Role of topical immunotherapy in the treatment ofalopecia areata

Quality analysis ofarticles published between January 1977 and January1988 about three treatments

Luigi Naldi, MD,a, b Fabio Parazzini, MD,b Tullio Cainelli, MD,a and the Reading Groupa,*Bergamo and Milan, Italy

We conducted a survey of clinical trials to assess the scientific evidences presented for thepractical use of dinitrochlorobenzene, squaric acid dibutylester, and diphencyprone in thetreatment of alopecia areata. Twenty-six papers published between January 1977 and Jan­uary 1988, in English, French, and Italian were selected. We used a standardized protocolof evaluation, which focused principally on the reporting ofmethods. Twelve papers were un­controlled studies. Of the controlled studies, 11 had a self-controlled design, two studies in­volved the use of parallel concurrent controls, and seven were randomized trials. With regardto criteria for entry, follow-up schedules, and criteria for evaluation ofresponse to treatment,the studies were scored generally poorly; therapeutic regimen, patients' characteristics, with­drawals, and description ofside effects in these studies were rated more highly. In light of ourresults, further and better-designed studies are needed for acceptance of dinitrochloroben­zene, squaric acid dibutylester, and diphencyprone in current therapy. (J AM ACAD DERMA­

TOL 1990;22:654-6.)

Since 1977 topical sensitizers (so-called topicalimmunotherapy) have been evaluated for the treat­ment of alopecia areata. Despite positive results,these drugs are not yet widely accepted and their ef­ficacy has been doubted.! To clarify the role of top­ical immunotherapy, we conducted a survey ofpublished clinical trials on dinitrochlorobenzene(DNCB), squaric acid dibuty1ester (SADBE), anddiphencyprone (DPCP).

MATERIAL AND METHODS

All papers published from January 1977 to January1988, in English, French, and Italian were eligible for thisstudy. A total of 26 articles were retrieved.2-27 The arti­cles were scored by a modified version of the qualityscoreoriginally developed by Chalmers et al.28 for randomizedcontrolled trials. Because of the number of uncontrolledtrials, the scoring system was substantially simplified and

From the Department of Dermatology, Ospedali Riuniti di Bergamo,­and The Laboratory of Clinical Pharmacology, Istituto di RicercheFarmacologiche M. Negri, Milan.b

Reprint requests: Luigi Naldi, MD, Divisione di Dermatologia, Ospe­dali Riunili, largo Barozzi 1,24100 Bergamo, Italy.

*Anna Di Landro, Pac,la Pini, Alberto Rossi, Costantino Grigis, GianLorenzo 1mberti, und Alberto Zucchi.

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adjusted to deal with uncontrolled as well as controlledstudies. The following items were considered in the qual­ityassessment: (1) criteria of entry and information oneligible patients who were not included (Le., reject log),(2) information on patients' characteristics, (3) descrip­tion ofthe therapeutic regimen, (4) type and frequency offollow-up, (5) criteria for response to treatment, (6)information about withdrawal ofsubjects, (7) analysis ofwithdrawals, and (8) information about side effects. Onthe basis of predefined criteria, quality control scores forindividual items were categorized as follows: "adequate"(information on the item completely reported), "partial"(only some information reported), "inadequate" (noinformation reported at all or unclear.)*

RESULTS

Table I provides information about the generaldesign ofthe studies. The median number ofpatientsexamined was 26 (range 8 to 119). Results of qual­ity assessment for individual items are reported inTable II. The median number ofmethodologic itemscorrectly reported in an article (items defined as"adequate" in the scoring system) was three for thegroup of DNCB studies, three for the SADBE

*The itemized checklist used to score the articles is not published withthis report but is available [rom the authors on request at the reprintaddress.

Volume 22Number 4April 1990

Table I. Information on general design of studies

~ N~,"""'~DNCB SADBE*~

No. of patients::;20 3 4 0 721-40 6 4 2 12>40 4 2 1 7

Type of controlsNone 6 5 1 12Historical 0 1 0 1Parallel concomitant 1 0 1 2Self-controlled:\: 6 4 1 11

Randomization§Not applied/unknown 2 3 1 6Applied 5 1 1 7

Blinding§Not considered 6 4 2 12Considered 1 0 0 1

DNCB, Dinitrochlorobenzene; DPCP, diphencyprone; SADBE, squaricacid dibu tylester.*Includes one study comparing SADBE with DNeB.tlncludes one study comparing DPCP, SADBE, and minoxidil withplacebo.tThat is. patients acted simultaneously as their own controls.§Only applicable to controlled (but not historically controlled) trials.

group, and two for the DPCP group; the overall me­dian was three, with a range of zero to five. No ar­ticle was given a fully "adequate" score. On the ba­sis of the conclusions presented by the authors, 19studies were judged to report positive results (effi­cacy ofthe examined drugs), four studies (two in theDNCB group, one for the SADBE group, and onefor the DPCP group) reported negative results(general failure of treatment), and in three (twoDNCB, one DPCP) judgment was uncertain (i.e.,conclusion did not clearly reject or support thetreatment).

DISCUSSION

According to our evaluation, the published liter­ature is of limited use in defining the role of topicalimmunotherapy in alopecia areata. Half the studiesexamined used informal methods (uncontrolled orhistorically controlled trials). The use of uncon­trolled trials for evaluating treatments is debat­able,29 particularly ifwe cannot reliably estimate theperformance in an untreated population.3o Of 13formal studies, 11 were self-controlled trials. Thisdesign is attractive because it can produce statisti­cally valid results with fewer patients than wouldotherwise be required.3! Unfortunately it is not suit­able for answering the relevant question in clinicalpractice of alopecia areata; that is, "What is the

Topical immunotherapy for alopecia areata 655

Table II. Quality analysis: Frequency distributionof different items

~ No. o,,""'~DNCB SADDE·~

Criteria for entryAdequate 0 0 0 0Partial 6 2 1 9Inadequate 7 8 2 17

Patients' characteristicsAdequate 9 9 2 20Inadequate 4 1 1 6

Therapeutic regimen9 3 23Adequate 11

Inadequate 2 1 0 3Follow-up schedules

0 0 1Adequate 1Inadequate 12 10 3 25

Criteria for evaluationAdequate 0 1 0 1Partial 5 5 0 10Inadequate 8 4 3 15

Withdrawal of patientsAdequate 10 7 1 18Inadequate 3 3 2 8

Analysis of withdrawalstAdequate 1 2 0 3Inadequate 3 3 1 7

Discussion of side effectsAdequate 4 5 1 10Partial 6 2 0 8Inadequate 3 3 2 8

DNCB, Dinitrochlorobenzene; DPCP, diphcncyprone;SADBE, squaricacid dibutylester.*Includes one study comparing SADBE with DNCB.tlncludcs One study comparing DPCP. SADBE, and minoxidil withplacebo.:j:Applicable to 10 studies that gave appropriate numeric information.

long-term. overall benefit of treatment (comparedwith other treatment modalities)?"

In general, the studies that we examined had se­rious drawbacks in reporting critical proceduressuch as assessing treatment and selecting and fol­lowing up patients. Information on patient selectionand inclusion criteria was not reported fully in anystudy. Most reports merely stated that a certainnumber of patients with a given diagnosis werestudied. This practice was especially unsuitable foruncontrolled trials, in which defining entry criteriaand assuring entry of consecutive patients are im­portant in making sense of the results. Despite thepotential influence offollow-up in establishing treat­ment success or failure, only one study providedcomplete information on follow-up. In all examinedreports, results were expressed as a percentage of

656 Naldi et al.

success at a "fixed" (arbitrarily selected) point oftime, and one naturally wondered whether theresults were in fact selected among many possibleendpoints. Another issue that was inadequatelyconsidered was criteria of outcome. In dealing with"soft" variables, which depend largely on subjectivejudgment (i.e., regrowth), defining outcome criteriain clear, unambiguous terms is essential to controlbias of assessment and to allow interpretation andcomparison of results. The majority ofthe studies weexamined yielded positive results. With reference torandomized clinical trials, it is a well-established be­lief, supported by convincing empiric evidence, thatpositive studies tend to be overrepresented in thepublished literature.32 "Publication bias" is proba­bly more serious and less quantifiable for uncon­trolled or historically controlled trials, in which de­cisions about publication may be influenced morestrongly by favorable outcome.

In conclusion, a definite role of topical immuno­therapy for alopeciaareata has yet to be establishedand this treatment should be offered only as an ex­perimental modality. In our opinion, however, for anunbiased estimate of the effect of treatment, betterdesigned controlled trials are needed that have aclinically relevant endpoint (i.e., long-term overallregrowth) in a well-selected population; that is, apopulation defined by appropriate entry criteria andstratification to reflect the claimed heterogeneity ofthe disease.

REFERENCES

1. Savin JA. Hair-raising notions and lotions [Editorial]. BrMed J 1982;284:445-6.

2. Happle R, Echternacht K. Induction of hair growth inalopecia areata with dinitrochlorobenzene. Lancet 1977;2:1002-3.

3. Breuillard F, Szapiro E. Dinitrochlorobenzene in alopeciaareata [Letter]. Lancet 1978;2:1304.

4. Daman LA, Rosenberg EW, Drake L. Treatment ofalopecia areata with dinitrochlorobenzene. Arch Dermatol1978;114: 1036-8.

5. Happle R, Cebulla K, Echternacht-Happle K. Dinitrochlo­robenzene therapy for alopecia areata. Arch Dermatol1978;114:1629-31.

6. De Prost Y, Paquez FR, Touraine R. Traitement de la pel­ade par applications locales de dinitrochlorobenzene. AnnDermatol Venereol 1979;106:437-40.

7. Friedmann PS. Dinitrochlorobenzene and alopecia [Let­ter]. Lancet 1979;1:1412.

8. Warin AP. Dinitrochlorobenzene in alopecia areata [Let­ter]. Lancet 1979;1:927-8.

9. Happle R, Kalveram KJ, Buchner U, et al. Contact allergyas a therapeutic tool for alopecia areata: application ofsquaric acid dibutylester. Dermatologica 1980;161 :289-97.

10. Friedmann PS. Response of alopecia areata to dinitrochlo-

Journal of theAmerican Academy of

Dermatology

robenzene: influence of auto-antibodies and route ofsensi­tization. Br J Dermatol 1981;105:285-9.

11. Swanson NA, Mitchell Al, Leahy MS, et al. Topicaltreatment of alopecia areata. Arch Dermatol 1981;117:384-7.

12. De Prost Y, Paquez F, Touraine R. Dinitrochlorobenzenetreatment of alopecia areata. Arch Dermatol 1982;118:542-5.

13. Flowers FP, Slazinski L, Fenske NA, et al. Topical squaricacid dibutylester therapy for alopecia areata. Cutis1982;30:733-6.

14. Giannetti A, Orecchia G. Clinical experience on the treat­ment of alopecia areata with squaric acid dibutylester.Dermatologica 1983;167:280-2.

15. Happle R, Hausen B, Wiesner-Menzel L. Diphencypronein the treatment of alopecia areata. Acta Derm Venereol(Stockh) 1983;63:49-52.

16. Case PC, Mitchell AJ, Swanson N A, et al. Topical therapyof alopecia areata with squaric acid dibutylester. J AMACAD DERMATOL 1984;10:447-51.

17. Temmerman L, de Weert J, de Keyser L, et al. Treatmentof alopecia areata with dinitrochlorobenzene. Acta DermVenereol (Stockh) 1984;64:441-3.

18. Tosti A, Veronesi S, Caponeri G. II dinitrochlorobenzenenella terapia della alopecia areata: nostra esperienzaclinica. G Ital Dermatol VenereoI1984;119:131-4.

19. Barth JR, Darley CR, Gibson JR. Squaric acid dibutyl e.~­

ter in the treatment of alopecia areata. Dermatologica1985;170:40-2.

20. Benoldi D, Alinovi A, Pezzarossa E, et al. Trattamentodella alopecia areata con dinitrochlorobenzene topico: risul­tatiefollow-up.G ItalDermatol VenereoI1985;120:231-3.

21. Orecchia G, Rabbiosi G. Treatment ofalopecia areata withdiphencyprone. Dermatologica 1985;171:193-6.

22. Pigatto PD, Gini R, Altomare GF. Alopecia areata e trat­tamento con dietilestere dell'acido squarico (DEAS): com­portamento delle sottopopolazioni linfocitarie.· G Ital Der­matol VenereolI985;120:227-30.

23. Valsecchi R, Cainelli T, Tornaghi, A, et al. Squaric aciddibutylester treatment of alopecia areata. Clin Exp Der­matoI1985;10:233-8.

24. Tosti A, Bardazzi F, Salardi S, et al. Alopecia areata: stu­dio clinico, immunologico e terapeutico su una popolazionepediatrica. G Ital Dermatol Venereol 1986;121:261-2.

25. Tosti A, De Padova M, Minghetti G, et al. Therapiesversus placebo in the treatment of patchy alopecia areata.J AM ACAD DERMATOL 1986;15:209-10.

26. Valsecchi R, Cainelli T, Foiadelli L, et al. Topical immu­notherapy ofalopecia areata: a follow-up study. Acta DermVenereol (Stockh) 1986;66:269-72.

27. Caserio RJ. Treatment of alopecia areata with squaric aciddibutylester. Arch Dermatol 1987;123:1036-41.

28. Chalmers TC, Smith H Jr, Blackburn B, et al. A methodfor assessing the quality of a randomized control trial. Con­trolled Clin Trials 1981 ;2:31-49.

29. Bailar JC III, Louis TA, Lavori PW, et al. Studies withoutinternal controls. N Engl J Med 1984;311:156-62.

30. Vestey JP, Savin JA. Natural history of severe alopeciaareata [Letter]. Br J Dermatol 1987;117:531.

31. Louis TA, Lavori PW, Bailar JC ITl, et al. Crossover andself-controlled designs in clinical research. N Engl J Moo1984;310:24-31.

32. Simes RJ. Publication bias: the case for an internationalregistry of clinical trials. J Clin Oncol 1986;4:1529-41.