* Reassess after 3 months and proceed escalating therapy if Moderate or High Disease Activity in all instances except after treatment with non-TNF biologic (rectangle D), where reassessment is recommended at 6-months due to a longer anticipated time for peak effect
1Definitions of disease activity are discussed in and and and were categorized as low, moderate or high
2Features of poor prognosis included the presence of one or more of the following: functional limitation (e.g., health assessment questionnaire (HAQ) score or similar valid tools); extra-articular disease (e.g., presence of rheumatoid nodules, RA vasculitis, Felty’s syndrome); positive rheumatoid factor (RF) or anti-cyclic citrullinated peptide (CCP) antibodies (–); bony erosions by radiograph ()
3Combination DMARD therapy with two DMARDs, which is most commonly methotrexate-based with few exceptions (for example, methotrexate + hydroxychloroquine, methotrexate + leflunomide, methotrexate + sulfasalazine, sulfasalazine + hydroxychloroquine) and triple therapy (methotrexate + hydroxychloroquine + sulfasalazine).
4Leflunomide can be added in patients with low disease activity after 3–6 months of minocycline, hydroxychloroquine, methotrexate or sulfasalazine
5If after 3 months of intensified DMARD combination-therapy or after a second DMARD has failed, the option is to add or switch to an anti-TNF biologic.
6Reassessment after treatment with non-TNF biologic is recommended at 6-months due to anticipation that a longer time to peak effect is needed for non-TNF compared to anti-TNF biologics.
7Any adverse event was defined as per the U.S. FDA as any undesirable experience associated with the use of a medical product in a patient. Serious adverse events were defined per the U.S. FDA (see below); all other adverse events were considered non-serious adverse events. The FDA definition of serious adverse event includes death, life-threatening event, initial or prolonged hospitalization, disability, congenital anomaly or an adverse event requiring intervention to prevent permanent impairment or damage.
For the level of evidence supporting each recommendation, please see .
MTX, methotrexate; LEF, leflunomide; HCQ, Hydroxychloroquine; TNF, Tumor-necrosis factor
DMARD, Disease-Modifying Anti-Rheumatic Drug include hydroxychloroquine, leflunomide, methotrexate, minocycline and sulfasalazine (therapies are listed alphabetically; azathioprine and cyclosporine were considered but not included)
DMARD monotherapy refers to treatment in most instances with hydroxychloroquine, leflunomide, methotrexate or sulfasalazine; in few instances, where appropriate, minocycline may also be used
Anti-TNF biologics include adalimumab, certolizumab, etanercept, infliximab, golimumab
Non-TNF biologics include abatacept, rituximab or tocilizumab (therapies are listed alphabetically)