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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.

Leprosy is a disease caused by Mycobacterium leprae where the clinical spectrum correlates with the patient immune response. Erythema Nodosum Leprosum (ENL) is an immune-mediated inflammatory complication, which causes significant morbidity in affected leprosy patients. The underlying cause of ENL is not conclusively known. However, immune-complexes and cell-mediated immunity have been suggested in the pathogenesis of ENL. The aim of this study was to investigate the regulatory T-cells in patients with ENL. Forty-six untreated patients with ENL and 31 non-reactional lepromatous leprosy (LL) patient controls visiting ALERT Hospital, Ethiopia were enrolled to the study. Blood samples were obtained before, during and after prednisolone treatment of ENL cases. Peripheral blood mononuclear cells (PBMCs) were isolated and used for immunophenotyping of regulatory T-cells by flow cytometry. Five markers: CD3, CD4 or CD8, CD25, CD27 and FoxP3 were used to define CD4+ and CD8+ regulatory T-cells. Clinical and histopathological data were obtained as supplementary information. All patients had been followed for 28 weeks. Patients with ENL reactions had a lower percentage of CD4+ regulatory T-cells (1.7%) than LL patient controls (3.8%) at diagnosis of ENL before treatment. After treatment, the percentage of CD4+regulatory T-cells was not significantly different between the two groups. The percentage of CD8+ regulatory T-cells was not significantly different in ENL and LL controls before and after treatment. Furthermore, patients with ENL had higher percentage of CD4+ T-ells and CD4+/CD8+ T-cells ratio than LL patient controls before treatment. The expression of CD25 on CD4+ and CD8+ T-cells was not significantly different in ENL and LL controls suggesting that CD25 expression is not associated with ENL reactions while FoxP3 expression on CD4+ T-cells was significantly lower in patients with ENL than in LL controls. We also found that prednisolone treatment of patients with ENL reactions suppresses CD4+ T-cell but not CD8+ T-cell frequencies. Hence, ENL is associated with lower levels of T regulatory cells and higher CD4+/CD8+ T-cell ratio. We suggest that this loss of regulation is one of the causes of ENL.

Background:Behçet’s disease (BD) is characterized by heterogeneity of clinical manifestations due to involvement of variable blood vessels.Objectives:to identify clinical phenotypes using cluster analysis.Methods:a model-based clustering relaying on 16 clinical variables was performed in a retrospective cohort of 120 BD patients, diagnosed and follow-up from January 1, 1980 to December 31, 2019 in 3 hospital at Northern Spain (Cantabria). Chi-square test and ANOVA were used to compare categorical and continuous variables among groups. Two-sample t-tests and the partition of Pearson’s chi-square statistic were used in pairwise comparisons.Results:Four groups were identified in this study: C1 (n=47; 39.2%), C2 (n=33; 27.5%), C3 (n=33; 27.5%) and C4 (n=7; 5.8%). The clusters were defined as follows: C1 as mucosal involvement, C2 as joint involvement and pseudofolliculitis, C3 as neurological and vascular involvement and C4 as uveitis and erythema nodosum. No baseline demographic differences between clusters and no differences in the application of classification criteria were observed (Table 1). Oral ulcers were predominant in all clusters, ranging from 85.7% (C4) to 95-97% (C1-C2), with no significant differences. However, a higher frequency of genital ulcers was observed in C1 compared to the other clusters. Similarly, a significantly higher frequency of erythema nodosum was observed in C4 (85.7%) and of pseudofolliculitis in C2 (93.9%) (p<0.001). In addition, arterial involvement was more prevalent in C4 (100%, p<0.001) but there were no differences in venous thrombotic involvement. Aneurysms were only observed in C4 (Figure 1).Conclusion:we have defined 4 BD phenotypes in our study. This cluster approach may be useful for better patient management due to early identification of clinical patterns.REFERENCES:NIL.Table 1.Characteristics of patients with Behçet’s syndrome after clustering on clinical manifestationsWhole cohort (N=120)C1 (n=47)C2 (n=33)C3 (n=33)C4(n=7)p-valueDemographicsAge at diagnosis, years±SD37.6±13.837.0±16.036.6±11.039.2±13.638.9±12.30.9Gender, females (%)58 (48.3)19 (40.4)15 (45.5)20 (60.6)4 (57.1)0.3Classification criteriaISG (%)59 (49.2)25 (53.2)18 (54.5)13 (39.4)3 (42.9)0.6ITR-ICBD (%)96 (80.0)39 (83.0)22 (66.7)28 (84.8)7 (100)0.1ITR-ICBD score, mean±SD4.8±1.64.8±1.64.7±1.64.9±1.65.6±1.30.6HLA-B51 (%)43 (35.8)19 (40.4)13 (39.4)10 (30.3)1 (14.3)0.5Clinical manifestationOral ulcer (%)113 (94.2)45 (95.7)32 (97.0)30 (90.9)6 (85.7)0.5Genital ulcer (%)71 (59.2)32 (68.1)14 (42.4)22 (66.7)3 (42.9)0.08Ocular involvement (%)54 (45.0)18 (38.3)17 (51.5)15 (45.5)4 (57.1)0.6Epiescleritis (%)4 (3.3)2 (4.3)1 (3.0)1 (3.0)00.9PUK (%)1 (0.8)01 (3.0)000.4Uveitis (%)47 (39.2)16 (34.0)13 (39.4)14 (42.4)4 (57.1)0.7Anterior17 (35.4)4 (25.0)7 (53.8)5 (33.3)1 (25.0)Intermediate3 (6.3)1 (6.3)02 (13.3)0Posterior15 (31.3)4 (25.0)4 (30.8)6 (40.0)1 (25.0)Panuveitis13 (27.1)7 (43.8)2 (15.4)2 (13.3)2 (50.0)Skin lesions (%)76 (63.3)27 (57.4)32 (97.0)11 (33.3)6 (85.7)<0.001Erythema nodosum32 (26.7)6 (12.8)12 (36.4)8 (24.2)6 (85.7)<0.001Pseudofolliculitis57 (47.5)22 (46.8)31 (93.9)3 (9.1)1 (14.3)<0.001Raynaud3 (2.5)3 (6.4)0000.2Joint involvement (%)79 (65.8)10 (21.3)33 (100)32 (97.2)4 (57.1)<0.001Arthralgia73 (60.8)4 (8.5)33 (100)32 (97.0)4 (57.1)<0.001Arthritis46 (38.3)7 (14.9)21 (63.6)14 (42.4)4 (57.1)<0.001Neurological involvement (%)23 (19.2)6 (12.8)2 (6.1)14 (42.4)1 (14.3)0.001Parenchymal13 (10.8)3 (6.4)2 (6.2)8 (24.2)00.03Non.parenchymal13 (10.8)3 (6.4)09 (27.3)1 (14.3)0.03Vascular involvement (%)12 (10.0)3 (6.4)08 (24.2)1 (14.3)0.08Arterial thrombosis14 (11.7)2 (4.3)2 (6.1)3 (9.1)7 (100)<0.001DVT1 (0.8)001 (3.0)00.4Aneurysms7 (5.8)0007 (100)<0.001Intestinal involvement (%)8 (6.7)2 (4.3)2 (6.1)4 (12.1)00.5SD: standard deviation; ISG: International Study Group; ITR-ICBD: International Team For The Revision of The International Criteria; DVT: Deep venous thrombosis.Figure 1.Dendrogram of the hierarchical clustering leading to four clusters.Acknowledgements:NIL.Disclosure of Interests:None declared.

Background Takayasu arteritis (TAK) is a systemic disease characterized by large vessel involvement. Although the vascular characteristics of TAK are well characterized, there is no well-organized study demonstrating the extravascular manifestations of TAK. We aimed to evaluate the characteristics of extravascular manifestations of TAK, and to identify the association between vascular and extravascular manifestations of TAK. Methods TAK patients from two independent cohorts between January 2012 and October 2017 were included in the study. Patient characteristics were retrospectively collected from the electronic dataset. The computed tomography scans of all subjects were reviewed to evaluate the pattern of vascular involvement and presence of sacroiliitis. Clinical findings including uveitis, skin lesions, oral ulcers, arthritis, and inflammatory bowel disease (IBD) were reviewed. Logistic regression analysis was performed to evaluate the association between vascular and extravascular manifestations. Results For the 268 TAK patients, the mean age at diagnosis was 41.2 ± 14.2 years and 88.1% were female. The extravascular manifestation of TAK was observed in 19.0% of patients, the most common being arthritis including sacroiliitis (11.9%) followed by recurrent oral ulcers (8.6%) and IBD (2.6%). A multivariate logistic regression analysis revealed type IIB vascular involvement (adjusted odds ratio (OR) 2.956, 95% confidence interval (CI) 1.337–6.537, p  = 0.007) and the erythrocyte sedimentation rate (ESR) (adjusted OR 1.014, 95% CI 1.003–1.025, p  = 0.012) as significantly associated with the presence of axial and peripheral arthritis. Conclusions Extravascular manifestations of TAK were observed in up to one-fifth of patients. The most common extravascular manifestation was arthritis, which was associated with a type IIB vascular involvement pattern and a high ESR.

Purpose Leprosy is a chronic infectious disease caused by Mycobacterium leprae affecting mainly skin and peripheral nerves. Acute inflammatory episodes in the borderline immunological spectrum of the disease cause severe nerve and tissue damage leading to deformities. Finding of any serological marker for leprosy reactions will help in prediction of reactions and in early treatment intervention. The objective of this study was to measure the serum circulatory levels of Interleukin 17F (IL 17F) and to correlate the levels with type 1 and type 2 reactional states and with clinico-histopathological spectrum of leprosy. We studied IL 17F to delineate its role and its clinical implications in leprosy reactions. Methods Patients were classified based on the Ridley DS and Jopling WH Classification and blood samples (5 ml each) were collected from 80 active untreated leprosy cases in Type 1 reaction (T1R), 21 cases in Type 2 (Erythema Nodosum Leprosum ENL) reaction (T2R), 80 cases without reaction (NR), and 94 non-leprosy cases (NL). Serum was separated and measured for IL 17F levels using ELISA (Commercial Kits, R&D Systems Inc., USA). Results IL 17F levels were significantly higher in the T1R group when compared to the NR group ( p  <  0.001 ). The borderline lepromatous group showed the highest levels of IL 17F among the other groups in the disease spectrum. Bacteriological index (BI) showed negative correlation with the IL 17F levels. Conclusion The results specify that serum circulatory levels of IL 17F are elevated during T1Rs in the borderline spectrum of the disease and thus may play a role in the regulation of inflammatory responses associated with reactions in leprosy.

Background:Behçet’s disease (BD) is a systemic, chronic, relapsing vasculitis with no pathognomonic diagnostic test. The most widely used classification criteria are those of the International Study Group (ISG) for BD (1). These criteria were repeatedly found to have low sensitivity. Therefore, the International Criteria for Behçet’s Disease (ICBD) were published in 2014 (2).Objectives:To compare the ISG with ICBD diagnostic criteria for BD.Methods:The study included all consecutive 111 patients diagnosed with definitive or possible BD by expert rheumatologists. They were diagnosed at a well-defined population in Northern Spain between 1980 and 2019. The ISG and ICBD diagnostic criteria for BD were applied to and compared among all patients.Results:We studied 111 patients (62 Women/49 Men), mean age 36.8±13.2 years. BD was diagnosed in 65 (58.5%) by ISGBD criteria and in 86 (77.5%) by ICBD criteria. No significant differences were observed between both criteria (p < 0.001). The overall concordance was fair (Kappa 0.3; p<0.001). Sensitivity was 58.6% for ICBD criteria and 80.2% for ISG. (TABLE-1)Conclusion:ICBD criteria exhibit higher sensitivity than ISG criteria. Thus, the application of these new criteria can achieve a more correct and earlier diagnosis of BD.References:[1]Criteria for diagnosis of Behcet’s disease, International Study Group for Behçet’s Disease,The Lancet, Volume 335, Issue 8697, 1078 – 1080[2]The International Criteria for Behçet’s Disease (ICBD): a collaborative study of 27 countries on the sensitivity and specificity of the new criteria, J Eur Acad Dermatol Venereol. 2014; 28:338-47TABLE 1Expert diagnosis (N=111)ISG criteria -(N=65)ICBD criteria (N=86)Age, mean (SD)36.7 (13.2)36 (12.8)36.7 (13)Gender, men/women, N (%)49/62 (44.1/55.8)29/36 (44.6/55.4)38/48 (44.2/55.8)Oral aphthosis110 (99)65 (100)85 (100) -Recurrent (3 times/year)91 (87.2)61 (93.8)74 (86)Genital aphthosis59 (53.1)42 (64.6)56 (65.1)Skin manifestations76 (68.4)56 (86.15)71 (70.9) -Pseudofolliculitis/ Erythema nodosum51 (67.1)/ 27 (35.5)38 (58.5)/ 21 (32.3)42 (68.8)/ 22 (36.1)Ocular lesions39 (35.1)32 (49.2)39 (45.3) -Anterior/ Posterior/ Panuveitis17 (43.6);12 (30.8)/ 016 (50)/ 8(25)/ 7 (21.9)17 (45.6); 0; 12 (30.8) -Retinal vasculitis4 (10.3)1 (3.1)4 (10.6)Joint manifestations76 (68.5)43 (66.1)58 (67.4) -Arthralgias / Arthritis69 (92.8)/ 45 (60)39 (90.7)/ 24 (55.8)52 (89.6)/ 33 (56.9)Neurological manifestations20 (18)11 (16.9)16 (18.6) -Peripheral / Central11 (55)/ 14 (70)7 (63.6)/ 7 (63.6)12 (75)/ 10 (62.5)Vascular manifestations9 (8.6)7 (10.8)10 (11.6) -Arterial/ Vein thrombosis/ Phlebitis0/ 5 (55)/ 1 (11.1)0/ 4 (57.1)/ 1 (14.3)1 (12.5)/ 5 (62.5)/0Gastrointestinal features4 (4.5)4 (6.1)4 (4.6)Pathergy test positive (available data; %)6 (28; 21.4)4 (19; 21)4 (25, 16)HLA B51 positive (available data; %)38 (86; 44.2)19 (47; 40.4)28 (63; 44.4)Disclosure of Interests:Carmen Alvarez Reguera: None declared, Alba Herrero Morant: None declared, Lara Sanchez Bilbao: None declared, David Martínez-López: None declared, José Luis Martín-Varillas Grant/research support from: AbbVie, Pfizer, Janssen and Celgene, Speakers bureau: Pfizer and Lilly, Guillermo Suárez Amorín: None declared, Patricia Setien Preciados: None declared, M. Cristina Mata Arnaiz: None declared, Miguel Á. González-Gay Grant/research support from: AbbVie, MSD and Roche, Speakers bureau: AbbVie, MSD and Roche, Ricardo Blanco Grant/research support from: Abbvie, MSD and Roche, Consultant of: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen and MSD, Speakers bureau: Abbvie, Pfizer, Roche, Bristol-Myers, Janssen, Lilly and MSD

Background The major factors contributing for nerve damage and permanent disabilities in leprosy are type 1 or reversal reactions (RR) and type 2 or erythema nodosum leprosum (ENL). Gene profiling of leprosy reactions have shown that different pathways are activated during the course of reactions, which is consistent with the exacerbated immune response exhibited by these patients. Methods We used qPCR to screen a panel of 90 genes related to the immune response in leprosy in RNA-derived peripheral leukocytes of patients with ( N  = 94) and without leprosy reactions ( N  = 57) in order to define expression signatures correlated to RR or ENL. Results Our results show that there is a marked signature for RR in the blood, comprising genes mostly related to the innate immune responses, including type I IFN components, autophagy, parkins and Toll like receptors. On the other hand, only Parkin was differentially expressed in the ENL group. Conclusions The data put together corroborates previous work that brings evidence that an acute uncontrolled exacerbated immune response designed to contain the spread of M. leprae antigens might be cause of RR pathogenesis. Identifying a blood profile useful to predict leprosy reactions prior to its development might help to reduce the morbidity associated to this disabling disease.

The panniculitides remain as one of the most challenging areas for clinicians, as they comprise a heterogeneous group of inflammatory diseases involving the subcutaneous fat with potentially-shared clinical and histopathological features. Clinically, most panniculitides present as red edematous nodules or plaques. Therefore, in addition to a detailed clinical history, a large scalpel biopsy of a recent-stage lesion with adequate representation of the subcutaneous tissue is essential to specific diagnosis and appropriate clinical management. Herein we review the panniculitides of particular interest to the rheumatologist.

Background: Melioidosis, caused by Burkholderia pseudomallei, is a severe and often underdiagnosed infection endemic to South Asia, Southeast Asia, and northern Australia. While pneumonia and sepsis are the classical presentations, the disease is increasingly recognized for its diverse and atypical clinical manifestations. Objective: The objective is to improve diagnostic accuracy and increase clinical awareness in both endemic and non-endemic settings by reviewing and classifying atypical presentations of melioidosis that have been documented in the literature. Methods: A narrative, case-based review was conducted using 238 published case reports and series from endemic and transitional regions during the period from 2000 to 2025. Cases with non-respiratory presentations or anatomical locations not commonly linked to melioidosis were classified as atypical. Clinical syndromes were used to classify the extracted cases, and common patterns in presentation, diagnosis, and outcome were examined. Results: One hundred and sixty published articles were included after a full text review. The most frequent atypical presentations included neurological involvement (e.g., brain abscess, encephalomyelitis), musculoskeletal infections (osteomyelitis, myositis), thyroid abscess, tubo-ovarian abscess, and dermatologic manifestations such as erythema nodosum. Imported and pediatric cases were also found. Numerous cases were misidentified as cancer, fungal infections, or tuberculosis. Among risk factors, diabetes mellitus was the most prevalent. Non-specific symptoms, a lack of laboratory capacity, and incorrect pathogen identification frequently resulted in delays in diagnosis. Conclusions: In endemic areas, melioidosis should be taken into account when making a differential diagnosis of a variety of clinical syndromes, especially in patients who have diabetes or have had relevant environmental exposure. Poor outcomes and diagnostic delays are greatly exacerbated by atypical presentations. Improving diagnostic capabilities and raising awareness are crucial to lessening the worldwide burden of this often ignored but potentially deadly infection.

Background This study reports on the analysis of the application and diagnostic predictability of the revised 2014 ICBD criteria in an unselected cohort of UK patients, and the ensuing organ associations and patterns of disease. Methods A retrospective cohort study was conducted using a database of electronic medical records. Three categories were recognised: clinically defined BD, incomplete BD and rejected diagnoses of BD. We applied the ISG 1990 and ICBD 2014 classification criteria to these subgroups to validate diagnostic accuracy against the multidisciplinary assessment. Results Between 2012 and 2015, 281 patients underwent initial assessment at an urban tertiary care centre: 190 patients with a confirmed diagnosis of BD, 7 with an incomplete diagnosis, and 84 with a rejected diagnosis. ICBD 2014 demonstrated an estimated sensitivity of 97.89% (95% CI: 94.70 to 99.42) and positive likelihood ratio of 1.21 (1.10 to 1.28). The strongest independent predictors were: Central nervous lesions (OR = 10.57, 95% CI: 1.34 to 83.30); Genital ulceration (OR = 9.05, 95% CI: 3.35 to 24.47); Erythema nodosum (OR = 6.59, 95% CI: 2.35 to 18.51); Retinal vasculitis (OR = 6.25, 95% CI: 1.47 to 26.60); Anterior uveitis (OR = 6.16, 95% CI: 2.37 to 16.02); Posterior uveitis (OR = 4.82, 95% CI: 1.25 to 18.59). Conclusions The ICBD 2014 criteria were more sensitive at picking up cases than ISG 1990 using the multidisciplinary assessment as the gold standard. ICBD may over-diagnose BD in a UK population. Patients who have an incomplete form of BD represent a distinct group that should not be given an early diagnostic label. Behçet’s disease is a complex disease that is best diagnosed by multidisciplinary clinical assessment. Patients in the UK differ in their clinical presentation and genetic susceptibility from the original descriptions. This study also highlights an incomplete group of Behçet’s patients that are less well defined by their clinical presentation.