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Background ICIs have strongly improved the outcome of NSCLC patients. However, primary and secondary resistance occur during treatment in most of the patients, with several of them developing fast progressions. Autoantibodies can be related with a dysfunctional immune system, although their association with immune-based anti-cancer therapies has never been investigated. Moreover, so far no reliable predictive factor is currently available to aid in treatment selection. CD137+T-cells are largely known to be the anti-tumor activated effector cells, but they have never been associated with the response to immunotherapies. Methods Forty-two patients with metastatic NSCLC receiving anti-PD-1 ICIs at Sant'Andrea Hospital and Policlinico Umberto I, from June 2016 to September 2018 were enrolled. Circulating levels of IgM-Rheumatoid Factor were evaluated at baseline and correlated with patients clinical response following the anti-PD-1 treatment. IgM-RF interaction and effect on T-cells in vivo and in vitro were investigated. Findings IgM-RF in NSCLC patient sera strongly predicted the development of early progression to ICIs. Also, a significant reduction of progression-free survival rate in anti-PD-1 treated patients could be identified when patients were stratified based on IgM-RF positivity and titers. IgM-RF bound preferentially circulating naive and central memory T-cells and a significant reduction of CD137+ anti-tumor T effector cells was found in IgM-RF positive patients. In addition, a higher percentage of CD137+T-cells in peripheral blood of NSCLC patients at baseline resulted as a strong independent prognostic factor for a better outcome in terms of PFS and OS after the anti-PD-1 treatment. Furthermore, T-cells exposed to IgM-RF showed a robust defect in their migratory ability in response to CCL19 chemokine. Interpretation In this study we showed that serum IgM-RF can be regarded as predictive factor for the development of early progression and prognostic factor of a reduced progression-free survival and overall-survival in anti-PD-1 treated NSCLC patients. The ability of IgM-RF to bind naive and central memory T-cells and impair their migration could make account for the reduction of the tumor-reactive CD137+ T-cells population that may cause a non-effectiveness of these T-cells targeting drugs. Fundings AIRC, MIUR and Sapienza University of Rome.

Autophagy is a lysosomal degradation mechanism with a crucial role in cell homeostasis and in stress conditions. Because autophagy was found to be dysregulated in several disorders, such as cancer and neurodegenerative diseases, several studies have taken into account this process as a therapeutic target in human diseases. Autophagy seems to be involved in immunity, contributing to MHC class II-mediated presentation of intracellular antigens to T lymphocytes, and it can also play a role in inducing an autoimmune response. B and T lymphocytes depend on autophagy for their development, survival, proliferation, and function. As a result, the role of autophagy in the pathogenesis of many autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, Sjogren syndrome, and inflammatory bowel disease, was investigated in many studies, suggesting that its modulation may be considered a target for clinical practice.

Objective The reproductive choices of women affected by rheumatic diseases (RD) can be influenced by several factors, including the quality of physician-patient communication. We conducted a survey on reproductive issues aiming at exploring the unmet needs of women with RD during childbearing age. Methods We administered 65 multiple-choice and 12 open-answer questions about pregnancy counselling, contraception, use of drugs during pregnancy and other women reproductive issues to 477 consecutive women with RD aged 18–55 years followed-up in 24 rheumatology centres in Italy. Analysis was restricted to 398 patients who received their diagnosis of RD before the age of 45. According to the RD diagnosis, patients were subdivided into 2 groups: connective tissue diseases (n = 249) and chronic arthritis (n = 149). Results At the time of interview, women in both groups had a mean age of 40 years. Nearly one third of patients in each group declared not to have received any counselling about either pregnancy desire nor contraception. A smaller family size than desired was reported by nearly 37% of patients, because of concerns related to maternal disease in one fourth of the cases. A “Disease Knowledge Index” (DKI) was created to investigate the degree of patients’ information about the implications of their RD on reproductive issues. Having received counselling was associated with higher DKI values and with a positive impact on family planning. Conclusion Italian women of childbearing age affected by RD reported several unmet needs in their knowledge about reproductive issues. Strategies are needed to implement and facilitate physician-patient communication.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by great heterogeneity in terms of autoantibodies production, clinical phenotypes, and outcomes. In the last years, a growing number of new evidences have been observed concerning the disease pathogenesis. In particular, new environmental factors involved in disease development have been suggested. Among these, microbiota and diet seem to play a fundamental role. Moving from pathogenesis, new biomarkers have been proposed, with focus on possible application in a real-life setting. Finally, new knowledge leads to development of therapeutical strategies. In particular, biological drugs have been proposed to treat SLE patients resistant or intolerant to conventional immunosuppressant drugs.

Pregnancy requires a special management in women with inflammatory rheumatic diseases (RDs), with the aim of controlling maternal disease activity and avoiding fetal complications. Despite the heterogeneous course of RDs during pregnancy, their impact on pregnancy largely relates to the extent of active inflammation at the time of conception. Therefore, accurate evaluation of disease activity is crucial for the best management of pregnant patients. Nevertheless, there are limitations in using conventional measures of disease activity in pregnancy, as some items included in these instruments can be biased by symptoms or by physiological changes related to pregnancy and the pregnancy itself may influence laboratory parameters used to assess disease activity. This article aims to summarize the current literature about the available instruments to measure disease activity during pregnancy in RDs. Systemic lupus erythematosus is the only disease with instruments that have been modified to account for several adaptations which might interfere with the attribution of signs or symptoms to disease activity during pregnancy. No modified-pregnancy indices exist for women affected by other RDs, but standard indices have been applied to pregnant patients. The current body of knowledge shows that the physiologic changes that occur during pregnancy need to be either adapted from existing instruments or developed to improve the management of pregnant women with RDs. Standardized instruments to assess disease activity during pregnancy would be helpful not only for clinical practice but also for research purposes. info:eu-repo/semantics/publishedVersion

Chronic infection with the hepatitis C virus (HCV) is among the most common aetiologic factors influencing vasculitis in humans. Long-term infection is associated with small-vessel vasculitis (HCV-associated cryoglobulinemic vasculitis [CV]) in less than 5% of cases, and it is associated more rarely with medium-size vasculitis (polyarteritis nodosa-like). In recent years, significant advances have been made in our understanding of the pathogenesis of HCV-associated CV and its long-term prognosis. Furthermore, new immunosuppressive agents such as rituximab (a B cell–depleting agent) have been shown to be efficacious with limited toxicity, providing a promising alternative to current immunosuppressives for the treatment of HCV-associated CV. This chapter presents the pathogenesis, clinical features and recent therapeutic options for HCV-associated CV and medium-size vasculitis.

We analyzed the association between the renal arterial resistive index (RI) and the histologic features of lupus nephritis. All consecutive patients with systemic lupus erythematosus (SLE) who required a kidney biopsy were enrolled. The study protocol included ultrasonographic assessment to measure the RI and kidney biopsy (International Society of Nephrology/Renal Pathology Society classification). A RI > 0.7 was considered pathologic. Patients with non-renal SLE and healthy patients were studied as control groups. We enrolled 42 patients with renal SLE, 10 with non-renal SLE and 14 healthy patients: their mean (±standard deviation) RI values were 0.64 ± 0.08, 0.60 ± 0.04 and 0.59 ± 0.01, respectively (p = not significant). RIs > 0.7 were recorded only in patients with renal SLE (5/42, 11.9%). The percentage of patients with a pathologic RI was significantly higher in class IV nephritis in comparison with other classes (p < 0.009). In conclusion, we found a significant correlation between pathologic RI and class IV nephritis, suggesting a role for RI as a severity marker.

The 'Task Force on Catastrophic Antiphospholipid Syndrome (CAPS)' was developed on the occasion of the 14th International Congress on Antiphospholipid Antibodies. The objectives of this Task Force were to assess the current knowledge on pathogenesis, clinical and laboratory features, diagnosis and classification, precipitating factors and treatment of this condition in order to address recommendations for future research. This article summarizes the studies analyzed by the Task Force, its recommendations and the future research agenda.

Anti-endothelial cell antibodies (AECA) represent a heterogeneous family of autoantibodies directed against structural endothelial proteins, as well as antigens adhering to endothelial cells. Although AECA immunoassays still show a high-interlaboratory variability, several findings suggest a pathogenic role of these autoantibodies in diseases characterized by endothelial damage. In this chapter, we analyze the knowledge about AECA prevalence, clinical relevance, and their pathogenic role in autoimmune diseases focusing in particular on systemic lupus erythematosus, antiphospholipid syndrome, systemic sclerosis (SSc), and systemic vasculitis.

Publisher Summary Castleman's disease (CD) is a rare lymphoproliferative disorder of unknown aetiology. Although CD is a distinct clinicopathology entity, it tends to frequently share some common histological features with other immunological disorders, especially autoimmune diseases. The chapter describes various evidences of CD-autoimmunity link. One of the first evidence of a CD-autoimmunity link came from the finding of immune complexes in the glomerular basement membrane of patients with CD-associated nephrotic syndrome. The clinical and immunological aspects that CD shares with autoimmune diseases are useful to understand the pathogenesis of this rare lymphoproliferative disorder.