No full-text available
To read the full-text of this research,
you can request a copy directly from the authors.
Emerging treatment for Sjögren's disease: a review of recent phase II and III trials
Abstract
Introduction:
Sjögren's Disease, SjD, is a systemic autoimmune disorder characterized by reduced function of the salivary and lacrimal glands. Patients suffer from dryness, fatigue, and pain and may present with or without extra-glandular organ involvement. Symptoms limit SjD patients' quality of life and are the most difficult to improve with therapy. SjD patients are heterogeneous and clustering them into biologically similar subgroups might improve the efficacy of therapies. The need for therapies that address both the symptoms and extra glandular organ involvement of SjD presents an unmet opportunity that has recently attracted a growing interest in the pharmaceutical industry.
Areas covered:
The goal of this report is to review recent phase II/III studies in SjD. To accomplish our goal, we performed a literature search for phase II/III studies and abstracts recently presented at conferences.
Expert opinion:
This review allows updates the reader on the multitude of recent phase II/III clinical trials. We speculate on how subtypes of SjD will drive future therapeutic targeting and inform pathogenesis.
Dry eye disease (DED) is a continuing medical challenge, further worsened in the autoimmune inflammatory hyperactivation milieu of Sjögren’s syndrome (SS) due to disturbances to innate and adaptive immunity with malfunctioning neuro-endocrine control. However, the pathogenetic mechanisms of SS DED are not fully established. This review summarized the available evidence, from systematic reviews, meta-analyses, and randomized clinical trials, for the efficacy and safety of the available ocular therapeutics for the management of SS DED. Relevant studies were obtained from major databases using appropriate keywords. The available largely empirical symptomatic, supportive, and restorative treatments have significant limitations as they do not alter local and systemic disease progression. Topical therapies have expanded to include biologics, surgical approaches, scleral lens fitting, the management of lid margin disease, systemic treatments, nutritional support, and the transplantation of stem cells. They are not curative, as they cannot permanently restore the ocular surface’s homeostasis. These approaches are efficacious in the short term in most studies, with more significant variability in outcome measures among studies in the long term. This review offers an interdisciplinary perspective that enriches our understanding of SS DED. This updated review addresses current knowledge gaps and identifies promising areas for future research to overcome this medical challenge.
Successful engineering of functional salivary glands necessitates the creation of cell‐instructive environments for ex vivo expansion and lineage specification of primary human salivary gland stem cells (hS/PCs). Herein, basement membrane mimetic hydrogels are prepared using hyaluronic acid, cell adhesive peptides, and hyperbranched polyglycerol (HPG), with or without sulfate groups, to produce “hyperGel+” or “hyperGel”, respectively. Differential scanning fluorescence experiments confirm the ability of the sulfated HPG precursor to stabilize fibroblast growth factor 10. The hydrogels are nanoporous, cytocompatible, and cell‐permissive, enabling the development of multicellular hS/PC spheroids in 14 days. The incorporation of sulfated HPG species in the hydrogel enhances cell proliferation. Culture of hS/PCs in hyperGel+ in the presence of a Rho kinase inhibitor Y‐27632 (Y‐27) leads to the development of spheroids with a central lumen, increases the expression of acinar marker aquaporin‐3 at the transcript level ( AQP3 ), and decreases the expression of ductal marker keratin 7 at both the transcript ( KRT7 ) and the protein levels (K7). Reduced expression of transforming growth factor beta (TGF‐β) targets SMAD2/3 is also observed in Y27‐treated cultures, suggesting attenuation of TGF‐β signaling. Thus, hyperGel+ cooperates with the Rho‐associated protein kinase inhibitor to promote the development of lumened spheroids with enhanced expression of acinar markers.
Objectives:
Primary Sjögren syndrome (pSjS) is a chronic autoimmune disorder characterized by mucosal dryness and systemic symptoms. We tested the effects of inhibition of cathepsin S using the potent and selective inhibitor RO5459072 on disease activity and symptoms of pSjS.
Methods:
This was a randomized, double-blind, placebo-controlled, parallel-group, Phase IIA study to investigate the effects of RO5459072 (100 mg twice daily [BID]; 200 mg per day). Seventy-five patients with pSjS were randomized 1:1 to receive either RO5459072 or placebo for 12 weeks. The primary outcome was the proportion of patients with a ≥ 3 point reduction from baseline in European League against Rheumatism (EULAR) Sjögren's Syndrome Disease Activity Index (ESSDAI) score. We also investigated the effects of RO5459072 on quality of life, exocrine gland function, biomarkers related to Sjögren's syndrome, and safety and tolerability.
Results:
The proportion of patients showing an improvement in ESSDAI score was not significantly different between the RO5459072 and placebo arms. No clinically meaningful treatment effects were observed in favor of RO5459072 for all secondary outcomes. Analysis of soluble biomarkers indicated target engagement between RO5459072 and cathepsin S. There were modest decreases in the number of circulating B-cells and T cells in the RO5459072 group, although these did not reach significance. RO5459072 was safe and well-tolerated.
Conclusions:
There was no clinically relevant improvement in ESSDAI score (primary end point), and no apparent benefit in favor of RO5459072 in any of the secondary endpoints. Further work is needed in order to understand the mechanisms of MHC-II-mediated immune stimulation in pSjS.
Trial registration:
ClinicalTrials.gov; NCT02701985.
Background
Primary Sjogren’s syndrome (pSS) is a systemic autoimmune disease involving multiple organ systems. The Janus kinase/signal transduction and activator of transcription (JAK/STAT) signaling pathway is a key pathway involving the pathogenesis of pSS. Baricitinib, a selective JAK1 and JAK2 inhibitor, has been approved for treatment of active rheumatoid arthritis and reported in treatment of some other autoimmune diseases including systemic lupus erythematosus. We have found that baricitinib might be effective and safe in pSS in a pilot study. However, there is no published clinical evidence of baricitinib in pSS. Hence, we conducted this randomized study to further explore the efficacy and safety of baricitinib in pSS.
Methods
This is a multi-center, prospective, open-label, randomized study to compare the efficacy of baricitinib + hydroxychloroquine (HCQ) with HCQ alone in pSS patients. We plan to involve 87 active pSS patients with European League Against Rheumatism pSS disease activity index (ESSDAI) ≥ 5 from eight different tertiary centers in China. Patients will be randomized (2:1) to receive baricitinib 4 mg per day + HCQ 400 mg per day or HCQ 400 mg per day alone. We will switch HCQ to baricitinib + HCQ if the patient in the latter group has no ESSDAI response at week 12. The final evaluation will be at week 24. The primary endpoint is the percentage of ESSDAI response, or minimal clinically important improvement (MCII), which was defined as an improvement of ESSDAI at least three points at week 12. The secondary endpoints include EULAR pSS patient-reported index (ESSPRI) response, change of Physician’s Global Assessment (PGA) score, serological activity parameters, salivary gland function test, and focus score on labial salivary gland biopsy.
Discussion
This is the first randomized controlled study to evaluate the clinical efficacy and safety of baricitinib in pSS. We hope that the result of this study can provide more reliable evidence of the efficacy and safety of baricitinib in pSS.
Trial registration
ClinicalTrials.gov NCT05016297. Registered on 19 Aug 2021.
BACKGROUND
Primary Sjögren's syndrome (pSS) is characterized by B cell hyperactivity and elevated B-lymphocyte stimulator (BLyS). Anti-BLyS treatment (e.g., belimumab) increases peripheral memory B cells; decreases naive, activated, and plasma B cell subsets; and increases stringency on B cell selection during reconstitution. Anti-CD20 therapeutics (e.g., rituximab) bind and deplete CD20-expressing B cells in circulation but are less effective in depleting tissue-resident CD20+ B cells. Combined, these 2 mechanisms may achieve synergistic effects.METHODS
This 68-week, phase II, double-blind study (GSK study 201842) randomized 86 adult patients with active pSS to 1 of 4 arms: placebo, s.c. belimumab, i.v. rituximab, or sequential belimumab + rituximab.RESULTSOverall, 60 patients completed treatment and follow-up until week 68. The incidence of adverse events (AEs) and drug-related AEs was similar across groups. Infections/infestations were the most common AEs, and no serious infections of special interest occurred. Near-complete depletion of minor salivary gland CD20+ B cells and a greater and more sustained depletion of peripheral CD19+ B cells were observed with belimumab + rituximab versus monotherapies. With belimumab + rituximab, reconstitution of peripheral B cells occurred, but it was delayed compared with rituximab. At week 68, mean (± standard error) total EULAR Sjögren's syndrome disease activity index scores decreased from 11.0 (1.17) at baseline to 5.0 (1.27) for belimumab + rituximab and 10.4 (1.36) to 8.6 (1.57) for placebo.CONCLUSION
The safety profile of belimumab + rituximab in pSS was consistent with the monotherapies. Belimumab + rituximab induced enhanced salivary gland B cell depletion relative to the monotherapies, potentially leading to improved clinical outcomes.TRIAL REGISTRATIONClinicalTrials.gov NCT02631538.FUNDINGFunding was provided by GSK.
Importance
Primary Sjögren syndrome (pSS) is a systemic autoimmune disease associated with dysregulated immune cells, with no efficient therapy. There is a need to study potential therapeutic approaches.
Objective
To investigate the efficacy, safety, and immune response of low-dose interleukin 2 (LD-IL-2) in the treatment of pSS.
Design, Setting, and Participants
A double-blind, placebo-controlled randomized clinical trial was conducted with a 2-group superiority design from June 2015 to August 2017. Sixty patients, aged 18 to 70 years, were recruited from Peking University People’s Hospital. Efficacy analyses were based on the intention-to-treat (ITT) principle. Data were analyzed from December 2018 to March 2020.
Interventions
Patients with pSS were treated with LD-IL-2 or placebo for 12 weeks and accompanied by 12 weeks of follow-up.
Main Outcomes and Measures
The primary end point was defined as a 3-point or greater improvement on the European League Against Rheumatism Sjögren’s Syndrome Disease Activity Index (ESSDAI) by week 24. The secondary end points included other clinical responses, safety, and changes of immune cell subsets at week 12 and 24.
Results
Sixty patients with pSS were recruited, with 30 in the LD-IL-2 group (mean [SD] age, 47.6 [12.8] years; 30 [100%] women) and 30 in the placebo group (mean [SD] age, 51.0 [11.9] years; 30 [100%] women), and 57 completed the trial. More patients in the LD-IL-2 group (20 [66.7%]) achieved ESSDAI score reduction of at least 3 points than in the placebo group (8 [26.7%]) at week 24 ( P = .004). There were greater resolutions of dryness, pain, and fatigue in the LD-IL-2 group than placebo group at week 12 (dryness: difference, −18.33 points; 95% CI, −28.46 to −8.21 points; P = .001; pain: difference, −10.33 points; 95% CI, −19.38 to −1.29 points; P = .03; fatigue: difference, −11.67 points; 95% CI, −20.65 to −2.68 points; P = .01). No severe adverse events were observed in either group. In addition, the LD-IL-2 group showed a significant decrease in infection compared with the placebo group (1 [3.3%] vs 9 [30.0%]; P = .006). Immunological analysis revealed that LD-IL-2 promoted an expansion of regulatory T cells and regulatory CD24 high CD27 ⁺ B cells.
Conclusions and Relevance
In this randomized clinical trial, LD-IL-2 was effective and well tolerated in patients with pSS, and it restored immune balance, with enhanced regulatory T cells and CD24 high CD27 ⁺ B cells.
Trial Registration
ClinicalTrials.gov Identifier: NCT02464319
Autoimmune diseases are characterized by the recognition of self‐antigens by the immune system, which leads to inflammation and tissue damage. B cells are directly and indirectly involved in the pathophysiology of autoimmunity, both via antigen‐presentation to T cells and production of proinflammatory cytokines and/or autoantibodies. Consequently, B lineage cells have been identified as therapeutic targets in autoimmune diseases. B cell depleting strategies have proven beneficial in the treatment of rheumatoid arthritis (RA), systemic lupus erythematous (SLE), ANCA‐associated vasculitis (AAV), multiple sclerosis (MS), and a wide range of other immune‐mediated inflammatory diseases (IMIDs). However, not all patients respond to treatment or may not reach (drug‐free) remission. Moreover, B cell depleting therapies do not always target all B cell subsets, such as short‐lived and long‐lived plasma cells. These cells play an active role in autoimmunity and in certain diseases their depletion would be beneficial to achieve disease remission. In the current review article we provide an overview of novel strategies to target B lineage cells in autoimmune diseases, with the focus on rheumatic diseases. Both advanced therapies that have recently become available and more experimental treatments that may reach the clinic in the near future are discussed. This article is protected by copyright. All rights reserved
Purpose:
To evaluate the efficacy and safety of 0.05% cyclosporine eye drops (II) for the treatment of primary Sjögren's syndrome-associated dry eye (PSSDE).
Methods:
Sixty patients with PSSDE were randomly divided into three groups, received treatment with 0.05% cyclosporine (C group), artificial tears (S group) or their combination (CS group). The evaluation indicators were evaluated at baseline and at weeks 2, 4 and 12.
Results:
The symptoms of C and CS groups were reduced significantly. The signs [schirmer I test (F = 4.838, p = .011), ocular staining score (F = 7.961, p = .001) and tear break-up time (F = 9.283, p < .001)] were significantly different between S and C groups as well as S and CS groups. The tear meniscus height (F = 3.197, p = .048) was significantly different between S and CS groups. No serious adverse events occurred.
Conclusion:
0.05% cyclosporine is an effective and safe treatment for patients with PSSDE.
Objective
Although symptom relief is a critical aspect for successful drug development in Sjögren's disease, patient experiences with Sjögren's‐related symptoms are understudied. Our objective was to determine how pain, dryness, and fatigue, the cardinal symptoms of Sjögren's disease, drive cluster phenotypes.
Methods
We used data from the Sjögren's International Collaborative Clinical Alliance (SICCA) Registry and a Sjögren's Foundation survey. We performed hierarchical clustering of symptoms by levels of dryness, fatigue, and pain. Using international and US cohorts, we performed multiple logistic regression analysis to compare the clusters, which included comparisons of differences in symptoms, quality of life (QoL), medication use, and systemic manifestations.
Results
Four similar clusters were identified among 1,454 SICCA registrants and 2,920 Sjögren's Foundation survey participants: 1) low symptom burden in all categories (LSB); 2) dry with low pain and low fatigue (DLP); 3) dry with high pain and low to moderate fatigue (DHP); and 4) high symptom burden in all categories (HSB). Distribution of SICCA registrants matching the symptom profile for each cluster was 10% in the LSB cluster, 30% in the DLP cluster, 23% in the DHP cluster, and 37% in the HSB cluster. Distribution of survey participants matching the symptom profile for each cluster was 23% in the LSB cluster, 14% in the DLP cluster, 21% in the DHP cluster, and 42% in the HSB cluster. Individuals in the HSB cluster had more total symptoms and lower QoL but lower disease severity than those in the other clusters. Despite having milder disease as measured by laboratory tests and organ involvement, individuals in the HSB cluster received immunomodulatory treatment most often.
Conclusion
We identified 4 symptom‐based Sjögren's clusters and showed that symptom burden and immunomodulatory medication use do not correlate with Sjögren's end‐organ or laboratory abnormalities. Findings highlight a discordance between objective measures and treatments and offer updates to proposed symptom‐based clustering approaches.
Objective
To develop a composite responder index in primary Sjögren’s syndrome (pSS): the Sjögren’s Tool for Assessing Response (STAR).
Methods
To develop STAR, the NECESSITY (New clinical endpoints in primary Sjögren’s syndrome: an interventional trial based on stratifying patients) consortium used data-driven methods based on nine randomised controlled trials (RCTs) and consensus techniques involving 78 experts and 20 patients. Based on reanalysis of rituximab trials and the literature, the Delphi panel identified a core set of domains with their respective outcome measures. STAR options combining these domains were proposed to the panel for selection and improvement. For each STAR option, sensitivity to change was estimated by the C-index in nine RCTs. Delphi rounds were run for selecting STAR. For the options remaining before the final vote, a meta-analysis of the RCTs was performed.
Results
The Delphi panel identified five core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options combining these domains were selected to be tested for sensitivity to change. After two Delphi rounds, a meta-analysis of the 20 remaining options was performed. The candidate STAR was then selected by a final vote based on metrological properties and clinical relevance.
Conclusion
The candidate STAR is a composite responder index that includes all main disease features in a single tool and is designed for use as a primary endpoint in pSS RCTs. The rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity to change and will be prospectively validated by the NECESSITY consortium in a dedicated RCT.
Objective:
To characterise filgotinib, lanraplenib, and tirabrutinib safety and efficacy in patients with active Sjögren's syndrome (SS).
Methods:
This multicentre, double-blind study randomised patients with active primary or secondary SS (European League Against Rheumatism [EULAR] SS disease activity index [ESSDAI] ≥5) to receive filgotinib 200 mg (Janus kinase-1 inhibitor), lanraplenib 30 mg (spleen tyrosine kinase inhibitor), tirabrutinib 40 mg (Bruton's tyrosine kinase inhibitor), or placebo. The composite primary end point was W12 proportion of patients fulfilling protocol-specified improvement criteria (based on C-reactive protein and SS-related symptoms). EULAR SS patient-reported index (ESSPRI) and ESSDAI change from baseline (CFB) were secondary endpoints. Exploratory endpoints included disease-related biomarkers. Treatment-emergent adverse events (AEs) represented safety outcomes.
Results:
Baseline mean ESSDAI was 10.1, and ESSPRI was 6.2 in the 150 patients who received study drug; 125 completed the 24-week placebo-controlled treatment period. At W12, 43.3% of the filgotinib group achieved the primary end point (p = 0.17 vs placebo) vs 42.3% (p = 0.16), 34.7% (p = 0.33), and 26.7% of lanraplenib, tirabrutinib, and placebo groups, respectively. Neither secondary end point was met. Biomarker reductions included immunoglobulins classically associated with SS disease activity. Filgotinib ESSDAI CFB appeared more pronounced in subgroups with baseline ESSDAI ≥14 or without disease-modifying antirheumatic drugs/corticosteroids. Most AEs were Grade 1 or 2.
Conclusions:
Three drugs with disparate mechanisms were tested, but no significant differences vs placebo in primary or secondary endpoints were observed. These results may be considered hypothesis-generating, given the drug tolerability, subgroup analysis, and biomarker findings.
Trial registration:
ClinicalTrials.gov, https://clinicaltrials.gov, NCT03100942.
Rheumatoid arthritis (RA) is an aggressive autoimmune arthritis, and current therapies remain unsatisfactory due to low remission rate and substantially adverse effects. Low-dose interleukin-2 (Ld-IL2) is potentially a therapeutic approach to further improve the disease. This randomized, double-blind, placebo-controlled trial was undertaken to evaluate the efficacy and safety of Ld-IL2 in patients with active RA. Patients were randomly assigned (1:1) to receive Ld-IL2, defined as a dose of 1 million IU, or placebo in a 12-week trial with a 12-week follow-up. Three cycles of Ld-IL2 or placebo were administered subcutaneously every other day for 2 weeks (a total of 7 doses), followed by a 2-week break. All patients received a stable dose of methotrexate (MTX). The primary outcomes were the proportion of patients achieving the ACR20, DAS28-ESR <2.6, and the change from baseline in CDAI or SDAI at week 24. Secondary endpoints included other clinical responses and safety. The primary outcomes were achieved in the per-protocol population. The improvements from baseline in CDAI and SDAI were significantly greater across time points for the Ld-IL2 + MTX group (n = 17) than for the placebo+MTX group (n = 23) (P = 0.018 and P = 0.015, respectively). More patients achieved ACR20 response in the Ld-IL2 + MTX group than those in the placebo+MTX group at week 12 (70.6% vs 43.5%) and at week 24 (76.5% vs 56.5%) (P = 0.014). In addition, low Treg and high IL-21 were associated with good responses to Ld-IL2. Ld-IL-2 treatment was well-tolerated in this study. These results suggested that Ld-IL2 was effective and safe in RA. ClinicalTrials.gov number: NCT 02467504.
Objective
To clarify the efficacy and safety of abatacept for glandular and extraglandular involvements in Sjögren’s syndrome (SS) associated with rheumatoid arthritis (RA).
Patients and methods
We performed an open-label, prospective, 1-year, observational multicenter study (ROSE and ROSE II trials) for SS with RA. The primary endpoint was the remission rate as measured by SDAI at 52 weeks after initiation of intravenous abatacept. The secondary endpoints included the changes in the Saxon’s test, Schirmer’s test, ESSDAI and ESSPRI. Adverse events and adherence rates during the study period were also analyzed.
Results
68 patients (36 in ROSE and 32 in ROSE II, all women) were enrolled in this study. The mean SDAI decreased significantly from 23.6±13.2 (±SD) at baseline to 9.9±9.5 at 52 weeks (P<0.05). Patients with SDAI remission increased from 0 (0 weeks) to 19 patients (27.9%) at 52 weeks. Saliva volume increased significantly from 2015.1±1695.4 (0 weeks) to 2311.3±1804.4 (24 weeks) mg/2 min (n=66, P<0.05). Tear volume increased significantly from 5.0±6.0 (0 weeks) to 5.6±6.3 (52 weeks) mm/5 min (n=52, P<0.05). Both ESSDAI and ESSPRI scores were significantly decreased at 12 weeks, and these responses were maintained up to 52 weeks. The rate of adherence to abatacept over the 52-week period was 83.8%. Twenty-two adverse events occurred in 15 patients, and 9 of these events were infections.
Conclusion
Abatacept ameliorated both glandular and extraglandular involvements, as well as the systemic disease activities and patient-reported outcomes based on composite measures, in patients with SS associated with RA.
Autoantibodies are increasingly recognized for their pathogenic potential in a growing number of neurological diseases. While myasthenia gravis represents the prototypic antibody (Ab)-mediated neurological disease, many more disorders characterized by Abs targeting neuronal or glial antigens have been identified over the past two decades. Depletion of humoral immune components including immunoglobulin G (IgG) through plasma exchange or immunoadsorption is a successful therapeutic strategy in most of these disease conditions. The neonatal Fc receptor (FcRn), primarily expressed by endothelial and myeloid cells, facilitates IgG recycling and extends the half-life of IgG molecules. FcRn blockade prevents binding of endogenous IgG to FcRn, which forces these antibodies into lysosomal degradation, leading to IgG depletion. Enhancing the degradation of endogenous IgG by FcRn-targeted therapies proved to be a powerful therapeutic approach in patients with generalized MG and is currently being tested in clinical trials for several other neurological diseases including autoimmune encephalopathies, neuromyelitis optica spectrum disorders, and inflammatory neuropathies. This review illustrates mechanisms of FcRn-targeted therapies and appraises their potential to treat neurological diseases.
Clinical development of BTK kinase inhibitors for treating autoimmune diseases has lagged behind development of these drugs for treating cancers, due in part from concerns over the lack of selectivity and associated toxicity profiles of first generation drug candidates when used in the long term treatment of immune mediated diseases. Second generation BTK inhibitors have made great strides in limiting off-target activities for distantly related kinases, though they have had variable success at limiting cross-reactivity within the more closely related TEC family of kinases. We investigated the BTK specificity and toxicity profiles, drug properties, disease associated signaling pathways, clinical indications, and trial successes and failures for the 13 BTK inhibitor drug candidates tested in phase 2 or higher clinical trials representing 7 autoimmune and 2 inflammatory immune-mediated diseases. We focused on rheumatoid arthritis (RA), multiple sclerosis (MS), and systemic lupus erythematosus (SLE) where the majority of BTK nonclinical and clinical studies have been reported, with additional information for pemphigus vulgaris (PV), Sjogren’s disease (SJ), chronic spontaneous urticaria (CSU), graft versus host disease (GVHD), and asthma included where available. While improved BTK selectivity versus kinases outside the TEC family improved clinical toxicity profiles, less profile distinction was evident within the TEC family. Analysis of genetic associations of RA, MS, and SLE biomarkers with TEC family members revealed that BTK and TEC family members may not be drivers of disease. They are, however, mediators of signaling pathways associated with the pathophysiology of autoimmune diseases. BTK in particular may be associated with B cell and myeloid differentiation as well as autoantibody development implicated in immune mediated diseases. Successes in the clinic for treating RA, MS, PV, ITP, and GVHD, but not for SLE and SJ support the concept that BTK plays an important role in mediating pathogenic processes amenable to therapeutic intervention, depending on the disease. Based on the data collected in this study, we propose that current compound characteristics of BTK inhibitor drug candidates for the treatment of autoimmune diseases have achieved the selectivity, safety, and coverage requirements necessary to deliver therapeutic benefit.
Background:
Pemphigus vulgaris and pemphigus foliaceus are potentially life-threatening autoimmune disorders triggered by immunoglobulin G (IgG) autoantibodies against mucosal and epidermal desmogleins. There is an unmet need for fast-acting drugs that enable patients to achieve early sustained remission with reduced corticosteroid reliance.
Objective:
To investigate efgartigimod, an engineered Fc fragment that inhibits the activity of the neonatal Fc receptor, thereby reducing serum IgG levels, for treating pemphigus.
Methods:
Thirty-four patients with mild to moderate pemphigus vulgaris or foliaceus were enrolled in an open-label phase 2 adaptive trial. In sequential cohorts, efgartigimod was dosed at 10 or 25 mg/kg intravenously with various dosing frequencies, as monotherapy or as add-on therapy to low-dose oral prednisone. Safety endpoints comprised the primary outcome.
Results:
Adverse events were mostly mild and reported by 16/19 (84%) patients receiving efgartigimod 10 mg/kg and 13/15 (87%) patients receiving the 25 mg/kg dose, with similar adverse event profiles between dose groups. A major decrease in serum total IgG and anti-desmoglein (Dsg) autoantibodies was observed and correlated with improved pemphigus disease area index (PDAI) scores. Efgartigimod, as monotherapy or combined with prednisone, demonstrated early disease control in 28/31 (90%) patients after a median of 17 days. Optimized, prolonged treatment with efgartigimod in combination with a median dose of 0.26 (range 0.06-0.48) mg/kg/day prednisone led to complete clinical remission in 14/22 (64%) patients within 2-41 weeks.
Conclusion:
Efgartigimod was well-tolerated and exhibited an early effect on disease activity and outcome parameters, providing support for further evaluation as a therapy for pemphigus. The study is registered at ClinicalTrials.gov (identifier: NCT03334058).
Rituximab is associated with prolonged B-cell depletion and secondary hypogammaglobulinemia and is associated with a dampened humoral response and increased infectious complications. To describe the potential impact of prior rituximab therapy on clinical outcomes from SARS-CoV-2 infection and development of COVID-19 antibodies, we conducted a retrospective study of adults across the Mount Sinai Health System diagnosed with COVID-19 who received rituximab for any indication from February 2019 to October 2020. Patients’ baseline characteristics, markers of disease severity, clinical outcomes, and antibody development were examined. Of the 49 patients included in the analysis, 63.2% required hospitalization for COVID-19, 24.5% required an ICU admission, and 32.7% died. Proximity of last rituximab infusion and COVID-19 diagnosis did not affect rates of hospitalization, admission to intensive care units or death. Over half (51.7%) of those whose antibodies were checked developed neutralizing anti-spike protein antibodies. The median time between rituximab administration and COVID-19 diagnosis was not significantly different between those who developed antibodies and those who did not (p = .323). Of the 14 patients with documented negative COVID-19 antibody titers, 11 of them survived SARS-CoV-2 infection, indicating that development of neutralizing antibodies may not be necessary for recovery from COVID-19.
Background
Sjogren’s syndrome (SS) is a heterogenous disease with various phenotypes. We aimed to provide a relevant subclassification based on symptom-based clustering for patients with primary (p) SS.
Methods
Data from patients in a prospective pSS cohort in Korea were analysed. Latent class analysis (LCA) was performed using patient reported outcomes, including pain, fatigue, dryness, and anxiety/depression. Clinical and laboratory differences between the classes were analysed. Latent transition analysis (LTA) was applied to the longitudinal data (annually for up to 5 years) to assess temporal stability of the classifications.
Results
LCA identified three classes among 341 patients with pSS (i.e., ‘high symptom burden’, ‘dryness dominant’, ‘low symptom burden’). Each group had distinct laboratory and clinical phenotypes. LTA revealed that class membership remained stable over time. Baseline class predicted future salivary gland function and damage accrual represented by a Sjogren’s syndrome disease damage index.
Conclusion
Symptom-based clustering of heterogenous patients with primary Sjogren’s syndrome provided a relevant classification supported by temporal stability over time and distinct phenotypes between the classes. This clustering strategy may provide more homogenous groups of pSS patients for novel treatment development and predict future phenotypic evolvement.
Primary Sjögren’s syndrome (pSS) is a systemic autoimmune diseases of the connective tissues, characteristic of the presentation of keratoconjunctivitis sicca and xerostomia. A cardinal pathogenetic feature of SS is B-cell hyperactivity, which has invited efforts on optimal B-cell targeted therapy, whereas conventional corticosteroids and disease-modifying antirheumatic drugs (DMARDs) are restricted to symptomatic relief. As per the first EULAR recommendation for pSS patients published in 2020, regimens with monoclonal antibodies targeting B cells may be initiated in patients with severe, refractory systemic disease, notably rituximab (RTX), a mouse-derived monoclonal antibody that targets CD20 antigen and contributes to B-cell depletion. Nonetheless, the data available from clinical trials with RTX are often controversial. Despite the lack of promising results from two large RCTs, several positive clinical efficacies were demonstrated. This current review addressed the efficacy and safety of clinical trials available and elucidated the potential of RTX on the immune system, especially B and T cells. Furthermore, plausible explanations for the discrepancy in clinical data were also presented.
Background
While 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.
Methods
Paraffin-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.
Results
With 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.
Conclusion
Transcriptomes 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.
Sphingosine-1-phosphate (S1P) is a bioactive lipid metabolite that exerts its actions by engaging 5 G-protein-coupled receptors (S1PR1-S1PR5). S1P receptors are involved in several cellular and physiological events, including lymphocyte/hematopoietic cell trafficking. An S1P gradient (low in tissues, high in blood), maintained by synthetic and degradative enzymes, regulates lymphocyte trafficking. Because lymphocytes live long (which is critical for adaptive immunity) and recirculate thousands of times, the S1P-S1PR pathway is involved in the pathogenesis of immune-mediated diseases. The S1PR1 modulators lead to receptor internalization, subsequent ubiquitination, and proteasome degradation, which renders lymphocytes incapable of following the S1P gradient and prevents their access to inflammation sites. These drugs might also block lymphocyte egress from lymph nodes by inhibiting transendothelial migration. Targeting S1PRs as a therapeutic strategy was first employed for multiple sclerosis (MS), and four S1P modulators (fingolimod, siponimod, ozanimod, and ponesimod) are currently approved for its treatment. New S1PR modulators are under clinical development for MS, and their uses are being evaluated to treat other immune-mediated diseases, including inflammatory bowel disease (IBD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. A clinical trial in patients with COVID-19 treated with ozanimod is ongoing. Ozanimod and etrasimod have shown promising results in IBD; while in phase 2 clinical trials, ponesimod has shown improvement in 77% of the patients with psoriasis. Cenerimod and amiselimod have been tested in SLE patients. Fingolimod, etrasimod, and IMMH001 have shown efficacy in RA preclinical studies. Concerns relating to S1PR modulators are leukopenia, anemia, transaminase elevation, macular edema, teratogenicity, pulmonary disorders, infections, and cardiovascular events. Furthermore, S1PR modulators exhibit different pharmacokinetics; a well-established first-dose event associated with S1PR modulators can be mitigated by gradual up-titration. In conclusion, S1P modulators represent a novel and promising therapeutic strategy for immune-mediated diseases.
In primary Sjögren syndrome (pSS), the function of the salivary glands is often considerably reduced. Multiple innate immune pathways are likely dysregulated in the salivary gland epithelium in pSS, including the nuclear factor-κB pathway, the inflammasome and interferon signalling. The ductal cells of the salivary gland in pSS are characteristically surrounded by a CD4⁺ T cell-rich and B cell-rich infiltrate, implying a degree of communication between epithelial cells and immune cells. B cell infiltrates within the ducts can initiate the development of lymphoepithelial lesions, including basal ductal cell hyperplasia. Vice versa, the epithelium provides chronic activation signals to the glandular B cell fraction. This continuous stimulation might ultimately drive the development of mucosa-associated lymphoid tissue lymphoma. This Review discusses changes in the cells of the salivary gland epithelium in pSS (including acinar, ductal and progenitor cells), and the proposed interplay of these cells with environmental stimuli and the immune system. Current therapeutic options are insufficient to address both lymphocytic infiltration and salivary gland dysfunction. Successful rescue of salivary gland function in pSS will probably demand a multimodal therapeutic approach and an appreciation of the complicity of the salivary gland epithelium in the development of pSS.
Safe and effective new oral therapies for autoimmune, allergic, and inflammatory conditions remain a significant therapeutic need. Here, we investigate the human pharmacokinetics, pharmacodynamics (PDs), and safety of the selective, covalent Bruton’s tyrosine kinase (BTK) inhibitor, remibrutinib. Study objectives were explored in randomized single and multiple ascending dose (SAD and MAD, respectively) cohorts with daily doses up to 600 mg, and a crossover food effect (FE) cohort, in adult healthy subjects without (SAD [n =80]/FE [n =12]) or with asymptomatic atopic diathesis (MAD [n =64]). A single oral dose of remibrutinib (0.5‒600 mg) was rapidly absorbed (time to maximum concentration = 0.5 h‒1.25 h) with an apparent blood clearance of 280‒560 L/h and apparent volume of distribution of 400‒15,000 L. With multiple doses (q.d. and b.i.d.), no pronounced accumulation of remibrutinib was detected (mean residence time was <3 h). Food intake showed no clinically relevant effect on remibrutinib exposure suggesting no need for dose adaptation. With remibrutinib doses greater than or equal to 30 mg, blood BTK occupancy was greater than 95% for at least 24 h (SAD). With MAD, remibrutinib reached near complete blood BTK occupancy at day 12 predose with greater than or equal to 10 mg q.d. Near complete basophil or skin prick test (SPT) inhibition at day 12 predose was achieved at greater than or equal to 50 mg q.d. for CD63 and at greater than or equal to 100 mg q.d. for SPT. Remibrutinib was well‐tolerated at all doses without any dose‐limiting toxicity. Remibrutinib showed encouraging blood and skin PDs with a favorable safety profile, supporting further development for diseases driven by mast cells, basophils, and B‐cells, such as chronic spontaneous urticaria, allergic asthma, or Sjögren’s syndrome.
Regulatory T cells (Treg) are crucial for the maintenance of peripheral tolerance and for the control of ongoing inflammation and autoimmunity. The cytokine interleukin-2 (IL-2) is essentially required for the growth and survival of Treg in the peripheral lymphatic tissues and thus plays a vital role in the biology of Treg. Most autoimmune and rheumatic diseases exhibit disturbances in Treg biology either at a numerical or functional level resulting in an imbalance between protective and pathogenic immune cells. In addition, in some autoimmune diseases, a relative deficiency of IL-2 develops during disease pathogenesis leading to a disturbance of Treg homeostasis, which further amplifies the vicious cycle of tolerance breach and chronic inflammation. Low-dose IL-2 therapy aims either to compensate for this IL-2 deficiency to restore a physiological state or to strengthen the Treg population in order to be more effective in counter-regulating inflammation while avoiding global immunosuppression. Here we highlight key findings and summarize recent advances in the clinical translation of low-dose IL-2 therapy for the treatment of autoimmune and rheumatic diseases.
Dry eye disease (DED) is one of the most common conditions presenting to eye care providers and is increasingly recognized to have poor outcomes on quality of life, activities of daily living, and social and emotional well-being. Here, we aim to understand the association between dry eye symptoms and workplace productivity experienced by patients with non-Sjögren’s dry eye and Sjögren’s Syndrome.
MEDLINE, PubMed, Embase, Cochrane Library, CINAHL, Healthstar, and PsycINFO were searched from inception to May 2019.
Thirty-one studies consisting of 50,446 study participants from 14 countries were included in this systematic review. Among non-Sjögren’s dry eye patients, there was significant absenteeism (ES = 0.19; 95% CI: [0.04, 0.35]), presenteeism (ES = 0.25; 95% CI: [0.15. 0.35]), productivity impairment (ES = 0.24; 95% CI: [0.20, 0.27]), activity impairment (ES = 0.30; 95% CI: [0.21, 0.38]), and subjective difficulties at work (ES = 0.58; 95% CI: [0.40, 0.75]). Patients with Sjögren’s Syndrome demonstrated significant absenteeism (ES = 0.13, 95% CI: [0.10, 0.17]), presenteeism (ES = 0.28, 95% CI: [0.24, 0.32]), productivity impairment (ES = 0.31, 95% CI: [0.27, 0.35]), and activity impairment (ES = 0.39, 95% CI: [0.32, 0.47]) in the workplace. In addition, patients with Sjögren’s Syndrome demonstrated significantly lower employment rate (ES = 0.42, 95% CI: [0.34, 0.50]), decreased number of hours worked (SMD = −0.21, 95% CI: [−0.39, −0.02]), and increased work disability (ES = 0.18; 95% CI: [0.09, 0.27]).
This is the first systematic review and meta-analysis to demonstrate the negative association between DED and several work productivity measures.
Article link: https://doi.org/10.1016/j.brs.2020.12.004
Background
Transcranial direct-current stimulation (tDCS) has shown promise to decrease fatigue. However, it has never been examined in primary Sjogren Syndrome (pSS).
Objective
To assess the effect of a tDCS protocol on fatigue in patients with pSS.
Methods
This is a parallel, double-blind pilot study (NCT04119128). Women aged 18–65 years, with pSS, on stable pharmacological therapy, with complaints of fatigue for at least three months, and with scores >5 on Fatigue Severity Scale (FSS) were included. We randomized 36 participants to receive five consecutive or sham tDCS sessions, with an intensity of 2 mA, for 20 min/day.
Results
After five tDCS sessions, fatigue severity assessed by the FSS (primary outcome) demonstrated a mean group difference of −0.85 [95% confidence interval (CI) −1.57, −0.13; effect size 0.80] favouring the active group. The active group presented significantly greater reductions in fatigue as measured by the EULAR Sjögren’s Syndrome Patient Reported Index after five tDCS sessions [mean group difference: 1.40; 95%CI -2.33, −0.48; effect size 1.04]. Although there were no between-group differences in the secondary outcomes of sleep, mood and anxiety, within-group comparisons evidenced a small but significant difference in the active group for pain and sleep. There were no significant cortisol changes. All reported adverse events were mild and transitory.
Conclusion
tDCS seems to be safe and reduce fatigue in pSS. A differential effect on pain and sleep may underlie its effects. Further studies are needed to optimise tDCS treatment strategies in pSS.
Objectives
To 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.
Methods
Eligible 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.
Results
Of 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.
Conclusions
Abatacept treatment did not result in significant clinical efficacy compared with placebo in patients with moderate-to-severe pSS, despite evidence of biological activity.
Objective
To evaluate the efficacy and safety of telitacicept in adult patients with primary Sjögren’s syndrome (pSS) in a phase II randomized double-blind placebo-controlled trial.
Methods
Patients with pSS with positive anti-SSA antibody and ESSDAI ≥ 5 were randomly assigned, in a 1:1:1 ratio, to receive weekly subcutaneous telitacicept 240 mg, 160 mg, or placebo for 24 weeks. The primary end point was the change from baseline in the ESSDAI at week 24. Safety was monitored.
Results
42 patients were enrolled and randomized (n = 14 per group). Administration of telitacicept 160 mg resulted in a significant reduction in ESSDAI score from baseline to week 24 compared with placebo (p< 0.05). The placebo-adjusted least-squares mean change from baseline was -4.3 (95% CI -7.0 to -1.6; p= 0·002). While, mean change of ESSDAI in telitacicept 240 mg was -2.7(-5.6–0.1) with no statistical difference when compared that in placebo group (p= 0.056). In addition, MFI-20 and serum immunoglobulins decreased significantly(p< 0.05) at week 24 in both telitacicept groups compared with placebo. No serious adverse events were observed in the telitacicept treating group.
Conclusion
Telitacicept showed clinical benefits and well tolerance and safety in the treatment of pSS.
Clinical trial registration number
ClinicalTrials.gov, https://clinicaltrials.gov, NCT04078386
Introduction:
Sjögren's syndrome (SS) is an immune-mediated inflammatory condition characterized by sicca syndrome, musculoskeletal pain, and fatigue. Extra-glandular manifestations are common and there is a markedly increased risk of lymphoma development. SS is associated with high health-economic burden driven largely by the symptom burden on patients. Currently, there is no approved disease-modifying treatment and management is based on empirical evidence. Progress in the understanding of SS pathogenesis has led to an expanding portfolio of more targeted therapies under development.
Areas covered:
This review summarizes the key development in targeted biological therapies in SS including emerging targets. It also highlights the challenges in therapeutic development in SS such as disease heterogeneity and defining appropriate disease assessment tools to evaluate therapeutic efficacy.
Expert opinion:
Early trials in SS failed to meet their primary outcomes which may in part due to the use of inappropriate or insensitive study endpoints. Recent trials targeting B-cells, B-T cell co-stimulation and IFN signaling have shown promising results. Development of composite endpoints including patient reported outcomes and objective disease measure may provide a more holistic approach to disease assessment. The impact of these new tools on therapeutic development that benefit patients remains to be fully evaluated.
Purpose: To compare the effectiveness of the topical use of cyclosporin A (CsA) 0.1%, diquafosol (DQS) tetrasodium 3% ophthalmic solution, and their combination in treating dry eye disease in a general health care setting. Methods: This prospective, nonrandomized, observational study analyzed 279 patients. Patients instilled topical CsA 0.1% (Ikervis®; Santen Pharmaceutical Co., Ltd., Japan) once daily and/or DQS tetrasodium 3% (Diquas-S®; Santen) six times a day for 12 weeks. Objective signs [tear break-up time (TBUT), National Eye Institute (NEI) corneal and conjunctival staining scores] and symptoms [Symptom Assessment in Dry Eye (SANDE) and Dry Eye-related Quality-of-Life Score (DEQS) questionnaires] were evaluated at baseline, week 4, and week 12. Results: Patients (n = 279) were mainly female (85.0%) with a mean (SD) age of 50.1 (14.8) years, and received CsA (n = 93), DQS (n = 99), or CsA/DQS (n = 87). Both monotherapies and CsA/DQS combination therapy significantly improved TBUT, NEI corneal and conjunctival staining scores, and SANDE and DEQS scores from baseline to week 12 (all P < 0.0001). The mean change in TBUT between baseline and week 12 was significantly higher in CsA/DQS combination therapy (2.13 ± 2.41 s) than in CsA monotherapy (1.07 ± 1.71 s; P = 0.0011). Conclusions: Monotherapy with CsA or DQS and CsA/DQS combination therapy all significantly improved the objective signs and symptoms of dry eyes during 12 weeks of treatment. CsA/DQS combination therapy provides an additional benefit in terms of TBUT compared with CsA alone; however, a randomized controlled trial still needs to be performed to confirm this result.
Background
Primary Sjögren’s syndrome (pSS) is a chronic, systemic autoimmune disease typically affecting the salivary and lacrimal glands and producing symptoms of dry mouth, dry eyes, fatigue and pain. Hydroxychloroquine (HCQ) have been shown to have various immunomodulatory and immunosuppressive effects, and currently have established roles in the management of rheumatoid arthritis and systemic lupus erythematosus (SLE). However, the use of HCQ in pSS is based in expert recommendations and in few studies with a low level of evidence. There are very few publications assessing HCQ use in a double-blind, randomized, and placebo-controlled studies. In Japan, HCQ is indicated for patients with SLE and cutaneous lupus erythematosus (CLE) and is off-label use for pSS patients without CLE. Recently, ESSPRI and ESSDAI have been developed by the European League Against Rheumatism (EULAR) SS study group as standardized outcome tools for measuring patients’ reported symptoms and disease-specific activity. ESSDAI and ESSPRI have been proven to be valid and reliable, they have been used to select patients or as the primary or secondary outcome measures in clinical trials.
Objectives
The aim of this study was to examine the efficacy of HCQ in pSS at 8 and 52 weeks after treatment evaluated by ESSPRI and ESSDAI.
Methods
Twenty-six pSS patients (26 female, mean age 51.6 ± 13.6 years) with CLE who fulfilled the ACR/EULAR classification criteria for SS and/or the Japanese Ministry of Health and Welfare criteria for SS were studied. The clinical indexes were evaluated by ESSDAI, ESSPRI, IgG and CH50 before and after HCQ treatment at 8 and 52weeks. ESSPRI components were calculated individually and as a single factor composed of the mean of the three components (pain, fatigue, and dryness: VAS 0-10). ESSDAI (0–123) proposes the evaluation of 12 domains or organ systems (constitutional, lymphadenopathy, glandular, articular, cutaneous, pulmonary, renal, peripheral nervous system, central nervous system, muscular, hematological and biology).
Results
ESSPRI and component of fatigue and pain were significantly lower at 8 and 52 weeks after treatment than HCQ pre-treatment (ESSPRI: 4.14±1.45 vs 3.38±1.57, 3.34±1.56, p=0.005, p=0.045, fatigue: 4.68±2.12 vs 3.68±1.96, 3.58±1.87, p=0.010, p=0.036, pain: 3.32±1.94 vs 2.09±1.60, 1.79±1.51, p=0.0043, p=0.0014). However, there was no significant difference in dryness component between HCQ pre-treatment and 8 and 52 weeks after treatment (4.41 ± 2.09 vs 4.32 ± 2.06, 4.21 ± 2.39, p = 0.71, p = 0.94), and the amount of saliva produced by the gum test also showed no significant difference between pre-HCQ treatment and 52 weeks after treatment (8.21 ± 6.72 vs 8.24 ± 6.79 mL / 10 minutes, p = 0.45). There was also a significant decrease in ESSDAI and constitutional, articular, cutaneous and biological domain at 52 weeks after treatment compared to HCQ pre-treatment (ESSDAI: 9.68±6.14 vs 4.74±6.43, p=0.0004; constitutional: 1.41±1.50 vs 0.63±1.26, p=0.034, articular: 1.00±1.02 vs 0.21±0.63, p=0.0027, cutaneous: 2.86±3.27 vs 1.11±2.49, p=0.010, biological: 1.14±0.83 vs 0.79±0.86, p=0.014). An improvement of at least 1 point or 15% in ESSPRI and at least 3 points in ESSDAI compared to HCQ pr-treatment were observed in 63.6% and 31.8% at 8 weeks and 73.7% and 68.4% at 52 weeks after treatment. In addition, IgG was significantly decreased at 52 weeks after treatment compared to HCQ pre-treatment (1934 ± 613 vs 1714 ± 564 mg / dL, p=0.0005).
Conclusion
HCQ treatment improved pain such as arthritis, fatigue, constitutional and cutaneous manifestations, but was not effective for salivary function and dryness. HCQ treatment was useful in improving ESSPRI and ESSDAI, and long-term treatment increased the number of effective cases from 8 weeks to 52 weeks.
Disclosure of Interests
None declared
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease of unknown etiology that primarily affects women of childbearing age. There is no disease more heterogeneous than SLE as patients experience a myriad of manifestations and unpredictable periods of heightened disease activity. This heterogeneity not only makes it difficult for treatment decisions and prognostication, but has made drug development quite challenging. Despite these challenges, belimumab, voclosporin, and anifromulab, approved by the United States Food and Drug Administration (FDA) to treat SLE or lupus nephritis (LN), enhanced our armamentarium of traditional therapies, such as hydroxychloroquine, corticosteroids, and immunosuppressives. However, there remains a dire need to develop therapies that offer greater efficacy and safety. Patients with SLE produce excessive amounts of autoantibodies and cytokines that result in inflammation and organ damage. While a considerable number of potential drug development targets exist, there has been much attention focused on B cells. Strategies have included direct B cell killing, modulation of B cell function, inhibition of molecules essential to B cell growth and survival, and acceleration of autoantibody clearance, to name just a few. In this article, we review SLE clinical trials evaluating experimental agents that target B cells or plasma cells.
Background
EULAR Sjögren’s syndrome disease activity index (ESSDAI) assesses systemic disease activity in patients (pts) with primary Sjögren’s syndrome (pSS); however, weaknesses include exclusion of patient-reported symptoms, tear and salivary gland function, and a marked placebo (PBO) response. Composite of Relevant Endpoints for Sjögren’s Syndrome (CRESS) is a recently developed composite outcome measure validated using data from three Phase 3 randomised controlled trials of pts with pSS. ¹ Concise CRESS (cCRESS) is used when ocular staining score and salivary gland ultrasonography are unavailable. ESSDAI was an endpoint in a Phase 2, PBO-controlled study, evaluating the safety and efficacy of belimumab (BEL) and rituximab (RTX) sequential administration (BEL/RTX), and BEL and RTX monotherapies in pts with pSS. Although the results numerically favoured BEL/RTX over PBO, this was not statistically significant.
Objectives
To evaluate the efficacy of BEL/RTX and monotherapies using cCRESS overall responses at Weeks (Wks) 24, 52, and 68, and individual item responses at Wk 24 in pts with pSS who completed the Phase 2 study.
Methods
In the Phase 2, double-blind, 68-Wk study ( NCT02631538 ) adults were randomised (2:2:2:1) into 4 treatment arms: BEL/RTX (n=24; weekly BEL 200 mg subcutaneous [SC] to Wk 24 followed by weekly PBO SC to Wk 52 + RTX 1000 mg intravenous [IV], Wk 8 + 10), BEL monotherapy (n=24; weekly BEL 200 mg SC to Wk 52), RTX monotherapy (n=25; RTX 1000 mg IV, Wk 8 + 10), or PBO (n=13). Pts were classified post hoc as cCRESS responders when ≥3 of the following 5 items were met: 1) Clinical (Clin)ESSDAI score <5 (low disease state); 2) decrease of ≥1 point or ≥15% from baseline (BL) in EULAR Sjögren’s Syndrome Patient Reported Index (ESSPRI); 3) increase of ≥5 mm from BL in abnormal Schirmer’s test, or no change to abnormal if normal at BL; 4) unstimulated whole saliva (UWS) increase of ≥25% from BL, or any increase from BL if score was 0 at BL; 5) decrease of ≥25% in the rheumatoid factor (RF) titre from BL, or decrease of ≥10% in IgG from BL. ¹
Results
Of 86 randomised pts, 60 completed follow-up to Wk 68 (completer population) and were included in the analysis. Most pts were female (95%, n=57); mean (SD) age was 49.6 (13.0) years. BL disease characteristics are presented in the Table 1.
Table 1. Clinical, functional, and laboratory parameters at BL and cCRESS responders at Wks 24, 52, and 68 (completer population)
PBO (n=8) BEL/RTX (n=17) BEL (n=19) RTX (n=16)
Pt parameters at BL, mean (SD )
ClinESSDAI
11.1 (3.76)
11.7 (5.47)
9.2 (3.77)
11.7 (4.76)
ESSPRI
6.4 (2.05)
6.0 (1.97)
6.5 (1.68)
5.9 (2.20)
Schirmer, mm/5 min
2.7 (3.25)
5.3 (6.44)
3.3 (3.16)
2.8 (3.15)
UWS, ml/min
0.1 (0.11)
0.1 (0.12)
0.1 (0.09)
0.1 (0.14)
RF, KU/l
60.8 (42.24)
30.9 (38.20)
37.0 (34.98)
105.0 (200.97)
IgG, g/l
20.4 (6.65)
16.7 (5.00)
18.1 (7.19)
16.5 (6.09)
cCRESS responders, n (% )
Wk 24
4 (50.0)
9 (52.9)
7 (36.8)
5 (31.3)
Wk 52
4 (50.0)
10 (58.8)
8 (42.1)
4 (25.0)
Wk 68
1 (12.5)
6 (35.3)
7 (36.8)
3 (18.8)
At Wks 24 and 52, the proportion of cCRESS responders was numerically higher with BEL/RTX than with either BEL, RTX, or PBO, but the difference was not significant (Table 1). At Wk 68, the proportion of cCRESS responders was numerically higher with BEL/RTX than with RTX or PBO (Table 1). The 5 cCRESS items contributed relatively equally to total cCRESS response, with the highest response observed in the RF/IgG item and the lowest in the tear gland item (Schirmer’s test; Figure 1).
Figure 1. cCRESS and individual item responders at Wk 24 (completer population )
Conclusion
At Wks 24, 52, and 68, BEL/RTX was generally associated with a numerically higher cCRESS response rate compared with the monotherapies or PBO. The PBO response for cCRESS was notable and similar to the PBO response for ClinESSDAI. The PBO response in the tear and salivary gland items was greater than in the other treatment arms, perhaps due to the use of cCRESS instead of CRESS. Due to the small sample size, the results should be interpreted with caution.
References
[1]Arends S, et al. Lancet Rheumatol 2021;3:553–62
Acknowledgements
This post hoc analysis of the GSK Study 201842 was funded by GlaxoSmithKline (GSK). Medical writing support was provided by Casmira Brazaitis, PhD, Fishawack Indicia Ltd, UK, part of Fishawack Health, and was funded by GSK.
Disclosure of Interests
Hendrika Bootsma Consultant of: BSM, Roche, Novartis, Medimmune and Union Chimique Belge, Grant/research support from: BSM and Roche, Suzanne Arends: None declared, Liseth de Wolff: None declared, Kenneth L Clark Shareholder of: GSK, Employee of: GSK, Andre van Maurik Shareholder of: GSK, Employee of: GSK, Prafull Mistry Shareholder of: GSK, Employee of: GSK, Pragya Shukla Shareholder of: GSK, Employee of: GSK, Svetlana Nihtyanova Shareholder of: GSK, Consultant of: Roche, Employee of: GSK, Norma Lynn Fox Shareholder of: GSK, Employee of: GSK, David Roth Shareholder of: GSK, Employee of: GSK
Background
Today, there are still no DMARDs licensed for primary Sjögren Syndrome (pSS) patients. Among the explanations, are the limitations of current outcome measures used as primary endpoints: e.g; high placebo response rate, evaluation of either symptoms or systemic activity, and important features not being assessed. The NECESSITY consortium ( https://www.necessity-h2020.eu/ ), including pSS experts from academia, pharmaceutical industry and patient groups formed to develop a new composite responder index, the Sjögren’s Tool for Assessing Response (STAR) that solve the issues of current outcome measures in pSS and is intended for use in clinical trials as an efficacy endpoint.
Objectives
To develop a composite responder index in primary Sjögren’s syndrome (pSS): the STAR.
Methods
To develop the STAR, the NECESSITY consortium used data-driven methods, based on 9 randomized controlled trials (RCTs), and consensus techniques, involving 78 experts and 20 patients. Based on reanalysis of rituximab trials (TRACTISS and TEARS) and literature review, the Delphi panel identified a core set of domains to include in the STAR, with their respective outcome measures. STAR options combining these domains were designed and proposed to the panel to select and improve them. For each STAR option, sensitivity to change was estimated by the C-index (derived from Effect size) in all 9 RCTs. Delphi rounds were run for selecting STAR among these options. The Delphi panel also voted to classify trials as positive, negative or “in between” in regards to primary but also key secondary endpoints. For the options remaining before the final vote, meta-analyses of the RCTs were performed separately for positive and “in between” trials together, and for negative trials.
Results
The Delphi panel identified 5 core domains (systemic activity, patient symptoms, lachrymal gland function, salivary gland function and biological parameters), and 227 STAR options, combining these domains, were selected to be tested for sensitivity to change. After two Delphi rounds, meta-analyses of the 20 remaining options were performed. The candidate STAR was selected by a final vote based on metrological properties and clinical relevance. In positive/in between trials, candidate STAR detected a difference between arms (OR 3.29, 95%-CI [2.07;5.22], whereas it did not in negative trials (OR 1.53, 95%-CI [0.81;2.91]).
Conclusion
The candidate STAR is a composite responder index, including in a single tool all main disease features, and is designed for use as a primary endpoint in pSS RCTs. Its rigorous and consensual development process ensures its face and content validity. The candidate STAR showed good sensitivity and specificity to change. The candidate STAR will be prospectively validated in a dedicated three arms RCT of the NECESSITY consortium that will evaluate combination of synthetic DMARDs (hydroxychloroquine + lefunomide or hydroxychloroquine + mycophenolate vs placebo). We encourage the use of STAR in any ongoing and future trials.
Table 1. Candidate STAR
Domain Point Definition of response
Systemic activity
3
Decrease of clinESSDAI ≥ 3
Patient reported outcome
3
Decrease of ESSPRI ≥ 1 point or ≥ 15%
Lachrymal gland function
1
Schirmer:
If abnormal score at baseline: increase ≥ 5 mm from baseline
If normal score at baseline: no change to abnormal
Or
Ocular Staining Score:
If abnormal score at baseline: decrease ≥ 2 points from baseline
If normal score at baseline: no change to abnormal
Salivary gland function
1
Unstimulated Whole Salivary Flow:
If score > 0 at baseline: increase ≥ 25% from baseline
If score is 0 at baseline: any increase from baseline
or
Ultrasound:
Decrease ≥ 25% in total Hocevar score from baseline
Biological
1
Serum IgG levels: decrease ≥ 10%
or
Rheumatoid Factor levels: decrease ≥ 25%
Candidate STAR responder
≥ 5 points
ESSDAI: EULAR Sjögren syndrome disease activity index; ESSPRI: EULAR Sjögren syndrome patient reported index; IgG: Immunoglobulin G;
Acknowledgements
NECESSITY WP5 STAR development participants: Suzanne Arends (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Francesca Barone (Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, UK), Albin Björk (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden), Coralie Bouillot (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Guillermo Carvajal Alegria (University of Brest, Inserm, CHU de Brest, LBAI, UMR1227, Brest, France; Service de Rhumatologie, Centre de Référence Maladies Autoimmunes Rares CERAINO, CHU Cavale Blanche, Brest, France), Wen-Hung Chen (GlaxoSmithKline, Research Triangle Park, North Carolina, USA), Kenneth Clark (GlaxoSmithKline Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom), Konstantina Delli (Department of Oral and Maxillofacial Surgery, University Medical Center Groningen (UMCG), University of Groningen, The Netherlands), Salvatore de Vita (Rheumatology Clinic, University Hospital of Udine, Italy), Liseth de Wolff (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Jennifer Evans (Novartis Pharmaceuticals corporation USA), Stéphanie Galtier (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Saviana Gandolfo (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Mickael Guedj (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Dewi Guellec (CHU de Brest, Service de Rhumatologie, Inserm, CIC 1412, Brest, France), Safae Hamkour (Center of Translational Immunology, Department of Immunology, University Medical Center Utrecht, Utrecht 3584 GA, Netherlands), Dominik Hartl (Novartis Institutes for BioMedical Research, Basel, Switzerland), Malin Jonsson (Section for Oral and Maxillofacial Radiology, Department of Clinical Dentistry, Faculty of Medicine and Dentistry, University of Bergen, Norway), Roland Jonsson (Broegelmann Research Laboratory, Department of Clinical Science, University of Bergen, Department of Rheumatology, Haukeland University Hospital, Bergen, Norway), Frans Kroese (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Aike Albert Kruize (University Medical Center Utrecht, Department Rheumatology and Clinical Immunology, Utrecht, Netherlands), Laurence Laigle (Institut de Recherches Internationales Servier (IRIS), Suresnes Cedex, France), Véronique Le Guern (AP-HP, Hôpital Cochin, Centre de référence maladies auto-immunes et systémiques rares, service de médecine interne, Paris, France), Wen-Lin Luo (Department of Biometrics and Statistical Science, Novartis Pharmaceuticals, East Hanover, New Jersey), Esther Mossel (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Wan-Fai Ng (Institute of Cellular Medicine, Newcastle University, Newcastle upon Tyne NE2 4HH, UK), Gaëtane Nocturne (Department of Rheumatology, Université Paris-Saclay, INSERM U1184: Centre for Immunology of Viral Infections and Autoimmune Diseases, Assistance Publique-Hôpitaux de Paris, Hôpital Bicêtre, Le Kremlin Bicêtre, Paris, France), Marleen Nys (Global Biometric Sciences, Bristol Myers Squibb, Braine L’Alleud, Belgium), Roald Omdal (Clinical Immunology Unit, Department of Internal Medicine, Stavanger University Hospital, PO Box 8100, 4068, Stavanger, Norway), Jacques-Olivier Pers (LBAI, UMR1227, University of Brest, Inserm, Brest, France and CHU de Brest, Brest, France), Maggy Pincemin (Association Française du Gougerot Sjögren et des Syndromes Secs, France), Manel Ramos-Casals (Department of Autoimmune Diseases, Hospital Clinic de Barcelona Institut Clinic de Medicinai Dermatologia, Barcelona, Catalunya, Spain), Philippe Ravaud (Centre d’Epidémiologie Clinique, Hôpital Hôtel-Dieu, Assistance Publique-Hôpitaux de Paris, Paris, France), Neelanjana Ray (Global Drug Development - Immunology, Bristol Myers Squibb Company, Princeton, New Jersey, USA), Alain Saraux (HU de Brest, Service de Rhumatologie, Univ Brest, Inserm, UMR1227, Lymphocytes B et Autoimmunité, Univ Brest, Inserm, LabEx IGO, Brest, France), Athanasios Tzioufas (Rheumatology Clinic, Department of Medical area, University of Udine, ASUFC, 33100 Udine, Italy), Gwenny Verstappen (University Medical Center Groningen, Department of Rheumatology and Clinical Immunology, Groningen 9700 RB, Netherlands), Arjan Vissink, Marie Wahren-Herlenius (Division of Rheumatology, Department of Medicine, Karolinska Institutet, Stockholm, Sweden). We thank the following experts: Esen Karamursel Akpek, Alan Baer, Chiara Baldini, Elena Bartoloni, Marí-Alfonso Begona, Johan Brun, Vatinee Bunya, Laurent Chiche, Troy Daniels, Paul Emery, Robert Fox, Roberto Giacomelli, John Gonzales, John Greenspan, Robert Moots, Susumu Nishiyama, Elizabeth Price, Christophe Richez, Caroline Shiboski, Roser Solans Laque, Muthiah Srinivasan, Peter Olsson, Tsutomu Takeuchi, Frederick Vivino, Paraskevi Voulgari, Daniel Wallace, Ava Wu, Wen Zhang. We thank the anonymous patients from the NECESSITY Patient Advisory Group and the Sjögren Foundation for their valuable contribution to the Delphi process. We thank EW StClair and AN Baer who generated the baminercept data and made them publicly available.
Disclosure of Interests
Raphaèle Seror Consultant of: GlaxoSmithKline, Boehringer, Janssen and Novartis, Grant/research support from: GlaxoSmithKline and Amgen, Gabriel Baron: None declared, Marine Camus: None declared, Divi Cornec Consultant of: GlaxoSmithKline, Bristol Myers Squibb, Janssen, Amgen, Pfizer and Roche, Elodie Perrodeau: None declared, Simon J. Bowman Consultant of: Abbvie, Astra Zeneca, Galapagos and Novartis Pharmaceuticals, Michele Bombardieri Consultant of: UCB, Amgen/Medimmune, Janssen, and GlaxoSmithKline, Grant/research support from: Amgen/Medimmune, Janssen, and GlaxoSmithKline, Hendrika Bootsma: None declared, Jacques-Eric Gottenberg Consultant of: AbbVie, Bristol Myers Squibb, Eli Lilly, Galapagos, Gilead, Pfizer, Roche, Sanofi, Novartis, MSD, CSL-Behring and Genzyme, Grant/research support from: Bristol Myers Squibb, Benjamin Fisher Speakers bureau: Bristol Myers Squibb and Novartis, Consultant of: Novartis, Bristol Myers Squibb, Janssen and Servier, Grant/research support from: Servier, Galapagos and Janssen, Wolfgang Hueber Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Joel van Roon: None declared, Valerie Devauchelle-Pensec: None declared, Peter Gergely Shareholder of: Novartis Pharma, Employee of: Novartis Pharma, Xavier Mariette Consultant of: Bristol Myers Squibb, Galapagos, GlaxoSmithKline, Janssen, Novartis, Pfizer and UCB, Grant/research support from: Ose Pharmaceuticals, Raphaël Porcher: None declared
Amongst the lysosomal cysteine cathepsin family of proteases, cathepsin S (CTSS) holds particular interest due to distinctive properties including a normal restricted expression profile, inducible upregulation and activity at a broad pH range. Consequently, while CTSS is well-established as a member of the proteolytic cocktail within the lysosome, degrading unwanted and damaged proteins, it has increasingly been shown to mediate a number of distinct, more selective roles including antigen processing and antigen presentation, and cleavage of substrates both intra and extracellularly. Increasingly, aberrant CTSS expression has been demonstrated in a variety of conditions and disease states, marking it out as both a biomarker and potential therapeutic target. This review seeks to contextualise CTSS within the cysteine cathepsin family before providing an overview of the broad range of pathologies in which roles for CTSS have been identified. Additionally, current clinical progress towards specific inhibitors is detailed, updating the position of the field in exploiting this most unique of proteases.
BACKGROUND: Patients with Sjögren syndrome (SjS) have substantial cost burden on the health care system; among these patients, those who develop interstitial lung disease (ILD) experience poorer quality of life and have a higher mortality risk. However, the economic burden of ILD has not been documented. OBJECTIVE: To estimate the direct health care costs associated with ILD among patients with SjS in a representative sample of the commercially insured population in the United States. METHODS: Individuals with a diagnosis of SjS between January 1, 2006, and September 30, 2015, with and without a diagnosis of ILD, were identified from the PharMetrics Plus for Academics database. The index date was defined as the later date of the first claim with a diagnosis of SjS or the first claim with a diagnosis of ILD for individuals with SjS and ILD (SjS-ILD), and the first claim with a diagnosis of SjS for SjS-only controls. All baseline variables were measured in the 180 days preindex period. A 5:1 propensity score matching was applied to controls for baseline demographic and geographic variables. The cost ratio and average marginal effect for total direct medical costs comparing SjS patients with and without ILD were estimated using a generalized linear model. Costs per health care resource utilization category were also reported. All costs were represented from a health plan payer perspective and inflated to 2020 US dollars. RESULTS: After applying the inclusion criteria, 815 SjS-ILD cases were identified and matched to 4,075 SjS-only controls based on the 5:1 propensity score matching procedure. The 180-day total cost of SjS-ILD cases was about 2 times higher compared with that of SjS-only controls (adjusted cost ratio = 1.95; 95% CI = 1.76-2.15). The average difference in total cost between patients with and without ILD was $8,814 (95% CI = $7,149-$10,479). Costs were mainly contributed from outpatient services other than physician office visit (such as radiological and pathological tests), inpatient services, and outpatient pharmacy cost components for both groups (39.4%, 38.8%, and 16.3% for SjS-ILD cases; 43.7%, 22.6%, and 22.9% for SjS-only controls, respectively). CONCLUSIONS: Total direct health care cost was substantially higher in patients with SjS and ILD compared with patients with SjS without ILD. Our findings provide the foundation for further economic evaluation for preventive strategies to reduce the clinical and economic burden imposed by ILD among patients with SjS.
Background
primary Sjogren’s syndrome (pSS) is a chronic autoimmune disease that affects the lacrimal, salivary and other exocrine glands. More and more studies have shown that B cells play a central role in the pathogenesis of SS.
Objectives
We intended to explore the expression of the transmembrane activator, calcium modulator and cyclophilin ligand interactor (TACI) on the B cells, its role in pSS, and possible signal transduction pathways.
Methods
We included 34 naive pSS patients who visited the rheumatology department of Peking University First Hospital, and 37 gender- and age-distribution matched healthy controls (HCs). (1) To compare the B cell subsets, expression of TACI and relevant receptors in pSS patients, peripheral blood mononuclear cells were separated to analyze the ratio of B subsets, TACI, and BAFF-R by flow cytometry; ELISA was applied to detect the serum BAFF and soluble TACI (sTACI) concentration. (2) As for functional research of TACI, CD19+ B cells separated by magnetic sorting were treated under in vitro culture circumstances with raw TACI, TACI knocked down by siRNA, and sTACI analog (telitacicept) intervention with varing doses. The apoptosis, proliferation, differentiation and regulatory capacity on T cells were analyzed by flow cytometry, inflammatory cytokines and immunoglobulin levels in the culture supernatants were detected by CBA. (3) As for TACI-associated signaling pathway exploration, based on our previous miRNA data and relevant report of high quality, miRNA associated with TACI with significantly biased expression was confirmed by RT-qPCR. Screening the target gene of the candidate miRNA, and miRNA overexpression and inhibition experiments were conducted to validate the targeted relationship in B cells. And TACI-associated signaling pathway was explored via overexpressing and inhibiting the target gene.
Results
(1) Compared to HC, peripheral blood B subsets of pSS patients exhibited a significant bias, manifesting as increased proportion of CD19+CD24hiCD38hi Breg and decreased ratio of CD19+CD24+CD38- memory B cells. The expression of TACI in all B subsets was down-regulated, while that of BAFF-R was up-regulated. Both the serum concentration of BAFF and sTACI in pSS patients increased significantly. (2) As for functional research of TACI, in the setting of raw TACI, B cells in the pSS group showed higher apoptosis rate than HC under culture in vitro, where the ligand of TACI (APRIL or BAFF) addition turned the rate comparable; more active proliferation, and impaired capacity of inducing Treg cells to secrete IL-10. When TACI was knocked down by 50%, B cells performed less late apoptosis, significantly increased proliferation, impaired differentiation, significant dysfunction of Breg itself and impaired induction of Treg cells to secrete IL-10. While telitacicept intervention increased early apoptosis rate of B cells, significantly inhibited proliferation in 500ng/mL group and impaired ability of Breg and Treg cells to secrete IL-10. Besides, increased TACI on B cells treated with telitacicept, decreased IgG and increased IgA in the culture supernatants were observed. (3) As for TACI-associated signaling pathway exploration, hsa-miR-30b-5p showed satisfactory correlation between both transmembrane and sTACI. Besides, the expression of hsa-miR-30b-5p was significantly down-regulated, and inhibition its expression in vitro could lead to differentiation retard, impaired secretion of IL-10 by Breg cells. SMAD1 was screened based on database and validated as its target gene by overexpressing and inhibiting hsa-miR-30b-5p in B cell. After targeted up- or down-regulating the transcription of SMAD1 further, the transcription of ID2 downstream the TGF-β/Hippo signaling pathway changed accordingly.
Conclusion
The expression of TACI on peripheral blood B cells was deficient in pSS patients. TACI deficiency was closely associated with the downregulation of hsa-miR-30b-5p, activating TGF-β/Hippo pathway mediated by its target gene SMAD1 and taking part in the pathogenesis of pSS.
Disclosure of Interests
None declared
Background:
Aqueous deficiency dry eye disease is a chronic and potentially sight-threatening condition, that occurs due to the dysfunction of the lacrimal glands. The aim of this review was to describe the various recent developments in the understanding, diagnosis and treatment of lacrimal gland insufficiency in aqueous deficiency dry eye disease.
Methods:
A MEDLINE database search using PubMed was performed using the keywords: "dry eye disease/syndrome", "aqueous deficient/deficiency dry eye disease", "lacrimal gland" and "Sjogren's syndrome". After scanning through 750 relevant abstracts, 73 eligible articles published in the English language from 2016 to 2021 were included in the review.
Results:
Histopathological and ultrastructural studies have revealed new insights into the pathogenesis of cicatrising conjunctivitis-induced aqueous deficiency, where the lacrimal gland acini remain uninvolved and retain their secretory property, while significant ultrastructural changes in the gland have been observed. Recent advances in diagnosis include the techniques of direct clinical assessment of the lacrimal gland morphology and secretion, tear film osmolarity, tear film lysozyme and lactoferrin levels, tear film interferometry and lacrimal gland confocal microscopy. Developments in the treatment of aqueous deficiency dry eye disease, apart from the nanoparticle-based tear substitutes, include secretagogues like diquafosol tetrasodium and rebamipide, anti-inflammatory topical agents like nanomicellar form of cyclosporine and lifitegrast, scleral contact lenses, neurostimulation, and acupuncture for increasing the amount of tear production, minor salivary gland transplantation, faecal microbial transplantation, lacrimal gland regeneration and mesenchymal stem cell therapy.
Conclusions:
Significant advances in the understanding, diagnosis and management of lacrimal gland insufficiency and its role in aqueous deficiency dry eye disease have taken place within the second half of the last decade. Of which, translational breakthroughs in terms of newer drug formulations and regenerative medicine are most promising.
Primary Sjögren’s syndrome (pSS) is a chronic autoimmune disease characterized by sicca symptoms, systemic manifestations and constitutional symptoms substantially diminishing patient´s quality of life. In this review, we summarize recent recommendations for management of pSS patients and current clinical studies in pSS addressing unmet medical needs. Expanding knowledge about disease pathogenesis and the introduction of validated outcome measures, such as capturing disease activity (ESSDAI) and patient-reported outcomes (ESSPRI) have shaped recent developments. In contrast, lack of evidence for current treatment options remarkably limits the management of pSS patients as reflected by the 2019 updated EULAR recommendations for management of Sjögren’s syndrome. In this context, symptomatic treatment is usually appropriate for sicca symptoms, whereas systemic treatment is reserved for moderate to severe organ manifestations including care by a multidisciplinary team in centers of expertise. Most promising targets for new treatment modalities are based on immunopathological insights and include direct B cell targeting strategies, targeting co-stimulation by CD40/CD40L blocking, inhibition of key cytokine activity (BLyS/BAFF, type I interferon) and intracellular signaling pathways.
Background/Aims
Randomised controlled trials (RCTs) of rituximab (RTX) in primary Sjogren’s syndrome (pSS) have failed to alleviate glandular symptoms and fatigue. The question remains as to whether B-cell depleting therapies have a place for the treatment of pSS. Post-hoc analyses from RCTs showed greater improvement in objective measures such as salivary flow rate, salivary gland ultrasound and histology scores in RTX-treated group vs placebo. Moreover, there are limited data on efficacy of the initial and repeat cycles of RTX on extra-glandular pSS. Here, our objectives were to assess the effectiveness of RTX on extra-glandular symptoms and identify predictors of short-term response with a view to personalised B-cell depleting therapy in pSS.
Methods
A retrospective longitudinal cohort study was conducted in 40 consecutive RTX-treated pSS patients in a single-centre for over 15 years. All patients fulfilled the 2002 AEG criteria and were CCP negative. Clinical response at 6 months was defined as ≥ 3 point reduction of ESSDAI from baseline. B-cell subsets were measured using highly sensitive flow cytometry. Predictors of short-term response were analysed using penalised logistic regression.
Results
38/40 (95%) patients were female, mean (SD) age 54 (13.7) years, median (IQR) disease duration 5 (2-9) years, 39/40 (98%) had positive ANA and 28/40 (70%) were on concomitant immunosuppressant (IS). Mean (SD) ESSDAI at RTX initiation was 11.5 (6.7) and main domains for RTX were articular (73%), skin (23%), haematological (18%), PNS (15%) and lungs (10%). 169 RTX cycles were administered with a total follow-up of 165PY. In Cycle 1 (C1) RTX, the proportion of patient achieving ESSDAI response from baseline was 29/40 (73%; 95% CI 58-87). There were significant reductions in ESSDAI, daily prednisolone dose and IgG levels at 6 months (all p < 0.05). Of C1 responders, 23/29 received retreatment on clinical relapse; of which 8/23 (35%) lost response [secondary non-depletion non-response (2NDNR) associated with anti-RTX antibodies as we previously observed in SLE=4 (17%)]; side effects=1; ineffective=3. Of C1 non-responders, 9/11 were retreated but only 2/9 responded in C2. Overall, 13/40 (33%) discontinued RTX within two cycles. In multivariable analysis, concomitant immunosuppressant [OR 0.07 (95% CI 0.01-0.52); p = 0.010] and achieving compete B-cell depletion in C1 [0.04 (0.02-0.82); 0.036] reduced non-response to RTX.
Conclusion
All patients with pSS should be co-prescribed immunosuppressant with RTX and future therapeutics should aim to achieve complete depletion. About one in six pSS patients lose response in repeat cycles which is associated with 2NDNR phenomenon. The use of humanised or next-generation type 2 anti-CD20 antibodies should overcome these issues and improve the clinical response of extra-glandular pSS.
Disclosure
S. Pepple: None. J. Arnold: None. E. M Vital: Consultancies; Dr Vital has received consulting fees from Roche. Grants/research support; Dr Vital has received funding for research from Roche. A. C Rawstron: None. C. Pease: None. S. Dass: None. P. Emery: Consultancies; Prof Emery has received consulting fees from Roche. Grants/research support; Prof Emery has received funding for research from Roche. M. Md Yusof: None.
Background
The British Isles Lupus Assessment Group-based Composite Lupus Assessment (BICLA) is a validated global measure of treatment response in systemic lupus erythematosus (SLE) clinical trials but does not include patient-reported outcomes. To evaluate the clinical meaningfulness of a BICLA response from the patient perspective, we aimed to analyse patient-reported outcomes by BICLA responses with anifrolumab or placebo in patients with moderate to severe SLE.
Methods
We did a post-hoc analysis of pooled data from the phase 3 TULIP-1 (NCT02446912) and TULIP-2 (NCT02446899) trials of anifrolumab, which assessed health-related quality of life using the Short Form 36 Health Survey (SF-36; version 2) and Lupus Quality of Life, fatigue using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), pain using the Numerical Rating Scale, and disease activity using Patient Global Assessment. Changes from baseline and proportions of patients reporting improvements in patient-reported outcomes greater than or equal to the minimum clinically important differences and scores greater than or equal to the normative values were compared in BICLA responders and non-responders and by treatment group (intravenous anifrolumab 300 mg or placebo).
Findings
726 patients were included in the TULIP trials, of whom 366 received placebo (184 patients in TULIP-1 and 182 in TULIP-2) and 360 received anifrolumab 300 mg (180 patients in each trial). The mean patient age was 41·8 years (SD 11·9). 674 (93%) patients were female, 52 (7%) were male, and 479 (66%) were White; 283 (39%) were BICLA responders and 443 (61%) were BICLA non-responders. Compared with non-responders, BICLA responders reported greater mean improvements from baseline at week 52 in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores (all nominal p<0·0053). Compared with non-responders, a greater proportion of BICLA responders reported improvements greater than or equal to the minimum clinically important difference across all SF-36 domains; eg, Physical Component Summary (165 [60%] of 277 for responders vs 63 [15%] of 416 for non-responders), Mental Component Summary (140 [51%] of 276 vs 59 [15%] of 416), and role physical (184 [70%] of 264 vs 76 [19%] of 398); Lupus Quality of Life domains; eg, physical health (151 [58%] of 262 vs 60 [15%] of 396), and intimate relationships (77 [41%] of 187 vs 33 [11%] of 286), and FACIT-F (155 [56%] of 276 vs 66 [15%] of 439). Similarly, a greater proportion of BICLA responders had scores equal to or greater than the normative values across all SF-36 domains and FACIT-F compared with BICLA non-responders at week 52. Patients who received anifrolumab reported greater numerical improvements in Patient Global Assessment, SF-36, Lupus Quality of Life, FACIT-F, and pain Numerical Rating Scale scores than those who received placebo.
Interpretation
BICLA responders reported significant and clinically meaningful improvements in Patient Global Assessment, health-related quality of life, fatigue, and pain compared with BICLA non-responders. More patients with moderate to severe SLE who received anifrolumab were BICLA responders and had improved health-related quality of life, fatigue, and pain than those who received placebo.
Funding
AstraZeneca.
Objective
To investigate treatment efficacy of long-term abatacept treatment in pSS patients.
Methods
The single-centre ASAP-III trial consisted of two phases: the randomised, double-blind, placebo-controlled phase (1:1 randomisation) from baseline to week 24, of which results have been published previously, and the open-label extension phase from week 24 to 48, in which all patients received abatacept. Main inclusion criteria were fulfilment of the AECG criteria, positive gland biopsy, disease duration ≤7 years and ESSDAI ≥5. Long-term treatment effects of abatacept on clinical, patient-reported, glandular and laboratory outcome measures were assessed in patients treated with abatacept from baseline to week 48. Furthermore, Composite of Relevant Endpoints in Sjögren's Syndrome (CRESS) response (response on ≥3 of 5 items) was analysed.
Results
In patients on abatacept treatment for 48 weeks (n=40), median ESSDAI improved from baseline 14.0 (IQR 9.0-16.8) to 4.0 (2.0-8.0) at week 48 (p<0.001), with 50% of patients reaching low disease activity (ESSDAI<5) at week 48. Median ESSPRI improved from 7.0 (IQR 5.4-7.7) to 5.0 (3.7-6.7) (p<0.001). Significant improvement was also seen in dry eye and laboratory tests. Combining response at multiple clinically relevant items, 73% of patients were CRESS responders at week 48. Additional improvement was seen between week 24 and week 48 of abatacept treatment.
Conclusion
In the open-label extension phase of the ASAP-III trial, improvement was seen up to 48 weeks of abatacept treatment in clinical, patient-reported, dry eye and laboratory outcomes. The majority of patients were CRESS responders at week 48.
Background
Sjögren's syndrome is an autoimmune disease characterised by dry eyes and mouth, systemic features, and reduced quality of life. There are no disease-modifying treatments. A new biologic, ianalumab (VAY736), with two modes of suppressing B cells, has previously shown preliminary efficacy. This dose-finding trial aimed to assess the safety and efficacy of different subcutaneous doses of ianalumab in patients with moderate to severe primary Sjögren's syndrome.
Methods
VAY736A2201 was a randomised, parallel, double-blind, placebo-controlled, phase 2b dose-finding study done in 56 centres in 19 countries. Patients aged 18–75 years with primary Sjögren's syndrome with moderate to severe disease activity (European Alliance of Associations for Rheumatology [EULAR] Sjögren's Syndrome Disease Activity Index [ESSDAI] score ≥6) and symptom severity (EULAR Sjögren's Syndrome Patient Reported Index score ≥5) were eligible. Participants were randomly assigned (1:1:1:1) to receive subcutaneous placebo or ianalumab (5 mg, 50 mg, or 300 mg) every 4 weeks for 24 weeks using a secure, online randomisation system. Randomisation was stratified by the ESSDAI score at baseline (≥10 or <10). Study personnel and patients were masked to treatment assignment. The primary outcome was the change in ESSDAI score from baseline to 24 weeks in all randomly assigned patients. Dose-related change in disease activity (ESSDAI) from baseline at week 24 was assessed by multiple comparison procedure with modelling analysis. Safety was measured in all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, NCT02962895.
Findings
Between June 27, 2017, and Dec 06, 2018, 293 patients were screened, 190 of whom were randomly assigned (placebo n=49, ianalumab 5 mg n=47, ianalumab 50 mg n=47, ianalumab 300 mg n=47). Statistically significant dose-responses were seen for overall disease activity (ESSDAI score) in four of the five dose-response models tested (p<0·025 in four models, p=0·060 in one model). The ESSDAI score decreased from baseline in all ianalumab groups, with the maximal ESSDAI score change from baseline observed in the ianalumab 300 mg group: placebo-adjusted least-squares mean change from baseline −1·92 points (95% CI −4·15 to 0·32; p=0·092). There were four serious adverse events in three patients considered treatment-related (pneumonia [n=1] and gastroenteritis [n=1] in the placebo group; appendicitis plus tubo-ovarian abscess in the same patient in the ianalumab 50 mg group).
Interpretation
The study met its primary objective, showing a dose-related decrease in disease activity as measured by ESSDAI at week 24. Overall, ianalumab was well tolerated and safe, with no increase in infections. To our knowledge, this is the first large, randomised, controlled trial in primary Sjögren's syndrome that met its primary endpoint, and its results mean there is potential for more studies of this mechanism in the future.
Funding
Novartis.
Objectives:
In this observational, analytical, cross-sectional study we aimed to describe the impact of primary Sjögren's syndrome (pSS) on work productivity and activities of daily living (ADL) to assess the association between ADL impairment and clinical manifestations and to compare ADL impairment according to patients' socioeconomic condition.
Methods:
Patients diagnosed with pSS attending 11 centres from Argentina were included. To evaluate work productivity and ADL impairment, a work productivity and activity impairment questionnaire (WPAI) was used. A multiple linear regression model was performed, considering deterioration on ADL due to health as a dependent variable, adjusted for potential confounders.
Results:
252 patients were included, 98.4% were women, with a mean age of 52.6 years (±14.8). The average percentage of time lost due to health was 15.7 hours (±30.1 95% CI: 9.6-21.9); the decrease in work productivity was 27.2 (±30.2 95% CI: 21.3-33.1), the total disability was 33.7 (±35.8 95% CI: 26.4-4) and ADL deterioration was 34.2 (±30.9. 95% CI: 30.4-38). In the multivariate analysis, xerostomia, arthritis and depression showed significant and independent association. The mean of ADL impairment was 38.2 (±30.7) in patients attending public centres versus 28 (± 30.6) in private centres, which was a statistically significant difference.
Conclusions:
We found a compromise in all WPAI domains. Arthritis, xerostomia and depression were associated significantly and independently with ADL impairment. Deterioration in ADL was greater in patients treated in public centres. Considering these aspects will allow a better understanding of patients who suffer from this disease.
Telitacicept (Tai'ai®) is fusion protein comprising a recombinant transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI) receptor fused to the fragment crystallizable (Fc) domain of human immunoglobulin G (IgG). Telitacicept is being developed by Yantai Rongchang Pharmaceutical through its subsidiary RemeGen for the treatment of B cell-mediated autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA) and multiple sclerosis (MS). Telitacicept binds to and neutralizes the activity of two cell-signalling molecules, B-lymphocyte stimulator (BLyS) and a proliferation-inducing ligand (APRIL), thereby suppressing the development and survival of plasma cells and mature B cells. In March 2021, telitacicept received its first approval in China for the treatment of patients with active SLE. Clinical studies of telitacicept in several other indications, including IgA nephropathy, MS, myasthenia gravis, neuromyelitis optica spectrum disorders, RA and Sjögren's syndrome are underway in China. This article summarizes the milestones in the development of telitacicept leading to this first approval for SLE.
A randomized, placebo-controlled trial has found the neonatal Fc receptor modulator efgartigimod to be an effective therapy for generalized myasthenia gravis. If a pending FDA application is approved, the treatment will be the first recombinant antibody-based therapy for selective IgG depletion, adding to a growing spectrum of treatment options for myasthenia gravis.
Primary Sjögren syndrome (pSS) is a systemic autoimmune disease that is characterized by a triad of symptoms that affect all patients (dryness, pain and fatigue). In addition, systemic involvement can affect between one-third and one-half of patients. The management of patients with pSS has been negatively affected by a lack of effective treatments; however, knowledge of the epidemiology of pSS has increased, and advances in developing classification criteria, systemic disease activity scoring and patient-reported outcomes have been made during the past decade. Progress has also been made in understanding the mechanisms that underlie the pathogenesis of pSS, which has enabled a more targeted therapeutic approach to be taken. At present, therapeutic decisions rely on the evaluation of symptoms and systemic manifestations and are mostly formed on the basis of experience rather than evidence, and on similarities with other autoimmune diseases, although the 2019 management recommendations from EULAR are now being used to inform clinical management of pSS. This Review summarizes the available evidence for systemic treatments for pSS and includes discussions of advances in outcome assessment, the current evidence for DMARD use and an overview of promising future therapeutics.
Background
Sjogren’s syndrome (SS) is an autoimmune disease affecting excretory glands and characterised by B-cell hyperactivity. Ianalumab (VAY736) is a human monoclonal antibody to B-cell activating factor receptor, engineered for direct ADCC-mediated B-cell depletion. A Phase 2b study evaluated the dose-response of VAY736 vs placebo (PBO) in EULAR SS Disease Activity Index (ESSDAI) change from baseline (CHB) and other secondary endpoints.
Objectives
Primary results at Week (Wk) 24 were reported previously¹. Here we report 52 Wk safety and efficacy from extended blinded treatment period 2 (TP2).
Methods
190 patients (pts) were randomised equally to receive s.c. doses of VAY736 (5, 50, 300 mg) or PBO every 4 Wks (q4w). Eligible pts fulfilled American European Consensus Group (AECG) criteria, were anti-Ro/SSA+, had ESSDAI ≥6 and EULAR SS Patient Reported Index (ESSPRI) ≥5. At Wk 24, after completion of the first blinded TP (TP1), PBO-treated pts were switched to VAY736 150 mg, and pts on 300 mg were re-randomised to continue 300 mg or PBO for 28 Wks in TP2. Pts were followed post-treatment for ≥20 Wks. Safety was assessed for all periods. Due to lack of PBO-control in TP2, descriptive efficacy analysis was performed for ESSDAI, ESSPRI, Functional Assessment of Chronic Illness Therapy Fatigue (FACIT-F), Physician’s (PhGA) and Patient’s Global Assessments (PaGA), SF-36, and SS symptom diary (SSSD).
Results
Overall, there was no dose dependency of treatment emergent adverse events (TEAEs) except for injection site reactions, which were mostly mild to moderate in severity. Lymphopenia and neutropenia were mostly grade (G)1 and G2, no G4. Most common TEAEs were infections and infestations in exposure-adjusted analysis of incidence rates. Nasopharyngitis and upper respiratory tract infections were the most common TEAEs, with no dose response (Table 1). Tracheobronchitis and pneumonia, were mild to moderate severity, not associated with absolute neutrophil count G3, and none led to treatment withdrawal.At Wk 52, efficacy was sustained for pts who continued 300 mg in TP2 (ESSDAI, ESSPRI, PaGA, PhGA CHB: –9.06, –1.91, –22.03, –35.80, respectively). Efficacy was partially lost for pts switched to PBO at Wk 24 (Figure 1). Improvement was noted for PBO pts switched to 150 mg. Stimulated whole salivary flow at Wk 24 was improved for 300 mg (PBO-adjusted CHB 0.20 ml/min; P=0·037); last measurement at Wk 48 was 0.45 and 0.22 ml/min CHB in pts who continued 300 mg or PBO in TP2, respectively.
Conclusion
Ianalumab 300 mg was well tolerated up to 52 Wks. Exploratory efficacy showed that continuous dosing of 300 mg s.c. q4w provided sustained clinical benefit. PaGA was the outcome that showed the most prominent change following switch to PBO or VAY736.
References
[1]Dörner T, et al. [OP0302]. Ann Rheum Dis. 2020; 79 (suppl 1).View this table:
• View inline
• View popup
Table 1. Key Safety Data (All Study Periods up to Week 52)*
• Download figure
• Open in new tab
• Download powerpoint
Disclosure of Interests
Thomas Dörner Consultant of: Novartis, GSK, Sanofi, Janssen, Eli Lilly, Grant/research support from: Deutsche Forschungsgemeinschaft, Simon J. Bowman Consultant of: Astrazeneca, Biogen, BMS, Celgene, Medimmune, MTPharma, Novartis, Ono, UCB, xtlbio, Robert Fox Consultant of: Novartis, Pfizer and Lilly, Xavier Mariette Consultant of: BMS, Galapagos, Gilead, Medimmune, GSK, Grant/research support from: Servier, Athena Papas Consultant of: Novartis, Grant/research support from: Novartis, Thomas Grader-Beck Consultant of: Novartis, Lilly, Grant/research support from: Abbvie, Celgene, Ben A Fisher Consultant of: Novartis, Roche, BMS and Servier, Filipe Barcelos Consultant of: Pfizer and Lilly, Salvatore De Vita Consultant of: Roche, Human Genome Science, Glaxo Smith Kline and Novartis, Hendrik Schulze-Koops Consultant of: Novartis, Robert J Moots Consultant of: Amgen, Chugai, Gilead, Lilly, Novartis, Pfizer, Roche, Grant/research support from: Amgen, Chugai, Gilead, Lilly, Novartis, Pfizer, Roche, Guido Junge Shareholder of: Novartis, Employee of: Novartis, Janice Woznicki Shareholder of: Novartis, Employee of: Novartis, Monika Sopala Shareholder of: Novartis, Employee of: Novartis, Wen-Lin Luo Shareholder of: Novartis, Employee of: Novartis, Wolfgang Hueber Shareholder of: Novartis, Employee of: Novartis
Introduction: Sjögren’s syndrome is a unique systemic autoimmune disease, placed in the center of systemic autoimmunity and at the crossroads of autoimmunity and lymphoproliferation. The diverse clinical picture of the disease, the inefficacy of current biologic treatments, and the co-existence with lymphoma conferring to the patients’ morbidity and mortality force the scientific community to review disease pathogenesis and reveal the major implicated cellular and molecular elements.
Areas covered: Biomarkers for early diagnosis, prediction, stratification, monitoring, and targeted treatments can serve as a tool to interlink and switch from the clinical phenotyping of the disease into a more sophisticated classification based on the underlying critical molecular pathways and endotypes. Such a transition may define the establishment of the so-called precision medicine era in which patients’ management will be based on grouping according to pathogenetically related biomarkers. In the current work, literature on Sjogren’s syndrome covering several research fields including clinical, translational, and basic research has been reviewed.
Expert opinion: The perspectives of clinical and translational research are anticipated to define phenotypic clustering of high-risk pSS patients and link the clinical picture of the disease with fundamental molecular mechanisms and molecules implicated in pathogenesis.
Objectives
No immunomodulatory drug has been approved for primary Sjögren’s syndrome, a systemic autoimmune disease affecting 0.1% of the population. To demonstrate the efficacy of targeting interleukin 6 receptor in patients with Sjögren’s syndrome-related systemic complications.
Methods
Multicentre double-blind randomised placebo-controlled trial between 24 July 2013 and 16 July 2018, with a follow-up of 44 weeks, involving 17 referral centres. Inclusion criteria were primary Sjögren’s syndrome according to American European Consensus Group criteria and score ≥5 for the EULAR Sjögren’s Syndrome Disease activity Index (ESSDAI, score of systemic complications). Patients were randomised to receive either 6 monthly infusions of tocilizumab or placebo. The primary endpoint was response to treatment at week 24. Response to treatment was defined by the combination of (1) a decrease of at least 3 points in the ESSDAI, (2) no occurrence of moderate or severe activity in any new domain of the ESSDAI and (3) lack of worsening in physician’s global assessment on a Visual Numeric Scale ≥1/10, all as compared with enrolment.
Results
110 patients were randomised, 55 patients to tocilizumab (mean (SD) age: 50.9 (12.4) years; women: 98.2%) and 55 patients to placebo (54.8 (10.7) years; 90.9%). At 24 weeks, the proportion of patients meeting the primary endpoint was 52.7% (29/55) in the tocilizumab group and 63.6% (35/55) in the placebo group, for a difference of −11.4% (95% credible interval −30.6 to 9.0) (Pr[Toc >Pla]=0.14).
Conclusion
Among patients with primary Sjögren’s syndrome, the use of tocilizumab did not improve systemic involvement and symptoms over 24 weeks of treatment compared with placebo.
Trial registration number
NCT01782235 .
Health-related quality of life (HRQoL) has an increasing role in medical decision-making. This review of the literature aims to provide an overview on HRQoL, costs, and work disability in SS, a disease characterized by focal lymphocytic infiltration of exocrine glands with no therapeutics of proven immunomodulatory potential. HRQoL is markedly reduced in SS in multiple studies across many countries when compared with HRQoL in healthy controls. The reduction in HRQoL is similar to that observed in other chronic diseases such as RA, SLE, FM and, interestingly, non-SS sicca syndrome. Impaired HRQoL in SS has been found to be associated with fatigue, pain/articular involvement, ocular and oral involvement, pruritus, sexual dysfunction, impaired sleep, pulmonary manifestations, psychological dysfunction and impaired physical function. Until now, no therapeutic has been shown to improve HRQoL in an adequately powered double-blind, placebo-controlled randomized controlled trial. Although primary SS does not, in general, impair life expectancy and is often inappropriately considered a benign ‘nuisanvce’ disease for those patients without systemic manifestations, the associated costs and work disability are striking. This, together with the significant reduction in HRQoL, strongly argues for the development of new therapeutic approaches to manage this neglected disease.