JEADV
DOI: 10.1111/jdv.12438
ORIGINAL ARTICLE
Use of biological treatments in patients with hidradenitis suppurativa ,2 M. Ferran,1 M. Sa nchez-Regan ~a,3 G. Martin-Ezquerra,1,*,† E. Masferrer,1,† M. Masferrer-Niubo 3 4 4 5 6 7 8 H. Collgros, X. Bordas, J. Notario, M. Alsina, I. Gil, N. Izquierdo, G. Aparicio, J. Mollet,8 V. Garcia-Patos,8 R.M. Pujol1 1
Dermatology Department, Hospital del Mar, Barcelona, n a Distancia UNED, Barcelona, Mathematic Department, Universidad Nacional de Educacio 3 Dermatology Department, Hospital Sagrat Cor, Barcelona, 4 Dermatology Department, Hospital de Bellvitge, Barcelona, 5 Dermatology Department, Hospital Clınic, Barcelona, 6 Dermatology Department, Hospital Sant Joan de Reus, Reus, 7 Dermatology Department, Hospital Son Espases, Palma de Mallorca, 8 Dermatology Department, Hospital de la Vall d ‘Hebron, Barcelona, Spain *Correspondence: G. Martin-Ezquerra. E-mail: [email protected] 2
Abstract Introduction Hidradenitis suppurativa (HS) is a chronic skin disease which causes a great impact in the quality of life. Multiple therapeutic options have been proposed, and recently the potential use of biological drugs in severe cases has been postulated. Material and Methods A retrospective study from seven tertiary Spanish centers reviewing the charts of patients with HS treated with biological drugs was performed. Retrieved information included epidemiological data, clinical features, pain intensity, Hurley stage, laboratory data and therapeutic outcomes. Results Nineteen patients were included in the study; 10 men (52.6%) and 9 women. Eight patients (42%) showed a Hurley severity stage II and 11 a stage III (57.8%). Adalimumab was prescribed as the first biological treatment in nine out of 19 cases (47.3%), whereas infliximab was prescribed in seven cases (36.8%), ustekinumab in two cases (10.5%) and etanercept in one (5.2%). A complete response was observed in three patients (two cases with infliximab and one case with ustekinumab), a partial improvement in 10 patients and in six patients no clinical improvement was noted. One patient referred worsening of the skin symptoms. In 6 cases, a second biological treatment was prescribed. In three of such cases, a partial improvement was noted, whereas in three cases no clinical improvement was observed. In two cases a switch to a third biological drug was indicated, with a partial improvement in one case. Discussion and Conclusions Biological drugs could be a potential and effective therapeutic option for patients with severe HS. Complete and persistent clinical responses are rarely obtained (15%) and partial responses are achieved in approximately 50% of patients. No specific markers for a therapeutic response have been identified. No definitive conclusions regarding the most effective biological drug for HS could be drawn. Higher dosage schedules seem to be associated with higher response rates. The lack of response of one particular drug does not preclude a potential efficacy to another biological treatment. Received: 4 December 2013; Accepted: 31 January 2014
Conflicts of interest E. Masferre has been reimbursed by Abbvie for international conference attendance. V. Garcia-Patos has been participated in clinical trials has served as consultants speaker's fees or funding to attend training events from Abbvie, Jansen, and Pfizer. J. Notario has participated in clinical trials and has received consultancy and speaking fees for activities funded by Abbott, Jansen, and Pzifer. M. Ferran has been reimbursed by MSD, Abbvie and Jansen for international conference attendance, conferences and consultant. X. Bordas has been reimbursed by Abbvie, Pfizer, Novartis and Jansen for international conference attendance or advisory boards. H. Collgros has been reimbursed by Abbvie and Jansen for national and international conference attendance. J. Mollet and M. Alsina has been reimbursed by Abbvie, Jansen , MSD and Pfizer for international conference attendance. G. Aparicio has been reimbursed by Abbvie, Jansen and Pfizer for
JEADV 2015, 29, 56–60
© 2014 European Academy of Dermatology and Venereology
Use of biologics in hidradenitis suppurativa
57
nchez-Regan ~a has been reimbursed by Abbvie, MSD and Jansen for internainternational conference attendance. M. Sa tional conference attendance.
Funding sources None declared.
Introduction Hidradenitis suppurativa (HS) is a chronic disease characterized by the appearance of painful and recurrent cutaneous nodules and abscesses localized mainly in armpits, groins and genital area.1 Lesions tend to evolve to hypertrophic scars and fistulas, with a great impact in the quality of life of the patient.2 The aetiology and the pathogeny of the illness remain to be elucidated. Occlusion of the pilosebaceous units leads to a follicular rupture, abscess formation and a subsequential sinus tracts generation.3 Clinical manifestations typically appear at young ages, with a peak of incidence in the third decade of life.4,5 Women have a higher incidence than men (3 : 1) and tend to have more lesions in the genital area.5 The prevalence of the disease tends to decrease in the fifth decade.5 Smoking and overweight have been described as risk factors and are directly related to the severity of the disease.6 HS may be associated with severe acne, dissecting cellulitis of the scalp and pilonidal disease. The association with inflammatory bowel disease has been reported in the 16% of cases.5–7 Multiple therapeutic options have been proposed for HS with variable success.1 The combination of systemic antibiotics and drainage of the lesions might be the first-line treatment. Other options include systemic steroids, antiandrogens, retinoids and immunosuppressive drugs. Excision of the affected areas, surgically or with CO2 laser, has also been postulated. Recent reports describe the efficacy of biological treatments achieving remission in cases of HS.8,9
Material and methods Patients diagnosed of HS treated with at least one biological drug throughout the evolution of the disease were included in the study. Databases from seven Spanish tertiary Hospitals were reviewed from November 2011 to December 2012. Retrieved data included gender, age at diagnosis, Body Mass Index (BMI), smoking habit, co-morbidities, previous treatments and acute or chronic complications derived from the disease itself or the therapy. The severity of the disease was scored using the Hurley scale,1 before the initiation of the biological drug and after 3 and 6 months. Response to the biological treatment was assessed by a scale with the items of ‘full response’, ‘partial response’, ‘no response’ †
These two authors contributed of equal form in the elaboration of the work.
JEADV 2015, 29, 56–60
and ‘worsening’ (answered by both the physician and the patient). Pain was also assessed before and after treatment according to the visual analog scale of pain intensity (VAS). This study was approved by the local ethics committees and was conducted in compliance with the protocol of Good Clinical Practices and Declaration of Helsinki principles. A statistical hypothesis testing using as estimator Mann– Whitney U Test was used to analyze differences between sample groups. The statistical analysis was performed with SPSS 19.0 (SPSS Inc. Chicago, IL, USA). A P ≤ 0.05 was considered as statistically significant.
Results General features
Nineteen patients (ten men and nine women) with an average age at diagnosis of 24 years (SD 8.8) were included in the study. Fifteen patients (78.9%) were current or former smokers. Seven patients (36.8%) were obese and the mean BMI was 29.5 kg/m2 (SD 7.73). The majority of the included patients had other concomitant illnesses: plaque-type psoriasis (three patients), pilonidal cysts (in two), rheumatoid arthritis (in two), spondyloarthropathy (one case), Still disease (one case) and SAPHO syndrome (one case). All patients were previously treated with different therapeutic strategies including wide spectrum antibiotics, oral retinoids (isotretinoin, acitretin), finasteride, zinc gluconate, cyclosporin A, colchicine, dapsone, oral and/or intralesional corticosteroids. All patients had required at least one surgical procedure. Before the initiation of the biological treatment, eight cases (42%) were in Hurley stage II and eleven cases (57.8%) in stage III. All patients referred having pain previously to the biological treatment in an average of 7.3 points (VAS scale). The mean levels of serum C-reactive protein (RCP) at the beginning of the biological treatment was of 3.54 mg/L (SD 5.04). Before starting the biological treatment, all patients had a baseline laboratory evaluation in the form of complete blood cell count, liver function test, blood urea nitrogen, serum creatinine level, chest X-ray and tuberculin skin sensitivity test (purified protein derivative). If a patient had a strong positive skin test, an abnormal chest X-ray or any risk factors, such as a family history of tuberculosis, isoniazid was administered with the biological drug.
© 2014 European Academy of Dermatology and Venereology
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0/1 (0%) 1/1 (100%) 1/1 (100%) 0/1 (0%) 0/1 (0%) 0/1 (0%)
0/2 (0%)
1/19 (5.55%) Etanercept
*One case was not assessed due to having a severe reaction after the first infusion.
0/1 (0%) 0/1 (0%)
1/6 (16%)
2/19 (11.1%) Ustekinumab
8
0/2 (0%) 0/2 (0%) 0/2 (0%) 1/2 (50%) 1/2 (50%) 1/2 (50%) 1/2 (50%) 1/2 (50%)
0/8 (0%)
7/19 (38.8%)*
18
1/6 (16%) 1/6 (16%) 0/6 (0%) 0/6 (0%) 3/6 (50%) 4/6 (66%) 2/6 (33%) 3/7 (42%)*
Patient
Infliximab
13
0/8 (0%)
Doctor Patient
2/9 (22%) 3/9 (33%)
Doctor Patient
5/9 (55%) 6/9 (66%)
Doctor Patient
2/9 (22%)
Doctor
0/9 (0%) 5/9 (55%) 9/19 (47.3%) Adalimumab
9
Worsening Ineffective Partial improvement Complete response Not discontin-ued Time kept on drug (mean in months)
HS is a disease with a great impact on the quality of life of the patients2 with no specific and effective treatment.8 The role of TNF-alpha in HS has been previously studied since reports showed that TNF-alpha inhibitors could be useful in its treatment. Serum TNF-alpha levels are higher in patients with HS when compared with healthy controls11 as well as levels in lesional and perilesional skin.12,13 In our series, biological drugs are indicated in cases of severe disease. The definition of severe HS includes: high Hurley stage, multiple lesions, severe pain and concomitant comorbidities. In previously published studies, biological
N
Discussion and conclusions
First Biological tested
The first biological drug of choice was adalimumab in nine out of 19 cases (47.3%), infliximab in seven cases (36.8%), ustekinumab in two cases (10.5%) and etanercept in one case (5.2%). The prescribed dosage was in the range recommended by the current European Guidelines of Psoriasis.10 Twelve patients received concomitant antibiotic therapy during the biological treatment. A complete response was observed in three patients (15.7%) (two cases treated with infliximab and one with ustekinumab). Ten patients (55%) (four men and six women) achieved a partial improvement (Fig. 1). No clinical improvement was noted in four cases and a worsening of the skin symptoms was observed in one patient. One patient presented a severe infusional reaction in the first dose of infliximab leading to withdrawal of the treatment (Table 1). No significant differences between physician and patients severity assessment were noted but patients had a tendency to refer a mild high efficacy (Table 1). The mean duration of the biological treatment was 12 months, with a range from 4 to 32 months. The first line biological treatment reduced pain in 3.27 points (SD 2.76) of the VAS scale (data of fifteen patients). The average pain reduction was 6.5 in women and 1.4 in men (P = 0.006). The media of RCP after 3 months of biological treatment was 1.5 mg/L (SD 0.40). Treatment withdrawal were due to inefficacy in controlling the concomitant skin or rheumatologic disease, even though it was effective for HS (two cases), severe side-effects (severe infusional reaction and hypertriglyceridemia) (two cases) or lack of clinical response (four cases). Due to lack of efficacy six cases switched to a second biological treatment: adalimumab in three patients (previously treated with infliximab (two cases) and etanercept (one case) (Table 2). Treatment duration ranged from 5 to 41 months (mean: 14 months). No clinical response was observed in three cases, whereas a partial improvement was observed in other three cases. Two cases switched to a third biological drug; one case to adalimumab (for 4 months) and another to infliximab (for 12 months); in both cases, a partial improvement was achieved.
Table 1 Biological treatments tested as first-line treatment. Response to the biological treatment was assessed using a scale with the items of ‘full response’, ‘partial response’, ‘no response’ and ‘worsening’ answered by both the physician and the patient
Use of biological drugs and response to treatment
0/1 (0%)
Martin-Ezquerra et al.
58
© 2014 European Academy of Dermatology and Venereology
Use of biologics in hidradenitis suppurativa
59
(a)
(b)
(c)
(d)
Figure 1 45 year-old female patient with Hurely II HS, before adalimumab treatment (a and b) and 6 months after beginning the drug 4 (c and d). Note the reduction in inflammatory signs.
Table 2 Biological treatments tested as second-line treatment Second Biological tested
N
Complete response
Partial improvement
Ineffective
Worsening
Adalimumab
3/6 (50%)
0/3 (0%)
1/3 (33.3%)
2/3 (66.6%)
0/3 (0%)
Infliximab
1/6 (38.8%)
0/1 (0%)
1/1 (100%)
0/1 (0%)
0/1 (0%)
Ustekinumab
1/6 (11.1%)
0/1 (0%)
1/1 (100%)
0/1 (0%)
0/1 (0%)
Etanercept
1/6 (11.1%)
0/1 (0%)
0/1 (0%)
1/1 (100%)
0/1 (0%)
drugs were also left as a last resort.1,8 However, early administration could avoid the appearance of scars. In our series, all patients had been previously treated with multiple courses of antibiotics, alone or in combination with extensive debridements. Over half of the patients had been treated with retinoids, immunosuppressants, finasteride or colchicine. Biological treatment was indicated when other treatment options had failed. The best biological drug and its dosage for the treatment of HS are not known. In our series, in cases of concomitant disease (psoriasis and other rheumatological diseases), the drug chosen
JEADV 2015, 29, 56–60
was the one recommended by the accepted clinical guidelines for the underlying disease. In patients without any concomitant disease, the used dosage was the recommended by in the European Guidelines for Psoriasis.10 Higher doses could be associated with a higher response rate and several authors have suggested that biological drugs in HS treatment should be used with higher doses than those applied to psoriasis.14 Studies between different biological drugs for HS are lacking,8,9 and there is no agreement on the first-line biological drug but it seems that etanercept would be the less effective.15 In our series, the only case treated with etanercept did not improve. It is also interesting to remark
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that in this series, the lack of efficacy of one particular drug does not seem to predict a further response to other biological drug. The response to the treatment is variable.16–19 In our series, physician assessment of clinical response was in the majority of cases a ‘partial improvement’ and in three out of nineteen a ‘complete response’ was assessed. In one case, worsening of the skin symptoms was observed. In some isolated cases this phenomenon on has been previously reported and cases of worsening or de novo appearance of psoriasis during biological treatments have been described.20,21 Pain reduction measured by VAS was significantly achieved and was much more significant in women. Female patients with severe pain associated to a HS may benefit from these treatments. Inflammatory markers like erythrocyte sedimentation rate and C-reactive protein are elevated in patients with HS and decrease during the biological treatment.22 Twelve patients received concomitantly antibiotic treatment. This group did not show better outcomes than patients who were not treated with antibiotics. No patient developed associated infectious complications, so the use of concomitant antibiotics might be unnecessary. The use of concomitant antibiotics was previously associated with a better response,16 this data could not be observed in our cases. Safety is always a concern when using biological therapies. We found a safe short-term profile. In our study, two patients developed adverse effects, which required discontinuation of the treatment. The new-onset of polyarthritis during the treatment of HS with infliximab has been described.23 There are several limitations in our study due to its retrospective nature and the involvement of multiple centres. The evaluation of clinical manifestations and treatment decisions were dependent on the physician, making direct comparisons difficult. The clinical features leading to the use of biological drugs in the current series of patients with HS were heterogeneous and the number of patients included was limited. These facts make it difficult to draw firm conclusions. In conclusion, biological treatments seem to be a useful and effective therapeutic option for severe cases of HS. The complete response is uncommon and partial responses are more frequent. The lack of response of one particular drug does not preclude a potential efficacy to another biological treatment. Further investigation involving biological and standard immunosuppressive drugs should be evaluated in properly designed randomized clinical trials.
References 1 Jemec GB. Clinical practice. Hidradenitis suppurativa. N Engl J Med 2012; 366: 158–164. 2 Matusiak Ł, Bieniek A, Szepietowski JC. Hidradenitis suppurativa markedly decreases quality of life and professional activity. J Am Acad Dermatol 2010; 62: 706–708. 3 Yu CC, Cook MG. Hidradenitis suppurativa: a disease of follicular epithelium, rather than apocrine glands. Br J Dermatol 1990; 122: 763–769.
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Martin-Ezquerra et al.
4 Vazquez BG, Alikhan A, Weaver AL, Wetter DA, Davis MD. Incidence of hidradenitis suppurativa and associated factors: a population-based study of Olmsted County, Minnesota. J Invest Dermatol 2013; 133: 97–103. 5 Revuz JE, Canoui-Poitrine F, Wolkenstein P et al. Prevalence and factors associated with hidradenitis suppurativa: results from two case-control studies. J Am Acad Dermatol 2008; 59: 596–601. 6 Sartorius K, Emtestam L, Jemec GB, Lapins J. Objective scoring of hidradenitis suppurativa reflecting the role of tobacco smoking and obesity. Br J Dermatol 2009; 161: 831–839. 7 van der Zee HH, van der Woude CJ, Florencia EF, Prens EP. Hidradenitis suppurativa and inflammatory bowel disease: are they associated? Results of a pilot study. Br J Dermatol 2010; 162: 195–197. 8 Rambhatla PV, Lim HW, Hamzavi I. A systematic review of treatments for hidradenitis suppurativa. Arch Dermatol 2012; 148: 439–446. 9 Alikhan A, Lynch PJ, Eisen DB. Hidradenitis suppurativa: a comprehensive review. J Am Acad Dermatol 2009; 60: 539–561. 10 Pathirana D, Ormerod AD, Saiag P et al. European S3-guidelines on the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol Venereol 2009; 23(Suppl 2): 1–70. 11 Matusiak L, Bieniek A, Szepietowski JC. Increased serum tumour necrosis factor-alpha in hidradenitis suppurativa patients: is there a basis for treatment with anti-tumour necrosis factor-alpha agents? Acta Derm Venereol 2009; 89: 601–603. 12 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: 51–56. 13 Mozeika E, Pilmane M, N€ urnberg BM, Jemec GB. Tumour necrosis factor-alpha and matrix metalloproteinase-2 are expressed strongly in hidradenitis suppurativa. Acta Derm Venereol 2013; 93: 301–304. 14 Kimball AB, Kerdel F, Adams D et al. Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012; 157: 846–855. 15 Adams DR, Yankura JA, Fogelberg AC, Anderson BE. Treatment of hidradenitis suppurativa with etanercept injection. Arch Dermatol 2010; 146: 501–504. 16 Miller I, Lynggaard CD, Lophaven S, Zachariae C, Dufour DN, Jemec GB. A double-blind placebo-controlled randomized trial of adalimumab in the treatment of hidradenitis suppurativa. Br J Dermatol 2011; 165: 391– 398. 17 Blanco R, Martınez-Taboada VM, Villa I et al. Long-term successful adalimumab therapy in severe hidradenitis suppurativa. Arch Dermatol 2009; 145: 580–584. 18 Amano M, Grant A, Kerdel FA. A prospective open-label clinical trial of adalimumab for the treatment of hidradenitis suppurativa. Int J Dermatol 2010; 49: 950–955. 19 Machet L, Samimi M, Delage M, Paintaud G, Maruani A. Systematic review of the efficacy and adverse events associated with infliximab treatment of hidradenitis suppurativa in patients with coexistent inflammatory diseases. J Am Acad Dermatol 2013; 69: 649–650. 20 Laga AC, Vleugels RA, Qureshi AA, Velazquez EF. Histopathologic spectrum of psoriasiform skin reactions associated with tumor necrosis factor-a inhibitor therapy. A study of 16 biopsies. Am J Dermatopathol 2010; 32: 568–573. 21 Bremmer M, Deng A, Gaspari AA. A mechanism-based classification of dermatologic reactions to biologic agents used in the treatment of cutaneous disease: Part 2. Dermatitis 2009; 20: 243–256. 22 Grant A, Gonzalez T, Montgomery MO, Cardenas V, Kerdel FA. Infliximab therapy for patients with moderate to severe hidradenitis suppurativa: a randomized, double-blind, placebo-controlled crossover trial. J Am Acad Dermatol 2010; 62: 205–217. 23 van Rappard DC, Limpens J, Mekkes JR. The off-label treatment of severe hidradenitis suppurativa with TNF-a inhibitors: a systematic review. J Dermatolog Treat 2013; 24: 392–404.
© 2014 European Academy of Dermatology and Venereology
DOI: 10.1111/jdv.12438
ORIGINAL ARTICLE
Use of biological treatments in patients with hidradenitis suppurativa ,2 M. Ferran,1 M. Sa nchez-Regan ~a,3 G. Martin-Ezquerra,1,*,† E. Masferrer,1,† M. Masferrer-Niubo 3 4 4 5 6 7 8 H. Collgros, X. Bordas, J. Notario, M. Alsina, I. Gil, N. Izquierdo, G. Aparicio, J. Mollet,8 V. Garcia-Patos,8 R.M. Pujol1 1
Dermatology Department, Hospital del Mar, Barcelona, n a Distancia UNED, Barcelona, Mathematic Department, Universidad Nacional de Educacio 3 Dermatology Department, Hospital Sagrat Cor, Barcelona, 4 Dermatology Department, Hospital de Bellvitge, Barcelona, 5 Dermatology Department, Hospital Clınic, Barcelona, 6 Dermatology Department, Hospital Sant Joan de Reus, Reus, 7 Dermatology Department, Hospital Son Espases, Palma de Mallorca, 8 Dermatology Department, Hospital de la Vall d ‘Hebron, Barcelona, Spain *Correspondence: G. Martin-Ezquerra. E-mail: [email protected] 2
Abstract Introduction Hidradenitis suppurativa (HS) is a chronic skin disease which causes a great impact in the quality of life. Multiple therapeutic options have been proposed, and recently the potential use of biological drugs in severe cases has been postulated. Material and Methods A retrospective study from seven tertiary Spanish centers reviewing the charts of patients with HS treated with biological drugs was performed. Retrieved information included epidemiological data, clinical features, pain intensity, Hurley stage, laboratory data and therapeutic outcomes. Results Nineteen patients were included in the study; 10 men (52.6%) and 9 women. Eight patients (42%) showed a Hurley severity stage II and 11 a stage III (57.8%). Adalimumab was prescribed as the first biological treatment in nine out of 19 cases (47.3%), whereas infliximab was prescribed in seven cases (36.8%), ustekinumab in two cases (10.5%) and etanercept in one (5.2%). A complete response was observed in three patients (two cases with infliximab and one case with ustekinumab), a partial improvement in 10 patients and in six patients no clinical improvement was noted. One patient referred worsening of the skin symptoms. In 6 cases, a second biological treatment was prescribed. In three of such cases, a partial improvement was noted, whereas in three cases no clinical improvement was observed. In two cases a switch to a third biological drug was indicated, with a partial improvement in one case. Discussion and Conclusions Biological drugs could be a potential and effective therapeutic option for patients with severe HS. Complete and persistent clinical responses are rarely obtained (15%) and partial responses are achieved in approximately 50% of patients. No specific markers for a therapeutic response have been identified. No definitive conclusions regarding the most effective biological drug for HS could be drawn. Higher dosage schedules seem to be associated with higher response rates. The lack of response of one particular drug does not preclude a potential efficacy to another biological treatment. Received: 4 December 2013; Accepted: 31 January 2014
Conflicts of interest E. Masferre has been reimbursed by Abbvie for international conference attendance. V. Garcia-Patos has been participated in clinical trials has served as consultants speaker's fees or funding to attend training events from Abbvie, Jansen, and Pfizer. J. Notario has participated in clinical trials and has received consultancy and speaking fees for activities funded by Abbott, Jansen, and Pzifer. M. Ferran has been reimbursed by MSD, Abbvie and Jansen for international conference attendance, conferences and consultant. X. Bordas has been reimbursed by Abbvie, Pfizer, Novartis and Jansen for international conference attendance or advisory boards. H. Collgros has been reimbursed by Abbvie and Jansen for national and international conference attendance. J. Mollet and M. Alsina has been reimbursed by Abbvie, Jansen , MSD and Pfizer for international conference attendance. G. Aparicio has been reimbursed by Abbvie, Jansen and Pfizer for
JEADV 2015, 29, 56–60
© 2014 European Academy of Dermatology and Venereology
Use of biologics in hidradenitis suppurativa
57
nchez-Regan ~a has been reimbursed by Abbvie, MSD and Jansen for internainternational conference attendance. M. Sa tional conference attendance.
Funding sources None declared.
Introduction Hidradenitis suppurativa (HS) is a chronic disease characterized by the appearance of painful and recurrent cutaneous nodules and abscesses localized mainly in armpits, groins and genital area.1 Lesions tend to evolve to hypertrophic scars and fistulas, with a great impact in the quality of life of the patient.2 The aetiology and the pathogeny of the illness remain to be elucidated. Occlusion of the pilosebaceous units leads to a follicular rupture, abscess formation and a subsequential sinus tracts generation.3 Clinical manifestations typically appear at young ages, with a peak of incidence in the third decade of life.4,5 Women have a higher incidence than men (3 : 1) and tend to have more lesions in the genital area.5 The prevalence of the disease tends to decrease in the fifth decade.5 Smoking and overweight have been described as risk factors and are directly related to the severity of the disease.6 HS may be associated with severe acne, dissecting cellulitis of the scalp and pilonidal disease. The association with inflammatory bowel disease has been reported in the 16% of cases.5–7 Multiple therapeutic options have been proposed for HS with variable success.1 The combination of systemic antibiotics and drainage of the lesions might be the first-line treatment. Other options include systemic steroids, antiandrogens, retinoids and immunosuppressive drugs. Excision of the affected areas, surgically or with CO2 laser, has also been postulated. Recent reports describe the efficacy of biological treatments achieving remission in cases of HS.8,9
Material and methods Patients diagnosed of HS treated with at least one biological drug throughout the evolution of the disease were included in the study. Databases from seven Spanish tertiary Hospitals were reviewed from November 2011 to December 2012. Retrieved data included gender, age at diagnosis, Body Mass Index (BMI), smoking habit, co-morbidities, previous treatments and acute or chronic complications derived from the disease itself or the therapy. The severity of the disease was scored using the Hurley scale,1 before the initiation of the biological drug and after 3 and 6 months. Response to the biological treatment was assessed by a scale with the items of ‘full response’, ‘partial response’, ‘no response’ †
These two authors contributed of equal form in the elaboration of the work.
JEADV 2015, 29, 56–60
and ‘worsening’ (answered by both the physician and the patient). Pain was also assessed before and after treatment according to the visual analog scale of pain intensity (VAS). This study was approved by the local ethics committees and was conducted in compliance with the protocol of Good Clinical Practices and Declaration of Helsinki principles. A statistical hypothesis testing using as estimator Mann– Whitney U Test was used to analyze differences between sample groups. The statistical analysis was performed with SPSS 19.0 (SPSS Inc. Chicago, IL, USA). A P ≤ 0.05 was considered as statistically significant.
Results General features
Nineteen patients (ten men and nine women) with an average age at diagnosis of 24 years (SD 8.8) were included in the study. Fifteen patients (78.9%) were current or former smokers. Seven patients (36.8%) were obese and the mean BMI was 29.5 kg/m2 (SD 7.73). The majority of the included patients had other concomitant illnesses: plaque-type psoriasis (three patients), pilonidal cysts (in two), rheumatoid arthritis (in two), spondyloarthropathy (one case), Still disease (one case) and SAPHO syndrome (one case). All patients were previously treated with different therapeutic strategies including wide spectrum antibiotics, oral retinoids (isotretinoin, acitretin), finasteride, zinc gluconate, cyclosporin A, colchicine, dapsone, oral and/or intralesional corticosteroids. All patients had required at least one surgical procedure. Before the initiation of the biological treatment, eight cases (42%) were in Hurley stage II and eleven cases (57.8%) in stage III. All patients referred having pain previously to the biological treatment in an average of 7.3 points (VAS scale). The mean levels of serum C-reactive protein (RCP) at the beginning of the biological treatment was of 3.54 mg/L (SD 5.04). Before starting the biological treatment, all patients had a baseline laboratory evaluation in the form of complete blood cell count, liver function test, blood urea nitrogen, serum creatinine level, chest X-ray and tuberculin skin sensitivity test (purified protein derivative). If a patient had a strong positive skin test, an abnormal chest X-ray or any risk factors, such as a family history of tuberculosis, isoniazid was administered with the biological drug.
© 2014 European Academy of Dermatology and Venereology
JEADV 2015, 29, 56–60
0/1 (0%) 1/1 (100%) 1/1 (100%) 0/1 (0%) 0/1 (0%) 0/1 (0%)
0/2 (0%)
1/19 (5.55%) Etanercept
*One case was not assessed due to having a severe reaction after the first infusion.
0/1 (0%) 0/1 (0%)
1/6 (16%)
2/19 (11.1%) Ustekinumab
8
0/2 (0%) 0/2 (0%) 0/2 (0%) 1/2 (50%) 1/2 (50%) 1/2 (50%) 1/2 (50%) 1/2 (50%)
0/8 (0%)
7/19 (38.8%)*
18
1/6 (16%) 1/6 (16%) 0/6 (0%) 0/6 (0%) 3/6 (50%) 4/6 (66%) 2/6 (33%) 3/7 (42%)*
Patient
Infliximab
13
0/8 (0%)
Doctor Patient
2/9 (22%) 3/9 (33%)
Doctor Patient
5/9 (55%) 6/9 (66%)
Doctor Patient
2/9 (22%)
Doctor
0/9 (0%) 5/9 (55%) 9/19 (47.3%) Adalimumab
9
Worsening Ineffective Partial improvement Complete response Not discontin-ued Time kept on drug (mean in months)
HS is a disease with a great impact on the quality of life of the patients2 with no specific and effective treatment.8 The role of TNF-alpha in HS has been previously studied since reports showed that TNF-alpha inhibitors could be useful in its treatment. Serum TNF-alpha levels are higher in patients with HS when compared with healthy controls11 as well as levels in lesional and perilesional skin.12,13 In our series, biological drugs are indicated in cases of severe disease. The definition of severe HS includes: high Hurley stage, multiple lesions, severe pain and concomitant comorbidities. In previously published studies, biological
N
Discussion and conclusions
First Biological tested
The first biological drug of choice was adalimumab in nine out of 19 cases (47.3%), infliximab in seven cases (36.8%), ustekinumab in two cases (10.5%) and etanercept in one case (5.2%). The prescribed dosage was in the range recommended by the current European Guidelines of Psoriasis.10 Twelve patients received concomitant antibiotic therapy during the biological treatment. A complete response was observed in three patients (15.7%) (two cases treated with infliximab and one with ustekinumab). Ten patients (55%) (four men and six women) achieved a partial improvement (Fig. 1). No clinical improvement was noted in four cases and a worsening of the skin symptoms was observed in one patient. One patient presented a severe infusional reaction in the first dose of infliximab leading to withdrawal of the treatment (Table 1). No significant differences between physician and patients severity assessment were noted but patients had a tendency to refer a mild high efficacy (Table 1). The mean duration of the biological treatment was 12 months, with a range from 4 to 32 months. The first line biological treatment reduced pain in 3.27 points (SD 2.76) of the VAS scale (data of fifteen patients). The average pain reduction was 6.5 in women and 1.4 in men (P = 0.006). The media of RCP after 3 months of biological treatment was 1.5 mg/L (SD 0.40). Treatment withdrawal were due to inefficacy in controlling the concomitant skin or rheumatologic disease, even though it was effective for HS (two cases), severe side-effects (severe infusional reaction and hypertriglyceridemia) (two cases) or lack of clinical response (four cases). Due to lack of efficacy six cases switched to a second biological treatment: adalimumab in three patients (previously treated with infliximab (two cases) and etanercept (one case) (Table 2). Treatment duration ranged from 5 to 41 months (mean: 14 months). No clinical response was observed in three cases, whereas a partial improvement was observed in other three cases. Two cases switched to a third biological drug; one case to adalimumab (for 4 months) and another to infliximab (for 12 months); in both cases, a partial improvement was achieved.
Table 1 Biological treatments tested as first-line treatment. Response to the biological treatment was assessed using a scale with the items of ‘full response’, ‘partial response’, ‘no response’ and ‘worsening’ answered by both the physician and the patient
Use of biological drugs and response to treatment
0/1 (0%)
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Use of biologics in hidradenitis suppurativa
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(a)
(b)
(c)
(d)
Figure 1 45 year-old female patient with Hurely II HS, before adalimumab treatment (a and b) and 6 months after beginning the drug 4 (c and d). Note the reduction in inflammatory signs.
Table 2 Biological treatments tested as second-line treatment Second Biological tested
N
Complete response
Partial improvement
Ineffective
Worsening
Adalimumab
3/6 (50%)
0/3 (0%)
1/3 (33.3%)
2/3 (66.6%)
0/3 (0%)
Infliximab
1/6 (38.8%)
0/1 (0%)
1/1 (100%)
0/1 (0%)
0/1 (0%)
Ustekinumab
1/6 (11.1%)
0/1 (0%)
1/1 (100%)
0/1 (0%)
0/1 (0%)
Etanercept
1/6 (11.1%)
0/1 (0%)
0/1 (0%)
1/1 (100%)
0/1 (0%)
drugs were also left as a last resort.1,8 However, early administration could avoid the appearance of scars. In our series, all patients had been previously treated with multiple courses of antibiotics, alone or in combination with extensive debridements. Over half of the patients had been treated with retinoids, immunosuppressants, finasteride or colchicine. Biological treatment was indicated when other treatment options had failed. The best biological drug and its dosage for the treatment of HS are not known. In our series, in cases of concomitant disease (psoriasis and other rheumatological diseases), the drug chosen
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was the one recommended by the accepted clinical guidelines for the underlying disease. In patients without any concomitant disease, the used dosage was the recommended by in the European Guidelines for Psoriasis.10 Higher doses could be associated with a higher response rate and several authors have suggested that biological drugs in HS treatment should be used with higher doses than those applied to psoriasis.14 Studies between different biological drugs for HS are lacking,8,9 and there is no agreement on the first-line biological drug but it seems that etanercept would be the less effective.15 In our series, the only case treated with etanercept did not improve. It is also interesting to remark
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that in this series, the lack of efficacy of one particular drug does not seem to predict a further response to other biological drug. The response to the treatment is variable.16–19 In our series, physician assessment of clinical response was in the majority of cases a ‘partial improvement’ and in three out of nineteen a ‘complete response’ was assessed. In one case, worsening of the skin symptoms was observed. In some isolated cases this phenomenon on has been previously reported and cases of worsening or de novo appearance of psoriasis during biological treatments have been described.20,21 Pain reduction measured by VAS was significantly achieved and was much more significant in women. Female patients with severe pain associated to a HS may benefit from these treatments. Inflammatory markers like erythrocyte sedimentation rate and C-reactive protein are elevated in patients with HS and decrease during the biological treatment.22 Twelve patients received concomitantly antibiotic treatment. This group did not show better outcomes than patients who were not treated with antibiotics. No patient developed associated infectious complications, so the use of concomitant antibiotics might be unnecessary. The use of concomitant antibiotics was previously associated with a better response,16 this data could not be observed in our cases. Safety is always a concern when using biological therapies. We found a safe short-term profile. In our study, two patients developed adverse effects, which required discontinuation of the treatment. The new-onset of polyarthritis during the treatment of HS with infliximab has been described.23 There are several limitations in our study due to its retrospective nature and the involvement of multiple centres. The evaluation of clinical manifestations and treatment decisions were dependent on the physician, making direct comparisons difficult. The clinical features leading to the use of biological drugs in the current series of patients with HS were heterogeneous and the number of patients included was limited. These facts make it difficult to draw firm conclusions. In conclusion, biological treatments seem to be a useful and effective therapeutic option for severe cases of HS. The complete response is uncommon and partial responses are more frequent. The lack of response of one particular drug does not preclude a potential efficacy to another biological treatment. Further investigation involving biological and standard immunosuppressive drugs should be evaluated in properly designed randomized clinical trials.
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