Search Results (82)

Background: Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) with severe ocular complications (SOCs) are devastating mucocutaneous disorders characterized by chronic ocular surface inflammation and epithelial damage. Although genome-wide association studies have identified IKZF1 as a susceptibility gene, its functional role in conjunctival epithelial cells remains unclear. Objective: This study aimed to characterize transcriptional changes and enrichment profiles associated with IKZF1 overexpression in primary human conjunctival epithelial cells. Methods: Primary human conjunctival epithelial cells (PHCjECs) were transfected with an IKZF1 expression plasmid or empty vector under matched transfection conditions, followed by microarray profiling, RT-qPCR validation, and Enrichr-based transcription factor enrichment analysis. Results: IKZF1 overexpression was associated with increased expression of CXCL8 and multiple stress-related transcripts, including DDIT3, and with enrichment of DDIT3-, ATF3-, and JUN-related transcriptional signatures. RT-qPCR confirmed significant induction of ER stress pathway genes, including ATF4, GRP78, and TRIB3. Furthermore, CHOP protein expression was markedly increased in conjunctival epithelium from patients with SJS/TEN compared with controls. Conclusions: IKZF1 overexpression is associated with inflammatory and stress-related transcriptional changes in conjunctival epithelial cells. These findings support a working hypothesis that epithelial IKZF1 upregulation may contribute to ocular surface pathology in SJS/TEN with severe ocular complications, but direct molecular mechanisms remain to be established. Full article

Background: Chimeric antigen receptor (CAR) T-cell therapy has transformed haematological-malignancy care, but its dermatologic safety profile remains incompletely characterised across products and indications. Methods: We analysed 8,431,841 deduplicated FDA Adverse Event Reporting System reports from 2016 Q3 to 2026 Q1. Seven approved CAR T-cell products were identified. The primary outcome was any dermatologic adverse event, defined using the MedDRA Skin and subcutaneous tissue disorders system organ class. Secondary outcomes included broad severe cutaneous adverse reactions, narrow Stevens-Johnson syndrome/toxic epidermal necrolysis, and 14 phenotype-specific categories. Multivariable models adjusted for demographics, polypharmacy, cancer, immune checkpoint inhibitor exposure, lymphodepleting chemotherapy and cytokine release syndrome. Additional sensitivity analyses evaluated HSCT/GVHD co-reporting proxies, infection and cytopenia/bleeding proxies, severe-event clinical characteristics, comparator robustness and multiplicity correction. Results: Dermatologic adverse events were identified in 996,654 reports, including 425 CAR-T-associated cases. CAR T-cell exposure was associated with reduced adjusted reporting odds for the primary outcome (adjusted odds ratio 0.13, 95% confidence interval 0.09–0.20) and broad severe cutaneous adverse reactions (0.35, 0.23–0.52). The primary SKIN_ANY reduced-reporting pattern was consistent across all-FAERS, haematological-malignancy and active haematology-oncology comparators. HSCT/GVHD proxy co-reporting was uncommon and did not materially alter estimates. Severe dermatologic reports frequently co-mentioned CRS and serious outcomes. The tisagenlecleucel vascular cutaneous signal was nominally significant but attenuated after excluding infection-attributable and cytopenia/bleeding-proxy reports. Conclusions: Within spontaneous reporting systems, CAR T-cell therapy showed reduced relative reporting of dermatologic adverse events across broad, phenotype-specific and product-level analyses. These results should be interpreted as differences in reporting behaviour, not as evidence of reduced true clinical incidence or lower patient-level risk. Early severe cutaneous reports frequently overlapped with cytokine release syndrome, while infection, cytopenia/bleeding proxies and supportive-care drugs were important alternative explanations for selected cutaneous signals. Full article

Necroptosis has been implicated in the pathogenesis of Stevens–Johnson syndrome and toxic epidermal necrolysis (SJS/TEN), with prior studies demonstrating tissue-level involvement of receptor-interacting protein kinases RIPK1 and RIPK3. However, their systemic expression in the circulatory compartment remains incompletely characterized. The objective of this study is to evaluate circulating levels of RIPK1 and RIPK3 in patients with SJS/TEN and explore their potential association with diseases. Serum samples from patients with SJS/TEN and control groups were analyzed for RIPK1 and RIPK3 levels using ELISA. Group differences were assessed using non-parametric statistical methods. Circulating levels of RIPK1 and RIPK3 were elevated in patients with SJS/TEN compared with controls. These findings were consistent across analyses; however, variability within groups and overlap between cohorts were observed. These results suggest an association between increased circulating RIPK1 and RIPK3 levels and SJS/TEN. Given the limited sample size, heterogeneous control populations, and lack of functional or phosphorylation-specific assays, these findings should be considered exploratory. Further studies incorporating larger cohorts and mechanistic validation are needed to clarify the role of necroptosis-related pathways in the systemic manifestations of SJS/TEN. Full article

Adverse drug reactions (ADRs) remain a major clinical challenge and a leading cause of morbidity and mortality worldwide. Among them, severe cutaneous adverse drug reactions (SCARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN), represent life-threatening immune-mediated hypersensitivity responses strongly associated with specific human leukocyte antigen (HLA) alleles. Despite well-established pharmacogenetic associations, current diagnostic strategies remain largely retrospective and lack predictive capability for novel drug–HLA risk pairs. Here, we present an integrative network-informed machine learning framework for predicting HLA-associated SCAR risk by combining pharmacogenomic features, drug chemical structure, and topological descriptors derived from drug–drug and drug–symptom interaction networks. An Extreme Gradient Boosting (XGBoost) classifier trained on integrated HLA allele and drug features, labeled using curated HLA–SCAR associations, achieved an accuracy of 0.860 ± 0.005, an F1-score of 0.689 ± 0.010, with an area under the receiver operating characteristic curve (AUROC) of 0.922 ± 0.003 and an area under the precision–recall curve (AUPRC) of 0.768 ± 0.007. Notably, several predicted positive associations absent from the training data corresponded to biologically plausible and literature-supported cases, including carbamazepine—HLA-B*15:11, supporting the model’s ability to generalize beyond known associations. Molecular docking provides structural evidence for the predicted associations, highlighting allele-specific binding patterns underlying these results. Overall, our results demonstrate that network-informed machine learning provides a proactive and integrative approach to SCAR risk prediction and may support early risk stratification and personalized drug safety assessment in precision medicine. Full article

Allopurinol, the most used urate-lowering drug for the treatment of gout, is associated with rare but life-threatening severe cutaneous adverse reactions (SCARs) such as Stevens–Johnson Syndrome (SJS), Toxic Epidermal Necrolysis (TEN), and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome, but not Acute Generalised Exanthematous Pustulosis (AGEP). They are characterised by severe skin and systemic involvement and are associated with substantial morbidity and a high risk of mortality. This narrative review summarises evidence on the clinical presentation, epidemiology, risk factors, and preventive strategies for allopurinol-induced SCARs. Key risk factors include the presence of the HLA-B*58:01 allele, renal impairment, older age, female sex, heart disease, higher starting doses of allopurinol, and certain ethnicities, e.g., South Asian, Han Chinese, and African populations likely due to the higher prevalence of the HLA-B*58:01 allele. Risk mitigation strategies include genetic testing for HLA-B*58:01 in high-risk ethnic groups and avoiding allopurinol in those that are positive for the HLA-B*58:01 allele, starting allopurinol at a low-dose (e.g., 50–100 mg/day) and up-titrating it gradually at 4-week intervals, and avoiding high-dose allopurinol in those with risk factors (e.g., chronic kidney disease stage ≥3). In addition, risk stratification using prediction tools may enable a safer use of allopurinol. Full article

Background/Objectives: Stevens–Johnson Syndrome (SJS) and toxic epidermal necrolysis (TEN) are rare, potentially fatal immunological conditions that affect cutaneous and mucosal surfaces and have the potential to involve the genitourinary tract. While genital involvement is common, urological manifestations are under-recognised clinically and there is a paucity of clear, evidence-based management pathways specific to urological manifestations of SJS/TEN. To map the spectrum of urological manifestations of SJS/TEN, to describe the short- and long-term outcomes of these manifestations, and to synthesise management and prevention strategies to inform clinical practice. Methods: This was a scoping review conducted in accordance with the Preferred Reporting Items for Systematic reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guideline. Data sources: Medline and PubMed articles published in English with publication date up to December 2025. Study selection: Eligible studies included case reports, case series, observational studies, clinical guidelines, and review articles describing urological manifestations, outcomes, management, or prevention strategies for patients with SJS/TEN. Articles limited to renal or isolated gynaecological involvement were excluded. Data extraction and synthesis: Articles were screened independently by two reviewers using a pre-defined data extraction template covering four domains: urological manifestations, outcomes and sequelae, management strategies, and prevention strategies. This criterion was refined after a pilot of 20 studies. Discrepancies were resolved by consensus with a third reviewer. Formal risk-of-bias assessment was not performed, consistent with scoping review methodology. Results: One hundred and four studies published between 1987 and 2025 were included in this review. Selected articles included case reports (n = 63), retrospective cohort studies (n = 23), prospective studies (n = 2), guidelines (n = 5), and summary articles (n = 11). Reported urological involvement ranged from genital cutaneous and mucosal disease including erosions, adhesions, and balanitis to urethral manifestations such as urethritis, stenosis, and strictures, as well as scarce upper urinary tract involvement including ureteric stricture and ureteric mucosal sloughing. While some manifestations resolved with supportive care, others progressed to chronic sequelae including persistent urethral strictures, voiding dysfunction, sexual dysfunction, recurrent infection, and in rare cases, obstructive uropathy. A multidisciplinary approach was recommended for all patients with SJS/TEN. Urological management centred around early and repeated urogenital examination, manual lysis of adhesions, urinary catheterisation, and timely intervention for urethral or ureteric obstruction. Long-term urological follow-up of 12 months was recommended for patients with significant urogenital involvement. Conclusions: Urological manifestations of SJS/TEN are diverse, clinically significant, and frequently under-recognised. Early urological involvement, systematic genital and urinary tract assessment, and proactive preventative measures may reduce long-term morbidity. This review provides a comprehensive synthesis of knowledge and recommendations to support urologists’ role in multidisciplinary care of patients with this pathology. This review also highlights the need for prospective research to guide further evidence-based management of urological complications of SJS/TEN. Full article

Background/Objectives: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely prescribed to help alleviate pain and treat inflammation, but they are also recognized as common causes of severe cutaneous adverse reactions (SCARs), including Stevens–Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN). Despite their clinical importance, pharmacogenetic markers to predict individual susceptibility to NSAID-induced SJS/TEN remain insufficiently defined. This study investigated associations between HLA class I and II alleles, CYP2C9 polymorphisms, and NSAID-induced SJS/TEN in a Thai population. Methods: A total of 18 patients with NSAID-induced SJS/TEN and 54 NSAID-tolerant controls were enrolled. Genotype data from 183 unrelated Thai individuals without a history of drug allergy were included as a general population control group. Genotyping was performed for HLA class I and II alleles and the CYP2C9*3 variant. Results: HLA-DQB1*03:02 was significantly associated with NSAID-induced SJS/TEN (OR = 9.23, 95% CI = 2.19–38.83, p = 0.0024, Pc = 0.0312), particularly those triggered by piroxicam (OR = 13.71, 95% CI = 2.81–66.86, p = 0.0012, Pc = 0.0156). Additional associations were identified for HLA-B*56:01 and HLA-A*68:01 in the overall NSAID-induced SJS/TEN group. The subgroup analysis suggested that these alleles, along with HLA-DRB1*04:03, were associated with an increased risk of piroxicam-induced SJS/TEN. However, these associations did not remain statistically significant after Bonferroni’s correction. No significant association was identified for CYP2C9*3. Conclusions: This study identified specific HLA alleles, particularly HLA-DQB1*03:02, as candidate pharmacogenetic risk factors for NSAID-induced SJS/TEN in a Thai population, especially in piroxicam-associated cases. However, these associations should be considered exploratory. Larger, multicenter, multi-ethnic studies are required to validate these findings and clarify their potential clinical utility. Full article

Mycoplasma pneumoniae is traditionally recognized as a leading cause of community-acquired pneumonia, yet growing evidence demonstrates that its clinical impact extends far beyond the respiratory tract. Increasing reports of neurologic, cardiac, hematologic, dermatologic, renal, gastrointestinal, and thrombotic complications indicate that M. pneumoniae should be viewed as a systemic pathogen capable of inducing multisystem disease. Extrapulmonary manifestations may arise through three major mechanisms: direct bacterial invasion of tissues, immune-mediated injury driven by molecular mimicry or immune complexes, and vascular or thrombotic events related to endothelial dysfunction. These processes frequently occur independently of, or temporally dissociated from, respiratory symptoms, complicating early diagnosis. The diagnostic approach remains challenging because respiratory PCR may reflect colonization, serology is delayed, and pathogen detection in sterile sites is uncommon. Consequently, diagnosis often depends on the integration of clinical features, laboratory markers, and organ-specific imaging. Management requires a combined strategy: antimicrobial therapy to reduce bacterial load, organ-targeted supportive measures, and immunomodulatory interventions such as corticosteroids, IVIG, or plasma exchange for severe immune-mediated complications. The emergence of macrolide-resistant strains further underscores the need for tailored antimicrobial strategies and close clinical monitoring. Although many extrapulmonary complications are reversible, severe forms—including encephalitis, ADEM, myocarditis, Stevens–Johnson syndrome, and major thromboses—can lead to lasting morbidity or death. Significant knowledge gaps persist, including determinants of host susceptibility, mechanisms linking CARDS toxin to systemic inflammation, the impact of macrolide resistance on disease severity, and the absence of standardized diagnostic criteria. Advances in molecular immunology, multicenter registries, and development of targeted therapies or vaccines represent crucial next steps. Overall, the breadth and clinical relevance of extrapulmonary involvement support a paradigm shift: Mycoplasma pneumoniae infection should be regarded and managed as a systemic disease rather than a purely respiratory pathogen. Full article

Reactive infectious mucocutaneous eruption (RIME) is a rare pediatric condition characterized by severe mucositis, minimal cutaneous involvement, and an infectious rather than drug-induced etiology. Mycoplasma pneumoniae (M. Pneumoniae) represents the most frequently identified trigger, although an increasing number of alternative pathogens have been reported. Its clinical overlap with Stevens–Johnson syndrome (SJS) makes early recognition difficult. We reviewed literature data on the topic and described our center’s experience with three pediatric cases of M. pneumoniae-associated RIME. Medical records, laboratory results, and imaging were systematically analyzed. All patients were male, aged 2 to 12 years and originated from rural communities. Etiologic confirmation was achieved via M. pneumoniae IgM serology and/or polymerase chain reaction. Clinical exam modifications included multi-site mucositis (oral, ocular, genital) with variable skin involvement: absent in one case, a solitary palm ulcer in another, and widespread rash in the third. One patient required two hospitalizations within a six-month interval, confirming the possible relapsing phenotype of RIME. Another patient developed pneumonia, sepsis, and systemic inflammation. All received macrolide therapy, antifungals, mucosal supportive care, and systemic management as indicated. Recovery occurred within 10–21 days, with one patient exhibiting skin hyperpigmentation. These cases illustrate the heterogeneity of RIME, emphasize the importance of prompt recognition, etiology confirmation, and multidisciplinary management. RIME is a rare clinical condition in pediatric population, an uncommon but significant mucocutaneous clinical entity, important to be acknowledged by clinicians as a complication and/or extra-pulmonary manifestation of M. pneumoniae infection. Full article

Background/Objectives: Cutaneous adverse drug reactions (CADRs) represent the most common manifestations of drug-induced allergy, with most unfavorable clinical outcomes seen in severe cutaneous adverse reactions (SCARs). To manage SCARs immediate cessation of the offending drug is needed; therefore, it is crucial to identify the list of medications associated with SCARs in real-world clinical practice. The objective of this study was to evaluate the structure of drugs associated with SCARs and to analyze drug-induced SCAR signals by calculating the reporting odds ratio (ROR) and proportional reporting ratio (PRR) based on spontaneous reports extracted from the Russian national pharmacovigilance database. Methods: A retrospective, descriptive pharmacoepidemiological analysis of spontaneous reports (SRs) registered in the pharmacovigilance database from 1 April 2019 to 31 March 2025. Results: A total of 7011 SRs with SCARs were finally revealed, with 907 identified drug triggers. The most frequently reported were antibacterial drugs for systemic use (22.8%), antineoplastic agents (17.8%), and antiepileptics (6.0%). The top five drugs involved in SCARs were dupilumab (2.14%, n = 244), piperacillin and beta-lactamase inhibitor (2.0%, n = 227), pembrolizumab (1.98%, n = 225), levofloxacin (1.95%, n = 222), and linagliptin (1.93%, n = 220). The strongest signals were detected for linagliptin (PRR = 15.37, 95% CI: 13.54–17.44; ROR = 17.24, 95% CI: 14.95–19.88), followed by clindamycin (PRR = 12.44, 95% CI: 10.89–14.21; ROR = 13.62, 95% CI: 11.77–15.77) and by piperacillin and beta-lactamase inhibitor (PRR = 10.02, 95% CI: 8.86–11.43; ROR = 10.81, 95% CI: 9.42–12.40). Conclusions: Pharmacovigilance databases facilitate the identification of diverse phenotypes of SCARs and the list of culprit drugs. The accumulated data serve as a valuable tool to enhance clinical practice outcomes and strengthen overall healthcare monitoring. Full article

Introduction: Toxic Epidermal Necrolysis (TEN) and Steven–Johnson Syndrome (SJS) are rare yet dangerous dermatological emergencies presenting as necrosis of the skin and mucous membranes due to an immune reaction which may be associated with the use of pharmaceuticals—predominantly non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, and antiretroviral drugs. During the postpartum period, women are administered numerous pharmaceuticals, including NSAIDs, analgesics, and antibiotics, due to pain and their susceptibility to infections, exposing them to potential adverse effects including allergies and immune reactions. Case Report and Review: The case reported here is a rare description of a patient in the early postpartum phase who presented with epidermal necrolysis whilst remaining hospitalized after a cesarean delivery. The multidisciplinary approach, early diagnosis, and treatment ensured the patient’s full recovery. Intravenous immunoglobulin treatment resulted in a rapid therapeutic effect. This literature review offers an insight into the epidemiology, diagnostic process, and treatment of this infrequent dermatological syndrome during the postpartum period. Results: Antibiotic treatment is a common culprit of TEN in this population; hence, clinicians should remain vigilant during antibiotic administration. Differential diagnosis with toxic shock syndrome is crucial, as TEN and SJS symptoms may mimic sepsis, which is a more common diagnosis in the postpartum period. Conclusions: The condition of the skin during the postpartum period should be closely monitored, as some systemic diseases may manifest abruptly as profound, postpartum hormonal changes affect the immunological response. Upon the discovery of suspicious skin lesions concomitant with systemic symptoms, an immediate multidisciplinary approach involving obstetricians and dermatologists is key to a rapid diagnosis and treatment to avoid maternal mortality. Full article

Changes in gut microbial composition may influence mucosal immune responses and contribute to systemic autoimmune manifestations. In this pilot exploratory study, we investigated and compared the gut microbiome in patients with Stevens–Johnson syndrome (SJS), patients with Sjögren’s disease (SjD), and healthy controls, using next-generation sequencing (NGS), and assessed correlations with dry eye parameters. The study included 10 patients with SJS matched by age and sex to 10 healthy controls, and 10 patients with SjD matched to an additional set of 10 healthy controls. Dry eye parameters were employed to evaluate dry eye disease (DED). Microbiome profiles were determined using next-generation sequencing of the 16S V3-V4 region and analyzed using the Silva database. The gut microbiome exhibited significant differences in the SJS group, including a reduced Chao1 index (p = 0.01) that was progressively correlated with increased ocular severity and a decrease in Faecalibacterium (p = 0.048) compared to the healthy control group. In the SJS group, strong correlations were observed between increased Christensenellaceae with decreased DED DEWS (Dry Eye Workshop score) (p = 0.04), increased Subdoligranulum with decreased NEI (National Eye Institute) score (p = 0.04), and increased Clostridia and longer TBUT (tear break-up time) (p = 0.009). In contrast, the gut microbiome of SjD patients was similar to that of healthy controls. Patients with SJS exhibited distinct alterations in gut microbial composition, characterized by reduced microbial richness and depletion of Faecalibacterium. Furthermore, a significant association was found between specific bacterial taxa and milder dry eye severity, suggesting a possible link between changes in the gut microbiome and inflammation of the ocular surface. Full article

Background: Eculizumab, Ravulizumab, and Zilucoplan are inhibitors of terminal complement protein C5 (C5IT) approved for the treatment of generalized Myasthenia Gravis (gMG). The aim of this study is to compare the administration schedules, efficacy, and safety of these new biological therapies in a real-life setting. Methods: We enrolled 31 patients with gMG who received C5IT (Eculizumab: 7 patients; Ravulizumab: 11 patients; Zilucoplan: 13 patients). We gathered demographic, clinical data by the difference between scores at baseline (T0) and after follow-up for the MG-ADL, QMG, and MGC scales. Results: All C5IT demonstrated similar clinical efficacy, resulting in a statistically significant reduction in clinical scales scores for the MG-ADL (F = 14.7; p < 0.001), QMG (F = 14.78; p < 0.001), and MGC (F = 9.466; p < 0.001), with no significant differences among drugs (p > 0.05). No significant differences were highlighted in terms of MSE (p > 0.05). There was a decrease in the mean dose of steroid taken by patients in all three treatment groups (Eculizumab: −37%; Ravulizumab: −62%; Zilucoplan: −37%, at W34 compared to baseline). No myasthenic crises requiring hospitalization occurred during follow-up. Most of the reported adverse events were mild to moderate; the more severe events included one case of Stevens–Johnson syndrome (Ravulizumab) and episodes of pneumonia (Eculizumab, Ravulizumab). Conclusions: The comparison of C5IT did not bring out significant differences in terms of clinical efficacy and safety, representing a valid therapeutic option when traditional therapies fail to control disease symptoms. Full article

Human allogeneic umbilical cord blood serum stands out as a potent adjunct to conventional therapies for ocular surface disorders related to severe Dry Eye Disease. By expediting ocular surface regeneration and fostering epithelial integrity, umbilical cord blood serum not only enhances subjective patient experiences but also improves objective clinical indicators. This makes it particularly useful in patients with corneal ulcers through ocular surface regeneration and anti-inflammatory activity. This retrospective, interventional, non-randomized clinical study aims to explore the efficacy of allogenic umbilical cord blood serum in patients who had previously received other treatments unsuccessfully. This study was a retrospective, non-comparative, interventional clinical study involving 55 patients (35 females and 20 males) aged 18–82 years with severe Dry Eye Disease who were unresponsive to standard treatments. The study was conducted at Eye Center “G.B. Morgagni-DSV”, Catania, Italy. Patients were categorized based on the etiology of severe Dry Eye Disease into four groups: group I consisted of 26 patients with filamentary keratitis and corneal ulcers associated with rheumatologic diseases such as Sjogren’s syndrome and systemic sclerosis; group II comprised 15 patients with graft-versus-host disease; group III consisted of 10 patients with corneal neurotrophic ulcers; group IV included four patients with Steven–Johnson syndrome. Outcomes evaluated before and after treatment were OSDI (Ocular Surface Disease Index) and SANDE (Symptom Assessment in Dry Eye) Questionnaires, VAS (Visual Analog Scale), Slit-Lamp Examination, Esthesiometry, Lissamine Green Staining, NIBUT (Non-Invasive Break-Up Time) and BUT, Fluorescein Staining with Photography and Oxford Classification, Schirmer Test, Best-Corrected Visual Acuity (BCVA), Meibography. We observed a significant improvement in SANDE, VAS and OSDI questionnaires, Schirmer Test, BUT, BCVA, and Oxford classification after treatment with allogeneic cord blood serum eyedrops. Clinical variables, such as corneal inflammation, conjunctivalization, corneal neovascularization, or pain, were also considered individually. Nevertheless, pain and inflammation reduced markedly over time until completely healed in all cases. Our study highlights the remarkable efficacy of allogeneic cord blood serum eyedrops in patients with severe Dry Eye Disease who have shown absent or inadequate response to usual treatments for dry eye. This underscores the need for further comprehensive investigations in this field. Full article

Background: Reactive Infectious Mucocutaneous Eruption (RIME) is a mucositis-predominant syndrome that usually follows respiratory infections in children. Although Mycoplasma pneumoniae is a well-established trigger, viral pathogens as triggers—especially SARS-CoV-2—have been increasingly reported. RIME is often misclassified as Stevens–Johnson syndrome (SJS), which may lead to inappropriate management. Case Presentation: We describe a 12-year-old previously healthy boy who presented with fever, dry cough, odynophagia, and vomiting for 9 days. On admission, he had severe oral ulcerations, bilateral conjunctivitis, and a non-blanching maculopapular rash. Laboratory tests confirmed co-infection with M. pneumoniae and SARS-CoV-2. Inflammatory markers were mildly elevated. Notably, the patient also developed asymptomatic sinus bradycardia, with no signs of structural heart disease. He was treated with antibiotics, intravenous corticosteroids, and supportive care. His mucosal symptoms improved rapidly, and he was discharged in stable condition on day 7. Follow-up at 12 days showed near-complete resolution of all lesions. Conclusions: This case illustrates several clinically relevant features. First, it highlights a dual infectious trigger—M. pneumoniae and SARS-CoV-2—that may have contributed to a more severe mucosal reaction. Second, the patient developed transient sinus bradycardia without myocardial involvement, suggesting a possible inflammatory autonomic response, rarely reported in RIME. Finally, this case supports the early use of corticosteroids in severe mucosal disease, with good outcomes and no complications. Prompt recognition of RIME, especially in the context of viral–bacterial coinfection, is essential to avoid misdiagnosis and to guide appropriate, multidisciplinary management. Full article