Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic autoimmune disease in which loss of immune tolerance drives inflammatory synovitis — most often a symmetric polyarthritis of the small joints of the hands and feet — that progresses to cartilage and bone erosion, joint deformity, and disability if left uncontrolled. Radiographic erosions can appear within the first year of untreated disease, which is why current guidance directs starting disease-modifying therapy immediately at diagnosis rather than simply controlling symptoms.^[1] RA also carries systemic disease burden independent of joint involvement — an increased risk of cardiovascular disease comparable to diabetes mellitus, osteoporosis, lymphoproliferative disease, interstitial lung disease, and depression — so routine RA care includes actively screening for and managing these comorbidities, not just the joints.

The hallmark presentation is a symmetric, additive polyarthritis most often involving the small joints of the hands (metacarpophalangeal and proximal interphalangeal joints, characteristically sparing the distal interphalangeal joints) and feet, plus the wrists — accompanied by morning stiffness lasting more than 30 minutes that improves with activity through the day. Pain, swelling, warmth, and tenderness on exam reflect active synovitis; over time, unresolved synovitis produces joint erosion, subluxation, and characteristic deformities (ulnar deviation, swan-neck and boutonnière deformities). Fatigue is a near-universal and often disabling symptom, frequently out of proportion to visible joint findings.

• Genetic susceptibility, including HLA-DRB1 "shared epitope" alleles.
• Cigarette smoking — the strongest modifiable risk factor, and one that also reduces DMARD treatment response.
• Female sex.
• Family history of RA or another autoimmune disease.
• Obesity.
• Periodontal disease — implicated in triggering the citrullination process linked to RA autoimmunity.
• Onset can occur at any age, including childhood, but most commonly begins in the fifth to sixth decade of life.

Differentiating RA from its common mimics

RA is most often confused with other causes of joint pain and swelling — distinguishing them changes the entire treatment approach.

History

• Severity of joint pain, duration of morning stiffness, physician and patient global assessment of disease activity, and functional limitation (e.g., a Health Assessment Questionnaire).

Physical examination

• Number of actively inflamed/swollen joints; mechanical problems (loss of motion, crepitus, instability, malalignment, deformity); extra-articular findings (dry eyes, rheumatoid nodules at pressure points, pulmonary findings, carpal tunnel signs).

Investigations

• Anti-CCP (anti-cyclic citrullinated peptide, also reported as ACPA) and rheumatoid factor (RF) — a negative result for either does not exclude RA.
• CBC, CRP, ESR, liver panel, and serum creatinine — baseline organ-function assessment before starting DMARD therapy, and CRP/ESR to support the diagnosis and track disease activity over time.
• Radiographs of the hands and feet — often normal early in disease; erosions typical of RA are sufficient to confirm the diagnosis when present, but their absence does not rule RA out.

2010 ACR/EULAR classification criteria

Objective joint swelling (by exam or imaging) must be present before applying these criteria, which support a timely diagnosis when typical erosive changes are not yet present. Score categories A-D; a total of 6 or more out of 10 supports a definite diagnosis of RA.^[3]

"Large joints" are shoulders, elbows, hips, knees, and ankles; "small joints" are the metacarpophalangeal, proximal interphalangeal, 2nd-5th metatarsophalangeal, thumb interphalangeal, and wrist joints. This is a closed, published points-based classification tool intended for a consistent case definition, and is presented here as a teaching table rather than an interactive calculator, since applying it correctly requires a hands-on joint examination.^[3]

Poor prognostic factors

The presence of these factors supports more intensive initial therapy and closer follow-up.

• Non-modifiable: moderate-high disease activity by a composite or individual measure; presence of RF and/or anti-CCP, especially at high titer; erosions present on baseline radiograph; failure of 2 or more csDMARDs; a high degree of physical disability at onset.
• Modifiable: smoking; a sedentary lifestyle; delay in starting treatment.

• Achieve at least 50% clinical improvement within 3 months of starting therapy.
• Achieve remission — or, if remission is not attainable, low disease activity — by 6 months, tracked with a validated composite measure (see Monitoring & Follow-Up).
• Fully control signs and symptoms: pain, stiffness, and fatigue.
• Halt radiographic progression and joint damage.
• Maintain physical function, work capacity, and quality of life.
• Adjust therapy at every visit against the defined target — never continue an unchanged regimen simply because the patient is "stable but not at target."

• Multidisciplinary team care — rheumatology, physical/occupational therapy, and patient education — improves outcomes beyond medication alone.
• Physical activity across all 4 domains (cardiorespiratory fitness, muscle strength, flexibility, and neuromotor performance) is safe and beneficial in RA and belongs in every treatment plan, not restricted because of joint disease.^[1]
• Energy conservation counselling, joint protection techniques, and pacing of activities and work roles.
• Heat and cold application for symptomatic pain modulation.
• Periodic evaluation for splints, foot orthoses, and proper footwear; surgical referral for severely damaged joints.
• Dietary omega-3 polyunsaturated fatty acids may provide a modest benefit on disease activity as an adjunct — not a substitute for DMARD therapy.
• There is insufficient evidence to support complementary/alternative therapies, and no evidence to support cannabis, for RA disease control.
• Smoking cessation — reduces cardiovascular risk and improves DMARD treatment response.

Preconception planning

• Methotrexate — stop at least 3 months before attempting conception in both male and female patients; continue folic acid supplementation.
• Leflunomide — contraindicated in pregnancy; if stopping to conceive, complete a drug-elimination washout (cholestyramine 8 g PO three times daily, or activated charcoal 50 g PO four times daily, for 11 days, not necessarily consecutive), then confirm plasma levels below 0.02 mg/L on 2 occasions at least 2 weeks apart before conceiving.
• Sulfasalazine may affect male fertility; consider a 3-month cessation trial if the couple is having difficulty conceiving, after investigating other causes of subfertility.

Breastfeeding

Corticosteroids, hydroxychloroquine, sulfasalazine (except in an infant with hyperbilirubinemia), and NSAIDs (short-acting agents preferred) are compatible with breastfeeding. Methotrexate and leflunomide are contraindicated. Data for bDMARDs/tsDMARDs in lactation are limited; biologics have low oral bioavailability and pass into breast milk in only small amounts given their large molecular size, so use is generally considered lower-risk and decided case-by-case with the treating specialist.

Pediatric

Juvenile idiopathic arthritis is a distinct disease from adult-onset RA, with its own classification criteria and specialist-directed treatment approach — this chapter covers adult RA only. A patient with childhood-onset inflammatory arthritis needs pediatric rheumatology referral rather than adult RA dosing.

Perioperative management

Elective surgery carries an elevated infection and wound-healing-complication risk in RA. Hold a bDMARD before elective surgery, timing withdrawal so surgery falls at the end of that agent's dosing cycle, and restart once the wound shows evidence of healing (about 14 days). Hold tofacitinib or baricitinib for at least 7 days before surgery. Methotrexate, leflunomide, hydroxychloroquine, sulfasalazine, and low-dose corticosteroids can typically continue through surgery. Confirm the specific plan with the treating rheumatologist for any individual patient.^[1]

Renal/hepatic impairment

Methotrexate is contraindicated in significant renal impairment and in hepatitis B or C infection; dose-adjust or avoid csDMARDs with significant hepatic disease given shared hepatotoxicity risk. Most bDMARD/tsDMARD dosing is not renally adjusted, but active infection and hepatic/renal function must be reconfirmed before every dose escalation.

Older adults

Apply the JAK-inhibitor cardiovascular/malignancy risk stratification specifically at age 65 and older (see Red Flags & Refer and Drug Tables) — favor a bDMARD over a JAK inhibitor as the first non-csDMARD step in this group unless TNF-inhibitor therapy has already failed or was not tolerated.^[2]

See patients at least every 3 months while disease is active; extend to every 6-12 months once well-controlled or in remission. Adjust therapy at every visit against the treat-to-target goal (see Treatment Targets) — a major regimen change (adding or switching an agent) is considered after 3 months of inadequate response to maximal current therapy; minor adjustments (a short corticosteroid course) can happen more often.^[1]

Disease activity measurement (DAS28)

The DAS28 is the most commonly used composite disease-activity measure — combining a 28-joint tender and swollen joint count, a patient global assessment, and CRP or ESR through a weighted mathematical formula. Because it uses continuously weighted terms rather than a simple point-per-criterion sum, and requires a hands-on 28-joint examination, it is a specialist/rheumatology-administered tool, not a bedside pharmacist point-of-care score — presented here as reference only, with no self-service calculator: remission is a score under 2.6, low disease activity under 3.2, moderate disease activity 3.2-5.1, and high disease activity above 5.1.

Pre-therapy and ongoing screening for bDMARD/tsDMARD therapy

• Tuberculosis: assess epidemiologic risk factors, obtain a chest x-ray, and perform a Mantoux (TST) skin test before starting any bDMARD or tsDMARD; a QuantiFERON-TB Gold test can help clarify a positive screen. Exclude active TB and start isoniazid prophylaxis in anyone who screens positive before proceeding.^[1]
• Hepatitis B and C serology — screen every patient before starting a bDMARD or tsDMARD, with particular attention for rituximab given its reactivation risk; antiviral prophylaxis may be required during treatment and for up to 12 months after the last rituximab dose.
• Routine Pneumocystis jirovecii pneumonia prophylaxis is not required on DMARD therapy alone, unless another risk factor (e.g., high-dose corticosteroids) is also present.

Vaccination around immunosuppression

Update vaccinations before starting therapy whenever possible, particularly for any live vaccine. Live vaccines are avoided during bDMARD or tsDMARD therapy given the risk of vaccine-strain disease; inactivated/recombinant vaccines remain recommended once therapy has started, since the humoral response may be blunted but effectiveness is not meaningfully reduced.^[1]

Use the recombinant (inactivated) herpes zoster vaccine, never the live formulation, in an RA patient on or starting immunosuppression.^[1]

Corticosteroid and bone-health monitoring

• Calcium (about 1200 mg/day total intake, preferably from diet) and vitamin D (800-2000 units/day) for anyone on prolonged corticosteroid therapy; add a bisphosphonate when the corticosteroid-induced-osteoporosis risk is significant.
• A single depot corticosteroid injection can cause clinically significant hyperglycemia for up to about 10 days — counsel patients with diabetes specifically.

Hydroxychloroquine retinopathy screening

Baseline ophthalmologic exam at or soon after starting (fundus exam, OCT, and wide-field fundus autofluorescence), then annual screening — deferring the first annual screen for up to 5 years is reasonable in an average-risk patient, but start annual screening immediately in a higher-risk patient (dose above 5 mg/kg/day actual body weight, treatment beyond 5 years, renal impairment, concurrent tamoxifen, or pre-existing retinal disease).^[6]

Lipid and cardiovascular monitoring

Check a lipid profile at baseline and periodically after starting an IL-6 inhibitor or JAK inhibitor (see Drug Tables for the exact schedule); do not withhold statin therapy for an inflammation-related lipid rise, since untreated RA disease activity itself independently drives cardiovascular risk beyond what standard risk calculators (e.g., Framingham) capture.^[1]

Malignancy surveillance

Apply routine age-appropriate cancer screening; use the JAK-inhibitor-specific caution in Red Flags & Refer and Special Populations for patients 65 or older, current or past smokers, or those with a malignancy history.^[2]

1. Confirm methotrexate was given an adequate trial before declaring failure — maximum tolerated dose (up to 25 mg weekly) for at least 3 months, using the subcutaneous route if oral absorption or GI tolerance is a concern.
2. Confirm adherence and correct administration technique (weekly dosing, folic acid co-administration) — a common, reversible cause of apparent nonresponse.
3. Reassess disease activity with a structured measure, not symptoms alone, to confirm the patient is genuinely not at target before escalating.
4. If moderate-high disease activity persists on maximal tolerated methotrexate at 3 months, add a biologic or targeted synthetic DMARD (conditionally preferred) or switch to triple csDMARD therapy — complete pre-biologic screening first if escalating to a bDMARD/tsDMARD.
5. If inadequate response to a first TNF inhibitor, switch to a biologic with a different mechanism of action (IL-6 inhibitor, abatacept, or rituximab if seropositive) rather than cycling to a second TNF inhibitor.
6. If inadequate response to a second bDMARD of any class, switch again to a different mechanism, or consider a JAK inhibitor — apply the cardiovascular/malignancy risk stratification before choosing a JAK inhibitor over another biologic class.
7. In a patient who has sustained remission, cautious, shared-decision-making dose tapering — rather than abrupt discontinuation — of a csDMARD, bDMARD, or tsDMARD can be considered; flare risk is higher after tapering, but many patients successfully reduce therapy, and most who flare regain control after restarting the reduced or stopped agent.^[7]
8. At any step, re-examine the original diagnosis if response remains genuinely inadequate despite confirmed adherence and adequate trials — reconsider an alternative or overlapping diagnosis (see the differential table in Assessment & Diagnosis).

• Delaying DMARD initiation while trialing NSAIDs or corticosteroids alone — these control symptoms but do not modify the disease course; a csDMARD should start as soon as the diagnosis is confirmed.
• Prescribing methotrexate without folic acid co-administration.
• Accidentally dosing methotrexate daily instead of weekly, or giving a leflunomide loading dose — dangerous, potentially fatal errors.
• Skipping tuberculosis and hepatitis B/C screening before starting a bDMARD or tsDMARD.
• Giving a live vaccine to a patient on a bDMARD or tsDMARD, or failing to update vaccinations before starting significant immunosuppression.
• Cycling to a second TNF inhibitor after inadequate response to the first, instead of switching to a different mechanism of action.
• Choosing a JAK inhibitor over a TNF inhibitor as the first non-csDMARD step in a patient 65 or older, a current/past smoker, or with cardiovascular risk factors or a malignancy history.
• Continuing a bDMARD or tsDMARD through a serious infection instead of holding it until resolution.
• Exceeding the hydroxychloroquine 5 mg/kg/day actual-body-weight ceiling, or missing scheduled ophthalmologic screening.
• Continuing methotrexate or leflunomide in a patient actively planning conception instead of switching to a pregnancy-compatible regimen with adequate lead time.
• Combining 2 biologic agents, or a biologic with a JAK inhibitor — not well studied, and associated with increased infection risk without an established efficacy benefit.
• Reaching for an opioid for RA pain instead of optimizing DMARD therapy — evidence for opioid efficacy in RA is limited, and disease-modifying treatment is the actual solution to the pain.

How to use this table: Doses are adult doses and require patient-specific confirmation, including renal/hepatic adjustment. Select any drug name to open its complete Pharmasist Drug Database page.

Conventional synthetic DMARDs (csDMARDs)

Methotrexate is the anchor csDMARD for essentially every patient without a contraindication.

Combination csDMARD therapy

Tumor necrosis factor (TNF) inhibitors

Most effective when combined with methotrexate or another csDMARD. Contraindicated with serious/recurrent infection; systemic lupus erythematosus, demyelinating disease, and heart failure are relative contraindications. Complete TB and hepatitis B/C screening (chest x-ray, TST/IGRA, hepatitis serology) before starting every agent in this class.

Interleukin-6 (IL-6) inhibitors

Effective as monotherapy if methotrexate is contraindicated, though combination with methotrexate is generally preferred. Complete the same pre-therapy infection screening as the TNF inhibitors.

T-cell costimulation inhibitor

B-cell depleting therapy

Interleukin-1 (IL-1) inhibitor

Not a first-line biologic — generally less effective than other bDMARD classes and rarely used now.

Janus kinase (JAK) inhibitors (tsDMARDs)

All 3 agents carry a class-wide boxed warning for serious infections, malignancy/lymphoma, major adverse cardiovascular events (MACE), and thrombosis (including fatal events), extrapolated across the class from trial data comparing tofacitinib with a TNF inhibitor.<cite data-reference-id="c0b2c1c7-231f-423c-b107-84f9d9600c60"></cite> Reserve for inadequate response to, or intolerance of, a bDMARD; use with added caution — favoring a TNF inhibitor first — in patients 65 or older, current or past smokers, or those with additional cardiovascular risk factors or a malignancy history. All are metabolized by CYP450 (mainly CYP3A4) — caution with potent CYP3A4 inhibitors/inducers.

Corticosteroids (bridging and flare management)

Route and dose scale with need — use the lowest effective dose for the shortest duration, and pair prolonged use with the bone-health measures in Monitoring & Follow-Up.

Adjunct and supportive therapy

Corticosteroid-induced osteoporosis prevention

For patients on prolonged corticosteroid therapy at significant fracture risk.

Pre-biologic infection prophylaxis

Leflunomide elimination (washout) protocol

Used before conception, or for significant leflunomide toxicity, to accelerate elimination of the active metabolite given its otherwise very long clearance time.