Arthritis - rheumatoid
Description
- Chronic symmetrical inflammatory polyarthritis of synovial joints, erosive and deforming if untreated
- Systemic disease with extra-articular manifestations - joints are the commonest, not the only, target
Serological subsets
| Anti-CCP / RF | Features | |
|---|---|---|
| Seropositive (~70%) | Positive | Erosive, extra-articular disease, nodules, worse prognosis, HLA-DRB1 shared epitope |
| Seronegative (~30%) | Negative | Less erosive on average; overlaps with PsA, PMR, CPPD - re-examine the diagnosis |
Joint distribution - the discriminator
- MCP, PIP, wrists, MTPs - symmetrical, small-joint
- *DIP joints spared (DIP involvement = PsA or OA*)
- Cervical spine involved (C1/2 atlanto-axial); thoracolumbar spine and SI joints spared
Established deformities
- Ulnar deviation at MCPs, Z-thumb
- Swan-neck - PIP hyperextension + DIP flexion
- Boutonniere - PIP flexion + DIP hyperextension
- Subluxation, carpal collapse, fixed flexion contracture
- Deformity is fixed - contrast Jaccoud's arthropathy of SLE, which reduces on making a fist
Epidemiology
- Prevalence 0.5-1% of adults; ~450,000 Australians
- F:M ~3:1 (falls toward 1:1 after age 70)
- Peak onset 30-50 yr
- Higher prevalence and severity in Aboriginal and Torres Strait Islander Australians
- Smoking: 2-4x risk, dose-dependent, strongest in shared-epitope carriers
Aetiopathogenesis
Genetic (~60% of risk)
- HLA-DRB1 "shared epitope" - conserved QKRAA motif in the peptide-binding groove
- Homozygosity -> more severe, erosive disease
- Presents citrullinated peptides to CD4 T cells
- PTPN22, PADI4, STAT4, TRAF1-C5
Environment -> citrullination
- Smoking - inc peptidylarginine deiminase (PAD) in lung -> arginine -> citrulline -> neo-antigen
- *Periodontitis (Porphyromonas gingivalis - the only bacterium with its own PAD)*, lung mucosa, gut dysbiosis
- Gene-environment interaction: smoking + shared epitope -> ~20-40x risk of anti-CCP+ RA
Preclinical phase
- Anti-CCP and RF appear years (up to 10) before symptoms - the "at-risk" window
- Progression: genetic risk -> mucosal autoimmunity -> systemic autoimmunity -> arthralgia -> synovitis
Joint destruction
- Synovial hyperplasia + neovascularisation + lymphoid aggregates -> pannus
- Pannus invades cartilage and bone at the unprotected "bare area" at the joint margin
- TNF-alpha, IL-6, IL-1 central; IL-6 also drives anaemia, fatigue, acute phase response
- inc RANKL -> osteoclast activation -> erosions + juxta-articular osteopenia
- MMPs -> cartilage loss -> joint space narrowing
- Neutrophils dominate the synovial FLUID; the SYNOVIUM is dominated by macrophages, T cells and fibroblasts
Diagnosis
2010 ACR/EULAR classification criteria
- Entry: >=1 joint with definite clinical synovitis, not better explained by another disease
- Classify RA if score >=6/10
| Domain | Points |
|---|---|
| Joints 1 large | 0 |
| 2-10 large | 1 |
| 1-3 small | 2 |
| 4-10 small | 3 |
| >10 joints (>=1 small) | 5 |
| Serology negative | 0 |
| Low-positive RF or anti-CCP | 2 |
| High-positive (>3x ULN) | 3 |
| Acute phase normal | 0 |
| Raised CRP or ESR | 1 |
| Duration <6 weeks | 0 |
| >=6 weeks | 1 |
- Designed to capture EARLY disease before erosions - erosive change is not in the criteria
Serology
| Sensitivity | Specificity | Note | |
|---|---|---|---|
| RF | ~70% | ~80% | Also Sjogren (90%), cryoglobulinaemia, endocarditis, HCV, sarcoid, TB, 5-10% healthy elderly |
| Anti-CCP | ~70% | ~95% | More specific; predates onset; predicts erosive disease |
- High-titre RF also predicts extra-articular disease and nodules (nodules are almost always RF+)
- ~30% seronegative at presentation - repeat serology; some seroconvert
Other bloods
- Normocytic anaemia (ACD - if microcytic think NSAID blood loss), thrombocytosis, leukocytosis
- inc ESR and CRP; low albumin, raised ALP without liver disease or drug toxicity
- Synovial fluid: inflammatory, neutrophil-predominant, low complement, fibrin. Always exclude septic arthritis and crystals
Imaging
- X-ray sequence: soft-tissue swelling -> juxta-articular (periarticular) osteopenia -> marginal erosions at the bare area of 2nd and 3rd MCPs -> uniform joint space narrowing -> subluxation, carpal collapse, ulnar styloid osteolysis
- Uniform joint space loss - contrast the focal loss of OA
- Cervical spine: widened predental space (atlanto-axial subluxation), stepwise subluxation C3-C6
- Flexion/extension views before any intubation
- MRI/US far more sensitive early: ~80% of early RA have a normal X-ray but ~80% have an abnormal MRI
- Bone marrow oedema on MRI = the precursor to erosion; US power Doppler confirms active synovitis
Examination for the discriminator
- Elbows: rheumatoid nodules vs gouty tophi vs psoriatic plaques
- Nails and extensor surfaces (psoriasis), DIP involvement (PsA/OA)
- Chest: fine crepitations (ILD); abdomen: splenomegaly (Felty)
Management
Axis: treat-to-target, escalating by response at fixed review points. Comorbidity management runs alongside.
Treat-to-target framework
- Start a DMARD as soon as the diagnosis is made - the "window of opportunity" is the first ~3 months
- Target: sustained remission, or low disease activity if remission is not achievable
- Measure with a composite index (DAS28, SDAI, CDAI) - not impression
- Assess every 1-3 months while active
- No improvement by 3 months, or target not met by 6 months -> change therapy
- Patient-reported measures: morning stiffness duration, pain VAS, fatigue score, patient global assessment
Phase 1 - csDMARD
- Methotrexate is the anchor drug in every strategy
- Oral or SC, 10-25 mg once weekly; SC if inadequate response or GI intolerance
- Folic acid 5 mg weekly (on a different day)
- Monitor FBE, LFT, creatinine - 2-4 weekly initially then 3-monthly
- Contraindicated in pregnancy; cease 3 months before conception in women AND men
- If MTX contraindicated: leflunomide or sulfasalazine
- Sulfasalazine and hydroxychloroquine are the DMARDs of choice in pregnancy
- Short-course glucocorticoid as a bridge whenever a csDMARD is started or changed - taper and stop as soon as feasible
- Systemic prednisolone slows radiographic progression; intra-articular steroid improves symptoms but does not
Phase 2 - add a bDMARD or tsDMARD
- Trigger: failure of the csDMARD strategy (PBS requires documented failure of >=2 DMARDs including MTX at adequate dose for >=6 months, with active disease)
- Combine with MTX where possible - inc efficacy, dec immunogenicity
- IL-6 inhibitors and JAK inhibitors retain most of their efficacy as monotherapy - the class to pick if MTX cannot be used
| Class | Agents |
|---|---|
| TNF inhibitor | Etanercept, adalimumab, infliximab, golimumab, certolizumab |
| IL-6R | Tocilizumab, sarilumab |
| T-cell co-stim | Abatacept |
| Anti-CD20 | Rituximab (best in seropositive disease) |
| JAK inhibitor | Tofacitinib, baricitinib, upadacitinib |
- JAK inhibitors: assess cardiovascular and malignancy risk BEFORE prescribing
- ORAL Surveillance - inc MACE, malignancy, VTE and all-cause mortality vs TNFi in patients >50 with >=1 CV risk factor
- Avoid, or use only after explicit risk discussion, in: age >65, current/past smoking, established CV disease, prior malignancy, VTE risk
- Also: herpes zoster (vaccinate with the recombinant vaccine first), lipid rise, cytopenias
Phase 3 - switch
- Failure of the first b/tsDMARD -> switch to another agent, of a different mechanism or within the same class
- Cycling within TNF inhibitors is reasonable once; a second failure argues for a mechanism change
Tapering
- Sustained remission -> taper is possible, but do not stop DMARDs entirely - flare rates are high, especially with b/tsDMARDs
- Taper glucocorticoid first, then space or reduce the biologic, then csDMARD last
Pre-biologic screening - all patients
- Latent TB (IGRA + CXR), hepatitis B and C, HIV
- TNF inhibitors reactivate TB - highest risk with infliximab (monoclonals > etanercept)
- Vaccinate: influenza, COVID, pneumococcal, recombinant zoster - before starting; live vaccines contraindicated afterwards
Comorbidity - not optional
- Cardiovascular risk assessment - RA multiplies risk; EULAR advises multiplying calculated risk by 1.5
- Smoking cessation (also reduces DMARD response)
- Osteoporosis screening, fall prevention
- Screen for depression, treat pain and fatigue
Specific problems
- Felty's syndrome (RA + neutropenia + splenomegaly): treat the RA aggressively; G-CSF for significant neutropenia; splenectomy rarely
- RA-ILD: avoid MTX if progressive; abatacept or rituximab preferred; nintedanib for progressive fibrosing phenotype
- Atlanto-axial subluxation: imaging before general anaesthesia; surgical stabilisation if myelopathy
- Vasculitis: high-dose glucocorticoid + cyclophosphamide or rituximab
- Surgery: synovectomy, joint replacement - much less needed since early treat-to-target
Associations
Ocular (commonest extra-articular)
- Sicca / secondary Sjogren ~30%
- Episcleritis and scleritis ~5%; scleromalacia perforans (painless, sight-threatening, severe seropositive disease)
Pulmonary
- ILD - UIP pattern is the commonest, lower zone, honeycombing
- Pleural effusion: exudate, lymphocyte-predominant, very low glucose (<2.2 mmol/L), low pH (<7.2) - the low glucose is the exam discriminator
- Rheumatoid nodules; Caplan syndrome (nodules + pneumoconiosis)
- *Methotrexate pneumonitis - usually within 2 years, NSIP pattern, BAL lymphocytosis with low CD4:CD8 (RA-ILD BAL is neutrophil-predominant*)
- Bronchiectasis, obliterative bronchiolitis, cricoarytenoid arthritis
Cardiovascular
- ~4x risk of cardiovascular disease and inc CV mortality
- Pericarditis, myocarditis (granulomatous or interstitial -> MR, conduction disease), accelerated CAD, heart failure
Neurological
- Carpal tunnel and other entrapment neuropathies
- Glove-and-stocking sensory neuropathy
- Mononeuritis multiplex (vasculitis - a major extra-articular feature)
- Cervical myelopathy from atlanto-axial subluxation
- Drug-induced myopathy (steroid)
Haematological
- Anaemia of chronic disease, thrombocytosis
- Felty's syndrome - RA + neutropenia + splenomegaly
- Large granular lymphocyte (LGL) leukaemia - neutropenia in ~85%; ~1 in 3 RA patients with neutropenia have LGL
- Lymphocytosis ~70%, anaemia ~50%, thrombocytopenia ~20%, splenomegaly 20-50%, clonal marrow infiltration
- Treated with immunosuppression (MTX, ciclosporin); infection is the leading cause of death
- ~3x risk of lymphoma (driven by disease activity, not by treatment)
Other
- Rheumatoid nodules ~25%, almost always RF-positive (may worsen on methotrexate)
- Vasculitis - palpable purpura, nail-fold infarcts, ischaemic ulcers, digital gangrene, mononeuritis multiplex
- Secondary AA amyloidosis -> proteinuria (also consider gold/penicillamine nephropathy)
- Osteoporosis (disease + steroid + immobility)
Extra-articular disease severity
- Minor: small nodules, episcleritis, pure sensory neuropathy, pleuropericardial disease
- Major: vasculitis, Felty's, motor neuropathy, ILD
Natural history & complications
- Without treatment: progressive erosion, deformity, functional loss and work disability
- With early treat-to-target, remission or LDA is achievable in the majority and erosive disease is now uncommon
- Cardiovascular disease is the leading cause of death; ~3-10 yr reduction in life expectancy
Poor prognostic markers
- High-titre RF or anti-CCP; ANCA positivity
- Early erosions
- Sustained high disease activity / persistently raised CRP
- Extra-articular disease - ILD, nodules, vasculitis
- Smoking
- HLA-DRB1 shared epitope homozygosity
- Low socioeconomic status, low education, delayed treatment
- Female sex, high joint count at presentation
Palindromic rheumatism
- Sudden migratory mono/oligoarthritis + periarthritis, peaks at 24-48 h, resolves completely without residual damage
- Antecedent syndrome in ~1 in 8 RA patients
- Outcome: ~2/3 progress to RA, ~15% remain palindromic, ~15% remit
- Hydroxychloroquine may reduce progression to RA
Complications
- Joint destruction, deformity, secondary OA
- Cervical myelopathy
- Infection - disease + immunosuppression
- Accelerated atherosclerosis
- Osteoporosis and fragility fracture
- Amyloidosis (now rare)
- Lymphoma
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