INTERNATIONAL JOURNAL OF LEPROSY^

Volume 65, Number 4Printed in the U.S.A.

(ISSN 0148-916X)

CORRESPONDENCE

This department is for the publication of informal communications that are of interest

because they are informative and stimulating, and for the discussion of controversial

matters. The mandate of this JouRNAL is to disseminate information relating to leprosy in

particular and also other mycobacterial diseases. Dissident comment or interpretation on

published research is of course valid, but personality attacks on individuals would seem

unnecessary. Political comments, valid or not, also are unwelcome. They might result in

interference with the distribution of the JOURNAL and thus interfere with its prime purpose.

A Multicenter Study of Recombinant Interferon-Alpha2bin the Treatment of Multibacillary Leprosy

To THE EDITOR:

Lepromatous leprosy has well-docu-mented deficiencies in the macrophage reg-ulation system (9). The role of cytokines,such as gamma-interferon (IFN-p, inter-leukin 2, tumor necrosis factor in macro-phage stimulation ('), natural killer (NK)cell activity and antibody-dependent cell-mediated cytotoxicity (ADCC) ( 3 ), havebeen described. Combination chemother-apy utilizing drugs like dapsone, rifampin,and clofazimine (h) and newer groups ofdrugs such as macrolides ( 7) and quinolones(") have been shown to be effective. Therate of fall of the bacterial index (BI) isabout 1 log per year. The search is now onto try to achieve a higher cell kill and toclear the dead bacilli faster.

The treatment of patients havinc ,

b

lepro-matous leprosy with local IFN-y has beentried before ( 2 . 5 . 12 ). They are shown to haverapid bacillary clearance and increasedH 2O, release by macrophages when IFN-ywas injected locally ( 13 ). IFN-y has a poormuscle and skin absorption along with ashort half-life of 25-30 min (4 ).

Alpha-interferon (IFN-a) has been usedextensively to treat malignancies (') and viralinfections ( 1 h). The role of IFN-a on NK cellactivity and ADCC has been documented invitro ( 3). The clinical efficacy of IFN-a inleprosy has not been evaluated before.

MATERIALS AND METHODSForty patients with lepromatous leprosy

were randomized to the multidrug therapy

(MDT) arm or MDT-interferon (MDTI)arm of our study. The treatment on theMDT arm consisted of dapsone 100 mg andclofazimine 50 mg daily along with ri-fampin 600 mg and clofazimine 300 mgmonthly, the duration of treatment being 24months. The MDTI arm consisted of theabove treatment along with alpha-interferon2b (IFN-a2b) at a dose of 3 million unitssubcutaneously twice a week for 6 weeks.The clinical features, BI, histology and lep-romin reactivity were documented at base-line and at 3 months. The clinical featureswill be followed up monthly for 24 monthsand yearly thereafter. While the BI was readas it normally is, the histology was scoredaccording to a predetermined histologicalscoring system.

Statistical methods. The Mann-Whit-ney U test for unpaired ordinal variablesand an unpaired t test for continuous vari-ables were used.

RESULTSWe were able to evaluate the histology

for 30 patients (20 on the MDTI arm and 10on the MDT arm). There were 37 patientsfor whom we were able to evaluate the BI(19 on the MDTI arm and 18 on the MDTarm). The baseline median histopatho-logical score was 3 for both the MDTI andthe MDT arms. The mean BIs also weresimilar, 3 and 3.1 for the MDTI and MDTarms, respectively. The mean fall in the BIwas 1.526 and 0.547 for the MDTI andMDT arms, respectively, the difference of0.98 (95%CI 0.45-1.50) being significant

495

496^ International Journal of Leprosy^ 1997

THE TABLE. Significance of clinical,bacteriological, histological and immuno-logical parameters studied.

Criteria^ Significance

Infiltration^p = 0.0009Erythema^p = 0.0001Bacterial index^p = 0.001Histopathology^p = 0.029Lepromin^p = 1.0

(p = 0.001) (The Table, The Figure). Themean fall in the histopathology score was0.85 and 0.2 in the MDTI and MDT arms,respectively, this too being significant (p =0.029).

Lepromin reactivity was negative in allpatients at baseline and continued to be soafter 3 months.

Clinical features studied included infiltra-tion and erythema, the differences in pre-and post-treatment scores were significant,p = 0.0009 and p = 0.0001, respectively.

There was one type 1 reaction on theMDT arm and one type 2 reaction on theMDTI arm. Apart from malaise and mildfever following the injections there was nomajor side effect attributable to IFN-a.

DISCUSSIONThe bacterial cell kill after chemotherapy

is probably effective, but dead bacilli re-maining in the soft tissue often contribute todisease morbidity. The fall in the BI is oneof the modes of following up the load ofdead bacteria. Cytokines play a role in theactivation of macrophages which is impor-tant in the removal of bacteria and cellsfrom the dermis. The addition of a shortcourse of IFN-a to the MDT seems to havesignificantly enhanced the fall in the BI atan early stage of the treatment itself.

The baseline histology in all of the pa-tients revealed a clear subepidermal layerand foam cells. The patients who weregiven IFN-a along with the MDT had amore rapid clearance of foam cells whichcould, again, signify an enhanced cell-me-diated clearing of the dead cells.

Lepromin testing is a measure of the cell-mediated activity manifested by the body;this did not seem to be altered by the addi-tion of IFN-a to the MDT during the periodof the study.

MDT^MDT +INFTherapy

THE FIGURE. Fall in bacterial index in the MDTand MDTI arms was 0.547 and 1.526, respectively, thedifference of 0.98 (95%Cl 0.45-1.50) being significant(p = 0.001).

While these are preliminary observations,IFN-a does seem to favorably influence theBI and the histology when added to MDTin patients with lepromatous leprosy. Thelong-term follow up of these patients willreveal a more definite picture of the alter-ations of the natural history of the disease,the observations of which will be a part offuture communication.

—Dr. R. GanapatiDr. V. V. Pai

Dr. Udai BanerjiBombay Leprosy ProjectVichiyan Bhavan11 V.N. Purav MargSion Chunnabhatti RoadBombay 400 001, India

—Dr. Jaykar ThomasInstitute for Child Health

and Hospital for ChildrenChennai, India

—Dr. B. SahaSchool of Tropical MedicineCalcutta, India

Reprint requests to Dr. Ganapati at theabove address or FAX 91-22-522-3040.

REFERENCES1. ALLEN, N. C., RicuAR0, S. M. and SHEPARD, P. C.

A. U.K. Medical Research Council randomizedmulticenter trial of interferon alpha for chronicmyeloid leukemia, improved survival irrespectiveof cytogenetic response. Lancet 345 (1995)1392-1397.

2. BHUTAN!, L. K., MEHRA, N. K., NUNDY, S. andNATii, I. Leprosy. Lancet 345 (1995) 697-703.

65, 4^ Corresp ondence^ 497

3. CIIIPLUNKAR, S. V., DESIIMUKII, M. V., SAMSON, P.D., BUTLIN, C. R., BIIATKI, W. S., CIIULLAWALA, R.G., Dm, M. G. and GANGAI., S. G. Natural killer-cell-mediated and antibody-dependent cellular cy-totoxicity in leprosy. Int. J. Lepr. 58 (1990)334-341.

4. CIREI.I.1, R. and TYRING, S. K. Major therapeuticuses of interferons. Clin. Inummother. 3 (1995)27-87.

5. DAMASCO, M. H. S., SARNO, E. N., LOBAO, A. S.,AI.VARENGA, F. B. F., PoRTo, J. A., ROSANKAIMER,

F. and KAPLAN, G. Effect of cutaneous cell-medi-ated immune response to HEN-gamma on My-cobacterium leprae viability in the lesions of lep-romatous leprosy. Braz. J. Med. Biol. Res. 35(1992) 457-465.

6. GANAPATI, R., PAL R., GANDEWAR, K. L. andTIIRESSIA, X. J. For how long should a multibacil-lary leprosy patient he treated? Indian J. Lepr. 61(1989)467-471.

7. Ji, B., JAMET, P., PERANI, E. G., Sow, S., LIEN-

IIARDT, C., PETINON, C. and GRossET, J.-H. Bacte-ricidal activities of a single dose of clarithromycinplus minocycline, with or without ofloxacin,against Mycobacterium leprae in patients. Antimi-crob. Agents Chemother. 40 (1996) 2137-2141.

8. KAPLAN, G. Recent advances in cytokine therapyin leprosy. J. Infect. Dis. 167 Suppl. 1 (1993)18 —//.

9. MAKONKAWKEYOON, S., KASINREK, W., SAPA-

JAIVRA, V., HIRUNPETCIIARAT, C. and VITHARASAI,

V. Immunological defects in leprosy patients; in-terleukin 1, interleukin 2, and interferon produc-tion in leprosy patients. Int. J. Lepr. 58 (1990)311-318.

10. MAURACIIER, E. H. Low dose interferon alpha 2bfor chronic hepatitis B in Asian countries. Gut 34Suppl. 2 (1993) 99-100.

I I. MOCIIIZUKI, Y., °ism, M., NISIIIYAMA, C. and IIDA,T. Active leprosy treated effectively withofloxacin. Intern. Med. (Tokyo) 35 (1996)749-751.

12. &Ammo, E. P., MALTA, A. M., SARNO, E. N. andKAPLAN, G. Effect of rhulNF-y treatment inmultihacillary leprosy patients. Int. J. Lepr. 64(1996) 268-273.

13. SHIVA SAI, K. S. R., PRASAD, H. K., MISIIRA, R. S.,RAMESH, V., WILFRED, D. and NATII, I. Effect ofrecombinant interferon gamma administration onlesional monocytes/macrophages in lepromatousleprosy patients. Int. J. Lepr. 61 (1993) 259-269.

Immunological Reactions to Mycobacterial Proteins inthe Spectrum of Leprosy

To THE EDITOR:

Leprosy, still a public health probelm inmany parts of the world, is a chronic my-cobacterial disease produced by an intracel-lular parasite, Mycobacterium leprae, whichmultiplies mainly within tissue macro-phages and Schwann cells in peripheralnerves. A good immunological response to-ward M. leprae depends on the developmentof a T-cell-mediated immune response.

It has not been established whether indi-vidual proteins are sufficient for the devel-opment of protective immunity in myco-bacterial infections. Also, the availability ofpurified and well-charaterized antigens is aprerequisite for studying the role of individ-ual molecules in the pathogenesis of thedisease.

We have previously studied the effect ofsoluble M. leprae extract on the prolifera-tive response of peripheral blood lympho-cytes from leprosy patients, their familymembers and other contacts. In tuberculoidpatients and in contacts we detected differ-ential reactivity to the various proteins iso-lated (9 ).

Using molecular biology techniques andmonoclonal antibodies, it has been possibleto obtain individual proteins from my-cobacterial antigens (I. 2 ' "' 5. 15 ), which hasbeen very helpful for understanding the bi-ology of this microorganism and its rela-tionship with the host.

In this study, we have compared cellularand humoral reactivity toward variouswhole, fractionated and recombinant my-cobacterial antigens from M. bovis and M.leprae in patients from the outpatient clinicof the Institute de Biomedicina, Caracas,Venezuela. These patients were clinicallyand histologically diagnosed according toRidley and Jopling's classification ("). Thegroup included 20 lepromatous (LL) andborderline lepromatous (BL) patients and20 tuberculoid (TT) patients, as well as agroup of 10 family and nonfamily Mitsuda-positive contacts. All LL and BL (85%males, 15% females) and TT (40% males,60% females) patients were adults.

The antigens used for this study were:bacilli from experimentally infected ar-madillo lesions purified using Draper'smethod, BP ( 4); soluble M. leprae extract