High Unemployment Rate in Patients with Hidradenitis Suppurativa despite High Educational Attainment.

BACKGROUND: Hidradenitis suppurativa (HS) is associated with lower socioeconomic status (SES). The adverse influence of HS on education and employment may explain this. It remains unknown whether HS causes downward social trajectories, i.e., social drift, or whether those affected are born into a lower SES. We aimed to assess the influence of HS on education and employment and compare the highest educational attainment of participants with their parents. METHODS: An anonymous online survey was distributed by patient-led organisations. Frequencies were compared with χ2 and disease interactions with one-way ANOVA. RESULTS: Among 335 respondents from 10 countries, 94.9% completed secondary/high school, 71.3% completed further education, 41.8% completed an undergraduate degree, 20% completed postgraduate education, 10.7% completed a masters, and 2.1% completed a doctorate. Participant education was greater than parental education (p < 0.001). Despite this, 24.2% were unemployed and 15.2% were receiving illness benefit. Compared to national statistics, HS participants from Ireland (p = 0.003), the USA (p < 0.001), and the UK (p < 0.001) were more likely to be unemployed/receiving illness benefit despite higher educational attainment in Ireland (p = 0.006) and the USA (p = 0.003) with similar education in the UK (p = 0.153). CONCLUSIONS: Social drift describes downward social trajectories due to the development of a disease. Participants in this study report greater education than their parents and the background population, but despite this, they are experiencing downward social trajectories with higher unemployment and receipt of illness benefit. Disease onset in HS tends to be at peak educational age. Education does not appear to be impaired by early disease with disease accumulation during employment years limiting opportunities.

Treatment of hidradenitis suppurativa with adalimumab in the PIONEER I and II trials reduced indices of systemic inflammation, recognised risk factors for cardiovascular disease.

BACKGROUND: Hidradenitis suppurativa (HS) is associated with increased cardiovascular disease (CVD) risk. Systemic immune inflammation index (SII), neutrophil/lymphocyte (NLR), platelet/lymphocyte (PLR) and monocyte/lymphocyte ratios (MLR) are biomarkers of systemic inflammation and CVD. One small study identified a lower NLR and PLR in patients treated with adalimumab. OBJECTIVES: Our aim was to assess changes in SII, NLR, PLR and MLR in a larger cohort, and to evaluate their association with disease severity and treatment response. METHODS: This was a post-hoc analysis of PIONEER I and PIONEER II, two phase 3 randomised placebo-controlled clinical trials of adalimumab for HS. SII, NLR, PLR and MLR were log10-transformed and linear mixed model was used to estimate treatment effect. RESULTS: SII, NLR, PLR and MLR reduced from baseline levels with adalimumab treatment by week 12, when the primary response endpoint was assessed. Significant changes first appeared at week 4 and were maintained to week 36. In contrast, no significant changes were observed in placebo-treated patients. In patients re-randomised at week 12 from placebo to adalimumab, SII, NLR, PLR and MLR also reduced within 4 weeks. In patients re-randomised from adalimumab to placebo, these biomarkers returned to baseline by week 36. In addition, SII, NLR and PLR correlated with draining fistula count (r=0.26-0.43, p<0.001). Adalimumab non-responders in PIONEER I had a higher SII, NLR and PLR at baseline and week 12, but this was not significant when adjusted for draining fistulae. CONCLUSIONS: Treatment of HS patients with adalimumab results in rapid sustained reduction in systemic inflammation measured by SII, NLR, PLR and MLR which correlate with CVD risk. SII, NLR and PLR may predict adalimumab response, although dependent on their interaction with the number of draining fistulae.

Metformin has anti-inflammatory effects and induces immunometabolic reprogramming via multiple mechanisms in hidradenitis suppurativa.

BACKGROUND: Targeting immunometabolism has shown promise in treating autoimmune and inflammatory conditions. Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease involving painful lesions in apocrine gland-bearing skin. Therapeutic options for HS are limited and often ineffective; thus, there is a pressing need for improved treatments. To date, metabolic dysregulation has not been investigated in HS. As HS is highly inflammatory, we hypothesized that energy metabolism is dysregulated in these patients. Metformin, an antidiabetic drug, which is known to impact on cellular metabolic and signalling pathways, has been shown to have anti-inflammatory effects in cancer and arthritis. While metformin is not licensed for use in HS, patients with HS taking metformin show improved clinical symptoms. OBJECTIVE: To assess the effect and mechanism of action of metformin in HS. METHODS: To assess the effect of metformin in vivo, we compared the immune and metabolic profiles of peripheral blood mononuclear cells (PBMCs) of patients with HS taking metformin vs. those not taking metformin. To examine the effect of metformin treatment ex vivo, we employed a skin explant model on skin biopsies from patients with HS not taking metformin, which we cultured with metformin overnight. We used enzyme-linked immunosorbent assays, multiplex cytokine assays and quantitative real-time polymerase chain reaction (RT-PCR) to measure inflammatory markers, and Seahorse flux technology and quantitative RT-PCR to assess glucose metabolism. RESULTS: We showed that metabolic pathways are dysregulated in the PBMCs of patients with HS vs. healthy individuals. In metformin-treated patients, these metabolic pathways were restored and their PBMCs had reduced inflammatory markers following long-term metformin treatment. In the skin explant model, we found that overnight culture with metformin reduced inflammatory cytokines and chemokines and glycolytic genes in lesions and tracts of patients with HS. Using in vitro assays, we found that metformin may induce these changes via the NLR family pyrin domain containing 3 (NLRP3) inflammasome and the AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR) pathway, which is linked to glycolysis and protein synthesis. CONCLUSIONS: Our study provides insight into the mechanisms of action of metformin in HS. The anti-inflammatory effects of metformin support its use as a therapeutic agent in HS, while its effects on immunometabolism suggest that targeting metabolism is a promising therapeutic option in inflammatory diseases, including HS.

Treatment of hidradenitis suppurativa with brodalumab in biologic treatment failures: experiences from a specialty clinic.

Hidradenitis suppurativa (HS) is characterized by increased interleukin (IL)-17A/C/F. Two open-label trials of brodalumab, an IL-17 receptor antagonist, have been completed, with 8 of 10 patients receiving brodalumab fortnightly and 10 of 10 patients receiving brodalumab weekly achieving 75% Hidradenitis Suppurativa Clinical Response. All patients were biologic 'experienced' but were not reported to have failed biologic treatment. We report outcomes for eight patients with HS who had failed at least one biologic, treated with brodalumab 210 mg fortnightly, to provide real-world evidence. Four of eight patients remain on brodalumab, with a mean treatment duration of 11.3 months. All patients who remain on brodalumab subjectively report continued treatment efficacy. The mean Dermatology Life Quality Index reduced from 20.6 to 16.8 at week 16. All patients required concurrent antibiotics due to flares. Brodalumab may be effective in patients who have previously failed multiple biologics, but efficacy in our real-world study falls short of the two open-label trials. This may reflect severe treatment-resistant disease. In the absence of further licensed treatments for HS, brodalumab may be a good option following adalimumab failure.

Shorter time to initiation of biologic therapy in the setting of a hidradenitis suppurativa specialty clinic.

Hidradenitis suppurativa (HS) is a chronic condition with a significant psychological and physical burden but a paucity of effective treatments. Early intervention with adalimumab improves disease outcomes. Two previous studies in Denmark and Northern Ireland have identified a time of 8.2 and 2.9 years, respectively, from first HS systemic/dermatology consultation to commencing a biologic. We aimed to evaluate the time from disease onset and from first specialty HS clinic review to the initiation of biologic therapy. We retrospectively reviewed 34 patients on biologic treatment for HS. The mean diagnostic delay was 12.4 years. The mean time from disease onset to biologic initiation was 14.8 years. Prior to a biologic, patients received a median of 3.3 treatments from the specialty HS clinic. The median time to biologic from first presentation at the specialty HS clinic was 1 year. This is shorter than the therapeutic delay reported in dermatology clinics in Denmark and Northern Ireland, providing evidence on the importance of specialized HS treatment. However, to make an impact with specialized HS care and earlier biologic initiation, diagnostic delay needs to be reduced.

Metformin Treatment of Hidradenitis Suppurativa: Effect on Metabolic Parameters, Inflammation, Cardiovascular Risk Biomarkers, and Immune Mediators.

Hidradenitis suppurativa (HS) is a common cutaneous and systemic inflammatory disease with a significant impact on mental health and quality of life. It is associated with obesity, insulin resistance, metabolic syndrome, cardiovascular (CV) disease, and increased all-cause mortality. Metformin is used frequently in HS treatment and is effective for some patients. The mechanism of action of metformin in HS is unknown. A case-control study of 40 patients with HS (20 on metformin and 20 controls) was conducted to assess differences in metabolic markers, inflammation (C-reactive protein [CRP], serum adipokines, and CV risk biomarkers), and serum immune mediators. Body mass index (BMI), insulin resistance (77%), and metabolic syndrome (44%) were high overall, but not significantly different between the groups. This highlights the need for co-morbidity screening and management. A significant reduction in fasting insulin and a trend towards a reduction in insulin resistance were identified in the metformin group compared with pre-treatment levels. CV risk biomarkers were significantly favourable in the metformin group (lymphocytes, monocyte-lymphocyte ratio, neutrophil-lymphocyte ratio, and platelet-lymphocyte ratio). CRP was lower in the metformin group but was not statistically significant. Adipokines were dysregulated overall but were not different between the two groups. Serum IFN-γ, IL-8, TNF-α, and CXCL1 trended lower in the metformin group but did not reach significance. These results suggest that metformin improves CV risk biomarkers and insulin resistance in patients with HS. When the results of this study are considered alongside other studies in HS and related conditions, it is likely that metformin also has beneficial effects on metabolic markers and systemic inflammation in HS (CRP, serum adipokines, and immune mediators), warranting further research.

Alcohol and Psoriasis for the Dermatologist: Know, Screen, Intervene.

Psoriasis patients are at increased risk of harmful alcohol use and alcohol dependency with many deleterious effects. Increasing alcohol use is associated with worsening psoriasis severity, is a risk factor for poor response to systemic treatments and may impact on comorbidities such as psoriatic arthritis, cardiovascular disease, cancer and liver disease. Harmful alcohol use and alcohol dependency can be defined by the updated ICD-11 coding system and screening can be completed using many tools including the Cut down, Annoyed, Guilty, Eye-Opener (CAGE), Alcohol Use Disorders Identification Test (AUDIT) and Michigan Alcohol Screening Test (MAST) questionnaires. Dermatologists may be able to complete brief interventions encouraging alcohol reduction in psoriasis patients. Psoriasis patients may respond to messages of gain with reduced psoriasis severity and loss with reduced cardiovascular risk. It is important for dermatologists to discuss alcohol with all psoriasis patients, to be aware of the impact of alcohol in psoriasis and to familiarise themselves with screening tools, brief intervention and local services available to patients who require specialist input for harmful alcohol use or alcohol dependency.

Real world use of biologic drug levels and anti-drug antibodies in patients with psoriasis - does therapeutic drug monitoring have a place in routine clinical practice?

Background: Psoriasis is a chronic disorder with increasing new treatments targeting the T-helper cell (Th)-1/Th17 axis. There remains a subset of patients who experience a primary or secondary failure to biologic treatments.Methods: We present ten patients with psoriasis who failed biologic therapy with measurement of serum drug levels and anti-drug antibody levels (ADAs) with review of the current literature. Our objective was to identify demographic factors, disease status, drug level and ADAs which might correlate with primary and secondary failure.Results: There are a number of factors affecting drug levels in patients with psoriasis on biologics including the presence of ADAs, patient adherence to treatment regimes, pharmacogenetics and the pharmacokinetic properties of the drug following subcutaneous injection. Our results demonstrate that biologic failure is related to low serum drug levels subtherapeutic in 80% of our cohort. Primary failure may correlate with the presence of ADAs but not with serum drug levels. All patients were ANA negative and there remains considerable debate on the utility of routine ANA testing.Conclusions: The role of therapeutic drug monitoring in dermatology remains uncertain and requires further study. We aim to promote debate in the dermatology community as to the utility of therapeutic drug monitoring in routine practice.

Association of beta-glucan endogenous production with increased stress tolerance of intestinal lactobacilli.

The exopolysaccharide beta-glucan has been reported to be associated with many health-promoting and prebiotic properties. The membrane-associated glycosyltransferase enzyme (encoded by the gtf gene), responsible for microbial beta-glucan production, catalyzes the conversion of sugar nucleotides into beta-glucan. In this study, the gtf gene from Pediococcus parvulus 2.6 was heterologously expressed in Lactobacillus paracasei NFBC 338. When grown in the presence of glucose (7%, wt/vol), the recombinant strain (pNZ44-GTF(+)) displayed a "ropy" phenotype, while scanning electron microscopy (SEM) revealed strands of polysaccharide-linking neighboring cells. Beta-glucan biosynthesis was confirmed by agglutination tests carried out with Streptococcus pneumoniae type 37-specific antibodies, which specifically detect glucan-producing cells. Further analysis showed a approximately 2-fold increase in viscosity in broth media for the beta-glucan-producing strain over 24 h compared to the control strain, which did not show any significant increase in viscosity. In addition, we analyzed the ability of beta-glucan-producing Lactobacillus paracasei NFBC 338 to survive both technological and gastrointestinal stresses. Heat stress assays revealed that production of the polysaccharide was associated with significantly increased protection during heat stress (60-fold), acid stress (20-fold), and simulated gastric juice stress (15-fold). Bile stress assays revealed a more modest but significant 5.5-fold increase in survival for the beta-glucan-producing strain compared to that of the control strain. These results suggest that production of a beta-glucan exopolysaccharide by strains destined for use as probiotics may afford them greater performance/protection during cultivation, processing, and ingestion. As such, expression of the gtf gene may prove to be a straightforward approach to improve strains that might otherwise prove sensitive in such applications.

Association of Biologic Treatment in Hidradenitis Suppurativa With Reduced Neutrophil-Lymphocyte Ratio and Platelet-Lymphocyte Ratio.

This cohort study assesses whether an association exists between biologic treatment for hidradenitis suppurativa and neutrophil-lymphocyte ratio, platelet-lymphocyte ratio, and monocyte-lymphocyte ratio.