Background The host immune responses associated with the clinical phenotypes of Mycobacterium leprae infection are not fully understood. The inflammatory complications of leprosy, leprosy reactions, particularly erythema nodosum leprosum (ENL), present therapeutic challenges. Thalidomide is an effective drug for ENL but is not widely available due to teratogenicity. Thalidomide binds cereblon (CRBN), a substrate receptor for the E3 ligase complex, promoting ubiquitination. Thus, we investigated the CRBN expression in human peripheral blood mononuclear cells (PBMCs) in response to in vitro stimulation with M. leprae with/without CRBN blockade peptide. Methods Blood samples were obtained from apparently BCG-vaccinated and BCGunvaccinated healthy volunteers. PBMC was isolated and stimulated with irradiated M. leprae with or without CRBN blockade peptide. CRBN, NF-kB, and PARK2 proteins were determined by ELISA, and their gene expression by qPCR. Results Stimulation with M. leprae significantly increased CRBN gene expression and protein production. Incubation of PBMCs with M. leprae with CRBN blockade significantly increased NF-kB expression. In a subgroup analysis, CRBN and NFkB gene expression following stimulation with M. leprae (p <= 0.05) was significantly higher in PBMCs from Mycobacterium bovis bacillus Calmette-Gu & eacute;rin (BCG)vaccinated individuals compared to those from unvaccinated participants. PARK2 gene expression and parkin protein were significantly decreased in PBMCs stimulated with M. leprae compared to unstimulated PBMCs (p <= 0.05). In a subgroup analysis, PARK2 gene expression and parkin protein were decreased in the PBMCs from BCGunvaccinated individuals following incubation with M. leprae compared to those from BCG-vaccinated individuals. Stimulation of the PBMCs with M. leprae with CRBN blockade increased PARK2 gene expression and parkin protein production (p <= 0.05). Conclusion The findings are evidence that CRBN may have a role in modulating PARK2 and NF-kB gene expression in response to M. leprae infection. This needs further investigation in individuals with leprosy. The differential gene expression of CRBN and PARK2 in BCG-vaccinated and BCG-unvaccinated individuals could be further explored to understand the mechanism of BCG protection against leprosy.

2024 marks the centenary of the charity, Lepra. Over the past 100 years of Lepra's existence, the world has seen many ground-breaking developments in the care, treatment and support for people affected by leprosy. It has been a century of progress from the early days of chaulmoogra oil to initial drug treatment trials of Promin and Diasone, through to the paradigm-shifting development of Dapsone, Clofazimine and Rifampicin, and the introduction of free Multi-Drug Therapy in the 1980s. All of these developments and advancements have been documented in the annals of this journal, the Leprosy Review, which has been published by Lepra since 1928. As Lepra looks back on its long history and reflects on the global progress that has been made, it is proud to have contributed to some of the ground-breaking advancements; and it is proud that Leprosy Review has been on-hand to document them all along the way. As Leprosy Review now enters a new era as an online-only journal, we can look ahead to a future of more research and innovation for the care, treatment and support for people affected by leprosy, knowing that Leprosy Review will continue to be at the forefront, documenting and disseminating findings and advancements - and contributing to the collective leprosy lexicon, moving us forwards to continue improving the management and control of leprosy and its consequences.

The year 2024 is the Centenary of the foundation of the Leprosy Relief Association (Lepra), formerly the British Empire Leprosy Relief Association (BELRA). The name of the organization changed to the LEProsy Relief Association (LEPRA) in 1976 but has been known as Lepra since 2008. Over the years it has worked closely with members and office holders of the Royal Society of Tropical Medicine and Hygiene. Its work has encompassed activities from the earliest initiatives to ensure appropriate living conditions for those with the disease to the development of leprosy chemotherapy. However, this has now evolved into a strong partnership between the UK- and India-based Lepra hubs, which are carrying out research and public health initiatives ranging from elimination of prejudice against those with leprosy to adopting the recently launched WHO programme for skin NTDs to facilitate integrated control and management regimens. The fight against leprosy has always been a partnership between a wide variety of disease-specific NGOs, health-care workers and international health agencies. The story of Lepra illustrates the central role of these partnerships and national as well as international collaboration.

Introduction The World Health Organization (WHO) recommends rifampicin, dapsone and clofazimine multi-drug therapy (MDT) for the treatment of leprosy. Severe adverse effects include dapsone hypersensitivity syndrome, skin pigmentation, haemolytic anaemia, and hepatitis. At the Hospital for Tropical Diseases (HTD), London, United Kingdom monthly rifampicin, ofloxacin and minocycline (mROM) is used as first line treatment for leprosy. Objectives To determine the clinical outcomes and experiences of individuals treated with mROM. Methods A retrospective study of individuals with leprosy who were prescribed mROM at HTD was conducted. Demographic and clinical data were collected on outcomes including relapses, leprosy reactions, bacterial index (BI) and adverse effects. Individuals were interviewed using a semi-structured questionnaire to understand their experiences of mROM. Results 29 individuals were identified and 20 interviewed. 26 (89.7%) individuals completed monthly mROM. 9 (31%) had switched from WHO MDT to mROM (five of whom (55.6%) were interviewed). BI reduced significantly following mROM treatment (p = 0.04). 17 individuals (58.6%) experienced a leprosy reaction. One of the 29 (3.4%) relapsed. The relapse rate was 9.5/1000 person years. 49 reports of adverse effects were either mild or moderate. The most frequent adverse effect (14/49) reported was orange discolouration of urine. No adverse effect required hospitalisation or discontinuation of mROM. Most individuals reported that skin lesions improved by the time they had completed mROM. Conclusions In this small study in a non-endemic setting mROM was safe, effective and acceptable. mROM therapy is associated with improvement in skin lesions, decline in bacterial index and acceptable adverse effects. Larger, prospective, randomised studies are needed to determine whether relapse rates with mROM are equivalent or better than WHO MDT and to provide robust data on the seemingly better adverse effect profile of mROM.

report on the 21st International Leprosy Congress held in Hyderabad in November 2022, with the theme "Better Knowledge -Early diagnosis -Improved care".It was hosted by the International Leprosy Association, with support from the Indian Association of Leprologists; the Indian Association of Dermatologists, Venereologists and Leprologists; and the Indian National Elimination Programme, as well as the World Health Organisation and ILEP members.This hybrid Congress had both physical and virtual sessions with large number of symposia, lead talks, paper presentations, poster and short video presentations.There were 8 plenary sessions, 72 faculty abstracts, 423 oral papers, 20 papers given different awards and 457 e-posters.Topics covered were clinical aspects (234), diagnostics (6) disability and rehabilitation (96) epidemiology and control (198) laboratory aspects (140), miscellaneous (49), programmatic management (8), rehabilitation, both social and physical (6), social aspects (132), surgery (1) and therapeutics (57).There were 1050 physical delegates and 450 people attended electronically.Delegates came from 56 countries with an age range of 25-75 years.

Background: Health-related quality of life (HRQoL) has now become an indispensable outcome measure in many randomized clinical trials and other studies. It provides the patient’s voice in measuring health improvement or decline and assessing treatment effectiveness. A validated Amharic version of HRQoL assessment tool was needed for leprosy clinical trials in Ethiopia. The SF-36 was chosen but a validated Amharic version was not available. We describe how this was developed. Methods: The SF-36 was translated from English into Amharic and evaluated for content acceptability in a patient focus group. Back translation was performed. Validity and reliability of Amharic SF-36 in leprosy affected individuals was tested with 100 patients with leprosy attending the leprosy clinic at ALERT hospital and compared to the Amharic version of the WHOQOL-BREF. Results: Amharic translations of both the WHOQOL-BREF and the SF-36 had good reliability and validity amongst leprosy affected individuals. Internal consistency reliability estimates for each domain/scale exceeded 0.70. The Amharic SF-36 had better convergent and discriminant validity than WHOQOL-BREF in this group of patients. Good known-group validity was seen in both WHOQOL-BREF and SF-36 in leprosy affected patients. Amharic SF-36 had good inter-rater reliability with seven out of 8 domains scoring above 0.8 in intra-class correlation. Conclusion: This Amharic version of the SF-36 is a valid instrument to measure HRQoL in clinical trials involving leprosy affected individuals in Ethiopia.

Background Leprosy is rare in the United Kingdom (UK), but migration from endemic countries results in new cases being diagnosed each year. We documented the clinical presentation of leprosy in a non-endemic setting. Methods Demographic and clinical data on all new cases of leprosy managed in the Leprosy Clinic at the Hospital for Tropical Diseases, London between 1995 and 2018 were analysed. Results 157 individuals with a median age of 34 (range 13-85) years were included. 67.5% were male. Patients came from 34 different countries and most contracted leprosy before migrating to the UK. Eighty-two (51.6%) acquired the infection in India, Sri Lanka, Bangladesh, Nepal and Pakistan. 30 patients (19.1%) acquired leprosy in Africa, including 11 from Nigeria. Seven patients were born in Europe; three acquired their leprosy infection in Africa, three in South East Asia, and one in Europe. The mean interval between arrival in the UK and symptom onset was 5.87 years (SD 10.33), the longest time to diagnosis was 20 years. Borderline tuberculoid leprosy (n = 71, 42.0%), and lepromatous leprosy (n =, 53 33.1%) were the commonest Ridley Jopling types. Dermatologists were the specialists diagnosing leprosy most often. Individuals were treated with World Health Organization recommended drug regimens (rifampicin, dapsone and clofazimine). Conclusion Leprosy is not a disease of travellers but develops after residence in an leprosy endemic area. The number of individuals from a leprosy endemic country reflect both the leprosy prevalence and the migration rates to the United Kingdom. There are challenges in diagnosing leprosy in non-endemic areas and clinicians need to recognise the symptoms and signs of leprosy.

In the last decade many leprologists around the world have been advocating the development and testing of new antimicrobial treatments for leprosy but limited new clinical data have emerged. 1,2Global guidelines have been published in which the World Health Organization (WHO) now recommends rifampicin, dapsone and clofazimine for all individuals diagnosed with leprosy. 3e propose that a large randomised controlled trial of fixed duration (12 doses) antimicrobial therapy for Mycobacterium leprae infection, with monthly rifampicin 600 mg,

Objectives We determined the male and female ratio of new leprosy cases detected over 15 years, allowing future exploration of inequalities pertaining to biological sex and social aspects of gender, which negatively impact women.Methods We extracted sex-disaggregated data from the annual Weekly Epidemiolog-ical Record (WER) Global leprosy situation reports, from 2004 to 2020, to determine the temporal pattern of new cases detected, by gender.Results Sex disaggregated leprosy data was only consistently reported in WER papers from 2004. The absolute number of female cases detected has remained static over the last 15 years (80,000-90,000 new cases annually). A 56.2% reduction in the number of male cases was observed from 2004-2019, whereas amongst females the reduction was only 37.5%. The difference in gender-specific reduction in case detection was similar in 5 of 6 WHO regions. There is a clear trend of increasing female percent amongst new cases detected from 2004 onwards; 30.8% of all new cases detected in 2004 were female, rising to 38.9% in 2019.Conclusions Sex-disaggregated data reporting at the national and international level needs to remain a priority. Further research is needed to understand why the percentage of new female cases detected amongst all new cases is increasing and the role biological factors play in leprosy transmission.

Background The numbers of circulating regulatory T cells (Tregs) are increased in lepromatous leprosy (LL) but reduced in erythema nodosum leprosum (ENL), the inflammatory complication of LL. It is unclear whether the suppressive function of Tregs is intact in both these conditions. Methods A longitudinal study recruited participants at ALERT Hospital, Ethiopia. Peripheral blood samples were obtained before and after 24 weeks of prednisolone treatment for ENL and multidrug therapy (MDT) for participants with LL. We evaluated the suppressive function of Tregs in the peripheral blood mononuclear cells (PBMCs) of participants with LL and ENL by analysis of TNFα, IFNγ and IL-10 responses to Mycobacterium leprae (M. leprae) stimulation before and after depletion of CD25+ cells. Results 30 LL participants with ENL and 30 LL participants without ENL were recruited. The depletion of CD25+ cells from PBMCs was associated with enhanced TNFα and IFNγ responses to M. leprae stimulation before and after 24 weeks treatment of LL with MDT and of ENL with prednisolone. The addition of autologous CD25+ cells to CD25+ depleted PBMCs abolished these responses. In both non-reactional LL and ENL groups mitogen (PHA)-induced TNFα and IFNγ responses were not affected by depletion of CD25+ cells either before or after treatment. Depleting CD25+ cells did not affect the IL-10 response to M. leprae before and after 24 weeks of MDT in participants with LL. However, depletion of CD25+ cells was associated with an enhanced IL-10 response on stimulation with M. leprae in untreated participants with ENL and reduced IL-10 responses in treated individuals with ENL. The enhanced IL-10 in untreated ENL and the reduced IL-10 response in prednisolone treated individuals with ENL was abolished by addition of autologous CD25+ cells. Conclusion The findings support the hypothesis that the impaired cell-mediated immune response in individuals with LL is M. leprae antigen specific and the unresponsiveness can be reversed by depleting CD25+ cells. Our results suggest that the suppressive function of Tregs in ENL is intact despite ENL being associated with reduced numbers of Tregs. The lack of difference in IL-10 response in control PBMCs and CD25+ depleted PBMCs in individuals with LL and the increased IL-10 response following the depletion of CD25+ cells in individuals with untreated ENL suggest that the mechanism of immune regulation by Tregs in leprosy appears independent of IL-10 or that other cells may be responsible for IL-10 production in leprosy. The present findings highlight mechanisms of T cell regulation in LL and ENL and provide insights into the control of peripheral immune tolerance, identifying Tregs as a potential therapeutic target.

There have been recent discussions in the leprosy world by people concerned that the current 12 months multi-drug treatment (MDT) regimens for multibacillary leprosy patients are inadequate and contribute to poor control of the disease.We argue here that recent studies show that the current regimens are good for treating the infection in individual patients and do not need extending.Patients with an initial high BI do not need longer treatments. 1,2Clinicians and patients should have a long time frame for patient improvement which can be years after treatment has finished.The WHO sponsored multi-drug regimens were introduced in 1982 and have been regularly altered since then. 3,4Initially patients with MB leprosy were treated until their slit skin smears were negative.In 1994 the WHO Expert Committee recommended fixed duration treatment of 24 months for MB patients.This was reduced to 12 months in 1998. 5,6These decisions were not supported by data from prospective drug trials.Fortunately, the relapse rate in leprosy has been very low, with about 1% of patients relapsing with a new study from Brazil showing a low relapse rate after treatment with 12 months MDT with a 12 year follow up. 1,7,8An early study in Ethiopia had a zero relapse rate after 24 months treatment. 9Patient outcomes after leprosy multi-drug treatment can be assessed by three measures: (1) Clinical improvement of the lesions, (2) Fall in the Bacterial Index and (3) relapse rate.Clinical improvement of skin lesions is variable.This is partly due to the ongoing inflammation in the lesions which is part of the clinical disease.Some patients' skin lesions resolve

BACKGROUND:Cutaneous leishmaniasis (CL) is frequent in travellers and can involve oro-nasal mucosae. Clinical presentation impacts therapeutic management.METHODOLOGY:Demographic and clinical data from 459 travellers infected in 47 different countries were collected by members of the European LeishMan consortium. The infecting Leishmania species was identified in 198 patients.PRINCIPAL FINDINGS:Compared to Old World CL, New World CL was more frequently ulcerative (75% vs 47%), larger (3 vs 2cm), less frequently facial (17% vs 38%) and less frequently associated with mucosal involvement (2.7% vs 5.3%). Patients with mucosal lesions were older (58 vs 30 years) and more frequently immunocompromised (37% vs 3.5%) compared to patients with only skin lesions. Young adults infected in Latin America with L. braziliensis or L. guyanensis complex typically had an ulcer of the lower limbs with mucosal involvement in 5.8% of cases. Typically, infections with L. major and L. tropica acquired in Africa or the Middle East were not associated with mucosal lesions, while infections with L. infantum, acquired in Southern Europe resulted in slowly evolving facial lesions with mucosal involvement in 22% of cases. Local or systemic treatments were used in patients with different clinical presentations but resulted in similarly high cure rates (89% vs 86%).CONCLUSION/SIGNIFICANCE:CL acquired in L. infantum-endemic European and Mediterranean areas displays unexpected high rates of mucosal involvement comparable to those of CL acquired in Latin America, especially in immunocompromised patients. When used as per recommendations, local therapy is associated with high cure rates.

Background: The coronavirus disease 2019 (COVID-19) pandemic has led to governments implementing a variety of public health measures to control transmission and has affected health services. Leprosy is a communicable neglected tropical disease caused by Mycobacterium leprae and is an important health problem in low- and middle-income countries. The natural history of leprosy means that affected individuals need long-term follow-up. The measures recommended to reduce transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can create barriers to health services. We evaluated the impact of the COVID-19 epidemic response on leprosy services and disease management. Methods: We conducted a cross-sectional online survey with healthcare professionals in leprosy referral centres. Results: Eighty percent of leprosy diagnostic services were reduced. All respondents reported that multidrug therapy (MDT) was available but two reported a reduced stock. Clinicians used alternative strategies such as telephone consultations to maintain contact with patients. However, patients were not able to travel to the referral centres. Discussion: This study highlights the effects of the initial phase of the SARS-CoV-2 pandemic on leprosy services in a range of leprosy-endemic countries. Many services remained open, providing leprosy diagnosis, MDT and leprosy reaction medications. Centres developed innovative measures to counter the negative impacts of the COVID-19 pandemic.

Objectives: Classification of new cases of leprosy into Paucibacillary (PB) or Multibacillary (MB) groups is important as it determines the duration of the treatment regimen, and predicts both complications of leprosy and risk of infection to contacts. Criteria have changed over the past 4 decades. We studied the published global leprosy statistics to reveal any major temporal changes in the proportion of PB cases. Results: Global data published by WHO over the past 40 years demonstrate a continuous decrease in the proportion of newly reported leprosy cases who are classified as paucibacillary (PB) from nearly 80% to around 40%. Independent validation of consistent and accurate classification is lacking. Conclusions: The decrease in PB proportion may be an artefactual, rather than an epidemiological, phenomenon. Whilst it is impossible to be certain, we suspect that a combination of changes in criteria and "overclassifying" to the MB group by field staff is the cause.

Background: Leishmania transmission to human hosts occurs through the bite of the female sandfly. Infection with Leishmania species may cause cutaneous, visceral or mucocutaneous disease, determined by the infecting species and the host immune response. This case series illustrates the wide spectrum of cutaneous disease, which may require different management strategies. Case Description: Four forty y old male friends travelled to Andalucía in southern Spain for a three-day holiday. Several ws after return, all developed persistent skin lesions on their trunk and limbs. The distribution, number of lesions and level of infiltration varied significantly between patients. All patients were systemically well. Skin biopsy histology of all four patients revealed chronic inflammatory changes with granulomas, and the presence of Leishmania donovani complex DNA was confirmed through polymerase chain reaction amplification. Giemsa staining for amastigotes was negative. All patients attended the Hospital for Tropical Diseases six m after their return. Two patients had resolving lesions and were managed conservatively. The third patient had four indurated lesions on the right upper limb, which were treated with wly intralesional injections of sodium stibogluconate for four ws. The fourth patient had extensive cutaneous leishmaniasis with over thirty lesions on the limbs, face and trunk. He was treated with daily intravenous sodium stibogluconate for ten days. Discussion: Treatment options for Old World cutaneous leishmaniasis include conservative management, intralesional injections with sodium stibogluconate and systemic therapy. Choice of management depends on patient preference and the extent, location and number of lesions. Conservative management is appropriate if there is evidence of spontaneous regression. Systemic treatment is usually reserved for patients with extensive lesions, refractory disease, mucocutaneous manifestations or those with immunosuppression. Conclusion: These four cases are unusual given the short history of exposure (less than seventy-two h) and diverse clinical manifestations requiring different modes of management. Cutaneous leishmaniasis should be included in the differential diagnosis of patients with persistent, painless cutaneous lesions that appear ws or even m after travel to an endemic region. With climate change it is likely that the transmission and prevalence of leishmaniasis will change according to effects on the distribution, survival and population size of sandflies and reservoir hosts.

Tumor necrosis factor (TNF)-α inhibitors increase susceptibility to tuberculosis, but the effect of biologics on susceptibility to leprosy has not been described. Moreover, biologics may play a role in treating erythema nodosum leprosum (ENL). The objectives of this systematic review were to determine whether the development of clinical leprosy is increased in patients being treated with biologics and to assess the use of biologics in treating leprosy reactions. A systematic literature review was completed of patients with leprosy who received treatment with biologics either before or after a diagnosis of leprosy was confirmed. All studies and case reports were included for qualitative evaluation. The search yielded 10 cases (including one duplicate publication) of leprosy diagnosed after initiation of TNF-α inhibitors and four case reports of refractory ENL successfully treated with infliximab or etanercept. An unpublished case of persistent ENL responsive to infliximab is also presented. These data demonstrate that the use of TNF-α inhibitors may be a risk factor for developing leprosy or reactivating subclinical infections. Leprosy can present with skin lesions and arthritis, so leprosy should be considered in patients presenting with these signs before starting treatment with these agents. Leprosy should be considered in patients who develop worsening eruptions and neurologic symptoms during treatment with TNF-α inhibitors. Finally, TNF-α inhibitors appear effective in some cases of refractory ENL.

BACKGROUND: Leprosy is rare in the UK, but migration from endemic countries results in new diagnoses annually. Early recognition, diagnosis and treatment can prevent harmful stigma and disability. METHODS: We conducted retrospective analysis from a database of new cases of leprosy seen at the Hospital for Tropical Diseases, London from 1995 to 2018. We aimed to identify typical demographics of patients presenting with leprosy and identify causes and consequences of delayed diagnosis. RESULTS: 157 cases were included. A large proportion were male (67.5%) with a median age of 34 years. Most were non-UK born and migrated in adulthood. 41.3% of cases were acquired in India, Sri Lanka or Bangladesh. Borderline tuberculoid (43.9%) was the most common type, followed by lepromatous leprosy (33.8%). The mean time between arrival in the UK and symptom onset was 5.87 years (SD 10.33). It took over 5 years for 12.8% of patients to be diagnosed. 93.6% of patients completed multidrug treatment following diagnosis. CONCLUSION: Male predominance and age at diagnosis reflects global epidemiology of leprosy. Patterns of acquisition reflect trends in UK migration from endemic countries. The typical patient presenting to the clinician is a young male who has migrated as an adult and developed symptoms in the years surrounding migration. Many patients may have developed disability before treatment commences as the time to diagnosis can be prolonged. Once diagnosed in the UK, treatment is of high quality, readily available, and effective: earlier recognition by clinicians can prevent disability and reduce the risk of transmission.

Objectives: To establish the rate of adverse drug reactions (ADR) when dapsone is given in leprosy multi-drug therapy (MDT). This paper reviews the reporting of ADRs by systematic review of the databases Ovid Medline, Ovid Embase and Global Health according to pre-specified eligibility criteria. Results: The search identified 5859 relevant citations. These publications were divided into two data sets and reviewed for their documentation of ADRs. One hundred and fourteen publications reported ADR as the primary outcome and 98 papers reported the efficacy of treatment. Of the 114 papers included, 79 were case reports, 23 retrospective studies, 7 prospective studies and 7 literature reviews. Dapsone Hypersensitivity Syndrome (DHS) was reported most frequently as an adverse effect, then anaemia (haemolytic and not otherwise specified), cutaneous eruptions, gastrointestinal disturbance and hepatitis. Eleven studies report a mean rate of DHS as 1.22% and an average fatality rate in 8 studies of 11.24%. Of the 98 papers reporting treatment efficacy, 33 papers reported ADRs to medications other than dapsone and 36 publications had no documentation of adverse effects. Conclusion: Most publications report ADRs in case reports, many from India. DHS was the most commonly reported ADR, followed by individual features of the syndrome. Many studies lack patient information with many not reporting ADRs. Our findings show that improved prospective monitoring of adverse events associated with dapsone is needed. We propose that all patients should be tested with a full blood count before starting MDT and repeated after 4-8 weeks with mandatory follow-up. This would facilitate detecting ADRs including DHS and dapsone-associated anaemias.