Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

UK Primary Sjögren's Syndrome Registry; Leeds CTRU; French ASSESS cohort

doi:10.1016/S2665-9913(19)30042-6

Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

UK Primary Sjögren's Syndrome Registry, Leeds CTRU, French ASSESS cohort

Research output: Contribution to journal › Article › peer-review

103 Citations (SciVal)

Abstract

Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. Video Abstract: [Figure presented]

Original language	English
Pages (from-to)	e85-e94
Number of pages	10
Journal	The Lancet Rheumatology
Volume	1
Issue number	2
Early online date	25 Sept 2019
DOIs	https://doi.org/10.1016/S2665-9913(19)30042-6
Publication status	Published - 1 Oct 2019

Funding

RS reports personal fees from GlaxoSmithKline (GSK), Bristol-Myers Squibb (BMS), Lilly, and UCB; and grants and personal fees from Pfizer, outside of the submitted work. SJB has provided consultancy services in the area of Sjögren's syndrome for Celgene, Eli Lilly, Glenmark, GSK, Medimmune, Novartis, Ono, Pfizer, Takeda, and UCB. PE has undertaken clinical trials and provided expert advice to Pfizer, MSD, Abbvie, BMS, UCB, Roche, Novartis, Samsung, Sandoz and Lilly. PE has received consultant fees from BMS, AbbVie, Pfizer, Merck Sharp & Dohme, Novartis, Roche, and UCB. PE has received research grants paid to his employer from AbbVie, BMS, Pfizer, MSD and Roche. JH reports personal fees from Alnylam Pharmaceuticals, outside of the submitted work. MB reports grants and personal fees from Medimmune, GSK, Celgene, and Janssen; and personal fees from UCB, outside of the submitted work. MR reports involvement of the conduction of a Gilead-sponsored Sjogren's trial. BD reports grants and personal fees from Roche Chugai; grants from Sanofi and Abbvie; and personal fees from BMS, outside of the submitted work. J-EG reports grants and personal fees from BMS; personal fees from Abbvie, Roche, Sanofi-Genzyme, UCB, and Pfizer, outside of the submitted work. W-FN reports personal fees from GlaxoSmithKline, MedImmune, Novartis, and BMS; personal fees and other support from Abbvie; and other support from Resolves Therapeutics, Nascient, outside of the submitted work. BMS funded the transcriptomic analysis of the ASSESS cohort (unrestricted grant) but had no access to any clinical, biological, or transcriptomic data. The Binding Site provided the measurements of FLC, B-cell activating factor, and β2-microglobulin of the UKPSSR serum samples free of charge but had no access to the associated clinical data and provided no input to the study design or data interpretation. All other authors declare no competing interests. We thank all the patients and healthy volunteers who joined the UKPSSR, Stavanger, and ASSESS cohorts. We thank Dr Arthur Pratt for critical appraisal of the manuscript. This work received infrastructure support from the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre and the NIHR Clinical Research Facility, based at Newcastle upon Tyne Hospitals NHS Foundation Trust and Newcastle University; and from the Arthritis Research UK and Versus Arthritis Newcastle upon Tyne Experimental Arthritis Treatment Centre. The UKPSSR received grant support from the UK Medical Research Council (G0800629 to WFN, SJB, BG) and British Sjögren's Syndrome Association. The establishment of the ASSESS cohort and biobank was funded by the French ministry of health (Programme Hospitalier de Recherche Clinique National 2006-AOM06133). The JOQUER study was sponsored by Assistance Publique-Hôpitaux de Paris with a grant from the French Ministry of Health (Programme Hospitalier de Recherche Clinique National 2007 P070125). The TRACTISS trial was undertaken at the Leeds Clinical Trials Unit on behalf of the chief investigator Prof Simon Bowman, funded by the Arthritis Research UK (grant 18810), Rituximab supplied free of charge from Roche. The re-analysis of the JOQUER and TRACTISS studies and the comparative analysis of the transcriptomic data were supported by the Foundation of Research in Rheumatology.

ASJC Scopus subject areas

Rheumatology
Immunology and Allergy
Immunology

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Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials. / UK Primary Sjögren's Syndrome Registry; Leeds CTRU; French ASSESS cohort.
In: The Lancet Rheumatology, Vol. 1, No. 2, 01.10.2019, p. e85-e94.

Research output: Contribution to journal › Article › peer-review

UK Primary Sjögren's Syndrome Registry, Leeds CTRU & French ASSESS cohort 2019, 'Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials', The Lancet Rheumatology, vol. 1, no. 2, pp. e85-e94. https://doi.org/10.1016/S2665-9913(19)30042-6

UK Primary Sjögren's Syndrome Registry, Leeds CTRU, French ASSESS cohort. Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials. The Lancet Rheumatology. 2019 Oct 1;1(2):e85-e94. Epub 2019 Sept 25. doi: 10.1016/S2665-9913(19)30042-6

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title = "Symptom-based stratification of patients with primary Sj{\"o}gren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials",

abstract = "Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sj{\"o}gren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sj{\"o}gren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sj{\"o}gren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sj{\"o}gren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. Video Abstract: [Figure presented]",

author = "{UK Primary Sj{\"o}gren's Syndrome Registry} and {Leeds CTRU} and {French ASSESS cohort} and Tarn, {Jessica R.} and Nadia Howard-Tripp and Lendrem, {Dennis W.} and Xavier Mariette and Alain Saraux and Valerie Devauchelle-Pensec and Raphaele Seror and Skelton, {Andrew J.} and Katherine James and Peter McMeekin and Shereen Al-Ali and Hackett, {Katie L.} and Lendrem, {B. Clare} and Ben Hargreaves and John Casement and Sheryl Mitchell and Bowman, {Simon J.} and Elizabeth Price and Pease, {Colin T.} and Paul Emery and Peter Lanyon and John Hunter and Monica Gupta and Michele Bombardieri and Nurhan Sutcliffe and Costantino Pitzalis and John McLaren and Annie Cooper and Marian Regan and Ian Giles and David Isenberg and Vadivelu Saravanan and David Coady and Bhaskar Dasgupta and Neil McHugh and Steven Young-Min and Robert Moots and Nagui Gendi and Mohammed Akil and Bridget Griffiths and Johnsen, {Svein J.A.} and Norheim, {Katrine B.} and Roald Omdal and Deborah Stocken and S. Brown and J. Gray and P. Smith and C. Reynolds and E. Skinner and John Pauling",

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TY - JOUR

T1 - Symptom-based stratification of patients with primary Sjögren's syndrome

T2 - multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

AU - UK Primary Sjögren's Syndrome Registry

AU - Leeds CTRU

AU - French ASSESS cohort

AU - Tarn, Jessica R.

AU - Howard-Tripp, Nadia

AU - Lendrem, Dennis W.

AU - Mariette, Xavier

AU - Saraux, Alain

AU - Devauchelle-Pensec, Valerie

AU - Seror, Raphaele

AU - Skelton, Andrew J.

AU - James, Katherine

AU - McMeekin, Peter

AU - Al-Ali, Shereen

AU - Hackett, Katie L.

AU - Lendrem, B. Clare

AU - Hargreaves, Ben

AU - Casement, John

AU - Mitchell, Sheryl

AU - Bowman, Simon J.

AU - Price, Elizabeth

AU - Pease, Colin T.

AU - Emery, Paul

AU - Lanyon, Peter

AU - Hunter, John

AU - Gupta, Monica

AU - Bombardieri, Michele

AU - Sutcliffe, Nurhan

AU - Pitzalis, Costantino

AU - McLaren, John

AU - Cooper, Annie

AU - Regan, Marian

AU - Giles, Ian

AU - Isenberg, David

AU - Saravanan, Vadivelu

AU - Coady, David

AU - Dasgupta, Bhaskar

AU - McHugh, Neil

AU - Young-Min, Steven

AU - Moots, Robert

AU - Gendi, Nagui

AU - Akil, Mohammed

AU - Griffiths, Bridget

AU - Johnsen, Svein J.A.

AU - Norheim, Katrine B.

AU - Omdal, Roald

AU - Stocken, Deborah

AU - Brown, S.

AU - Gray, J.

AU - Smith, P.

AU - Reynolds, C.

AU - Skinner, E.

AU - Pauling, John

PY - 2019/10/1

Y1 - 2019/10/1

N2 - Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. Video Abstract: [Figure presented]

AB - Background: Heterogeneity is a major obstacle to developing effective treatments for patients with primary Sjögren's syndrome. We aimed to develop a robust method for stratification, exploiting heterogeneity in patient-reported symptoms, and to relate these differences to pathobiology and therapeutic response. Methods: We did hierarchical cluster analysis using five common symptoms associated with primary Sjögren's syndrome (pain, fatigue, dryness, anxiety, and depression), followed by multinomial logistic regression to identify subgroups in the UK Primary Sjögren's Syndrome Registry (UKPSSR). We assessed clinical and biological differences between these subgroups, including transcriptional differences in peripheral blood. Patients from two independent validation cohorts in Norway and France were used to confirm patient stratification. Data from two phase 3 clinical trials were similarly stratified to assess the differences between subgroups in treatment response to hydroxychloroquine and rituximab. Findings: In the UKPSSR cohort (n=608), we identified four subgroups: Low symptom burden (LSB), high symptom burden (HSB), dryness dominant with fatigue (DDF), and pain dominant with fatigue (PDF). Significant differences in peripheral blood lymphocyte counts, anti-SSA and anti-SSB antibody positivity, as well as serum IgG, κ-free light chain, β2-microglobulin, and CXCL13 concentrations were observed between these subgroups, along with differentially expressed transcriptomic modules in peripheral blood. Similar findings were observed in the independent validation cohorts (n=396). Reanalysis of trial data stratifying patients into these subgroups suggested a treatment effect with hydroxychloroquine in the HSB subgroup and with rituximab in the DDF subgroup compared with placebo. Interpretation: Stratification on the basis of patient-reported symptoms of patients with primary Sjögren's syndrome revealed distinct pathobiological endotypes with distinct responses to immunomodulatory treatments. Our data have important implications for clinical management, trial design, and therapeutic development. Similar stratification approaches might be useful for patients with other chronic immune-mediated diseases. Funding: UK Medical Research Council, British Sjogren's Syndrome Association, French Ministry of Health, Arthritis Research UK, Foundation for Research in Rheumatology. Video Abstract: [Figure presented]

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Symptom-based stratification of patients with primary Sjögren's syndrome: multi-dimensional characterisation of international observational cohorts and reanalyses of randomised clinical trials

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