[CAR T-cell therapy in rheumatology-What we know so far?] / CAR-T-Zell-Therapie in der Rheumatologie ­ Was wissen wir bisher?

Autoreactive B­cells play a key role in the pathogenesis of autoimmune diseases, such systemic lupus erythematosus (SLE). An efficient depletion of B­cells therefore plays a special role in autoimmune diseases, especially in cases with a severe course of the disease. Treatment with chimeric antigen receptor (CAR) T­cells, which was originally developed for the treatment of B­cell lymphomas and leukemias, provides the possibility to deplete B­cells even in deep tissues. The initial results from case series with this procedure for SLE, myositis and systemic sclerosis were very positive. This review article gives an overview of the course, mechanism of action, results so far and the research agenda of CAR T­cell therapy in autoimmune diseases.

Non-invasive metabolic profiling of inflammation in joints and entheses by multispectral optoacoustic tomography.

OBJECTIVE: To explore the metabolic characteristics of arthritis and enthesitis using multispectral opto-acoustic tomography (MSOT), a technology using near-infrared multispectral laser to stimulate tissues and detect the emitted acoustic energy, enabling non-invasive quantification of tissue components in vivo based on differential absorbance at multiple wavelengths. METHODS: We performed a cross-sectional study in patients with RA or PsA and healthy controls (HCs). Participants underwent clinical, ultrasonographic and MSOT examination of MCP and wrist joints as well as the entheses of the common extensor tendon at the lateral humeral epicondyles and of the patellar, quadriceps and Achilles tendon. MSOT-measured haemoglobin (Hb), oxygen saturation, collagen and lipid levels were quantified and scaled mean differences between affected and unaffected joints and entheses were calculated as defined by clinical examination or ultrasonography using linear mixed effects models. RESULTS: We obtained 1535 MSOT and 982 ultrasonography scans from 87 participants (34 PsA, 17 RA, 36 HCs). Entheseal tenderness was not associated with significant metabolic changes, whereas enthesitis-related sonographic changes were associated with increased total Hb, oxygen saturation and collagen content. In contrast, the presence of arthritis-related clinical and sonographic findings showed increased Hb levels, reduced oxygen saturation and reduced collagen content. Synovial hypertrophy was associated with increased lipid content in the joints. CONCLUSION: MSOT allows determination of distinct metabolic differences between arthritis and enthesitis in a non-invasive setting in humans in vivo.

Impact of Cytokine Inhibitor Therapy on the Prevalence, Seroconversion Rate, and Longevity of the Humoral Immune Response Against SARS-CoV-2 in an Unvaccinated Cohort.

OBJECTIVE: To investigate the impact of biologic disease-modifying antirheumatic drug (bDMARD) treatment on the prevalence, seroconversion rate, and longevity of the humoral immune response against SARS-CoV-2 in patients with immune-mediated inflammatory diseases (IMIDs). METHODS: Anti-SARS-CoV-2 IgG antibodies were measured in a prospective cohort of health care professional controls and non-health care controls and IMID patients receiving no treatment or receiving treatment with conventional or biologic DMARDs during the first and second COVID-19 waves. Regression models adjusting for age, sex, sampling time, and exposure risk behavior were used to calculate relative risks (RRs) of seropositivity. Seroconversion rates were assessed in participants with polymerase chain reaction (PCR)-positive SARS-CoV-2 infection. Antibody response longevity was evaluated by reassessing participants who tested positive during the first wave. RESULTS: In this study, 4,508 participants (2,869 IMID patients and 1,639 controls) were analyzed. The unadjusted RR (0.44 [95% confidence interval (95% CI) 0.31-0.62]) and adjusted RR (0.50 [95% CI 0.34-0.73]) for SARS-CoV-2 IgG antibodies were significantly lower in IMID patients treated with bDMARDs compared to non-health care controls (P < 0.001), primarily driven by treatment with tumor necrosis factor inhibitors, interleukin-17 (IL-17) inhibitors, and IL-23 inhibitors. Adjusted RRs for untreated IMID patients (1.12 [95% CI 0.75-1.67]) and IMID patients receiving conventional synthetic DMARDs (0.70 [95% CI 0.45-1.08]) were not significantly different from non-health care controls. Lack of seroconversion in PCR-positive participants was more common among bDMARD-treated patients (38.7%) than in non-health care controls (16%). Overall, 44% of positive participants lost SARS-CoV-2 antibodies by follow-up, with higher rates in IMID patients treated with bDMARDs (RR 2.86 [95% CI 1.43-5.74]). CONCLUSION: IMID patients treated with bDMARDs have a lower prevalence of SARS-CoV-2 antibodies, seroconvert less frequently after SARS-CoV-2 infection, and may exhibit a reduced longevity of their humoral immune response.

Increased expression of olfactomedin-1 and myocilin in podocytes during puromycin aminonucleoside nephrosis.

BACKGROUND: The olfactomedin domain proteins Olfm-1 and myocilin are expressed in podocytes. Myocilin stimulates the formation of focal contacts and actin stress fibres in podocytes and other cell types, effects that are mediated through the Wnt signalling pathway. Here, we tested if the expression of both proteins is modified during puromycin aminonucleoside (PAN) nephrosis, which leads to structural changes in the actin cytoskeleton of podocytes. METHODS: Rats were treated with PAN, and the effectiveness of treatment was analysed by electron microscopy of podocytes and protein detection in the urine. The expression of Olfm-1 and myocilin was studied by immunohistochemistry, western blot analysis of glomerular proteins and real-time RT-PCR of glomerular proteins. In parallel experiments, the expression of Olfm-1 was studied in cultured podocytes treated with dexamethasone, TGF-ß, TNF-α and PAN. RESULTS: Between Days 5 and 22 after treatment, the amounts of the BMZ and BMY splice variants of Olfm-1 and their mRNA were markedly elevated in proteins and mRNA from isolated glomeruli. Immunohistochemistry showed that the expression of Olfm-1 was confined to podocytes. Essentially, comparable results were obtained for myocilin. The BMZ variant of Olfm-1 appeared to be secreted from podocytes and was found in high amounts in urine of treated animals. Treatment of cultured podocytes with dexamethasone and PAN caused an increase in Olfm-1 expression, while treatment with recombinant Olfm-1 increased the formation of actin stress fibres. CONCLUSIONS: Olfm-1 and myocilin are markedly induced in podocytes during PAN nephrosis and appear to be involved in the processes that govern the reorganization of the actin cytoskeleton during podocyte repair.