Arends, Suzanne

Bootsma, Hendrika

de Wolff, Liseth

Kroese, Frans G. M.

Verstappen, Gwenny M.

Vissink, Arjan

English

ARTS repository - University of Groningen

   University of GroningenCorrespondence on 'Interleukin 6 receptor inhibition in primary Sjogren syndromede Wolff, Liseth; Arends, Suzanne; Verstappen, Gwenny M.; Vissink, Arjan; Kroese, Frans G.M.; Bootsma, HendrikaPublished in:Annals of the Rheumatic DiseasesDOI:10.1136/annrheumdis-2021-220198IMPORTANT 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:2023Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Wolff, L., Arends, S., Verstappen, G. M., Vissink, A., Kroese, F. G. M., & Bootsma, H. (2023).Correspondence on 'Interleukin 6 receptor inhibition in primary Sjogren syndrome: a multicentre double-blind randomised controlled trial'. Annals of the Rheumatic Diseases, 82(6), Article e148. Advance onlinepublication. https://doi.org/10.1136/annrheumdis-2021-220198CopyrightOther 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: 01-11-2023  1 of 1Ann Rheum Dis June 2023 Vol 82 No 6Correspondence on ‘Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised controlled trial’We read with interest the correspondence related to the article ‘Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial’ in which possible explanations for nega-tive findings in recent phase III randomised controlled trials (RCTs) for primary Sjögren’s syndrome (pSS) are discussed, including the RCT with tocilizumab.1–3 This is an important issue to raise, since there is still an unmet need for effective treatment in pSS.As discussed in these letters,2 3 most recent RCTs used the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) as primary endpoint. The ESSDAI is widely applied and seems suit-able to assess systemic disease activity in clinical practice and in cohort studies in a standardised way. However, there are some limitations to the ESSDAI as primary endpoint in trials.4 In addition to the points made by our colleagues, it is important to note that in several RCTs, including the tocilizumab trial, large response rates for the ESSDAI minimal clinically important improve-ment (≥3 points decrease) were seen in both the active treatment and placebo groups.1 5 6 With >50% placebo response rates, it is very difficult to demon-strate superiority of active treatment.As suggested by Wang et al,2 salivary and lacrimal gland- centred outcome measures might be better suited to use as endpoint. We agree this is relevant, since these organs are primarily affected in pSS. In addition, symptoms like fatigue and dryness should be evaluated, since patient- reported symptoms are important for quality of life of patients with pSS, even more than systemic disease activity.7 8 Also, the ESSDAI and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) can best be used together to assess disease activity, since they are complementary indices.9 Therefore, we argue that a composite endpoint including multiple important pSS features is more appropriate than only ESSDAI or only gland function as primary endpoint in this complex disease.Within our multidisciplinary team, we have developed the composite of rele-vant endpoints for Sjögren’s syndrome (CRESS), consisting of five items: systemic disease activity, patient- reported symptoms, tear gland, salivary gland and serology. CRESS response is defined as achieving response on at least three of the five items.10 Since with a composite endpoint response needs to be achieved on multiple items, placebo response is expected to be lower, which is crucial to demonstrate treat-ment efficacy. In the tocilizumab RCT of Felten et al,1 ESSDAI response rates were 53% in the tocilizumab and 64% in the placebo group. Clinical, patient- reported, gland- centred and immunological outcomes showed negative results, suggesting no beneficial treatment effect from tocilizumab. Presumably, a composite endpoint could have confirmed these results with lower response rates. Another advantage is that a composite endpoint may facilitate a broader inclusion of patients with pSS, since response is not only measured by systemic disease activity, but also, for example, by improvement on fatigue and dryness. Especially in early disease, these complaints can be very prominent.In the CRESS, both the tear and salivary gland items consist of two comple-mentary measurements. The tear gland item includes Schirmer’s Test and Ocular Staining Score (OSS) and the salivary gland item includes unstimulated whole salivary flow (UWS) and salivary gland ultrasonography (SGUS). We believe that combining two measurements, each assessing different aspects, gives a broad reflection of the glands. If OSS and SGUS are not available, the concise CRESS can be used, leaving Schirmer’s Test and UWS for evaluation of these items. Besides saliva production and SGUS, salivary gland biopsy might be considered as additional tool for evaluation of the salivary glands. This would preferably be included as secondary endpoint in clinical trials, since it is not feasible to perform repeated biopsies in all patients. Although the relationship between salivary gland histopathology and clinical symptoms is not fully understood, evaluating histological changes in salivary glands is of great importance to understand the mechanism of action of a treatment, especially as salivary glands are a target organ that can easily be accessed. Measurements of interest for this evaluation are area of infiltrate (CD45+ fraction), B- cell and T- cell numbers, level of organisation (eg, number of CD21+ networks and germinal centres) and presence and severity of lympho-epithelial lesions. When combined with response on a composite endpoint, this would add to our understanding of which histological changes occur in patients who are (non- )responders.To conclude, we agree with Wang et al2 and Felten and Gottenberg3 that improvements in trial design are needed, with focus on the choice of a valid, reliable, sensitive to change primary endpoint that lowers placebo effect and can discriminate between treatment arms. The use of a composite endpoint, combining disease activity and functional and serological parameters, like the newly developed CRESS,10 would benefit the search of effective treatments in pSS.Liseth de Wolff   ,1 Suzanne Arends   ,1 Gwenny M Verstappen   ,1 Arjan Vissink   ,2 Frans G M Kroese,1 Hendrika Bootsma   11Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands2Oral and Maxillofacial Surgery, University Medical Centre Groningen, University of Groningen, Groningen, The NetherlandsCorrespondence to Professor Hendrika Bootsma, Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, Groningen 30 001, 9700, The Netherlands;  h. bootsma@ umcg. nlContributors All authors contributed to the concept, design and writing of the letter and have approved the final version.Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not- for- profit sectors.Competing interests None declared.Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.Patient consent for publication Not required.Provenance and peer review Not commissioned; internally peer reviewed.© Author(s) (or their employer(s)) 2023. No commercial re- use. See rights and permissions. Published by BMJ.To cite de Wolff L, Arends S, Verstappen GM, et al. Ann Rheum Dis 2023;82:e148.Received 19 February 2021Accepted 20 February 2021Published Online First 23 March 2021 ► http:// dx. doi. org/ 10. 1136/ annrheumdis- 2021- 220220Ann Rheum Dis 2023;82:e148. doi:10.1136/annrheumdis-2021-220198ORCID iDsLiseth de Wolff http://orcid.org/0000-0002-7917-5449Suzanne Arends http://orcid.org/0000-0002-4422-7640Gwenny M Verstappen http://orcid.org/0000-0002-5682-6085Arjan Vissink http://orcid.org/0000-0003-2581-4361Hendrika Bootsma http://orcid.org/0000-0001-7126-9785REFERENCES 1 Felten R, Devauchelle- Pensec V, Seror R, et al. Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial. Ann Rheum Dis 2021;80:329–38.  2 Wang B, Chen S, Xuan J, et al. Correspondence on "Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial". Ann Rheum Dis 2023;82:e67.  3 Felten R, Gottenberg J- E. Response to: "Correspondence on ’Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial’" by Wang, et al. Ann Rheum Dis 2023;82:e68.  4 de Wolff L, Arends S, van Nimwegen JF, et al. Ten years of the ESSDAI: is it fit for purpose? Clin Exp Rheumatol 2020;38 (Suppl 126):283–90. 5 Baer A, Gottenberg J- E S, Clair EW, et al. Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo- controlled trial. Ann Rheum Dis 2021;80:339–48.  6 van Nimwegen JF, Mossel E, van Zuiden GS, et al. Abatacept treatment for patients with early active primary Sjögren’s syndrome: a single- centre, randomised, double- blind, placebo- controlled, phase 3 trial (ASAP- III study). Lancet Rheumatol 2020:1–11. doi:10.1016/S2665-9913(19)30160-2 7 Lendrem D, Mitchell S, McMeekin P, et al. Health- Related utility values of patients with primary Sjögren’s syndrome and its predictors. Ann Rheum Dis 2014;73:1362–8. 8 Hammitt KM. Sjögren’s: the patients’ perspective. Clin Exp Rheumatol 2020;38 Suppl 126:25–6. 9 Seror R, Theander E, Brun JG, et al. Validation of EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 2015;74:859–66. 10 Arends S, de WolffL, van NimwegenJ, et al. Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS) [abstract]. Arthritis Rheumatol 2020;72.Correspondencecopyright. on July 10, 2023 at University of Groningen. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2021-220198 on 23 March 2021. Downloaded from 

Correspondence on 'Interleukin 6 receptor inhibition in primary Sjogren syndrome:a multicentre double-blind randomised controlled trial'

   University of GroningenCorrespondence on 'Interleukin 6 receptor inhibition in primary Sjogren syndromede Wolff, Liseth; Arends, Suzanne; Verstappen, Gwenny M.; Vissink, Arjan; Kroese, Frans G.M.; Bootsma, HendrikaPublished in:Annals of the Rheumatic DiseasesDOI:10.1136/annrheumdis-2021-220198IMPORTANT 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:2023Link to publication in University of Groningen/UMCG research databaseCitation for published version (APA):de Wolff, L., Arends, S., Verstappen, G. M., Vissink, A., Kroese, F. G. M., & Bootsma, H. (2023).Correspondence on 'Interleukin 6 receptor inhibition in primary Sjogren syndrome: a multicentre double-blind randomised controlled trial'. Annals of the Rheumatic Diseases, 82(6), Article e148. Advance onlinepublication. https://doi.org/10.1136/annrheumdis-2021-220198CopyrightOther 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: 11-09-2023  1 of 1Ann Rheum Dis June 2023 Vol 82 No 6Correspondence on ‘Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised controlled trial’We read with interest the correspondence related to the article ‘Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial’ in which possible explanations for nega-tive findings in recent phase III randomised controlled trials (RCTs) for primary Sjögren’s syndrome (pSS) are discussed, including the RCT with tocilizumab.1–3 This is an important issue to raise, since there is still an unmet need for effective treatment in pSS.As discussed in these letters,2 3 most recent RCTs used the European League Against Rheumatism (EULAR) Sjögren’s Syndrome Disease Activity Index (ESSDAI) as primary endpoint. The ESSDAI is widely applied and seems suit-able to assess systemic disease activity in clinical practice and in cohort studies in a standardised way. However, there are some limitations to the ESSDAI as primary endpoint in trials.4 In addition to the points made by our colleagues, it is important to note that in several RCTs, including the tocilizumab trial, large response rates for the ESSDAI minimal clinically important improve-ment (≥3 points decrease) were seen in both the active treatment and placebo groups.1 5 6 With >50% placebo response rates, it is very difficult to demon-strate superiority of active treatment.As suggested by Wang et al,2 salivary and lacrimal gland- centred outcome measures might be better suited to use as endpoint. We agree this is relevant, since these organs are primarily affected in pSS. In addition, symptoms like fatigue and dryness should be evaluated, since patient- reported symptoms are important for quality of life of patients with pSS, even more than systemic disease activity.7 8 Also, the ESSDAI and EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) can best be used together to assess disease activity, since they are complementary indices.9 Therefore, we argue that a composite endpoint including multiple important pSS features is more appropriate than only ESSDAI or only gland function as primary endpoint in this complex disease.Within our multidisciplinary team, we have developed the composite of rele-vant endpoints for Sjögren’s syndrome (CRESS), consisting of five items: systemic disease activity, patient- reported symptoms, tear gland, salivary gland and serology. CRESS response is defined as achieving response on at least three of the five items.10 Since with a composite endpoint response needs to be achieved on multiple items, placebo response is expected to be lower, which is crucial to demonstrate treat-ment efficacy. In the tocilizumab RCT of Felten et al,1 ESSDAI response rates were 53% in the tocilizumab and 64% in the placebo group. Clinical, patient- reported, gland- centred and immunological outcomes showed negative results, suggesting no beneficial treatment effect from tocilizumab. Presumably, a composite endpoint could have confirmed these results with lower response rates. Another advantage is that a composite endpoint may facilitate a broader inclusion of patients with pSS, since response is not only measured by systemic disease activity, but also, for example, by improvement on fatigue and dryness. Especially in early disease, these complaints can be very prominent.In the CRESS, both the tear and salivary gland items consist of two comple-mentary measurements. The tear gland item includes Schirmer’s Test and Ocular Staining Score (OSS) and the salivary gland item includes unstimulated whole salivary flow (UWS) and salivary gland ultrasonography (SGUS). We believe that combining two measurements, each assessing different aspects, gives a broad reflection of the glands. If OSS and SGUS are not available, the concise CRESS can be used, leaving Schirmer’s Test and UWS for evaluation of these items. Besides saliva production and SGUS, salivary gland biopsy might be considered as additional tool for evaluation of the salivary glands. This would preferably be included as secondary endpoint in clinical trials, since it is not feasible to perform repeated biopsies in all patients. Although the relationship between salivary gland histopathology and clinical symptoms is not fully understood, evaluating histological changes in salivary glands is of great importance to understand the mechanism of action of a treatment, especially as salivary glands are a target organ that can easily be accessed. Measurements of interest for this evaluation are area of infiltrate (CD45+ fraction), B- cell and T- cell numbers, level of organisation (eg, number of CD21+ networks and germinal centres) and presence and severity of lympho-epithelial lesions. When combined with response on a composite endpoint, this would add to our understanding of which histological changes occur in patients who are (non- )responders.To conclude, we agree with Wang et al2 and Felten and Gottenberg3 that improvements in trial design are needed, with focus on the choice of a valid, reliable, sensitive to change primary endpoint that lowers placebo effect and can discriminate between treatment arms. The use of a composite endpoint, combining disease activity and functional and serological parameters, like the newly developed CRESS,10 would benefit the search of effective treatments in pSS.Liseth de Wolff   ,1 Suzanne Arends   ,1 Gwenny M Verstappen   ,1 Arjan Vissink   ,2 Frans G M Kroese,1 Hendrika Bootsma   11Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, Groningen, The Netherlands2Oral and Maxillofacial Surgery, University Medical Centre Groningen, University of Groningen, Groningen, The NetherlandsCorrespondence to Professor Hendrika Bootsma, Rheumatology and Clinical Immunology, University Medical Centre Groningen, University of Groningen, Groningen 30 001, 9700, The Netherlands;  h. bootsma@ umcg. nlContributors All authors contributed to the concept, design and writing of the letter and have approved the final version.Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not- for- profit sectors.Competing interests None declared.Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.Patient consent for publication Not required.Provenance and peer review Not commissioned; internally peer reviewed.© Author(s) (or their employer(s)) 2023. No commercial re- use. See rights and permissions. Published by BMJ.To cite de Wolff L, Arends S, Verstappen GM, et al. Ann Rheum Dis 2023;82:e148.Received 19 February 2021Accepted 20 February 2021Published Online First 23 March 2021 ► http:// dx. doi. org/ 10. 1136/ annrheumdis- 2021- 220220Ann Rheum Dis 2023;82:e148. doi:10.1136/annrheumdis-2021-220198ORCID iDsLiseth de Wolff http://orcid.org/0000-0002-7917-5449Suzanne Arends http://orcid.org/0000-0002-4422-7640Gwenny M Verstappen http://orcid.org/0000-0002-5682-6085Arjan Vissink http://orcid.org/0000-0003-2581-4361Hendrika Bootsma http://orcid.org/0000-0001-7126-9785REFERENCES 1 Felten R, Devauchelle- Pensec V, Seror R, et al. Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial. Ann Rheum Dis 2021;80:329–38.  2 Wang B, Chen S, Xuan J, et al. Correspondence on "Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial". Ann Rheum Dis 2023;82:e67.  3 Felten R, Gottenberg J- E. Response to: "Correspondence on ’Interleukin 6 receptor inhibition in primary Sjögren syndrome: a multicentre double- blind randomised placebo- controlled trial’" by Wang, et al. Ann Rheum Dis 2023;82:e68.  4 de Wolff L, Arends S, van Nimwegen JF, et al. Ten years of the ESSDAI: is it fit for purpose? Clin Exp Rheumatol 2020;38 (Suppl 126):283–90. 5 Baer A, Gottenberg J- E S, Clair EW, et al. Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo- controlled trial. Ann Rheum Dis 2021;80:339–48.  6 van Nimwegen JF, Mossel E, van Zuiden GS, et al. Abatacept treatment for patients with early active primary Sjögren’s syndrome: a single- centre, randomised, double- blind, placebo- controlled, phase 3 trial (ASAP- III study). Lancet Rheumatol 2020:1–11. doi:10.1016/S2665-9913(19)30160-2 7 Lendrem D, Mitchell S, McMeekin P, et al. Health- Related utility values of patients with primary Sjögren’s syndrome and its predictors. Ann Rheum Dis 2014;73:1362–8. 8 Hammitt KM. Sjögren’s: the patients’ perspective. Clin Exp Rheumatol 2020;38 Suppl 126:25–6. 9 Seror R, Theander E, Brun JG, et al. Validation of EULAR primary Sjögren’s syndrome disease activity (ESSDAI) and patient indexes (ESSPRI). Ann Rheum Dis 2015;74:859–66. 10 Arends S, de WolffL, van NimwegenJ, et al. Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS) [abstract]. Arthritis Rheumatol 2020;72.Correspondencecopyright. on July 10, 2023 at University of Groningen. Protected byhttp://ard.bmj.com/Ann Rheum Dis: first published as 10.1136/annrheumdis-2021-220198 on 23 March 2021. Downloaded from 

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Correspondence on 'Interleukin 6 receptor inhibition in primary Sjogren syndrome:a multicentre double-blind randomised controlled trial'

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