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Summary This post hoc analysis of the UNITI studies found ustekinumab (UST) did not significantly improve overall extraintestinal manifestations (EIMs) of Crohn's disease compared to placebo‐treated patients at weeks 6 and 52. Background and Aims The UNITI trials demonstrated that UST was effective in inducing and maintaining clinical remission in Crohn's disease (CD). However, limited data exists regarding its effectiveness for treatment of EIMs. This post hoc analysis evaluated the efficacy of UST in treatment of EIMs. Methods Data from UNITI‐1/2 and IM‐UNITI (NCT01369329, NCT01369342, NCT01369355) were obtained from the Yale Open Data Access Project (2019‐4104). Nine hundred and fourty‐one patients eligible for UST induction and 263 patients eligible for maintenance UST were included. The primary outcome of interest was EIM resolution at Week 6 in UST and placebo‐treated patients using the chi‐square test. EIM resolution at Week 52 was also assessed. McNemar's test was used to compare the proportion of patients who reported active EIMs at weeks 6 and 52 versus baseline. Results From 941 UST‐treated patients in UNITI‐1/2, 504 had 527 EIMs at baseline. Overall, there was no significant difference in EIM resolution observed in UST‐treated patients (186/504, 36.9%) compared to placebo (90/230, 39.1%; p = 0.564) at Week 6. Patients treated with continuous UST (91/119, 76.4%) had no significant difference in overall EIMs resolved at Week 52 compared to placebo (72/90, 80.0%; p = 0.542). Although many EIMs demonstrated reduction in prevalence compared to baseline at initiation of UST, only erythema nodosum was more likely to improve at Week 52 on treatment versus placebo. Conclusion Overall, UST did not lead to significant resolution of EIMs for CD compared to placebo at weeks 6 and 52. Key Summary Summarise the established knowledge on this subject Summarise the established knowledge on this subject In a systematic review, ustekinumab was found to be effective in treating dermatologic manifestations such as psoriasis, pyoderma gangrenosum and erythema nodosum, and rheumatologic manifestations such as arthralgias and psoriatic arthritis in IBD However, existing evidence is limited due to retrospective evaluations, small sample sizes and lack of comparator groups Overall, there is a paucity of data regarding the effectiveness of ustekinumab for treatment of extraintestinal manifestations in Crohn's disease What are the significant and/or new findings of this study? Patients with Crohn's disease treated with ustekinumab had overall no significant resolution of EIMs as compared to those treated with placebo at week 6 and week 52 Among individual EIMs, only erythema nodosum was significantly reduced in patients treated with ustekinumab at week 52 compared to placebo‐treated patients

IntroductionErythema nodosum leprosum (ENL) is an immunological complication of leprosy. ENL results in morbidity and disability and if it is not treated can lead to death. The current treatment consists of thalidomide or high doses of oral corticosteroids for prolonged periods. Thalidomide is not available in many leprosy endemic countries. The use of corticosteroids is associated with morbidity and mortality. Identifying treatment regimens that reduce the use of corticosteroids in ENL is essential. Methotrexate (MTX) is used to treat many inflammatory diseases and has been used successfully to treat patients with ENL not controlled by other drugs, including prednisolone and thalidomide. We present the protocol of the ‘MTX and prednisolone study in ENL’ (MaPs in ENL) a randomised controlled trial (RCT) designed to test the efficacy of MTX in the management of ENL.Methods and analysisMaPs in ENL is an international multicentre RCT, which will be conducted in leprosy referral centres in Bangladesh, Brazil, Ethiopia, India, Indonesia and Nepal. Patients diagnosed with ENL who consent to participate will be randomly allocated to receive 48 weeks of weekly oral MTX plus 20 weeks of prednisolone or 48 weeks of placebo plus 20 weeks of prednisolone. Participants will be stratified by type of ENL into those with acute ENL and those with chronic and recurrent ENL. The primary objective is to determine whether MTX reduces the requirement for additional prednisolone. Patients’ reported outcome measures will be used to assess the efficacy of MTX. Participants will be closely monitored for adverse events.Ethics and disseminationResults will be submitted for publication in peer-reviewed journals. Ethical approval was obtained from the Observational/Interventions Research Ethics Committee of the London School of Hygiene & Tropical Medicine (15762); The Leprosy Mission International Bangladesh Institutional Research Board (in process); AHRI-ALERT Ethical Review Committee, Ethiopia; Ethics Committee of the Managing Committee of the Bombay Leprosy Project; and The Leprosy Mission Trust India Ethics Committee; the Nepal Health and Research Council and Health Research Ethics Committee Dr. Soetomo, Indonesia. This study is registered at www.clinicaltrials.gov. This is the first RCT of MTX for ENL and will contribute to the evidence for the management of ENL.Trial registration numberNCT 03775460.

Erythema Nodosum Leprosum (ENL) is a serious complication of leprosy. It is normally treated with high dose steroids, but its recurrent nature leads to prolonged steroid usage and associated side effects. There is little evidence on the efficacy of alternative treatments for ENL, especially for patients who have become steroid resistant or have steroid side effects. These two pilot studies compare the efficacy and side effect profile of ciclosporin plus prednisolone against prednisolone alone in the treatment of patients with either new ENL or chronic and recurrent ENL. Thirteen patients with new ENL and twenty patients with chronic ENL were recruited into two double-blinded randomised controlled trials. Patients were randomised to receive ciclosporin and prednisolone or prednisolone treatment only. Patients with acute ENL had a delay of 16 weeks in the occurrence of ENL flare-up episode, with less severe flare-ups and decreased requirements for additional prednisolone. Patients with chronic ENL on ciclosporin had the first episode of ENL flare-up 4 weeks earlier than those on prednisolone, as well as more severe ENL flare-ups requiring 2.5 times more additional prednisolone. Adverse events attributable to prednisolone were more common that those attributable to ciclosporin. This is the first clinical trial on ENL management set in the African context, and also the first trial in leprosy to use patients' assessment of outcomes. Patients on ciclosporin showed promising results in the management of acute ENL in this small pilot study. But ciclosporin, did not appear to have a significant steroid-sparing effects in patients with chronic ENL, which may have been due to the prolonged use of steroids in these patients in combination with a too rapid decrease of steroids in patients given ciclosporin. Further research is needed to determine whether the promising results of ciclosporin in acute ENL can be reproduced on a larger scale.

Background The predictive value of the serology to detection of IgM against the Mycobacterium leprae -derived phenolic glycolipid-I/PGL-I to identify leprosy patients who are at higher risk of developing reactions remains controversial. Whether baseline results of the ML Flow test can predict leprosy reactions was investigated among a cohort of patients enrolled in The Clinical Trial for Uniform Multidrug Therapy for Leprosy Patients in Brazil (U-MDT/CT-BR). Methods This was a descriptive study focusing on the main clinical manifestations of leprosy patients enrolled in the U-MDT/CT-BR from March 2007 to February 2012 at two Brazilian leprosy reference centers. For research purposes, 753 leprosy patients were categorized according to a modified Ridley-Jopling (R&J) classification and according to the development of leprosy reactions (reversal reaction/RR and erythema nodosum leprosum/ENL), and whether they had a positive or negative bacillary index/BI. Results More than half of the patients (55.5 %) reported leprosy reaction: 18.3 % (138/753) had a RR and 5.4 % (41/753) had ENL. Leprosy reactions were more frequent in the first year following diagnosis, as seen in 27 % (205/753) of patients, while 19 % (142/753) developed reactions during subsequent follow-up. Similar frequencies of leprosy reactions and other clinical manifestations were observed in paucibacillary (PB) and multibacillary (MB) leprosy patients treated with U-MDT and regular MDT (R-MDT) ( P  = 0.43 and P  = 0.61, respectively). Compared with PB patients, leprosy reactions were significantly more frequent in MB patients with a high BI, and more patients developed RR than ENL. However, RR and neuritis were also reported in patients with a negative BI. At baseline, the highest rate of ML Flow positivity was observed in patients with a positive BI, especially those who developed ENL, followed by patients who had neuritis and RR. Among reaction-free patients, 81.9 % were ML Flow positive, however, the differences were not statistically significant compared to reactional patients ( P  = 0.45). Conclusions MB and PB patients treated with R-MDT and U-MDT showed similar frequencies of RR and other clinical manifestations. Positive ML Flow tests were associated with MB leprosy and BI positivity. However, ML Flow test results at baseline showed limited sensitivity and specificity for predicting the development of leprosy reactions.

Erythema nodosum leprosum (ENL) is a severe immunological complication of leprosy, characterised by painful nodules, fever, arthralgia, oedema, and systemic symptoms. Temporal classifications-acute, recurrent, and chronic-are inconsistently applied, complicating data comparisons. Standardised and agreed definitions are essential to ensure consistency in diagnosis, research, and clinical management. To examine how temporal classifications of ENL are used in modern literature and compare them to descriptions from the pre-corticosteroid era. We conducted a semi-systematic review of historical and contemporary literature. Historical texts published before 1940, prior to the introduction of sulfone antibiotics and corticosteroids, were purposively selected to capture descriptions of the natural history of ENL. For modern studies, we systematically searched PubMed, EMBASE, LILACS, SciELO, Scopus, African Index Medicus, Cochrane, and ClinicalTrials.gov from May 2024 to March 2025. The systematic review identified 572 articles after de-duplication, and 41 met inclusion criteria for providing definitions of ENL subtypes. Five historical treatises were selected. Their clinical observations of nodular skin lesions with systemic symptoms-ranging in duration from weeks to months or even years-align with contemporary understandings of ENL. 41 studies included, at least one of the three temporal classifications (acute, recurrent, or chronic). The six-month criterion distinguishing acute and chronic ENL is used in all current definitions. However, definitions for recurrent and chronic ENL frequently overlapped, both referring to prolonged or multiple episodes after initial treatment, underscoring a lack of conceptual clarity. The absence of standardised ENL terminology impedes data comparison, meta-analysis, and clinical guideline development. A Delphi consensus process and longitudinal observational studies are recommended to refine, standardise agreed ENL classifications.

Idiopathic granulomatous mastitis (IGM) is a rare chronic inflammatory breast disease of unknown etiology, typically presenting with breast pain, swelling, and mass formation. Erythema nodosum (EN) is an inflammatory panniculitis that can occur as a systemic manifestation of various conditions, and arthritis has occasionally been observed alongside granulomatous mastitis (GM), suggesting an underlying autoimmune component. This narrative review synthesizes reported cases of GM with EN, with or without arthritis-termed \"GMENA\" syndrome-to characterize its clinical features and management. We searched PubMed and EMBASE for case reports and case series describing GM with co-occurring EN, with or without arthritis. Reports fulfilling these criteria were reviewed, and data on demographics, clinical presentation, laboratory and histological findings, treatment strategies, and outcomes were extracted and summarized descriptively. We identified 45 reported patients with GMENA in the literature. All patients were women of reproductive age (median age approximately 32 years), and about one-third presented during pregnancy or in the postpartum period. Breast involvement was exclusively unilateral, manifesting as painful inflammatory masses often mimicking carcinoma. EN was universal (100%), usually affecting both shins and ankles, and approximately two-thirds of patients developed acute, non-erosive oligoarthritis, most commonly involving the ankles. Laboratory work-ups consistently showed elevated inflammatory markers with negative autoantibodies and sterile cultures. Histology typically revealed lobulocentric, non-caseating granulomas with neutrophilic microabscesses. Corticosteroids induced remission in more than 75% of cases, while methotrexate or azathioprine provided steroid-sparing benefit in refractory disease. Antibiotics and anti-tuberculous regimens were generally ineffective, and surgery was mainly used for biopsy, drainage, or limited excision. Relapses (about 13%) were uncommon and often followed rapid tapering of corticosteroids. GMENA appears to represent a distinct clinicopathologic entity within the spectrum of IGM, characterized by the triad of granulomatous mastitis, EN, and frequently acute oligoarthritis in women of childbearing age. The available evidence supports an underlying immune-mediated mechanism and favors systemic corticosteroids, with early introduction of steroid-sparing immunosuppressants in refractory or relapsing disease. Antibiotics and extensive surgery have limited roles. Further prospective and mechanistic studies are needed to clarify pathogenesis and to optimize long-term management strategies.

Leprosy reactions (LRs) are inflammatory responses observed in 30%-50% of people with leprosy. First-line treatment is glucocorticoids (GCs), often administered at high doses with prolonged courses, resulting in high morbi-mortality. Methotrexate (MTX) is an immunomodulating agent used to treat inflammatory diseases and has an excellent safety profile and worldwide availability. In this study, we describe the efficacy, GCs-sparing effect and safety of MTX in LRs. We conducted a retrospective multicentric study in France consisting of leprosy patients receiving MTX for a reversal reaction (RR) and/or erythema nodosum leprosum (ENL) since 2016. The primary endpoint was the rate of good response (GR) defined as the complete disappearance of inflammatory cutaneous or neurological symptoms without recurrence during MTX treatment. The secondary endpoint was the GCs-sparing effect, safety and clinical relapse after MTX discontinuation. Our study included 13 patients with LRs (8 men, 5 women): 6 had ENL and 7 had RR. All patients had had at least one previous course of GCs and 2 previous treatment lines before starting MTX. Overall, 8/13 (61.5%) patients had GR, allowing for GCs-sparing and even GCs withdrawal in 6/11 (54.5%). No severe adverse effects were observed. Relapse after MTX discontinuation was substantial (42%): the median relapse time was 5.5 months (range 3-14) after stopping treatment. MTX seems to be an effective alternative treatment in LRs, allowing for GCs-sparing with a good safety profile. Furthermore, early introduction during LRs may lead to a better therapeutic response. However, its efficacy seems to suggest prolonged therapy to prevent recurrence.

Erythema nodosum leprosum (ENL) is a severe multisystem immune mediated complication of borderline lepromatous leprosy and lepromatous leprosy. ENL is associated with skin lesions, neuritis, arthritis, dactylitis, eye inflammation, osteitis, orchitis, lymphadenitis and nephritis. The treatment of ENL requires immunosuppression, which is often required for prolonged periods of time and may lead to serious adverse effects. ENL and its treatment is associated with increased mortality and economic hardship. Improved, evidence-based treatments for ENL are needed; however, defining the severity of ENL and outcome measures for treatment studies is difficult because of the multiple organ systems involved. A cross-sectional study was performed, by the members of the Erythema Nodosum Leprosum International STudy (ENLIST) Group, of patients with ENL attending seven leprosy referral centres in Brazil, Ethiopia, India, Nepal, the Philippines and the United Kingdom. We systematically documented the clinical features and type of ENL, its severity and the drugs used to treat it. Patients with chronic ENL were more likely to be assessed as having severe ENL. Pain, the most frequent symptom, assessed using a semi-quantitative scale was significantly worse in individuals with \"severe\" ENL. Our findings will determine the items to be included in a severity scale of ENL which we are developing and validating. The study also provides data on the clinical features of ENL, which can be incorporated into a definition of ENL and used for outcome measures in treatment studies.

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.

Background Idiopathic granulomatous mastitis (IGM) is a rare, chronic inflammatory disease of the breast. The aetiology is unknown. Erythema nodosum (EN) is a rare skin disease associated with IGM. EN is a disease in which the aetiologic factors include infection, malignancy, autoimmune diseases, and pregnancy. Objective The objective of this study was to evaluate the incidence and coexistence of EN with IGM and the approach to treatment. Methods Patients who were admitted to the General Surgery and Dermatology Department of our hospital and diagnosed with EN and IGM were evaluated. Demographic data, symptoms, examination findings, number of birth, smoking, diagnosis and treatment methods, recurrence, and follow‐up periods of the patients were evaluated. Results EN was seen in six of the patients admitted to the clinic for IGM. Four patients with EN had pregnancy and all had arthritis. Two patients were not pregnant. Oral methylprednisolone treatment was started in patients whose IGM diagnosis was verified pathologically. Conclusion IGM may be associated with extramammary symptoms such as EN, arthralgia, and episcleritis. These extramammary findings suggest that IGM may be an autoimmune disease. For this reason, breast examination and history of IGM of the breast should be questioned in female patients admitted to different clinics with EN. This way, delays in the diagnosis and treatment of IGM can be prevented.