Unexpected non-steroidal anti-inflammatory drugs-induced systemic hypersensitivity reaction in a pediatric patient unveiling Systemic Lupus ErythematosusKeywords : pediatric systemic lupus erythematosus (SLE); systemic autoimmune diseases; adverse drug reactions (ADR); non-steroidal anti-inflammatory drugs (NSAID); systemic NSAID hypersensitivity reactions.Word count: 1183Number of figures: 1To the Editor,Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder characterized by a broad spectrum of clinical manifestations affecting multiple organ systems. While the etiology of SLE remains elusive, it is widely acknowledged that both genetic predisposition and environmental factors play pivotal roles in its pathogenesis1. SLE diagnosis is often challenging due to the vast heterogeneity of clinical manifestations, and it is often called ”the great imitator”2.We present a case of severe non-steroidal anti-inflammatory drugs (NSAID)-induced systemic hypersensitivity in a female Chinese adolescent patient, otherwise healthy except for autoimmune thyroiditis on replacement therapy, who developed clinical and serological features consistent with SLE. A 15-year-old female adolescent presented to our pediatric emergency room (ER) due to urticarial rash and facial edema (Figure 1A ), low-grade fever, dyspnea, abdominal pain, and nausea two hours after taking ketoprofen (40 mg) for migraine. The girl has previously taken ibuprofen (400 mg twice daily) for 11 days, then acetaminophen 1000 mg for two days, associated with 80 mg ketoprofen, and finally, on the same day of admission to the ER, ibuprofen 400 mg together with 40 mg ketoprofen due to diffuse arthralgia and migraine. Anaphylaxis was suspected in the ER, and intramuscular epinephrine, intravenous corticosteroid therapy, and intravenous antihistamines were administered. During observation, for persistent hypotension not responsive to epinephrine, fluid resuscitation with saline was initiated. Empirical broad-spectrum antibiotic therapy was initiated due to suspected sepsis, although subsequent blood cultures were negative. Considering the poor clinical response, the patient was transferred to the intensive care unit. During hospitalization, serum inflammatory markers [C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), procalcitonin, and ferritin] increased. The urticarial rash on the face evolved into a malar rash with vesiculo-bullous lesions, and oral aphthae were observed (Figure 1 B-C ). Instrumental exams revealed pleural, pericardial, and peritoneal effusions. The increased inflammatory markers, the hematologic profile observed since admission (leukopenia, anemia, and thrombocytopenia), and the characteristic clinical manifestations raised suspicion of a possible connective tissue disease (CTD).Further hematological investigations revealed antinuclear antibodies (ANA) titer of 1:320 with a speckled pattern of large granules, positive anti-dsDNA antibodies (enzyme immunoassay: 116 IU/ml, normal values < 10 IU/ml; immunofluorescence: 1:160, normal values < 1:10), and complement fraction (C3, C4) consumption. Based on the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) 2019 criteria3, a diagnosis of SLE was made. High-dose intravenous steroid therapy (steroid pulses 1 g for three consecutive days, followed by gradual tapering) and oral hydroxychloroquine (200 mg daily) were initiated, with clinical improvement (Figure 1D ).Among the above-mentioned environmental factors involved in SLE pathogenesis, drug-induced lupus erythematosus (DILE) represents a distinct subset of SLE triggered by certain medications. DILE typically shares clinical and serological features with idiopathic SLE but is often reversible upon discontinuing the offending agent. Several medications can produce positive results on an ANA test with or without evidence of clinical lupus4.Nonetheless, DILE is not the only drug-related manifestation of SLE. In particular, NSAIDs are associated with a wide spectrum of manifestations in SLE patients. To date, only a few cases of systemic hypersensitivity reaction to ibuprofen have been described in SLE patients. Finch et al. in 1979 first described a NSAID-induced systemic hypersensitivity acute reaction in three young adult women with SLE presenting with profound hypotension, fever, and headaches developed within hours of reinstitution of therapy after voluntarily discontinuation of long-term treatment for arthritis5. Agus et al. identified among 33 patients with ibuprofen hypersensitivity several patients with rheumatological disorders (52% SLE, 12% mixed CTD, 6% undifferentiated CTD, 3% Juvenile Idiopathic Arthritis)6. Ibuprofen is also known to be the causative agent of aseptic meningitis in patients with SLE. Lortholary et al. reported a case of aseptic meningoencephalitis induced by ibuprofen in a 24-year-old woman, revealing unrecognised underlying SLE7. However, limited evidence is available regarding NSAID-induced systemic hypersensitivity acute reaction in the pediatric population. In 2005, Mou et al. described the only pediatric case reported to date of an 11-year-old Thai male who presented with fever, rash, altered mental status, and hypotension after oral administration of ibuprofen, leading to the diagnosis of SLE 8.ADR are heterogeneous and multifactorial diseases due to an exaggerated immune-mediated reaction, not fully described by models of immunologic mechanisms (mainly based on Gell and Coombs classification), which is why several classifications including pseudoallergic reactions and drug hypersensitivity reaction endotypes have been advanced in recent years. In addition, various cofactors such as viral infections, HLA haplotypes, and altered drug metabolism must be considered9. Systemic hypersensitivity reaction to ibuprofen syndrome in patients with known CTD generally consists of fever, gastrointestinal symptoms, myalgia, aseptic meningitis, and, in some, profound hypotension. The mechanism has yet to be discovered. Many of the described symptoms can be explained by a histamine-mediated anaphylactoid reaction, for which patients with CTD, especially SLE, seem to have a higher susceptibility5. All reported cases occurred after prior exposure to the drug.Nevertheless, Schoenfeld et al. reported an in vitro study describing specific cell-mediated immunity to ibuprofen in SLE, suggesting that even without prior exposure to ibuprofen, patients with SLE may exhibit sensitization to this drug10. Severe systemic reactions to ibuprofen can occur in patients with SLE, potentially occurring at any time, even after years of using the drug. The reaction is reproducible within hours of re-exposure11. Indeed, most patients who have developed ibuprofen hypersensitivity have tolerated other NSAIDs without difficulty.Moreover, autoantibodies belonging to the IgE class have been described in various autoimmune contexts, including SLE12. Recently, two studies have focused on IgE ANA in SLE, showing the presence of IgE ANA in 31.5% 13 and 65%14 of SLE patients. Numerous papers have proved that mast cells play a significant role in the pathogenesis of SLE, and it has been speculated that IgE and anti-IgE antibodies, and FcεRI and anti‐FcεRI antibodies activate mast cells through autoimmune pathways and participate in the disease process of SLE. The level of FcεRIα in the serum of patients with SLE was significantly higher than that in healthy controls, with the autoimmune result of FcεRIα and anti‐FcεRI antibody triggering tissue inflammatory damage caused by mast cell activation15.Few cases of systemic hypersensitivity to ibuprofen in adults with systemic inflammatory connective tissue disease are reported in the literature, with only one case in the pediatric population, in which the mechanism of reaction is unknown. The patient presented here represents the second case of ibuprofen severe systemic hypersensitivity reaction as onset manifestation of pediatric-SLE, and the first one after multiple (triple) NSAIDs co-administration occurred without discontinuation of drugs and therefore without a period of sensitization. In addition, our patient also presented with severe hypotension at onset (only 7 cases described in the literature), which was refractory to infusion therapy, the reason why she required amine therapy and admission to the intensive care unit.We aimed to highlight the clinical presentation, diagnostic challenges, and management strategies associated with this unusual drug-induced systemic hypersensitivity reaction in a patient with SLE. We also wanted to underscore the importance of considering underlying systemic autoimmune conditions in patients with severe and uncommon drug-induced reactions, emphasizing the significance of a comprehensive medication history and vigilant monitoring for ADR.Ivan Taietti1,2, M.D., https://orcid.org/0000-0002-0372-523X,Daniele Veraldi1,2 M.D.,Silvia Maria Elena Caimmi2, M.D., https://orcid.org/0000-0003-0515-524X,Elisabetta De Sando2, M.D.,Valeria Brazzelli3,4, M.D., https://orcid.org/0000-0001-5898-6448,Grazia Bossi2, M.D., https://orcid.org/0000-0001-8287-9757,Gian Luigi Marseglia1,2,M.D., https://orcid.org/0000-0003-3662-0159,Amelia Licari1,2, M.D., https://orcid.org/0000-0002-1773-6482,Riccardo Castagnoli1,2, M.D., PhD, https://orcid.org/0000-0003-0029-9383Pediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, ItalyPediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, ItalyInstitute of Dermatology, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, ItalyInstitute of Dermatology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy*Correspondence:Riccardo CastagnoliPediatric Unit, Department of Clinical, Surgical, Diagnostic, and Pediatric Sciences, University of Pavia, Pavia, Italy.Pediatric Clinic, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy.Piazzale Golgi, 19 27100 Pavia.