What are the latest treatment guidelines and updates for managing rheumatological conditions, such as rheumatoid arthritis, as per the 22nd Edition of Harrison's Rheumatology?

Rheumatoid Arthritis Treatment Updates from Harrison's 22nd Edition

Initial Treatment Strategy

Methotrexate monotherapy is the strongly recommended first-line DMARD for DMARD-naive patients with moderate-to-high disease activity, rapidly escalated to 20-25 mg weekly, combined with short-term glucocorticoids as bridging therapy. 1, 2, 3

• Start methotrexate at 15 mg/week orally with rapid escalation to 25-30 mg/week or the highest tolerable dose 3
• Add low-dose glucocorticoids (≤10 mg/day prednisone equivalent) when starting DMARDs for patients with moderate or high disease activity 2
• Limit glucocorticoid duration to less than 3 months and taper as rapidly as clinically feasible 1, 2
• Initiation of a csDMARD without longer-term (≥3 months) glucocorticoids is strongly recommended over initiation with longer-term glucocorticoids 1

For patients with low disease activity at diagnosis, hydroxychloroquine is conditionally recommended over other csDMARDs, and sulfasalazine is conditionally recommended over methotrexate 1

Treatment Targets and Monitoring

Treatment should be aimed at reaching sustained remission or low disease activity in every patient, with disease activity monitored every 1-3 months using validated measures (SDAI, CDAI, or DAS28). 1, 2, 3

• If there is no improvement by at most 3 months after starting treatment, therapy should be adjusted 1
• If the target has not been reached by 6 months, therapy must be adjusted 1
• Patients should be at target (remission or low disease activity) for at least 6 months before considering tapering 1, 3
• Therapeutic response usually begins within 3 to 6 weeks, with continued improvement for another 12 weeks or more 4

Treatment Escalation After Methotrexate Failure

If methotrexate monotherapy fails after 3 months in patients with moderate-to-high disease activity, add a biologic DMARD (preferably a TNF inhibitor) or targeted synthetic DMARD (JAK inhibitor) in combination with methotrexate. 1, 2, 3

The 2021 ACR guideline establishes a clear hierarchy:

• Methotrexate monotherapy is strongly recommended over bDMARD or tsDMARD monotherapy 1
• Methotrexate monotherapy is strongly recommended over combination of methotrexate plus a non-TNF inhibitor bDMARD or tsDMARD 1
• Methotrexate monotherapy is conditionally recommended over combination of methotrexate plus a TNF inhibitor 1

Alternative csDMARD Options

For patients with contraindications to methotrexate or early intolerance:

• Leflunomide or sulfasalazine should be considered as part of the first treatment strategy 1, 5
• Methotrexate monotherapy is conditionally recommended over leflunomide 1
• Methotrexate monotherapy is conditionally recommended over dual or triple csDMARD therapy 1
• Triple therapy (methotrexate, sulfasalazine, hydroxychloroquine) is an alternative to biologic therapy in some patients 3

Biologic DMARD Selection

TNF inhibitors (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) are the preferred first biologic agents after failure of conventional DMARDs. 2, 5

• bDMARDs in the 2021 ACR guideline include TNF inhibitors, T cell costimulatory inhibitor (abatacept), IL-6 receptor inhibitors (tocilizumab, sarilumab), and anti-CD20 antibody (rituximab) 1
• Recommendations referring to bDMARDs exclude rituximab unless patients have had an inadequate response to TNF inhibitors or have a history of lymphoproliferative disorder 1
• Biosimilars are considered equivalent to FDA-approved originator bDMARDs 1

Sequential Biologic Therapy

When a TNF inhibitor fails:

• Switching to a different TNF inhibitor may be effective in 50-70% of cases 5
• Switching to a non-TNF biologic with a different mechanism of action is also an option 5
• After sequential failure of both a TNF inhibitor and abatacept, rituximab is recommended for patients with high disease activity or moderate disease activity with poor prognostic features 5

Biomarker-Guided Selection

• Presence of rheumatoid factor, anti-citrullinated protein antibodies, or elevated serum IgG may predict better response to rituximab 5
• Seronegative patients may respond better to abatacept or tocilizumab 5

Targeted Synthetic DMARDs (JAK Inhibitors)

JAK inhibitors (tofacitinib, baricitinib, upadacitinib) have shown efficacy in patients with RA, including those with refractory disease. 1, 5, 3

• tsDMARDs are included in the 2021 ACR treatment algorithm as alternatives to bDMARDs 1
• JAK inhibitors have shown efficacy in patients with inadequate response to TNF inhibitors 5

Special Population Considerations

Cardiovascular Disease

• For patients with heart failure (NYHA class III or IV), use non-TNF inhibitor biologics or targeted synthetic DMARDs instead of TNF inhibitors, as TNF inhibitors can worsen heart failure 2

Infectious Disease Screening

• Perform tuberculosis screening (TST or IGRA) before initiating biologics or JAK inhibitors 2, 5
• Perform hepatitis B and C screening before initiating biologics 2, 5
• For patients with hepatitis B infection, prophylactic antiviral therapy is strongly recommended for those initiating rituximab who are hepatitis B core antibody positive 2
• Do not use rituximab in untreated chronic hepatitis B or treated hepatitis B with Child-Pugh Class B or higher 5

Malignancy History

• Rituximab may be preferred over other biologics in patients with a history of lymphoproliferative malignancy, previously treated solid malignancy within the past 5 years, previously treated melanoma, or previously treated non-melanoma skin cancer within the past 5 years 5

Integrative and Rehabilitation Interventions

Consistent engagement in exercise is strongly recommended over no exercise for patients with RA. 1

Exercise Recommendations

• Aerobic exercise is conditionally recommended over no exercise (very low to low certainty evidence) 1
• Aquatic exercise is conditionally recommended over no exercise (low certainty evidence) 1
• Resistance exercise is conditionally recommended over no exercise (very low certainty evidence) 1
• Mind-body exercise (yoga, Tai Chi, Qigong) is conditionally recommended over no exercise (very low to low certainty evidence) 1

Rehabilitation Interventions

• Comprehensive occupational therapy is conditionally recommended over no comprehensive occupational therapy (very low certainty evidence) 1
• Comprehensive physical therapy is conditionally recommended over no comprehensive physical therapy (very low certainty evidence) 1
• For patients with hand involvement, performing hand therapy exercises is conditionally recommended (low certainty evidence) 1
• For patients with hand and/or wrist involvement, use of splinting, orthoses, and/or compression is conditionally recommended (very low certainty evidence) 1
• Joint protection techniques are conditionally recommended (low certainty evidence) 1

Treatment De-escalation

For patients in sustained remission (at least 6 months of low disease activity or remission), consider cautious de-escalation of therapy through shared decision-making. 2, 5, 3

• Dose reduction refers to lowering the dose or increasing the dosing interval of a DMARD 1
• Gradual discontinuation is defined as gradually lowering the dose of a DMARD and subsequently stopping it 1
• Approximately 15-25% of patients may achieve sustained drug-free remission, particularly those with shorter symptom duration, absence of rheumatoid factor or anti-CCP antibodies, lower disease activity before remission, and less baseline disability 2, 5
• When methotrexate is discontinued, arthritis usually worsens within 3 to 6 weeks 4
• If tapering is pursued, bDMARDs should be reduced first while maintaining csDMARD therapy 3

Methotrexate-Specific Considerations

Dosing and Administration

• For adult RA, recommended starting dosage is single oral doses of 7.5 mg once weekly or divided oral dosages of 2.5 mg at 12-hour intervals for 3 doses given as a course once weekly 4
• For polyarticular-course juvenile RA, the recommended starting dose is 10 mg/m² given once weekly 4
• Dosages may be adjusted gradually to achieve optimal response, but experience shows significant increase in serious toxic reactions at doses greater than 20 mg/week in adults 4
• Children receiving 20 to 30 mg/m²/week may have better absorption and fewer gastrointestinal side effects if methotrexate is administered intramuscularly or subcutaneously 4

Monitoring Requirements

• Assessment of hematologic, hepatic, renal, and pulmonary function should be made by history, physical examination, and laboratory tests before beginning, periodically during, and before reinstituting methotrexate therapy 4
• Maximal myelosuppression usually occurs in seven to ten days 4
• If vomiting, diarrhea, or stomatitis occur, which may result in dehydration, methotrexate should be discontinued until recovery occurs 4
• Methotrexate should be stopped immediately if there is a significant drop in blood counts 4

Drug Interactions

• NSAIDs (including salicylates) may increase methotrexate toxicity through decreased tubular secretion 4
• Vitamin preparations containing folic acid or its derivatives may decrease responses to systemically administered methotrexate 4
• Trimethoprim/sulfamethoxazole has been reported rarely to increase bone marrow suppression 4
• Use of nitrous oxide anesthesia potentiates the effect of methotrexate on folate-dependent metabolic pathways; avoid concomitant nitrous oxide anesthesia 4

Common Pitfalls to Avoid

• Delaying DMARD initiation: Therapy with DMARDs should be started as soon as the diagnosis of RA is made 1
• Inadequate methotrexate dosing: Failure to escalate to 20-25 mg weekly or maximum tolerated dose 5, 3
• Insufficient treatment trial duration: Not waiting at least 3 months before concluding treatment failure 1, 5
• Prolonged glucocorticoid use: Long-term use beyond 1-2 years increases risks of cataracts, osteoporosis, and cardiovascular disease 5
• Failure to adjust therapy: Not escalating treatment when targets are not met within 3-6 months 2, 3
• Overlooking comorbidities: Not screening for tuberculosis, hepatitis, or considering heart failure before selecting biologics 2, 5
• Inadequate monitoring: Not using validated disease activity measures every 1-3 months 2, 3