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Original Investigation |

Effects of Hydroxychloroquine on Symptomatic Improvement in Primary Sjögren Syndrome:  The JOQUER Randomized Clinical Trial

Jacques-Eric Gottenberg, MD, PhD1; Philippe Ravaud, MD, PhD2; Xavier Puéchal, MD, PhD3; Véronique Le Guern, MD3; Jean Sibilia, MD1; Vincent Goeb, MD, PhD4; Claire Larroche, MD5; Jean-Jacques Dubost, MD6; Stéphanie Rist, MD7; Alain Saraux, MD8; Valérie Devauchelle-Pensec, MD, PhD8; Jacques Morel, MD, PhD9; Gilles Hayem, MD10; Pierre Hatron, MD11; Aleth Perdriger, MD12; Damien Sene, MD, PhD13; Charles Zarnitsky, MD 14; Djilali Batouche, MSc15; Valérie Furlan, MD16; Joelle Benessiano, MD17; Elodie Perrodeau, MSc2; Raphaele Seror, MD, PhD15; Xavier Mariette, MD, PhD15
[+] Author Affiliations
1Department of Rheumatology, Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, Centre de Référence National Pour les Maladies Auto-Immunes Systémiques Rares, Université de Strasbourg, Strasbourg, France
2Department of Epidemiology and Public Health, Hotel Dieu, Assistance Publique-Hôpitaux de Paris (AP-HP), Paris, France
3Department of Internal Medicine, Cochin Hospital, AP-HP, Paris, France
4Department of Rheumatology, Amiens University Hospital, Amiens, France
5Department of Internal Medicine, Avicenne Hospital, AP-HP, Bobigny, France
6Department of Rheumatology, Clermont-Ferrand University Hospital, Clermont-Ferrand, France
7Department of Rheumatology, Orléans Hospital, Orléans, France
8Department of Rheumatology, Brest University Hospital, Brest, France
9Department of Rheumatology, Montpellier University Hospital, Montpellier, France
10Department of Rheumatology, Hôpital Bichat, AP-HP, Paris, France
11Department of Internal Medicine, Lille University Hospital, Lille, France
12Department of Rheumatology, Rennes University Hospital, Rennes, France
13Department of Internal Medicine, Lariboisère Hospital, AP-HP, Paris, France
14Department of Rheumatology, Le Havre Hospital, Le Havre, France
15Department of Rheumatology, Hôpitaux Universitaires Paris-Sud, AP-HP, INSERM U 1012, Université Paris Sud, Le Kremlin Bicêtre, France
16Department of Pharmacy, Hôpitaux Universitaires Paris-Sud, AP-HP, Le Kremlin Bicêtre, France
17Department of Centre de Ressources Biologiques, Bichat Hospital, AP-HP, Paris, France
JAMA. 2014;312(3):249-258. doi:10.1001/jama.2014.7682.
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Importance  Primary Sjögren syndrome is a systemic autoimmune disease characterized by mouth and eye dryness, pain, and fatigue. Hydroxychloroquine is the most frequently prescribed immunosuppressant for the syndrome. However, evidence regarding its efficacy is limited.

Objective  To evaluate the efficacy of hydroxychloroquine for the main symptoms of primary Sjögren syndrome: dryness, pain, and fatigue.

Design, Setting, and Participants  From April 2008 to May 2011, 120 patients with primary Sjögren syndrome according to American-European Consensus Group Criteria from 15 university hospitals in France were randomized in a double-blind, parallel-group, placebo-controlled trial. Participants were assessed at baseline, week 12, week 24 (primary outcome), and week 48. The last follow-up date for the last patient was May 15, 2012.

Interventions  Patients were randomized (1:1) to receive hydroxychloroquine (400 mg/d) or placebo until week 24. All patients were prescribed hydroxychloroquine between weeks 24 and 48.

Main Outcomes and Measures  The primary end point was the proportion of patients with a 30% or greater reduction between weeks 0 and 24 in scores on 2 of 3 numeric analog scales (from 0 [best] to 10 [worst]) evaluating dryness, pain, and fatigue.

Results  At 24 weeks, the proportion of patients meeting the primary end point was 17.9% (10/56) in the hydroxychloroquine group and 17.2% (11/64) in the placebo group (odds ratio, 1.01; 95% CI, 0.37-2.78; P = .98). Between weeks 0 and 24, the mean (SD) numeric analog scale score for dryness changed from 6.38 (2.14) to 5.85 (2.57) in the placebo group and 6.53 (1.97) to 6.22 (1.87) in the hydroxychloroquine group. The mean (SD) numeric analog scale score for pain changed from 4.92 (2.94) to 5.08 (2.48) in the placebo group and 5.09 (3.06) to 4.59 (2.90) in the hydroxychloroquine group. The mean (SD) numeric analog scale for fatigue changed from 6.26 (2.27) to 5.72 (2.38) in the placebo group and 6.00 (2.52) to 5.94 (2.40) in the hydroxychloroquine group. All but 1 patient in the hydroxychloroquine group had detectable blood levels of the drug. Hydroxychloroquine had no efficacy in patients with anti-SSA autoantibodies, high IgG levels, or systemic involvement. During the first 24 weeks, there were 2 serious adverse events in the hydroxychloroquine group and 3 in the placebo group; in the last 24 weeks, there were 3 serious adverse events in the hydroxychloroquine group and 4 in the placebo group.

Conclusions and Relevance  Among patients with primary Sjögren syndrome, the use of hydroxychloroquine compared with placebo did not improve symptoms during 24 weeks of treatment. Further studies are needed to evaluate longer-term outcomes.

Trial Registration  clinicaltrials.gov Identifier: NCT00632866

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Figure 1.
Flowchart of the Study of Hydroxychloroquine for Symptoms of Primary Sjögren Syndrome
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Figure 2.
Sensitivity Analyses of the Evolution in Numeric Analog Scale Scores for Pain, Fatigue, and Dryness Among Patients With Primary Sjögren Syndrome

The numeric analog scale ranges from 0 (best) to 10 (worst). MCII indicates minimally clinically important improvement. Actual values of odds ratio are plotted on a log scale.

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