Medicine chapters
Rheumatoid arthritis
A chronic autoimmune symmetrical polyarthritis of the small joints: who gets it, deformities and extra-articular features, RF and anti-CCP, the 2010 criteria, and treatment with methotrexate, other DMARDs and biologics.
- RA is an autoimmune symmetrical polyarthritis of the MCP, PIP, wrist and MTP joints with long morning stiffness; DIP joints are spared.
- Anti-CCP (ACPA) is the most specific test; RF is positive in about 75–80%; ESR/CRP rise with activity; X-rays show juxta-articular osteopenia and marginal erosions.
- Start a DMARD early (within 3 months): methotrexate is the anchor drug; add biologics (anti-TNF etc.) if targets are not met.
On this page
Overview
Rheumatoid arthritis (RA) is a chronic autoimmune disease in which inflamed synovium attacks joints, tendon sheaths and bursae. It typically causes a symmetrical polyarthritis of the small hand and foot joints, plus systemic inflammation.
It affects about 0.5–1% of people, with women affected three times as often as men, and usually starts between 30 and 50 years. Untreated, it destroys joints within months, which is why early DMARD treatment is the key message.
Aetiology
- Genetics: strong link with HLA-DR4 (in 50–75% of patients) and the "shared epitope" alleles of HLA-DRB1; also PTPN22. HLA-DR4 predicts more severe disease.
- Smoking: the main environmental trigger; it promotes citrullination of proteins in the lung and raises the risk of anti-CCP positive RA.
- Other: periodontal disease and gut microbiome changes.
- Citrullination alters self proteins so that they fit the shared epitope, and the immune system makes anti-citrullinated peptide antibodies (ACPA, anti-CCP).
Pathology and pathogenesis
- Synovium becomes thick, boggy and full of lymphocytes, plasma cells and macrophages, with new blood vessels.
- TNF-alpha is the master cytokine; it drives IL-6 and IL-1. This is why anti-TNF and anti-IL-6 drugs work.
- The inflamed synovium spreads over cartilage as pannus, which destroys cartilage and bone.
- Erosions start at the joint margins (the "bare areas" where synovium touches bone not covered by cartilage).
- Damage begins in the first few months, before erosions show on X-ray. Hence the "window of opportunity" for early DMARDs.
- Rheumatoid factor (RF) is an autoantibody (usually IgM) against the Fc portion of IgG. It forms immune complexes in the joint.
Clinical features
Typical onset
- Gradual (about 70%): pain, swelling and stiffness of small joints over weeks to months.
- Acute (about 15%): explosive polyarthritis over days, more often in the elderly.
- Other starts: monoarthritis (knee, shoulder), carpal tunnel syndrome, palindromic rheumatism (attacks of a single hot joint lasting 24–48 hours that clear completely; about half later develop RA), or a polymyalgia-like picture in the elderly.
Joint features
- Symmetrical involvement of MCP, PIP, wrist and MTP joints. DIP joints are spared.
- Morning stiffness lasting hours, easing with activity. Fatigue and poor sleep.
- Warm, tender, soft (boggy) swelling; squeezing the MCPs or MTPs is painful.
RA spares the DIP joints. DIP disease points to OA (Heberden nodes) or psoriatic arthritis.
Deformities (established disease)
| Site | Deformity |
|---|---|
| MCP joints | Ulnar deviation (drift) and palmar subluxation |
| PIP joint flexed, DIP hyperextended | Boutonniere (buttonhole) deformity |
| PIP hyperextended, DIP flexed | Swan-neck deformity |
| Thumb | Z-shaped thumb |
| Wrist | Dorsal subluxation of the ulnar styloid; may rupture extensor tendons of the ring and little fingers |
| Feet | Painful MTP joints, broad forefoot, hammer toes, calluses under metatarsal heads |
| Knee | Effusion, Baker cyst (rupture mimics DVT), valgus or varus |
| Hip | Protrusio acetabuli |
| Cervical spine | Atlantoaxial subluxation (C1–C2) |
Atlantoaxial subluxation happens in RA, not ankylosing spondylitis. It can compress the cord. Flexion and extension neck X-rays (or MRI) are needed before general anaesthesia/intubation in long-standing RA. New leg weakness or sphincter loss is a neurosurgical emergency.
Extra-articular features
| System | Features |
|---|---|
| General | Fever, weight loss, fatigue |
| Skin | Rheumatoid nodules over pressure points (elbows, fingers, Achilles), in seropositive disease; vasculitic nail-fold infarcts, leg ulcers |
| Eyes | Keratoconjunctivitis sicca (secondary Sjogren), episcleritis, scleritis, scleromalacia perforans |
| Lungs | Pleural effusion (exudate, very low glucose), interstitial lung disease (basal fibrosis), nodules, Caplan syndrome, bronchiectasis, obliterative bronchiolitis |
| Heart | Pericarditis (usually silent), raised cardiovascular risk |
| Nerves | Carpal tunnel syndrome, mononeuritis multiplex (vasculitis), peripheral neuropathy, cord compression |
| Blood | Normocytic normochromic anaemia of chronic disease, high platelets in active disease, iron deficiency from NSAIDs |
| Spleen | Felty syndrome |
| Kidney | AA amyloidosis (nephrotic syndrome); drug toxicity |
| Bone | Osteoporosis |
- Felty syndrome = RA + splenomegaly + neutropenia. Recurrent infections and leg ulcers. HLA-DR4 in about 95%.
- Caplan syndrome = RA + pneumoconiosis (e.g. coal miners) + multiple rounded lung nodules.
- RA is the commonest cause of secondary (AA) amyloidosis.
Felty = Few neutrophils + Fat spleen. Caplan = Coal + nodules.
Investigations
| Test | Finding |
|---|---|
| FBC | Normocytic normochromic anaemia; raised platelets; low neutrophils in Felty |
| ESR and CRP | Raised in proportion to activity; used to monitor |
| Rheumatoid factor | Positive in about 75–80%; not specific (also in Sjogren, SLE, chronic infection, elderly); high titre = worse prognosis |
| Anti-CCP (ACPA) | Most specific test; can appear years before disease; predicts erosive disease |
| ANA | Low titre in about 30% |
| X-ray hands and feet | Early: soft tissue swelling, juxta-articular osteopenia. Later: marginal erosions, joint space narrowing, subluxation |
| Ultrasound / MRI | Show synovitis and erosions earlier than X-ray |
| Joint aspirate | Cloudy, inflammatory fluid with many white cells; exclude sepsis |
Anti-CCP is more specific than RF. RF plus anti-CCP together are even more specific.
Seronegative RA exists. A negative RF does not rule out RA.
Diagnosis: ACR/EULAR 2010 classification criteria
Apply to a patient with at least one swollen joint not better explained by another disease. A score of 6 or more out of 10 = RA.
| Domain | Points |
|---|---|
| Joints: 1 large joint | 0 |
| 2–10 large joints | 1 |
| 1–3 small joints | 2 |
| 4–10 small joints | 3 |
| More than 10 joints (at least one small) | 5 |
| Serology: RF and ACPA negative | 0 |
| Low positive RF or ACPA | 2 |
| High positive RF or ACPA | 3 |
| Acute-phase reactants: normal CRP and ESR | 0 |
| Raised CRP or ESR | 1 |
| Duration: under 6 weeks | 0 |
| 6 weeks or more | 1 |
A woman has swelling of 6 small hand joints for 8 weeks, high-positive anti-CCP and a raised CRP.
Joints 4–10 small = 3; serology high positive = 3; CRP raised = 1; duration 6 weeks or more = 1
Total = 3 + 3 + 1 + 1 = 8 → 8 is 6 or more → classified as RA
Poor prognostic factors
- Female sex, insidious onset, many joints involved, high disability at onset.
- High-titre RF and anti-CCP, high ESR/CRP, anaemia.
- Early erosions, extra-articular disease, smoking, HLA-DR4.
Differential diagnosis
- Viral polyarthritis (rubella, hepatitis B, parvovirus/erythrovirus): self-limiting.
- Psoriatic arthritis (DIP joints, dactylitis, nail pitting, RF negative).
- SLE (non-erosive arthritis, Jaccoud deformity that corrects).
- Polymyalgia rheumatica in the elderly.
- Nodal OA of the hands, gout, pseudogout, reactive arthritis.
Management
Principles
- Refer early (persistent synovitis of small joints, more than one joint, or symptoms over 3 months).
- Treat to target: aim for remission (or low disease activity) with frequent review and dose escalation.
- Disease activity is measured with DAS28 (tender and swollen counts in 28 joints, ESR, and patient global score): over 5.1 = active, under 3.2 = low activity, under 2.6 = remission.
- Multidisciplinary team: physiotherapy, occupational therapy, podiatry, support to stay at work; stop smoking; control cardiovascular risk.
Drugs
1. Symptom control
- NSAIDs or coxibs for pain and stiffness (add a PPI if over 65 or GI risk). They do not change the course of disease.
- Corticosteroids as a bridge until DMARDs work: intramuscular depot methylprednisolone, short oral courses or intra-articular injections. Avoid long-term use; give bone protection if used for more than 3 months.
2. Conventional synthetic DMARDs (take 2–3 months to work; start within 3 months of onset)
| Drug | Key points | Main toxicity and monitoring |
|---|---|---|
| Methotrexate | Anchor (first-line) drug; once weekly, starting 7.5–10 mg and increased up to 25 mg; oral or subcutaneous; give folic acid | Mouth ulcers, nausea, marrow suppression, liver toxicity, pneumonitis; teratogenic; check FBC and LFTs. Overdose antidote: folinic acid |
| Sulfasalazine | Well tolerated; safe in pregnancy | Rash, neutropenia, abnormal LFTs |
| Hydroxychloroquine | Mild disease or in combination | Retinopathy: eye screening |
| Leflunomide | Blocks pyrimidine synthesis (dihydro-orotate dehydrogenase) | Diarrhoea, hypertension, liver toxicity; very long half-life, avoid when planning pregnancy (washout needed) |
Combinations (e.g. methotrexate + sulfasalazine + hydroxychloroquine, with steroid) are often used.
3. Biological DMARDs (when at least two csDMARDs fail; usually given with methotrexate)
| Target | Drugs |
|---|---|
| TNF-alpha | Infliximab (IV), adalimumab, etanercept, certolizumab, golimumab |
| CD20 on B cells | Rituximab (best in RF-positive disease) |
| T-cell co-stimulation | Abatacept (CTLA4-Ig) |
| IL-6 receptor | Tocilizumab, sarilumab |
4. Targeted synthetic DMARDs: oral JAK inhibitors (tofacitinib, baricitinib).
Before anti-TNF therapy, screen for latent TB (history, chest X-ray, IGRA) because these drugs can reactivate TB. Also check hepatitis B and C, and avoid them in severe heart failure.
Methotrexate is taken once a week, not daily. Daily dosing by mistake causes marrow failure and mouth ulcers. Trimethoprim with methotrexate also raises the risk of marrow suppression.
Surgery
Synovectomy, tendon repair, joint fusion, and joint replacement (hip, knee, MCP, shoulder, elbow) for pain and loss of function.
Complications
- Joint destruction and disability; tendon rupture.
- Septic arthritis (may be masked by immunosuppression).
- Cervical cord compression.
- Cardiovascular disease (main cause of excess death), infections, lymphoma.
- Secondary amyloidosis, osteoporosis, drug toxicity.
Pregnancy
- RA often improves in pregnancy and flares after delivery.
- Stop methotrexate (and leflunomide with washout) before conception.
- Sulfasalazine and hydroxychloroquine are considered safe.
Expect: symmetrical small-joint arthritis sparing DIP joints, long morning stiffness, HLA-DR4, anti-CCP as the most specific test and RF in about 75–80%, normocytic anaemia of chronic disease, swan-neck and boutonniere deformities, atlantoaxial subluxation before anaesthesia, Felty and Caplan syndromes, AA amyloidosis, the 2010 criteria (6 or more points), methotrexate weekly with folic acid and its toxicity, TB screening before anti-TNF, and DMARD choice in pregnancy.
Quick revision
- Female 3:1; HLA-DR4; smoking.
- Symmetrical MCP, PIP, wrist, MTP; DIP spared; stiffness for hours.
- Anti-CCP most specific; RF 75–80%.
- X-ray: juxta-articular osteopenia then marginal erosions.
- Felty: splenomegaly + neutropenia. Caplan: pneumoconiosis + nodules.
- C1–C2 subluxation: image neck before intubation.
- 2010 criteria: 6 or more of 10.
- Methotrexate weekly + folic acid = first-line DMARD; biologics if it fails.
- Screen for TB before anti-TNF.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine).
FAQ
Which joints does rheumatoid arthritis usually spare?
The distal interphalangeal joints of the fingers, and usually the lumbar and thoracic spine.
Why is anti-CCP preferred to rheumatoid factor?
It is much more specific for RA, can be present years before symptoms, and predicts erosive disease.
What type of anaemia is typical in RA?
A normocytic normochromic anaemia of chronic disease, with low serum iron, low TIBC and normal or high ferritin.
Why is folic acid given with methotrexate?
It reduces side effects such as mouth ulcers, nausea and liver upset.
What is the most important investigation before starting an anti-TNF drug?
Screening for latent tuberculosis, because anti-TNF drugs can reactivate it.