Rheumatology: assessment, investigations and drugs
🩺 Rheumatology: assessment, investigations and drugs -page 1 of the Rheumatology chapter. Rheumatology covers inflammatory joint disease, connective tissue diseases and vasculitis. The key skill is telling inflammatory from mechanical problems, and then recognising the pattern of joints involved. Treatment has changed hugely -early DMARDs and biologics now prevent joint damage -but these drugs need careful monitoring. Septic arthritis is on the Trauma and Orthopaedics page; osteoporosis is in the Bone Medicine chapter.
Your four questions for every patient: Is this inflammatory or mechanical? What is the pattern -how many joints, which ones, symmetrical or not, and are there features outside the joints? Could this be an emergency (septic joint, GCA, vasculitis)? If treatment is needed, is the patient safe to start it -infection screening, pregnancy plans, monitoring?
The Rheumatology History
- Inflammatory or mechanical?
| Feature | Inflammatory | Mechanical (e.g. osteoarthritis) |
|---|
| Morning stiffness | Over 30–60 minutes | Brief (under 30 minutes) |
| Effect of activity | Better with movement, worse with rest | Worse with use, better with rest |
| Swelling | Soft, boggy (synovitis), warm | Bony, hard |
| Systemic features | Fatigue, fever, weight loss | None |
| Blood tests | Raised CRP and ESR (usually) | Normal |
| Response to NSAIDs | Often good | Modest |
- Onset -sudden (minutes to hours -gout, septic arthritis, trauma) or gradual (weeks -RA).
- Course -persistent, flitting (rheumatic fever, gonococcal), episodic (gout, palindromic rheumatism).
- Ask about features outside the joints:
- Skin -psoriasis, rashes (malar, photosensitive), nail changes, ulcers, Raynaud's, tight skin.
- Eyes -red painful eye (uveitis -spondyloarthritis, Behçet's; scleritis -RA, vasculitis), dry eyes (Sjögren's), visual loss (GCA).
- Mouth -ulcers (SLE, Behçet's, reactive arthritis), dry mouth.
- Gut -diarrhoea (IBD, reactive arthritis), swallowing problems (systemic sclerosis).
- Genitourinary -urethritis, genital ulcers.
- Lungs and kidneys -breathlessness, cough, haemoptysis, haematuria, frothy urine (vasculitis, SLE).
- Nerves -numbness, foot drop (mononeuritis multiplex -vasculitis).
- Muscles -weakness (myositis) versus pain and stiffness (PMR).
- Background -family history (psoriasis, spondyloarthritis, IBD, autoimmune disease), recent infection (gut or sexually transmitted -reactive arthritis), travel, sexual history, drugs (diuretics -gout; statins -myopathy; hydralazine -drug-induced lupus), occupation.
- Function -dressing, washing, walking, work, mood and sleep -guides treatment goals.
Patterns of Joint Disease
| Pattern | Common causes |
|---|
| Monoarthritis (one joint) | Septic arthritis (exclude first), gout, pseudogout (CPPD), trauma (haemarthrosis), reactive arthritis, spondyloarthritis, early inflammatory arthritis |
| Oligoarthritis (2–4 joints) | Spondyloarthritis (psoriatic, reactive, enteropathic) -often asymmetrical, large lower-limb joints; gout; gonococcal |
| Polyarthritis (5 or more), symmetrical, small joints | Rheumatoid arthritis, SLE and other connective tissue disease, viral arthritis (parvovirus B19, hepatitis B and C, rubella, chikungunya), psoriatic arthritis |
| Distal interphalangeal joints | Osteoarthritis (Heberden's nodes), psoriatic arthritis, gout |
| Spine and sacroiliac joints | Axial spondyloarthritis, psoriatic and enteropathic arthritis |
| Shoulder and hip girdle pain and stiffness | Polymyalgia rheumatica, late-onset RA, myositis (weakness rather than pain) |
| Widespread pain without joint swelling | Fibromyalgia, hypermobility, hypothyroidism, vitamin D deficiency, depression, statin myalgia |
- Viral arthritis -often sudden, symmetrical small-joint polyarthritis that settles within about 6 weeks; parvovirus B19 (contact with children with "slapped cheek"), hepatitis B (urticarial rash), rubella (and vaccine). Check serology; review -persistence beyond 6 weeks suggests RA.
- Polyarthralgia (pain without swelling) is much more common than polyarthritis -examine carefully for true synovitis.
Examination and GALS Screen
- GALS screen -a quick screen of the musculoskeletal system:
- Questions -any pain or stiffness in muscles, joints or back? Can you dress yourself without difficulty? Can you walk up and down stairs?
- Gait -symmetry, smoothness, arm swing, turning.
- Arms -hands behind head (shoulders), arms straight (elbows), hands out palms down then up (wrists, fingers), make a fist, pinch grip, squeeze across the knuckles (MCP tenderness -a sign of synovitis).
- Legs -knee flexion and extension, hip rotation, knee effusion (patellar tap), squeeze across the metatarsals, inspect feet.
- Spine -inspect from behind and side, lateral flexion of the neck, touch toes (lumbar flexion -Schober's test for spondyloarthritis).
- Look, feel, move for affected joints -swelling, redness, deformity, wasting, warmth, tenderness, range of movement (active and passive), function.
- Swelling -synovitis (soft, warm, tender, joint line) versus bony swelling (OA) versus effusion versus soft tissue (bursitis, tendons).
- Look beyond the joints:
- Skin -psoriasis (scalp, behind ears, umbilicus, natal cleft), nail pitting and onycholysis, rheumatoid nodules, tophi, vasculitic rash (palpable purpura), livedo reticularis, sclerodactyly, Gottron's papules.
- Eyes, mouth, lymph nodes, chest (crackles -ILD), heart (murmurs), abdomen (spleen), neurology (neuropathy).
- Blood pressure and urine dipstick -essential in suspected SLE, vasculitis or systemic sclerosis.
- Enthesitis -inflammation where tendons attach to bone (Achilles, plantar fascia) -spondyloarthritis.
- Dactylitis ("sausage digit") -whole finger or toe swollen -psoriatic and reactive arthritis.
The Hot Swollen Joint
- An acutely hot, swollen joint is septic arthritis until proven otherwise -joint destruction can happen within days, and mortality is significant in older people.
- Aspirate the joint before antibiotics (if this won't cause a dangerous delay) -Gram stain, culture, crystal microscopy, cell count; blood cultures; FBC, CRP, urate, U&E.
- Septic arthritis can coexist with crystals -finding urate or CPP crystals does not rule out infection.
- Higher risk of septic arthritis -prosthetic joints, RA, diabetes, immunosuppression (including biologics and steroids -may have little fever or redness), IV drug use, skin infection, recent joint injection, older age.
- Gonococcal arthritis -young sexually active adults; migratory polyarthralgia, tenosynovitis (wrists, hands) and pustular skin lesions; culture from urethra, cervix, rectum and throat (NAAT); ceftriaxone.
- Management of suspected septic arthritis -IV antibiotics per local guidance after aspiration (flucloxacillin is common first choice; add cover for MRSA, gram-negatives or gonococcus based on risk); orthopaedic review for washout (prosthetic joints -orthopaedics should aspirate). See the Trauma and Orthopaedics page.
- Other causes of a hot joint -gout, CPPD (pseudogout), reactive arthritis, haemarthrosis (trauma, anticoagulants, haemophilia), first presentation of inflammatory arthritis, Lyme disease, TB (more chronic).
⚠️ Safety Pearl -patients on biologics, JAK inhibitors or steroids may have septic arthritis with no fever and a normal-looking joint. A low threshold for aspiration and blood cultures is essential.
Inflammatory Markers and Routine Bloods
- CRP -rises and falls quickly (hours to days); useful for monitoring RA, infection, vasculitis.
- ESR -rises more slowly; raised by age, anaemia, pregnancy and high immunoglobulins (myeloma).
- High ESR with a normal CRP -classic in active SLE (unless infection or serositis), myeloma, and Sjögren's.
- Normal inflammatory markers don't exclude inflammatory disease (some RA and spondyloarthritis); very high ESR (over 100) -GCA, myeloma, infection (endocarditis, osteomyelitis), malignancy, vasculitis.
- FBC -anaemia of chronic disease; cytopenias (SLE -leucopenia, lymphopenia, thrombocytopenia, haemolysis; drug toxicity; Felty's syndrome); eosinophilia (EGPA); thrombocytosis (inflammation).
- U&E and urine -kidney involvement (SLE, vasculitis, systemic sclerosis); NSAID and drug toxicity. Always dipstick the urine (blood and protein) and send urine protein–creatinine ratio if positive.
- LFTs -baseline before DMARDs; raised ALP (PMR, bone disease).
- Urate -may be normal during a gout flare (check again 2 weeks later).
- CK -myositis (very high), statins, hypothyroidism, exercise.
- Bone profile and vitamin D -osteomalacia, hyperparathyroidism (CPPD).
- TFTs -hypothyroidism causes myalgia, arthralgia, raised CK, carpal tunnel syndrome.
- Ferritin -very high in adult-onset Still's disease and macrophage activation syndrome; haemochromatosis (2nd/3rd MCP arthropathy).
- Serum protein electrophoresis -myeloma (bone pain, high ESR, PMR-like symptoms).
Autoantibodies
| Antibody | Associations and points |
|---|
| Rheumatoid factor (RF) | RA (about 70%); also Sjögren's (very common), SLE, chronic infections (endocarditis, hepatitis C), cryoglobulinaemia, older people -not specific |
| Anti-CCP (anti-citrullinated peptide) | Highly specific for RA (over 95%); can appear years before symptoms; predicts erosive disease |
| ANA (antinuclear antibody) | Very sensitive for SLE (over 95%) but not specific -positive at low titre in many healthy people (especially older women), other CTDs, autoimmune liver and thyroid disease. Don't test without clinical suspicion |
| Anti-dsDNA | Specific for SLE; levels rise with disease activity, especially lupus nephritis |
| Anti-Sm | Very specific for SLE (but only in about 20–30%) |
| Anti-histone | Drug-induced lupus |
| Anti-Ro (SSA) and anti-La (SSB) | Sjögren's, SLE; in pregnancy -congenital heart block and neonatal lupus |
| Anti-centromere | Limited cutaneous systemic sclerosis (pulmonary hypertension risk) |
| Anti-Scl-70 (anti-topoisomerase I) | Diffuse systemic sclerosis -interstitial lung disease |
| Anti-RNA polymerase III | Diffuse systemic sclerosis -rapid skin change, scleroderma renal crisis, cancer |
| Anti-Jo-1 (and other anti-synthetase) | Antisynthetase syndrome -myositis, ILD, arthritis, mechanic's hands, Raynaud's |
| Anti-U1 RNP | Mixed connective tissue disease |
| ANCA -PR3 (c-ANCA) and MPO (p-ANCA) | PR3 -granulomatosis with polyangiitis; MPO -microscopic polyangiitis, EGPA; also drugs (hydralazine, propylthiouracil), IBD, endocarditis |
| Antiphospholipid antibodies | Lupus anticoagulant, anticardiolipin, anti-beta-2 glycoprotein I -antiphospholipid syndrome; must be positive on two occasions 12 weeks apart |
| Anti-GBM | Anti-GBM disease (Goodpasture's) -kidney and lung bleeding |
| HLA-B27 (a genetic marker, not an antibody) | Axial spondyloarthritis (about 90%), reactive arthritis, anterior uveitis -but present in about 8% of the UK population |
- Complement (C3, C4) -low in active SLE (consumed), especially nephritis; also cryoglobulinaemia; normal or high in most vasculitis (an acute phase protein).
- Test thoughtfully -a positive autoantibody without symptoms rarely means disease; interpret in context.
Synovial Fluid Analysis
| Type | Appearance | White cells (per mm3) | Causes |
|---|
| Normal | Clear, straw-coloured, viscous | Under 200 | - |
| Non-inflammatory | Clear, yellow | Under 2,000 | Osteoarthritis, trauma |
| Inflammatory | Cloudy, less viscous | 2,000–50,000 | RA, spondyloarthritis, gout, CPPD |
| Septic | Turbid, purulent | Usually over 50,000 (mostly neutrophils) | Bacterial infection (but overlap with crystals) |
| Haemorrhagic | Bloody | Variable | Trauma (ligament tears, fracture -fat globules), anticoagulants, haemophilia, PVNS |
- Crystals under polarised light:
- Gout (monosodium urate) -needle-shaped, negatively birefringent (yellow when parallel to the axis).
- CPPD (calcium pyrophosphate) -rhomboid-shaped, weakly positively birefringent (blue when parallel).
- Gram stain is negative in many septic joints -always wait for culture; send in blood culture bottles to increase yield.
- Glucose and protein levels are not helpful.
Imaging in Rheumatology
- Plain X-ray:
- RA -periarticular osteopenia, soft tissue swelling, erosions (margins of joints), symmetrical joint space loss, subluxation. X-ray hands and feet at baseline (feet often erode first).
- Osteoarthritis -joint space narrowing (asymmetric), osteophytes, subchondral sclerosis and cysts.
- Psoriatic arthritis -DIP erosions, "pencil-in-cup" deformity, new bone formation, arthritis mutilans.
- Gout -"punched-out" erosions with overhanging edges, soft tissue tophi, preserved joint space until late.
- CPPD -chondrocalcinosis (calcium in cartilage -knee menisci, triangular fibrocartilage of the wrist).
- Ankylosing spondylitis -sacroiliitis, squaring of vertebrae, syndesmophytes, "bamboo spine" (late).
- Ultrasound -detects synovitis and erosions earlier than X-ray, effusions, tendon problems, guides injections; temporal artery ultrasound ("halo sign") in GCA; "double contour" sign in gout.
- MRI -sacroiliac joint inflammation (bone marrow oedema) in early axial spondyloarthritis; spinal cord compression; myositis (muscle oedema to guide biopsy); osteomyelitis; avascular necrosis.
- Dual-energy CT -shows urate deposits (gout).
- PET-CT -large vessel vasculitis (GCA aortitis, Takayasu's), occult malignancy (dermatomyositis), fever of unknown origin.
- HRCT chest and pulmonary function tests (FVC, TLCO) -interstitial lung disease in RA, systemic sclerosis, myositis.
- Echocardiogram -pulmonary hypertension screening in systemic sclerosis; pericarditis.
NSAIDs and Analgesia
- NSAIDs (naproxen, ibuprofen, diclofenac, etoricoxib, celecoxib) -reduce pain and stiffness in inflammatory arthritis; don't alter disease progression in RA (but are first-line in axial spondyloarthritis).
- Use the lowest effective dose for the shortest time, with a PPI (NICE).
- Risks:
- GI bleeding and ulcers -higher in older people, previous ulcers, with steroids, anticoagulants, SSRIs.
- Kidney injury -especially with ACE inhibitors or ARBs and diuretics ("triple whammy"), dehydration, CKD.
- Cardiovascular risk -COX-2 inhibitors and diclofenac most; naproxen and low-dose ibuprofen lowest risk.
- Fluid retention, worsening heart failure and hypertension; asthma (aspirin-sensitive); lithium and methotrexate interactions.
- Topical NSAIDs -knee and hand osteoarthritis; few side effects.
- Paracetamol -limited benefit in osteoarthritis alone (NICE NG226 advises against routine use alone); useful in combination.
- Opioids -little long-term benefit in chronic musculoskeletal pain; avoid strong opioids for osteoarthritis and chronic primary pain.
- Intra-articular steroid injections -fast relief for a single inflamed joint (after infection excluded); limit frequency (e.g. no more than 3–4 times a year per joint).
- Non-drug treatment -physiotherapy, exercise, occupational therapy, splints, weight loss, education and self-management.
Glucocorticoids
- Uses -fast control of inflammation: bridging while DMARDs start working (RA), flares, PMR, GCA, SLE, vasculitis, myositis.
- Routes -oral (prednisolone), intramuscular (methylprednisolone 80–120 mg for a flare), intra-articular, IV pulses (methylprednisolone 500 mg–1 g for organ-threatening disease).
- Aim for the lowest dose for the shortest time -long-term use causes many harms.
- Side effects:
- Bone -osteoporosis and fractures, avascular necrosis.
- Metabolic -diabetes (check glucose and HbA1c), weight gain, hypertension, dyslipidaemia.
- Infection -including PJP (consider co-trimoxazole prophylaxis on high doses with other immunosuppressants), shingles, TB reactivation.
- Eyes -cataracts, glaucoma; skin -thinning, bruising; muscle -proximal myopathy.
- Mood -insomnia, mania, depression, psychosis.
- GI -peptic ulcers (especially with NSAIDs).
- Adrenal suppression -risk of adrenal crisis on stopping suddenly or during illness.
- Bone protection -anyone likely to take prednisolone for 3 months or more (any dose, especially 7.5 mg daily or more) -calcium and vitamin D, and a bisphosphonate (start immediately if 70 or over, previous fragility fracture or high FRAX risk) (NOGG).
- Steroid safety -Steroid Emergency Card for those at risk of adrenal insufficiency (e.g. 5 mg prednisolone daily or more for 4 weeks or more), sick day rules (double the dose during febrile illness), taper slowly after long courses (see the Adrenal Disease chapter).
Conventional DMARDs
- Disease-modifying antirheumatic drugs (DMARDs) -slow or stop joint damage; take weeks to months to work (bridging steroids meanwhile).
- Methotrexate -the anchor drug in RA; also psoriatic arthritis, vasculitis, myositis, SLE, PMR (steroid sparing):
- Taken ONCE WEEKLY -daily dosing errors have caused deaths; prescribe and dispense one strength (2.5 mg tablets); state the day of the week. Oral or subcutaneous (better absorbed, fewer GI effects).
- Folic acid 5 mg once weekly (on a different day) -reduces side effects.
- Side effects -nausea, mouth ulcers, hair thinning, raised liver enzymes (avoid alcohol excess), bone marrow suppression, pneumonitis (new cough and breathlessness -stop and seek urgent advice), infections.
- Interactions -trimethoprim and co-trimoxazole (both antifolates -severe marrow toxicity), NSAIDs (in kidney impairment), live vaccines.
- Reduce the dose or avoid in kidney impairment (it is renally excreted).
- Teratogenic -stop before conception (women -1–3 months; men can usually continue -BSR 2022).
- Toxicity treatment -folinic acid (calcium folinate) rescue.
- Sulfasalazine -RA, peripheral spondyloarthritis, enteropathic arthritis; side effects -nausea, rash, orange urine and tears (stains contact lenses), reversible low sperm count, marrow suppression, hepatitis, haemolysis in G6PD deficiency. Safe in pregnancy (with folic acid 5 mg daily).
- Hydroxychloroquine -mild RA, palindromic rheumatism, SLE (all patients unless contraindicated), Sjögren's:
- Generally well tolerated; safe in pregnancy.
- Retinal toxicity -dose no more than 5 mg/kg/day; baseline eye check within 1 year and annual retinal screening after 5 years of use (earlier -after 1 year -with risk factors such as kidney impairment, tamoxifen or higher doses) (RCOphth).
- Can rarely cause QT prolongation, cardiomyopathy, hypoglycaemia, rash, worsening psoriasis.
- Leflunomide -RA and psoriatic arthritis; side effects -diarrhoea, hypertension, hepatotoxicity, weight loss, marrow suppression, peripheral neuropathy, pneumonitis. Very long half-life -teratogenic (men and women need a washout with colestyramine before conception).
DMARD Monitoring
- Before starting (BSR) -FBC, U&E and creatinine (eGFR), LFTs (ALT and albumin), CRP or ESR; height, weight and BP; chest X-ray (and baseline PFTs if lung disease, for methotrexate); hepatitis B, hepatitis C and HIV screening; varicella immunity if needed; pregnancy plans and contraception.
- Routine blood monitoring (most conventional DMARDs -methotrexate, leflunomide, sulfasalazine, azathioprine, mycophenolate):
- FBC, creatinine and LFTs every 2 weeks until on a stable dose for 6 weeks.
- Then monthly for 3 months.
- Then every 12 weeks (more often with kidney impairment or new combinations).
- Sulfasalazine -monitoring can usually stop after 12 months on a stable dose.
- Hydroxychloroquine -no routine blood monitoring (eye screening instead).
- Act on results (stop the drug and discuss with rheumatology) -e.g. WCC under 3.5, neutrophils under 1.6, platelets under 140, ALT or AST over 100 (or over 3 times normal), unexplained fall in albumin, significant creatinine rise, MCV over 105 (check B12, folate, TSH).
- Tell patients to report sore throat, fever, mouth ulcers, bruising or bleeding (check FBC urgently), rash, new cough or breathlessness, and to avoid live vaccines.
- Shared care -rheumatology starts the drug; primary care often continues prescribing and monitoring under agreed protocols.
- During infection -usually pause DMARDs and biologics during significant infection (and around major surgery for biologics -timing by drug half-life), restarting when recovered; continue steroids (and increase if needed).
Other Immunosuppressants
| Drug | Main rheumatology uses | Key points and side effects |
|---|
| Azathioprine | SLE, vasculitis maintenance, myositis, steroid sparing | Check TPMT activity before starting (low -high risk of marrow suppression); avoid with allopurinol or febuxostat (dangerous marrow toxicity); hepatitis, pancreatitis, skin cancer; safe in pregnancy |
| Mycophenolate mofetil | Lupus nephritis, systemic sclerosis (skin and ILD), vasculitis, myositis | GI upset, marrow suppression, infections; highly teratogenic -contraception, stop at least 6 weeks before conception (MHRA: men also use condoms) |
| Cyclophosphamide | Severe organ-threatening SLE and vasculitis, systemic sclerosis ILD | IV pulses; haemorrhagic cystitis (mesna, fluids), infertility (fertility preservation), marrow suppression, infections, bladder cancer and other cancers, teratogenic |
| Ciclosporin and tacrolimus | Psoriatic arthritis, lupus nephritis (voclosporin), uveitis, myositis | Nephrotoxicity, hypertension, hyperkalaemia, gum hypertrophy and hirsutism (ciclosporin), tremor, diabetes (tacrolimus); many drug interactions (CYP3A4); level monitoring; usable in pregnancy |
| IV immunoglobulin | Myositis, Kawasaki disease, some vasculitis | Expensive; headache, thrombosis, aseptic meningitis, kidney injury, anaphylaxis (IgA deficiency) |
| Colchicine | Gout, CPPD, pericarditis, Behçet's, familial Mediterranean fever | Diarrhoea, toxicity with kidney impairment and clarithromycin and other CYP3A4/P-gp inhibitors, myopathy with statins |
Biologics
- Biologics -antibodies or proteins targeting specific parts of the immune system; injections or infusions; prescribed by specialists under NICE criteria. Biosimilars (cheaper copies of off-patent biologics) are now widely used.
| Target | Examples | Uses | Specific cautions |
|---|
| TNF-alpha | Adalimumab, etanercept, infliximab, certolizumab, golimumab | RA, axial SpA, PsA, IBD, uveitis | TB reactivation, serious infections, avoid in moderate–severe heart failure and demyelinating disease, drug-induced lupus, skin cancers |
| CD20 (B cells) | Rituximab | RA (especially seropositive), ANCA vasculitis, SLE (off-label), myositis | Hepatitis B reactivation, infusion reactions, low immunoglobulins (check levels), poor vaccine responses, PML (rare) |
| IL-6 receptor | Tocilizumab, sarilumab | RA, GCA, adult-onset Still's | CRP stays low even with infection, raised lipids and ALT, neutropenia, diverticular perforation |
| T-cell costimulation | Abatacept | RA | Infections; fewer serious infections than some others |
| IL-17 | Secukinumab, ixekizumab, bimekizumab | Psoriatic arthritis, axial SpA, psoriasis | Worsening or new IBD, candida infections |
| IL-12/23 and IL-23 | Ustekinumab, guselkumab, risankizumab | Psoriatic arthritis, psoriasis, IBD | Not effective for axial disease |
| IL-1 | Anakinra, canakinumab | Adult-onset Still's, autoinflammatory diseases, severe gout (specialist) | Injection site reactions, infections |
| BLyS / BAFF | Belimumab | SLE including nephritis | Infections, depression |
| Type I interferon receptor | Anifrolumab | SLE | Shingles, respiratory infections |
- NICE criteria for RA biologics -usually after at least two conventional DMARDs (including methotrexate) have failed, with moderate (DAS28 over 3.2) or severe (DAS28 over 5.1) disease; continue only if there is a good response (DAS28 fall of at least 1.2) at 6 months.
- Usually given with methotrexate (improves response and reduces antibody formation against the drug).
JAK Inhibitors
- Oral targeted synthetic DMARDs -tofacitinib, baricitinib, upadacitinib, filgotinib -block Janus kinase signalling (many cytokines at once).
- Uses -RA, psoriatic arthritis, axial spondyloarthritis, IBD, atopic dermatitis, alopecia areata.
- Advantages -tablets, fast onset, work as monotherapy.
- Risks:
- Shingles (herpes zoster) -consider Shingrix vaccination before starting.
- Serious infections, TB reactivation.
- VTE (DVT and PE).
- Major cardiovascular events and malignancy (ORAL Surveillance trial with tofacitinib).
- Raised lipids, cytopenias, raised CK and LFTs.
- MHRA advice -in people aged 65 or over, current or past long-term smokers, or with other cardiovascular or malignancy risk factors, use JAK inhibitors only if no suitable alternative is available; use caution in people with VTE risk factors.
- Teratogenic -avoid in pregnancy and breastfeeding.
Before Starting Biologics -Screening and Vaccines
- Infection screening:
- TB -history (previous TB, contacts, country of birth), chest X-ray, IGRA (interferon-gamma release assay); treat latent TB (e.g. 3 months of isoniazid and rifampicin) before or alongside starting (usually at least 1 month before anti-TNF) (BTS / NICE NG33).
- Hepatitis B (surface antigen and core antibody) -antiviral prophylaxis for carriers or past infection (especially with rituximab); hepatitis C; HIV.
- Varicella immunity if no history of chickenpox or shingles.
- Vaccines (Green Book):
- Inactivated vaccines are safe -annual influenza, pneumococcal, COVID-19; give ideally 2 weeks before starting immunosuppression (response is poorer during, especially with rituximab -vaccinate before or several months after).
- Shingrix (non-live shingles vaccine) -offered to severely immunosuppressed adults under the UK programme (age criteria per current schedule).
- Live vaccines (MMR, yellow fever, BCG, oral typhoid, live shingles -Zostavax) -avoid during biologics and significant immunosuppression; give at least 4 weeks before starting if needed.
- Babies exposed to biologics in late pregnancy -avoid live vaccines (rotavirus, BCG) until about 6 months old (except certolizumab, which barely crosses the placenta -seek advice).
- Other checks -skin check (history of skin cancer), heart failure, demyelinating disease (anti-TNF), diverticulitis (IL-6), IBD (IL-17), malignancy history, pregnancy plans, baseline immunoglobulins (rituximab).
- Education -sick day rules (pause during infection), alert cards, sun protection, report fever early.
Rheumatology Drugs at a Glance
| Drug | Must-know adverse effect | Pregnancy |
|---|
| Methotrexate | Weekly only; pneumonitis, marrow, liver; trimethoprim interaction | Avoid -stop before conception |
| Sulfasalazine | Orange urine, oligospermia, marrow | Safe (folic acid 5 mg) |
| Hydroxychloroquine | Retinopathy -annual screening after 5 years | Safe -continue |
| Leflunomide | Hypertension, liver, long half-life | Avoid -colestyramine washout |
| Azathioprine | Check TPMT; avoid with allopurinol | Safe |
| Mycophenolate | GI upset, infections | Avoid -highly teratogenic |
| Cyclophosphamide | Haemorrhagic cystitis, infertility | Avoid |
| Prednisolone | Osteoporosis, diabetes, adrenal suppression | Usable (lowest dose) |
| Anti-TNF | TB reactivation; avoid in heart failure and MS | Usable in pregnancy (specialist plan); infant live vaccine timing |
| Rituximab | Hepatitis B reactivation, low immunoglobulins | Generally avoid (specialist advice) |
| Tocilizumab | Masks CRP; bowel perforation | Generally avoid (limited data) |
| IL-17 inhibitors | IBD, candida | Limited data |
| JAK inhibitors | Shingles, VTE, CV events, cancer | Avoid |
Spot the Diagnosis
| Clue | Diagnosis |
|---|
| Morning stiffness for 2 hours that eases with activity | Inflammatory arthritis |
| Symmetrical hand polyarthritis after contact with a child with slapped cheek | Parvovirus B19 arthritis |
| Hot swollen knee in a man on adalimumab with no fever | Septic arthritis until proven otherwise -aspirate |
| Migratory joint pains, wrist tenosynovitis and pustules in a 20-year-old | Disseminated gonococcal infection |
| Positive RF but negative anti-CCP in a patient with endocarditis | False positive RF (chronic infection) |
| Strongly positive anti-CCP | Rheumatoid arthritis (highly specific) |
| Low-titre ANA in a well 70-year-old woman | Probably no disease -common in healthy people |
| Anti-histone antibodies in a patient on hydralazine | Drug-induced lupus |
| High ESR with a normal CRP and low C3 | Active SLE |
| Needle-shaped negatively birefringent crystals | Gout |
| Rhomboid weakly positively birefringent crystals | CPPD (pseudogout) |
| Punched-out erosions with overhanging edges | Chronic gout |
| Pencil-in-cup deformity at the DIP joints | Psoriatic arthritis |
| Calcified knee menisci on X-ray | Chondrocalcinosis (CPPD) |
| New cough and breathlessness 3 months after starting methotrexate | Methotrexate pneumonitis |
| Pancytopenia after trimethoprim in a patient on methotrexate | Antifolate interaction -folinic acid |
| Orange contact lenses | Sulfasalazine |
| Bull's-eye maculopathy after years of a lupus drug | Hydroxychloroquine retinopathy |
| Severe marrow suppression when allopurinol is added | Azathioprine interaction |
| Hepatitis after rituximab in a hepatitis B core antibody-positive patient | Hepatitis B reactivation |
| Perforated diverticulum with a normal CRP | Tocilizumab (IL-6 blockade) |
| New bloody diarrhoea after starting secukinumab | IL-17 inhibitor-associated IBD |
| Shingles and a DVT on a new oral RA drug | JAK inhibitor |
| Cavitating lung lesion on infliximab | TB reactivation |
Exam-style Scenarios
1. A 74-year-old man with rheumatoid arthritis on etanercept has a 1-day hot, swollen right knee. He feels slightly unwell; temperature 37.4°C. CRP 95. Joint fluid is turbid with gram-positive cocci; calcium pyrophosphate crystals are also seen.
Answer: Septic arthritis (with coexisting CPPD).
- Crystals do not exclude infection; the Gram stain confirms sepsis.
- Blood cultures; IV antibiotics per local guidance (e.g. flucloxacillin, adding MRSA cover if risk); urgent orthopaedic washout.
- Stop etanercept until the infection has fully resolved; review steroids (sick day rules).
2. A 58-year-old woman on methotrexate 15 mg weekly for RA is prescribed trimethoprim for a UTI. A week later she has mouth ulcers, fever and bruising. Neutrophils 0.3, platelets 35.
Answer: Methotrexate toxicity (marrow suppression) from a trimethoprim interaction.
- Stop methotrexate and trimethoprim; treat as neutropenic sepsis (blood cultures, IV broad-spectrum antibiotics within 1 hour).
- Give folinic acid (calcium folinate) rescue; check kidney function (reduced clearance worsens toxicity); haematology and rheumatology input.
- Future -avoid trimethoprim and co-trimoxazole with methotrexate; use another antibiotic (e.g. nitrofurantoin).
3. A 45-year-old man with psoriatic arthritis is about to start adalimumab. He was born in India and had a cough 15 years ago. His IGRA is positive; chest X-ray is normal.
Answer: Latent TB before anti-TNF therapy.
- Refer to the TB service; treat latent TB (e.g. 3 months of isoniazid plus rifampicin, or 6 months of isoniazid) -start the biologic after at least 1 month of treatment (or per TB team).
- Also screen for hepatitis B and C and HIV; give inactivated vaccines (influenza, pneumococcal, COVID-19) and consider Shingrix.
- Warn about infection symptoms -anti-TNF can cause TB reactivation even after screening.
4. A 66-year-old woman is starting prednisolone 40 mg for giant cell arteritis. She will likely need steroids for over a year. She has had no fractures.
Answer: Long-term glucocorticoid therapy -prevent complications.
- Bone protection -calcium and vitamin D and a bisphosphonate (e.g. alendronic acid) now; consider DEXA.
- Check glucose or HbA1c, BP and weight regularly; PPI if GI risk; Steroid Emergency Card and sick day rules.
- Taper slowly; consider a steroid-sparing drug (tocilizumab) if relapsing (see the Vasculitis page).
5. A 32-year-old woman with RA well controlled on methotrexate and sulfasalazine wants to try for a baby.
Answer: Pre-conception planning in rheumatic disease.
- Stop methotrexate (1–3 months before conception per BSR); continue sulfasalazine (with folic acid 5 mg daily) and consider adding hydroxychloroquine to keep disease controlled.
- If more is needed -anti-TNF (e.g. certolizumab) can be used in pregnancy with specialist planning; low-dose prednisolone for flares.
- Aim for stable remission before conception; plan postnatal treatment and breastfeeding compatibility (see the Emergencies and Pregnancy page).
Key Points
- Inflammatory joint pain -long morning stiffness, better with movement, soft swelling, raised CRP.
- Pattern matters -monoarthritis (septic, crystals), asymmetric lower-limb oligoarthritis (spondyloarthritis), symmetrical small-joint polyarthritis (RA, viral, SLE).
- A hot swollen joint is septic until proven otherwise -aspirate before antibiotics; crystals don't exclude sepsis.
- Viral polyarthritis usually settles within 6 weeks.
- Anti-CCP is specific for RA; RF is not.
- ANA is sensitive but not specific; anti-dsDNA and anti-Sm are specific for SLE.
- Low complement and high ESR with normal CRP -active SLE.
- Gout crystals -needle, negative; CPPD -rhomboid, positive.
- Methotrexate is weekly, with weekly folic acid; never with trimethoprim; folinic acid for toxicity.
- Hydroxychloroquine -annual eye screening after 5 years; safe in pregnancy.
- Check TPMT before azathioprine; avoid allopurinol with it.
- Mycophenolate, methotrexate, leflunomide and cyclophosphamide are teratogenic.
- DMARD bloods -every 2 weeks until stable for 6 weeks, monthly for 3 months, then every 12 weeks.
- Before biologics -screen for TB, hepatitis B and C, HIV; give inactivated vaccines; no live vaccines.
- Anti-TNF -avoid in heart failure and demyelination; rituximab -hepatitis B and low immunoglobulins; tocilizumab -masks CRP.
- JAK inhibitors -shingles, VTE, CV events, cancer; avoid in over-65s and smokers unless no alternative.
- Long-term steroids -bone protection, steroid card, sick day rules.
Guidelines and Further Reading
- British Society for Rheumatology (BSR): Guideline for the prescription and monitoring of non-biologic DMARDs
- BSR: Guideline on prescribing drugs in pregnancy and breastfeeding (2022)
- BSR: Guidelines on the safety of biologic therapies; Management of the hot swollen joint in adults
- Royal College of Ophthalmologists: Hydroxychloroquine and chloroquine retinopathy -recommendations on monitoring
- MHRA Drug Safety Updates: Methotrexate once-weekly dosing; JAK inhibitors; Mycophenolate pregnancy prevention
- NICE NG33: Tuberculosis (latent TB testing and treatment before immunosuppression)
- UKHSA: Immunisation against infectious disease (the Green Book)
- National Osteoporosis Guideline Group (NOGG): Glucocorticoid-induced osteoporosis
- Arthritis Research UK / Versus Arthritis: Clinical assessment of the musculoskeletal system (GALS)
- BNF -for current doses
