Target/therapies for chronic recurrent erythema nodosum leprosum.

A Type 2 lepra reaction or erythema nodosum leprosum is an anticipated complication in the lepromatous spectrum of leprosy cases. It is an example of an immune complex-mediated complement activated disease (Type III hypersensitivity reaction). Hence, we tried to target the inflammatory mediators and the mental stressors for the possible management strategies.

Löfgren Syndrome with Hypercalcemia and Neuroendocrinological Involvement: A Case Report.

BACKGROUND: Sarcoidosis is a systemic inflammatory disease of unknown etiology that can affect virtually any organ. Löfgren syndrome, characterized by erythema nodosum, hilar lymphadenopathy, fever and polyarthritis, represents only 20-30% of the cases of sarcoidosis. Only 2- 10% of the cases feature hypercalcemia. CASE: The case of a 42-year-old Hispanic woman with a history of erythema nodosum and three weeks of nausea, emesis, constipation, asthenia, adynamia, polydipsia, and somnolence, concomitant with hypercalcemia, but normal parathyroid hormone (PTH) and 25-hydroxyvitamin D has been presented. The initial diagnostic approach was based upon the suspicion of multiple myeloma or bone metastases; however, further findings of bilateral hilar lymphadenopathy, elevated serum angiotensin-converting enzyme (ACE) and a right inguinal lymphadenomegaly suggested an alternate diagnosis. Biopsy of the latter supported sarcoidosis as the diagnosis. She was successfully treated in the hospital with zoledronic acid and as an outpatient with immunosuppressive therapy. Persistence of a previously undisclosed symptom of oligomenorrhea led to the detection of hyperprolactinemia secondary to hypophyseal infiltration, refractory to immunosuppressive therapy but with an adequate response to cabergoline. CONCLUSION: This case strays from Löfgren Syndrome's expected behavior, presenting a more progressive, multisystemic disease. This case report was written in adherence to the CARE guidelines of 2013 to include information in it.

Differential Expression of IFN-γ, IL-10, TLR1, and TLR2 and Their Potential Effects on Downgrading Leprosy Reaction and Erythema Nodosum Leprosum.

Leprosy reactions are acute immunological events that occur during the evolution of chronic infectious disease causing neural damage and disabilities. A study using blood samples of 17 leprosy reaction patients and 17 reaction-free was carried out by means of associations between antigens, receptors, and expression of cytokines, using path analysis providing new insights into the immunological mechanisms involved in triggering leprosy reactions. Toll-like receptors (TLR) such as TLR1 and TLR2, presented balanced expression in the reaction-free multibacillary (MB) group (TLR1: 1.01 ± 0.23, TLR2: 1.22 ± 0.18; p = 0.267). On the other hand, downgrading type 1 reaction (T1R) (TLR1: 1.24 ± 0.17, TLR2: 2.88 ± 0.37; p = 0.002) and erythema nodosum leprosum (ENL) (TLR1: 1.93 ± 0.17, TLR2: 2.81 ± 0.15; p = 0.004) revealed an unbalance in relation to the expression of these receptors. When the path analysis was approached, it was noted that interleukin 10 (IL-10) expression showed a dependence relation with phenolic glycolipid I (PGL-I) in downgrading T1R (direct effect = 0.503 > residual effect = 0.364), whereas in ENL, such relationship occurred with lipoarabinomannan (LAM) (direct effect = 0.778 > residual effect = 0.280). On the contrary, in the reaction-free leprosy group, interferon-gamma (IFN-γ) levels were dependent on the association between TLR2 and TLR1 (0.8735). The high TLR2 expression associated with IL-10 levels, in the leprosy reaction groups, may be hypothetically related to the formation of TLR2/2 homodimers and/or TLR2/6 heterodimers linked to evasion mechanisms in downgrading reactions and pathophysiology of ENL.

Elevated neutrophil to lymphocyte ratio as an indicator of secondary erythema nodosum, a retrospective observational study

Background/aim: Erythema nodosum (EN) is an inflammatory disorder of subcutaneous tissue. Although etiopathogenesis of the disease is unknown, many predisposing factors such as infections, systemic disease, and drugs have been identified. Neutrophil to lymphocyte ratio (NLR) has been shown to be a novel inflammatory marker in many dermatological diseases. The aim of our study is to investigate NLR in EN patients and evaluate its relation to the underlying cause of the disease. Materials and methods: Between 2014 and 2018, clinical and laboratory data of 395 patients diagnosed with EN and 395 controls were extracted from patient files. EN patients were grouped as idiopathic EN and secondary EN (EN with an identified underlying cause). Clinical and laboratory characteristics of the two groups were compared Results: NLR was elevated in EN patients compared to controls (median of 2.38 vs. 1.55, P < 0.001). Among EN patients, NLR was also elevated in patients with secondary EN. In multivariate logistic regression model NLR (> 2.11), RDW-CV (> 13.65), and CRP (> 5.5) were identified as risk factors for secondary EN (relative risks were 17.16, 2.69, and 2, respectively). Conclusion: Elevated NLR (> 2.11) may be used as a parameter to discriminate secondary EN from idiopathic EN.

Pluripotent Stem Cell Model of Nakajo-Nishimura Syndrome Untangles Proinflammatory Pathways Mediated by Oxidative Stress.

Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction of the immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokines in NNS, the underlying mechanisms of the autoinflammation are still largely unknown. To investigate and understand the mechanisms and signal pathways in NNS, we established a panel of isogenic pluripotent stem cell (PSC) lines with PSMB8 mutation. Activity of the immunoproteasome in PSMB8-mutant PSC-derived myeloid cell lines (MT-MLs) was reduced even without stimulation compared with non-mutant-MLs. In addition, MT-MLs showed an overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS) and phosphorylated p38 MAPK levels. Treatment with p38 MAPK inhibitor and antioxidants decreased the abnormal production of cytokines and chemokines. The current PSC model revealed a specific ROS-mediated inflammatory pathway, providing a platform for the discovery of alternative therapeutic options for NNS and related immunoproteasome disorders.

Expression Patterns of TNFα, MAdCAM1, and STAT3 in Intestinal and Skin Manifestations of Inflammatory Bowel Disease.

BACKGROUND: Pathogenesis of cutaneous extraintestinal manifestations [EIM] in inflammatory bowel disease [IBD] remains elusive. Efficacy of anti-TNF agents suggests TNF-dependent mechanisms. The role of other biologics, such as anti-integrins or JAK-inhibitors, is not yet clear. METHODS: We performed immunohistochemistry for TNFα, NFκB, STAT1/STAT3, MAdCAM1, CD20/68, caspase 3/9, IFNγ, and Hsp-27/70 on 240 intestinal [55 controls, 185 IBD] and 64 skin biopsies [11 controls, 18 erythema nodosum [EN], 13 pyoderma gangenosum [PG], 22 psoriasis]. A semiquantitative score [0-100%] was used for evaluation. RESULTS: TNFα was upregulated in intestinal biopsies from active Crohn`s disease [CD] vs controls [36.2 vs 12.1, p < 0.001], but not ulcerative colitis [UC: 17.9]. NFκB, however, was upregulated in intestinal biopsies from both active CD and UC [43.2 and 34.5 vs 21.8, p < 0.001 and p = 0.017, respectively]. TNFα and NFκB were overexpressed in skin biopsies from EN, PG, and psoriasis. No MAdCAM1 overexpression was seen in skin tissues, whereas it was upregulated in active UC vs controls [57.5 vs 35.4, p = 0.003]. STAT3 was overexpressed in the intestinal mucosa of active and non-active IBD, and a similar upregulation was seen in skin biopsies from EN [84.7 vs 22.3, p < 0.001] and PG [60.5 vs 22.3, p = 0.011], but not in psoriasis. Caspase 3 and CD68 overexpression in skin biopsies distinguished EN/PG from psoriasis and controls. CONCLUSIONS: Upregulation of TNFα/NFκB in EN and PG is compatible with the efficacy of anti-TNF in EIM management. Data on overexpressed STAT3, but not MAdCAM1, support a rationale for JAK-inhibitors in EN and PG, while questioning the role of vedolizumab.

Treatment of severe refractory erythema nodosum leprosum with tumor necrosis factor inhibitor Etanercept.

Erythema nodosum leprosum (ENL) is a common complication of lepromatous leprosy. Some patients unresponsive to conventional, first-line therapeutics develop recurrent, recalcitrant ENL. Here, we report a case of severe refractory ENL that was successfully treated with Etanercept. Biologics may be considered as therapeutic alternatives in management of severe, recalcitrant ENL.

Clinical, histopathological, and immunological evaluation of a series of patients with erythema nodosum.

BACKGROUND: The pathogenesis of erythema nodosum (EN) is still poorly understood, and studies evaluating the involvement of a cytokine network are very scarce. OBJECTIVES: To investigate clinical and pathological features, the cytokine profiles, and the balance of T-regulatory (Treg) and T-helper (Th)17 cells in serum and lesional skin of patients with EN. METHODS: Patients with a diagnosis of EN were consecutively enrolled, and their clinical and histopathological features were recorded. A panel of cytokines was evaluated in both serum and lesional skin using enzyme-linked immunosorbent assay. Real-time polymerase chain reaction was performed to evaluate the Treg/Th17 cell balance. RESULTS: Histopathological examination of skin biopsy specimens from all patients (four women and one man) showed classical features of EN. The most widely expressed cytokines were innate immunity cytokines (mainly tumor necrosis factor alpha, interleukin-8 and -6) and growth factors (mainly granulocyte colony-stimulating factor and monocyte chemoattractant protein-1). The Treg/Th17 balance was highly different between patients. CONCLUSIONS: The present study emphasizes the crucial role of neutrophils in the pathogenesis of EN, as high levels of cytokines and growth factors mainly involved in neutrophil recruitment and activation were detected.

Elastophagocytosis and Elastolysis in Leprosy.

Elastophagocytosis is the engulfment of the elastic fibres by the histiocytes, multinucleated giant cells, or both. The cutaneous lesions showing elastophagocytosis are annular elastolytic giant cell granuloma, actinic keratoses, persistent insect-bite reactions, elastosis perforans serpiginosa, foreign body granuloma. Occasionally, it may occur in infectious diseases like leprosy, granulomatous syphilis, North-American blastomycosis, bacterial folliculitis, and cutaneous leishmaniasis. We report a case of lepromatous leprosy with necrotic erythema nodosum leprosum with secondary anetoderma. Histopathology from the atrophic macule of anetoderma revealed periappendageal, perineural infiltration, elastophagocytosis and reduction in elastic fibres.

Erythema nodosum leprosum: report of two cases.

Erythema nodosum leprosum (ENL) or type 2 lepra reaction is an inflammatory reaction, which may occur in the course of hanseniasis, may compel the patient to seek medical attention and may result in nerve function impairment and subsequent disability. Thus, recognition and timely management of these patients is critical in order to avoid permanent disability. Fine-needle aspiration cytology is simple and effective tool that aids in the correct diagnosis and management of ENL. Herein, we present two cases of ENL, one with typical and another with atypical presentation.

Serum BAFF levels and skin mRNA expression in patients with Behçet's disease.

OBJECTIVE: Serum levels of the B-cell activating factor in the tumor necrosis factor family (BAFF), a potent contributor to B-cell survival, are elevated in patients with systemic autoimmune diseases. The objective of this study was to determine serum BAFF levels and to link the results to the clinical features in patients with skin manifestations. METHODS: Serum BAFF levels were examined by an enzyme-linked immunosorbent assay (ELISA) in 42 patients with BD (16 with active disease), 20 healthy controls, and in 20 patients with systemic lupus erythematosus (SLE) and 15 patients with multiple sclerosis (MS), who served as the disease control groups. Expression of BAFF messenger RNA (mRNA) in the skin was quantified by a real-time reverse transcription-polymerase chain reaction; the expression of BAFF receptor (BAFF-R) on CD19+ B cells was assessed by flow cytometry; and ELISA was used to evaluate the production of IgG, interleukin-6 (IL-6) and IL-10 by isolated B cells. RESULTS: Serum BAFF levels were elevated in patients with active BD compared to the healthy controls, and correlated positively with the extent of skin lesions. Disease remission was accompanied by decreased BAFF levels. SLE patients had the highest serum BAFF levels. Skin biopsies showed BAFF mRNA expression to be up-regulated in active BD patients. BAFF-R expression on B cells was increased in BD patients with vasculitis. Furthermore, in BD patients the ability to produce IgG and IL-6 (but not IL-10) was enhanced in BAFF-stimulated B lymphocytes. CONCLUSION: These results suggest that BAFF and its signalling in B cells contribute to B cell abnormalities and the development of skin disease in patients with BD.

Clinical, immunological and histological aspects of an uncommon type II reaction in patients with lepromatous leprosy.

This study reports three cases of an unusual leprotic reaction characterized by superficial bullous ulcerative cutaneous lesions associated with high fever, malaise and oedema in patients with leprosy. Two patients responded to thalidomide treatment, with regression of the symptoms and skin ulcers. The third patient responded to thalidomide plus prednisone. Analysis of the ulcerated skin lesions showed dermal oedema with mononuclear cell infiltrate enriched for gammadelta-positive T lymphocytes and an increased number of Mycobaterium leprae bacilli within capillary endothelium. In contrast, gammadelta+ cells were decreased in or absent from the blood. Tumour necrosis factor-alpha and interleukin-6 were raised in the serum of the patients at the onset of the reaction. After the episode, cytokine levels and the percentage of gammadelta+ cells in the blood returned to normal. These cases characterize an uncommon leprotic reaction with clinical similarities to type II reaction and may indicate a significant role for gammadelta+ T cells in its pathogenesis.

Increased expression of interleukin-23 p19 mRNA in erythema nodosum-like lesions of Behçet's disease.

BACKGROUND: Behçet's disease (BD) is a multisystemic chronic inflammatory disease with unknown aetiology. Interleukin (IL)-12, which is involved in the pathogenesis of BD, is a 70-kDa cytokine made of p35 and p40 subunits. Recently, IL-23, which is composed of a p19 subunit and a shared p40 subunit of IL-12, was discovered; as a consequence, this raises the need to re-examine previous IL-12 reports to determine whether IL-23 is also involved in BD pathogenesis. OBJECTIVES: To determine whether there are changes in IL-23 in skin lesions and sera of patients with BD. METHODS: For quantitative reverse transcription-polymerase chain reaction, the total cellular RNA of erythema nodosum (EN)-like skin lesions from patients with BD, psoriasis skin lesions and skin biopsy samples from normal individuals was analysed. To determine cytokine levels, sera from patients with BD and normal individuals were analysed. RESULTS: Increased IL-23 p19 mRNA levels were observed for both EN-like lesions of patients with BD and skin lesions of patients with psoriasis compared with normal individuals. Although we observed an elevation of IL-12/23 p40 mRNA expression in the BD lesions, this was not significant. Moreover, the levels of IL-12 p35 mRNA in BD lesions were also not significantly different from the levels in normal control skin. In addition, no significant changes were detected in serum IL-12 and IL-23 levels between patients with BD and normal control individuals, or in patients with BD before and after treatment. CONCLUSIONS: Increased expression of IL-23 p19 mRNA in BD lesions suggests that IL-23 may be associated with the development of the EN-like lesions in patients with active BD.

Serum proteome of leprosy patients undergoing erythema nodosum leprosum reaction: regulation of expression of the isoforms of haptoglobin.

Validated proteome profile allows better understanding of disease progression, subtype classification, susceptibility patterns, and disease prognosis. Leprosy is a spectral disease, with clinically, histologically, immunologically, and bacteriologically distinguishable subtypes. In addition, a significant fraction of patients undergo immune mediated reactions even after multidrug therapy (MDT). Erythema nodosum leprosum (ENL) is an immune complex mediated reactional condition in leprosy, characterized by a systemic inflammatory condition afflicting borderline lepromatous (BL) and lepromatous leprosy patients (LL). In this study, we have analyzed serum proteome of leprosy patients undergoing ENL reactions and compared it with that of healthy noncontact controls. Depletion of albumin and immunoglobulin G (IgG) was optimized using Aurum serum protein mini kit (Bio-Rad), and then two-dimensional gel electrophoresis (2-DE) of these serum samples was performed. Differentially expressed proteins were identified by MALDI-TOF and MALDI-TOF MS/MS mass spectrometry. Significant increase in one of the isoforms of alpha2 chain of haptoglobin was observed in ENL condition. In addition, haptoglobin phenotype was determined for healthy controls and leprosy patients. Hp 0-0 phenotype was detected in 21.4% of the ENL patients undergoing treatment, which on follow up examination showed typable phenotype, thus showing a condition of acquired anhaptoglobinemia. Since ENL still remains a threat to leprosy disease management, the above findings may provide new insights in understanding the development and progression of this inflammatory condition.

The expression of NGFr and PGP 9.5 in leprosy reactional cutaneous lesions: an assessment of the nerve fiber status using immunostaining.

The effects of reactional episodes on the cutaneous nerve fibers of leprosy patients was assessed in six patients (three with reversal reactions and three with erythema nodosum leprosum). Cryosections of cutaneous biopsy of reactional lesions taken during the episode and of another sample during the remission period were immunostained with anti-NGFr and anti-PGP 9.5 (indirect immunofluorescence). We found no significant statistical difference in the number of NGFr- and PGP 9.5-positive fibers between the reactional and post-reactional groups. A significant difference was detected between the number of NGFr and PGP 9.5-stained fibers inside of the reactional group of biopsy cryosections but this difference was ascribed to the distinct aspects of the nerve fibers displayed whether stained with anti-NGFr or with anti-PGP 9.5; NGFr-positive branches looked larger and so interpreted as containing more fibers. In addition, a substantial number NGFr-positive fibers were PGP 9.5-negative. No differences in the number of stained fibers among the distinct cutaneous regions examined (epidermis + upper dermis, mid and deep dermis) was detected. In conclusion, the number of PGP- and NGFr-positive fibers were not significantly different in the reactional and post-reactional biopsies in the present study. NGFr-staining of the nerve fibers is different from their PGP-imunoreactivity and the evaluation of the nerve fiber status on an innervated target organ should be carried out choosing markers for both components of nerve fibers (Schwann cells and axons).

Anti-inflammatory drugs block cytokine mRNA accumulation in the skin and improve the clinical condition of reactional leprosy patients.

The aim of this study was to investigate in what ways in vivo anti-inflammatory treatment affects cytokine mRNA expression in situ in both erythema nodosum leprosum and reversal reaction patients. Serial biopsies were collected from the patients undergoing leprosy reactions before and during pentoxifylline (n = 7) or thalidomide (n = 3) treatment for erythema nodosum leprosum and prednisone (n = 3) for reversal reaction. Clinical evolution of the skin lesion was assessed during the study and semiquantitative reverse transcription-polymerase chain reaction was used to investigate cytokine mRNA expression at the lesion site. Results showed expression of interferon-gamma, interleukin-6, interleukin-10, interleukin-12 p40, and tumor necrosis factor-alpha in all patients tested at the onset of reactional episodes, but interleukin-4 mRNA was rarely detected in the lesions (n = 4). Follow-up analysis showed that, irrespective of the drugs used, tumor necrosis factor-alpha mRNA was diminished in 10 of the 13 patients tested. A concomitant decrease of mRNA accumulation was also observed for interferon-gamma (nine of 11 patients), interleukin-6 (nine of 11), and interleukin-12 p40 (six of eight). An inhibitory effect on interleukin-10 mRNA was likewise seen after thalidomide and pentoxifylline, but not subsequent to prednisone treatment. The data also demonstrated that cytokine mRNA inhibition correlates to the resolution of the inflammatory response in situ (n = 10), whereas the persistence/enhancement of cytokine message expression after treatment was associated with worsening of the skin condition, as seen in three erythema nodosum leprosum patients whose maintenance of local inflammation was accompanied by the appearance/persistence of interleukin-4 gene expression in situ subsequent to anti-inflammatory treatment. In summary, the participation of cytokines in leprosy inflammatory episodes seems to be directly associated with the patients' clinical evolution following therapy for reaction.

Histopathologic features of erythema nodosum--like lesions in Behçet disease: a comparison with erythema nodosum focusing on the role of vasculitis.

Many patients with Behçet disease (BD) develop lesions that clinically resemble those of erythema nodosum (EN) but differ from that condition with regard to their microscopic features. We examined 11 sections of EN-like lesions in BD and compared them with 9 sections of classic EN using routine histopathology and immunohistochemistry so as to form a comprehensive picture of the pathologic findings in BD and to determine the role of vasculitis in the formation of lesions. Erythema nodosum-like lesions of BD are characterized by panniculitis, usually lobular or mixed septal and lobular in pattern, with variable numbers of neutrophils, lymphocytes, and histiocytes as well as variable numbers of necrotic adipocytes. Vasculitis was noted in most EN-like lesions in BD. Scattered vessels showing lymphocytic vasculitis were evident in 6 sections, and foci of leukocytoclastic vasculitis were obvious in 4 sections, sometimes with phlebitis or arteriolitis. In specimens with classic EN, we did not observe vasculitis. Only the percentages of CD3+ lymphocytes and chloroacetate esterase-positive neutrophils in the infiltrating cells showed statistically significant differences (P < 0.05) between EN-like lesions in BD and EN through immunohistochemical and enzyme cytochemical studies. Because vasculitis in the EN-like lesions in BD was extensive and not limited to areas of severe inflammation, we believe that it is primary vasculitis. We suggest that vasculitis is an important pathologic event in EN-like lesions in BD but cannot determine the extent to which other pathologic changes such as septal or lobular panniculitis, fat necrosis, neutrophilic infiltration, or microabscess formation are secondary features.

Adhesion molecule expression in erythema nodosum-like lesions in Behçet's disease. A histopathological and immunohistochemical study.

Behçet's (BD) is a systemic inflammatory disease with histological evidence for vasculitis. Leucocyte-leucocyte and leucocyte-endothelial cell interactions are critical in inflammatory reactions that are influenced by the expression, activation and shedding of adhesion molecules. We investigated the expression of some adhesion molecules (E- and L-selectin, VLA-4, ICAM-1, PECAM-1, VCAM-1 and CD18 and CD11c chains of beta-2 integrins) on endothelial and inflammatory cells by immunohistochemistry on cryostat sections of erythema nodosum lesions taken from 15 patients with BD and 12 patients with erythema nodosum of unknown cause. Hematoxylin-eosin stained sections of all specimens were also assessed. The major histopathological findings were perivascular mononuclear cell infiltration and secondary vasculitic changes with no difference between the two groups (P > 0.05). However, the frequency of thrombophlebitis was higher in BD (P < 0.001). Endothelial and inflammatory cell adhesion molecule expression did not show any significant difference between groups (P > 0.05). Although VCAM-1 expression and intensity on endothelial cells of BD patients seemed to be lower, this did not reach statistical significance (P = 0.056). We concluded that subcutaneous thrombophlebitis is an important feature of erythema nodosum like lesions in BD, which is almost impossible to understand by physical examination alone. Colchicine, which is known to have some influence on adhesion molecules, might have affected our results, as these showed no significant difference regarding adhesion molecules between the two groups.

Pentoxifylline decreases in vivo and in vitro tumour necrosis factor-alpha (TNF-alpha) production in lepromatous leprosy patients with erythema nodosum leprosum (ENL).

Increasing evidence has implicated TNF-alpha as a pivotal molecule involved in the systemic inflammatory manifestations of ENL, an acute inflammatory complication that may occur in the chronic course of leprosy. In the present study, the mechanism of action of pentoxifylline (PTX) as an alternative therapy for management of leprosy reactions has been evaluated. The effect of PTX on TNF-alpha production was examined in leprosy patients at the protein level and at the transcriptional level as well. Treatment of ENL patients with PTX (1200 mg daily) ameliorated the systemic symptoms and favoured the evolution of reactional leprosy lesions. Serum TNF-alpha was assayed before and during treatment with PTX in 15 patients. The increased TNF-alpha levels seen in the circulation during the reaction were dramatically reduced within 3-7 days of therapy. No significant effect on serum IL-6 was noted. In vitro TNF-alpha production was assayed upon culture stimulation with Mycobacterium leprae. A reduction of inducible TNF-alpha in peripheral blood mononuclear cells (PBMC) was seen after 1-2 weeks of in vivo administration of PTX. Furthermore, no effect of the drug on IL-10 secretion was detected in these cultures. A kinetic analysis of the expression of TNF-alpha and IL-6 mRNA at the site of leprosy lesion was performed in six reactional patients by semiquantitative reverse transcriptase-polymerase chain reaction (RT-PCR). The amount of TNF-alpha mRNA was increased in the tissue during ENL compared with before the reaction, and decreased thereafter following treatment for reaction (either PTX or thalidomide). These data suggest that PTX inhibits TNF-alpha production in ENL patients both in vivo and in vitro, and it may be useful in the treatment of leprosy patients undergoing ENL.