Systemic Sclerosis and ME/CFS: Cross-Disease Mechanisms
1 van Eeden et al. 2023 — Mitochondrial Signature in SSc Patients with ME/CFS
Full Citation: van Eeden C, Redmond D, Mohazab N, Larché MJ, Mason AL, Cohen Tervaert JW, Osman MS. Evidence of a Novel Mitochondrial Signature in Systemic Sclerosis Patients with Chronic Fatigue Syndrome. Int J Mol Sci. 2023;24(15):12057. [CITATION MISSING] DOI:: 10.3390/ijms241512057 PMID:: 37569433 | PMC: PMC10418481 Article Type:: Cross-sectional exploratory study Sample Size:: 12 SSc-CFS, 12 SSc-NCFS, 10 healthy controls (early SSc, disease duration <5 years) Key Findings::
- SSc patients formally meeting ME/CFS criteria (SSc-CFS) showed reduced CyB (Complex III) vs. SSc-NCFS (p=0.044) and healthy controls (p=0.030)
- Cox7C (Complex IV) elevated in SSc-CFS (p=0.031); ND4 (Complex I) reduced trend (p=0.051)
- No difference in SSc disease markers (mRSS skin score, digital ulcers, autoantibody type, lung DLCO) between SSc-CFS and SSc-NCFS groups
- Mitochondrial ETC signature is independent of organ-damage burden
- 50% of SSc-CFS patients also met fibromyalgia criteriaConclusion:: ME/CFS-phenotype in early SSc is associated with a distinct mitochondrial electron transport chain gene expression profile not explained by fibrotic disease activity. Hypothesis-generating; requires functional replication. Limitations:: n=12 per group; single-centre (Edmonton, Canada); gene expression not validated by functional mitochondrial assays; cross-sectional; limited ethnic diversity; not replicated. ME/CFS Relevance:: Strongest available evidence that ME/CFS as a formal complication of SSc produces a mitochondrial signature separable from SSc organ damage. Supports use of SSc as a model disease for studying ME/CFS metabolic mechanisms. Aligns with broader ME/CFS mitochondrial dysfunction literature but is the first to show the signature within a rheumatic disease context. Use with caution: n=12 is severely underpowered. Certainty Assessment::
- *Quality:* Low (exploratory, n=12/group, gene expression not functionally validated)
- *Sample:* n=34 total
- *Replication:* Not replicated
- *Score:* 0.302 van Eeden, Osman & Cohen Tervaert 2022 — Fatigue in AAV/SSc and ME/CFS Similarities
Full Citation: van Eeden C, Osman MS, Cohen Tervaert JW. Fatigue in ANCA-associated vasculitis (AAV) and systemic sclerosis (SSc): similarities with Myalgic encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). A critical review of the literature. Expert Rev Clin Immunol. 2022;18(10):1049–1070. [CITATION MISSING] DOI:: 10.1080/1744666X.2022.2116002 PMID:: 36045606 Article Type:: Critical narrative review Key Findings::
- "Immune and metabolic commonalities exist between ME/CFS, SSc, and PSVs" --- shared pathophysiological pathways proposed
- Persistent fatigue in SSc and AAV often persists after clinical remission, independent of standard disease activity markers
- Sleep disturbance, cognitive impairment, and functional disability shared across ME/CFS, SSc, and AAV
- Recommends physicians identify patients with SARD meeting ME/CFS criteria as requiring different management
- Does not provide new primary data; synthesises existing literature across conditionsConclusion:: Fatigue in SSc and AAV shares mechanistic features with ME/CFS; the overlap is not merely symptomatic but reflects common immune-metabolic pathways. Formal ME/CFS assessment in rheumatic disease patients is warranted. Limitations:: Narrative review (not systematic); heterogeneous underlying studies; most SSc/AAV fatigue studies did not apply formal ME/CFS diagnostic criteria; post-exertional malaise not assessed in reviewed studies; publication bias possible. ME/CFS Relevance:: Directly supports the ch14d cross-disease framing: SSc as a mechanistic model for ME/CFS-type fatigue. Provides the conceptual framework for the other SSc papers in this section. Certainty Assessment::
- *Quality:* Medium (narrative review; not systematic/meta-analytic)
- *Sample:* Review of existing literature
- *Replication:* Consistent with other reviews of SARD fatigue
- *Score:* 0.503 Kwakkenbos et al. 2025 — Fatigue in SSc: 2385 SPIN Cohort Participants
Full Citation:: Kwakkenbos L, Levis B, Henry RS, et al. Fatigue levels and associated factors in systemic sclerosis: a cross-sectional study of 2385 SPIN Cohort participants. Rheumatology (Oxford). 2025;64(5):2810–2820. [CITATION MISSING] DOI:: 10.1093/rheumatology/keae570 PMID:: 39447026 | PMC: PMC12048050 Article Type:: Cross-sectional multicenter cohort study Sample Size:: n=2,385 (mean age 54.9; 87% female; 38% diffuse cutaneous SSc) Key Findings::
- Mean PROMIS fatigue T-score 54.6 (general population mean 50) --- substantially elevated
- 53% reported clinically meaningful fatigue (mild to severe)
- Strongest disease predictor: GI involvement (+4.21 points)
- Pain (+2.19 per unit), smoking, higher BMI, non-married status independently elevated fatigue
- Fatigue does NOT primarily track skin fibrosis (mRSS)Conclusion:: SSc fatigue is driven by functional, GI, and pain-related factors rather than skin fibrosis extent. The decoupling of fatigue from fibrotic burden parallels ME/CFS, where structural damage does not predict symptom severity. Limitations:: Cross-sectional; patient-reported outcomes only; participation bias possible; causal mechanisms not assessable; no post-exertional malaise assessment. ME/CFS Relevance:: Large-sample evidence that SSc fatigue is not simply a fibrosis by-product — supports the SSc-as-model argument for ME/CFS. The GI-fatigue link echoes gut-microbiome/dysautonomia pathways in ME/CFS. Null result for skin fibrosis as a fatigue driver is important context for ch14d. Certainty Assessment::
- *Quality:* High (large multicenter cohort, validated PROMIS tool)
- *Sample:* n=2,385
- *Replication:* Consistent with Basta 2018 systematic review findings
- *Score:* 0.724 Basta, Afeltra & Margiotta 2018 — SSc Fatigue: Systematic Review
Full Citation: Basta F, Afeltra A, Margiotta DPE. Fatigue in systemic sclerosis: a systematic review. Clin Exp Rheumatol. 2018;36(4 Suppl 113):150–160. [CITATION MISSING] PMID:: 29303706 Article Type:: Systematic review Key Findings::
- Fatigue is "one of the most prevalent and debilitating symptoms experienced by SSc patients"
- Correlates: psychosocial factors (depression, pain, sleep disturbance), pulmonary and GI manifestations
- "Relationship with scores of disease activity is uncertain" --- fatigue does not reliably track SSc severity
- Pharmacological interventions largely unsuccessful; physical activity showed more promiseConclusion:: SSc fatigue is multifactorial, partially independent of fibrotic/immune disease activity, and resistant to standard pharmacological management. This profile parallels ME/CFS fatigue. Limitations:: English-language studies only; heterogeneous measurement tools; no ME/CFS diagnostic criteria applied; no PEM assessment; pre-2018 studies only. ME/CFS Relevance:: Historical baseline establishing SSc fatigue independence from disease activity. Supports the framing that SSc fatigue requires different management beyond immunosuppression — same argument applied in ME/CFS context. Certainty Assessment::
- *Quality:* Medium (systematic review; older literature base; no meta-analysis)
- *Sample:* Systematic review of available studies
- *Replication:* Confirmed by Kwakkenbos 2025 SPIN cohort
- *Score:* 0.555 Hartmann et al. 2023 — ADRA2A and IRX1: Putative Risk Genes for Raynaud’s Phenomenon
Full Citation: Hartmann S, Yasmeen S, Jacobs BM, et al. ADRA2A and IRX1 are putative risk genes for Raynaud’s phenomenon. Nat Commun. 2023;14(1):6156. [CITATION MISSING] DOI:: 10.1038/s41467-023-41876-5 PMID:: 37828025 Article Type:: GWAS using electronic health records Sample Size:: 5,147 Raynaud’s cases; 439,294 controls Key Findings::
- ADRA2A (alpha-2A adrenoreceptor) identified as top candidate causal gene: rs7090046, OR=1.26/allele, p\<9.6×10⁻²⁷
- Functional validation: ADRA2A-deficient smooth muscle cells --- reduced cold contraction; ADRA2A-overexpressing --- increased contraction
- IRX1 (microvascular transcription factor) is second locus
- Alpha-2A (not alpha-2C) adrenoreceptor is the genetic risk signal for Raynaud'sConclusion:: ADRA2A is the primary genetic risk locus for Raynaud’s phenotype, implicating catecholamine-induced vasoconstriction via alpha-2A adrenoreceptors. Limitations:: European ancestry only; EHR diagnosis codes may miss mild cases; does not include ME/CFS subjects; alpha-2C role in SSc-associated Raynaud’s not directly tested. ME/CFS Relevance:: The ME/CFS vasospasm hypothesis invokes alpha-2C adrenoreceptor upregulation. This study maps genetic risk to alpha-2A. These are different subtypes — overlap exists (both mediate vasoconstriction in small vessels; co-expressed in vascular smooth muscle) but the receptor subtype distinction matters for therapeutic targeting. The Raynaud’s prevalence in ME/CFS (~20–28%) remains unexplained by this GWAS but the shared adrenergic pathway is relevant context. Certainty Assessment::
- *Quality:* High (GWAS; large sample; functional validation)
- *Sample:* n=444,441 total
- *Replication:* Confirmed by Tervi 2024 meta-analysis
- *Score:* 0.806 Tervi et al. 2024 — Raynaud’s Genetics: Vasculature and Immunity Loci
Full Citation: Tervi A, Ramste M, Abner E, et al. Genetic and functional analysis of Raynaud’s syndrome implicates loci in vasculature and immunity. Cell Genomics. 2024;4(9):100630. [CITATION MISSING] DOI:: 10.1016/j.xgen.2024.100630 PMID:: 39142284 | PMC: PMC11480858 Article Type:: GWAS meta-analysis + functional genomics Sample Size:: 11,358 cases; 1,106,871 controls (4 biobanks: FinnGen, UK Biobank, Estonian Biobank, MGB) Key Findings::
- Eight loci: ADRA2A, IRX1, NOS3, HLA, ACVR2A, TMEM51, PCDH10-DT, RAB6C
- ADRA2A: temperature-dependent adrenergic signalling (confirmed from Hartmann 2023)
- NOS3: endothelial eNOS pathway --- CRISPRi of rs3918226 significantly decreased NOS3 expression (functional confirmation)
- HLA class I: immune/autoimmune mechanism especially in secondary Raynaud's
- IRX1: microvascular effects
- Paper explicitly identifies Raynaud's as ME/CFS and long-COVID comorbidityConclusion:: Raynaud’s genetic architecture spans adrenergic signalling, endothelial function, microvasculature, and immune pathways — multi-mechanism disorder. NOS3/eNOS pathway is functionally confirmed. Limitations:: European ancestry only; EHR-based; primary vs. secondary Raynaud’s not fully distinguished in all cohorts; functional studies focused on cold-triggered mechanisms. ME/CFS Relevance:: NOS3/eNOS endothelial dysfunction independently documented in ME/CFS vascular pathology (Scherbakov 2020). Shared genetic architecture between Raynaud’s and ME/CFS vascular features (eNOS, adrenergic, HLA immune signals) supports a common endothelial-adrenergic vulnerability model. The ~20–28% Raynaud’s prevalence in ME/CFS may reflect this shared genetic background rather than secondary SSc-type structural disease. Certainty Assessment::
- *Quality:* High (GWAS meta-analysis, 4 independent biobanks, functional CRISPRi validation)
- *Sample:* n=1,118,229 total across 4 cohorts
- *Replication:* Consistent and extended Hartmann 2023
- *Score:* 0.827 Masini et al. 2021 — Autonomic Dysfunction Correlates with Microvascular Damage in SSc
Full Citation:: Masini F, Galiero R, Pafundi PC, et al. Autonomic nervous system dysfunction correlates with microvascular damage in systemic sclerosis patients. J Scleroderma Relat Disord. 2021;6(3):256–263. (Masini et al. 2021) DOI:: 10.1177/23971983211020617 PMID:: 35387218 | PMC: PMC8922659 Article Type:: Cross-sectional pilot study Sample Size:: n=26 SSc patients; 26 healthy controls Key Findings::
- 50% of SSc patients met cardiac autonomic neuropathy (CAN) criteria
- CAN significantly associated with active nailfold videocapillaroscopy pattern (p=0.032) --- autonomic dysfunction tracks microvascular injury, not skin fibrosis
- Anti-Scl-70 (anti-topoisomerase I) positivity independently associated with autonomic dysfunction
- Autonomic dysfunction described as common and early feature, potentially predating fibrosisConclusion:: Autonomic dysfunction in SSc is tightly coupled to microvascular damage and may precede fibrosis, suggesting a vascular-first sequence. Anti-topoisomerase I antibodies associate independently with autonomic impairment. Limitations:: Small n=26; single-centre pilot; cross-sectional; no ME/CFS comparison; HRV-based autonomic assessment only (no tilt table); no causal inference; underpowered for subgroup analyses. ME/CFS Relevance:: Autonomic dysfunction (orthostatic intolerance) is a core ME/CFS diagnostic criterion (IOM 2015). SSc autonomic dysfunction follows the same vascular-damage pathway, supporting the hypothesis that vascular endothelial injury is upstream of dysautonomia in both conditions. The anti-Scl-70 association provides a differential diagnostic marker: anti-topoisomerase I positive points toward SSc, not ME/CFS. Note: no study has detected anti-Scl-70 or anti-centromere antibodies in ME/CFS cohorts — this is an untested gap, not a confirmed negative. Certainty Assessment::
- *Quality:* Low-Medium (pilot; n=26; single-centre; cross-sectional)
- *Sample:* n=26
- *Replication:* Not replicated in ME/CFS context; SSc autonomic dysfunction replicated elsewhere
- *Score:* 0.40