Arends, Suzanne

Bootsma, Hendrika

Meijer, Jiska M

Meiners, Petra M

Moerman, Rada V

Spijkervet, Fred

Vissink, Arjan

English

ARTS repository - University of Groningen

   University of GroningenEfficacy of retreatment with rituximab in patients with primary Sjögren's syndromeMeiners, Petra M; Arends, Suzanne; Meijer, Jiska M; Moerman, Rada V; Spijkervet, Fred;Vissink, Arjan; Bootsma, HendrikaPublished in:Clinical and Experimental RheumatologyIMPORTANT NOTE: You are advised to consult the publisher's version (publisher's PDF) if you wish to cite fromit. Please check the document version below.Document VersionPublisher's PDF, also known as Version of recordPublication date:2015Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):Meiners, P. M., Arends, S., Meijer, J. M., Moerman, R. V., Spijkervet, F., Vissink, A., & Bootsma, H. (2015).Efficacy of retreatment with rituximab in patients with primary Sjögren's syndrome. Clinical andExperimental Rheumatology, 33(3), 443-444. http://europepmc.org/abstract/med/25897541CopyrightOther than for strictly personal use, it is not permitted to download or to forward/distribute the text or part of it without the consent of theauthor(s) and/or copyright holder(s), unless the work is under an open content license (like Creative Commons).The publication may also be distributed here under the terms of Article 25fa of the Dutch Copyright Act, indicated by the “Taverne” license.More information can be found on the University of Groningen website: https://www.rug.nl/library/open-access/self-archiving-pure/taverne-amendment.Take-down policyIf you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediatelyand investigate your claim.Downloaded from the University of Groningen/UMCG research database (Pure): http://www.rug.nl/research/portal. For technical reasons thenumber of authors shown on this cover page is limited to 10 maximum.Download date: 08-06-2022443Letters to the EditorsEfficacy of retreatment with rituximab in patients with primary Sjögren’s syndrome Sirs,In primary Sjögren’s syndrome (pSS), the majority of open-label studies and ran-domised controlled trials (RCT) showed the efficacy of rituximab in improving objective signs of disease activity, patients’ symptoms, and health-related quality of life. Most alle-viation of symptoms was observed within 24 weeks of treatment (1, 2). The beneficial ef-fect on salivary flow seemed to be dependent on the residual function of the glands (1).  Recently, Gottenberg et al. found good phy-sician-reported efficacy and tolerance dur-ing retreatment with rituximab in 41 initially responding pSS patients (3). Furthermore, Carubbi et al. showed sustained clinical response and a good safety profile during 6 courses of rituximab (given every 24 weeks) in 19 early pSS patients with active disease (4).To add to these two studies on the efficacy of retreatment, we analysed data of pSS pa-tients who received their first two courses of rituximab within our previously report-ed RCT (5) and extension study (6). From these studies, 15 pSS patients (14 female) could be included. Patients had median age of 39 years (range 27–65) and median dis-ease duration of 37 months (range 3–154). Each course consisted of 1000 mg rituximab intravenously (given with 100 mg methyl-prednisolone) on days 1 and 15. Median interval between courses was 103 weeks (range 60–136).Table I. Clinical and laboratory parameters during the first and second course of rituximab in patients with pSS.Parameter Course Week 0 Week 24 p-value*  Week 48 p-value**ESSDAI First 9.0 (4.0-13.0) 2.5 (0.0-9.0) 0.006 8.0 (2.0-17.0) 0.009ESSDAI Second 8.0 (2.0-18.0) 3.0 (0.0-10.0) 0.005 5.0 (1.0-26.0) 0.028SWS (ml/minute) First 0.47 (0.11-2.49) 0.52 (0.07-2.24) 0.694 0.37 (0.07-2.95) 0.048SWS (ml/minute) Second 0.40 (0.02-1.47) 0.35 (0.06-1.72) 0.320 0.34 (0.04-1.69) 0.691B-cells (109/l) First 0.20 (0.01-0.40) 0.05 (0.00-0.31) 0.002 0.16 (0.05-0.31) 0.011B-cells (109/l) Second 0.22 (0.02-0.52) 0.00 (0.00-0.24) 0.001 0.15 (0.01-0.41) 0.002RF (kI U/l) First 88 (8-241) 30 (10-120) 0.001 72 (8-400) 0.003RF (kI U/l) Second 95 (12-230) 37 (13-160) 0.002 43 (11-354) 0.056IgG (g/l) First 22.9 (13.0-44.3) 19.3 (13.9-26.1) 0.001 21.4 (14.1-35.6) 0.004IgG (g/l) Second 22.2 (13.7-41.5) 18.9 (12.1-25.0) 0.002 18.3 (11.5-33.3) 0.320Patient GDA First 62 (43-74) 25 (0-61) 0.011 53 (4-84) 0.037Patient GDA Second 52 (15-93) 38 (0-85) 0.060 37 (3-82) 0.410MFI-GF First 16 (4-20) 12 (5-20) 0.016 16 (4-20) 0.081MFI-GF Second 16 (4-20) 13 (7-20) 0.019 15 (10-20) 0.168VAS oral dryness First 58 (0-91) 25 (0-67) 0.021 50 (0-88) 0.010VAS oral dryness Second 60 (1-92) 37 (0-84) 0.053 65 (1-88) 0.115VAS ocular dryness First 63 (0-88) 33 (0-89) 0.041 55 (0-90) 0.624VAS ocular dryness Second 55 (0-91) 53 (0-94) 0.802 59 (4-87) 0.463Values are presented as median (range).*p-value compared with values recorded at baseline.**p-value compared with values recorded at week 24.pSS: primary Sjögren’s syndrome; ESSDAI: EULAR Sjögren’s Syndrome Disease Activity Index; SWS: stimulated whole salivary flow rate; RF: rheumatoid factor; GDA: global disease activity; MFI-GF: multidimensional fatigue inventory general fatigue; VAS: visual analogue scale.Fig. 1. Absolute change over time during the first and second course of rituximab in patients with pSS. A: ESSDAI, B: stimulated whole saliva C: CD19+ B-cells, D: rheumatoid factor, E: IgG level, F: MFI general fatigue, G: VAS oral dryness, H: VAS ocular dryness. Values for change from baseline to week 24 and from week 24 to week 48 of individual patients are presented, together with the median of all patients.444Letters to the EditorsDuring both courses, patients were evalu-ated at baseline and 24 and 48 weeks after rituximab treatment. Assessments includ-ed EULAR Sjögren’s Syndrome Disease Activity Index (ESSDAI) (7), stimulated whole saliva (SWS), B-cells, rheumatoid factor (RF), IgG levels, patient global dis-ease activity (GDA), multidimensional fa-tigue inventory general fatigue (MFI-GF) and visual analogue scale (VAS) for oral and ocular dryness (see references 5, 6 and 8 for details). Variables within patients were analysed using the Wilcoxon signed-rank test.Retreatment with rituximab was well-tol-erated. One patient developed mild serum-sickness-like disease after the first infusion of both courses (second infusions were not administered). Both courses of rituximab resulted in significant improvement of ES-SDAI, B-cells, RF, IgG and MFI-GF at week 24 compared with baseline. Patient GDA and VAS oral dryness improved sig-nificantly during the first course and showed a trend for improvement during the second course. Improvement in VAS ocular dryness was observed only during the first course. All these variables, except for VAS ocular dryness, showed significant deterioration at week 48 compared with week 24 dur-ing the first course. The same pattern was found during the second course, although deterioration seemed less pronounced. SWS remained stable during the first 24 weeks of both courses, but a significant decrease was seen at week 48 of the first course (Table I). Absolute changes per patient over time dur-ing both courses are shown in Figure 1. The main strength of this analysis is no selection regarding initial response to rituximab. Our group consisted of 15 well-characterised pSS patients in whom a vari-ety of objective and subjective parameters was assessed in a standardised way at fixed times after administration of rituximab dur-ing both courses. The main limitations are the small sample size and the varying time between courses, because retreatment was started after completion of the entire RCT and after recurrence of symptoms. No rela-tion was found between the interval between courses and the effect of the second course.  In conclusion, retreatment with rituximab after recurrence of symptoms resulted in comparable beneficial effects as initial treat-ment on objective parameters, including ESSDAI, whereas the effect on patient-re-ported parameters was somewhat less pro-nounced. The latter finding is in line with an earlier study in pSS (9). Because goals of retreatment include maintenance of effi-cacy and prevention of flare, further studies are needed to investigate optimal timing of retreatment of rituximab in pSS patients. Furthermore, it would be of interest to in-vestigate the clinical value of a combination therapy of biological agents (10).AcknowledgementsWe are grateful to Janita Bulthuis-Kuiper for her contribution to the data collection.P.M. MEINERS1* S. ARENDS2*J.M. MEIJER3R.V. MOERMAN2F.K.L. SPIJKERVET1A. VISSINK1H. BOOTSMA2*These authors contributed equally to this work.1Department of Oral and Maxillofacial Surgery, 2Department of Rheumatology and Clinical Immunology, and 3Department of General Practice, University of Groningen, University Medical Center Groningen, The Netherlands.Please address correspondence to: Prof. Dr A. Vissink, Department of Oral and Maxillofacial Surgery, University Medical Center Groningen, P.O. Box 30.001, 9700 RB Groningen, The Netherlands.E-mail: a.vissink@umcg.nlFunding: this investigator-driven study was financially supported by Roche, Woerden, The Netherlands, which also supplied the study medication.  This funding source was not involved in the study design, patient recruitment, data collection, analysis and interpretation, and writing of the report. Competing interests: none declared.References   1. MEINERS PM, VISSINK A, KALLENBERG CGM et al.: Treatment of primary Sjögren’s syndrome with anti-CD20 therapy (rituximab). A feasible approach or just a starting point? Expert Opin Biol Ther 2011; 11: 1381-94.   2. DEVAUCHELLE-PENSEC V, MARIETTE X, JOUSSE-JOUILIN S et al.: Treatment of primary Sjögren syndrome with rituximab: a randomized trial. Ann Intern Med 2014; 160: 233-42.  3. GOTTENBERG JE, CINQUETTI G, LARROCHE C et al.: Efficacy of rituximab in systemic manifesta-tions of primary Sjögren’s syndrome: Results in 78 patients of the AutoImmune and rituximab registry. Ann Rheum Dis 2013; 72: 1026-31.   4. CARUBBI F, CIPRIANI P, MARRELI A et al.: Efficacy and safety of rituximab treatment in early primary Sjögren’s syndrome: a prospective, multi-center, follow-up study. Arthritis Res Ther 2013; 15: R172.   5. MEIJER JM, MEINERS PM, VISSINK A et al.: Effectiveness of rituximab treatment in primary Sjögren’s syndrome: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 2010; 62: 960-8.   6. MEINERS PM, ARENDS S, BROUWER E, SPIJKER-VET FK, 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: 1297-302.   7. SEROR R, RAVAUD P, BOWMAN SJ et al.: EULAR Sjögren’s syndrome disease activity index: Devel-opment of a consensus systemic disease activity index for primary Sjögren’s syndrome. Ann Rheum Dis 2010; 69: 1103-9.   8. MOERMAN RV, ARENDS S, MEINERS PM et al.: EULAR Sjögren’s Syndrome Disease Activity In-dex (ESSDAI) is sensitive to show efficacy of ritux-imab treatment in a randomized controlled trial. Ann Rheum Dis 2014; 73: 472-4.  9. SEROR R, GOTTENBERG JE, DEVAUCHELLE-PENSEC V et al.: ESSDAI and ESSPRI: EULAR indexes for a complete picture of primary Sjögren’s syndrome patients. Arthritis Care Res 2013; 65: 1358-64. 10. De VITA S, QUARTUCCIO L, SALVIN S et al.: Sequential therapy with belimumab followed by rituximab in Sjögren’s syndrome associated with B-cell lymphoproliferation and overexpression of BAFF: evidence for long-term efficacy. Clin Exp Rheumatol 2014; 32: 490-4.

Efficacy of retreatment with rituximab in patients with primary Sjögren's syndrome

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Efficacy of retreatment with rituximab in patients with primary Sjögren's syndrome

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