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OBJECTIVE: B cell depletion with the anti-CD20 antibody rituximab has proven efficacy in patients with rheumatoid arthritis (RA). The effects on B cell homeostasis after repeated treatments and the relationship of certain B cell subsets to clinical response or relapse are currently not known. METHODS: In this open-label study, 17 patients with RA refractory to standard therapy were treated with 1 cycle of rituximab. Of these 17 patients, 11 received a second cycle of rituximab therapy. Immunophenotyping was performed before therapy and during B cell recovery. RESULTS: Twelve of 17 patients showed a good European League Against Rheumatism response after receiving 1 cycle of rituximab therapy. At the time of B cell recovery, the IgD+,CD27+ memory B cell subset was significantly larger (P = 0.019) in the nonresponder group. Within the group of 12 responders, 6 patients, whose disease was characterized by a significantly higher proportion of overall CD27+ memory B cells before therapy, experienced an early relapse (weeks 24-40 posttreatment). Eleven patients were re-treated, again resulting in a good clinical response. B cell reconstitution followed a similar pattern after each cycle. The early reconstitution phase was characterized by immature CD38++,IgD+,CD10+ B cells, whereas the number of naive B cells increased continuously thereafter. The number of memory B cells was still reduced at the time of the second depletion but recovered to levels similar to those following the first cycle of therapy. CONCLUSION: Data derived from repeated B lymphocyte depletion with rituximab in patients with RA suggest that analysis of certain memory B cell subsets provides information on efficacy, response, and late as well as early relapse, consistent with the conclusion that targeting memory B cells is a key to its mechanism of action. [ABSTRACT FROM AUTHOR]

Gamma/delta T (γδ T)cells possess a unique mechanism for killing tumors, making them highly promising and distinguished among various cell therapies for tumor treatment. This review focuses on the major histocompatibility complex (MHC)-independent recognition of antigens and the interaction between γδ T cells and solid tumor cells. A comprehensive review is provided regarding the classification of human gamma-delta T cell subtypes, the characteristics and mechanisms underlying their functions, as well as their r545egulatory effects on tumor cells. The involvement of γδ T cells in tumorigenesis and migration was also investigated, encompassing potential therapeutic targets such as apoptosis-related molecules, the TNF receptor superfamily member 6(FAS)/FAS Ligand (FASL) pathways, butyrophilin 3A-butyrophilin 2A1 (BTN3A-BTN2A1) complexes, and interactions with CD4, CD8, and natural killer (NK) cells. Additionally, immune checkpoint inhibitors such as programmed cell death protein 1/Programmed cell death 1 ligand 1 (PD-1/PD-L1) have the potential to augment the cytotoxicity of γδ T cells. Moreover, a review on gamma-delta T cell therapy products and their corresponding clinical trials reveals that chimeric antigen receptor (CAR) gamma-delta T therapy holds promise as an approach with encouraging preclinical outcomes. However, practical issues pertaining to manufacturing and clinical aspects need resolution, and further research is required to investigate the long-term clinical side effects of CAR T cells. In conclusion, more comprehensive studies are necessary to establish standardized treatment protocols aimed at enhancing the quality of life and survival rates among tumor patients utilizing γδ T cell immunotherapy. [ABSTRACT FROM AUTHOR]

In the last two decades, ultrasound has been fully implemented in the diagnosis and management of rheumatoid arthritis. Several studies have been published that have demonstrated better availability of this technique in the identification of elementary inflammatory joint and tendon injuries, as joint and tendon sheath synovial hypertrophy, joint effusion, and Power Doppler signal. Ultrasonography has good properties to identify changes with different treatments, have predictive value for relapse in patients in clinical remission and in structural damage. Furthermore, ultrasound tools have been developed that allow prospective evaluation of patients. Joint and tendon ultrasound evaluation indexes have been used for disease diagnosis and monitoring. Initially, indexes have been integrated only for joint, but more recently have appeared mixed indexes, integrated for ultrasound evaluation and other types of variables. There are still important objectives to be achieved to complete the development of ultrasound in rheumatoid arthritis, which makes ultrasound a great aid tool in decision-making in clinical practice. [ABSTRACT FROM AUTHOR]

Apical hypertrophic cardiomyopathy (ApHCM) is an HCM variant, affecting frequently males in midlife. It is characterized by apical obliteration and persistent diastolic contraction, often resulting in microvascular ischaemia. We report five cases of ApHCM, with evidence of intramyocardial calcification on echocardiogram. On cardiac magnetic imaging (MRI), a hypointense component at early gadolinium enhancement (EGE) sequences, compatible with calcium, and a deep layer, with hyperintensity at late gadolinium enhancement (LGE) sequences, referable to fibrosis, suggest an endomyocardial fibrosis (EMF) diagnosis. EMF pathologic hallmark is endocardium and myocardium scarring, evolving to dystrophic calcification. It is found only in few ApHCM patients. Our series is the largest one described until now. Analysing patients' history, coexistent inflammatory triggers were evident in all of them, so their co‐morbidities could represent a further cause of small vessel disease, in the context of ischaemic microvascular stress due to hypertrophy, leading to fibrosis and dystrophic calcification. This series could demonstrate the relation between apical fibrosis/calcification and microvascular ischaemia due to hypertrophy and inflammatory triggers. [ABSTRACT FROM AUTHOR]

Patients with rheumatoid arthritis (RA) who receive immunosuppressive medications have a heightened risk of infection. The goal of our study was to calculate the pooled cumulative incidence and risk of infection in patients with RA treated with Janus kinase inhibitors (JAKi). The PubMed and EMBASE databases were queried for randomized controlled trials comparing patients with RA treated with JAKi (upadacitinib, baricitinib, tofacitinib, peficitinib, or filgotinib), defined as the treatment group, compared with control subjects, defined as participants receiving placebo or treatment regimen that was similar to that of participants in the treatment group, with the exception of JAKi. The primary study endpoint was the relative risk (RR) of any-grade and severe infection. The secondary endpoints were RR and cumulative incidence of opportunistic infections, herpes zoster, and pneumonia. The Stata v17 software was used for all data analysis. Results showed that treatment with baricitinib was associated with an increased risk of any-grade (RR 1.34; 95% CI: 1.19–1.52) and opportunistic (RR 2.69; 95% CI: 1.22–5.94) infection, whereas treatment with filgotinib (RR 1.21; 95% CI: 1.05–1.39), peficitinib (RR 1.40; 95% CI: 1.05–1.86) and upadacitinib (RR 1.30; 95% CI: 1.09–1.56) was associated with increased risk of any-grade infection only. Analysis based on type of infection showed a pooled cumulative incidence of 32.44% for any-grade infections, 2.02% for severe infections, 1.74% for opportunistic infections, 1.56% for herpes zoster, and 0.49% for pneumonia in patients treated with any JAKi during the follow-up period. Treatment with specific JAKi in patients with RA is associated with an increased risk of any-grade and opportunistic infections but not severe infection. Close clinical monitoring of patients with RA treated with JAKi is required to establish the long-term infection risk profile of these agents. [ABSTRACT FROM AUTHOR]

Background: The incidence of severe infections (SIs) in patients with autoimmune nephropathy after rituximab (RTX) treatment varies significantly. Our study aims to identify high-risk populations, specifically by comparing the differences in the risk of SIs between patients with primary nephropathy and those with nephropathy in the context of systemic autoimmune diseases (referred to as secondary nephropathy). Methods: This retrospective cohort study investigated the occurrence of SIs in adult patients with immune-related kidney disease who received RTX treatment at our institution from 2017 to 2022. Multivariable COX regression models were used to analyze the association between the type of nephropathy (primary or secondary) and SIs. Propensity score analyses, subgroup analyses, and E-value calculations were performed to ensure the reliability of the results. Results: Out of 123 patients, 32 (26%) developed 39 cases of SIs during a mean follow-up period of 19.7 ± 14.6 months post-RTX treatment, resulting in an incidence rate of 18.9/100 patient-years. The multivariable COX regression analysis indicated that patients with secondary nephropathy had a significantly higher risk of SIs compared to those with primary nephropathy (HR = 5.86, 95% CI: 1.05-32.63, P = 0.044), even after accounting for confounding variables including gender, age, BMI, history of prior SIs, baseline eGFR, lymphocyte counts, IgG levels, and the utilization of other immunosuppressive therapies. Various sensitivity analyses consistently supported these findings, with an E-value of 5.99. Furthermore, advanced age (HR: 1.03; 95% CI: 1.01-1.06; P = 0.023), low baseline IgG levels (HR: 0.75; 95% CI: 0.64-0.89; P < 0.001), and recent history of SIs (HR: 5.68; 95% CI: 2.2-14.66; P < 0.001) were identified as independent risk factors. Conclusion: The incidence of SIs following RTX administration in patients with autoimmune nephropathy is significant. It is crucial to note that there are distinct differences between the subgroups of primary and secondary nephropathy. Patients with secondary nephropathy, particularly those who are elderly, have low baseline IgG levels, and have a recent history of SI, are more susceptible to SIs. [ABSTRACT FROM AUTHOR]

Background: ccRCC is the prevailing form of RCC, accounting for the majority of cases. The formation of cancer and the body's ability to fight against tumors are strongly connected to Gamma delta (γδ) T cells. Methods: We examined and analyzed the gene expression patterns of 535 individuals diagnosed with ccRCC and 72 individuals serving as controls, all sourced from the TCGA-KIRC dataset, which were subsequently validated through molecular biology experiments. Results: In ccRCC, we discovered 304 module genes (DEGRGs) that were ex-pressed differentially and linked to γδ T cells. A risk model for ccRCC was constructed using 13 differentially DEGRGs identified through univariate Cox and LASSO regression analyses, which were found to be associated with prognosis. The risk model exhibited outstanding performance in both the training and validation datasets. The comparison of immune checkpoint inhibitors and the tumor immune microenvironment between the high- and low-risk groups indicates that immunotherapy could lead to positive results for low-risk patients. Moreover, the inhibition of ccRCC cell proliferation, migration, and invasion was observed in cell culture upon knocking down TMSB10, a gene associated with different types of cancers. Conclusions: In summary, we have created a precise predictive biomarker using a risk model centered on γδ T cells, which can anticipate clinical results and provide direction for the advancement of innovative targeted therapies. [ABSTRACT FROM AUTHOR]

Background: Immunotherapy targeting factors related to immune imbalance has been widely employed for RA treatment. This study aimed to evaluate the efficacy and safety of low-dose interleukin (IL)-2 combined with tocilizumab (TCZ), a biologics targeting IL-6, in RA patients. Methods: Fifty adults with active RA who met the criteria with complete clinical data were recruited, and divided into three groups: control group (n=15), IL-2 group (n=26), and IL-2+TCZ group (n=9). In addition to basic treatment, participants in the IL-2 group received IL-2 (0.5MIU/day),while participants in the IL-2+TCZ group received IL-2 (0.5 MIU/day) along with one dose of TCZ (8mg/kg, maximum dose: 800 mg). All subjects underwent condition assessment, laboratory indicators and safety indicators detection, and records before treatment and one week after treatment. Results: Compared with the baseline, all three groups showed significant improvement in disease conditions, as evidenced by significantly reduced disease activity indicators. The low-dose IL-2 and combination treatment groups demonstrated a violent proliferation of Tregs, while the absolute number of Th1, Th2, and Th17 cells in the latter group showed a decreasing trend. The decrease in the Th17/Treg ratio was more pronounced in the IL-2 + CZ groups. No significant adverse reactions were observed in any of the patients. Conclusion: Exogenous low doses of IL-2 combined TCZ were found to be safe and effective in reducing effector T cells and appropriately increasing Treg levels in RA patients with high effector T cell levels. This approach helps regulate immune homeostasis and contributes to the prevention of disease deterioration. Clinical trial registration: https://www.chictr.org.cn/showprojEN.html? proj=13909, identifier ChiCTR-INR-16009546. [ABSTRACT FROM AUTHOR]

Purpose: To report the uveitic manifestations of patients with systemic lupus erythematosus (SLE). Methods: This was a retrospective analysis of all SLE cases with ocular manifestations seen by a single ophthalmologist between 2015 and December 2021. Results: In total, seven patients with a median age of 40 (range 18-50) years were included in the study. Female (85.7%) predominance was noted. Ocular findings were bilateral in 71% (five patients) of cases. Majority (10 eyes, 83%) of the patients had retinal vasculitis as the common finding. Antinuclear antibodies were positive in all the patients. The vision improved in two (16.6%) eyes, was stable in eight (66%) eyes, and worsened in one (8%) eye. All the patients were treated with oral steroids along with immunosuppressive agents. Conclusion: Though SLE is rare cause of uveitis, it can be associated with significant ocular morbidity. Hence, early diagnosis and treatment can salvage vision in many cases. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is a chronic, incurable, multisystem, inflammatory disease characterized by synovitis and extra-articular features. Although several advanced therapies targeting inflammatory mechanisms underlying the disease are available, no advanced therapy is universally effective. Therefore, a ceiling of treatment response is currently accepted where no advanced therapy is superior to another. The current challenge for medical research is the discovery and integration of predictive markers of drug response that can be used to personalize medicine so that the patient is started on "the right drug at the right time". This review article summarizes our current understanding of predicting response to anti-rheumatic drugs in RA, obstacles impeding the development of personalized medicine approaches and future research priorities to overcome these barriers. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Psoriatic arthritis (PsA) is a chronic inflammatory disorder affecting the joints, skin and entheses. Despite the importance of the topic, few studies have investigated the association between PsA and sexual function. The purpose of this study was to assess sexuality and the prevalence of sexual dysfunction (SD) in patients with PsA. METHODS: This was an observational, cross-sectional single-center study on 23 PsA patients (male=12; female=11) evaluated with 2 male questionnaires (MSQ= Male Sexual Quotient, and IIEF=International Index of Erectile Function) and 2 female questionnaires (FSQ= Female Sexual Quotient, and FSFI=Female Sexual Function Index) validated for Brazilian Portuguese, in order to determine changes in sexual function. Clinical parameters, musculoskeletal activity and skin activity were also analyzed to identify factors associated with SD. RESULTS: The mean age was 52.1±9.7 years (males) and 49.1±9.6 years (females). Clinically, the patients had low skin and peripheral joint disease activity or were in remission. The mean time of PsA was 10±6.2 years, and 65.2% had a steady sexual partner. The mean MSQ score was 75.8±16.8. The prevalence of SD was 91.7% in men (IIEF), with a predominance of mild SD. The mean FSQ score was 64.9±24.1. The prevalence of SD was 72.7% in women (FSFI), with low domain scores. Also, a significant association was found between female age and total and domain-specific FSFI scores. PASI (Psoriasis Area and Severity Index) and the general satisfaction domain (IIEF) were significantly correlated. CONCLUSION: This study found a high prevalence of SD in PsA patients. Age had a negative impact on female sexual function. Physicians need to be more aware of SD in this population to provide early multidisciplinary treatment and minimize the impact of the disease on the quality of life of patients and their partners. [ABSTRACT FROM AUTHOR]

Thymic epithelial tumors (TETs) are rare mediastinal cancers originating from the thymus, classified in two main histotypes: thymoma and thymic carcinoma (TC). TETs affect a primary lymphoid organ playing a critical role in keeping T-cell homeostasis and ensuring an adequate immunological tolerance against "self". In particular, thymomas and not TC are frequently associated with autoimmune diseases (ADs), with Myasthenia Gravis being the most common AD present in 30% of patients with thymoma. This comorbidity, in addition to negatively affecting the quality and duration of patients' life, reduces the spectrum of the available therapeutic options. Indeed, the presence of autoimmunity represents an exclusion criteria for the administration of the newest immunotherapeutic treatments with checkpoint inhibitors. The pathophysiological correlation between TETs and autoimmunity remains a mystery. Several studies have demonstrated the presence of a residual and active thymopoiesis in adult patients affected by thymomas, especially in mixed and lymphocytic-rich thymomas, currently known as type AB and B thymomas. The aim of this review is to provide the state of art in regard to the histological features of the different TET histotype, to the role of the different immune cells infiltrating tumor microenvironments and their impact in the break of central immunologic thymic tolerance in thymomas. We discuss here both cellular and molecular immunologic mechanisms inducing the onset of autoimmunity in TETs, limiting the portfolio of therapeutic strategies against TETs and greatly impacting the prognosis of associated autoimmune diseases. [ABSTRACT FROM AUTHOR]

Bisphosphonates frequently provoke a cytokine-driven acute clinical response (ACR) characterized by fever, chills, arthralgias, and myalgias. More rarely, an association between aminobisphosphonates, such as alendronate and zoledronic acid, and rheumatologic and/or immune-mediated syndromes (RIMS) has been described. Herein we report 2 patients, one with a prior history of rheumatic disease and one without, who developed giant cell arteritis meeting the American College of Rheumatology 2022 criteria following zoledronic acid infusion. We subsequently review existing mechanistic and clinical literature supporting this link. The duration of symptoms and elevation of inflammatory markers may serve as indicators for differentiating between the more common ACR and less frequent but potentially morbid RIMS. Although the benefit of bisphosphonates will outweigh the risk of RIMS for most patients with high fracture risk, clinicians should be aware of this phenomenon to assist earlier diagnosis and treatment in affected individuals. [ABSTRACT FROM AUTHOR]

Autoimmune inflammation is caused by the loss of tolerance to specific self-antigens and can result in organ-specific or systemic disorders. Systemic autoimmune diseases affect a significant portion of the population with an increasing rate of incidence, which means that is essential to have effective therapies to control these chronic disorders. Unfortunately, several patients with systemic autoimmune diseases do not respond at all or just partially respond to available conventional synthetic disease-modifying antirheumatic drugs and targeted therapies. However, during the past few years, some new medications have been approved and can be used in real-life clinical settings. Meanwhile, several new candidates appeared and can offer promising novel treatment options in the future. Here, we summarize the newly available medications and the most encouraging drug candidates in the treatment of systemic lupus erythematosus, rheumatoid arthritis, Sjögren's disease, systemic sclerosis, systemic vasculitis, and autoimmune myositis. [ABSTRACT FROM AUTHOR]

Vγ9Vδ2 T cells represent a promising cancer therapy platform because the implementation of allogenic, off-the-shelf product candidates is possible. However, intravenous administration of human Vγ9Vδ2 T cells manufactured under good manufacturing practice (GMP)-compliant, serum-free conditions are not tested easily inmostmousemodels,mainly because they lack the ability to migrate from the blood to tissues or tumors. We demonstrate that these T cells do not migrate from the circulation to the mouse bone marrow (BM), the site of many malignancies. Thus, there is a need to better characterize human γδ T-cell migration in vivo and develop strategies to direct these cells to in vivo sites of therapeutic interest. To better understand the migration of these cells and possibly influence their migration, NSG mice were conditioned with agents to clear BM cellular compartments, i.e., busulfan or total body irradiation (TBI), or promote T-cell migration to inflamed BM, i.e., incomplete Freund's adjuvant (IFA), prior to administering γδ T cells. Conditioning with TBI, unlike busulfan or IFA, increases the percentage and number of γδ T cells accumulating in the mouse BM, and cells in the peripheral blood (PB) and BM display identical surface protein profiles. To better understand the mechanism by which cells migrate to the BM, mice were conditioned with TBI and administered γδ T cells or tracker-stained red blood cells. The mechanism by which γδ T cells enter the BM after radiation is passive migration from the circulation, not homing. We tested if these ex vivo-expanded cells can migrate based on chemokine expression patterns and showed that it is possible to initiate homing by utilizing highly expressed chemokine receptors on the expanded γδ T cells. γδ T cells highly express CCR2, which provides chemokine attraction to C-C motif chemokine ligand 2 (CCL2)-expressing cells. IFNγ-primed mesenchymal stromal cells (MSCs) (γMSCs) express CCL2, and we developed in vitro and in vivo models to test γδ T-cell homing to CCL2-expressing cells. Using an established neuroblastoma NSG mouse model, we show that intratumorally-injected γMSCs increase the homing of γδ T cells to this tumor. These studies provide insight into the migration of serum-free, ex vivo-expanded Vγ9Vδ2 T cells in NSG mice, which is critical to understanding the fundamental properties of these cells. [ABSTRACT FROM AUTHOR]

Objectives: This study compared the secukinumab treatment responses and adverse effects in psoriatic arthritis patients who received secukinumab as second-line with those that received secukinumab after two or more tumor necrosis factor-alpha (TNF-a) inhibitors. Patients and methods: The retrospective study included 68 psoriatic arthritis patients followed up between October 2018 and October 2021. The patients were divided into two groups according to their anti-TNF-a treatment history. Group 1 consisted of 29 patients (11 males, 18 females; mean age: 45.3±13.3 years; range, 21 to 69 years) who had previously received one anti-TNF-a agent, while Group 2 included 39 patients (18 males, 21 females; mean age: 46.4±13.0 years; range, 24 to 70 years) who had been treated with two or more anti-TNF-a agents. Treatment responses of the groups were measured and compared using the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Visual Analog Scale (VAS). A posttreatment BASDAI score =4 was used as a criterion for remission. Results: The mean duration of secukinumab treatment was 16.6±12.7 months for Group 1 and 16.0±11.6 months for Group 2 (p=0.84). Both groups responded significantly to secukinumab in terms of BASDAI and VAS scores (p<0.001 and p<0.001, respectively). Group 1 had a greater decline in BASDAI and VAS scores than Group 2 (p=0.045 and p=0.032, respectively). Furthermore, the remission rate was greater in Group 1 compared to Group 2 (58% vs. 34%, p=0.03). The adverse effects of secukinumab treatment were an allergic reaction in Group 1 and one case of ulcerative colitis in Group 2. Conclusion: Second-line secukinumab treatment resulted in a greater decline in BASDAI and VAS scores. Moreover, secukinumab achieved a significantly higher rate of remission when it was used as second-line therapy after one anti-TNF-a agent. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Rheumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

There is an interesting and complex relationship between rheumatic diseases and malignancy. Paraneoplastic arthritis is caused by the effects of many hormones and cytokines secreted from the underlying hidden tumor tissue. There is no direct invasion or mechanical pressure of the tumor tissue. In particular, in the early rheumatological disease period, the diagnosis should be reconsidered in cases unresponsive to conventional treatment. It should be noted that there may be another underlying etiological factor in cases unresponsive to treatment. In this review, we discussed in detail three breast cancer cases that presented with early arthritis and were found to have breast cancer in the follow-up. In the literature, serological markers, pathological diagnosis, and imaging in breast cancer-associated paraneoplastic arthritis cases are not presented in detail. In our cases, serological markers, pathological diagnosis, and breast magnetic resonance imaging are presented in detail. [ABSTRACT FROM AUTHOR]

Background: Patients with coronavirus disease‐2019 (COVID‐19) are characterized by hyperinflammation. Calprotectin (S100A8/S100A9) is a calcium‐ and zinc‐binding protein mainly secreted by neutrophilic granulocytes or macrophages and has been suggested to be correlated with the severity and prognosis of COVID‐19. Aim: To thoroughly evaluate the diagnostic and prognostic utility of calprotectin in patients with COVID‐19 by analyzing relevant studies. Methods: PubMed, Web of Science, and Cochrane Library were comprehensively searched from inception to August 1, 2023 to retrieve studies about the application of calprotectin in COVID‐19. Useful data such as the level of calprotectin in different groups and the diagnostic efficacy of this biomarker for severe COVID‐19 were extracted and aggregated by using Stata 16.0 software. Results: Fifteen studies were brought into this meta‐analysis. First, the pooled standardized mean differences (SMDs) were used to estimate the differences in the levels of circulating calprotectin between patients with severe and non‐severe COVID‐19. The results showed an overall estimate of 1.84 (95% confidence interval [CI]: 1.09–2.60). Diagnostic information was extracted from 11 studies, and the pooled sensitivity and specificity of calprotectin for diagnosing severe COVID‐19 were 0.75 (95% CI: 0.64–0.84) and 0.88 (95% CI: 0.79–0.94), respectively. The AUC was 0.89 and the pooled DOR was 18.44 (95% CI: 9.07–37.51). Furthermore, there was a strong correlation between elevated levels of circulating calprotectin and a higher risk of mortality outcomes in COVID‐19 patients (odds ratio: 8.60, 95% CI: 2.17–34.12; p < 0.1). Conclusion: This meta‐analysis showed that calprotectin was elevated in patients with severe COVID‐19, and this atypical inflammatory cytokine might serve as a useful biomarker to distinguish the severity of COVID‐19 and predict the prognosis. [ABSTRACT FROM AUTHOR]

Cellular immunotherapy, particularly CAR-T cells, has shown potential in the improvement of outcomes in patients with refractory and recurrent malignancies of the blood. However, achieving sustainable long-term complete remission for blood cancer remains a challenge, with resistance and relapse being expected outcomes for many patients. Although many studies have attempted to clarify the mechanisms of CAR-T cell therapy failure, the mechanism remains unclear. In this article, we discuss and describe the current state of knowledge regarding these factors, which include elements that influence the CAR-T cell, cancer cells as a whole, and the microenvironment surrounding the tumor. In addition, we propose prospective approaches to overcome these obstacles in an effort to decrease recurrence rates and extend patient survival subsequent to CAR-T cell therapy. [ABSTRACT FROM AUTHOR]

Cellular therapies, including chimeric antigen receptor T cell therapies (CAR-T), while generally successful in hematologic malignancies, face substantial challenges against solid tumors such as glioblastoma (GBM) due to rapid growth, antigen heterogeneity, and inadequate depth of response to cytoreductive and immune therapies, We have previously shown that GBM constitutively express stress associated NKG2D ligands (NKG2DL) recognized by gamma delta (gd) T cells, a minor lymphocyte subset that innately recognize target molecules via the gd T cell receptor (TCR), NKG2D, and multiple other mechanisms. Given that NKG2DL expression is often insufficient on GBM cells to elicit a meaningful response to gd T cell immunotherapy, we then demonstrated that NKG2DL expression can be transiently upregulated by activation of the DNA damage response (DDR) pathway using alkylating agents such as Temozolomide (TMZ). TMZ, however, is also toxic to gd T cells. Using a p140K/MGMT lentivector, which confers resistance to TMZ by expression of O(6)-methylguanine-DNA-methyltransferase (MGMT), we genetically engineered gd T cells that maintain full effector function in the presence of therapeutic doses of TMZ. We then validated a therapeutic system that we termed Drug Resistance Immunotherapy (DRI) that combines a standard regimen of TMZ concomitantly with simultaneous intracranial infusion of TMZ-resistant gd T cells in a first-in-human Phase I clinical trial (NCT04165941). This manuscript will discuss DRI as a rational therapeutic approach to newly diagnosed GBM and the importance of repeated administration of DRI in combination with the standard-of-care Stupp regimen in patients with stable minimal residual disease. [ABSTRACT FROM AUTHOR]

Melittin, a main component of bee venom, is a cationic amphiphilic peptide with a linear α-helix structure. It has been reported that melittin can exert pharmacological effects, such as antitumor, antiviral and anti-inflammatory effects in vitro and in vivo. In particular, melittin may be beneficial for the treatment of diseases for which no specific clinical therapeutic agents exist. Melittin can effectively enhance the therapeutic properties of some first-line drugs. Elucidating the mechanism underlying melittin-mediated biological function can provide valuable insights for the application of melittin in disease intervention. However, in melittin, the positively charged amino acids enables it to directly punching holes in cell membranes. The hemolysis in red cells and the cytotoxicity triggered by melittin limit its applications. Melittin-based nanomodification, immuno-conjugation, structural regulation and gene technology strategies have been demonstrated to enhance the specificity, reduce the cytotoxicity and limit the off-target cytolysis of melittin, which suggests the potential of melittin to be used clinically. This article summarizes research progress on antiviral, antitumor and anti-inflammatory properties of melittin, and discusses the strategies of melittin-modification for its future potential clinical applications in preventing drug resistance, enhancing the selectivity to target cells and alleviating cytotoxic effects to normal cells. [ABSTRACT FROM AUTHOR]

Objective: This study was to investigate the role of hsa-miR-155-3p and hsa-miR-155-5p as biomarkers and regulators of biological behavior in Systemic Sclerosis. Methods: A total of 10 SSc patients and 10 healthy controls were selected for the study. The expression levels of hsa-miR-155-3p and hsa-miR-155-5p in peripheral blood mononuclear cells of SSc patients and healthy controls were measured using RT-qPCR. The diagnostic value of these miRNAs was explored using Receiver Operating Characteristic curve analysis. Pearson or Spearman correlation analysis was performed to assess the correlation between miRNAs and clinical indicators in SSc patients. Potential target genes of hsa-miR-155-3p and hsa-miR-155-5p were predicted using miRDB, Targetscan, and miRDIP databases. GO functional annotation, KEGG pathway enrichment analysis, protein-protein interaction network construction, and selection of central genes were conducted. Results: The expression levels of hsa-miR-155-3p and hsamiR- 155-5p were significantly higher in PBMCs of SSc patients compared to healthy controls (P<0.001). The ROC curve analysis showed that hsa-miR-155-3p and hsa-miR-155-5p had a high diagnostic value for SSc (AUC=1, P<0.001). Correlation analysis revealed that hsamiR- 155-3p, hsa-miR-155-5p, and clinical indicators such as high-resolution CT, neutrophil percentage, lymphocyte percentage, and albumin to globulin ratio were correlated (P<0.05). The signaling pathways enriched with target genes of hsa-miR-155-3p and hsa-miR-155- 5p were closely associated with the occurrence and development of SSc fibrosis, immunity, and inflammation. Conclusions: hsa-miR-155-3p and hsa-miR-155-5p may be involved in regulating the occurrence and development of SSc fibrosis, immunity, and inflammation. They have the potential to serve as biomarkers for clinical diagnosis and treatment of SSc. [ABSTRACT FROM AUTHOR]

Copyright of Zeitschrift für Rheumatologie is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

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. [ABSTRACT FROM AUTHOR]

Background: Patients with autoimmune/inflammatory conditions on anti- CD20 therapies, such as rituximab, have suboptimal humoral responses to vaccination and are vulnerable to poorer clinical outcomes following SARSCoV-2 infection. We aimed to examine how the fundamental parameters of antibody responses, namely, affinity and concentration, shape the quality of humoral immunity after vaccination in these patients. Methods: We performed in-depth antibody characterisation in sera collected 4 to 6 weeks after each of three vaccine doses to wild-type (WT) SARS-CoV- 2 in rituximab-treated primary vasculitis patients (n = 14) using Luminex and pseudovirus neutralisation assays, whereas we used a novel microfluidicbased immunoassay to quantify polyclonal antibody affinity and concentration against both WT and Omicron (B.1.1.529) variants. We performed comparative antibody profiling at equivalent timepoints in healthy individuals after three antigenic exposures to WT SARS-CoV-2 (one infection and two vaccinations; n = 15) and in convalescent patients after WT SARS-CoV-2 infection (n = 30). Results: Rituximab-treated patients had lower antibody levels and neutralisation titres against both WT and Omicron SARS-CoV-2 variants compared to healthy individuals. Neutralisation capacity was weaker against Omicron versus WT both in rituximab-treated patients and in healthy individuals. In the rituximab cohort, this was driven by lower antibody affinity against Omicron versus WT [median (range) KD: 21.6 (9.7-- 38.8) nM vs. 4.6 (2.3--44.8) nM, p = 0.0004]. By contrast, healthy individuals with hybrid immunity produced a broader antibody response, a subset of which recognised Omicron with higher affinity than antibodies in rituximabtreated patients [median (range) KD: 1.05 (0.45--1.84) nM vs. 20.25 (13.2--38.8) nM, p = 0.0002], underpinning the stronger serum neutralisation capacity against Omicron in the former group. Rituximab-treated patients had similar anti-WT antibody levels and neutralisation titres to unvaccinated convalescent individuals, despite two more exposures to SARS-CoV-2 antigen. Temporal profiling of the antibody response showed evidence of affinity maturation in healthy convalescent patients after a single SARS-CoV- 2 infection, which was not observed in rituximab-treated patients, despite repeated vaccination. Discussion: Our results enrich previous observations of impaired humoral immune responses to SARS-CoV-2 in rituximab-treated patients and highlight the significance of quantitative assessment of serum antibody affinity and concentration in monitoring anti-viral immunity, viral escape, and the evolution of the humoral response. [ABSTRACT FROM AUTHOR]

Background: Assessment of disease activity in rheumatoid arthritis (RA) is crucial to optimize the response to treatment and prevent radiographic progression. DAS28 is the most commonly used disease activity index, which incorporates either erythrocyte sedimentation rate (ESR) or C-reactive protein (CRP). Several studies showed that using ESR and/or CRP in assessing disease activity falls short of detecting a significant portion of patients with active disease. Calprotectin (CLP) is an interesting protein that was found to be a promising biomarker of disease activity in RA patients' sera when CRP is normal. This study aimed to measure serum CLP level in 50 RA patients with different grades of disease activity and compare its level with age- and sex-matched control. Results: In this case–control study, the mean serum CLP level was significantly lower in RA patients (25.94 ± 25.87 ng/ml) compared to the control group values (53.02 ± 77.93 ng/ml), p < 0.001. The measured serum CLP in RA patients was lower than its level in other published studies. No significant difference was found between patients with different disease activity grades in the serum CLP level (H = 4.28, p = 0.23). Serum samples were collected and stored from RA patients over 4 months and from the control subjects over 1.5 months and were stored at –80 °C until analysis was performed according to the manufacturer's instruction. Conclusion: The low level of serum CLP among RA patients is most probably due to proteolysis related to storage conditions. Pre-analytic factors like the type of blood sample, whether the sample is fresh or frozen, and duration of storage exert an effect on serum CLP level when measured by enzyme-linked immunosorbent assay. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic stem cell transplantation (aHSCT) represents an effective treatment option in patients with severe forms of systemic sclerosis (SSc) by resetting the immune system. Nevertheless, secondary autoimmune disorders and progressive disease after aHSCT might necessitate renewed immunosuppressive treatments. This is particularly challenging when organ dysfunction, i.e., end-stage kidney failure, is present. In this case report, we present the unique case of a 43-year-old female patient with rapidly progressive diffuse systemic sclerosis who underwent aHSCT despite end-stage renal failure as consequence of SSc-renal crisis. Therefore, conditioning chemotherapy was performed with melphalan instead of cyclophosphamide with no occurrence of severe adverse events during the aplastic period and thereafter. After aHSCT, early disease progression of the skin occurred and was successfully treated with secukinumab. Thereby, to the best of our knowledge, we report the first case of successful aHSCT in a SSc-patient with end-stage kidney failure and also the first successful use of an IL-17 inhibitor to treat early disease progression after aHSCT. [ABSTRACT FROM AUTHOR]

Copyright of Immunology Quarterly / Immunológiai Szemle is the property of Medicina Konyvkiado Zrt. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Dry eye disease (DED) is a multifactorial disorder characterized by loss of tear film homeostasis with an estimated worldwide prevalence of 5% to 50%. In DED, dysfunction of the ocular structures that create and regulate the tear film components—including the lacrimal glands, meibomian glands, cornea, and conjunctiva—causes a qualitative and/or quantitative tear deficiency with resultant tear film instability and hyperosmolarity. This initiates a vicious cycle of ocular surface inflammation and damage that may ultimately impair the quality of life and vision of affected patients. Many factors can contribute to the development of DED, including ocular and systemic diseases, topical and systemic medications, and environmental conditions. Because DED is a chronic disorder, treatment is most often long term and may utilize both pharmacologic and nonpharmacologic interventions to address all etiologic components. The long-term management of DED can be challenging and most often should involve eye care specialist referral. However, primary care clinicians (PCCs) are often the first points of contact for patients with DED and importantly provide initial diagnosis and preliminary patient education about the disease process. Consideration of DED is also vital for the practice of various specialties due to the large number of comorbidities and medications that can contribute to DED pathogenesis and progression. Therefore, it is important that PCCs and clinical specialists be aware of the etiology of DED and its available therapeutic options. This manuscript provides an overview of DED pathophysiology and treatment and discusses specific considerations regarding DED management for PCCs and clinical specialists. Successful management of dry eye disease often requires the use of various pharmacologic and/or nonpharmacologic therapies, as well as environmental and lifestyle modifications, to mitigate the underlying etiologies and restore tear film homeostasis. Primary care clinicians play an essential role in dry eye disease management by establishing a diagnosis, educating patients about the disorder, and providing referrals to eye care specialists for initiation of specialized treatment and long-term follow-up. Primary care clinicians and clinical specialists should consider prescribing medications with fewer ocular surface effects whenever possible in patients at risk for or with existing dry eye disease. [ABSTRACT FROM AUTHOR]

Although γδ T cells comprise a small population of T cells, they perform important roles in protecting against infection and suppressing tumors. With their distinct tissue-localizing properties, combined with their various target recognition mechanisms, γδ T cells have the potential to become an effective solution for tumors that do not respond to current therapeutic procedures. One such tumor, glioblastoma (GBM), is a malignant brain tumor with the highest World Health Organization grade and therefore the worst prognosis. The immune-suppressive tumor microenvironment (TME) and immune-evasive glioma stem cells are major factors in GBM immunotherapy failure. Currently, encouraged by the strong anti-tumoral function of γδ T cells revealed at the preclinical and clinical levels, several research groups have shown progression of γδ T cell-based GBM treatment. However, several limitations still exist that block effective GBM treatment using γδ T cells. Therefore, understanding the distinct roles of γδ T cells in anti-tumor immune responses and the suppression mechanism of the GBM TME are critical for successful γδ T cell-mediated GBM therapy. In this review, we summarize the effector functions of γδ T cells in tumor immunity and discuss current advances and limitations of γδ T cell-based GBM immunotherapy. Additionally, we suggest future directions to overcome the limitations of γδ T cell-based GBM immunotherapy to achieve successful treatment of GBM. [ABSTRACT FROM AUTHOR]

Detlef Zillikens, MD, director and chair of the Department of Dermatology at the University of Lübeck, Lübeck, Germany, died in September 2022, aged only 64. He dedicated his professional life to autoimmune blistering diseases (AIBDs) and built his department into one of the world's leading centers for these diseases. Herein, his professional life and the impact on the field of AIBDs and the research landscape at the University of Lübeck are addressed. With his warm, integrative, open-minded, ever-optimistic attitude, he was a highly reliable colleague, mentor, and friend to many in the field including each of the authors. Combined with his in-depth knowledge of dermatology, interest in many fields of life science, and hard work, Detlef Zillikens initiated the founding of two independent research institutes, the Lübeck Institute of Experimental Dermatology and the Institute and Comprehensive Center for Inflammation Medicine. He was also instrumental in establishing the Center for Research on Inflammation of the Skin, where in a new research building, over 140 scientists pursue research questions related to skin inflammation. By inviting numerous researchers and clinicians to his department and hosting two large international meetings, he brought the field of AIBDs much closer together and inspired multiple national and international research initiatives. His ideas will live on and grow in many of his colleagues and mentees. [ABSTRACT FROM AUTHOR]

Summary: The structurally and functionally related interleukin‐4 (IL‐4) and IL‐13 cytokines play pivotal roles in shaping immune activity. The IL‐4/IL‐13 axis is best known for its critical role in T helper 2 (Th2) cell‐mediated Type 2 inflammation, which protects the host from large multicellular pathogens, such as parasitic helminth worms, and regulates immune responses to allergens. In addition, IL‐4 and IL‐13 stimulate a wide range of innate and adaptive immune cells, as well as non‐hematopoietic cells, to coordinate various functions, including immune regulation, antibody production, and fibrosis. Due to its importance for a broad spectrum of physiological activities, the IL‐4/IL‐13 network has been targeted through a variety of molecular engineering and synthetic biology approaches to modulate immune behavior and develop novel therapeutics. Here, we review ongoing efforts to manipulate the IL‐4/IL‐13 axis, including cytokine engineering strategies, formulation of fusion proteins, antagonist development, cell engineering approaches, and biosensor design. We discuss how these strategies have been employed to dissect IL‐4 and IL‐13 pathways, as well as to discover new immunotherapies targeting allergy, autoimmune diseases, and cancer. Looking ahead, emerging bioengineering tools promise to continue advancing fundamental understanding of IL‐4/IL‐13 biology and enabling researchers to exploit these insights to develop effective interventions. [ABSTRACT FROM AUTHOR]

Ultrasonography is an imaging technique based on sound waves used for the evaluation of soft tissues. Sound waves have been used for a long time in nonmedical fields, including military defense systems, radar systems, and detection of icebergs. Technological advances resulted in new techniques becoming available for medical imaging, including ultrasonography, magnetic resonance imaging, and computed tomography. Nowadays, the use of imaging has become a gold standard protocol in the diagnosis of many diseases, and recently developed diagnosis and therapy options provide more efficient treatment of rheumatic diseases. Thus, it has become possible to prevent structural damage and disability in patients with rheumatic disease. Musculoskeletal ultrasonography is becoming a preferred imaging technique for rheumatic diseases, as it has many advantages. Among its advantages are being inexpensive, being radiation-free, having a dynamic image capacity, helping to detect disease activity, and helping with early detection and diagnosis of structural damage. This review summarizes the use of ultrasonography in rheumatic diseases. [ABSTRACT FROM AUTHOR]

Background: Malignant neoplasms are a well-recognized global public health concern, with significant impacts on human health and quality of life. The interplay between tumors and autoimmune rheumatic diseases is complex, and the resulting tumor-associated rheumatic diseases represent a rare and intricate group of conditions that occur in the context of malignant tumors. In addition, various rheumatic diseases can arise as a consequence of oncology treatment. These diseases present with intricate clinical manifestations and pathological features, often rendering them challenging to diagnose and impacting patients' quality of life. Despite this, they have yet to be fully recognized. Methods: This article presents a literature review of published original articles and review articles concerning paraneoplastic rheumatic syndromes and rheumatic diseases associated with cancer treatment. We conducted a comprehensive literature search in PubMed, Web of Science and Google Scholar databases, excluding duplicated and irrelevant studies. In cases of duplicated research, we selected articles with higher impact factors for the review. Results: This review focuses on the clinical features, diagnosis, and treatment of paraneoplastic rheumatic diseases, as well as the pathogenesis of these diseases. Additionally, we summarize the autoimmune rheumatic diseases associated with cancer treatment. Ultimately, the goal of this review is to enhance recognition and improve the management of autoimmune rheumatic diseases related to tumors. [ABSTRACT FROM AUTHOR]

Objective: B‐cell depletion using the anti‐CD20 monoclonal antibody rituximab is a cornerstone in the therapeutic concept of multiple autoimmune diseases. B‐cell depletion is associated with a higher risk for severe infections, and the time span of B‐cell repopulation differs greatly between individuals. Data on factors influencing B‐cell repopulation kinetics are limited. This study aims to identify patient‐specific and therapy‐associated covariates that modulate B‐cell repopulation. Methods: This single‐center retrospective observational study presents data of 839 subjects receiving 2,017 courses of rituximab for autoimmune diseases. Assessed covariates are patient‐specific factors (sex, age, kidney function, and underlying disease) and co‐immunosuppression with common agents (azathioprine, cyclosporine A, cyclophosphamide, hydroxychloroquine, methotrexate, mycophenolate mofetil, tacrolimus, and corticosteroids). The primary end point is the time to B‐cell repopulation (≥5/μl). The secondary end point is the time to B‐cell reconstitution (≥50/μl). Multivariate time‐to‐event analysis and logistic regression models were applied to estimate the influence of covariates. Results: Age over 60 years (hazard ratio [HR] 0.71 for repopulation, P = 0.008), impaired kidney function (HR 0.72, P = 0.001), antineutrophil cytoplasmic antibody‐associated vasculitis (HR 0.61, P < 0.001), solid organ transplantation (HR 0.4, P < 0.001), and co‐immunosuppression with corticosteroids (HR 0.64, P < 0.001) or azathioprine (HR 0.49, P < 0.001) were associated with impaired B‐cell repopulation and reconstitution. Effects of corticosteroids (P = 0.043) and azathioprine (P = 0.025) were dose dependent. Conclusion: Prolonged rituximab dosing intervals may be effective to achieve B‐cell depletion and reduce risk of infection in advanced age or patients with impaired kidney function. Co‐medication with corticosteroids or azathioprine prolongs B‐cell recovery, which may increase therapeutic effects but also the rate of adverse events. [ABSTRACT FROM AUTHOR]