A review of JAK-STAT signalling in the pathogenesis of spondyloarthritis and the role of JAK inhibition.

Spondyloarthritis (SpA) comprises a group of chronic inflammatory diseases with overlapping clinical, genetic and pathophysiological features including back pain, peripheral arthritis, psoriasis, enthesitis and dactylitis. Several cytokines are involved in the pathogenesis of SpA, variously contributing to each clinical manifestation. Many SpA-associated cytokines, including IL-23, IL-17, IL-6, type I/II interferon and tumour necrosis factor signal directly or indirectly via the Janus kinase (JAK)-signal transducer and activator of transcription pathway. JAK signalling also regulates development and maturation of cells of the innate and adaptive immune systems. Accordingly, disruption of this signalling pathway by small molecule oral JAK inhibitors can inhibit signalling implicated in SpA pathogenesis. Herein we discuss the role of JAK signalling in the pathogenesis of SpA and summarize the safety and efficacy of JAK inhibition by reference to relevant SpA clinical trials.

Upadacitinib for psoriatic arthritis refractory to biologics: SELECT-PsA 2.

BACKGROUND: Upadacitinib is a Janus kinase inhibitor under evaluation for the treatment of psoriatic arthritis (PsA). We evaluated upadacitinib in patients with PsA and prior inadequate response or intolerance to at least one biologic disease-modifying antirheumatic drug (DMARD). METHODS: In this 24-week randomised, placebo-controlled, double-blind, phase 3 trial, 642 patients were randomised (2:2:1:1) to once per day upadacitinib 15 mg or 30 mg, placebo followed by upadacitinib 15 mg or placebo followed by upadacitinib 30 mg at week 24. The primary endpoint was the proportion of patients achieving American College of Rheumatology (ACR) 20 response at week 12. Achievement of minimal disease activity (MDA) was assessed at week 24. Treatment-emergent adverse events are reported for all patients who received at least one dose of trial drug. RESULTS: At week 12, significantly more patients receiving upadacitinib 15 mg and 30 mg versus placebo achieved ACR20 (56.9% and 63.8% vs 24.1%; p<0.001 for both comparisons). At week 24, MDA was achieved by more upadacitinib 15 mg-treated (25.1%) and 30 mg-treated patients (28.9%) versus placebo (2.8%; p<0.001 for both comparisons). Generally, the rates of treatment-emergent adverse events were similar with placebo and upadacitinib 15 mg and higher with upadacitinib 30 mg at week 24. Rates of serious infections were 0.5%, 0.5% and 2.8% with placebo, upadacitinib 15 mg and upadacitinib 30 mg, respectively. CONCLUSION: In this trial of patients with active PsA who had inadequate response or intolerance to at least one biologic DMARD, upadacitinib 15 mg and 30 mg was more effective than placebo over 24 weeks in improving signs and symptoms of PsA. CLINICAL TRIAL REGISTRATION NUMBER: NCT03104374.

Lower vitamin D is associated with metabolic syndrome and insulin resistance in systemic lupus: data from an international inception cohort.

OBJECTIVES: Vitamin D (25(OH)D) deficiency and metabolic syndrome (MetS) may both contribute to increased cardiovascular risk in SLE. We aimed to examine the association of demographic factors, SLE phenotype, therapy and vitamin D levels with MetS and insulin resistance. METHODS: The Systemic Lupus International Collaborating Clinics (SLICC) enrolled patients recently diagnosed with SLE (<15 months) from 33 centres across 11 countries from 2000. Clinical, laboratory and therapeutic data were collected. Vitamin D level was defined according to tertiles based on distribution across this cohort, which were set at T1 (10-36 nmol/l), T2 (37-60 nmol/l) and T3 (61-174 nmol/l). MetS was defined according to the 2009 consensus statement from the International Diabetes Federation. Insulin resistance was determined using the HOMA-IR model. Linear and logistic regressions were used to assess the association of variables with vitamin D levels. RESULTS: Of the 1847 patients, 1163 (63%) had vitamin D measured and 398 (34.2%) subjects were in the lowest 25(OH)D tertile. MetS was present in 286 of 860 (33%) patients whose status could be determined. Patients with lower 25(OH)D were more likely to have MetS and higher HOMA-IR. The MetS components, hypertension, hypertriglyceridemia and decreased high-density lipoprotein (HDL) were all significantly associated with lower 25(OH)D. Increased average glucocorticoid exposure was associated with higher insulin resistance. CONCLUSIONS: MetS and insulin resistance are associated with lower vitamin D in patients with SLE. Further studies could determine whether vitamin D repletion confers better control of these cardiovascular risk factors and improve long-term outcomes in SLE.

Efficacy and safety of continuing versus withdrawing adalimumab therapy in maintaining remission in patients with non-radiographic axial spondyloarthritis (ABILITY-3): a multicentre, randomised, double-blind study.

BACKGROUND: Success of treatment withdrawal in patients with non-radiographic axial spondyloarthritis who are in remission remains unknown. The ABILITY-3 study explored the ability to withdraw adalimumab treatment in patients with non-radiographic axial spondyloarthritis who achieved sustained clinical remission after open-label treatment with adalimumab. METHODS: ABILITY-3 was a multicentre, two-period study done in 107 sites in 20 countries. We enrolled adult patients (≥18 years) diagnosed with non-radiographic axial spondyloarthritis, fulfilling Assessment of SpondyloArthritis international Society classification criteria but not the modified New York radiologic criterion, who had objective evidence of active inflammation, active disease, and inadequate response to at least two non-steroidal anti-inflammatory drugs. Patients who achieved Ankylosing Spondylitis Disease Activity Score (ASDAS) inactive disease (<1·3) with open-label adalimumab (40 mg subcutaneously every other week for 28 weeks) at weeks 16, 20, 24, and 28 were randomly assigned (1:1) using an interactive voice or web response system to 40-week, double-blind treatment with adalimumab (continuation) or placebo (withdrawal). The primary efficacy endpoint was the proportion of patients who did not experience a flare (defined as ASDAS ≥2·1 at two consecutive visits) during the double-blind period. Patients who flared were rescued with open-label adalimumab. This study is registered with ClinicalTrials.gov, number NCT01808118. FINDINGS: Between June 27, 2013, and October 22, 2015, 673 patients were enrolled to the study. The trial completed on April 14, 2017. Of 673 enrolled patients, 305 (45%) achieved sustained remission and were randomly assigned to double-blind treatment (152 patients to adalimumab and 153 to placebo). A greater proportion of patients continuing adalimumab than those receiving placebo did not experience a flare (107 [70%] of 152 patients vs 72 [47%] of 153 patients; p<0·0001) up to and including week 68. Among 673 patients receiving adalimumab at any time, 516 (77%) patients reported an adverse event and 28 (4%) experienced a serious adverse event. The most common adverse events in both the adalimumab and placebo groups were nasopharyngitis (25 [16%] vs 20 [13%]), upper respiratory tract infection (20 [13%] vs 12 [8%]), and worsening of axial spondyloarthritis (ten [7%] vs 21 [14%]). INTERPRETATION: In patients with active non-radiographic axial spondyloarthritis who achieved sustained remission with adalimumab, continued therapy was associated with significantly fewer patients flaring than was treatment withdrawal. FUNDING: AbbVie.

Palmoplantar Pustulosis has a Greater Disease Burden than Plaque Psoriasis: Real-World Evidence From the CorEvitas Psoriasis Registry.

Background: Palmoplantar pustulosis (PPP) is a rare skin disease characterized by episodes of neutrophilic pustules on the palms of the hands and soles of the feet. Current treatments for PPP have limited efficacy, and there is little real-world evidence characterizing the disease burden of PPP in patients. Objective: To describe and compare the clinical characteristics and patient-reported outcomes (PROs) of patients with PPP with those of patients with plaque psoriasis. Methods: This real-world study used data from patients with PPP or plaque psoriasis enrolled in the CorEvitas Psoriasis Registry. Disease characteristics, historical medical data, PROs, and quality-of-life measures were compared between patients with PPP and those with plaque psoriasis. These measures were also compared following patient stratification by body surface area involvement or Psoriasis Area and Severity Index. This study is purely descriptive; no hypothesis testing was performed. Results: In this data set, patients with PPP (n = 64) reported higher mean overall pain, using the visual analog scale, relative to those with plaque psoriasis (n = 4894). Patients with PPP also reported a greater proportion of work hours missed or affected; greater impairment of work; and greater impairment of daily activity than patients with plaque psoriasis. Similar effects were observed irrespective of patient stratification. Conclusion: Generally, PPP was associated with worse PROs and a greater impact on quality of life compared with plaque psoriasis. These findings highlight a need to develop effective therapies for PPP to improve disease management.

Disease Control with Upadacitinib in Patients with Psoriatic Arthritis: A Post Hoc Analysis of the Randomized, Placebo-Controlled SELECT-PsA 1 and 2 Phase 3 Trials.

INTRODUCTION: Low disease activity (LDA)/remission is the target of treatment in patients with psoriatic arthritis (PsA). We assessed the proportions of patients with PsA receiving upadacitinib who achieved LDA/remission over 1 year. METHODS: This was a post hoc analysis of the double-blind, placebo-controlled SELECT-PsA 1 (also adalimumab-controlled) and SELECT-PsA 2 trials. Treatment targets assessed included LDA/remission defined by Disease Activity in Psoriatic Arthritis (≤ 14/ ≤ 4) and Psoriatic Arthritis Disease Activity Scores (≤ 3.2/ ≤ 1.9), as well as minimal disease activity (MDA)/very low disease activity (VLDA) states (5/7 and 7/7 components, respectively, of MDA criteria). Targets were assessed at 24 and 56 weeks. For binary outcomes, non-responder imputation was used for missing data. Data from patients receiving upadacitinib 30 mg was not included in the analysis. RESULTS: Overall, 1386 patients were analyzed. Disease control (i.e., LDA/MDA) was achieved at 24 weeks in upadacitinib 15 mg-treated patients across both studies: LDA/MDA was achieved by 25-48% of patients receiving upadacitinib 15 mg versus 2-16% of patients receiving placebo, and remission/VLDA rates were 7-14% with upadacitinib 15 mg versus 0-4% with placebo. The proportions of patients achieving treatment targets were numerically similar to upadacitinib 15 mg and adalimumab. All responses were sustained at 56 weeks. CONCLUSIONS: Remission and LDA are feasible targets with upadacitinib treatment in patients with PsA. TRIAL REGISTRATION: ClinicalTrial.gov identifiers NCT03104400 (SELECT-PsA 1) and NCT03104374 (SELECT-PsA 2).

Psoriatic arthritis is a disease that causes inflammation of the skin and joints. Doctors measure how bad a patient's disease is by measuring signs and symptoms of the disease, and using these to make a "score." The aim of treatment is to reduce the score to low levels (known as "low disease activity") or very low levels ("remission"). This study looked at results from two clinical trials that compared upadacitinib, a medicine used to treat psoriatic arthritis, with no medicine (placebo) to see how many patients had low disease activity or were in remission after 1 year of treatment. The results showed that more patients who were taking upadacitinib had low disease activity or were in remission after the first 6 months of treatment compared with those who took placebo. This difference between upadacitinib and placebo could still be seen after 1 year of treatment. These results show that treatment with upadacitinib is effective enough for some patients with psoriatic arthritis to achieve low disease activity or remission and to stay at this level, even after more than 1 year of treatment.

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.

Risk factors for changes in carotid intima media thickness and plaque over 5 years in women with systemic lupus erythematosus.

OBJECTIVE: To investigate the occurrence of and risk factors for progression of carotid intima media thickness (IMT) and plaque in women with and without SLE. METHODS: A cohort of 149 women with SLE and 126 controls participated in SOLVABLE (Study of Lupus Vascular and Bone Long-term Endpoints). Demographics, cardiovascular and SLE factors, and laboratory assessments were collected at baseline. Carotid IMT and plaque were measured using B-mode ultrasound at baseline and at 5-year follow-up. Regression models were used to identify predictors of progression in carotid IMT and plaque; multivariate models were adjusted for age, hypertension and total cholesterol to high-density lipoprotein ratio. RESULTS: The mean±SD follow-up time was 5.35±0.60 years in cases and 5.62±0.66 years in controls. The mean IMT change per year was 0.008±0.015 mm in cases and 0.005±0.019 mm in controls (p=0.24). At follow-up, 31.5% of cases and 15% of controls had plaque progression, with a relative risk for plaque progression of 2.09 (95% CI 1.30 to 3.37). In SLE cases, higher fasting glucose and lower fibrinogen were associated with IMT progression after adjustment. Larger waist circumference and non-use of hydroxychloroquine were associated with plaque progression after adjustment. CONCLUSION: Potential modifiable risk factors for carotid IMT and plaque progression in women with SLE were identified, suggesting that monitoring of glucose and waist circumference and use of hydroxychloroquine may be beneficial.

Patient-Reported Outcomes in Psoriatic Arthritis Patients with an Inadequate Response to Biologic Disease-Modifying Antirheumatic Drugs: SELECT-PsA 2.

INTRODUCTION: Psoriatic arthritis (PsA) has a major impact on health-related quality of life (HRQOL) and other patient-reported outcomes (PROs), important components in the assessment of therapeutic efficacy. We evaluated the impact of upadacitinib on PROs in PsA patients with inadequate responses or intolerance to biologic disease-modifying anti-rheumatic drugs (bDMARD-IR). METHODS: Patients enrolled in the phase 3 SELECT-PsA 2 randomized controlled trial (RCT) received 56 weeks of oral upadacitinib 15 mg QD, upadacitinib 30 mg QD, or placebo switched to either dose of upadacitinib at week 24. PROs included patient global assessment of disease activity (PtGA), pain, physical function (HAQ-DI), health-related quality of life (SF-36 physical (PCS) and mental (MCS) component summary and domain scores), fatigue (FACIT-F), psoriasis symptom severity (SAPS), and work productivity (WPAI). Mean changes from baseline in PROs, improvements ≥ minimum clinically important differences (MCID) and scores ≥ normative values, and maintenance of improvements were assessed. RESULTS: At weeks 12 and 24, patients treated with either upadacitinib dose reported statistically and nominally significant improvements from baseline across all PROs versus placebo (p ≤ 0.05), except the WPAI absenteeism domain, which were maintained or further improved to week 56. A significantly greater proportion of patients receiving either upadacitinib dose reported improvements ≥ MCID and scores ≥ normative values versus placebo (nominal p ≤ 0.01) in most PROs at weeks 12 and 24, with clinically meaningful improvements continuing to week 56. Improvements ≥ MCID were reported as early as week 2 in PtGA, pain, and HAQ-DI. CONCLUSIONS: Upadacitinib provides rapid, clinically meaningful, and sustained improvements in PROs reported by bDMARD-IR PsA patients. SELECT-PsA 2 ClinicalTrials.gov number, NCT03104374.

Upadacitinib in Patients with Psoriatic Arthritis and Inadequate Response to Biologics: 56-Week Data from the Randomized Controlled Phase 3 SELECT-PsA 2 Study.

INTRODUCTION: Upadacitinib is a Janus kinase inhibitor under investigation in patients with psoriatic arthritis (PsA). This study assessed the 56-week efficacy and safety of upadacitinib in patients with PsA and an inadequate response or intolerance to biologic therapy. METHODS: In the phase 3 SELECT-PsA 2 study, patients were randomized to 56 weeks of blinded treatment with oral upadacitinib 15 or 30 mg once daily, or placebo switched to upadacitinib 15 or 30 mg once daily at week 24. Efficacy endpoints included the proportion of patients achieving 20/50/70% improvement in American College of Rheumatology criteria (ACR20/50/70), 75/90/100% improvement in Psoriasis Area and Severity Index (PASI75/90/100), and minimal disease activity. Safety was assessed throughout the study. RESULTS: Of 641 patients who received ≥ 1 dose of study drug, 479 (74.7%) completed 56 weeks of treatment. Improvements in the proportion of patients achieving ACR20/50/70, PASI75/90/100, and minimal disease activity were maintained with both doses of upadacitinib through 56 weeks. Week 56 results for patients who switched from placebo to upadacitinib at week 24 were similar to those for patients originally randomized to the upadacitinib groups. The exposure-adjusted event rate for serious infections was 2.6 and 6.1 events/100 patient-years in the upadacitinib 15 and 30 mg groups, respectively. Herpes zoster occurred more frequently with upadacitinib 30 versus 15 mg; most cases were non-serious. CONCLUSION: In patients with PsA who had an inadequate response or intolerance to biologic therapy, the efficacy of upadacitinib was maintained over 56 weeks with no new significant safety signals observed. TRIAL REGISTRATION: NCT03104374.

Predictors of remission in patients with non-radiographic axial spondyloarthritis receiving open-label adalimumab in the ABILITY-3 study.

Background: This analysis assessed baseline predictors of remission in patients with non-radiographic axial spondyloarthritis (nr-axSpA) who received open-label adalimumab therapy. Methods: ABILITY-3 enrolled 673 adult patients with nr-axSpA who had objective evidence of inflammation by MRI or elevated high-sensitivity C reactive protein at screening, active disease and an inadequate response to two or more non-steroidal anti-inflammatory drugs. Patients received adalimumab 40 mg every other week during a 28-week open-label lead-in period. Clinical remission was defined as Ankylosing Spondylitis Disease Activity Score inactive disease (ASDAS ID; score <1.3) and Assessment of SpondyloArthritis international Society partial remission (ASAS PR; score <2/10 in each of the four ASAS domains). Stepwise logistic regression was used to identify baseline predictors of remission at week 12 and at final visit (last postbaseline visit up to week 28). Only patients without missing data were included. Results: Overall, 593 patients were included in the ASDAS ID and 596 in the ASAS PR analysis at week 12. Younger age (≤45 years), male sex, positive human leucocyte antigen (HLA)-B27 and higher Spondyloarthritis Research Consortium of Canada (SPARCC) MRI sacroiliac joint score were consistent predictors of remission by both ASAS ID and ASDAS PR at week 12. Results were generally similar in the final visit analysis. Other variables did not consistently predict remission. Conclusions: In ABILITY-3, consistent and strong baseline predictors of remission included younger age, male sex, HLA-B27 positivity and higher SPARCC MRI sacroiliac joint score among patients with active nr-axSpA receiving adalimumab therapy, similar to previous findings in ankylosing spondylitis.

Depression and Progression of Subclinical Cardiovascular Disease in Systemic Lupus Erythematosus.

OBJECTIVE: Women with systemic lupus erythematosus (SLE) have an increased incidence of premature cardiovascular disease (CVD). A relationship between depression and increased inflammation leading to CVD has been proposed. The aim of this study was to evaluate the relationship between depression and the progression of subclinical atherosclerosis in women with SLE. METHODS: In this prospective case-control study, 149 participants with SLE and 126 controls were followed over 5 years. Evaluation included laboratory studies, assessment of CVD risk factors, depression screening, ultrasound evaluations of carotid intima-media thickness (CIMT) and carotid plaque, and assessment of SLE disease activity for the SLE cases. RESULTS: The SLE group had a higher rate of depression: 29% compared with 11% in the control group (P = 0.003). When controlling for traditional CVD risk factors, the presence of baseline depression correlated with increased progression of CIMT in the SLE group, but not in the control group. The mean increase in CIMT was 0.026 mm in the SLE group without depression versus 0.064 mm in the depressed SLE group (P = 0.0096). There was no association between depression and carotid plaque in either group, with a calculated odds ratio for plaque progression in the depressed SLE group of 1.118 (95% confidence interval 0.476, 2.623) in the adjusted model. CONCLUSION: Women with SLE and concomitant depression have an increased risk of developing subclinical atherosclerosis, as measured by CIMT, but not by carotid plaque. The data suggest that depression, a potentially modifiable risk factor, may contribute to the increased risk of subclinical atherosclerosis in women with SLE.

Risk factors in the progression of subclinical atherosclerosis in women with systemic lupus erythematosus.

OBJECTIVE: To investigate risk factors in subclinical atherosclerosis progression as measured by coronary artery calcium (CAC) and aorta calcium (AC) in women with systemic lupus erythematosus (SLE; cases) and in comparison with a control population. METHODS: A cohort of 149 cases and 124 controls participated in the Study of Lupus Vascular and Bone Long-Term Endpoints. Demographic information, cardiovascular and SLE risk factors, and laboratory assessments were collected at an initial visit. CAC and AC were measured by electron beam computed tomography (CT) or multidetector CT at an initial visit and at a followup visit. Logistic regression models were used to identify predictors of progression in CAC and AC; multivariate models were adjusted for age, hypertension, and total cholesterol to high-density lipoprotein ratio. RESULTS: Higher modified Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score (odds ratio [OR] 2.15, 95% confidence interval [95% CI] 1.33-3.57), use of a corticosteroid (OR 2.93, 95% CI 1.14-7.86), and use of aspirin (OR 4.23, 95% CI 1.53-11.74) were associated with CAC progression in multivariate models. Presence of SLE (OR 2.64, 95% CI 1.26-5.72), lower C3 (OR 0.54, 95% CI 0.33-0.87), lower C4 (OR 0.49, 95% CI 0.27-0.86), use of a corticosteroid (OR 2.73, 95% CI 1.03-7.64), higher corticosteroid dose (OR 1.77, 95% CI 1.12-3.00), higher lipoprotein(a) (OR 1.80, 95% CI 1.11-2.98), and higher homocysteine (OR 2.06, 95% CI 1.06-4.29) were associated with AC progression in multivariate models. CONCLUSION: Higher disease damage at the first study visit, as measured by the modified SDI, may predict increased risk in CAC progression, whereas higher disease activity at the first study visit, as measured by hypocomplementemia and use of corticosteroids, may predict increased risk in AC progression.

Relation of platelet C4d with all-cause mortality and ischemic stroke in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with significant morbidity, including premature cardiovascular disease, and mortality. Platelets bearing complement protein C4d (P-C4d) were initially determined to be specific for diagnosis of SLE and were later found to be associated with acute ischemic stroke in non-SLE patients. P-C4d may identify a subset of SLE patients with a worse clinical prognosis. This study investigated the associations of P-C4d with all-cause mortality and vascular events in a lupus cohort. A cohort of 356 consecutive patients with SLE was followed from 2001 to 2009. Primary outcome was all-cause mortality. Secondary outcomes were vascular events (myocardial infarction, coronary artery bypass graft, percutaneous coronary transluminal angioplasty, ischemic stroke, venous thromboembolism, pulmonary embolism, or other thrombosis). P-C4d was measured at study baseline. Seventy SLE patients (19.7%) had P-C4d. Mean follow-up was 4.7 years. All-cause mortality was 4%. P-C4d was associated with all-cause mortality (hazard ratio 7.52, 95% confidence interval (CI) 2.14-26.45, p = 0.002) after adjusting for age, ethnicity, sex, cancer, and anticoagulant use. Vascular event rate was 21.6%. Patients with positive P-C4d were more likely to have had vascular events compared to those with negative P-C4d (35.7 vs. 18.2%, p = 0.001). Specifically, P-C4d was associated with ischemic stroke (odds ratio 4.54, 95% CI 1.63-12.69, p = 0.004) after adjusting for age, ethnicity, and antiphospholipid antibodies. Platelet-C4d is associated with all-cause mortality and stroke in SLE patients. P-C4d may be a prognostic biomarker as well as a pathogenic clue that links platelets, complement activation, and thrombosis.

25-hydroxyvitamin D and cardiovascular disease in patients with systemic lupus erythematosus: data from a large international inception cohort.

OBJECTIVE: An association between 25-hydroxyvitamin D (25[OH]D; vitamin D) deficiency and increased cardiovascular (CV) risk factors and CV disease (CVD) has been shown in general population studies. Vitamin D deficiency has been noted in systemic lupus erythematosus (SLE), and CVD is a major cause of morbidity and mortality in SLE. The objectives of this study were to estimate the associations of 25(OH)D levels with CV risk factors and to determine whether low baseline 25(OH)D levels predict future CV events in patients participating in an international inception cohort. METHODS: Data were collected on 890 participants, including demographics, SLE activity and damage assessments, CV risk factors and events, medications, laboratory assessments of 25(OH)D levels, and inflammatory markers. Multiple logistic and Cox regressions were used to estimate the associations of baseline 25(OH)D levels with baseline CV risk factors and CVD events. The models were adjusted for age, sex, race, season, and country, with and without body mass index. RESULTS: Patients in the higher quartiles of 25(OH)D were less likely to have hypertension and hyperlipidemia and were more likely to have lower C-reactive protein levels and lower Systemic Lupus Erythematosus Disease Activity Index 2000 scores at baseline when compared with the first quartile. Vitamin D levels were not independently associated with CVD event incidence; however, hazard ratios for CVD event incidence decreased with successively higher quartiles. CONCLUSION: Lower baseline 25(OH)D levels are associated with higher risk for CV risk factors and more active SLE at baseline. There may be a trend toward a lower likelihood of CVD events in those with higher baseline 25(OH)D levels.

Relation of carotid intima-media thickness and plaque with incident cardiovascular events in women with systemic lupus erythematosus.

Patients with systemic lupus erythematosus (SLE) are at increased risk for cardiovascular (CV) disease. The aim of this study was to investigate the association between subclinical CV disease as measured by carotid intima-media thickness (IMT) and plaque using B-mode carotid ultrasound and incident CV events in a combined cohort of female patients with SLE. This was a prospective, 2-center observational study of 392 adult women with SLE and no previous CV events with a mean 8 years of follow-up. Incident CV events confirmed by clinicians were defined as angina, myocardial infarction, percutaneous transluminal coronary angioplasty, coronary artery bypass graft, fatal cardiac arrest, transient ischemic attack, and cerebrovascular accident. Incident hard CV events excluded angina and transient ischemic attack. The mean age was 43.5 years, and most patients were Caucasian (77.3%). During follow-up, 38 patients had incident CV events, and 17 had incident hard CV events. Patients with incident hard CV events had higher mean carotid IMT (0.80 vs 0.64 mm, p <0.01) and presence of carotid plaque (76.5% vs 30.4%, p <0.01) compared with those without incident hard CV events. Baseline carotid IMT and presence of plaque were predictive of any incident hard CV event (hazard ratio 1.35, 95% confidence interval 1.12 to 1.64, and hazard ratio 4.26, 95% confidence interval 1.23 to 14.83, respectively), independent of traditional CV risk factors and medication use. In conclusion, in women with SLE without previous CV events, carotid IMT and plaque are predictive of future CV events. This suggests that carotid ultrasound may provide an additional tool for CV risk stratification in patients with SLE.