Contact immunotherapy with squaric acid dibutylester for the treatment of recalcitrant warts

| Contact i m m u n o t h e r a p y with squaric acid dibutylester for the treatment o f recalcitrant warts Mice N. Lee, MD, and Susan B. Mallory, MD St Louis, Missouri

Background: Contact immunotherapy has been shown to be effective for warts. Two previous studies on the use of squaric acid dibutylester (SADBE) for warts have reported widely divergent cure rates (10% and 60%).

Objective: Our purpose was to determine the efficacy of SADBE in the treatment of recalcitrant warts.

Methods: We treated 29 patients with SADBE for warts that were resistant to other therapies. The patient population had warts for a mean duration of 2.1 years. Patients were sensitized with 1% or 2% SADBE in acetone under occlusion, then treated with 0.5% to 5% SADBE applied to their warts every 2 to 4 weeks in the office.

Results: Clearing of all warts was seen in 20 of 29 patients (69%), improvement in 3 patients (10%), and no change in 6 patients (21%). For the cured patients, mean duration of treatment was 4.2 months (range, 1 to 12 months) and mean number of treatments was 5.7 (range, 2 to 15). Adverse effects included acute contact dermatitis with 6 patients experiencing blisters and one experiencing hypopigmentation.

Conclusion: SADBE treatment is worth considering in patients with recalcitrant warts, especially in those who tolerate painful procedures poorly. (J Am Acad Dermatol 1999;41:595-9.)

T

he treatment of warts is sometimes frustrating for both physician and patient. Modalities for therapy include physical destruction (ie, cryotherapy, surgical removal, carbon dioxide laser), chemical destruction (ie, salicylic acid, glutaraldehyde, podophyllin, cantharidin), and immunomodulatory therapy (ie, interferons, retinoids, contact immunotherapy). Despite the large array of therapeutic options, no therapy is consistently effective in every case. The choice of therapy is guided by considering the side effects, such as pain and scarring, the rate of response, and the expense. Treatment usually begins with the more simple methods that have fewer side effects, then progresses to m o r e complicated modalities if earlier treatments have failed) Contact immunotherapy is believed to work for the treatment of warts by inducing a type IV hyperFrom the Division of Dermatology, Departments of Internal Medicine and Pediatrics, Washington University School of Medicine. Reprint requests: Susan B. Mallory, MD, Director, Pediatric Dermatology, St Louis Children's Hospital, One Children's Place, 3N48, St Louis,MO 63110. Copyright 9 1999 by the American Academy of Dermatology, Inc. 0190-9622/99/$8.00 + 0 16111100408

sensitivity reaction. This cell-mediated response is believed to act against a complex of contact agent hapten bound to protein of viral or human origin,2, 3 with the Langerhans cell as the site of antigen formation and presentation. 4 This results in the disappearance of the wart when the contact agent is applied, enhancing spontaneous wart regression. The s p o n t a n e o u s clearing of warts shows evidence of an immune response. Tagami et a15 showed a dermal mononuclear cell infiltrate on histologic examination of spontaneously involuting flat warts. In a n o t h e r study, a dense dermal infiltrate of mononuclear cells was observed in involuting common warts after topical application of salicylic acid, but was noticeably absent in c o m m o n warts, which were resistant. 6 Dinitrochlorobenzene (DNCB), diphenylcyclop r o p e n o n e (DPCP), and squaric acid dibutylester (SADBE) have all been used to treat warts by inducing a type IV hypersensitivity reaction. 7 These agents are preferred because they are available, can sensitize at least 95% of normal individuals, are not easily found in human environments, are chemically stable, are not expensive, and have few adverse effects. Although DPCP and SADBE are less stable than DNCB (DPCP requires shielding from light, SADBE

595

596

Lee andMallory

I AM ACADDERMATOL OCTOBER1999

T a b l e I. Patient characteristics, t r e a t m e n t parameters, and results Age at treatment (y)

Duration of wart history (y)

Duration of treatment (mo)

1 2 3

12 6 6

1 Unknown 4.5

6 12 2

5 15 2

4 5 6 7 8 9 I0 11 12 13

15 40 8 34 12 6 1.8 32 5 12

Unknown 3 3 2 2 2 0.25 1.5 0.25 3.5

1 1 7 7 10 4 I 8 4 8

2 3 10 12 6 2 2 11 4 10

14

23

1.6

16

45

15 16 17 18

5 25 12 6

Unknown 0.75 2 S

4 2 1 6

9 2 2 6

19 20 21

6 7 8

3 2 2

3 6 6

5 10 3

22 23 24 25 26 27

8 12 7 11 12 4

Unknown I 2 I 0.5 I

2 I 2 5 34 7

4 I 2 6 17 4

Hands, feet Hands, feet Hands, legs, arms, abdomen Hands-periungual Hands Hands Hands Hands Ankle Hands-digits Hands Ankle, feet Hands, knees, ankle, feet, perianal Hands-palmar, feet-plantar Unknown Hands Hands, feet Hands, shoulder, elbow, feet Hands, legs, feet Hands, feet Hands-periungual, legs, ankle Hands, knee, feet Hands Hands, elbows, ankle Hands Hands, axilla, legs, feet Hands-periungual

28 29

15 4

6 28

8 23

Knees Hands, arms, legs, feet

Patient

6 2

No. of visits

Sites of treatment*

Result

Resistant (IC) Cured Improved (lost to follow-up) Cured Cured Cured Cured Resistant Cured Cured Cured Cured Resistant Resistant Cured Cured Cured Improved (withdrew from study) Cured Cured Cured Cured Cured Cured Cured Resistant Improved (lost to follow-up) Cured Resistant (IC)

Cured, 20/29 (69%);IC, immunocompromised; improved, 3/29 (10%);resistant, 6/29 (21OYo). *Hands = all surfacesunless specified,feet = all surfaces unless specified.

requires refrigeration), they have been shown to be nonmutagenic by the Ames test, whereas DNCB is mutagenic by that same standard. SADBE tends to be more expensive than DPCP and DNCB. The main adverse effect of SADBE and DPCP is acute contact dermatitis, although dyshidrosiform hand dermatitis has been reported in 2 cases.8 All 3 agents have been shown to be effective against warts, with cure rates of 69% to 91% for DNCB,8-11 62% for DPCP, 12 and 60% for SADBE) 3 This study aims to assess the efficacy of SADBE in the treatment of recalcitrant warts. In 1981, Claudy

and Roche 14 r e p o r t e d that only 2 of 18 patients achieved complete clearing of their warts after squaric acid treatment. In 1993, Iijima and Otsuka 13 reported a cure rate of 60% in 20 subjects with recalcitrant warts. PATIENTS

AND

METHODS

From November 1993 through September 1998, 29 patients whose ages ranged from 22 months to 40 years (Table I) were treated with SADBE at the Washington University Medical Center outpatient dermatology clinics and the St Louis Children's Hospital outpatient dermatol-

j AM ACAD DERMATOL VOLUME 41, NUMBER4

ogy clinic. Inclusion criteria were that the patients were in good general health and had at least one wart that had not responded to previous therapies. Exclusion criteria were intolerance to SADBE, pregnancy, and chronic allergic contact dermatitis. The study population was composed of 11 male and 18 female patients, and the mean age was 12.5 years. Of the 29 patients, 22 (76%) were younger than 15 years; 7 (24%) were 15 years old or older. Previous unsuccessful therapies were cryotherapy, salicylic acid preparations, cantharidin, pulsed dye laser, and cimetidine. Two patients were immunocompromised. The mean length of time these patients had warts before beginning SADBE therapy was 2.1 years (range, 3 months-5 years). Sensitization was achieved by applying 1% or 2% SADBE in acetone under occlusion to a 2-cm 2 area of normal skin on the upper arm overnight, after which the patient was instructed to wash the area thoroughly with soap and water. Of 29 patients, 26 (90%) were successfully sensitized after one application of SADBE. All patients were reactive at the site of application on challenge, otherwise they were deemed unsensitized. Sensitization was determined to have occurred when application of a second or third dose was applied to a different area, inducing erythema and pruritus in the new area of application. A maximum of 6 attempts were made at sensitization. After sensitization occurred, 0.5% to 1% SADBE was applied directly to the warts during office visits scheduled every 2 to 4 weeks. A concentration of 0.5% SADBE was used on warts in sensitive areas such as the perianal region and on warts of patients who experienced an exuberant contact dermatitis. The applied concentration of SADBE was increased to 2% and occasionally to 5% if no change in the warts appeared after several treatments, especially on the palms or soles. Squaric acid was not applied to the face. Instead, facial warts were treated with cryotherapy. On each visit, any regression or worsening of the lesions was documented. Twelve patients received adjunctive therapy such as cryotherapy, salicylic acid applied at home, soaking and paring, and cimetidine (one case). The remaining 17 patients received only squaric acid treatment while enrolled in the study. Patients who experienced the adverse reaction of acute contact dermatitis were treated with topical class I corticosteroids, by decreasing the concentration of SADBE applied, or with systemic corticosteroids (2 patients), depending on the severity of the reaction.

RESULTS C l e a r i n g o f all w a r t s was a c h i e v e d in 20 o f 29 patients (69%), as d o c u m e n t e d by physical examination o r by p a t i e n t r e p o r t by p h o n e . Clearing of warts was d e f i n e d as d i s a p p e a r a n c e o f all l e s i o n s for at least 1 m o n t h . T h r e e p a t i e n t s s h o w e d i m p r o v e m e n t (10%), b u t 2 o f t h e s e w e r e lost to follow-up a n d 1 d r o p p e d o u t o f t h e s t u d y b e c a u s e o f side effects. This p a t i e n t e x p e r i e n c e d h a n d e d e m a that prevented her from attending school. The remaining 6 p a t i e n t s w e r e r e s i s t a n t (21%) (Table I). T h e m e a n d u r a t i o n o f t r e a t m e n t was 4.2 m o n t h s (range, 1-12

Lee

andMallory 597

m o n t h s ) for t h e 20 c u r e d patients. The m e a n numb e r o f visits at w h i c h SADBE was a p p l i e d w a s 8.0 (range, 2-45) for all 29 patients, a n d 5.7 (range, 2-15) for t h e 20 c u r e d patients. All patients e x c e p t 3 w e r e successfully sensitized after one application of SADBE. O n e h e a l t h y p a t i e n t r e q u i r e d 3 a p p l i c a t i o n s a n d a n o t h e r r e q u i r e d 2 sensitizations. A third p a t i e n t was i m m u n o c o m p r o m i s e d b u t e v e n t u a l l y b e c a m e sensitized after 6 a t t e m p t s a n d a d e c r e a s e in azathiop r i n e dose. Follow-up p h o n e calls w e r e m a d e to 21 p a t i e n t s (72%) with a m e a n follow-up t i m e o f 15.2 m o n t h s (range, 3-30 m o n t h s ) . Of t h e 21 patients called, 13 w e r e c u r e d patients w h o r e p o r t e d no r e c u r r e n c e o f warts, a n d 4 r e p o r t e d n e w warts at 11 m o n t h s , at 22 m o n t h s , a n d at 13 m o n t h s (2 patients) after SADBE therapy. T h e r e m a i n i n g 4 p a t i e n t s w e r e r e s i s t a n t . T h e m e a n f o l l o w - u p t i m e for t h e s u b s e t o f c u r e d p a t i e n t s w i t h o u t r e c u r r e n c e was 14.7 m o n t h s (range, 3-30 m o n t h s ) . Of t h e 6 resistant patients, 2 w e r e i m m u n o c o m p r o m i s e d (1 was receiving c h e m o t h e r a p y for pre-B cell a c u t e l y m p h o b l a s t i c l e u k e m i a and 1 was taking i m m u n o s u p p r e s s i v e agents after cardiac transplantation). O n e resistant p a t i e n t r e p o r t e d d i s a p p e a r a n c e of all warts e x c e p t for a solitary w a r t that r e m a i n e d at 15 m o n t h s after SADBE. T h r e e p a t i e n t s c o n t i n u e d to have n u m e r o u s warts after 10, 17, a n d 45 t r e a t m e n t s , respectively. O f these, 1 e x p e r i e n c e d h y p o p i g m e n t a tion o n h e r legs w h e r e squaric acid (1% a n d 2%) h a d b e e n applied. T h e s e areas r e m a i n e d h y p o p i g m e n t e d at 14 m o n t h s after SADBE therapy. A d v e r s e r e a c t i o n s i n c l u d e d a c u t e c o n t a c t dermatitis (significantly s y m p t o m a t i c p r u r i t u s o r blisters), a n d h y p o p i g m e n t a t i o n . Six p a t i e n t s (21%) e x p e r i e n c e d blisters o n t h e t r e a t e d areas. Of these, 2 p a t i e n t s c o n t i n u e d t r e a t m e n t at t h e s a m e c o n c e n t r a tion o f SADBE (1% a n d 2%, respectively), 2 r e c e i v e d a d e c r e a s e d d o s e o f SADBE (1% to 0.5%), 1 p a t i e n t h a d t r e a t m e n t h e l d for o n e visit, a n d 1 p a t i e n t was treated with prednisone, cephalexin, and topical antibiotic o i n t m e n t b e c a u s e his blisters w e r e large a n d r e q u i r e d d r a i n a g e a n d unroofing. H e r e c e i v e d n o f u r t h e r squaric acid a n d was cured. T h e p a t i e n t w h o h a d t r e a t m e n t h e l d for o n e visit e x p e r i e n c e d a s e c o n d a d v e r s e r e a c t i o n u p o n n e g l e c t i n g to w a s h h e r h a n d s after r e m o v i n g t h e o c c l u s i o n b a n d a g e . She a w o k e t h e next m o r n i n g with a rash a n d e d e m a o f h e r face a n d right eye a n d was t r e a t e d with a 5-day p r e d n i s o n e t a p e r a n d topical c o r t i c o s t e r o i d s .

DISCUSSION O u r c u r e rate o f 69% is c o m p a r a b l e to t h e rates r e p o r t e d for similar studies assessing DNCB, DPCP, a n d SADBE. 9-13 C o m p a r e d with s o m e o f t h e s e previ-

598

Lee andMallory

ous reports,9,1~ 12 o u r study may have had b e t t e r patient compliance because the contact i m m u n o therapy agent was applied in clinic by a physician, rather than by the patient at home. A previous report also supports our practice of not using SADBE on the face. Lewis 9 r e c o m m e n d e d against using contact i m m u n o t h e r a p y for refractory facial warts because facial skin reacted m o r e strongly to DNCB. All facial warts were treated with liquid nitrogen in our study. The study of SADBE treatment of warts by Claudy and Roche 14 in 1981 reported a cure rate of about 10% within 11 weeks of weekly applications with an average of 9.5 treatments. They concluded that SADBE was not effective therapy for multiple recurring warts c o m p a r e d with liquid nitrogen, electrocautery, or irritant substances. In 1993, Iijima and Otsuka 13 r e p o r t e d that 60% of patients achieved wart regression within 3 months with an average of 6 treatments and concluded that SADBE therapy was effective in the treatment of warts resistant to other therapies or in patients w h o find cryotherapy too painful. Our data corroborate the findings of Iijima and Otsuka. Our subset of 69% cured patients had a m e a n duration of therapy of 4.4 m o n t h s and achieved complete regression within 12 months with a mean of 5.9 treatments. In c o m p a r i s o n with the study of Claudy and Roche and the study of Iijima and Otsuka, our use of a higher SADBE concentration may have affected our outcomes. Claudy and Roche used 0.01% to 0.5% SADBE weekly (most often using 0.01% or 0.1%), and Iijima and Otsuka used 0.01% or 0.1% SADBE weekly or biweekly. We used a higher concentration of SADBE at less frequent intervals (0.5%, 1%, 2%, and 5% every 2-4 weeks), which may have contributed to our higher cure rate. Our rate of cases of severe contact dermatitis was greater than that of Iijima and Otsuka (21% vs 15%), also probably resulting from our use of a higher SADBE concentration. Hypopigmentation at sites of SADBE application was seen in one patient who was resistant to SADBE therapy. This effect has not been reported previously. Iijima and Otsuka 13 also r e p o r t e d higher cure rates in patients younger than 15 years (87.5%) compared with those 15 years and older (41.7%) and raised the possibility that contact i m m u n o t h e r a p y o u t c o m e might be a g e - d e p e n d e n t . Our study showed an opposite trend with a 62% cure rate for patients younger than 15 years and an 86% cure rate for patients 15 years and older. It is not surprising that the two i m m u n o c o m p r o mised patients in our study were resistant to therapy. The difficulty in adequately m o u n t i n g a type 1V response to squaric acid was well illustrated in the patient who was successfully sensitized only after a

l AM ACAD DERMATOL OCTOBER1999

decrease in his azathioprine dose. This had no harmful effects (ie, rejection) on his transplanted heart. In a study on the natural history of u n t r e a t e d warts in 1000 mentally deficient patients, Massing and Epstein 15 reported complete regression in 67% of patients over 2 years. A subset of these patients w h o were c h e c k e d b i m o n t h l y yielded regression rates of 11% in 2 months, 13% in 4 months, and 24% in 6 to 7 months. In comparison to these observations, Iijima and Otsuka 13 posited that the shorter regression time for treated patients r e p r e s e n t e d a r e s p o n s e to SADBE treatment, not natural involution. The s a m e reasoning applies to o u r data. However, spontaneous regression cannot be totally ruled out. Clinical observations of erythema, pruritus, swelling, and slight scaling with gradual diminution in size are also characteristics of spontaneously involuting fiat warts, 5 and of spontaneously involuting c o m m o n and plantar warts. 16,17 Because the clinical appearance of spontaneously involuting warts and warts treated with SADBE can be the same, it is possible that we observed some spontaneous regression. However, it should be noted that we aimed for p r o d u c i n g a mild contact dermatitis a r o u n d each treated wart once sensitization was achieved, thus making it m u c h m o r e likely that wart regression occurred because of squaric acid treatment. Adjunctive therapy was performed on 12 of our patients (41%), 16 patients were treated solely with SADBE (55%), and information regarding adjunctive therapy was unavailable for one patient. The use of treatments in addition to SADBE makes it difficult to attribute the results purely to SADBE. However, of the 20 cured patients, 13 received no adjunctive therapy and 6 received adjunctive therapy. Adjunctive therapy was used to hasten clearing, usually on the palms and soles where penetration of SADBE was probably poorer than other areas. Four of the 17 r e s p o n d e r s e x p e r i e n c e d recurrence within 2 years. Of these 4 patients, 2 had new warts at different sites and 2 had warts at unknown sites. There are a few explan.ations for this. First, the m e c h a n i s m of i m m u n o t h e r a p y involves a haptenh u m a n protein complex rather than a hapten-viral protein complex. It is possible that either or both of these o c c u r r e d in o u r patients, and those w h o r e s p o n d e d via a h a p t e n - h u m a n protein c o m p l e x m e c h a n i s m had recurrence. Another explanation might be that a different i m m u n o t y p e of h u m a n papillomavirus was responsible for the recurrence. Our study of the clinical efficacy of SADBE shows a 69% cure rate for patients with recalcitrant warts, corroborating findings of previous studies. 13 As a contact i m m u n o t h e r a p y agent, SADBE is favorable for its lack of mutagenicity measured by the Ames

Lee andMallory

J AM ACAD DERMATOL VOLUME41, NUMBER4

test, scarcity in c o m m o n human environments, and ease of sensitization. Treatment was well tolerated by our patients. Cryotherapy, which is painful, is not tolerated very well in younger patients. The efficacy of SADBE therapy is comparable to reported efficacies of c r y o t h e r a p y (70%-80%) and salicylic and lactic acids (70%-80%), c o m p o n e n t s of widely a c c e p t e d first-line physician-administered and over-thecounter treatments. 18 The fact that the majority of treated warts cleared within 12 months is an indication that SADBE t r e a t m e n t leads to wart clearing. The use of SADBE for eradication of recalcitrant warts, especially in younger patients who do not tolerate painful procedures, might be considered in the armamentarium of wart therapies. REFERENCES

I. Benton EC. Therapy of cutaneous warts. Clin Dermatol 1997;I 5:449-55. 2. Elder D, Elenitsas R, Jaworsky J, Johnson B Jr, editors. Lever's Histopathology of the skin. 8th ed. Philadelphia: JB Lippincott; 1997. p.212-3. 3. Eisen HN, Orris L, 8elman S. Elicitation of delayed allergic skin reactions with haptens: the dependence of elicitation on hapten combination with protein. J Exp Med 1952;95:473-87. 4. Shelley WB, Juhlin L. Selective uptake of contact allergens by the Langerhans cell.Arch Dermato11977;I 13:187-92. 5. Tagami H, Ogino A, Takigawa M, Imamura S, Ofuji S. Regression of plane warts following spontaneous inflammation. Br J Dermatol 1974;90:147-54.

599

6. Berman A, Winkelmann RK. Involuting common warts. J Am Acad Dermato11980;3:356-62. 7. Siegfried EC.Warts on children: an approach to therapy. Pediatr Ann 1996;25:79-90. 8. Dunagin WG, Millikan LE. Dinitrochlorobenzene immunotherapy for verrucae resistant to standard treatment modalities. J Am Acad Dermato11982;6:40-5. 9. Lewis HM.Topical immunotherapy of refractory warts. Cutis 1973;12:863-7. 10. Bekhor PS, Entwisle BR, McKenzie IFC.Topical DNCB therapy for resistant warts. Australas J Dermatol 1978;19:28-30. 11. Eriksen K.Treatment of the common wart by induced allergic inflammation. Dermatologica 1980;160:161-6. 12. Naylor MF, Neldner KH,Yarbrough GK, Rosio TJ, Iriondo M, Yeary J. Contact immunotherapy of resistant warts. J Am Acad Dermatol 1988;19:679-83. 13. lijima S, Otsuka F. Contact immunotherapy with squaric acid dibutylester for warts. Dermatology 1993;187:115-8. 14. Claudy AL, Roche H.Traitement des verrues multiples et recidivantes par induction d'une hypersensibilite retardee. II. etude critique de I'utilisation du dibutylester de I'acide squarique. Ann Dermatol Venereol 1981 ;108:765-7. 15. Massing AM, Epstein WL. Natural history of warts: a two-year study. Arch Dermatol 1963;87:306-10. 16. Rasmussen KA. On the spontaneous cure of plantar warts. Acta Derm Venereol (Stockh) 1954;34:144-51. 17. Brodersen I, Genner J.Histological and immunological observations on common warts in regression. Acta Derm Venereol (Stockh) 1973;53:461-4. 18. Bunney MH, Nolan MW, Williams DA. An assessment of methods of treating viral warts by comparative treatment trials based on a standard design. Br J Dermato11976;94:667-79.

RECEIVE TABLE OF CONTENTS BY E-MAIL

To receive the tables of contents by e-mail, send an e-mail message to: [email protected] Leave the subject line blank, and type the following as the body of your message: Subscribe aem_tocjaad You can also sign up through our website at: http://www, mosby.com/aemjaad You will receive an e-mail to confirm that you have been added to the mailing list. Note that table of contents e-mails will be sent out when a new issue is posted to the website.