Safety Profile of Upadacitinib up to 5 Years in Psoriatic Arthritis, Ankylosing Spondylitis, and Non-radiographic Axial Spondyloarthritis: An Integrated Analysis of Clinical Trials.

INTRODUCTION: This integrated analysis of the phase 2/3 and phase 3 SELECT trials describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, for up to 5 years of exposure across psoriatic arthritis (PsA), ankylosing spondylitis (AS), and non-radiographic axial spondyloarthritis (nr-axSpA) (including pooled axial spondyloarthritis [axSpA]). METHODS: Safety data from five trials of upadacitinib in PsA (2 trials), AS (2 trials), and nr-axSpA (1 trial) were analyzed up to a data cut-off of August 15, 2022. One PsA study included adalimumab as an active comparator. Treatment-emergent adverse events (TEAEs) were summarized for PsA (pooled upadacitinib 15 mg once daily and adalimumab 40 mg biweekly), AS (pooled upadacitinib 15 mg), nr-axSpA (upadacitinib 15 mg), and pooled axSpA (pooled upadacitinib 15 mg from axSpA trials). TEAEs were reported as exposure-adjusted event rates per 100 patient-years (E/100 PY). RESULTS: A total of 1789 patients (PsA, n = 907; AS, n = 596; nr-axSpA, n = 286) received ≥ 1 dose of upadacitinib 15 mg for 3689 PY of exposure or adalimumab (n = 429) for 1147 PY of exposure. Overall TEAEs and serious TEAEs were highest in PsA and numerically higher with upadacitinib versus adalimumab; rates were similar between AS and nr-axSpA. In PsA, higher rates of serious infection, herpes zoster (HZ), lymphopenia, and nonmelanoma skin cancer (NMSC) were observed with upadacitinib versus adalimumab. Rates of malignancy excluding NMSC, adjudicated major adverse cardiovascular events, and adjudicated venous thromboembolic events were comparable between upadacitinib and adalimumab in PsA and were similar across diseases. CONCLUSION: Higher rates of serious infection, HZ, lymphopenia, and NMSC were observed with upadacitinib versus adalimumab in PsA; slightly elevated rates for most of these TEAEs were seen with upadacitinib in PsA versus axSpA. Upadacitinib 15 mg demonstrated a generally consistent safety profile across disease states with no new safety signals identified. TRIAL REGISTRATION: SELECT-AXIS 1: NCT03178487; SELECT-AXIS 2: NCT04169373; SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Psoriatic arthritis, ankylosing spondylitis, and non-radiographic axial spondyloarthritis are a group of diseases that cause pain and inflammation of the joints and/or spine. Safety data were combined from five studies: two in psoriatic arthritis, two in ankylosing spondylitis, and one in non-radiographic axial spondyloarthritis. Patients were treated with upadacitinib or adalimumab for up to 5 years. Adalimumab was only used for patients participating in one of the two psoriatic arthritis studies. Side effects from treatment were more common in patients with psoriatic arthritis than those with ankylosing spondylitis and non-radiographic axial spondyloarthritis; more patients with psoriatic arthritis had side effects with upadacitinib than adalimumab. A similar number of patients across treatment groups and diseases had side effects that made them stop treatment. The number of cancer cases (except cancer of the upper layer of the skin), cardiovascular issues, and blood clots were similar between the upadacitinib and adalimumab groups in psoriatic arthritis and across diseases. Serious infections, painful rashes that cause blisters (herpes zoster, also commonly referred to as shingles), low levels of white blood cells, and cancer of the upper layer of the skin were more common with upadacitinib than adalimumab in patients with psoriatic arthritis; overall, these events occurred more often with upadacitinib in patients with psoriatic arthritis than with ankylosing spondylitis and non-radiographic axial spondyloarthritis. Our results showed that the safety of upadacitinib was generally similar across diseases, and patients could tolerate it well for up to 5 years. No new safety risks were found with upadacitinib treatment.

Identifying and Quantifying the Role of Inflammation in Pain Reduction for Patients With Psoriatic Arthritis Treated With Tofacitinib: A Mediation Analysis.

INTRODUCTION: Pain is a multidimensional factor and core domain of psoriatic arthritis (PsA). This analysis aimed to quantify the role of potential inflammation-associated outcomes on pain reduction in patients with PsA receiving tofacitinib, using mediation modeling. METHODS: Pooled data were from two phase 3 studies (OPAL Broaden and OPAL Beyond) of patients with active PsA treated with tofacitinib 5 mg twice daily or placebo. Mediation modeling was utilized to quantify the indirect effects (via Itch Severity Item [ISI], C-reactive protein [CRP] levels, swollen joint count [SJC], Psoriasis Area and Severity Index [PASI], and enthesitis [using Leeds Enthesitis Index]) and direct effects (representing all other factors) of tofacitinib treatment on pain improvement. RESULTS: The initial model showed that tofacitinib treatment affects pain, primarily indirectly, via ISI, CRP, SJC, PASI, and enthesitis (overall 84.0%; P = 0.0009), with 16.0% (P = 0.5274) attributable to the direct effect. The model was respecified to exclude SJC and PASI. Analysis of the final model revealed that 29.5% (P = 0.0579) of tofacitinib treatment effect on pain was attributable to the direct effect, and 70.5% (P < 0.0001) was attributable to the indirect effect. ISI, CRP, and enthesitis mediated 37.4% (P = 0.0002), 15.3% (P = 0.0107), and 17.8% (P = 0.0157) of the tofacitinib treatment effect on pain, respectively. CONCLUSIONS: The majority of the effect of tofacitinib on pain was collectively mediated by itch, CRP, and enthesitis, with itch being the primary mediator of treatment effect. TRIAL REGISTRATION: NCT01877668, NCT01882439. GRAPHICAL PLS.

Patient Perception of Medical Care for Psoriatic Arthritis in North America and Europe: Results from a Global Patient Survey.

INTRODUCTION: To compare perceptions of disease control and treatment satisfaction between patients with psoriatic arthritis (PsA) in North America and Europe, and between participating countries within each region. METHODS: Data were collected from patients with self-reported PsA diagnoses using an online survey. Results from questions on perceptions of overall health, disease severity, PsA symptoms, PsA impacts, and treatment satisfaction/preferences were reported using descriptive statistics and Chi-square tests. RESULTS: A total of 456 patients from North America (Canada, n = 155; US, n = 301) and 417 patients from Europe (France, n = 123; Spain, n = 135; UK, n = 159) were included in this analysis. Patients in North America were more likely to rate their overall health as excellent/good compared with those in Europe (49 vs. 14%), but also rate their disease as severe (27 vs. 15%). Despite treatment, patients in North America and Europe still experienced musculoskeletal (92 vs. 91%) and skin/nail (62 vs. 58%) symptoms. Similar proportions of patients in North America vs. Europe experienced a social impact (81 vs. 85%); more patients in Europe vs. North America experienced PsA-related work impacts (83 vs. 74%). Satisfaction with PsA medication was more common in North America (89%) vs. Europe (79%), and more common in Spain (91%) vs. the UK (82%) or France (66%). Across all regions and countries, ≥ 75% of patients agreed that symptoms were controlled. However, ≥ 66% wished they had more medication choices, and ≥ 84% wanted to change something about their medication. CONCLUSIONS: Although perception of overall health and disease severity varied, many patients from both regions still experienced symptoms despite receiving medications for PsA, wished they had greater choice of medications, and/or would like to change an aspect of their medications. While these survey findings are subject to selection bias, they do indicate there is scope to improve the treatment of PsA.

Psoriatic arthritis (PsA) is a disease that can cause joint pain and stiffness, and is often associated with a skin rash called psoriasis. These symptoms can affect quality of life, and patients and doctors should work together when choosing treatment. There has not been a lot of information on what patients think about their disease and their medicines. We found that patients from different regions and countries had different opinions, and that treatment of PsA can be improved. For example, patients in North America were more likely to say that their overall health was excellent or good, compared with patients in Europe. However, more patients in North America than in Europe described their PsA disease as severe. Similar numbers of patients in both regions experienced impacts on their social life due to their PsA, but patients in Europe were more likely to report that PsA affected their work life compared with patients in North America. More patients in North America than in Europe were satisfied with their medicines, but patients across all regions and countries still had symptoms even when they took medicines. Many patients also wished they had more options and wanted to change something about their medicines. These findings were based on an online survey. Patients from North America (Canada and the US) and Europe (France, Spain, and the UK) answered questions about their PsA disease and medicines. We only compared answers between patients from North America and Europe, and between countries within each region.

Endpoints for extraintestinal manifestations in inflammatory bowel disease trials: the EXTRA consensus from the International Organization for the Study of Inflammatory Bowel Diseases.

Extraintestinal manifestations occur frequently in patients with inflammatory bowel disease (IBD) and remain a diagnostic and therapeutic challenge. The aim of the Endpoints for Extraintestinal Manifestations in Inflammatory Bowel Disease Trials (EXTRA) initiative was to achieve international expert consensus on how to assess these manifestations in IBD trials. A systematic literature review was done to identify methods to diagnose extraintestinal manifestations in patients with IBD and measure treatment outcomes. A consensus meeting involving a panel of 41 attendees, including gastroenterologists and referral specialists, was held on March 31, 2021, as part of an International Organization for the Study of Inflammatory Bowel Diseases initiative. The panel agreed that a specialist's expertise is needed to confirm the diagnosis of extraintestinal manifestations before the inclusion of a patient in IBD trials, except for axial spondyloarthritis, for which typical symptoms and MRI can be sufficient. Easy-to-measure endpoints were identified to assess the response of extraintestinal manifestations to treatment without needing specialist involvement. For uveitis, peripheral spondyloarthritis, and arthralgia, endpoint measurements need specialist expertise. The timing of endpoint measurements was discussed for individual extraintestinal manifestations. The EXTRA consensus proposes guidelines on how to thoroughly evaluate extraintestinal manifestations within IBD trials, and recommends that these guidelines are implemented in future trials to enable prospective assessment of these manifestations and comparison between studies.

Efficacy and safety of tofacitinib by background methotrexate dose in psoriatic arthritis: post hoc exploratory analysis from two phase III trials.

OBJECTIVE: Analyze tofacitinib efficacy and safety by background methotrexate (MTX) dose in patients with psoriatic arthritis (PsA). METHODS: This post hoc analysis pooled data from two phase III, double-blind trials (OPAL Broaden, NCT01877668; OPAL Beyond, NCT01882439) including patients receiving tofacitinib 5 or 10 mg twice daily (BID), or placebo, with stable MTX. Efficacy outcomes at month 3 stratified by MTX dose (≤ 15 month 3 stratified by MTX dose vs > 15 mg/week) were American College of Rheumatology (ACR)20/50/70, Health Assessment Questionnaire-Disability Index (HAQ-DI); Psoriasis Area and Severity Index (PASI)50/75; change from baseline in HAQ-DI; physician's global assessment of PsA (PGA-PsA-visual analog scale [VAS]); patient's global joint and skin assessment (PGJS-VAS), Leeds Enthesitis Index (LEI); and Dactylitis Severity Score (DSS). Safety assessments included adverse events and laboratory parameters. RESULTS: Five hundred fifty-six patients received tofacitinib 5 mg BID (n = 186), 10 mg BID (n = 178), or placebo (n = 192), plus MTX (≤ 15 mg/week, n = 371; > 15 mg/week, n = 185). At month 3, tofacitinib efficacy was generally greater than placebo. Patients receiving tofacitinib 5 mg BID demonstrated greater numerical improvements in efficacy outcomes at month 3 with MTX > 15 mg/week vs MTX ≤ 15 mg/week; patients receiving tofacitinib 10 mg BID displayed the opposite. The safety profile was generally consistent between groups; headache was associated with MTX > 15 mg/week; decreased hemoglobin levels were observed in patients receiving tofacitinib 10 mg BID and MTX ≤ 15 mg/week. CONCLUSION: Efficacy of tofacitinib was generally numerically greater than placebo, regardless of MTX dose. Tofacitinib 5 mg BID was generally more efficacious with MTX > 15 mg/week vs ≤ 15 mg/week; the opposite was observed for tofacitinib 10 mg BID. Headache was more frequent with MTX > 15 mg/week. TRIAL REGISTRATION: ClinicalTrials.gov . Identifier: NCT01877668 (registration: June 14, 2013) and NCT01882439 (registration: June 20, 2013). Key Points • Methotrexate is widely used in the treatment of psoriatic arthritis; however, there are limited data on the impact of varying background methotrexate doses on the efficacy and safety of Janus kinase inhibitors in patients with psoriatic arthritis. • This post hoc analysis assessed the impact of background methotrexate dose (≤ 15 or > 15 mg/week) on tofacitinib efficacy and safety in patients with psoriatic arthritis. • Results indicated that tofacitinib efficacy was generally numerically greater than placebo, regardless of methotrexate dose. Tofacitinib 5 mg twice daily, in combination with a higher dose of background methotrexate, was more efficacious compared with a lower dose of background methotrexate; the opposite was observed for tofacitinib 10 mg twice daily. • Headache was more frequent with the higher methotrexate dose. Data should be interpreted with caution due to the small sample sizes.

Prevention and management of herpes zoster in patients with rheumatoid arthritis and psoriatic arthritis: a clinical review.

The risk of herpes zoster (HZ) and HZ-related complications is increased in patients with rheumatoid arthritis (RA) and psoriatic arthritis (PsA) relative to the general population; therefore, HZ vaccination is recommended in these patient groups. In this literature-based review, we summarise the available evidence on the use of HZ vaccines in patients with RA and PsA, and discuss strategies for managing breakthrough infection. Currently available data show suboptimal rates of HZ vaccination among these patients and highlight a need for strategies to improve HZ vaccination programmes in clinical practice. Further clinical studies are also required to optimise the use of HZ vaccines in patients with RA and PsA, particularly with regard to determining the impact of different immunosuppressive therapy regimens on vaccine immunogenicity and, ultimately, efficacy, as well as the impact of vaccination on disease activity and safety.

Frequency and Duration of Early Non-serious Adverse Events in Patients with Rheumatoid Arthritis and Psoriatic Arthritis Treated with Tofacitinib.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA) and psoriatic arthritis (PsA). This post hoc analysis assessed frequency or duration of early select non-serious adverse events (AEs; excluding infections), and their impact on treatment discontinuation, in patients with RA or PsA treated with tofacitinib 5 or 10 mg twice daily, or placebo. METHODS: Data were pooled from five phase 3 and one phase 3b/4 studies in patients with moderate-to-severe RA, and two phase 3 studies in patients with active PsA. Select all-causality, non-serious AEs, reported to month 3 (placebo-controlled period), were headache, diarrhea, nausea, vomiting, and gastric discomfort (including dyspepsia, gastritis, epigastric discomfort, and abdominal discomfort or pain); incidence rates (unique patients with events per 100 patient-years of follow-up), duration of, and discontinuations due to these non-serious AEs were reported. RESULTS: We analyzed 3871 and 710 patients with RA and PsA, respectively. Incidence of non-serious AEs to month 3 was generally similar with tofacitinib and placebo. The most frequent non-serious AEs were headache and diarrhea with tofacitinib, and dyspepsia, nausea, and headache with placebo. Most events were mild or moderate in severity, lasting ≤ 4 weeks. Permanent discontinuations due to non-serious AEs were not observed in patients with PsA, and were < 1.0% in patients with RA across treatment groups. The most frequent cause of temporary discontinuation across all groups was gastric discomfort (0.3-0.8%). CONCLUSIONS: Non-serious AE incidence was generally similar in patients with RA or PsA receiving tofacitinib or placebo. Most events were mild or moderate and generally resolved within 4 weeks. TRIAL REGISTRATION: ClinicalTrials.gov identifiers: NCT00960440; NCT00847613; NCT00814307; NCT00856544; NCT00853385; NCT01877668; NCT01882439; NCT02187055.

Tofacitinib is a medicine that can be taken by patients to treat rheumatoid arthritis (RA) or psoriatic arthritis (PsA). Serious side effects that might occur in patients taking tofacitinib are more frequently discussed than the mild, non-serious side effects that patients might consider to be more of a 'nuisance', which often occur shortly (< 3 months) after starting treatment. Here we looked at patients with RA or PsA who were taking tofacitinib or placebo (no medicine) during clinical trials, to find out how often they had certain non-serious side effects, how long they lasted, and whether they caused the patients to stop taking their medication. A similar number of patients with RA or PsA taking tofacitinib or placebo had non-serious side effects. The most common non-serious side effects in patients taking tofacitinib were a headache and diarrhea. The most common non-serious side effects in patients taking placebo (no medicine) were indigestion, a feeling of sickness, and/or headache. Most non-serious side effects were mild or moderate and stopped within about 4 weeks. Fewer than one in every 100 patients with RA, and no patients with PsA, stopped taking their medication because of non-serious side effects. Most patients who stopped taking their medication did so due to a feeling of gastrointestinal (stomach) discomfort.

Safety Profile of Upadacitinib up to 3 Years in Psoriatic Arthritis: An Integrated Analysis of Two Pivotal Phase 3 Trials.

INTRODUCTION: This integrated analysis describes the safety profile of upadacitinib, an oral Janus kinase inhibitor, at 15 and 30 mg once daily for up to 3 years of exposure in patients with active psoriatic arthritis (PsA) who had a prior inadequate response or intolerance to ≥ 1 non-biologic or biologic disease-modifying antirheumatic drug. METHODS: Safety data were pooled and analyzed from two randomized, placebo-controlled phase 3 trials. Both trials evaluated upadacitinib 15 mg and 30 mg once daily, and one trial also evaluated adalimumab 40 mg every other week. Treatment-emergent adverse events (TEAEs) and laboratory data were summarized for four groups: pooled placebo, pooled upadacitinib 15 mg, pooled upadacitinib 30 mg, and adalimumab. TEAEs were reported as exposure-adjusted event rates (events per 100 patient-years [E/100 PY]) up to a data cut-off of June 29, 2020. RESULTS: A total of 2257 patients received ≥ 1 dose of upadacitinib 15 mg (N = 907) or 30 mg (N = 921) for 2504.6 PY of exposure or adalimumab (N = 429) for 549.7 PY of exposure. Upper respiratory tract infection, nasopharyngitis, and increased creatine phosphokinase (CPK) were the most common TEAEs with upadacitinib. Rates of malignancies, adjudicated major adverse cardiovascular events (MACEs) and venous thromboembolic events (VTEs), and deaths were similar across treatment groups. Rates of herpes zoster (HZ) and opportunistic infections (OI; excluding tuberculosis, HZ, and oral candidiasis) were higher with upadacitinib versus adalimumab. Serious infection, anemia, and CPK elevations were most frequent with upadacitinib 30 mg. Potentially clinically significant laboratory abnormalities were uncommon. CONCLUSIONS: Upadacitinib 15 mg and adalimumab had similar safety profiles with the exception of HZ and OIs, consistent with what was observed in rheumatoid arthritis. Rates of malignancies, MACEs, VTEs, and deaths were comparable among patients receiving upadacitinib and adalimumab. No new safety risks emerged with longer-term exposure to upadacitinib. TRIAL REGISTRATION NUMBERS: SELECT-PsA 1: NCT03104400; SELECT-PsA 2: NCT03104374.

Psoriatic arthritis is a disease that causes inflammation of the skin and joints. Upadacitinib and adalimumab are medicines that can be used to treat this condition. This analysis combined safety data from two studies of adults with psoriatic arthritis who took upadacitinib, adalimumab, or placebo (no medicine) for up to 3 years. The most common side effects of treatment with upadacitinib were infection and inflammation of the nose and throat and higher amounts of a protein in the blood called creatinine phosphokinase. The total number of cancer cases, heart (cardiovascular) problems, blood clots (embolisms), and deaths were similar across treatment groups, including the placebo (no medicine) group. However, more patients who took upadacitinib than adalimumab or placebo (no medicine) had a painful rash that causes blisters known as herpes zoster (shingles) and infections usually seen in people with a weakened immune system. Most patients had normal blood test results and continued their treatment. Overall, upadacitinib was well tolerated for up to 3 years in patients with psoriatic arthritis. These results agree with what has been found in studies of upadacitinib in patients with rheumatoid arthritis. Safety data of upadacitinib use over a longer time will be reported later.

Exploring the Quality of Communication Between Patients with Psoriatic Arthritis and Physicians: Results of a Global Online Survey.

INTRODUCTION: Effective communication between patients with psoriatic arthritis (PsA) and their physicians is important for optimizing treatment outcomes. We assessed the quality of patient-physician communication in terms of awareness and impact of PsA symptoms, their levels of satisfaction, and their perceptions of communications. METHODS: A global online survey was conducted by The Harris Poll in adult patients with PsA and physicians managing patients with PsA in eight countries. Participating physicians were either rheumatologists or dermatologists seeing ≥ 10 and ≥ 5 patients with PsA per month, respectively. Patient and physician groups were unmatched. Patient-physician communication was assessed with 35-60 questions regarding discussion topics during consultations, levels of satisfaction with communication, and specific communication issues. RESULTS: A total of 1286 patients with PsA (983 and 303 whose primary treating physician was a rheumatologist or dermatologist, respectively) and 1553 physicians (795 rheumatologists and 758 dermatologists) completed the survey. Regardless of whether they were primarily treated by a rheumatologist or dermatologist, most patients reported a social (84% and 81%, respectively) or work (81% and 80%, respectively) impact of PsA, and a major/moderate negative impact on their physical activity levels (79% and 74%, respectively) or emotional/mental wellbeing (69% and 68%, respectively). Physician responses were generally consistent with this; however, physicians often appeared to under-recognize the extent to which PsA affects patients. Most (≥ 85%) patients and physicians were very/somewhat satisfied with their patient-physician communication, and most (≥ 86%) patients were comfortable raising their concerns/fears with their physician. However, > 40% of patients were identified as being at risk of suboptimal communication. These patients were significantly less likely to report their PsA symptoms even when asked, were less comfortable discussing the impacts of PsA with their physician, and were more likely to experience major/moderate impacts of PsA on their health-related quality of life (HRQoL). CONCLUSIONS: Physicians often underestimate the impacts of PsA, compared with patients, and some patients may be at risk of suboptimal communication with their attending physician, which may worsen the HRQoL impacts of PsA. These findings highlight a need for ways to improve communication between patients with PsA and their healthcare providers.

Psoriatic arthritis (PsA) is a disease that can cause swollen and painful joints, as well as skin psoriasis. To effectively treat PsA, it is important that doctors and patients communicate well. We used a survey to ask patients with PsA and doctors from around the world about their communications about PsA. We also asked how PsA affects patients' quality of life. In total, 1286 patients and 1553 doctors took the survey. Most patients said that PsA affected their social and work lives. Similarly, PsA had a negative impact on physical activity and on emotional and/or mental wellbeing in most patients who answered the survey. Doctors answered similarly, but they were generally less likely to recognize how severely PsA can impact patients, compared with patients themselves. Most patients and doctors were happy with their patient­doctor communication, and most patients felt comfortable talking about their worries and/or fears with their doctor. However, some patients (about four out of 10) felt that communication with their doctors was not good; these patients were less likely/comfortable to talk about their PsA symptoms and the impacts of PsA with their doctor. PsA was also more likely to negatively impact these patients' quality of life. This survey shows that it is important to find ways to improve communication between patients with PsA and their doctors.

Prevalence, demographics, and clinical characteristics of Latin American patients with spondyloarthritis.

Large epidemiologic and clinical estimates of spondyloarthritis (SpA) in Latin America are not available. In this narrative review, our goal was to descriptively summarize the prevalence and features of SpA in Latin America, based on available small studies. A review of peer-reviewed literature identified 41 relevant publications. Of these, 11 (mostly based on Mexican data) estimated the prevalence of SpA and its subtypes, which varied from 0.28 to 0.9% (SpA), 0.02 to 0.8% (ankylosing spondylitis), 0.2 to 0.9% (axial SpA), and 0.004 to 0.08% (psoriatic arthritis). Demographic and/or clinical characteristics were reported in 31 of the 41 publications, deriving data from 3 multinational studies, as well as individual studies from Argentina, Brazil, Chile, Colombia, Costa Rica, Mexico, Peru, Uruguay, and Venezuela. Data relating to treatment, disease manifestations (articular and extra-articular), and comorbidities were summarized across the countries. Available data suggest that there is a variability in prevalence, manifestations, and comorbidities of SpA across Latin America. Basic epidemiologic and clinical data are required from several countries not currently represented. Data relating to current treatment approaches, patient outcomes, and socioeconomic impact within this large geographic region are also needed.

Prevalence, demographics, and clinical characteristics of Latin American patients with spondyloarthritis

Abstract Large epidemiologic and clinical estimates of spondyloarthritis (SpA) in Latin America are not available. In this narrative review, our goal was to descriptively summarize the prevalence and features of SpA in Latin America, based on available small studies. A review of peer-reviewed literature identified 41 relevant publications. Of these, 11 (mostly based on Mexican data) estimated the prevalence of SpA and its subtypes, which varied from 0.28 to 0.9% (SpA), 0.02 to 0.8% (ankylosing spondylitis), 0.2 to 0.9% (axial SpA), and 0.004 to 0.08% (psoriatic arthritis). Demographic and/or clinical characteristics were reported in 31 of the 41 publications, deriving data from 3 multinational studies, as well as individual studies from Argentina, Brazil, Chile, Colombia, Costa Rica, Mexico, Peru, Uruguay, and Venezuela. Data relating to treatment, disease manifestations (articular and extra-articular), and comorbidities were summarized across the countries. Available data suggest that there is a variability in prevalence, manifestations, and comorbidities of SpA across Latin America. Basic epidemiologic and clinical data are required from several countries not currently represented. Data relating to current treatment approaches, patient outcomes, and socioeconomic impact within this large geographic region are also needed.(AU)

An Integrated Analysis of the Safety of Tofacitinib in Psoriatic Arthritis across Phase III and Long-Term Extension Studies with Comparison to Real-World Observational Data.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). OBJECTIVE: Our objective was to compare the incidence rates (IRs) of adverse events in tofacitinib clinical trials and real-world observational data for alternative treatments. METHODS: The tofacitinib "dose-comparison cohort" included months 0-12 of two phase III studies (tofacitinib 5 [n = 238] and 10 [n = 236] mg twice daily [BID]); the "all-tofacitinib comparison cohort" (n = 783) included two phase III and one ongoing long-term extension study (data cutoff May 2016). An "observational comparison cohort" (n = 5799) comprised patients initiating a conventional synthetic disease-modifying antirheumatic drug (DMARD), biologic DMARD, or apremilast in the US Truven MarketScan database from 2010 to 2015. IRs for serious infections (SIEs; requiring hospitalization), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, and major adverse cardiovascular events (MACE) across cohorts were qualitatively compared. RESULTS: IRs (patients with events/100 patient-years) for SIEs were similar between the tofacitinib dose-comparison cohort (5 mg BID: 1.3; 10 mg BID: 2.0) and the observational comparison cohort (1.1-7.9; treatment dependent). The tofacitinib dose-comparison cohort had a higher rate of HZ (5 mg BID: 2.0; 10 mg BID: 2.7) than did the observational comparison cohort (0.8-2.0). IRs for NMSC were generally lower in the all-tofacitinib comparison cohort (0.5) than in the observational comparison cohort (0.4-6.0). IRs for MACE, malignancies excluding NMSC, and NMSC were similar between cohorts. CONCLUSION: In patients with PsA, tofacitinib had a safety profile similar to that of other systemic therapies in real-world settings, except for the risk of HZ, a known risk of tofacitinib. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01877668; NCT01882439; NCT01976364.

TNF-α-induced protein 3 (TNFAIP3)/A20 acts as a master switch in TNF-α blockade-driven IL-17A expression.

BACKGROUND: Anti-TNF inhibitors successfully improve the quality of life of patients with inflammatory disease. Unfortunately, not all patients respond to anti-TNF therapy, and some patients show paradoxical immune side effects, which are poorly understood. Surprisingly, anti-TNF agents were shown to promote IL-17A production with as yet unknown clinical implications. OBJECTIVE: We sought to investigate the molecular mechanism underlying anti-TNF-driven IL-17A expression and the clinical implications of this phenomenon. METHODS: Fluorescence-activated cell sorting, RNA sequencing, quantitative real-time PCR, Western blotting, small interfering RNA interference, and kinase inhibitors were used to study the molecular mechanisms in isolated human CD4+ T cells from healthy donors. The clinical implication was studied in blood samples of patients with inflammatory bowel disease (IBD) receiving anti-TNF therapy. RESULTS: Here we show that anti-TNF treatment results in inhibition of the anti-inflammatory molecule TNF-α-induced protein 3 (TNFAIP3)/A20 in memory CD4+ T cells. We found an inverse relationship between TNFAIP3/A20 expression levels and IL-17A production. Inhibition of TNFAIP3/A20 promotes kinase activity of p38 mitogen-activated protein kinase and protein kinase C, which drives IL-17A expression. Regulation of TNFAIP3/A20 expression and cognate IL-17A production in T cells are specifically mediated through TNF receptor 2 signaling. Ex vivo, in patients with IBD treated with anti-TNF, we found further evidence for an inverse relationship between TNFAIP3/A20 expression levels and IL-17A-producing T cells. CONCLUSION: Anti-TNF treatment interferes in the TNFAIP3/A20-mediated anti-inflammatory feedback loop in CD4+ T cells and promotes kinase activity. This puts TNFAIP3/A20, combined with IL-17A expression, on the map as a potential tool for predicting therapy responsiveness or side effects of anti-TNF therapy. Moreover, it provides novel targets related to TNFAIP3/A20 activity for superior therapeutic regimens in patients with IBD.

Tofacitinib for Psoriatic Arthritis in Patients with an Inadequate Response to TNF Inhibitors.

BACKGROUND: Tofacitinib is an oral Janus kinase inhibitor that is under investigation for the treatment of psoriatic arthritis. We evaluated tofacitinib in patients with active psoriatic arthritis who had previously had an inadequate response to tumor necrosis factor (TNF) inhibitors. METHODS: In this 6-month randomized, placebo-controlled, double-blind, phase 3 trial, we randomly assigned 395 patients, in a 2:2:1:1 ratio, to four regimens: 5 mg of tofacitinib administered orally twice daily (132 patients); 10 mg of tofacitinib twice daily (132 patients); placebo, with a switch to 5 mg of tofacitinib twice daily at 3 months (66 patients); or placebo, with a switch to 10 mg of tofacitinib twice daily at 3 months (65 patients). Data from the patients who received placebo during the first 3 months of the trial were pooled. The primary end points were the percentage of patients who had at least 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) and the change from baseline score on the Health Assessment Questionnaire-Disability Index (HAQ-DI; scores range from 0 to 3, with higher scores indicating greater disability) at the month 3 analysis. RESULTS: At 3 months, the rates of ACR20 response were 50% with the 5-mg dose of tofacitinib and 47% with the 10-mg dose, as compared with 24% with placebo (P<0.001 for both comparisons); the corresponding mean changes from baseline in HAQ-DI score were -0.39 and -0.35, as compared with -0.14 (P<0.001 for both comparisons). Serious adverse events occurred in 4% of the patients who received the 5-mg dose of tofacitinib continuously and in 6% who received the 10-mg dose continuously. Over the course of 6 months, there were four serious infections, three herpes zoster infections, one myocardial infarction, and one ischemic stroke among the patients who received tofacitinib continuously. Elevations of aspartate and alanine aminotransferase concentrations of three or more times the upper limit of the normal range occurred in more patients who received tofacitinib continuously than in patients who received placebo followed by tofacitinib. CONCLUSIONS: In this trial involving patients with active psoriatic arthritis who had had an inadequate response to TNF inhibitors, tofacitinib was more effective than placebo over 3 months in reducing disease activity. Adverse events were more frequent with tofacitinib than with placebo. (Funded by Pfizer; OPAL Beyond ClinicalTrials.gov number, NCT01882439 .).

Proceedings of the GRAPPA 2016 Retreat.

In advance of its 2016 annual meeting, members of the steering committee of the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) convened for a strategic planning meeting. The purpose of this advance meeting was to review the work of GRAPPA since its inception in 2003, ascertain and review the current priorities of the group, and devise a strategy for proceeding. The key accomplishments of GRAPPA to date, priorities and objectives for the next 5 years, and goals and opportunities for the GRAPPA committees were discussed. GRAPPA has a responsibility and commitment to patients, its members, and partners to innovate, inspire, and improve knowledge and the ability to care for people with psoriasis and psoriatic arthritis.

Quality of life in spondyloarthritis: analysis of a large Brazilian cohort.

OBJECTIVE: To analyze quality of life and demographic and clinical variables associated to its impairment in a large Brazilian cohort of patients with spondyloarthritis (SpA). METHODS: A common protocol of investigation was applied to 1465 Brazilian patients classified as SpA according to the European Spondyloarthropaties Study Group (ESSG) criteria, attended at 29 reference centers for Rheumatology in Brazil. Clinical and demographic variables were recorded. Quality of life was analyzed through the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire. RESULTS: The mean ASQoL score was 7.74 (+5.39). When analyzing the specific diseases in the SpA group, the ASQoL scores did not present statistical significance. Demographic data showed worse scores of ASQoL associated with female gender (p=0.014) and African-Brazilian ethnicity (p<0.001). The analysis of the clinical symptoms showed that buttock pain (p=0.032), cervical pain (p<0.001) and hip pain (p=0.001) were statistically associated with worse scores of ASQoL. Continuous use of nonsteroidal anti-inflammatory drugs (p<0.001) and biologic agents (p=0.044) were associated with higher scores of ASQoL, while the other medications did not interfere with the ASQoL scores. CONCLUSION: In this large series of patients with SpA, female gender and African-Brazilian ethnicity, as well as predominant axial symptoms, were associated with impaired quality of life.

Qualidade de vida nas espondiloartrites: análise de uma grande coorte brasileira / Quality of life in spondyloarthritis: analysis of a large Brazilian cohort

Resumo Objetivo: Analisar as variáveis demográficas e clínicas associadas à diminuição da qualidade de vida em uma grande coorte brasileira de pacientes com espondiloartrite (EpA). Métodos: Foi aplicado um protocolo de pesquisa único a 1.465 pacientes brasileiros classificados como tendo EpA de acordo com os critérios do European Spondyloarthropaties Study Group (ESSG), atendidos em 29 centros de referência em reumatologia do Brasil. Foram registradas as variáveis clínicas e demográficas. A qualidade de vida foi analisada por meio do questionário Ankylosing Spondylitis Quality of Life (ASQoL). Resultados: A pontuação média do ASQoL foi de 7,74 (+ 5,39). Ao analisar doenças específicas no grupo de EpA, as pontuações do ASQoL não apresentaram diferença estatisticamente significativa. Os dados demográficos mostraram piores escores de ASQoL associados ao gênero feminino (p = 0,014) e etnia negra (p < 0,001). Quanto aos sintomas clínicos, a dor na região glútea (p = 0,032), a dor cervical (p < 0,001) e a dor no quadril (p = 0,001), estiveram estatisticamente associadas a piores escores no ASQoL. O uso contínuo de fármacos anti-inflamatórios não esteroides (p < 0,001) e agentes biológicos (p = 0,044) esteve associado a escores mais elevados de ASQoL, enquanto outros medicamentos não interferiram nos escores do ASQoL. Conclusão: Nesta grande série de pacientes com EpA, o sexo feminino e a etnia negra, bem como sintomas predominantemente axiais, estiveram associados a uma qualidade de vida reduzida.

Abstract Objective: To analyze quality of life and demographic and clinical variables associated to its impairment in a large Brazilian cohort of patients with spondyloarthritis (SpA). Methods: A common protocol of investigation was applied to 1465 Brazilian patients classified as SpA according to the European Spondyloarthropaties Study Group (ESSG) criteria, attended at 29 reference centers for Rheumatology in Brazil. Clinical and demographic variables were recorded. Quality of life was analyzed through the Ankylosing Spondylitis Quality of Life (ASQoL) questionnaire. Results: The mean ASQoL score was 7.74 (± 5.39). When analyzing the specific diseases in the SpA group, the ASQoL scores did not present statistical significance. Demographic data showed worse scores of ASQoL associated with female gender (p = 0.014) and African-Brazilian ethnicity (p < 0.001). Regarding clinical symptoms, buttock pain (p = 0.032), cervical pain (p < 0.001) and hip pain (p = 0.001), were statistically associated with worse scores of ASQoL. Continuous use of nonsteroidal anti-inflammatory drugs (p < 0.001) and biologic agents (p = 0.044) were associated with higher scores of ASQoL, while the other medications did not interfere with the ASQoL scores. Conclusion: In this large series of patients with SpA, female gender and African-Brazilian ethnicity, as well as predominant axial symptoms, were associated with impaired quality of life.

Effect of pegylated phosphatidylserine-containing liposomes in experimental chronic arthritis.

BACKGROUND: Phosphatidylserine-containing liposomes (PSL) have been shown to reduce inflammation in experimental models of acute arthritis, by mimicking the apoptotic process. The aim of this study was to evaluate the effect of pegylated PSL (PEG-PSL) on chronic inflammation of collagen induced arthritis (CIA) in DBA/1J mice. METHODS: CIA was induced in 24 DBA/1J mice (n = 6/group), which were divided into control (0.9 % saline) or treated with PEG-PSL (5, 10 and 15 mg/kg/day, subcutaneously for 20 days). Clinical score, limb histology and measurement of cytokines in knee joints of animals by ELISA and cytometric bead array (CBA) were evaluated. The in vitro study employed macrophage cultures stimulated with 100 ng/ml of LPS plus 10 ng/ml of PMA and treated with 100 µM PEG-PSL. RESULTS: Resolution of the disease in vivo and the inflammatory process in vitro were not observed. PEG-PSL, in doses of 10 and 15 mg/kg, were not shown to reduce the score of the disease in animals, whereas with the dose of 5 mg/kg, the animals did not show the advanced stage of the disease when compared to the controls. The PEG- PSL 5, 10 and 15 mg/kg treatment groups did not show significant reduction of TNF-α, IL-1ß, IL-6, IL-2 and IFN-γ when compared to the controls. Disease incidence and animal weights were not affected by treatment. Regarding the paw histology, PEG-PSL did not yield any reductions in the infiltrating mononuclear, synovial hyperplasia, extension of pannus formation, synovial fibrosis, erosion of cartilage, bone erosion or cartilage degradation. The concentration of 100 µM of PEG-PSL has not been shown to reduce inflammation induced by LPS/PMA in the in vitro study. Treated groups did not show any reduction in inflammatory cytokines in the knee joints of animals affected by the disease compared to the control, although there were higher concentrations of TGF-ß1 in all experimental groups. CONCLUSION: The experimental model showed an expression of severe arthritis after the booster. TGF-ß1 as well other pro inflammatory cytokines were presented in high concentrations in all groups. PEG-PSL had no impact on the clinical score, the histopathology from tibial-tarsal joints or the production of cytokines in the knee joints. Other alternatives such as dosage, route of administration, and as an adjunct to a drug already on the market, should be evaluated to support the use of PEG-PSL as a new therapeutic tool in inflammatory diseases.

Avaliação do desempenho do BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) numa coorte brasileira de 1492 pacientes com espondiloartrites: dados do Registro Brasileiro de Espondiloartrites (RBE) / Evaluation of performance of BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) in a Brazilian cohort of 1492 patients with spondyloarthritis: data from the Brazilian Registry of Spondyloarthritides (RBE)

Objetivo Avaliar os resultados da aplicação do Índice de Atividade de Doença da Espondilite Anquilosante de Bath (BASDAI) numa série de pacientes brasileiros com EpA e estabelecer suas correlações com as variáveis específicas do grupo. Métodos Um protocolo comum de investigação foi prospectivamente aplicado em 1.492 pacientes brasileiros classificados como EpA pelos critérios do Grupo Europeu de Estudo das Espondiloartropatias (ESSG), acompanhados em 29 centros de referência em reumatologia no Brasil. Variáveis clínicas, demográficas e índices de doença foram colhidos. Os valores totais do BASDAI foram comparados com a presença das diferentes variáveis. Resultados O valor médio do BASDAI foi de 4,20 ± 2,38. Os escores médios do BASDAI foram mais elevados nos pacientes com forma clínica combinada, comparado às formas axiais e periféricas isoladas, nos pacientes do sexo feminino e nos sedentários. Com relação ao componente axial, valores mais altos do BASDAI estiveram significativamente associados à lombalgia inflamatória, à dor alternante em nádegas, à dor cervical e ao acometimento de coxofemorais. Houve associação estatística entre os valores do BASDAI e o comprometimento periférico, relacionado ao número de articulações inflamadas, tanto dos membros inferiores quanto dos membros superiores, e às entesites. A positividade do HLA-B27 e a presença de manifestações extra-articulares não estiveram correlacionadas com os valores médios do BASDAI. Valores mais baixos do BASDAI estiveram associados ao uso de agentes biológicos (p < 0,001). Conclusão Nesta série heterogênea de pacientes brasileiros com EpA, o BASDAI conseguiu demonstrar “atividade de doença” tanto nos pacientes com acometimento axial quanto naqueles com envolvimento periférico. .

Objective To analyze the results of the application of the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) in a large series of Brazilian patients with the diagnosis of SpA and establish its correlations with specific variables into the group. Methods A common protocol of investigation was prospectively applied to 1492 Brazilian patients classified as SpA according to the European Spondyoarthropathies Study Group (ESSG), attended at 29 referral centers of Rheumatology in Brazil. Clinical and demographic variables, and disease indices (BASDAI, Basfi, Basri, Mases, ASQol) were applied. The total values of BASDAI were compared to the presence of the different variables. Results The mean score of BASDAI was 4.20 ± 2.38. The mean scores of BASDAI were higher in patients with the combined (axial + peripheral + entheseal) (4.54 ± 2.38) clinical presentation, compared to the pure axial (3.78 ± 2.27) or pure peripheral (4.00 ± 2.38) clinical presentations (P < 0.001). BASDAI also presented higher scores associated with the female gender (P < 0.001) and patients who did not practice exercises (P < 0.001). Regarding the axial component, higher values of BASDAI were significantly associated with inflammatory low back pain (P < 0.049), alternating buttock pain (P < 0.001), cervical pain (P < 0.001) and hip involvement (P < 0.001). There was also statistical association between BASDAI scores and the peripheral involvement, related to the lower (P = 0.004) and upper limbs (P = 0.025). The presence of enthesitis was also associated to higher scores of BASDAI (P = 0.040). Positive HLA-B27 and the presence of cutaneous psoriasis, inflammatory bowel disease, uveitis and urethritis were not correlated with the mean scores of BASDAI. Lower scores of BASDAI were associated with the use of biologic agents (P < 0.001). Conclusion In this heterogeneous Brazilian series of SpA patients, BASDAI was able to demonstrate “disease ...

Etanercept biosimilars.

Etanercept was the first tumour necrosis factor alpha antagonist approved in the USA for the treatment of rheumatoid arthritis, in 1998, and then for other diseases. With the etanercept patent set to expire in the EU in 2015, a number of etanercept copies have reached the production phase and are undergoing clinical trials, with the promise of being cheaper alternatives to the reference product. In a global scenario that is favourable to the entry of biosimilars, this article discusses the stage of development, manufacture, clinical trials and the regulatory process involved in the approval of etanercept biosimilars, compiling the literature data. Reducing treatment cost is the principal attraction for biosimilars to emerge in the global market. It is essential for the doctors' decision on the prescription of these medications, as well as for payers, to have clearly defined studies of clinical equivalence, quality, and safety in order to better evaluate the various copies of etanercept. The authors discuss the need to harmonize different national regulations and the introduction of effective pharmacosurveillance systems for prompt recognition of adverse effects in copies of biopharmaceuticals that differ from those found in the reference products.