CD4+CD8αlow T cells in rheumatoid arthritis are clonally expanded and dependent on co-stimulation.

OBJECTIVES: CD4+CD8+ T cells are increased in patients with rheumatoid arthritis (RA). They are not only associated with joint erosions in established disease, but are also present in the pre-clinical stages of RA. This study aims to further investigate their expansion in the context of T cell clonality in patients with RA, as well as their responsiveness to T cell targeted treatment. METHODS: Single-cell-(sc)RNA- and scTCR-sequencing data were used to determine co-receptor expression and T cell receptor sequences to assess clonality of CD4+CD8+ T cells in RA (n=3) patients and healthy controls (n=2). Peripheral CD4+CD8+ T cells and their subpopulations were measured in patients with RA (n=53), PsA (n=52) and healthy donors (n=50) using flow cytometry. In addition, changes in CD4+CD8+ T cell frequency were prospectively followed in RA patients receiving therapy with abatacept for 12 weeks. RESULTS: We observed an increase of CD4+ T cells expressing CD8α in RA patients, both in comparison to PsA patients and to healthy controls. Clonality analysis revealed, that these CD4+CD8αlow T cells are part of large T cell clones, which cluster separately from CD4+CD8- T cell clones in the scRNA-seq gene expression analysis. Treatment with abatacept significantly reduced the frequency of peripheral CD4+CD8αlow T cells, and this was linked to reduction in disease activity. CONCLUSION: In RA, clonal expansion of CD4+ T cell clones culminates in the emergence of peripheral CD4+CD8αlow T cells, which are associated with disease activity and diminished upon abatacept treatment, and which could contribute to disease pathogenesis.

Methotrexate - Safe Backbone for the Treatment of Rheumatoid Arthritis.

Methotrexate (MTX) is the primarily used disease-modifying antirheumatic drug (DMARD) for the treatment of Rheumatoid Arthritis (RA). MTX is a safe agent, even when used for years - provided that treatment is regularly monitored and prescribers follow some simple rules, such as prescribing tablets of a single strength only. Proper patient education contributes greatly to safe treatment. The knowledge of important pharmacologic facts, possible interactions, and clinical warning signs also helps to prevent or recognize intoxications early. Therefore, this review addresses key aspects regarding the safety of MTX. In this respect, it includes adverse events, possible interactions with frequently used drugs and details on the rare but life-threatening intoxication, e.g., due to erroneous daily intake.

Symptoms and Severity of COVID-19 in Patients with Immune-Mediated Inflammatory Diseases: Experience of a University Medical Center.

Background: The pandemic situation of the novel coronavirus (severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)) and its associated disease (coronavirus disease 2019 (COVID-19)) represents a challenging condition with a plethora of aspects. The course of COVID-19 in patients with immune-mediated inflammatory diseases (IMID) such as inflammatory bowel disease (IBD) and rheumatic diseases (RD) is not well known. Our study is one step toward closing this gap by collecting data on vaccination rates, infection-free survival, and individual symptom severity. Methods: We conducted a prospective questionnaire-based study between April 2022 and October 2022 at our university hospital. Outward patients over the age of 18 years were screened for participation and reported about their infection/infection-free survival since the start of the pandemic. Results: Finally, 156 patients were included in the study, 117 (75.0%) of which had inflammatory bowel disease and 39 (25.0%) patients with rheumatic disease. Altogether, 143 (91.7%) persons had received at least one vaccination against SARS-CoV-2. A total of 153 patients provided information regarding their COVID-19 history: 81 patients (52.0%) self-reported about their SARS-CoV-2 infection. In general, courses of infection were mild: only two patients (2.5% of patients with reported COVID-19) were hospitalized due to COVID-19 with one (1.2%) of the two needing intensive care. Asymptomatic COVID-19 had been described by 7 persons (8.6% of patients with reported COVID-19). Acute COVID-19 was accompanied by fatigue/tiredness in 58 persons (71.6% of patients with history of COVID-19) as the most frequent symptom. Other complaints were common cold (55 patients = 67.9%), cough (51 patients = 63.0%), headache (44 patients = 54.3%), and fever (35 patients = 43.2%). Stratified by vaccination status (unvaccinated vs. at least once vaccinated), the time to infection differed significantly (logrank test: p = 0.04, Chi2 4.1). At least once vaccinated people had a median COVID-19-free survival of 28.5 months (confidence interval (CI): 23.6 months-not reached). Without any vaccination, the estimated time to infection was 25.1 months (CI: 23.6 months-not reached). Conclusion: Our IMID patients have a high rate of vaccination against SARS-CoV-2. Data show a significantly longer infection-free survival in vaccinated IMID patients as compared to unvaccinated patients. Discrimination between symptoms of COVID-19 and a concomitant inflammatory disease is difficult as complaints might be overlapping. This trial is registered with DRKS00028880.

[Fibromyalgia as a Rheumatic Pain Syndrome]. / Das Fibromyalgiesyndrom als Schmerzsyndrom in der Rheumatologie.

Epidemiology and pathophysiology: Fibromyalgia is significantly more common in people with rheumatic diseases than in the general population. Nevertheless, it can occur independent of other diseases. Physical and psychosocial factors are responsible for the genesis for fibromyalgia making it a multifactorial disease. Most importantly, central pain processing seems to be abnormal. The relevance of a small fibre neuropathy is yet to be determined. For the very first time, a study was able to demonstrate that fibromyalgia might be passively transferred from one organism to another in an experimental setting.Diagnosis: Fibromyalgia is a clinical diagnose. Besides generalized pain, sleep disturbances and fatigue are common features. Furthermore, there can be an association with depressive disorders. Determining the Widespread Pain Index (WPI) and the Symptom Severity Score (SSS) can help in diagnosing Fibromyalgia and to determine severity of the disease.Therapy: Cornerstones of the treatment are patient education, physical exercise, physical therapy, and cognitive behavioural therapy. In therapy-resistant cases, a multimodal approach might be considered. Analgesic drugs, particularly opioids, should basically be avoided or only be used for a short period of time. Naltrexone, an opioid antagonist, is a promising treatment candidate. Another possible approach might be the use of TENS. While there are positive observational studies on the therapeutic use of cannabinoids, evidence from controlled trials is still missing.

Influenza, Pneumococcal and Herpes Zoster Vaccination Rates in Patients with Autoimmune Inflammatory Rheumatic Diseases.

BACKGROUND: Vaccination rates are known to be low in patients with autoimmune inflammatory rheumatic diseases (AIIRD). We therefore aimed to determine current vaccination rates against influenza, Streptococcus pneumoniae and herpes zoster in a cohort of patients with AIIRD in Germany. METHODS: Consecutive adult patients with an AIIRD were recruited from our outpatient clinic during their regular consultations. The individual vaccination status regarding influenza, Streptococcus pneumoniae and herpes zoster was obtained by reviewing the vaccination documents. RESULTS: A total of 222 AIIRD patients (mean age 62.9 ± 13.9 years) were included. In total, 68.5% were vaccinated against influenza, 34.7% against Streptococcus pneumoniae and 13.1% against herpes zoster (HZ). The pneumococcal vaccination was outdated in 29.4% of the vaccinated patients. Vaccination rates were significantly higher in patients ≥60 years old (odds ratio (OR) 2.167, 95% confidence interval (CI) 1.213-3.870, p = 0.008 for influenza, OR 4.639, 95% CI 2.555-8.422, p < 0.0001 for pneumococcal and OR 6.059, 95% CI 1.772-20.712, p = 0.001 for HZ vaccination). Ages > 60 years, female sex, glucocorticoid use and influenza vaccination were all independently associated with a pneumococcal vaccination. Regarding influenza vaccination, only a positive pneumococcal vaccination history remained independently associated. In patients with HZ vaccination, glucocorticoid use and a preceding pneumococcal vaccination were independently associated with HZ protection. CONCLUSIONS: The frequencies of vaccinations against influenza, Streptococcus pneumoniae and HZ have increased during recent years. While this can be partly explained by continuous efforts in patient education during the outpatient visits, the COVID-19 pandemic might also have contributed. Nevertheless, the persistently high incidence and mortality of these preventable diseases in patients with AIIRDs mandates further efforts to increase vaccination coverage, particularly in SLE patients.

[ANCA-associated vasculitis]. / ANCA-assoziierte Vaskulitis.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides (AAV) are rheumatic diseases characterized by small-to-medium vessel vasculitis. Three different entities can be distinguished: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). While lung and renal involvement are typical manifestations of both GPA and MPA, EGPA usually shows paranasal sinus and lung involvement as well as a history of bronchial asthma. Furthermore, EGPA is frequently associated with cardiac disease and peripheral neuropathy. Cyclophosphamide or rituximab, combined with glucocorticoids, are used to induce remission of severe disease. Maintenance therapy options include rituximab as the first-line treatment, as well as methotrexate or azathioprine plus low-dose glucocorticoids.

Macrophages in obesity are characterised by increased IL-1ß response to calcium-sensing receptor signals.

OBJECTIVE: Obesity is complicated by inflammatory activation of the innate immune system. Stimulation of the calcium-sensing receptor (CaSR) by extra-cellular calcium ions ([Ca2+]ex) can trigger NLRP3 inflammasome activation and inflammation. We hypothesised, that this mechanism might contribute to the activation of adipose tissue (AT) in obesity, and investigated [Ca2+]ex-induced, CaSR mediated IL-1ß release by macrophages in obesity. METHODS: [Ca2+]ex-induced IL-1ß release was investigated in monocyte-derived macrophages (MDM) generated from peripheral blood of patients with obesity and from normal-weight controls. Visceral and subcutaneous AT biosamples were stimulated with [Ca2+]ex, and IL-1ß release, as well as expression of NLRP3 inflammasome and cytokine genes, was determined. RESULTS: Both MDM and AT readily responded with concentration-dependent IL-1ß release already at low, near physiological concentrations to addition of [Ca2+]ex, which was more than 80 fold higher than the LPS-induced effect. IL-1ß levels induced by [Ca2+]ex were significantly higher not only in MDM from patients with obesity compared to controls, but also in visceral versus subcutaneous AT. This fat-depot difference was also reflected by mRNA expression levels of inflammasome and cytokine genes. CONCLUSIONS: Obesity renders macrophages more susceptible to [Ca2+]ex-induced IL-1ß release and pyroptosis. Increased susceptibility was independent of the response to LPS and circulating CRP arguing against mere pro-inflammatory pre-activation of monocytes. Instead, we propose that CaSR mediated signalling is relevant for the deleterious innate immune activation in obesity.

IL-10 Induced by mTNF Crosslinking-Mediated Reverse Signaling in a Whole Blood Assay Is Predictive of Response to TNFi Therapy in Rheumatoid Arthritis.

(1) Background: To date, the response of patients with rheumatoid arthritis (RA) to the various biologic DMARD available cannot be predicted due to a lack of reliable biomarkers. Based on our preliminary work on tmTNF reverse signaling, we developed a whole-blood assay measuring tmTNF crosslinking-induced IL-10 production to predict the response to TNF inhibitor (TNFi) therapy. (2) Methods: This prospective study included patients with active RA. Depending on the clinical judgment of the attending rheumatologist, either therapy with a TNF or JAK inhibitor was initiated. Clinical parameters and blood samples were obtained at baseline and after 8 weeks of therapy. The blood samples were collected using a newly developed whole-blood assay based on the principle of tmTNF reverse signalling. Subsequently, IL-10 was measured via enzyme-linked immunosorbent assay (ELISA) technique. (3) Results: 63 patients with RA were enrolled. In fifteen patients, TNFi therapy was initiated, while eight patients started a JAKi treatment. The cross-sectional analysis of all patients showed a positive correlation between tmTNF crosslinking-induced IL-10 and parameters of disease activity (CRP [r = 0.4091, p = 0.0009], DAS28 [r = 0.3303, p = 0.0082]) at baseline. In the TNFi treatment study, IL-10 was found to be significantly higher in EULAR responders than in non-responders (p = 0.0033). After initiation of JAKi treatment, in contrast, IL-10 induction was not linked to response. Longitudinal analysis of the TNFi-treated patients revealed IL-10 to decrease in responders (p = 0.04), but not in non-responders after 8 weeks of therapy. Of importance, the IL-10 production at baseline correlated inversely with TNFi response determined by ΔDAS28 in patients with TNFi treatment (r = -0.5299, p = 0.0422) while no such link was observed under JAKi therapy (p = 0.22). Receiver operation characteristics (ROC) analysis demonstrated a high performance of tmTNF/crosslinking-induced IL-10 in predicting a TNFi therapy response according to the EULAR criteria (AUC = 0.9286, 95% Confidence interval 0.7825-1.000, p = 0.0055). (4) Conclusions: In this pilot investigation, we demonstrated the feasibility of a whole-blood assay measuring tmTNF-induced IL-10 to predict clinical response to TNF inhibitor treatment. This approach might support rheumatologists in their decision for an individually tailored RA therapy.

[Osteoarthritis: what's new?] / Arthrose ­ neue therapeutische Ansätze.

Osteoarthritis (OA) is a very common disease. As a consequence of the ageing society, osteoarthritis prevalence will further increase. Age itself, trauma, unequal load distribution and overweight are risk factors. Cellular senescence and overweight have been in the focus of scientific interest for the last few years. Both risk factors are able to facilitate joint inflammation, independent of a mechanical approach. Senescent chondrocytes as well as adipocytes can produce increased amounts of inflammatory cytokines. Cornerstones of the therapy are patient education including information on the character/course of the disease and intentional weight loss. Although NSAIDs can be recommended as analgesics, their contraindications limit the widespread use. Alternatively, acetaminophen or low-potency opioids such as tramadol might be considered. Topical NSAIDs and intraarticular glucocorticoid injections can be helpful in pain reduction particularly in knee osteoarthritis. There is still no general recommendation for nutritional supplements including chondroitin or glycosaminoglycan, but they might be considered as an accompanying therapy. With the current non-approval of the nerve growth factor (NGF)-antibody tanezumab, a new therapeutical option for OA suffered a setback. Unfortunately, the results of the phase 2 study on the Wnt inhibitor lorecivivint are barely encouraging. However, the results of the according phase 3 study are eagerly awaited.

COVID-19 Vaccination Coverage in Patients with Rheumatic Diseases in a German Outpatient Clinic: An Observational Study.

BACKGROUND: In the second year of the COVID-19 pandemic, highly effective and safe vaccines became available. Since patients with rheumatic diseases show increased susceptibility to infections and typical medications raise the risk of severe COVID-19, high vaccination coverage is of significant importance to these patients. METHODS: Consecutive patients with different rheumatic diseases were asked for their vaccination status regarding COVID-19, influenza and Streptococcus pneumoniae during their routine consultations. Any reported vaccination was validated with their personal vaccination card and/or by reviewing the CovPass smartphone app. Reasons for not having a COVID-19 vaccination were documented. RESULTS: A total of 201 patients (mean age 62.3 ± 14.1 years) were included, the majority of them (44.3%) with rheumatoid arthritis, followed by spondyloarthritis (27.4%) and connective tissue diseases (21.4%). Vaccination coverage for SARS-CoV-2 was 80.1%; 85.6% got at least the first vaccination shot. Both valid influenza and pneumococcus coverage were associated with a higher probability of SARS-CoV-2 vaccination (odds ratio (OR) 6.243, 95% confidence interval (CI) 2.637-14.783, p < 0.0001 and OR 6.372, 95% CI 2.105-19.282, p = 0.0003, respectively). The main reason for a missing SARS-CoV-2 vaccination (70%) was being sceptical about the vaccine itself (i.e., the subjective impression that the vaccine was not properly tested and fear of unwanted side effects). CONCLUSIONS: Vaccination coverage against SARS-CoV-2 is high in patients with rheumatic diseases. Nevertheless, there are unmet needs regarding vaccination education to further increase vaccination rates.

Humoral and cellular response to COVID-19 vaccination in patients with autoimmune inflammatory rheumatic diseases under real-life conditions.

OBJECTIVES: Successful vaccination is key to overcoming the COVID-19 pandemic. Immunosuppressive medication is known to potentially compromise vaccination responses, and expansion of our knowledge on vaccination efficacy in patients with autoimmune inflammatory rheumatic diseases (AIIRD) is therefore of utmost importance. METHODS: We conducted a single-centre observational study and evaluated the efficacy of approved COVID-19 vaccines in 303 adult AIIRD patients. Serum levels of IgG antibodies against the S1 subunit of SARS-CoV-2 spike proteins (anti-S IgG) were measured at least two weeks after vaccination. In a subgroup of patients without humoral response, T-cell responses were determined using an interferon-γ gamma release assay. RESULTS: Overall seropositivity rate was 78.5% and was significantly lower in patients under immunosuppressive therapy (75.7 vs 93.2%, P = 0.009). No difference regarding the vaccination type was observed. Glucocorticoids, mycophenolate-mofetil, TNF inhibitors, tocilizumab, abatacept and rituximab were all associated with non-response after proper vaccination. The risk was highest under RTX therapy (OR 0.004, 95% CI 0.001, 0.023, P < 0.0001). A strong negative correlation was observed between time since vaccination with an mRNA vaccine and anti-S antibody levels (r=-0.6149, P < 0.0001). In patients without humoral response, a T-cell response was found in 50%. CONCLUSIONS: COVID-19 vaccination in patients with AIIRD is effective using any approved vaccine. Humoral response might be impaired depending on the individual immunosuppressive medication. The risk of non-response is highest under rituximab therapy. Anti-S IgG antibody levels wane over time after mRNA vaccination. Importantly, 50% of humoral non-responders showed a T-cellular response, suggesting T-cell-mediated protection to a certain extent.

Sepsis Mortality Is high in Patients With Connective Tissue Diseases Admitted to the Intensive Care Unit (ICU).

OBJECTIVES: Patients with connective tissue diseases (CTD) such as systemic lupus erythematosus (SLE) have an increased risk for infections. This study investigated the outcome and characteristics of CTD patients under intensive care unit (ICU) treatment for sepsis. METHODS: A single-center retrospective analysis was conducted and reviewed all patients with a CTD diagnosis admitted to the ICU of a university hospital for sepsis between 2006 and 2019. Mortality was computed and multivariate logistic regression was used to detect independent risk factors for sepsis mortality. Furthermore, the positive predictive value of ICU scores such as Sequential Organ Failure Assessment (SOFA) score was evaluated. RESULTS: This study included 44 patients with CTD (mean age 59.8 ± 16.1 years, 68.2% females), most of them with a diagnosed SLE (61.4%) followed by systemic sclerosis (15.9%). 56.8% (n = 25) were treated with immunosuppressives and 81.8% (n = 36) received glucocorticoids. Rituximab was used in 3 patients (6.8%). The hospital mortality of septic CTD patients was high with 40.9%. It was highest among systemic sclerosis (SSc) patients (85.7%). SOFA score and diagnosis of SSc were independently associated with mortality in multivariate logistic regression (P = 0.004 and 0.03, respectively). The Simplified Acute Physiology Score II (SAPS II), SOFA and Acute Physiology and Chronic Health Evaluation II (APACHE II) scores were good predictors of sepsis mortality in the investigated cohort (SAPS II AUC 0.772, P = 0.002; SOFA AUC 0.756, P = 0.004; APACHE II AUC 0.741, P = 0.007). CONCLUSIONS: In-hospital sepsis mortality is high in CTD patients. SSc diagnoses and SOFA were independently associated with mortality. Additionally, common ICU scores were good predictors for mortality.

Expansion of CD4+CD8+ double-positive T cells in rheumatoid arthritis patients is associated with erosive disease.

OBJECTIVES: CD4+CD8+ double-positive (DP) T cells are expanded in the peripheral blood of a subset of patients with RA. This study examines the clinical significance of DP T cells in RA. METHODS: In 70 RA patients, DP T cells were measured by flow cytometry. Clinical data were obtained, and hand and feet radiographs were scored according to the Sharp/van der Heijde (SvdH) method. The association between DP T cell frequency and erosive joint destruction was analysed by correlation and multiple logistic regression analysis. RESULTS: Nineteen RA patients (27.1%) displayed increased DP T cell frequencies, which correlated with age (r = 0.288, P =0.016). Expansion of DP T cells was associated with the occurrence of erosions (94,7% vs 43,1%, P <0.001), with a higher SvdH joint damage score (24.5 vs 6, P =0.008) and with more frequent use of biologic or targeted-synthetic DMARDs (68.4% vs 38%, P =0.02). In patients with non-erosive disease, DP T cell frequencies correlated with the joint space narrowing score (n = 28, r = 0.44, P =0.02). Logistic regression revealed DP T cells to be associated with erosive disease (OR 1.90, P <0.05). CONCLUSION: Expansion of DP T cells is associated with joint damage and frequent escalation of therapy, possibly suggesting a contribution to more severe RA.

[Thoracolumbar back pain as the leading symptom of a marked COVID-19 pneumonia]. / Thorakolumbaler Rückenschmerz als führendes Symptom einer ausgeprägten COVID-19-Pneumonie.

HISTORY: A 49-year-old male patient visited the surgical outpatient clinic with new onset low back pain. The pain was increasing for nine days and he did not have any signs of a respiratory infection, in particular neither fever nor cough. INVESTIGATIONS: During the further examination and unclothing, mild dyspnea was apparent. According to the patient, the dyspnea was also progressive in the last days but would not affect everyday life. Furthermore, the patient reported a significant and unintended weight loss. Outpatient chest X-ray revealed bilateral, peripheral, fine-speckled infiltrates that became increasingly confluent. Polymerase chain reaction analysis of the nasopharyngeal swab was positive for SARS-CoV-2 (wild type). TREATMENT AND COURSE: Due to progressive dyspnea, the patient was referred to inpatient treatment within the day, where he rapidly developed severe acute respiratory failure. To provide respiratory support, a combined intermittent non-invasive ventilation and nasal high flow-therapy was started. Moreover, a probatory antiviral therapy with remdesivir was initiated. Since a bacterial superinfection was suspected, additional antibiotic therapy was ordered. After 13 days of inpatient treatment, the patient was discharged. The low back pain receded completely during inpatient treatment without any specific therapy. CONCLUSIONS: Low back pain can be a symptom of COVID-19. In our case report, it was the only complain that led to the outpatient consultation. Even though back pain is a very common symptom in everyday practice, one should keep unusual causes in mind.