Infectious Disease Screening Prior to Systemic Immunomodulatory Therapy in Hidradenitis Suppurativa: Consensus Guidelines from the Asia-Pacific Hidradenitis Suppurativa Foundation.

BACKGROUND: Current infectious disease screening recommendations for hidradenitis suppurativa (HS) are adopted from recommendations in chronic plaque psoriasis. No HS-specific guidelines for infectious disease screening prior to immunomodulatory therapy have been developed. OBJECTIVES: To establish an expert Delphi consensus of recommendations regarding infectious disease screening prior to systemic immunomodulatory therapy in HS. METHODS: Participants were identified via recent publications in the field and were sent a questionnaire regarding infectious diseases encountered in the setting of HS, and opinions regarding infectious disease screening prior to various systemic immunomodulatory therapies. All questions were informed by a systematic literature review regarding infections exacerbated or precipitated by immunomodulatory therapy. Questionnaire responses were followed by round-table discussion with a core group of 8 experts followed by a final round of questionnaires resulting in achievement of consensus. RESULTS: 44 expert HS physicians from 12 countries on 5 continents participated in the development of the expert consensus recommendations. Consensus recommendations include screening for hepatitis B, hepatitis C and tuberculosis in all individuals with HS prior to therapy. All immunomodulatory therapies (biologic and systemic immunosuppressant therapy) should be preceded by infectious disease screening including patient and location specific considerations for endemic local diseases and high-risk activities and occupations. Clinical assessment has a significant role in determining the need for laboratory screening in the setting of many uncommon or tropical diseases such as leprosy, leishmaniasis and strongyloidiasis. CONCLUSIONS: The presented consensus recommendations are the first specifically developed for pre-treatment infectious disease screening in Hidradenitis Suppurativa.

The road to biologics in patients with hidradenitis suppurativa: a nationwide drug utilization study.

BACKGROUND: Prolonged systemic antibiotic treatment is often a part of management of hidradenitis suppurativa (HS). Although biologic therapies are now available, the patient's treatment journey leading to biologic therapy is unclear. OBJECTIVES: To examine treatment patterns and duration of systemic treatment use in patients with HS preceding biologic therapy. METHODS: We identified all patients with HS receiving treatment with biologics in the Danish National Patient Registry from 2010 to 2018 and extracted their entire prescription history of specific systemic treatments from the Danish National Prescription Registry since its inception in 1995. The patients' treatment journeys are graphically displayed through Sankey diagrams and box plots generated to show temporal distributions. Descriptive patient characteristics were presented as frequencies with percentages for categorical variables and as means with SDs or medians with interquartile ranges (IQRs) for continuous variables. RESULTS: A total of 225 patients with HS were included. Patients had most frequently been treated with penicillin (n = 214; 95·1%), dicloxacillin (n = 194; 86·2%), tetracycline (n = 145; 64·4%) and rifampicin/clindamycin (n = 111; 49·3%), as well as the retinoids isotretinoin and acitretin, and dapsone. Prior to biologic therapy, patients received a mean of 4·0 (SD 1·3) different systemic therapies, across a mean of 16·9 (SD 11·3) different treatment series. The mean time from first systemic therapy until biologic therapy was initiated was 15·3 (SD 5·1) years [8·2 (SD 5·9) years when excluding penicillin and dicloxacillin]. CONCLUSIONS: Patients with HS who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS. Delay in the initiation of biologic therapy may represent a missed opportunity to prevent disease progression. What is already known about this topic? The treatment journey leading to biologic therapy in patients with HS has not previously been investigated. What does this study add? Our data from 225 patients with HS illustrate that patients who receive biologic therapy have long preceding treatment histories with multiple drug classes and treatment series, many of which are supported by relatively weak evidence in HS.

Clinical, microbiological, immunological and imaging characteristics of tunnels and fistulas in hidradenitis suppurativa and Crohn's disease.

Hidradenitis suppurativa (HS) tunnels and Crohn's disease (CD) fistulas are a challenge to treat. Although pathogenic similarities have been described between HS and CD, recent studies indicate that clinical, microbiological, immunological and imaging characteristics differ between these diseases. This review highlights the differences between HS tunnels and CD fistulas. Next-generation sequencing studies demonstrate a microbiome in HS tunnels dominated by Porphyromonas spp., Prevotella spp. whereas no specific bacteria have been associated with cutaneous CD. Immunologically, TNF has been found upregulated in HS tunnels along with various interleukins (IL-8, IL-16, IL-1α and IL-1ß). In CD fistulas, Th1, Th17, IL-17, IFN-ɤ, TNF and IL-23 are increased. US imaging is an important tool in HS. US of HS tunnels depict hypoechoic band-like structure across skin layers in the dermis and/or hypodermis connected to the base of a widened hair follicle. In CD, MR imaging of simple perianal fistulas illustrates a linear, non-branching inflammatory tract relating to an internal opening in the anus or low rectum and an external opening to the skin surface. An increased awareness of the immediate potential differences between HS tunnels and CD fistulas may optimize treatment regimens of these intractable skin manifestations.

Bacterial aggregate size determines phagocytosis efficiency of polymorphonuclear leukocytes.

The ability of bacteria to aggregate and form biofilms impairs phagocytosis by polymorphonuclear leukocytes (PMNs). The aim of this study was to examine if the size of aggregates is critical for successful phagocytosis and how bacterial biofilms evade phagocytosis. We investigated the live interaction between PMNs and Pseudomonas aeruginosa, Staphylococcus aureus, Escherichia coli and Staphylococcus epidermidis using confocal scanning laser microscopy. Aggregate size significantly affected phagocytosis outcome and larger aggregates were less likely to be phagocytized. Aggregates of S. epidermidis were also less likely to be phagocytized than equally-sized aggregates of the other three species. We found that only aggregates of approx. 5 µm diameter or smaller were consistently phagocytosed. We demonstrate that planktonic and aggregated cells of all four species significantly reduced the viability of PMNs after 4 h of incubation. Our results indicate that larger bacterial aggregates are less likely to be phagocytosed by PMNs and we propose that, if the aggregates become too large, circulating PMNs may not be able to phagocytose them quickly enough, which may lead to chronic infection.

Bacterial biofilm is associated with higher levels of regulatory T cells in unaffected hidradenitis suppurativa skin.

BACKGROUND: The role of bacterial biofilm in hidradenitis suppurativa (HS) is highly debated. Less biofilm is found in clinically unaffected axillary perilesional skin of HS patients compared with healthy controls. OBJECTIVE: To study the correlation between biofilm and the phenotypical characterization of the preclinical inflammatory infiltrate. MATERIALS AND METHODS: An exploratory comparative study of punch biopsies from unaffected axillary HS skin compared to similarly biopsies from healthy controls underwent standard staining procedures for CD4, CD8, CD25, FoxP3 and IL17. Standard-sized inflammatory histological hotspots were identified manually. Slides were scanned into Leica Biosystems' Digital Image Hub. Number of stained cells per slide and hotspot was found using an algorithm. RESULTS: 12.5% of HS had biofilm compared to 85% of controls. For full slides, HS patients had more CD4+ cells than controls; HS patients with biofilm had higher CD4+ cell number than controls with or without biofilm and HS patients without biofilm. For hotspots, HS patients with biofilm had higher number of CD4+FoxP3+ cells than HS patients without biofilm and controls with biofilm. CONCLUSION: The association between biofilm and the number of regulatory T cells in HS patients supports the concept of dysbiosis as a factor in the preclinical HS lesions.

Haematoxylin and eosin staining identifies medium to large bacterial aggregates with a reliable specificity: A comparative analysis of follicular bacterial aggregates in axillary biopsies using peptide nucleic acid-fluorescence in situ hybridization and haematoxylin and eosin staining.

Although peptide nucleic acid (PNA), fluorescence in situ hybridization (FISH) and confocal laser scanning microscopy (CLSM) are the reference tools in the study of bacterial aggregates/biofilms, it may also be rather time-consuming. This study aimed to investigate the sensitivity and specificity between bacterial aggregates identified by haematoxylin and eosin (HE) staining vs bacterial aggregates in corresponding PNA-FISH samples. Axillary biopsies were obtained in 24 healthy controls. HE-stained and PNA-FISH samples were investigated using traditional light microscopy and CLSM, respectively. The data demonstrate that HE staining identifies large bacterial aggregates (>10 µm) with a sensitivity of 0.43 and specificity of 1. The methods, however, are not equivalent as demonstrated by a McNemar's test (P=.04). Where bacterial aggregates >10 µm in diameter, HE staining may offer a rapid and practical low-cost tool to evaluate bacterial aggregates.

Normal Skin Microbiota is Altered in Pre-clinical Hidradenitis Suppurativa.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease defined by recurrent nodules, tunnels (sinus tracts) and scarring involving the intertriginous regions. The clinical course of HS is compatible with a biofilm-driven disease, and biofilm has been described in lesional HS skin. We therefore hypothesized that clinically unaffected HS skin would also have an increased presence of biofilm compared with that of healthy controls. We conducted a case-control study, investigating the morphology of the axillary skin microbiota. Peptide nucleic acid - fluorescence in situ hybridization probes were used in combination with confocal laser scanning microscopy. Significant differences were found in both distribution and quantity of the cutaneous microbiota in clinically non-affected axillary skin of patients with HS compared with healthy controls. Surprisingly, we detected fewer bacteria and less biofilm in patients with HS. The reduced microbiota in patients with HS may play an important role in the early course of the disease.

Leukocyte Profile in Peripheral Blood and Neutrophil-Lymphocyte Ratio in Hidradenitis Suppurativa: A Comparative Cross-Sectional Study of 462 Cases.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, inflammatory skin disease. Increasing evidence suggests that HS involves dysfunctional immune responses in both the adaptive and the innate immune system. The recently proposed association of HS with metabolic syndrome may further add to the inflammatory state in HS. OBJECTIVE: To investigate the status of inflammation and leukocyte profile in the peripheral blood of HS patients. MATERIALS AND METHODS: Using a comparative cross-sectional study design, we investigated blood samples of high-sensitivity C-reactive protein (hs-CRP) and leukocyte profile in hospital-treated HS patients (HS-HOSP), self-reported population-based HS patients (HS-POP) and population controls. RESULTS: Our study comprised 32 individuals in the HS-HOSP group, 430 in the HS-POP group, and 20,780 controls. The median hs-CRP for the HS-HOSP group was 5.1 mg/l (quartile range 2.6-8.2), 2.2 mg/l (1.0-4.3) for the HS-POP group and 1.3 mg/l (0.7-2.9) for the controls. An age-sex-adjusted analysis revealed a significantly higher hs-CRP for both HS groups compared to controls (p < 0.0001). When performing age-sex-adjusted analysis, both HS groups had significantly higher odds of leukocytosis when compared to controls with an odds ratio for the HS-HOSP group of 4.38 (95% CI = 2.18-8.80; p < 0.0001) and 1.95 (95% CI = 1.58-2.42; p < 0.0001) for the HS-POP group. The age-sex-adjusted leukocyte differential count yielded significantly higher neutrophil (p < 0.0001) and monocyte (p = 0.0014, p = 0.0004) levels in the HS groups compared with controls. CONCLUSION: The hs-CRP levels associated with HS appear to be intermediate (2.2-5.1 mg/l), implying systemic inflammation rather than infection. The peripheral blood leukocytosis in HS was dominated by neutrophils and monocytes.

Disutility in Patients with Hidradenitis Suppurativa: A Cross-sectional Study Using EuroQoL-5D.

Disutility reflects the disability caused by a disease. The EuroQoL-5D (EQ-5D) questionnaire is a measure of health-related overall utility. The questionnaire has only been applied previously to a small number of patients with hidradenitis. In this study a survey of 421 patients with hidradenitis suppurativa was conducted using the EQ-5D questionnaire. Questions regarding pain, malodour and pruritus were included to determine quantitatively whether these factors are associated with low EQ-5D index and visual analogue scale (VAS) scores. The index and VAS scores obtained were compared with reference values for the general population in Denmark. A significantly decreased utility in patients with hidradenitis suppurativa was found for all age group levels, except for 65-74-year-olds. The total index score in the cohort was 0.705 (population mean 0.887) and the VAS was 62.25 (population mean 82.6). Multivariate analysis found significant associations between loss of utility and pain, malodour and pruritus (p < 0.0001). Patients with hidradenitis suppurativa had a significantly decreased EQ-5D compared with the background population. Malodour and pruritus were found to be associated with low index values, and pain and malodour with low VAS. Patient-reported pain and discomfort had the most negative overall effect on mean index scores.

The bacteriology of hidradenitis suppurativa: a systematic review.

Hidradenitis suppurativa (HS) is a chronic inflammatory disabling skin disease consisting of recurrent nodules, sinuses, fistulas and scarring involving the intertriginous regions. HS is often a therapeutic challenge and most treatments are off-label. A better understanding of aetiology and pathogenesis of HS may facilitate the development of effective treatment. Although the clinical presentation is strongly reminiscent of bacterial infection, the role of bacteria remains controversial. Studies have isolated an array of different bacteria specimens. Consistent findings of Gram-positive cocci and Gram-positive rods including Staphylococus aureus, coagulase-negative staphylococci (CoNS) and Corynebacterium species in deep tissue samples have been demonstrated in HS and may constitute a central target for the immune system. Efficacy of antibiotics, that is rifampicin, clindamycin or tetracycline, supports a microbial role in disease pathogenesis. However, these antibiotics also work as immunomodulators of especially T cells, and the underlying mechanisms may therefore be more complex. We performed a systematic review of previous studies investigating the bacterial flora in hidradenitis suppurativa. We searched PubMed, EMBASE, Royal Danish Library and Cochrane library (search date 11 December 2014). A total of 66 papers were identified and nine papers published between 1988 and 2014 matched our inclusion criteria, yielding bacteriological data of a total of 324 patients with HS (mean age 36.8 years and female/male ratio 215/109). This overview of the bacteriology may aid researchers and physicians exploring the potential role of bacteria in HS. Furthermore, to stimulate a broader debate, we also present different viewpoints on the possible role of bacteria in HS.