J. L. Blok

Systemic therapy with immunosuppressive agents and retinoids in hidradenitis suppurativa: a systematic review.

Hidradenitis suppurativa (HS) is a difficult disease to treat. Although the pathogenesis of this inflammatory skin disease is largely unknown, the important role of the immune system has been demonstrated in both experimental and clinical studies. Clinicians are therefore increasingly prescribing systemic treatments with immunosuppressive agents, but the more traditionally used systemic retinoids, especially isotretinoin, also remain relatively common therapies. In order to provide an overview of all currently available systemic immunosuppressive agents and retinoids for the treatment of HS, a systematic search was performed using the Medline and Embase databases. All published papers concerning systemic retinoids or immunosuppressive treatments for HS in adults were included. The primary endpoints were the percentages of significant responders, moderate responders and nonresponders. Other endpoints were the relapse rate and adverse events. In total 87 papers were included, comprising 518 patients with HS who were treated with systemic retinoids, biological agents or another immunosuppressive agents, including colchicine, ciclosporin, dapsone or methotrexate. The highest response rates were observed with infliximab, adalimumab and acitretin. Overall, the quality of evidence was low and differed between the agents, making direct comparisons difficult. However, based on the amount of evidence, infliximab and adalimumab were the most effective agents. Acitretin was also effective in HS, although the quality of the evidence was low. The therapeutic effect of isotretinoin is questionable. Randomized controlled trials are needed to confirm the effectiveness of acitretin, and to identify the most effective immunosuppressive agents in HS.

Ustekinumab in hidradenitis suppurativa: clinical results and a search for potential biomarkers in serum

Treatment of hidradenitis suppurativa (HS) is difficult and the search for effective therapies continues.

Surgery under general anaesthesia in severe hidradenitis suppurativa: a study of 363 primary operations in 113 patients

Treatment of hidradenitis suppurativa (HS) is a difficult undertaking, especially as there is no consensus on what surgical technique is preferred. At our centre severe HS (Hurley II/III) is operated under general anaesthesia, mostly with the STEEP procedure.

Skin-Tissue-sparing Excision with Electrosurgical Peeling (STEEP) : a surgical treatment option for severe hidradenitis suppurativa Hurley stage II/III

Surgery is the only curative treatment for removal of the persistent sinus tracts in the skin that are characteristic of severe hidradenitis suppurativa (HS). Complete resection of the affected tissue by wide excision is currently regarded as the preferred surgical technique in these cases. However, relatively large amounts of healthy tissue are removed with this method and suitable skin‐tissue‐saving techniques aiming at creating less‐extensive surgical defects are therefore needed in severe HS.

The possible association of hidradenitis suppurativa and Down syndrome: is increased amyloid precursor protein expression resulting in impaired Notch signalling the missing link?

Cutis 1981; 28:541–2. 4 Ishizaki S, Sawada M, Suzaki R et al. Tinea faciei by Microsporum gypseum mimicking allergic reaction following cosmetic tattooing of the eyebrows. Med Mycol J 2012; 53:263–6. 5 Choong KY, Roberts LJ. Ritual Samoan body tattooing and associated sporotrichosis. Australas J Dermatol 1996; 37:50–3. 6 Bary P, Kuriata MA, Cleaver LJ. Lymphocutaneous sporotrichosis: a case report and unconventional source of infection. Cutis 1999; 63:173–5. 7 Parker C, Kaminski G, Hill D. Zygomycosis in a tattoo, caused by Saksenaea vasiformis. Australas J Dermatol 1986; 27:107–11. 8 Kluger N. Cutaneous infections related to permanent tattooing. Med Mal Infect 2011; 41:115–22. 9 Camus M, Anyfantakis V, Dammak A et al. Primary cutaneous aspergillosis in an immunocompetent farmworker. Ann Dermatol Venereol 2010; 137:373–6. 10 Kl€ ugl I, Hiller KA, Landthaler M, B€aumler W. Incidence of health problems associated with tattooed skin: a nation-wide survey in German-speaking countries. Dermatology 2010; 221:43–50.

Gene expression profiling of skin and blood in hidradenitis suppurativa

DEAR EDITOR, Hidradenitis suppurativa (HS) is characterized by recurrent abscesses, nodules and sinus tract formation and is localized mainly in the body folds. The pathogenesis is poorly understood. Mutations in genes encoding essential compounds of the transmembrane protease c-secretase, including NCSTN, PSEN1 and PSENEN, have been identified in familial HS. These mutations may result in impaired Notch signalling, promoting cyst formation and continuing inflammatory activity. Additionally, certain single-nucleotide polymorphisms at the promoter region of the tumour necrosis factor (TNF)-a gene were found to be associated with HS. Furthermore, elevated levels of interleukin (IL)-1, TNF-a and IL-10 were demonstrated in both lesional and perilesional skin of patients with HS, and increased expression of the IL-23/T helper 17 pathway was found in lesional skin. A recent study demonstrated that the production of proinflammatory cytokines in HS is compartmentalized, as the levels were elevated in pus collected from lesional skin but suppressed in circulating blood mononuclear cells. To acquire a better understanding of the molecular pathogenesis of HS, we performed mRNA microarray studies to compare gene expression in lesional skin vs. healthy skin of patients with HS. Also, the gene expression profiles in whole blood of patients and unaffected individuals were determined. The study was approved by the university medical ethics committee. Seventeen patients with HS were included. Whole blood was collected from all patients and 10 healthy controls. Skin biopsies of 3 mm were obtained from inflammatory lesions in all 17 subjects. Additionally, an extra biopsy from clinically healthy skin of the upper arm or leg was obtained from 13 of these 17 individuals. The skin samples were immediately frozen in liquid nitrogen and subsequently stored at 80 °C. mRNA was extracted from skin samples using the Qiagen RNeasy Fibrous Tissue Mini Kit (Qiagen Inc., Valencia, CA, U.S.A.) and from whole blood with the Qiagen PAXgene Blood RNA Kit according to the manufacturer’s instructions. RNA was hybridized to the GeneChip HT HG-U133+PM Array (Affymetrix, Santa Clara, CA, U.S.A.). The raw data have been deposited in the National Center for Biotechnology Information’s Gene Expression Omnibus under accession number GSE72702. Pathway analyses were conducted with Qiagen’s Ingenuity Pathway Analysis. Array Studio software version 8.0 (OmicSoft Corp., St Morrisville, NC, U.S.A.) was used to analyse microarray data. Dysregulated genes were identified using a general linear model with multiple testing correction. Expression modulation with a fold change > 2 or < 2 and a false-discovery-rate-adjusted P-value < 0 05 were considered significant. A significant difference was observed in mRNA expression between lesional and clinically healthy skin of patients with HS, with 1145 probe sets representing over 800 genes having at least a twofold change (P < 0 05) (Table S1; see Supporting Information). Patients with the most dysregulated gene profiles were more likely to have long-standing disease (> 15 years) (Fig. 1a). Pathway analyses of the modulated genes showed that they were related mostly to inflammation, including cell adhesion, diapedesis and extravasation, as well as immune cell signalling and communication pathways (Fig. 1b; Table S2; see Supporting Information). An interesting finding is involvement of the atherosclerosis signalling pathway in lesional HS skin, as it supports the current thought that the inflammatory response in HS is associated with metabolic syndrome. Expression of NCSTN, PSEN1 and PSENEN was not modulated in lesional vs. clinically healthy skin of patients. No significant differences were identified in whole-blood mRNA expression between patients (n = 17) and healthy controls (n = 10) (Fig. S1; see Supporting Information). Nonetheless, the top 50 probe set that were differentially expressed based on raw P-value are provided in Table S3 (see Supporting Information). The lack of differences between patients with HS and healthy controls in whole blood supports the hypothesis of Kanni et al., proposing that decreased cytokine production in the blood circulation of patients with HS is regulated at a post-transcriptional level. The authors suggest that elevated TNF-a levels in serum of patients with HS, as previously demonstrated by Matusiak et al., may have a role in this decreased production, as the number of mononuclear cells was shown to be equal to or even greater than the number in healthy controls. In summary, we have demonstrated significantly altered gene expression in lesional skin compared with clinically healthy skin of patients with HS. This, in addition to the finding that whole-blood RNA expression did not differ between patients with HS and healthy subjects, indicates that activated cells in HS reside in affected tissue. This may be due to activation and migration of leucocytes from the circulation into skin

Hurley staging refined: A proposal by the dutch hidradenitis suppurativa expert group

Sir, Hidradenitis suppurativa (HS) is a chronic, recurring, debilitating inflammatory skin disease, which mainly affects the inverse areas of the body leading to scarring and disfigurement (1, 2). The European S1 guideline for the treatment of HS summarized all published treatments for HS (1). The quality of evidence for these treatments is generally low, as was recently demonstrated in a Cochrane Review on interventions for HS, which identified only 12 randomized controlled trials (RCTs) (3). Moreover, HS is a heterogeneous disease with distinct clinical phenotypes that may require different treatment strategies, further complicating the therapeutic decision-making process (4). The European S1 guideline proposed a “Hurley severity grade-relevant treatment algorithm” (1). More recently Gulliver et al. (5) proposed another treatment algorithm based on disease severity measured by Hurley grade or PGA. Hurley stage is a 3-stage classification of severity. Hurley stage I is characterized by abscess formation with out sinus tracts and scarring. In Hurley II, patients have single or multiple separated areas of recurrent abscesses with sinus tracts and scarring, whereas in stage III the multiple interconnected sinus tracts and abscesses cover the whole affected anatomical area. This classification in its original form was created mainly for surgical purposes and does not take into account the inflammatory component. In addition, the extension of the disease, i.e. the number of anatomical areas involved, is not assessed. Accurate stratification of the wide variety of HS clinical phenotypes is therefore not possible with the original Hurley score. Furthermore, the recently invented dynamic scoring system Hidradenitis Suppurativa Clinical Response (6) focuses mainly on the inflammatory component and is more or less comparable with a PASI 50 improvement in psoriasis and therefore is mainly suitable for the follow-up of systemic treatments. How ever, these scores do not calculate or include the extensiveness of the disease. The number of anatomical areas involved is important in designing a holistic treatment plan as this should take into account the estimated number of surgical interventions needed (Fig. S11). Here, we (the Dutch HS expert group and as a part of the European Hidradenitis Suppurativa Foundation e.V.) propose a refinement of the current Hurley staging. Briefly, a 3 stepwise algorithm, including assessing the presence of sinus tracts, degree of inflammation and the extensiveness, enables the clinician to assess severity across the different phenotypes of HS and helps to guide treatment (Fig. 1). In the first step of the algorithm the presence of sinus tracts is assessed, clearly separating Hurley I from Hurley II and III. In Hurley I the differentiation between fixed and migratory lesions is essential. Hurley 1C is considered as severe HS and is characterized by the presence of migratory lesions and corresponds with the recently proposed scarring folliculitis and frictional furuncle phenotype (4). Since migratory lesions point to a strong inflammatory component, the cornerstone of treatment Hurley Staging Refined: A Proposal by the Dutch Hidradenitis Suppurativa Expert Group

Increased Expression of Integrin alpha 6 beta 4 in the Basement Membrane Zone Lining the Sebaceous Glands in Hidradenitis Suppurativa

Hidradenitis suppurativa (HS) is an inflammatory skin disease characterized by painful nodules, abscesses and sinus tracts. The disease is located primarily in the apocrine gland-bearing skin, including the armpits and groins (1). Previous studies have shown that follicular occlusion is present in the majority of patients at an early stage of the disease (2–5); however, the driving mechanism behind this follicular occlusion is unknown. Recently, diminished periodic acid-Schiff (PAS) staining was found in the basement membrane zone (BMZ) of the sebofollicular junction (SFJ) at the folliculopilosebaceous units (FPSU) in perilesional HS skin (6). The authors suggest that the PAS-negative gaps represent primary defects in the BMZ, leading to fragility of the hair follicle. Diminished expression in one of the glycoproteins in the BMZ of the SFJ might explain these PAS-negative gaps; however, there was no staining for specific glycoproteins in this study. Therefore, we investigated the expression of the most important BMZ components, including type XVII collagen, type VII collagen, laminin-332, and integrin α6β4, of the follicular epidermis relative to the interfollicular epidermis in HS and compared the expression ratio with that of healthy controls.

Interventions for hidradenitis suppurativa: an important step towards evidence-based medicine.

Hidradenitis suppurativa (HS) is an inflammatory skin disease impairing quality of life to a great extent. Its multifactorial pathogenesis remains elusive and HS treatment remains a big challenge. To date, no curative treatment exists; therapy includes inhibiting the inflammatory response with topical and/or systemic agents. As the nature of the inflammation is not yet fully understood, clinical trials have focused on targeting varying presumed key players, by use of antibiotics, retinoids and immunosuppressive agents. It is generally accepted that in cases where sinus tracts have been formed, anti-inflammatory treatment should be combined with surgical interventions. Recommendations regarding the preferred surgical strategy vary between tissue-saving techniques to wide excision. The main problem in choosing between these multiple treatment options is that the quality of evidence provided by the majority of studies is low. Even the recently published general treatment recommendations for HS are mainly based on expert opinion rather than evidence-based medicine. Ingram et al. have taken an important step towards introducing evidence-based medicine in the field of HS by performing a systematic review on all medical and surgical interventions, which was recently published in The Cochrane Library. In this issue of the BJD, the authors report a clear summary of this review. They included only randomized controlled trials (RCTs) and evaluated these studies based on predefined outcome measurements. Quality of life and adverse effects were primary outcomes. Secondary outcomes were patientand physicianreported outcomes, as well as the duration of remission. The lack of high-quality studies is striking, as only 12 trials with a total of 615 participants met the eligible criteria. Included trials investigated topical therapies, systemic therapies, surgical interventions and the so-called ‘other interventions’. Trials providing the highest quality of evidence were found within the subgroup of tumour necrosis factor-a-inhibitors; efficacy of weekly adalimumab was confirmed. Additionally, the beneficial results of infliximab were regarded as being only ‘potentially clinically relevant’, as the quantity of evidence was sparse. No RCTs were identified on surgical interventions, except for one trial showing no benefit of inserting a gentamycin sponge before primary closure was performed. Although the scientific attention regarding HS is rising, the review clearly points out that there is still much left to be done. Currently, adalimumab is the only registered systemic agent for HS. There is a need for high-quality trials supporting the efficacy of the less expensive and more regularly used systemic medications, including antibiotics and retinoids, which are currently regarded as first treatment options. Furthermore, experts agree that surgery is an essential part of treatment, but supporting evidence is completely lacking in terms of efficacy, timing of surgery and type of surgical technique. It is remarkable that RCTs providing the highest quality of evidence are mainly company-driven, while investigator-initiated RCTs on other interventions, such as surgery, are lacking. There is a whole field of interventions requiring further investigation, including laser and light therapies as well as treatments targeting the endocrine system, which remains a suspect in the pathogenesis of HS after many years of debate.