What is the effect of methotrexate (MTX) with and without steroid combination in patients with inflammatory conditions?

Methotrexate and Steroid Combination Therapy in Inflammatory Conditions

Methotrexate combined with steroids provides significant benefits over methotrexate monotherapy, particularly as a steroid-sparing agent that allows for lower cumulative steroid doses, fewer relapses, and improved outcomes in various inflammatory conditions. 1

Methotrexate with Steroids: Benefits

• Methotrexate serves as an effective steroid-sparing agent in several inflammatory conditions, allowing for reduced steroid doses while maintaining disease control 1
• In giant-cell arteritis, methotrexate (7.5-17.5 mg/week) combined with high-dose prednisone leads to higher prednisone discontinuation rates (HR 2.84), significantly lower cumulative steroid doses, and fewer relapses after one year 1
• In polymyalgia rheumatica, methotrexate (10 mg/week) with steroids results in significantly more prednisone discontinuation, fewer relapses, and a trend toward lower prednisone duration and cumulative dose 1
• In systemic lupus erythematosus, methotrexate (7.5-20 mg/week) with steroids leads to significantly more prednisone reduction and fewer skin and joint flares, though with more adverse events 1
• In juvenile dermatomyositis, concomitant methotrexate therapy allows patients to discontinue prednisone significantly earlier and have lower cumulative prednisone doses 1

Methotrexate without Steroids: Efficacy

• As monotherapy, methotrexate demonstrates efficacy in controlling inflammation in various conditions but may be less effective than when combined with steroids 1
• In DMARD-naive rheumatoid arthritis patients, methotrexate monotherapy is generally favored over combinations with conventional DMARDs due to the balance of efficacy and toxicity 1
• Methotrexate monotherapy shows effects on articular swelling and tenderness as early as 3-6 weeks in rheumatoid arthritis patients 2
• While methotrexate ameliorates symptoms of inflammation (pain, swelling, stiffness), there is no evidence it induces remission of rheumatoid arthritis or has beneficial effects on bone erosions when used alone 2
• In inflammatory bowel disease, methotrexate monotherapy has shown moderate efficacy for inflammation control and steroid-sparing effects, particularly in Crohn's disease 1, 3

Combination Strategies

• In early rheumatoid arthritis, intensive treatment strategies that include methotrexate plus steroids show more rapid clinical response and better radiographic outcomes than sequential monotherapy or step-up DMARD therapy 1
• The COBRA study demonstrated that a combination of methotrexate and sulfasalazine with high-dose steroids in a step-down therapeutic strategy resulted in protracted effects on radiographic progression compared to sulfasalazine monotherapy in early rheumatoid arthritis 1
• The FIN-RACo study showed that a four-drug regimen with methotrexate, sulfasalazine, hydroxychloroquine, and prednisolone (5 mg/day) was more effective than a single DMARD in early rheumatoid arthritis 1
• In non-infectious uveitis, methotrexate demonstrates efficacy in inflammation control, steroid-sparing ability, and maintenance and improvements of visual acuity 1

Mechanism of Action

• The mechanism of action of methotrexate in inflammatory conditions is not fully understood but may involve effects on immune function 2
• Methotrexate inhibits dihydrofolic acid reductase, interfering with DNA synthesis, repair, and cellular replication, which affects rapidly proliferating cells 2
• Some studies suggest methotrexate inhibits DNA precursor uptake by stimulated mononuclear cells and may correct spleen cell hyporesponsiveness and suppressed IL-2 production in animal models of arthritis 2, 4
• Current evidence suggests methotrexate acts primarily on the non-specific efferent arc of the immuno-inflammatory process rather than directly on T cells 4

Clinical Considerations and Caveats

• When choosing between methotrexate monotherapy and combination therapy with steroids, consider disease severity, prior treatment response, and risk of adverse effects 1
• Methotrexate combined with steroids may increase the risk of adverse events, particularly infections, so careful monitoring is required 1
• In DMARD-naive patients, the balance of efficacy/toxicity generally favors methotrexate monotherapy over combination with other conventional DMARDs, but this does not contradict the established superiority of combinations including prednisone 1
• For patients with moderate to severe disease activity or those who have failed previous treatments, combination therapy with methotrexate and steroids is often more effective than either agent alone 1
• Methotrexate can be safely continued in the perioperative period in rheumatoid arthritis patients undergoing elective orthopedic surgery, which may reduce disease flares 1