VOLUME 152 - No. 4 - AUGUST 2017 OFFICIAL ...

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Aug 4, 2017 - Several clinical trials with apremilast, anti-IL17 drugs and anti-interleukin-1 alpha are currently ongoing. (Cite this article as: Martin-Ezquerra G, ...
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OFFICIAL JOURNAL OF THE SOCIETÀ ITALIANA DI DERMATOLOGIA MEDICA, CHIRURGICA, ESTETICA E DELLE MALATTIE SESSUALMENTE TRASMESSE (SIDeMaST)

VOLUME 152 - No. 4 - AUGUST 2017

© 2016 EDIZIONI MINERVA MEDICA Online version at http://www.minervamedica.it

Giornale Italiano di Dermatologia e Venereologia 2017 August;152(4):373-8 DOI: 10.23736/S0392-0488.16.05530-9

REVIEW

Use of biological treatments in patients with hidradenitis suppurativa Gemma MARTIN-EZQUERRA 1 *, Emili MASFERRER 2, Ramon M. PUJOL 1 1Dermatology

Department, Hospital del Mar, Barcelona, Spain; 2Dermatology Department, Hospital Universitari Mútua de Terrassa, Barcelona, Spain *Corresponding author: Gemma Martin-Ezquerra, Department of Dermatology Hospital del Mar, Passeig Marítim 25-29, 08003 Barcelona, Spain. E-mail: [email protected]

A B S TRA C T Pilosebaceous unit occlusion and secondary inflammatory perifollicular lympho-histiocytic infiltration seem to be the underlying etiopathogenic mechanisms giving rise to hidradenitis suppurativa (HS). Increased levels of tumor necrosis factor (TNF)-alpha and other cytokines such as interleukins 12 and 23 (IL12/23) and interleukins 10 and 17 have been observed in HS lesional skin. Biological drugs have been reported to be effective for HS, but the level and duration of the response are quite variable. Among anti-TNF drugs, adalimumab and infliximab seem to obtain better results in HS. Adalimumab is the only registered systemic agent for HS and results from multicenter clinical trials demonstrate that 58.9% of patients may achieve clinical response without significant adverse events. Continuous treatment seems to maintain the therapeutic response, but discontinuation of the treatment usually results in a rapid relapse of the disease. Infliximab may also obtain a good response profile with 50% improvement of HS lesions. Treatment with ustekinumab for HS resulted in variable results showing a moderate-to-marked improvement in 82% of patients. Anakinra, a recombinant IL-1 receptor antagonist, has been also been postulated as a potential systemic treatment for HS. A reduction in the disease activity in 67% of patients has been reported. Biological drugs seem to represent an effective therapeutic option for HS, but complete and persistent resolution of the disease is rarely achieved. Flares of the disease usually develop regardless the prescribed treatment. Combined treatments including antibiotics and retinoids seem to be a potential additional therapeutic approach. In chronic and severe cases, a surgical approach is mandatory in order to remove persistent scarring tissue. New drugs are currently being evaluated as new insights in the pathogenesis of the disease are elucidated. Several clinical trials with apremilast, anti-IL17 drugs and anti-interleukin-1 alpha are currently ongoing. (Cite this article as: Martin-Ezquerra G, Masferrer E, Pujol RM. Use of biological treatments in patients with hidradenitis suppurativa. G ������������� Ital Dermatol Venereol 2017;152:373-8. DOI: 10.23736/S0392-0488.16.05530-9) Key words: Hidradenitis suppurativa - Tumor Necrosis Factor-alpha - Biological therapy.

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he etiology of hidradenitis suppurativa (HS) remains unclear and it is probably multifactorial. Considered for many years a primary apocrine disorder, further studies showed a primary inflammation of the hair follicles. The occlusion of the pilosebaceous unit leading to a perifollicular lympho-histiocytic infiltration seems to be a prominent phenomenon in HS.1 Recent studies have focused on such inflammatory response, which seems crucial for the pathogenesis of the disease.2 An underlying immune dysregulation with over-

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expression of certain cytokines may lead to a persistent inflammatory response giving rise to the characteristic lesions of HS. Several studies have been focused on the pathogenic mechanisms implicated in the inflammatory response in HS. Once elucidated, potential rational targeted therapies could be designed. Biologic therapies would be a potential therapeutic strategy in HS by blocking the inflammatory response. Most reported studies have been focused on tumor necrosis factor-alpha (TNF-α) inhibi-

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tors. TNFα is a proinflammatory cytokine that has been related to numerous inflammatory conditions.3 Van der Zee et al. showed that TNFα and other cytokines were significantly elevated in HS lesional skin samples, correlating positively with disease severity.4 Serum levels of TNF-α are also increased in patients with HS.5 Recent studies indicate that TNF-α, interleukins 12 and 23 (IL12/23) and interleukins 10 and 17, play an important role in many inflammatory conditions, including HS. HS is a chronic and recurrent disease of a variable severity that usually leads to a significant impact in the quality of life of patients. Multiple therapeutic strategies have been proposed; however, no curative treatment exists. Classical treatments include topical and systemic antibiotics, retinoids and immunosuppressive drugs, but a significant and maintained benefit on the severity of the disease is usually not achieved. Besides, classical treatments are supported by low quality of evidence studies.6 Surgery remains one of the most successful treatments for severe HS; however wide excisions are usually necessary and are associated with a significant morbidity.7 In that scenario, biologic treatments represent a potential and attractive option for patients with HS. Multiple case reports of HS responding to different biologic drugs have been reported. Recently, randomized controlled trials have been published, and nowadays biologic treatments discard more robust evidence among all available HS interventions.6 The main aim of this article was to describe the different biological treatments in HS by reviewing previously reported series in the literature. Etanercept Etanercept is a fully humanized fusion protein composed of the TNF-α receptor and the protein component of the immunoglobulin G1 receptor. This protein binds to transmembrane TNF-α but does not bind to soluble TNF-α.8 Initially, several cohort studies demonstrated positive results on the use of etanercept for patients with HS.9-11 However, one randomized double-blind trial 12 and a systematic review on the use of TNF-α inhibitors 13 found that etanercept was not associated with a significant improvement of HS.

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Adalimumab Adalimumab is a fully humanized monoclonal antibody, which exhibits specificity for human TNF-α with a high affinity to both soluble and membranebound TNF-α, blocking its biological effect.14 Currently, adalimumab is the only registered systemic agent for HS. Both case reports and retrospective case series have reported improvement of HS lesions in patients treated with adalimumab with a cumulative response rate of 58.9%.15 The beneficial effect is usually observed between 4 and 12 weeks and is maintained throughout the treatment. A slower clinical response in comparison to infliximab is observed, but with a better safety profile.16 Miller et al. in 2011 17 treated 21 patients with adalimumab (80 mg at week 0 and 40 mg every second week) or placebo for three months. An early clinical Improvement was detected at week 6, but no significant changes in Hurley or Sartorius score could be demonstrated at week 12. Kimball et al.18 in 2012 published a prospective placebo-controlled study of adalimumab treatment (40 mg sc once weekly: 40 mg sc every other week) including 154 patients with moderate to severe HS treated during 16 weeks. At the end of the study, 17.6% of patients treated with adalimumab 40 mg weekly achieved statistically higher clinical response, compared to 9.6% of patients dosed 40 mg every other week and 3.9% of placebo patients. Similar adverse events were observed in all evaluated groups. Recently, results from two multicenter double-blind placebo controlled phase III clinical trials including large number of patients (PIONEER I; 307 patients and PIONEER II: 326) have been published.19 Patients were randomized into the placebo or adalimumab group (160 mg week 0, 80 mg week 2, and 40 mg weeks 4-12) for 24 weeks. The primary end-point was to evaluate the clinical response HiSCR defined as at least a 50% reduction from the baseline in inflammatory and suppurative lesions. At week 12, HiSCR achievement rate was significantly higher for patients randomized to weekly adalimumab vs. placebo in both PIONEER I (41.8% vs. 26.0%) and PIONEER II (58.9% vs. 27.6%) clinical trials. Significant differences were detected also in the Sartorius score and pain intensity. There were no significant differences among adverse events between the groups in both studies.

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Efficacy of adalimumab is maintained at least two years, if weekly dosage is used.20 Relapses occur at a mean of 11 weeks after discontinuation of the treatment.15 Retreatment seems equally effective. Treatment is usually maintained at long-term except if adverse effects appear. Similarly to paradoxical psoriasiform reactions, HS development in patients treated with adalimumab has occasionally been reported.21, 22 Pathogenesis of the psoriasiform reaction is thought to be due a disruption of the cytokine balance leading to an increase in interferon gamma and IL-1 by dendritic cells in genetically predisposed patients. The same etiopathogenesis could be assumed in HS, as it shares a similar cytokine profile. Infliximab Infliximab is an anti-TNF-α chimeric monoclonal antibody that binds both transmembrane and soluble TNF-α.8 Some case series and several cohort studies have demonstrated the potential usefulness of infliximab in HS.16, 23 The only double blind placebo-controlled study published for HS showed a 50% improvement with infliximab compared with placebo.24 There is only one retrospective study comparing the efficacy of two biological therapies (infliximab and adalimumab) in HS: two cohorts of ten patients who received either three infusions of infliximab at weeks 0, 2 and 6, or adalimumab 40 mg every other week were evaluated. Both groups were closely followed up for 1 year. The authors concluded that both treatments were effective, but infliximab showed slightly better results.25 However, the obtained results should be interpreted with caution, since the prescribed dose of adalimumab was lower than that currently recommended to treat HS. Additional studies comparing both drugs in the standard doses are needed in order to establish definite conclusions. Ustekinumab Ustekinumab is a human IgG1K monoclonal antibody that binds with high affinity to the p40 subunit of IL-12 and IL-23. Case series and case reports have shown variable results, often achieving only partial responses. Gulliver et al.26 treated three patients with moderate to severe

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HS, resistant to previous treatments including biological drugs. One patient showed complete clearance of the disease, another showed a partial response and the third patient showed no improvement.27 Sharon et al. described one patient with HS resistant to adalimumab who presented a partial response with ustekinumab 90 mg every 8 weeks. Recently, two additional cases showing complete remissions with 45 mg every 12 weeks have been reported. 28, 29 Blok et al.30 conducted an open-label prospective study in 17 patients with moderate-to-severe HS. Patients were treated with a similar regime to that used in psoriasis. In 82% of the patients a moderate-to-marked improvement of the modified Sartorius score was achieved at week 40 and in 47% of patients improvement of the HiSCR was observed. Adverse events were mild, except for one patient who discontinued the treatment due to urticaria. The authors pointed out that dosing might be intensified to achieve sufficient immune suppression, similarly to other more severe inflammatory diseases, such as in Crohn’s disease. Anakinra Anakinra is a recombinant IL-1 receptor antagonist (IL-1β) that has shown to be effective in rheumatoid arthritis.31 IL-1β is a potent proinflammatory cytokine that has been demonstrated to be elevated in HS lesional skin.4 Isolated reports have reported either a partial efficacy or no response to IL-1 antagonists in patients with HS.31, 32-38 In 2014 Leslie et al.39 presented an open-label pilot study, where all patients received active therapy with anakinra for 8 weeks, followed by an additional 8 weeks of follow-up. Six patients were enrolled and five patients completed the treatment. A significant mean decrease in modified Sartorius Score, physician global assessment, and patient subjective evaluations (pain, discharge, odor, and presence of new lesions) was observed. Limitations of this study include the absence of a control group and the small number of participants. Rapid recurrences of the disease were noted after withdrawing the treatment. In 2015 Tzanetakou et al. presented a double-blind, randomized, placebo-controlled clinical trial with a 12-week treatment and a 12-week follow-up.40 Twenty patients were enrolled, including 10 patients random-

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ized to the placebo arm and 10 patients to the anakinra arm. The disease activity score was decreased at the end of treatment (week 12) in 20% of placebo-treated patients compared with 67% of anakinra-treated patients (P=0.04). A more prolonged time to a new HS relapse was noted in the anakinra arm. A major question that cannot be answered at this time is whether patients who show an insufficient response to an anti-TNF treatment will benefit from anakinra therapy. Reliable biomarkers predictors for therapeutic response to the different treatments are lacking. In a separate study, van der Zee demonstrated that high concentrations of both IL-1β and TNF are present in the drainage from lesions of patients with HS. Some patients exhibited mainly TNF, others IL-1β and cases presenting both cytokines were also identified.4 The relevance of this observation regarding the therapeutic response in cases of HS should be evaluated in future studies. An important point that should be taken into account is the current cost of both treatments. As listed by Epocrates,41 Anakinra’s annual cost is $22,516 compared with weekly adalimumab, which costs $50,700 per year.39

Safety concerns Nowadays, adalimumab is the only approved systemic agent for HS. There are no safety studies on biologics in HS. However, the safety of anti-TNF-α drugs has been investigated in randomized controlled trials and registry studies for rheumatoid arthritis or psoriasis. The safety information gained from these sources can generally be applied to patients with HS.45 In Southern European countries, one of the most important adverse effect is the increased risk of developing tuberculosis. Recent studies failed to demonstrate an association between anti-TNF biologics and an increased risk in solid or hematologic malignancies.46, 47 Role for combinations

No curative treatment for HS is currently available. Numerous medical options, besides from biological treatments, have been proposed with a mild to moderate efficacy. Surgery remains a good therapeutic option for chronic, recurrent and scarring lesions, but can be associated, when large areas are excised, with a significant morbidity. None of these treatments, except for radical surgery, is curative. European guidelines for the treatment of HS were published in 2015.48 Biologics are placed to treat unreOther biologics sponsived cases to antibiotic combinations and acitreNew drugs and new indications of classic biological tin. Similarly but more precisely, Italian Guidelines drugs are being studied as new insights in the patho- placed antiTNF drugs in moderate to severe HS with genesis of cutaneous inflammatory diseases are discov- contraindication or inadequate response to oral antibiotered.42 Several authors have suggested a pathogenic role ics and acitretin.49 of IL-17 in HS. An increased expression of IL17 mRNA As none of the treatments offers a complete remisin HS lesions has been demonstrated. These observa- sion of the disease, flares develop and rescue treatments tions suggest that inhibition of IL-17 may be a viable are often necessary. When suppurative lesions develop potential therapy for HS. A clinical trial with a biologic in patients under biologic therapy, a microbiological drug targeting IL17 is underway (ClinicalTrials.gov culture is obtained and specific antibiotic treatment is Identifier: NCT02421172). Currently, there is also an prescribed. Incision and drainage can be useful in seopen-label study to evaluate the efficacy of apremilast lected lesions. In patients who present sinuses, tunnels, in HS (ClinicalTrials.gov Identifier: NCT02695212). A bridges or cords, biologics will not be effective and clinical trial is currently designed to evaluate the effica- surgical debridement is mandatory. To our knowledge, cy of MABp1, a human antibody targeting Interleukin-1 no guidelines describing the role of surgery in patients alpha (ClinicalTrials.gov Identifier: NCT02643654). treated with biologics have been published. In Crohn’s Recently a case report involving golimumab showed disease, biologic therapy in the pre- or postoperative clearance of HS lesions in a patient with the association period does not appear to significantly increase the risk of HS, ulcerative colitis and pyostomatitis vegetans.43 A of postoperative complications.50 In some patients, biocase of HS with pyoderma gangrenosum responding to logic drugs can be used as adjuvant treatment to cool an canakinumab has also been reported.44 area before surgery.51 In other patients, wider surgical

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debridements can be performed, with lower recurrences. As secondary healing is often used, infection can be an issue in those patients. Therefore, an individualized and multidisciplinary approach seems advisable. Conclusions Biological treatments have shown a robust evidence of efficacy in the management of HS. Adalimumab is the only approved treatment, exhibiting efficacy in 60% of patients with moderate-to-severe disease. Higher doses than those used in psoriasis are required, since a greater immunosuppression has to be achieved in HS. Safety concerns have been pointed out, but adverse events do not seem to be higher than those observed with lower dose regimes. Surgery will remain as the mainstay for removal of chronic and scarring persistent lesions. Combination therapies with antibiotics, surgery or retinoids are recommended when reactivation of the disease develops. New drugs are currently been investigated as new insights in the pathogenesis of the diseases are discovered. References   1. Kurzen H, Kurokawa I, Jemec GBE, Emtestam L, Sellheyer K, Giamarellos-Bourboulis EJ, et al. What causes hidradenitissuppurativa? Exp Dermatol 2008;17:455-72.   2. Schlapbach C, Hänni T, Yawalkar N, Hunger RE. Expression of the IL-23/Th17 pathway in lesions of hidradenitissuppurativa. J Am Acad Dermatol 2011;65:790-8.   3. Brenner D, Blaser H, Mak TW. Regulation of tumour necrosis factor signalling: live or letdie. Nat Rev Immunol 2015;15:362-74.   4. van der Zee HH, de Ruiter L, van den Broecke DG, Dik WA, Laman JD, Prens EP. Elevated levels of tumour necrosis factor (TNF)-α, interleukin (IL)-1β and IL-10 in hidradenitis suppurativa skin: a rationale for targeting TNF-α and IL-1β. Br J Dermatol 2011;164:1292-8.   5. 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 2009:89:601-3.   6. Ingram JR, Woo PN, Chua SL, Ormerod AD, Desai N, Kai AC, et al. Interventions for hidradenitis suppurativa: a Cochrane systematic review incorporating GRADE assessment of evidence quality. Br J Dermatol 2016;174:970-8.   7. Mahmoud BH, Tierney E, Hexsel CL, Pui J, Ozog DM, Hamzavi IH. Prospective controlled clinical and histopathologic study of hidradenitis suppurativa treated with the long pulsed neodymium:yttriumaluminium-garnet laser. J Am Acad Dermatol 2010;62:637-45.   8. Lee RA, Eisen DB. Treatment of hidradenitis suppurativa with biologic medications. J Am Acad Dermatol 2015;73:S82-8.   9. Cusack C, Buckley C. Etanercept: effective in the management of hidradenitissuppurativa. Br J Dermatol 2006;154:726-9. 10. Giamarellos-Bourboulis EJ, Pelekanou E, Antonopoulou A, Petropoulou H, Baziaka F, Karagianni V, et al. An open-label phase II

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study of the safety and efficacy of etanercept for the therapy of hidradenitis suppurativa. Br J Dermatol 2008;158:567-72. 11. Sotiriou E, Apalla Z, Ioannidos D. Etanercept for the treatment of hidradenitis suppurativa. Acta Derm Venereol 2009;89:82-3. 12. Adams DR, Yankura JA, Fogelberg AC, Anderson BE. Treatment of hidradenitis suppurativa with etanercept injection. Arch Dermatol 2010;146:501-4. 13. Gisondi P, Girolomoni G. Impact of TNF-α antagonists on the quality of life in selected skin diseases. G Ital Dermatol Venereol 2013;148:243-8. 14. Tracey D, Klareskog L, Sasso EH, Salfeld JG, Tak PP. Tumor necrosis factor antagonist mechanisms of action: a comprehensive review. Pharmacol Ther 2008;117:244-79. 15. Zouboulis CC. Adalimumab for the treatment of hidradenitis suppurativa/acne inversa. Expert Rev ClinImmunol 2016;12:1015-26. 16. BahilloMonné C, Honorato Guerra S, Schoendorff Ortega C, Gargallo Quintero AB. Management of hidradenitis suppurativa with biological therapy: report of four cases and review of the literature. Dermatology 2014;229:279-87. 17. 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;165:391-8. 18. Kimball AB, Kerdel F, Adams D, Mrowietz U, Gelfand JM, Gniadecki R, et al. Adalimumab for the treatment of moderate to severe Hidradenitis suppurativa: a parallel randomized trial. Ann Intern Med 2012;157:846-55. 19. Kimball AB, Okun MM, Williams DA, Gottlieb AB, Papp KA, Zouboulis CC, et al. Two phase 3 trials of adalimumab treatment of hidradenitis suppurativa. N Engl J Med 2016;375:422-34. 20. Zouboulis CC, Okun MM, Gniadecki R. Adalimumab efficacy in hidradenitis suppurativa patients is sustained at least two years with weekly dosing: Results from a Phase 3 open-label extension study (PIONEER). Abstract, 25th EADV Congress, 28.9-2.10.2016, Vienna, Austria. 21. Faivre C, Villani AP, Aubin F, Lipsker D, Bottaro M, Cohen JD, et al. Hidradenitis suppurativa (HS): An unrecognized paradoxical effect of biologic agents (BA) used in chronic inflammatory diseases. J Am Acad Dermatol 2016;74:1153-9. 22. Harvin G, Kasarala G. Two cases of paradoxical hidradenitis suppurativa while on adalimumab. Case Rep Gastroenterol 2016;19;10:88-94. 23. Moriarty B, Jiyad Z, Creamer D. Four-weekly infliximab in the treatment of severe hidradenitis suppurativa. Br J Dermatol 2014;170:986-7. 24. 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;62:205-17. 25. van Rappard DC, Leenarts MF, Meijerink-van ‘t Oost L, Mekkes JR. Comparing treatment outcome of infliximab and adalimumab in patients with severe hidradenitis suppurativa. J Dermatolog Treat 2012;23:284-9. 26. Gulliver WP, Jemec GB, Baker KA. Experience with ustekinumab for the treatment of moderate to severe hidradenitis suppurativa. J Eur Acad Dermatol Venereol 2012;26:911-4. 27. Sharon VR, Garcia MS, Bagheri S, Goodarzi H, Yang C, Ono Y, et al. Management of recalcitrant hidradenitis suppurativa with ustekinumab. Acta Derm Venereol 2012;92:320-1. 28. Baerveldt EM, Kappen JH, Thio HB, van Laar JA, van Hagen PM, Prens EP. Successful long-term triple disease control by ustekinumab in a patient with Behcet’s disease, psoriasis and hidradenitis suppurativa. Ann Rheum Dis 2013;72:626-7. 29. Santos-Pérez MI, García-Rodicio S, Del Olmo-Revuelto MA, PozoRomán T. Ustekinumab for hidradenitis suppurativa: a case report. Actas Dermosifiliogr 2014;105:720-2. 30. Blok JL, Li K, Brodmerkel C, Horvátovich P, Jonkman MF, Horváth B. Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum. Br J Dermatol 2016;174:839-46.

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31. van der Zee HH, Prens EP. Failure of anti-interleukin-1 therapy in severe hidradenitis suppurativa: a case report. Dermatology 2013;226:97-100. 32. Hsiao JL, Antaya RJ, Berger T, Maurer T, Shinkai K, Leslie KS. Hidradenitis suppurativa and concomitant pyoderma gangrenosum: a case series and literature review. Arch Dermatol 2010;146:1265-70. 33. Braun-Falco M, Kovnerystyy O, Lohse P, Ruzicka T. Pyoderma gangrenosum, acne, and suppurative hidradenitis (PASH)-a new autoinflammatory syndrome distinct from PAPA syndrome. J Am Acad Dermatol 2012;66:409-15. 34. Zarchi K, Dufour DN, Jemec GB. Successful treatment of severe hidradenitis suppurativa with anakinra. JAMA Dermatol 2013;149:11924. 35. Leuenberger M, Berner J, Di Lucca J, Fischer L, Kaparos N, Conrad C, et al. PASS Syndrome: An IL-1-Driven Autoinflammatory Disease. Dermatology 2016;232:254-8. 36. Abbara S, Georgin-Lavialle S, Stankovic Stojanovic K, Bachmeyer C, Senet P, Buob D, et al. Association of hidradenitis suppurativa and familial Mediterranean fever: A case series of 6 patients. Joint Bone Spine 2017;84:159-62. 37. Menis D, Maroñas-Jiménez L, Delgado-Marquez AM, PostigoLlorente C, Vanaclocha-Sebastián F. Two cases of severe hidradenitis suppurativa with failure of anakinra therapy. Br J Dermatol 2015;172:810-1. 38. Russo V, Alikhan A. Failure of Anakinra in a Case of Severe Hidradenitis suppurativa. J Drugs Dermatol 2016 Jun 1;15:772-4. 39. Leslie KS, Tripathi SV, Nguyen TV, Pauli M, Rosenblum MD. An open-label study of anakinra for the treatment of moderate to severe hidradenitis suppurativa. J Am Acad Dermatol 2014;70:243-51. 40. Tzanetakou V, Kanni T, Giatrakou S, Katoulis A, Papadavid E, Netea MG, et al. Safety and Efficacy of Anakinra in Severe Hidradenitis Suppurativa: A Randomized Clinical Trial. JAMA Dermatol 2016;152:52-9. 41. Epocrates; [Internet]. Available from: https://online.epocrates.com/ home [cited 2016, Dec 12].

42. Kelly G, Hughes R, McGarry T, van den Born M, Adamzik K, Fitzgerald R, et al. Dysregulated cytokine expression in lesional and nonlesional skin in hidradenitis suppurativa. Br J Dermatol 2015;173:1431-9. 43. Tursi A. Concomitant hidradenitis suppurativa and pyostomatitis vegetans in silent ulcerative colitis successfully treated with golimumab. Dig Liver Dis 2016;48:1511-2. 44. Jaeger T, Andres C, Grosber M, Zirbs M, Hein R, Ring J, et al. Pyoderma gangrenosum and concomitant hidradenitis suppurativa--rapid response to canakinumab (anti-IL-1β). Eur J Dermatol 2013;23:40810. 45. Girolomoni G, Altomare G, Ayala F, Berardesca E, Calzavara-Pinton P, Chimenti S, et al. Safety of anti-TNFα agents in the treatment of psoriasis and psoriatic arthritis. Immunopharmacol Immunotoxicol 2012;34:548-60. 46. Moulis G, Sommet A, Béné J, Montastruc F, Sailler L, Montastruc JL, et al. Cancer risk of anti-TNF-α at recommended doses in adult rheumatoid arthritis: a meta-analysis with intention to treat and per protocol analyses. PLoS One 2012;7:e48991. 47. Pereira R, Lago P, Faria R, Torres T. Safety of Anti-TNF Therapies in Immune-Mediated Inflammatory Diseases: Focus on Infections and Malignancy. Drug Dev Res 2015;76:419-27. 48. Zouboulis CC, Desai N, Emtestam L, Hunger RE, Ioannides D, Juhász I, et al. European S1 guideline for the treatment of hidradenitis suppurativa/acne inversa. J Eur Acad Dermatol Venereol 2015;29:619-44. 49. Megna M, Bettoli V, Chimenti S, Chiricozzi A, Naldi L, Virgili A, et al. Hidradenitis suppurativa: guidelines of the Italian Society of Dermatology and Venereology (SIDeMaST) for the use of anti-TNF-α agents.G Ital Dermatol Venereol 2015;150:731-9. 50. Paulson EC. Biologic Therapy and Surgery for Crohn Disease. Clinics in Colon and Rectal Surgery 2013;26:128-34. 51. DeFazio M, Economides JM, King KS, Han KD, Shanmugam VK, Attinger CE, et al. Outcomes after combined radical resection and targeted biologic therapy for the management of recalcitrant hidradenitis suppurativa. Ann Plast Surg 2016;77:217-22.

Conflicts of interest.—Gemma Martin-Ezquerra has received consultation fees from Abbvie. Article first published online: December 16, 2016.

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