A phase 2 open trial of pentoxifylline for the treatment of leprosy reactions

International Journal of Leprosy and Other Mycobacterial Diseases, Mar 2002 by Dawlah, Zubaer M, Cabrera, Aloys, Ahern, Kathleen, Levis, William R

TO THE EDITOR:

Pentoxifylline (PTX) is an immunomodulatory agent with rheologic properties.(11) It diminishes the effect of TNF-alpha and IL-1 on polymorphonuclear cell (PMN) chemotaxis, adhesion and toxic radical formation. (23, 24.3) PTX may modulate endothelial adhesion receptors leading to reduced PMN adhesion. (8) PTX has been shown to inhibit TNF-alpha production at both mRNA and protein levels in murine macrophages. (22.4) On the other hand, PTX has little effect on IL- I and IL-6 production but decreases induced leukocyte responsiveness. (5, 27) PTX inhibits human dermal fibroblasts in vitro and the production of collagen, glycosaminoglycan and fibronectin. (2) PTX also has a suppressive effect on natural killer cells. (13) PTX is thought to operate in part by increasing intracellular cyclic AMP. (18, 16)

Thalidomide is another agent that inhibits TNF-alpha production which it does by enhancing the degradation of TNF-alpha mRNA. (10) Thalidomide has been used extensively along with corticosteroids in the treatment of erythema nodosum leprosum (ENL) in Hansen's disease. (17) Thalidomide is wellknown for its teratogenic effects.

Hansen's disease is a chronic mycobacterial disease marked by multifaceted immunologic involvement in its pathogenesis. The spectrum of Hansen's disease is classified according to Ridley and Jopling into five categories. (15) The disease status is further complicated by different reactional states mainly erythema nodosum leprosum (ENL) and reversal reaction (RR). Clinically ENL is characterized by development of crops of new, small, tender subcutaneous nodules, which usually subside after a few days along with systemic features like pyrexia, arthralgia, neuritis, and adenopathy. RR, on the other hand, presents as brawny, indurated, erythematous skin plaques with neuritis. TNF-alpha is thought to be a key mediator in Hansen's disease and reactional states. (2,13, 18) It has been suggested that PTX may be beneficial in Hansen's disease reactions. (16) Because PTX inhibits TNF-alpha, transcription and production and because TNF-alpha has been implicated as a major mediator of leprosy reactions, we evaluated the effect of PTX in the treatment of leprosy reactions.

Patients were selected from the New York Regional Hansen's Disease Clinic, after obtaining Institutional Review Boardapproved informed consent. Patients were classified according to Ridley and Jopling. (15) All leprosy patients with reactions were evaluated and eligible for entry into the study. Reactional states were identified and classified according to patients' symptoms and signs and in some patients according to their skin biopsy. Patients were randomly assigned to different treatment regimens of PTX ranging between 1200 mg to 2400 mg in divided doses. If patients were already on therapy for reactional states with corticosteroids, they were recruited if reactional states worsened with that dose and, rather than increasing the steroid, PTX was added. Patients were followed by one observer (Dr. William Levis) for evaluation of responses, which were determined at each clinic visit (average 4 assessments per patient). The range of time on PTX was from 0.8 months to 16.3 months with a median of 8.3 months.

Responses were defined into five categories with a descriptive and numerical value. Definition of responses: excellent (5)-complete resolution of all symptoms and signs; good (4)-resolution of most symptoms and signs but persistence of some minimal features; fair (3)-resolution of some symptoms and signs but persistence of most features; no response (2)-no effect of therapy on symptoms and signs; and worse (1)-worsening of symptoms and signs after initiation of therapy. Statistical analysis of the scaled response was done using the nonparametric test of differences, the Mann Whitney and the Fisher's Exact Probability Test.

A total of 21 patients completed the study. The age range of the patients varied between 22 years to 79 years. All the patients in the study were born outside the United States. Table 1 gives the classification and demography of patients. Of the 21 patients, 16 were lepromatous or borderline lepromatous and 5 patients were tuberculoid or borderline tuberculoid. Thirteen among the 21 patients had reversal reaction (RR) and 8 patients had erythema nodosum leprosum (ENL). Patients were treated with PTX in a dose range of 1.2 gm to 2.4 gm in three or four divided doses. Table 2 gives the response of leprosy reactions to PTX therapy. Of the 8 patients with ENL, 5 patients (62.5%) had fair responses, 2 patients (25%) had good responses, and 1 patient's (12.5%) reaction worsened. Among 13 patients with RR, 5 patients (38%) had fair responses and 1 patient (8%) had a good response, 4 patients (30%) had nonresponse and in 3 patients (24%) their reaction worsened. None of the patients had excellent responses. Response to PTX was considered from the scaled score with a range of 4 to 1. Four was considered a good response, 3 was a fair response, 2 was a nonresponse, and 1 was a worsening response. The scaled responses were analyzed by the Mann Whitney test of differences for nonparametric testing. No significant differences were noted between the ENL and RR on response (p