Sjögren's: Hydroxychloroquine No Better Than Placebo

Neil Osterweil

July 15, 2014

A drug commonly prescribed for the treatment of primary Sjögren's syndrome was no better than placebo at relieving symptoms of dryness, pain, or fatigue over the course of 24 weeks, results of a randomized clinical trial show.

At 24 weeks, 17.9% of patients randomly assigned to receive hydroxychloroquine (Plaquenil, sanofi-aventis) had a 30% or greater reduction in symptoms on at least 2 of 3 analog symptom scales compared with 17.2% of patients assigned to receive a placebo, report Jacques-Eric Gottenberg, MD, PhD, from the University Hospitals Strasbourg in France, and colleagues.

"In the present study, hydroxychloroquine did not demonstrate efficacy for the main disabling symptoms — dryness, pain, and fatigue — of primary Sjögren syndrome compared with placebo," the investigators write in an article published in the July 16 issue of JAMA.

Although hydroxychloroquine, an immunomodulating agent, is the drug most frequently prescribed to treat the symptoms of arthralgia, myalgia, and fatigue in patients with Sjögren's syndrome, evidence supporting the practice has been sparse, Dr. Gottenberg said in an interview with Medscape Medical News.

"We lacked a randomized controlled trial of [hydoxychloroquine]. We all use this drug very often, and sometimes it works for some of our patients. We wanted to design a study to demonstrate it was working. The result was negative, but we can imagine in some subsets of patients this drug can still work," continued Dr. Gottenberg.

Patients with synovitis or purpura associated with high serum levels of immunoglobulin G may be most likely to benefit from treatment with hydroxychloroquine, he said. The investigators were unable to determine a skin benefit for hydroxychloroquine, however, because only 3 study patients had purpura, and all 3 were in the placebo group, Dr. Gottenberg noted.

"This is an important paper," commented Neil I. Stahl, MD, a member of the Medical & Scientific Advisory Board of the Sjögren's Syndrome Foundation, who treats patients with Sjögren's syndrome at Arthritis & Rheumatic Disease Associates, PC, in Burke, Virginia.

"We've been using hydroxychloroquine mainly for fatigue and articular symptoms in patients with Sjögren's, and we've told them that it might also help with dryness, but we weren't sure," he told Medscape Medical News.

Dr. Stahl, who was not involved in the study, agreed with Dr. Gottenberg that hydroxychloroquine may benefit patients with articular symptoms but said the benefit may have been masked by the stringent efficacy criteria used in the study: a minimum 30% improvement on 2 of 3 analog symptoms scales. In contrast, American College of Rheumatology criteria for rheumatoid arthritis consider a treatment to be effective if patients have a 20% or greater improvement in 3 of 5 categories, he noted.

Collaborative Study

Dr. Gottenberg and colleagues enrolled 120 patients from 15 university hospitals in France who had a diagnosis of primary Sjögren's syndrome according to American-European Consensus Group criteria.

The patients were randomly assigned to receive either hydroxychloroquine 400 mg/day or placebo for 24 weeks, with both investigators and patients masked to treatment assignment.

All patients then received hydroxychloroquine for an additional 24 weeks, to a total of 48 weeks. The investigators decided to give all patients the active drug for the second half of the study because "hydroxychloroquine has a progressive action, could perhaps be more efficacious long term, and is commonly prescribed in daily practice," they explain.

Among patients receiving hydroxychloroquine, the mean numeric analog scale score (from 0 for best to 10 for worst) for dryness changed from 6.53 (standard deviation [SD], 1.97) at baseline to 6.22 (SD, 1.87) at week 24 compared with 6.38 (SD, 2.14) to 5.85 (SD, 2.57) in the placebo group.

Mean scores on the pain scale decreased slightly among patients receiving hydroxychloroquine, going from 5.09 (SD, 3.06) at baseline to 4.59 (SD, 2.90) at week 24. In the placebo group, the mean pain score increased slightly, going from 4.92 (SD, 2.94) at baseline to 5.08 (SD, 2.48) at week 24.

Mean scores for fatigue for patients on the drug went from 6.00 (SD, 2.52) at baseline to 5.94 (SD, 2.40) at week 24 compared with 6.26 (SD, 2.27) to 5.72 (SD, 2.38), respectively, for patients receiving placebo.

None of the differences were statistically significant, and there were no significant differences in analog scale scores between weeks 24 and 48 for patients who were originally assigned to placebo and then received hydroxychloroquine in the extension phase.

The only significant differences between the treatment groups was a greater mean decline in erythrocyte sedimentation rate at week 24 among patients receiving hydroxychloroquine, which was related to a decrease in serum levels of immunoglobulin M.

"The fact that there was improvement in erythrocyte sedimentation rates and [immunoglobulin M] suggests that the drug may be helpful in people who have inflammatory manifestations, such as arthritis," Dr. Stahl said.

It is possible that the 6-month duration of the controlled phase of the trial was not long enough to show a difference with hydroxychloroquine, Dr. Gottenberg and Dr. Stahl both said, noting that investigators saw a nonsignificant trend in pain scale scores among patients receiving the active drug.

The study was sponsored by Assistance Publique-Hôpitaux de Paris, with a grant from the French Ministry of Research. Sanofi-aventis provided hydroxychloroquine and placebo. Dr. Gottenberg disclosed grants from Abbvie, Pfizer, and Roche and personal fees from Bristol-Myers Squibb, Merck Sharpe and Dohme, and Pfizer. One coauthor reports receiving fees for consulting from Roche; another reports receiving consulting fees from Roche, Bristol-Myers Squibb, and Pfizer and grants from the European League Against Rheumatism and GlaxoSmithKline for research on Sjögren syndrome. One coauthor reports receiving fees from Roche, Pfizer, UCB, Bristol-Myers Squibb, and GlaxoSmithKline and grants from Roche, Pfizer, Bristol-Myers Squibb, GlaxoSmithKline, and Biogen. The other authors and Dr. Stahl have disclosed no relevant financial relationships.

JAMA. 2014;312:249-258.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.