[Recommendations for defining giant cell arteritis fast-track clinics]. / Empfehlungen zur Definition von Riesenzellarteriitis-Fast-Track-Kliniken.

An expert committee recommends defining fast-track clinics (FTC) for the acute diagnostics of giant cell arteritis (GCA) as follows: low-threshold, easy and prompt reachability at least on weekdays, scheduling appointments ideally within 24 h, examination by a specialist with GCA expertise, ≥ 2 experts per FTC, ≥ 50 patients with suspected GCA per year, sonologists with ≥ 300 (≥ 50) temporal and axillary artery examinations, adherence to standard operating procedures, availability of an ≥ 18 (≥ 15) MHz and a lower frequency linear ultrasound probe and collaboration with partners for fast performance of neurological and ophthalmological examinations, magnetic resonance imaging (MRI), positron emission tomography-computed tomography (PET-CT, possibly CT) and for temporal artery biopsy.

Inflammatory tissue priming: novel insights and therapeutic opportunities for inflammatory rheumatic diseases.

Due to optimised treatment strategies and the availability of new therapies during the last decades, formerly devastating chronic inflammatory diseases such as rheumatoid arthritis or systemic sclerosis (SSc) have become less menacing. However, in many patients, even state-of-the-art treatment cannot induce remission. Moreover, the risk for flares strongly increases once anti-inflammatory therapy is tapered or withdrawn, suggesting that underlying pathological processes remain active even in the absence of overt inflammation. It has become evident that tissues have the ability to remember past encounters with pathogens, wounds and other irritants, and to react more strongly and/or persistently to the next occurrence. This priming of the tissue bears a paramount role in defence from microbes, but on the other hand drives inflammatory pathologies (the Dr Jekyll and Mr Hyde aspect of tissue adaptation). Emerging evidence suggests that long-lived tissue-resident cells, such as fibroblasts, macrophages, long-lived plasma cells and tissue-resident memory T cells, determine inflammatory tissue priming in an interplay with infiltrating immune cells of lymphoid and myeloid origin, and with systemically acting factors such as cytokines, extracellular vesicles and antibodies. Here, we review the current state of science on inflammatory tissue priming, focusing on tissue-resident and tissue-occupying cells in arthritis and SSc, and reflect on the most promising treatment options targeting the maladapted tissue response during these diseases.

Intensive receptor blockade and plasma exchange to treat refractory scleroderma renal crisis in patients with agonistic autoantibodies targeting the angiotensin II type 1 and endothelin-1 type A receptors.

Scleroderma renal crisis is a rare complication of systemic sclerosis characterized by a rapid decline in kidney function due to acute renal vascular injury. Recently, activating autoantibodies targeting the angiotensin II type 1 receptor and the endothelin-1 type A receptor have been implicated in the pathophysiology of scleroderma renal crisis by sensitizing the angiotensin II type 1 receptor and endothelin-1 type A receptor in renal resistance arteries to their natural ligands. Here, we describe a cohort of 10 patients with scleroderma renal crisis refractory to standard treatment, including blockade of the renin-angiotensin system. Multimodal therapy was initiated, targeting at the removal of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies by plasma exchange and the reduction of vasoconstrictive activity. Further treatment options included angiotensin II type 1 receptor and endothelin-1 type A receptor blockade, iloprost, intravenous immunoglobulins, and immunosuppression. Six patients were hypertensive. On kidney biopsy, concentric intimal sclerosis was present in all patients, whereas acute vascular injury was evident in eight. Levels of anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies were significantly reduced by multimodal treatment. Kidney function improved in three patients with histological signs of severe acute renal vascular damage. This report demonstrates that intensive multimodal therapy taking account of potentially pathogenic anti-angiotensin II type 1 receptor and anti-endothelin-1 type A receptor autoantibodies in concert with other vasodilatory interventions provides a salvage option for patients with refractory scleroderma renal crisis.

[Immune-mediated inflammatory diseases in Germany : A cross-sectional analysis of comorbidities and pharmacotherapy]. / Chronische Entzündungserkrankungen in Deutschland : Eine Querschnittanalyse über Begleiterkrankungen und Arzneimitteleinsatz.

BACKGROUND: Immune-mediated inflammatory diseases (IMID) can lead to a substantial disease burden for those affected, in particular by the concomitant occurrence of other IMIDs or in the presence of comorbidities. The care of patients with IMIDs is complex and involves various medical disciplines. OBJECTIVE: To describe the burden of disease and the current routine drug treatment of patients with IMID. MATERIAL AND METHODS: The retrospective cross-sectional analysis was based on statutory health insurance claims data from the InGef database. Prevalent patients with psoriasis (Pso), psoriatic arthritis (PsA), spondylarthritis (SpA), rheumatoid arthritis (RA), Crohn's disease (MC), ulcerative colitis (CU), or connective tissue disease were identified among 3,988,695 insured patients in 2018. The concomitant occurrence of different IMIDs and the extent to which patients with IMID are affected by other comorbidities compared to a reference population were investigated. The current routine drug treatment was described based on the use of predefined forms of treatment. RESULTS: In the database 188,440 patients with IMID (4.7%) were identified. Compared to the reference population the prevalence of comorbidities, such as depressive episodes and cardiovascular risk factors was higher in patients with IMID. For MC, CU, RA, and PsA disease-modifying antirheumatic drugs (DMARD) and classical systemic forms of treatment were used most commonly. In Pso, SpA, and connective tissue disease nonsteroidal anti-inflammatory drugs (NSAID) were the most frequently used treatment often in combination with other drugs. CONCLUSION: A considerable number of patients with IMIDs (16.9-27.5%) suffer from different diseases of the IMID group. They are frequently affected by accompanying illnesses and require interdisciplinary medical treatment.

Does the Impact of COVID-19 on Patients With Systemic Sclerosis Change Over Time?

OBJECTIVE: The outcome of patients with COVID-19 improved over the pandemic, including patients with systemic rheumatic diseases. However, data on patients with systemic sclerosis (SSc) are lacking. This study aimed to assess the outcome of patients with both SSc and COVID-19 over several waves. METHODS: Patients with both SSc and COVID-19 who were registered in the European Scleroderma Trials and Research group (EUSTAR) were collected between April 2020 and April 2021. Patients were assigned to waves 1, 2, or 3 depending on the date of their COVID-19 diagnosis. Primary endpoints were death, intensive care unit stay, or ventilatory support (severe outcome). Subgroup analyses of patients who were hospitalized or died were conducted. General and SSc-specific characteristics and treatment were compared over the waves. Descriptive statistics and multivariate logistic regression were applied. RESULTS: A total of 333 patients were included; 57 patients (17%) had a severe outcome, and 30 patients (9%) died. Compared to wave 1, significantly fewer patients with SSc suffered from severe COVID-19 in waves 2 and 3 (28.2% vs 9.8% and 12.7%; P < 0.001), fewer patients required hospitalization (46.7% vs 19.6% and 25.5%; P < 0.001) or ventilatory support (24.0% vs 8.7% and 10.9%; P = 0.001), and fewer patients died (15.7% vs 5.0% and 7.5%; P = 0.011). Patients were significantly younger, more often men, had less frequent arterial hypertension, and less SSc cardiac involvement over waves 1 to 3. Patients received significantly less medium to high doses of corticosteroids as they did SSc treatment. CONCLUSION: The outcome of patients with both SSc and COVID-19 improved significantly over time because of intrinsic and extrinsic factors.

Impact of Systemic Sclerosis-Associated Interstitial Lung Disease With and Without Pulmonary Hypertension on Survival: A Large Cohort Study of the German Network for Systemic Sclerosis.

BACKGROUND: Pulmonary involvement is the leading cause of death in systemic sclerosis (SSc) and may manifest as interstitial lung disease (ILD), pulmonary arterial hypertension (PAH), or in combination of both (ILD with pulmonary hypertension [ILD-PH]). The aim of this analysis was to determine prevalence, clinical characteristics, and survival of these different forms within the registry of the German Network for Systemic Sclerosis. RESEARCH QUESTION: Does SSc-associated ILD-PH or ILD without PH affect survival differently, and are there any risk factors that have an additional impact? STUDY DESIGN AND METHODS: Clinical data of 5,831 patients with SSc were collected in the German Network for Systemic Sclerosis registry. Kaplan-Meier estimates were used to compare overall survival in patients with SSc-associated ILD-PH and ILD without PH with patients without pulmonary involvement and those with PAH. The Cox proportional hazard model was used to analyze the influence of pulmonary involvement and other potential predictors on patient survival. RESULTS: Clinical data of 3,257 patients with a mean follow-up time of 3.45 ± 1.63 years have been included in our analysis. At baseline, ILD was present in 34.5%, whereas PH without ILD had a lower prevalence with 4.5%. At the end of follow-up, 47.6% of patients with SSc had ILD, 15.2% had ILD-PH, and 6.5% had PAH. ILD was more frequent in the diffuse cutaneous form (57.3%), whereas PAH did not differ significantly between SSc subtypes. Significant differences in baseline characteristics between PAH vs ILD-PH vs ILD without PH were found for age at diagnosis, sex, SSc subsets, antibody status, FVC, diffusing capacity of the lung for carbon monoxide, and therapy. Overall survival at 5 years was 96.4% for patients without pulmonary involvement and differed significantly between patients with ILD without PH, PAH, and being worst in patients with ILD-PH. Female sex (hazard ratio [HR], 0.3), higher BMI (HR, 0.9), and higher diffusing capacity of the lung for carbon monoxide values (HR, 0.98) were associated with a lower mortality risk. INTERPRETATION: ILD is the most prevalent pulmonary involvement in SSc, whereas the combination of ILD and PH is associated with the most detrimental survival.

[Epidemiological data and medical care situation of patients with chronic inflammatory diseases in Germany : Real-world evidence on prevalence, disease combinations, care]. / Epidemiologische Daten und medizinische Versorgungssituation von Patienten mit chronischen Entzündungserkrankungen in Deutschland : Real-World-Evidenz zu Prävalenz, Erkrankungskombinationen, Versorgung.

BACKGROUND: Chronic inflammatory diseases (immune-mediated inflammatory diseases, IMID) can overlap or occur simultaneously due to clinical similarities. The resulting utilization of heathcare structures has not yet been investigated across disciplines but is of potential importance for optimizing the treatment of patients with IMID. AIM OF THE WORK: Analysis of epidemiological data including utilization of care services in patients with selected IMIDs: psoriasis, psoriatic arthritis (PsA), rheumatoid arthritis (RA), ankylosing spondylitis, ulcerative colitis, Crohn's disease and connective tissue disease. MATERIAL AND METHODS: In a retrospective cross-sectional analysis based on health insurances accounting data with a sample of approximately 4 million insured persons, the prevalence of the abovementioned IMID and the frequency of IMID combinations were analyzed based on documented diagnoses (ICD-10 GM). The frequency of hospitalizations and utilization of outpatient physician contacts was recorded in predefined specialist disciplines (general medicine, dermatology, gastroenterology, rheumatology) and compared with an age-adjusted and gender-adjusted reference population. RESULTS: A total of 188,440 patients had at least 1 of the IMID diagnoses analyzed (4.7%), with an age peak of 61-70 years. The highest prevalence was observed for psoriasis (1.85%), followed by rheumatoid arthritis (1.38%). Combinations with at least one other IMID were relatively common (29%), with this being most common in patients with psoriatic arthritis (82.9%, of which 68.2% had psoriasis), followed by ankylosing spondylitis (27.5%) and Crohn's disease (21.6%). Compared to the reference population, patients with IMID were hospitalized more often and more frequently utilized the outpatient disciplines. DISCUSSION: The study results describe that IMIDs occur in combination and that the patients make comparatively more use of care structures of different disciplines. A multidisciplinary approach could increase the efficiency of care; an evaluation is still pending.

Regulatory T cells inhibit autoantigen-specific CD4+ T cell responses in lupus-prone NZB/W F1 mice.

Introduction: Progressive loss of regulatory T cell (Treg)-mediated control over autoreactive effector T cells contributes to the development of systemic lupus erythematosus (SLE). Accordingly, we hypothesized that Treg may also have the capacity to suppress the activation of autoreactive CD4+ T cells that are considered to drive autoimmunity. Methods: To investigate whether Treg are involved in the control of autoreactive CD4+ T cells, we depleted CD25+ Treg cells either in vivo or in vitro, or combined both approaches before antigen-specific stimulation with the SLE-associated autoantigen SmD1(83-119) in the NZB/W F1 mouse model either after immunization against SmD1(83-119) or during spontaneous disease development. Frequencies of autoantigen-specific CD4+ T cells were determined by flow cytometry using the activation marker CD154. Results: Both in vitro and in vivo depletion of CD25+ Treg, respectively, increased the frequencies of detectable autoantigen-specific CD4+ T cells by approximately 50%. Notably, the combined in vivo and in vitro depletion of CD25+ Treg led almost to a doubling in their frequencies. Frequencies of autoantigen-specific CD4+ T cells were found to be lower in immunized haploidentical non-autoimmune strains and increased frequencies were detectable in unmanipulated NZB/W F1 mice with active disease. In vitro re-addition of CD25+ Treg after Treg depletion restored suppression of autoantigen-specific CD4+ T cell activation. Discussion: These results suggest that the activation and expansion of autoantigen-specific CD4+ T cells are partly controlled by Treg in murine lupus. Depletion of Treg therefore can be a useful approach to increase the detectability of autoantigen-specific CD4+ T cells allowing their detailed characterization including lineage determination and epitope mapping and their sufficient ex vivo isolation for cell culture.

Autoantibodies against the chemokine receptor 3 predict cardiovascular risk.

BACKGROUND AND AIMS: Chronic inflammation and autoimmunity contribute to cardiovascular (CV) disease. Recently, autoantibodies (aAbs) against the CXC-motif-chemokine receptor 3 (CXCR3), a G protein-coupled receptor with a key role in atherosclerosis, have been identified. The role of anti-CXCR3 aAbs for CV risk and disease is unclear. METHODS: Anti-CXCR3 aAbs were quantified by a commercially available enzyme-linked immunosorbent assay in 5000 participants (availability: 97.1%) of the population-based Gutenberg Health Study with extensive clinical phenotyping. Regression analyses were carried out to identify determinants of anti-CXCR3 aAbs and relevance for clinical outcome (i.e. all-cause mortality, cardiac death, heart failure, and major adverse cardiac events comprising incident coronary artery disease, myocardial infarction, and cardiac death). Last, immunization with CXCR3 and passive transfer of aAbs were performed in ApoE(-/-) mice for preclinical validation. RESULTS: The analysis sample included 4195 individuals (48% female, mean age 55.5 ± 11 years) after exclusion of individuals with autoimmune disease, immunomodulatory medication, acute infection, and history of cancer. Independent of age, sex, renal function, and traditional CV risk factors, increasing concentrations of anti-CXCR3 aAbs translated into higher intima-media thickness, left ventricular mass, and N-terminal pro-B-type natriuretic peptide. Adjusted for age and sex, anti-CXCR3 aAbs above the 75th percentile predicted all-cause death [hazard ratio (HR) (95% confidence interval) 1.25 (1.02, 1.52), P = .029], driven by excess cardiac mortality [HR 2.51 (1.21, 5.22), P = .014]. A trend towards a higher risk for major adverse cardiac events [HR 1.42 (1.0, 2.0), P = .05] along with increased risk of incident heart failure [HR per standard deviation increase of anti-CXCR3 aAbs: 1.26 (1.02, 1.56), P = .03] may contribute to this observation. Targeted proteomics revealed a molecular signature of anti-CXCR3 aAbs reflecting immune cell activation and cytokine-cytokine receptor interactions associated with an ongoing T helper cell 1 response. Finally, ApoE(-/-) mice immunized against CXCR3 displayed increased anti-CXCR3 aAbs and exhibited a higher burden of atherosclerosis compared to non-immunized controls, correlating with concentrations of anti-CXCR3 aAbs in the passive transfer model. CONCLUSIONS: In individuals free of autoimmune disease, anti-CXCR3 aAbs were abundant, related to CV end-organ damage, and predicted all-cause death as well as cardiac morbidity and mortality in conjunction with the acceleration of experimental atherosclerosis.

Vasoregulatory Autoantibodies and Clinical Outcome After Ischemic Stroke-PROSCIS-B.

BACKGROUND: Vasoregulatory autoantibodies including autoantibodies targeting G-protein-coupled receptors might play a functional role in vascular diseases. We investigated the impact of vasoregulatory autoantibodies on clinical outcome after ischemic stroke. METHODS AND RESULTS: Data were used from the PROSCIS-B (Prospective Cohort With Incident Stroke-Berlin). Autoantibody-targeting receptors such as angiotensin II type 1 receptor (AT1R), endothelin-1 type A receptor, complement factor-3 and -5 receptors, vascular endothelial growth factor receptor-1 and -2, vascular endothelial growth factor A and factor B were measured. We explored associations of high antibody levels with (1) poor functional outcome defined as modified Rankin Scale >2 or Barthel Index <60 at 1 year after stroke, (2) Barthel Index scores over time using general estimating equations, and (3) secondary vascular events (recurrent stroke, myocardial infarction) or death up to 3 years using Cox proportional hazard models. We included 491 patients with ischemic stroke with data on autoantibody levels and outcome. In models adjusted for demographics and vascular risk factors, high autoantibody concentrations (quartile 4) targeting complement factor C3a receptor, vascular endothelial growth factor receptor-2, and vascular endothelial growth factor B were associated with poor functional outcome at 1 year: (odds ratio, 2.0 [95% CI, 1.1-3.6]; odds ratio, 1.8 [95% CI, 1.1-3.2]; and odds ratio, 2.1 [95% CI, 1.2-3.6], respectively) and with lower Barthel Index scores over 3 years (complement factor C3a receptor: adjusted ß=-3.3 [95% CI, -5.7 to -0.5]; VEGF-B: adjusted ß=-2.4 [95% CI, -4.8 to -0.06]). Patients with high autoantibody levels were not at higher risk for secondary vascular events or death. CONCLUSIONS: High levels of autoantibodies against vascular endothelial growth factor receptor-2, vascular endothelial growth factor B, and complement factor C3a receptor measured are associated with poor functional outcome after stroke but not with recurrent vascular events or death. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01363856.

Autoantibodies from patients with kidney allograft vasculopathy stimulate a proinflammatory switch in endothelial cells and monocytes mediated via GPCR-directed PAR1-TNF-α signaling.

Non-HLA-directed regulatory autoantibodies (RABs) are known to target G-protein coupled receptors (GPCRs) and thereby contribute to kidney transplant vasculopathy and failure. However, the detailed underlying signaling mechanisms in human microvascular endothelial cells (HMECs) and immune cells need to be clarified in more detail. In this study, we compared the immune stimulatory effects and concomitant intracellular and extracellular signaling mechanisms of immunoglobulin G (IgG)-fractions from kidney transplant patients with allograft vasculopathy (KTx-IgG), to that from patients without vasculopathy, or matched healthy controls (Con-IgG). We found that KTx-IgG from patients with vasculopathy, but not KTx-IgG from patients without vasculopathy or Con-IgG, elicits HMEC activation and subsequent upregulation and secretion of tumor necrosis factor alpha (TNF-α) from HMECs, which was amplified in the presence of the protease-activated thrombin receptor 1 (PAR1) activator thrombin, but could be omitted by selectively blocking the PAR1 receptor. The amount and activity of the TNF-α secreted by HMECs stimulated with KTx-IgG from patients with vasculopathy was sufficient to induce subsequent THP-1 monocytic cell activation. Furthermore, AP-1/c-FOS, was identified as crucial transcription factor complex controlling the KTx-IgG-induced endothelial TNF-α synthesis, and mircoRNA-let-7f-5p as a regulatory element in modulating the underlying signaling cascade. In conclusion, exposure of HMECs to KTx-IgG from patients with allograft vasculopathy, but not KTx-IgG from patients without vasculopathy or healthy Con-IgG, triggers signaling through the PAR1-AP-1/c-FOS-miRNA-let7-axis, to control TNF-α gene transcription and TNF-α-induced monocyte activation. These observations offer a greater mechanistic understanding of endothelial cells and subsequent immune cell activation in the clinical setting of transplant vasculopathy that can eventually lead to transplant failure, irrespective of alloantigen-directed responses.

Understanding, diagnosing, and treating Myalgic encephalomyelitis/chronic fatigue syndrome - State of the art: Report of the 2nd international meeting at the Charité Fatigue Center.

Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a devastating disease affecting millions of people worldwide. Due to the 2019 pandemic of coronavirus disease (COVID-19), we are facing a significant increase of ME/CFS prevalence. On May 11th to 12th, 2023, the second international ME/CFS conference of the Charité Fatigue Center was held in Berlin, Germany, focusing on pathomechanisms, diagnosis, and treatment. During the two-day conference, more than 100 researchers from various research fields met on-site and over 700 attendees participated online to discuss the state of the art and novel findings in this field. Key topics from the conference included: the role of the immune system, dysfunction of endothelial and autonomic nervous system, and viral reactivation. Furthermore, there were presentations on innovative diagnostic measures and assessments for this complex disease, cutting-edge treatment approaches, and clinical studies. Despite the increased public attention due to the COVID-19 pandemic, the subsequent rise of Long COVID-19 cases, and the rise of funding opportunities to unravel the pathomechanisms underlying ME/CFS, this severe disease remains highly underresearched. Future adequately funded research efforts are needed to further explore the disease etiology and to identify diagnostic markers and targeted therapies.

Luteolin peracetate and gossypolone inhibit immune complex-mediated neutrophil activation in vitro and dermal-epidermal separation in an ex vivo model of epidermolysis bullosa acquisita.

Introduction: Natural products have been shown to an important source of therapeutics for human disease. In this study, we aimed to identify natural compounds as potential therapeutics for epidermolysis bullosa acquisita (EBA), an autoimmune disease caused by autoantibodies to type VII collagen (COL7). Methods: Utilizing an in vitro experimental system, we screened a natural product library composed of 800 pure compounds for their inhibitory effect on COL7-anti-COL7 IgG immune complex (IC)-mediated neutrophil activation and on neutrophil-mediated tissue damage. Results: Three natural compounds, namely luteolin peracetate, gossypol, and gossypolone were capable in inhibiting the IC-induced neutrophil adhesion and oxygen burst in vitro. Furthermore, luteolin peracetate and gossypolone were able to inhibit the anti-COL7 IgG induced dermal-epidermal separation in an ex vivo model for EBA. Discussion: In summary, this study demonstrates that luteolin peracetate and gossypolone are potential therapeutics for experimental EBA, which deserves further investigation.

Severe COVID-19 patients exhibit elevated levels of autoantibodies targeting cardiolipin and platelet glycoprotein with age: a systems biology approach.

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) severity due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, and chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health and disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 severity (71 mild, 61 moderate, and 27 with severe symptoms) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multiple linear regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid ß peptide, ß catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition and hierarchical clustering analysis based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe COVID-19 patients ≥50 years of age. Follow-up analysis using binomial logistic regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies significantly increased the likelihood of developing a severe COVID-19 phenotype with aging. These findings provide key insights to explain why aging increases the chance of developing more severe COVID-19 phenotypes.

Fighting Post-COVID and ME/CFS - development of curative therapies.

The sequela of COVID-19 include a broad spectrum of symptoms that fall under the umbrella term post-COVID-19 condition or syndrome (PCS). Immune dysregulation, autoimmunity, endothelial dysfunction, viral persistence, and viral reactivation have been identified as potential mechanisms. However, there is heterogeneity in expression of biomarkers, and it is unknown yet whether these distinguish different clinical subgroups of PCS. There is an overlap of symptoms and pathomechanisms of PCS with postinfectious myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). No curative therapies are available for ME/CFS or PCS. The mechanisms identified so far provide targets for therapeutic interventions. To accelerate the development of therapies, we propose evaluating drugs targeting different mechanisms in clinical trial networks using harmonized diagnostic and outcome criteria and subgrouping patients based on a thorough clinical profiling including a comprehensive diagnostic and biomarker phenotyping.

Increased circulating fibronectin, depletion of natural IgM and heightened EBV, HSV-1 reactivation in ME/CFS and long COVID.

Myalgic Encephalomyelitis/ Chronic Fatigue syndrome (ME/CFS) is a complex, debilitating, long-term illness without a diagnostic biomarker. ME/CFS patients share overlapping symptoms with long COVID patients, an observation which has strengthened the infectious origin hypothesis of ME/CFS. However, the exact sequence of events leading to disease development is largely unknown for both clinical conditions. Here we show antibody response to herpesvirus dUTPases, particularly to that of Epstein-Barr virus (EBV) and HSV-1, increased circulating fibronectin (FN1) levels in serum and depletion of natural IgM against fibronectin ((n)IgM-FN1) are common factors for both severe ME/CFS and long COVID. We provide evidence for herpesvirus dUTPases-mediated alterations in host cell cytoskeleton, mitochondrial dysfunction and OXPHOS. Our data show altered active immune complexes, immunoglobulin-mediated mitochondrial fragmentation as well as adaptive IgM production in ME/CFS patients. Our findings provide mechanistic insight into both ME/CFS and long COVID development. Finding of increased circulating FN1 and depletion of (n)IgM-FN1 as a biomarker for the severity of both ME/CFS and long COVID has an immediate implication in diagnostics and development of treatment modalities.

When natural antibodies become pathogenic: autoantibodies targeted against G protein-coupled receptors in the pathogenesis of systemic sclerosis.

Systemic sclerosis (SSc) is a chronic, multisystem connective tissue, and autoimmune disease with the highest case-specific mortality and complications among rheumatic diseases. It is characterized by complex and variable features such as autoimmunity and inflammation, vasculopathy, and fibrosis, which pose challenges in understanding the pathogenesis of the disease. Among the large variety of autoantibodies (Abs) present in the sera of patients suffering from SSc, functionally active Abs against G protein-coupled receptors (GPCRs), the most abundant integral membrane proteins, have drawn much attention over the last decades. These Abs play an essential role in regulating the immune system, and their functions are dysregulated in diverse pathological conditions. Emerging evidence indicates that functional Abs targeting GPCRs, such as angiotensin II type 1 receptor (AT1R) and the endothelin-1 type A receptor (ETAR), are altered in SSc. These Abs are part of a network with several GPCR Abs, such as those directed to the chemokine receptors or coagulative thrombin receptors. In this review, we summarize the effects of Abs against GPCRs in SSc pathologies. Extending the knowledge on pathophysiological roles of Abs against GPCRs could provide insights into a better understanding of GPCR contribution to SSc pathogenesis and therefore help in developing potential therapeutic strategies that intervene with pathological functions of these receptors.

Functional autoantibodies: Definition, mechanisms, origin and contributions to autoimmune and non-autoimmune disorders.

A growing body of evidence underscores the relevance of functional autoantibodies in the development of various pathogenic conditions but also in the regulation of homeostasis. However, the definition of functional autoantibodies varies among studies and a comprehensive overview on this emerging topic is missing. Here, we do not only explain functional autoantibodies but also summarize the mechanisms underlying the effect of such autoantibodies including receptor activation or blockade, induction of receptor internalization, neutralization of ligands or other soluble extracellular antigens, and disruption of protein-protein interactions. In addition, in this review article we discuss potential triggers of production of functional autoantibodies, including infections, immune deficiency and tumor development. Finally, we describe the contribution of functional autoantibodies to autoimmune diseases including autoimmune thyroid diseases, myasthenia gravis, autoimmune pulmonary alveolar proteinosis, autoimmune autonomic ganglionopathy, pure red cell aplasia, autoimmune encephalitis, pemphigus, acquired thrombotic thrombocytopenic purpura, idiopathic dilated cardiomyopathy and systemic sclerosis, as well as non-autoimmune disorders such as allograft rejection, infectious diseases and asthma.

Spectrum of ANCA-specificities in eosinophilic granulomatosis with polyangiitis. A retrospective multicentre study.

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.

The Exciting Future for Scleroderma: What Therapeutic Pathways Are on the Horizon?

Emerging evidence shows that a complex interplay between cells and mediators and extracellular matrix factors may underlie the development and persistence of fibrosis in systemic sclerosis. Similar processes may determine vasculopathy. This article reviews recent progress in understanding how fibrosis becomes profibrotic and how the immune system, vascular, and mesenchymal compartment affect disease development. Early phase trials are informing about pathogenic mechanisms in vivo and reverse translation for observational and randomized trials is allowing hypotheses to be developed and tested. In addition to repurposing already available drugs, these studies are paving the way for the next generation of targeted therapeutics.