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Revisiting the JOQUER trial: stratification of primary Sjögren’s syndrome and the clinical and interferon response to hydroxychloroquine

Lookup NU author(s): Dr Alexis Collins, Dr Dennis LendremORCiD, Professor James WasonORCiD, Dr Jessica Tarn, Dr Nadia Howard-Tripp, Professor Fai NgORCiD



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


© 2021, The Author(s). To re-analyse the clinical outcomes and interferon (IFN) activity data from the JOQUER trial, a phase III trial investigating hydroxychloroquine (HCQ) in patients with primary Sjögren’s syndrome (pSS), after stratifying patients into putative pathobiological subgroups utilizing the Newcastle Sjögren’s Stratification Tool (NSST) based on patient-reported symptoms of dryness, pain, fatigue, anxiety and depression. 107 patients were assigned to one of four subgroups using NSST at baseline—the high symptom burden (HSB), pain dominant with fatigue (PDF), dryness dominant with fatigue (DDF) and low symptom burden (LSB). Endpoints were re-analysed after stratification, testing for treatment differences within subgroups and adjusting for baseline differences using a repeated measures covariate model. The HSB subgroup (n = 32) showed a relative improvement in ESSPRI of 1.49 points (95% CI 0.54–2.43; p = 0.002) within 12 weeks in patients taking HCQ compared to placebo, with no further changes after 24 weeks. For the LSB subgroup (n = 14), the ESSPRI worsened in the placebo but not the HCQ arm after 12 weeks (mean difference 1.44, 95% CI 0.05–2.83, p = 0.042). Neither the HSB nor the LSB patients showed significant changes in IFN activity at 24 weeks. There were no significant differences in ESSPRI in the PDF (n = 39) and DDF (n = 22) patients taking HCQ. However, significant reductions in overall IFN score at 24 weeks were seen in both PDF (difference at 24 weeks; 6.41, 95% CI, 2.48–10.34, p = 0.002) and DDF (difference at 24 weeks; 7.23, 95% CI, 1.85–12.6, p = 0.009) without improvement in ESSPRI. Although the JOQUER trial reported no overall benefit from HCQ in pSS patients, stratification suggests that both HSB and LSB subgroups may respond to HCQ. However, these patients may benefit through mechanisms other than the reduction of IFN activities.

Publication metadata

Author(s): Collins A, Lendrem D, Wason J, Tarn J, Howard-Tripp N, Bodewes I, Versnel MA, Gottenberg J-E, Seror R, Mariette X, Ng W-F

Publication type: Article

Publication status: Published

Journal: Rheumatology International

Year: 2021

Volume: 41

Pages: 1593-1600

Print publication date: 01/09/2021

Online publication date: 24/06/2021

Acceptance date: 14/06/2021

Date deposited: 08/07/2021

ISSN (print): 0172-8172

ISSN (electronic): 1437-160X

Publisher: Springer Science and Business Media Deutschland GmbH


DOI: 10.1007/s00296-021-04927-y


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Funder referenceFunder name
... receiving support from the European Union’s Horizon 2020 research and innovation program and EFPIA.
also funded by the Innovative Medicines Initiative 2 Joint Undertaking (JU) (NECESSITY grant agreement No 806975) ...
AFC’s work was funded by the Academic Foundation Programme at the Northern Foundation School.
DL’s work has also been funded by NIHR Newcastle Biomedical Research Centre.
Medical Research Council funded the work leading to the development of the Newcastle Sjögren’s Stratification Tool (NSST)
JOQUER trial was sponsored by Assistance Publique-Hôpitaux de Paris (AP-HP) with a grant from the French Ministry of Research (Programme Hospitalier de Recherche Clinique National 2007 P070125).
The Foundation for Research in Rheumatology (FOREUM) funded the work for the re-analysis of the clinical trials and included funding for JRT and DL