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Original Research |

Treatment of Primary Sjögren Syndrome With Rituximab: A Randomized Trial

Valérie Devauchelle-Pensec, MD, PhD; Xavier Mariette, MD, PhD; Sandrine Jousse-Joulin, MD; Jean-Marie Berthelot, MD; Aleth Perdriger, MD, PhD; Xavier Puéchal, MD, PhD; Véronique Le Guern, MD, PhD; Jean Sibilia, MD, PhD; Jacques-Eric Gottenberg, MD, PhD; Laurent Chiche, MD, PhD; Eric Hachulla, MD, PhD; Pierre Yves Hatron, MD; Vincent Goeb, MD, PhD; Gilles Hayem, MD; Jacques Morel, MD, PhD; Charles Zarnitsky, MD; Jean Jacques Dubost, MD; Jacques Olivier Pers, MD, PhD; Emmanuel Nowak, PhD; and Alain Saraux, MD, PhD
[+] Article and Author Information

From Centre Hospitalier Universitaire de la Cavale Blanche, Université Bretagne Occidentale, Centre Hospitalier Universitaire Morvan, and Institut National de la Santé et de la Recherche Médicale, Centre d’Investigation Clinique 0502, Centre Hospitalier Universitaire Brest, Brest, France; Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, Institut National de la Santé et de la Recherche Médicale U1012, Université Paris-Sud, Le Kremlin Bicêtre; Hôtel-Dieu, Centre Hospitalier Universitaire Nantes, Nantes; Centre Hospitalier Universitaire Hôpital Sud, Rennes; Centre Hospitalier du Mans, Le Mans; Hopital Cochin and Hôpital Bichat, Paris; Hôpitaux Universitaires de Strasbourg, Université de Strasbourg, Strasbourg; Hôpital de la Conception, Marseille; Claude Huriez Hospital, Lille2 University, Lille; Centre Hospitalier de Rouen, Bois-Guillaume; Centre Hospitalier Universitaire Lapeyronie, Montpellier; Centre Hospitalier Monod, Montivilliers; Gabriel Montpied Teaching Hospital, Place H. Dunant, Clermont-Ferrand.

Acknowledgment: The authors thank the physicians who recruited the patients (Loic Guillevin [Paris Cochin], Olivier Meyer [Paris Bichat], Mohamed Hamidou [Nantes], Olivier Vittecoq [Rouen], and Didier Alcaix [Le Havre)]; the coordinators of the ophthalmologic evaluations (Béatrice Cochener [Brest]), pathologic studies (Isabelle Quintin-Roué [Brest]), and immunologic tests (Yves Renaudineau and Christophe Jamin [Brest]); and the team that organized and supervised the study (particularly Valentine Guiton, Lucie Auzanneau, Hélène Fortin-Prunier, Nathalie Bihannic, Elise Poulhazan, and Marie Jezequel at Centre Hospitalier Universitaire Brest). They also thank Raphaël Porcher (Centre d’Epidémiologie Clinique, Hôtel-Dieu, Paris), Agnès Caille and Bruno Giraudeau (Groupement Interrégional de Recherche Clinique et d’Innovation Grand Ouest), and Maelenn Gouillou (Centre d’Investigation Clinique de Brest) for constructive discussions on statistics. Finally, the authors thank the patients who participated in the TEARS study and the rheumatologists and internists who referred their patients to the study.

Financial Support: By the Programme Hospitalier de Recherche Clinique 2010. Rituximab was donated free of charge by Roche (Boulogne Billancourt, France).

Potential Conflicts of Interest: Disclosures can be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M13-1085.

Reproducible Research Statement: Study protocol and statistical code: Available from the authors (e-mail, alain.saraux@chu-brest.fr). Data set: Available to the public after publication of the results obtained by merging this data set with those of the TRACTISS (Trial of Anti-B-Cell Therapy in Patients With Primary Sjögren's Syndrome) trial, which is ongoing.

Requests for Single Reprints: Alain Saraux, MD, PhD, Rheumatology Unit, Hôpital de la Cavale Blanche, BP 824, F 29609 Brest Cedex, France; e-mail, alain.saraux@chu-brest.fr.

Current Author Addresses: Drs. Devauchelle-Pensec, Jousse-Joulin, and Saraux: Service de Rhumatologie, Centre Hospitalier Universitaire de la Cavale Blanche, Boulevard Tanguy Prigent, 29609 Brest, France.

Dr. Mariette: Service de Rhumatologie, Assistance Publique-Hôpitaux de Paris, Hôpitaux Universitaires Paris-Sud, 78 Rue du Général Leclerc, 94275 Le Kremlin Bicêtre, France.

Dr. Berthelot: Service de Rhumatologie, Hôtel-Dieu, Centre Hospitalier Universitaire Nantes, 44093, Nantes Cedex 01, France.

Dr. Perdriger: Service de Rhumatologie, Centre Hospitalier Universitaire Hôpital Sud, 35 000 Rennes, France.

Drs Puéchal and Le Guern: National Referral Center for Rare Systemic Autoimmune Diseases, 27 Rue du Faubourg Saint Jacques, 75014 Cochin Hospital, France.

Drs. Sibilia and Gottenberg: Service de Rhumatologie, Hôpitaux Universitaires de Strasbourg, 1 Avenue Molière, 67098 Strasbourg Cedex, France.

Dr. Chiche: Service de Médecine Interne, Hôpital de la Conception, 147 Boulevard Baille, 13005 Marseille, France.

Drs. Hachulla and Hatron: Department of Internal Medicine, Claude Huriez Hospital, Lille2 University, 59037 Lille Cedex, France.

Dr. Goeb: Service de Rhumatologie, Centre Hospitalier Universitaire d'Amiens, Place Victor Pauchet 80054 Amiens Cedex 1, France.

Dr. Hayem: Service de Rhumatologie, Hôpital Bichat, 46 Rue Henri Huchard, 75877 Paris Cedex 18, France.

Dr. Morel: Service d’Immuno-Rhumatologie, Centre Hospitalier Universitaire Lapeyronie, 34 295 Montpellier, France.

Dr. Zarnitsky: Service de Rhumatologie, Centre Hospitalier Monod, Montivilliers, France.

Dr. Dubost: Rheumatology Department, Gabriel Montpied Teaching Hospital, Place H. Dunant, Clermont-Ferrand 63000, France.

Dr. Pers: Odontology, Centre Hospitalier Universitaire Morvan, 29609 Brest, France and EA 2216, Université Bretagne Occidentale, 29200 Brest, France.

Dr. Nowak: Institut National de la Santé et de la Recherche Médicale, Centre d’Investigation Clinique 0502, Centre Hospitalier Universitaire de la Cavale Blanche, Boulevard Tanguy Prigent, 29609 Brest, France.

Author Contributions: Conception and design: V. Devauchelle-Pensec, X. Mariette, S. Jousse-Joulin, X. Puéchal, V. Le Guern, J. Sibilia, J.E. Gottenberg, J.O. Pers, E. Nowak, A. Saraux.

Analysis and interpretation of the data: V. Devauchelle-Pensec, X. Mariette, S. Jousse-Joulin, J. Sibilia, J.E. Gottenberg, L. Chiche, E. Hachulla, J.O. Pers, E. Nowak, A. Saraux.

Drafting of the article: V. Devauchelle-Pensec, X. Mariette, J. Sibilia, L. Chiche, E. Nowak, A. Saraux.

Critical revision of the article for important intellectual content: V. Devauchelle-Pensec, X. Mariette, J.M. Berthelot, J. Sibilia, J.E. Gottenberg, E. Hachulla, J.O. Pers, A. Saraux.

Final approval of the article: V. Devauchelle-Pensec, X. Mariette, S. Jousse-Joulin, A. Perdriger, X. Puéchal, V. Le Guern, J. Sibilia, J.E. Gottenberg, L. Chiche, E. Hachulla, P.Y. Hatron, V. Goeb, G. Hayem, J. Morel, J.J. Dubost, J.O. Pers, E. Nowak, A. Saraux.

Provision of study materials or patients: V. Devauchelle-Pensec, X. Mariette, S. Jousse-Joulin, J.M. Berthelot, X. Puéchal, V. Le Guern, J.E. Gottenberg, L. Chiche, E. Hachulla, P.Y. Hatron, V. Goeb, G. Hayem, J. Morel, C. Zarnitsky, A. Saraux.

Statistical expertise: V. Devauchelle-Pensec, E. Nowak, A. Saraux.

Obtaining of funding: A. Saraux.

Administrative, technical, or logistic support: V. Devauchelle-Pensec, L. Chiche, V. Goeb, A. Saraux.

Collection and assembly of data: V. Devauchelle-Pensec, X. Mariette, J.M. Berthelot, A. Perdriger, X. Puéchal, V. Le Guern, J. Sibilia, J.E. Gottenberg, L. Chiche, E. Hachulla, V. Goeb, J.J. Dubost, A. Saraux.


Ann Intern Med. 2014;160(4):233-242. doi:10.7326/M13-1085
Text Size: A A A

Background: Primary Sjögren syndrome (pSS) is an autoimmune disorder characterized by ocular and oral dryness or systemic manifestations.

Objective: To evaluate efficacy and harms of rituximab in adults with recent-onset or systemic pSS.

Design: Randomized, placebo-controlled, parallel-group trial conducted between March 2008 and January 2011. Study personnel (except pharmacists), investigators, and patients were blinded to treatment group. (ClinicalTrials.gov: NCT00740948)

Setting: 14 university hospitals in France.

Patients: 120 patients with scores of 50 mm or greater on at least 2 of 4 visual analogue scales (VASs) (global disease, pain, fatigue, and dryness) and recent-onset (<10 years) biologically active or systemic pSS.

Intervention: Randomization (1:1 ratio) to rituximab (1 g at weeks 0 and 2) or placebo.

Measurements: Primary end point was improvement of at least 30 mm in 2 of 4 VASs by week 24.

Results: No significant difference between groups in the primary end point was found (difference, 1.0% [95% CI, −16.7% to 18.7%]). The proportion of patients with at least 30-mm decreases in at least two of the four VAS scores was higher in the rituximab group at week 6 (22.4% vs. 9.1%; P = 0.036). An improvement of at least 30 mm in VAS fatigue score was more common with rituximab at weeks 6 (P < 0.001) and 16 (P = 0.012), and improvement in fatigue from baseline to week 24 was greater with rituximab. Adverse events were similar between groups except for a higher rate of infusion reactions with rituximab.

Limitation: Low disease activity at baseline and a primary outcome that may have been insensitive to detect clinically important changes.

Conclusion: Rituximab did not alleviate symptoms or disease activity in patients with pSS at week 24, although it alleviated some symptoms at earlier time points.

Primary Funding Source: Programme Hospitalier de Recherche Clinique 2010.

Figures

Grahic Jump Location
Figure 1.

Study flow diagram.

pSS = primary Sjögren syndrome; VAS = visual analogue scale.

* Primary outcome is improvement in ≥2 of 4 VAS scores at week 24.

Grahic Jump Location
Grahic Jump Location
Figure 2.

LSMs and 95% CIs for VAS scores for global disease, pain, fatigue, and dryness after adjustment for baseline characteristics (mixed model) in the rituximab(solid line) and placebo (dotted line) groups.

LSM = least-squares mean; VAS = visual analogue scale.

* Global P values are based on type III test evaluated with longitudinal regression analyses.

Grahic Jump Location

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Comments

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Rituximab for Sjögren’s Syndrome
Posted on March 20, 2014
Denise Faustman, M.D., Ph.D., Frederick B. Vivino, M.D., Steven E. Carsons, M.D.
Harvard Medical School, Penn Presbyterian Medical Center University of Pennsylvania, Winthrop University Hospital Stony Brook School of Medicine
Conflict of Interest: Denise Faustman, M.D., Ph.D. - No potential conflicts to report

Frederick B. Vivino, M.D. - Consultant: Daiichi Sankyo, Parion Sciences, Biogen Idec, Takeda Pharmaceuticals.

Steven E. Carsons, M.D. - Grants: Amgen Inc., Janssen Pharmaceuticals. Consultant Biogen Idec.
Devauchelle-Pensec et al (1) conclude that their data do not support the use of rituximab in the majority of patients with recent onset or systemic primary Sjögren’s syndrome (pSS). We agree with the authors that the best outcome measure for assessing treatment efficacy in pSS is debatable. ESSDAI is a major step toward the development of standardized outcome measures for pSS; however does not incorporate assessments of dryness. ESSDAI is responsive to disease activity in RTX treated pSS (2) when examined in a prospective single center trial; however, ESSDAI has not been extensively validated in controlled trials. The primary outcome measure reported by Devauchelle-Pensec is attainment of a 30mm improvement from baseline at week 24, on a VAS scale for 2 of 4 measures derived from expert opinion. If a subject had a baseline VAS of 51mm, a 30 mm improvement would amount to a 60% response. As the editors’ caution, outcome measurements may have been insensitive for detecting improvement. A dryness VAS may not capture improvement in moisture production, nor subsequent amelioration of tissue damage as was demonstrated for salivary flow and lissamine green staining in a smaller randomized controlled trial of rituximab in pSS (3). Devauchelle-Pensec reports significant improvement for individual outcome measures in their study which utilized 2 RTX infusions 14 days apart. Fig. 2 demonstrates improvement (global P =0.022) in VAS for dryness when analyzed longitudinally after adjustment for baseline characteristics.
The optimal RTX regimen required to demonstrate improvement in pSS is unclear. Salivary gland B cells deplete by 16 weeks following 2 RTX infusions and repopulate by 52 weeks (4). However, exactly when during this interval repopulation occurs is unknown. Pers et al. suggest that increasing the number of RTX infusions may prolong tissue B cell depletion. Carubbi et al. (5) demonstrated significant improvement by administering RTX at 24 week intervals, resulting in subjects receiving ~ 5 RTX cycles over 120 weeks. This cohort had a disease duration of 1 year compared to 5-6 years reported by Devauchelle-Pensec (1) and Meijer (4 ) and these subjects had a higher baseline ESSDAI (19.8) compared to 10.0 (1). As we believe that B cell depletion may be considered as a therapeutic option for certain patients with pSS, the issues mentioned above underscore the need for continued development of sensitive and reproducible outcome measures for pSS as well as further study of B cell depletion regimens.

Sincerely,

Denise L. Faustman, M.D., Ph.D.
Harvard Medical School
Chair, Medical and Scientific Advisory Board, Sjögren’s Syndrome Foundation

Frederick B. Vivino, M.D.
Penn Presbyterian Medical Center, University of Pennsylvania Health System
Past Chair, Medical and Scientific Advisory Board, Sjögren’s Syndrome Foundation

Steven E. Carsons, M.D.
Winthrop-University Hospital, Stony Brook University School of Medicine
Past Chair, Medical and Scientific Advisory Board, Sjögren’s Syndrome Foundation

References
1. Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puechal X, Le Guern V, Sibilia J, Gottenberg JE, Chiche L, Hachulla E, Hatron PY, Goeb V, Hayem G, Morel J, Zamitsky C, Dubost JJ, Pers JO, Nowak E, Saraux A. Treatment of Primary Sjögren’s Syndrome With Rituximab. A Randomized Trial. Ann Intern Med. 2014;160:233-242
2. Meiners PM, Arends S, Brouwer E, Spijkervet FKL, Vissink A, Bootsma H. Responsiveness of disease activity indices ESSPRI and ESSDAI in patients with primary Sjögren’s syndrome treated with rituximab. Ann Rheum Dis. 2012;71:1297-1302.
3. Meijer JM, Meiners PM, Vissink A, Spijkervet FKL, Abdulahad W, Kamminga N, Brouwer E, Kallenberg CGM, Bootsma H. Effectiveness of Rituximab Treatment in Primary Sjögren’s Syndrome. A Randomized, Double-Blind, Placebo-Controlled Trial. Arthritis Rheum. 2010;62 (4) 960-968.
4. Pers JO, Devauchelle V, Daridon C, Bendaoud B, Le Berre R, Bordron A, Hutin P, Renaudineau Y, Dueymes M, Loisel S, Berthou C, Saraux A, Youinou P. BAFF-Modulated Repopulation of B Lymphocytes in the Blood and Salivary Glands of Rituximab-Treated Patients with Sjögren’s Syndrome. Arthritis Rheum. 2007;56(5):1464-1477.
5. Carubbi F, Cipriani P, Marrelli A, DiBenedetto P, Ruscitti P, Berardicurti O, Pantano I, Liakouli V, Alvaro S, Alunno A, Manzo A, Ciccia F, Gerli R, Triolo G, Giacomelli R. Efficacy and safety of rituximab treatment in early Sjogren’s syndrome: a prospective, multi-center, follow-up study. Arthritis Research & Therapy 2013,15:R172
Author's Response
Posted on April 21, 2014
Alain Saraux MD, PhD, Emmanuel Nowak, PhD and Valerie Devauchelle-Pensec, MD, PhD
Brest University Medical Center
Conflict of Interest: None Declared
We thank D Faustman, F Vivino, and S Carsons for their comment about our article. We fully agree that the ideal primary endpoint for assessing treatment efficacy in pSS remains unknown and that the best option among those available to date (visual analog score [VAS], ESSPRI (1), ESSDAI (2), and physician opinion) is undecided. We also concur that the best cutoff for defining a VAS score improvement in millimeters or percentage cannot be reliably determined, as we have no data on the minimal clinically important differences (MCID) for these measures. Therefore, there is no sound basis on which to found the selection of patients for biologic treatment, choose the best treatment regimen (rituximab dosage, concomitant medications, re-treatment), or chose the primary efficacy endpoint for assessing treatments.
The TEARS study (3) is the first large randomized study showing a small but rapid effect of rituximab on fatigue and a delayed response on sicca with substantial variability in the response (Figure 1). Post hoc analyses of the results will be of use to define parameters for future studies. The effects of rituximab in the TEARS study invites a discussion about the usefulness of new studies of anti-B-cell treatments in pSS. Our feeling is that such studies are needed to obtain definite conclusions and should benefit from the TEARS experience. The TEARS data indicate that using fatigue and/or sicca at week 6, or perhaps later in the event of re-treatment, as the primary objective would be expected to show an effect of rituximab. However, we need evidence on which to base cutoff values. Also needed are new validated efficacy criteria, including objective signs; and an evaluation of the relevance of these criteria for patients, clinicians, and payers.
We anticipate that the ongoing TRACTISS protocol (4) will show efficacy of rituximab, given the patient inclusion criteria and the use, as the primary endpoint, of a 30% improvement in the VAS for fatigue or oral dryness. Our objectives now, which we are pursuing in collaboration with physicians and researchers previously involved in metrology assessments in pSS, are as follows: (a) to determine, before the end of TRACTISS, the MCIDs for both ESSDAI and ESSPRI, to allow an assessment of the relevance of the TRACTISS protocol results; (b) to suggest a new primary efficacy endpoint based on a post hoc analysis of the TEARS study data then to apply this primary endpoint to TRACTISS results; and (c) to use data from both the ASSESS cohort (5) and the TEARS study (3) to estimate the required sample size for future studies in pSS according to the chosen primary endpoint.

References
1- Seror R, Ravaud P, Mariette X, Bootsma H, Theander E, Hansen A, Ramos-Casals M, Dörner T, Bombardieri S, Hachulla E, Brun JG, Kruize AA, Praprotnik S, Tomsic M, Gottenberg JE, Devauchelle V, Devita S, Vollenweider C, Mandl T, Tzioufas A, Carsons S, Saraux A, Sutcliffe N, Vitali C, Bowman SJ; EULAR Sjögren's Task Force. EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI): development of a consensus patient index for primary Sjogren's syndrome. Ann Rheum Dis. 2011 Jun;70(6):968-72. doi: 10.1136/ard.2010.143743. Epub 2011 Feb 22.
2- Seror R, Ravaud P, Bowman SJ, Baron G, Tzioufas A, Theander E, Gottenberg JE, Bootsma H, Mariette X, Vitali C; EULAR Sjögren's Task Force EULAR Sjogren's syndrome disease activity index: development of a consensus systemic disease activity index for primary Sjogren's syndrome. Ann Rheum Dis. 2010 Jun;69(6):1103-9. doi: 10.1136/ard.2009.110619. Epub 2009 Jun 28. Erratum in: Ann Rheum Dis. 2011 May;70(5):880.
3- Devauchelle-Pensec V, Mariette X, Jousse-Joulin S, Berthelot JM, Perdriger A, Puechal X, Le Guern V, Sibilia J, Gottenberg JE, Chiche L, Hachulla E, Hatron PY, Goeb V, Hayem G, Morel J, Zamitsky C, Dubost JJ, Pers JO, Nowak E, Saraux A. Treatment of Primary Sjögren’s Syndrome With Rituximab. A Randomized Trial. Ann Intern Med. 2014;160:233-242
4- Brown S, Navarro Coy N, Pitzalis C, Emery P, Pavitt S, Gray J, Hulme C, Hall F, Busch R, Smith P, Dawson L, Bombardieri M, Wan-Fai N, Pease C, Price E, Sutcliffe N, Woods C, Ruddock S, Everett C, Reynolds C, Skinner E, Poveda-Gallego A, Rout J, Macleod I, Rauz S, Bowman S; TRACTISS trial team. The TRACTISS protocol: a randomised double blind placebo controlled clinical trial of anti-B-cell therapy in patients with primary Sjögren's Syndrome. BMC Musculoskelet Disord. 2014 Jan 17;15:21.
5- Tobón GJ, Saraux A, Gottenberg JE, Quartuccio L, Fabris M, Seror R, Devauchelle-Pensec V, Morel J, Rist S, Mariette X, De Vita S, Youinou P, Pers JO. Role of Fms-like tyrosine kinase 3 ligand as a potential biologic marker of lymphoma in primary Sjögren's syndrome. Arthritis Rheum. 2013 Dec;65(12):3218-27.

Alain Saraux, Emmanuel Nowak and Valerie Devauchelle-Pensec
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Summary for Patients

Does Rituximab Help Patients With Primary Sjögren Syndrome?

The full report is titled “Treatment of Primary Sjögren Syndrome With Rituximab. A Randomized Trial.” It is in the 18 February 2014 issue of Annals of Internal Medicine (volume 160, pages 233-242). The authors are V. Devauchelle-Pensec, X. Mariette, S. Jousse-Joulin, J.M. Berthelot, A. Perdriger, X. Puéchal, V. Le Guern, J. Sibilia, J.E. Gottenberg, L. Chiche, E. Hachulla, P.Y. Hatron, V. Goeb, G. Hayem, J. Morel, C. Zarnitsky, J.J. Dubost, J.O. Pers, E. Nowak, and A. Saraux.

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