Fatigue affects 35–82% of patients with musculoskeletal disease and roughly one in two reports it as severe — yet it correlates poorly with CRP, DAS28 and even MRI-detected synovitis. This review covers what fatigue is, how to measure it, the biology proposed to explain it, why remission so often fails to resolve it, and what actually works: biologics, exercise, CBT and the EULAR non-pharmacological recommendations.
Sex differences in rheumatic disease are usually pinned on oestrogen, but this review argues the picture is far more tangled. Oestradiol drives disease in SLE while appearing protective in Sjögren’s and RA; X chromosome dosage raises risk independently of hormones — triple X carries a 2.9-fold higher Sjögren’s prevalence; and gut bacteria reactivate oestrogen through β-glucuronidase, closing a loop between all three mechanisms.
RHO is a phase 2 proof-of-concept RCT of the FcRn antagonist efgartigimod in Sjögren’s disease, testing whether removing pathogenic IgG autoantibodies improves disease. It met its exploratory objective (CRESS response 45.5% vs 11.1% at week 24) with deep, selective IgG reduction — but systemic activity improved while patient-reported symptoms did not, and the tiny sample means this justifies phase 3, not practice change.
A 2026 narrative review arguing that B cells are the single through-line of Sjögren disease — connecting autoantibodies, glandular pathology, the highest lymphoma risk of any autoimmune disease, and the emerging drug pipeline. Endotyping by B-cell activity may identify who develops lymphoma and who responds to B-cell-targeted therapy, as newer BAFF/APRIL, CD40L, BTK and FcRn agents succeed where rituximab failed.
The 2026 Sjögren’s Foundation clinical practice guideline for peripheral nervous system involvement in Sjögren’s disease — an aligned neuro-rheumatology nomenclature, 31 evaluation good-practice statements, and 20 treatment recommendations (6 strong), covering mononeuropathies, polyneuropathies, and autonomic disease. Evidence is very low certainty, so most guidance rests on expert consensus.
RepurpSS-II is a phase 2b, placebo-controlled RCT of leflunomide plus hydroxychloroquine in active systemic Sjögren’s disease, given without any background immunomodulatory therapy. The combination met its primary endpoint — a clinically meaningful ESSDAI improvement (−4.14) at 24 weeks, replicating RepurpSS-I — but dryness and patient-reported symptoms (ESSPRI) did not separate from placebo.