Methotrexate is widely regarded as one of the safest drugs for rheumatoid arthritis. It is a disease-modifying antirheumatic drug (DMARD) that not only reduces pain and swelling but can also slow joint damage and disease progression over time. Methotrexate is often used as first-line therapy for patients with rheumatoid arthritis, psoriatic arthritis, and juvenile idiopathic arthritis. It is effective, but not everyone who takes it gains adequate relief from joint pain, swelling, morning stiffness, and other symptoms. Fortunately, combining methotrexate with other medications will usually do the job. Most often, methotrexate is combined with other DMARDs, such as leflunomide, cyclosporine, sulfasalazine, and hydroxychloroquine. Doctors may also try pairing methotrexate with biologic drugs in people who don’t respond well to DMARD combinations. However, the choice of medication depends on the patients symptoms and disease severity. Hydroxychloroquine is another relatively safe and well-tolerated agent for the treatment of rheumatoid arthritis. It is the least immunosuppressive of the DMARDs and is often used for patients with low disease activity.