Rheumatoid arthritis: diagnosis and treat-to-target care

01OverviewDefinition, clinical context and the essential points that orientate the chapter.

Rheumatoid arthritis is a chronic systemic inflammatory disease whose central clinical lesion is synovitis. Diagnosis is clinical and supported by distribution, duration, serology and imaging. Examine all peripheral joints, tendon sheaths, nodules and function, and ask about eye, lung, cardiac, neurological and constitutional symptoms. A classification score supports research consistency but should not replace specialist judgement in early or seronegative disease.

Early treatment changes outcome. NICE recommends specialist referral for persistent synovitis and initiation of a conventional synthetic DMARD as soon as possible after diagnosis. Methotrexate is widely used unless contraindicated; leflunomide or sulfasalazine are alternatives, with hydroxychloroquine an option in selected mild disease. Explain delayed onset, infection precautions and blood monitoring before the first dose. Methotrexate and leflunomide are incompatible with pregnancy; suspected or planned pregnancy on leflunomide requires urgent specialist cessation and washout advice.

Treat-to-target care makes reassessment explicit. Record a composite activity measure such as DAS28 where appropriate, but examine feet, tendons and extra-articular disease not captured by the score. If the target is not reached despite adherence and adequate dose, optimise or add conventional therapy and consider biologic or targeted synthetic DMARDs under NICE eligibility and specialist safety pathways. Patient preference and comorbidity shape sequencing.

Long-term care includes annual review of disease activity, function, cardiovascular risk, blood pressure, lipids, smoking, bone health, vaccination, cervical and foot problems, mood and work. Minimise cumulative glucocorticoids. Before surgery, pregnancy or serious infection, coordinate DMARD interruption or continuation with rheumatology rather than stopping all treatment without a plan.

Key points

Suspect rheumatoid arthritis in persistent synovitis, especially symmetrical MCP, PIP, wrist and MTP disease with prolonged morning stiffness; DIP joints are usually not the dominant site.
Refer every adult with suspected persistent synovitis of undetermined cause. Mark the referral urgent, even with normal inflammatory markers or negative serology, when small hand or foot joints are affected, more than one joint is affected, or at least three months elapsed before medical advice was sought.
RF supports but does not diagnose rheumatoid arthritis; anti-CCP is more specific and may indicate greater risk of radiographic progression.
Obtain baseline FBC, renal and liver profile, inflammatory markers and appropriate infection, pregnancy and vaccination assessment without delaying referral.
Start cDMARD monotherapy as soon as possible and ideally within 3 months of persistent-symptom onset: offer oral methotrexate, leflunomide or sulfasalazine, or consider hydroxychloroquine for mild or palindromic disease; escalate the selected dose as tolerated.
Short-term glucocorticoid bridging may control inflammation while a new DMARD takes effect, but needs an explicit stop or taper plan and infection, glucose, bone and cardiovascular review.
Measure disease activity regularly and escalate against an agreed target of remission or low activity rather than continuing an ineffective regimen by inertia.
Separate active synovitis from fixed damage, osteoarthritis, fibromyalgia, infection and treatment toxicity before declaring DMARD failure.

02AetiologyUnderlying causes, associations and risk factors, with why each one matters.

Genetic immune susceptibility

Polygenic susceptibility, including HLA-related antigen presentation, interacts with environmental factors to permit loss of tolerance and persistent autoimmune synovial inflammation.

Smoking and mucosal triggers

Cigarette smoking and mucosal inflammation can promote protein citrullination and autoantibody development, particularly in genetically susceptible individuals.

Sex, hormones and environment

Rheumatoid arthritis is more common in women, while hormonal, microbial and occupational exposures modify risk without acting as a single sufficient cause.

03PathophysiologyThe causal sequence from the underlying abnormality to symptoms and harm.

1
Autoantibody and cytokine activation
RF, anti-citrullinated-protein immunity and activated lymphocytes amplify TNF, interleukin-6 and other cytokine networks within susceptible synovium.
2
Pannus and structural erosion
Proliferative synovium invades cartilage and activates osteoclasts at the bone margin, producing erosions, joint-space loss and progressive instability.
3
Systemic inflammatory disease
Inflammatory mediators affect blood vessels, lung, eye, nerves and metabolism, increasing fatigue, anaemia, osteoporosis and cardiovascular risk beyond the joints.

04Clinical features and red flagsSymptoms, examination findings, patterns of presentation and time-critical warnings.

Small-joint synovitis

Boggy MCP, PIP, wrist or MTP swelling with squeeze pain, prolonged stiffness and reduced grip supports active rheumatoid synovitis and early referral.

Markers of radiographic progression

Anti-CCP positivity or baseline erosions indicate increased risk of radiographic progression and support close treat-to-target monitoring.

Extra-articular rheumatoid diseaseRed flag

Breathlessness, dry cough, painful red eye, nodules, neuropathy, pleuritic pain or constitutional decline requires organ-specific assessment rather than a joint-only review.

Possible septic jointRed flag

One acutely hotter joint, bacteraemia risk or systemic illness during immunosuppression requires urgent aspiration and culture before assuming rheumatoid flare.

Damage or pain discordance

Pain with little synovitis may arise from deformity, osteoarthritis, tendon disease or fibromyalgia and should not trigger automatic immunosuppression escalation.

05InvestigationsWhat to request, why it matters and how to interpret it.

Investigation order

Read from the initial assessment onwards. Tests may run in parallel in urgent care; first-line, preferred, confirmatory, definitive and gold-standard labels appear only when the chapter explicitly states them.

01
Clinical joint examination and disease activity measureFirst step
Why
Confirm synovitis, establish baseline burden and support repeated treat-to-target decisions.
Interpretation and limitations
Record swollen and tender joints separately and account for feet, tendons, damage and pain amplification that a summary score may miss.
02
RF, followed by anti-CCP when indicated
Why
Support diagnosis and estimate prognosis within a compatible persistent-synovitis phenotype without gating referral.
Interpretation and limitations
Offer RF when examination confirms synovitis; if RF is negative, consider anti-CCP. After diagnosis, measure anti-CCP if it has not already been measured. Negative serology does not exclude disease.
03
FBC, renal, liver, CRP and ESR
Why
Assess inflammation, alternative disease, organ status and baseline safety before DMARD treatment.
Interpretation and limitations
Normal markers can occur with active synovitis. Cytopenia, renal or liver abnormalities alter drug selection and may signal another systemic process.
04
Baseline hand and foot radiographs
Why
Document erosions, joint-space loss and alternative structural disease for prognosis and later comparison.
Interpretation and limitations
Normal early radiographs do not exclude rheumatoid arthritis; ultrasound may support uncertain synovitis when it changes specialist decisions.
05
Pre-immunosuppression infection and reproductive assessment
Why
Reduce preventable reactivation, fetal and vaccine-related harm before conventional, biologic or targeted therapy.
Interpretation and limitations
Before starting an adult conventional DMARD other than hydroxychloroquine or mepacrine, screen for hepatitis B, hepatitis C and HIV. Use risk-based latent-TB testing for conventional DMARDs and agent-specific TB screening before biologic or targeted treatment. Review pregnancy, varicella history and age-appropriate UKHSA immunisations.

06Differential diagnosisRealistic alternatives and the features that help distinguish them.

Psoriatic or peripheral spondyloarthritis

Psoriasis, nail dystrophy, DIP disease, dactylitis, enthesitis or asymmetric lower-limb arthritis suggests a spondyloarthritis rather than classic rheumatoid pattern.

Viral or crystal arthritis

Abrupt onset, exposure, rash, hepatitis, episodic attacks or synovial crystals supports infectious, post-infectious or crystal inflammation, although patterns may overlap.

Connective-tissue disease

Photosensitive rash, ulcers, Raynaud phenomenon, sicca, cytopenia, renal abnormality or low complement redirects assessment towards lupus or another systemic autoimmune disorder.

Osteoarthritis or pain amplification

Bony DIP change, brief stiffness and load-related pain support osteoarthritis, while widespread tenderness without synovitis suggests a non-inflammatory pain mechanism.

07ManagementImmediate care, first-line treatment, alternatives and escalation.

01Suspected early RARefer on synovitis, not test positivityFirst stepPersistent objective peripheral-joint swelling is present without an immediate septic-joint emergency.

1Document joint distribution, duration, stiffness, function and extra-articular features; offer RF and, if it is negative, consider anti-CCP. Obtain baseline bloods and radiographs in parallel without delaying referral.
2Refer every suspected persistent synovitis without awaiting tests. For more than 1 joint or the small joints of the hands or feet, refer within 3 working days of primary-care presentation; also mark it urgent when symptoms began at least 3 months before medical advice was sought. Provide proportionate analgesia and avoid unreviewed prolonged glucocorticoids.
3At specialist confirmation, start cDMARD monotherapy as soon as possible and ideally within 3 months of persistent-symptom onset; QS33 measures treatment starting within 6 weeks of referral. Provide education and monitor active disease monthly until the agreed remission or low-activity target is achieved.

02Target not reachedOptimise, then escalate purposefullyEscalationActive synovitis persists at scheduled review despite an initiated disease-modifying regimen.

1Check adherence, dose, duration, adverse effects and whether pain reflects active inflammation rather than damage, infection or fibromyalgia.
2EscalationEscalate conventional DMARD dose or combination and use only short reviewed bridging therapy, measuring response at the planned interval.
3If activity remains above target, assess NICE eligibility and safety for biologic or targeted therapy with shared decision-making and infection screening.

03New illness on treatmentSeparate flare from infection and toxicityAn immunosuppressed patient develops fever, breathlessness, cytopenia, liver-test change or an acutely hot joint.

1Assess physiology and the threatened organ, obtain cultures and appropriate imaging or aspiration, and review the exact DMARD and corticosteroid exposure.
2For a serious infection, follow the acute and specialist withholding plan until recovery; many minor infections do not require automatic conventional-DMARD interruption. Never stop established long-term glucocorticoids abruptly or intensify immunosuppression before infection assessment.
3AlternativeAgree restart, dose adjustment or alternative therapy after recovery and report suspected serious adverse reactions through the appropriate safety route.

Key medicines and prescribing safety5 treatments · regimens, roles and cautions

Anchor conventional DMARD for active rheumatoid arthritis when no contraindication exists, with dose escalation against disease activity and tolerability.

Methotrexate with folic acid

Usually 7.5–15 mg once weekly initially, titrated by rheumatology within the product-specific maximum. Prescribe only 2.5 mg tablets, agree one fixed weekly day and co-prescribe folic acid at least 5 mg once weekly on a different day.

Never prescribe or take it daily. Check risk-stratified FBC, renal function, ALT or AST and albumin; review liver, alcohol, lung, infection and interaction risks, especially trimethoprim or co-trimoxazole. Withhold during a serious infection until recovery and specialist review. For maternal exposure, low-dose methotrexate must be stopped at least 1 month before planned conception and is not compatible with pregnancy or breastmilk exposure; accidental pregnancy needs immediate cessation, folic acid 5 mg/day and specialist fetal-risk review. BSR regards paternal exposure at no more than 25 mg/week as compatible.

Alternative or additional conventional DMARD for peripheral inflammatory arthritis, including when methotrexate is unsuitable in selected patients.

Sulfasalazine

Commonly started at 500 mg once daily and increased gradually toward 1 g twice daily according to tolerance and specialist protocol.

Monitor FBC, liver and renal function and counsel about rash, blood dyscrasia, gastrointestinal effects, sulfonamide allergy and reversible oligospermia. Use a specialist withholding and restart plan for serious infection. Sulfasalazine is compatible in pregnancy; prescribe folic acid 5 mg daily during periconception and the first trimester.

Rapid temporary suppression of active inflammation while a newly initiated or adjusted DMARD has not yet achieved effect.

Prednisolone bridging course

Use the lowest effective oral dose for the shortest agreed period, with an explicit taper and review rather than indefinite repeat prescriptions.

Exclude infection, assess diabetes, blood pressure, mood, eye and bone risk, protect against prolonged exposure and never stop established long-term therapy abruptly.

NICE first-choice cDMARD monotherapy option for newly diagnosed active rheumatoid arthritis when selected with the patient and rheumatology team.

Leflunomide

Specialist treatment: 10–20 mg orally once daily according to disease activity and tolerance. The SmPC permits a 100 mg once-daily loading dose for 3 days but states that omission may reduce adverse events; loading should not be routine unless the prescriber’s protocol uses it.

Check pregnancy status, blood pressure, FBC including platelets, liver tests and renal function before treatment and monitor under the BSR or specialist shared-care schedule. Avoid in pregnancy or breastfeeding, severe liver disease, serious infection or marked cytopenia. Because the active metabolite persists, planned maternal conception or serious toxicity requires specialist accelerated elimination and verification under the SmPC; do not improvise a washout.

NICE alternative first-choice cDMARD for mild or palindromic rheumatoid disease and an option in a later step-up combination.

Hydroxychloroquine

Usually 200–400 mg orally daily with food, using the minimum effective dose and a target no higher than 5 mg/kg actual body weight per day; rheumatology selects the dose and formulation and reduces exposure when toxicity risk requires it.

Avoid in pre-existing maculopathy and review renal impairment, visual symptoms, hypoglycaemia, cardiac disease and QT-prolonging combinations. Arrange annual retinal monitoring after 5 years, or after 1 year when high risk: dose above 5 mg/kg actual body weight, eGFR below 60 mL/min/1.73 m², tamoxifen use or previous chloroquine. BSR considers it compatible with pregnancy, breastmilk and paternal exposure.

08ComplicationsImportant consequences, why they occur and why they matter clinically.

Erosion, deformity and disability

Uncontrolled synovitis causes cartilage loss, marginal erosions, tendon rupture, subluxation and fixed deformity with irreversible loss of hand, foot and mobility function.

Extra-articular organ disease

Rheumatoid nodules, interstitial lung disease, pleuritis, scleritis, neuropathy, vasculitis and cervical instability can determine morbidity independently of peripheral joint activity.

Cardiovascular and skeletal harm

Inflammation, inactivity and corticosteroid exposure accelerate atherosclerosis, sarcopenia and osteoporosis, increasing myocardial, fracture and frailty risk.

Infection and treatment toxicity

DMARDs, glucocorticoids and comorbidity raise infection, cytopenia, hepatic and reproductive risks, requiring prevention, laboratory monitoring and rapid review of symptoms.

09Monitoring and follow-upTreatment response, safety checks and longer-term review.

Measure disease activity monthly in active disease until the agreed target is reached, then at an interval appropriate to stability and treatment.
Follow FBC, renal and liver tests at the schedule required for each DMARD and after dose changes.
Ask about infection, breathlessness, mouth ulcers, bruising, pregnancy plans and adverse effects at every prescribing review.
Review vaccination, cardiovascular risk, smoking, bone health, foot care, work and functional support at least annually.
Track total glucocorticoid exposure and implement a reduction plan whenever disease-modifying control permits.

10Special situationsVariants, exceptions and circumstances that change the usual approach.

Referral is clinical

Normal markers, negative antibodies and normal early films must not delay specialist assessment of persistent synovitis.

Weekly means weekly

Methotrexate must have one specified weekly day and separate folic-acid instructions to prevent fatal dosing confusion.

DAS28 has blind spots

Feet, tendon disease, extra-articular inflammation, damage and pain amplification may not be represented by the score.

Pain is not always activity

Escalating immunosuppression without confirming synovitis can worsen infection risk while leaving mechanical or central pain untreated.

Prevention is treatment

Vaccination, smoking cessation, exercise, cardiovascular assessment and bone protection materially alter long-term rheumatoid outcomes.

11Common pitfallsFrequent interpretation and management errors.

01
Waiting for positive RF or erosions before referring persistent synovitis.
02
Prescribing methotrexate daily or failing to specify the weekly dose day.
03
Repeating glucocorticoid bridging courses without a disease-modifying escalation plan.
04
Calling fever or one hot joint a flare in an immunosuppressed patient without infection assessment.
05
Using a composite score without examining feet, tendons and extra-articular organs.