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Pilot study of baricitinib for active Sjogren’s syndrome
... Very recently, the efficacy and safety of baricitinib for active pSS patients have been explored in a pilot non-controlled trial. [67] , Phisycian Global Assessment Score (PGA), Immunoglobulin G (IgG), and remission/improvement of single-organ manifestations have been also collected and evaluated. Patients were treated with baricitinib 2 mg per day and followed up at 3 months and 6 months after starting the therapy. ...
... At 6 months, 88.9% patients achieved minimal clinical improvement of ESSDAI. [67] A decreasing trend in IgG and ESR (Erythrocyte sedimentation rate) levels was also observed. Main clinical manifestations showing improvement compared with baseline were skin rash and arthritis, consistent with the study of baricitinib in active SLE patients, [68] weight loss, anemia, and cytopenia. ...
... A flare of HBV (hepatitis B virus) was the only adverse event reported. [67] Besides major limitations of the study, mainly the absence of a control group, the treatment with baricitinib appears promising in pSS, and high-quality randomized controlled clinical trials are needed to confirm these preliminary results. ...
Primary Sjögren's syndrome (pSS) is an autoimmune systemic disease mainly affecting exocrine glands and resulting in disabling symptoms, as dry eye and dry mouth. Mechanisms underlying pSS pathogenesis are intricate, involving multiplanar and, at the same time, interlinked levels, e.g., genetic predisposition, epigenetic modifications and the dysregulation of both immune system and glandular-resident cellular pathways, mainly salivary gland epithelial cells. Unravelling the biological and molecular complexity of pSS is still a great challenge but much progress has been made in recent years in basic and translational research field, allowing the identification of potential novel targets for therapy development. Despite such promising novelties, however, none therapy has been specifically approved for pSS treatment until now. In recent years, growing evidence has supported the modulation of Janus kinases (JAK) - signal transducers and activators of transcription (STAT) pathways as treatment strategy immune mediated diseases. JAK-STAT pathway plays a crucial role in autoimmunity and systemic inflammation, being involved in signal pathways of many cytokines. This review aims to report the state-of-the-art about the role of JAK-STAT pathway in pSS, with particular focus on available research and clinical data regarding the use of JAK inhibitors in pSS.
... Baricitinib contributes to improving disease activity, achieves minimal clinically important improvement, and ameliorates symptoms (e.g., weight loss, skin rash, arthritis, anemia, and cytopenia) in patients with pSS. [120] However, a randomized-controlled study of filgotinib in patients with pSS with moderate-tohigh disease activity found no significant improvement in prespecified criteria based on C-reactive protein and SSrelated symptoms at week 12. But the results of a subgroup analysis indicated the potential effectiveness of filgotinib in patients with severe disease activity and with no concomitant medications. ...
... Most studies on the role of JAK-STAT pathway in pSS have revealed the increases in JAK and STAT molecules (i.e., JAK-STAT pathway activation), the aberrant expression of negative regulatory proteins, and downstream pathologic effects related to corresponding clinical symptoms in patients. However, there are some conflicting experimental [93] SS patients No significant improvement, but potentially effective in severe SS (NCT03100942) [121] Baricitinib (non-selective) Salivary gland ductal cells from pSS patients Inhibit aberrant high expression of tissue-type plasminogen activator [97] pSS patients Effective and well-tolerated (NCT04916756) [120] pSS patients NCT05016297 À Tofacitinib findings among these studies. For instance, the changes in the expression levels of negative regulatory proteins vary in some cases. ...
Primary Sjögren's syndrome (pSS) is a systemic autoimmune disease with high prevalence and possible poor prognosis. Though the pathogenesis of pSS has not been fully elucidated, B cell hyperactivity is considered as one of the fundamental abnormalities in pSS patients. It has long been identified that Janus kinases-signal transducer and activator of transcription (JAK-STAT) signaling pathway contributes to rheumatoid arthritis and systemic lupus erythematosus. Recently, increasing numbers of studies have provided evidence that JAK-STAT pathway also has an important role in the pathogenesis of pSS via direct or indirect activation of B cells. Signal transducer and activator of transcription 1 (STAT1), STAT3, and STAT5 activated by various cytokines and ribonucleic acid contribute to pSS development, respectively or synergically. These results reveal the potential application of Janus kinase inhibitors for treatment of pSS, which may fundamentally improve the quality of life and prognosis of patients with pSS.
... According to the results of our pilot study [24] and clinical experiments, the expected response rate is 70% (μ) in baricitinib + HCQ group, and 30% (μ0) in HCQ group. We use this formula to calculate the sample size: ...
... In the pilot study, we involved 11 pSS patients with ESSDAI ≥ 5 and treated them with baricitinib 2 mg per day on the basis of the original treatment. We found that baricitinib significantly improved the ESSDAI score and might be helpful for the management of various manifestations of pSS, such as constitutional symptoms, arthritis, skin rash, hematological involvement, and even interstitial lung disease [24]. Since it is a pilot study with no controlled group, and we did not test the dosage of 4 mg baricitinib per day in pSS, which was involved in the clinical trial of SLE [20], and proven to be effective and safe for the management of RA [29], we designed this prospective, randomized controlled study to better evaluate the potential therapeutic efficacy of baricitinib in pSS. ...
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.
... In the context of the complex cytokine landscape characterizing pSS, numerous JAK inhibitors, including baricitinib, filgotinib, tofacitinib, oclacitinib, and upadacitinib, have found applications in the treatment of autoimmune diseases (Tanaka et al., 2022). In a recent pilot trial of 11 active pSS patients, the JAK1 and JAK2 inhibitor, baricitinib, showed promise in reducing immune cell infiltration and improving clinical manifestations, although controlled trials are needed for validation (Bai et al., 2022). Filgotinib, a JAK1 inhibitor, has shown potential in reducing IFN-related genes and BAFF in pSS. ...
Primary Sjögren’s Syndrome (pSS) is a complex autoimmune disorder characterized by exocrine gland dysfunction, leading to dry eyes and mouth. Despite growing interest in biologic therapies for pSS, FDA approval has proven challenging due to trial complications. This review addresses the absence of a molecular-target-based approach to biologic therapy development and highlights novel research on drug targets and clinical trials. A literature search identified potential pSS treatment targets and recent advances in molecular understanding. Overlooking extraglandular symptoms like fatigue and depression is a notable gap in trials. Emerging biologic agents targeting cytokines, signal pathways, and immune responses have proven efficacy. These novel therapies could complement existing methods for symptom alleviation. Improved grading systems accounting for extraglandular symptoms are needed. The future of pSS treatment may involve gene, stem-cell, and tissue-engineering therapies. This narrative review offers insights into advancing pSS management through innovative biologic interventions.
... Very recently, the efficacy and safety of baricitinib for active SS patients have been explored in a pilot non-controlled trial. Baricitinib contributes to improving disease activity and main clinical manifestations, promising for the treatment of SS (113). The main active ingredient of total paeoniflorin is paeoniflorin (Pae), which has been used clinically for the treatment of autoimmune diseases (114). ...
Sjögren’s syndrome (SS) is a chronic systemic autoimmune disease that typically presents with lymphocyte, dendritic cell, and macrophage infiltration of exocrine gland ducts and the formation of ectopic germinal centers. The interactions of lymphocyte homing receptors and addressins and chemokines and their receptors, such as α4β7/MAdCAM-1, LFA-1/ICAM-1, CXCL13/CXCR5, CCL25/CCR9, CX3CL1/CX3CR1, play important roles in the migration of inflammatory cells to the focal glands and the promotion of ectopic germinal center formation in SS. A variety of molecules have been shown to be involved in lymphocyte homing, including tumor necrosis factor-α, interferon (IFN)-α, IFN-β, and B cell activating factor. This process mainly involves the Janus kinase-signal transducer and activator of transcription signaling pathway, lymphotoxin-β receptor pathway, and nuclear factor-κB signaling pathway. These findings have led to the development of antibodies to cell adhesion molecules, antagonists of chemokines and their receptors, compounds interfering with chemokine receptor signaling, and gene therapies targeting chemokines and their receptors, providing new targets for the treatment of SS in humans. The aim of this study was to explore the relationship between lymphocyte homing and the pathogenesis of SS, and to provide a review of recent studies addressing lymphocyte homing in targeted therapy for SS.
... Lee et al. reported that FLG, a selective inhibitor of JAK1, suppressed IFN-related genes and B cellactivating factors in the human SG epithelial cells of patients with SS [86]. The clinical effects of BAR on SS, which were reflected as an improvement in ESSDAI, were observed in a relatively small patient group with SS [87], which has yet to be clarified in a randomized controlled study [88]. In contrast, the therapeutic effects of FLG on active SS, another class of JAKi, have already been studied in a randomized double-blind, placebo-controlled study, which did not reach statistical significance [89]. ...
Sjögren’s syndrome (SS) is a rheumatic disease characterized by sicca and extraglandular symptoms, such as interstitial lung disease and renal tubular acidosis. SS potentially affects the prognosis of patients, especially in cases of complicated extraglandular symptoms; however, only symptomatic therapies against xerophthalmia and xerostomia are currently included in the practice guidelines as recommended therapies for SS. Considering that SS is presumed to be a multifactorial entity caused by genetic and environmental factors, a multidisciplinary approach is necessary to clarify the whole picture of its pathogenesis and to develop disease-specific therapies for SS. This review discusses past achievements and future prospects for pursuing the pathophysiology and therapeutic targets for SS, especially from the perspectives of viral infections, toll-like receptors (TLRs), long-noncoding RNAs (lncRNAs), and related signals. Based on the emerging roles of viral infections, TLRs, long-noncoding RNAs and related signals, antiviral therapy, hydroxychloroquine, and vitamin D may lower the risk of or mitigate SS. Janus-kinase (JAK) inhibitors are also potential novel therapeutic options for several rheumatic diseases involving the JAK-signal transducer and activator of transcription pathways, which are yet to be ascertained in a randomized controlled study targeting SS.
... Baricitinib is a selective JAK1/2 inhibitor and has therapeutic effects in RA patients. In a pilot study, baricitinib improved symptoms of arthritis and skin rash in patients with SS [201]. PI3Kδ is involved in B cell receptor signaling. ...
Sjögren’s syndrome (SS) is an autoimmune disease characterized by the involvement of exocrine glands such as the salivary and lacrimal glands. The minor salivary glands, from which tissue samples may be obtained, are important for the diagnosis, evaluation of therapeutic efficacy, and genetic analyses of SS. In the onset of SS, autoantigens derived from the salivary glands are recognized by antigen-presenting dendritic cells, leading to the activation of T and B cells, cytokine production, autoantibody production by plasma cells, the formation of ectopic germinal centers, and the destruction of salivary gland epithelial cells. A recent therapeutic approach with immune checkpoint inhibitors for malignant tumors enhances the anti-tumor activity of cytotoxic effector T cells, but also induces SS-like autoimmune disease as an adverse event. In the treatment of xerostomia, muscarinic agonists and salivary gland duct cleansing procedure, as well as sialendoscopy, are expected to ameliorate symptoms. Clinical trials on biological therapy to attenuate the hyperresponsiveness of B cells in SS patients with systemic organ involvement have progressed. The efficacy of treatment with mesenchymal stem cells and chimeric antigen receptor T cells for SS has also been investigated. In this review, we will provide an overview of the pathogenesis of salivary gland lesions and recent trends in therapeutic approaches for SS.
... 30 )), tofacitinib could suppress IL-6 production caused by deficient autophagy 171 . Another JAK inhibitor, baricitinib, indicated possible efficacy in a small pilot study involving 11 patients with pSS 172 . ...
In primary Sjögren syndrome (pSS), chronic inflammation of exocrine glands results in tissue destruction and sicca symptoms, primarily of the mouth and eyes. Fatigue, arthralgia and myalgia are also common symptoms, whereas extraglandular manifestations that involve the respiratory, nervous and vascular systems occur in a subset of patients. The disease predominantly affects women, with an estimated female to male ratio of 14 to 1. The aetiology of pSS, however, remains incompletely understood, and effective treatment is lacking. Large-scale genetic and epigenetic investigations have revealed associations between pSS and genes in both innate and adaptive immune pathways. The genetic variants mediate context-dependent effects, and both sex and environmental factors can influence the outcome. As such, genetic and epigenetic studies can provide insight into the dysregulated molecular mechanisms, which in turn might reveal new therapeutic possibilities. This Review discusses the genetic and epigenetic features that have been robustly connected with pSS, putting them into the context of cellular function, carrier sex and environmental challenges. In all, the observations point to several novel opportunities for early detection, treatment development and the pathway towards personalized medicine.
... Suppression of IFN-stimulated JAK-STAT signalling by oral JAK-inhibitors is currently considered in ongoing clinical trials (such as with tofacitinib, a dual JAK 1/2 inhibitor) [120]. In a pilot phase I/II proof-of-concept study, baricitinib proved effective in providing benefit in the majority of patients with high disease activity [121]. Lastly, Anifrolumab, a monoclonal antibody, which directly targets IFN-1 [122] and was recently approved for the treatment of SLE [123,124], is under investigation, and the results of current trials in pSS are eagerly awaited [125]. ...
Sjögren’s syndrome is one of the most prevalent autoimmune diseases after rheumatoid arthritis, with a preference for middle age, and is characterised by exocrine glandular involvement leading to xerostomia and xerophthalmia. It can have systemic implications with vascular, neurological, renal, and pulmonary involvement, and in some cases, it may evolve to non-Hodgkin’s lymphoma. For a long time, B- and T-lymphocytes have been the focus of research and have been considered key players in Sjögren’s syndrome pathogenesis and evolution. With the development of new technologies, including omics, more insights have been found on the different signalling pathways that lead to inflammation and activation of the immune system. New evidence indicates that a third actor linking innate and adaptive immunity plays a leading role in the Sjögren’s syndrome play: the monocyte. This review summarises the recent insights from transcriptomic, proteomic, and epigenetic studies that help us to understand more about the Sjögren’s syndrome pathophysiology and redefine the involvement of monocytes in this disease.
Introduction:
Sjögren's syndrome is a heterogeneous autoimmune condition that impairs quality of life because of dryness, fatigue, pain, and systemic involvements. Current treatment largely depends on empirical evidence, with no effective therapy approved. Clinical trials on targeted drugs often fail to report efficacy due to common factors.
Areas covered:
This review summarizes the pathogenesis and what caused the failure of new investigational drugs in clinical trials, highlighting solutions for more effective investigations, with greater consistency between research outcomes, clinical use, and patient needs.
Expert opinion:
Unlinked pathobiology with symptoms resulted in misidentified targets and disappointing trials. Useful stratification tools are necessary for the heterogeneous SS patients. Composite endpoints or improvements in ESSDAI scores are needed, considering the high placebo response, and the unbalance between symptom burden and disease activity. Compared to classic biologics, targeted cell therapy will be a more promising field of investigation in the coming years.
The four Janus kinase (JAK) proteins and the seven Signal Transducers of Activated Transcription (STAT) mediate intracellular signal transduction downstream of cytokine receptors, which are involved in the pathology of allergic, autoimmune, and inflammatory diseases. The development of targeted small-molecule treatments with diverse selective inhibitory profiles, such as JAK inhibitors (JAKi), has supported an important change in the treatment of multiple disorders. Indeed, JAKi inhibit intracellular signalling controlled by numerous cytokines implicated in the disease process of rheumatoid arthritis and several other inflammatory and immune diseases. Therefore, JAKi have the capacity to target multiple pathways of those diseases. Other autoimmune diseases treated with JAKi include systemic sclerosis, systemic lupus erythematosus, dermatomyositis, primary Sjogren's syndrome, and vasculitis. In all of these cases, innate immunity stimulation activates adaptive immunity, resulting in the production of autoreactive T cells as well as the stimulation and differentiation of B cells. Mechanism-based treatments that target JAK-STAT pathways have the possibility of improving outcomes by reducing the consumption of glucocorticoids and/or non-specific immunosuppressive drugs in the management of systemic immune-mediated inflammatory diseases.
Sjögren’s syndrome (SS) is a chronic autoimmune disease targeting salivary and lacrimal glands. C-X-C motif chemokine ligand 10 (CXCL10) expression is upregulated in lip salivary glands (LSGs) of primary SS (pSS) patients, and CXCL10 involved in SS pathogenesis via immune-cell accumulation. Moreover, interferon (IFN)-γ enhances CXCL10 production via the Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway. We investigated the effects of baricitinib, a selective JAK1/2 inhibitor, on both IFN-γ-induced CXCL10 production and immune-cell chemotaxis. We used immunohistochemical staining to determine the expression levels and localization of JAK1 and JAK2 in LSGs of SS patients (n = 12) and healthy controls (n = 3). We then evaluated the effect of baricitinib in an immortalized normal human salivary gland ductal (NS-SV-DC) cell line. Immunohistochemical analysis of LSGs from pSS patients revealed strong JAK1 and JAK2 expression in ductal and acinar cells, respectively. Baricitinib significantly inhibited IFN-γ-induced CXCL10 expression as well as the protein levels in an immortalized human salivary gland ductal-cell clone in a dose-dependent manner. Additionally, western blot analysis showed that baricitinib suppressed the IFN-γ-induced phosphorylation of STAT1 and STAT3, with a stronger effect observed in the case of STAT1. It also inhibited IFN-γ-mediated chemotaxis of Jurkat T cells. These results suggested that baricitinib suppressed IFN-γ-induced CXCL10 expression and attenuated immune-cell chemotaxis by inhibiting JAK/STAT signaling, suggesting its potential as a therapeutic strategy for pSS.
The dysregulation of the JAK–STAT pathway is associated with various immune disorders. Four JAK inhibitors have been approved for rheumatoid arthritis (RA), and numerous JAK inhibitors are currently being tested in phase II and III trials for the treatment of various autoimmune inflammatory diseases. In this narrative review, we elucidate the involvement of the JAK–STAT signaling pathway in the pathogenesis of connective tissue diseases (CTDs). We also discuss the efficacy of the first- and second-generation JAK inhibitors (tofacitinib, baricitinib, ruxolitinib, peficitinib, filgotinib, upadacitinib, solcitinib, itacitinib, decernotinib, R333, and pf-06651600) for CTDs including RA, systemic lupus erythematosus, dermatomyositis, systemic sclerosis, Sjögren’s syndrome, and vasculitis, based on laboratory and clinical research findings. JAK inhibitors have great potential for the treatment of various CTDs by reducing multiple cytokine production and suppressing inflammation, with the advantages of rapid onset in an oral formulation and decreased corticosteroid dependence and the associated adverse events, especially in refractory cases. We also highlight the safety of novel JAK inhibitors, which can cause opportunistic infections, especially viral infections. Being a very recent therapeutic option, information regarding the safety of JAK inhibitors during pregnancy and for pediatric use is limited. However, it is recommended that JAK inhibitors should be avoided in pregnant and breastfeeding women. More clinical data, especially on highly selective inhibitors, are required to judge the efficacy and safety of JAK inhibition in CTDs.
Chronic kidney disease (CKD) affects 8 to 16% people worldwide, with an increasing incidence and prevalence of end-stage kidney disease (ESKD). The effective management of CKD is confounded by the inability to identify patients at high risk of progression while in early stages of CKD. To address this challenge, a renal biopsy transcriptome-driven approach was applied to develop noninvasive prognostic biomarkers for CKD progression. Expression of intrarenal transcripts was correlated with the baseline estimated glomerular filtration rate (eGFR) in 261 patients. Proteins encoded by eGFR-associated transcripts were tested in urine for association with renal tissue injury and baseline eGFR. The ability to predict CKD progression, defined as the composite of ESKD or 40% reduction of baseline eGFR, was then determined in three independent CKD cohorts. A panel of intrarenal transcripts, including epidermal growth factor (EGF), a tubule-specific protein critical for cell differentiation and regeneration, predicted eGFR. The amount of EGF protein in urine (uEGF) showed significant correlation (P < 0.001) with intrarenal EGF mRNA, interstitial fibrosis/tubular atrophy, eGFR, and rate of eGFR loss. Prediction of the composite renal end point by age, gender, eGFR, and albuminuria was significantly (P < 0.001) improved by addition of uEGF, with an increase of the C-statistic from 0.75 to 0.87. Outcome predictions were replicated in two independent CKD cohorts. Our approach identified uEGF as an independent risk predictor of CKD progression. Addition of uEGF to standard clinical parameters improved the prediction of disease events in diverse CKD populations with a wide spectrum of causes and stages.
To define disease activity levels, minimal clinically important improvement (MCII) and patient-acceptable symptom state (PASS) with the primary Sjögren's syndrome (SS) disease activity indexes: European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and EULAR SS patient-reported index (ESSPRI).
For 790 patients from two large prospective cohorts, ESSDAI, physician evaluation of disease activity, ESSPRI and patients' satisfaction with their current health status were recorded. Receiver operating characteristic curve analyses and anchoring methods were used to estimate disease activity levels of ESSDAI and the PASS of ESSPRI. At follow-up visit, patients and physicians assessed, respectively, whether symptoms and disease activity have improved or not. An anchoring method based on this evaluation was used to estimate MCII of ESSDAI and ESSPRI.
Low-activity (ESSDAI<5), moderate-activity (5≤ESSDAI≤13) and high-activity (ESSDAI≥14) levels were defined. MCII of ESSDAI was defined as an improvement of at least three points. The PASS estimate was defined as an ESSPRI<5 points and MCII as a decrease of at least one point or 15%.
This study determined disease activity levels, PASS and MCII of ESSDAI and ESSPRI. These results will help designing future clinical trials in SS. For evaluating systemic complications, the proposal is to include patients with moderate activity (ESSDAI≥5) and define response to treatment as an improvement of ESSDAI at least three points. For addressing patient-reported outcomes, inclusion of patients with unsatisfactory symptom state (ESSPRI≥5) and defining response as an improvement of ESSPRI at least one point or 15% seems reasonable.
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Sodium–glucose cotransporter- 2 inhibitors (SGLT- 2i) have recently been demonstrated to exert profound cardio- and nephroprotection in large cardiovascular outcome trials. They reduce progression of chronic kidney disease (CKD) including albuminuria and improve outcomes in heart failure patients with and without type 2 diabetes on top of angiotensin-blocking agents. These benefits translate into improved mortality in cardiorenal risk patients. While the detailed molecular mechanisms underlying these surprising clinical outcomes are not fully understood, their antidiabetic properties are not causative. Rather reduction of glomerular hyperfiltration and tubuloprotection are involved as root cause mechanisms of their clinical effects. Finally, their side effect profile is advantageous especially in non-diabetic patients also reducing the risk of acute kidney injury. Among the independent risk factors for excess mortality, CKD is still one of the strongest predictors of a poor prognosis in patients with both ANCA- associated vasculitis (AAV) and lupus nephritis (LN). Since patients with autoimmune disease were excluded from all recent large renal outcome trials with SGLT-2i and given their strong nephroprotective potential, we herein advocate to study this unique class of disease-modifying therapies when it comes to kidney and cardiovascular health in patients with AAV and LN.
Background:
Patients with chronic kidney disease have a high risk of adverse kidney and cardiovascular outcomes. The effect of dapagliflozin in patients with chronic kidney disease, with or without type 2 diabetes, is not known.
Methods:
We randomly assigned 4304 participants with an estimated glomerular filtration rate (GFR) of 25 to 75 ml per minute per 1.73 m2 of body-surface area and a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of 200 to 5000 to receive dapagliflozin (10 mg once daily) or placebo. The primary outcome was a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes.
Results:
The independent data monitoring committee recommended stopping the trial because of efficacy. Over a median of 2.4 years, a primary outcome event occurred in 197 of 2152 participants (9.2%) in the dapagliflozin group and 312 of 2152 participants (14.5%) in the placebo group (hazard ratio, 0.61; 95% confidence interval [CI], 0.51 to 0.72; P<0.001; number needed to treat to prevent one primary outcome event, 19 [95% CI, 15 to 27]). The hazard ratio for the composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal causes was 0.56 (95% CI, 0.45 to 0.68; P<0.001), and the hazard ratio for the composite of death from cardiovascular causes or hospitalization for heart failure was 0.71 (95% CI, 0.55 to 0.92; P = 0.009). Death occurred in 101 participants (4.7%) in the dapagliflozin group and 146 participants (6.8%) in the placebo group (hazard ratio, 0.69; 95% CI, 0.53 to 0.88; P = 0.004). The effects of dapagliflozin were similar in participants with type 2 diabetes and in those without type 2 diabetes. The known safety profile of dapagliflozin was confirmed.
Conclusions:
Among patients with chronic kidney disease, regardless of the presence or absence of diabetes, the risk of a composite of a sustained decline in the estimated GFR of at least 50%, end-stage kidney disease, or death from renal or cardiovascular causes was significantly lower with dapagliflozin than with placebo. (Funded by AstraZeneca; DAPA-CKD ClinicalTrials.gov number, NCT03036150.).
Background
Baricitinib is a JAK inhibitor that blocks intracellular signalling pathways of inflammatory cytokines recommended for Rheumatoid arthritis (RA) patients not responding to initial treatment. Among RA extrareticular features, interstitial lung involvement is primarly characterized by fibrotic evolution. The aim of the present study was to analyse the effects of baricitinib in a population of RA and RA-ILD patients in a real-life setting, describing any changes in lung function parameters, serum inflammatory biomarkers and fibrotic biomarkers after 6 months of treatment.
Materials and methods
15 patients (median (IQR) 65 (55–66); 13% males and 74% smokers) treated with baricitinib were enrolled. 4 patients (27%) were classified as RA-ILD before baricitinib therapy. Our study is the first to evaluate adipokine levels in RA patients (including a small population with RA-ILD) after six months of baricitinib treatment with a novel multiplex method.
Results
The modulatory effects of baricitinib on lipid mediators were associated with clinical and functional improvement, demonstrated by the significant increase in DLco and KCO percentages after six months of treatment. Baricitinib decreased the systemic inflammation by lowering expression of IL-6 and CRP and reducing ESR and serum concentrations of adiponectin. A significant reduction of KL-6 levels in RA-ILD patients after six months of baricitinib therapy reflects the stability of interstitial lung involvement in these patients.
Conclusion
Baricitinib was demonstrated to be a safe immune modulator that reduces the concentrations biomarkers of lung fibrosis and inflammation in RA patients, including a subgroup with interstitial lung involvement.
Background:
Pharmacological SGLT2 inhibition is being examined as a renal protection strategy in non-diabetic chronic kidney disease (CKD). We quantified renal sodium-glucose linked cotransporter (SGLT) mRNA expression in healthy controls (HC), glomerulonephritis (GN) and diabetic kidney disease (DKD) to identify differences in expression across a spectrum of renal diseases.
Methods:
SGLT1 and SGLT2 mRNA expression in renal tubules and glomeruli, obtained using microdissection and microarray techniques, were evaluated in two large cohorts. The European Renal cDNA bank (ERCB) included HC, GN, and DKD (98 glomeruli and 93 tubulointerstitium). The Nephrotic Syndrome Study Network (NEPTUNE) cohort included 124 adults with membranous nephropathy (MN), minimal change disease (MCD), focal segmental glomerulosclerosis (FSGS) and IgA nephropathy (IgAN).
Results:
Within ERCB, SGLT2 tubular and glomerular log2-mRNA expression significantly differed across HC, GN and DKD (p=0.0009 and p=0.0004), with highest expression in HC. Within NEPTUNE, there were no differences in SGLT log2-mRNA expression across GN subtypes. Tubular SGLT2 log2-mRNA expression positively correlated with estimated glomerular filtration rate (eGFRMDRD) and glycated hemoglobin (A1c) (r=0.33 & 0.34, p<0.05); and inversely correlated with interstitial fibrosis (r=-0.21, p<0.05).
Conclusions:
SGLT2 mRNA expression was lower in DKD compared to HC or GN, and inversely related to interstitial fibrosis. The relationships between SGLT mRNA, protein expression, and transporter activity requires further elucidation.
Background:
Patients with systemic lupus erythematosus have substantial unmet medical need. Baricitinib is an oral selective Janus kinase (JAK)1 and JAK2 inhibitor that we hypothesised might have therapeutic benefit in patients with systemic lupus erythematosus.
Methods:
In this double-blind, multicentre, randomised, placebo-controlled, 24-week phase 2 study, patients were recruited from 78 centres in 11 countries. Eligible patients were aged 18 years or older, had a diagnosis of systemic lupus erythematosus, and had active disease involving skin or joints. We randomly assigned patients (1:1:1) to receive once-daily baricitinib 2 mg, baricitinib 4 mg, or placebo for 24 weeks. The primary endpoint was the proportion of patients achieving resolution of arthritis or rash at week 24, as defined by Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K). Efficacy and safety analyses included all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, number NCT02708095.
Findings:
Between March 24, 2016, and April 27, 2017, 314 patients were randomly assigned to receive placebo (n=105), baricitinib 2 mg (n=105), or baricitinib 4 mg (n=104). At week 24, resolution of SLEDAI-2K arthritis or rash was achieved by 70 (67%) of 104 patients receiving baricitinib 4 mg (odds ratio [OR] vs placebo 1·8, 95% CI 1·0-3·3; p=0·0414) and 61 (58%) of 105 patients receiving baricitinib 2 mg (OR 1·3, 0·7-2·3; p=0·39). Adverse events were reported in 68 (65%) patients in the placebo group, 75 (71%) patients in the baricitinib 2 mg group, and 76 (73%) patients in the baricitinib 4 mg group. Serious adverse events were reported in ten (10%) patients receiving baricitinib 4 mg, 11 (10%) receiving baricitinib 2 mg, and five (5%) receiving placebo; no deaths were reported. Serious infections were reported in six (6%) patients with baricitinib 4 mg, two (2%) with baricitinib 2 mg, and one (1%) with placebo.
Interpretation:
The baricitinib 4 mg dose, but not the 2 mg dose, significantly improved the signs and symptoms of active systemic lupus erythematosus in patients who were not adequately controlled despite standard of care therapy, with a safety profile consistent with previous studies of baricitinib. This study provides the foundation for future phase 3 trials of JAK1/2 inhibition with baricitinib as a new potential oral therapy for systemic lupus erythematosus.
Funding:
Eli Lilly and Company.
Background
Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis.
Methods
We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti–tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire–Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24.
Results
More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol.
Conclusions
In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358.)
Objectives
To develop and validate an international set of classification criteria for primary Sjögren's syndrome (SS) using guidelines from the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR). These criteria were developed for use in individuals with signs and/or symptoms suggestive of SS.
Methods
We assigned preliminary importance weights to a consensus list of candidate criteria items, using multi-criteria decision analysis. We tested and adapted the resulting draft criteria using existing cohort data on primary SS cases and non-SS controls, with case/non-case status derived from expert clinical judgement. We then validated the performance of the classification criteria in a separate cohort of patients.
Results
The final classification criteria are based on the weighted sum of five items: anti-SSA/Ro antibody positivity and focal lymphocytic sialadenitis with a focus score of ≥1 foci/4 mm², each scoring 3; an abnormal Ocular Staining Score of ≥5 (or van Bijsterveld score of ≥4), a Schirmer's test result of ≤5 mm/5 min and an unstimulated salivary flow rate of ≤0.1 mL/min, each scoring 1. Individuals with signs and/or symptoms suggestive of SS who have a total score of ≥4 for the above items meet the criteria for primary SS. Sensitivity and specificity against clinician-expert—derived case/non-case status in the final validation cohort were high, that is, 96% (95% CI92% to 98%) and 95% (95% CI 92% to 97%), respectively.
Conclusion
Using methodology consistent with other recent ACR/EULAR-approved classification criteria, we developed a single set of data-driven consensus classification criteria for primary SS, which performed well in validation analyses and are well suited as criteria for enrolment in clinical trials.
:106748. the 2019 EULAR recommendations. Patients from CREDIT were eligible for inclusion in the present study if they had newly diagnosed RA based on the
- Alessandro M Perillo
- Metella Refini
d'Alessandro M, Perillo F, Metella Refini R, et al. Efficacy of baricitinib in treating
rheumatoid arthritis: modulatory effects on fibrotic and inflammatory biomarkers in a
real-life setting. Int Immunopharmacol 2020;86:106748.
the 2019 EULAR recommendations.
Patients from CREDIT were eligible for inclusion in the present
study if they had newly diagnosed RA based on the 2010 American
College of Rheumatology (ACR)/EULAR RA classification criteria,
moderate to high disease activity (clinical disease activity index