Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disorder influenced by genetic and environmental factors. Vitamin D deficiency and vitamin D receptor (VDR) gene polymorphisms are suggested to modulate immune dysregulation in SLE. This study aimed to investigate the association of VDR polymorphisms (BsmI, ApaI, TaqI and FokI), serum 25-hydroxyvitamin D [25-OH vitamin D] levels and clinical phenotypes in Indian SLE patients. A hospital-based case-control study was conducted on clinically diagnosed SLE patients (n = 297) fulfilling American College of Rheumatology (ACR) criteria and healthy controls (n = 100). Serum 25-OH vitamin D levels, autoantibody profile and complement components were evaluated by immunofluorescence, enzyme-linked immunosorbent assay (ELISA) and nephelometry. Genotyping for VDR polymorphisms BsmI (rs1544410) B/b, ApaI (rs7975232) A/a, TaqI (rs731236) T/t and FokI (rs2228570) F/f was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Data were statistically analysed using chi-square tests, logistic regression and correlation analysis. The median age at evaluation in SLE patients was 29 years, with a female predominance (91.9%). Median serum 25-OH vitamin D levels were 30.4 ng/mL, with lower levels observed in patients with arthritis (p = 0.012), neurological involvement (p = 0.015) and active disease (p = 0.025). Serum 25-OH vitamin D inversely correlated with disease activity (r = -0.127, p = 0.032), anti-cardiolipin antibody (ACLA) immunoglobulin G (IgG) (p < 0.001) and anti-phospholipid antibody (APLA) IgG (p = 0.030). Among VDR polymorphisms, BsmI b allele conferred reduced disease risk (odds ratio [OR] = 1.85, p < 0.001). TaqI genotypes (Tt: OR = 2.29 and tt: OR = 6.48, p < 0.05) and t allele (OR = 2.15, p < 0.001) and FokI genotypes (Ff: OR = 4.13 and ff: OR = 3.14, p <0.05) were strongly associated with increased susceptibility to SLE. ApaI variants were significantly associated with alopecia, haematological manifestations, disease activity and low complement component 3 (C3) levels, whereas BsmI and FokI polymorphisms were associated with neurological manifestations (p < 0.05). Vitamin D receptor gene (VDR gene) polymorphisms may contribute to phenotypic variability and immune dysregulation in Indian SLE patients, suggesting that gene-environment interactions between vitamin D status and VDR variants may influence SLE susceptibility and clinical heterogeneity.

Autoimmune polyglandular syndrome type 2 (APS2) is characterized by the coexistence of primary adrenal insufficiency with autoimmune thyroid disease and/or type 1 diabetes. APS2 frequently includes conditions affecting non-endocrine organs, such as alopecia, vitiligo, celiac disease, and autoimmune gastritis associated with vitamin B12 deficiency. We report the case of a 30-year-old male with a history of Hashimoto's disease and alopecia universalis, who presented with diarrhea, anorexia, hypoglycemia, and abdominal pain. Physical examination revealed orthostatic hypotension, a non-tender abdomen, and generalized hair loss. Initial laboratory workup showed hyponatremia and hyperkalemia. Further testing, including serum cortisol, ACTH, aldosterone, and 21-hydroxylase antibodies, confirmed the diagnosis of Addison's disease. The patient was treated with prednisone and fludrocortisone. Only two previous cases of APS2 associated with alopecia universalis have been reported: one with concurrent Crohn's disease and another with hypoparathyroidism. This case highlights the importance of recognizing non-endocrine manifestations in patients with autoimmune endocrinopathies to facilitate earlier diagnosis and management.

Biotinidase deficiency (BTD) is a treatable, inherited metabolic disorder commonly characterised by alopecia, dermatitis, seizures and developmental delay. It can also manifest as optic neuritis and myelitis; however, these are infrequently described in the literature. We report three cases who presented with quadriplegia and vision loss, initially managed as neuromyelitis optica spectrum disorder (NMOSD), based on neuroimaging findings. Two of them initially responded to immune therapy but relapsed after a few months, while one case showed no clinical improvement with immune therapy. The clinical presentation and neuroimaging findings in all three cases were consistent with NMOSD, leading to a delayed diagnosis of BTD. Antiaquaporin4 and antimyelin oligodendrocyte glycoprotein antibodies were negative in all patients. Urine organic acids reported raised markers of biotinidase or holocarboxylase synthase deficiency. Two of them had a dramatic response to biotin supplementation, showing significant improvement in motor function and vision.

Autoimmune polyendocrine syndrome type 1 (APS-1) is a life-threatening, autosomal recessive syndrome caused by autoimmune regulator (AIRE) deficiency. In APS-1, self-reactive T cells escape thymic negative selection, infiltrate organs, and drive autoimmune injury. The effector mechanisms governing T-cell-mediated damage in APS-1 remain poorly understood. We examined whether APS-1 could be classified as a disease mediated by interferon-γ. We first assessed patients with APS-1 who were participating in a prospective natural history study and evaluated mRNA and protein expression in blood and tissues. We then examined the pathogenic role of interferon-γ using Aire-/-Ifng-/- mice and Aire-/- mice treated with the Janus kinase (JAK) inhibitor ruxolitinib. On the basis of our findings, we used ruxolitinib to treat five patients with APS-1 and assessed clinical, immunologic, histologic, transcriptional, and autoantibody responses. Patients with APS-1 had enhanced interferon-γ responses in blood and in all examined autoimmunity-affected tissues. Aire-/- mice had selectively increased interferon-γ production by T cells and enhanced interferon-γ, phosphorylated signal transducer and activator of transcription 1 (pSTAT1), and CXCL9 signals in multiple organs. Ifng ablation or ruxolitinib-induced JAK-STAT blockade in Aire-/- mice normalized interferon-γ responses and averted T-cell infiltration and damage in organs. Ruxolitinib treatment of five patients with APS-1 led to decreased levels of T-cell-derived interferon-γ, normalized interferon-γ and CXCL9 levels, and remission of alopecia, oral candidiasis, nail dystrophy, gastritis, enteritis, arthritis, Sjögren's-like syndrome, urticaria, and thyroiditis. No serious adverse effects from ruxolitinib were identified in these patients. Our findings indicate that APS-1, which is caused by AIRE deficiency, is characterized by excessive, multiorgan interferon-γ-mediated responses. JAK inhibition with ruxolitinib in five patients showed promising results. (Funded by the National Institute of Allergy and Infectious Diseases and others.).

Primary atopic disorders (PAD) are monogenic disorders caused by pathogenic gene variants encoding proteins that are key for the maintenance of a healthy skin barrier and a well-functioning immune system. Physicians face the challenge to find single, extremely rare PAD patients/families among the millions of individuals with common allergic diseases. We describe case scenarios with signature PAD. We review the literature and deduct specific clinical red flags for PAD detection. They include a positive family history and/or signs of pathological susceptibility to infections, immunodysregulation, or syndromic disease. Results of conventional laboratory and most immunological lab studies are not sufficient to make a definitive diagnosis of PAD. In the past, multistep narrowing of differential diagnoses by various immunological and other laboratory tests led to testing of single genes or gene panel analyses, which was a time-consuming and often unsuccessful approach. The implementation of whole-genomic analyses in the routine diagnostics has led to a paradigm shift. Upfront genome-wide analysis by whole genome sequencing (WGS) will shorten the time to diagnosis, save patients from unnecessary investigations, and reduce morbidity and mortality. We propose a rational, clinical landmark-based approach for deciding which cases pass the filter for carrying out early WGS. WGS result interpretation requires a great deal of caution regarding the causal relationship of variants in PAD phenotypes and absence of proof by adequate functional tests. In case of negative WGS results, a re-iteration attitude with re-analyses of the data (using the latest data base annotation)) may eventually lead to PAD diagnosis. PAD, like many other rare genetic diseases, will only be successfully managed, if physicians from different clinical specialties and geneticists interact regularly in multidisciplinary conferences.