Extra-articular manifestations of rheumatoid arthritis

Extra-articular manifestations (EAMs) affect roughly 40–50% of people with rheumatoid arthritis (RA), though no agreed definition exists, and add to its excess mortality. Most seem to have declined, probably with better treatment; lung disease is the notable exception.

Risk factors include high-titre rheumatoid factor (RF), antinuclear and anti-CCP antibodies, joint erosions, smoking and HLA-DRB1*04 homozygosity. Sources disagree on male sex.

Nodules are the principal skin lesion, seen in up to 30% of those with EAMs, on extensor and pressure areas; they correlate with seropositivity and disease activity. Small-vessel vasculitis causes nail-fold infarcts, purpura, painful ulcers and digital gangrene.

About 18% have eye involvement. Keratoconjunctivitis sicca, often with secondary Sjögren's syndrome, is commonest (artificial tears), then episcleritis, scleritis, peripheral ulcerative keratitis and anterior uveitis. Scleritis can lead to scleromalacia; prompt high-dose steroids can save sight.

Interstitial lung disease (ILD) has a pooled prevalence of 11%, with perhaps another 10–30% subclinical, and can predate the arthritis. About 50% show usual interstitial pneumonia, with worse survival. Risk factors: older age, male sex, smoking, seropositivity and high disease activity.

Guidelines differ and evidence is thin (4 trials, 335 patients). ACR/CHEST starts with mycophenolate, azathioprine or rituximab; EULAR/ERS treats active arthritis with any DMARD, then, if ILD stays active, JAK inhibitors or abatacept. Both consider antifibrotics for progression.

Also: bronchiectasis, obliterative bronchiolitis, pleural effusion (70% in one review, setting not stated; symptomatic pleuritis 3–5%) and lung nodules (can mimic malignancy).

Cardiovascular disease (coronary disease, heart failure, stroke) is the leading cause of death: about 48% more events and 52% higher cardiovascular mortality, not fully explained by traditional risk factors.

Pericardial effusion is 30–50% in that review (setting not stated), symptomatic pericarditis under 10%.

Rheumatoid vasculitis is rare, involving small and medium vessels, chiefly skin and peripheral nerves, in RF- and ACPA-positive patients, 10–14 years after diagnosis, when joint inflammation is low.

Anaemia is the commonest: chronic disease, which can coexist with NSAID-related iron deficiency.

Felty's syndrome is a rare complication of long-standing seropositive RA: neutropenia, splenomegaly and severe recurrent skin and respiratory infections. In uncomplicated cases treatment is mainly methotrexate; splenectomy is controversial.

Entrapment neuropathy is commonest, especially carpal tunnel syndrome. Mononeuritis multiplex (wrist or foot drop) reflects vasculitis of the vasa nervorum and is urgent; one review lists high-dose intravenous steroids with cyclophosphamide.

In a meta-analysis, anterior atlantoaxial subluxation occurred in 27% (falling from 36% to 24% since the 1970s), vertical subluxation in 11%, subaxial in 13% and myelopathy in 5%, unchanged over time. Subluxations are often silent or cause only neck pain, but once severe neurological complications develop the prognosis can be grave.

Renal impairment affects 7–10% but is not usually caused directly by RA; older age, NSAIDs and some older DMARDs contribute. Biopsies most often show mesangial glomerulonephritis, membranous nephropathy (linked to gold and D-penicillamine) or secondary amyloidosis.

Amyloidosis results from uncontrolled inflammation and is now less common.

Beyond ILD, a 2017 review found no clear-cut guidelines, and patients with EAMs were mostly excluded from controlled trials. Drug toxicity and infection often mimic EAMs.

Elderly-onset RA (after 60) has a sex ratio nearer 1:1 and more systemic features. Older patients get fewer subcutaneous nodules; one short review says more lung and cardiac EAMs. Older age at onset is linked to ILD.

NSAIDs are not usually first-line; NSAIDs and steroids add cardiovascular risk; comorbidity, polypharmacy and cognitive dysfunction complicate treatment. Osteoporosis: inflammatory bone loss, falls and steroids raise fracture risk.