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Sarcoidosis and Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) are two rare entities primarily characterised by the development of Interstitial Lung Disease (ILD) in the context of systemic immune dysregulation. These two conditions partially share the immunological background and pathologic findings, with granuloma as the main common feature. In this narrative review, we performed a careful comparison between sarcoidosis and GLILD, with an overview of their main similarities and differences, starting from a clinical perspective and ending with a deeper look at the immunopathogenesis and possible target therapies. Sarcoidosis occurs in immunocompetent individuals, whereas GLILD occurs in patients affected by common variable immunodeficiency (CVID). Moreover, peculiar extrapulmonary manifestations and radiological and histological features may help distinguish the two diseases. Despite that, common pathogenetic pathways have been suggested and both these disorders can cause progressive impairment of lung function and variable systemic granulomatous and non-granulomatous complications, leading to significant morbidity, reduced quality of life, and survival. Due to the rarity of these conditions and the extreme clinical variability, there are still many open questions concerning their pathogenesis, natural history, and optimal management. However, if studied in parallel, these two entities might benefit from each other, leading to a better understanding of their pathogenesis and to more tailored treatment approaches.

Ustekinumab is a monoclonal antibody targeting the p40 subunit of IL-12 and IL-23, approved for treating psoriasis, psoriatic arthritis, and inflammatory bowel disease. Despite a remarkable success in treating chronic inflammatory conditions and a generally favorable safety profile, its role in inducing rare adverse events, such as interstitial pneumonia and acute respiratory distress syndrome (ARDS), remains largely uncharted. We report a case of a 66-year-old male patient treated with Ustekinumab for severe psoriasis who, after almost two years of treatment, developed dyspnea, asthenia, and fever progressing to non-infectious pneumonia and ARDS leading to ICU admission. Moreover, we conducted a literature review on Ustekinumab-associated pulmonary complications. Our case underscores the importance of appropriate and long-term clinical monitoring in patients on Ustekinumab treatment, particularly considering the potential lung complications. The possibility of non-infectious pneumonitis should be considered alongside infectious causes, facilitating prompt management in the case of negative infectious screening. Additionally, the severity of ARDS underscores the importance of timely recognition and proper management. Further investigations are recommended to investigate the immunological basis of Ustekinumab-induced ARDS for designing appropriate monitoring strategies.

Introduction: Inborn errors of immunity (IEI) represent a heterogeneous group of diseases in which the true prevalence of GI involvement is not well-known. This study evaluates the prevalence of lower GI manifestations in patients with common variable immunodeficiency (CVID), analysing the histologic findings in colonic samples and assessing any correlations with biochemical abnormalities. Materials and Methods: A retrospective study was performed by collecting the data of IEI adult patients followed up at two main Northern Italian centres. Demographic and clinical data, and blood tests were collected. A colonoscopy with multiple biopsies in standard sites, in addition to a biopsy for any macroscopic lesion, was performed. The gastrointestinal Symptom Rating Scale for Irritable Bowel Syndrome (GSRS-IBS) and the short Inflammatory Bowel Disease Questionnaire (sIBDQ) were used to assess GI symptoms. Results: 141 patients were included: 121 (86.5%) with CVID, 17 (12.1%) with IgG subclass deficiency, and 2 (1.4%) with X-linked agammaglobulinemia. Of the patients, 72 (51%) complained of GI symptoms. No differences were seen between patients receiving or not IgRT. GI infections were found in 9 patients (6.4%). No significant correlations were found between gut infections and symptoms or leukocyte infiltrates. Colonoscopy alterations were present in 79 patients (56%), and the most common were colon polyps (42%). Microscopical abnormalities were seen in 60 histologic samples (42.5%) and the most frequent was nodular lymphoid hyperplasia (40%). A leukocyte infiltrate was present in 67 samples (47.5%), and the most common was a lymphocyte infiltrate (33%). No correlation was found between GI symptoms and macroscopic alterations, whereas a positive correlation between symptoms and microscopic alterations was detected. Conclusions: GI symptoms and microscopic alterations in colon samples are closely related; hence, it is important to carry out serial colonic biopsies in every CVID patient, even in the absence of macroscopic lesions.

Background: Granulomatous and Lymphocytic Interstitial Lung Diseases (GLILD) is a severe non-infectious complication of Common Variable Immunodeficiency (CVID), often associated with extrapulmonary involvement. Due to a poorly understood pathogenesis, GLILD diagnosis and management criteria still lack consensus. Accordingly, it is a relevant cause of long-term loss of respiratory function and is closely associated with a markedly reduced survival. The aim of this study was to describe clinical, immunological, laboratory and functional features of GLILD, whose combination in a predictive model might allow a timely diagnosis.Methods: In a multicenter retrospective cross-sectional study we enrolled 73 CVID patients with radiologic features of interstitial lung disease (ILD) associated to CVID (CVID-ILD) and 125 CVID patients without ILD (controls). Of the 73 CVID-ILD patients, 47 received a definite GLILD diagnosis while 26 received a clinical-radiologic diagnosis of CVID related ILD defined as uILD.Results: In GLILD group we found a higher prevalence of splenomegaly (84.8 vs. 39.2%), autoimmune cytopenia (59.6 vs. 6.4%) and bronchiectasis (72.3 vs. 28%), and lower IgA and IgG serum levels at CVID diagnosis. GLILD patients presented lower percentage of switched-memory B cells and marginal zone B cells, and a marked increase in the percentage of circulating CD21lo B cells (14.2 vs. 2.9%). GLILD patients also showed lower total lung capacity (TLC 87.5 vs. 5.0%) and gas transfer (DLCO 61.5 vs. 5.0%) percent of predicted. By univariate logistic regression analysis, we found IgG and IgA levels at CVID diagnosis, presence of splenomegaly and autoimmune cytopenia, CD21lo B cells percentage, TLC and DCLO percent of predicted to be associated to GLILD. The joint analysis of four variables (CD21lo B cells percentage, autoimmune cytopenia, splenomegaly and DLCO percent of predicted), together in a multiple logistic regression model, yielded an area under the ROC curve (AUC) of 0.98 (95% CI: 0.95-1.0). The AUC was only slightly modified when pooling together GLILD and uILD patients (0.92, 95% CI: 0.87-0.97).Conclusions: we propose the combination of two clinical parameters (splenomegaly and autoimmune cytopenia), one lung function index (DLCO%) and one immunologic variable (CD21lo%) as a promising tool for early identification of CVID patients with interstitial lung disease, limiting the use of aggressive diagnostic procedures.