Vedolizumab for the Management of Refractory Behçet's Disease: From a Case Report to New Pieces of Mosaic in a Complex Disease.

Objectives: When treating Behçet's disease (BD), anti-tumor necrosis factor (TNF)-α agents have become a second-line therapy when conventional immunosuppressive drugs have failed. However, in the case of failure of treatment with anti-TNFα drugs, further options are limited. Based on previous reports of the efficacy of vedolizumab (VDZ) in inflammatory bowel diseases, we decided to administer VDZ to treat a patient with intestinal BD. Methods: We present the case of a 49-year-old female patient with BD. Her clinical manifestations included erythema nodosum, oro-genital ulcers, positive Pathergy test, positive HLA-B51, and biopsy-proven intestinal BD. The patient was unsuccessfully treated with conventional immunosuppressive and several biological agents. Results: Treatment with VDZ was started intravenously at a dose of 300 mg at 0, 2, and 6 weeks and then every 4 weeks. After the second dose of VDZ, the patient reported a marked improvement of intestinal BD and a concomitant amelioration of arthralgia, erythema nodosum lesions and aphthosis. Clinical remission was achieved at 6 months after starting VDZ. Conclusion: VDZ might represent a valid option to treat patients with BD who are non-responsive to standard treatments or anti-TNFα agents, particularly, those cases with intestinal involvement.

Extraintestinal Manifestations in Vedolizumab and Anti-TNF-Treated Patients With Inflammatory Bowel Disease.

BACKGROUND: Extra-intestinal manifestations (EIMs) can impact morbidity in patients with inflammatory bowel diseases (IBD; Crohn's disease [CD] and ulcerative colitis [UC]). This study compared incidence rates of EIMs in patients with moderate to severe IBD receiving gut-selective vedolizumab (VDZ) vs those receiving systemic anti-tumor necrosis factor (anti-TNF) therapies. METHODS: Adult IBD patients receiving VDZ or anti-TNFs were identified from the MarketScan claims database from September 28, 2012, through September 30, 2016. Incidence rates of EIMs were compared between the 2 cohorts. Descriptive analyses were performed for all courses of treatment. Generalized linear models estimated the impact of treatment on the likelihood of developing EIMs. RESULTS: Compared with patients receiving anti-TNF therapy, VDZ-treated CD patients were 28% more likely to develop "any EIMs" (adjusted incident rate ratio [IRR], 1.28; 95% confidence interval [CI], 1.02-1.62). Specifically, CD patients treated with VDZ were more likely to develop erythema nodosum (IRR, 4.29; 95% CI, 1.73-10.64), aphthous stomatitis (IRR, 3.73; 95% CI, 1.51-9.23), episcleritis/scleritis (IRR, 2.51; 95% CI, 1.02-6.14), arthropathy (IRR, 1.45; 95% CI, 1.15-1.84), primary sclerosing cholangitis (PSC) (IRR, 7.79; 95% CI, 3.32-18.27), and uveitis/iritis (IRR, 2.89; 95% CI, 1.35-6.18). UC patients receiving VDZ did not have a statistically significant increase in "any EIMs" vs patients receiving anti-TNFs, but were more likely to develop specific EIMs (aphthous stomatitis: IRR, 3.67; 95% CI, 1.30-10.34; pyoderma gangrenosum: IRR, 4.42; 95% CI, 1.00-19.45; and PSC: IRR, 3.44; 95% CI, 1.23-9.68). CONCLUSIONS: IBD patients receiving VDZ may be more likely to develop EIMs vs patients receiving anti-TNF therapies. The gut-selective inflammatory control of VDZ may potentially limit its clinical effect on EIM prevention.

Prevention of repeated episodes of type 2 reaction of leprosy with the use of thalidomide 100 mg/day.

BACKGROUND: Leprosy can have its course interrupted by type 1 and 2 reactional episodes, the last named of erythema nodosum leprosum (ENL). Thalidomide has been the medication of choice for the control of ENL episodes since 1965. OBJECTIVES: These episodes can repeat and cause damages to the patient. In order to prevent these episodes, an extra dose of 100 mg/day thalidomide was used during six months, followed by a follow-up period of six more months after thalidomide discontinuation. METHODS: We included 42 patients with multibacillary (MB) leprosy who had episodes of ENL. They were male and female patients aged between 18 and 84 years. RESULTS: Of the 42 patients, 39 (92.85%) had the lepromatous form and three (7.15%) had the borderline form. We found that 100% of patients had no reactional episode during the use of the drug. During the follow-up period after thalidomide discontinuation, 33 (78.57%) patients had no reactional episode and nine (21.43%), all of them with the lepromatous form, had mild episodes, which were controlled using non-steroidal anti-inflammatory. There were no thalidomide-related side effects. CONCLUSION: A maintenance dose of 100 mg/day of thalidomide showed to be effective to prevent repeated type 2 reactional episodes of ENL.

Prevention of repeated episodes of type 2 reaction of leprosy with the use of thalidomide 100 mg/day

BACKGROUND: Leprosy can have its course interrupted by type 1 and 2 reactional episodes, the last named of erythema nodosum leprosum (ENL). Thalidomide has been the medication of choice for the control of ENL episodes since 1965. OBJECTIVES: These episodes can repeat and cause damages to the patient. In order to prevent these episodes, an extra dose of 100 mg/day thalidomide was used during six months, followed by a follow-up period of six more months after thalidomide discontinuation. METHODS: We included 42 patients with multibacillary (MB) leprosy who had episodes of ENL. They were male and female patients aged between 18 and 84 years. RESULTS: Of the 42 patients, 39 (92.85%) had the lepromatous form and three (7.15%) had the borderline form. We found that 100% of patients had no reactional episode during the use of the drug. During the follow-up period after thalidomide discontinuation, 33 (78.57%) patients had no reactional episode and nine (21.43%), all of them with the lepromatous form, had mild episodes, which were controlled using non-steroidal anti-inflammatory. There were no thalidomide-related side effects. CONCLUSION: A maintenance dose of 100 mg/day of thalidomide showed to be effective to prevent repeated type 2 reactional episodes of ENL. .

Predictive factors for erythema nodosum and pyoderma gangrenosum in inflammatory bowel disease.

BACKGROUND AND AIM: To identify predictive factors related to the development of erythema nodosum and pyoderma gangrenosum, in patients with inflammatory bowel disease (IBD). METHODS: Epidemiological and clinical data from 270 patients with Crohn's disease (CD) and 125 patients with ulcerative colitis (UC) were collected between 2003 and 2011. The variables retrospectively analyzed were: gender, age at diagnosis, type of IBD (CD or UC), smoking habit, pattern of disease (IBD), location and extension, family history, previous IBD-related surgery, other extraintestinal manifestations (EIMs), and previous biological and immunosuppressive therapy. RESULTS: Thirty-seven patients showed at least one cutaneous manifestation. These lesions were more frequent in women (15.4%) than in men (4.2%; P = 0.0001) and in CD (12.2%) than in UC patients (3.2%; P = 0.005). These manifestations were more frequently associated with other EIMs (25% vs 7.2%; P = 0.0001), and they were less frequent in patients who received a previous biological therapy for IBD (6.8% vs 11.2%; P = 0.1). Patients with skin manifestations were younger at diagnosis of IBD than those patients without them (26.3 ± 10 vs 32.9 ± 14.5, P = 0.008). Independent variables significantly associated with development of skin manifestations were: female (P = 0.008), previous biological therapy (P = 0.007), age at diagnosis (young, P = 0.026), type of IBD (CD, P = 0.043) and presence of other EIMs (P = 0.0001). CONCLUSION: Predictive factors involved in the development of main cutaneous manifestations are: female, CD, young age at diagnosis of IBD, and presence of other EIMs. Early use of biological therapies prevents the development of cutaneous manifestations.

Does clofazimine prevent erythema nodosum leprosum (ENL) in leprosy? A retrospective study, comparing the experience of multibacillary patients receiving either 12 or 24 months WHO-MDT.

OBJECTIVE: To compare the occurrence, duration and severity of ENL in leprosy patients treated with either 12 or 24 months of standard multi-drug therapy (MDT). STUDY POPULATION: 296 patients treated with MDT for 2 years, between 1985 and 1992 and followed up as part of a relapse study; and 293 patients, treated between 1998 and 2004, with MDT for 1 year and also followed up as part of a relapse study. The Chi squared test and multiple logistic regression analysis were used to test for statistical significance. RESULTS: ENL was not significantly more common, but it was longer-lasting and more severe in patients receiving only 12 months of MDT, as compared with those receiving 24 months treatment. A high BI at the start of treatment significantly increased the risk of severe ENL by a factor of between 6 and 12, while treatment with 12 instead of 24 months of MDT significantly increased the risk by a factor of between 3 and 10. CONCLUSIONS: This study provides further evidence that a high initial BI is the key risk factor for ENL. It also suggests that the difference between these two cohorts in their experience of ENL as demonstrated in this study, may be related to the different amounts of clofazimine which the two cohorts were given in the early years of their treatment. Further studies are needed to determine whether clofazimine could be used more specifically to reduce the severity of ENL in the small group of patients at high risk for the condition.

Clinical course of erythema nodosum leprosum: an 11-year cohort study in Hyderabad, India.

Erythema nodosum leprosum (ENL) or type 2 lepra reactions complicate lepromatous leprosy and borderline lepromatous leprosy. We report an 11-year retrospective case record analysis of 481 outpatients with borderline lepromatous and lepromatous leprosy at the Dhoolpet Leprosy Research Center in Hyderabad, India.. The overall prevalence of ENL was 24%, 49.4% among cases of lepromatous leprosy (LL) and 9% among cases of borderline lepromatous (BL) leprosy. Logistic regression analysis identified LL (odds ratio [OR] = 8.4, 95% confidence interval [CI] = 4.6-15.4, P < 0.001) and BL with a bacterial index > or = 4+ (OR = 5.2, 95% CI = 2.1-12.9, P = 0.001) as major risk factors. The average patient with ENL was male, 34.7 years of age, and had multiple episodes of ENL (mean = 3.1) over an 18.5-month period. Three types of ENL were identified: single acute ENL, multiple acute ENL (repeated discrete episodes), and chronic ENL (continuous episodes). Acute single ENL is rare, accounting for only 8% of cases. Chronic ENL accounted for 62.5% of the cohort. Chronic ENL was of longer duration and more severe. An age > or = 35 years was a risk factor for developing chronic ENL. Patients with chronic ENL were more compliant with multi-drug therapy, especially during the first six doses of multi-drug therapy. Distinguishing these different types of ENL would be useful for patient management and developing improved treatment of these debilitating reactions. Improved strategies for treatment and management of these reactions need to be developed.

Treatment of leprosy: science or politics?

OBJECTIVE: To review the history of the treatment of leprosy and leprosy reactions after World War II. METHODS: Treatments based on experience and clinical evidence are compared with those advised by the WHO in their quest to eliminate leprosy by the year 2000, later extended to 2005. RESULTS: Leprosy is not eliminated. Analyses of data on reaction treatment suggest that the treatment regimens for leprosy reactions as advised by the WHO may lead to more impairment among leprosy patients than the 'old' established regimes. CONCLUSION: WHO policies to eliminate leprosy may have jeopardized the proper treatment of leprosy for years to come.

A double-blind trial of colchicine in Behçet's syndrome.

OBJECTIVE: Colchicine is a widely used treatment for Behçet's syndrome, even though in a previous 6-month controlled study, it was shown to be effective only in controlling erythema nodosum and arthralgias. We reassessed the effect of colchicine in Behçet's syndrome in a study conducted among a larger group of patients for 2 years. METHODS: We randomized 116 patients with Behçet's syndrome (60 male/56 female), who had active mucocutaneous disease without eye or major organ involvement, to receive either placebo or colchicine (1-2 mg/day, adjusted to body weight) in a double-blind trial for 2 years. The primary outcome measure was the sustained absence of any lesions during treatment (complete response). The secondary outcome measure was the difference in the number of mucocutaneous lesions or arthritic joints between the active drug and placebo arms. Women and men were analyzed separately. RESULTS: Eighty-four patients (72%; 45 male, 39 female) completed the 24-month study. Kaplan-Meier analyses showed significantly more complete responses in the colchicine treatment group in terms of reduced occurrence of genital ulcers (P = 0.004), erythema nodosum (P = 0.004), and arthritis (P = 0.033) among the women, and reduced occurrence of arthritis (P = 0.012) among the men. The mean numbers of genital ulcers (P = 0.001), erythema nodosum lesions (P = 0.002), and arthritic joints (P = 0.014) among the women were less in the colchicine group, and the mean number of arthritic joints (P = 0.026) among the men was less in the colchicine group. Adverse effects were similar in both groups. CONCLUSION: Colchicine may be useful for treating some of the manifestations of Behçet's syndrome, especially among women. This might be a reflection of less severe disease among the women.

Cytokine regulation of disease progression in leprosy and tuberculosis.

Studies in our laboratory have focussed on the role of cytokines in the regulation of the cellular immune response and disease progression in two important mycobacterial infection of man, namely leprosy and tuberculosis. Our studies in leprosy have involved the use of key regulatory cytokines such as IFN-gamma in the modulation of the cellular response of infected patients. We have investigated the effect of intradermal administration of low dose IFN-gamma on the lesions of anergic lepromatous patients and have reported an accelerated bacillary clearance from the skin. This was associated with the local accumulation of mononuclear cells and killing of infected macrophages. However, IFN-gamma administration also resulted in the induction of erythema nodosum leprosum, a toxic syndrome associated with excess TNF-alpha production. Both the toxic symptoms and the high levels of TNF-alpha production could be inhibited by thalidomide treatment, a drug we have shown reduces the half life of TNF-alpha mRNA. In preliminary clinical trials in tuberculosis patients we have attempted to use thalidomide to reduce TNF-alpha production and toxicities. These results are discussed.

Immunotherapy with Mycobacterium w vaccine decreases the incidence and severity of type 2 (ENL) reactions.

Immunotherapy with Mycobacterium w (M.w) vaccine was given to 45 patients with multibacillary (MB) leprosy; 41 similarly classified patients served as controls. All patients received standard multidrug therapy (MDT). Incidence, severity and frequency of type 2 (ENL) reactional episodes were monitored in both groups in a follow-up extending up to 4 years. Reactions were seen in fewer vaccinated (10/37) BL and LL patients than in the control group (12/34). A total of 20 episodes were recorded in the vaccine group as against 29 in the controls, 75% of reactions were mild in vaccinated and 51.72% were mild in the control group patients, and 3 patients in the control group had more than 3 reactional episodes. None of the vaccinated patients showed this. No additional incidence of neuritis were seen among vaccinated individuals during reactional episodes.