• Volume 70 , Number 1
  • Page: 38–43

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

Zubaer M. Dawlah; Aloys Cabrera; Kathleen Ahern; William R. Levis






To the Editor:

Pentoxifylline (PTX) is an immunomodulatory agent with rhcologic properties.(11) It diminishes the effect of TNF-α 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-α production at both mRNA and protein levels in murine macrophages. (22,4) On the other hand, PTX has little effect on IL-1 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-α production which it does by enhancing the degradation of TNF-α 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-α 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. Because PTX inhibits TNF-α, transcription and production and because TNF-α 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 (l)-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 <0.15) with a Z value -1.41. This result was also noted when the ENL and RR groups were divided into responders (good or fair) and non-responders (nonor worse). The ENL group had 7 responders and 1 non-responder. The RR group had 7 responders and 6 non-responders. The Fisher's exact probability test was used to examine the differences between groups and the result was non-significant at p < 0.17. Spearman's rho was used to test the correlation between response and dose, as response rates were ordinal data (ranked scoring) and more appropriate for nonparametric testing. The higher the dose, the lower the scaled response. Therefore, higher doses were moderately, negatively correlated with lower responses. Spearman's rho -0.48.

 

 

 

Table 3 shows the side effects associated with PTX therapy. Seven patients receiving PTX had side effects ranging from nausea, abdominal discomfort, headache and dizziness. PTX had to be discontinued in three patients (patients 2, 10 and 13). One patient (19) tolerated PTX after lowering the dose. The other three patients had minimal symptoms and did not require alteration of therapy. Spearman's rho = 0.31 for the correlation between dose and side effect. The result is a weak positive correlation. The higher doses appear to be positively correlated with the increased incidence of side effects.

 

 

Our results suggest that PTX may have some minimal efficacy in the treatment of reactional states in Hansen's disease possibly due to inhibition of TNF-α production. Mycobacterial lipoarabinomannan (LAM) has been shown to stimulate TNF-ot and nitric oxide (NO) synthesis in mouse macrophages. (20) LAM also has immunosuppressive effects like inhibition of T-cell proliferation. (9) There is a wide spectrum of immunological manifestations seen in Hansen's disease. LL type is characterized by low cellular immunity and high TNF-α level and they frequently have ENL type of reaction, (2I) partly due to the increased release of LAM and subsequent induction of TNF-α and inhibition of cellular immunity. TT-BT types on the other hand have increased cellular response, lower TNF-α level and they frequently have RR type of reaction. (I3' 16) In our study we did not see a statistically significant better result in ENL, but there was a hint of greater response in ENL.

Eight (38%) of our patients were on clofazimine and all the patients were on dapsone. The precise role played by dapsone and clofazimine is not clear yet. They may have variable effects on eicosanoids, (1) but since patients developed reactional states even with clofazimine and dapsone it indicates they probably do not play an important role. All the patients in our study were followed by one observer, thereby, eliminating interobserver variability in this complex disease. Overall patients in our study did not respond to PTX as well as we had hoped. Six out of 21 patients (29%) subsequently required prednisone or an increased dose of prednisone.

PTX has been noted to be an incomplete inhibitor of TNF-α. (19) Unlike corticosteroids, PTX has not been shown to affect the eicosanoid pathway of inflammation. (26) Eicosanoids are thought to be terminal mediators of cell injury. TNF-α induces the synthesis of eicosanoids (7). In experimental models inhibition of eicosanoids has attenuated TNF-α mediated sepsis. (6) In this regard we have found zafirlukast, a leukotriene 4 receptor antagonist, to be more promising as a nonsteroidal treatment for leprosy reactions than PTX. (2h) We have also found PTX to be a poor inhibitor of nitric oxide (NO) production. (14) The poor inhibition of NO, coupled with incomplete inhibition of TNF-α and failure to affect the eicosanoids could account for the breakthrough and worsening of reactions found in up to 20% of the subjects with ENL. (12) At this time, considering the large number of nonsteroidal anti-inflammatory agents currently in development we would recommend pursuing agents other than PTX as alternatives for the treatment of leprosy reactions.

 

- Zubaer M. Dawlah, M.D.1
Aloys Cabrera, R.N. P.H.N.1, 2
Kathleen Ahern, Ph.D., R.N.1
William R. Levis, M.D., Director1, 2

1Staten Island University Hospital
New York City-Regional Hansen's Disease Program
475 Seaview Avenue
Staten Island, New York 10305

2Bellevue Hospital-NYU Medical Center
New York City-Regional Hansen's Disease Program
462 First Avenue & 27th Street
New York City, NY 10016

Address for reprint request: William R. Levis, M.D., Director Bellevue Hospital - Hansen's Disease Program

 

REFERENCES

1. ANDERSON, R. Enhancement by clofazimine and inhibition by dapsone of production of prostaglandin E, by homan polymorphonuclear leukocytes in vitro. Antimicrob. Agents Chemother. 27 (1985) 257-262.

2. BARNES, P. F., CHATTERJEE, D., BRENNAN, P. J., REA, T. H. and MODLIN. R. L. Tumor necrosis factor production in patients with leprosy. Infect. Immun. 60(1992)1441-1446.

3. BOOGAERTS, M. A., Mi.li s. P. and SCHEERS, W. Pentoxifylline and analogues: effects on normal and diseased granulocyte function in vitro. In: Pentoxifylline and Analogues: Effects on Leukocyte Function. Hakim, J., Mandel, G. J. and Novick, W. J. Jr., eds. Somerville, NJ: Hoechst-Roussel Pharmaceuticals, 1989, pp. 9-16.

4. DOHERTY, G. M., JENSEN, J. C, ALEXANDER, H. R., BURESH, C. M. and NORTON, J. A. Pentoxifylline suppression of tumor necrosis factor gene transcription. Surgery 110(1991)192-198.

5. ENDRES, S., FÜLLE, H. J., SINUA, B., STOLE, D., DINARELLO. C. A., GERZER, R. and WEBER, P. C. Cyclic nucleotides differentially regulate the synthesis of tumor necrosis factor-alpha and interleukin-! beta by human mononuclear cells. Immunology 72(1991) 56-60.

6. EVANS, D. A., JACOBS, D. O., REVHAUG, A. and WILMORE, B. W. The effects of tumor necrosis factor and their selective inhibition by ibuprofen. Ann. Surg. 209(1989)312-321.

7. FLETCHER, J. R.. COLLINS, J. N., GRAVES, E. D. 3RD, LUTERMAN, A., WILLIAMS. M. D.. IZEN-BERG, S. D. and RODNING, C. B. Tumor necrosis factor induced mortality is reversed with cycloxygenase inhibition. Ann. Surg. 217(1993)668-675.

8. MEGE, J. L., EON, B. and SAUX. P. Inhibition of granulocyte adhesion by pentoxiphylline. In: Pentoxifylline and Analogues: Effects on LeukocyteFunction. Hakim. J.. Mandel, G. .1. and Novick. W. J. Jr., eds. Somerville, NJ: Hoechst-Roussel Pharmaceuticals. 1989, pp. 17-23.

9. MOLLOY, A., GAUDERNACK, G., LEVIS, W. R.. COIIN, Z. A. and KAPLAN, G. Suppression of T cell proliferation by Mycobacterium leprae and its products: the role of lipopolysaccharide. Proc. Natl. Acad. Sci. U.S.A. 87 (1990) 973-977.

10. MOREIRA, A. L., SAMPAIO, E. P., ZMU1DZINAS, A.. FRINDT, P.. SMITH, K. A. and KAPLAN. G. Thalidomide exerts its inhibitory action on tumor necrosis factor α by enhancing mRNA degradation. J. Exp. Med. 177(1993)1675-1680.

11. NEES, S. and SCHONHARTING, M. Role of different blood cell types in blood rhcology. In: Pentoxifylline and Leukocyte Function. Mandel, G. J. and Novick. W. J., Jr., eds. Somerville, NJ: Hoechst-Roussel Pharmaceuticals. 1988, pp. 105-114.

12. NERY, J. A. C, PERISSE, A. R. S., SALES, A. M., VIEIRA, L. M. M., SOUZA. R. V., SAMPAIO, E. P. and SARNO, E. N. The use of pentoxifylline in the treatment of Type 2 reactional episodes in leprosy. Indian J. Lepr. 72 (2000) 460-467.

13. PARIDA, S. K., GRAU, G. E., ZAHEER, S. A. and MUKHERJEE, R. Serum tumor necrosis factor and interleukin 1 in leprosy and during lepra reactions. Clin. Immunol. Immunopathol. 63 (1992) 23-27.

14. PARK, EUNKYUE, SCHULLER-LEVIS, GEORGIA, PARK, SEUNG YOUNG, JUN HIJA, CHAEKYUN KIM and LEVIS, WILLIAM R. Pentoxifylline downregulates nitric oxide and tumor necrosis factor-α induced by mycobacterial lipoarabinomannan in a macrophage cell line. Int. J. Lepr. 69(2001)225-233.

15. RIDLEY. D, S. and JOPLING. W. H. Classification of leprosy according to immunity. A five-group system. Int. J. Lepr. 34 (1966) 255-273.

16. SAMLASKA. C. P. and WINFIELD, E. A. Pentoxifylline. J. Am. Acad. Dermatol. 30 (1994) 603-621.

17. SAMPAIO, E. P., KAPLAN, G., MIRANDA, A.. NERY. J. A.. MIGUEL. C. P.. VIANA, S. M. and SARNO, G. N. The influence of thalidomide on the clinical and immunological manifestation of erythema nodosum. J. Infect. Dis. 168(1993)408-414.

18. SARNO. E. N.. GRAU. G. E., VIEIRA, L. M. M. and NERY. J. A. Serum levels of tumor necrosis factoralpha and interleukin-1β during leprosy reactional states. Clin. Exp. Immunol. 84(1991)103-108.

19. SATHE, S. S., SARAI, A., TSIGLER, D. and NEDUNCHEZIAN, D. Pentoxifylline aggravates impairment in tumor necrosis factor-alpha secretion and increases mycobacterial load in macrophages from AIDS patients with disseminated Mycobacterium avium-intracellulare complex infection. J. Infect. Dis. 170(1994)484-187.

20. SCHULLER-LEVIS, G. B., LEVIS , W. R., AMMAZZALORSO, M., NOSRATI, A. and PARK, E. Mycobacterial lipoarabinomannan induces nitric oxide and tumor necrosis factor alpha production in a macrophage cell line: down regulation of taurine chloramine. Infect. Immun. 62(1994)4671-4674.

21. SEHGAL, V. N.. BHATTACHARYA, S. N., CHATTOPADHAYA, D. and SAHA, K. Tumor necrosis factor: status in reactions in leprosy before and after treatment. Int. J. Dermatol. 32 (1993) 436-439.

22. STREITER, R. M, REMICK, D. G. and WARD, R A. Cellular and molecular regulation of tumor necrosis factor-alpha production by pentoxifylline. Biochem. Biophys. Res. Commun. 155(1988)1230-1236.

23. SULLIVAN, G. W., CARPER, H. T., NOVICK, W. J., JR. and MANDELL, G. L. Inhibition of the inflammatory action of interleukin-1 and tumor necrosis factor (alpha) on neutrophil function by pentoxifylline. Infect. Immun. 66(1988)1722-1729.

24. SULLIVAN, G. W., CARPER, H. T., NOVICK, W. J., JR. and MANDELL, G. L. Pentoxifylline inhibits the inflammatory effects of endotoxin and endotoxin induced cytokines on neutrophil function. In: Pentoxifylline and Leukocyte Function. Mandel, G. J and Novick, W. J. Jr., eds. Somerville, NJ: Hoechst-Roussel Pharmaceuticals, 1988, pp. 37-48.

25. TRUOG, W. E., GIBSON, R. L., JR., HENDERSON, W. R., JR., REDDING. G. J. and STANDAERT, T. A. Effect of pentoxifylline on cytokine- and eieosanoidindueed acute pulmonary hypertension in piglets. Pediatr. Res. 31 (1992) 163-169.

26. VIDES, E. A., CABRERA, A., AHERN, K. P. and LEVIS, W. R. Effect of zafirlukast on leprosy reactions. Int. J. Lepr. 67(1999)71-74.

27. ZABEL, P.. SCHADE, F. U. and SCHLAAK, M. Inhibition of endogenous TNF formation by pentoxifylline. Immunobiology 187(1993)447-463.

 

 

 

 

 

 

 

 

 

 

Address for reprint request:
William R. Levis, M.D.
Director Bellevue Hospital - Hansen's Disease Program

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