Hydroxychloroquine for Everyone Save

Nearly 25 years ago, while lecturing on best therapies for rheumatoid arthritis (RA), I loudly stated that hydroxychloroquine was “useless” and, deservedly, I was “boo-ed” off stage. My point then was that rheumatologists needed to be aggressive, if not overly aggressive, in treating all RA patients. And my view was that HCQ was representative of under-treatment.

I have reconsidered the use of HCQ in RA substantially in the last few years, based on its merit. This has been most obvious in treating lupus patients where HCQ is uniformly recommended in all SLE patients because of its tremendous up-side benefits with very little safety risks or cost.

Hence, in lupus HCQ use leads to fewer flares, better disease control, improved survival, less pregnancy loss, anti-thrombotic effects, anti-diabetogenic effects and significant lowering of plasma lipids. Moreover, recent 2024 ACR Guidelines for Lupus nephritis strongly recommend that HCQ is a key background agent upon which they build “Triple Therapy” (Steroid + 2 other immunosuppressive regimens). In the 1980s and 1990s, HCQ gained popularity as part of the TRIPLE DMARD regimen (HCQ, SSZ & MTX) advocated by O’Dell and the RAIN investigators. In several trials, it was shown that two DMARDs (including the addition of HCQ) were superior to monotherapy with MTX alone.

The 2021 ACR Guidelines for the Treatment of Rheumatoid Arthritis strongly prefer MTX to HCQ as monotherapy for RA management, primarily because of its superior disease-modifying effects. On the other hand, with there is a need for combination DMARD therapy, the ACR conditionally recommends the addition of HCQ, primarily because of its superior tolerability and safety.

While no one claims HCQ is integral in preventing structural joint damage in RA, when it is used with other csDMARDs or b/tsDMARDs, optimal clinical (e.g., LDA or remission) and radiographic (no progression) is to be expected in most.

For these reasons alone, every RA patient should be on HCQ, preferably in combination with other DMARDS.

This becomes a no brainer if we examine whether the effects seen with HCQ in lupus are also evidence in RA?

YES, is the resounding answer, as evidenced in RA studies below:

• Less Flares: in the 1995 HERA (early RA) trial, HCQ was superior to placebo, and the HCQ group required less interventional intraarticular steroid injections. A study by Clegg et al showed that chronic HCQ therapy in RA significantly reduced RA flares.
• More Remissions: most studies of MTX+HCQ have shown significantly better clinical outcomes compared to non-HCQ regimens. Also, data from the tREACH and Leiden early RA clinic shows that biologic treated patients never achieved remission, yet those not requiring biologics, often achieved remission on csDMARDs (including HCQ).
• Improved RA Survival: several studies have documented a significantly reduced mortality risk among HCQ users. Clinical Rheumatology published a lower risk of all-cause mortality when comparing HCQ to non-users (HR 0.54; 95% CI: 0.45- 0.64). RA patients taking HCQ for more than 36 consecutive months were 70% less likely to have an incident cardiovascular event than those not taking it.
• Better Pregnancy Outcomes: ACR Reproductive Guidelines and numerous authorities state that HCQ can be used safely in pregnancy to control maternal disease activity without harm to the fetus.
• Anti-thrombotic effects: a TriNetX EMR study of >2 million patients showed that HCQ significantly lowered the risk of MACE (HR 0.827), cerebral infarction (HR 0.824), and acute MI (HR 0.9).
• Anti-Diabetogenic effects: A meta-analysis of 15 studies showed that HCQ (and TNFi, MTX) lowered the risk of incident diabetes (meta-HR 0.61)
• Lipid lowering effects: Meta-analysis in the Annals of the Rheumatic Diseases shows HCQ improves Lipid profiles and significantly reduces cardiovascular events in RA patients.

Why put every RA patient on HCQ?

1. Its efficacy and safety and cost profile is unmatched
2. HCQs added benefits (flares, mortality, lipids, diabetes, CV events) are a gigantic plus for severe chronic inflammatory patients like RA.
3. Over time, RA is incredibly hard to control. To add this simple but powerful agent can only increase each patients chance at an optimal long-term outcome.

References

Adams EM, Yocum DE, Bell CL. Hydroxychloroquine in the treatment of rheumatoid arthritis. Am J Med. 1983 Aug;75(2):321-6. A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA Study.

Am J Med. 1995 Feb;98(2):156-68. Heutz JW, de Jong PHP, Verstappen M, van der Helm-van Mil AHM, van Mulligen E. Sustained DMARD-free remission in subgroups of patients with rheumatoid arthritis: an analysis of two prospective cohorts with early arthritis. Lancet Rheumatol. 2025
Apr;7(4): e252-e260.

Clegg DO, Dietz F, Duffy J, Willkens RF, Hurd E, Germain BF, Wall B, Wallace DJ, Bell CL, Sleckman J. Safety and efficacy of hydroxychloroquine as maintenance therapy for rheumatoid arthritis after combination therapy with methotrexate and hydroxychloroquine. J Rheumatol. 1997 Oct;24(10):1896-902.

Cordova Sanchez A, Khokhar F, Olonoff DA, Carhart RL. Hydroxychloroquine and Cardiovascular Events in Patients with Rheumatoid Arthritis. Cardiovasc Drugs Ther. 2024 Apr;38(2):297-304. Rempenault C, Combe B, Barnetche T, Gaujoux-Viala C, Lukas C, Morel J, Hua C. Metabolic and cardiovascular benefits of hydroxychloroquine in patients with rheumatoid arthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2018 Jan;77(1):98-103

Xie W, Yang X, Ji L, Zhang Z. Incident diabetes associated with hydroxychloroquine, methotrexate, biologics and glucocorticoids in rheumatoid arthritis: A systematic review and meta-analysis. Semin Arthritis Rheum. 2020 Aug;50(4):598-607