Rheumatoid arthritis - clinical features, RF/anti-CCP, DMARDs, MTX monitoring

1. Definition and clinical relevance

Rheumatoid arthritis (RA) is a chronic, immune-mediated inflammatory arthritis characterised by symmetrical synovitis, most commonly of the small joints of the hands and feet.

Why it matters:

• Untreated persistent synovial inflammation leads to irreversible joint erosion, deformity and disability
• RA is a systemic disease with numerous extra-articular manifestations
• Carries excess cardiovascular and lymphoma risk

Outcome depends on speed:

• Sustained remission and prevention of irreversible joint damage depend on introducing disease-modifying agents as early as possible
• Modern treat-to-target (T2T) approach: therapy is escalated and optimised at frequent review until low disease activity or remission is achieved

Practical implications for junior doctors:

• Recognise inflammatory (as opposed to mechanical) joint pain
• Avoid applying a firm label of "RA" on doubtful grounds and starting drugs prematurely
• Refer all patients with suspected RA to rheumatology for diagnosis and initiation of treatment

2. Key values, thresholds and decision rules

• RA is a clinical diagnosis supported by serology and imaging.
• A classification framework (scoring joint involvement, serology, acute-phase reactants and symptom duration) is used, where a score of 6 or more indicates definite RA.

A pragmatic early-treatment rule: at least one swollen joint for more than 6 weeks, with no prior injury, no personal or family history of spondyloarthritis or associated conditions such as psoriasis, plus a positive anti-citrullinated peptide antibody (ACPA) test, is the best way to select patients for earlier treatment to avoid joint damage.

Poor prognostic features in undifferentiated polyarthritis:

Commonly used DMARDs and monitoring principles:

3. Approach: presentation and differential

History

• Ask about joint pain, swelling and morning stiffness, typically affecting small joints symmetrically.
• Establish symptom duration (persistence beyond 6 weeks is significant) and the pattern of involvement.
• Screen for extra-articular symptoms: fatigue, dry eyes or mouth, breathlessness (interstitial lung disease), sensory symptoms suggesting nerve entrapment.
• Ask about impact on home and work, as functional impact drives management.
• Screen for a personal or family history of psoriasis or spondyloarthritis, which points away from RA.

Examination

• Look for chronic symmetrical joint swelling, classically involving the proximal interphalangeal (PIP), metacarpophalangeal (MCP), metatarsophalangeal (MTP) joints, wrists and knees.
• RA affects the cervical but not the lumbar spine.
• Assess each affected joint's range of motion.
• Examine for extra-articular signs: subcutaneous nodules (usually on extensor surfaces), pallor of anaemia, lymphadenopathy, splenomegaly, episcleritis or scleritis, signs of carpal tunnel syndrome, and pleuropericardial involvement.

Differential

• Acute viral polyarthritis: chikungunya, hepatitis B and C, rubella.
• Parvovirus: self-limited over weeks; history of rash, IgM antibodies.
• Connective tissue diseases (e.g. SLE): symmetric polyarthritis usually without joint deformity; look for multisystem features. When peripheral hand disease is prominent, consider RA, SLE and systemic sclerosis together.
• Septic arthritis: usually acute monoarthritis; requires immediate aspiration for Gram stain and culture, plus antibiotics, to prevent joint destruction.
• Fibromyalgia: diffuse pain without inflammation, with insomnia and fatigue.
• Reactive arthritis: asymmetric oligoarthritis.
• Psoriatic arthropathy: polyarthropathy resembling RA but less symmetrical and rheumatoid factor negative; may show distal interphalangeal joint involvement.
• Osteoarthritis: mechanical pattern with joint-space narrowing and proliferative changes on X-ray.

A key clinical caution: avoid applying a broad label such as "arthritis" or a precise diagnosis such as "RA" on doubtful grounds and starting drugs prematurely.

4. Investigations

Bedside

• Urinalysis before and during DMARD therapy.
• Baseline weight and blood pressure.
• A pre-treatment functional and joint assessment to allow objective monitoring against target.

Bloods

• FBC: normochromic anaemia of chronic disease is common; a baseline is essential before starting marrow-suppressing DMARDs.
• Inflammatory markers: ESR and CRP support activity assessment (ESR may be normal).
• Rheumatoid factor and anti-citrullinated peptide antibodies (ACPA): ACPA positivity is a poor prognostic marker and helps select patients for early treatment.
• Liver function tests and renal function: baseline and for ongoing DMARD monitoring.

Imaging

• Plain X-ray of affected joints (hands and feet): joint erosions at presentation are a poor prognostic feature. Early films may be normal.
• Chest radiography where extra-articular lung disease is suspected: rheumatoid nodules, pulmonary fibrosis or pleural effusion (typically low glucose content). In patients on methotrexate it can be impossible to distinguish drug-induced from disease-related fibrosis, in which case methotrexate is substituted for an alternative agent.

5. Management

• Management aims to reduce inflammation, pain and stiffness, alleviate systemic symptoms such as fatigue, and slow or stop long-term progression.
• It is best delivered in collaboration with a rheumatologist, with all patients referred initially.
• Step 1 - Non-pharmacological and general measures.
• Daily full range-of-motion movement of each affected joint keeps it mobile and reduces stiffness.
• Encourage a nourishing, well-balanced diet and avoidance of obesity; there is some evidence for Mediterranean and vegetarian diets, and for avoiding animal fats while using fish oils.
• Address the impact on home and work.
• Step 2 - Standard initial DMARD therapy. Methotrexate monotherapy (occasionally another DMARD) is the standard first-line agent, given as a single weekly dose.
• It reduces damage to joints and other tissues and improves pain and swelling.
• Improvement may take several months to appear.
• Fewer than 20% reach remission on monotherapy; if remission is not achieved, increase the dose or move to combination therapy.
• Step 3 - Combination csDMARD therapy (treat-to-target).
• For patients not reaching low disease activity or remission, the treat-to-target approach intensifies therapy at frequent review, often using csDMARDs in combination at effective doses.
• A common combination is standard triple therapy: methotrexate + sulfasalazine + hydroxychloroquine.
• Serial csDMARDs (methotrexate plus at least one of sulfasalazine or leflunomide) are typically trialled before escalation.

Step 4 - Biological and targeted synthetic DMARDs. Patients who fail to achieve the target with serial csDMARDs move to biological DMARDs (bDMARDs):

• Anti-TNF agents: infliximab, etanercept, adalimumab, golimumab, certolizumab pegol.
• Anti-CD20: rituximab.
• CTLA-4 Ig: abatacept.
• Anti-IL-6: tocilizumab.
• If efficacy is not achieved or is later lost, switch to an alternative bDMARD. Do not use two biologicals together. Janus kinase inhibitors (targeted synthetic DMARDs) are an additional class: upadacitinib at a usual adult dose of 15 mg once daily, or tofacitinib, used when disease is active and standard treatments have failed, with efficacy reviewed at around 12 to 16 weeks.
• These may be combined with methotrexate, steroids or NSAIDs but not with another biological.
• Adjuncts.
• Corticosteroids may be used for flares or while awaiting DMARD onset; refer if a patient is ill and corticosteroids are being contemplated.
• NSAIDs help symptomatic pain.
• Surgery (joint fusion, replacement or excision, tendon repair, nerve decompression) is considered for pain relief and function once risks, benefits and timing are weighed.

Methotrexate and other DMARD monitoring

• For sulfasalazine, FBC and LFTs are especially important early: every 2 to 3 weeks for the first 3 months, then 3 to 6 monthly, or as directed by the rheumatologist, with the interval tightened when combined with methotrexate or leflunomide.
• Note that antimalarials (chloroquine, hydroxychloroquine) require caution in G6PD deficiency.

6. Australian-specific considerations

• Shared care model: RA should be managed in collaboration with a specialist. Rheumatology referral is indicated for all patients initially, for persistent joint inflammation, when the patient is ill and corticosteroids are contemplated, and when surgery is being considered. The GP is informed of the monitoring schedule and shares responsibility for blood test follow-up.

Clinical pearls

• Speed is outcome: the window to prevent irreversible joint erosion is narrow. Any suspected inflammatory polyarthritis persisting beyond 6 weeks warrants urgent rheumatology referral rather than a watch-and-wait approach.
• ACPA positivity is the single strongest predictor of erosive disease in early undifferentiated polyarthritis and supports early DMARD initiation even before a firm RA label is established.
• Methotrexate is a weekly drug: prescribe, dispense and instruct with that point explicit. Daily dosing errors are a recognised cause of serious toxicity, including fatal pancytopenia.
• The treat-to-target principle means therapy is not set and forgotten. If low disease activity or remission is not achieved, the dose is escalated or the regimen changed at the next scheduled review.
• Chest imaging in a methotrexate-treated patient with new breathlessness requires clinical caution: drug-induced pneumonitis and RA-related interstitial lung disease can be indistinguishable, and methotrexate should be substituted for an alternative agent while the cause is investigated.
• Do not combine two biologicals: the increased infection risk without added efficacy makes this combination contraindicated. JAK inhibitors may be combined with methotrexate, steroids or NSAIDs, but not with another biological.
• Sulfasalazine monitoring is front-loaded: FBC and LFTs every 2 to 3 weeks for the first 3 months reflects the period of highest risk for haematological adverse effects, with the interval shortened further when used in combination with methotrexate or leflunomide.
• Antimalarials and G6PD: hydroxychloroquine and chloroquine require specific screening for G6PD deficiency before use, a point especially relevant in Australian populations with higher rates of G6PD deficiency among some Indigenous and migrant communities.