Leflunomide–hydroxychloroquine combination therapy in patients with primary Sjögren's syndrome (RepurpSS-I): a placebo-controlled, double-blinded, randomised clinical trial

Heijden, Eefje Hanna Martine van der; Blokland, Sofie L M; Hillen, Maarten R; Lopes, Ana P; Vliet-Moret, Fréderique M van; Rosenberg, Antoine J.W.P.; Janssen, Nard G.; Welsing, Paco; Iannizzotto, Valentina; Tao, Weiyang; Pandit, Aridaman; Barone, Francesca; Kruize, Aike A.; Radstake, Timothy R. D. J.; Roon, Joël A G van

doi:10.1016/s2665-9913(20)30057-6

Cited by 49 publications

(24 citation statements)

References 22 publications

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“…We neither observed differences in other clinical parameters (e.g., ESSDAI, UWSF) between these clusters, emphasizing the complex relationship between local inflammation and clinical parameters assessed cross-sectionally. An apparent discrepancy between biological activity and patient-reported dryness symptoms in pSS has also been noted in several clinical trials (51)(52)(53)(54), and may be partly attributed to symptom adaptation. Trial design is further complicated by clinical and biological patient heterogeneity (55).…”

Section: Discussionmentioning

confidence: 84%

The Transcriptome of Paired Major and Minor Salivary Gland Tissue in Patients With Primary Sjögren’s Syndrome

et al. 2021

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BackgroundWhile all salivary glands (SGs) can be involved in primary Sjögren’s syndrome (pSS), their respective role in pathogenesis remains unclear. Our objective was to assess immunopathway activation in paired parotid and labial gland tissue from biopsy-positive and biopsy-negative pSS and non-SS sicca patients.MethodsParaffin-embedded, paired parotid and labial salivary gland tissue and peripheral blood mononuclear cells were obtained from 39 pSS and 20 non-SS sicca patients. RNA was extracted, complementary DNA libraries were prepared and sequenced. For analysis of differentially expressed genes (DEGs), patients were subdivided based on fulfillment of ACR-EULAR criteria and histopathology.ResultsWith principal component analysis, only biopsy-positive pSS could be separated from non-SS sicca patients based on SG gene expression. When comparing the transcriptome of biopsy-positive pSS and biopsy-negative non-SS sicca patients, 1235 and 624 DEGs (FDR<0.05, log2FC<-1 or >1) were identified for parotid and labial glands, respectively. The number of DEGs between biopsy-negative pSS and non-SS sicca patients was scarce. Overall, transcript expression levels correlated strongly between parotid and labial glands (R2 = 0.86, p-value<0.0001). Gene signatures present in both glands of biopsy-positive pSS patients included IFN-α signaling, IL-12/IL-18 signaling, CD3/CD28 T-cell activation, CD40 signaling in B-cells, DN2 B-cells, and FcRL4+ B-cells. Signature scores varied considerably amongst pSS patients.ConclusionTranscriptomes of paired major and minor SGs in pSS were overall comparable, although significant inter-individual heterogeneity in immunopathway activation existed. The SG transcriptome of biopsy-negative pSS was indistinguishable from non-SS sicca patients. Different patterns of SG immunopathway activation in pSS argue for personalized treatment approaches.

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Section: Discussionmentioning

confidence: 84%

The Transcriptome of Paired Major and Minor Salivary Gland Tissue in Patients With Primary Sjögren’s Syndrome

et al. 2021

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“…Olink® Explore is a powerful tool offering a high-multiplex protein biomarker platform with a tremendously high throughput capacity in combination with minimal sample volume requirements and with high specificity and sensitivity. The technology is based on the already proven high-multiplex PEA technology that has primarily been applied for screening of proteins in blood (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31) but is now also used for other sample matrices e.g., CSF (32), cell (33)-and tissue (34) lysate, saliva (35), urine (36), interstitial fluid (37), cell culture media (38), peritoneal fluid (39), breast milk (40), BALF (41) and synovial fluid (42). Moreover, as minimal sample volumes are required, the technology has also been applied to samples of minimal sample volume, for example single cells (43), exosomes (44), dried blood spots (45), aqueous humour (46) and fineneedle biopsies (47).…”

Section: Discussionmentioning

confidence: 99%

Proximity Extension Assay in Combination with Next-Generation Sequencing for High-throughput Proteome-wide Analysis

Wik

Nordberg

Broberg

et al. 2021

Molecular & Cellular Proteomics

108

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This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

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“…8 There are currently no approved diseasemodifying treatments for pSS. Small, open-label, uncontrolled and controlled clinical efficacy studies of methotrexate, 9 leflunomide, 10 hydroxychloroquine, 11 rituximab, [12][13][14] epratuzumab (B-celltargeted agents), 15 belimumab (B-cell-activating factor-blocking agent) 16 What does this study add? ► Abatacept treatment did not result in significant clinical efficacy versus placebo in this randomised controlled trial, but it showed evidence of disease-relevant biological activity.…”

Section: Introductionmentioning

confidence: 99%

“… 8 There are currently no approved disease-modifying treatments for pSS. Small, open-label, uncontrolled and controlled clinical efficacy studies of methotrexate, 9 leflunomide, 10 hydroxychloroquine, 11 rituximab, 12–14 epratuzumab (B-cell-targeted agents), 15 belimumab (B-cell-activating factor-blocking agent) 16 and infliximab (tumour necrosis factor-α-blocking agent) 17 have shown mixed results using a variety of outcome measures. Additionally, randomised placebo-controlled trials of hydroxychloroquine 18 and rituximab 12 13 for pSS have been negative.…”

Section: Introductionmentioning

confidence: 99%

Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial

Baer¹,

Gottenberg

Clair

et al. 2020

Ann Rheum Dis

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ObjectivesTo evaluate efficacy and safety of abatacept in adults with active primary Sjögren’s syndrome (pSS) in a phase III, randomised, double-blind, placebo-controlled trial.MethodsEligible patients (moderate-to-severe pSS [2016 ACR/European League Against Rheumatism (EULAR) criteria], EULAR Sjögren’s Syndrome Disease Activity Index [ESSDAI] ≥5, anti-SS-related antigen A/anti-Ro antibody positive) received weekly subcutaneous abatacept 125 mg or placebo for 169 days followed by an open-label extension to day 365. Primary endpoint was mean change from baseline in ESSDAI at day 169. Key secondary endpoints were mean change from baseline in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI) and stimulated whole salivary flow (SWSF) at day 169. Other secondary clinical endpoints included glandular functions and patient-reported outcomes. Selected biomarkers and immune cell phenotypes were examined. Safety was monitored.ResultsOf 187 patients randomised, 168 completed double-blind period and 165 continued into open-label period. Mean (SD) baseline ESSDAI and ESSPRI total scores were 9.4 (4.3) and 6.5 (2.0), respectively. Statistical significance was not reached for primary (ESSDAI −3.2 abatacept vs −3.7 placebo, p=0.442) or key secondary endpoints (ESSPRI, p=0.337; SWSF, p=0.584). No clinical benefit of abatacept over placebo at day 169 was seen with other clinical and PRO endpoints. Relative to baseline, abatacept was associated with significant differences vs placebo in some disease-relevant biomarkers (including IgG, IgA, IgM-rheumatoid factor) and pathogenic cell subpopulations (post hoc analyses). No new safety signals were identified.ConclusionsAbatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.

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Leflunomide–hydroxychloroquine combination therapy in patients with primary Sjögren's syndrome (RepurpSS-I): a placebo-controlled, double-blinded, randomised clinical trial

Cited by 49 publications

References 22 publications

The Transcriptome of Paired Major and Minor Salivary Gland Tissue in Patients With Primary Sjögren’s Syndrome

The Transcriptome of Paired Major and Minor Salivary Gland Tissue in Patients With Primary Sjögren’s Syndrome

Proximity Extension Assay in Combination with Next-Generation Sequencing for High-throughput Proteome-wide Analysis

Efficacy and safety of abatacept in active primary Sjögren’s syndrome: results of a phase III, randomised, placebo-controlled trial

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