Reynolds Syndrome

Autoimmune MONDO:0013276 Pathograph 17 Show in embeddings browser Autoimmune Disease Connective Tissue Disease Liver Disease

Reynolds syndrome is the co-occurrence of primary biliary cholangitis (PBC) with limited cutaneous systemic sclerosis, described by Telfer Reynolds in 1971. It is curated here as a disease entry rather than as an incidental comorbidity because the overlap is not simply two independent diagnoses in one patient: a 2026 systematic review of case-control studies concluded that it "represents a distinct clinical and immunological entity", with higher anticentromere and antimitochondrial antibody positivity than either isolated disease, a predominance of the limited cutaneous rather than diffuse cutaneous SSc subset, and more extrahepatic autoimmunity. The other half of that distinctness is clinical: visceral involvement is milder than in SSc alone -- less interstitial lung disease, reflux and musculoskeletal disease -- without that amounting to a better prognosis, since SSc-related mortality and oesophageal varices run higher in some cohorts. The pathograph is deliberately modelled as two autoimmune arms sharing a common host predisposition rather than as one linear chain, because that is what the evidence supports. The hepatic arm runs from loss of tolerance to the pyruvate dehydrogenase complex E2 subunit through immune destruction of small intrahepatic bile ducts to cholestasis and biliary cirrhosis. The sclerodermatous arm runs from loss of tolerance to centromere protein B through microvascular endothelial injury and dermal fibroblast activation to the CREST features. What ties the arms together is serological rather than mechanistic: the two autoantibody systems co-occur far more often than chance would predict, and no shared downstream effector has been demonstrated. That gap is recorded as a knowledge gap rather than papered over with a speculative shared node. One point of caution about this entity's identity. MONDO gives Reynolds syndrome two parents -- "hereditary disease" and "autoimmune disease" -- and attributes a causal gene, LBR (hgnc:6518), while OMIM assigns it MIM#613471. This entry follows the autoimmune parent and not the hereditary one, because the genetic attribution rests on a single patient reported in 2010 with a single heterozygous LBR missense variant, whose own authors concluded only that "LBR mutations might thus be associated with Reynolds syndrome". A commentary published the same year asked directly whether the syndrome is a genetic laminopathy and answered that the case was not yet made, and no replication has been reported since. The clinical and serological literature treats the syndrome as autoimmune. So the LBR hypothesis is recorded as an open question in `discussions`, with the genetic association typed as a susceptibility hypothesis rather than as a causal mechanism.

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6
Pathophys.
1
Histopath.
11
Phenotypes
2
Hypotheses
2
Gaps
17
Pathograph
1
Genes
2
Medical Actions
5
References
🏷

Classifications

Harrison's Part
IMMUNE RHEUMATOLOGIC
◈

Mechanistic Hypotheses

2
Shared autoimmune predisposition model
autoimmune_overlap_model CANONICAL
Reynolds syndrome arises from a host predisposition to epithelial and endothelial autoimmunity that manifests concurrently in the biliary tree and in the skin microvasculature, evidenced by the co-occurrence of AMA and ACA and by the excess of other extrahepatic autoimmune disease in overlap patients.
Pathograph links
Loss of Immune Tolerance to Pyruvate Dehydrogenase Complex E2 -> Autoimmune Destruction of Small Intrahepatic Bile Ducts DIRECT Broken tolerance to PDC-E2 licenses the innate and adaptive attack on the biliary epithelium.
Autoimmune Destruction of Small Intrahepatic Bile Ducts -> Intrahepatic Cholestasis DIRECT Progressive loss of small bile ducts obstructs bile flow.
Loss of Immune Tolerance to Centromere Protein B -> Microvascular Endothelial Injury INDIRECT UNKNOWN INTERMEDIATES The ACA-defined limited cutaneous subset is the one in which obliterative microvasculopathy dominates.
Loss of Immune Tolerance to Centromere Protein B -> Dermal Fibroblast Activation and Skin Fibrosis INDIRECT UNKNOWN INTERMEDIATES Immune dysregulation in this subset drives the stromal programme responsible for skin thickening.
Loss of Immune Tolerance to Centromere Protein B -> Dysphagia INDIRECT UNKNOWN INTERMEDIATES Oesophageal dysmotility belongs to the same limited cutaneous subset, but the intermediates between the autoantibody response and visceral smooth muscle involvement are not modelled here.
LBR laminopathy model
lbr_laminopathy_model EMERGING
An alternative reading in which Reynolds syndrome is a nuclear-envelope disorder caused by LBR variants acting in a tissue-specific dominant negative fashion. Supported by one patient to date; the confirmatory experiments proposed by contemporaneous commentary have not been reported.
?

Discussions and Knowledge Gaps

2
Is Reynolds syndrome a genetic laminopathy caused by LBR variants, or an autoimmune overlap in which the reported LBR variant is incidental?
KNOWLEDGE GAP lbr_causality_unresolved
Attached to
genetic#LBR mechanistic_hypotheses#lbr_laminopathy_model
MONDO classifies Reynolds syndrome as a hereditary disease and OMIM (MIM#613471) attributes it to LBR, but the entire genetic claim rests on one patient with one heterozygous missense variant. The functional work in that report was done on patient fibroblasts and lymphoblastoid lines, not on the affected liver, and contemporaneous commentary in the same year stated explicitly that the pathogenicity claim remained to be demonstrated and that larger PBC and SSc series were needed. No replication has been reported. This matters for curation because it decides whether the entry's root cause is a nuclear-envelope defect or a break in immune tolerance.
Show evidence (1 reference)
PMID:20800400 SUPPORT Other
"It remains to be shown, however, that this is really the case by testing directly the liver and skin fibroblasts of the patient."
Contemporaneous commentary stating that the pathogenicity of the LBR variant was not established by the original report.
What shared upstream mechanism causes anti-PDC-E2 and anti-CENP-B autoimmunity to co-occur so much more often than chance?
KNOWLEDGE GAP shared_upstream_mechanism_unknown
Attached to
pathophysiology#Loss of Immune Tolerance to Pyruvate Dehydrogenase Complex E2 pathophysiology#Loss of Immune Tolerance to Centromere Protein B
Candidate shared mechanisms exist and none is established as causal for the overlap. Shared HLA alleles (HLA-DQB1, HLA-DRB1, HLA-DQA1) and the non-HLA loci IRF5 and STAT4 are reported in both diseases, both are marked by elevated TGF-beta and IL-6, and antibodies in the overlap preferentially recognise CENP-C rather than CENP-B alone. But the HLA associations are explicitly not exclusive to either disease, and none of these has been shown to explain why the two diseases co-occur rather than simply being features each has separately. The pathograph therefore stops at two parallel arms rather than asserting a common upstream node. Establishing one is the main thing that would distinguish this entity from the coincidence of two common autoimmune diseases in a predisposed host.
Show evidence (3 references)
PMID:42256626 SUPPORT Human Clinical
"The overlap group predominantly included patients with limited cutaneous SSc and had a higher prevalence of extrahepatic autoimmune diseases, particularly Sjögren's syndrome and Hashimoto's thyroiditis."
Documents the broader autoimmune excess that a shared upstream mechanism would need to account for.
PMID:42256626 SUPPORT Human Clinical
"non-HLA susceptibility genes IRF5 and STAT4 have been identified in both PBC and SSc"
A named shared-susceptibility candidate. Cited as a candidate rather than as an explanation, since the same review notes these loci are not exclusive to either disease.
PMID:42256626 SUPPORT Human Clinical
"Both diseases are marked by elevated TGF-β (transforming growth factor-beta) and IL-6 (Interleukin-6)"
A shared profibrotic cytokine signature, the closest thing to a common effector, still not shown to drive the co-occurrence itself.
⚙

Pathophysiology

6
Loss of Immune Tolerance to Pyruvate Dehydrogenase Complex E2
Aberrant exposure of the mitochondrial autoantigen PDC-E2, released from apoptotic biliary epithelial cells, breaks tolerance and drives the antimitochondrial antibody response that defines the hepatic arm of this overlap.
Shared autoimmune predisposition model
Downstream
Autoimmune Destruction of Small Intrahepatic Bile Ducts Broken tolerance to PDC-E2 licenses the innate and adaptive attack on the biliary epithelium. Shared autoimmune predisposition model
Show evidence (1 reference)
PMID:41112296 SUPPORT Other
"apoptosis of biliary epithelial cells releases antigens (e.g., PDC-E2), triggering aberrant innate and adaptive immune responses"
Establishes the source of the PDC-E2 autoantigen and the immune response it provokes.
Autoimmune Destruction of Small Intrahepatic Bile Ducts
Immune-mediated injury of cholangiocytes lining the small intrahepatic bile ducts, the lesion shared with isolated primary biliary cholangitis.
Shared autoimmune predisposition model
cholangiocyte CL:1000488 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves cholangiocyte (CL:1000488). CL:1000488 is a cell type from the Cell Ontology.
Downstream
Intrahepatic Cholestasis Progressive loss of small bile ducts obstructs bile flow. Shared autoimmune predisposition model
Show evidence (1 reference)
PMID:41112296 SUPPORT Other
"collectively initiating autoimmune targeting of biliary epithelial cells"
Identifies the biliary epithelium as the target of the autoimmune attack.
Intrahepatic Cholestasis
Impaired bile flow following duct loss, detected biochemically as a cholestatic liver enzyme pattern and clinically as pruritus. Persistent cholestatic enzymes in a CREST patient are the trigger for considering this diagnosis.
Downstream
Pruritus Retained biliary constituents drive cholestatic itch.
Elevated circulating alkaline phosphatase concentration The cholestatic enzyme pattern that flags the hepatic arm.
Biliary cirrhosis Sustained cholestasis and periportal injury progress to biliary fibrosis and cirrhosis.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"Reynolds Syndrome should be suspected in CREST patients with persistent cholestatic liver enzymes, since delayed diagnosis allows portal hypertension and variceal bleeding to develop."
Ties the cholestatic biochemical picture to this diagnosis and to the consequences of missing it.
Loss of Immune Tolerance to Centromere Protein B
The anticentromere response that marks the limited cutaneous sclerodermatous arm. Strong anti-CENP-B reactivity is itself enriched for AMA-M2 positivity and for cirrhosis, which is the serological link between the two arms of this syndrome.
Shared autoimmune predisposition model
Downstream
Microvascular Endothelial Injury The ACA-defined limited cutaneous subset is the one in which obliterative microvasculopathy dominates. Shared autoimmune predisposition model
Dermal Fibroblast Activation and Skin Fibrosis Immune dysregulation in this subset drives the stromal programme responsible for skin thickening. Shared autoimmune predisposition model
Dysphagia Oesophageal dysmotility belongs to the same limited cutaneous subset, but the intermediates between the autoantibody response and visceral smooth muscle involvement are not modelled here. Shared autoimmune predisposition model
Show evidence (1 reference)
PMID:42618734 SUPPORT Human Clinical
"strong anti-CENP-B reactivity was associated with enrichment of centromere ANA patterns (64.05%), AMA-M2 positivity (31.44%), and liver cirrhosis (11.76%)"
In a 1736-patient ACA-positive cohort, strong anti-CENP-B reactivity travels with AMA-M2 and with cirrhosis, which is the serological co-occurrence this syndrome is built on.
Microvascular Endothelial Injury
Widespread injury of the cutaneous and digital microvasculature, producing cold-triggered vasospasm, visible telangiectasia, and in severe cases digital ischemia and tissue loss.
endothelial cell of vascular tree CL:0002139 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves endothelial cell of vascular tree (CL:0002139). CL:0002139 is a cell type from the Cell Ontology.
Downstream
Raynaud phenomenon Vasospastic digital colour change on cold or stress exposure.
Telangiectasia Dilated superficial vessels on face and hands.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"SSc is a connective tissue disorder with widespread microvascular injury, immune dysregulation, and excessive collagen deposition, affecting the skin and internal organs"
Names microvascular injury as a core lesion of the sclerodermatous arm.
Dermal Fibroblast Activation and Skin Fibrosis
Activation of dermal fibroblasts with excess collagen deposition, producing the distal skin thickening and joint restriction of the limited cutaneous subset.
fibroblast of dermis CL:0002551 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves fibroblast of dermis (CL:0002551). CL:0002551 is a cell type from the Cell Ontology.
collagen fibril organization GO:0030199 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased collagen fibril organization (GO:0030199). GO:0030199 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Sclerodactyly Fibrotic thickening of the skin of the digits.
Calcinosis cutis Dystrophic calcification within chronically injured dermis.
Show evidence (1 reference)
PMID:41974602 SUPPORT Other
"We highlight emerging cellular- and molecular-level insights into vasculopathy, immune dysregulation, and fibroblast activation in SSc."
Places fibroblast activation alongside vasculopathy and immune dysregulation as the core compartments of SSc pathogenesis.
✶

Histopathology

1
Compartment-specific fibrosis
The two arms produce fibrosis in different compartments, which is what a biopsy distinguishes: periportal in the hepatic arm, perivascular or interstitial in the sclerodermatous arm.
Show evidence (1 reference)
PMID:42256626 SUPPORT Human Clinical
"The shared immunological environment ultimately leads to characteristic fibrotic histology: predominantly around the periportal region in PBC and perivascular or interstitial region in SSc."
Gives the compartment-level localisation that separates the two arms histologically despite their shared profibrotic drivers.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Reynolds Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

11
Cardiovascular 2
Raynaud phenomenon HP:0030880 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Raynaud phenomenon (HP:0030880). HP:0030880 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"she had a history of amputation of her right‐hand index finger due to severe digital ischemia and gangrene"
Documents the severe ischemic end of the digital vascular phenotype in a patient with this syndrome.
Telangiectasia HP:0001009 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Telangiectasia (HP:0001009). HP:0001009 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"Physical examination revealed sclerodactyly with digital ulcers on her fingers, telangiectasias on her face and hands, and limited range of motion in her fingers and wrists."
Records telangiectasia on examination in this syndrome.
Digestive 2
Dysphagia HP:0002015 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Dysphagia (HP:0002015). HP:0002015 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"She reported difficulty swallowing solid foods and experienced frequent episodes of discoloration of fingers and toes, often triggered by cold temperatures or stress."
Records oesophageal dysmotility alongside Raynaud phenomenon in the same patient.
Biliary cirrhosis HP:0002613 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Biliary cirrhosis (HP:0002613), qualified as course progressive. HP:0002613 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Immune 1
Autoimmunity HP:0002960 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Autoimmunity (HP:0002960). HP:0002960 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42256626 SUPPORT Human Clinical
"The overlap group predominantly included patients with limited cutaneous SSc and had a higher prevalence of extrahepatic autoimmune diseases, particularly Sjögren's syndrome and Hashimoto's thyroiditis."
Quantifies the extrahepatic autoimmune excess that characterises the overlap group.
Integument 2
Sclerodactyly HP:0011838 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sclerodactyly (HP:0011838), qualified as course progressive. HP:0011838 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"A 64‐year‐old woman presented to the rheumatology clinic with a 3‐year history of progressive skin thickening and tightening, particularly affecting her hands, face, and feet."
Describes the progressive distal skin thickening characteristic of the limited cutaneous subset.
Pruritus HP:0000989 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pruritus (HP:0000989). HP:0000989 is a phenotype from the Human Phenotype Ontology.
Metabolism 1
Elevated circulating alkaline phosphatase concentration HP:0003155 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Elevated circulating alkaline phosphatase concentration (HP:0003155). HP:0003155 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"liver function tests (LFTs) showed alanine aminotransferase (ALT) 49 U/L, aspartate aminotransferase (AST) 90 U/L, and alkaline phosphatase (ALP) 927 U/L"
A markedly cholestatic enzyme profile, with ALP disproportionately raised relative to the transaminases.
Musculoskeletal 1
Calcinosis cutis HP:0025520 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Calcinosis cutis (HP:0025520). HP:0025520 is a phenotype from the Human Phenotype Ontology.
Respiratory 1
Interstitial lung disease Abnormal pulmonary interstitial morphology HP:0006530 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Interstitial lung disease, annotated with Abnormal pulmonary interstitial morphology (HP:0006530). HP:0006530 is a phenotype from the Human Phenotype Ontology.
Show evidence (4 references)
PMID:42499963 SUPPORT Human Clinical
"computed tomography (HRCT) chest was suggestive of interstitial lung disease (ILD)"
HRCT-confirmed interstitial lung disease in a patient with this syndrome, establishing that it occurs.
PMID:42256626 SUPPORT Human Clinical
"Clinically, patients with overlap disease demonstrate milder systemic involvement than SSc-only patients, with lower occurrence of interstitial lung disease, gastro-oesophageal reflux and musculoskeletal involvement."
The comparison against isolated SSc: ILD is less frequent in the overlap, part of a broader milder visceral profile.
PMID:42256626 SUPPORT Human Clinical
"Compared with PBC-only, overlap patients have higher rates of renal complications, interstitial lung disease and extrahepatic autoimmune diseases such as SjS and Hashimoto’s thyroiditis."
The comparison in the other direction: ILD is more frequent than in isolated PBC. Together with the item above this is why the frequency is stated as intermediate rather than high or low.
+ 1 more reference
Other 1
Milder systemic involvement than isolated systemic sclerosis
Show evidence (1 reference)
PMID:42256626 SUPPORT Human Clinical
"Clinical manifestations such as ILD, digital ulcers, GERD and musculoskeletal involvement were less common in overlap patients compared with patients with SSc, supporting the notion of a milder systemic phenotype."
The review's cross-study synthesis of the milder systemic phenotype, naming the four manifestations it rests on.
🧬

Genetic Associations

1
LBR
Gene: LBR hgnc:6518 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is LBR (hgnc:6518). hgnc:6518 is a gene from the HUGO Gene Nomenclature Committee. relationship_type: SUSCEPTIBILITY
Show evidence (3 references)
PMID:20522425 SUPPORT Human Clinical
"revealing a single heterozygous missense mutation in LBR exon 9 (c.1114C/T; p.R372C). This variant was absent in 400 control chromosomes."
Reports the variant and its absence from 400 control chromosomes, the whole of the genetic evidence for this association.
PMID:20522425 SUPPORT In Vitro
"The fibroblast specific abnormalities observed suggest that this particular LBR mutation might have dominant negative deleterious effects in a tissue specific fashion"
The proposed mechanism, from patient-derived fibroblasts rather than affected liver tissue.
PMID:20800400 REFUTE Other
"the new mutation has been found neither in a group of 27 other patients with SSc"
Cited against a general causal role: the variant was not found in any other SSc patient tested, so it cannot account for the syndrome broadly.
💊

Medical Actions

2
Ursodeoxycholic Acid
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: ursodeoxycholic acid CHEBI:9907 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses ursodeoxycholic acid (CHEBI:9907). CHEBI:9907 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
First-line therapy for the cholestatic hepatic arm, started promptly once the PBC component is identified.
Mechanism Target:
Intrahepatic Cholestasis — Improves bile flow and the cholestatic biochemical profile.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"Early anti-mitochondrial antibody screening and prompt ursodeoxycholic acid therapy improve outcomes, and these patients need multidisciplinary follow-up for lung and thyroid disease."
States the therapeutic strategy for the hepatic arm and the rationale for early serological screening.
Cyclophosphamide
Action: PharmacotherapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Pharmacotherapy (NCIT:C15986). NCIT:C15986 is a clinical intervention from the NCI Thesaurus. NCIT:C15986
Agent: cyclophosphamide CHEBI:4027 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cyclophosphamide (CHEBI:4027). CHEBI:4027 is a therapeutic agent from Chemical Entities of Biological Interest.
Platform: Small molecule
Used for severe systemic sclerosis complications, notably interstitial lung disease, in the sclerodermatous arm.
Mechanism Target:
Interstitial lung disease — Immunosuppression aimed at the interstitial lung disease of the sclerodermatous arm.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"She was started on intravenous cyclophosphamide 750 mg/m2 monthly for 6 months, with monthly monitoring of blood counts and renal function"
Documents the regimen used for the interstitial lung disease complicating this patient's sclerodermatous arm.
🔬

Biochemical Markers

2
Antimitochondrial antibody
Show evidence (1 reference)
PMID:41715235 SUPPORT Human Clinical
"Among 165 SSc patients (20% diffuse cutaneous disease, 33% interstitial lung disease, 7.3% pulmonary arterial hypertension; 51% positive for anticentromere antibodies, 29% anti-topoisomerase I, 12% anti-RNA polymerase III), 37 (22%) were AMA-positive."
In a systematically screened SSc cohort, 22% were AMA-positive, which supports proactive screening for the hepatic arm.
Anticentromere antibody
Show evidence (3 references)
PMID:42499963 SUPPORT Human Clinical
"Laboratory tests showed positive antinuclear antibodies (ANA) with a centromere pattern."
Records the centromere ANA pattern in a patient with this syndrome.
PMID:42256626 SUPPORT Human Clinical
"sera from patients with PBC–SSc more frequently reacted with (CENP-C) compared with sera from patients with SSc alone"
CENP-C reactivity is the most overlap-specific serological finding available: it separates the overlap from isolated SSc, rather than merely marking the limited cutaneous subset.
PMID:42256626 SUPPORT Human Clinical
"STAT4 has been associated with ACA positivity in PBC, an autoantibody already present in over 50% of patients with limited cutaneous SSc (lcSSc)."
Links the anticentromere response to a shared non-HLA susceptibility locus reported in both diseases.
🔬

Diagnosis

1
Antimitochondrial antibody screening in a CREST patient with cholestasis
The practical diagnostic route to this entity. A patient already carrying a CREST or limited cutaneous SSc diagnosis who develops a cholestatic liver enzyme pattern should be tested for antimitochondrial antibodies rather than observed, because the delay is what allows portal hypertension and variceal bleeding to develop.
Show evidence (1 reference)
PMID:42499963 SUPPORT Human Clinical
"Reynolds Syndrome should be suspected in CREST patients with persistent cholestatic liver enzymes, since delayed diagnosis allows portal hypertension and variceal bleeding to develop."
States the trigger for suspecting the diagnosis and the cost of missing it.
📊

Prevalence

2
Patients with systemic sclerosis
Point Prevalence 3000.0 per 100,000 (2000.0–3000.0) >1 in 1,000
Frequency of the overlap within an SSc population, not a general-population prevalence. Reported as 2-3% of SSc patients, and separately as a weighted prevalence of 3.0%.
Show evidence (2 references)
PMID:42256626 SUPPORT Human Clinical
"prevalence studies have demonstrated that 2–3% of patients with SSc have overlapping PBC, whereas the prevalence of SSc in PBC has been estimated to be around 8%."
Gives the frequency of the overlap in both directions.
PMID:42256626 SUPPORT Human Clinical
"This overlap between PBC and SSc has been reported with a weighted prevalence of 3.0% among patients with SSc."
The pooled weighted estimate, consistent with the 2-3% range above.
Patients with primary biliary cholangitis
Point Prevalence 8000.0 per 100,000 >1 in 1,000
Frequency of SSc within a PBC population; the reciprocal of the record above, and the reason cholestatic patients are screened for sclerodermatous features as well as the reverse.
Show evidence (1 reference)
PMID:42256626 SUPPORT Human Clinical
"the prevalence of SSc in PBC has been estimated to be around 8%"
Gives the frequency of the sclerodermatous arm among PBC patients.
{ }

Source YAML

click to show 
name: Reynolds Syndrome
creation_date: '2026-09-07T00:00:00Z'
category: Autoimmune
synonyms:
- PBC-SSc overlap syndrome
- SSc-PBC overlap syndrome
- primary biliary cirrhosis and systemic scleroderma
- primary biliary cholangitis with CREST syndrome
parents:
- Autoimmune Disease
- Connective Tissue Disease
- Liver Disease
disease_term:
  preferred_term: Reynolds syndrome
  term:
    id: MONDO:0013276
    label: Reynolds syndrome
description: >-
  Reynolds syndrome is the co-occurrence of primary biliary cholangitis (PBC)
  with limited cutaneous systemic sclerosis, described by Telfer Reynolds in
  1971. It is curated here as a disease entry rather than as an incidental
  comorbidity because the overlap is not simply two independent diagnoses in
  one patient: a 2026 systematic review of case-control studies concluded that
  it "represents a distinct clinical and immunological entity", with higher
  anticentromere and antimitochondrial antibody positivity than either isolated
  disease, a predominance of the limited cutaneous rather than diffuse
  cutaneous SSc subset, and more extrahepatic autoimmunity. The other half of
  that distinctness is clinical: visceral involvement is milder than in SSc
  alone -- less interstitial lung disease, reflux and musculoskeletal disease --
  without that amounting to a better prognosis, since SSc-related mortality and
  oesophageal varices run higher in some cohorts.

  The pathograph is deliberately modelled as two autoimmune arms sharing a
  common host predisposition rather than as one linear chain, because that is
  what the evidence supports. The hepatic arm runs from loss of tolerance to
  the pyruvate dehydrogenase complex E2 subunit through immune destruction of
  small intrahepatic bile ducts to cholestasis and biliary cirrhosis. The
  sclerodermatous arm runs from loss of tolerance to centromere protein B
  through microvascular endothelial injury and dermal fibroblast activation to
  the CREST features. What ties the arms together is serological rather than
  mechanistic: the two autoantibody systems co-occur far more often than chance
  would predict, and no shared downstream effector has been demonstrated. That
  gap is recorded as a knowledge gap rather than papered over with a
  speculative shared node.

  One point of caution about this entity's identity. MONDO gives Reynolds
  syndrome two parents -- "hereditary disease" and "autoimmune disease" -- and
  attributes a causal gene, LBR (hgnc:6518), while OMIM assigns it MIM#613471.
  This entry follows the autoimmune parent and not the hereditary one, because
  the genetic attribution rests on a single patient reported in 2010 with a
  single heterozygous LBR missense variant, whose own authors concluded only
  that "LBR mutations might thus be associated with Reynolds syndrome". A
  commentary published the same year asked directly whether the syndrome is a
  genetic laminopathy and answered that the case was not yet made, and no
  replication has been reported since. The clinical and serological literature
  treats the syndrome as autoimmune. So the LBR hypothesis is recorded as an
  open question in `discussions`, with the genetic association typed as a
  susceptibility hypothesis rather than as a causal mechanism.
mechanistic_hypotheses:
- hypothesis_group_id: autoimmune_overlap_model
  hypothesis_label: Shared autoimmune predisposition model
  status: CANONICAL
  description: >-
    Reynolds syndrome arises from a host predisposition to epithelial and
    endothelial autoimmunity that manifests concurrently in the biliary tree
    and in the skin microvasculature, evidenced by the co-occurrence of AMA and
    ACA and by the excess of other extrahepatic autoimmune disease in overlap
    patients.
- hypothesis_group_id: lbr_laminopathy_model
  hypothesis_label: LBR laminopathy model
  status: EMERGING
  description: >-
    An alternative reading in which Reynolds syndrome is a nuclear-envelope
    disorder caused by LBR variants acting in a tissue-specific dominant
    negative fashion. Supported by one patient to date; the confirmatory
    experiments proposed by contemporaneous commentary have not been reported.
pathophysiology:
- name: Loss of Immune Tolerance to Pyruvate Dehydrogenase Complex E2
  biological_scale: MOLECULAR
  description: >-
    Aberrant exposure of the mitochondrial autoantigen PDC-E2, released from
    apoptotic biliary epithelial cells, breaks tolerance and drives the
    antimitochondrial antibody response that defines the hepatic arm of this
    overlap.
  downstream:
  - target: Autoimmune Destruction of Small Intrahepatic Bile Ducts
    causal_link_type: DIRECT
    description: >-
      Broken tolerance to PDC-E2 licenses the innate and adaptive attack on
      the biliary epithelium.
    hypothesis_groups:
    - autoimmune_overlap_model
    evidence:
    - reference: PMID:41112296
      reference_title: "Innate immunity of bile and cholangiocytes in primary biliary cholangitis."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: "These DAMPs encompass autoantigens such as the mitochondrial Antigen Pyruvate Dehydrogenase Complex- E2 (PDC-E2), whose aberrant exposure disrupts normal immune tolerance"
      explanation: >-
        Identifies aberrant PDC-E2 exposure as the tolerance-breaking event
        upstream of the biliary attack.
  evidence:
  - reference: PMID:41112296
    reference_title: "Innate immunity of bile and cholangiocytes in primary biliary cholangitis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "apoptosis of biliary epithelial cells releases antigens (e.g., PDC-E2), triggering aberrant innate and adaptive immune responses"
    explanation: >-
      Establishes the source of the PDC-E2 autoantigen and the immune response
      it provokes.
- name: Autoimmune Destruction of Small Intrahepatic Bile Ducts
  biological_scale: TISSUE
  description: >-
    Immune-mediated injury of cholangiocytes lining the small intrahepatic
    bile ducts, the lesion shared with isolated primary biliary cholangitis.
  cell_types:
  - preferred_term: cholangiocyte
    term:
      id: CL:1000488
      label: cholangiocyte
  downstream:
  - target: Intrahepatic Cholestasis
    causal_link_type: DIRECT
    description: >-
      Progressive loss of small bile ducts obstructs bile flow.
    hypothesis_groups:
    - autoimmune_overlap_model
    evidence:
    - reference: PMID:42499963
      reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Primary biliary cholangitis (PBC) is a chronic, progressive cholestatic liver disease marked by immune‐mediated destruction of intrahepatic bile ducts, eventually leading to fibrosis and cirrhosis"
      explanation: >-
        States the causal sequence from duct destruction through cholestasis to
        fibrosis and cirrhosis.
  evidence:
  - reference: PMID:41112296
    reference_title: "Innate immunity of bile and cholangiocytes in primary biliary cholangitis."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "collectively initiating autoimmune targeting of biliary epithelial cells"
    explanation: >-
      Identifies the biliary epithelium as the target of the autoimmune attack.
- name: Intrahepatic Cholestasis
  biological_scale: ORGANISM
  description: >-
    Impaired bile flow following duct loss, detected biochemically as a
    cholestatic liver enzyme pattern and clinically as pruritus. Persistent
    cholestatic enzymes in a CREST patient are the trigger for considering
    this diagnosis.
  downstream:
  - target: Pruritus
    causal_link_type: DIRECT
    description: Retained biliary constituents drive cholestatic itch.
  - target: Elevated circulating alkaline phosphatase concentration
    causal_link_type: DIRECT
    description: The cholestatic enzyme pattern that flags the hepatic arm.
  - target: Biliary cirrhosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Sustained cholestasis and periportal injury progress to biliary
      fibrosis and cirrhosis.
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reynolds Syndrome should be suspected in CREST patients with persistent cholestatic liver enzymes, since delayed diagnosis allows portal hypertension and variceal bleeding to develop."
    explanation: >-
      Ties the cholestatic biochemical picture to this diagnosis and to the
      consequences of missing it.
- name: Loss of Immune Tolerance to Centromere Protein B
  biological_scale: MOLECULAR
  description: >-
    The anticentromere response that marks the limited cutaneous
    sclerodermatous arm. Strong anti-CENP-B reactivity is itself enriched for
    AMA-M2 positivity and for cirrhosis, which is the serological link between
    the two arms of this syndrome.
  downstream:
  - target: Microvascular Endothelial Injury
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      The ACA-defined limited cutaneous subset is the one in which obliterative
      microvasculopathy dominates.
    hypothesis_groups:
    - autoimmune_overlap_model
  - target: Dermal Fibroblast Activation and Skin Fibrosis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Immune dysregulation in this subset drives the stromal programme
      responsible for skin thickening.
    hypothesis_groups:
    - autoimmune_overlap_model
  - target: Dysphagia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >-
      Oesophageal dysmotility belongs to the same limited cutaneous subset, but
      the intermediates between the autoantibody response and visceral smooth
      muscle involvement are not modelled here.
    hypothesis_groups:
    - autoimmune_overlap_model
  evidence:
  - reference: PMID:42618734
    reference_title: "Anti-centromere antibody positivity: a spectrum of clinical diagnoses and immunological patterns in a large patient cohort."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "strong anti-CENP-B reactivity was associated with enrichment of centromere ANA patterns (64.05%), AMA-M2 positivity (31.44%), and liver cirrhosis (11.76%)"
    explanation: >-
      In a 1736-patient ACA-positive cohort, strong anti-CENP-B reactivity
      travels with AMA-M2 and with cirrhosis, which is the serological
      co-occurrence this syndrome is built on.
- name: Microvascular Endothelial Injury
  biological_scale: TISSUE
  description: >-
    Widespread injury of the cutaneous and digital microvasculature, producing
    cold-triggered vasospasm, visible telangiectasia, and in severe cases
    digital ischemia and tissue loss.
  cell_types:
  - preferred_term: endothelial cell of vascular tree
    term:
      id: CL:0002139
      label: endothelial cell of vascular tree
  downstream:
  - target: Raynaud phenomenon
    causal_link_type: DIRECT
    description: Vasospastic digital colour change on cold or stress exposure.
  - target: Telangiectasia
    causal_link_type: DIRECT
    description: Dilated superficial vessels on face and hands.
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "SSc is a connective tissue disorder with widespread microvascular injury, immune dysregulation, and excessive collagen deposition, affecting the skin and internal organs"
    explanation: >-
      Names microvascular injury as a core lesion of the sclerodermatous arm.
- name: Dermal Fibroblast Activation and Skin Fibrosis
  biological_scale: CELLULAR
  description: >-
    Activation of dermal fibroblasts with excess collagen deposition,
    producing the distal skin thickening and joint restriction of the limited
    cutaneous subset.
  cell_types:
  - preferred_term: fibroblast of dermis
    term:
      id: CL:0002551
      label: fibroblast of dermis
  biological_processes:
  - preferred_term: collagen fibril organization
    term:
      id: GO:0030199
      label: collagen fibril organization
    modifier: INCREASED
  downstream:
  - target: Sclerodactyly
    causal_link_type: DIRECT
    description: Fibrotic thickening of the skin of the digits.
  - target: Calcinosis cutis
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Dystrophic calcification within chronically injured dermis.
  evidence:
  - reference: PMID:41974602
    reference_title: "Cellular and molecular mechanisms of systemic sclerosis: Translation to targeted therapies and clinical practice."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "We highlight emerging cellular- and molecular-level insights into vasculopathy, immune dysregulation, and fibroblast activation in SSc."
    explanation: >-
      Places fibroblast activation alongside vasculopathy and immune
      dysregulation as the core compartments of SSc pathogenesis.
discussions:
- discussion_id: lbr_causality_unresolved
  kind: KNOWLEDGE_GAP
  attaches_to:
  - genetic#LBR
  - mechanistic_hypotheses#lbr_laminopathy_model
  prompt: >-
    Is Reynolds syndrome a genetic laminopathy caused by LBR variants, or an
    autoimmune overlap in which the reported LBR variant is incidental?
  rationale: >-
    MONDO classifies Reynolds syndrome as a hereditary disease and OMIM
    (MIM#613471) attributes it to LBR, but the entire genetic claim rests on
    one patient with one heterozygous missense variant. The functional work in
    that report was done on patient fibroblasts and lymphoblastoid lines, not
    on the affected liver, and contemporaneous commentary in the same year
    stated explicitly that the pathogenicity claim remained to be demonstrated
    and that larger PBC and SSc series were needed. No replication has been
    reported. This matters for curation because it decides whether the entry's
    root cause is a nuclear-envelope defect or a break in immune tolerance.
  evidence:
  - reference: PMID:20800400
    reference_title: "Is Reynolds syndrome a genetic laminopathy?"
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "It remains to be shown, however, that this is really the case by testing directly the liver and skin fibroblasts of the patient."
    explanation: >-
      Contemporaneous commentary stating that the pathogenicity of the LBR
      variant was not established by the original report.
- discussion_id: shared_upstream_mechanism_unknown
  kind: KNOWLEDGE_GAP
  attaches_to:
  - pathophysiology#Loss of Immune Tolerance to Pyruvate Dehydrogenase Complex E2
  - pathophysiology#Loss of Immune Tolerance to Centromere Protein B
  prompt: >-
    What shared upstream mechanism causes anti-PDC-E2 and anti-CENP-B
    autoimmunity to co-occur so much more often than chance?
  rationale: >-
    Candidate shared mechanisms exist and none is established as causal for
    the overlap. Shared HLA alleles (HLA-DQB1, HLA-DRB1, HLA-DQA1) and the
    non-HLA loci IRF5 and STAT4 are reported in both diseases, both are marked
    by elevated TGF-beta and IL-6, and antibodies in the overlap preferentially
    recognise CENP-C rather than CENP-B alone. But the HLA associations are
    explicitly not exclusive to either disease, and none of these has been
    shown to explain why the two diseases co-occur rather than simply being
    features each has separately. The pathograph therefore stops at two
    parallel arms rather than asserting a common upstream node. Establishing
    one is the main thing that would distinguish this entity from the
    coincidence of two common autoimmune diseases in a predisposed host.
  evidence:
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overlap group predominantly included patients with limited cutaneous SSc and had a higher prevalence of extrahepatic autoimmune diseases, particularly Sjögren's syndrome and Hashimoto's thyroiditis."
    explanation: >-
      Documents the broader autoimmune excess that a shared upstream mechanism
      would need to account for.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "non-HLA susceptibility genes IRF5 and STAT4 have been identified in both PBC and SSc"
    explanation: >-
      A named shared-susceptibility candidate. Cited as a candidate rather than
      as an explanation, since the same review notes these loci are not
      exclusive to either disease.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Both diseases are marked by elevated TGF-β (transforming growth factor-beta) and IL-6 (Interleukin-6)"
    explanation: >-
      A shared profibrotic cytokine signature, the closest thing to a common
      effector, still not shown to drive the co-occurrence itself.
phenotypes:
- category: Vascular
  name: Raynaud phenomenon
  description: >-
    Episodic cold- or stress-triggered discoloration of the digits, and in
    severe disease digital ulceration, ischemia and tissue loss.
  phenotype_term:
    preferred_term: Raynaud phenomenon
    term:
      id: HP:0030880
      label: Raynaud phenomenon
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "she had a history of amputation of her right‐hand index finger due to severe digital ischemia and gangrene"
    explanation: >-
      Documents the severe ischemic end of the digital vascular phenotype in a
      patient with this syndrome.
- category: Cutaneous
  name: Telangiectasia
  description: Dilated superficial cutaneous vessels, typically on face and hands.
  phenotype_term:
    preferred_term: Telangiectasia
    term:
      id: HP:0001009
      label: Telangiectasia
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Physical examination revealed sclerodactyly with digital ulcers on her fingers, telangiectasias on her face and hands, and limited range of motion in her fingers and wrists."
    explanation: Records telangiectasia on examination in this syndrome.
- category: Cutaneous
  name: Sclerodactyly
  description: >-
    Fibrotic thickening and tightening of the skin of the digits, with reduced
    range of motion.
  phenotype_term:
    preferred_term: Sclerodactyly
    term:
      id: HP:0011838
      label: Sclerodactyly
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A 64‐year‐old woman presented to the rheumatology clinic with a 3‐year history of progressive skin thickening and tightening, particularly affecting her hands, face, and feet."
    explanation: >-
      Describes the progressive distal skin thickening characteristic of the
      limited cutaneous subset.
- category: Cutaneous
  name: Calcinosis cutis
  description: Dystrophic subcutaneous calcification, the "C" of the CREST pattern.
  phenotype_term:
    preferred_term: Calcinosis cutis
    term:
      id: HP:0025520
      label: Calcinosis cutis
- category: Gastrointestinal
  name: Dysphagia
  description: >-
    Difficulty swallowing solids from oesophageal dysmotility, the "E" of the
    CREST pattern.
  phenotype_term:
    preferred_term: Dysphagia
    term:
      id: HP:0002015
      label: Dysphagia
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She reported difficulty swallowing solid foods and experienced frequent episodes of discoloration of fingers and toes, often triggered by cold temperatures or stress."
    explanation: >-
      Records oesophageal dysmotility alongside Raynaud phenomenon in the same
      patient.
- category: Hepatic
  name: Pruritus
  description: Cholestatic itch, often the earliest symptom of the hepatic arm.
  phenotype_term:
    preferred_term: Pruritus
    term:
      id: HP:0000989
      label: Pruritus
- category: Hepatic
  name: Elevated circulating alkaline phosphatase concentration
  description: >-
    The cholestatic enzyme pattern that should prompt antimitochondrial
    antibody testing in a patient already carrying a CREST diagnosis.
  phenotype_term:
    preferred_term: Elevated circulating alkaline phosphatase concentration
    term:
      id: HP:0003155
      label: Elevated circulating alkaline phosphatase concentration
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "liver function tests (LFTs) showed alanine aminotransferase (ALT) 49 U/L, aspartate aminotransferase (AST) 90 U/L, and alkaline phosphatase (ALP) 927 U/L"
    explanation: >-
      A markedly cholestatic enzyme profile, with ALP disproportionately raised
      relative to the transaminases.
- category: Hepatic
  name: Biliary cirrhosis
  description: >-
    End-stage consequence of the hepatic arm, with portal hypertension and
    variceal bleeding when the diagnosis is delayed.
  phenotype_term:
    preferred_term: Biliary cirrhosis
    term:
      id: HP:0002613
      label: Biliary cirrhosis
    clinical_course: PROGRESSIVE
- category: Respiratory
  name: Interstitial lung disease
  description: >-
    Occurs in this syndrome and is the indication for immunosuppression when it
    does, but its frequency sits between the two isolated diseases rather than
    above them: lower than in SSc alone, higher than in PBC alone. That
    direction matters, because the overlap's milder visceral phenotype is half
    of what makes it a distinct entity.

    Do not read a whole-SSc ILD frequency as this syndrome's. The 33% figure in
    the AMA-screening cohort cited under the antimitochondrial antibody
    biomarker is that cohort's overall SSc rate, not an overlap-specific one.
  phenotype_term:
    preferred_term: Interstitial lung disease
    term:
      id: HP:0006530
      label: Abnormal pulmonary interstitial morphology
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "computed tomography (HRCT) chest was suggestive of interstitial lung disease (ILD)"
    explanation: >-
      HRCT-confirmed interstitial lung disease in a patient with this syndrome,
      establishing that it occurs.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinically, patients with overlap disease demonstrate milder systemic involvement than SSc-only patients, with lower occurrence of interstitial lung disease, gastro-oesophageal reflux and musculoskeletal involvement."
    explanation: >-
      The comparison against isolated SSc: ILD is less frequent in the overlap,
      part of a broader milder visceral profile.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Compared with PBC-only, overlap patients have higher rates of renal complications, interstitial lung disease and extrahepatic autoimmune diseases such as SjS and Hashimoto’s thyroiditis."
    explanation: >-
      The comparison in the other direction: ILD is more frequent than in
      isolated PBC. Together with the item above this is why the frequency is
      stated as intermediate rather than high or low.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overlap group also had fewer digital ulcers and a lower frequency of interstitial lung disease (ILD)."
    explanation: >-
      The Lepri multinational cohort, an independent cohort-level report of the
      same direction against isolated SSc.
- category: Constitutional
  name: Milder systemic involvement than isolated systemic sclerosis
  description: >-
    Taken as a profile rather than a single finding: interstitial lung disease,
    digital ulcers, gastro-oesophageal reflux and musculoskeletal involvement
    are all less frequent than in SSc alone. This is not the same as a better
    prognosis -- some cohorts report more SSc-related mortality and more
    oesophageal varices -- so it is curated as an organ-involvement profile,
    not as a severity or outcome claim.
  evidence:
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Clinical manifestations such as ILD, digital ulcers, GERD and musculoskeletal involvement were less common in overlap patients compared with patients with SSc, supporting the notion of a milder systemic phenotype."
    explanation: >-
      The review's cross-study synthesis of the milder systemic phenotype,
      naming the four manifestations it rests on.
- category: Immunologic
  name: Autoimmunity
  description: >-
    Excess of additional autoimmune disease, particularly Sjogren syndrome and
    Hashimoto thyroiditis, compared with either isolated disease.
  phenotype_term:
    preferred_term: Autoimmunity
    term:
      id: HP:0002960
      label: Autoimmunity
  evidence:
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The overlap group predominantly included patients with limited cutaneous SSc and had a higher prevalence of extrahepatic autoimmune diseases, particularly Sjögren's syndrome and Hashimoto's thyroiditis."
    explanation: >-
      Quantifies the extrahepatic autoimmune excess that characterises the
      overlap group.
biochemical:
- name: Antimitochondrial antibody
  notes: >-
    The serological hallmark of the hepatic arm. AMA are considerably more
    frequent in SSc than routine practice assumes, which is the basis for
    screening CREST patients rather than waiting for symptomatic liver disease.

    No biomarker_term is bound. NCIT and the biomarker enum caches were
    searched for an autoantibody-analyte term covering AMA/AMA-M2 and nothing
    matching the analyte was found; left unbound rather than bound to a
    broader immunology term that would not identify the analyte.
  evidence:
  - reference: PMID:41715235
    reference_title: "Prevalence and clinical relevance of systematically tested antimitochondrial antibodies in systemic sclerosis."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Among 165 SSc patients (20% diffuse cutaneous disease, 33% interstitial lung disease, 7.3% pulmonary arterial hypertension; 51% positive for anticentromere antibodies, 29% anti-topoisomerase I, 12% anti-RNA polymerase III), 37 (22%) were AMA-positive."
    explanation: >-
      In a systematically screened SSc cohort, 22% were AMA-positive, which
      supports proactive screening for the hepatic arm.
- name: Anticentromere antibody
  notes: >-
    The serological marker of the limited cutaneous sclerodermatous arm,
    present with a centromere ANA pattern.

    No biomarker_term is bound, for the same reason recorded on the
    antimitochondrial antibody entry.
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Laboratory tests showed positive antinuclear antibodies (ANA) with a centromere pattern."
    explanation: Records the centromere ANA pattern in a patient with this syndrome.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "sera from patients with PBC–SSc more frequently reacted with (CENP-C) compared with sera from patients with SSc alone"
    explanation: >-
      CENP-C reactivity is the most overlap-specific serological finding
      available: it separates the overlap from isolated SSc, rather than
      merely marking the limited cutaneous subset.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "STAT4 has been associated with ACA positivity in PBC, an autoantibody already present in over 50% of patients with limited cutaneous SSc (lcSSc)."
    explanation: >-
      Links the anticentromere response to a shared non-HLA susceptibility
      locus reported in both diseases.
genetic:
- name: LBR
  notes: >-
    Reported in a single patient with Reynolds syndrome as a heterozygous
    missense variant with a proposed tissue-specific dominant negative effect.
    Recorded here as an unreplicated hypothesis, not as an established cause
    of this syndrome; see the LBR knowledge gap in `discussions`. LBR is
    otherwise the gene of Pelger-Huet anomaly and Greenberg dysplasia.
  gene_term:
    preferred_term: LBR
    term:
      id: hgnc:6518
      label: LBR
  relationship_type: SUSCEPTIBILITY
  evidence:
  - reference: PMID:20522425
    reference_title: "LBR mutation and nuclear envelope defects in a patient affected with Reynolds syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "revealing a single heterozygous missense mutation in LBR exon 9 (c.1114C/T; p.R372C). This variant was absent in 400 control chromosomes."
    explanation: >-
      Reports the variant and its absence from 400 control chromosomes, the
      whole of the genetic evidence for this association.
  - reference: PMID:20522425
    reference_title: "LBR mutation and nuclear envelope defects in a patient affected with Reynolds syndrome."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "The fibroblast specific abnormalities observed suggest that this particular LBR mutation might have dominant negative deleterious effects in a tissue specific fashion"
    explanation: >-
      The proposed mechanism, from patient-derived fibroblasts rather than
      affected liver tissue.
  - reference: PMID:20800400
    reference_title: "Is Reynolds syndrome a genetic laminopathy?"
    supports: REFUTE
    evidence_source: OTHER
    snippet: "the new mutation has been found neither in a group of 27 other patients with SSc"
    explanation: >-
      Cited against a general causal role: the variant was not found in any
      other SSc patient tested, so it cannot account for the syndrome broadly.
treatments:
- name: Ursodeoxycholic Acid
  description: >-
    First-line therapy for the cholestatic hepatic arm, started promptly once
    the PBC component is identified.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: ursodeoxycholic acid
      term:
        id: CHEBI:9907
        label: ursodeoxycholic acid
  target_mechanisms:
  - target: Intrahepatic Cholestasis
    description: Improves bile flow and the cholestatic biochemical profile.
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early anti-mitochondrial antibody screening and prompt ursodeoxycholic acid therapy improve outcomes, and these patients need multidisciplinary follow-up for lung and thyroid disease."
    explanation: >-
      States the therapeutic strategy for the hepatic arm and the rationale for
      early serological screening.
- name: Cyclophosphamide
  description: >-
    Used for severe systemic sclerosis complications, notably interstitial
    lung disease, in the sclerodermatous arm.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: cyclophosphamide
      term:
        id: CHEBI:4027
        label: cyclophosphamide
  target_mechanisms:
  - target: Interstitial lung disease
    description: >-
      Immunosuppression aimed at the interstitial lung disease of the
      sclerodermatous arm.
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "She was started on intravenous cyclophosphamide 750 mg/m2 monthly for 6 months, with monthly monitoring of blood counts and renal function"
    explanation: >-
      Documents the regimen used for the interstitial lung disease complicating
      this patient's sclerodermatous arm.
prevalence:
- population: Patients with systemic sclerosis
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 3000.0
  rate_low: 2000.0
  rate_high: 3000.0
  rate_denominator: POPULATION
  notes: >-
    Frequency of the overlap within an SSc population, not a general-population
    prevalence. Reported as 2-3% of SSc patients, and separately as a weighted
    prevalence of 3.0%.
  evidence:
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "prevalence studies have demonstrated that 2–3% of patients with SSc have overlapping PBC, whereas the prevalence of SSc in PBC has been estimated to be around 8%."
    explanation: >-
      Gives the frequency of the overlap in both directions.
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This overlap between PBC and SSc has been reported with a weighted prevalence of 3.0% among patients with SSc."
    explanation: >-
      The pooled weighted estimate, consistent with the 2-3% range above.
- population: Patients with primary biliary cholangitis
  measure_type: POINT_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 8000.0
  rate_denominator: POPULATION
  notes: >-
    Frequency of SSc within a PBC population; the reciprocal of the record
    above, and the reason cholestatic patients are screened for sclerodermatous
    features as well as the reverse.
  evidence:
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "the prevalence of SSc in PBC has been estimated to be around 8%"
    explanation: >-
      Gives the frequency of the sclerodermatous arm among PBC patients.
diagnosis:
- name: Antimitochondrial antibody screening in a CREST patient with cholestasis
  description: >-
    The practical diagnostic route to this entity. A patient already carrying a
    CREST or limited cutaneous SSc diagnosis who develops a cholestatic liver
    enzyme pattern should be tested for antimitochondrial antibodies rather
    than observed, because the delay is what allows portal hypertension and
    variceal bleeding to develop.
  evidence:
  - reference: PMID:42499963
    reference_title: "Overlap of Primary Biliary Cholangitis and Systemic Sclerosis: A Case of Reynolds Syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Reynolds Syndrome should be suspected in CREST patients with persistent cholestatic liver enzymes, since delayed diagnosis allows portal hypertension and variceal bleeding to develop."
    explanation: >-
      States the trigger for suspecting the diagnosis and the cost of missing it.
histopathology:
- name: Compartment-specific fibrosis
  description: >-
    The two arms produce fibrosis in different compartments, which is what a
    biopsy distinguishes: periportal in the hepatic arm, perivascular or
    interstitial in the sclerodermatous arm.
  evidence:
  - reference: PMID:42256626
    reference_title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The shared immunological environment ultimately leads to characteristic fibrotic histology: predominantly around the periportal region in PBC and perivascular or interstitial region in SSc."
    explanation: >-
      Gives the compartment-level localisation that separates the two arms
      histologically despite their shared profibrotic drivers.
classifications:
  harrisons_chapter:
  - classification_value: IMMUNE_RHEUMATOLOGIC
references:
- reference: PMID:5553949
  title: Primary biliary cirrhosis with scleroderma, Raynaud's phenomenon and telangiectasia. New syndrome.
- reference: PMID:33971338
  title: "Primary biliary cholangitis and systemic sclerosis (Reynolds syndrome): A case-control study."
- reference: PMID:42256626
  title: "Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes."
- reference: PMID:20522425
  title: LBR mutation and nuclear envelope defects in a patient affected with Reynolds syndrome.
- reference: PMID:20800400
  title: Is Reynolds syndrome a genetic laminopathy?
📚

References & Deep Research

References

5
PMID:5553949
Primary biliary cirrhosis with scleroderma, Raynaud's phenomenon and telangiectasia. New syndrome.
No top-level findings curated for this source.
PMID:33971338
Primary biliary cholangitis and systemic sclerosis (Reynolds syndrome): A case-control study.
No top-level findings curated for this source.
PMID:42256626
Systemic sclerosis and primary biliary cholangitis: a systematic review of case-control studies comparing isolated and overlapping disease phenotypes.
No top-level findings curated for this source.
PMID:20522425
LBR mutation and nuclear envelope defects in a patient affected with Reynolds syndrome.
No top-level findings curated for this source.
PMID:20800400
Is Reynolds syndrome a genetic laminopathy?
No top-level findings curated for this source.