Targeting dendritic cell-specific TNFR2 improves skin and joint inflammation by inhibiting IL-12/ IFN-γ pathways in a mouse model of psoriatic arthritis.

Psoriasis (PsO) and Psoriatic arthritis (PsA) are immune-mediated inflammatory diseases affecting the skin and joints. Approximately, 30% of patients with PsO develop PsA over time with both conditions being associated with elevated tumor necrosis factor-alpha (TNF-α) expression. TNF-α mediates its effect through two membrane receptors, TNFR1 and TNFR2. While current TNF-α-neutralizing agents, targeting both TNFR1 and TNFR2 receptors, constitute the primary treatment for psoriatic diseases, their long-term use is limited due to an increase in opportunistic infections, tuberculosis reactivation and malignancies likely attributed to TNFR1 inactivation. Recent findings suggest a pivotal role of TNFR2 in psoriatic disease, as evidenced by its amelioration in global TNFR2-knockout (TNFR2KO) mice, but not in TNFR1KO mice. The diminished disease phenotype in TNFR2KO mice is accompanied by a decrease in DC populations. However, the specific contribution of TNFR2 in dendritic cells (DCs) remains unclear. Here, utilizing a mannan-oligosaccharide (MOS)-induced PsA model, we demonstrate a significant reduction in PsA-like skin scaling and joint inflammation in dendritic cell-specific TNFR2 knockout mice (DC-TNFR2KO). Notably, MOS treatment in control mice (TNFR2 fl/fl) led to an increase in conventional type 1 dendritic cells (cDC1) population in the spleen, a response inhibited in DC-TNFR2KO mice. Furthermore, DC-TNFR2KO mice exhibited reduced levels of interleukin-12 (IL-12), a Th1 cell activator, as well as diminished Th1 cells, and interferon-gamma (IFN-γ) levels in the serum compared to controls following MOS stimulation. In summary, our study provides compelling evidence supporting the role of TNFR2 in promoting PsA-like inflammation through cDC1/Th1 activation pathways.

Advancing Basic and Translational Science: Highlights From the Basic Science Workshop at the GRAPPA 2023 Annual Meeting.

Contemporary translational and clinical research advances in psoriatic disease (PsD) were highlighted at the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting basic science workshop. This year's workshop focused on key topics, including the significance of the annual GRAPPA meetings as a platform for collaboration and knowledge exchange. Discussions centered around expanding our understanding of tumor necrosis factor inhibitor (TNFi) treatment in PsD and enhancing early detection strategies for PsD comorbidities, specifically for the timely intervention and management of cardiovascular (CV) comorbidities. Insights on the role of the C-C chemokine receptor type 6 (CCR6) in PsD and psoriatic arthritis were provided, suggesting that blockade of CCR6 can reduce psoriasis-like dermatitis and joint inflammation in mouse models.

Insights and Innovations: A Review of the GRAPPA 2023 Trainee Symposium.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2023 annual meeting started with the trainee symposium. This symposium showcased the exceptional research activities of dermatology and rheumatology trainees in the field of psoriatic diseases (PsDs). The following report is a summary account of the 5 oral presentations and 21 poster presentations that earned the privilege of being featured at our annual meeting. These presentations span a comprehensive spectrum, encompassing basic/translational, clinical, and outcomes research, which collectively underscore GRAPPA's profound impact on both national and international fronts in the realm of PsDs.

Efficacy and Safety of Bimekizumab in Patients With Psoriatic Arthritis With or Without Methotrexate: 52-Week Results From Two Phase 3 Studies.

OBJECTIVE: The objective of this study was to assess 52-week efficacy and safety of bimekizumab in patients with active psoriatic arthritis (PsA) with or without concomitant methotrexate (+/-MTX) treatment at baseline. METHODS: We conducted a post hoc analysis of patients in BE OPTIMAL (NCT03895203; biologic disease-modifying antirheumatic drug [bDMARD]-naïve), BE COMPLETE (NCT03896581; prior inadequate response or intolerance to tumor necrosis factor inhibitors [TNFi-IR]), and the BE VITAL open-label extension (NCT04009499) study. Patients were randomized to one of the following treatment groups: bimekizumab 160 mg every four weeks, placebo, or a reference drug (adalimumab 40 mg every two weeks; BE OPTIMAL only). From Week 16, placebo-randomized patients received bimekizumab. Missing data were imputed using non-responder imputation, multiple imputation, or worst-category imputation. RESULTS: Through Week 52, similar proportions of bimekizumab-treated patients achieved American College of Rheumatology 50% (ACR50) response criteria for both +MTX and -MTX (BE OPTIMAL: 54.4% +MTX, 54.7% -MTX; BE COMPLETE: 56.3% +MTX, 48.0% -MTX). Similar proportions of bimekizumab-treated patients achieved complete skin clearance (Psoriasis Area and Severity Index 100% [PASI100] response) and minimal disease activity in both +MTX and -MTX groups. Similar trends were seen in placebo/bimekizumab-treated patients. Through Week 52, the proportion of bimekizumab-treated patients with ≥1 treatment-emergent adverse event were similar between the +MTX and -MTX groups (BE OPTIMAL 325 of 410 [79.3%] vs 230 of 292 [78.8%], BE COMPLETE 105 of 168 [62.5%] vs 138 of 220 [62.7%]). The safety profile was comparable between subgroups and consistent with the prior safety profile of bimekizumab. CONCLUSION: Treatment with bimekizumab demonstrated consistent, sustained efficacy to 52 weeks in bDMARD-naïve and TNFi-IR patients with PsA and was well tolerated, irrespective of concomitant MTX.

Diagnosis of Inflammatory Bowel Disease-Associated Peripheral Arthritis: A Systematic Review.

BACKGROUND: Inflammatory bowel disease (IBD)-associated peripheral spondyloarthritis (pSpA) decreases quality of life and remains poorly understood. Given the prevalence of this condition and its negative impact, it is surprising that evidence-based disease definitions and diagnostic strategies are lacking. This systematic review summarizes available data to facilitate development and validation of diagnostics, patient-reported outcomes, and imaging indices specific to this condition. METHODS: A literature search was conducted. Consensus or classification criteria, case series, cross-sectional studies, cohort studies, and randomized controlled trials related to diagnosis were included. RESULTS: A total of 44 studies reporting data on approximately 1500 patients with pSpA were eligible for analysis. Data quality across studies was only graded as fair to good. Due to large heterogeneity, meta-analysis was not possible. The majority of studies incorporated patient-reported outcomes and a physical examination. A total of 13 studies proposed or validated screening tools, consensus, classification, or consensus criteria. A total of 28 studies assessed the role of laboratory tests, none of which were considered sufficiently accurate for use in diagnosis. A total of 17 studies assessed the role of imaging, with the available literature insufficient to fully endorse any imaging modality as a robust diagnostic tool. CONCLUSIONS: This review highlights existing inconsistency and lack of a clear diagnostic approach for IBD-associated pSpA. Given the absence of an evidence-based approach, a combination of existing criteria and physician assessment should be utilized. To address this issue comprehensively, our future efforts will be directed toward pursuit of a multidisciplinary approach aimed at standardizing evaluation and diagnosis of IBD-associated pSpA.

This systematic review highlights the lack of an evidence-based approach to the diagnosis of inflammatory bowel disease­associated peripheral spondyloarthritis and the need to standardize evaluation and diagnosis via multidisciplinary collaboration with development of patient-reported outcomes and imaging indices.

What Clinical Factors Affect Length of Transition to Psoriatic Arthritis in Patients With Psoriasis?

OBJECTIVE: We aimed to identify clinical and demographic features associated with the interval between psoriasis (PsO) and psoriatic arthritis (PsA). METHODS: We identified patients with PsO and PsA diagnoses from our tertiary care psoriatic disease biorepository: a longitudinal, real-world database including clinical information and patient-reported outcomes. We used a multivariable a zero-inflated negative binomial model to evaluate several clinical and demographic features that may be associated with the time between PsO and PsA onset. RESULTS: A total of 384 patients were included, of whom 52.2% were female. The mean age of PsO onset was 31.5 years. Advanced age at PsO onset was associated with a shorter interval between PsO and PsA. Based on our model, patients with PsO onset at age 42.6 years (upper end of the interquartile range [IQR]) had a 62% shorter expected interval compared with patients with PsO onset at age 18.9 years (lower end of IQR) (P < 0.001) and were more likely to have concurrent (onset within 6 months) diagnoses (odds ratio 4.56; 95% confidence interval 2.9-7.17). Patients with a body mass index (BMI) of 34 compared with a BMI of 26 had a 10% shorter interval between PsO and PsA, which trended toward statistical significance (P = 0.053). CONCLUSION: Our study demonstrated that patients with a diagnosis of PsO at an older age have a shorter interval between PsO and PsA diagnoses and are more likely to have concurrent diagnoses compared with patients with an onset of PsO at a younger age. These results suggest that patients with a later onset of PsO may benefit from earlier PsA screening.

Post-traumatic Stress Disorder: The Influence of the Environmental Context and Analysis of Oxidative Stress and Inflammatory and Glycemic Markers in Women Living in Kurdistan Regional Government-Iraq.

Background Internally displaced persons (IDP) camps are still home to a large number of female survivors of the Yazidi genocide carried out in Iraq in 2014 by the Islamic organization known as the Islamic State of Iraq and Syria (ISIS). Many of these women suffer from a persistent form of post-traumatic stress disorder (PTSD), which can last for many years. On the other hand, little is known about the intricate etiology of PTSD. Objectives In this observational cross-sectional study, the biochemical parameters, including inflammatory and oxidative stress (OXS) markers, were evaluated in two groups: the case group (women with newly diagnosed PTSD) and the control group (apparently healthy women). Furthermore, how the environment impacts the biochemical and OXS parameters of people not diagnosed with PTSD but living in IDP camps was also analyzed. Materials and methods The PTSD group (n=55, age=30.0 years) was made up of women survivors of genocide-related events living in IDP camps in the Kurdistan region of Iraq. The studied parameters in the PTSD group have been compared to two healthy control groups: (1) internal control group (n=55, age=28.1 years): healthy women living inside the IDP camps; and (2) external control group (n=55, age=28.3 years): healthy women living outside the IDP camps. The diagnosis of PTSD was conducted using a validated Kurdish version of the PTSD Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) (PCL-5) scale. Blood samples were collected to determine the level of glycated hemoglobin (HbA1c) and the concentrations of fasting serum glucose (FSG), C-reactive protein (CRP), ceruloplasmin (CP), 8-hydroxydeoxyguanosine (8-OHdG), glutathione (GSH), malondialdehyde (MDA), protein carbonyls (PC), and catalase (CAT) activity. Results Women with PTSD presented increased values of FSG (4.41%, p<0.05), HbA1c (4.74%, p<0.05), and CRP (114.29%, p<0.05), as well as increased levels of 8-OHdG (185.97%, p<0.001), CP (27.08%, p<0.001), MDA (141.97%, p<0.001), and PC (63.01%, p<0.001), besides increased CAT activity (121.5%, p<0.001), when compared with the control groups. A significant reduction of GSH (-20.33%, p<0.05) was observed in PTSD patients as compared to the external control group. In relation to the internal control group, women diagnosed with PTSD presented significantly increased levels of FSG (3.88%, p<0.05), HbA1c (2.83%, p<0.05), CRP (77.97%, p<0.05), and PC (41.3%, p<0.05), as well as increased levels of 8-OHdG (118.84%, p<0.001), CP (22.72%, p<0.001), MDA (90.67%, p<0.001), and CAT activity (55.31%, p<0.001). Healthy individuals residing in IDP camps, compared with external healthy control, presented significantly elevated levels of 8-OHdG (30.68%, p<0.001), MDA (26.91%, p<0.001), PC (15.37%, p<0.001), and CAT activity (42.62%, p<0.001). Conclusion Our findings indicate that PTSD significantly influences glycemic, inflammatory, oxidant, and antioxidant parameters, as evidenced by increased levels of FSG, HbA1C, CRP, PC, MDA, 8-OHdG, and CP, as well as increased CAT activity and a reduced GSH concentration in the PTSD group in comparison to the external control group. Additionally, our results suggest that the environmental context in IDP camps by itself can potentially affect oxidant and antioxidant parameters, as evidenced by the increased concentrations of 8-OHdG, MDA, and PC and increased CAT activity found in individuals not diagnosed with PTSD but living inside the camps.

Screening Tools for Spondyloarthritis in Patients With Psoriasis, Uveitis, and Inflammatory Bowel Disease: A Scoping Review.

OBJECTIVE: Extramusculoskeletal manifestations of spondyloarthritis (SpA) may precede the development of articular features. Patients seen in ophthalmology, dermatology, and gastroenterology clinics with uveitis, psoriasis, or inflammatory bowel disease (IBD) may have undiagnosed SpA. We set out to identify and evaluate screening tools for SpA in patients with psoriasis, uveitis, and IBD and determine factors that influence the performance of these instruments. METHODS: This scoping review followed Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed, Embase, and Web of Science were searched from inception to January 2022. RESULTS: We identified 13 screening tools for psoriatic arthritis, 2 SpA screening tools for uveitis, and 3 SpA screening tools for IBD. All screening tools were patient-oriented questionnaires except for the Dublin Uveitis Evaluation Tool, a physician-applied algorithm. The questionnaires varied in length, scoring method, cutoff score, and spectrum of included SpA features. Average completion time was less than five minutes. Across the three patient populations, the sensitivities and specificities of these screening tools were comparable in the primary validation cohorts. Sensitivities and specificities were generally lower in secondary validation studies, with marked variability among cohorts. CONCLUSION: Our results highlight the heterogeneity and limitations of existing SpA screening tools. Although these tools show promise for use within a specific target population, none are generalizable to all patients with extramusculoskeletal manifestations at risk of SpA. Future studies should explore the utility of a generic patient-oriented SpA screening tool that can be applied to patients with psoriasis, uveitis, or IBD; is easy to use and comprehend; and captures all clinical domains of SpA.

Mechanistic insights into bone remodelling dysregulation by human viral pathogens.

Bone-related diseases (osteopathologies) associated with human virus infections have increased around the globe. Recent findings have highlighted the intricate interplay between viral infection, the host immune system and the bone remodelling process. Viral infections can disrupt bone homeostasis, contributing to conditions such as arthritis and soft tissue calcifications. Osteopathologies can occur after arbovirus infections such as chikungunya virus, dengue virus and Zika virus, as well as respiratory viruses, such as severe acute respiratory syndrome coronavirus 2 and enteroviruses such as Coxsackievirus B. Here we explore how human viruses dysregulate bone homeostasis, detailing viral factors, molecular mechanisms, host immune response changes and bone remodelling that ultimately result in osteopathologies. We highlight model systems and technologies to advance mechanistic understanding of viral-mediated bone alterations. Finally, we propose potential prophylactic and therapeutic strategies, introduce 'osteovirology' as a research field highlighting the underestimated roles of viruses in bone-related diseases, and discuss research avenues for further investigation.

Use of the Bath Ankylosing Spondylitis Disease Activity Index in Patients With Psoriatic Arthritis With and Without Axial Disease.

OBJECTIVE: To evaluate whether the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) is a responsive instrument in psoriatic arthritis (PsA) and whether it differentiates between axial and peripheral disease activity in PsA. METHODS: Individuals with PsA initiating therapy in a longitudinal cohort study based in the United States were included. Axial PsA (axPsA), most often also associated with peripheral disease, was defined as fulfillment of the Assessment of Spondyloarthritis international Society axial spondyloarthritis classification criteria or presence of axial disease imaging features. Baseline BASDAI, individual BASDAI items, patient global assessment, patient pain, and Routine Assessment of Patient Index Data 3, and score changes following therapy initiation were descriptively reported. Standardized response means (SRMs) were calculated as the mean change divided by the SD of the change. RESULTS: The mean (SD) baseline BASDAI score at the time of therapy initiation was 5.0 (2.2) among those with axPsA (n = 40) and 4.8 (2.0) among those with peripheral-only disease (n = 79). There was no significant difference in patient-reported outcome scores between the groups. The mean change for BASDAI was similar among axial vs peripheral disease (-0.75 vs -0.83). SRMs were similar across axial vs peripheral disease for BASDAI (-0.37 vs -0.44) and the individual BASDAI items. CONCLUSION: BASDAI has reasonable responsiveness in PsA but does not differentiate between axPsA and peripheral PsA. (ClinicalTrials.gov: NCT03378336).

Dataset of bird's eye chilies farm for stereo image semantic segmentation.

This paper presents a dataset of bird's eye chilies in a single farm for semantic segmentation. The dataset is generated using two cameras that are aligned left and right forming a stereo-vision video capture. By analyzing the disparity between corresponding points in the left and right images, algorithms can calculate the relative distance of objects in the scene. This depth information is useful in various applications, including 3D reconstruction, object tracking, and autonomous navigation. The dataset consists of 1150 left and right compressed images extracted from ten sets of stereo videos taken at ten different locations within the chili farm from the same ages of the bird's eye chilies. Since the dataset is used for semantic segmentation, the ground truth images of manually semantic segmented images are also provided in the dataset. The dataset can be used for 2D and 3D semantic segmentation of the bird's eye view chili farm. Some of the object classes in this dataset are the sky, living things, plantation, flat, construction, nature, and misc.

Proceedings of the GRAPPA 2022 Executive Retreat.

The Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) leadership congregated for a strategic planning meeting before the 2022 GRAPPA annual meeting in New York, USA. Meeting aims were to review GRAPPA's performance in relation to its 2016 goals and identify successes and areas for further improvement, identify key GRAPPA priorities and activities for the next 5 years, and explore committee structures to best support these aims.

GRAPPA 2022 Trainee Symposium: A Summary of Oral and Poster Presentations.

One of the highlights of the 2022 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) annual meeting was the trainee symposium. Dermatology and rheumatology trainees presented their research related to psoriasis and psoriatic arthritis. This report briefly reviews 5 oral presentations and 15 posters that were selected for this annual meeting. Topics include basic/translational, clinical, and outcomes research reflecting the spectrum of GRAPPA's effort and influence nationally and internationally in the area of psoriatic diseases.

Polycyclic aromatic hydrocarbons and risk of rheumatoid arthritis: a cross-sectional analysis of the National Health and Nutrition Examination Survey, 2007-2016.

OBJECTIVE: While there are several well-established environmental risk factors for rheumatoid arthritis (RA), a paucity of evidence exists linking environmental toxicants with RA prevalence. We aimed to examine the associations between various environmental toxicants and RA among adults in the U.S. general population while adjusting for non-heritable risk factors. DESIGN: Cross-sectional study. SETTING: National Health and Nutrition Examination Survey conducted from 2007 to 2016. PARTICIPANTS: The study included 21 987 adult participants (no RA: 20 569; RA: 1418). Participants were excluded (n=7214) if they did not answer questions related to self-reporting of RA, had another or unknown type of arthritis, or did not have interview or biospecimen data. PRIMARY AND SECONDARY OUTCOME MEASURES: Association between individual toxicants and body burden scores for polycyclic aromatic hydrocarbons (PAH), phthalates and plasticisers (PHTHTEs) metabolites or volatile organic compounds (VOCs) and participant self-reported RA based on multivariable logistic regression models while adjusting for age, sex, urine creatinine, body mass index, smoking, race, education, family poverty income ratio, any vigorous or moderate activity and dietary fibre. RESULTS: While increased prevalence of RA was observed in participants with the highest quartile of various individual PAHs, only 1-hydroxynaphthalene (OR: 1.8 (1.1 to 3.1); p=0.020) remained associated in a fully adjusted model. PAH body burden was found to be associated with RA (Q4 vs Q1, OR: 2.2 (1.09 to 4.2); p=0.028) in a fully adjusted model. Interestingly, after accounting for PAH body burden, smoking was not associated with RA (OR: 1.4 (0.89 to 2.3); p=0.13). A mediation analysis demonstrated that PAH body burden accounted for 90% of the total effect of smoking on RA. PHTHTE and VOC metabolites were not associated with RA in fully adjusted models. CONCLUSIONS AND RELEVANCE: PAHs are associated with RA prevalence, mediate the majority of the effects of smoking on RA, and are associated with RA independent of smoking status.

Responsiveness and Minimum Clinically Important Difference in Patient-Reported Outcome Measures Among Patients With Psoriatic Arthritis: A Prospective Cohort Study.

OBJECTIVE: To determine the responsiveness to therapy and minimum clinically important improvement (MCII) for patient-reported outcome measures in psoriatic arthritis (PsA) and to examine the impact of baseline disease activity on the ability to demonstrate change. METHODS: A longitudinal cohort study was performed within the PsA Research Consortium. Patients completed several patient-reported outcomes, including the Routine Assessment of Patient Index Data, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), the Psoriatic Arthritis Impact of Disease 12-item (PsAID12) questionnaire, and others. The mean change in the scores between visits and standardized response means (SRMs) were calculated. The MCII was calculated as the mean change in score among patients who reported minimal improvement. SRMs and MCIIs were compared among subgroups with moderate to highly active PsA and those with lower disease activity. RESULTS: Among 171 patients, 266 therapy courses were included. The mean ± SD age was 51 ± 13.8 years, 53% were female, and the mean swollen and tender joint counts were 3 and 6, respectively, at baseline. SRMs and MCII for all measures were small to moderate, although greater among those with higher baseline disease activity. BASDAI had the best SRM overall and for less active PsA, and the clinical Disease Activity of PsA (cDAPSA) and PsAID12 were best for those with higher disease activity. CONCLUSION: SRMs and MCII were relatively small in this real-world population, particularly among those with lower disease activity at baseline. BASDAI, cDAPSA, and PsAID12 had good sensitivity to change, but selection for use in trials should consider the baseline disease activity of patients to be enrolled.

Management of Concomitant Inflammatory Bowel Disease or Uveitis in Patients with Psoriatic Arthritis: An Updated Review Informing the 2021 GRAPPA Treatment Recommendations.

OBJECTIVE: Several advanced therapies have been licensed across the related conditions of psoriatic arthritis (PsA), Crohn disease (CD), ulcerative colitis (UC), and noninfectious uveitis. We sought to summarize results from randomized controlled trials (RCTs) investigating the efficacy and safety of advanced therapies for these related conditions in patients with PsA. METHODS: We updated the previous systematic search conducted in 2013 with literature reviews of MEDLINE, Embase, and the Cochrane Library (from February 2013 to August 2020) on this subject; only those new studies are presented here. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) framework. RESULTS: The number of RCTs meeting eligibility criteria were 12 for CD, 15 for UC, and 5 for uveitis. The tumor necrosis factor inhibitor (TNFi) class appears to be efficacious and safe across CD, UC, and uveitis, with the exception of etanercept. Interleukin 12/23 inhibitors (IL-12/23i) are efficacious for CD and UC. Phase II and III RCTs of Janus kinase inhibitors (JAKi) and IL-23i in CD and UC are promising in terms of efficacy and safety. IL-17i must be used with great caution in patients with PsA at high risk of inflammatory bowel disease (IBD). RCTs in uveitis have mainly studied adalimumab. CONCLUSION: We have identified 32 recent RCTs in IBD and uveitis and updated recommendations for managing patients with PsA and these related conditions. A multispecialty approach is essential to effectively, safely, and holistically manage such patients. Advanced therapies are not equally efficacious across these related conditions, with dosing regimens and safety varying.

Recommendations for the Use of Nonsteroidal Anti-inflammatory Drugs and Cardiovascular Disease Risk: Decades Later, Any New Lessons Learned?

Nonsteroidal anti-inflammatory drugs (NSAIDs) are among the most prescribed pharmacologic therapies worldwide due to their therapeutic analgesic efficacy and relative tolerability. In the past several decades, various cardiovascular (CV) adverse events have emerged regarding both traditional NSAIDs (tNSAIDs) and cyclo-oxygenase 2 (COX-2) selective (coxibs). This review will provide an updated report on the CV risk profile of NSAIDs, focusing on several of the larger clinical trials, meta-analyses, and registry studies. We aim to provide rheumatologists with a framework for NSAID use in the context of rheumatologic chronic pain management. Recent findings: In patients with and without CV diseases, the use of NSAIDs, both tNSAIDs and coxibs, is associated with an increased risk of adverse CV events, myocardial infarction, heart failure, and cerebrovascular events. These CV risks have increased within weeks of coxib use and higher doses of tNSAIDs. The risk of adverse CV events is heterogenous across NSAIDs; naproxen and low-dose ibuprofen appear to have lower increased CV risk among NSAIDs. A variation in CV risk is associated with multiple factors, including NSAID class, COX-2 selectivity, treatment dose and duration, and baseline patient risk. Summary: Many important questions remain regarding the safety of NSAIDs and whether the culmination of research performed could inform us whether specific patient subtypes or NSAID class may have a more favorable profile. tNSAIDs such as naproxen and low-dose ibuprofen may have a lower CV risk profile, while coxibs have a more favorable GI risk profile. In general, any NSAID can be optimized if used at the lowest effective dose for the shortest amount of time, especially among individuals with increased CV risk.