What is the next treatment step for rheumatoid arthritis (RA) that is unresponsive to methotrexate (MTX) and prednisone (a corticosteroid) taper, and should biologics be combined with methotrexate (MTX)?

From the Guidelines

For rheumatoid arthritis not responding to methotrexate and prednisone taper, the next step typically involves adding a biologic agent, such as a TNF inhibitor, while continuing methotrexate, as recommended by the most recent guidelines 1. When considering the next treatment step, it's crucial to prioritize the patient's quality of life, morbidity, and mortality. The European League Against Rheumatism (EULAR) recommendations from 2020 1 emphasize the importance of treating rheumatoid arthritis (RA) with a target of sustained remission or low disease activity.

Key Considerations

• The guidelines suggest that biologic DMARDs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs) should be combined with a conventional synthetic DMARD (csDMARD) like methotrexate, as this combination has shown superior efficacy compared to either agent alone 1.
• TNF inhibitors, such as adalimumab, etanercept, or infliximab, are commonly used first-line biologics and should be considered for patients who have not responded to methotrexate and prednisone taper.
• If TNF inhibitors fail, alternative biologics with different mechanisms of action, such as abatacept, tocilizumab, or rituximab, can be tried, as well as JAK inhibitors like tofacitinib or baricitinib.

Treatment Approach

• The typical approach involves maintaining the methotrexate dose (15-25 mg weekly) while adding the biologic according to its specific dosing schedule.
• Regular monitoring for infection risk and other side effects is essential, and patients should receive appropriate vaccinations before starting biologics.
• The choice between biologics depends on patient-specific factors, including comorbidities, preference for administration route, and insurance coverage.

Prioritizing Patient Outcomes

• The primary goal of treatment is to achieve sustained remission or low disease activity, which can significantly improve the patient's quality of life and reduce morbidity and mortality.
• By following the most recent guidelines and considering patient-specific factors, healthcare providers can make informed decisions to optimize treatment outcomes for patients with rheumatoid arthritis.

From the FDA Drug Label

1. 3 Rheumatoid Arthritis (RA) RITUXAN, in combination with methotrexate, is indicated for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies.

The next treatment for rheumatoid arthritis not responding to methotrexate and prednisone taper is Rituximab in combination with methotrexate.

• Biologicals should be combined with methotrexate for the treatment of adult patients with moderately- to severely-active rheumatoid arthritis who have had an inadequate response to one or more TNF antagonist therapies 2.
• The dose for RA in combination with methotrexate is two-1,000 mg intravenous infusions separated by 2 weeks (one course) every 24 weeks or based on clinical evaluation, but not sooner than every 16 weeks 2.

From the Research

Treatment Options for Rheumatoid Arthritis Not Responding to Methotrexate and Prednisone Taper

• If methotrexate monotherapy is ineffective, or when rheumatoid arthritis is initially severe, adding a TNF-alpha antagonist can be beneficial 3
• A combination of methotrexate and a TNF-alpha antagonist was more effective than methotrexate monotherapy on functional status and symptoms, especially in initially severe rheumatoid arthritis 3
• In patients in whom TNF-alpha antagonists had failed, a combination of rituximab and methotrexate was more effective than methotrexate alone 3

Combination Therapy with Methotrexate and Biologic Disease Modifying Anti-Rheumatic Drugs

• Methotrexate + sulfasalazine + hydroxychloroquine (triple therapy) or methotrexate + most biologic DMARDs or tofacitinib were similarly effective in controlling disease activity and generally well tolerated in methotrexate-naïve patients or after an inadequate response to methotrexate 4
• Methotrexate + some biologic DMARDs were superior to methotrexate in preventing joint damage in methotrexate-naïve patients, but the magnitude of these effects was small over one year 4

Leflunomide Based Triple Therapy in Methotrexate Refractory Rheumatoid Arthritis

• Leflunomide based csDMARD therapy is non-inferior to Sulfasalazine based csDMARD therapy in Methotrexate-failed Rheumatoid arthritis patients with comparable safety profile 5

Assessing Adequate Treatment Response in Patients with Rheumatoid Arthritis

• There is no consensus as to what represents a practical definition of treatment failure or clinical remission in clinical studies 6
• Standard definitions of treatment failure or clinical remission/response are needed, and aggressive treatment strategies with specific clinical goals may result in better long-term outcomes 6