Informe técnico N. 001/22 - Hanseníase: orientações para a prescrição e dispensação do medicamento talidomida / Technical report N. 001/22 - Leprosy: guidelines for prescribing and dispensing thalidomide drug

A Talidomida é um medicamento de uso controlado, cuja utilização exige uma série de medidas relacionadas à produção, prescrição e dispensação pelos seus efeitos teratogênicos comprovados ­ Resolução n° 11 de 22 de março de 2011

Thalidomide is a drug for controlled use, whose use requires a series of measures related to production, prescription and dispensing for their teratogenic effects proven - Resolution No. 11 of March 22, 2011

Comparative analysis of the use and control of thalidomide in Brazil and different countries: is it possible to say there is safety?

INTRODUCTION: One of the biggest drug disasters in history has not prevented thalidomide from being used to treat various clinical conditions. Currently, Brazil has a worrying scenario: high consumption of the drug and, cases of pregnant women using thalidomide, even after adopting restrictive legislation. AREAS COVERED: This review of the literature and legislation sought to comparatively analyze the monitoring of thalidomide use in Brazil and other countries that use this drug. Finally, we discuss the differences between the countries. EXPERT OPINION: This analysis allows us to think beyond the safe use of thalidomide, but the safety provided by any type of monitoring system. It seems that out-patients that use unsafe drugs are exposed to some degree of risk. To improve safety, more extensive improvements are needed than monitoring systems related to the use of thalidomide. Its safe use depends on a drastic reduction in the incidence of leprosy and Erythema Nodosum Leprosum in the world; investment in research and development of safe and effective therapeutic alternatives to thalidomide; improvement of health systems and their health surveillance systems, particularly in primary health care; awareness of health professionals and patients for greater responsibility in the use of medicines, especially thalidomide.

Case Report: Rapid Response to Low-Dose Thalidomide in a Case of Severe Steroid Recalcitrant Erythema Nodosum Leprosum.

Erythema nodosum leprosum (ENL), or type 2 lepra reaction, presents with crops of evanescent, tender erythematous nodules accompanied by fever, arthralgia, malaise and organ-specific manifestations and is seen in borderline and lepromatous leprosy. The drugs approved for ENL include nonsteroidal anti-inflammatory drugs, systemic steroids, thalidomide and clofazimine. The management of ENL is challenging because long-term steroid use leads to steroid dependence. The present patient had severe steroid recalcitrant ENL with vesicular and pustular lesions mimicking Sweet's syndrome and was treated effectively with a low-dose thalidomide regimen (100 mg/d) as opposed to high dose (400 mg/d) recommended in literature. We discuss the patho-mechanics and clinical utility of a low-dose thalidomide regimen as an effective treatment option for ENL.

A drug repositioning success: The repositioned therapeutic applications and mechanisms of action of thalidomide.

BACKGROUND: Thalidomide is the most teratogenic human medicine ever marketed and was associated with birth defects in approximately 10,000 children in the 1960s. The pharmacological effects of thalidomide are attributed to its anti-angiogenic, anti-inflammatory and modulatory effect on cytokines principally tumor necrosis factor-α, while the teratogenic effects are linked to two molecular targets, namely cereblon and tubulin. Teratogenicity is the gravest adverse effect of thalidomide depending on the dose and time of exposure. Nonetheless, with System for Thalidomide Education and Prescribing Safety program, the possibility of teratogenicity can be completely avoided. The sensitive period during pregnancy for thalidomide teratogenicity in humans is approximately 20-34 days after fertilization. METHODS: Relevant articles were identified from Google scholar and PubMed (MEDLINE) using different search strategies. CONCLUSION: Clinical trials showed that thalidomide has been found effective in the treatment of advanced renal cancer, esophageal cancer, chemotherapy refractory endometrial cancer and pancreatic cancer, which can suggest its future therapeutic potential in cancer treatment. Thalidomide is also used in the treatment of inflammatory skin disorders and has shown promising effect in the treatment of autoimmune disorders and inflammatory bowel disease. Despite thalidomide being a renowned teratogen and neurotoxin, it has been successfully repositioned and FDA approved for the treatment of erythema nodosum leprosum and multiple myeloma under strict control.

Population Pharmacokinetic Model to Assess the Impact of Disease State on Thalidomide Pharmacokinetics.

A population pharmacokinetic (PPK) model to describe the pharmacokinetics of thalidomide in different patient populations was developed using data pooled from healthy subjects and patients with Hansen's disease, human immunodeficiency virus (HIV), and multiple myeloma (MM). The analysis data set had a total of 164 evaluable subjects who received various doses (50 to 400 mg) of oral thalidomide in single- and/or multiple-dose regimens. The plasma thalidomide concentrations were adequately described by a linear 1-compartment PPK model with first-order absorption and first-order elimination. Inclusion of MM as a covariate on apparent clearance (CL/F) accounted for 4.4% of the interindividual variability (IIV) of CL/F. Body weight as a covariate on CL/F and apparent volume of distribution (V/F) also improved model fitting slightly, accounting for 7.2% and 20% of IIV, respectively. Although inclusion of body weight and MM as covariates of CL/F and body weight on V/F improved the goodness of fit of the model in a statistically significant manner, the impact of this difference in CL/F is not considered clinically relevant. Other factors such as age, sex, race, creatinine clearance, and alanine transaminase had no effect on thalidomide pharmacokinetics. MM, HIV, and Hansen's disease have no clinically relevant effect on thalidomide disposition relative to healthy volunteers.

Neutrophil extracellular traps contribute to the pathogenesis of leprosy type 2 reactions.

Up to 50% of patients with the multibacillary form of leprosy are expected to develop acute systemic inflammatory episodes known as type 2 reactions (T2R), thus aggravating their clinical status. Thalidomide rapidly improves T2R symptoms. But, due to its restricted use worldwide, novel alternative therapies are urgently needed. The T2R triggering mechanisms and immune-inflammatory pathways involved in its pathology remain ill defined. In a recent report, we defined the recognition of nucleic acids by TLR9 as a major innate immunity pathway that is activated during T2R. DNA recognition has been described as a major inflammatory pathway in several autoimmune diseases, and neutrophil DNA extracellular traps (NETs) have been shown to be a prime source of endogenous DNA. Considering that neutrophil abundance is a marked characteristic of T2R lesions, the objective of this study was to investigate NETs production in T2R patients based on the hypothesis that the excessive NETs formation would play a major role in T2R pathogenesis. Abundant NETs were found in T2R skin lesions, and increased spontaneous NETs formation was observed in T2R peripheral neutrophils. Both the M. leprae whole-cell sonicate and the CpG-Hlp complex, mimicking a mycobacterial TLR9 ligand, were able to induce NETs production in vitro. Moreover, TLR9 expression was shown to be higher in T2R neutrophils, suggesting that DNA recognition via TLR9 may be one of the pathways triggering this process during T2R. Finally, treatment of T2R patients with thalidomide for 7 consecutive days resulted in a decrease in all of the evaluated in vivo and ex vivo NETosis parameters. Altogether, our findings shed light on the pathogenesis of T2R, which, it is hoped, will contribute to the emergence of novel alternative therapies and the identification of prognostic reactional markers in the near future.

Late-onset ulnar neuritis following treatment of lepromatous leprosy infection.

Neuritis is a frequent complication of Myocobacteria leprae infection and treatment due to the variety of mechanisms through which it can occur. Not only can mycobacterial invasion into peripheral nerves directly cause damage and inflammation, but immune-mediated inflammatory episodes (termed leprosy reactions) can also manifest as neuritis at any point during infection. Treatment of leprosy reactions with thalidomide can also lead to neuritis due to an adverse drug effect. Neuritis can emerge years after initial diagnosis and treatment, although it is most frequently found at time of diagnosis or early into the treatment course. Treatment of neuritis is dependent on high-dose corticosteroid therapy as well as therapy for suspected underlying etiology. Here, we present a case of ulnar neuritis presenting in a patient with lepromatous leprosy four years after treatment of initial infection, with subsequent improvement after corticosteroid burst while maintained on thalidomide therapy.

NR3C1, ABCB1, TNF and CYP2C19 polymorphisms association with the response to the treatment of erythema nodosum leprosum.

Aim: To evaluate the effects of gene polymorphisms in the treatment of erythema nodosum leprosum with prednisone/thalidomide. Patients & methods: A total of 152 patients from different regions of Brazil were included. Generalized estimating equation was used to evaluate the influence of polymorphisms and haplotypes on the drug dose variation throughout the treatment. Results: An association between the genotype tuberculoid of polymorphism ABCB1 3435C>T (rs1045642; p = 0.02) and prednisone dose was found in the recessive model. An association between the haplotypes 1031T/-863C/-857C/-308A/-238G (p = 0.006) and 1031T/-863C/-857T/-308A/-238G (p = 0.040) of the TNF gene and the CYP2C19*2 polymorphism were also identified, in relation to thalidomide dosage variation over the course of treatment. Conclusion: This work presents the first pharmacogenetic report of association between gene polymorphisms and erythema nodosum leprosum treatment with prednisone/thalidomide.

Dose-dependent thalidomide induced bradycardia in young erythema nodosum leprosum patient.

The distressing consequences of immunology in leprosy is the lepra reaction. Erythema nodosum leprosum(ENL) in special cases need to be managed with capsule thalidomide in varying doses. We report such a case of bradycardia in thalidomide dose dependent manner in a young ENL male.

Safety of important dermatological drugs (retinoids, immune suppressants, anti androgens and thalidomide) in reproductively active males with respect to pregnancy outcome: A brief review of literature.

Paternally transmitted damage to offspring is recognized as a complex issue. Each parent contributes 23 chromosomes to a child; hence, it is necessary to know the effects of both maternal and paternal pre-and peri-conceptional exposure to drugs on pregnancy outcome. While there are many studies on the effects of maternal drug exposure on pregnancy outcome, literature on paternal exposure is scarce. Of late however, paternal exposure has been receiving increasing attention. We present a brief review on the safety of commonly used drugs in dermatology, focused on retinoids, immune suppressants, anti androgens and thalidomide.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles.

INTRODUCTION: Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS: Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS: Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS: Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Anti-phospholipid syndrome in seven leprosy patients with thrombotic events on corticosteroid and/or thalidomide regimen: insights on genetic and laboratory profiles

Abstract INTRODUCTION Corticosteroids and/or thalidomides have been associated with thromboembolism events (TBE) in multibacillary (MB) leprosy. This report aimed to determine genetic and laboratory profiles associated with leprosy and TBE. METHODS Antiphospholipid antibodies (aPL), coagulation-related exams, prothrombin and Leiden's factor V mutations, and ß2-glycoprotein-I (ß2GPI) Val247Leu polymorphism were assessed. RESULTS Six out of seven patients with leprosy were treated with prednisone and/or thalidomide during TBE and presented at least one positive aPL. All patients presented ß2GPI polymorphism, and one showed prothrombin mutation. CONCLUSIONS Corticosteroid or thalidomide adverse effects and aPL and ß2GPI polymorphisms may cause TBE in patients with MB leprosy.

Elevated Pentraxin-3 Concentrations in Patients With Leprosy: Potential Biomarker of Erythema Nodosum Leprosum.

Background: Leprosy, the leading infectious cause of disability worldwide, remains a major public health challenge in the most severely affected countries despite the sharp decline in new cases in recent years. The search for biomarkers is essential to achieve a better understanding of the molecular and cellular mechanisms underlying the disease. Methods: Pentraxin-3 (PTX3) analyses of sera from 87 leprosy patients with or without reactions were conducted via enzyme-linked immunosorbent assay. In situ identification of PTX3 in skin lesion was confirmed by quantitative reverse-transcription polymerase chain reaction, immunohistochemistry, and immunofluorescence assays. Results: We found that PTX3 serum levels were higher in multibacillary patients when evaluated before the onset of acute erythema nodosum leprosum (ENL) and persistently elevated during reaction. Thalidomide treatment reduced PTX3 in the serum 7 days after starting treatment. In situ analyses have also demonstrated enhancement of PTX3 in ENL lesions and showed that treatment with thalidomide reduced its expression and the prominent neutrophilic infiltrate, a hallmark of the disease. Conclusions: In summary, our study provides in vivo evidence that PTX3 is enhanced during ENL but not in reversal reaction and provides a new molecular target in ENL pathogenesis.

Therapeutic Dilemma of Refractory Erythema Nodosum Leprosum.

AbstractErythema nodosum leprosum (ENL), also known as type II leprosy reaction, is a severe immune-mediated complication of multibacillary leprosy. For ENL, corticosteroids and thalidomide are the mainstays of treatment. Other immunosuppressants, such as clofazimine, cyclosporine, and azathioprine have also been used. Although most patients with ENL respond well to conventional treatments, a small number are refractory to these therapies and have severe morbidity or mortality. We report the case of a 24-year-old man with refractory ENL treated with high-dose corticosteroids for 15 months. The patient developed steroid-dependence and serious adverse effects, and died of an intracranial infection.

"The legacy of thalidomide" - A multidisciplinary meeting held at the University of York, United Kingdom, on September 30, 2016.

BACKGROUND: Between 1957 and 1962 thalidomide was used as a nonaddictive, nonbarbiturate sedative that also was successful in relieving the symptoms of morning sickness in early pregnancy. Infamously, thousands of babies were subsequently born with severe birth defects. The drug is used again, today, to successfully treat leprosy, and tragically, there is a new generation of thalidomide damaged children in Brazil. While the outward damage in babies has been documented, the effects of the damage upon the survivors as they grow up, the lifestyle changes and adaptations required to be made, as well as studies into ageing in survivors, has received little attention and remains understudied. METHODS: A unique multidisciplinary meeting was organized at the University of York bringing together thalidomide survivors, clinicians, scientists, historians, and social scientists to discuss the past, the current and the future implications of thalidomide. RESULTS: There is still much to learn from thalidomide, from its complex history and ongoing impact on peoples' lives today, to understanding its mechanism/s to aid future drug safety, to help identify new drugs retaining clinical benefit without the risk of causing embryopathy. CONCLUSION: For thalidomide survivors, the original impairments caused by the drug are compounded by the consequences of a lifetime of living with a rare disability, and early onset age-related health problems. This has profound implications for their quality of life and need for health and social care services. It is vital that these issues are addressed in research, and in clinical practice if thalidomide survivors are to "age well". Birth Defects Research 109:296-299, 2017. © 2017 Wiley Periodicals, Inc.

Administración de esteroides y talidomida para el control del eritema nodoso leproso durante 17 años en el hospital para enfermedades tropicales de Londres / No disponible

Objetivos: La prednisolona y la talidomida se administran frecuentemente en el control del eritema nodoso leproso (ENL) y proporcionan alivio a los pacientes con esta condición en todo el mundo. Sin embargo, tanto el ENL como sus tratamientos causan gran morbilidad. Este trabajo describe el espectro del ENL observado en el Hospital para Enfermedades Tropicales de Londres (HTD), la utilización de esteroides y el uso de esteroides y talidomida en su control y las consiguientes complicaciones. Metodología: Se llevó a cabo una revisión retrospectiva de los pacientes diagnosticados con ENL entre 1996 y 2013. Los datos se obtuvieron de los archivos clínicos, incluyendo la severidad y duración del episodio, además del tratamiento y efectos adversos. Resultados: Entre 1996 y 2013 se diagnosticaron 30 pacientes con ENL. El índice bacteriológico (IB) promedio en el momento del diagnóstico fue > 4.65, superior al aceptado en otros estudios. La mayoría de los pacientes desarrollaron ENL durante el tratamiento (67%) y presentaron ENL crónico (57%). La duración media del ENL fue de 60 meses (rango 9-192); los pacientes con IB > 4.5 presentaron períodos de tiempo más largos. El 87% de los pacientes recibieron prednisolona durante 9 meses; 33% desarrolló efectos adversos, incluyendo diabetes e hipertensión; el 87% de los pacientes recibió talidomida durante 16 meses y el 65% presentó efectos adversos. No hubo casos de embarazo o tromboembolismo. El 77% de los pacientes dejó la prednisolona a los dos meses de iniciar la talidomida. No hubo casos de fallecimiento en nuestro grupo. Conclusión: Describimos el curso clínico del ENL en un país no endémico con acceso a la talidomida y prednisolona. El ENL puede durar mucho más que el tiempo descrito anteriormente y tiene un gran impacto sobre la salud del paciente. En el Reino Unido, la talidomida es esencial para cesar la administración de los esteroides, prevenir efectos adversos y la mortalidad por esteroides, lo cual esté documentado en otros trabajos

Objectives: Prednisolone and thalidomide are commonly used in the management of erythema nodosum leprosum (ENL) and bring relief to patients with this condition worldwide. However, both ENL and its treatments can cause significant morbidity. This study describes the spectrum of ENL seen at The Hospital for Tropical Diseases, London (HTD), the use of steroids and thalidomide in its management and the complications of their use. Study Design: We conducted a retrospective audit of patients diagnosed with ENL between 1996 and 2013. Data were obtained from hospital records including severity and length of disease, together with treatments received and adverse effects. Results: Between 1996 and 2013, 30 patients were diagnosed with ENL. The median bacillary index (BI) at diagnosis was 4.65, higher than in previous studies. Most patients developed ENL during leprosy treatment (67%) and had chronic ENL (57%). The median length of ENL was 60 months (range 9-192); patients with BI. 4.5 had significantly longer duration of disease. 87% patients received prednisolone for median nine months; 35% developed adverse effects including diabetes and hypertension. 87% patients received thalidomide for median 16 months; 65% complained of side effects. There were no pregnancies or venous thromboembolisms. 77% patients stopped prednisolone within two months of starting thalidomide. There were no deaths in our cohort. Conclusion: We describe the clinical course of ENL in a non-endemic country with access to thalidomide and prednisolone. ENL may last far longer than previously described and has significant impact on a patient’s health. In the UK, thalidomide is essential as a steroid-sparing agent, to prevent the adverse effects and mortality of longterm steroids which have been documented elsewhere

Erythema Necroticans - A Case Report.

Erythema Nodosum Leprosum (ENL) is characterized by evanescent, erythematous, painful raised nodules which fade within 48-72 hours. Necrotic and ulcerative forms are rare presentations of severe ENL. A 27 year old male patient presented with multiple erythematous nodules on trunk and extremities associated with high grade fever, joint pain and pedal edema. Patient developed ulceration of nodules associated with pain and burning sensation over another 3 days. Slit smear showed clumps of granular bacilli. Biopsy showed superficial dermis showing edema with dense focal perivascular infiltrate of lymphocytes, macrophages and few scattered neutrophils. Fite-Faraco stain was negative. Patient was diagnosed as a case of erythema necroticans and started on oral steroids and thalidomide. The histological findings illustrate the need to consider leprosy diagnosis in necrotizing vasculitis even when Virchow's cells are not found in the infiltrate. Thalidomide is the drug of choice in such cases. This patient showed a marked response to the drug with healing of all ulcers within 2 weeks of starting thalidomide.

Lucio's leprosy: a clinical and therapeutic challenge.

Leprosy has been a challenge in different areas of medicine; in underdeveloped countries it remains a public health problem, in which the social and economic problems facilitate the disease persistence. The diagnosis and consequently the treatment are delayed due to the clinical polymorphism of leprosy, which especially at the beginning the manifestations are not as evident, as is the case of diffuse lepromatous leprosy. This favors the disabilities and the development of the reaction episodes. Fortunately, reaction episodes have decreased with the use of multidrug therapy, and better control of the type 2 reactions has been managed with the use of thalidomide, as in Lucio's phenomenon.

Successful long-term thalidomide therapy for discoid lupus erythematosus-lichen planus overlap syndrome.

Although thalidomide is a U.S. Food and Drug Admistration (FDA) approved medication for erythema nodosum leprosum and multiple myeloma, it has many off-label uses, including for discoid lupus erythematosus (DLE), Behçet's disease, apththous ulcers in HIV patients, and prurigo nodularis. Herein, we present a patient with an overlap of discoid lupus erythematosus and lichen planus who was successfully treated with thalidomide for over 19 years without significant side effects. We propose that some of the most common side effects, including peripheral neuropathy, numbness, parasthesias, sedation, and constipation, can be avoided at lower doses, typically less than 100mg/day.

Steven's Johnson syndrome with toxic epidermal necrolysis due to thalidomide in a case of multiple myeloma.

Thalidomide developed in 1954 for morning sickness had proven to be a teratogen and hence was withdrawn from market. Resurgence of thalidomide began as an immunomodulator when it was shown to be effective in the management of multiple myeloma and many conditions like erythema nodosum leprosum, graft versus host disease, recurrent aphthous ulcers etc. We report a case of Stevens Johnson syndrome-toxic epidermal necrolysis developing in an elderly male who was prescribed thalidomide after being diagnosed with multiple myeloma.