Biology of Interleukin-17 and Novel Therapies for Hidradenitis Suppurativa.

Skin disorders affect ∼40% of the human population. One of the most debilitating cutaneous disorders is Hidradenitis suppurativa (HS), a noncommunicable chronic inflammatory disease with an estimated global prevalence of 0.4% to 2.5%. In January 2011, high levels of IL-17 were discovered in skin lesions of HS patients. In the following years, translational and clinical research led to a better understanding of the pathogenesis of HS. In June 2023, more than 12 years after the initial note, secukinumab, an anti-IL-17A monoclonal antibody, was approved for the treatment of moderate to severe HS. This is the next milestone in improving the treatment of these patients after the approval of the anti-TNF-α monoclonal antibody adalimumab in 2015. In this review article, we present the IL-17 pathway in HS and discuss the use of secukinumab as a therapeutic option for this disease. Our review starts with a description of the epidemiology, clinical features, etiology, and pathogenesis of HS. An overview of the IL-17/IL-17 receptor system in general and a detailed description of the known facts about the expression and action of IL-17 in HS follow. Afterward, we consider the results of clinical trials evaluating the safety and efficacy of IL-17 inhibitors in HS. Finally, a comparison is made between secukinumab and adalimumab and the characteristics of the patients that may be particularly suitable for each of these biologics are described.

Neutrophilic granulocyte-derived B-cell activating factor supports B cells in skin lesions in hidradenitis suppurativa.

BACKGROUND: Hidradenitis suppurativa (HS) is a chronic inflammatory disease characterized by painful inflamed nodules, abscesses, and pus-draining tunnels appearing in axillary, inguinal, and perianal skin areas. HS lesions contain various types of immigrated immune cells. OBJECTIVE: This study aimed to characterize mediators that support lesional B/plasma cell persistence in HS. METHODS: Skin samples from several cohorts of HS patients and control cohorts were assessed by mRNA sequencing, quantitative PCR on reverse-transcribed RNA, flow cytometry, and immunohistofluorescence. Blood plasma and cultured skin biopsy samples, keratinocytes, dermal fibroblasts, neutrophilic granulocytes (neutrophils), monocytes, and B cells were analyzed. Complex systems biology approaches were used to evaluate bulk and single-cell RNA sequencing data. RESULTS: Proportions of B/plasma cells, neutrophils, CD8+ T cells, and M0 and M1 macrophages were elevated in HS lesions compared to skin of healthy and perilesional intertriginous areas. There was an association between B/plasma cells, neutrophils, and B-cell activating factor (BAFF, aka TNFSF13B). BAFF was abundant in HS lesions, particularly in nodules and abscesses. Among the cell types present in HS lesions, myeloid cells were the main BAFF producers. Mechanistically, granulocyte colony-stimulating factor in the presence of bacterial products was the major stimulus for neutrophils' BAFF secretion. Lesional upregulation of BAFF receptors was attributed to B cells (TNFRSF13C/BAFFR and TNFRSF13B/TACI) and plasma cells (TNFRSF17/BCMA). Characterization of the lesional BAFF pathway revealed molecules involved in migration/adhesion (eg, CXCR4, CD37, CD53, SELL), proliferation/survival (eg, BST2), activation (eg, KLF2, PRKCB), and reactive oxygen species production (eg, NCF1, CYBC1) of B/plasma cells. CONCLUSION: Neutrophil-derived BAFF supports B/plasma cell persistence and function in HS lesions.

Patient-reported Outcomes and Clinical Response in Patients with Moderate-to-severe Plaque Psoriasis Treated with Tonsillectomy: A Randomized Controlled Trial.

Psoriasis is a chronic inflammatory skin disease with profound effects on patients' health-related quality of life (HRQoL). Twenty-nine patients with plaque psoriasis and a history of streptococcal-associated psoriasis exacerbations were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and followed for 24 months. Patients were evaluated with the Psoriasis Disability Index, Psoriasis Life Stress Inventory and Psoriasis Area and Severity Index. HRQoL and psoriasis-related stress improved significantly in the tonsillectomy group compared with the control group (p = 0.037 and p = 0.002, respectively), with a mean 50% improvement in HRQoL and a mean 59% improvement in psoriasis-induced stress. Clinical improvement correlated significantly with improved HRQoL (r = 0.297, p = 0.008) and psoriasis-related stress (r = 0.310, p = 0.005). Of the tonsillectomized patients, 87% concluded that the procedure was worthwhile. Tonsillectomy may improve quality of life for selected patients with plaque psoriasis.

Psoriatic arthritis and onycholysis -- results from the cross-sectional Reykjavik psoriatic arthritis study.

OBJECTIVE: To measure the associations between subtypes of nail changes and psoriatic arthritis (PsA) among patients with psoriasis. METHODS: Patients age 18 years and older with active psoriasis were examined for skin and nail changes and asked if they had been diagnosed with PsA. Patients with arthritis were invited for a separate study 1-6 years after their initial visit. Univariate and multivariate analyses were used to test the strength of associations between subtypes of nail changes and arthritis. RESULTS: Of 1116 patients with psoriasis, 37% (95% CI 34%-40%) had nail changes. Age, any nail change, onycholysis, and pitting were each associated with PsA on univariate analysis. Multivariate analysis showed that onycholysis was the only type of nail change independently associated with PsA (OR 2.05, p < 0.001). Nail changes persisted and had increased in prevalence at the followup examination at a mean of 3.8 (median 4 yrs, interquartile range 3-4) years later. Previously reported associations between psoriasis location and arthritis were not seen in this dataset. CONCLUSION: PsA is associated with onycholysis. Associations with pitting and subungual hyperkeratosis were not statistically significant. Subtypes of nail changes should be analyzed separately in future studies of PsA.

Improvement of psoriasis after tonsillectomy is associated with a decrease in the frequency of circulating T cells that recognize streptococcal determinants and homologous skin determinants.

Exacerbation of chronic psoriasis can be associated with streptococcal throat infections, and T cells that respond to peptide sequences common to streptococcal M proteins and skin keratins have been detected in patients' blood. To our knowledge, we have conducted the first blinded, prospective study to assess the impact of tonsillectomy on psoriasis. Twenty-nine patients with chronic psoriasis and history of exacerbation after sore throat were randomly assigned to tonsillectomy (n = 15) or control (n = 14) groups and monitored for 2 y clinically and by enumeration of circulating skin homing T cells that respond to short homologous M protein or keratin peptides. Thirteen patients (86%) showed sustained improvement after tonsillectomy ranging from 30 to 90% reduction in disease severity. Furthermore, there was a close correlation between the degree of clinical improvement in individual patients and reduction in the frequency of peptide-reactive skin-homing T cells in their circulation. No corresponding clinical or immunologic changes were observed among the controls. These findings indicate that tonsillectomy may have a beneficial effect on chronic psoriasis because the palatine tonsils generate effector T cells that recognize keratin determinants in the skin.

Psoriatic arthritis in Reykjavik, Iceland: prevalence, demographics, and disease course.

OBJECTIVE: To determine the prevalence, demographics, and course of psoriatic arthritis (PsA) in the Reykjavik area of Iceland. METHODS: In total 220 patients >/= 18 years of age living in the Reykjavik area of Iceland were located in a community registry of psoriatic patients and in hospital records. Of these, 156 (71%) were interviewed and examined for verification of skin and joint disease according to published criteria. RESULTS: Prevalence of PsA in the adult population was estimated to be 164 per 100,000 (95% CI 143-187), adjusted to 139 per 100,000 (95% CI 112-169) after exclusion of 25 individuals. The female to male ratio was close to 2:1. The mean age at skin disease onset was 23 years, with significantly earlier onset in women (age 20 yrs in women vs 26 yrs in men; p = 0.01), but there was no significant difference for age at the time of onset of joint disease. Mean duration of PsA was 20 years. Oligoarthritis was the most common (44%), followed by polyarthritis (31%), enthesitis (8%), and inflammatory back pain (7%). According to patients' recall of clinical features at onset, 78 patients (60%) had changed categories of PsA at the time of the study, most frequently from polyarthritis to oligoarthritis (48%), followed by oligoarthritis to polyarthritis (36%). These changes seemed independent of use of disease modifying drugs, which 54% had received. CONCLUSION: PsA in Reykjavik, Iceland, has a prevalence of at least 0.14% and is strikingly more common in women. The majority of patients reported a change in the pattern of affected joints during the course of their disease.

Narrowband-UVB irradiation decreases the production of pro-inflammatory cytokines by stimulated T cells.

Narrow-band ultraviolet B (UVB) phototherapy is an effective treatment for psoriasis. Owing to its limited penetration, the direct effects of UVB are mostly restricted to cells residing in the epidermis and papillary dermis, and are associated with epidermal depletion of Langerhans' cells (LC) and T cells. It has been argued that the depletion of the skin-resident T-cell population may be due to a combination of UVB-induced apoptosis and decreased recruitment from the blood due to lower expression of the required adhesion and homing molecules. We have previously demonstrated that UVB treatment can alter the expression of adhesion molecules by blood lymphocytes, and as these can be influenced by cytokines, the aim of this study was to investigate whether UVB irradiation can also influence the cytokine production of circulating T cells. Four patients with active chronic plaque psoriasis were treated daily with narrow-band 312 nm UVB irradiation and blood samples obtained before treatment and weekly thereafter for 2 weeks. Peripheral blood mononuclear cells (PBMCs) were isolated and cultured with a streptococcal superantigen or a conventional streptococcal antigen preparation, and cell culture supernatants were assayed for various cytokines. When stimulated with the superantigen, PBMCs from UVB-treated psoriasis patients secreted greater amounts of the anti-inflammatory cytokine IL-10, and showed markedly decreased production of IL-1beta, IL-2, IL-5 and IL-6 compared to the pre-treatment values; the production of IFN-gamma, IL-8 and IL-12p70 were also decreased but did not reach statistical significance. Thus, the combination of UVB-induced apoptosis, increased secretion of anti-inflammatory cytokines and decreased trafficking to the skin may help to explain the beneficial effects of UVB treatment on psoriasis and why disease remission can sometimes be sustained for a prolonged period.

The anti-inflammatory action of methotrexate is not mediated by lymphocyte apoptosis, but by the suppression of activation and adhesion molecules.

Low-dose methotrexate (MTX) is an established and highly effective treatment for severe psoriasis and rheumatoid arthritis; however, its mechanism of action remains unclear. We investigated the effects of low-dose MTX on antigen-stimulated peripheral blood mononuclear cells and explored through which cellular pathways these effects are mediated. We show that MTX caused a dose-dependent suppression of T cell activation and adhesion molecule expression, and this was not due to lymphocyte apoptosis. The suppression of intercellular adhesion molecule (ICAM)-1 was adenosine and folate-dependent, while MTX suppression of the skin-homing cutaneous lymphocyte-associated antigen (CLA) was adenosine-independent. The effect of MTX on CLA, but not ICAM-1, required the constant presence of MTX in cultures. Thus, the suppression of T cell activation and T cell adhesion molecule expression, rather than apoptosis, mediated in part by adenosine or polyglutamated MTX or both, are important mechanisms in the anti-inflammatory action of MTX.

Methotrexate markedly reduces the expression of vascular E-selectin, cutaneous lymphocyte-associated antigen and the numbers of mononuclear leucocytes in psoriatic skin.

A positive correlation between disease severity and the frequency of cutaneous lymphocyte-associated antigen (CLA)-positive T cells in the blood of untreated patients with psoriasis has been previously observed. A dose-dependent inverse relationship between disease severity and the frequency of circulating CLA(+) T cells in psoriasis patients on methotrexate (MTX) treatment is reported. Circulating T cells from a patient with psoriasis were monitored for CLA expression on a daily basis for 5 weeks. A decrease in the intensity and frequency of CLA(+) mononuclear leucocytes was consistently observed in the blood during the first 3-4 days after each MTX intake, but the CLA expression increased thereafter until the next weekly dose was taken. The MTX treatment of this patient was then discontinued for 16 days, and a marked subjective exacerbation was reported within 9 days, which was confirmed objectively (laser Doppler perfusion imaging) after 11 and 16 days. Biopsies taken 4 days after the last MTX intake showed only a few mononuclear leucocytes in lesional skin, but the exacerbation coincided with a marked increase in CLA expression by mononuclear blood leucocytes, followed by an increase in endothelial E-selectin and a striking influx of CLA(+) mononuclear cells into lesional skin. Conversely, a clinical improvement after the patient resumed the MTX treatment was associated with reduction in CLA expression by mononuclear cells in the blood, downregulation of endothelial E-selectin and an approximate threefold decrease in mononuclear leucocyte infiltration of lesional skin. No MTX-associated changes were detected in the expression of very late antigen-4, vascular cell-adhesion molecule-1 nor the late activation marker CD25. It is concluded that MTX decreases the expression of CLA and E-selectin and that this may be a major mechanism for the therapeutic effect of MTX on psoriatic skin lesions.

Differential effects of interleukin 12 and interleukin 10 on superantigen-induced expression of cutaneous lymphocyte-associated antigen (CLA) and alphaEbeta7 integrin (CD103) by CD8+ T cells.

At both cutaneous and mucosal sites, interleukin (IL)-10, IL-12 and transforming growth factor (TGF)-beta are important regulators of chronic inflammatory disease, where cutaneous lymphocyte-associated antigen (CLA) and alphaE integrin (CD103) may be expressed. Stimulation with streptococcal pyrogenic exotoxin C (SpeC) increased the expression of CD103 by CD8+ but not CD4+ T cells. While adding IL-12 augmented the expression of CLA, superantigen-induced expression of CD103 was markedly suppressed by IL-12, which could be reversed by TGF-beta. Antibodies against TGF-beta inhibited, and a combination of anti-TGF-beta and IL-12 completely abrogated the induced CD103 expression. IL-10 strongly decreased the frequency of CLA+ and although not increasing the frequency of CD103+CD8+ T cells, the amount of CD103 expressed per cell was markedly increased. Thus, the expression of CLA and CD103 may be antagonistically regulated by IL-10 and IL-12 and the balance between these cytokines could influence the T cell migration of inflammatory cells into epithelial tissues.