IL-17A Inhibitor Research Articles

Adherence to therapy of ixekizumab and secukinumab in psoriatic arthritis patients using first- or second-line IL-17A inhibitor treatment: a Danish population-based cohort study.

To assess the effectiveness and tolerability of first- and second-line interleukin (IL)-17A inhibitor treatment in PsA patients from 2014 to 2021 using data from the Danish Rheumatology Registry (DANBIO) by investigating adherence to therapy. PsA patients recorded in the DANBIO who received a first- or second-line IL-17A inhibitor treatment were included in this study. All patients included had previously received one or more TNF inhibitor treatment. Baseline characteristics were analysed in subgroups as first-line IL-17A inhibitor treatment and second-line IL-17A inhibitor treatment. Adherence to therapy of first- or second-line IL-17A inhibitor treatments was reported as Kaplan-Meier plots. A total of 534 patients were included in the study, with 534 first-line switchers (secukinumab: 510, ixekizumab: 24) and 102 second-line switchers (secukinumab: 35, ixekizumab: 67). Baseline characteristics showed a similar HAQ and visual analogue scale (VAS) for pain. VAS global, 28-joint DAS with CRP and the previous number of biologic DMARD treatments were similar, with a greater value for second-line switchers. First-line ixekizumab-treated patients present a younger age, greater percentage of females, a lower disease duration and a lower CRP value. Concomitant MTX use was greater for the first-line secukinumab-treated patients. First- and second-line switchers had a similar adherence to therapy. Second-line secukinumab and second-line ixekizumab switchers showed a similar adherence to treatment. PsA patients receiving first- or second-line IL-17A inhibitors showed homogeneous baseline characteristics and similar adherence to therapy. Treatment failure of the first IL-17A inhibitor treatment should not preclude a second-line IL-17A inhibitor treatment.

The efficiency of the combination of topical and biological therapy in the treatment of nails psoriasis: a prospective study

Introduction. The severity of the psoriatic process is associated with the involvement of the scalp, genitals, fold zones and nails in the process. The selection of effective therapy for psoriasis of difficult localizations is an urgent task of modern dermatology.Aim. To evaluate the effectiveness of treatment of moderate psoriasis and nail psoriasis with an IL-17A inhibitor in combination with a combined betamethasone dipropionate + salicylic acid ointment.Material and methods. A 12-week prospective study included data from 60 patients who were under observation at the Moscow Scientific and Practical Center of Dermatovenereology and Cosmetology in 2020-2021. Group 1 included 30 patients who received only the biological drug IL-17 inhibitor. Group 2 included 30 patients who received an IL-17 inhibitor in combination with topical therapy with an ointment of 0.05% betamethasone dipropionate and 3% salicylic acid (Rederm). The ointment was applied twice a day in two courses of 3 weeks with a break of 6 weeks between courses. When comparing indicators between groups, Student’s t-test was used for normal samples and the Mann- Whitney test for non- Gaussian samples.Results. When comparing PASI and NAPSI in patients of group 2 who received an IL-17 inhibitor in combination with external therapy with an ointment of 0.05% betamethasone dipropionate and 3% salicylic acid 2 times a day for two courses of 3 weeks with a break of 6 weeks between courses, the index values statistically significantly decreased after 12 weeks of therapy (p = 0.003) compared to group 1 (p = 0.015).Conclusions. The study showed that patients who received an IL-17 inhibitor in combination with a combined betamethasone dipropionate + salicycylic acid ointment achieved a significantly greater effect compared to patients who received only biologics. In addition, the combination with Rederm ointment has shown greater efficacy in the treatment of psoriatic onychodystrophy, which is difficult to treat even with biologics.

Psoriasis with facial skin lesions that arose against background of withdrawal of ixekizumab (clinical case)

Facial skin lesions in psoriasis, one of the most common dermatoses, are traditionally considered a relatively rare manifestation of the disease, especially in adult patients, but according to modern data, it is observed in at least 40 % of patients. It is believed that facial skin lesions are more typical for young patients with severe widespread skin lesions, involvement of the nail plates and a protracted course. Localization of rashes on the skin of the face – in a cosmetically and socially significant area – is accompanied by significant impairments in the quality of life of patients. The treatment of facial psoriasis is difficult, and few algorithms have been developed for the management of patients with facial psoriatic lesions. We present a patient with psoriasis involving facial skin that first developed after discontinuation of systemic therapy with an IL-17A inhibitor (ixekizumab). During the follow-up of the patient, it became necessary to re-administer systemic biological therapy with the potential risk of an escape effect. In the article, we discuss the clinical manifestations of facial psoriasis and the impact on the quality of life of patients. A description of the observation of a patient with lesions of the facial skin in severe plaque psoriasis and the role of biological therapy in this direction is presented.

The Flavonoid Cyanidin Shows Immunomodulatory and Broad-Spectrum Antiviral Properties, Including SARS-CoV-2.

New antiviral treatments are needed to deal with the unpredictable emergence of viruses. Furthermore, vaccines and antivirals are only available for just a few viral infections, and antiviral drug resistance is an increasing concern. Cyanidin (a natural product also called A18), a key flavonoid that is present in red berries and other fruits, attenuates the development of several diseases, through its anti-inflammatory effects. Regarding its mechanism of action, A18 was identified as an IL-17A inhibitor, resulting in the attenuation of IL-17A signaling and associated diseases in mice. Importantly, A18 also inhibits the NF-κB signaling pathway in different cell types and conditions in vitro and in vivo. In this study, we report that A18 restricts RSV, HSV-1, canine coronavirus, and SARS-CoV-2 multiplication, indicating a broad-spectrum antiviral activity. We also found that A18 can control cytokine and NF-κB induction in RSV-infected cells independently of its antiviral activity. Furthermore, in mice infected with RSV, A18 not only significantly reduces viral titers in the lungs, but also diminishes lung injury. Thus, these results provide evidence that A18 could be used as a broad-spectrum antiviral and may contribute to the development of novel therapeutic targets to control these viral infections and pathogenesis.

Randomized study of the efficacy of monoclonal antibodies in patients with refractory psoriasis

BACKGROUND: The main vector of psoriasis therapy is suppression of proliferative activity of keratinocytes, normalization of their differentiation, neutralization of immune inflammation in the dermis and normalization of cytokine balance.
 AIM: of the study was to study the efficacy and tolerability of an IL-17A inhibitor (secukinumab) as monotherapy and in combination with methotrexate in patients with moderate and severe psoriasis vulgaris.
 MATERIALS AND METHODS: The severity of psoriasis was assessed by the Psoriasis Prevalence and Severity Index (Psoriasis Area and Severity Index, PASI). To assess the damage to the nail plates of the hands and feet in psoriasis, the NAPSI index (Nail Psoriasis Severity Index) was used. In order to assess the quality of life of patients with psoriasis, a Russian-language version of the dermatological quality of life index (DQLI) was used. Patients' quality of life was assessed before the prescribed therapy and at 12 weeks of treatment. Assessment of the severity of itching and its impact on the daily life of patients was carried out according to the Prurindex questionnaire.
 RESULTS: All patients were divided into two groups by a randomized method. The first group included 25 patients who received therapy with secukinumab in the age category of 55 (3067) years. The second group included 25 patients aged 56 (3469) years of moderate and severe psoriasis who were treated with secukinumab after initiation (300 mg) 150 mg subcutaneously in combination with methotrexate 15 mg intramuscularly for 24 weeks. Thus, in the first group PASI 90 was achieved after 24 weeks ― in 69%, PASI 100 ― in 31% patients; in the second group ― PASI 90 ― in 68%, PASI 100 ― in 32% patients respectively. In both groups, it was possible to maintain clinical remission (PASI 90) in 87.3% of patients throughout the year. During therapy in patients of both groups, there was a decrease in DLQI values from 25.63.7 to 3.53.1 (p 0.01) in the first group and from 23.33.7 up to 3.12.6 in the second group.
 CONCLUSIONS: Treatment of patients with moderate and severe psoriasis vulgaris with secukinumab has shown its high efficacy and safety. Moreover, it was estimated that the combination of secukinumab and methotrexate is comparable in effectiveness to secukinumab monotherapy. It has been established that the use of secukinumab as monotherapy and in combination with methotrexate significantly improves the quality of life of patients with moderate and severe psoriasis vulgaris.

Neutrophil function following treatment of psoriatic arthritis patients with secukinumab: altered cytokine signalling but no impairment of host defence.

Identifying that dysfunction of the IL-23/17 axis underlies PsA has led to the development of effective targeted therapies such as the IL-17A inhibitor secukinumab. As IL-17A stimulates the secretion of neutrophil chemoattractants, such as CXCL8 (IL-8), we examined the effect of secukinumab on neutrophil function in PsA. Nineteen patients with active PsA were treated with secukinumab. Clinical response [PsA Response Criteria (PsARC) and Psoriasis Area and Severity Index (PASI)] and peripheral blood neutrophil function (apoptosis, receptor expression, phagocytosis/killing, chemotaxis and RNA expression) were measured at 12 week intervals for 48 weeks and compared with age- and sex-matched healthy controls. At 12 weeks, 12/16 (75%) patients had a PsARC response (100% at 36 weeks) and 10/14 (71%) achieved a 90% PASI response. At baseline, there were no differences in PsA neutrophil reactive oxygen species generation, constitutive or cytokine-delayed apoptosis, chemotaxis or phagocytosis of opsonized Staphylococcus aureus compared with healthy controls. Similarly, there were no differences in these functions from baseline to 12 weeks of therapy. However, surface levels of CD11b/CD18 and CD63 increased and expression of CD16 decreased during therapy. In addition, in a subgroup of early (12 week) responders to secukinumab, RNA sequencing revealed transcriptome changes predicting down-regulation of cytokine signalling and chemotaxis pathways and up-regulation of de novo gene expression pathways, including translation initiation, mRNA catabolism and translation. Complex changes in the properties of circulating neutrophils occur with secukinumab treatment in PsA that may indicate altered responsiveness to changes in both local and systemic levels of pro-inflammatory cytokines. However, host defence processes of neutrophils were unaltered.

Psoriasis improvements and inflammatory biomarker normalization with secukinumab: the randomized ObePso-S study

BackgroundThe IL-17A inhibitor secukinumab has demonstrated consistent efficacy and safety in patients with moderate-to-severe plaque psoriasis, with normalization of molecular and histopathologic psoriasis markers. ObjectiveTo investigate treatment effects of secukinumab on clinical signs and psoriatic inflammation markers over 52 weeks in patients with psoriasis. MethodsIn the ObePso-S study (NCT03055494), patients with psoriasis were randomized 2:1 to receive secukinumab 300 mg (n = 54) or placebo (n = 28), stratified by body weight (<90 or ≥90 kg), for 52 weeks. At Week 12, patients receiving placebo were switched to secukinumab. Psoriasis Area and Severity Index improvement of 90% (PASI90) and Investigator’s Global Assessment modified 2011 0/1 responses were assessed at Weeks 12 and 52. Immunohistochemistry for keratin 16 (K16) and gene expression profiles were evaluated in lesional and non-lesional skin biopsies collected at baseline, Week 12, and Week 52. ResultsOf patients receiving secukinumab, 55.8% and 59.6% achieved PASI90 at Weeks 12 and 52, respectively. K16 was absent in 93.1% of Week 12 PASI90 responders and 93.6% of Week 52 PASI90 responders, which mirrored the down-regulated expression of psoriatic inflammation. Week 52 PASI90 non-responders experienced regression of clinical and inflammatory marker responses toward baseline levels. Lower control of inflammatory gene expression at Week 12 was associated with suboptimal clinical responses at Week 52. ConclusionSustained clinical responses with secukinumab were associated with rapid and sustained normalization of K16 and inflammatory gene expression in most patients. Molecular anti-inflammatory effects of secukinumab at Week 12 were associated with clinical responses at Week 52.

Pustular psoriasis treated with IL-17a antibody secukinumab

The article presents clinical cases of treatment of acute generalized pustular psoriasis (GPP) with the use of an interleukin IL-17A inhibitor, secukinumab, which showed a remarkable response with almost complete disappearance of pustules after the first injection. To the best of our knowledge, there are limited data in the literature on evaluating the effectiveness of therapy with genetically engineered drugs in the treatment of GPP.

056 Highly Multiplexed Digital Spatial Profiling of Resolved Psoriasis Skin From Dead Sea Climatotherapy or Secukinumab Treated Patients

Dead Sea climatotherapy (DSC) and the IL-17A inhibitor secukinumab (SEC) are used as treatments for psoriasis resulting in complete skin clearance among numerous patients. A kind of disease memory is present in resolved skin indicated by the relapse of psoriasis in previously affected areas at the cessation of effective treatment. CD103+ tissue-resident memory T-cells are believed to contribute to this disease memory. We compared skin from patients obtaining complete skin clearance at end of treatment (EOT) with either DSC or SEC using highly multiplexed digital spatial profiling on the GeoMX platform.

Successful treatment with secukinumab of psoriasis-like dermatitis in a patient with holocarboxylase synthetase deficiency.

Holocarboxylase synthetase deficiency (HSD) is a rare autosomal recessive disorder of biotin metabolism. Typical manifestations include irreversible metabolic disorders and erythroderma-like dermatitis. Most patients respond well to biotin supplementation. Psoriasis-like phenotype associated with this disease has been rarely reported in the literature and experiences with the use of biologics in patients with HSD are still lacking. We reported a rare case of recurrent psoriasis-like skin lesions in a 6-year-old child with HSD. The patient did not respond to initial therapy with high-dose oral biotin. Immunofluorescence stainingshowed an increased number of interleukin (IL)-17A+ cells in his skin lesions. Based on this finding, the patient was successfully treated with human anti-IL-17A monoclonal antibody (secukinumab). He did not report any side effects and remained healthy during the 2-year follow-up. We provide a comprehensive review of the reported cases of HSD with psoriasis-like dermatitis to date. The psoriasis-like phenotype of HSD is controversial in treatment and IL-17A inhibitor is an alternative therapeutic option.

Chronic inflammatory demyelinating polyneuropathy and psoriasis comorbidity with significantly alleviated in symptoms after secukinumab: case report

BackgroundChronic inflammatory demyelinating polyneuropathy (CIDP) is an autoimmune disease that involves damage to the peripheral nervous system. The course of the disease can progress for more than 8 weeks, with frequent incidences of relapse-remission courses. This article reported a rare combination of CIDP with fluctuating symptoms, recurrence-remission, and comorbidity with psoriasis.Case presentationA 29-year-old male patient with repeated limb weakness and numbness was admitted to the hospital several times in the past six months. He had a history of psoriasis for 6 years, and the medications (clobetasol propionate ointment and calcipotriol ointment) treated for psoriasis were discontinued 1 year ago. During the hospitalization, repeated intravenous injections of human immunoglobulin G (IVIg), immunoadsorption, and secukinumab were performed. Nerve electrophysiology tests, ganglioside autoantibody spectrum tests, and clinical MRC muscle strength scores were performed on a regular basis to confirm the diagnosis of CIDP. The patient was regularly followed up.ResultsAfter repeated rounds of human IVIg and immunoadsorption, the patient’s MRC score was increased by ≥ 6 points. The first ganglioside autoantibody spectrum test showed anti-GQ1b IgG ( +) and anti-GM1 IgM ( +) antibodies, and all were negative after re-examination. Finally, the patient was treated with the IL-17A inhibitor secukinumab for psoriasis. During 7 months of follow-up, the CIDP and psoriasis symptoms are relatively stable.ConclusionCombination of IVIg and immunoadsorption was highly effective in treating CIDP complicated with psoriasis. The clinical manifestations of CIDP are diverse. When relapse-remission occurs in the course of the disease, it is necessary to clarify whether it is combined with other autoimmune diseases and should control the autoimmune diseases as soon as possible.

The effectiveness of the IL-17A inhibitor in generalized pustular psoriasis: a clinical case

The first clinical case of the effective use of a domestic biological drug inhibitor netakimab ― IL-17A ― in a patient with persistently progressive, torpid to therapy generalized pustular psoriasis Tsumbush is presented. This rare systemic dermatosis refers to severe forms of psoriasis that threaten the patients life and require intensive therapy from the very first hours of the manifestation of the disease. The development of pustular psoriasis can be promoted by: long-term therapy with systemic glucocorticosteroids, cytostatics, oral contraceptives, as well as prolonged use of irritating external agents. In some cases, the disease is associated with high emotional stress, stress. In severe generalized pustular psoriasis, biological drugs, cyclosporine, methotrexate, and acitretin are effective.&#x0D; The article presents summary data on the effectiveness of first- and second-line drugs in the treatment of pustular psoriasis. According to the literature, patients with severe pustular psoriasis, torpid to standard therapy, demonstrate a positive response to treatment with biological drugs in most cases. Anti-TNF- are the most available biological drugs for the treatment of pustular psoriasis, and anti-IL-12/23 and anti-IL-17A can be considered as the first or second line of therapy for moderate-severe and refractory pustular psoriasis.&#x0D; The choice of effective therapy for the treatment of pustular psoriasis is an urgent problem of modern dermatology and the presented clinical case demonstrates the effectiveness and pronounced positive therapeutic effect of the IL-17A inhibitor for 1 day in the treatment of generalized pustular psoriasis resistant to previously conducted therapy, which allows us to count on the prospect of further successful use of this targeted drug in the treatment of severe pustular psoriasis.

481 Pityriasis rubra pilaris transcriptomics further implicate IL-17 signaling and correlate with response to IL-17A inhibitor therapy

Pityriasis rubra pilaris (PRP) is a rare inflammatory skin disorder associated with significant patient morbidity. The pathophysiology of PRP has been under ongoing investigation with studies implicating alterations in Th17 signaling, phospholipase processing, and novel germline CARD14 gene variations. In this study, 11 patients with moderate-to-severe PRP (as defined by a Psoriasis Area and Severity Index [PASI] ≥ 10) had lesional skin biopsies taken prior to and following 24 weeks of Il-17A inhibitor therapy for RNA sequencing analysis.

The role of autophagy-related proteins in the pathogenesis of neuromyelitis optica spectrum disorders

ABSTRACT This study aimed to investigate the expression of autophagy-related proteins in a mouse model of neuromyelitis optica (NMO). Mice were assigned to one of four groups: an animal experimental model group (NMO-EAE group, given with exogenous IL-17A), Interleukin-17 monoclonal antibody intervention group (NMO-EAE_0IL17inb), No exogenous interleukin-17 enhanced immune intervention group (NMO-EAE_0IL17), and a control group. Behavioral scores were assessed in each group, and the protein expressions of sequestosome 1 (P62), Beclin-1, the mammalian target of rapamycin (mTOR), phosphoinositide 3-kinase (PI3K-I), and LC3II/LC3I were detected using Western blotting. In the NMO-EAE_0IL17 group, the expression of Beclin-1 decreased, the LC3II/LC3I ratio was lower, and the expressions of P62, mTOR, and PI3K-I increased; after administration of IL-17A inhibitor into the brain tissue, however, the expression of Beclin-1 increased significantly, along with the LC3II/LC3I ratio, while the expressions of P62, mTOR and PI3K-I protein decreased significantly. In terms of behavioral scores, the scores of optic neuritis and myelitis were more serious, onset occurred earlier and the progress was faster, after the administration of IL-17A. In the mechanism of NMO animal model, IL-17A may regulate autophagy and affect the disease process through the activation of the PI3K–mTOR signaling pathway.

Circulating Brodalumab Levels and Therapy Outcomes in Patients With Psoriasis Treated With Brodalumab

Given the possible treatment modalities in psoriasis management, little is known about whether drug monitoring is associated with response rate. To determine whether drug monitoring is associated with response to brodalumab therapy. A multicenter case series study of patients with psoriasis treated with brodalumab whose treatment with previous IL-17A inhibitor therapy failed. Patients were recruited from the Departments of Dermatology at Gentofte and Aarhus University Hospitals, Denmark, between 2018 and 2020. Patient visits were conducted after 4 and 12 weeks of therapy. Patients not achieving Psoriasis Area and Severity Index 75% improvement from baseline (PASI 75) after 12 weeks were discontinued and considered nonresponders. Patients maintaining PASI 75 response were followed up for up to 52 weeks. Treatment with brodalumab, 210 mg, at weeks 0, 1, 2, then every 2 weeks. Outcome measures were PASI reductions vs brodalumab levels and antibrodalumab antibodies. Twenty patients with psoriasis (13 [65%] were male; median age, 50 years [range, 19-66 years]) were included. After 12 weeks of therapy, patients with quantifiable levels of brodalumab (≥0.05 μg/mL) experienced significantly higher PASI reductions than those without (median, 93%; range, 61%-100% vs median, -3; range, -49% to 94%, respectively; P = .006). After 12 weeks of therapy, 4 of 5 patients (80%) not achieving PASI 75 had subquantifiable drug levels (<0.05 μg/mL), although this finding was seen for only 3 of 14 PASI 75 responders (21%). None of 7 patients (35%) with subquantifiable drug levels after 12 weeks of therapy maintained response. No antibrodalumab antibodies were detected in any of the tested samples. Results of this case series study suggest that circulating brodalumab level is a factor associated with clinical treatment response. Monitoring patient levels of circulating brodalumab may aid clinical decision-making and help prevent ineffective therapy.

Biological therapy of psoriasis in the era of COVID-19: discussing the risks and benefits

BACKGROUND: The new coronavirus infection COVID-19 in 2020 has spread widely around the world, including the Russian Federation. Risk factors for adverse outcomes of COVID-19, such as obesity, diabetes, chronic heart and kidney diseases, non-alcoholic fatty liver hepatosis, often accompany psoriasis, especially severe. Assessment and reduction of these risks have become an integral task of psoriasis therapy. An important issue was the use of immunosuppressive therapy in patients during the pandemic.&#x0D; AIMS: In this article, we tried to analyze the international experience of colleagues with a focus on psoriasis and correlate it with our own experience. To assess the impact of psoriasis, concomitant syndromes and applied biological and non-biological systemic therapy on the risk of infection and the nature of the course of COVID-19.&#x0D; MATERIALS AND METHODS: The analysis of available scientific publications on the effect of psoriasis, concomitant comorbidities and the therapy used on the incidence, nature of the course and outcomes of the new coronavirus infection COVID-19 was carried out. Data collection (questionnaire and analysis of available medical documentation on transferred COVID-19 cases and detection of antibodies) and a retrospective analysis of the history of COVID-19 disease in psoriasis patients in the Republic of Crimea who are on dispensary registration and receiving systemic (biological and targeted) therapy (n=146) were performed. The search for articles on the topic was carried out in the PubMed database in English and Russian, published in the period from 2019 to 2021.&#x0D; RESULTS: According to available literature data, systemic biological drugs from the group of interleukin inhibitors for the treatment of psoriasis did not worsen the course of COVID-19.&#x0D; Established a proactive anti-inflammatory effect for drugs from the group of IL-17 inhibitors.&#x0D; According to the latest version 14 of the recommendations for the treatment of COVID from 27.12.2021, the IL-17A inhibitor netakimab is included in the group of drugs of proactive anti-inflammatory therapy. Out of 146 patients with psoriasis receiving biological and targeted therapy, 8 patients underwent acute respiratory infections in 18 months, confirmed COVID-19 was established in 26 cases, antibodies were detected in 54 patients. Out of the patients with pneumonia and COVID-19, hospitalization for biological therapy was not required and only one case of hospitalization for therapy with apremilast (CT 1) was recorded. It should be noted that in the families of patients undergoing biological therapy, there were cases of COVID-19 (CT 23) and even a fatal outcome, however, no clinical manifestations of the disease were observed in our patients, and antibodies were detected during laboratory examination.&#x0D; CONCLUSIONS: To date, there is no convincing evidence that drugs for systemic therapy of psoriasis can worsen the course of COVID-19. A proactive anti-inflammatory effect was noted for drugs from the group of IL-17 inhibitors. The existing international and Russian recommendations on the management of patients on biological therapy in the COVID-19 pandemic reflect the current experience and views of the expert community, it is necessary to further accumulate new data and exchange clinical experience along with the evolution of the pandemic. Available vaccines against COVID-19 that are not live may be used with caution during immunosuppressive therapy.

P275 Association of the improvement of synovitis and enthesitis with quality of life/patient reported outcomes in patients with psoriatic arthritis treated with ixekizumab

Abstract Background/Aims Psoriatic arthritis (PsA) is an inflammatory rheumatic disease with manifestations including synovitis and enthesitis. During extensive study programs, IXE has shown a treatment effect across domains affected by PsA. Ixekizumab (IXE) is an IL17A inhibitor approved for the treatment of active PsA and axial SpA. We sought to determine whether there is any association between the improvement of synovitis with that of enthesitis from baseline (BL) through week (wk) 52 in patients (pts) with PsA treated with IXE. Additionally, the association between the improvement of synovitis and enthesitis on health-related quality of life and patient-reported outcomes was investigated. Methods Data from SPIRIT-P1 (NCT01695239), SPIRIT-P2 (NCT02349295) and SPIRIT-H2H (NCT03151551) were analysed. These were randomized, phase 3 trials involving pts with active PsA either biologic DMARD-naïve (P1, H2H) or TNF-inhibitor-experienced (P2). We examined the patient population randomised to IXE-treatment (80 mg of ixekizumab every 4 weeks [IXEQ4W]), that had both synovitis and enthesitis at BL. For each study, a standardisation procedure was applied to each study data in order to overcome the differences in score range between LEI and SJC. The Pearson correlation coefficient between improvement from BL in enthesitis and synovitis was calculated at each time point. The mean improvement in the SF-36 Physical Component Summary score [PCS], the Patient’s Global Assessment of Disease Activity [Pt GA], and the EuroQOL five dimensions [EQ5D]-visual analogue [VAS] score) was calculated over time for pts who reached or did not reach resolution of both enthesitis and synovitis at wk 52. Missing data were imputed with modified Baseline Carried Out Forward (mBOCF) for continuous outcomes. Non-responder imputation was used for pts with missing resolution of enthesitis or synovitis. Results At BL, 68 (63% of patients treated with IXEQ4W in the ITT population), 68 (56%) and 159 (56%) pts from P1, P2 and H2H respectively, had both synovitis and enthesitis. In all 3 trials, the standardized mean change from baseline in synovitis and enthesitis showed a similar pattern over time. When statistically significant, Pearson correlation coefficient values ranged from 0.16 to 0.40, indicating a positive association between mean improvement in synovitis and enthesitis. We observed an improvement of SF-36 over the 52 wks regardless of the resolution of synovitis or enthesitis. The most pronounced improvement was shown by pts achieving resolution of both synovitis and enthesitis, followed by the pts achieving one or the other. Conclusion Across the SPIRIT trials, treatment with IXE led to the significant improvement in synovitis and enthesitis with a positive association between the improvement of both. Furthermore, pts that resolved both measures at wk 52 experienced an earlier and greater improvement in the SF-36 Physical Component Scale. Disclosure D. McGonagle: Corporate appointments; D. McGonagle has undertaken research and/or educational program activity with: AbbVie, Celgene, Johnson &amp; Johnson, Merck Sharp &amp; Dohme, Pfizer, and UCB Pharma. L. Kristensen: Consultancies; AbbVie, Amgen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, and UCB Pharma. Member of speakers’ bureau; AbbVie, Amgen, Biogen, Bristol Myers Squibb, Celgene, Eli Lilly and Company, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, and UCB Pharma. Grants/research support; Biogen, Janssen Cilag, and UCB Pharma. M. Rudwaleit: Consultancies; AbbVie, Bristol Myers Squibb, Celgene, Chugai Pharmaceutical/Roche, Eli Lilly and Company, Janssen, Merck Sharp &amp; Dohme, Novartis, Pfizer, and UCB Pharma. H. Kameda: Consultancies; AbbVie, Asahi Kasei Pharma, Astellas, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe Pharma, Novartis, Sanofi, and Takeda. Member of speakers’ bureau; AbbVie, Asahi Kasei Pharma, Astellas, Bristol Myers Squibb, Chugai Pharmaceutical, Eisai, Eli Lilly and Company, Janssen, Mitsubishi Tanabe Pharma, Novartis, Sanofi, and Takeda. T. Holzkaemper: Shareholder/stock ownership; Eli Lilly and Company. C. El Baou: Other; C. El Baou is an independent contractor working for: Eli Lilly and Company. J. Smolen: Consultancies; AbbVie, Amgen, AstraZeneca, Astro Pharma, Bristol Myers Squibb, Celgene, Celltrion, Chugai Pharmaceutical, Eli Lilly and Company. Grants/research support; Gilead Sciences, GlaxoSmithKline, ILTOO Pharma, Janssen, MedImmune, Merck Sharp &amp; Dohme, Novartis-Sandoz, Pfizer, Roche, Samsung, Sanofi, and UCB Pharma.

Transcriptomic Profiling of Plaque Psoriasis and Cutaneous T-Cell Subsets during Treatment with Secukinumab

The IL-17A inhibitor secukinumab is efficacious for the treatment of psoriasis. To better understand its mechanism of action, we investigated its impact on psoriatic lesions from 15 patients with moderate-to-severe plaque psoriasis undergoing secukinumab treatment. We characterized the longitudinal transcriptomic changes of whole lesional skin tissue as well as cutaneous CD4+ and CD8+ T effector cells and CD4+ T regulatory cells across 12 weeks of treatment. Secukinumab was clinically effective and reduced disease-associated overexpression of IL17A, IL17F, IL23A, IL23R, and IFNG in whole tissue as soon as 2 weeks after initiation of treatment. IL17A overexpression in T-cell subsets, primarily CD8+ T cells, was also reduced. Although secukinumab treatment resolved 89‒97% of psoriasis-associated expression differences in bulk tissue and T-cell subsets by week 12 of treatment, we observed expression differences involved in IFN signaling and metallothionein synthesis that remained unresolved at this time point as well as potential treatment-associated expression differences involved in IL-15 signaling. These changes were accompanied by shifts in broader immune cell composition on the basis of deconvolution of RNA-sequencing data. In conclusion, our study reveals several phenotypic and cellular changes within the lesion that underlie clinical improvement from secukinumab.

Ixekizumab: an IL-17A inhibitor for the treatment of axial Spondylarthritis

ABSTRACT Introduction Axial spondyloarthritis (axSpA) is an inflammatory arthritis which affects primarily the entheses of the spine and sacroiliac joints with peripheral joint synovitis and extra-articular manifestations. In 2017, the first IL-17A inhibitor (IL-17Ai) secukinumab was approved for the treatment of radiographic axSpA not responding adequately to conventional therapies, and this was followed in 2019 by a second IL-17Ai, ixekizumab. These agents represent the first alternative class of biological treatments after the TNF inhibitor which dominated the therapeutic landscape of axSpA for over a decade. Areas covered This review discusses the role of IL-17Ais in the treatment in axSpA focusing on the newest IL-17Ai ixekizumab. It provides a detailed overview of the drug pharmacodynamic, pharmacokinetics, and clinical trial data, including areas of future research needed in the post-marketing era. Expert opinion Early trials of ixekizumab for axSpA have shown encouraging results and an acceptable safety profile. Future phase IV trials should focus on direct head-to-head comparisons between ixekizumab and other biologic drugs, and stratify patients according to important disease characteristics known to affect treatment response including sex, HLA-B27 status, presence of MRI bone marrow edema at baseline, disease duration and any extra-articular manifestations.

Bimekizumab: a dual IL-17A and IL-17F inhibitor for the treatment of psoriasis and psoriatic arthritis

ABSTRACT Introduction Interleukin (IL)-17 is critical in the pathogenesis of psoriasis and psoriatic arthritis (PsA) with most data suggesting that IL-17A alone was the key cytokine. However, in vitro and in vivo studies have suggested dual blockade of IL-17A and IL-17 F may be more effective than IL-17 A blockade alone. Bimekizumab is the first human monoclonal antibody to exert simultaneous specific inhibition of IL-17A and IL-17 F, and has been studied in several phase II/III trials for psoriasis and PsA. Areas covered Bimekizumab is not currently licensed for use. A literature search identified clinical trials examining the efficacy and safety of bimekizumab for psoriasis and PsA, and these were critically appraised. Expert opinion Clinical trials of bimekizumab have been promising, demonstrating a rapid onset of response and superior efficacy compared to three currently licensed biologics: secukinumab, ustekinumab, and adalimumab. Bimekizumab maintains a high level of efficacy with maintenance dosing intervals of 8 weeks, compared with 4 weeks for currently licensed IL-17A antagonists. No unexpected adverse events have been identified, although mild-to-moderate fungal infections occur in approximately 10%. Studies over longer time periods involving additional active comparators would be valuable in further defining the role of bimekizumab amongst currently available treatments.