Early diagnosis and intervention have revolutionized the treatment of rheumatoid arthritis (RA). Methotrexate, biologics, and JAK inhibitors are key in managing RA and improve the outcomes of some patients, although novel therapies and possible combinations are still needed because many individuals remain unresponsive to current therapies.

Rheumatologists worldwide now recognize the importance of early diagnosis and intervention. Extra-articular disease is significantly less prevalent now than it was 30 years ago, possibly due to earlier intervention with methotrexate. For patients with RA not responding to methotrexate, the American College of Rheumatology (ACR) guidelines conditionally recommend adding a biologic over triple therapy. For patients not responding to a biologic, the guidelines recommend moving to a drug with a different mechanism of action rather than cycling to another agent within the class. For patients who fail multiple options, including anti-TNF therapy, other biologics, and JAK inhibitors, we would consider rituximab.

Over the last 5 years, we have learned a lot about drug withdrawal and tapering. Studies of biologics with or without background methotrexate have found that many patients with low disease activity or in remission have flares within 6 months of a biologic being stopped. Further, if patients restart the biologic, not all of them recapture their previous clinical response, whereas patients who lower the methotrexate dose but continue a biologic typically maintain their response. The challenge with stopping methotrexate is that methotrexate helps restrict the development of antidrug antibodies to the biologic. Antidrug antibodies reduce the clinical effect of biologics, so, in clinical practice, I generally only try to lower the dose of methotrexate, to no less than 10 mg per week. Studies suggest that this dose of methotrexate is needed to reduce antidrug antibodies.

The JAK inhibitors are remarkably effective, consistently “beating” methotrexate in head-to-head studies and, in some studies, being better than adalimumab. Until recently, there was great interest in seeing if they could accelerate ahead of anti-TNF therapy. JAK inhibitors work quickly and have a reasonably defined safety profile. However, the US Food and Drug Administration (FDA)–mandated post-approval ORAL Surveillance trial of tofacitinib in patients with RA aged 50 or older and with one additional cardiovascular risk factor found a greater number of major adverse cardiovascular events and cancer with tofacitinib than with anti-TNF therapies. Based on this study, the FDA changed the label for all JAK inhibitors to be used only after an anti-TNF therapy. I follow the FDA indication and do not use JAK inhibitors before anti-TNF drugs, and I am careful not to use JAK inhibitors in patients who have cardiovascular risk factors.

There has been a lot of interest in combination therapies because, over time, some of our patients stop taking biologics and JAK inhibitors because they still have high or moderate disease activity despite taking these therapies. So far, studies of combination therapies have been negative, but combinations may still be the next best step in trying to improve disease activity. We just have not yet figured out the right combinations.

I think the key takeaways are that we have not cured RA, but earlier intervention and the use of all the drugs in our armamentarium lead to remarkable responses in more than 60% of our patients, which is fantastic. However, many of our patients with RA remain with active arthritis, so we need newer strategies and drugs.