Summary
Background
The interleukin‐17 cytokine family plays a central role in psoriasis pathogenesis.
Objectives
To evaluate the efficacy and safety of brodalumab, a human anti‐interleukin‐17 ...receptor antibody, in treating patients with moderate‐to‐severe plaque psoriasis.
Methods
In this phase III, double‐blind, placebo‐controlled study (NCT01708590; AMAGINE‐1), adult patients in the U.S.A., Canada and Europe were randomized to brodalumab (140 or 210 mg) or placebo every 2 weeks (Q2W), with an additional dose at week 1, for a 12‐week induction phase. At week 12, patients receiving brodalumab who achieved static Physician's Global Assessment 0 or 1 (sPGA success) were rerandomized to the placebo or induction dose. After week 16, patients with sPGA ≥ 3 were re‐treated with the induction dose. After ≥ 12 weeks of retreatment, patients with sPGA 2 for ≥ 4 weeks or sPGA ≥ 3 were rescued with brodalumab 210 mg Q2W. At week 12, patients randomized to brodalumab with sPGA ≥ 2 or placebo received brodalumab 210 mg Q2W. Coprimary end points were the percentage of patients with ≥ 75% improvement in Psoriasis Area and Severity Index score (PASI 75) and sPGA success at week 12.
Results
There were 661 patients randomized: 220 placebo, 219 brodalumab 140 mg and 222 brodalumab 210 mg. At week 12, 60% (140 mg) and 83% (210 mg) vs. 3% (placebo) achieved PASI 75, and 54% (140 mg) and 76% (210 mg) vs. 1% (placebo) achieved sPGA success. The safety profile was considered acceptable.
Conclusions
Brodalumab therapy resulted in significant clinical benefit and an acceptable safety profile in patients with moderate‐to‐severe plaque psoriasis.
What's already known about this topic?
Anti‐interleukin (anti‐IL)‐17 receptor A and anti‐IL‐17A antibodies have been shown to be efficacious in treating patients with moderate‐to‐severe plaque psoriasis.
What does this study add?
This study further demonstrates that brodalumab therapy in patients with moderate‐to‐severe plaque psoriasis results in a high degree of complete skin clearance.
This study also further elucidates the safety profile of brodalumab.
Linked Comment: Ormerod. Br J Dermatol 2016; 175:243–244
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Summary
Background
Tildrakizumab is a high‐affinity, humanized, IgG1/κ, anti‐interleukin (IL)‐23p19 monoclonal antibody that does not bind human IL‐12 or p40 is being developed for the treatment of ...chronic plaque psoriasis.
Objectives
To evaluate the safety and efficacy of subcutaneous tildrakizumab in patients with moderate‐to‐severe chronic plaque psoriasis.
Methods
A three‐part, randomized, double‐blind, phase IIb trial was conducted in 355 adults with chronic plaque psoriasis. Participants were randomized to receive subcutaneous tildrakizumab (5, 25, 100, 200 mg) or placebo at weeks 0 and 4 (part I) and every 12 weeks thereafter until week 52 (part II). Study drug was discontinued at week 52 and participants were followed through week 72 (part III). Primary efficacy end point was Psoriasis Area and Severity Index (PASI) 75 response at week 16. Adverse events (AEs) and vital signs were monitored throughout the study.
Results
At week 16, PASI 75 responses were 33·3% (n = 14), 64·4% (n = 58), 66·3% (n = 59), 74·4% (n = 64) and 4·4% (n = 2) in the 5‐, 25‐, 100‐ and 200‐mg tildrakizumab and placebo groups, respectively (P ≤ 0·001 for each tildrakizumab dose vs. placebo). PASI 75 response was generally maintained through week 52; only eight of 222 participants who achieved PASI 75 response at week 52 and continued to part III relapsed following discontinuation up to week 72. Possible drug‐related serious AEs included bacterial arthritis and lymphoedema (part I), and melanoma, stroke, epiglottitis and knee infection (part II).
Conclusions
Tildrakizumab had treatment effects that were superior to placebo, maintained for 52 weeks of treatment, and persisted for 20 weeks after cessation. Tildrakizumab was generally safe and well tolerated. These results suggest that IL‐23p19 is a key target for suppressing psoriasis.
What's already known about this topic?
Immune mechanism‐specific targeted biological treatments have successfully demonstrated improvements in clinical outcomes in patients with chronic plaque psoriasis.
Selective interleukin (IL)‐23 inhibition has been a recent target for novel therapies and small initial phase I trials have confirmed safety and preliminary efficacy in humans.
What does this study add?
This is the first large‐scale phase II trial to evaluate a monoclonal antibody that selectively inhibits IL‐23 in patients with chronic plaque psoriasis
.
Linked Comment: Strober, Br J Dermatol 2015; 173: 887–888.
Summary
Background
GP2015 is a proposed etanercept biosimilar.
Objectives
To demonstrate equivalent efficacy, and comparable safety and immunogenicity of GP2015 and the etanercept originator (ETN, ...Enbrel®) in patients with moderate‐to‐severe chronic plaque‐type psoriasis.
Methods
In total, 531 eligible patients were randomized 1 : 1 to self‐administer GP2015 or ETN twice weekly subcutaneously. Patients with ≥ 50% improvement in Psoriasis Area and Severity Index (PASI 50) at week 12 were rerandomized to continue the same treatment on a once‐weekly dosing schedule or to undergo a sequence of three treatment switches between GP2015 and ETN until week 30. Thereafter, patients continued treatment with the product they had been assigned to last, up to week 52.
Results
The difference in PASI 75 (75% improvement from baseline PASI score) response rates at week 12 between GP2015 and ETN (primary end point) was −2·3%. The 95% confidence interval (−9·85 to 5·30) was well contained within the prespecified margin range of −18 to 18. The incidence of treatment‐emergent adverse events up to week 52 was comparable between continued GP2015 (59·8%) and ETN (57·3%); switching treatments revealed comparable safety profiles. Antidrug antibodies, all non‐neutralizing, were limited to five patients on ETN during treatment period 1, and one patient in the switched ETN group, who had been treated with GP2015 for 12 weeks at the time of the finding.
Conclusions
The EGALITY study demonstrated equivalent efficacy and comparable safety and immunogenicity of GP2015 and ETN. The study results provide the final clinical confirmation of biosimilarity and contribute to the totality of the evidence proposing that GP2015 is an etanercept biosimilar.
What's already known about this topic?
Etanercept is a tumour necrosis factor inhibitor successfully used in clinical practice for the treatment of various immune‐mediated inflammatory diseases.
A biosimilar is a biological medicinal product designed to be essentially the same as the reference biologic (authorized biological medicine – the originator).
Biosimilarity is established on the basis of the totality of the evidence based on the data from analytical, nonclinical, pharmacokinetic and clinical comparisons with the originator product.
What does this study add?
GP2015 is a proposed etanercept biosimilar.
EGALITY, the first etanercept biosimilar study in patients with moderate‐to‐severe chronic plaque‐type psoriasis, was conducted with the purpose of gathering confirmatory clinical evidence of biosimilarity between GP2015 and the etanercept originator in a sensitive indication.
GP2015 was shown to possess equivalent efficacy to and comparable safety and immunogenicity with the etanercept originator, with no new or unexpected safety issues.
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Summary
Background
Atopic dermatitis is a chronic inflammatory skin disease that may require systemic therapy. Ciclosporin A (CsA) is a widely used, potent immunosuppressant but it is not effective ...in all patients with atopic dermatitis, and side‐effects limit its use. Dupilumab, a fully human anti‐interleukin 4 receptor‐alpha monoclonal antibody, inhibits signaling of IL‐4 and IL‐13, key drivers of Type 2/Th2‐mediated inflammation, and is approved in the U.S.A. and the European Union for the treatment of inadequately‐controlled moderate‐to‐severe atopic dermatitis in adults.
Objectives
To evaluate efficacy and safety of dupilumab with concomitant topical corticosteroids (TCS) in adults with atopic dermatitis with inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable.
Methods
In this 16‐week, double‐blind, randomized, placebo‐controlled, phase III trial, patients were randomized 1 : 1 : 1 to subcutaneous dupilumab 300 mg weekly (qw) or every 2 weeks (q2w) or placebo. All received concomitant medium‐potency TCS from Week −2 through Week 16; dosage could be tapered if lesions cleared, or stopped for adverse reactions to TCS.
Results
In total, 390 patients were screened, 325 were randomized, and 318 completed the trial. Treatment groups had similar baseline characteristics. Significantly more patients in the dupilumab qw + TCS and q2w + TCS groups achieved ≥ 75% improvement from baseline in the Eczema Area and Severity Index at Week 16 vs. the placebo + TCS group (primary end point) (59·1% and 62·6% vs. 29·6%, respectively; P < 0·001 vs. placebo + TCS, both doses). Other clinical outcomes and atopic dermatitis symptoms were significantly improved in the dupilumab qw + TCS and q2w + TCS groups, including pruritus, pain, sleep disturbance, symptoms of anxiety and depression, and quality of life (QoL). Treatment groups had similar overall rates of adverse events (qw + TCS, q2w + TCS and placebo + TCS groups: 69·1%, 72·0% and 69·4%, respectively) and serious adverse events (1·8%, 1·9% and 1·9%, respectively). Conjunctivitis was more frequent with dupilumab + TCS; skin infections were more frequent with placebo + TCS.
Conclusions
Dupilumab + TCS significantly improved signs and symptoms of atopic dermatitis and QoL in adults with a history of inadequate response to/intolerance of CsA, or for whom CsA treatment was medically inadvisable. No new safety signals were identified.
What's already known about this topic?
Patients with atopic dermatitis that is inadequately controlled with topical therapy have few systemic treatment options.
Ciclosporin A (CsA) is a systemic immunosuppressant approved for atopic dermatitis in most European countries and Japan, but not all patients respond, and side‐effects limit its use.
Dupilumab (monoclonal antibody against interleukin‐4 receptor‐alpha) with/without topical corticosteroids (TCS) is approved in the U.S.A. and the European Union for the treatment of adults with inadequately‐controlled moderate‐to‐severe atopic dermatitis.
What does this study add?
In this 16‐week trial in adults with atopic dermatitis and history of inadequate response or intolerance to CsA, or for whom CsA treatment was medically inadvisable, dupilumab administered weekly or every 2 weeks with concomitant TCS significantly improved signs and symptoms and quality of life, with no new safety signals.
These data support the use of dupilumab in this difficult‐to‐treat population.
Linked Editorial: Schmitt. Br J Dermatol 2018; 178:992–993.
Linked Letter: Thyssen. Br J Dermatol 2018; 178:1220.
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Summary
Background
With several million microbes per square centimetre of skin, the task of mapping the physiological cutaneous microbiome is enormous. Indeed, the reliance on bacterial culture to ...identify cutaneous bacterial communities has led to a systematic underappreciation of cutaneous microbial diversity, potentially limiting our understanding of common inflammatory skin diseases, including psoriasis. However, based heavily on developments in molecular biology and bioinformatics, including next‐generation sequencing, the last decade has witnessed a marked increase in our understanding of the extent and composition of the cutaneous microbiome. It is already clear that skin‐specific (skin site and skin microenvironment), individual‐specific (hygiene, sex, age and hormonal status), disease‐specific (atopic eczema, acne) and genetic factors can all influence the cutaneous microbiome, albeit to varying and, as yet, ill‐defined extents.
Objectives
To investigate the role of the microbiome in psoriasis and to outline how microbiome studies can be harnessed to provide new insights into disease pathogenesis and treatment selection.
Methods
This review briefly describes the process of 16S ribosomal RNA sequencing and then charts our current understanding of the cutaneous microbiome in health and the alterations (dysbiosis) associated with chronic inflammatory diseases, with particular reference to psoriasis.
Results
The possibility and clinical relevance of intraindividual cross‐talk between the various microbiomes is discussed and potential mechanisms underpinning the interactions between resident skin flora and the immune system are highlighted.
Conclusions
Ultimately, in the age of personalized medicine, the integration of cutaneous microbiome signatures and comprehensive disease and drug response endotypes will herald a novel approach in the clinical management of chronic multisystem inflammatory diseases.
What's already known about this topic?
The human integument hosts an extensive microbial ecosystem, which has been underestimated owing to the reliance on bacterial culture for its identification.
16S ribosomal RNA sequencing has shed new light on the extent and diversity (interindividual and intraindividual) of the cutaneous microbiome and its potential role in health and chronic inflammatory diseases, including psoriasis.
The mechanisms underpinning interactions between resident skin flora and the immune system are not completely understood.
What does this study add?
This review outlines the evidence for, and clinical relevance of, differences in the composition of cutaneous microbiota in terms of inflammatory skin disease.
In the age of personalized medicine, the integration of cutaneous microbiome signatures, combined with comprehensive genotyping and phenotyping of patients and their diseases, may facilitate treatment selection and consequently optimize treatment efficacy.
Linked Comment: Schalwijk. Br J Dermatol 2018; 178:999–1000.
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Summary
Background
Tildrakizumab is a specific anti‐interleukin‐23p19 monoclonal antibody approved for the treatment of plaque psoriasis.
Objectives
To evaluate the long‐term efficacy and safety of ...tildrakizumab treatment for patients with moderate‐to‐severe psoriasis for up to 148 weeks.
Methods
Pooled analysis from two double‐blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50–75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4‐week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all‐patients‐as‐treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2).
Results
At week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100‐mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200‐mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events tildrakizumab 100 mg: 1·7 per 100 patient‐years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs and exposure‐adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low.
Conclusions
Tildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab.
What's already known about this topic?
Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short‐term use in the treatment of patients with moderate‐to‐severe plaque psoriasis.
What does this study add?
High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab.
There is a favourable long‐term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years.
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Summary
Background
Secukinumab, an anti‐interleukin‐17A monoclonal antibody, has demonstrated rapid and sustained efficacy in phase 3 psoriasis trials.
Objectives
To examine whether partial ...responders could achieve improved responses with intravenous (IV) secukinumab vs. the same or a higher subcutaneous (SC) dose.
Methods
Forty‐three participants with moderate‐to‐severe psoriasis and partial response Psoriasis Area and Severity Index (PASI) score improvement of ≥ 50% but < 75% after 12 weeks of 300 or 150 mg SC secukinumab therapy were randomized 1 : 1 to secukinumab 10 mg kg−1 IV (baseline, weeks 2 and 4, respectively) or secukinumab 300 mg SC (baseline, week 4). All participants subsequently received secukinumab 300 mg SC every 4 weeks (weeks 8–36). Co‐primary end points were PASI 75 and Investigator's Global Assessment 2011 modified version (IGA mod 2011) 0/1 response rates at week 8 (IV vs. SC).
Results
Higher IGA mod 2011 0/1 response rates (66·7% vs. 33·3%; P = 0·03) and a trend towards higher PASI 75 response rates (90·5% vs. 66·7%; P = 0·06) were observed with secukinumab IV vs. SC at week 8. The primary objective was not met, as the difference was not significant for both co‐primary end points. Improved responses in both groups were maintained at week 40 in most participants. Safety profiles for IV and SC secukinumab were similar. The trial was underpowered owing to its small sample size.
Conclusions
Improved response may be attained in patients with psoriasis achieving partial response after 12 weeks of SC secukinumab treatment by continued dosing with 300 mg SC or treatment with higher doses.
What's already known about this topic?
Secukinumab has demonstrated rapid, strong and sustained efficacy in treating moderate‐to‐severe psoriasis ˜70–75% Psoriasis Area and Severity Index (PASI) 90 achievement by week 16.
What does this study add?
The present trial suggests that responses to secukinumab in participants who are partial responders (PASI improvement ≥ 50% but < 75%) after 12 weeks of subcutaneous (SC) therapy may be improved by continued dosing with 300 mg SC or treatment with higher doses short‐term intravenous secukinumab or a higher SC dose (300 vs. 150 mg).
Background
Secukinumab, a fully human monoclonal antibody that selectively neutralizes IL‐17A, has been shown to have significant efficacy and a favourable safety profile in the treatment of ...moderate‐to‐severe psoriasis and psoriatic arthritis.
Objective
To assess the efficacy and safety of secukinumab through 5 years of treatment in moderate‐to‐severe psoriasis.
Methods
In the core SCULPTURE study, Psoriasis Area and Severity Index (PASI) 75 responders at Week 12 continued receiving subcutaneous secukinumab until Year 1. Thereafter, patients entered the extension phase and continued treatment as per the core trial. Treatment was double‐blinded until the end of Year 3 and open‐label from Year 4. Here, we focus on the 300 mg fixed‐interval (every 4 weeks) treatment, the recommended per label dose. Efficacy data are primarily reported as observed, but multiple imputation (MI) and last observation carried forward (LOCF) techniques were also undertaken as supportive analyses.
Results
At Year 1, 168 patients entered the extension study and at the end of Year 5, 126 patients completed 300 mg (every 4 weeks) treatment. PASI 75/90/100 responses at Year 1 (88.9%, 68.5% and 43.8%, respectively) were sustained to Year 5 (88.5%, 66.4% and 41%). PASI responses were consistent regardless of the analysis undertaken (as observed, MI, or LOCF). The average improvement in mean PASI was approximately 90% through 5 years compared with core study baseline. DLQI (dermatology life quality index) 0/1 response also sustained through 5 years (72.7% at Year 1 and 65.5% at Year 5). The safety profile of secukinumab remained favourable, with no cumulative or unexpected safety concerns identified.
Conclusion
Secukinumab 300 mg treatment delivered high and sustained levels of skin clearance and improved quality of life through 5 years in patients with moderate‐to‐severe psoriasis. Favourable safety established in the secukinumab phase 2/3 programme was maintained through 5 years.
Summary
Background
Guselkumab, a fully human interleukin‐23 antibody, is approved for systemic treatment of patients with moderate‐to‐severe plaque psoriasis.
Objectives
To compare the efficacy and ...safety of guselkumab with those of fumaric acid esters (FAE) in patients with moderate‐to‐severe plaque psoriasis who are naive to systemic treatment.
Methods
Eligible patients were randomized to this multicentre, randomized, open‐label, assessor‐blinded, active‐comparator‐controlled phase IIIb study to receive guselkumab 100 mg by subcutaneous injection or oral FAE according to local label guidelines.
Results
Through week 24, 56 of 60 patients completed guselkumab treatment and 36 of 59 completed FAE treatment. The primary endpoint (proportion of patients with ≥ 90% improvement from their baseline Psoriasis Area and Severity Index; PASI 90 response) was achieved by significantly more patients receiving guselkumab than FAE at week 24 (82% vs. 14%, P < 0·001). Analysis of the major secondary endpoints confirmed a statistically significant difference between the treatments with regards to PASI 75 response (90% vs. 27%, P < 0·001) and Dermatology Life Quality Index score of 0 or 1 (no effect at all on the patient's quality of life; 62% vs. 17%, P < 0·001). More patients in the guselkumab group achieved completely clear skin (PASI 100 response) than in the FAE group (32% vs. 3%, P < 0·001). The incidence of adverse events was lower with guselkumab than with FAE (73% vs. 98%). Overall, 28% of patients on FAE discontinued due to an adverse event, compared with none receiving guselkumab. No new safety findings were observed for guselkumab.
Conclusions
Guselkumab demonstrated superiority over FAE in systemic‐treatment‐naive patients with moderate‐to‐severe plaque psoriasis through 24 weeks.
What's already known about this topic?
Guselkumab is approved as treatment for patients with moderate‐to‐severe plaque psoriasis who are candidates for systemic therapy.
Guselkumab is a monoclonal antibody that specifically targets the p19 subunit of the immune‐regulatory cytokine interleukin‐23, a key driver of immune response in psoriasis.
Fumaric acid esters (FAE) are among the most commonly prescribed first‐line systemic therapies for plaque psoriasis in Germany and they are increasingly being used in other countries.
What does this study add?
In patients with psoriasis who are naive to systemic treatment, guselkumab was superior to FAE in achieving ≥ 75%, ≥ 90% and 100% improvement in Psoriasis Area and Severity Index, and Dermatology Life Quality Index scores of 0 or 1 at week 24.
Guselkumab showed a favourable safety profile, and fewer patients discontinued treatment due to adverse events compared with FAE‐treated patients.
The results support the use of guselkumab in systemic‐treatment‐naive patients with moderate‐to‐severe plaque psoriasis.
Linked Comment: Meier and Ghoreschi. Br J Dermatol 2020; 183:201–202.
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Summary
Background
Assessment of disease severity is an essential component of psoriasis management. Moderate‐to‐severe disease qualifies for systemic treatment but different definitions are used.
...Objectives
To analyse the impact of different severity definitions for psoriasis in real‐world healthcare.
Methods
Cross‐sectional data on 3274 patients with psoriasis from more than 200 dermatology offices and clinics across Germany were analysed for disease severity based on Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI). The proportions of patients having moderate‐to‐severe disease were determined accordingly.
Results
The proportion of patients meeting the European consensus criteria for moderate‐to‐severe psoriasis (PASI AND DLQI > 10) was 14·0%, although 45·3% attained at least PASI OR DLQI > 10. Consideration of all patients on systemic drugs as being ‘moderate‐to‐severe’ increased these proportions to 56·9% and 75·2%, respectively. When only PASI > 10 was used, moderate‐to‐severe disease affected 35·3% and 69·3%, respectively.
Conclusions
The proportion of patients with psoriasis under dermatological care considered to have moderate‐to‐severe disease varies considerably according to how the latter is defined, resulting in uncertainty and inequity of access to systemic therapy. We propose an international standardisation in this for the sake of more reliable treatment and healthcare planning.
What's already known about this topic?
Measurement of psoriasis severity is generally based on the Psoriasis Area and Severity Index (PASI) and Dermatology Life Quality Index (DLQI). In practice, different definitions are used.
What does this study add?
There are large variations in the patient subgroups having moderate‐to‐severe psoriasis depending on the use of existing definitions for PASI and DLQI.
A subgroup of patients with severe psoriasis in routine care has less chance of access to systemic treatments due to uncertainty in severity assessment with DLQI and PASI.
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