Editorial: Case reports in autoimmune and autoinflammatory disorders, volume II

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Autoimmune and autoinflammatory disorders remain among the most diagnostically and therapeutically challenging conditions in clinical medicine. They cross every organ boundary, present with high levels of both immunological and phenotypic heterogeneity, and are increasingly present against a background of potent immunomodulatory therapy that can itself provoke, unmask, or reshape immune-mediated disease. It is on this background that the atypical case is very often where the field's assumptions are tested first. It is in the single, carefully documented patient that a novel autoantibody is first tied to a syndrome, that an off-label therapy is first seen to work or to fail, and that an unfamiliar toxicity of an established drug is first flagged (often years before any of these observations accumulate into the numbers required for systematic study).Volume I of this Research Topic set out to demonstrate the value of the well-constructed case report in supplementing the wider literature, and the appetite for that format has, if anything, grown. Volume II comprises fifty-two contributions, drawn from centers across Europe, Asia, North America and the Caribbean, spanning neurology, nephrology, rheumatology, endocrinology, dermatology and haematooncology. The breadth of what has been submitted is a fair reflection of how porous the borders of this discipline have become, and of how much of its most clinically useful knowledge still enters the literature one patient at a time. Case reports carry well-recognized limitations, noting that they cannot establish causation, they are vulnerable to publication and reporting bias, and a single striking observation may not generalize. However, their value lies precisely in signaling early, and each of the reports that follows should be read in that spirit.Early findings from case reports have arguably become more, not less, important in the biologic era. As the therapeutic armamentarium has shifted from broad immunosuppression toward agents defined by a single molecular target or cell population, the number of possible drug-disease pairings has expanded far faster than the capacity of randomized trials to test them, and much of the earliest evidence for using a targeted agent outside its licensed indication necessarily takes the form of the individual report. The same era has produced entirely new disease entities, including the immunerelated adverse events of checkpoint inhibition and the secondary autoimmunity of lymphocytedepleting therapy, which were first described one patient at a time. A well-documented case is therefore not merely a supplement to trial evidence but, for a substantial part of this field, the format in which new knowledge first becomes available at all. Rather than catalogue these reports by organ alone, we have organized this Editorial around a structure that follows both where disease presents and how the field is moving. Two clusters are grounded in clinical territory (autoimmune neurology and systemic / organ-specific autoimmunity). Three further clusters cut across organ boundaries and capture the mechanistic and practical themes that recur throughout the collection, including the rapid expansion of the targeted-therapy toolkit, the growing problem of iatrogenic and checkpoint-inhibitor-associated autoimmunity, and the perennial challenge of diagnostic complexity, overlap and mimicry. Many reports could sit comfortably in more than one grouping, which is itself the point.The single largest body of work in this volume concerns the nervous system, and it captures both the diagnostic precision that antibody-defined syndromes now permit and the therapeutic modulation they invite. Several reports address the antibody-negative or treatment-refractory patient in whom conventional treatment algorithms are insufficient to bring about control of symptoms. Zheng et al. describe rituximab in antibody-negative combined central and peripheral demyelination presenting with acute respiratory failure, a presentation that sits between recognized categories and forces a pragmatic therapeutic decision 1 . Cao et al. report a COVID-19-associated, delayed-onset, MuSKpositive myasthenia gravis whose sole manifestation was respiratory failure, a reminder that neuromuscular autoimmunity can present without the classical fatigable weakness that usually prompts the diagnosis 2 . Pan et al. add a focused account of unilateral ophthalmoplegia as the presenting feature of anti-GQ1b antibody syndrome, extending the recognized phenotypic range of that entity 3 .A recurring strength of the neurological submissions is the willingness to reach for newer biologic agents when established immunosuppression fails. Tan et al. contribute the only case series in the collection, describing sequential neonatal Fc receptor (FcRn) blockade followed by B cell depletion in three patients with treatment-refractory relapsing autoimmune encephalitis 4 . This acts as an explicit attempt to combine antibody clearance with a durable reduction in antibody production. Deng et al. and Watanabe et al. both explore FcRn antagonism with efgartigimod, the former in Guillain-Barré syndrome and the latter in refractory anti-GQ1b antibody syndrome coexisting with myasthenia gravis, together illustrating how a mechanism developed for one antibody-mediated disease is being tested rapidly across the antibody-mediated neurological spectrum 5,6 . Lin et al. report telitacicept, a dual BAFF/APRIL inhibitor, in glial fibrillary acidic protein (GFAP) autoimmune astrocytopathy 7 , and Chen et al. describe satralizumab in the rare co-occurrence of neuromyelitis optica spectrum disorder (NMOSD) with capillary leak syndrome 8 . Beyond the antibody-defined syndromes, von Zedtwitz et al. examine acute polymorphic psychosis in the presence of serum NMDA-receptor IgG antibodies, a report that engages carefully with the difficult question of when a serum antibody is pathogenically relevant to a psychiatric presentation 9 , and Bayraktar Eltutan et al. describe pediatric CNTN1 antibodyassociated neuropathy with concurrent nephropathy, a nodo-paranodal syndrome whose renal involvement underscores that these antigens are not confined to the nervous system 10 . What unites these otherwise disparate reports is a common clinical logic highlighting that as the target antigen is defined with ever greater precision, the phenotype attached to it widens rather than narrows, and treatment is increasingly chosen to match the presumed effector mechanism. The nervous system, where the antigens are best characterized, is where this logic is currently most visible, but it is not confined there.The second major cluster gathers reports across the systemic autoimmune disease, the vasculitides, and organ-specific autoimmunity of the kidney, endocrine system and skin, where the recurring lesson is the unexpected site or severity of involvement. Systemic lupus erythematosus is well represented and, characteristically, rarely behaves conventionally. Huang et al. describe lupus mesenteric vasculitis masquerading as urticaria with abdominal pain, followed over ten months 11 . Wang et al. report bilateral adrenal hemorrhage in a patient with lupus and antiphospholipid syndrome 12 . Zhang et al. present neuropsychiatric lupus complicated by primary central nervous system diffuse large B cell lymphoma, a juxtaposition that raises difficult questions about the interplay of chronic immune activation and lymphomagenesis 13 . Liu et al. add a pediatric account of Fabry disease overlapping with lupus, a metabolic-autoimmune overlap that is easily missed 14 . Primary Sjögren's disease likewise appears in unexpected guises with Tang et al. reporting simultaneous cerebral and coronary arterial involvement as the initial presentation 15 , while Duan et al. describe membranoproliferative glomerulonephritis-like lesions within cryoglobulinemic glomerulonephritis 16 .The vasculitides and their mimics recur

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