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OBJECTIVE: Rheumatoid arthritis (RA) is recognized as a chronic autoimmune disorder with systemic inflammation and joint damage. Its potential role as a risk factor for cardiovascular diseases (CVD) is increasingly noted. This review delves into the causal relationship between RA and CVD, with Mendelian randomization (MR) offering a genetic perspective. METHODS: An extensive search was conducted in PubMed, Cochrane and Web of Science to identify MR studies addressing the RA-CVD link. Out of 530 studies, 9 met the inclusion criteria, which were rigorously assessed using a critical appraisal checklist. These were further stratified by a sensitivity analysis into categories reflecting the strength of their evidence, from not evaluable to robust. RESULTS: From the nine included studies, eight supported a causal association between RA and an increased risk of CVD, specifically coronary artery disease (CAD) and one did not support a link between RA and heart failure. The results suggest that genetic factors associated with RA may contribute to an elevated risk for CVD. Chronic inflammation, prevalent in RA, emerges as a key mediator in this connection. CONCLUSION: The systematic review corroborates a genetic causal link between RA and CVD, as evidenced by eight of the nine MR studies reviewed. This suggests a need for integrated cardiovascular risk management in the treatment of RA patients. The findings advocate considering anti-inflammatory treatment that can reduce cardiovascular risk. The overarching evidence signifies a potential direction for new therapeutic strategies aimed at enhancing cardiovascular health in RA patients.
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OBJECTIVES: B-cell depletion time after rituximab (RTX) treatment is prolonged in antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) compared with other autoimmune diseases. We investigated central and peripheral B-cell development to identify the causes for the defect in B-cell reconstitution after RTX therapy. METHODS: We recruited 91 patients with AAV and performed deep phenotyping of the peripheral and bone marrow B-cell compartment by spectral flow and mass cytometry. B-cell development was studied by in vitro modelling and the role of BAFF receptor by quantitative PCR, western blot analysis and in vitro assays. RESULTS: Treatment-naïve patients with AAV showed low transitional B-cell numbers, suggesting impaired B-lymphopoiesis. We analysed bone marrow of treatment-naïve and RTX-treated patients with AAV and found reduced B-lymphoid precursors. In vitro modelling of B-lymphopoiesis from AAV haematopoietic stem cells showed intact, but slower and reduced immature B-cell development. In a subgroup of patients, after RTX treatment, the presence of transitional B cells did not translate in replenishment of naïve B cells, suggesting an impairment in peripheral B-cell maturation. We found low BAFF-receptor expression on B cells of RTX-treated patients with AAV, resulting in reduced survival in response to BAFF in vitro. CONCLUSIONS: Prolonged depletion of B cells in patients with AAV after RTX therapy indicates a B-cell defect that is unmasked by RTX treatment. Our data indicate that impaired bone marrow B-lymphopoiesis results in a delayed recovery of peripheral B cells that may be further aggravated by a survival defect of B cells. Our findings contribute to the understanding of AAV pathogenesis and may have clinical implications regarding RTX retreatment schedules and immunomonitoring after RTX therapy.
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OBJECTIVE: Rheumatoid Arthritis (RA) is a systemic autoimmune disease involving pro-inflammatory cytokines that can be therapeutically targeted by antibodies or kinase inhibitors. Nevertheless, these drugs fail in a subset of patients independent of the abundance of the targeted cytokines. We aim to explore the cellular basis of this phenomenon by analyzing the relation of cytokine abundance and activation of downstream signaling pathways in RA. METHODS: The study included 62 RA patients and 9 healthy controls (HC). Phosphorylation of STAT 1-6 in various immune cell subsets was determined ex vivo using a novel robust flow cytometry-based protocol. Serum concentrations of IL-6, IL-10, IL-12p70, IL-17 A, interferon gamma, and TNFα in the same samples were measured using highly sensitive single molecule array (SIMOA). RESULTS: We found an increase in circulating cytokines in RA patients, while STAT activity was lower in RA patients compared to HC. Based on STAT activity we determined three endotypes in active RA patients (cDAI>10, n = 28): 1) those with active STAT5a/b signaling in T cells (n = 7/28), 2) those with a low STAT activity in all assessed cell types (n = 14/28), and 3) those with active STAT1 and STAT3 signaling mainly in myeloid cells (n = 7/28). Integrating intracellular STAT activation and cytokine analysis revealed diminished JAK/STAT signaling in a subset of patients (n = 8/20) despite elevated serum cytokine concentrations. CONCLUSION: Diminished JAK/STAT signaling in active RA may partly explain unresponsiveness to therapy targeting cytokine signaling. Analysis of JAK/STAT phosphorylation may identify patients at risk for non-response to these therapies.
Subject(s)
Arthritis, Rheumatoid , Cytokines , Janus Kinases , STAT Transcription Factors , Signal Transduction , Humans , Arthritis, Rheumatoid/blood , Arthritis, Rheumatoid/immunology , Middle Aged , Female , Male , Cytokines/blood , Janus Kinases/metabolism , Adult , STAT Transcription Factors/metabolism , Aged , Phosphorylation , STAT5 Transcription Factor/metabolism , Leukocytes/metabolism , Leukocytes/immunology , STAT1 Transcription Factor/metabolism , STAT1 Transcription Factor/bloodABSTRACT
OBJECTIVES: Prospective long-term observational data on the disease course of anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) were missing in Germany to date. Therefore, the Joint Vasculitis Registry in German-speaking countries (GeVas) has been established to follow the course of patients with AAV. The aim of this study is to present baseline data of patients with newly diagnosed and relapsing AAV enrolled in the GeVas registry. METHODS: GeVas is a prospective, web-based, multicentre, clinician-driven registry for the documentation of organ manifestations, damage, long-term outcomes, and therapy regimens in various types of vasculitis. Recruitment started in June 2019. RESULTS: Between June 2019 and October 2022, 266 patients with AAV were included in the GeVas registry: 173 (65%) with new-onset and 93 (35%) with relapsing AAV. One hundred and sixty-two (61%) patients were classified as granulomatosis with polyangiitis (GPA), 66 (25%) as microscopic polyangiitis (MPA), 36 (13%) as eosinophilic granulomatosis with polyangiitis (EGPA), and 2 (1%) as renal limited AAV. The median age was 59 years (51-70 years, IQR), 130 (51%) patients were female. Most patients were ANCA positive (177; 67%) and affected by general symptoms, pulmonary, ear nose throat (ENT), renal and neurological involvement. For induction of remission, the majority of patients received glucocorticoids (247, 93%) in combination with either rituximab (118, 45%) or cyclophosphamide (112, 42%). CONCLUSIONS: Demographic characteristics are comparable to those in other European countries. Differences were found regarding ANCA status, frequencies of organ manifestations, and therapeutic regimens. The GeVas registry will allow longitudinal observations and prospective outcome measures in AAV.
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Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Registries , Humans , Female , Middle Aged , Male , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/epidemiology , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/drug therapy , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Aged , Prospective Studies , Germany/epidemiology , Immunosuppressive Agents/therapeutic use , Treatment Outcome , Granulomatosis with Polyangiitis/drug therapy , Granulomatosis with Polyangiitis/epidemiology , Granulomatosis with Polyangiitis/diagnosis , Granulomatosis with Polyangiitis/immunology , Granulomatosis with Polyangiitis/therapy , Recurrence , Microscopic Polyangiitis/epidemiology , Microscopic Polyangiitis/drug therapy , Microscopic Polyangiitis/diagnosis , Microscopic Polyangiitis/therapy , Microscopic Polyangiitis/immunology , Churg-Strauss Syndrome/epidemiology , Churg-Strauss Syndrome/drug therapy , Churg-Strauss Syndrome/diagnosis , Churg-Strauss Syndrome/immunology , Disease Progression , Time Factors , Rituximab/therapeutic useABSTRACT
OBJECTIVES: Giant cell arteritis (GCA) is one of the most common forms of vasculitis. There is an abundance of studies which are conducted in a randomised controlled trial setting but limited with respect to cohort size and follow-up time. GeVas is the first large-scale registry for vasculitides in German-speaking countries that enables to evaluate this rare disease. Herein we focus on the subgroup of GCA patients including follow-up data up to one year. METHODS: GeVas is a prospective, web-based, multicentre registry for the documentation of organ manifestations, outcomes, and therapy regimens in vasculitides. Recruitment started in June 2019. By April 2023, 15 centres were initiated and have started to enrol patients. RESULTS: After 4 years, 195 GCA-patients were included in the registry, of which 64% were female and 36% were male. The average age was 76 years at the time of recruitment (IQR=69-82). Seventy-nine percent were included in the registry because of a newly diagnosed GCA and 21% because of a relapse. At the first assessment most of the patients (89%) described general symptoms. Thirty-one percent stated ocular symptoms. Cranial symptoms were documented in 78% of the cases. All patients were documented with immunosuppressive treatment at start, of whom 95% received prednisolone, 16% cyclophosphamide, 20% methotrexate, and 48% tocilizumab. After three months 62% and after one year 91% of the patients achieved remission. CONCLUSIONS: Regarding demographics, clinical manifestations and diagnostics, our study showed a similar composition compared to other studies. However, our data differed in terms of treatment regimens.
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Giant Cell Arteritis , Immunosuppressive Agents , Registries , Humans , Giant Cell Arteritis/drug therapy , Giant Cell Arteritis/epidemiology , Giant Cell Arteritis/diagnosis , Male , Female , Aged , Aged, 80 and over , Prospective Studies , Immunosuppressive Agents/therapeutic use , Germany/epidemiology , Treatment Outcome , Time Factors , RecurrenceABSTRACT
BACKGROUND: Individuals with anti-citrullinated protein antibodies (ACPAs) and subclinical inflammatory changes in joints are at high risk of developing rheumatoid arthritis. Treatment strategies to intercept this pre-stage clinical disease remain to be developed. We aimed to assess whether 6-month treatment with abatacept improves inflammation in preclinical rheumatoid arthritis. METHODS: The abatacept reversing subclinical inflammation as measured by MRI in ACPA positive arthralgia (ARIAA) study is a randomised, international, multicentre, double-blind, placebo-controlled trial done in 14 hospitals and community centres across Europe (11 in Germany, two in Spain, and one in the Czech Republic). Adults (aged ≥18 years) with ACPA positivity, joint pain (but no swelling), and signs of osteitis, synovitis, or tenosynovitis in hand MRI were randomly assigned (1:1) to weekly subcutaneous abatacept 125 mg or placebo for 6 months followed by a double-blind, drug-free, observation phase for 12 months. The primary outcome was the proportion of participants with any reduction in inflammatory MRI lesions at 6 months. The primary efficacy analysis was done in the modified intention-to-treat population, which included participants who were randomly assigned and received study medication. Safety analyses were conducted in participants who received the study medication and had at least one post-baseline observation. The study was registered with the EUDRA-CT (2014-000555-93). FINDINGS: Between Nov 6, 2014, and June 15, 2021, 139 participants were screened. Of 100 participants, 50 were randomly assigned to abatacept 125 mg and 50 to placebo. Two participants (one from each group) were excluded due to administration failure or refusing treatment; thus, 98 were included in the modified intention-to-treat population. 70 (71%) of 98 participants were female and 28 (29%) of 98 were male. At 6 months, 28 (57%) of 49 participants in the abatacept group and 15 (31%) of 49 participants in the placebo group showed improvement in MRI subclinical inflammation (absolute difference 26·5%, 95% CI 5·9-45·6; p=0·014). Four (8%) of 49 participants in the abatacept group and 17 (35%) of 49 participants in the placebo group developed rheumatoid arthritis (hazard ratio [HR] 0·14 [0·04-0·47]; p=0·0016). Improvement of MRI inflammation (25 [51%] of 49 participants in the abatacept group, 12 [24%] of 49 in the placebo group; p=0·012) and progression to rheumatoid arthritis (17 [35%] of 49, 28 [57%] of 49; HR 0·14 [0·04-0·47]; p=0·018) remained significantly different between the two groups after 18 months, 12 months after the end of the intervention. There were 12 serious adverse events in 11 participants (four [8%] of 48 in the abatacept group and 7 [14%] of 49 in the placebo group). No deaths occurred during the study. INTERPRETATION: 6-month treatment with abatacept decreases MRI inflammation, clinical symptoms, and risk of rheumatoid arthritis development in participants at high risk. The effects of the intervention persist through a 1-year drug-free observation phase. FUNDING: Innovative Medicine Initiative.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Adult , Male , Humans , Female , Adolescent , Abatacept/adverse effects , Antirheumatic Agents/adverse effects , Treatment Outcome , Arthritis, Rheumatoid/diagnostic imaging , Arthritis, Rheumatoid/drug therapy , Inflammation/drug therapy , Arthralgia/chemically inducedABSTRACT
Defective FAS (CD95/Apo-1/TNFRSF6) signaling causes autoimmune lymphoproliferative syndrome (ALPS). Hypergammaglobulinemia is a common feature in ALPS with FAS mutations (ALPS-FAS), but paradoxically, fewer conventional memory cells differentiate from FAS-expressing germinal center (GC) B cells. Resistance to FAS-induced apoptosis does not explain this phenotype. We tested the hypothesis that defective non-apoptotic FAS signaling may contribute to impaired B cell differentiation in ALPS. We analyzed secondary lymphoid organs of patients with ALPS-FAS and found low numbers of memory B cells, fewer GC B cells, and an expanded extrafollicular (EF) B cell response. Enhanced mTOR activity has been shown to favor EF versus GC fate decision, and we found enhanced PI3K/mTOR and BCR signaling in ALPS-FAS splenic B cells. Modeling initial T-dependent B cell activation with CD40L in vitro, we showed that FAS competent cells with transient FAS ligation showed specifically decreased mTOR axis activation without apoptosis. Mechanistically, transient FAS engagement with involvement of caspase-8 induced nuclear exclusion of PTEN, leading to mTOR inhibition. In addition, FASL-dependent PTEN nuclear exclusion and mTOR modulation were defective in patients with ALPS-FAS. In the early phase of activation, FAS stimulation promoted expression of genes related to GC initiation at the expense of processes related to the EF response. Hence, our data suggest that non-apoptotic FAS signaling acts as molecular switch between EF versus GC fate decisions via regulation of the mTOR axis and transcription. The defect of this modulatory circuit may explain the observed hypergammaglobulinemia and low memory B cell numbers in ALPS.
Subject(s)
Hypergammaglobulinemia , Lymphoproliferative Disorders , Humans , Apoptosis/genetics , Germinal Center , Lymphoproliferative Disorders/genetics , TOR Serine-Threonine KinasesABSTRACT
OBJECTIVES: To develop treat-to-target (T2T) recommendations in giant cell arteritis (GCA) and polymyalgia rheumatica (PMR). METHODS: A systematic literature review was conducted to retrieve data on treatment targets and outcomes in GCA/PMR as well as to identify the evidence for the effectiveness of a T2T-based management approach in these diseases. Based on evidence and expert opinion, the task force (29 participants from 10 countries consisting of physicians, a healthcare professional and a patient) developed recommendations, with consensus obtained through voting. The final level of agreement was provided anonymously. RESULTS: Five overarching principles and six-specific recommendations were formulated. Management of GCA and PMR should be based on shared decisions between patient and physician recognising the need for urgent treatment of GCA to avoid ischaemic complications, and it should aim at maximising health-related quality of life in both diseases. The treatment targets are achievement and maintenance of remission, as well as prevention of tissue ischaemia and vascular damage. Comorbidities need to be considered when assessing disease activity and selecting treatment. CONCLUSION: These are the first T2T recommendations for GCA and PMR. Treatment targets, as well as strategies to assess, achieve and maintain these targets have been defined. The research agenda highlights the gaps in evidence and the need for future research.
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Giant Cell Arteritis , Polymyalgia Rheumatica , Humans , Giant Cell Arteritis/complications , Polymyalgia Rheumatica/epidemiology , Quality of Life , ComorbidityABSTRACT
INTRODUCTION: Psoriasis (Pso) and psoriatic arthritis (PsA) can reduce the quality of life (QoL) and are known to be associated with depression. Within this study, we aimed to assess the burden of disease, functional capacity, quality of life, and depressive symptoms and identify factors predicting functional impairment and depression in patients with psoriatic disease. METHODS: A cross-sectional survey was conducted in a cohort of 300 patients with psoriatic disease including 150 patients from a university hospital dermatology outpatient clinic and 150 patients from a university hospital rheumatology outpatient clinic. Questionnaire-based assessment of signs of arthritis (Psoriasis Epidemiology Screening Tool; PEST), functional status (Functional Questionnaire Hannover; FFbH), quality of life (World Health Organization Quality of Life Brief Version; WHOQOL-BREF), and depressive symptoms (Patient health questionnaire 9; PHQ-9) and retrospective medical chart analysis were performed. RESULTS: Despite treatment, burden of disease was high. Joint pain was reported in multiple regions in patients with Pso (n = 111) and patients with PsA (n = 189), but with differences in frequency and distribution patterns of symptoms. Functional impairment in everyday life was independently associated with diagnosis of PsA (odds ratio [OR] 9.56, p = 0.005), depressive symptoms (OR 5.44, p < 0.001) and age (OR 1.04, p = 0.033). At least mild depressive symptoms were demonstrated in 54% and 69% of patients with Pso and PsA, respectively. In a logistic regression model, depressive symptoms were independently associated with functional impairment (OR 4.50, p = 0.003), axial complaints (OR 2.80, p = 0.030), diagnosis of psoriatic arthritis (OR 2.69, p = 0.046), and number of joint regions with complaints (OR 1.10, p = 0.032). CONCLUSION: Functional impairment, QoL, and depressive symptoms are mutually interdependent. Early diagnosis of PsA and initiation of anti-inflammatory therapy are essential to avoid long-term damage, disability, and mental health complications. However, despite therapy many patients with PsA, and especially female patients, report a substantial residual disease burden due to their psoriatic disease which will need to be addressed by a more patient-centered approach.
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In recent decades, insights into the molecular pathways involved in disease have revolutionized the treatment of autoimmune diseases. A plethora of targeted therapies have been identified and are at varying stages of clinical development in renal autoimmunity. Some of these agents, such as rituximab or avacopan, have been approved for the treatment of immune-mediated kidney disease, but kidney disease lags behind more common autoimmune disorders in new drug development. Evidence is accumulating as to the importance of adaptive immunity, including abnormalities in T-cell activation and signaling, and aberrant B-cell function. Furthermore, innate immunity, particularly the complement and myeloid systems, as well as pathologic responses in tissue repair and fibrosis, play a key role in disease. Collectively, these mechanistic studies in innate and adaptive immunity have provided new insights into mechanisms of glomerular injury in immune-mediated kidney diseases. In addition, inflammatory pathways common to several autoimmune conditions exist, suggesting that the repurposing of some existing drugs for the treatment of immune-mediated kidney diseases is a logical strategy. This new understanding challenges the clinical investigator to translate new knowledge into novel therapies leading to better disease outcomes. This review highlights promising immunomodulatory therapies tested for immune-mediated kidney diseases as a primary indication, details current clinical trials and discusses pathways that could be targeted in the future.
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Immunomodulating Agents , Kidney Diseases , Humans , Immunity, Innate , Kidney , Kidney Diseases/drug therapy , Adaptive ImmunityABSTRACT
ANCA-associated vasculitides (AAV) are rare, complex systemic diseases that are often difficult to diagnose, because of unspecific clinical symptoms at presentation. However, the clinical course may be very dramatic and even life-threatening, necessitating prompt diagnosis and treatment.Therefore, it is important to increase disease awareness among physicians and support colleagues who are not confronted with these rare diseases on a regular basis. Here, the Austrian Society of Nephrology (ÖGN) and the Austrian Society of Rheumatology (ÖGR) provide a joint consensus on how to best diagnose and manage patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA).
Subject(s)
Granulomatosis with Polyangiitis , Microscopic Polyangiitis , Nephrology , Rheumatology , Humans , Microscopic Polyangiitis/diagnosis , Microscopic Polyangiitis/therapy , Austria , Consensus , Granulomatosis with Polyangiitis/diagnosis , Granulomatosis with Polyangiitis/therapy , Intercellular Signaling Peptides and ProteinsABSTRACT
BACKGROUND: Eosinophilic granulomatosis with polyangiitis (EGPA) is often associated with glucocorticoid-dependent asthma and/or ear, nose and throat (ENT) manifestations. When immunosuppressants and/or mepolizumab are ineffective, dupilumab could be an option. We describe the safety and efficacy of off-label use of dupilumab in relapsing and/or refractory EGPA. PATIENTS AND METHODS: We conducted an observational multicentre study of EGPA patients treated with dupilumab. Complete response was defined by Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone dose ≤4 mg/day, and partial response by BVAS=0 and prednisone dose >4 mg/day. Eosinophilia was defined as an eosinophil count >500/mm3. RESULTS: Fifty-one patients were included. The primary indication for dupilumab was disabling ENT symptoms in 92%. After a median follow-up of 13.1 months, 18 patients (35%) reported adverse events (AEs), including two serious AEs. Eosinophilia was reported in 34 patients (67%), with a peak of 2195/mm3 (IQR 1268-4501) occurring at 13 weeks (IQR 4-36) and was associated with relapse in 41%. Twenty-one patients (41%) achieved a complete response and 12 (24%) a partial response. Sixteen (31%) patients experienced an EGPA relapse while on dupilumab, which was associated with blood eosinophilia in 14/16 (88%) patients. The median eosinophil count at the start of dupilumab was significantly lower in relapsers than in non-relapsers, as was the median time between stopping anti-IL-5/IL-5R and switching to dupilumab. CONCLUSION: These results suggest that dupilumab may be effective in treating patients with EGPA-related ENT manifestations. However, EGPA flares occurred in one-third of patients and were preceded by eosinophilia in 88%, suggesting that caution is required.
Subject(s)
Asthma , Churg-Strauss Syndrome , Eosinophilia , Granulomatosis with Polyangiitis , Humans , Granulomatosis with Polyangiitis/complications , Granulomatosis with Polyangiitis/drug therapy , Granulomatosis with Polyangiitis/diagnosis , Churg-Strauss Syndrome/complications , Churg-Strauss Syndrome/drug therapy , Retrospective Studies , Prednisone/therapeutic use , Treatment Outcome , Asthma/drug therapy , Asthma/complications , Eosinophilia/drug therapy , Eosinophilia/complications , RecurrenceABSTRACT
Objective: Chronic back pain (CBP) constitutes one of the most common complaints in primary care and a leading cause of disability worldwide. CBP may be of mechanical or inflammatory character and may lead to functional impairment and reduced quality of life. In this study, we aimed to assess and compare burden of disease, functional capacity, quality of life and depressive symptoms in axial spondyloarthritis (axSpA) patients with orthopedic chronic back pain patients (OBP). We further aimed to identify factors associated with quality of life. Methods: Cross-sectional survey of a cohort of 300 CBP patients including 150 patients from a University Hospital Orthopedic Back Pain Outpatient Clinic with OBP and 150 patients with confirmed axSpA from a University Hospital Rheumatology Outpatient Clinic. Questionnaire-based assessment of pain character (Inflammatory Back Pain, MAIL-Scale), functional status (FFbH, BASFI), quality of life (WHOQOL-Bref) and depressive symptoms (Phq9) and retrospective medical chart analysis. Results: Both, OBP and axSpA patients reported on average intermediate pain levels of mostly mixed pain character. Both groups demonstrated a reduced health-related quality of life and the presence of depressive symptoms. However, axSpA patients reported a significantly better subjective quality of life, more satisfaction with their health status and better functional capacity compared to OBP patients (all p < 0.001). In a multivariate regression model, depressive symptoms, mechanical back pain, pain level and age were negative predictors of subjective quality of life, whereas functional capacity was a positive predictor. Conclusion: Chronic back pain was associated with a high morbidity and reduced quality of life regardless of pain character. We identified multiple factors associated with reduced quality of life. Awareness and addressing of these factors may help to overcome unmet needs and improve quality of life for these patients.
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OBJECTIVES: Axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) may have a profound impact on sleep and health-related quality of life. The aim of this study was to assess sleep quality and quality of life and determine associated factors in patients treated with spondyloarthritides (SpA). METHODS: Cross-sectional questionnaire-based assessment of sleep behaviour, quality of life, functional impairment and depression (Regensburg Insomnia Scale, WHO Quality of Life questionnaire, Funktionsfragebogen Hannover questionnaire, Beck Depression Inventory II, Patient health questionnaire 9) and retrospective medical chart analysis of a monocentric cohort of 330 patients with SpA (n=168 PsA and n=162 axSpA). RESULTS: 46.6% of patients with SpA demonstrated abnormal sleep behaviour. Linear regression models showed HLA-B27 positivity, Bath Ankylosing Spondylitis Disease Activity Index, depressive symptoms, functional capacity and disease duration to be predictive of insomnia symptoms in axSpA, respectively, depressive symptoms, female sex and Disease Activity Score 28 in patients with PsA. Patients with unrestful sleep had a significantly reduced health-related quality of life (p<0.001) as well as significantly more depressive symptoms (p<0.001). Satisfaction with health was rated significantly lower (p<0.001), indicating poor sleep as a burden on general well-being.In particular, female patients had a significantly worse sleep quality with a prolonged sleep latency (p=0.009), increased sleep disturbances (p=0.014) and unrestful sleep (p<0.001) as well as a reduced physical and mental health-related quality of life (p=0.015, p<0.001) and more depressive symptoms (p=0.015). CONCLUSION: Despite treatment, many patients with SpA demonstrate abnormal sleep behaviour with symptoms of insomnia and a reduced quality of life with significant differences between male and female patients. An interdisciplinary and holistic approach may be needed to address unmet needs.
Subject(s)
Arthritis, Psoriatic , Axial Spondyloarthritis , Sleep Initiation and Maintenance Disorders , Spondylarthritis , Spondylitis, Ankylosing , Humans , Male , Female , Arthritis, Psoriatic/complications , Arthritis, Psoriatic/epidemiology , Quality of Life , Depression/epidemiology , Depression/etiology , Retrospective Studies , Cross-Sectional Studies , Sleep Initiation and Maintenance Disorders/epidemiology , Sleep Initiation and Maintenance Disorders/etiology , Spondylarthritis/complications , Spondylarthritis/diagnosis , Spondylarthritis/epidemiology , SleepABSTRACT
OBJECTIVES: To determine the spectrum of anti-neutrophil cytoplasmic antibody (ANCA) antigen-specificities in eosinophilic granulomatosis with polyangiitis (EGPA), an ANCA-associated vasculitis (AAV) entity. METHODS: We conducted a retrospective analysis of 73 EGPA patients from three German tertiary referral centres for vasculitis. In addition to in-house ANCA testing, pentraxin 3 (PTX3)- and olfactomedin 4 (OLM4)-ANCA were determined using a prototype cell-based assay for research (EUROIMMUN, Lübeck, Germany). Patient characteristics and clinical manifestations were evaluated and compared based on ANCA status. RESULTS: Myeloperoxidase (MPO)-ANCA positive patients (n=8; 11%) significantly more frequently displayed peripheral nervous system (PNS) and pulmonary involvement and less frequently heart involvement compared to MPO-ANCA negative patients. PTX3-ANCA positive patients (n=5; 6.8%) had a significantly higher prevalence of ear, nose and throat, pulmonary, gastrointestinal and PNS involvement, and a lower prevalence of renal and central nervous system involvement compared to PTX3-ANCA negative patients. Proteinase 3 (PR3)-ANCA and OLM4-ANCA were detected in 2 patients (2.7%) each with multiorgan involvement. One PR3-ANCA positive patient was also positive for bactericidal permeability increasing protein (BPI)-ANCA. CONCLUSIONS: In addition to MPO, the spectrum of ANCA antigen specificities includes various other target antigens such as PR3, BPI, PTX3, and OLM4, potentially segregating further EGPA subgroups. A lower prevalence of MPO-ANCA was detected in this study compared with other studies. OLM4 is reported as novel ANCA antigen-specificity in EGPA, and thus AAV.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Churg-Strauss Syndrome , Granulomatosis with Polyangiitis , Humans , Antibodies, Antineutrophil Cytoplasmic , Retrospective Studies , Granulomatosis with Polyangiitis/diagnosis , Churg-Strauss Syndrome/diagnosis , Myeloblastin , PeroxidaseABSTRACT
Background: Janus kinase (JAK) inhibitors have been approved for the treatment of several immune-mediated diseases (IMIDs) including rheumatoid arthritis (RA) and psoriatic arthritis and are in clinical trials for numerous other IMIDs. However, detailed studies investigating the effects of different JAK inhibitors on B cells are missing. Within this study, we therefore aimed to characterize the effect of JAK inhibition on the B cell compartment. Methods: To this end, we investigated the B cell compartment under JAK inhibition and compared the specific effects of the different JAK inhibitors tofacitinib (pan-JAK), baricitinib (JAK1/2), ruxolitinib (JAK1/2), upadacitinib (JAK1/2) as well as filgotinib (selective JAK1) on in-vitro B cell activation, proliferation, and class switch recombination and involved pathways. Results: While B cell phenotyping of RA patients showed an increase in marginal zone (MZ) B cells under JAK inhibition, comparison with healthy donors revealed that the relative frequency of MZ B cells was still lower compared to healthy controls. In an in-vitro model of T-cell-independent B cell activation we observed that JAK1/2 and selective JAK1 inhibitor treatment led to a dose-dependent decrease of total B cell numbers. We detected an altered B cell differentiation with a significant increase in MZ-like B cells and an increase in plasmablast differentiation in the first days of culture, most pronounced with the pan-JAK inhibitor tofacitinib, although there was no increase in immunoglobulin secretion in-vitro. Notably, we further observed a profound reduction of switched memory B cell formation, especially with JAK1/2 inhibition. JAK inhibitor treatment led to a dose-dependent reduction of STAT3 expression and phosphorylation as well as STAT3 target gene expression and modulated the secretion of pro- and anti-inflammatory cytokines by B cells. Conclusion: JAK inhibition has a major effect on B cell activation and differentiation, with differential outcomes between JAK inhibitors hinting towards distinct and unique effects on B cell homeostasis.
Subject(s)
Arthritis, Rheumatoid , Janus Kinase Inhibitors , Humans , Janus Kinase Inhibitors/pharmacology , Janus Kinase Inhibitors/therapeutic use , Immunomodulating Agents , Arthritis, Rheumatoid/drug therapy , Anti-Inflammatory Agents/pharmacology , Cell DifferentiationABSTRACT
OBJECTIVES: ANCA-associated vasculitis (AAV) includes granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA). ANCA triggers neutrophil extracellular trap formation, which releases either mitochondrial (mt) DNA or nuclear DNA (n) DNA, contributing to inflammation. Our aim was to prospectively examine the extent and nature of circulating DNA in AAV and the clinical utility of DNA quantification. METHODS: DNA was isolated from platelet-free plasma of consecutive GPA and MPA patients and healthy controls (HCs). mtDNA and nDNA copy numbers were quantified by PCR. Clinical data, including the BVAS, were collected. RESULTS: Ninety-two HCs (median age 51 years, 58.7% female) and 101 AAV patients (80 GPA, 21 MPA, median age 64 years, 50.5% female, BVAS range: 0-30) were included. Median mtDNA copies were 13-fold higher in patients with AAV than in HCs; nDNA concentrations did not differ. Patients with active AAV (BVAS > 0) had 4-fold higher median mtDNA copies than patients in remission (P = 0.03). mtDNA, unlike nDNA, correlated with BVAS (r = 0.30, P = 0.002) and was associated with AAV activity at multivariable analysis. Receiver operating characteristic curve analysis indicated that mtDNA quantification differentiates patients with active AAV (BVAS > 0) from HCs with 96.1% sensitivity and 98.9% specificity (area under the curve 0.99). In 27 AAV patients with follow-up, mtDNA changes but not CRP or ANCA-titres correlated with BVAS changes (r = 0.56, P = 0.002). CONCLUSIONS: mtDNA, unlike nDNA, is elevated in the plasma of AAV patients and may contribute to systemic inflammation. mtDNA could be superior to established biomarkers in the laboratory monitoring of AAV activity.
Subject(s)
Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis , Granulomatosis with Polyangiitis , Microscopic Polyangiitis , Humans , Female , Middle Aged , Male , Antibodies, Antineutrophil Cytoplasmic , DNA, Mitochondrial/genetics , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/diagnosis , Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis/genetics , InflammationABSTRACT
The network of IL-17 cytokines is considered a key component of autoimmune and inflammatory processes. Blocking IL-17 showed great success in psoriasis as well as psoriatic arthritis, and in patients with axial spondyloarthritis. Secukinumab is one of the approved IL-17A inhibitors for these diseases and is now routinely used. In giant cell arteritis, a large vessel vasculitis, there is accumulating evidence for a pathogenic role of IL-17 and Th17 cells, which are part of the CD4+ T-cell subset. Giant cell arteritis occurs in individuals over 50 years of age and many have relative contraindications to glucocorticoid therapy, which today still represents the mainstay therapy. Despite the approval of tocilizumab, which targets the IL-6 receptor, a high demand for glucocorticoid-sparing agents remains that combine the effective suppression of the acute inflammation observed in giant cell arteritis with a safety profile that matches the needs of an older patient population. The first results from a phase II proof-of-principle study (TitAIN) support an optimistic outlook on a potential new treatment option with secukinumab in giant cell arteritis.
Subject(s)
Giant Cell Arteritis , Humans , Middle Aged , Interleukin-17/metabolism , Glucocorticoids/pharmacology , Cytokines/metabolismABSTRACT
BACKGROUND: The treatment of giant cell arteritis with glucocorticoid-sparing agents is an unmet medical need. We evaluated the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in patients with giant cell arteritis. METHODS: We conducted a Bayesian randomised, parallel-group, double-blind, placebo-controlled, multicentre, phase 2 study at 11 clinics or hospitals in Germany. Patients aged 50 years or older with new-onset or relapsing giant cell arteritis who were naive to biological therapy and already receiving glucocorticoids with a prednisolone equivalent dose of 25-60 mg/day were eligible for inclusion. Participants were assigned (1:1) to receive 300 mg secukinumab or placebo subcutaneously once a week up to week 4 and every 4 weeks thereafter. In both treatment groups, prednisolone dose was tapered down to 0 mg over a 26-week period. Patients, investigator staff, and clinical trial team were masked to the treatment assignment. The primary endpoint was the median proportion (Bayesian analysis) of patients with sustained remission until week 28 in the full analysis set (ie, all patients who received at least one dose of assigned treatment, analysed according to treatment assigned at randomisation). Sustained remission rate of the placebo group from a previous trial of tocilizumab in patients with giant cell arteritis was used to derive the prior distribution of placebo sustained remission rate for the primary endpoint. The safety of secukinumab was assessed in the safety set (ie, all patients who received at least one dose of study treatment, analysed according to study treatment received). This trial is completed and is registered with ClinicalTrials.gov, NCT03765788. FINDINGS: Of the 65 patients who were assessed for eligibility, 52 patients (median age 75 years [IQR 69-79]; 35 [67%] female and 17 [33%] male, 52 [100%] White) were enrolled between Jan 30, 2019 and March 30, 2020 and were randomly assigned to receive secukinumab (n=27) or placebo (n=25). Four of 27 patients in the secukinumab group and eight of 25 patients in the placebo group discontinued treatment by week 28 of the study. On the basis of the Bayesian analysis, the median proportion of patients in sustained remission until week 28 was 70% (95% credibility interval 52-85) in the secukinumab group versus 20% (12-30) in the placebo group. The incidence of adverse events was similar in the secukinumab (27 [100%] of 27 patients had any adverse event) and placebo groups (24 [96%] of 25 patients had any adverse event); the most common adverse events were hypertension (six [22%] of 27 patients in the secukinumab group and eight [32%] of 25 patients in the placebo group) and nasopharyngitis (five [19%] of 27 patients in the secukinumab group and five [20%] of 25 patients in the placebo group). Two patients (one in each group) died during the study, neither of which was considered to be related to study treatment. INTERPRETATION: Patients with active giant cell arteritis had a higher sustained remission rate in the secukinumab group than in the placebo group at week 28, in combination with glucocorticoid taper regimen. Secukinumab was tolerated well with no new safety concerns. This proof-of-concept phase 2 study further supports the development of secukinumab as a treatment option for people with giant cell arteritis. FUNDING: Novartis Pharma.
Subject(s)
Antibodies, Monoclonal, Humanized , Giant Cell Arteritis , Aged , Female , Humans , Male , Bayes Theorem , Giant Cell Arteritis/drug therapy , Glucocorticoids , Prednisolone , Double-Blind MethodABSTRACT
Respiratory tract infections (RTIs) are the most common infections in patients with rheumatic diseases under immunosuppressive treatment and may contribute to morbidity and mortality as well as increased healthcare costs. However, to date only limited data on infection risk in spondyloarthritis (SpA) patients are available. In this study we assessed the occurrence of respiratory tract infections in a monocentric real-world cohort consisting of 330 patients (168 psoriatic arthritis and 162 axial spondyloarthritis patients) and determined factors associated with increased infection risk. Out of 330 SpA patients, 89.3% had suffered from ≥ 1 upper respiratory tract infection (URTI) and 31.1% from ≥ 1 lower respiratory tract infection (LRTI) within the last two years. The most common URTIs were rhinitis and laryngitis/pharyngitis with 87.3% and 36.1%, respectively. Bronchitis constituted the most common LRTI, reported in 29.7% of patients. In a multivariate binomial logistic regression model occurrence of LRTI was associated with chronic lung disease (OR 17.44, p=0.006), glucocorticoid therapy (OR 9.24, p=0.012), previous history of severe airway infections (OR 6.82, p=0.013), and number of previous biological therapies (OR 1.72, p=0.017), whereas HLA B27 positivity was negatively associated (OR 0.29, p=0.025). Female patients reported significantly more LRTIs than male patients (p=0.006) and had a higher rate of antibiotic therapy (p=0.009). There were no significant differences between axSpA and PsA patients regarding infection frequency or antibiotic use. 45.4% of patients had required antibiotics for respiratory tract infections. Antibiotic therapy was associated with smoking (OR 3.40, p=0.008), biological therapy (OR 3.38, p=0.004), sleep quality (OR 1.13, p<0.001) and age (OR 0.96, p=0.030). Hypogammaglobulinemia (IgG<7g/l) was rare (3.4%) in this SpA cohort despite continuous immunomodulatory treatment. Awareness of these risk factors will assist physicians to identify patients with an increased infection risk, who will benefit from additional preventive measures, such as vaccination and smoking cessation or adjustment of DMARD therapy.