Can I add hydroxychloroquine to my rheumatoid arthritis regimen of methotrexate and upadacitinib?

Adding Hydroxychloroquine to Methotrexate and Upadacitinib

Yes, you can add hydroxychloroquine to your current regimen of methotrexate and upadacitinib, but this combination is not evidence-based and offers no meaningful clinical benefit. Hydroxychloroquine has weak disease-modifying effects and no proven structural efficacy in rheumatoid arthritis, making it an inappropriate addition when you are already on a potent JAK inhibitor like upadacitinib 1, 2.

Why This Combination Is Not Recommended

Hydroxychloroquine is reserved for patients with very mild disease or as part of triple conventional DMARD therapy (methotrexate + sulfasalazine + hydroxychloroquine) in patients who have not yet escalated to biologic or JAK inhibitor therapy 1, 2. Once you have progressed to a targeted synthetic DMARD like upadacitinib, adding hydroxychloroquine provides no additional disease control and does not align with treat-to-target principles 1, 2.

Evidence Against This Combination

• The European League Against Rheumatism and American College of Rheumatology guidelines state that hydroxychloroquine has limited clinical efficacy and no structural benefit in preventing joint damage 1, 2, 3
• Hydroxychloroquine is appropriate only in three specific scenarios: (1) patients with very mild disease activity and low propensity for joint destruction, (2) as part of triple therapy (methotrexate + sulfasalazine + hydroxychloroquine) when escalating from methotrexate monotherapy before starting biologics or JAK inhibitors, or (3) when methotrexate is contraindicated and you need an alternative conventional DMARD 1, 2
• You are already on upadacitinib, a JAK inhibitor that provides potent intracellular signaling blockade—adding hydroxychloroquine to this regimen has no evidence base and will not enhance your disease control 1, 2

What You Should Do Instead

Optimize Your Current Regimen

• Ensure your methotrexate dose is optimized at 25–30 mg weekly with folic acid supplementation 1, 2, 3
• If you are taking oral methotrexate and experiencing inadequate response or gastrointestinal side effects, switch to subcutaneous administration, which shows higher ACR20 response rates (85% vs 77% oral) 1
• Continue upadacitinib at the prescribed dose and monitor disease activity every 1–3 months using validated composite measures (DAS28, SDAI, or CDAI) 4, 1, 2

Treatment Targets and Monitoring

• Your therapeutic goal should be sustained remission (SDAI ≤ 3.3 or CDAI ≤ 2.8) or low disease activity (SDAI ≤ 11 or CDAI ≤ 10) 1, 2, 3
• Expect at least 50% improvement in disease activity within 3 months of any therapeutic change; if this is not achieved, your regimen must be adjusted 1, 2, 3
• The treatment target must be reached within 6 months—failure to do so mandates further escalation or modification 1, 2, 3

If Your Disease Remains Active

• If you have not achieved adequate disease control on methotrexate plus upadacitinib after 3–6 months, consider switching to a biologic DMARD (TNF inhibitor, IL-6 receptor antagonist, or abatacept) combined with methotrexate 1, 2, 3
• After JAK inhibitor failure, switching to a biologic with a different mechanism of action is preferred over adding ineffective conventional DMARDs like hydroxychloroquine 1, 2, 3

Critical Pitfalls to Avoid

• Do not add hydroxychloroquine when you are already on a JAK inhibitor—this delays recognition of treatment failure and does not improve outcomes 1, 2
• Do not continue ineffective therapy—if no improvement by 3 months or target not reached by 6 months, therapy must be adjusted 1, 2, 3
• Do not use hydroxychloroquine as first-line monotherapy or as an add-on to advanced therapies when methotrexate optimization or biologic switching is appropriate 1, 2

Perioperative Consideration

• If you are planning elective total hip or knee arthroplasty, hydroxychloroquine can be continued through surgery without interruption, whereas upadacitinib should be withheld for at least 3 days prior to surgery 4