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1 THERAPEUTICS DOI /j x An open-label phase II study of the safety and efficacy of etanercept for the therapy of hidradenitis suppurativa E.J. Giamarellos-Bourboulis, E. Pelekanou, A. Antonopoulou, H. Petropoulou, F. Baziaka, V. Karagianni, N. Stavrianeas* and H. Giamarellou 4th Department of Internal Medicine and *2nd Department of Dermatology and Venereology, University of Athens, Medical School, University General Hospital ATTIKON, 1 Rimini Str, Athens, Greece Summary Correspondence Evangelos J. Giamarellos-Bourboulis. giamarel@ath.forthnet.gr Accepted for publication 15 May 2007 Key words etanercept, hidradenitis suppurativa, lymphocytes Conflicts of interest None declared. Objective To evaluate the safety and efficacy of etanercept for the management of hidradenitis suppurativa. Methods In a prospective open-label phase II study, etanercept was administered subcutaneously in a dose of 50 mg once weekly for 12 weeks in 10 patients. They were followed up to 24 weeks and their disease activity and Sartorius score were assessed, with also a self-evaluation by visual analogue scale (VAS). Disease activity was an assessment of the extent of the disease by the attending physicians who were unaware of the protocol. Results A > 50% score improvement was found in six patients at week 12 and in seven patients at week 24. The VAS was decreased compared with baseline in seven patients at week 12 and in six patients at week 24. All changes were statistically significant. All patients reported a decrease of local pain at the site of lesions after week 4. Drainage of pus from the affected areas recurred in eight patients within 4 8 weeks after the end of administration of etanercept. The treatment was well-tolerated. Conclusions Etanercept is a safe and effective therapy for hidradenitis suppurativa and decreases the extent of the disease and improves the quality of life. A double-blind, placebo-controlled trial is required to elucidate fully the role of etanercept for hidradenitis suppurativa. Hidradenitis suppurativa is a skin disorder of unknown aetiology characterized by inflammation and secondary infection of skin areas rich in apocrine glands. 1 Various bacterial pathogens are considered to be implicated in its pathogenesis so that patients are commonly referred to Infectious Diseases Outpatient clinics where they are often prescribed various antimicrobial regimens; however disease recurs early after cessation of antibiotics. 1 A recent survey by our group in 56 patients disclosed a severe derangement of the monocyte function and of subsequent antigen processing in these patients. 2 The percentage of natural killer (NK) cells was increased and that of CD4 lymphocytes decreased compared with healthy controls, probably implying the existence of an autoimmune predisposition for the disorder. The similarities of hidradenitis suppurativa to other chronic inflammatory disorders led to the initiation of two trials with antitumour necrosis factor (TNF) treatment. In the first trial five patients were treated with infliximab, a chimeric antibody targeted against TNF-a; 3 in the second six patients were treated with etanercept, a soluble receptor of TNF-a. 4 Efficacy of both TNF-a-targeted therapies was based on the patients selfevaluation and the results showed significant improvement of the disease. Moreover in these trials the duration of treatment was modified according to the patients response. The present study was designed based on the need to evaluate a standardized dose and duration of treatment of etanercept in hidradenitis suppurativa. The objective of this prospective phase II trial was to evaluate the safety and the efficacy of 12 weeks therapy with etanercept in 10 patients. Based also on the former results of our group showing an increase of NK cells and decrease of CD4 lymphocytes in patients with hidradenitis suppurativa, 2 we evaluated the effect of etanercept on subpopulations of lymphocytes. Patients and methods A prospective, open-label, phase II study was conducted during the period September 2005 November Ten patients with hidradenitis suppurativa who were followed up in the Outpatient Department of Immunology of Infectious Diseases 1

2 2 Etanercept in hidradenitis suppurativa, E.J. Giamarellos-Bourboulis et al. of the ATTIKON University Hospital participated. The protocol of the study was approved by the Ethics Committee of the hospital and by the National Organization for Medicines (Competent Authority of Greece). The protocol was given the EudraCT number and registered in clinicaltrials.gov (NCT: ) (accessed 18 August 2007). The inclusion criteria were (i) written informed consent provided by the patient, (ii) age above 16 years, (iii) diagnosis of hidradenitis suppurativa, and (iv) activity index > 20. The latter was arbitrarily defined by the following equation: (greatest diameter of the largest involved skin area in cm) (severity of the largest involved area) (number of involved body areas), where the severity of the involved areas was scored by the attending physician from 0 to 4 (0: no disease, 1: too mild, 2: mild, 3: moderate with redness, and 4: severe with heavy inflammation and purulence). The diagnosis of hidradenitis suppurativa was made by clinical criteria 1,5,6 comprising (i) onset after puberty, (ii) the presence of subcutaneous nodules in areas of skin rich in apocrine glands, and (iii) a compatible history of recurrent drainage of pus from the affected areas. The exclusion criteria were (i) administration of any live (attenuated) vaccine over the last 4 weeks; (ii) history of recurrent vein thrombosis or embolism compatible with anticardiolipin syndrome; (iii) any present or smoldering infection; (iv) hepatic dysfunction defined as any value of transaminases, of c-glutamyl transpeptidase or of bilirubin > 2 upper normal limit; (v) history of coronary heart disease, diabetes mellitus, haematological or solid tumour malignancy, arterial hypertension, liver cirrhosis, HIV infection and hepatitis B or C; (vi) history of episodes mimicking demyelinating disorders or a definite diagnosis of multiple sclerosis; (vii) any creatinine value above 1Æ5 mgdl )1 ; (viii) intake of corticosteroids; (ix) history of rheumatoid arthritis, systemic lupus erythematosus or inflammatory bowel disease; (x) neutropenia defined as < 1000 neutrophils mm )3 ; (xi) thrombocytopenia defined as < platelets mm )3 ; and (xii) pregnancy or lactation. The lack of presence of any concomitant or smouldering infection was based on (i) a negative history and physical examination, (ii) a negative lung X-ray and (iii) a negative skin tuberculin test. All patients were given etanercept (Enbrel Ò, Wyeth Hellas S.A., Athens, Greece) for 12 consecutive weeks at a dose of 50 mg subcutaneously once weekly. The applied dose regimen was selected by comparison with the therapy of patients with psoriasis with etanercept. 7 The injection was performed on the same day of each week by the patients themselves. A consultation was made at baseline and then in weeks 4, 8, 12 and 24. After enrolment, all patients were provided with a medication pack containing four ready-to-use syringes and four ampoules with lyophilized powder of the drug. Patients were instructed to return the pack at the next visit so as to assure administration. The patients were not given any other concomitant antimicrobial regimen or any other medication. At each visit, all patients had a thorough clinical examination by two attending physicians who were unaware of the study. The physicians measured the diameter of all involved areas with a ruler in mm and they scored the severity of each lesion as described above. They then asked the patient to provide an impression of the severity of the disease using the visual analogue scale (VAS). Patients were told that 0 represented no disease activity and 10 cm very severe disease activity. They were also asked to provide data about the frequency of exacerbations of their disease and about the time interval between exacerbations. Blood tests were performed comprising (i) haematocrit, haemoglobin, white blood cell count and platelet count; (ii) glucose, urea, creatinine and electrolytes; and (iii) serum levels of aspartate (AST) and alanine transaminases (ALT) and alkaline phosphatase (SAP). An adverse event was considered as serious in the case that the event (i) resulted in death, (ii) put the patient s life in danger, (iii) prolonged hospitalization, (iv) resulted in persistent or significant disability or incapacity, or (v) resulted in cancer or in any important medical event. All other adverse events were considered as not serious. All serious adverse events occurring over follow-up were reported to the Greek Competent Authority and the Ethics Committee of the hospital. At each visit, disease activity was evaluated. The latter was arbitrarily defined as the sum of lesions of each patient, with each lesion evaluated with the following formula: (multiplication of both diameters in each affected area in cm) (severity of the corresponding lesion), where severity was assessed by the attending physician as described above. The number of patients presenting with a > 30% and a > 50% decrease of their disease activity was also assessed. The number of fistulas and nodules per involved region and per patient were counted and summarized with the median and 95% confidence intervals (CI). Differences of disease activity, of VAS and of number of lesions during each visit, compared with baseline, were evaluated by Wilcoxon s ranked sum test. Any value of P < 0Æ05 was considered as significant. The severity of the disease was also assessed both for the baseline visits and for the follow-up visits according to the following scoring system proposed by Sartorius et al.: 8 (i) anatomical region involved (left and or right axilla, groin, gluteal, inframammary or other region: 3 points per region involved); (ii) number and scores of lesions (points per lesion of each region involved: deep ulcers 16; fistulas 4; nodules 2; scars 1); (iii) the longest distance between two relevant lesions in each region, or size if there was only one lesion (< 5 cm 2; 5 10 cm 4; > 10 cm 8); (iv) clear separation of lesions from adjacent normal skin (yes 0; no 6). The sum of scores per region involved represented the score of each assessment. Differences compared with baseline were evaluated with Wilcoxon s ranked sum test (P <0Æ05). The number of patients with a > 30% and a > 50% decrease of their disease activity was also calculated. Disease activity, the number of fistulas and the scoring system defined above at each visit were correlated by the Spearman s rank order correlation coefficient (P < 0Æ05).

3 Etanercept in hidradenitis suppurativa, E.J. Giamarellos-Bourboulis et al. 3 At baseline and at week 24, subpopulations of lymphocytes were estimated. Three millilitres of blood were drawn with a heparinized syringe from each patient after venepuncture of a peripheral vein under sterile conditions and collected into a heparin-coated tube (Becton Dickinson, Cockeysville, MD, U.S.A.). Red blood cells were lysed with ammonium chloride 1Æ0 mmol L )1. White blood cells were washed three times with phosphate-buffered saline (PBS) (ph 7Æ2) (Merck, Darmstadt, Germany) and subsequently incubated for 15 min in the dark with the monoclonal antibodies anti-cd3 and anti-cd19 at the fluorocolour fluorescein isothiocyanate (emission 520 nm, Immunotech, Marseille, France) and with the monoclonal antibodies anti-cd4, anti-cd8 and anti- CD( ) at the fluorocolour phycoerythrin (emission 550 nm, Immunotech). The following combinations were applied: anti-cd3 anti-cd4, anti-cd3 anti-cd8, anti-cd3 anti-cd( ); anti-cd19 was applied alone. Cells staining positive for the above antibodies were analysed after running through the EPICS XL MSL flow cytometer (Beckman Coulter Co., Miami, FL, U.S.A.) with gating for mononuclear cells. Any > 10% changes of CD3 CD4, CD3 CD8, CD3 CD( ) and CD19 lymphocytes and any > 30% changes of CD3( ) CD( )(+) cells, i.e. of NK cells, were reported as significant. Results The demographic characteristics of patients enrolled in the study, the number of their lesions and their affected skin areas are given in Table 1. Changes of disease activity over the 12- week treatment period as well as at week 24 for each of the enrolled patients are shown in Table 2. A > 30% decrease of disease activity was found in six patients at week 4; in seven patients at week 8; in eight patients at week 12; and in eight patients at week 24. A > 50% decrease of disease activity was found in six patients at week 12 and in seven patients at week 24 (Table 2). Statistically significant differences were found between baseline and week 4 (P = 0Æ005); between baseline and week 8 (P =0Æ005); between baseline and week 12 (P =0Æ005); and between baseline and week 24 (P =0Æ009). Changes of VAS during therapy and at follow-up for each of the enrolled patients are shown in Table 3. The VAS was decreased compared with baseline in five patients at week 4, in eight patients at week 8, in seven patients at week 12 and in six patients at week 24. The differences compared with baseline were significant between baseline and week 8 (P =0Æ019); between baseline and week 12 (P =0Æ024); and between baseline and week 24 (P = 0Æ042). All patients reported a decrease of local pain at the site of lesions as early as the first month of therapy. The first eight patients reported a recurrence of drainage of pus from the affected areas within 4 8 weeks after the end of administration of etanercept (median period for relapse 4 weeks; 75% percentile 5Æ5 weeks). Changes of the scoring system proposed by Sartorius et al. 8 over the 12-week treatment period as well as at week 24 for each of the enrolled patients are shown in Table 4. A > 30% decrease of that score was found in six patients at week 4; in six patients at week 8; in all patients at week 12; and in eight patients at week 24. A > 50% decrease of that score was found in one patient at week 4; in four patients at week 8; in six patients at week 12; and in seven patients at week 24 (Table 4). Statistically significant differences were found between baseline and week 4 (P = 0Æ005); between baseline and week 8 (P =0Æ005); between baseline and week 12 (P =0Æ005); and between baseline and week 24 (P =0Æ005). The change in the number of fistulas and nodules of patients over treatment is shown in Fig. 1. Statistically significant Table 1 Demographic characteristics of ten patients with hidradenitis suppurativa enrolled in the study Patient Sex (M F) Age (years) Years since diagnosis Number of skin lesions Involved skin areas 1 F Both axillae, both submammary areas, sternum, both inguinal folds 2 M Left axilla, right inguinal fold, hypogastric area, scrotum, perianal area 3 F Right axilla, both inguinal folds, hypogastric area 4 M Both gluteal areas 5 M Both axilla, both inguinal folds, both gluteal areas, scrotum, hypogastric area 6 F Pubes, right inner femoral area 7 F Both axillae, both inguinal folds, both gluteal areas, both submammary folds 8 F Both axillae, both inguinal folds, right gluteal area 9 F Both axillae, both inner femoral areas, left inguinal fold 10 F Both axillae, left gluteal area, left inguinal fold, both submammary folds, both inner femoral areas

4 4 Etanercept in hidradenitis suppurativa, E.J. Giamarellos-Bourboulis et al. Table 2 Disease activity score over follow-up for each of 10 patients administered etanercept for 12 weeks for the treatment of hidradenitis suppurativa Patient Baseline Week 4 Week 8 Week 12 Week Æ0 756Æ0 2515Æ0 842Æ0 604Æ Æ0 2200Æ0 146Æ0 108Æ0 72Æ Æ0 2236Æ0 1524Æ0 1424Æ0 1068Æ Æ0 540Æ0 159Æ0 100Æ8 76Æ Æ0 1401Æ0 1683Æ8 1355Æ5 634Æ Æ0 800Æ0 838Æ0 1072Æ0 800Æ Æ0 1562Æ8 1829Æ5 1417Æ Æ Æ0 388Æ8 198Æ5 171Æ5 170Æ Æ0 486Æ0 369Æ0 246Æ0 244Æ Æ0 7832Æ0 7614Æ0 7032Æ5 7671Æ0 Table 3 Changes in visual analogue scale (VAS) over follow-up of 10 patients given etanercept for 12 weeks for the treatment of hidradenitis suppurativa (cm) Patient Baseline Week 4 Week 8 Week 12 Week Æ0 5Æ0 3Æ0 4Æ0 4Æ5 2 8Æ0 5Æ0 3Æ0 3Æ0 3Æ0 3 10Æ0 9Æ0 9Æ0 8Æ0 3Æ0 4 4Æ0 4Æ0 3Æ0 4Æ0 4Æ0 5 10Æ0 8Æ0 6Æ0 4Æ0 5Æ0 6 8Æ0 6Æ0 9Æ0 9Æ0 6Æ5 7 7Æ0 7Æ0 6Æ0 6Æ0 7Æ0 8 10Æ0 10Æ0 8Æ0 6Æ0 8Æ0 9 8Æ0 5Æ0 5Æ0 5Æ0 4Æ0 10 6Æ0 6Æ0 6Æ0 5Æ0 7Æ5 Table 4 Assessment of the efficacy of etanercept administered for 12 weeks to each of 10 patients with hidradenitis suppurativa according to the scoring system proposed by Sartorius et al. 8 Patient Baseline Week 4 Week 8 Week 12 Week differences in the number of fistulas compared with baseline were found over all weeks of follow-up. No differences were found involving the number of nodules. At baseline a positive correlation was found between disease activity and the number of fistulas (r s ; +0Æ657, P =0Æ039); between disease activity and the scoring system (r s :+0Æ643, P =0Æ048) and between the scoring system and the number of fistulas (r s : +0Æ979, Fig 1. Changes in the number of fistulas and nodules over follow-up of 10 patients given etanercept for 12 weeks for therapy of hidradenitis suppurativa. a P =0Æ015 compared to baseline; b P =0Æ005 compared to baseline. P <0Æ0001). Similar correlations at week 4 were found between disease activity and scoring system (r s : +0Æ770, P =0Æ009) and between scoring system and the number of fistulas. Similar correlations at week 8 were found only between the scoring system and the number of fistulas (r s : +0Æ845, P =0Æ002). At week 12, positive correlations were found between disease activity and the number of fistulas (r s :+0Æ732, P =0Æ016); between disease activity and scoring system (r s : +0Æ682, P =0Æ008); and between scoring system and the number of fistulas (r s : +0Æ884, P =0Æ001). At week 24 positive correlations were found between disease activity and the number of fistulas (r s :+0Æ663, P =0Æ037); between disease activity and scoring system (r s : +0Æ758, P =0Æ011); and between scoring system and the number of fistulas (r s :+0Æ912, P <0Æ0001). No serious adverse events were observed; three patients presented self-limited redness at the injection site. Patient 4 presented with an abscess of the right gluteal area within 6 weeks after discontinuing etanercept; it was treated by surgical incision and oral administration of amoxicillin clavulanate 1 g every 6 h for 10 days, and resolved. No other infectious complication was observed. In patients 2, 3, 6, 7 and 9 the percentage of CD3 CD4 lymphocytes was increased > 10% of the baseline value at week 24. In patients 4, 6, 7, 8, 9 and 10 the percentage of NK cells, i.e. of CD3( ) CD( ) cells decreased to > 30% of their baseline values at week 24. CD19 cells remained unaltered.

5 Etanercept in hidradenitis suppurativa, E.J. Giamarellos-Bourboulis et al. 5 Discussion The results of this prospective open-label phase II study in hidradenitis suppurativa revealed that the administration of etanercept resulted in considerable benefit to all 10 patients. This group was representative of the disease population since it comprised patients whose disease started early after puberty and was of considerable extent (Table 1). Etanercept was welltolerated. This is not the first study of the beneficial effect of agents blocking TNF-a in hidradenitis suppurativa. Former casereport studies enrolled a smaller number of patients. In one study infliximab was administered in five patients 3 and in another, etanercept was given in six patients. 4 The dose and duration of treatment was not a standardized one and was dependent on the response of the patient. The dose of etanercept administered in the latter study was either 50 mg once weekly or 50 mg twice weekly. 4 The efficacy of treatment was evaluated either by a VAS or by the Dermatology Life Quality Index (DLQI). Although these scales may show whether treatment brings any benefit to the patient, they are based on his self-opinion. In the present study, evaluation of the efficacy of etanercept was based on changes in disease activity. The latter was defined by consecutive measurements of the extent of the involved surface area as modified by the severity of the inflammation according to the judgment of the attending physician who was unaware of the protocol. There is no doubt that complete avoidance of bias cannot be achieved when the study is open-label with one arm of intervention. However, disease activity was positively correlated with the scoring system proposed by Sartorius et al., 8 proving that the best possible was done in order to keep the attending physician unaware of the protocol. Despite the existing differences between the design of our study and those of other investigators, the findings are in agreement. Despite the demonstrated decrease in disease activity and VAS scale in all patients within the first 4 months of treatment with etanercept (Tables 2 and 3), considerable benefit might be considered only for those presenting with a > 50% decrease of the baseline disease activity. This was achieved in seven of the 10 patients by 12 weeks after the end of treatment, i.e. 6 months after initiation of treatment. That goal was achieved even when disease severity was assessed by the scoring system proposed by Sartorius et al. 8 (Table 4). Most patients reported relapse of their disorder within 4 8 weeks of discontinuing therapy. However, even in a state of relapse, their disease activity 12 weeks after stopping etanercept remained below 50% of baseline. That observation might reduce the need for prolongation of therapy to longer than 12 weeks. Cusack and Buckley 4 administered etanercept to all their six patients for a period ranging between 16 and 33 weeks whereas in a recent case report of one patient successfully treated with infliximab, duration of therapy was 104 weeks. 9 Standard treatment for hidradenitis suppurativa was until now based on its understanding by the physician as either an infectious process or as a form of acne. 10 Only three randomized clinical trials have been published with a limited number of patients enrolled in each one. The first trial comprised a total of 27 patients and showed that topical clindamycin for 3 months was effective in the reduction of the number of nodules and abscesses. 11 The activity of topical clindamycin proved to be similar to that of oral tetracycline in a later trial enrolling 46 patients. 12 In another trial in 24 women, administration of androgens achieved disease remission in seven patients. 13 All three trials have enrolled patients with less severe disease than those of the present study. As a consequence, anti-tnf therapies like etanercept might offer a new strategy for hidradenitis suppurativa. Their use should however be viewed with scepticism until the results of large randomized, placebo-controlled trials have been published. The mechanism of action of etanercept might be based on the improvement of the immune function of the host. A former study by our group showed that the immune response of patients with hidradenitis suppurativa is characterized by lower CD4 lymphocytes and increased NK cells compared with those of healthy volunteers. 2 Other investigators revealed that severe hidradenitis suppurativa is seen with a marked reduction of T lymphocytes. 14 In the present study, administration of etanercept was accompanied by a > 10% increase of CD4 lymphocytes in five patients of 10 and a > 30% drop of NK cells in six of 10 patients. However these observations do not allow us to conclude that etanercept reversed the alterations of the immune responses occurring in hidradenitis suppurativa, as no comparative group was used. Results of the present prospective open-label phase II trial suggest that etanercept is a safe and effective therapy for hidradenitis suppurativa, decreasing the extent of the disease and improving the quality of life. These results in combination with those of former case studies that showed an improvement of patients with the application of TNF-a-targeted therapy, mandate the need for a double-blind, placebo-controlled trial to fully elucidate the exact role of etanercept in the management of hidradenitis suppurativa. References 1 Slade DEM, Powell BW, Mortimer PS. Hidradenitis suppurativa: pathogenesis and management. Br J Plast Surg 2003; 56: Giamarellos-Bourboulis EJ, Antonopoulou A, Petropoulou C et al. Altered innate and adaptive immune responses in patients with hidradenitis suppurativa. Br J Dermatol 2007; 156: Sullivan TP, Welsh E, Kerdel FA et al. Infliximab for hidradenitis suppurativa. Br J Dermatol 2003; 149: Cusack C, Buckley C. Etanercept: effective in the management of hidradenitis suppurativa. Br J Dermatol 2006; 154: Wiseman MC. Hidradenitis suppurativa: a review. Dermatol Ther 2004; 17: Shah N. Hidradenitis suppurativa: a treatment challenge. Am Fam Physician 2005; 1554: Leonardi CL, Powers JL, Matheson RT et al. Etanercept as monotherapy in patients with psoriasis. N Engl J Med 2003; 349:

6 6 Etanercept in hidradenitis suppurativa, E.J. Giamarellos-Bourboulis et al. 8 Sartorius K, Lapins J, Emstestam L, Jemec GBE. Suggestions for uniform outcome variables when reporting treatment effects in hidradenitis suppurativa. Br J Dermatol 2003; 149: Thielen AM, Barde C, Saurat JH. Long-term infliximab for severe hidradenitis suppurativa. Br J Dermatol 2006; 154: Jemec GB. Medical treatment of hidradenitis suppurativa. Expert Opin Pharmacother 2004; 5: Clemmensen OJ. Topical treatment of hidradenitis suppurativa with clindamycin. Int J Dermatol 1983; 22: Jemec GB, Wendelboe P. Topical clindamycin versus systemic tetracycline in the treatment of hidradenitis suppurativa. J Am Acad Dermatol 1998; 39: Mortimer PS, Dawber RP, Gales MA, Moore RA. A double-blind controlled cross-over trial of cyproterone acetate in females with hidradenitis suppurativa. Br J Dermatol 1986; 115: O Loughlin S, Woods R, Kirke PN et al. Hidradenitis suppurativa. Glucose tolerance, clinical microbiologic, and immunologic features and HLA frequencies in 27 patients. Arch Dermatol 1988; 124: