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Data evaluating the chronological order of appearance of extraintestinal manifestations (EIMs) relative to the time of inflammatory bowel disease (IBD) diagnosis is currently lacking. We aimed to assess the type, frequency, and chronological order of appearance of EIMs in patients with IBD.MethodsData from the Swiss Inflammatory Bowel Disease Cohort Study were analyzed.ResultsThe data on 1249 patients were analyzed (49.8% female, median age: 40 [interquartile range, 30–51 yr], 735 [58.8%] with Crohn's disease, 483 [38.7%] with ulcerative colitis, and 31 [2.5%] with indeterminate colitis). A total of 366 patients presented with EIMs (29.3%). Of those, 63.4% presented with 1, 26.5% with 2, 4.9% with 3, 2.5% with 4, and 2.7% with 5 EIMs during their lifetime. Patients presented with the following diseases as first EIMs: peripheral arthritis 70.0%, aphthous stomatitis 21.6%, axial arthropathy/ankylosing spondylitis 16.4%, uveitis 13.7%, erythema nodosum 12.6%, primary sclerosing cholangitis 6.6%, pyoderma gangrenosum 4.9%, and psoriasis 2.7%. In 25.8% of cases, patients presented with their first EIM before IBD was diagnosed (median time 5 mo before IBD diagnosis: range, 0–25 mo), and in 74.2% of cases, the first EIM manifested itself after IBD diagnosis (median: 92 mo; range, 29–183 mo).ConclusionsIn one quarter of patients with IBD, EIMs appeared before the time of IBD diagnosis. Occurrence of EIMs should prompt physicians to look for potential underlying IBD.

Data on the frequency of extraintestinal manifestations (EIMs) in Crohn's disease (CD) and ulcerative colitis (UC) and analyses of their risk factors are scarce. We evaluated their prevalence and risk factors in a large nationwide cohort of inflammatory bowel disease (IBD) patients. IBD patients from an adult clinical cohort in Switzerland (Swiss IBD cohort study) were prospectively included. Data from validated physician enrolment questionnaires were analyzed. A total of 950 patients were included, 580 (61%) with CD (mean age 41 years) and 370 (39%) with UC (mean age 42 years). Of these, 249 (43%) of CD and 113 (31%) of UC patients had one to five EIMs. The following EIMs were found: arthritis (CD 33%, UC 21%), aphthous stomatitis (CD 10%, UC 4%), uveitis (CD 6%, UC 4%), erythema nodosum (CD 6%, UC 3%), ankylosing spondylitis (CD 6%, UC 2%), psoriasis (CD 2%, UC 1%), pyoderma gangrenosum (CD and UC each 2%), and primary sclerosing cholangitis (CD 1%, UC 4%). Multiple logistic regression identified the following risk factors for ongoing EIM in CD: active disease (odds ratio (OR)=1.95, 95% confidence interval (CI)=1.17-3.23, P=0.01), and positive IBD family history (OR=1.77, 95% CI=1.07-2.92, P=0.025). No risk factors were identified in UC patients. EIMs are a frequent problem in CD and UC patients. Active disease and positive IBD family history are associated with ongoing EIM in CD patients. Identification of EIM prevalence and associated risk factors may result in increased awareness for this problem and thereby facilitating their diagnosis and therapeutic management.

PurposeImmune checkpoint inhibitors (ICIs) are increasingly used to treat advanced malignancy but can induce immune-related adverse events (irAE). The mechanisms behind these sporadic and sometimes life-threatening irAEs remain largely unexplored. Here, we present a case report and in-depth molecular analysis of an erythema nodosum (EN) like irAE occurring in a melanoma patient with isolated brain metastasis, aiming to explore the potential mechanism of this irAE.MethodsWe performed RNA and T cell receptor (TCR) sequencing on the patient’s resected brain metastasis and biopsy of EN-like irAE. Single cell RNA/TCR sequencing was conducted on the patient’s peripheral blood mononuclear cells (PBMC) at baseline, 3 weeks after ipilimumab and nivolumab combination therapy, during EN toxicity and after resolution.ResultsThe site of EN-like irAE showed a distinct accumulation of pro-inflammatory immune cells, accompanied by the upregulation of inflammatory and interferon response signatures. In addition, clonal expansion and activation of irAE-associated CD8 T cells and upregulation of monocyte-specific interferon signatures occurred concurrently with irAE onset.ConclusionThe unique immune landscape at the EN-like irAE could indicate that this irAE is distinct from anti-tumor immune and analogous non-ICI autoimmune milieus. Our data also suggests that systemic immune activation induced by ICI treatment, as reflected in PBMC, may help monitor the patient’s treatment response and access irAE risk.

BackgroundLeprosy reactions represent immunologically mediated episodes of acute inflammation that, if not diagnosed and treated promptly, can cause irreversible impairment of nerve function and permanent disabilities. A frequent type of reaction experienced by patients with lepromatous leprosy (LL) and borderline lepromatous leprosy (BL) is erythema nodosum leprosum (ENL), an inflammatory complication that may become chronic or recur in multiple episodes. Although ENL is commonly described as a neutrophil-mediated immune disease, the role of neutrophils is not fully understood. In this study, we assess neutrophilic leukocytosis in a retrospective cohort of patients affected by BL or LL leprosy.Materials and methodsA retrospective observational study was performed using data from 146 patients with BL and LL leprosy diagnosed and treated at the Souza Araújo Outpatient Clinic, Fiocruz, Rio de Janeiro, Brazil. Clinical, demographic, and hematological data were extracted from medical records. Skin biopsy samples obtained from patients for ENL diagnosis were used for histopathological evaluations.ResultsMost patients were male (75%) and had a reactional episode (85%), of which 65% were ENL. Multiple episodes were common, 55% of the 80 patients with ENL presented more than 2 episodes (average of 2.6 episodes). In treatment-naive BL/LL patients, the median blood neutrophil counts of patients who developed ENL at some points of their disease course were higher than those who did not experience any reaction (median= 4,567 cells/mm3 vs 3,731 cells/mm3 respectively, p=0.0286). A correlation between the increase in median neutrophil counts and ENL severity was confirmed (6,066 cells/mm3 for mild ENL vs 10,243 cells/mm3 for moderate/severe ENL, p=0.0009). A longitudinal assessment was also performed in 34 patients, confirming the neutrophilic leukocytosis (BL/LL: 4896 cells/mm3 vs ENL: 8408 cells/mm3, p<0.0001). Moreover, increased NLR was associated with a greater neutrophilic infiltration in ENL lesions.ConclusionWe demonstrate that ENL episodes in patients affected by leprosy are associated with elevated blood leukocyte and neutrophil counts and an increased NLR. These findings highlight the significant involvement of neutrophils in the ENL immunological/inflammatory process.

Erythema nodosum (EN), although relatively uncommon in the pediatric population, is the most frequent type of panniculitis in children. The present study aimed to report all the cases of children admitted to our tertiary pediatric hospital with the diagnosis of EN to evaluate the epidemiology, clinical manifestations, etiology, treatment, and the course of this disease in the pediatric age. This observational study retrospectively considered all children evaluated to the emergency room (ER) of Meyer Children’s University Hospital, Florence, Italy, discharged with a diagnosis of EN over a 12-year period (from January 2009 to December 2021). Clinical and laboratory data were recorded using a standardized report form. Sixty-eight patients with EN were included. The etiologic diagnosis of EN was made in 38 children (55.9%): 29 (42.6%) had infection-related EN (in particular EBV and β-hemolytic streptococcus), 6 (8.8%) had Crohn’s disease, 1 celiac disease, 1 Sjogren syndrome, and 1 Hodgkin lymphoma. In 30 patients (45%), no definitive diagnosis was reached, and they were defined as having idiopathic EN. Most of the laboratory tests were nonspecific. No statistical differences were found in the demographic and clinical data, and the main diagnostic laboratory parameters between patients with idiopathic EN versus those with secondary EN.   Conclusion : Since EN can be isolated or the first manifestation of heterogeneous underlying pathologies, some of which can be severe and life-threatening, it is important to recognize it and carry out all the necessary etiological diagnostic investigations to understand its etiology and start the specific treatment. What is Known: • Erythema nodosum (EN) is the most frequent type of panniculitis in children. • It has been associated with a wide spectrum of disorders, such as different types of infection, malignancies, chronic inflammations, and drugs. What is New: • No statistical differences can be found in clinical features as well as laboratory data, between patients with idiopathic EN versus those with secondary EN. • A broad spectrum of investigations and a proper follow-up should be taken into account in order to prevent a delayed or missed secondary EN diagnosis.

Extraintestinal cutaneous manifestations of IBD represent a severe disease complication and an early and accurate treatment might positively influence the disease course. Using the patient collective of the Swiss IBD Cohort Study (SIBDCS), we analysed epidemiological as well as clinical factors being associated with the onset of pyoderma gangrenosum, erythema nodosum and aphthous ulcers in IBD patients. We included 3266 SIBDCs patients, 1840 with Crohn's disease (CD) and 1426 with ulcerative colitis (UC) or IBD unclassified (IBDU) and analysed the association of cutaneous manifestations with age, age at diagnosis time, type of disease, gender, family history, HLA-allotype, smoking, intestinal disease activity, therapy and other extraintestinal manifestations (EIM). 354 CD patients and 136 UC/IBDU patients presented with skin manifestations at any time during their disease course. In both, CD and UC, female gender and younger age at IBD diagnosis were significantly associated with extraintestinal skin manifestations. For CD, we also detected a positive family history as associated factor. As an indicator of more intensive intestinal disease activity, patients with cutaneous manifestations of IBD needed more frequently therapy with antibiotics, steroids, immunomodulators and anti-TNF. Multivariate analysis revealed female gender, younger age at diagnosis and presence of other extraintestinal manifestations as factors being associated with skin EIM in IBD patients and anti-TNF as well as immunomodulatory treatment in CD patients. Our results suggest that young females with a positive family history of IBD might be at increased risk for the onset of skin manifestations and require a careful screening for such complications.

VEXAS syndrome (Vacuoles, E1-enzyme, X-linked, Autoinflammation, and Somatic) is a recently identified late-onset autoinflammatory disorder characterized by a unique interplay between hematological and inflammatory manifestations. It results from somatic mutations in the UBA1 gene, located on the short arm of the X chromosome. Initially, females were considered mere carriers, with the syndrome primarily affecting males over 50. However, recent evidence indicates that heterozygous females can exhibit symptoms as severe as those seen in hemizygous males. The disease manifests as systemic inflammation, macrocytic anemia, thrombocytopenia, chondritis, neutrophilic dermatoses, and steroid-dependent inflammatory symptoms. Due to its overlap with autoimmune and hematologic disorders such as relapsing polychondritis, Still’s disease, and myelodysplastic syndromes, misdiagnosis is common. At the molecular level, VEXAS syndrome is driven by impaired ubiquitination pathways, resulting in dysregulated immune responses and clonal hematopoiesis. A key diagnostic marker is the presence of cytoplasmic vacuoles in myeloid and erythroid precursors, though definitive diagnosis requires genetic testing for UBA1 mutations. Traditional immunosuppressants and TNF inhibitors are generally ineffective, while JAK inhibitors and IL-6 blockade provide partial symptom control. Azacitidine and decitabine have shown promise in reducing disease burden, but hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, albeit with significant risks. This review provides a comprehensive analysis of VEXAS syndrome, examining its clinical features, differential diagnoses, diagnostic challenges, and treatment approaches, including both pharmacological and non-pharmacological strategies. By enhancing clinical awareness and optimizing therapeutic interventions, this article aims to bridge emerging genetic insights with practical patient management, ultimately improving outcomes for those affected by this complex and often life-threatening disease.

Abstract Background Dermatological conditions such as erythema nodosum (EN), pyoderma gangrenosum, Sweet’s syndrome, and aphthous stomatitis can occur with inflammatory bowel disease (IBD) and are considered dermatological extraintestinal manifestations (D-EIMs). Rarely, they may precede IBD. Other common conditions such as psoriasis have also been associated with IBD. This study examined the risk of a subsequent IBD diagnosis in patients presenting with a D-EIM. Methods A retrospective cohort study compared patients with D-EIMs and age-/sex-matched patients without D-EIMs. Hazard ratios (HRs) were adjusted for age, sex, body mass index, deprivation, comorbidity, smoking, loperamide use, anemia, and lower gastrointestinal symptoms. Logistic regression was used to produce a prediction model for the diagnosis of IBD within 3 years of EN diagnosis. Results We matched 7447 patients with D-EIMs (74% female; median age 38 years (interquartile ratio [IQR], 24-65 years) to 29,297 patients without D-EIMs. We observed 131 (1.8%) subsequent IBD diagnoses in patients with D-EIMs compared with 65 (0.2%) in those without D-EIMs. Median time to IBD diagnosis was 205 days (IQR, 44-661 days) in those with D-EIMs and 1594 days (IQR, 693-2841 days) in those without D-EIMs. The adjusted HR for a later diagnosis of IBD was 6.16 (95% confidence interval [CI], 4.53-8.37; P < 0.001), for ulcerative colitis the HR was 3.30 (95% CI, 1.98-5.53; P < 0.001), and for Crohn’s disease the HR was 8.54 (95% CI, 5.74-12.70; P < 0.001). Patients with psoriasis had a 34% increased risk of a subsequent IBD diagnosis compared with the matched control patients (HR, 1.34; 95% CI, 1.20-1.51; P < 0.001). We included 4043 patients with an incident EN diagnosis in the prediction model cohort, with 87 patients (2.2%) diagnosed with IBD within 3 years. The model had a bias-corrected c-statistic of 0.82 (95% CI, 0.78-0.86). Conclusions Patients with D-EIMs have a 6-fold increased risk of a later diagnosis of IBD. Younger age, smoking, low body mass index, anemia, and lower gastrointestinal symptoms were associated with an increased risk of diagnosis of IBD within 3 years in patients with EN.

Erythema nodosum migrans (ENM) is usually considered as a rare clinical variant of erythema nodosum and is characterized by unilateral, migratory, relatively painless, nodular lesions. ENM cases are rarely reported and most cases are idiopathic. Therefore, the appropriate treatment modality of ENM is unknown. We report a 72-year-old woman with highly suspected valsartan-induced ENM. She experienced painful, infiltrated, centrifugally spreading, slightly morpheaform, erythematous plaques on the flexor side of her left leg. Her symptoms were relieved after discontinuation of valsartan and temporary administration of oral prednisone once daily (20 mg for the first 7 days and 10 mg for the next 7 days).