Prevalence of Small Fibre Pathology in Fibromyalgia: An Updated Systematic Review and Meta-Analysis Showing Increasing Heterogeneity

Abstract

Background. Small fibre pathology has been proposed as a peripheral substrate for a subset of patients with fibromyalgia. A 2019 meta-analysis of 8 studies (222 patients) reported a pooled prevalence of 49% with moderate heterogeneity, and concluded that this supported a distinct fibromyalgia phenotype. The evidence base has since expanded substantially. Methods. We systematically searched PubMed for original human studies reporting the proportion of adults with fibromyalgia showing abnormal small fibre findings on an objective structural or functional test (skin biopsy with intraepidermal nerve fibre density, corneal confocal microscopy, sudomotor testing, microneurography, or laser-evoked potentials). Proportions were pooled with a random-effects model on the logit scale (REML). We pre-specified subgroup analyses by diagnostic method and assessment site, meta-regression on publication year and sample size, leave-one-out sensitivity analysis, and risk-of-bias appraisal with the JBI prevalence checklist. Where cohorts overlapped, the most complete report was retained. Search and initial screening were AI-assisted; eligibility, extraction and appraisal were performed independently by two reviewers with consensus. Results. Of 83 records, 34 studies met eligibility and 21 (1,268 patients) provided extractable proportions. Applying a uniform rule of abnormality at any assessed site, the pooled prevalence was 46.5% (95% CI 34.3-59.1), with I2=92.7% and a 95% prediction interval of 8.6% to 89.0%. Individual estimates ranged from 0% to 85.2%. Contrary to our pre-specified hypothesis, diagnostic method did not explain heterogeneity (QM p=0.89, R2=0). Assessment site was the dominant moderator: using each study's site-specific data, distal-leg assessment yielded 30.5% (22.4-40.1; 15 studies) and proximal-thigh assessment 73.9% (53.5-87.4; 4 studies). Three studies assessed both sites in the same patients and all three found more abnormality proximally (31.6% vs 46.2%; 12.3% vs 85.2%; 9.7% vs 83.9%). Publication year (p=0.50) and sample size (p=0.24) were not associated with prevalence. Leave-one-out estimates remained between 44.4% and 49.6%. Conclusions. More than tripling the evidence base did not stabilise the pooled prevalence estimate and more than doubled heterogeneity (I2 68% to 93%). The prediction interval now spans almost the entire possible range, and the method difference reported in 2019 is no longer detectable. Studies do not share a common definition of abnormality, and several do not report one at all. A pooled prevalence figure for small fibre pathology in fibromyalgia is therefore not currently interpretable; a standardised case definition is a prerequisite for meaningful synthesis. The anatomical site of assessment, not the technique, emerges as the dominant source of variation and should be treated as a primary moderator in future work.