The Epidemiology of Hospital-Treated Alopecia Areata in Denmark, 1995-2016.

INTRODUCTION: Alopecia areata (AA) is an autoimmune skin disease presenting as nonscarring hair loss. Information on the epidemiology of AA, especially the occurrence of AA and its subtypes within the general population, is scarce. The study aimed to estimate the incidence rates and prevalence of hospital-treated AA and its subtypes in Denmark and to examine the demographic and clinical characteristics of patients with AA, including comorbidities and use of prescription medications. METHODS: This was a cohort study based on data from administrative and health registers in Denmark in 1995-2016. The study included individuals who were (1) registered with a hospital inpatient or hospital-based outpatient clinic diagnosis of AA between 1995 and 2016 in the Danish National Patient Registry covering encounters at all Danish hospitals, (2) alive and resided in Denmark anytime between 1995 and 2016, (3) aged ≥ 12 years, and (4) resided uninterrupted in Denmark during the 12 months before the first AA diagnosis during the study period. RESULTS: During the study period, 2778 individuals with an incident hospital-based diagnosis of AA were identified; 63.1% were female and 28.7% of the patients were aged ≥ 50 years. Over the study period, the overall incidence rate for any hospital-treated AA per 100,000 person-years was 2.62 (95% confidence interval [CI], 2.53-2.72), and the overall prevalence in 2016 was 71.7 (95% CI 69.4-74.1) per 100,000 persons. Both incidence rate and prevalence increased over time. Prevalence of most hospital-treated comorbidities or history of medication use was below 10% and was similar in the alopecia totalis (AT)/alopecia universalis (AU) and non-AT/AU subtypes of AA. CONCLUSION: This cohort study reported incidence rates and prevalence over time and characteristics of individuals with hospital-treated AA in Denmark, which are in agreement with those previously reported in this population.

Integrated Safety Analysis of Ritlecitinib, an Oral JAK3/TEC Family Kinase Inhibitor, for the Treatment of Alopecia Areata from the ALLEGRO Clinical Trial Program.

BACKGROUND: The ALLEGRO phase 2a and 2b/3 studies demonstrated that ritlecitinib, an oral JAK3/TEC family kinase inhibitor, is efficacious at doses of ≥ 30 mg in patients aged ≥ 12 years with alopecia areata (AA). OBJECTIVE: The objective of this study was to evaluate the safety of ritlecitinib in an integrated analysis of four studies in AA. METHODS: Two cohorts were analyzed: a placebo-controlled and an all-exposure cohort. Proportions and study size-adjusted incidence rates (IRs) of adverse events (AEs) of interest and laboratory abnormalities are reported. RESULTS: In the placebo-controlled cohort (n = 881; median exposure: 169 days), the proportion of ritlecitinib-treated patients with AEs was 70.2-75.4% across doses versus 69.5% in the placebo group; serious AEs occurred in 0-3.2% versus 1.9% for the placebo. A total of 19 patients permanently discontinued due to AEs (5 while receiving the placebo). In the all-exposure cohort (n = 1294), median ritlecitinib exposure was 624 days [2091.7 total patient-years (PY)]. AEs were reported in 1094 patients (84.5%) and serious AEs in 57 (4.4%); 78 (6.0%) permanently discontinued due to AEs. The most common AEs were headache (17.7%; 11.9/100 PY), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) positive test (15.5%; 9.8/100 PY), and nasopharyngitis (12.4%; 8.2/100 PY). There were two deaths (breast cancer and acute respiratory failure/cardiorespiratory arrest). Proportions (IRs) were < 0.1% (0.05/100 PY) for opportunistic infections, 1.5% (0.9/100 PY) for herpes zoster, 0.5% (0.3/100 PY) for malignancies (excluding nonmelanoma skin cancer), and 0.2% (0.1/100 PY) for major adverse cardiovascular events. CONCLUSIONS: Ritlecitinib is well tolerated with an acceptable safety profile up to 24 months in patients aged ≥ 12 years with AA (video abstract and graphical plain language summary available). TRIAL REGISTRIES: ClinicalTrials.gov: NCT02974868 (date of registration: 11/29/2016), NCT04517864 (08/18/2020), NCT03732807 (11/07/2018), and NCT04006457 (07/05/2019).

Hair Loss Profiles and Ritlecitinib Efficacy in Patients with Alopecia Areata: Post Hoc Analysis of the ALLEGRO Phase 2b/3 Study.

INTRODUCTION: Ritlecitinib demonstrated efficacy in patients with alopecia areata (AA) in the ALLEGRO phase 2b/3 study (NCT03732807). However, hair loss presentation may vary based on location (e.g., scalp, eyebrow/eyelash, body). Here, we sought to identify distinct hair loss profiles at baseline and evaluate whether they affected the efficacy of ritlecitinib. METHODS: Patients with AA aged ≥ 12 years with ≥ 50% scalp hair loss were randomized to daily ritlecitinib 10 mg (assessed for dose ranging only), 30 or 50 mg (± 4-week, 200-mg loading dose), or placebo for 24 weeks. Latent class analysis (LCA) identified hair loss profiles based on four baseline measurements: clinician-reported extent of scalp (Severity of Alopecia Tool score), eyebrow hair loss, eyelash hair loss, and patient-reported body hair loss. Logistic regression evaluated ritlecitinib (50 and 30 mg) efficacy vs placebo using Patient Global Impression of Change (PGI-C) and Patient Satisfaction with Hair Growth (P-Sat; amount, quality, and overall satisfaction) responses at Week 24, adjusting for key covariates, including latent class membership. RESULTS: LCA identified five latent classes: (1) primarily non-alopecia totalis (AT; complete loss of scalp hair); (2) non-AT with moderate non-scalp involvement; (3) extensive scalp, eyebrow, and eyelash involvement; (4) AT with moderate non-scalp involvement; and (5) primarily alopecia universalis (complete scalp, face, and body hair loss). Adjusting for latent class membership, patients receiving ritlecitinib 30 or 50 mg were significantly more likely to achieve PGI-C response (30 mg: odds ratio, 8.62 [95% confidence interval, 4.42-18.08]; 50 mg: 12.29 [6.29-25.85]) and P-Sat quality of hair regrowth (30 mg: 6.71 [3.53-13.51]; 50 mg: 8.17 [4.30-16.46]) vs placebo at Week 24. Results were similar for P-Sat overall satisfaction and amount of hair regrowth. CONCLUSION: Distinct and clinically relevant hair loss profiles were identified in ALLEGRO-2b/3 participants. Ritlecitinib was efficacious compared with placebo, independent of hair loss profile at baseline. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03732807.

Utilization of Rosuvastatin and Endogenous Biomarkers in Evaluating the Impact of Ritlecitinib on BCRP, OATP1B1, and OAT3 Transporter Activity.

PURPOSE: Ritlecitinib, an inhibitor of Janus kinase 3 and tyrosine kinase expressed in hepatocellular carcinoma family kinases, is in development for inflammatory diseases. This study assessed the impact of ritlecitinib on drug transporters using a probe drug and endogenous biomarkers. METHODS: In vitro transporter-mediated substrate uptake and inhibition by ritlecitinib and its major metabolite were evaluated. Subsequently, a clinical drug interaction study was conducted in 12 healthy adult participants to assess the effect of ritlecitinib on pharmacokinetics of rosuvastatin, a substrate of breast cancer resistance protein (BCRP), organic anion transporting polypeptide 1B1 (OATP1B1), and organic anion transporter 3 (OAT3). Plasma concentrations of coproporphyrin I (CP-I) and pyridoxic acid (PDA) were assessed as endogenous biomarkers for OATP1B1 and OAT1/3 function, respectively. RESULTS: In vitro studies suggested that ritlecitinib can potentially inhibit BCRP, OATP1B1 and OAT1/3 based on regulatory cutoffs. In the subsequent clinical study, coadministration of ritlecitinib decreased rosuvastatin plasma exposure area under the curve from time 0 to infinity (AUCinf) by ~ 13% and maximum concentration (Cmax) by ~ 27% relative to rosuvastatin administered alone. Renal clearance was comparable in the absence and presence of ritlecitinib coadministration. PK parameters of AUCinf and Cmax for CP-I and PDA were also similar regardless of ritlecitinib coadministration. CONCLUSION: Ritlecitinib does not inhibit BCRP, OATP1B1, and OAT3 and is unlikely to cause a clinically relevant interaction through these transporters. Furthermore, our findings add to the body of evidence supporting the utility of CP-I and PDA as endogenous biomarkers for assessment of OATP1B1 and OAT1/3 transporter activity.

A plain language summary on ritlecitinib treatment for adults and adolescents with alopecia areata.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of the results of the ALLEGRO phase 2b/3 clinical trial, originally published in The Lancet. ALLEGRO-2b/3 looked at how well and safely the study medicine, ritlecitinib, works in treating people with alopecia areata ('AA' for short). The immune system protects your body from outside invaders such as bacteria and viruses. AA is an autoimmune disease, meaning a disease in which one's immune system attacks healthy cells of the body by mistake. In AA, the immune system attacks hair follicles, causing hair to fall out. AA causes hair loss ranging from small bald patches to complete hair loss on the scalp, face, and/or body. Ritlecitinib is a medicine taken as a pill every day, by mouth, that is approved for the treatment of severe AA. It blocks processes that are known to play a role in causing hair loss in patients with AA. WHAT WERE THE RESULTS OF THE STUDY?: Adults and adolescents (12 years and older) took part in the ALLEGRO-2b/3 study. They either took ritlecitinib for 48 weeks or took a placebo (a pill with no medicine) for 24 weeks. Participants taking placebo later switched to taking ritlecitinib for 24 weeks. The study showed that participants taking ritlecitinib had more hair regrowth on their scalp after 24 weeks than those taking the placebo. Hair regrowth was also seen on the eyebrows and eyelashes in participants taking ritlecitinib. Hair regrowth continued to improve to week 48 with continued ritlecitinib treatment. In addition, more participants taking ritlecitinib reported that their AA had 'moderately' or 'greatly' improved after 24 weeks than those taking the placebo. Similar numbers of participants taking ritlecitinib or placebo had side effects after 24 weeks. Most side effects were mild or moderate. WHAT DO THE RESULTS OF THE STUDY MEAN?: Ritlecitinib was an effective and well-tolerated treatment over 48 weeks for people with AA. Clinical Trial Registration: NCT03732807 (phase 2b/3 ALLEGRO study).

Efficacy and safety of ritlecitinib in adolescents with alopecia areata: Results from the ALLEGRO phase 2b/3 randomized, double-blind, placebo-controlled trial.

BACKGROUND/OBJECTIVES: This subgroup analysis of the ALLEGRO phase 2b/3 trial (NCT03732807) evaluated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, for the treatment of alopecia areata (AA) in patients aged 12-17 years. METHODS: In ALLEGRO-2b/3, patients aged ≥12 years with AA and ≥50% scalp hair loss received once-daily ritlecitinib 50 or 30 mg (±4-week 200-mg loading dose) or 10 mg or placebo for 24 weeks. In a subsequent 24-week extension period, ritlecitinib groups continued their doses, and patients initially assigned to placebo switched to 200/50 or 50 mg daily. Clinician- and patient-reported hair regrowth outcomes and safety were assessed. RESULTS: In total, 105 adolescents were randomized. At Week 24, 17%-28% of adolescents achieved a Severity of Alopecia Tool (SALT) score ≤20 (≤20% scalp without hair) in the ritlecitinib 30 mg and higher treatment groups versus 0% for placebo. At Week 48, 25%-50% of patients had a SALT score ≤20 across ritlecitinib treatment groups (30 mg and higher). Adolescents reporting that their AA "moderately" or "greatly" improved were 45%-61% in the ritlecitinib groups (30 mg and higher) (vs. 10%-22% for placebo) at Week 24 and 44%-80% at Week 48. The most common adverse events in adolescents were headache, acne, and nasopharyngitis. No deaths, major adverse cardiovascular events, malignancies, pulmonary embolisms, opportunistic infections, or herpes zoster infections were reported. CONCLUSION: Ritlecitinib treatment demonstrated clinician-reported efficacy, patient-reported improvement, and an acceptable safety profile through Week 48 in adolescents with AA with ≥50% scalp hair loss.

Prevalence of autoimmune and inflammatory diseases and mental health conditions among an alopecia areata cohort from a US administrative claims database.

Alopecia areata (AA) is associated with an increased burden of autoimmune and inflammatory disease and mental health conditions that may have a negative impact on quality of life. However, the exact burden of comorbidities on US patients with AA and the clinical subtypes alopecia totalis (AT) and alopecia universalis (AU) compared with those without AA is not well understood. This retrospective cohort study aimed to assess the incidence rates and prevalence of AA and its clinical subtypes and examine the autoimmune and inflammatory disease and mental health condition diagnosis burden in US patients with AA and a matched cohort without AA. The Optum Clinformatics Data Mart database was used to select patients aged ≥12 years enrolled between October 1, 2016, and September 30, 2020, who had two or more AA diagnosis codes for the AA cohort. Three patients without AA were age-, sex-, and race-matched to each patient with AA. Autoimmune and inflammatory diseases and mental health conditions were evaluated at baseline and up to 2 years after the index date. In total, 8784 patients with AA (599 with AT/AU) and 26 352 matched patients without AA were included. The incidence rate of AA was 17.5 per 100 000 person-years (PY; AT/AU: 1.1 per 100 000 PY; non-AT/AU: 16.3 per 100 000 PY), and the prevalence was 54.9 per 100 000 persons (AT/AU: 3.8; non-AT/AU: 51.2). Patients with AA had a higher prevalence of autoimmune and inflammatory diseases than the matched non-AA cohort, including allergic rhinitis (24.0% vs 14.5%), asthma (12.8% vs 8.8%), atopic dermatitis (8.3% vs 1.8%), and psoriasis (5.0% vs. 1.6%). The proportions of anxiety (30.7% vs 21.6%) and major depressive disorder (17.5% vs 14.0%) were higher in patients with AA than those without AA. Patients with AT/AU generally had a greater prevalence of autoimmune and inflammatory disease and mental health conditions than patients with non-AT/AU AA.

Incidence Rates of Infections, Malignancies, Thromboembolism, and Cardiovascular Events in an Alopecia Areata Cohort from a US Claims Database.

INTRODUCTION: Alopecia areata (AA) is an autoimmune disease with an underlying immuno-inflammatory pathogenesis. Treatments can include systemic corticosteroids and immunomodulators (such as Janus kinase inhibitors); these medications may be associated with a risk of some adverse events. However, large-scale observational studies of baseline incidence rates (IRs) of infection, cardiovascular disease, malignancy, and thromboembolism in US patients with AA, including those with alopecia totalis or alopecia universalis (AT/AU), are limited. This real-world, US claims-based study aimed to estimate the incidence of events in patients with AA compared with matched patients without AA. METHODS: Patients aged ≥ 12 years enrolled in the Optum Clinformatics Data Mart database from 1 October 2016 to 30 September 2020, with ≥ 2 AA diagnosis codes were included in the AA cohort. Patients without AA were age-, sex-, and race-matched 3:1 to patients with AA. Baseline comorbidities were evaluated during the 12-month period pre-index date. Incident cases of serious/herpes infections, malignancies, major adverse cardiovascular events (MACE), and thromboembolic events were evaluated post-index date. Data are presented using descriptive statistics, proportional percentages, frequencies, and IRs (calculated with 95% CI). RESULTS: Overall, 8784 patients with AA, 599 of whom had AT/AU, were matched to 26,352 patients without AA. IRs per 1000 person-years among the AA and non-AA cohorts, respectively, were 18.5 and 20.6 for serious infections, 19.5 and 9.7 for herpes simplex infections, 7.8 and 7.6 for herpes zoster infections, 12.5 and 11.6 for primary malignancies, 16.0 and 18.1 for MACE, and 4.9 and 6.1 for venous thromboembolisms. Compared with patients with non-AT/AU AA, patients with AT/AU largely had higher IRs for most baseline comorbidities and outcome events evaluated. CONCLUSION: Patients with AA had a higher IR of herpes simplex infection than the matched non-AA cohort. Patients with AT/AU generally had higher rates of outcome events than patients without AT/AU.

Efficacy and safety of ritlecitinib in adults and adolescents with alopecia areata: a randomised, double-blind, multicentre, phase 2b-3 trial.

BACKGROUND: Alopecia areata is characterised by non-scarring loss of scalp, face, or body hair. We investigated the efficacy and safety of ritlecitinib, an oral, selective dual JAK3/TEC family kinase inhibitor, in patients with alopecia areata. METHODS: In this randomised, double-blind, multicentre, phase 2b-3 trial done at 118 sites in 18 countries, patients aged 12 years and older with alopecia areata and at least 50% scalp hair loss were randomly assigned to oral ritlecitinib or placebo once-daily for 24 weeks, with or without a 4-week loading dose (50 mg, 30 mg, 10 mg, 200 mg loading dose followed by 50 mg, or 200 mg loading dose followed by 30 mg), followed by a 24-week extension period during which ritlecitinib groups continued their assigned doses and patients initially assigned to placebo switched to ritlecitinib 50 mg or 200 mg loading dose followed by 50 mg. Randomisation was done by use of an interactive response system and was stratified by baseline disease severity and age. The sponsor, patients, and investigators were masked to treatment, and all patients received the same number of tablets to maintain masking. The primary endpoint was Severity of Alopecia Tool (SALT) score 20 or less at week 24. The primary endpoint was assessed in all assigned patients, regardless of whether they received treatment. This study was registered with ClinicalTrials.gov, NCT03732807. FINDINGS: Between Dec 3, 2018, and June 24, 2021, 1097 patients were screened and 718 were randomly assigned to receive ritlecitinib 200 mg + 50 mg (n=132), 200 mg + 30 mg (n=130), 50 mg (n=130), 30 mg (n=132), 10 mg (n=63), placebo to 50 mg (n=66), or placebo to 200 mg + 50 mg (n=65). 446 (62%) of 718 patients were female and 272 (38%) were male. 488 (68%) were White, 186 (26%) were Asian, and 27 (4%) were Black or African American. Of 718 patients randomly assigned, 104 patients discontinued treatment (34 withdrew, 19 adverse events [AEs], 12 physician decision, 12 lack of efficacy, 13 lost to follow up, five rolled over to long-term study transfer, four pregnancies, two protocol deviations, one declined to attend follow-up due to COVID-19, one attended last visit very late due to COVID-19, and one non-compliance). At week 24, 38 (31%) of 124 patients in the ritlecitinib 200 mg + 50 mg group, 27 (22%) of 121 patients in the 200 mg + 30 mg group, 29 (23%) of 124 patients in the 50 mg group, 17 (14%) of 119 patients in the 30 mg group, and two (2%) of 130 patients in the placebo group had a response based on SALT score 20 or less. The difference in response rate based on SALT score 20 or less between the placebo and the ritlecitinib 200 mg + 50 mg group was 29·1% (95% CI 21·2-37·9; p<0·0001), 20·8% (13·7-29·2; p<0·0001) for the 200 mg + 30 mg group, 21·9% (14·7-30·2; p<0·0001) for the 50 mg group, and 12·8% (6·7-20·4; p=0·0002) for the 30 mg group. Up to week 48 and including the follow-up period, AEs had been reported in 108 (82%) of 131 patients in the ritlecitinib 200 mg + 50 mg group, 105 (81%) of 129 patients in the 200 mg + 30 mg group, 110 (85%) of 130 patients in the 50 mg group, 106 (80%) of 132 patients in the 30 mg group, 47 (76%) of 62 patients in the 10 mg group, 54 (83%) of 65 patients placebo to ritlecitinib 200 mg + 50 mg in the extension period, and 57 (86%) of 66 patients in the placebo to 50 mg group. The incidence of each AE was similar between groups, and there were no deaths. INTERPRETATION: Ritlecitinib was effective and well tolerated in patients aged 12 years and older with alopecia areata. Ritlecitinib might be a suitable treatment option for alopecia areata in patients who are candidates for systemic therapy. FUNDING: Pfizer.

Evaluation of the effect of ritlecitinib on the pharmacokinetics of caffeine in healthy participants.

AIMS: This clinical study was conducted to evaluate the impact of ritlecitinib on the pharmacokinetics of caffeine, a cytochrome P450 1A2 (CYP1A2) substrate. METHODS: In this single-centre, single-arm, open-label, fixed-sequence study, healthy participants received a single 100-mg dose of caffeine on 2 separate occasions: on Day 1 of Period 1 as monotherapy and on Day 8 of Period 2 after oral administration of ritlecitinib 200 mg once daily for 8 days. Serial blood samples were collected and analysed using a validated liquid chromatography-mass spectrometry assay. Pharmacokinetic parameters were estimated by using a noncompartmental method. Safety was monitored by physical examination, vital signs, electrocardiograms and laboratory assessments. RESULTS: Twelve participants were enrolled and completed the study. Coadministration of caffeine 100 mg in the presence of steady-state levels of ritlecitinib (200 mg once daily) increased caffeine exposure compared with caffeine given alone. Area under the curve to infinity and maximum concentration of caffeine increased by approximately 165 and 10%, respectively, when coadministered with ritlecitinib. The ratios of the adjusted geometric means (90% confidence interval) for caffeine area under the curve to infinity and maximum concentration were 265.14% (234.12-300.26%) and 109.74% (103.90-15.91%), respectively, when caffeine was coadministered with steady-state ritlecitinib (test) compared with its administration alone (reference). Multiple doses of ritlecitinib when coadministered with a single dose of caffeine were generally safe and well tolerated in healthy participants. CONCLUSION: Ritlecitinib is a moderate inhibitor of CYP1A2 and can increase systemic exposures of CYP1A2 substrates.

Evaluation of the Impact of Ritlecitinib on Organic Cation Transporters Using Sumatriptan and Biomarkers as Probes.

Ritlecitinib, an inhibitor of Janus kinase 3 and hepatocellular carcinoma family kinases, is in development as potential treatment for several inflammatory diseases. In vitro studies presented ritlecitinib as an inhibitor of hepatic organic cation transporter (OCT) 1, renal transporters OCT2 and multidrug and toxin extrusion (MATE) proteins 1/2K using multiple substrates, and ritlecitinib's major inactive metabolite M2, as an inhibitor of OCT1. A clinical interaction study with an OCT1 drug probe (sumatriptan) and relevant probe biomarkers for OCT/MATE was conducted to assess the effect of ritlecitinib on these transporters in healthy adult participants. The selectivity of sumatriptan for OCT1 was confirmed through a series of in vitro uptake assays. A simple static model was used to help contextualize the observed changes in sumatriptan area under the plasma concentration-time curve (AUC). Coadministration of a single 400-mg dose of ritlecitinib increased sumatriptan AUC from time 0 to infinity (AUCinf ) by ≈30% relative to a single 25-mg sumatriptan administration alone. When administered 8 hours after a ritlecitinib dose, sumatriptan AUCinf increased by ≈50% relative to sumatriptan given alone. Consistent with OCT1 inhibition, the AUC from time 0 to 24 hours of isobutyryl-L-carnitine decreased by ≈15% after ritlecitinib. Based on the evaluation of the renal clearance of N1 -methylnicotinamide, ritlecitinib does not exert clinically meaningful inhibition on renal OCT2 or MATE1/2K. This study confirmed that ritlecitinib and M2 are inhibitors of OCT1 but not OCT2 or MATE1/2K in healthy adults.

Early Quantification of Systemic Inflammatory Proteins Predicts Long-Term Treatment Response to Tofacitinib and Etanercept.

The application of machine learning to longitudinal gene-expression profiles has demonstrated potential to decrease the assessment gap, between biochemical determination and clinical manifestation, of a patient's response to treatment. Although psoriasis is a proven testing ground for treatment-response prediction using transcriptomic data from clinically accessible skin biopsies, these biopsies are expensive, invasive, and challenging to obtain from certain body areas. Response prediction from blood biochemical measurements could be a cheaper, less invasive predictive platform. Longitudinal profiles for 92 inflammatory and 65 cardiovascular disease proteins were measured from the blood of psoriasis patients at baseline, and 4-weeks, following tofacitinib (janus kinase-signal transducer and activator of transcription-inhibitor) or etanercept (tumor necrosis factor-inhibitor) treatment, and predictive models were developed by applying machine-learning techniques such as bagging and ensembles. This data driven approach developed predictive models able to accurately predict the 12-week clinical endpoint for psoriasis following tofacitinib (area under the receiver operating characteristic curve [auROC] = 78%), or etanercept (auROC = 71%) treatment in a validation dataset, revealing a robust predictive protein signature including well-established psoriasis markers such as IL-17A and IL-17C, highlighting potential for biologically meaningful and clinically useful response predictions using blood protein data. Although most blood classifiers were outperformed by simple models trained using Psoriasis Area Severity Index scores, performance might be enhanced in future studies by measuring a wider variety of proteins.

Changes in Lipid Levels and Incidence of Cardiovascular Events Following Tofacitinib Treatment in Patients With Psoriatic Arthritis: A Pooled Analysis Across Phase III and Long-Term Extension Studies.

OBJECTIVE: The risk of cardiovascular disease (CVD) is higher in patients with psoriatic arthritis (PsA) compared to the general population. Tofacitinib is an oral Janus kinase inhibitor for the treatment of PsA. Because tofacitinib increases circulating lipid levels in some patients, we evaluated CVD risk factors and major adverse cardiovascular events (MACE) in patients with active PsA receiving tofacitinib 5 or 10 mg twice daily plus conventional synthetic disease-modifying antirheumatic drugs. METHODS: Data were pooled from 2 phase III studies (Efficacy and Safety of Tofacitinib in Psoriatic Arthritis [OPAL Broaden] and Tofacitinib in Patients with Psoriatic Arthritis With Inadequate Response to TNF Inhibitors [OPAL Beyond]) and 1 ongoing long-term extension (Open-Label Extension Study of Tofacitinib in Psoriatic Arthritis [OPAL Balance], data cutoff January 2017; database not locked). Outcomes included fasting lipid levels, blood pressure, hypertension-related adverse events (AEs; including hypertension, high blood pressure, and increased blood pressure), and MACE. RESULTS: Overall, 783 tofacitinib-treated patients were included. Percentage increases from baseline in low-density lipoprotein cholesterol (LDL-c) and high-density lipoprotein cholesterol (HDL-c) levels ranged from 9% to 14% for tofacitinib 5 mg and 10 mg at 3 and 6 months; no meaningful changes in LDL-c:HDL-c or total cholesterol:HDL-c ratios were observed. Blood pressure remained stable for 24 months. Fifty-eight patients (7.4%) had hypertension-related AEs; none were fatal (incidence rate [IR] per 100 patient-years 4.81 [95% confidence interval (95% CI) 3.65-6.22]). Five patients (0.6%) had MACE (IR 0.24 [95% CI 0.05-0.70]); 2 were fatal. CONCLUSION: Serum lipid level increases at month 3 following tofacitinib treatment in PsA were consistent with observations in rheumatoid arthritis and psoriasis. The IR of hypertension-related AEs and MACE was low; long-term follow-up is ongoing.

Pharmacokinetic Characteristics of Tofacitinib in Adult Patients With Moderate to Severe Chronic Plaque Psoriasis.

Tofacitinib is an oral Janus kinase (JAK) inhibitor. This study characterized the pharmacokinetics of tofacitinib in patients with psoriasis and evaluated the impact of patient factors on disposition. Pooled phase 2/3 data (2981 patients: 9735 concentrations, dose range: 2-15 mg twice daily) up to 56 weeks were used for modeling. A one-compartment model parameterized in terms of apparent oral clearance (CL/F), apparent volume of distribution, zero-order absorption (duration, D), with interindividual variability and inter-occasion variability terms, described tofacitinib pharmacokinetics. A full covariate model incorporated effects for age, sex, race, ethnicity, and baseline variables (body weight, Psoriasis Area Severity Index [PASI], C-reactive protein [CRP], creatinine clearance [CrCl]). The parameter estimates (95%CI) for CL/F, Vd/F, and D in a typical individual (white, male, 86 kg, 46 years, CrCl 121 mL/min, PASI 19.8, and CRP 0.267 mg/dL) were 26.7 (25.9, 27.5) L/h, 125 (120.8, 128.3) liters, and 0.69 (0.646, 0.735) hours, respectively. Only CrCl led to clinically relevant changes in exposure. The analysis suggested no dosing modifications for age, body weight, sex, race, ethnicity, baseline PASI, or CRP based on the magnitude of exposure change. Dosing adjustments for renal impairment were derived from a separate phase 1 study.

Reduction of Inflammatory and Cardiovascular Proteins in the Blood of Patients with Psoriasis: Differential Responses between Tofacitinib and Etanercept after 4 Weeks of Treatment.

Patients with psoriasis have an increased risk of myocardial infarction, and psoriasis is now recognized as an independent risk factor for coronary heart disease and cardiovascular mortality. To understand the effects of psoriasis medications on systemic inflammation associated with cardiovascular risks, we studied blood proteins related to inflammation and cardiovascular disease archived from a phase 3 clinical trial of tofacitinib and etanercept in adults with moderate-to-severe psoriasis. A total of 157 blood proteins were quantified by a proximity extension assay from 266 patients at baseline and week 4. Protein changes in the blood after 1 month of treatment were compared between tofacitinib (10 mg two times a day) and etanercept (50 mg biweekly), and by response status at week 12. Tofacitinib and etanercept commonly reduced IL-6, CCL20, and CXCL10, but IL-17A was significantly reduced only in responders of either treatment. Compared with etanercept, tofacitinib showed a wider spectrum of cardiovascular blood protein reduction, but the protein reduction effects of tofacitinib were strictly confined to treatment responders. Tumor necrosis factor receptor 1, E-selectin, hK11, tumor necrosis factor-related activation-induced cytokine, CHI3L1, IL-16, and matrix metalloproteinase-12 were cardiovascular proteins significantly reduced only in tofacitinib responders. Our data suggest that a short-term systemic psoriasis treatment can cause reductions in circulating inflammatory and other proteins associated with cardiovascular risks.

Effect of tofacitinib on lipid levels and lipid-related parameters in patients with moderate to severe psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory disease associated with increased cardiovascular (CV) risk and altered lipid metabolism. Tofacitinib is an oral Janus kinase inhibitor. OBJECTIVE: The aim of the study was to investigate the effects of tofacitinib on traditional and nontraditional lipid parameters and CV risk markers in patients with psoriasis from a phase III study, OPT Pivotal 1. METHODS: Patients with psoriasis were randomized to tofacitinib 5 or 10 mg twice daily (BID) or placebo BID. Serum samples were collected at baseline, week 4, and week 16. Analyses included serum cholesterol levels, triglycerides, lipoproteins, lipid particles, lipid-related parameters/CV risk markers, and high-density lipoprotein (HDL) function analyses. RESULTS: At week 16, small concurrent increases in mean low-density lipoprotein cholesterol (LDL-C) and HDL cholesterol (HDL-C) levels were observed with tofacitinib; total cholesterol/HDL-C ratio did not change. There was no significant change in the number of small dense LDL particles, which are considered to be more atherogenic than large particles, and oxidized LDL did not increase. Paraoxonase 1 activity, linked to HDL antioxidant capacity, increased, and HDL-associated serum amyloid A, which reduces the anti-atherogenic potential of HDL, decreased. HDL capacity to promote cholesterol efflux from macrophages did not change. Lecithin-cholesterol acyltransferase activity, which is associated with reverse cholesterol transport, increased. Markers of systemic inflammation, serum amyloid A and C-reactive protein, decreased with tofacitinib. CONCLUSION: While small increases in lipid levels are observed with tofacitinib treatment in patients with psoriasis, effects on selected lipid-related parameters and other circulating CV risk biomarkers are not suggestive of an increased CV risk [NCT01276639].

Effectiveness of Lipid-Lowering Statin Therapy in Patients With and Without Psoriasis.

BACKGROUND: Psoriasis is associated with dyslipidemia and metabolic syndrome, and has been linked to an increased cardiovascular risk. The aim of this study was to compare baseline characteristics and effects of statin therapy on lipid levels and cardiovascular outcomes in patients with and without psoriasis. METHODS: This post-hoc analysis assessed patients from one primary cardiovascular prevention statin trial (Collaborative AtoRvastatin Diabetes Study [CARDS]) and two secondary cardiovascular prevention statin trials (Treating to New Targets [TNT] and Incremental Decrease in End Points Through Aggressive Lipid Lowering [IDEAL]). Baseline characteristics, lipid changes from baseline, and cardiovascular event rates were analyzed. TNT and IDEAL data were pooled. RESULTS: Baseline characteristics and lipid profiles differed minimally in patients with and without psoriasis. In CARDS and TNT/IDEAL, similar apolipoprotein B, total cholesterol, and low-density lipoprotein cholesterol reductions occurred with statin therapy in patients with or without psoriasis. High-dose atorvastatin significantly reduced cardiovascular events vs. standard/low-dose statins in patients without psoriasis in TNT/IDEAL; similar numeric differences in event rates were observed in patients with psoriasis. CONCLUSIONS: In this post-hoc analysis, statins improved lipid levels and cardiovascular outcomes in patients with and without psoriasis, supporting statin use in patients with psoriasis. Trial registration (ClinicalTrials.gov) NCT00327418, registered 16 May, 2006; NCT00327691, registered 16 May, 2006; NCT00159835, registered 8 September, 2005.

Early clinical response to tofacitinib treatment as a predictor of subsequent efficacy: Results from two phase 3 studies of patients with moderate-to-severe plaque psoriasis.

BACKGROUND: The ability to predict response to psoriasis treatments has important implications. Tofacitinib is an oral JAK inhibitor being investigated for psoriasis. OBJECTIVE: The objective of this study is to identify and validate the clinical predictors of responses in psoriasis patients treated with tofacitinib. METHODS: Selected baseline characteristics or early improvement in Psoriasis Area and Severity Index (PASI) in the phase 3 tofacitinib study OPT 1 (NCT01276639) were evaluated as predictors for a clinical response (75% improvement in PASI [PASI75]) at week 16. Predictive ability was assessed by the area-under-the-receiver operating characteristic curve (AUC-ROC). The predictive ability of the identified variables was validated with study OPT 2 (NCT01309737). RESULTS: PASI improvement at weeks 8 and 12 demonstrated good discriminatory abilities to predict PASI75 response at week 16 (AUC-ROC ≥86% and 94%, respectively) in OPT 1. Validation with PASI50 response at week 8 in OPT 2 to predict PASI75 response at week 16 showed that the sensitivity, specificity, PPV, and NPV were 88%, 69%, 80%, and 81%, respectively, in tofacitinib-treated subjects. CONCLUSION: Achieving a PASI50 response after 8 weeks of treatment with tofacitinib in psoriasis patients appears to be a reliable predictor of achieving a PASI75 response at week 16. TRIAL REGISTRATION: clinicaltrials.gov: NCT01276639 and NCT01309737.

Effects of tofacitinib on cardiovascular risk factors and cardiovascular outcomes based on phase III and long-term extension data in patients with plaque psoriasis.

BACKGROUND: Psoriasis is a systemic inflammatory condition that is associated with a higher risk of cardiovascular (CV) disease. Tofacitinib is being investigated as a treatment for psoriasis. OBJECTIVE: We sought to evaluate the effects of tofacitinib on CV risk factors and major adverse CV events (MACEs) in patients with plaque psoriasis. METHODS: Changes in select CV risk factors and the incidence rate (IR) of MACEs were evaluated in patients who were treated with tofacitinib. RESULTS: Tofacitinib treatment was associated with small, dose-dependent increases in total cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) cholesterol, while the total/HDL cholesterol ratio was unchanged. There were no changes in blood pressure and glycated hemoglobin levels; C-reactive protein levels decreased. The IRs of a MACE were low and similar for both tofacitinib doses. Among 3623 subjects treated with tofacitinib, the total patient-years of exposure was 5204, with a median follow-up of 527 days, and the IR of MACEs was 0.37 (95% confidence interval, 0.22-0.57) patients with events per 100 patient-years. LIMITATIONS: There was relatively short follow-up time for patients who had MACEs. CONCLUSIONS: While treatment with tofacitinib is associated with a small increase in cholesterol levels, the total/HDL cholesterol ratio does not change, there are no unfavorable changes in several CV risk factors, and the incidence of MACEs is low.

Prognostic Value of Adipokines in Predicting Cardiovascular Outcome: Explaining the Obesity Paradox.

OBJECTIVE: To evaluate the cardiovascular (CV) prognostic value of adipokines in a large prospective cohort of patients participating in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial. PATIENTS AND METHODS: The effects of the adipokine levels at baseline and change from baseline on the composite outcome (CV death, myocardial infarction, and stroke) were analyzed using unadjusted and fully adjusted Cox models in 2330 patients with type 2 diabetes and coronary artery disease who had participated in the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial (from January 1, 2001, through December 1, 2008). RESULTS: In a fully adjusted model, baseline leptin and change from baseline leptin were protective for CV events, whereas baseline adiponectin, baseline tumor necrosis factor α (TNF-α), change from baseline TNF-α, baseline C-reactive protein (CRP), and change from baseline CRP were harmful. The effect of baseline leptin on CV events depended on the body mass index (BMI), such that the hazard ratios (HRs) varied between 0.6 and 1.4 across the BMI quintiles (interaction P=.03). The same was true for baseline adiponectin (HR varied from 0.7 to 1.7; interaction P=.01), change from baseline monocyte chemoattractant protein-1 (HR varied from 0.8 to 1.8; interaction P=.03), change from baseline TNF-α (HR varied from 0.9 to 1.4; interaction P=.02), and change from baseline IL-6 (HR varied from 0.7 to 1.8; interaction P=.005). CONCLUSION: Adipokines are independent predictors of CV events in patients with type 2 diabetes and coronary artery disease. The association between the specific adipokines and CV outcome varies depending on BMI. This reflects the complex pathophysiology of CV disease in obesity and may help explain the "obesity paradox." TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00006305.