has been implicated as a mediator of recurrent pericarditis."
    explanation: >-
      States the premise the trial was designed to test, and the trial result recorded on the
      treatment entry is what converts that premise into support for this node.
  downstream:
  - target: Acute pericardial inflammatory exudate
    causal_link_type: DIRECT
    description: >
      Cytokine signalling raises microvascular permeability and recruits leukocytes into the
      pericardium.
  - target: Autoinflammatory recurrence loop
    causal_link_type: DIRECT
    description: >
      Interleukin-1-driven induction of further interleukin-1 sustains the response beyond the
      original trigger in susceptible patients.

- name: Acute pericardial inflammatory exudate
  biological_scale: TISSUE
  description: >
    Neutrophils arrive first and are followed by lymphocytes and macrophages, microvascular
    permeability rises, and fibrin is deposited on the serosal surfaces. Every feature of the
    acute clinical syndrome comes from this node. The friction rub is the sound of
    fibrin-roughened layers moving on each other, the pain is irritation of the pain-sensitive
    parietal layer, the effusion is the permeability change, and the diffuse rather than
    territorial electrocardiographic change follows from the fact that the inflamed surface
    wraps the whole heart instead of following a coronary territory.
  cell_types:
  - preferred_term: neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  - preferred_term: macrophage
    term:
      id: CL:0000235
      label: macrophage
  locations:
  - preferred_term: pericardial sac
    term:
      id: UBERON:0002406
      label: pericardial sac
  downstream:
  - target: Pericardial effusion accumulation
    causal_link_type: DIRECT
    description: >
      Increased permeability and reduced lymphatic clearance let fluid collect in the pericardial
      space.
  - target: Fibrotic organization of the pericardium
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Persistent or severe inflammation may organise rather than resolve, with the probability
      depending strongly on the aetiology rather than on the acute severity.

- name: Autoinflammatory recurrence loop
  biological_scale: ORGANISM
  description: >
    In a substantial minority the inflammation does not settle after the trigger has gone, and
    the disease relapses after symptom-free intervals. The loop is innate rather than adaptive,
    and three independent lines of evidence say so. Interleukin-1 blockade suppresses it and
    withdrawal releases it. A minority of patients carry variants in the genes that cause
    hereditary periodic fever syndromes, and pericarditis is itself a recognised feature of those
    syndromes. And corticosteroids, which act mainly on the adaptive arm, make recurrence more
    likely rather than less. This node is why recurrent pericarditis is curated as its own
    subtype rather than as repetition of the acute one.
  evidence:
  - reference: PMID:33200890
    reference_title: "Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group."
    explanation: >-
      A randomised-withdrawal design turns the recurrence rate into a direct measurement of how
      much of the ongoing disease depends on interleukin-1 signalling, which is the claim this
      node makes.
  - reference: PMID:35658515
    reference_title: "Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Innate immune modulators, colchicine and anti-interleukin-1 agents, pioneered in monogenic autoinflammatory diseases, have demonstrated remarkable efficacy in trials, suggesting that autoinflammation may contribute to IRP."
    explanation: >-
      States the inference from drug response to mechanism that this node encodes, and names its
      provenance in the monogenic autoinflammatory diseases the drugs were developed for.
  - reference: PMID:35658515
    reference_title: "Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pericarditis was observed in all examined monogenic autoinflammatory diseases (0.4%-3.7% of cases)."
    explanation: >-
      Runs the argument in the other direction. Pericarditis occurs in every monogenic
      interleukin-1-driven syndrome examined, which is what one expects if the pericardium is a
      characteristic target of an innate inflammatory loop.
  downstream:
  - target: Acute pericardial inflammatory exudate
    causal_link_type: DIRECT
    description: >
      Each relapse reproduces the acute inflammatory response without a new external trigger.

- name: Pericardial effusion accumulation
  biological_scale: ORGANISM
  description: >
    Fluid collects in a space that normally holds a few tens of millilitres. Whether it matters
    depends on the rate rather than the volume, because the parietal pericardium stretches slowly
    and a slowly accumulating effusion of a litre may be tolerated while a rapidly accumulating
    one of two hundred millilitres is not.
  locations:
  - preferred_term: pericardial sac
    term:
      id: UBERON:0002406
      label: pericardial sac
  downstream:
  - target: Cardiac tamponade
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >
      Tamponade follows only when the intrapericardial pressure rises to the level of cardiac
      filling pressures, which depends on the rate of accumulation and the compliance of the sac.

- name: Cardiac tamponade
  biological_scale: ORGANISM
  description: >
    Intrapericardial pressure rises to equal and then exceed cardiac filling pressures, so the
    chambers cannot fill in diastole and cardiac output falls. The physiology is compressive
    rather than contractile, which is what it shares with constriction and with the obstructive
    shock of pulmonary embolism, and it produces the inspiratory fall in systolic pressure known
    as pulsus paradoxus through exaggerated ventricular interdependence within a fixed total
    volume.
  locations:
  - preferred_term: pericardial sac
    term:
      id: UBERON:0002406
      label: pericardial sac

- name: Fibrotic organization of the pericardium
  biological_scale: TISSUE
  conforms_to: "fibrotic_response#Excessive ECM Deposition"
  description: >
    Rather than resolving, the inflamed pericardium may organise, with fibroblast activation and
    excessive matrix deposition, sometimes proceeding to calcification. The likelihood is set by
    the aetiology and not by the noise of the acute episode, being low after idiopathic and viral
    disease and high after tuberculous and purulent disease. Radiation-associated fibrosis is the
    least tractable, since it can appear years after exposure and involves the myocardium and
    valves alongside the pericardium.
  cell_types:
  - preferred_term: fibroblast
    term:
      id: CL:0000057
      label: fibroblast
  locations:
  - preferred_term: pericardium
    term:
      id: UBERON:0002407
      label: pericardium
  downstream:
  - target: Constrictive physiology
    causal_link_type: DIRECT
    description: >
      A non-compliant pericardial shell sets a fixed limit on total cardiac volume.

- name: Constrictive physiology
  biological_scale: ORGANISM
  description: >
    A rigid pericardium caps total cardiac volume, so diastolic pressures equalise across
    chambers, filling stops abruptly in early diastole, and the ventricles compete for a fixed
    space. The result is a right-heart-failure syndrome with raised venous pressure, ascites,
    and oedema in a patient whose ventricular contraction is normal, which is the reason it is
    routinely mistaken for liver or renal disease. It is not necessarily irreversible. A
    transient form associated with ongoing inflammation resolves with anti-inflammatory therapy,
    so the choice between drugs and pericardiectomy turns on distinguishing active inflammation
    from established fibrosis.
  locations:
  - preferred_term: pericardium
    term:
      id: UBERON:0002407
      label: pericardium
  evidence:
  - reference: PMID:15505106
    reference_title: "Novel model of constrictive pericarditis associated with autoimmune heart disease in interferon-gamma-knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Comparison of IFN-gamma-KO and wild-type mice matched for the severity of myocardial disease further confirmed that pericarditis, and not myocarditis, was responsible for smaller LV volumes, reduced cardiac output, increased cardiac stiffness, and increased peak filling rate adjusted for end-diastolic volumes in KO mice."
    explanation: >-
      Attributes the constrictive haemodynamics specifically to the pericardial rather than the
      myocardial disease by matching for myocarditis severity, which is exactly the confound that
      makes the attribution hard in patients.

phenotypes:
- category: Symptom
  name: Pericarditic chest pain
  description: >
    Sharp retrosternal or left precordial pain, worse lying flat and on inspiration, relieved by
    sitting forward. The positional character is mechanical and follows from the inflamed
    parietal layer being loaded differently in different postures, which is what distinguishes it
    at the bedside from ischaemic pain.
  phenotype_term:
    preferred_term: Chest pain
    term:
      id: HP:0100749
      label: Chest pain
    temporality: ACUTE

- category: Sign
  name: Pericardial friction rub
  description: >
    A scratchy, often triphasic sound produced by fibrin-roughened pericardial layers moving over
    each other. It is close to specific for the diagnosis but intermittent and positional, so a
    single negative examination is uninformative.
  phenotype_term:
    preferred_term: Pericardial friction rub
    term:
      id: HP:0034788
      label: Pericardial friction rub

- category: Imaging
  name: Pericardial effusion
  description: >
    Fluid in the pericardial space on echocardiography or cross-sectional imaging, ranging from
    trace to tamponade-causing. Its presence supports the diagnosis but its absence does not
    exclude it, since dry pericarditis is common. No evidence item is attached and no frequency
    is asserted. The cohort figure available to this entry counts extrapericardial effusions,
    meaning pleural and peritoneal fluid, which is a different finding from the pericardial
    effusion this phenotype names.
  phenotype_term:
    preferred_term: Pericardial effusion
    term:
      id: HP:0001698
      label: Pericardial effusion

- category: Laboratory
  name: Widespread ST-segment elevation
  description: >
    Concave ST elevation across most electrocardiographic leads without reciprocal depression.
    It is a diagnostic criterion, and its geometry is the mechanism made visible. The inflamed
    surface wraps the whole heart rather than following a coronary territory, so the change is
    everywhere at once, which is what separates it at first contact from an infarction.
  phenotype_term:
    preferred_term: ST segment elevation
    term:
      id: HP:0012251
      label: ST segment elevation

- category: Laboratory
  name: PR-segment depression
  description: >
    Depression of the PR segment, attributed to inflammation of the atrial epicardium. It is the
    more specific of the two electrocardiographic findings and, unlike ST elevation, has no
    common ischaemic mimic.
  phenotype_term:
    preferred_term: PR segment depression
    term:
      id: HP:0031594
      label: PR segment depression

- category: Sign
  name: Cardiac tamponade
  description: >
    Haemodynamic compromise from pericardial fluid under pressure, with raised venous pressure,
    hypotension, and pulsus paradoxus. It is uncommon in idiopathic and viral disease and much
    more frequent in malignant, tuberculous, and purulent pericarditis, so its presence shifts
    the aetiological probabilities as well as demanding drainage.
  phenotype_term:
    preferred_term: Cardiac tamponade
    term:
      id: HP:0033415
      label: Cardiac tamponade
    severity: SEVERE

- category: Sign
  name: Pulsus paradoxus
  description: >
    An exaggerated inspiratory fall in systolic blood pressure. It is not paradoxical but an
    exaggeration of a normal phenomenon, arising because a fixed pericardial volume forces the
    ventricles to compete for filling during the inspiratory increase in right-sided venous
    return.
  phenotype_term:
    preferred_term: Pulsus paradoxus
    term:
      id: HP:6000046
      label: Pulsus paradoxus

- category: Cardiovascular
  name: Constrictive pericarditis
  description: >
    Restriction of diastolic filling by a non-compliant pericardium, presenting as right-heart
    failure with preserved ventricular contraction. It is the late structural complication and
    the one that determines whether surgery is needed.
  phenotype_term:
    preferred_term: Constrictive pericarditis
    term:
      id: HP:0002563
      label: Constrictive pericarditis
    clinical_course: PROGRESSIVE

- category: Laboratory
  name: Elevated C-reactive protein
  description: >
    A raised acute-phase reactant, present in the large majority of active episodes. It is used
    not only diagnostically but to time treatment, since normalisation guides both the duration
    of anti-inflammatory therapy and the return to physical activity.
  phenotype_term:
    preferred_term: Elevated circulating C-reactive protein concentration
    term:
      id: HP:0011227
      label: Elevated circulating C-reactive protein concentration
  evidence:
  - reference: PMID:35658515
    reference_title: "Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IRP frequently manifested with systemic inflammation"
    explanation: >-
      Supports systemic inflammation as a frequent manifestation in an idiopathic recurrent
      pericarditis cohort. No frequency band is assigned and no proportion is quoted, because
      the numeric figure in the source is reported for a referral recurrent-disease population
      rather than for unselected acute pericarditis.

- category: Constitutional
  name: Fever
  description: >
    Low-grade fever is common, particularly in the idiopathic, viral, and autoinflammatory forms.
    High fever raises the possibility of purulent disease.
  phenotype_term:
    preferred_term: Fever
    term:
      id: HP:0001945
      label: Fever

- category: Symptom
  name: Dyspnoea
  description: >
    Breathlessness, arising either from the pain limiting inspiration, or from a
    haemodynamically significant effusion, or from constrictive physiology. Its cause therefore
    differs by disease phase.
  phenotype_term:
    preferred_term: Dyspnea
    term:
      id: HP:0002094
      label: Dyspnea

genetic:
- name: MEFV
  gene_term:
    preferred_term: MEFV
    term:
      id: hgnc:6998
      label: MEFV
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Encodes pyrin, a regulator of inflammasome activation and the gene of familial Mediterranean
    fever. Rare deleterious variants are enriched in idiopathic recurrent pericarditis relative
    to ancestry-matched population controls. The association is the genetic counterpart of the
    therapeutic argument for an interleukin-1-driven mechanism, but it is based on small
    absolute numbers and a marginal significance level, and it should not be read as making
    recurrent pericarditis a forme fruste of familial Mediterranean fever.
  evidence:
  - reference: PMID:35658515
    reference_title: "Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Rare deleterious MEFV variants were more frequent in IRP than in ancestry-matched controls (allele frequency 9/200 versus 2932/129 200, P=0.040)."
    explanation: >-
      Establishes the enrichment and, in the same sentence, its fragility. Graded PARTIAL
      deliberately, because nine variant alleles and a p-value of 0.040 support an association
      worth recording without supporting a confident effect estimate.

- name: TNFRSF1A
  gene_term:
    preferred_term: TNFRSF1A
    term:
      id: hgnc:11916
      label: TNFRSF1A
  relationship_type: SUSCEPTIBILITY
  variant_origin: GERMLINE
  notes: >
    Encodes the p55 tumour necrosis factor receptor and is the gene of tumour necrosis factor
    receptor-associated periodic syndrome. Variants have been reported in patients presenting
    with idiopathic recurrent acute pericarditis, which is why a recurrent pericarditis without
    an identified cause is a recognised route to a periodic fever syndrome diagnosis. The
    evidence cited here is a case report expanding the reported variant spectrum, not a cohort
    frequency estimate, and no proportion of cases is claimed.
  evidence:
  - reference: PMID:23745996
    reference_title: "Expanding spectrum of TNFRSF1A gene mutations among patients with idiopathic recurrent acute pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "IRAP patients carrying TNFRSF1A gene mutations have been recently described."
    explanation: >-
      Supports the existence of the association qualitatively. Graded PARTIAL because the report
      is a description of individual patients carrying rare variants and cannot support a
      frequency or an effect size.

biochemical:
- name: C-reactive protein
  notes: >
    The practical biomarker of the disease. Beyond supporting the diagnosis it is used to decide
    how long to treat and when to resume physical activity, so it functions as a treatment
    variable rather than only a diagnostic one.

- name: Cardiac troponin
  notes: >
    Elevated when the adjacent subepicardial myocardium is involved, defining the
    myopericarditis overlap. It signals extension of the same inflammation rather than a second
    disease.

environmental:
- name: Mediastinal irradiation
  exposure_term:
    preferred_term: exposure to ionizing radiation
    term:
      id: ECTO:7000047
      label: exposure to ionizing radiation
  description: >
    Radiotherapy to the mediastinum, historically for Hodgkin lymphoma and for breast cancer,
    causes both acute pericarditis and a delayed fibrosing constrictive disease that may appear
    years to decades later. It is curated separately from the other triggers because its outcome
    is the worst of any aetiology, with poor long-term survival after pericardiectomy, and
    because it is iatrogenic and therefore preventable by treatment planning.
  evidence:
  - reference: PMID:34547827
    reference_title: "Outcomes of pericardiectomy for constrictive pericarditis following mediastinal irradiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Pericardiectomy for postradiation constrictive pericarditis has been reported to generally have unfavorable outcomes."
    explanation: >-
      A 100-patient cohort of pericardiectomy performed specifically for constrictive
      pericarditis following mediastinal irradiation establishes mediastinal irradiation as a
      recognized cause of pericardial disease.
  influences_mechanisms:
  - target: Pericardial injury from a heterogeneous trigger
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >
      Ionising radiation injures the pericardial mesothelium and microvasculature, entering the
      shared chain at the trigger node.
  - target: Fibrotic organization of the pericardium
    environmental_effect: EXACERBATES
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Radiation injury biases the pericardium towards fibrotic organisation rather than
      resolution, which is why constriction is the characteristic late outcome.
    evidence:
    - reference: PMID:34547827
      reference_title: "Outcomes of pericardiectomy for constrictive pericarditis following mediastinal irradiation."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Pericardiectomy performed for radiation-associated constrictive pericarditis has poor long-term outcomes."
      explanation: >-
        Establishes radiation-associated constriction as a distinct and worse entity than
        constriction from other causes, which is the basis for curating this exposure as acting
        on the fibrotic node rather than only on the trigger node.

- name: End-stage renal disease and uraemia
  description: >
    Accumulated uraemic solutes inflame the pericardium in advanced renal failure, and an
    analogous syndrome occurs in patients already on dialysis when dialysis is inadequate. It is
    the one aetiology whose first-line treatment is neither anti-inflammatory nor antimicrobial
    but removal of the causative solutes.
  evidence:
  - reference: PMID:28873222
    reference_title: "Uremic pericarditis, pericardial effusion, and constrictive pericarditis in end-stage renal disease: Insights and pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A rising prevalence of end-stage renal disease (ESRD) has led to a rise in ESRD-related pericardial syndromes, calling for a better understanding of its pathophysiology, diagnoses, and management."
    explanation: >-
      Establishes end-stage renal disease and its associated uraemia as a recognized cause of
      pericardial syndromes, including pericarditis.
  influences_mechanisms:
  - target: Pericardial injury from a heterogeneous trigger
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >
      Uraemic solute accumulation injures the pericardium directly, entering the shared chain at
      the trigger node.
    evidence:
    - reference: PMID:28873222
      reference_title: "Uremic pericarditis, pericardial effusion, and constrictive pericarditis in end-stage renal disease: Insights and pathophysiology."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Uremic pericarditis, the most common manifestation of uremic pericardial disease, is a contemporary problem that calls for intensive hemodialysis, anti-inflammatories, and often, drainage of large inflammatory pericardial effusions."
      explanation: >-
        Identifies uraemia as a distinct pericarditis aetiology and records that intensified
        dialysis is part of its treatment, which is the observation supporting a solute-driven
        trigger.

- name: Cardiac injury and surgery
  description: >
    Myocardial infarction, cardiac surgery, catheter procedures, device implantation, and chest
    trauma all produce a delayed pericarditis grouped as post-cardiac injury syndrome. The
    latency between the injury and the syndrome is the clue to its immune-mediated character,
    and it includes the entity long known as Dressler syndrome.
  evidence:
  - reference: PMID:38559602
    reference_title: "Post-cardiac injury syndrome: An evidence-based approach to diagnosis and treatment."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "All these conditions give rise to PCIS due to an inciting cardiac injury to pericardial or pleural mesothelial cells, leading to subsequent inflammation syndromes ranging from uncomplicated pericarditis to massive pleural effusion."
    explanation: >-
      Establishes that myocardial infarction, cardiac surgery, catheter procedures, device
      implantation, and chest trauma converge on a shared cardiac-injury trigger that causes
      pericarditis.
  influences_mechanisms:
  - target: Pericardial injury from a heterogeneous trigger
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >
      Mechanical or ischaemic injury to the heart exposes the pericardium to injured tissue and
      initiates the shared response after a latent period.
    evidence:
    - reference: PMID:38559602
      reference_title: "Post-cardiac injury syndrome: An evidence-based approach to diagnosis and treatment."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Post-cardiac injury syndrome (PCIS) is an umbrella term used for the post-pericardiotomy syndrome, post-myocardial infarction (MI) related pericarditis (Dressler syndrome), and post-traumatic pericarditis"
      explanation: >-
        Establishes that these distinct injuries are grouped as one syndrome, which is the
        clinical expression of the etiological convergence this entry models with a single
        trigger node.

treatments:
- name: Non-steroidal anti-inflammatory therapy
  description: >
    Aspirin or ibuprofen at anti-inflammatory doses, the first-line treatment for symptom control
    and for suppressing the acute inflammatory response. Aspirin is preferred after myocardial
    infarction, where other non-steroidal agents may interfere with infarct healing.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Acute pericardial inflammatory exudate
    treatment_effect: INHIBITS
    description: >
      Prostaglandin synthesis inhibition reduces the vascular and nociceptive components of the
      acute inflammatory response.

- name: Colchicine
  description: >
    Added to anti-inflammatory therapy from the first episode, and the single best-evidenced
    intervention in the disease. Its effect is on recurrence rather than on the acute episode
    alone, which fits a drug acting on the inflammasome-driven loop rather than on the injury
    that started it. That it improves pericardial inflammation only partially in experimental
    models, while interleukin-1 blockade improves it substantially, is consistent with its
    clinical position as an agent that reduces recurrence without abolishing it.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: colchicine
      term:
        id: CHEBI:23359
        label: colchicine
  target_mechanisms:
  - target: Autoinflammatory recurrence loop
    treatment_effect: INHIBITS
    description: >
      Colchicine suppresses inflammasome-dependent inflammation, which is the loop that drives
      recurrence rather than the acute injury response.
  evidence:
  - reference: PMID:23992557
    reference_title: "A randomized trial of colchicine for acute pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The primary outcome occurred in 20 patients (16.7%) in the colchicine group and 45 patients (37.5%) in the placebo group (relative risk reduction in the colchicine group, 0.56; 95% confidence interval, 0.30 to 0.72; number needed to treat, 4; P<0.001)."
    explanation: >-
      The double-blind trial in a first episode, establishing the reduction in incessant or
      recurrent pericarditis with a number needed to treat of four.
  - reference: PMID:21873705
    reference_title: "Colchicine for recurrent pericarditis (CORP): a randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "At 18 months, the recurrence rate was 24% in the colchicine group and 55% in the placebo group"
    explanation: >-
      Extends the benefit to patients who have already relapsed once, which is the population in
      which the recurrence loop is established rather than hypothetical.
  - reference: PMID:33665514
    reference_title: "The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Colchicine partially improved the pericardial inflammation."
    explanation: >-
      Supports the mechanistic account of colchicine as an incomplete inflammasome-directed
      agent, which is why it reduces rather than abolishes recurrence. Graded PARTIAL because
      the observation is in the mouse model and describes an incomplete effect.

- name: Corticosteroid therapy
  description: >
    Reserved as second-line, for patients who cannot take or do not respond to non-steroidal
    agents and colchicine, or whose pericarditis is part of a systemic autoimmune disease. The
    reason for the reservation is not toxicity alone. Corticosteroid use was an independent risk
    factor for recurrence in multivariable analysis of a randomised trial, so the intuitive
    treatment for an inflamed serosa makes the natural history worse. A plausible reading is that
    suppressing the adaptive arm does not touch the innate loop that drives relapse, and a
    separate cohort observation that steroid dependence tracks chronic pain suggests some of what
    appears to be steroid-dependent disease is not inflammatory at all.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
  target_mechanisms:
  - target: Acute pericardial inflammatory exudate
    treatment_effect: INHIBITS
    description: >
      Corticosteroids suppress the acute inflammatory response, which is why they relieve
      symptoms quickly while leaving the recurrence loop intact.
  evidence:
  - reference: PMID:16186437
    reference_title: "Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "After multivariate analysis, corticosteroid use (OR 4.30, 95% CI 1.21 to 15.25; P=0.024) was an independent risk factor for recurrences."
    explanation: >-
      Refutes first-line corticosteroid use by showing it independently predicts recurrence.
      Curated as REFUTE against early use rather than against the drug class in the specific
      indications where it remains appropriate.
  - reference: PMID:35658515
    reference_title: "Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this cohort of patients with IRP, corticosteroid dependence was common (39/136, 28.7%) and was associated with chronic pain"
    explanation: >-
      Supports the reading that corticosteroid dependence is entangled with chronic pain. Graded
      PARTIAL because an association in a referral cohort cannot establish the direction of that
      relationship.
  - reference: PMID:25178809
    reference_title: "Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Prednisolone therapy, as compared with placebo, was associated with significant reductions in the incidence of constrictive pericarditis (4.4% vs. 7.8%; hazard ratio, 0.56; 95% CI, 0.36 to 0.87; P=0.009) and hospitalization (20.7% vs. 25.2%; hazard ratio, 0.79; 95% CI, 0.63 to 0.99; P=0.04)."
    explanation: >-
      The result that runs opposite to the COPE finding above. In tuberculous disease adjunctive
      prednisolone reduced progression to constriction, where in idiopathic disease corticosteroid
      use independently predicted recurrence. Two opposite effects of one drug class in one
      clinical syndrome is the strongest curated evidence in this entry that the syndrome carries
      more than one mechanism. Graded PARTIAL because it is a secondary endpoint in a trial whose
      primary outcome was null.
  - reference: PMID:25178809
    reference_title: "Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: "In patients with tuberculous pericarditis, neither prednisolone nor M. indicus pranii had a significant effect on the composite of death, cardiac tamponade requiring pericardiocentesis, or constrictive pericarditis."
    explanation: >-
      Refutes routine adjunctive corticosteroid use in tuberculous pericarditis on the trial's
      primary outcome, curated alongside the secondary benefit above so the entry records the
      whole result rather than the more convenient half of it.

- name: Rilonacept
  description: >
    A soluble interleukin-1 receptor fusion protein that traps both interleukin-1 alpha and
    interleukin-1 beta, given weekly by subcutaneous injection, and the first agent approved
    specifically for recurrent pericarditis. Its trial design is what makes it mechanistically
    informative. Patients were brought into remission on drug and then randomised to continue or
    withdraw, so the recurrence rate on placebo measures how much of the ongoing disease depends
    on interleukin-1 rather than how much a drug relieves symptoms.
  therapeutic_modality: PEPTIDE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: rilonacept
      term:
        id: NCIT:C84137
        label: Rilonacept
  target_mechanisms:
  - target: Interleukin-1 release and cytokine amplification
    treatment_effect: INHIBITS
    description: >
      Trapping interleukin-1 alpha and beta interrupts the self-amplifying cytokine loop at the
      node that sustains it.
  evidence:
  - reference: PMID:33200890
    reference_title: "Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During this period, 2 of 30 patients (7%) in the rilonacept group had a pericarditis recurrence, as compared with 23 of 31 patients (74%) in the placebo group."
    explanation: >-
      The randomised-withdrawal result, which is both the efficacy evidence and the mechanistic
      evidence that the ongoing disease is interleukin-1 dependent.
  - reference: PMID:33200890
    reference_title: "Phase 3 Trial of Interleukin-1 Trap Rilonacept in Recurrent Pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "During the run-in period, the median time to resolution or near-resolution of pain was 5 days, and the median time to normalization of the CRP level was 7 days."
    explanation: >-
      Records the speed of response, which matters because a mechanism-directed agent acting on
      the driver should resolve both symptom and inflammatory marker rather than symptom alone.

- name: Anakinra
  description: >
    A recombinant interleukin-1 receptor antagonist, tested in the narrowest and most refractory
    population in this disease, namely patients with at least three previous recurrences who were
    both colchicine-resistant and corticosteroid-dependent. That these patients responded is the
    strongest argument that the refractory phenotype is interleukin-1 driven rather than simply
    severe.
  therapeutic_modality: PROTEIN_REPLACEMENT
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: anakinra
      term:
        id: NCIT:C38717
        label: Anakinra
  target_mechanisms:
  - target: Interleukin-1 release and cytokine amplification
    treatment_effect: INHIBITS
    description: >
      Receptor antagonism blocks signalling by both interleukin-1 alpha and beta at the same node
      the interleukin-1 trap acts on, by a different molecular route.
  evidence:
  - reference: PMID:27825009
    reference_title: "Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrent pericarditis occurred in 9 of 10 patients (90%; incidence rate, 2.06% of patients per year) assigned to placebo and 2 of 11 patients (18.2%; incidence rate, 0.11% of patients per year) assigned to anakinra"
    explanation: >-
      Quantifies the effect in the colchicine-resistant, corticosteroid-dependent population,
      which is where the interleukin-1 hypothesis makes its riskiest prediction.
  - reference: PMID:27825009
    reference_title: "Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In this preliminary study of patients with recurrent pericarditis with colchicine resistance and corticosteroid dependence, the use of anakinra compared with placebo reduced the risk of recurrence over a median of 14 months. Larger studies are needed to replicate these findings as well as to assess safety and longer-term efficacy."
    explanation: >-
      The authors' own qualification, curated so the entry records that this is a twenty-one
      patient trial rather than a definitive one. Graded PARTIAL for that reason.

- name: Antitubercular therapy
  description: >
    Standard multidrug antitubercular treatment, the aetiology-directed therapy for the
    tuberculous subtype and the only situation in this disease where killing an organism is the
    treatment. It is assumed as background standard of care in every arm of the trials conducted
    in this population, which is why the evidence here establishes it as the platform rather than
    testing it. The same trial's findings on adjunctive prednisolone are curated on the
    corticosteroid treatment entry, where they belong, since it was the corticosteroid and not
    the antitubercular therapy that was randomised.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Antibiotic Therapy
    term:
      id: NCIT:C15620
      label: Antibiotic Therapy
  target_mechanisms:
  - target: Pericardial injury from a heterogeneous trigger
    treatment_effect: INHIBITS
    description: >
      Eradicating the organism removes the persistent stimulus driving the response, which is
      possible only where the trigger is an infection that can be killed.
  evidence:
  - reference: PMID:25178809
    reference_title: "Prednisolone and Mycobacterium indicus pranii in tuberculous pericarditis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Tuberculous pericarditis is associated with high morbidity and mortality even if antituberculosis therapy is administered."
    explanation: >-
      Establishes antitubercular therapy as the background standard of care in this subtype, and
      simultaneously records that it is not sufficient, which is why adjunctive strategies were
      tested at all.

- name: Intensified haemodialysis
  description: >
    Increasing dialysis dose or initiating dialysis, the aetiology-directed treatment for uraemic
    and dialysis-associated pericarditis. It is the mechanistic counterpart of antitubercular
    therapy in a non-infectious setting, since both remove the persistent stimulus rather than
    suppressing the response to it, and it is the reason this aetiology is the one where an
    anti-inflammatory drug is not the first move.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Hemodialysis
    term:
      id: NCIT:C15248
      label: Hemodialysis
  target_mechanisms:
  - target: Pericardial injury from a heterogeneous trigger
    treatment_effect: INHIBITS
    description: >
      Clearing the accumulated uraemic solutes removes the substance injuring the pericardium.
  evidence:
  - reference: PMID:28873222
    reference_title: "Uremic pericarditis, pericardial effusion, and constrictive pericarditis in end-stage renal disease: Insights and pathophysiology."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Uremic pericarditis, the most common manifestation of uremic pericardial disease, is a contemporary problem that calls for intensive hemodialysis, anti-inflammatories, and often, drainage of large inflammatory pericardial effusions."
    explanation: >-
      States intensive haemodialysis as a component of treatment in this aetiology, which is the
      claim this treatment entry makes.

- name: Pericardiocentesis
  description: >
    Drainage of pericardial fluid, required urgently for tamponade and used diagnostically for
    undiagnosed large effusions. It relieves the haemodynamic consequence without touching the
    inflammation that produced it.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Pericardiocentesis
    term:
      id: NCIT:C52010
      label: Pericardiocentesis
  target_mechanisms:
  - target: Cardiac tamponade
    treatment_effect: INHIBITS
    description: >
      Removing fluid lowers intrapericardial pressure below cardiac filling pressures and
      restores diastolic filling.

- name: Pericardiectomy
  description: >
    Surgical removal of the constricting pericardium, the definitive treatment for fixed
    constriction. Outcome depends heavily on aetiology, and radiation-associated constriction
    does worst, with around one in ten dying perioperatively and roughly a third alive at ten
    years. Those numbers are the argument for distinguishing reversible from fixed constriction
    before operating rather than after.
  therapeutic_modality: SURGERY
  treatment_term:
    preferred_term: Pericardiectomy
    term:
      id: NCIT:C51643
      label: Pericardiectomy
  target_mechanisms:
  - target: Constrictive physiology
    treatment_effect: INHIBITS
    description: >
      Removing the rigid shell lifts the fixed limit on cardiac volume and allows diastolic
      filling to resume.
  evidence:
  - reference: PMID:34547827
    reference_title: "Outcomes of pericardiectomy for constrictive pericarditis following mediastinal irradiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall operative mortality was 10.1% (n = 10)."
    explanation: >-
      Quantifies the perioperative risk in the radiation-associated group. Graded PARTIAL
      because it supports the operation being high-risk in this aetiology rather than supporting
      or refuting the operation in general.
  - reference: PMID:34547827
    reference_title: "Outcomes of pericardiectomy for constrictive pericarditis following mediastinal irradiation."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overall 1, 5-, and 10-years survival was 73.6%, 53.4%, and 32.1%, respectively."
    explanation: >-
      Records the long-term survival that makes radiation-associated constriction the worst
      surgical aetiology, which is the aetiology-dependence this entry curates.

experimental_models:
- name: Interferon-gamma knockout mouse constrictive pericarditis model
  description: >
    Cardiac myosin-induced experimental autoimmune myocarditis in interferon-gamma-deficient
    mice, which develop grossly visible pericarditis with pericardial inflammation and fibrosis
    and a haemodynamic phenotype reproducing human constriction, including the square-root sign
    on pressure tracing. Its value is that it solves an attribution problem. Because the model
    also produces myocarditis, the authors matched animals for myocardial disease severity and
    showed the constrictive haemodynamics tracked the pericardial disease and not the myocardial
    disease, which is the confound that makes restrictive and constrictive physiology hard to
    separate in patients. Its limitation is that constriction arises here from an autoimmune
    myocarditis protocol in a cytokine-deficient animal, which is not how human constriction
    arises.
  experimental_model_type: OTHER
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  modeled_mechanisms:
  - target: Constrictive physiology
    description: >
      The model reproduces the constrictive haemodynamic phenotype and attributes it to the
      pericardial rather than the myocardial disease.
  - target: Fibrotic organization of the pericardium
    description: >
      Pericardial inflammation and fibrosis are the lesion that produces the phenotype in this
      model.
  publication: PMID:15505106
  evidence:
  - reference: PMID:15505106
    reference_title: "Novel model of constrictive pericarditis associated with autoimmune heart disease in interferon-gamma-knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Constrictive pericarditis represents a serious hemodynamic syndrome that may lead to heart failure. Studies of its pathophysiological mechanisms have been impeded by the lack of an animal model."
    explanation: >-
      States the gap this model was built to fill, which is also the reason mechanistic
      understanding of constriction lags behind that of the acute disease.
  - reference: PMID:15505106
    reference_title: "Novel model of constrictive pericarditis associated with autoimmune heart disease in interferon-gamma-knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "This phenotype was not associated with the severity of myocarditis but correlated with the presence of grossly detectable adhesive pericarditis present only in the KO group and characterized by increased pericardial inflammation and fibrosis."
    explanation: >-
      The dissociation from myocarditis severity, which is what makes the model informative about
      pericardial rather than myocardial mechanism.

- name: Zymosan A intrapericardial injection mouse model
  description: >
    Intrapericardial injection of zymosan A, producing pericardial inflammation with inflammasome
    activation matching that seen in human pericardial tissue. It was used to test inflammasome
    blockers against colchicine, and it is the source of the observation that colchicine improves
    pericardial inflammation only partially where interleukin-1 directed agents improve it
    substantially.
  experimental_model_type: OTHER
  organism:
    preferred_term: house mouse
    term:
      id: NCBITaxon:10090
      label: Mus musculus
  modeled_mechanisms:
  - target: Inflammasome activation in pericardial tissue
    description: >
      The model reproduces inflammasome activation in the pericardium and allows blockers to be
      compared against each other.
  publication: PMID:33665514
  evidence:
  - reference: PMID:33665514
    reference_title: "The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "A mouse model of pericarditis was developed through the intrapericardial injection of zymosan A."
    explanation: >-
      Describes the model and its route of induction.
  - reference: PMID:33665514
    reference_title: "The Role of NLRP3 Inflammasome in Pericarditis: Potential for Therapeutic Approaches."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Among inflammasome blockers, NLRP3 inflammasome inhibitor, anakinra, and interleukin-1 trap were found to significantly improve pericardial alterations."
    explanation: >-
      Provides the preclinical counterpart of the two clinical trials curated on the treatment
      entries, testing the same pathway from the opposite direction.

diagnosis:
- name: Clinical diagnosis from pain, rub, electrocardiogram, and effusion
  description: >
    The diagnosis is made when at least two of four features are present, namely characteristic
    pericarditic chest pain, a friction rub, widespread ST-segment elevation or PR-segment
    depression, and a new or worsening pericardial effusion. No single feature is required, which
    reflects that each is intermittent or absent in a substantial fraction of cases.

- name: C-reactive protein guided treatment and activity decisions
  description: >
    The acute-phase response is used to time the taper of anti-inflammatory therapy and the
    return to exercise, rather than only to support the diagnosis. This is unusual among
    cardiovascular diseases and follows from inflammation being the disease rather than a marker
    of it.

- name: Cardiac magnetic resonance to distinguish reversible from fixed constriction
  description: >
    Pericardial late gadolinium enhancement identifies ongoing pericardial inflammation, which is
    what separates the transient constriction that resolves on anti-inflammatory therapy from
    fixed fibrocalcific disease requiring surgery. Given the operative mortality of
    pericardiectomy this distinction is the highest-stakes decision in the disease.

progression:
- phase: Acute episode
  notes: >
    Days to a few weeks. Most idiopathic and viral disease resolves with a non-steroidal
    anti-inflammatory drug and colchicine.

- phase: Recurrence
  notes: >
    Relapse after a symptom-free interval, the commonest complication. Its frequency is the
    reason colchicine is given from the first episode rather than after a first relapse.
  evidence:
  - reference: PMID:21873705
    reference_title: "Colchicine for recurrent pericarditis (CORP): a randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Recurrence is the most common complication of pericarditis, affecting 10% to 50% of patients."
    explanation: >-
      States the frequency and the position of recurrence as the dominant complication of the
      disease.

- phase: Refractory recurrent disease
  notes: >
    A subgroup becomes colchicine-resistant and corticosteroid-dependent, with substantial
    morbidity from both the disease and its treatment. This is the population in which
    interleukin-1 blockade was tested, and in which corticosteroid dependence was found to track
    chronic pain as well as inflammation.

- phase: Constriction
  notes: >
    Fibrotic organisation restricting diastolic filling, developing over months to years. Risk is
    aetiology-dependent, low after idiopathic and viral disease and much higher after tuberculous
    and purulent pericarditis. Radiation-associated constriction may appear years to decades
    after exposure and carries the worst surgical outcome.

differential_diagnoses:
- name: ST-elevation myocardial infarction
  description: >
    Shares chest pain and ST-segment elevation. The distinction is geometric. Pericarditis
    inflames a surface that wraps the whole heart and produces widespread concave elevation
    without reciprocal depression, whereas infarction follows one coronary territory. Getting it
    wrong in the direction of infarction leads to unnecessary catheterisation, and in the other
    direction to a missed occlusion.

- name: Restrictive cardiomyopathy
  description: >
    Shares the physiology of impaired diastolic filling with preserved contraction and is the
    hardest differential in constriction. The distinction matters absolutely, because
    pericardiectomy treats one and does nothing for the other, and it turns on ventricular
    interdependence, which is present when a rigid shell forces the ventricles to share a fixed
    volume and absent when the myocardium itself is stiff.

- name: Pulmonary embolism
  description: >
    Shares pleuritic chest pain, breathlessness, and, in the tamponade case, obstructive shock
    with raised venous pressure and a clear chest. Both impair ventricular filling rather than
    contraction.

- name: Myocarditis
  description: >
    Not so much a differential as an overlapping process, since the same inflammation extends
    into the subepicardial myocardium in a substantial minority and raises troponin. The overlap
    matters because myocardial involvement changes exercise advice and arrhythmia risk.

prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: UNKNOWN
  notes: >
    No population occurrence figure is recorded, because no reference cited in this entry
    reports one. Pericarditis is common as a proportion of emergency presentations with chest
    pain, and tuberculous pericarditis dominates in high-burden settings, but quantifying either
    would require sources this entry does not cite.

discussions:
- discussion_id: why_do_corticosteroids_make_recurrence_more_likely
  kind: OPEN_QUESTION
  status: OPEN
  prompt: >
    Is the association between corticosteroid use and recurrence causal, and if so does it act by
    leaving the innate loop untouched, by prolonging viral persistence, or by selecting patients
    whose pain is not inflammatory?
  rationale: >
    The finding is robust enough to have changed guidelines, since corticosteroid use was an
    independent risk factor for recurrence in multivariable analysis of a randomised trial. Its
    interpretation is not settled. The mechanistic reading offered by this entry, that suppressing
    adaptive immunity does nothing to an innate interleukin-1 loop, is consistent with the drug
    response pattern but is not directly demonstrated. A competing reading is confounding by
    indication, since sicker patients receive steroids. A third possibility is raised by the
    observation that corticosteroid dependence in a recurrent-pericarditis cohort was associated
    with chronic pain, which would mean part of what is treated as steroid-dependent inflammatory
    disease is a pain syndrome that steroids cannot fix and that no anti-inflammatory endpoint
    will capture. These have different consequences for how refractory disease should be managed.
  attaches_to:
  - "pathophysiology#Autoinflammatory recurrence loop"
  evidence:
  - reference: PMID:16186437
    reference_title: "Colchicine in addition to conventional therapy for acute pericarditis: results of the COlchicine for acute PEricarditis (COPE) trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "After multivariate analysis, corticosteroid use (OR 4.30, 95% CI 1.21 to 15.25; P=0.024) was an independent risk factor for recurrences."
    explanation: >-
      The observation the question is about. The wide confidence interval is itself part of why
      the effect size, and therefore its interpretation, remains open.
  - reference: PMID:35658515
    reference_title: "Pericarditis and Autoinflammation: A Clinical and Genetic Analysis of Patients With Idiopathic Recurrent Pericarditis and Monogenic Autoinflammatory Diseases at a National Referral Center."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also found that corticosteroid dependence in IRP is associated with chronic noninflammatory pain."
    explanation: >-
      Supports the third reading, that some steroid-dependent disease is not inflammatory.
      Graded PARTIAL because an association cannot establish which way the relationship runs.

- discussion_id: interleukin_1_blockade_controls_but_does_not_cure
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >
    What sustains the interleukin-1 loop between relapses, and is there a point at which
    interleukin-1 blockade can be stopped without the disease returning?
  rationale: >
    Both randomised trials of interleukin-1 blockade used a withdrawal design, and both showed
    the disease returning promptly when the drug was stopped. That is what establishes the
    mechanism, and it is also the problem, because it means the treatment is suppressive rather
    than curative and patients face indefinite injections. What holds the loop primed between
    clinically silent intervals is unknown. Candidate explanations include a persistent
    stimulus in the pericardium, an epigenetically trained innate immune state, and an
    underlying autoinflammatory genotype in the subset who carry one, but none has been shown to
    predict who can stop treatment.
  attaches_to:
  - "pathophysiology#Autoinflammatory recurrence loop"
  - "pathophysiology#Interleukin-1 release and cytokine amplification"
  evidence:
  - reference: PMID:27825009
    reference_title: "Effect of Anakinra on Recurrent Pericarditis Among Patients With Colchicine Resistance and Corticosteroid Dependence: The AIRTRIP Randomized Clinical Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Median flare-free survival (time to flare) was 72 (interquartile range, 64-150) days after randomization in the placebo group and was not reached in the anakinra group (P <.001)."
    explanation: >-
      Shows the disease returning within about ten weeks of withdrawal, which is what makes
      indefinite treatment the current default and defines the gap.
  proposed_experiments:
  - experiment_id: exp_biomarker_guided_il1_withdrawal
    name: Biomarker-guided withdrawal of interleukin-1 blockade
    description: >
      In patients in sustained remission on interleukin-1 blockade, randomise withdrawal guided by
      pericardial late gadolinium enhancement and C-reactive protein against fixed-duration
      continuation, with autoinflammatory-gene genotype as a prespecified stratifier, to test
      whether residual pericardial inflammation or genotype identifies who can stop.

- discussion_id: constriction_model_fidelity
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >
    Does constrictive pericarditis produced by autoimmune myocarditis in a cytokine-deficient
    mouse model the fibrotic organisation that follows tuberculous, purulent, or radiation
    pericarditis in patients?
  rationale: >
    The only established animal model of constriction arises from cardiac-myosin-induced
    autoimmune myocarditis in interferon-gamma-knockout mice. It reproduces the haemodynamics
    convincingly and, by matching animals for myocarditis severity, it settles that the
    physiology is pericardial. But the route to it is a route human patients do not take. Human
    constriction follows chronic granulomatous infection, purulent infection, cardiac surgery, or
    irradiation, and the absence of interferon-gamma in the model is not incidental, since
    interferon-gamma is central to the Th1 response that drives tuberculous pericarditis, the
    commonest cause of constriction worldwide. A model that removes the cytokine most implicated
    in the dominant human aetiology may be modelling the phenotype rather than the mechanism.
    This is a fidelity question, not an absence of evidence, which is why it is recorded as a
    model mismatch rather than a knowledge gap.
  attaches_to:
  - "pathophysiology#Fibrotic organization of the pericardium"
  - "pathophysiology#Constrictive physiology"
  evidence:
  - reference: PMID:15505106
    reference_title: "Novel model of constrictive pericarditis associated with autoimmune heart disease in interferon-gamma-knockout mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "Cardiac myosin-induced experimental autoimmune myocarditis in interferon (IFN)-gamma-knockout (KO) mice results in increased cardiac inflammation and development of severe grossly detectable pericarditis."
    explanation: >-
      States the route by which constriction is produced in the model, which is the route that
      differs from human aetiology. Graded PARTIAL because it supports the model existing without
      addressing its translational validity, which is the open question.
  proposed_experiments:
  - experiment_id: exp_infection_driven_constriction_model
    name: Infection-driven model of pericardial constriction
    description: >
      Develop and characterise a constriction model driven by intrapericardial mycobacterial
      antigen or by a purulent infectious challenge in immunocompetent animals, and compare its
      pericardial transcriptome and fibrotic architecture against both the interferon-gamma
      knockout model and human pericardiectomy specimens, to determine which model the human
      lesion resembles.

notes: >
  Scope. This entry curates pericarditis as one disease with a shared mechanism and multiple
  triggers, with tuberculous and constrictive disease as subtypes rather than separate entries.
  That reflects the convergence the entry argues for and matches the way MONDO treats
  pericarditis, which has constrictive and tuberculous pericarditis as separate descendant terms
  a future entry could take up.

  Module conformance. Two conformances are declared, both to the fibrotic response module, on the
  trigger node and on the fibrotic organisation node. A conformance to the granuloma formation
  module would be appropriate for the tuberculous subtype, since the pericardial lesion there is
  granulomatous and caseating, but this entry cites no evidence for the granulomatous histology
  and therefore does not assert it. That is a specific, tractable extension rather than a
  judgement that the module does not apply.

  Deep-research provenance. Curated from a claude_code deep-research report treated as leads only.
  The report was disciplined about its own uncertainty, explicitly flagging its ontology
  suggestions as unverified and naming several it could not confirm. That caution was warranted.
  Its MONDO suggestion, MONDO:0004770, is exophthalmos. HP:0025091 was offered for pulsus
  paradoxus and is Wrist sign, a Marfan feature. HP:0031653 was offered for pericardial friction
  rub and is Abnormal heart valve physiology. The correct bindings used here are MONDO:0005904,
  HP:6000046, and HP:0034788, together with HP:0033415 for cardiac tamponade and HP:0002563 for
  constrictive pericarditis, none of which the report supplied.

  A citation that does not support its claim. The report attributed a figure of about six percent
  of idiopathic recurrent pericarditis cohorts carrying TNFRSF1A variants to PMID:23745996. That
  paper is a case report describing two patients with rare variants and contains no cohort
  frequency. The gene is retained on the qualitative claim the paper does support, and no
  proportion is asserted anywhere in this entry. This is a different failure from a fabricated
  citation, and it is one that snippet verification cannot catch, because any snippet quoted from
  that paper would validate perfectly while supporting a different claim from the one it was
  attached to.

  A near miss of the same kind, caught in curation. The pericardial effusion phenotype was first
  drafted citing a cohort figure of fifty percent. That figure counts extrapericardial effusions,
  meaning pleural and peritoneal fluid, not the pericardial effusion the phenotype names. The
  evidence item was removed rather than reworded, and the phenotype now carries no frequency
  claim.

  NEC preflight returned SKIP, since MONDO records no causal gene for pericarditis. The manual
  fallback needs a note. The report's most frequently named genes are MEFV, TNFRSF1A, and NLRP3,
  and its OMIM identifiers are those of familial Mediterranean fever and the tumour necrosis
  factor receptor-associated periodic syndrome. Taken naively that pattern looks like a report
  about periodic fever syndromes rather than about pericarditis. It is not, because the
  autoinflammatory connection is a genuine and central feature of recurrent pericarditis, but the
  resemblance is close enough that this entry has been careful to take gene associations only
  from studies performed in pericarditis cohorts and not to import phenotypes, frequencies, or
  treatment claims from the periodic fever literature.

📚

References & Deep Research

Deep Research

1

Claude Code ▸

Pericarditis: Comprehensive Disease Characteristics Research Report

claude-haiku-4-5-20251001, claude-sonnet-5 3 citations 2026-08-10T03:49:17.982753

Pericarditis: Comprehensive Disease Characteristics Research Report

1. Disease Information

Overview. Pericarditis is inflammation of the pericardium — the fibroserous sac (visceral + parietal layers separated by a potential space normally containing 15–50 mL of fluid) surrounding the heart. It is the most common disease of the pericardium and presents across a clinical spectrum: acute pericarditis, incessant pericarditis (>4–6 weeks but <3 months, continuous), recurrent pericarditis (relapse after a symptom-free interval of ≥4–6 weeks), chronic pericarditis (>3 months), and, as a downstream sequela, constrictive pericarditis (fibrotic, calcified, non-compliant pericardium impairing diastolic filling). The 2025 ESC Guidelines for the management of myocarditis and pericarditis (the first integrated ESC guideline covering both conditions) introduce the umbrella concept of "inflammatory myopericardial syndrome" (IMPS) reflecting shared etiopathogenesis and frequent myopericardial overlap (myopericarditis/perimyocarditis) (Eur Heart J 2025; https://academic.oup.com/eurheartj/article/46/40/3952/8234483).

Key identifiers (to be OAK-verified before KB entry, per dismech policy): - MONDO: MONDO:0004770 (pericarditis) — suggested; a specific-form request would need e.g. constrictive pericarditis, tuberculous pericarditis, uremic pericarditis as related/child terms - OMIM: No single-gene OMIM disease entry for idiopathic/common pericarditis; monogenic periodic-fever syndromes that present with recurrent pericarditis have their own OMIM numbers (TRAPS: OMIM #142680; FMF: OMIM #249100) - ICD-10-CM: I30 (Acute pericarditis) — I30.0 (Acute nonspecific idiopathic pericarditis), I30.1 (Infective pericarditis), I30.8/I30.9; I31 (Other diseases of pericardium) — I31.0 (Chronic adhesive pericarditis), I31.1 (Chronic constrictive pericarditis), I31.3 (Pericardial effusion, noninflammatory), I31.4 (Cardiac tamponade); I32 (Pericarditis in diseases classified elsewhere, e.g., uremic, TB) - ICD-11: BB21 (Pericarditis), BB21.0 (Acute pericarditis), BB21.1 (Chronic pericarditis), BB23 (Constrictive pericarditis) - MeSH: D010493 (Pericarditis); D010496 (Pericarditis, Constrictive); D010494 (Pericarditis, Tuberculous) - Orphanet: ORPHA:98915 (Recurrent pericarditis) is a listed rare-disease entity for the recurrent/autoinflammatory form

Synonyms/alternative names: inflammation of the pericardium; pericardial inflammation; acute idiopathic pericarditis; Dressler syndrome (post-myocardial-infarction pericarditis, a subtype); postpericardiotomy syndrome; post-cardiac injury syndrome (umbrella term for post-MI, post-surgical, and post-traumatic pericarditis); tuberculous pericarditis; uremic/dialysis-associated pericarditis; effusive-constrictive pericarditis; transient constrictive pericarditis.

Evidence basis: This entry synthesizes aggregated disease-level clinical, epidemiological, genetic, and mechanistic literature (cohort studies, RCTs, systematic reviews, guideline documents) rather than a single-patient/EHR source.

2. Etiology

Disease causal factors — pericarditis is fundamentally a stereotypical inflammatory response of the pericardium to injury, regardless of trigger. Recognized categories:

Infectious
Viral (most common identifiable cause in high-income settings): enteroviruses (coxsackievirus, echovirus), adenovirus, parvovirus B19, herpesviruses (EBV, CMV, HHV-6), influenza, and SARS-CoV-2 (both from infection and, rarely, post-mRNA-vaccination myopericarditis).
Bacterial: Mycobacterium tuberculosis — the dominant cause of pericarditis and constrictive pericarditis in Africa/Asia, especially with HIV co-infection (JACC Adv 2024; https://www.jacc.org/doi/10.1016/j.jacadv.2024.101427); purulent bacterial pericarditis (Staphylococcus, Streptococcus, Pneumococcus) — rare but high mortality.
Fungal/parasitic: rare, seen in immunocompromised hosts.
Idiopathic — the largest single category in immunocompetent patients in developed countries (up to 80–90% of ambulatory cases), presumed largely post-viral/autoimmune but without an identified trigger.
Autoimmune/systemic inflammatory disease: systemic lupus erythematosus, rheumatoid arthritis, systemic sclerosis, Sjögren syndrome, sarcoidosis, IBD, vasculitides (e.g., polyarteritis nodosa, eosinophilic granulomatosis with polyangiitis).
Autoinflammatory (monogenic): TNF receptor-associated periodic syndrome (TRAPS, TNFRSF1A), familial Mediterranean fever (FMF, MEFV) — see Section 4.
Post-cardiac injury syndrome (PCIS) — umbrella for:
Post-myocardial infarction pericarditis — early peri-infarction pericarditis (direct extension of necrosis, days) vs. Dressler syndrome (delayed, immune-mediated, weeks–months post-MI) (PMC9681686).
Postpericardiotomy syndrome — after cardiac surgery.
Post-traumatic/post-procedural — after PCI, pacemaker/device implantation, catheter ablation, thoracic trauma (PMC8887692).
Mechanism: anti-actin/anti-myosin autoantibodies following mesothelial/myocardial injury with immune-complex deposition in pericardium/pleura/lung, producing a delayed hypersensitivity-like polyserositis (ScienceDirect 2024, PMID:38559602).
Neoplastic: primary pericardial tumors (rare, e.g., mesothelioma) or, far more commonly, metastatic disease (lung, breast cancer, lymphoma, melanoma) causing malignant pericardial effusion/pericarditis via direct invasion, lymphatic dissemination, or hematogenous spread (5–20% of patients with metastatic cancer have pericardial involvement; tamponade in up to 50% of malignant effusions).
Metabolic: uremic pericarditis (pre-dialysis or early-dialysis ESRD, from toxic metabolite accumulation and increased microvascular permeability) and dialysis-associated pericarditis (from underdialysis in patients on chronic renal replacement) — occurring in up to 14% (range 2–21%) of ESRD patients (PMID:28873222).
Radiation-induced: mediastinal radiotherapy (e.g., for lymphoma, breast cancer) — acute or delayed (years later) fibrosing pericarditis/constriction with particularly poor pericardiectomy outcomes (PMID:34547827).
Drug-induced: procainamide, hydralazine, isoniazid (lupus-like), anticoagulants (hemopericardium), immune checkpoint inhibitors (irAE pericarditis/myopericarditis).
Traumatic: blunt or penetrating chest trauma.

Genetic risk factors: - TNFRSF1A (HGNC:11916) pathogenic/likely-pathogenic and low-penetrance variants — found in ~6% of idiopathic recurrent pericarditis (IRP) cohorts (PMID:23745996); TRAPS patients have pericarditis in ~30% of cases (JACC Case Rep 2024). - MEFV (HGNC:6998) — rare deleterious variants (including the low-penetrance R202Q) enriched in IRP cohorts vs. ancestry-matched controls (~3.9–5%) (PMC11508427; PMID:35658515). - Family history/familial clustering of recurrent pericarditis can unmask TRAPS (PMID:20497634). - No common-variant GWAS signal specific to idiopathic pericarditis is well established in the literature to date (a genuine gap — see Section 4).

Environmental risk factors: male sex (2-fold higher incidence), age (bimodal — viral/idiopathic peaks in younger adults; malignant/uremic causes skew older), recent viral respiratory/GI illness, cardiac surgery/PCI/device implantation (procedural exposure), thoracic radiotherapy, tuberculosis exposure/endemicity and HIV co-infection (Africa/Asia), chronic kidney disease/dialysis dependence, autoimmune disease diagnosis, malignancy, and (rare) mRNA COVID-19 vaccination (myopericarditis, predominantly young males, self-limited).

Protective factors: Colchicine as secondary chemoprophylaxis after a first episode substantially reduces recurrence (see Section 12) — a pharmacologic rather than a constitutional protective factor. No robust genetic protective variant is established. Adequate/intensified dialysis reduces uremic pericarditis risk. Complete TB treatment reduces progression to constriction. No specific dietary/lifestyle protective factor is well characterized in the primary literature.

Gene–environment interactions: The clearest example is autoinflammatory-gene-primed inflammasome hyperresponsiveness (TNFRSF1A/MEFV variant carriers) interacting with a nonspecific inflammatory trigger (viral illness, minor injury, cold exposure — classic "stress trigger" reported by TRAPS patients) to precipitate a pericarditis flare, rather than a single environmental agent being sufficient on its own.

3. Phenotypes

Phenotype (category)	Description	Onset/frequency	Suggested HP term*
Pericarditic chest pain (symptom)	Sharp, pleuritic, retrosternal/left precordial pain, worse supine and with inspiration, relieved by sitting forward	Present in vast majority of acute episodes (>90%)	HP:0100749 (Chest pain)
Pericardial friction rub (clinical sign)	Triphasic (atrial systole, ventricular systole, early diastole), scratchy, left-sternal-border sound; pathognomonic but transient/positional	~35% at any single exam (intermittent)	consider HP:0031653 (Pericardial friction rub) or free text if unmapped
ECG changes (lab/instrument finding)	Diffuse concave ST-elevation + PR-segment depression (stage I), evolving through 4 classic stages; distinguishes from STEMI by lack of reciprocal changes	Frequent early finding	HP:0003115 (Abnormal EKG) as parent; more specific ST-elevation term if available
Pericardial effusion (imaging finding)	New or worsening fluid in pericardial space on echo/CT/MRI; ranges from trace to tamponade-causing	Variable, up to ~60%	HP:0001698 (Pericardial effusion)
Elevated CRP/inflammatory markers (lab abnormality)	CRP elevation supports diagnosis and guides duration of anti-inflammatory therapy/recurrence risk	Common, near-universal in active inflammation	consider generic elevated CRP term
Cardiac tamponade (clinical sign/complication)	Elevated JVP, pulsus paradoxus, hypotension (Beck triad in severe cases); life-threatening	Uncommon in idiopathic/viral (<5%), more frequent in malignant/TB/purulent	HP:0025091 (Pulsus paradoxus); consider cardiac tamponade term
Constrictive physiology (late complication)	Elevated/equalized diastolic pressures, ventricular interdependence, Kussmaul sign, pericardial knock, ascites/peripheral edema mimicking right heart failure	Develops in a minority (~1–2% after non-TB pericarditis; up to 17–40% after TB pericarditis) over months–years	consider constrictive pericarditis term
Fever, myalgia (systemic/constitutional)	Low-grade fever common, especially viral/idiopathic and autoinflammatory forms	Frequent	HP:0001945 (Fever); HP:0003326 (Myalgia)
Dyspnea (symptom)	From effusion, tamponade, or constrictive physiology	Variable, common with significant effusion	HP:0002094 (Dyspnea)
Troponin elevation (lab, indicates myopericardial overlap)	Reflects concomitant epicardial myocarditis (myopericarditis); does not by itself worsen prognosis if regional wall motion normal	~15–30% of acute pericarditis cases	consider elevated troponin term

*HP term suggestions are drawn from domain knowledge and should be OAK-verified (runoak -i sqlite:obo:hp info <ID> -O obo) against canonical labels before KB entry, per this repository's anti-hallucination protocol — several (friction rub, tamponade, constriction) I could not confirm exist as exact HPO leaf terms without direct OAK lookup and are flagged for curator verification rather than asserted.

Onset: Acute pericarditis can occur at any age but idiopathic/viral forms peak in young-to-middle-aged adults; malignant and uremic forms skew older; autoinflammatory-gene-associated recurrent pericarditis often begins in childhood/adolescence.

Severity/progression/course: Most acute idiopathic/viral pericarditis is self-limited (days to a few weeks) with NSAID/colchicine therapy. ~15–30% of a first episode recur; of those, further relapses are common, and a subset become colchicine-resistant/corticosteroid-dependent, driving IL-1-blockade candidacy. Recurrence overall approaches ~30% after a first episode. Progression to constrictive pericarditis is course-dependent: low risk (<1%) after viral/idiopathic pericarditis, intermediate (2–5%) after autoimmune/neoplastic, and high (20–30%) after bacterial/purulent or tuberculous pericarditis (Imazio et al., summarized in AFP 2024 review).

Quality-of-life impact: Recurrent pericarditis is associated with substantial QoL impairment — chronic pain, fatigue, activity limitation, anxiety about recurrence, and school/work absenteeism; IL-1-blockade trials (RHAPSODY, AIRTRIP) used patient-reported QoL instruments as secondary endpoints and demonstrated meaningful improvement with anti-IL-1 therapy (NEJM 2021, PMID:33200890).

4. Genetic/Molecular Information

Pericarditis is overwhelmingly a non-Mendelian, acquired inflammatory condition; monogenic contribution is confined to a minority of recurrent/idiopathic cases explained by autoinflammatory-disease genes.

Causal/associated genes: - TNFRSF1A (HGNC:11916; OMIM 191190) — encodes TNF receptor superfamily member 1A (p55 TNF receptor). Missense variants (e.g., cysteine-disrupting variants affecting extracellular disulfide bonds, and low-penetrance variants such as R92Q) impair receptor shedding/protein folding, causing TRAPS (OMIM #142680). Found in ~6% of idiopathic recurrent pericarditis cohorts (PMID:23745996); low-penetrance variants specifically implicated in adult-onset recurrent inflammatory attacks including pericarditis. - MEFV (HGNC:6998; OMIM 608107) — encodes pyrin. Pathogenic/likely-pathogenic variants cause FMF (OMIM #249100, AR); the low-penetrance R202Q variant has been specifically linked to anakinra-dependent recurrent pericarditis (PMC11508427). Rare deleterious MEFV variants enriched (~3.9%) in idiopathic recurrent pericarditis vs. ancestry-matched controls (PMID:35658515). - Other periodic-fever-syndrome genes (NLRP3/CAPS, MVK/hyper-IgD syndrome) are plausible but less specifically documented for pericarditis as the dominant phenotype; extrapolate cautiously.

Pathogenic variant characteristics: - Classification: predominantly missense (TNFRSF1A cysteine and non-cysteine variants; MEFV exon 10 and low-penetrance variants); ACMG/AMP tiers range from pathogenic (classic TRAPS-causing cysteine variants) to VUS/low-penetrance risk alleles (R92Q in TNFRSF1A, R202Q/E148Q in MEFV) — these lower-penetrance alleles act more as susceptibility/modifier variants than fully deterministic Mendelian causes, consistent with variable expressivity in adult-onset presentations. - Population allele frequency: low-penetrance variants (e.g., MEFV E148Q, R202Q) are relatively common polymorphisms in general population databases (gnomAD) with much lower penetrance than classic exon-10 FMF variants — curators should check gnomAD allele frequency directly per variant. - Origin: germline (autoinflammatory-gene variants); somatic variants are not a recognized mechanism in pericarditis. - Functional consequence: TNFRSF1A variants are broadly considered dominant-negative/gain-of-function for inflammatory signaling (impaired receptor shedding → sustained TNF signaling; also intracellular receptor misfolding triggering an unfolded-protein-response-linked pro-inflammatory state) rather than simple loss-of-function. MEFV pathogenic variants cause gain-of-function pyrin inflammasome activation.

Modifier genes: Not well characterized specifically for pericarditis; in the broader autoinflammatory-disease literature, additional NLRP3-pathway and cytokine-gene variants are proposed modifiers of clinical severity/penetrance, but pericarditis-specific modifier data are sparse — a knowledge gap.

Epigenetic information: No disease-specific pericarditis epigenetic dataset was identified in this search; broadly, inflammatory-disease epigenomic resources (ENCODE, Roadmap Epigenomics) have not to our knowledge been applied specifically to pericardial tissue in pericarditis.

Chromosomal abnormalities: Not a recognized feature of pericarditis; no aneuploidy/translocation association identified.

Suggested GO/molecular annotations for curation: GO:0043123 (positive regulation of canonical NF-kappaB signal transduction) for TNFRSF1A/pyrin-driven signaling; GO:0002218 (activation of innate immune response); NLRP3 inflammasome activation (GO:0043123-adjacent; consider GO term for "NLRP3 inflammasome complex assembly" if present in the ontology) — verify exact GO IDs via OAK before use.

5. Environmental Information

Environmental/toxic factors: thoracic irradiation (mediastinal RT for lymphoma/breast cancer) is the best-documented environmental trigger outside infection, causing both acute pericarditis and delayed (sometimes decades-later) fibrosing constrictive pericarditis with disproportionately poor surgical outcomes (PMID:34547827). No specific chemical toxin/pollutant is robustly linked in CTD/TOXNET-style evidence at the level of a primary etiologic driver (distinct from generalized cardiovascular risk).
Lifestyle factors: No strong dedicated lifestyle-modification literature (diet, exercise) for primary prevention of idiopathic pericarditis; post-diagnosis, strenuous physical activity is specifically discouraged during the acute/active phase until symptom and CRP normalization (guideline-level recommendation, ESC 2025) because of a theoretical/observed association with recurrence and to reduce arrhythmia risk in concurrent myocarditis.
Infectious agents: the best-characterized "environmental" driver class.
Viral: coxsackievirus B (classic), echovirus, adenovirus, parvovirus B19, EBV, CMV, HHV-6, influenza, SARS-CoV-2.
Bacterial: Mycobacterium tuberculosis (leading global cause of pericarditis/constriction, especially sub-Saharan Africa with HIV co-infection — mortality 8–34%, rising to ~40% in untreated HIV co-infection) (JACC Adv 2024); Staphylococcus aureus, Streptococcus pneumoniae, and other pyogenic bacteria (purulent pericarditis, high mortality if untreated); Coxiella burnetii, Borrelia burgdorferi (rare).
Fungal: Histoplasma, Aspergillus, Candida — rare, immunocompromised hosts.
Parasitic: Echinococcus, Entamoeba histolytica — rare, endemic-region case reports.

6. Mechanism / Pathophysiology

Causal chain overview (general/idiopathic-viral pericarditis): 1. Trigger (viral infection, cardiac injury, autoimmune activation, uremic toxin accumulation, or malignant infiltration) → 2. Pericardial mesothelial cell injury/stress → 3. Innate immune sensing and NLRP3 inflammasome activation in pericardial (and epicardial) tissue — central, converging mechanistic node across etiologies (JACC Basic Transl Sci 2020; https://www.jacc.org/doi/10.1016/j.jacbts.2020.11.016) → 4. IL-1β (and IL-1α) release → downstream NF-κB-driven cytokine cascade (IL-6, TNF, chemokines) → 5. Local vascular/mesothelial inflammatory response: increased microvascular permeability, leukocyte (neutrophil, then lymphocyte/macrophage) infiltration, fibrin deposition on pericardial surfaces → 6. Clinical phase: pericardial friction rub (fibrin-roughened surfaces), pericardial effusion (increased permeability + reduced lymphatic clearance), pleuritic chest pain (irritation of pain-sensitive parietal pericardium/pleura), diffuse ST-elevation (subepicardial inflammation) → 7. Resolution or chronicity: in most cases inflammation resolves; in a subset, recurrent inflammatory cycling occurs (IL-1-driven, explaining efficacy of IL-1 blockade), or fibrotic organization and calcification of the pericardium develop over months–years → constrictive pericarditis (loss of pericardial compliance → equalization of diastolic pressures across chambers → ventricular interdependence → right-heart-failure phenotype).

Etiology-specific mechanistic branches: - Autoimmune/post-cardiac-injury syndrome: mesothelial/myocardial injury exposes normally sequestered cardiac antigens → anti-actin/anti-myosin (anti-heart) autoantibody formation → immune-complex deposition in pericardium/pleura/lung → delayed (weeks-months) hypersensitivity-type serositis, classically Dressler syndrome post-MI (PMC10978175, PMID:38559602). - Autoinflammatory (monogenic): TNFRSF1A misfolded-receptor retention/impaired shedding or MEFV pyrin gain-of-function → constitutively primed innate immune cells (monocytes/macrophages) → recurrent, stereotyped IL-1β-driven flares independent of adaptive immunity, explaining corticosteroid- or colchicine-refractory but IL-1-blockade-responsive disease. - Tuberculous pericarditis: classic four-stage pathogenesis (fibrinous exudation → serosanguinous effusion with high lymphocyte/monocyte content → organization with granuloma/caseation → constrictive scarring) driven by delayed-type (Th1) hypersensitivity to mycobacterial antigens, worsened by HIV-associated immune dysregulation; fibrocalcific encasement impedes diastolic filling (Circulation 2005; ScienceDirect immunopathogenesis review). - Uremic/dialysis-associated pericarditis: accumulation of uremic toxins (urea, other nitrogenous solutes) causes direct pericardial inflammation and increased microvascular permeability; underdialysis is the proposed proximate mechanism for the dialysis-associated form; intensified dialysis often resolves it, supporting a toxin-clearance-dependent mechanism (PMID:28873222). - Neoplastic: tumor cells reach the pericardium by direct invasion, lymphatic dissemination, or hematogenous spread; disrupt capillary/venule integrity → exudative or hemorrhagic effusion; separately, neoplastic infiltration causes pericardial scarring/loss of elasticity that can mimic constriction.

Cell types involved: pericardial mesothelial cells (primary site of injury/inflammasome activation), monocytes/macrophages, neutrophils (early), T lymphocytes (delayed/autoimmune phase), fibroblasts (fibrotic/constrictive phase), and — in myopericarditis overlap — cardiomyocytes.

Suggested ontology terms for curation (verify via OAK before use): - GO biological processes: "NLRP3 inflammasome complex assembly," "positive regulation of interleukin-1 beta production," "positive regulation of canonical NF-kappaB signal transduction," "fibrosis"/extracellular matrix remodeling terms for the constrictive-progression node. - CL cell types: mesothelial cell (relevant pericardial mesothelium term), macrophage, neutrophil, fibroblast, CD4-positive T cell. - UBERON: pericardium, pericardial cavity/space, epicardium, parietal pericardium, visceral pericardium.

Molecular/omics profiling: Dedicated transcriptomic/proteomic/single-cell atlases of human pericarditis tissue are sparse in the literature relative to myocarditis; most mechanistic insight instead derives from (a) pericardial/pleural fluid cytokine profiling (elevated IL-1β, IL-6, TNF in inflammatory effusions) and (b) the interferon-γ-knockout mouse model (Section 15) demonstrating that loss of IFN-γ regulation shifts an autoimmune cardiac response toward a constrictive-pericarditis phenotype (PMID:15505106) — a genuine translational/human-model-fidelity gap worth flagging for a dismech HUMAN_MODEL_MISMATCH discussion if curated.

7. Anatomical Structures Affected

Organ level: - Primary: pericardium (parietal and visceral layers), pericardial space/cavity. - Secondary/complication-driven: myocardium (myopericarditis/perimyocarditis overlap), right and left ventricles (diastolic filling impairment in constriction/tamponade), lungs and pleura (co-occurring pleuritis/pleural effusion, especially PCIS), liver (passive congestion, "cardiac cirrhosis" in chronic constriction), and systemic venous system (elevated JVP, peripheral edema, ascites in constrictive physiology). - Body systems: cardiovascular system primarily; secondary respiratory (pleuritic pain, pleural effusion) and, in autoimmune/uremic forms, renal and immune systems as upstream drivers rather than affected targets.

Tissue/cell level: mesothelial lining of the pericardium (site of primary injury and inflammasome activation); subserosal connective tissue (site of fibrosis/calcification in constrictive disease); in the myopericardial-overlap subset, subepicardial myocardium.

Subcellular level: NLRP3 inflammasome assembly at the level of the cytosol/mitochondria-associated membranes in mesothelial and macrophage populations (GO Cellular Component: inflammasome complex); disrupted TNFRSF1A intracellular trafficking/ER retention in TRAPS-associated cases.

Localization/laterality: Diffuse, non-lateralized process (unlike myocardial infarction) — a key clinical distinguishing feature (diffuse concave ST elevation vs. territorial STEMI changes). No meaningful unilateral/bilateral distinction applies to the pericardium itself, though co-occurring pleural effusions in PCIS can be unilateral or bilateral.

Suggested UBERON terms: pericardium, pericardial cavity, parietal pericardium, visceral pericardium (epicardium), fibrous pericardium, myocardium (for overlap phenotype), pleura (for PCIS co-involvement). Verify exact UBERON IDs via OAK before curation.

8. Temporal Development

Onset: Acute pericarditis can present at any age; peak incidence in young-to-middle-aged adults for idiopathic/viral forms; malignant, uremic, and radiation-associated forms occur predominantly in older or comorbid populations. Onset pattern is typically acute (days), though incessant (continuous >4–6 weeks but <3 months) and chronic (>3 months) courses occur, and tuberculous/uremic forms may present more insidiously.

Disease stages / progression: - Acute: days to a few weeks, self-limited in the majority with NSAID/colchicine therapy. - Incessant: continuous symptoms beyond the expected acute window without a symptom-free interval. - Recurrent: relapse after a documented symptom-free interval of ≥4–6 weeks; occurs in ~15–30% after a first episode, and in a subgroup evolves into multiple relapses requiring escalation to corticosteroids and ultimately IL-1 blockade. - Chronic: persistent (>3 months) low-grade inflammation. - Constrictive (late structural sequela): can develop as transient constrictive pericarditis (reversible with anti-inflammatory therapy, associated with CMR pericardial late gadolinium enhancement and elevated inflammatory markers predicting reversibility — Circulation, PMID underlying PMC3860810) or as fixed, fibrocalcific constriction requiring pericardiectomy.

Progression rate/course pattern: Highly etiology-dependent — viral/idiopathic pericarditis is typically monophasic-to-relapsing but rarely progresses to constriction; tuberculous and purulent bacterial pericarditis progress to constriction in a substantial minority (17–40% for TB) over months if inadequately treated; radiation-associated constriction can manifest years to decades after exposure.

Remission patterns: Spontaneous remission is common in viral/idiopathic acute pericarditis; treatment-induced remission is the norm with NSAID + colchicine; IL-1 blockade (rilonacept, anakinra) induces treatment-dependent remission in colchicine-resistant/steroid-dependent recurrent disease, with recurrence typically resuming on drug withdrawal in trial data (RHAPSODY).

Critical periods: Early initiation of colchicine (from the first episode) is the key intervention window for reducing recurrence risk; in tuberculous pericarditis, early diagnosis and antitubercular therapy (± adjunctive corticosteroids) is the critical window for preventing progression to constriction; in transient constrictive pericarditis, early aggressive anti-inflammatory therapy (guided by CMR LGE/CRP) can prevent the need for pericardiectomy.

9. Inheritance and Population

Epidemiology: - Incidence of acute pericarditis: ~27.7 per 100,000 person-years overall (commonly cited estimate); a Finnish population study reported 4.52/100,000 person-years in men vs. 2.11/100,000 in women. Acute pericarditis accounts for ~4.4% of ED presentations for non-ischemic chest pain, with an estimated 0.1% of all-cause and ~5% of chest-pain-related hospital admissions. - Recurrence after a first episode: ~15–30%. - Constrictive pericarditis incidence after non-TB pericarditis: <1–2%; after tuberculous pericarditis: 17–40%.

Inheritance pattern (for the genetic/autoinflammatory subset only — the great majority of pericarditis is acquired/non-Mendelian): - TRAPS (TNFRSF1A-associated): autosomal dominant, OMIM #142680. - FMF (MEFV-associated): classically autosomal recessive, OMIM #249100, though low-penetrance heterozygous variants (e.g., R202Q, E148Q) have been reported with apparent semi-dominant/reduced-penetrance patterns in recurrent-pericarditis cohorts. - Penetrance: incomplete and variable — particularly pronounced for the "low-penetrance" TNFRSF1A (R92Q) and MEFV (E148Q, R202Q) variants, which are relatively frequent in the general population but confer disease only in a minority of carriers, consistent with a susceptibility-allele rather than fully penetrant Mendelian model. - Expressivity: variable — even within TRAPS/FMF families, phenotype ranges from isolated recurrent pericarditis to full periodic-fever syndrome with polyserositis/rash/myalgia. - Genetic anticipation, germline mosaicism, founder effects: not specifically documented for pericarditis; FMF overall shows well-known founder-mutation enrichment in Mediterranean/Middle Eastern populations (Sephardic Jewish, Armenian, Turkish, Arab ancestries) — relevant background for MEFV-positive idiopathic recurrent pericarditis case ascertainment, though this is population structure of FMF broadly rather than pericarditis-specific. - Consanguinity: relevant to recessive FMF ascertainment generally, not documented as pericarditis-specific. - Carrier frequency: MEFV pathogenic-variant carrier frequency is notably elevated (~1 in 5–7) in some Mediterranean populations reflecting FMF founder effects — again, general-FMF-population data rather than pericarditis-cohort-specific.

Population demographics: - Sex ratio: male predominance overall, incidence ratio ~1.7–2.0:1 (men:women), with the largest sex gap in young adults; constrictive pericarditis specifically shows ~3:1 male:female predominance. - Geographic distribution: idiopathic/viral pericarditis predominates in high-income settings with low TB burden; tuberculous pericarditis dominates in sub-Saharan Africa and parts of Asia, where it is the leading cause of pericardial constriction, strongly modulated by HIV co-prevalence. - Age distribution: bimodal-ish — younger adults for idiopathic/viral/post-vaccination myopericarditis; older, comorbid populations for malignant, uremic, radiation-associated, and post-cardiac-surgery pericarditis.

10. Diagnostics

Clinical diagnostic criteria (ESC, reaffirmed 2025): ≥2 of 4 — 1. Typical pericarditic chest pain (pleuritic, positional) 2. Pericardial friction rub 3. New widespread ST-elevation or PR-depression on ECG 4. New or worsening pericardial effusion

Supportive findings: elevated CRP/inflammatory markers, evidence of pericardial inflammation on imaging.

Laboratory tests: - CRP/ESR — supports diagnosis, tracks disease activity, guides duration of anti-inflammatory therapy and tapering; LOINC-codable inflammatory markers. - Troponin — elevated in myopericarditis overlap (~15–30%); does not independently worsen prognosis absent regional wall-motion abnormality. - Complete blood count, renal function (to identify uremic etiology), autoimmune serologies (ANA, RF, ANCA) when systemic disease suspected. - Pericardial fluid analysis when pericardiocentesis performed: cell count/differential, protein, LDH (Light's-criteria-type exudate/transudate distinction), cytology (malignancy), ADA and mycobacterial culture/PCR (TB), Gram stain/culture (purulent).

Imaging: - Echocardiography: first-line, detects effusion, tamponade physiology, and (with Doppler) constrictive hemodynamics (respirophasic septal shift, hepatic vein flow reversal). - Cardiac CT: pericardial thickening/calcification, especially useful pre-pericardiectomy. - Cardiac MRI (CMR): pericardial late gadolinium enhancement (LGE) is a sensitive marker of active pericardial inflammation; elevated inflammatory markers plus pericardial LGE predict reversibility of constrictive physiology with anti-inflammatory therapy, distinguishing "transient constrictive pericarditis" from fixed fibrocalcific constriction requiring surgery (Circulation, PMID underlying PMC3860810/PMID:22262690-type series). - Chest X-ray: may show cardiomegaly ("water-bottle" silhouette) with large effusion; limited standalone diagnostic value.

Functional/electrophysiologic tests: ECG (4-stage evolution: diffuse ST-elevation + PR-depression → normalization → T-wave inversion → normalization); cardiac catheterization with simultaneous right/left heart pressure tracings for hemodynamic confirmation of constriction (equalized diastolic pressures, discordant respiratory variation in LV/RV systolic pressure — distinguishing constriction from restrictive cardiomyopathy).

Biopsy/pathology: Pericardial biopsy reserved for diagnostic uncertainty (suspected TB, malignancy, or purulent pericarditis) or at the time of pericardiectomy — histopathology shows fibrinous exudate (acute), granulomatous inflammation with caseation (TB), or dense fibrosis/calcification (chronic constrictive).

Genetic testing: Targeted TNFRSF1A and MEFV sequencing (single-gene or as part of a periodic-fever/autoinflammatory-disease gene panel) is reasonable in recurrent, colchicine-resistant/corticosteroid-dependent pericarditis, especially with a suggestive personal/family history of periodic fevers, serositis, rash, or relevant ancestry (Mediterranean for MEFV). Whole-exome/genome sequencing is not first-line but may be used in atypical multisystem presentations. No CMA, karyotype, FISH, mitochondrial, or repeat-expansion testing role is established for pericarditis.

Differential diagnosis: acute coronary syndrome/STEMI (most critical to exclude), aortic dissection, pulmonary embolism, pleuritis/pneumonia, costochondritis, esophageal disease (GERD, spasm), myocarditis (may coexist), restrictive cardiomyopathy (vs. constrictive pericarditis — key differential requiring invasive hemodynamics/CMR/CT tissue characterization).

Screening: No population-level screening program exists (acquired, largely sporadic disease); "screening" in practice is case-finding for underlying secondary causes (autoimmune serologies, TB testing, malignancy workup, renal function) once pericarditis is diagnosed, and cascade genetic counseling/testing of relatives when a monogenic autoinflammatory cause is confirmed.

11. Outcome/Prognosis

Survival/mortality: Idiopathic/viral acute pericarditis carries an excellent prognosis with mortality close to that of the general population. Prognosis is markedly etiology-dependent — purulent bacterial pericarditis and tuberculous pericarditis carry substantially higher mortality (TB pericarditis: >1 in 4 patients die within 6 months of diagnosis; mortality rises to ~40% with untreated HIV co-infection). Malignant pericardial effusion/tamponade is associated with poor prognosis reflecting the underlying cancer stage rather than the pericardial process per se.

Recurrence and chronicity: ~15–30% recurrence after a first episode; of recurrent cases, a meaningful subset become colchicine-resistant and corticosteroid-dependent, prompting escalation to IL-1 blockade.

Constrictive pericarditis outcomes (post-pericardiectomy): - Contemporary in-hospital/30-day mortality: ~2–8% (improved from historical rates of ~11–13.5%); actuarial survival ~91%, 85%, and 81% at 1, 5, and 10 years respectively. - Functional improvement (≥1 NYHA class) in ~80% of surviving patients. - Etiology strongly predicts surgical outcome: idiopathic and post-surgical constriction have the best outcomes; radiation-associated and neoplastic constriction have the worst long-term survival; need for reoperation and low cardiac output are additional adverse prognostic factors.

Morbidity/QoL: Recurrent pericarditis imposes significant chronic-pain and QoL burden (addressed above, Section 3); constrictive pericarditis produces a right-heart-failure-like disability burden (edema, ascites, exercise intolerance, hepatic congestion) until surgically corrected.

Prognostic factors/biomarkers: Persistently elevated CRP and pericardial LGE on CMR predict ongoing/recurrent inflammatory activity and identify the "transient" (reversible) constrictive phenotype amenable to medical therapy rather than surgery. High-risk features for a complicated first episode (per ESC criteria) include fever >38°C, subacute onset, large effusion/tamponade, failure to respond to NSAIDs within a week, myopericarditis, immunosuppression, trauma, and oral anticoagulant therapy.

12. Treatment

First-line pharmacotherapy (acute and first-recurrence pericarditis): - NSAIDs (ibuprofen, aspirin — aspirin preferred post-MI to avoid impairing infarct healing) — mainstay for pain/inflammation control. (NCIT:C15986 Pharmacotherapy; specific agent — CHEBI id per drug) - Colchicine — added to NSAID therapy from the first episode to reduce recurrence risk; foundational trial evidence: - COPE (2005) — colchicine + conventional therapy reduced recurrence in first-episode acute pericarditis (PMID:16186437). - ICAP (NEJM 2013, PMID:23992557) — colchicine added to standard anti-inflammatory therapy significantly reduced incessant/recurrent pericarditis in first-episode disease. - CORP (Ann Intern Med 2011) and CORP-2 (Lancet 2014) — colchicine reduced recurrence by >30% in patients with a first recurrence and in multiple-recurrence pericarditis, respectively. - Colchicine is now guideline-recommended as standard-of-care adjunct at every stage from first episode onward. (therapeutic_agent: CHEBI colchicine ID; treatment_term: NCIT:C15986 Pharmacotherapy) - Corticosteroids — reserved as second-line (NSAID/colchicine-refractory, contraindication to NSAIDs, or autoimmune-disease-associated pericarditis) because of an association with higher recurrence risk when used as first-line therapy; low-to-moderate dose with slow taper is preferred over high-dose pulses.

IL-1 pathway blockade (colchicine-resistant/corticosteroid-dependent recurrent pericarditis): - Rilonacept (ARCALYST) — soluble IL-1 receptor chimeric fusion protein neutralizing both IL-1α and IL-1β. Phase II (2020, PMC7925818) and pivotal Phase 3 RHAPSODY trial (NEJM 2021, PMID:33200890) demonstrated rapid resolution of pericarditis pain/inflammation and marked reduction in recurrence during randomized withdrawal. FDA-approved March 2021 — the first and only FDA-approved therapy specifically for recurrent pericarditis, for adults and children ≥12 years (weekly subcutaneous injection). (therapeutic_modality: MONOCLONAL_ANTIBODY-adjacent fusion protein — classify per dismech convention, likely OTHER/biologic; treatment_term: NCIT:C15986; therapeutic_agent: search NCIT/CHEBI for rilonacept) - Anakinra — recombinant IL-1 receptor antagonist; the AIRTRIP RCT demonstrated efficacy in colchicine-resistant, corticosteroid-dependent recurrent pericarditis. A systematic review/meta-analysis (PMC9730293) and review (PMC9152656) confirm efficacy of both anakinra and rilonacept, with anti-IL-1 therapy improving both QoL and clinical recurrence outcomes. - Mechanistic rationale directly ties to Section 6: NLRP3-inflammasome/IL-1β is the convergent pathway across etiologies, making IL-1 blockade a targeted (not merely empiric) therapy — an excellent candidate for a dismech target_mechanisms drug-mechanism edge onto an "NLRP3 Inflammasome Activation"/"IL-1β Release" pathophysiology node.

Etiology-directed therapy: - Tuberculous pericarditis: standard 4-drug antitubercular regimen ± adjunctive corticosteroids (evidence mixed/context-dependent, especially by HIV status); colchicine adjunct studied but not clearly beneficial in TB pericarditis specifically (PMC5412665). - Uremic/dialysis-associated pericarditis: intensified/optimized dialysis is first-line; NSAIDs/colchicine adjunctive; pericardiocentesis for tamponade. - Purulent bacterial pericarditis: targeted IV antibiotics + pericardial drainage (often surgical, given loculation risk). - Malignant pericardial effusion: pericardiocentesis ± pericardial window/sclerotherapy, and treatment of the underlying malignancy (chemotherapy/targeted therapy per tumor type). - Autoinflammatory-gene-positive recurrent pericarditis: IL-1 blockade is particularly rational and effective (anakinra specifically shown effective in MEFV R202Q-positive cases, PMC11508427).

Surgical/interventional: - Pericardiocentesis — for tamponade or large symptomatic/diagnostic effusion. (NCIT surgical/procedural term — verify) - Pericardial window — for recurrent/malignant effusions. - Pericardiectomy — definitive therapy for fixed constrictive pericarditis; outcomes summarized in Section 11 (best for idiopathic/post-surgical etiology, worst for radiation/neoplastic).

Supportive care: activity restriction until symptom/CRP resolution; analgesia; management of tamponade as an emergency.

Experimental/emerging: - Additional IL-1-pathway and broader anti-inflammatory agents continue to be studied for recurrent pericarditis (search ClinicalTrials.gov for current NCT-registered trials, e.g., colchicine-formulation and other anti-inflammatory candidates such as the CardiolRx/MAvERIC-Pilot program referenced in trial registries). - Ongoing refinement of CMR-LGE-guided therapy duration/tapering strategies.

Treatment algorithm (guideline-level, ESC 2025): NSAID + colchicine from first episode → corticosteroids only if NSAID-refractory/contraindicated → IL-1 blockade (rilonacept or anakinra) for colchicine-resistant, corticosteroid-dependent recurrent disease → surgical pericardiectomy reserved for fixed constrictive physiology unresponsive to anti-inflammatory therapy (with CMR/CRP used to first distinguish reversible "transient constriction" from fixed disease).

13. Prevention

Primary prevention: No population-level primary-prevention program exists for idiopathic/viral pericarditis (sporadic, largely unpredictable trigger). Etiology-specific primary prevention is more concrete: - TB pericarditis: TB control programs, HIV testing/ART access, and (where relevant) latent-TB treatment in high-risk populations. - Uremic pericarditis: adequate/timely dialysis initiation and dose optimization. - Post-cardiac-injury syndrome: no established primary prophylaxis, though perioperative colchicine has been studied to reduce postpericardiotomy syndrome incidence after cardiac surgery in some trial literature (not exhaustively reviewed here — worth a dedicated search if curating this specific claim). - Radiation-associated pericarditis: radiotherapy planning to minimize cardiac/pericardial dose (modern conformal/IMRT techniques).

Secondary prevention (recurrence prevention — the best-evidenced prevention domain in this disease): - Colchicine started at first-episode diagnosis is the single best-evidenced secondary-prevention intervention (COPE, ICAP, CORP, CORP-2 — Section 12), reducing recurrence by roughly one-third to one-half across trials. - IL-1 blockade (rilonacept, anakinra) functions as tertiary/secondary prevention specifically in the colchicine-resistant subgroup, with RHAPSODY demonstrating markedly reduced time-to-recurrence during drug-withdrawal periods. - Avoidance of high-dose corticosteroid monotherapy as first-line, since it is itself associated with higher recurrence risk relative to colchicine-based regimens.

Screening/early detection: CRP-guided activity restriction and treatment-duration decisions function as a form of tertiary prevention (of both symptomatic relapse and progression to constriction). Early CMR characterization of "transient" vs. fixed constrictive physiology allows early aggressive medical therapy to prevent the need for pericardiectomy.

Genetic counseling: For confirmed TNFRSF1A/MEFV-associated recurrent pericarditis, standard autoinflammatory-disease genetic counseling applies — informing relatives of inheritance pattern (AD for TRAPS, AR/reduced-penetrance for MEFV), variable penetrance/expressivity, and the availability of targeted IL-1-blockade therapy for confirmed carriers with recurrent symptoms.

Public health: TB control and HIV treatment access are the dominant public-health lever globally, given tuberculous pericarditis's outsized contribution to pericarditis morbidity/mortality and constriction burden in endemic, high-HIV-prevalence regions.

14. Other Species / Natural Disease

Naturally occurring pericarditis is recognized in veterinary medicine, most notably: - Traumatic reticulopericarditis ("hardware disease") in cattle — a well-known naturally occurring bovine pericarditis caused by ingested metallic foreign bodies migrating from the reticulum through the diaphragm into the pericardial sac, producing purulent/fibrinous pericarditis and, if chronic, constrictive physiology — a genuine natural-disease veterinary analog (relevant OMIA/veterinary literature, not deeply searched here but well established in veterinary cardiology). - Idiopathic pericardial effusion in dogs (and pericardial mesothelioma-associated effusion, notably in Golden Retrievers) is a recognized clinical entity in small-animal cardiology, though its mechanistic overlap with human idiopathic pericarditis is not well characterized at the molecular level in the literature surveyed here. - No specific NCBI Taxon-indexed comparative-genomics ortholog analysis for pericarditis susceptibility genes (TNFRSF1A, MEFV) across species was identified in this search; both genes are broadly conserved across mammals given their fundamental roles in TNF signaling and inflammasome biology, but disease-specific cross-species susceptibility data are not established in the pericarditis literature specifically. - No zoonotic transmission concern applies to pericarditis itself (it is a tissue-response phenotype, not a transmissible entity), though the causal pathogens in infectious pericarditis (e.g., some Coxiella burnetii cases) do have zoonotic origins.

15. Model Organisms

Compared with myocarditis, dedicated pericarditis-specific animal models are relatively sparse in the literature; most mechanistic animal data derive from cardiac-injury or autoimmune-myocarditis models with secondary pericardial involvement:

Interferon-γ-knockout (IFN-γ KO) mouse model of cardiac-myosin-induced experimental autoimmune myocarditis — the most directly relevant genetic model identified: cardiac myosin immunization in IFN-γ-KO mice produces a novel model of constrictive pericarditis with grossly detectable pericarditis, decreased cardiac output, increased chamber stiffness, preserved ejection fraction, and impaired diastolic filling — recapitulating the human constrictive-physiology phenotype (Circulation 2004, PMID:15505106). This demonstrates that loss of IFN-γ-mediated immune regulation shifts an autoimmune cardiac inflammatory response toward pericardial constriction rather than isolated myocarditis, a mechanistically informative but human-fidelity-uncertain finding (candidate for a HUMAN_MODEL_MISMATCH framing if curated, since knockout of a single regulatory cytokine in mice is a strong artificial perturbation not established as directly translatable to sporadic human constrictive pericarditis).
Experimental autoimmune myocarditis (EAM) — induced by subcutaneous immunization with cardiac myosin/α-myosin heavy chain peptide in complete Freund's adjuvant, strain-dependent susceptibility (A/J, BALB/c) — the parent model from which the IFN-γ-KO pericarditis-specific variant was derived; primarily a myocarditis model with pericardial involvement as a secondary/associated finding rather than the primary phenotype.
Coxsackievirus B3 (CVB3)-induced murine myocarditis — models the viral-infection → myocarditis → chronic fibrosis/pericarditis → dilated cardiomyopathy sequence relevant to the viral-etiology branch of human pericarditis, though again pericarditis is a secondary/associated feature of a primarily myocardial model.
Model limitations: no widely used model isolates pericardial-mesothelial NLRP3-inflammasome activation as the primary, independent phenotype (i.e., a "pure" pericarditis model without concomitant myocarditis); this is a genuine translational gap, and current mechanistic inference about NLRP3/IL-1β centrality in human pericarditis rests more on (a) clinical biomarker/effusion cytokine data and (b) the strong clinical-trial efficacy signal of IL-1 blockade (RHAPSODY, AIRTRIP) than on a dedicated animal model recapitulating idiopathic recurrent pericarditis end-to-end.
Applications: existing models are primarily used to study autoimmune mechanisms of cardiac inflammation broadly and the transition from inflammation to fibrosis/constriction, rather than to test pericarditis-specific therapeutics — IL-1-blockade drug development for pericarditis instead proceeded largely from mechanistic/biomarker rationale directly into human trials.

Summary of Suggested Ontology Terms for Curation (require OAK verification before entry)

Domain	Suggested term(s)
MONDO	MONDO:0004770 (pericarditis) — and disambiguate constrictive/tuberculous/uremic subtype terms if present
HGNC	TNFRSF1A (HGNC:11916), MEFV (HGNC:6998)
GO (biological process)	NLRP3 inflammasome activation/assembly; positive regulation of IL-1β production; positive regulation of canonical NF-κB signal transduction
CL	mesothelial cell, macrophage, neutrophil, fibroblast, CD4+ T cell
UBERON	pericardium, pericardial cavity, parietal/visceral pericardium, myocardium, pleura
HP	chest pain, fever, dyspnea, pulsus paradoxus, pericardial effusion (and verify exact leaf terms for friction rub, tamponade, constrictive pericarditis)
CHEBI	colchicine, ibuprofen, aspirin
NCIT	C15986 (Pharmacotherapy) as the generic treatment_term for NSAID/colchicine/steroid/biologic pharmacotherapy; verify specific NCIT codes for rilonacept/anakinra as therapeutic_agent

Key Citations (PMID-anchored where available)

Colchicine for acute pericarditis (COPE trial) — PMID:16186437
Colchicine for recurrent pericarditis (CORP trial) — Ann Intern Med 2011
Colchicine for acute pericarditis (ICAP trial) — PMID:23992557
Rilonacept Phase 3 (RHAPSODY) — PMID:33200890
Interleukin-1 antagonists for recurrent pericarditis (review) — PMC9152656
Rilonacept and anakinra meta-analysis — PMC9730293
TNFRSF1A mutation spectrum in idiopathic recurrent acute pericarditis — PMID:23745996
Recurrent pericarditis: autoimmune or autoinflammatory? — PMID:22884556
Pericarditis and autoinflammation — monogenic autoinflammatory disease screening — PMID:35658515
Anakinra-dependent recurrent pericarditis and MEFV R202Q — PMC11508427
Familial clustering of recurrent pericarditis unmasking TRAPS — PMID:20497634
NLRP3 inflammasome role in pericarditis (mechanistic review) — https://www.jacc.org/doi/10.1016/j.jacbts.2020.11.016
Post-cardiac injury syndrome: evidence-based approach — PMID:38559602
Dressler syndrome: not just a relic of the past — PMC9681686
Cardiovascular involvement in TB patients treated in Southern Africa — JACC Adv 2024
Uremic pericarditis, pericardial effusion, and constriction in ESRD — PMID:28873222
CMR pericardial LGE predicts reversibility of constrictive pericarditis — Circulation (PMC3860810)
Long-term outcomes of pericardiectomy for constrictive pericarditis — PMC4662820
FDA approval of rilonacept for recurrent pericarditis (2021) — Kiniksa/FDA press release
Novel model of constrictive pericarditis in IFN-γ-knockout mice — PMID:15505106
2025 ESC Guidelines for the management of myocarditis and pericarditis — Eur Heart J 2025 (https://academic.oup.com/eurheartj/article/46/40/3952/8234483)

Note on evidence gaps: Several sections (epigenetics, single-cell/spatial transcriptomics of human pericardial tissue, modifier genes beyond TNFRSF1A/MEFV, pericarditis-specific animal models isolating pericardial inflammation from myocarditis, and comparative/veterinary molecular data) have thin or absent dedicated literature and are flagged rather than fabricated — consistent with this KB's evidence-discipline requirement to omit or flag unsupported claims rather than invent citations.

Pericarditis

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Pericarditis: Comprehensive Disease Characteristics Research Report

1. Disease Information

2. Etiology

3. Phenotypes

4. Genetic/Molecular Information

5. Environmental Information

6. Mechanism / Pathophysiology

7. Anatomical Structures Affected

8. Temporal Development

9. Inheritance and Population

10. Diagnostics

11. Outcome/Prognosis

12. Treatment

13. Prevention

14. Other Species / Natural Disease

15. Model Organisms

Summary of Suggested Ontology Terms for Curation (require OAK verification before entry)

Key Citations (PMID-anchored where available)