Toxoplasma gondii infection and high levels of IgE are associated to erythema nodosum leprosy (ENL).

Leprosy is a chronic infectious disease caused by the bacillus Mycobacterium leprae. The disease may evolve for inflammatory reactions, reversal reaction (RR) and erythema nodosum leprosum (ENL), the major cause of irreversible neuropathy in leprosy, which occur in 1 in 3 people with leprosy, even with effective treatment of M. leprae. Leprosy remains persistently endemic in our region where it predominantly affects lowest socioeconomic conditions people, as Toxoplasma gondii infection in the municipality studied. Previously, we have shown T. gondii coinfection as a risk marker for leprosy, mainly in its severe form. This present study assessed whether T. gondii infection is also a risk factor for leprosy reactions and the predictive value of immunoglobulin production prior to development of leprosy reactions. Patients with leprosy (n = 180), co-infected or not with T. gondii, had their serum investigated for levels of IgA, IgE, IgG1, IgG2, IgG3 and IgG4 anti-PGL-1 by ELISA prior to development of leprosy reactions. The serologic prevalence for T. gondii infection was 87.7% in leprosy reaction patients reaching 90.9% in those with ENL. The leprosy reaction risk increased in T. gondii seropositive individuals was two-fold ([OR] = 2.366; 95% confidence interval [CI 95%]: 1.024-5.469) higher than those seronegative, and considering the risk of ENL, this increase was even more evident (OR = 6.753; 95% CI: 1.050-72.85) in coinfected individuals. When evaluated the prediction of anti-PGL-1 immunoglobulin levels for development of leprosy reactions in patients coinfected or not with T. gondii, only the increase IgE levels were associated to occurrence of reactional episodes of leprosy, specifically ENL type, in patients coinfected with T. gondii, compared to those not coinfected or no reaction. Thus, the immunomodulation in co-parasitism T. gondii-M. leprae suggest increased levels of IgE as a biomarker for early detection of these acute inflammatory episodes and thereby help prevent permanent neuropathy and disability in leprosy patients.

Erythema nodosum in northern Finland between 1996 and 2019: A register-based study.

Erythema nodosum (EN) is seen at any age with varying and often unidentified etiology. We studied the etiology and characteristics of EN in Northern Finland. Medical records of all patients with a diagnosis code for EN between 1996 and 2019 from Oulu University Hospital were retrieved and analyzed. There were in total 142 EN cases with a female predominance (n = 112, 72.9%). The mean age of the patients was 35.9 years. There were five cases diagnosed with EN in those younger than 2 years of age. Almost one third had EN nodules in multiple anatomical locations. In addition to skin findings, systemic symptoms were common (81.0%), and seen more often in men (p < 0.05). In children and adolescents, the most common etiological factors were gastroenteritis caused by 'Yersinia, Salmonella or Campylobacter', followed by inflammatory bowel diseases and hormonal contraception. Bacterial infections were the most common etiological factor among adults. In 28.2% of the cases there was no identified causative factor. In this study, EN was seen surprisingly often in small children. Etiological factors varied markedly among different age groups and symptoms differed between the sexes in adults. These aspects should be taken into account when diagnosing EN patients.

Whole blood transcriptomics reveals the enrichment of neutrophil activation pathways during erythema nodosum leprosum reaction.

Introduction: Patients with the multibacillary form of leprosy can develop reactional episodes of acute inflammation, known as erythema nodosum leprosum (ENL), which are characterized by the appearance of painful cutaneous nodules and systemic symptoms. Neutrophils have been recognized to play a role in the pathogenesis of ENL, and recent global transcriptomic analysis revealed neutrophil-related processes as a signature of ENL skin lesions. Methods: In this study, we expanded this analysis to the blood compartment, comparing whole blood transcriptomics of patients with non-reactional lepromatous leprosy at diagnosis (LL, n=7) and patients with ENL before administration of anti-reactional treatment (ENL, n=15). Furthermore, a follow-up study was performed with patients experiencing an ENL episode at the time of diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Validation in an independent cohort (ENL=8; LL=7) was performed by RT-qPCR. Results: An enrichment of neutrophil activation and degranulation-related genes was observed in the ENL group, with the gene for the neutrophil activation marker CD177 being the most enriched gene of ENL episode when compared to its expression in the LL group. A more pro-inflammatory transcriptome was also observed, with increased expression of genes related to innate immunity. Validation in an independent cohort indicated that S100A8 expression could discriminate ENL from LL. Supernatants of blood cells stimulated in vitro with Mycobacterium leprae sonicate showed higher levels of CD177 compared to the level of untreated cells, indicating that the leprosy bacillus can activate neutrophils expressing CD177. Of note, suggestive higher CD177 protein levels were found in the sera of patients with severe/moderate ENL episodes when compared with patients with mild episodes and LL patients, highlighting CD177 as a potential systemic marker of ENL severity that deserves future confirmation. Furthermore, a follow-up study was performed with patients at the time of ENL diagnosis and after 7 days of thalidomide treatment (THAL, n=10). Enrichment of neutrophil pathways was sustained in the transcriptomic profile of patients undergoing treatment; however, important immune targets that might be relevant to the effect of thalidomide at a systemic level, particularly NLRP6 and IL5RA, were revealed. Discussion: In conclusion, our study reinforces the key role played by neutrophils in ENL pathogenesis and shed lights on potential diagnostic candidates and novel therapeutic targets that could benefit patients with leprosy.

To ASLO or Not to ASLO: Utility of the ASLO Test in Dermatology.

BACKGROUND: Group A Streptococcus (GAS) causes a wide spectrum of acute infections and immune-related diseases, most of which include a dermatological presentation. However, dermatological findings have a wide range of other possible etiologies. The diagnosis of GAS-related disease requires an indication of preceding GAS infection by direct culture or by measuring antistreptolysin O (ASLO) titer. OBJECTIVES: To explore the correlation between ASLO positivity and dermatological diseases. METHODS: We analyzed clinical data from all cases of patients over 18 years of age who underwent ASLO testing between the years 2016 and 2020 in the Department of Dermatology at Rambam Health Care Campus. RESULTS: Of 152 adult patients with ASLO tests, 100 had diagnoses that were potentially related to streptococcal infection. Vasculitis and psoriasis were the most suspected diagnoses. Positive ASLO test was found in 44 (29%) patients. The diagnoses showing the highest ratio of positive ASLO were psoriasis (60%), erythema nodosum (46%), skin infections (43%), Sweet syndrome (33%), and vasculitis (15%). Psoriasis types included plaque psoriasis (8 patients), guttate psoriasis (3 patients), and palmoplantar pustulosis and erythroderma (2 patients each). CONCLUSIONS: Although the applicability of ASLO for the spectrum of dermatological diseases remains unclear, our results enhance the practical relevance of the test. We showed a higher prevalence of positive ASLO tests in psoriasis and erythema nodosum cases and a lower prevalence in vasculitis. Notably, ASLO was positive in all psoriasis subtypes, suggesting high utility of the test for psoriasis.

Successful treatment of erythema nodosum with salazosulfapyridine in a 9-year-old patient with chronic non-bacterial osteomyelitis.

We report a 9-year-old Japanese girl with chronic non-bacterial osteomyelitis (CNO) accompanied by recurrent erythema nodosum (EN) which was successfully treated with salazosulfapyridine (SASP). She was referred to our hospital because of recurrent erythema on her lower extremities and persistent knee and ankle arthralgia, which had been present for approximately 1 year. Although naproxen, a nonsteroidal anti-inflammatory drug, was initiated, her symptoms frequently recurred. Magnetic resonance imaging demonstrated multiple distinct high-intensity signals in the talus bones suggestive of multiple bone oedemas. Additionally, a histological examination of erythematous lesions was consistent with the histopathological findings of EN. She was diagnosed as having CNO complicated by EN, and received 250 mg/day of SASP as a second-line treatment, which showed partial response of both skin and bone lesions. Following increase in the dose of SASP to 500 mg/day resulted in complete remission of her skin and bone lesions. In conclusion, our findings suggest that SASP is effective not only for CNO bone lesions but also for EN. SASP could serve as a second-line therapeutic option at least for some cases of CNO complicated by EN refractory to nonsteroidal anti-inflammatory drugs.

A retrospective clinicopathological study of erythema nodosum.

Erythema nodosum (EN) may be idiopathic or secondary, and usually resolves naturally within 1-2 months. In atypical EN cases, the rash extends beyond the lower limbs to the upper limbs and trunk, and histopathological findings may be accompanied by vasculitis in addition to septal panniculitis. Few studies have examined the differences in the clinical characteristics of patients with EN based on rash distribution. We retrospectively examined whether there was a correlation with clinical information, such as the presence or absence of underlying diseases, by classifying the patients into two groups: the lower limbs group (the EN rash was confined to the lower limbs) and the beyond lower limbs group (the EN rash appeared beyond the lower limbs). Among the 86 adult patients diagnosed with EN at the Dermatology Department of Fujita Medical University between 2015 and 2020, there were 65 cases of the lower limbs group and 21 cases of the beyond lower limbs group. The frequency of underlying diseases was significantly higher in the beyond lower limbs group (76.2%, 16 cases) than in the lower limbs group (40.0%, 26 cases; P < 0.005). Vasculitis was more notable in the beyond lower limbs group (P < 0.05). Significantly higher vasculitis was noted in the EN group with underlying diseases (30.2%, 13 cases) than in the idiopathic EN group without underlying diseases (11.6%, 5 cases; P < 0.05). Neutrophil extracellular traps were positive in approximately 40% of cases in both groups. In the beyond lower limbs group, the possibility of severe cases with underlying diseases, vasculitis, and inflammation must be considered for effective treatment.

Immune pathogenesis of idiopathic granulomatous mastitis: from etiology toward therapeutic approaches.

Idiopathic granulomatous mastitis (IGM) is a noncancerous, chronic inflammatory disorder of breast with unknown causes, posing significant challenges to the quality of life due to its high refractoriness and local aggressiveness. The typical symptoms of this disease involve skin redness, a firm and tender breast mass and mastalgia; others may include swelling, fistula, abscess (often without fever), nipple retraction, and peau d'orange appearance. IGM often mimics breast abscesses or malignancies, particularly inflammatory breast cancer, and is characterized by absent standardized treatment options, inconsistent patient response and unknown mechanism. Definite diagnosis of this disease relies on core needle biopsy and histopathological examination. The prevailing etiological theory suggests that IGM is an autoimmune disease, as some patients respond well to steroid treatment. Additionally, the presence of concurrent erythema nodosum or other autoimmune conditions supports the autoimmune nature of the disease. Based on current knowledge, this review aims to elucidate the autoimmune-favored features of IGM and explore its potential etiologies. Furthermore, we discuss the immune-mediated pathogenesis of IGM using existing research and propose immunotherapeutic strategies for managing this condition.

Causal relationship between inflammatory bowel disease and erythema nodosum: A two-sample bidirectional Mendelian randomization study.

BACKGROUND: Previous studies have demonstrated the coexistence of erythema nodosum (EN) and inflammatory bowel disease (IBD), while the exact etiology of the co-occurrence of the two disorders remains uncertain. METHODS: A bidirectional two-sample Mendelian randomization (MR) design was employed to determine the causal link between EN and IBD. Genetic variations associated with Crohn's disease (CD) and ulcerative colitis (UC) were derived from accessible genome-wide association studies pertaining to European ancestry. The FinnGen database was used to find the genetic variations containing EN. In the forward model, IBD was identified as the exposure, whereas in the reverse model, EN was identified as the exposure. The causal link between IBD and EN was examined using a range of different analysis techniques, the primary one being the inverse variance weighted (IVW) method, including inverse variance weighted-fixed effects (IVW-FE) and inverse-variance weighted-multiplicative random effects (IVW-MRE). To strengthen the results, assessments of sensitivity, heterogeneity, and pleiotropy were also conducted. RESULTS: MR results showed that IBD increased the risk of EN (IVW-MRE: OR = 1.242, 95% CI = 1.068-1.443, p = 0.005). Furthermore, there was a strong correlation found between CD and a higher risk of EN (IVW-FE: OR = 1.250, 95% CI = 1.119-1.396, p = 8.036 × 10-5 ). However, UC did not appear to be linked to EN (IVW-FE: OR = 1.104, 95% CI = 0.868-1.405, p = 0.421). The reverse MR analysis findings did not imply that EN was linked to IBD. Horizontal pleiotropy did not appear to exist, and the robustness of these findings was confirmed. CONCLUSION: The current investigation found that in European populations, IBD and its subtype CD could raise the incidence of EN.

[Hansen's Disease: An Unusual Manifestation of an Ancient Disease]. / Doença de Hansen: Apresentação Incomum de uma Doença Antiga.

Hansen's disease, commonly known as leprosy, is an infectious disease caused by Mycobacterium leprae. Being rare in developed countries, it is an increasingly common imported disease due to the migratory flow from countries where it is endemic. We present the case of a 21-year-old man who went to the emergency department with complaints of additive polyarthralgia involving large joints, papules, and erythematous plaques on the limbs with bullae and central necrosis and fever with chills for one week. Skin biopsy was performed revealing neutrophilic infiltrate with perineural granulomas. The bacilloscopy detected acid-alcohol resistant bacilli. The diagnosis of multibacillary HD with type 2 lepromatous reaction (erythema nodosum leprosum - ENL) was established, showing clinical improvement under corticosteroid therapy. ENL usually presents with painful lesions, being an atypical presentation of leprosy, especially in the presence of bullae and necrosis, making diagnosis difficult and challenging. Social stigma is often present making it difficult to accept the disease as well as adherence to treatment.

A doença de Hansen, vulgarmente conhecida como lepra, é uma doença infecciosa causada por Mycobacterium leprae. Sendo rara nos países desenvolvidos, configura uma doença de importação cada vez mais frequente considerando o fluxo migratório de países onde é endémica. Apresentamos o caso de um homem de 21 anos que recorreu ao serviço de urgência por poliartralgias de caráter aditivo envolvendo grandes articulações, pápulas e placas eritematosas nos membros com bolhas e necrose central e febre com calafrio com uma semana de evolução. Foi realizada biópsia cutânea que revelou infiltrado neutrofílico com granulomas de distribuição perineural e baciloscopia com deteção de bacilos ácido-álcool resistentes. Foi estabelecido o diagnóstico de DH multibacilar com reação lepromatosa tipo 2 (eritema nodoso leproso), apresentando melhoria clínica sob corticoterapia. O eritema nodoso leproso cursa habitualmente com lesões dolorosas, configurando uma apresentação atípica de lepra, sobretudo na presença de bolhas e necrose, tornando este diagnóstico altamente desafiante. O estigma social é frequentemente limitativo na aceitação da doença e adesão ao tratamento.

Atypical and Typical Presentation of Erythema Nodosum: Clinical Differences in Treatment and Outcome.

INTRODUCTION: Erythema nodosum (EN) is the most common form of panniculitis that predominantly affects the shins. While EN in atypical sites has been described by many authors, there are currently only case studies published on this topic. This study aimed to evaluate clinical differences between patients suffering from EN on the shins, compared to patients with EN in atypical locations. METHODS: We analyzed 105 patients in a retrospective, single-center study at a university hospital in Switzerland. Typical EN was defined as lesions, found only on the lower legs, while atypical EN as lesions on the upper legs, trunk, arms, or face, only or in addition to lesions on the lower legs. The patients were assessed for age, gender, dermatologic history, time until first medical consultation, time to diagnosis, and time until remission. Further, etiology, symptoms, and applied therapies were investigated. Findings were then compared between the typical and atypical EN cohorts. RESULTS: Overall, we included 70 patients (37.99 ± 15.67 [3-81] years) with EN solely on the shins and 35 patients (41.27 ± 16.85 [9-76] years) with EN on other locations. Interestingly, time until diagnosis was significantly shorter in atypical EN (p = 0.034, 1.14 ± 4.68 vs. 0.46 ± 1.14 months). Time to remission was similar in both groups (3.61 ± 2.73 vs. 3.05 ± 2.86 months, respectively). Sarcoidosis was the only etiologic factor significantly more frequent in atypical EN compared to typical EN (23% vs. 9%, p = 0.042). Besides that, solely subtle differences were seen regarding etiology, gender, age at onset, course of the disease, and symptoms. CONCLUSIONS: Our study suggests that only minor alterations between both study populations exist. Significant differences were found in time to diagnosis (shorter for atypical EN), as well as in sarcoidosis as an etiologic factor (more frequent in atypical EN). While adalimumab was only prescribed in atypical EN cases, prognosis seems to be similar for typical and atypical EN (similar time to remission, similar amount of reoccurring cases). Due to the limited sample size, however, our study population may have been too small to detect the relevant differences, and bigger studies may be needed.

MicroRNAs correlate with bacillary index and genes associated to cell death processes in leprosy.

Mycobacterium leprae infects skin and peripheral nerves causing a broad of clinical forms. MicroRNAs (miRNAs) control immune mechanisms such as apoptosis, autophagy as well as to target genes leading to abnormal proliferation, metastasis, and invasion of cells. Herein we evaluated miRNAs expression for leprosy phenotypes in biopsies obtained from patients with and without reactions. We also correlated those miRNAs with both, bacillary index (BI) and genes involved in the micobacteria elimination process. Our results show a significant increase in the miR-125a-3p expression in paucibacillary (PB) patients vs multibacillary (MB) subjects (p = 0.007) and vs reversal reactions (RR) (p = 0.005), respectively. Likewise, there was a higher expression of miR-125a-3p in patients with erythema nodosum leprosum (ENL) vs MB without reactions (p = 0.002). Furthermore, there was a positive correlation between miR-125a-3p, miR-146b-5p and miR-132-5p expression and BI in patients with RR and ENL. These miRNAS were also correlated with genes such as ATG12 (miR-125a-3p), TNFRSF10A (miR-146b-5p), PARK2, CFLAR and STX7 (miR-132-5p). All together we underpin a role for these miRNAs in leprosy pathogenesis, implicating mechanisms such as apoptosis and autophagy in skin. The miR-125a-3p might have a distinct role associated with PB phenotype and ENL in MB patients.

Clinical Characteristics of Erythema Nodosum and Associations With Chronicity and Recurrence.

This cohort study characterizes the presentation, causes, treatment, and disease course of erythema nodosum, as well as identifies associations with chronicity and recurrence.

Reverse Koebner phenomenon in erythema nodosum leprosum.

BACKGROUND: Erythema nodosum leprosum (ENL) is an immunologically mediated phenomenon complicating the course of leprosy. Reverse Koebner phenomenon is the term used to describe the sparing of previously injured or diseased skin by new skin lesions of the disease. METHODS: A middle-aged woman with a known case of lepromatous leprosy for the past year presented with an eruption of reddish painful nodules over her body. The lesions were found to characteristically spare the sites of previous scars. RESULTS: This sparing phenomenon of previous scar sites has been termed reverse Koebner phenomenon, a site of the body that offers greater resistance than the rest of the body to the onset of the disease, seen in various diseases, but it has never been described in ENL. CONCLUSION: This sparing of scar sites in ENL can be attributed to reverse Koebner phenomenon.

Azathioprine hypersensitivity: A Sweet-like syndrome.

INTRODUCTION: Azathioprine hypersensitivity can occasionally present as Sweet-like syndrome, a dose-independent side effect characterized by the unanticipated onset of macules, papules, and pustules. CASE PRESENTATION: A 35-year-old woman with systemic lupus erythematosus presented with complaints of generalized maculopapular rash, facial swelling, and bilateral lower extremity edema with a duration of 4 days and a 2-day history of constitutional symptoms within 2 weeks of the beginning of azathioprine therapy to treat existing lupus nephritis (class 2/3). DISCUSSION: Patients who experience azathioprine hypersensitivity syndrome can present with erythema nodosum, small-vessel vasculitis, acute generalized exanthematous pustulosis, Sweet syndrome, and nonspecific dermatosis. The following signs and symptoms are used as criteria to diagnose drug-induced Sweet syndrome: (a) abrupt onset of painful erythematous plaques, (b) histopathological evidence of dense neutrophilic infiltrate without evidence of leukocytoclastic vasculitis, (c) temperature higher than 39.7°C, (d) temporal relationship between drug ingestion and clinical presentation, and (e) temporal resolution of lesions after drug withdrawal. Our patient met three out of five criteria and was diagnosed with Sweet-like syndrome. CONCLUSION: Our case highlights the uncommonly presented azathioprine-induced Sweet-like syndrome that occurs abruptly after the commencement of the offending drug. This diagnosis can be established through basic laboratory workup and skin biopsy findings.

Case Report: Melioidosis-Related Severe Cutaneous Features of Erythema Nodosum in a Thai Child.

Erythema nodosum (EN) is characterized by rapidly developing, painful, erythematous subcutaneous nodules, most of which are located in the pretibial areas. This cutaneous finding can be caused by a variety of conditions, however Burkholderia pseudomallei is rarely the cause. This particular patient presented with a high-grade fever with characteristic EN on both pretibial areas. All of the typical EN causes were investigated, but the findings were all negative. The lesions progressed to severe hemorrhagic bleb features, and because the patient resided in Northeast Thailand, a melioidosis-endemic region, testing for B. pseudomallei was performed. Because a high level of melioidosis serology of more than 1:10,240 was detected, melioidosis therapy was started. At the 12-week follow-up after melioidosis therapy, the titer had declined to 1:1,280, indicating that melioidosis-related severe, cutaneous EN symptoms were the most likely diagnosis in this patient. We discovered a case of EN with severe hemorrhagic bleb features as a unique clinical manifestation of melioidosis. When a patient resides in an endemic area, B. pseudomallei should always be considered as a possible causative organism.

Chronic type 2 reaction in lepromatous leprosy with underlying Plasmodium falciparum infection: A case report.

Tropical diseases prevalent in leprosy-endemic areas may alter the immunological patient response and also complicate the presentation of leprosy reactional episodes. The introduction of anti-malarial drugs in our case produced a subsidence of reaction. With dwindling manpower skilled in leprosy, the reactional episodes are very often treated with non-steroidal anti-inflammatory drugs, steroids and thalidomide, neglecting the possibility of other co-existing infections, tropical or other. Our case emphasises the importance of history, examination and balanced investigation in the context of tropical diseases in endemic areas before injudicious intervention.