Phytotherapeuthics Affecting the IL-1/IL-17/G-CSF Axis: A Complementary Treatment Option for Hidradenitis Suppurativa?

Hidradenitis suppurativa (HS; also designated as acne inversa) is a chronic inflammatory disease characterized by painful skin lesions that occur in the axillary, inguinal, gluteal and perianal areas of the body. These lesions contain recurring deep-seated, inflamed nodules and pus-discharging abscesses and fistulas. Affecting about 1% of the population, this common disease has gained appropriate clinical attention in the last years. Associated with numerous comorbidities including metabolic syndrome, HS is considered a systemic disease that severely impairs the quality of life and shortens life expectancy. Therapeutic options for HS are limited, comprising long-term antibiotic treatment, the surgical removal of affected skin areas, and neutralization of TNF-α, the only approved systemic treatment. Novel treatment options are needed to close the therapeutic gap. HS pathogenesis is increasingly better understood. In fact, neutrophilic granulocytes (neutrophils) seem to be decisive for the development of the purulent destructive skin inflammation in HS. Recent findings suggest a key role of the immune mediators IL-1ß, IL-17A and G-CSF in the migration into and activation of neutrophils in the skin. Although phytomedical drugs display potent immunoregulatory properties and have been suggested as complementary therapy in several chronic disorders, their application in HS has not been considered so far. In this review, we describe the IL-1/IL-17/G-CSF axis and evaluate it as potential target for an integrated phytomedical treatment of HS.

Altered keratinization and vitamin D metabolism may be key pathogenetic pathways in syndromic hidradenitis suppurativa: a novel whole exome sequencing approach.

BACKGROUND: Diagnosis of pyoderma gangrenosum, acne and hidradenitis suppurativa (PASH) and pyogenic arthritis, pyoderma gangrenosum, acne, and hidradenitis suppurativa (PAPASH) patients, in spite of recently identified genetic variations, is just clinical, since most patients do not share the same mutations, and the mutations themselves are not informative of the biological pathways commonly disrupted in these patients. OBJECTIVE: To reveal genetic changes more closely related to PASH and PAPASH etiopathogenesis, identifying novel common pathways involved in these diseases. METHODS: Cohort study on PASH (n = 4) and PAPASH (n = 1) patients conducted using whole exome sequencing (WES) approach and a novel bioinformatic pipeline aimed at discovering potentially candidate genes selected from density mutations and involved in pathways relevant to the disease. RESULTS: WES results showed that patients presented 90 genes carrying mutations with deleterious and/or damage impact: 12 genes were in common among the 5 patients and bared 237 ns ExonVar (54 and 183 in homozygosis and heterozygosis, respectively). In the pathway enrichment analysis, only 10 genes were included, allowing us to retrieve 4 pathways shared by all patients: (1) Vitamin D metabolism, (2) keratinization, (3) formation of the cornified envelope and (4) steroid metabolism. Interestingly, all patients had vitamin D levels lower than normal, with a mean value of 10 ng/mL. CONCLUSION: Our findings, through a novel strategy for analysing the genetic background of syndromic HS patients, suggested that vitamin D metabolism dysfunctions seem to be crucial in PASH and PAPASH pathogenesis. Based on low vitamin D serum levels, its supplementation is envisaged.

Lipidomics Profiling of Hidradenitis Suppurativa Skin Lesions Reveals Lipoxygenase Pathway Dysregulation and Accumulation of Proinflammatory Leukotriene B4.

Hidradenitis suppurativa (HS) is a chronic, recurring inflammatory dermatosis characterized by abscesses, deep-seated nodules, sinus tracts, and fibrosis in skin lesions around hair follicles of the axillary, inguinal, and anogenital regions. Whereas the exact pathogenesis remains poorly defined, clear evidence suggests that HS is a multifactorial inflammatory disease characterized by innate and adaptive immune components. Bioactive lipids are important regulators of cutaneous homeostasis, inflammation, and resolution of inflammation. Alterations in the lipid mediator profile can lead to malfunction and cutaneous inflammation. We used targeted lipidomics to analyze selected omega-3 and omega-6 polyunsaturated fatty acids in skin of patients with HS and of healthy volunteers. Lesional HS skin displayed enrichment of 5-lipoxygenase (LO)‒derived metabolites, especially leukotriene B4. In addition, 15-LO‒derived metabolites were underrepresented in HS lesions. Changes in the lipid mediator profile were accompanied by transcriptomic dysregulation of the 5-LO and 15-LO pathways. Hyperactivation of the 5-LO pathway in lesional macrophages identified these cells as potential sources of leukotriene B4, which may cause neutrophil influx and activation. Furthermore, leukotriene B4-induced mediators and pathways were elevated in HS lesions, suggesting a contribution of this proinflammatory lipid meditator to the pathophysiology of HS.

Biologic therapies for the treatment of hidradenitis suppurativa.

Introduction: Hidradenitis suppurativa (HS) is a chronic skin disorder characterized by inflammatory nodules, abscesses, and fistulae. Patients tend to present in young adulthood and are predominantly female. The pathogenesis of HS involves apopilosebaceous gland follicle occlusion and affected areas often occur where this type of gland predominates. Treatment selection depends on HS severity, which is included in different scoring systems. In recent years, biological therapies have been evaluated and used with increasing frequency in moderate-to-severe HS disease.Areas covered: This review focuses on biological therapies for HS as assessed in case reports, case series, and clinical trials. The efficacy, hidradenitis suppurativa scoring systems, and long-term results of these therapies are discussed depending on the studies' endpoints.Expert opinion: Adalimumab is currently the only FDA-approved HS biological therapy. Some patients do not experience treatment efficacy with adalimumab at 40 mg/week, which may result in increasing the dose or seeking other treatments. Infliximab is the next line of HS treatment with demonstrated efficacy. Other biological therapies being studied have demonstrated efficacy in small patient groups, but lack study power. Further studies may provide answers to seeking treatment options for patients who fail to improve on current standard HS treatment.

Combination hyperbaric oxygen therapy and ustekinumab for severe hidradenitis suppurativa.

Hidradenitis suppurativa is a painful chronic inflammatory skin condition characterized by inflammatory nodules that can lead to sinus tracts and scarring. Numerous treatments have been reported, though none have reliable efficacy. Antiinflammatory agents, such as tumor necrosis factor-alpha inhibitors and interleukin inhibitors, have been used as medical therapy for refractory cases. We describe here a case of severe hidradenitis suppurativa in a pediatric patient successfully treated with a combination of high-dose ustekinumab and hyperbaric oxygen therapy.

Successful control of hidradenitis suppurativa with verapamil: a case report.

An inappropriate immunologic response has been suggested to play a role in the pathogenesis of hidradenitis suppurativa (HS). Adalimumab was the first TNF-α inhibitor approved for moderate to severe HS. We report on a case of HS (Hurley stage 2) in a 39-year-old man, who had received fusidic acid and isotretinoin treatments without evident benefit during the last 8 years. The patient noticed a reduction in the number of lesions and quality of life (DLQI from 27 to 6) in the 2 months following verapamil initiation for cluster headache. When verapamil was stopped, the lesions recurred within 1.5 months. The patient resumed taking verapamil as before and a remission occurred. Verapamil has been shown to inhibit TNF-α and IL-1ß in vitro and in vivo. We hypothesize that verapamil inhibits the inflammatory process through the TNF-α/IL-1 pathway involved in the HS physiopathology. Compared to biologic agents as anti-TNF-α (adalimumab) and anti-IL1 (anakinra), verapamil is safer and cheaper. Given its possible role on TNF-α/IL-1, verapamil may represent an alternative therapeutic option in mild and moderate HS.

Efficacy of rifampin-moxifloxacin-metronidazole combination therapy in hidradenitis suppurativa.

BACKGROUND: Antibiotics have been shown to improve hidradenitis suppurativa (HS) patients but complete remission is rare using these treatments. OBJECTIVE: To assess the efficacy and safety of a combination of oral rifampin, moxifloxacin and metronidazole in long-lasting refractory HS. METHODS: We retrospectively studied 28 consecutive HS patients including 6, 10 and 12 Hurley stage 1, 2 and 3 patients, respectively. Complete remission, defined as a clearance of all inflammatory lesions including hypertrophic scars, was the main outcome criterion of the study. RESULTS: Complete remission was obtained in 16 patients, including 6/6, 8/10 and 2/12 patients with Hurley stage 1, 2 and 3, respectively (p=0.0004). The median duration of treatment to obtain complete remission was 2.4 (range 0.9-6.5) and 3.8 months (range 1.6-7.4) in stage 1 and 2 patients, respectively, and 6.2 and 12 months in the 2 stage 3 patients. Main adverse events of the treatments were gastrointestinal disorders (64% of patients) and vaginal candidiasis (35% of females). Reversible tendinopathy and hepatitis occurred in 4 and 1 patient, respectively. CONCLUSIONS: Complete remission of refractory HS can be obtained using broad-spectrum antibiotics and Hurley staging is a prognostic factor of response to the treatment.

ALA-PDT and blue light therapy for hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic, often suppurative skin condition which affects primarily apocrine glands. A variety of therapies have been used to treat HS, often with unsatisfactory results. Photodynamic therapy (PDT), utilizing topical 20% 5-aminolevulinic acid (ALA) is being used to treat a variety of dermatologic skin concerns, including photorejuvenation and associated actinic keratoses, and acne vulgaris, and other skin tumors. OBJECTIVE: The purpose of these case reports is to evaluate the effectiveness of ALA-PDT in treating recalcitrant cases of HS. METHODS: Four patients, not responding to standard HS therapy, underwent short-contact ALA-PDT therapy utilizing a blue light for activation. One to two week intervals between therapies was utilized for 3-4 total treatments and follow-up was for 3 months following the last treatment. RESULTS: All four of the patients tolerated the therapies well. Clinical improvements from 75-100% were noted n 11 of the patients. No adverse effects were seen during the treatments. The treatments were pain free and there was no downtime associated with these ALA-PDT treatments. CONCLUSIONS: HS is a chronic disease which most dermatologists find difficult to treat. The use of ALA-PDT is finding an ever-expanding role in dermatology. These case studies support the use of ALA-PDT in cases of HS. Although all advertising material is expected to conform to ethical and medical standards, inclusion in this publication does not constitute a guarantee or endorsement by the Journal or its staff of the quality or value of such products or of the claims of any manufacturer.