Immune reconstitution inflammatory syndrome associated with HIV and leprosy.

BACKGROUND: Immune reconstitution inflammatory syndrome (IRIS) is an unusual inflammatory reaction to an opportunistic infection that occurs in human immunodeficiency virus (HIV)-positive patients with profound immunosuppression during the reconstitution of the immune system in the initial months of highly active antiretroviral treatment. OBSERVATIONS: We describe 3 cases of leprosy occurring in patients treated with a combination of 3 antiretroviral drugs who fulfilled the criteria for IRIS. A reactional state occurred in all 3 cases. Two of the 3 patients presented an unusual ulcerous progression of the lesions not generally observed in cases of leprosy. The outcome was favorable in all 3 cases. The frequency of IRIS associated with leprosy in French Guiana and Martinique is estimated at 3 cases per 1000 HIV-positive patients receiving highly active antiretroviral treatment. CONCLUSION: Leprosy should be recognized as an IRIS-associated infection with possibility of atypical presentation.

Dermatologic and nondermatologic uses of thalidomide.

OBJECTIVE: To review published data on thalidomide, with emphasis on current knowledge about mechanism of action, new and/or potential dermatologic and nondermatologic therapeutic applications, well-known and emerging adverse effects, and current indications for its safe use. DATA SOURCES: Review articles, in vitro research studies, references from retrieved articles, case reports, and clinical trials were identified from a computerized literature search using MEDLINE and OVID (1966-January 2003) and on the Cochrane Clinical Trials Register (January 2003). Information available from meetings' abstract books, Internet, or pharmaceutical companies was also considered. STUDY SELECTION AND DATA EXTRACTION: All articles identified as relevant, including those from non-English literature, were considered in an attempt to provide to the reader both the theoretical basis and practical guidelines for thalidomide pharmacotherapy. DATA SYNTHESIS: Thalidomide has hypnosedative, antiangiogenic, antiinflammatory, and immunomodulatory properties. Moreover, it has been shown to selectively inhibit the production of tumor necrosis factor-alpha and reduce the expression of various integrin receptors on the membrane of leukocytes and other cell types in a dose-dependent fashion. Controlled trials demonstrated the efficacy of thalidomide in a number of diseases, including erythema nodosum leprosum, lupus erythematosus, aphthosis, graft-versus-host disease, prurigo nodularis, and actinic prurigo. Single case reports or studies in small series have also suggested a possible role for thalidomide in numerous other dermatologic and nondermatologic disorders. Possibly severe and sometimes irreversible risks related to the clinical use of thalidomide include teratogenicity and neurotoxicity. CONCLUSIONS: Although teratogenicity and neurotoxicity are significant adverse effects requiring cautious use, thalidomide is an effective therapeutic modality in a variety of difficult-to-treat disorders and, providing careful selection of patients, should offer an acceptable risk-to-benefit ratio.

Thalidomide: a review of approved and investigational uses.

BACKGROUND: Thalidomide is best known as a major teratogen that caused birth defects in up to 12,000 children in the 1960s. More recently, this agent has been approved by the US Food and Drug Administration for the treatment of erythema nodosum leprosum (ENL) through a restricted-use program. Its immunomodulatory, anti-inflammatory, and antiangiogenic properties are currently under study in a number of clinical conditions. OBJECTIVE: This article reviews the pharmacology of thalidomide; its approved and off-label uses in dermatologic, oncologic, and gastrointestinal conditions; and adverse events associated with its use. METHODS: Relevant articles were identified through searches of MEDLINE (1966-June 2002), International Pharmaceutical Abstracts (1970-June 2002), and EMBASE (1990-June 2002). Search terms included but were not limited to thalidomide, pharmacokinetics, pharmacology, therapeutic use, and teratogenicity, as well as terms for specific disease states and adverse events. Further publications were identified from the reference lists of the reviewed articles. Abstracts of recent symposia were obtained from the American Society of Clinical Oncology Web site. RESULTS: Thalidomide is thought to exert its therapeutic effect through the modulation of cytokines, particularly tumor necrosis factor-alpha. In addition to its approved indication for ENL, thalidomide has been studied in various other conditions, including graft-versus-host disease, discoid lupus erythematosus, sarcoidosis, relapsed/refractory multiple myeloma, Waldenstrom's macroglobulinemia, myelodysplastic syndromes, acute myeloid leukemia, myelofibrosis with myeloid metaplasia, renal cell carcinoma, malignant gliomas, prostate cancer, Kaposi's sarcoma, colorectal carcinoma, oral aphthous ulcers, Behçet's disease, Crohn's disease, and HIV/AIDS-associated wasting. Adverse events most frequently associated with its use include somnolence, constipation, rash, peripheral neuropathy, and thromboembolism. CONCLUSIONS: Use of thalidomide is limited by toxicity, limited efficacy data, and restricted access. Evidence of its efficacy in conditions other than ENL awaits the results of controlled clinical trials.

Thalomid (Thalidomide) capsules: a review of the first 18 months of spontaneous postmarketing adverse event surveillance, including off-label prescribing.

The sedative/hypnotic thalidomide was withdrawn from the worldwide market nearly 40 years ago, because of its teratogenic and neurotoxic effects. Thalidomide was later found to very effectively suppress erythema nodosum leprosum (ENL). The US Food and Drug Administration (FDA) has approved Thalomid (thalidomide) capsules for the acute treatment of the cutaneous manifestations of moderate to severe ENL. Thalidomide is currently under investigation for the treatment of a wide variety of diseases, including conditions thought to have an inflammatory or immune basis, malignancies and complications of infection with HIV. Interest in the potential anti-inflammatory, immunomodulatory and anti- angiogenic effects of thalidomide has resulted in off-label use of prescription thalidomide. During the first 18 months of spontaneous postmarketing adverse event surveillance for Thalomid, 1210 spontaneous postmarketing adverse event reports were received for patients treated with prescription thalidomide for all therapeutic indications, including off-label use. The most common adverse events spontaneously reported would have been expected on the basis of the current Thalomid labelling/product information. The current labelling/product information reflects what was known about the risks associated with thalidomide therapy in limited patient populations at the time of the approval of Thalomid. With the postmarketing use of thalidomide in populations other than patients with ENL, it becomes increasingly important to identify patient groups that may be particularly susceptible to specific adverse drug effects and to identify conditions under which specific adverse events may be more likely to occur. Oncology patients may represent a patient population with increased susceptibility to thalidomide-associated adverse effects, including thromboembolic events. Consideration of the spontaneous postmarketing safety surveillance data may help to identify and characterise factors associated with increased risk in this and other patient groups. Serious unexpected adverse events reported with sufficient frequency to signal previously undetected product-event associations for which there may potentially be plausible evidence to suggest a causal relationship have included seizures and Stevens-Johnson syndrome. The potential effects of thalidomide on wound healing are also being closely monitored. Premarketing human clinical trials of drug products are inherently limited in their ability to detect adverse events. Broader postmarketing experience with thalidomide in more varied patient populations and more experience in the setting of long term thalidomide use will increase our ability to detect rare adverse events and to identify signals that may need to be evaluated in more controlled settings.

The re-emergence of thalidomide: results of a scientific conference.

BACKGROUND: The use of thalidomide during the 1950s resulted in teratogenic effects in thousands of infants. Although thalidomide is currently approved for the treatment of a complication of leprosy, it is commercially available to treat other diseases through a controlled distribution system. This article presents a summary of a scientific conference organized to assess clinical research on thalidomide, its new clinical applications, and the social and ethical implications for its use. METHODS: Summaries of 10 presentations and two panel discussions were developed from the authors's, oral presentations, conference slides, responses to questions, and supporting literature. RESULTS: Thalidomide shows promise in treating several diseases, including HIV/AIDS, rheumatoid arthritis, Crohn's disease, and multiple myeloma. The STEPStrade mark (System for Thalidomide Education and Prescribing Safety) Program has been developed by Celgene, the commercial manufacturer of thalidomide, to ensure compliance with prescription and usage protocols. A surveillance system is also in place to monitor and report compliance patterns. CONCLUSIONS: Despite the tragic past associated with thalidomide, the drug shows promise as a treatment for many clinical disorders. The challenge is to answer lingering questions of risks and benefits through clinical trials and discovery, to monitor participation and compliance with protocols developed to avoid use of the drug during pregnancy, and to continue to search for safer and more effective treatment options.