Follicular helper T cell signature of replicative exhaustion, apoptosis, and senescence in common variable immunodeficiency.

Common variable immunodeficiency (CVID) is the most frequent primary antibody deficiency whereby follicular helper T (Tfh) cells fail to establish productive responses with B cells in germinal centers. Here, we analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh (cTfh) cells in CVID patients displaying autoimmunity as an additional phenotype. A group of patients showed a high frequency of cTfh1 cells and a prominent expression of PD-1 and ICOS as well as a cTfh mRNA signature consistent with highly activated, but exhausted, senescent, and apoptotic cells. Plasmatic CXCL13 levels were elevated in this group and positively correlated with cTfh1 cell frequency and PD-1 levels. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were identified in four patients belonging to this group. Their blood lymphocytes showed shortened telomeres, while their cTfh were more prone to apoptosis. These data point toward a novel pathogenetic mechanism in CVID, whereby alterations in DNA repair and telomere elongation might predispose to antibody deficiency. A Th1, highly activated but exhausted and apoptotic cTfh phenotype was associated with this form of CVID.

Comparison of clinical features between patients with anti-synthetase syndrome and dermatomyositis: Results from the MYONET registry.

OBJECTIVES: To compare clinical characteristics, including the frequency of cutaneous, extramuscular manifestations, and malignancy, between adults with anti-synthetase syndrome (ASyS) and dermatomyositis (DM). METHODS: Using data regarding adults from the MYONET registry, a cohort of DM patients with anti-Mi2/-TIF1É£/-NXP2/-SAE/-MDA5 autoantibodies, and a cohort of ASyS patients with anti-tRNA synthetase autoantibodies (anti-Jo1/-PL7/-PL12/-OJ/-EJ/-Zo/-KS) were identified. Patients with DM sine dermatitis or with discordant dual autoantibody specificities were excluded. Sub-cohorts of patients with ASyS with or without skin involvement were defined based on presence of DM-type rashes (heliotrope rash, Gottron's papules/sign, violaceous rash, shawl sign, V sign, erythroderma, and/or periorbital rash). RESULTS: In total 1,054 patients were included (DM, n = 405; ASyS, n = 649). In ASyS cohort, 31% (n = 203) had DM-type skin involvement (ASyS-DMskin). A higher frequency of extramuscular manifestations, including Mechanic's hands, Raynaud's phenomenon, arthritis, interstitial lung disease, and cardiac involvement differentiated ASyS-DMskin from DM (all p< 0.001), whereas higher frequency of any of four DM-type rashes: heliotrope rash (n = 248, 61% vs n = 90, 44%), violaceous rash (n = 166, 41% vs n = 57, 9%), V sign (n = 124, 31% vs n = 28, 4%), and shawl sign (n = 133, 33% vs n = 18, 3%) differentiated DM from ASyS-DMskin (all p< 0.005). Cancer-associated myositis (CAM) was more frequent in DM (n = 67, 17%) compared with ASyS (n = 21, 3%) and ASyS-DMskin (n = 7, 3%) cohorts (both p< 0.001). CONCLUSION: DM-type rashes are frequent in patients with ASyS; however, distinct clinical manifestations differentiate these patients from classical DM. Skin involvement in ASyS does not necessitate increased malignancy surveillance. These findings will inform future ASyS classification criteria and patient management.

The Impact of SARS-CoV-2 Infection in Patients with Inborn Errors of Immunity: the Experience of the Italian Primary Immunodeficiencies Network (IPINet).

COVID-19 manifestations range from asymptomatic to life-threatening infections. The outcome in different inborn errors of immunity (IEI) is still a matter of debate. In this retrospective study, we describe the experience of the of the Italian Primary Immunodeficiencies Network (IPINet). Sixteen reference centers for adult or pediatric IEI were involved. One hundred fourteen patients were enrolled including 35 pediatric and 79 adult patients. Median age was 32 years, and male-to-female ratio was 1.5:1. The most common IEI were 22q11.2 deletion syndrome in children (26%) and common variable immunodeficiency (CVID) in adults (65%). Ninety-one patients did not require hospital admission, and among these, 33 were asymptomatic. Hospitalization rate was 20.17%. Older age (p 0.004) and chronic lung disease (p 0.0008) represented risk factors for hospitalization. Hospitalized patients mainly included adults suffering from humoral immunodeficiencies requiring immunoglobulin replacement therapy and as expected had lower B cell counts compared to non-hospitalized patients. Infection fatality rate in the whole cohort was 3.5%. Seroconversion was observed is 86.6% of the patients evaluated and in 83.3% of CVID patients. 16.85% of the patients reported long-lasting COVID symptoms. All but one patient with prolonged symptoms were under IgRT. The fatality rate observed in IEI was slightly similar to the general population. The age of the patients who did not survive was lower compared to the general population, and the age stratified mortality in the 50-60 age range considerable exceeded the mortality from 50 to 60 age group of the Italian population (14.3 vs 0.6%; p < 0.0001). We hypothesize that this is due to the fact that comorbidities in IEI patients are very common and usually appear early in life.

Intravenous immunoglobulin as an important adjunct in the prevention and therapy of coronavirus 2019 disease.

The coronavirus disease-19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) challenged globally with its morbidity and mortality. A small percentage of affected patients (20%) progress into the second stage of the disease clinically presenting with severe or fatal involvement of lung, heart and vascular system, all contributing to multiple-organ failure. The so-called 'cytokines storm' is considered the pathogenic basis of severe disease and it is a target for treatment with corticosteroids, immunotherapies and intravenous immunoglobulin (IVIg). We provide an overview of the role of IVIg in the therapy of adult patients with COVID-19 disease. After discussing the possible underlying mechanisms of IVIg immunomodulation in COVID-19 disease, we review the studies in which IVIg was employed. Considering the latest evidence that show a link between new coronavirus and autoimmunity, we also discuss the use of IVIg in COVID-19 and anti-SARS-CoV-2 vaccination related autoimmune diseases and the post-COVID-19 syndrome. The benefit of high-dose IVIg is evident in almost all studies with a rapid response, a reduction in mortality and improved pulmonary function in critically ill COVID-19 patients. It seems that an early administration of IVIg is crucial for a successful outcome. Studies' limitations are represented by the small number of patients, the lack of control groups in some and the heterogeneity of included patients. IVIg treatment can reduce the stay in ICU and the demand for mechanical ventilation, thus contributing to attenuate the burden of the disease.

The Italian Registry for Primary Immunodeficiencies (Italian Primary Immunodeficiency Network; IPINet): Twenty Years of Experience (1999-2019).

Primary immunodeficiencies (PIDs) are heterogeneous disorders, characterized by variable clinical and immunological features. National PID registries offer useful insights on the epidemiology, diagnosis, and natural history of these disorders. In 1999, the Italian network for primary immunodeficiencies (IPINet) was established. We report on data collected from the IPINet registry after 20 years of activity. A total of 3352 pediatric and adult patients affected with PIDs are registered in the database. In Italy, a regional distribution trend of PID diagnosis was observed. Based on the updated IUIS classification of 2019, PID distribution in Italy showed that predominantly antibody deficiencies account for the majority of cases (63%), followed by combined immunodeficiencies with associated or syndromic features (22.5%). The overall age at diagnosis was younger for male patients. The minimal prevalence of PIDs in Italy resulted in 5.1 per 100.000 habitants. Mortality was similar to other European registries (4.2%). Immunoglobulin replacement treatment was prescribed to less than one third of the patient cohort. Collectively, this is the first comprehensive description of the PID epidemiology in Italy.

The EuroMyositis registry: an international collaborative tool to facilitate myositis research.

AIMS: The EuroMyositis Registry facilitates collaboration across the idiopathic inflammatory myopathy (IIM) research community. This inaugural report examines pooled Registry data. METHODS: Cross-sectional analysis of IIM cases from 11 countries was performed. Associations between clinical subtypes, extramuscular involvement, environmental exposures and medications were investigated. RESULTS: Of 3067 IIM cases, 69% were female. The most common IIM subtype was dermatomyositis (DM) (31%). Smoking was more frequent in connective tissue disease overlap cases (45%, OR 1.44, 95% CI 1.09 to 1.90, p=0.012). Smoking was associated with interstitial lung disease (ILD) (OR 1.32, 95% CI 1.06 to 1.65, p=0.013), dysphagia (OR 1.43, 95% CI 1.16 to 1.77, p=0.001), malignancy ever (OR 1.78, 95% CI 1.36 to 2.33, p<0.001) and cardiac involvement (OR 2.40, 95% CI 1.60 to 3.60, p<0.001).Dysphagia occurred in 39% and cardiac involvement in 9%; either occurrence was associated with higher Health Assessment Questionnaire (HAQ) scores (adjusted OR 1.79, 95% CI 1.43 to 2.23, p<0.001). HAQ scores were also higher in inclusion body myositis cases (adjusted OR 3.85, 95% CI 2.52 to 5.90, p<0.001). Malignancy (ever) occurred in 13%, most commonly in DM (20%, OR 2.06, 95% CI 1.65 to 2.57, p<0.001).ILD occurred in 30%, most frequently in antisynthetase syndrome (71%, OR 10.7, 95% CI 8.6 to 13.4, p<0.001). Rash characteristics differed between adult-onset and juvenile-onset DM cases ('V' sign: 56% DM vs 16% juvenile-DM, OR 0.16, 95% CI 0.07 to 0.36, p<0.001). Glucocorticoids were used in 98% of cases, methotrexate in 71% and azathioprine in 51%. CONCLUSION: This large multicentre cohort demonstrates the importance of extramuscular involvement in patients with IIM, its association with smoking and its influence on disease severity. Our findings emphasise that IIM is a multisystem inflammatory disease and will help inform prognosis and clinical management of patients.

Facilitated Subcutaneous Immunoglobulin (fSCIg) in Autoimmune Cytopenias Associated with Common Variable Immunodeficiency.

BACKGROUND: Common variable immunodeficiency (CVID) is the most common symptomatic primary immune deficiency of adulthood. Besides recurrent infections, autoimmune disorders-mainly cytopenias-affect 30% of patients with CVID. OBJECTIVES: To describe the efficacy and safety of facilitated subcutaneous immunoglobulin (fSCIg), which is a combination of 10% [human] SCIg with recombinant human hyaluronidase for the treatment of CVID-linked cytopenias. METHODS: We describe four women (mean age 54 years) with CVID associated with idiopathic thrombocytopenic purpura (ITP) (n=3) and autoimmune hemolytic anemia (AIHA) (n=1). Diagnosis of CVID was made according to the European Society of Immune Deficiencies / Pan-American Group for Immune Deficiency criteria. All were treated with fSCIg (bi-monthly, 20 g). RESULTS: After a median follow-up of 22 months, all patients achieved a stable remission from the cytopenias, characterized by increased platelet values in ITP (mean values 93000/mmc), and resolution of anemia. A reduction of the daily prednisone dose was documented in the patient with AIHA. No systemic adverse drug reactions were observed. CONCLUSIONS: Our preliminary data documented the efficacy and safety of fSCIg in the treatment of CVID associated with autoimmune cytopenias, with a good tolerability. We also noted the role of fSCIg as a steroid sparing agent. It is thus possible to suppose an immunomodulatory role for fSCIg, but linked to different mechanisms than IVIg, due to the peculiar pharmacokinetic and administration route of fSCIg.

Hymenoptera Venom Allergy and Anaphylaxis.

Hymenoptera stings can induce allergic and occasionally fatal reactions, and are responsible for significant morbidity and deterioration in health-related quality of life. The diagnostic work-up must consider the medical history of patients, in the context of venom allergy epidemiology and Hymenoptera taxonomy, and the clinical manifestations of the reactions, to channel the available in vivo and in vitro tests towards the most accurate diagnosis and the consequent appropriate management, also considering the risk profile of the patients on a precision-medicine approach. All these aspects are covered by this work that aims at providing an up-to-date review to increase the awareness of this topic among interested stakeholders, like healthcare professionals and political decision makers, who can contribute to the proper immediate and long-term management of venom allergy and anaphylaxis.

A machine learning analysis to evaluate the outcome measures in inflammatory myopathies.

OBJECTIVE: To assess the long-term outcome in patients with Idiopathic Inflammatory Myopathies (IIM), focusing on damage and activity disease indexes using artificial intelligence (AI). BACKGROUND: IIM are a group of rare diseases characterized by involvement of different organs in addition to the musculoskeletal. Machine Learning analyses large amounts of information, using different algorithms, decision-making processes and self-learning neural networks. METHODS: We evaluate the long-term outcome of 103 patients with IIM, diagnosed on 2017 EULAR/ACR criteria. We considered different parameters, including clinical manifestations and organ involvement, number and type of treatments, serum creatine kinase levels, muscle strength (MMT8 score), disease activity (MITAX score), disability (HAQ-DI score), disease damage (MDI score), and physician and patient global assessment (PGA). The data collected were analysed, applying, with R, supervised ML algorithms such as lasso, ridge, elastic net, classification, and regression trees (CART), random forest and support vector machines (SVM) to find the factors that best predict disease outcome. RESULTS AND CONCLUSION: Using artificial intelligence algorithms we identified the parameters that best correlate with the disease outcome in IIM. The best result was on MMT8 at follow-up, predicted by a CART regression tree algorithm. MITAX was predicted based on clinical features such as the presence of RP-ILD and skin involvement. A good predictive capacity was also demonstrated on damage scores: MDI and HAQ-DI. In the future Machine Learning will allow us to identify the strengths or weaknesses of the composite disease activity and damage scores, to validate new criteria or to implement classification criteria.

Low-dose intravenous immunoglobulin (IVIg) in different immune-mediated conditions.

IVIg has been used for a long time as a replacement therapy for primary and secondary immunodeficiencies. Beside this supplementary role, when used at higher doses (i.e., 2 g/kg/monthly) it exerts an immunomodulatory role able to control multiple autoimmune and systemic inflammatory diseases. Several mechanisms of action have been described and hypothesized, nonetheless a synergistic action on the different component of the immune response seems to be crucial. The other side of the coin are the costs which showed an increase during the years due to the production of highly purified preparations which limit side reactions. This renders the product not easily accessible especially for low-income countries. Moreover, it is based on plasma donations that experienced a significant shrinkage after the COVID-19 pandemic and the consequences are still impactful. Due to the above-mentioned problems different authors tried to find out if a lower dosage of IVIg (< 2 g/kg/monthly) might exert an immunoregulatory role. In this review we aimed to summarize the current literature about a possible beneficial effect of a lower dosage of IVIg in multiple conditions that would help to treat a vast majority of patients. Even though in some cases (e.g., Kawasaki disease and immune thrombocytopenia) results are promising, for other conditions more research is needed.

Oxidative stress, mitochondrial dysfunction, and respiratory chain enzyme defects in inflammatory myopathies.

We investigated the relationship between oxidative stress and inflammatory myopathies. We searched in the current literature the role of mitochondria and respiratory chain defects as sources of oxidative stress and reactive oxygen species production that led to muscle weakness and fatigue. Different molecules and pathways contribute to redox milieu, reactive oxygen species generation, accumulation of misfolded and carbonylated proteins that lose their ability to fulfil cellular activities. Small peptides and physical techniques proved, in mice models, to reduce oxidative stress. We focused on inclusion body myositis, as a major expression of myopathy related to oxidative stress, where mitochondrial abnormalities are causative agents as well. We described the effect of physical exercise in inclusion body myositis that showed to increase strength and to reduce beta amyloid accumulation with subsequent improvement of the mitochondrial functions. We illustrated the influence of epigenetic control on the immune system by non-coding genetic material in the interaction between oxidative stress and inflammatory myopathies.

Machine learning application in autoimmune diseases: State of art and future prospectives.

Autoimmune diseases are a group of disorders resulting from an alteration of immune tolerance, characterized by the formation of autoantibodies and the consequent development of heterogeneous clinical manifestations. Diagnosing autoimmune diseases is often complicated, and the available prognostic tools are limited. Machine learning allows us to analyze large amounts of data and carry out complex calculations quickly and with minimal effort. In this work, we examine the literature focusing on the use of machine learning in the field of the main systemic (systemic lupus erythematosus and rheumatoid arthritis) and organ-specific autoimmune diseases (type 1 diabetes mellitus, autoimmune thyroid, gastrointestinal, and skin diseases). From our analysis, interesting applications of machine learning emerged for developing algorithms useful in the early diagnosis of disease or prognostic models (risk of complications, therapeutic response). Subsequent studies and the creation of increasingly rich databases to be supplied to the algorithms will eventually guide the clinician in the diagnosis, allowing intervention when the pathology is still in an early stage and immediately directing towards a correct therapeutic approach.

ANCA-negative EGPA: only eosinophils without vasculitis? Insights from anti-T2 biologics.

The pathogenic role of p-ANCA in eosinophilic granulomatosis with polyangiitis (EGPA) is a long-standing matter of debate. In this work, we report our real-life experience with EGPA patients, treated with biologics targeting type 2 (T2)-eosinophilic inflammation (Mepolizumab, Benralizumab, Dupilumab). Interestingly, we observed EGPA extrarespiratory relapses only in p-ANCA-positive patients (2/5 cutaneous vasculitis, 3/5 constitutional symptoms), with new rise of p-ANCA and normal eosinophil blood count. Notably, revising our cohort with the new ACR 2022 criteria, these five patients were the only ones to satisfy the entry criterion of vasculitis' defined diagnosis at disease onset. These observations may suggest that biologics, selectively turning off T2 inflammation, may have unmasked p-ANCA exclusive role in the pathogenesis of vasculitis in EGPA. Therefore, we raise the question whether EGPA vasculitis exists only in p-ANCA-positive patients, and whether p-ANCA-negative disease is "only eosinophils without vasculitis".

A machine learning analysis to predict the response to intravenous and subcutaneous immunoglobulin in inflammatory myopathies. A proposal for a future multi-omics approach in autoimmune diseases.

OBJECTIVE: To evaluate the response to treatment with intravenous (IVIg) and subcutaneous (20%SCIg) immunoglobulin in our series of patients with Inflammatory idiopathic myopathies (IIM) by the means of artificial intelligence. BACKGROUND: IIM are rare diseases mainly involving the skeletal muscle with particular clinical, laboratory and radiological characteristics. Artificial intelligence (AI) represents computer processes which allows to perform complex calculations and data analyses, with the least human intervention. Recently, the use an AI in medicine significantly expanded, especially through machine learning (ML) which analyses huge amounts of information and accordingly makes decisions, and deep learning (DL) which uses artificial neural networks to analyse data and automatically learn. METHODS: In this study, we employed AI in the evaluation of the response to treatment with IVIg and 20%SCIg in our series of patients with IIM. The diagnoses were determined on the established EULAR/ACR criteria. The treatment response was evaluated employing the following: serum creatine kinase levels, muscle strength (MMT8 score), disease activity (MITAX score) and disability (HAQ-DI score). We evaluated all the above parameters, applying, with R, different supervised ML algorithms, including Least Absolute Shrinkage and Selection Operator, Ridge, Elastic Net, Classification and Regression Trees and Random Forest to estimate the most important predictors for a good response to IVIg and 20%SCIg treatment. RESULTS AND CONCLUSION: By the means of AI we have been able to identify the scores that best predict a good response to IVIg and 20%SCIg treatment. The muscle strength as evaluated by MMT8 score at the follow-up is predicted by the presence of dysphagia and of skin disorders, and the myositis activity index (MITAX) at the beginning of the treatment. The relationship between muscle strength and MITAX indicates a better action of IVIg therapy in patients with more active systemic disease. Considering our results, Elastic Net and similar approaches were seen to be the most viable, efficient, and effective ML methods for predicting the clinical outcome (MMT8 and MITAX at most) in myositis.

Alarmins in autoimmune diseases.

Alarmins are endogenous, constitutively expressed, chemotacting and immune activating proteins or peptides released because of non-programmed cell death (i.e. infections, trauma, etc). They are considered endogenous damage-associated molecular patterns (DAMPs), able to induce a sterile inflammation. In the last years, several studies highlighted a possible role of different alarmins in the pathogenesis of various autoimmune and immune-mediated diseases. We reviewed the relevant literature about this topic, for about 160 articles. Particularly, we focused on systemic autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, idiopathic inflammatory myopathies, ANCA-associated vasculitides, Behçet's disease) and cutaneous organ-specific autoimmune diseases (vitiligo, psoriasis, alopecia, pemphigo). Finally, we discussed about future perspectives and potential therapeutic implications of alarmins in autoimmune diseases. In fact, identification of receptors and downstream signal transducers of alarmins may lead to the identification of antagonistic inhibitors and agonists, with the capacity to modulate alarmins-related pathways and potential therapeutic applicability.

Common Variable Immunodeficiency in Elderly Patients: A Long-Term Clinical Experience.

Background: Common variable immunodeficiency (CVID) is a complex, predominantly antibody deficiency usually diagnosed between 20−40 years. Few data about elderly patients are reported in the literature. Our aim was to evaluate the clinical phenotypes of elderly patients with CVID. Method: A retrospective analysis of adult patients with CVID was performed in our Referral Centre, focusing on the main differences between "older" patients (≥65 years at the diagnosis) and "younger" patients (<65 years). Results: The data from 65 younger and 13 older patients followed up for a median period of 8.5 years were available. At diagnosis, recurrent infections represented the only clinical manifestation in 61% and 69% of younger and older patients, respectively. The incidence of autoimmune diseases was higher in elderly patients compared with younger ones (30 vs. 18%, respectively). During the follow-up, the incidence of autoimmune disorders and enteropathy increased in the younger patients whereas neoplasia became the most prevalent complication in the elderly (38%). All patients received a replacement therapy with immunoglobulin, with good compliance. Conclusion: CVID occurrence in elderly patients is rarely described; therefore, the clinical characteristics are not completely known. In our series, neoplasia became the most prevalent complication in the elderly during the follow-up. In elderly patients, 20% SCIg was as safe as in the younger ones, with good compliance. A genetic analysis is important to confirm the diagnosis, identify specific presentations in the different ages, clarify the prognosis and guide the treatment. Future clinical research in this field may potentially help to guide their care.