INTERNATIONAL JOURNAL OF LEPROSY^ Volume 58, Number I

Printed in the U.S.A.

Relapses in Paucibacillary LeprosyAfter MDT—A Clinical Study'

Antonio Grugni, Nitin J. Nadkarni,Manjunath S. Kini, and Vinay R. Mehta2

The two most important criteria for theevaluation of a treatment regimen in anyinfectious disease are: a) the ameliorationof symptoms and signs, and b) the incidenceof relapse (16).

More than 6 years have elapsed since theworldwide introduction of the World HealthOrganization (WHO) recommended mul-tidrug therapy (MDT) for both paucibacil-lary and multibacillary forms of leprosy (28).

Its efficacy is well recognized; however, veryfew studies have been undertaken to assessrelapses following MDT, especially underfield conditions (18, 20, 21

). We felt, therefore,

that such a study in paucibacillary leprosywould be relevant.

MATERIALS AND METHODSThis study was carried out in a field-based

leprosy control unit covering two large mu-nicipal wards of Greater Bombay, India,with a population of over one million. Pa-tients with a negative skin smear beforestarting therapy (including pure neuriticcases) were included. The cases were clas-sified broadly according to the classificationadopted by the Indian Association of Lep-rologists (8). However, in the case of a singlelesion, the suggestion of Job and Chackowas followed, in that if a single patch hadsatellite lesions, it was classified as border-line leprosy ("). MDT was administered ac-cording to the WHO guidelines for pauci-bacillary (PB) leprosy with a fewmodifications: a) MDT was given to thepoint of clinical inactivity (7, 19) and not ar-bitrarily stopped at six doses. Inactivity was

' Received for publication on 24 May 1989; acceptedfor publication in revised form on 10 October 1989.

2 A. Grugni, M.D., Medical Superintendent; N. J.Nadkarni, M.D., D.V.&D., D.D.V.; M. S. Kini, M.B.,B.S., Lok Seva Sangam, D/1 Everard Nagar, SionTrombay Road, Bombay 400022, Maharashtra, India.V. R. Mehta, D.V.&D., F.C.P.S., Emeritus Professorof Dermatology, L.T.M.M. College and L.T.M.G.Hospital, Sion, Bombay 400022, Maharashtra, India.

defined as the absence of the signs of activitywhich are: i) thickening or erythema of skinlesions, ii) change in size or number of skinlesions, iii) thickening and tenderness ofnerves (4). If the patient was still active at12 doses, clofazimine was usually added asper the schedule recommended by WHO formultibacillary (MB) leprosy. The discretionfor starting clofazimine at this stage was leftto the responsible physician. However, ifthe patient was still active at 18 doses, thenclofazimine was given in all cases and thetriple MDT was continued to the point ofinactivity. b) Patients with more than fivelesions were usually given clofazimine fromthe outset.

Compliance was checked by random tab-let counts and urine tile testing for dapsone.

In all cases, inactivity was decided onclinical grounds alone, which are known tobe rather subjective and ill-defined. In pa-tients in whom, after adequate doses of ri-fampin, the achievement of inactivity wasuncertain, dapsone (DDS) was continued fora minimum period of 6 months or until wewere reasonably assured of clinical inactiv-ity. Eventually, 57% of our patients weregiven post-MDT dapsone.

Patients were followed up, either at theclinics or at their homes, by doctors or para-medical workers at 6-month intervals. Theywere also asked to report immediately ifthey observed signs of relapse (which wereexplained to them at the time of release fromtreatment). We have included in this studyonly those cases in whom at least one6-month post-therapy assessment was made.Of the 2219 PB cases who had completedtheir schedule of treatment, 1509 fulfilledthis criterion and are reported here.

The criteria of relapse were predomi-nantly clinical (12' 15): a) extension, thick-ening, erythema or infiltration of existinglesions or the appearance of new lesionssuggestive of leprosy; b) thickened tender

19

Profile at startof MDT

Skin lesionsSkin lesions

and neuritisNeuritis

Total

Profile at relapse

Neuri-Skin^Mixed^.tis

39^38

43^2131^5^93^_^_^3

85^67^5^13

Type

IndeterminateTuberculoidBorderlinePure neuritic

Relapses^(Yo

3^2.8525^3.6654^7.86

3^8.82

Totalcases

105683687

34

Totalpa-

tients

20^ International Journal of Leprosy^ 1990

TABLE 1 . Clinical presentation of re-lapsed cases.

TABLE 2. Correlation between clinical typeand relapse rate.

nerves and new paralysis of muscles, and c)bacteriological positivity. However, we didnot have any patient relapsing with MB lep-rosy during the study period.

Histology was done in only 10 cases. Ineach of these cases, a 5-8 mm punch biopsywas taken from the suspect lesion and sub-jected to hematoxylin and eosin and Fite-Faraco stains.

In all cases of relapse, MDT was rec-ommended with three drugs—dapsone, ri-fampin, and clofazimine.

The surveillance period ranged from 6months to 5 years, and the total number ofperson years at risk (PYR) was 4842. Lep-romin testing was done at random in 874patients at the commencement of treat-ment. Skin smears were repeated at yearlyintervals.

RESULTSWe diagnosed 85 relapses with a relapse

rate (RR) of 5.63% (17.5/1000 PYR): 79%of the patients relapsed with skin lesions,15% had neuritis, and 6% had a mixed pat-tern. Of those who relapsed in the skin, 63%manifested reactivation in the original le-sions, 31% had new lesions, while the resthad both. Of the nerve relapses, 67% hadrecurrence in the original nerves, 22% hadnew nerve involvement, and the remaininghad both (Table 1).

Twelve patients, all borderline (B) typeleprosy, had lesions suggestive of type 1 re-action (erythema, swelling, scaling) andcould well have been cases of the so-calledlate reversal reaction (27).

The RR was significantly higher in theborderline compared to the tuberculoidgroup (p < 0.01) (Table 2). The RR in pa-tients with multiple lesions was significantlyhigher than in those with 1-5 lesions (x2 =

16.03 with Yates' correction; p <0.001; DF= 1) (Table 3).

Our data did not indicate any significantcorrelation in the RR with either regularityor treatment or lepromin status. Among thepatients given six doses, the RR was 6.55%;the corresponding figures for those given 7—12 doses and more were 5.23% and 3.92%,respectively. Although there was a trend forhigher relapse rates in those given shorterMDT courses, this was not statistically sig-nificant (Table 4). This trend was also ap-parent when relapse rates were correlatedwith the type of regimen and number ofdoses given (Table 5). For this purpose, pa-tients who were started on clofazimine at12 or 18 doses were considered to be in thethree-drug group.

We analyzed the borderline cases to seeif the RR correlated with nerve involve-ment and the type of therapy given. Gen-erally, there was a trend of higher RR withincreasing nerve involvement, although itwas not statistically significant. Also, thethree-drug regimen seemed to reduce theRR, even when nerve involvement was moreextensive (Table 6). For this purpose also,those patients in whom clofazimine wasstarted at 12/18 doses were considered tobe in the three-drug group.

The RR was significantly reduced in thosepatients in whom dapsone was continuedbeyond cessation of MDT (p < 0.01) (Table7).

Seventy-four percent of our relapses weredetected between 7 and 24 months after ces-sation of therapy, 12% were detected within6 months, and the rest after 2 years. Thiswas statistically significant (p < 0.01).

The histopathology in 10 cases can besummarized as follows: Epidermal changes,comprising atrophy with short distorted reteridges indicating the latter's regeneration,were observed in eight slides. Vacuolar de-

58, 1^Grugni, et al.: Relapses in PB Leprosy After MDT

TABLE 3. Relapse rate correlated withnumber of lesions.

TABLE 4. Relapse rate according to num-ber of MDT doses.

No. lesions Totalcases Relapses No. MDT

dosesTotalcases Relapses

737 34 4.61 6 656 43 6.552-5 515 4.07 7-12 649 34 5.23>5 113 12.10 > 12 204 8 3.92

generation of basal cells was seen in twoslides, indicating their participation in ac-tive disease. Dermal changes were docu-mented by the scarring of the papillary andreticular pars with paucity of nerves andadnexac in six cases. The capillaries andvenulcs were dilated with endothelial cellproliferation. A mononuclear infiltrate con-taining many plasma cells interspersed withgross edema surrounded the vessels. Gran-uloma formation in the reticular derm is wasobserved in six cases. The histiocytes weredominantly noncommitted but occasional.Epithelioid cells, vacuolar and mulberry-likecells were noted. Bulky granulomas (22) wereseen in two sections.

Seven of the ten slides could be labeledas relapses by the occurrence ofgranulomas,vascular changes, and inflammatory phe-nomena in a scarred dermis. The epidermalchanges described above and the scarreddermis suggested a healed milieu. Super-imposition of inflammatory pathology sug-gested recurrence, and the large number ofplasma cells indicated an altered immunity.All of the slides could be placed in the BT-BL leprosy spectrum.

DISCUSSIONAn assessment of the relapse rate (RR)

provides a good operational indicator of theultimate value of any therapeutic regimenin leprosy (29). Ideally, the aim of any treat-ment is to have a zero RR; in practice, es-pecially under field conditions, this may notbe possible. Our overall RR of 5.63% iscomparable to that reported by others whohad relapse rates of 2.9% (24), 4% (21), 5.9%(20), 12% ,18,,) and 13.9% (13). Other workershave reported substantially lower rates of0.28% (6), 0.42% ('), and 0.7% ('°). Even azero RR has been reported (3). We feel thesediscrepancies could largely be due to thedifferent criteria for the diagnosis of relapse

(e.g., some exclude the late reversal reactionfrom its scope) and the differing periods offollow up.

The cumulative years of follow up is alsoimportant. Our RR is 1.75/100 PYR. Pat-tyn, et al. (17) reported an overall RR of2.84/100 PYR with various combinationsof dapsone and rifampin. When clinical re-lapses were considered alone, the rate washalved. We find that these RR are higherthan those reported with monothcrapy(5' 9' 14). As more studies are undertaken, thepicture may become clearer. It is felt thatstandardized criteria should be formulatedfor diagnosing relapses, especially under fieldconditions.

We found a higher RR in the borderlineleprosy group compared to the other groups.Similar findings have been reported withboth MDT (20) and with monotherapy(9, 16,23).

It is stated that the differentiation of re-lapse from the late reversal reaction is dif-ficult (26,27\,j although some attempt to doso ('). We feel that such a distinction is notmeaningful under field conditions, espe-cially since reactions and neuritis can bemanifestations of relapse (7, 21, 23, 30 ) . Hence,we did not attempt to differentiate betweenthe two except to note the fact that 12 caseshad a reaction-like presentation.

The histological picture is not the idealcriterion for diagnosing relapse since it doesnot reflect the bacteriological event. Fur-thermore, it is difficult if not impossible todistinguish relapses from late reversal re-actions, both on clinical grounds and by his-topathology (17). We have a similar viewand, hence, have not attempted to differ-entiate these two phenomena. We also feelthat due to operational constraints, relapseswill have to be diagnosed and managed onclinical grounds alone in the vast majorityof patients.

22^ International Journal of Leprosy^ 1990

TABLE 5. Relapse rate correlated with clinical type, drug regimen, and number of doses.Data presented as number of patients (number relapsing) and percent relapsing.

Regimen

Leprosy typeD + R' D + R + Cb

No. doses No. doses

6 7-12 > 12 12 13-24 > 24

Indeterminate 71(3) 32 (0) 2 (0)4.22%

Tuberculoid 380 (16) 284 (9) 10(0) 1(0) 8(0)4.21% 3.16%

Borderline 187 (23) 309(21) 48(4) 7(2) 106(3) 30(1)12.29% 6.79% 8.33% 28.57% 2.83% 3.33%

Pure neuritic 18(1) 16 (2)5.56% 12.5%

Dapsone and rifampin.b Dapsone, rifampin, and clofazimine.

The RR increased with increasing num-ber of lesions, as reported by others (9).

Contrary to Jesudasan, eta!. 's findings (9),

we had a similar RR in both lepromin-pos-itive and lepromin-negative individuals.Katoch, et al. (12) reported that 80% of thepatients in whom treatment had to be re-started were lepromin positive. Regularityin treatment also did not make much dif-ference in our series, similar to the findingsof Pandian, eta!. ('5) and Rangaraj and Ran-garaj (20). However, other workers (9) havedifferent opinions.

Eighty-seven percent of our patients whorelapsed did so within the first 2 years ofdiscontinuation of therapy; around 75%were detected between 7 and 24 months of

follow up. Similar data have been reportedby others (2, 5, 16). Thus, a minimum sur-veillance period of 2 years is mandatory.

Does the administration of MDT lowerthe relapse rate? It is probably too early todraw a conclusion. Unlike others (25), wefeel that it does not. However, we did notethat in patients in whom dapsone was con-tinued after clinical inactivity was achievedand MDT stopped, there was a lower inci-dence of relapse. Katoch, et al. (13) reportedsimilar findings. This could possibly be ex-plained by the fact that it is often very dif-ficult to decide, under field conditions, ifthe patient is definitely inactive, and there-fore the point at which therapy should bestopped is bound to be subjective (16). Some

TABLE 6. Correlation between regimens used, number of lesions, and number of nervesinvolved in borderline cases. Data presented as number of patients (number relapsing) andpercent relapsing.

Regimen

No. D + Ra D + R + Cblesions No. nerves involved No. nerves involved

1 Multiple 0 1 Multiple

1 145 (8) 42 (7) 15 (2) 2(0) 1(0)5.51% 16.66% 13.33%

2-5 155 (6) 47 (6) 47(4) 2(0) 8(0) 6(0)3.87% 12.76% 8.51%

>5 41(6) 18(3) 34 (6) 39(2) 15(2) 70(2)14.63% 16.66% 17.64% 5.12% 13.33% 2.85%

Dapsone and rifampin.b Dapsone, rifampin and clofazimine.

58, 1^Grugni, et al.: Relapses in PB Leprosy After MDT^23

TABLE 7. Relapse rate correlated withpost-MDT dapsone administration.

No. pa- Re-tients^lapses

Stopped with MDT 654 53 8.10Continued after MDT 855 32 3.74

patients may be discharged when still ac-tive, and in these patients the chances ofrelapse would be higher. In this context, theWHO recommendation for giving only sixdoses of MDT in all PB patients (irrespec-tive of the number oflesions, nerve involve-ment, etc.) needs further investigation.

Individualization of treatment would belikely to achieve satisfactory cure rates andacceptably low relapse rates.

SUMMARYA study was undertaken in a field-based

project to assess the incidence and clinicalprofile of relapses occurring in paucibacil-lary leprosy patients after adequate doses ofmultidrug therapy (MDT). Of the 1509 pau-cibacillary patients who had received notless than 6 doses of MDT (WHO regimen),85 relapsed; a relapse rate of 5.63% (17.5/1000 person years at risk). These relapsesincluded 12 cases with features of reversalreaction. Seventy-nine percent of the pa-tients relapsed with skin lesions. The relapserate was higher in borderline cases and inthose with more lesions, and it was lowerin those who had received dapsone for atleast 6 months after cessation of MDT. Sev-enty-four percent of the relapses were de-tected between 7 and 24 months of followup. We feel that uniform clinical criteriashould be formulated for the diagnosis ofrelapse. Individualization of therapy, ratherthan adhering to a fixed duration of MDT,would be likely to achieve satisfactory curerates and fewer relapses.

RESUMENSe realizO un estudio de campo para establecer la

incidencia de recaidas y su perfil clinico, en pacientescon lepra paucibacilar despues de administrar una te-rapia adecuada con mUltiples drogas (TMD). De los1509 pacientes paucibacilares que habian recibido nomenos de 6 dOsis con mUltiples drogas (MD) (esquemade la OMS), 85 recayeron; una incidencia de recaidadel 5.63% (17.5/1000 personas en riesgo). Estas recai-

das incluyeron 12 casos con las caracteristicas de unareacciOn reversa. El 79% de los pacientes recayeroncon lesiones en la piel. La incidencia de recaidas fuemayor en los casos limitrofes y en aquellos con máslesiones, y fue menor en aquellos que habian recibidodapsona cuando menos 6 meses despues de terminarla TN1D. El 74% de las recaidas se detectO entre 7 y24 meses de seguimiento. Pensamos quc deben for-mularse criterios clinicos uniformes para el diagnOsticode las recaidas. La terapia individualizada más que eltratamiento general con MD por un tiempo preesta-blecido, aseguraria mejores niveles de curaciOn y me-nos recaidas.

RÉSUMÉ

Dans un projet sur le terrain, on a entrepris une etudeafin d'evaluer l'incidence et le profil clinique des re-cidives qui surviennent chez des malades atteints delepre paucibacillaire, apres un traitement par des dosesadequates de polychimiotherapie (MDT). Parmi les1509 malades paucibacillaires qui avaient recu 6 dosesou davantage de MDT (posologic de l'OMS), 85 ontpresente des recidives. Le taux de recidive a ete de5,63% (17,5 pour mille personne/annees A risque). Cesrêcidives comprenaient douze cas qui temoignaient descaracteristiques d'une reaction reverse. Soixante dix-neuf pour cent des malades ont presente des lesionscutanees lors de la recidive. Le taux de recidive a eteplus Cleve que dans les cas dimorphes et que chez lesmalades qui prósentaient davantage de lesions. Ce tauxetait plus faible chez les patients ayant recu de la dap-sone pour au moms 6 mois apres l'interruption de lapolychimiotherapie. Soixante quatorze pour cent desrecidives ont ete detectêes entre 7 et 24 mois. On estimeque des criteres cliniques uniformes devraient etre eta-blis pour diagnostiquer les recidives. Plutelt que de s'entenir A une duree fixe de polychimiotherapie, il faudraitindividualiser la therapeutique, car on obtiendrait vrai-semblablement ainsi des taux de guerison satisfaisants,avec moms de recidives.

REFERENCES1. BOERRIGTER, G., PoNNIGHAus, J. M. and FINE, P.

E. M. Preliminary appraisal of a WHO-recom-mended multiple drug regimen in paucibacillaryleprosy patients in Malawi. Int. J. Lepr. 56 (1988)408-417.

2. BOURLAND, J., JANSSENS, L., GROENEN, G., PATTYN,S. R. and THE COLLABORATIVE STUDY GROUP ON

THE TREATMENT OF LEPROSY. Incubation time ofrelapses after treatment of paucibacillary leprosy.(Abstract) Int. J. Lepr. 52 (1984) 686.

3. DAY, R. S. and TETERISSA, M. R. Field trial ofshort course combined chemotherapy in pauci-bacillary leprosy. (Abstract) Int. J. Lepr. 57 Suppl.(1989) 340.

4. DHARMENDFtA. Sulphone therapy. In: Leprosy,Volume I. Dharmendra, ed. Bombay: KothariMedical Publishing House, 1978, pp. 359-412.

Dapsone

24^ International Journal of Leprosy^ 1990

5. EKAMBARAM, V. Duration of treatment for dis-ease arrest of non-lepromatous cases and relapserates in these patients. Lepr. Rev. 50 (1979) 297-302.

6. GANAPATI, R. Efficacy of chemotherapy in pau-cibacillary leprosy; epidemiological issues and as-sessment problems. In: Indo-U.K. Workshop onLeprosy Research. Agra: Central JALMA Institutefor Leprosy (ICMR), 1989.

7. GIRDHAR, B. K. Multidrug therapy in leprosy.Indian J. Lepr. 59 (1987) 145-151.

8. INDIAN ASSOCIATION OF LEPROLOGISTS. Clinical,

histopathological and immunological features ofthe five-type classification approved by the IndianAssociation of Leprologists. Lepr. India 54 (1982)

?_/5.9. JESUDASAN, K., CHRISTIAN, M. and BRADLEY, D.

Relapse rate among nonlepromatous patients re-leased from control. Int. J. Lepr. 52 (1984) 304-310.

10. JESUDASAN, K., PANNIKAR, V. K., MANI MOZHI,N. and CHRISTIAN, M. Relapse rates in pauciba-ciliary leprosy-WHO regimen versus dapsoncmonotherapy. (Abstract) Int. J. Lepr. 57 Suppl.(1989) 340.

11. JOB, C. K. and CHACKO, C. J. G. A simplified 6group classification of leprosy. Lepr. India 54 (1982)26-32.

12. KATOCH, K., RAMU, G. and RAMANATHAN, U.

Short term WHO advised multiple drug treatmentof paucibacillary patients. (Letter) Indian J. Lepr.58 (1986) 351-353.

13. KATOCH, K., RAMU, G. and RAMANATHAN, U.Evaluation of three short term regimens contain-ing rifampin for the treatment of paucibacillaryleprosy. (Abstract) Int. J. Lepr. 57 Suppl. (1989)340.

14. PANDYAN, T. D., SEETHAMBARAM, M., BHARATHI,

R. and RAMU, G. A study of relapse in nonlepro-matous and intermediate forms of leprosY in theELEP leprosy control project, Dharampuri. (Ab-stract) Int. J. Lepr. 52 Suppl. (1984) 686.

15. PANDYAN, T. D., SEETHAMBARAM, M., BHARATHI,

R. and RAMU, G. A study of relapse in nonlepro-matous and intermediate group of leprosy. IndianJ. Lepr. 57 (1985) 149-158.

16. PArryN, S. R. Incubation time for relapses aftertreatment of paucibacillary leprosy. Lepr. Rev. 55(1984) 115-120.

17. PATTYN, S. R., GROENEN, G., BOURLAND, J.,GRILLONE, S., JANSSENS, L. and THE COLLABOR-

ATIVE STUDY GROUP FOR THE TREATMENT OF

LEPROSY IN ZAIRE AND RWANDA. A controlledtherapeutic trial in paucibacillary leprosy com-paring a single dose of rifampicin followed by 1year of daily dapsone with 10 weekly doses ofrifampicin. Lepr. Rev. 58 (1987) 349-358.

18. PAVITHRAN, K. Relapse of paucibacillary leprosyafter short course of multidrug therapy. Indian J.Lepr. 60 (1988) 225-229.

19. RArstu, G. Multidrug therapy of leprosy. IndianJ. Lepr. 57 (1985) 465-477.RANGARAJ, M. and RANGARAJ, J. Experience withmultidrug therapy in Sierra Leone: clinical, op-erational and managerial analysis. Lepr. Rev. 57Suppl. 3 (1985) 77-91.

1 REDDY, K. P. and MOHINUDDIN, S. K. Pattern ofrelapses in paucibacillary leprosy patients treatedwith MDT (WHO 1982). Indian J. Lepr. 60 (1988)581-588.

22. RIDLEY, D. S. Skin Biopsy in Leprosy. 2nd ed.Basle: CIBA-GEIGY, 1985, pp. 37-39.

23. TOUW-LANGENDUK, E. M. J. and NAAFS, B. Re-lapse in leprosy after release from control. Lcpr.Rev. 50 (1979) 123-127.

24. VAN BRAKEL, W., KIST, P., NOBLE, S. and O'TooLE,S. Relapses after multidrug therapy for leprosy:a preliminary report of 22 cases in west Nepal.Lepr. Rev. 60 (1989) 45-50.WARNDORFF VAN D1EPEN, T. and MENGISTU, G.Effect of short term supplementary treatment ofthe overall relapse rate and the incidence of dap-sone resistant leprosy in lepromatous patients.(Abstract) Int. J. Lepr. 52 Suppl. (1984) 710.

26. WATERS, M. F. R., RIDLEY, D. S. and RIDLEY, M.

J. Clinical problems in the initiation and assess-ment of multidrug therapy. Lepr. Rev. 57 Suppl.3 (1986) 92-100.

27. WATERS, M. F. R. The chemotherapy of leprosy.In: The Biology of the Mycobacteria Volume 3:Clinical Aspects of Mycobacterial Disease. Ra-tledge, C., Stanford, J. and Grange, J. M., eds.London: Academic Press, 1989, pp. 406-473.

28. WHO STUDY GROUP. Chemotherapy of leprosyfor control programmes. Geneva: World HealthOrganization, 1982. Tech. Rep. Ser. 675.

29. WHO STUDY GROUP. Epidemiology of leprosy inrelation to control. Geneva: World Health Orga-nization, 1985. Tech. Rep. Ser. 716.

30. WHEATE, H. W. Six months MDT for pauciba-ciliary leprosy: nerve damage and relapse. (Letter)Lepr. Rev. 57 (1986) 179.