Oral Retinoids for Hidradenitis Suppurativa 17

Chapter 17 Oral Retinoids for Hidradenitis Suppurativa 17

Jurr Boer

Key points 17.1 Introduction

Q Therapy with isotretinoin for patients Isotretinoin is well recognized as the most suc- with HS has only limited therapeutic cessful therapy for acne vulgaris. It is tradition- benefit ally thought that hidradenitis suppurativa (HS) and acne are closely related, and because of this Q There are claims that etretinate and isotretinoin has also been tested in HS, as have acitretin are superior to isotretinoin. the related compounds etretinate and acitretin. These data, however, wait confirmation in larger patient series 17.2 Isotretinoin

17.2.1 Mechanism of Action [1, 2]

#ONTENTS The mechanism of action of isotretinoin in HS is unknown. In HS, the initial event is believed 17.1 Introduction ...... 128 to be poral occlusion. Retinoids can normalize 17.2 Isotretinoin ...... 128 follicular cornification, although etretinate and 17.2.1 MechanismofAction[1,2] ...... 128 acitretin have a clearly greater effect than 17.2.2 Clinical Experience ...... 129 17.2.2.1 Isotretinoin Monotherapy for HS ...... 129 isotretinoin in disorders of keratinization [3]. It 17.2.3 IsotretinoinTherapyinPatients has also been shown that isotretinoin can re- with Acne and Coexistent HS ...... 129 duce ductal hypercornification [4]. Isotretinoin 17.2.4 IsotretinoininthePre- possesses anti-inflammatory effects, reduces and Postoperative Phase ...... 131 the chemotaxis of polymorphonuclear leuco- 17.2.5 Isotretinoin in Combination Treatment cytes and has been reported to enhance immune of HS ...... 131 function [5, 6]. These properties may be of ben- 17.2.6 Side-Effects ...... 131 efit in the treatment of HS. The main effect of 17.3 Etretinate and Acitretin ...... 132 isotretinoin is to decrease of the size and secre- 17.3.1 MechanismofAction ...... 132 tions of the sebaceous glands. 17.3.2 Clinical Experience: Etretinate and Acitretin for HS ...... 132 However, in contrast to what happens in 17 17.3.3 Side-Effects ...... 134 acne, the size of sebaceous glands is not increased in HS. Isotretinoin also reduces the References ...... 134 ductal population of Propionibacterium acnes, and although this has a very important effect on acne pathogenesis, it does not appear to be useful for the treatment of HS, because Propioni- bacterium acnes has not been cultured in HS lesions. Isotretinoin does not affect the size of apocrine glands. Oral Retinoids for Hidradenitis Suppurativa Chapter 17 129

17.2.2 Clinical Experience culoid lesions exist and undermining sinus tracts have not yet developed, isotretinoin alone 17.2.2.1 Isotretinoin Monotherapy for HS can produce complete suppression and pro- longed remission. Boer and van Gemert [12] Isotretinoin monotherapy for patients with HS also found some indication that the response of has limited therapeutic benefit. This is both the HS to isotretinoin is more successful in the general overall impression of many experts as milder (furunculoid, papulo-pustular lesions) well as the outcome of a study in which a large cases. It may be that treatment with isotretinoin case series of 68 patients were followed over a at the earliest stages of HS corrects the follicular period of almost 9 years [7–12]. The results of abnormality that is the root of this chronic dis- case reports and studies with case series are ease [15]. summarized in Table 17.1. All studies lack control groups with antibiotics or other agents as a comparison, so no state- 17.2.3 Isotretinoin Therapy in Patients ment as to relative efficacy can be made. How- with Acne and Coexistent HS ever, in all the referred case studies many patients did not respond to oral antibiotics or It is well known that acne and HS can occur in surgery, or relapsed after such treatment. the same person. In addition to the coexistence It is well known that acne patients with epi- of acne and HS, there are the so-called acne tri- thelial sinus tracts with recurrent inflammation ad (acne conglobata, HS and perifolliculitis ca- respond poorly to isotretinoin and are in fact pitis abscedens et suffodiens) and acne tetrad most of the isotretinoin “failures,” at a high cu- (original acne triad and pilonidal sinus) condi- mulative dose of isotretinoin as well [6, 13, 14]. tions [16]. This clinical overlap of acne and HS These lesions are identical to those found in the has led to the inclusion of inhomogeneous pa- axillae and groin in patients with HS [13, 14]. tients in the treatment groups. It concerns two Shalita and co-workers [13] suggested that in possible different types of HS; firstly the disease early cases in which only inflammatory furun- that only affects the inguinal folds and the axil-

Table 17.1. Reported results of isotretinoin therapy for hidradenitis suppurativa (HS) No.ofpatientswithan

- (almost) clear score Author (s) No.ofpa tients Dose (mg/kg per day) Duration of treatment (months) Follow-up (months) Duration of HS (years) Severity of HS

At the end At the end of treatment of follow-up

Jones et al. [7] 3 1.0 4 – 20–30 Severe 0 (0%) – Dicken et al. 8 0.71–1.2 4 2–6 5–35 Severe 4 (50%) 1 (12.5%) [8] Norris and 6 1.0 4 2 many years Severe 0 (0%) – Cunliffe [9] Brown et al. 1 1.0 4 4 3 Severe 1 (100%) 1 (100%) [10] Mengesha 1 1.0 8 12 1 Severe 0 (0%) – et al. [11] Boer and 68 0.5–0.81 4–6 6–107 1–30 Mild to 16 (23.5%) 11 (16.2%) van Gemert severe [12] 130 Jurr Boer

Table 17.2. Reported results of isotretinoin treatment of patients with acne and coexisting HS Author (s) No. of Dose (mg/kg Duration Improvement of HS Recurrence patients per day) of treatment (months)

Jones et al. [18] 1 0.1–1.0 4 No change – Plewig et al. [19] Un- 1.0–2.0 3 To a certain extent – specified Peck et al. [20] 2 High, No data Improvement – no precise data Shalita et al. [13] Uns- 0.5–1.0 4–5 Only suppressed – pecified furunculoid lesions. No change in sinus tracts Harms [21] 2 0.5–1.0 6 Improvement – Harms [2] 5 No data No data Considerable improve- No ment in 4 out of 5 patients Libow and Friar [22] 1 0.2–1.0 9 Quiescent No

lae (“Verneuil’s disease”), and secondly inguinal apy did not always totally suppress this type of and axillary involvement in patients with acne lesion. The conclusion of the authors was that affecting the face and back [2, 13, 17]. The last sinus tracts require surgical removal [13, 14]. disease has also been called acne ectopica and In several initial trials of isotretinoin in acne, acne tetrad. the investigators often included some patients It has been suggested that patients of these with HS in addition to their severe acne. Jones, two categories would respond to isotretinoin in Blanc, and Cunliffe reported one case who failed different ways [2, 13, 14, 17]. The data are sum- to respond after a 4-month course on an un- marized in Table 17.2. specified dose of between 0.1 and 1.0 mg/kg per Harms [2] treated eight patients suffering day [18]. Plewig and colleagues treated an un- from HS, of whom five had concurrent acne of specified number of patients with acne tetrad the face and three did not. Four out of five who responded to a certain extent [19]. Peck et patients with the combination of acne and HS al. included two patients with HS in the groin improved considerably under treatment with and axilla in addition to their cystic acne, who isotretinoin and did not suffer any recurrence. showed improvement of the HS after the cystic The three patients who had only inguinal in- acne had begun to improve and when the dos- volvement did not improve (data about the dosage had been further increased above the level es, duration of isotretinoin course and follow- required to improve their acne (the actual doses up were not mentioned). It was concluded that used were high but not specified) [20]. Harms patients with lesions only in inverse areas (axil- described in a case series of 56 patients with 17 lae, groin) should not be treated with isotreti- nodulocystic acne including two patients with noin and that there may be patients with HS ano-inguinal lesions which only improved on who respond very well to isotretinoin, namely isotretinoin at a dosage of 0.5–1.0 mg/kg per day those with a combination of acne and additional for 6 months [21]. Libow and Friar reported ef- HS [2, 17]. fective treatment of a patient with arthropathy Other authors [13, 14] found that patients with associated acne triad condition with with sinus tracts in the areas of acne with coex- isotretinoin [22]. A patient has been described isting HS of the axillae and groin were often with arthropathy associated with cystic acne, isotretinoin “failures,” in that isotretinoin ther- HS (in this case papulo-pustules and cysts in- Oral Retinoids for Hidradenitis Suppurativa Chapter 17 131 volving the genital and inguinal areas, no sinus only poorly to oral antibiotics and isotretinoin tracts), and perifolliculitis capitis abscedens et (dose were not mentioned) [27]. The authors did suffodiens who showed a dramatic response to not observe preoperative “conditioning” of the isotretinoin (1.0 mg/kg per day) for 6 months, HS regions and in their case series they did not followed by isotretinoin (0.5 mg/kg per day ev- recognize any minimalization of the areas in- ery other day) for another 3 months before be- volved by the HS lesions. No controlled trials ing discontinued. At the completion of 6 months are available to assess the claims of the useful- of therapy, his cutaneous disease was quiescent ness of this pre- and postoperative treatment and there was no recurrence of either joint or with oral isotretinoin. cutaneous disease (a follow-up period was not mentioned). So, the results of these case reports [2, 13, 17.2.5 Isotretinoin in Combination 18–22] are at best equivocal compared to the ex- Treatment of HS cellent results in acne treatment. In the same patients the acne seemed to clear completely or One author reported on a patient with Crohn’s was much improved, while in most case reports disease and HS who showed a satisfactory out- the HS lesions obviously remained and showed come following treatment with azathioprine only a limited response. A follow-up period was (150 mg/day) and methylprednisolone (16 mg/ never mentioned. A (partial) response of HS le- day) combined with isotretinoin (0.7 mg/kg per sions to isotretinoin was also more slow to de- day) and periodic administration of antibiotics velop than the response to acne. Moreover, [28]. Another report details a patient with mul- isotretinoin has a very poor effect on sinus tiple pustular and cystic lesions located on swol- tracts, whether located in the same area as the len and red labia majora. She was successfully acne or in the axillae and groin [13, 14, 16, 23]. treated with prednisolone and erythromycin for months and then long-term isotretinoin (mostly 1.0 mg/kg per day) for 15 months, and no sig- 17.2.4 Isotretinoin in the Pre- nificant relapse of the so-called vulval apocrine and Postoperative Phase acne occurred during a follow-up period of 10 months [29]. The use of oral isotretinoin has been recommended by Plewig and co-workers during the weeks or months before surgery and even post- 17.2.6 Side-Effects operatively [16, 24]. The drug has anti-inflammatory activity and may drastically reduce sup- The side-effects of isotretinoin are very numer- puration and edema [24]. It also reduces the ous [2, 30–32]. In the studies mentioned, no se- volume of the sebaceous glands and alternates rious side-effects are reported. In patients who the pattern of keratinization within the follicle are treated with isotretinoin (mostly for 16 [25]. It has been suggested that in this way the weeks), liver function tests and determination area involved by HS lesions can be significantly of lipid profiles have to be performed at baseline reduced [25, 26], although isotretinoin by itself and on one occasion after 4 weeks [31]. Terato- is insufficient to stop the disease [16, 24]. genicity is by far the most serious of all the side- In various German trials, patients were treat- effects of retinoids and requires responsible pre- ed with an unspecified dose of between 0.2 and scribing by physicians and reliable patients [31, 2.0 mg/kg per day for the 2–4 months before 32]. Women of child-bearing age must not start surgical intervention until some days postoper- therapy until a negative pregnancy test result atively and, if indicated, in combination with within 1 week before starting therapy has been glucocorticosteroids for 2–3 weeks at a dose of obtained. Adequate contraception, i.e., two reli- 0.2–1.0 mg/kg per day and systemic antibiotics able forms of birth control, must be used before [24–26]. Lentner, Rübben and Wienert then re- and during oral isotretinoin therapy, as well as ported on 28 patients with HS who responded for 6 weeks post-therapy. Therapy should start 132 Jurr Boer

on the second or third day after the onset of the 4 months of isotretinoin at a dose of 1.4 and 2.0 next normal menstrual period. It is strongly mg/kg per day, respectively [38]; two courses at recommended that prescribers write prescrip- a dose of 0.8 mg/kg per day for 4 and 3 months, tions for no more than a 1-month supply at a respectively [36]; two full courses for 5 months time and that patients undergo monthly preg- at a dose of 2 mg/kg per day [35], and in one nancy testing [32]. patient a 4-month course of isotretinoin (1 mg/ kg per day), which cleared the patient’s acne conglobata but was singularly unhelpful for his 17.3 Etretinate and Acitretin HS lesions [37]. Stewart [34] treated his six patients with ongoing doses of etretinate and they 17.3.1 Mechanism of Action were observed over periods of 6–39 months. Af- ter 3 months of treatment, three patients showed There is a broad base of clinical experience with good clearing of disease (50%–75%) and after etretinate and acitretin in the treatment of 12 months of treatment all patients eventually chronic keratinizing disorders [33]. If ductal hy- had an excellent response. The criteria for clear- perkeratinization is crucial in the pathogenesis ing in the HS patients were: disappearance of of HS, etretinate and acitretin could be good al- sinuses and cessation of discharge. Two patients ternatives to isotretinoin, because these drugs were taken off etretinate, and it took 4 months have a clearly greater effect on hyperkeratiniza- for them to begin to show signs of disease recur- tion [3]. In addition, etretinate and acitretin rence (increasing discharge and formation of show considerable immunomodulatory and the old sinus tracts). Hogan and Light [35] treat- anti-inflammatory effects [33]. Acitretin, the ed a 24-year-old women with a 6-month course active retinoid metabolite, has generally re- of acitretin at a dosage of 0.5 mg/kg per day. Af- placed etretinate in retinoid therapy, certainly ter 2 months of treatment with acitretin a 50% in psoriasis because of its more favorable phar- decrease in induration of the axillae was noted. macokinetic profile, including a significantly After 4 months of treatment there was no longer shorter half-life. any induration or abscess formation in her axillae. Her HS remained in remission until 11 months after discontinuation of acitretin. 17.3.2 Clinical Experience: Etretinate Therapy was reinstituted with success [35]. and Acitretin for HS Vahlquist and Griffiths [36] treated a 47- year-old man with etretinate (0.7 mg/kg per Etretinate and acitretin were of great benefit in day). Within a few weeks the lesions had be- all ten patients with HS, as described in five case come less painful. After a treatment period of reports [33–38]. In 1984 Stewart [34] was the 11 months, the patient was essentially free of ac- first to report on HS treatment with etretinate tive lesions and the etretinate therapy was dis- in a study of six patients; four other case reports continued. Although scarring was still a prob- followed in the period from 1988 until 2002 lem, the patient had no longer pain. A minor [35–38]. The data are summarized in Table relapse was recorded 1 year after stopping etret- 17.3. inate and this was successfully controlled by a Overall, eight patients were treated with short course of oral antibiotics [36]. Chow and 17 etretinate at a dose of 0.35–1.0 mg/kg per day Mortimer [37] treated a 31-year-old man with [34, 36, 37] and two patients with acitretin at a etretinate (0.5 mg/kg per day) for 9 months, the dose of 0.5–1.0 mg/kg per day [35, 38]. Six out of first 3 months together with erythromycin 1 g ten patients were on isotretinoin (0.8–2 mg/kg daily. Within 2 months, he was showing signs of per day) before starting etretinate and acitretin, improvement, with less pain, less discharge, of whom two were in Stewart’s series [34] and and a decrease in the number of acute exacer- their dosage is not mentioned. The results were bations. After 3 months there was no sign of dis- unsatisfactory in all cases. The doses of isotreti- ease activity, although linear fibrotic bands of noin were usually high, i.e., two full courses for scarring remained. Disease was still in remis- Oral Retinoids for Hidradenitis Suppurativa Chapter 17 133 of follow-up At the end clear with antibiotics with clear Clear with ongoing ongoing with Clear treatment a b At the end of treatment Improvement Duration of HS (years) treatment 11 months; clear clear 11 months; acitretin with (months) Follow-up - ment (months) 12 3 5 clear Clear 11 Years 12 clear flare 12 months; Minor 3–39 3–39 data No Clear Duration of treat dose 0.5 0.7 10 clear flare Mild (mg/kg per day) 0.35–1.1 months Region Retinoid Mixed Etretinate 1M: 31 Mixed Etretinate 1M: 47 Buttocks Etretinate 1F: 24 1F: Mixed Acitretin patients, sex, age (in years) 3M: 31, 32, 55 Reported results of etretinate/acitretin therapy for hidradenitis suppurativa (HS) Scheman [38]Scheman 0.6–0.9 1M: 41 12 Groin Acitretin 12 data No clear ongoing Clear with Chow and and Chow [37] Mortimer Vahlquist and and Vahlquist Griffiths [36] Hogan and and Hogan [35] Light 0.5 6 least 11 At Author (s) No. of Stewart [34]Stewart 34, 36, 64 3F: Clear defined as no disease activity; fibrotic bands and scarring remain patients discontinued etretinate after 3 months, for reasons not mentioned Two Table 17.3. Table a b 134 Jurr Boer

sion 3 months after stopping etretinate [37]. or isotretinoin for as many as 15 years and had Scheman [38] treated a 41-year-old man, who not developed any signs of severe toxicity [39]. presented with severe nodulocystic facial acne Acitretin has been established as a safe, effective and HS on the inguinal folds, with acitretin treatment for psoriasis [39–41]. Retinoids, in- (0.6 mg/kg per day). After 2 months, the pa- cluding etretinate and acitretin, are potent tient’s HS was completely controlled, and his teratogens, leading to strict requirements for very severe acne improved to only a few in- pregnancy prevention during and after their use flamed nondraining facial cysts. With a dosage [39–41]. Etretinate can be prescribed for male of acitretin of 0.9 mg/kg per day the patient was patients or postmenopausal female patients [41]. completely free of inflammatory lesions on his Premenopausal fertile woman should not be face and groin. After 4 months on this dosage, treated with etretinate but can be considered for however, alopecia and unacceptable joint pain acitretin therapy providing they use adequate developed. After 1 month off acitretin, the pa- contraception during therapy and for 24 months tient’s side-effects resolved. Treatment was re- [39, 41] or even 36 months [40] after discontinu- sumed back at a dose of 0.6 mg/kg per day, with ation. In fertile female patients it is also sug- results similar to those when the patient was gested to do a pre-treatment pregnancy test and previously on this dosage. After 5 months of repeated pregnancy tests every month of thera- therapy, improvement continued to be satisfac- py [41]. tory [38]. It is of concern that no controlled studies have been published. Nevertheless, there seem References to be some striking points in these case studies. All patients (n=10) treated with etretinate or 1. Ward A, Brogden RN, Heel RC, Speight TM, Avery acitretin at a dose of 0.35–1.1 mg/kg per day re- GS. Isotretinoin: a review of its pharmacological sponded excellently. All patients were essential- properties and therapeutic efficacy in acne and re- ly free of active lesions [36], and were completely lated disorders. Drugs 1984; 28: 6–37 2. Harms M. Systemic isotretinoin. A unique therapeu- free of inflammatory cysts [38] and sinus tracts tic effect and its implications in the pathogenesis of [34]; any induration and abscess formation dis- acne. Editiones Roche, Basel, Switzerland, 1994 appeared [35–37], although linear fibrotic bands 3. Dalziel K, Barton S, Marks R. The effect of isotreti- of scarring remained [36, 37]. These excellent noin on follicular and sebaceous gland differentia- responses were obviously not obtained by earlier tion. Br J Dermatol 1987; 117:317–323 courses with isotretinoin in the same patients. 4. Cunliffe WJ, Jones DH, Pritlove J, Parkin D. Long- In addition, the decrease of disease activity term benefits of isotretinoin in acne. Clinical and laboratory studies. In: Saurat JH, Ed. Retinoids: new seemed to start after approximately 2 months of trends in research and therapy. Karger, Basel, 1985; treatment. However, in a panel discussion Cun- pp 242–251 liffe stated that their group treated three or four 5. Pigatto PD, Floroni A, Riva F, Brugo MA, Morandot- patients with etretinate without too much suc- ti A, Altomare GF, Finzi AF. Effects of isotretinoin cess (unpublished observations). The treatment on the neutrophil chemotaxis in cystic acne. Derma- with etretinate was stopped after 6 or 8 months tologica 1983; 167:16–18 [39]. 6. Layton AM, Knaggs H, Taylor J, Cunliffe WJ. Isotret- inoin for acne vulgaris – 10 years later: a safe and successful treatment. Br J Dermatol 1993; 129:292–296 17 7. Jones DH, Cunliffe WJ, King K. Hidradenitis suppu- 17.3.3 Side-Effects rativa – lack of success with 13-cis-retinoic acid (let- ter). Br J Dermatol 1982; 107:252 Etretinate is a prodrug of acitretin with a mo- 8. Dicken CH, Powell ST, Spear KL. Evaluation of lecular weight about 10% greater than that of isotretinoin treatment of hidradenitis suppurativa. acitretin, with the consequence that the daily J Am Acad Dermatol 1984; 11:500–502 dose, usually 30–75 mg etretinate, corresponds 9. Norris JFB, Cunliffe WJ. Failure of treatment of familial widespread hidradenitis suppurativa with to 20–50 mg acitretin. In the early 1990s, many isotretinoin. Clin Exp Dermatol 1986; 11:579–583 patients had been treated with either etretinate Oral Retinoids for Hidradenitis Suppurativa Chapter 17 135

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