Genetic epidemiology of autoinflammatory disease variants in Indian population from 1029 whole genomes

Background Autoinflammatory disorders are the group of inherited inflammatory disorders caused due to the genetic defect in the genes that regulates innate immune systems. These have been clinically characterized based on the duration and occurrence of unprovoked fever, skin rash, and patient’s ancestry. There are several autoinflammatory disorders that are found to be prevalent in a specific population and whose disease genetic epidemiology within the population has been well understood. However, India has a limited number of genetic studies reported for autoinflammatory disorders till date. The whole genome sequencing and analysis of 1029 Indian individuals performed under the IndiGen project persuaded us to perform the genetic epidemiology of the autoinflammatory disorders in India. Results We have systematically annotated the genetic variants of 56 genes implicated in autoinflammatory disorder. These genetic variants were reclassified into five categories (i.e., pathogenic, likely pathogenic, benign, likely benign, and variant of uncertain significance (VUS)) according to the American College of Medical Genetics and Association of Molecular pathology (ACMG-AMP) guidelines. Our analysis revealed 20 pathogenic and likely pathogenic variants with significant differences in the allele frequency compared with the global population. We also found six causal founder variants in the IndiGen dataset belonging to different ancestry. We have performed haplotype prediction analysis for founder mutations haplotype that reveals the admixture of the South Asian population with other populations. The cumulative carrier frequency of the autoinflammatory disorder in India was found to be 3.5% which is much higher than reported. Conclusion With such frequency in the Indian population, there is a great need for awareness among clinicians as well as the general public regarding the autoinflammatory disorder. To the best of our knowledge, this is the first and most comprehensive population scale genetic epidemiological study being reported from India.

TBK1 and TNFRSF13B mutations and an autoinflammatory disease in a child with lethal COVID-19

Among children, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections are typically mild. Here, we describe the case of a 3.5-year-old girl with an unusually severe presentation of coronavirus disease (COVID-19). The child had an autoinflammatory disorder of unknown etiology, which had been treated using prednisolone and methotrexate, and her parents were half cousins of Turkish descent. After 5 days of nonspecific viral infection symptoms, tonic-clonic seizures occurred followed by acute cardiac insufficiency, multi-organ insufficiency, and ultimate death. Trio exome sequencing identified a homozygous splice-variant in the gene TBK1, and a homozygous missense variant in the gene TNFRSF13B. Heterozygous deleterious variants in the TBK1 gene have been associated with severe COVID-19, and the variant in the TNFRSF13B gene has been associated with common variable immunodeficiency (CVID). We suggest that the identified variants, the autoinflammatory disorder and its treatment, or a combination of these factors probably predisposed to lethal COVID-19 in the present case.

Chemerin as a Diagnostic Marker for Fmf in Egyptian Patients

Familial Mediterranean fever (FMF) is the most common autoinflammatory disorder characterized by chronic subclinical inflammation. The aim of the work is to access if chemerin can be used as a diagnostic index in FMF patients. Methods: A total of 66 FMF patients and 60 controls matching age and sex were enrolled in the study. Serum chemerin, lipid profile and vitamin D were determined by ELISA assay. Results: Chemerin level which suggested chronic inflammation was significantly elevated as compared to the controls. The FMF patients had highly significant levels of total cholesterol, total triglycerides and LDL, while the HDL significantly inversely correlated in the FMF patients compared to controls. Moreover, the vitamin D level was significantly lower in FMF patients. Conclusion: chemerin that acts as a pro-inflammatory adipokine, could be used as a biomarker reflecting the chronic pro-inflammatory status in the FMF patients. Vitamin D supplementation is recommended in the FMF patients.

Novel Adenosine Deaminase 2 (ADA2) Mutations Associated With Hematological Manifestations

Recent progress in laboratory techniques, particularly, identification of novel disease-causing genes, has led to the detection of different gene mutations that might be implicated in the pathogenesis of different hematological disorders like pure red cell aplasia (PRCA) and neutropenia. An autoinflammatory disorder known as deficiency of adenosine deaminase 2 (DADA2) has been recently noticed to present with variable hematologic abnormalities. We report 2 patients who presented with hematologic abnormalities in which 2 ADA2 gene mutations were detected. The first case is a 5-year-old girl who presented with severe PRCA and autoimmune hemolytic anemia without any other manifestation of DADA2 that resulted from a novel CECR1 c.714_738dup, p. (Ala247Glnfs*16) homozygous variant. The second case is a 10-year-old boy, known to have Hodgkin lymphoma and was under follow-up for 6 years; he presented with persistent neutropenia and was discovered to be homozygous for ADA2 c.1447_1451del, p. (Ser483Profs*5). In conclusion, we report two different novels ADA2 variants in two children; the first presented with PRCA and the second presented with persistent neutropenia. This report aims to raise the concerns regarding the use of genetic testing in different hematologic diseases with indefinite etiology, as it will lead to the best therapeutic strategies without the need for unnecessary interventions.

Efficacy of interleukin-1 blockade in Schnitzler’s syndrome without detectable monoclonal gammopathy: a case-based review

Schnitzler’s syndrome (SchS) is a rare autoinflammatory disorder characterized by urticarial rash and monoclonal gammopathy which is currently regarded as IL-1 mediated disease. We present the case of a 21-year-old woman presenting with urticarial rash, arthralgias, and elevated inflammatory markers. She has been suffering these symptoms for 2 years and was treated with antihistamines, omalizumab, steroids, and non-steroidal anti-inflammatory drugs (NSAIDs) without success. After an extensive diagnostic workout, we suspected SchS even without monoclonal gammopathy, and started Anakinra 100 mg daily with a dramatic response and achieving complete remission after 48 h of the beginning of the treatment, so we decided to confirm SchS diagnosis. We performed a search of the literature and found seven more cases of patients diagnosed with SchS without monoclonal gammopathy at the presentation. Five were treated with IL-1 blocking therapies and all achieved remission. We, therefore, prompt the possible role of IL-1 blockade therapy remission as support in diagnosing SchS without monoclonal gammopathy.

Novel variants of MEFV and NOD2 genes in familial hidradenitis suppurativa: A case report

We report a two-generation Canadian family of Armenian ancestry with hidradenitis suppurativa where novel mutations in MEVF and NOD2 genes were identified. The father and both children shared a mild-to-moderate hidradenitis suppurativa phenotype together with the features of follicular occlusion (e.g. acne and scalp folliculitis). Based on our findings and previous literature, we recommend considering genetic testing with a periodic fever/autoinflammatory disorder panel in patients with a strong family history of hidradenitis suppurativa and lack of common triggers such as smoking and being overweight.

A Diagnosis of Adult-Onset Still’s Disease after Multiple Urgent Care Visits

A 34-year-old man with recent treatment and resolution of community-acquired pneumonia presents to the emergency department with protracted fever, rash, and sore throat. Sustained fever and greater than two-fold increase in leukocytosis despite appropriate antibiotic therapy prompted hospital admission for infectious disease and rheumatologic evaluations which ultimately revealed adult-onset Still’s disease, a rare autoinflammatory disorder with potentially life-threatening complications.

9. Successful use of IL-6 pathway blockade to treat autoinflammation occurring in the context of a novel TNFRS1A gene mutation

Introduction Autoinflammatory fever syndromes are rare and present significant diagnostic and treatment challenges. We present a case which illustrates some key concepts regarding the diagnosis and treatment of a patient with an autoinflammatory disorder, and also touches on the management of active autoinflammation in pregnancy. Case description A 29-year-old woman with a recently identified autoinflammatory disorder was referred to the local rheumatology service in September 2018. She reported having been symptomatic of fever, rashes and arthralgia since the age of 10, and TNF receptor 1 associated periodic syndrome (TRAPS) was suspected on the basis of an N71 deletion on axon 2 of the TNFRS1A gene when tested by a national reference centre 9 months previously. At the time of presentation she was 25 weeks into her sixth pregnancy, the first with a new partner. She reported significant pregnancy morbidity having given birth to a daughter with multiple congenital abnormalities who unfortunately died two days after birth. She suffered 4 subsequent miscarriages at 5-7 weeks gestation with the same partner and underwent extensive genetic testing. At her initial review in the obstetric clinic, she was already receiving low-molecular-weight heparin with aspirin. Colchicine 1 mg tds, did not confer significant symptomatic benefit. One month later, with careful counselling about pregnancy exposure to this biological treatment, IL-1 receptor antagonist (anakinra) therapy was instituted but discontinued after three weeks for generalised rash, as well as lack of efficacy manifesting in raised inflammatory markers. Infection was excluded during a subsequent hospital admission, and prednisolone treatment resulted in significant improvement in clinical course and acute phase response. The patient gave birth to a healthy infant at 37 weeks’ gestation. In the postpartum period, a recurrence of symptoms was observed. IL-6 receptor antagonist (tocilizumab) treatment was commenced at 12 weeks postpartum but discontinued owing to reports of sore throat, cough, headache and fever on the day of the injection. The patient had also discontinued prednisolone on the day of the injection and tocilizumab was rechallenged with good symptomatic response, normalisation of inflammatory markers, and successful reduction in prednisolone dose. Discussion This case highlights some interesting points with relation to the treatment of autoinflammatory disorders refractory to IL-1 pathway blockade, and also, of the management of flares of autoinflammation during pregnancy. Firstly, this lady failed to respond to IL-1 receptor antagonist anakinra which has been associated with efficacy in several reports for individuals with TRAPS, and has supplanted TNF blockade with agents such as etanercept for this condition. Only a handful of case reports describe successful IL-6 inhibitor administration for this condition, and this merits further study. This patient’s flare of autoinflammation was treated in the post-partum period, but the demographic characteristics of the autoinflammatory diseases are such that people of child-bearing age may be required to receive treatment in order to prevent pregnancy morbidity as a result of uncontrolled inflammation. IL-6 blockade has not to date been associated with adverse pregnancy outcomes, although this data requires extension and validation. 2 cases of renal agenesis have been reported in children born to mothers with anakinra, but the very small numbers of exposed parents warrants further examination of this observation and the careful study of ongoing pharmacovigilance data to explore this observation. Secondly, success with IL-6 inhibition has been reported in a series of patients with familial Mediterranean fever, the most common autoinflammatory disorder, but this treatment does not feature in the most recent European guidelines for this condition. IL-6 inhibition is well-established in the treatment of adult-onset Still’s disease (AoSD) however, and this lady’s presentation shares important features with that condition. The existence of TNF-receptor 1 mutations has been reported in patients with AoSD, and it may be that this patient’s presentation is more akin to adult-onset Still’s disease and that her TNF receptor mutation is an incidental finding. Key learning points This report adds to the handful cases in which IL-6 blockade has been used successfully to treat the autoinflammatory manifestations of suspected TNF receptor 1 associated periodic syndrome (TRAPS) after the failure of IL-1 receptor blockade with anakinra. Careful history and examination are required to differentiate between potentially overlapping symptoms of drug reaction, autoinflammation, and infection in patients with systemic autoinflammatory disorders (SAIDs). Once a history consistent with autoinflammatory flare was established, cautiously rechallenging with an IL-6 pathway inhibitor ensured this effective treatment was not discounted due to concerns over a drug reaction. With a degree of commonality between the more common conditions in the SAID family, a detailed examination of the clinical phenotype is essential to the interpretation of genetic tests used for the diagnosis of TRAPS and related disorders. Uncontrolled inflammatory disease is associated with pregnancy morbidity and very limited information is available about the short and long-term safety of treatments for autoinflammatory diseases in general. Current guidelines do not recommend the use of IL-6 inhibitor therapy in pregnancy. Conflict of interest The authors declare no conflicts of interest.