This Summary of Research overviews the results of the VOLTAIRE-X study (NCT03210259), which looked at what happened when people with plaque psoriasis continually took the adalimumab reference product ...(adalimumab RP; known by the brand name Humira
®
) or switched three times between taking the adalimumab RP and BI 695501 (adalimumab-adbm, known by the brand name Cyltezo
®
), an adalimumab biosimilar. The VOLTAIRE-X study showed that the pharmacokinetics of adalimumab were similar in people who stayed continuously on adalimumab RP and people who switched between adalimumab RP and adalimumab-adbm. There were no differences in effectiveness, side effects, or antibodies to adalimumab when comparing people who stayed continuously on adalimumab RP with those who switched between adalimumab RP and the adalimumab biosimilar adalimumab-adbm. On the basis of these results, adalimumab-adbm was approved by the US Food and Drug Administration (FDA) as interchangeable with adalimumab RP, meaning that a pharmacist can substitute the biosimilar adalimumab-adbm for adalimumab RP without requiring permission from the original prescriber (unless required to by state law).
Background IL-23 is associated with plaque psoriasis susceptibility and pathogenesis. BI 655066 is a fully human IgG1 mAb specific for the IL-23 p19 subunit. Objective This first-in-human ...proof-of-concept study evaluated the clinical and biological effects of BI 655066 in patients with moderate-to-severe plaque psoriasis. Methods We performed a single-rising-dose, multicenter, randomized, double-blind, placebo-controlled, within-dose cohort phase I trial. Patients received 0.01, 0.05, 0.25, 1, 3, or 5 mg/kg BI 655066 intravenously, 0.25 or 1 mg/kg BI 655066 subcutaneously, or matched placebo. The primary objective was safety evaluation. Results Thirty-nine patients received single-dose BI 655066 intravenously (n = 18) or subcutaneously (n = 13) or placebo (n = 8). Adverse events were reported with similar frequency in the BI 655066 and placebo groups. Four serious adverse events (not considered treatment related) were reported among BI 655066–treated patients. BI 655066 was associated with clinical improvement from week 2 and maintained for up to 66 weeks after treatment. At week 12, 75%, 90%, and 100% decreases in the Psoriasis Area and Severity Index were achieved by 87%, 58%, and 16% of BI 655066–treated patients (any dose), respectively, versus none receiving placebo. BI 655066 treatment resulted in reduced expression of lesional skin genes associated with IL-23/IL-17 signaling pathways and normalization of psoriatic lesion gene expression profiles to a profile approaching that of nonlesional skin. Significant correlation between treatment-associated molecular changes and psoriasis area and severity index improvement was observed ( r = 0.73, P = 2 × 10−6 ). Conclusions BI 655066 was well tolerated and associated with rapid, substantial, and durable clinical improvement in patients with moderate-to-severe psoriasis, supporting a central role for IL-23 in psoriasis pathogenesis.
Psoriasis is a systemic inflammatory disease associated with numerous comorbidities and a profound impact on patients’ quality of life. While its complex immune pathogenesis is still not fully ...delineated, current evidence supports a fundamental role of the T-helper-17 (TH-17) pathway and its related interleukin-17 (IL-17) cytokine. Thus, new antipsoriatic therapies have been developed to block this key cytokine and its downstream effects. Secukinumab is a fully humanized, monoclonal anti-IL-17A antibody, and the first in its class to be approved by the US Food and Drug Administration for the treatment of moderate to severe plaque psoriasis. It has also been approved for the treatment of active psoriatic arthritis and ankylosing spondylitis. Its clinical efficacy in plaque psoriasis has been well demonstrated in numerous phase II and III clinical trials. In addition, it has shown superiority in clinical trials to current biologic agents including etanercept and ustekinumab, with a safe adverse event profile. In correlation with excellent skin improvements, secukinumab is also associated with significant improvements in health-related quality of life measures. Thus, secukinumab offers the potential for equal, or improved, therapeutic effects compared with other biologics, and is a valuable addition to our current antipsoriatic armamentarium.
The use of cyclosporine in dermatology: Part I Amor, Karrie T., MD; Ryan, Caitriona, MBBCh, BAO; Menter, Alan, MD
Journal of the American Academy of Dermatology,
12/2010, Letnik:
63, Številka:
6
Journal Article
Recenzirano
Cyclosporine is a calcineurin inhibitor that acts selectively on T cells. It has been used in dermatology since 1997 for its US Food and Drug Administration indication of psoriasis and off-label for ...various other inflammatory skin conditions, including atopic dermatitis, blistering disorders, and connective tissue diseases. In the last decade, many dermatologists have hesitated to use this important drug in their clinical practices because of its toxicity profile. The purpose of this article is to review the mechanism of action of cyclosporine and its current uses and dosing schedules. It is our goal to create a framework in which dermatologists feel comfortable and safe incorporating cyclosporine into their prescribing regimens. Learning objectives After completing this learning activity, participants should be able to describe the mechanism of action of cyclosporine, recognize the potential role of cyclosporine in dermatology and the evidence to support this role, and incorporate cyclosporine into his or her prescribing regimens.
Summary Background Ixekizumab is a humanised monoclonal antibody against the proinflammatory cytokine interleukin 17A. We report two studies of ixekizumab compared with placebo or etanercept to ...assess the safety and efficacy of specifically targeting interleukin 17A in patients with widespread moderate-to-severe psoriasis. Methods In two prospective, double-blind, multicentre, phase 3 studies (UNCOVER-2 and UNCOVER-3), eligible patients were aged 18 years or older, had a confirmed diagnosis of chronic plaque psoriasis at least 6 months before baseline (randomisation), 10% or greater body-surface area involvement at both screening and baseline visits, at least a moderate clinical severity as measured by a static physician global assessment (sPGA) score of 3 or more, and a psoriasis area and severity index (PASI) score of 12. Participants were randomly assigned (1:2:2:2) by computer-generated random sequence with an interactive voice response system to receive subcutaneous placebo, etanercept (50 mg twice weekly), or one injection of 80 mg ixekizumab every 2 weeks, or every 4 weeks after a 160 mg starting dose. Blinding was maintained with a double-dummy design. Coprimary efficacy endpoints were proportions of patients achieving sPGA score 0 or 1 and 75% or greater improvement in PASI at week 12. Analysis was by intention to treat. These trials are registered with ClinicalTrials.gov , numbers NCT01597245 and NCT01646177. Findings Between May 30, 2012, and Dec 30, 2013, 1224 patients in UNCOVER-2 were randomly assigned to receive subcutaneous placebo (n=168), etanercept (n=358), or ixekizumab every 2 weeks (n=351) or every 4 weeks (n=347); between Aug 11, 2012, and Feb 27, 2014, 1346 patients in UNCOVER-3 were randomly assigned to receive placebo (n=193), etanercept (n=382), ixekizumab every 2 weeks (n=385), or ixekizumab every 4 weeks (n=386). At week 12, both primary endpoints were met in both studies. For UNCOVER-2 and UNCOVER-3 respectively, in the ixekizumab every 2 weeks group, PASI 75 was achieved by 315 (response rate 89·7%; effect size 87·4% (97·5% CI 82·9–91·8) vs placebo; 48·1% (41·2–55·0) vs etanercept) and 336 (87·3%; 80·0% (74·4–85·7) vs placebo; 33·9% (27·0–40·7) vs etanercept) patients; in the ixekizumab every 4 weeks group, by 269 (77·5%; 75·1% (69·5–80·8) vs placebo; 35·9% (28·2–43·6) vs etanercept) and 325 (84·2%; 76·9% (71·0–82·8) vs placebo; 30·8% (23·7–37·9) vs etanercept) patients; in the placebo group, by four (2·4%) and 14 (7·3%) patients; and in the etanercept group by 149 (41·6%) and 204 (53·4%) patients (all p<0·0001 vs placebo or etanercept). In the ixekizumab every 2 weeks group, sPGA 0/1 was achieved by 292 (response rate 83·2%; effect size 80·8% (97·5% CI 75·6–86·0) vs placebo; 47·2% (39·9–54·4) vs etanercept) and 310 (80·5%; 73·8% (67·7–79·9) vs placebo; 38·9% (31·7–46·1) vs etanercept) patients; in the ixekizumab every 4 weeks group by 253 (72·9%; 70·5% (64·6–76·5) vs placebo; 36·9% (29·1–44·7) vs etanercept) and 291 (75·4%; 68·7% (62·3–75·0) vs placebo; 33·8% (26·3–41·3) vs etanercept) patients; in the placebo group by four (2·4%) and 13 (6·7%) patients; and in the etanercept group by 129 (36·0%) and 159 (41·6%) patients (all p<0·0001 vs placebo or etanercept). In combined studies, serious adverse events were reported in 14 (1·9%) of 734 patients given ixekizumab every 2 weeks, 14 (1·9%) of 729 given ixekizumab every 4 weeks, seven (1·9%) of 360 given placebo, and 14 (1·9%) of 739 given etanercept; no deaths were noted. Interpretation Both ixekizumab dose regimens had greater efficacy than placebo and etanercept over 12 weeks in two independent studies. These studies show that selectively neutralising interleukin 17A with a high affinity antibody potentially gives patients with psoriasis a new and effective biological therapy option. Funding Eli Lilly and Co.
IMPORTANCE: Other than single-center case studies, little is known about generalized pustular psoriasis (GPP) flares. OBJECTIVE: To assess GPP flares and their treatment, as well as differences ...between patients with and patients without flares documented in US electronic health records (EHRs). DESIGN, SETTING, AND PARTICIPANTS: This retrospective cohort study included adult patients with GPP (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code L40.1) identified in Optum deidentified EHR data between July 1, 2015, and June 30, 2020. The index GPP diagnosis was the first occurrence in the EHR, with no coded history of GPP for at least 6 months prior. Flare episodes were identified using an algorithm based on diagnosis coding, care setting, type of clinician, GPP disease terms, and flare terms and attributes in the EHR. MAIN OUTCOMES AND MEASURES: Flare episodes were characterized by the frequency of occurrence per patient, the care setting in which they were identified, the type of specialist managing the episode, associated symptoms, and the type of treatment before, during, and after the episode. Patients were divided into groups based on whether or not they had a flare episode documented in their EHR. Comparisons were made between the groups based on demographic characteristics, comorbidity burden, health care use, and treatments. RESULTS: Of 1535 patients with GPP (1018 women 66.3%; mean SD age, 53.4 14.7 years), 271 had 513 flares documented. Compared with patients without flares, patients with flares had a 34% higher mean (SD) Charlson Comorbidity Index score (2.80 3.11 vs 2.09 2.52), were almost 3 times more likely to have inpatient visits (119 of 271 44% vs 194 of 1264 15%), were more than twice as likely to have emergency department (ED) visits (126 of 271 47% vs 299 of 1264 24%), and had higher use of almost all treatment classes. Flares were identified in outpatient (271 of 513 53%), inpatient (186 of 513 36%), and ED (48 of 513 9%) settings. The most common treatments during flares were topical corticosteroids (35% of episodes 178 of 513), opioids (21% 106 of 513), other oral treatments, (eg, methotrexate, cyclosporine, tacrolimus; 13% 67 of 513), and oral corticosteroids (11% 54 of 513). Almost one-fourth of flare episodes (24% 122 of 513) had no dermatologic treatment 30 days before, during, or 30 days after a flare episode. CONCLUSIONS AND RELEVANCE: This cohort study suggests that there is significant unmet need for the treatment of GPP and its flares, as evidenced by patients seeking treatment in inpatient and ED settings, as well as the lack of advanced treatments.
The development of several highly effective biologic drugs in the past decade has revolutionized the treatment of moderate-to-severe plaque psoriasis. With increased understanding of the ...immunopathogenesis of psoriasis, the emphasis has turned toward more specific targets for psoriasis drugs. Although the complex immunological pathway of psoriasis is not yet completely understood, current models emphasize the significant importance of interleukin (IL)-23 and IL-17. Several biologic drugs targeting these cytokines are now in various stages of drug development. Drugs targeting IL-23 include BI-655066, briakinumab, guselkumab, tildrakizumab, and ustekinumab. Drugs targeting IL-17 include brodalumab, ixekizumab, and secukinumab. While many of these have shown safety and good efficacy in clinical trials of moderate-to-severe plaque psoriasis, long-term safety is still to be established.
Background Brodalumab (anti–interleukin-17-receptor antibody) was effective in treating moderate to severe psoriasis in a 12-week, dose-ranging, placebo-controlled trial. Objective We sought to ...evaluate efficacy and safety of long-term brodalumab treatment. Methods In this interim analysis at week 120 of an open-label extension study, patients received brodalumab 210 mg every 2 weeks. Protocol amendments reduced the dose (140 mg) in patients weighing 100 kg or less and subsequently increased the dose (210 mg) in patients with inadequate responses. Efficacy was measured by static physician global assessment and 75% or greater, 90% or greater, or 100% improvement in Psoriasis Area and Severity Index score (PASI-75, PASI-90, and PASI-100, respectively). Results Of 181 patients, 144 completed week 120. Static physician global assessment scores of clear/almost clear and clear were achieved by 90% and 63% of patients, respectively, at week 12 and by 72% and 51% at week 120. The PASI-75, PASI-90, and PASI-100 response rates at week 12 (95%/85%/63%) were sustained through week 120 (86%/70%/51%). Most commonly reported adverse events were nasopharyngitis (26.5%), upper respiratory tract infection (19.9%), arthralgia (16.0%), and back pain (11.0%). Four patients had grade-2 absolute neutrophil count. Limitations There was no control group in this open-label extension. Conclusion Brodalumab demonstrated sustained clinical response and an acceptable safety profile through 120 weeks in patients with moderate to severe psoriasis.
Psoriasis is a common, chronic, inflammatory, multisystem disease with predominantly skin and joint manifestations affecting approximately 2% of the population. In the first 5 parts of the ...AmericanAcademy of Dermatology Psoriasis Guidelines of Care, we have presented evidence supporting the use of topical treatments, phototherapy, traditional systemic agents, and biological therapies for patients with psoriasis and psoriatic arthritis. In this sixth and final section of the Psoriasis Guidelines of Care, we will present cases to illustrate how to practically use these guidelines in specific clinical scenarios. We will describe the approach to treating patients with psoriasis across the entire spectrum of this fascinating disease from mild to moderate to severe, with and without psoriatic arthritis, based on the 5 prior published guidelines. Although specific therapeutic recommendations are given for each of the cases presented, it is important that treatment be tailored to meet individual patients’ needs. In addition, we will update the prior 5 guidelines and address gaps in research and care that currently exist, while making suggestions for further studies that could be performed to help address these limitations in our knowledge base.
PDF
