Editorial: Case Reports in Autoimmune and Autoinflammatory Disorders. Volume I

gian marco ghiggeri^1*Chris Wincup²Augusto Vaglio³Stefano Volpi⁴

• ¹Giannina Gaslini Institute (IRCCS), Genoa, Italy
• ²King's College London, London, United Kingdom
• ³Azienda Ospedaliero Universitaria Meyer, Florence, Italy
• ⁴Istituto Giannina Gaslini Clinica Pediatrica e Reumatologia, Genoa, Italy

Autoimmune and autoinflammatory disorders include a vast area of multi-system clinical conditions, which have either autoimmunity or an exaggerate and persisting inflammatory responses as a basic mechanism. In recent years, research investigating the basic science, immunology and translational medicine has played a crucial role in increasing our knowledge of mechanisms involved in the pathogenesis of autoimmune diseases. Technology for detecting proteins and small molecules, and the development of system analysis of large amounts of data (refined with advances in machine learning and artificial intelligence) have played a central role in identifying new auto-antibodies and mediators of inflammation, whilst further still contributing to defining the new borders of this evolving area. The availability of new drugs, particularly targeted monoclonal antibodies, immune-therapies and cell-based therapies, have also transformed the management of patients who for decades have experiences the effects of less targeted therapies, such as long-term steroids, and anti-inflammatory agents. Given that many of these conditions are both rare and heterogeneous in terms of clinical manifestations and immunological drivers, many large clinical trials have sadly failed to achieve primary endpoint. However, data from case reports, cases series and open label studies have seen many of these agents adopted for use in clinical practice, particularly in severe, refractory or atypical cases.Single case reports contain many elements that may help clinicians to resolve medical conditions in the setting of either challenging or difficult solutions, and represent a reasonable approach that may impact research through the generation of new data that may prompt further future investigation. Publishing case reports also involves an editorial effort associated with the risk that a new finding would not be directly linked to the pathogenesis of a disease but represent an epiphenomenon useless to be reported. However, the simple observation of well reported cases may provide a solid basis for future discoveries and stimulate further discussion in the field (particularly in rare or atypical cases).The Special Issue was not dedicated to simple descriptions of single cases, but was also open to either systematic reviews of the literature and original researches describing proteomics laboratory platforms focusing on exceptional, severe or rare conditions. This first volume of the special issue of Frontiers of Immunology was characterized by a high amplitude and variability of topics treated, the strong laboratory basis of single reports, and, in those cases describing new therapeutic approaches, the possibility that they may significantly impact clinical medicine.We commend the reviewers for their efforts when evaluating the quality and interest of the submitted manuscripts to this special edition. The interest in this area was high with 150 submission in total with nearly half being accepted for publication in this issue, which is in line with the general acceptance of the journal and highlights the high degree of rigor with which the reviewers evaluated all submissions.It is of interest three areas of medicine (Neurology, Dermatology and Rheumatology) accounted for 85% of papers published, which is in line with the growing innovation that these areas are witnessing. Neurology was the major topic (39% of papers accepted), followed respectively by Dermatology (24%) and Rheumatology (22%). Other important areas, such as Hemato-Oncology, Nephrology, Gastroenterology, and Ocular diseases, accounted for a total of 15% of cases published.When considering specific disorders, encephalitis was the main neurological topic of the Special Issue and included anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis presenting with atypical features (psychosis, cerebellar symptoms) and its treatments (chimeric anti-CD20 monoclonal antibody-Rituximab)(1-4), anti-Purkinje antibodies in PCA2 encephalitis (5), and one case of seronegative limbic encephalitis (6). Treatment of myasthenia gravis with Telitacicept (2) and of autoimmune necrotizing myopathy with the humanized anti-CD20 monoclonal antibody Ofatumumab (7) highlighted the role of targeting B cells in these diseases and may indicated this as an interesting area for new therapies. Furthermore, the role of TNFα inhibitors (TNF-αi) in neurological disorders was also discussed in one paper in this issue (8).Several neurological cases with clinical atypical presentation that required novel laboratory approaches to reach a correct diagnosis were also submitted. Of note, one case reported a patient with Guillain-Barrè syndrome presenting with paralytic ileus. The diagnosis of Guillen-Barrè was reached based on autoimmune tests for anti-sulfatide antibodies, anti-GD1a antibodies, and anti-GT1a antibodies. On this basis, the patient was treated and rapidly improved after plasma exchange and intravenous immunoglobulin treatment, thus avoiding significant bowel surgery (9).Neuropathic pain as the unique sign of nerve hyperexcitability occuring in the context of in autoimmune targeting of the potassium channel complex was described in a young female presenting high serum levels of anti-contactin-associated protein-like 2 (10). This case highlighted in the setting of this specific type of neuropathic pain, complete resolution can be brought about through the use of corticosteroids and immunoglobulin. It also highlights how pain may be the first clinical signal of a severe pathology, which is difficult to be treated in advanced stages.The major focus of the Dermatology collection of articles was the use of innovative immunotherapies in cutaneous disease. This included Spesolimab and Secukinumab for psoriasis and Hallopeau acrodermatitis (11), the use of Baricitinib with Dupilumab for severe alopecia associated with atopic dermatitis (12), the role of Etanercept in necrotic-epidermolysis (13), and the first case of perforating collagenosis treated with Baricitinib (14). Adverse events were also reported in a case of dermatomyositis induced by Imatinib (15) an antineoplastic drug tyrosine kinase inhibitor utilized, principally, in leukemia and in stromal gastrointestinal cancer.Rheumatologically focused case reports were predominantly descriptive of rare associations such as in the case of VEXAS (Vacuoles, enzyme E1, X-linked, autoinflammatory, somatic) (16,17), antiphospholipid syndrome (18), and a case of lethal IL-1 deficiency supported by IL1-rec mutations (19). VEXAS syndrome is an acquired autoinflammatory disease characterized in most cases by myelodisplasic disorders with cytopenias and macrocytic anemia, fever, skin vasculitis, pleuropulmonary disorders. It is believed to be caused by somatic mutations in the UBA1 gene that leads to aberrant activation of the innate immune system and production of proinflammatory cytokines. Despite its rarity, this Special Issued included the description of seven cases of VEXAS classified according the WHO 2022 suggestions based on morphological, cytogenetic and molecular characteristics that might help proper treatments (16). Another VEXAS case reported was a patient presenting atypically with sacroiliitis as indolent symptom responsive to azacitidine (17).Antiphospholipid syndrome was the topic in which several reports were submitted, including in association with COVID 19 infection (20). A case of complex tachycardia with atrio-ventricular block plus Wolf Parkinson White syndrome (WPW) transmitted to the fetus by a mother positive for anti-SSA antibodies supports the importance of a clear medical characterization prior pregnancy in patients with a potential autoimmune conditions (18). Further, a case of rheumatoid arthritis treated with Etanercept who developed aseptic meningitis was reported indicating that this drug may cross the blood-brain barrier and exert toxicity. This highlights the challenges faced clinically with infections that are a well-known risk also with immunosuppressive therapy (13).Additional cases included in Volume I were the first described a case of DRESS syndrome following sulfasalazine taken for COVID (21), and the successful treatment Evans syndrome (hemolytic anemia with thrombocytopenia) with JAK inhibition (22). The potential occurrence of renal complication following immunotherapy with humanized monoclonal antibody against the programmed death cell protein (anti-PD1), which are now more frequently being used in the treatment of malignancy, was discussed in a paper reporting a case of IgA glomerulonephritis following pembrolizumab in a patient with non-small cell lung carcinoma (23). Recognition of adverse effects of anti-PD1 therapy is very important in view of the rapid increase in use of these checkpoint inhibitors (24) for different cancer types in which these antibodies are utilized (including melanoma, cancer of major organs such as liver and lungs, colon and others).Autoimmune gastritis is a form of atrophic gastritis that may evolve to gastric neuroendocrine cancer and should be recognized and treated at early stages. Diffuse homogeneous atrophy of the gastric body is a major endoscopic characteristic of advanced cases, but is not always present at the onset of the disease. The endoscopic characteristics of two cases of early autoimmune gastritis were described and discussed in Volume I of this Special Issue. The presence of anti-parietal cell antibodies confirmed in both cases the diagnosis, allowing a direct therapy for the autoimmune condition (25).The Special Issue also contained two papers that can be considered atypical for a 'Case report collection'. One of the two atypical papers was a systematic review of the literature reporting fiftythree cases of pemphigus associated with end stage renal failure and also included eight relevant studies on the topic (24). The efficacy of major therapies based on immunosuppression was widely discussed. The second was an original research describing a proteomic laboratory platform focusing on exceptionally severe patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CF) and hypermobility spectrum disorders (26). The correct diagnosis of ME/CF was reached by profiling the Th2 cytokine levels that highlighted synergism between mast cells and eosinophils, which is of interest for potential future biomarker investigation.Following the success of Volume I, Volume II proposes to expand on the same topics and represents a continuation of Volume I. Description of single cases including those in the setting of an accompanying review of the literature continue to be encouraged for submission, in addition to welcoming systematic reviews of the literature in rare conditions. Original research will be considered if reporting and validating new laboratory assays for identifying biomarkers, such as auto-antibodies and cytokines that either facilitate the diagnosis or potentially anticipate the clinical outcome of autoimmune or auto-inflammatory conditions.We welcome manuscripts focusing on, but not limited to, the following areas: Description of new links between autoimmunity and diseases of any kind  Identification of new autoantibodies  Identification of immune mechanisms involved in inflammation. Factors predicting relapses and non-response to therapies  New therapeutic targets and description of 'side effects' with emphasis to immunotherapies Therapies will have a special space in Volume II and, in consideration of the incredible evolution that we are witnessing in the area of 'immunotherapies', we hope that Volume II could attract the interest of clinicians involved in testing new human monoclonal antibodies targeting specific immune cells (anti-CD20, anti-CD38 and others) / cytokines, JAK inhibitors and anti-PD1/PD-1L in cancer. There is a vast area of autoimmune conditions potentially responsive to newer monoclonal antibodies that is still to be investigated and now represents the new frontier.Case-control studies of small/medium size also represent an important area contrasting to single case and we appreciate studies that present the positive effects of new treatments that could form the basis for important trials in the future. The description of adverse effects of new therapies are also welcomed if they indicate a direct relationship, that is rapid onset after the start of a therapy and also the stop of symptoms after the withdraw.