Current issues of ACP Journal Club are published in Annals of Internal Medicine


Hydroxychloroquine was effective and safe in early rheumatoid arthritis

ACP J Club. 1995 July-Aug;123:4. doi:10.7326/ACPJC-1995-123-1-004

Source Citation

The HERA Study Group. A randomized trial of hydroxychloroquine in early rheumatoid arthritis: the HERA study. Am J Med. 1995 Feb;98:156-68.



To evaluate the safety and efficacy of hydroxychloroquine sulfate (HCQ) in patients with early rheumatoid arthritis (RA).


36-week randomized, double-blind, placebo-controlled trial.


2 hospitals and 4 community practices in Canada.


119 patients were > 18 years old (mean age 53 y, 76% women); had had RA (American Rheumatism Association [ARA] criteria) for < 2 years (mean duration 9 mo); had had persistent synovitis for ≥ 6 weeks; had ≥ 6 actively inflamed joints and ≥ 45 minutes of morning stiffness or a Wintrobe erythrocyte sedimentation rate of ≥ 25 mm/h; and had given informed consent. Exclusion criteria were ARA functional class IV disease; previous therapy with any second-line agent or antimalarial drug; use of intra-articular or systemic corticosteroids within 1 month of entry; possible retinopathy; surgery within 2 months of entry; vasculitis; the Felty syndrome; an abnormally low platelet or total leukocyte count or a polymorphonuclear leukocyte count < 1500 cells/mm3; a serum creatinine level > 1.5 mg/dL, proteinuria, or abnormal liver function test results; other serious disease; and potential for pregnancy. Follow-up was 97%.


Patients were stratified by center and received HCQ, 200 mg/d (n = 59), or placebo (n = 60). If no side effects occurred after 2 weeks, study group patients were prescribed HCQ, 7 mg/kg of body weight per day or a maximum dose of 400 mg/d. Compliance was assessed by patient interview, review of the patient diary, and pill count.

Main outcome measures

Joint synovitis, pain, physical function, and psychological function.

Main results

At 36 weeks, patients receiving HCQ, compared with patients receiving placebo, showed benefit in measures of joint synovitis (mean change from baseline in scores on the composite joint index 0.64 vs 0.31, P = 0.004), pain (mean change from baseline in scores on the composite pain index 1.11 vs 0.56, P = 0.007), and physical function (mean change from baseline in scores on the composite physical function index 0.75 vs 0.36, P = 0.02) but did not differ in measures of psychological function. The groups did not differ for adverse effects.


Hydroxychloroquine was effective in alleviating joint synovitis, pain, and physical disability but did not improve psychological status in patients with early rheumatoid arthritis.

Sources of funding: Medical Research Council and Arthritis Society of Canada.

For article reprint: Dr. J.M. Esdaile, Arthritis Society, 895 West 10th Avenue, Vancouver, BC V5Z 1L7, Canada. FAX 604-871-4501.


Contrary to previous thought, RA is not a benign disease that evolves slowly and often remits spontaneously. About 50% of patients show evidence of joint destruction within the first 2 years of disease that almost always progresses. Prescribing symptom-directed therapy, such as nonsteroidal anti-inflammatory drugs (NSAIDs), and then waiting is no longer an acceptable approach. Rather, disease-modifying antirheumatic drugs (DMARDs) should be given as early as possible in the course of RA to every patient with aggressive synovitis to prevent permanent articular damage. An ideal DMARD should be effective and have a low toxicity profile, thereby resulting in a low discontinuation rate and satisfactory long-term outcome. Several DMARDs are available, but much of the evidence supporting their use does not come from randomized, double-blind trials, and choosing among them is a clinical and often arbitrary decision (1).

The HERA investigators are to be commended for a meticulously designed and executed short-term study that clearly and convincingly shows that HCQ administration alleviates synovitis and pain and improves function in early RA. This strongly confirms previous observations of HCQ, a drug that exerts varied anti-inflammatory and immunomodulatory activities, among them selective inhibition of inflammatory cytokines (2).

HCQ may be the least toxic of currently used DMARDs. The very low frequency of adverse effects reported in this study has been previously documented. The low cost of monitoring HCQ (an ophthalmologic examination every 6 to 12 months but no need for regular blood or urine tests) is another advantage of the drug. In the future, it may be possible to identify a subset of patients with early RA and particularly aggressive disease who may be candidates for combination DMARD therapy (e.g., methotrexate plus HCQ). Meanwhile, because some patients with early RA remit spontaneously, even if not for long (as occurred in the placebo groups of this and similar studies), the addition of an effective but safe DMARD to NSAID therapy is indicated within the first weeks of disease. HCQ appears to be a good choice for this purpose.

Ami Schattner, MD
Hebrew University & Hadassah Medical SchoolJerusalem, Israel


1. Felson DT, Anderson JJ, Meenan RF. Use of short-term efficacy/toxicity tradeoffs to select second-line drugs in rheumatoid arthritis. A metaanalysis of published clinical trials. Arthritis Rheum. 1992;35:1117-25.

2. Sperber K, Quraishi H, Kalb TH, et al. Selective regulation of cytokine secretion by hydroxychloroquine: inhibition of interleukin 1 alpha (IL-1-alpha) and IL-6 in human monocytes and T cells. J Rheumatol. 1993;20:803-8.