Major adverse cardiovascular events and mortality with opioids versus NSAIDs initiation in patients with rheumatoid arthritis.

OBJECTIVE: Assess major adverse cardiovascular event (MACE) risk with opioids compared with non-steroidal anti-inflammatory drugs (NSAIDs) in patients with rheumatoid arthritis (RA) METHODS: We conducted a new-user active comparator cohort study among patients with RA within FORWARD, The National Databank for Rheumatic Diseases, with ≥1 year participation between 1998 and 2021. Each opioid initiator was matched to two NSAID initiators by propensity scores (PSs). Patients were followed until the occurrence of the composite endpoint of MACE (myocardial infarction, stroke, heart failure, cardiovascular disease (CVD) death, venous thromboembolism (VTE)) and all-cause mortality. The risk of outcomes was estimated using Cox proportional hazards with adjustment for PS weights and imbalanced covariables. RESULTS: Among 6866 opioid initiators and 13 689 NSAID initiators, 212 vs 253 MACE (20.6/1000 person-years (PY) vs 18.9/1000 PY) and 144 vs 150 deaths (13.5/1000 PY vs 10.8/1000 PY) occurred, respectively. The risk of MACE with opioids was similar to NSAIDs (HR=1.02, 95% CI 0.85 to 1.22), whereas all-cause mortality with opioids was 33% higher than NSAIDs (HR=1.33, 95% CI 1.06 to 1.67) in PS-weighted models. Among the individual outcomes of MACE, VTE risk tended to be higher in opioid initiators than NSAID initiators (HR=1.41, 95% CI 0.84 to 2.35). Strong opioids had a higher risk for all-cause mortality and VTE than weak opioids compared with NSAIDs suggesting a dose-dependent association. CONCLUSION: Opioids had similar MACE risk compared with NSAIDs in patients with RA with increased all-cause mortality and likely VTE, which suggests that opioids are not safer than NSAIDs, as clinicians have perceived.

Medications associated with fracture risk in patients with rheumatoid arthritis.

OBJECTIVE: To examine the fracture risk with use of disease-modifying antirheumatic drugs (DMARDs), statins, proton pump inhibitors (PPIs), opioids, non-opioid analgesics and psychotropic medications in a US-wide observational rheumatoid arthritis (RA) cohort. METHODS: Patients with RA without prior fracture from 2001 through 2017 in FORWARD, a longitudinal observational registry, were assessed for osteoporosis-related site fractures (vertebra, hip, forearm and humerus). DMARD exposure was assessed in four mutually exclusive groups: (1) methotrexate monotherapy-reference, (2) tumour necrosis factor-α inhibitors (TNFi), (3) non-TNFi biologics and (4) others. Non-DMARDs and glucocorticoids were classified as current/ever use and based on treatment duration. Fracture Risk Assessment Tool (FRAX) scores estimating for 10-year major osteoporotic fractures were calculated. Cox proportional hazard models stratified by FRAX were used to adjust for confounders. RESULTS: During median (IQR) 3.0 (1.5-6.0) years of follow-up in 11 412 patients, 914 fractures were observed. The adjusted models showed a significant fracture risk increase with use of any dose glucocorticoids ≥3 months (HR (95% CI) for <7.5 mg/day 1.26 (1.07 to 1.48) and for ≥7.5 mg/day 1.57 (1.27 to 1.94)), opioids (for weak: 1.37 (1.18 to 1.59); strong: 1.53 (1.24 to 1.88)) and selective serotonin reuptake inhibitors (SSRIs) (1.37 (1.15 to 1.63)). Fracture risk with opioids increased within 1 month of use (1.66 (1.36 to 2.04)) and with SSRIs >3 months of use (1.25 (1.01 to 1.55)). Statins (0.77 (0.62 to 0.96)) and TNFi (0.72 (0.54 to 0.97)) were associated with reduction in vertebral fracture risk only. PPIs and other psychotropic medications were not associated with increased fracture risk. CONCLUSION: Use of opioids, SSRIs and glucocorticoids were associated with increased risk of any fracture in patients with RA, whereas statins and TNFi were associated with decreased vertebral fractures.

Risk of diabetes mellitus associated with disease-modifying antirheumatic drugs and statins in rheumatoid arthritis.

OBJECTIVE: To investigate the rate of incident diabetes mellitus (DM) in patients with rheumatoid arthritis (RA) and the impact of disease-modifying antirheumatic drug (DMARD) and statin treatments. METHODS: We studied patients with RA and ≥1 year participation in the National Data Bank for Rheumatic Diseases without baseline DM from 2000 through 2014. DM was determined by self-report or initiating DM medication. DMARDs were categorised into four mutually exclusive groups: (1) methotrexate monotherapy (reference); (2) any abatacept with or without synthetic DMARDs (3) any other DMARDs with methotrexate; (4) all other DMARDs without methotrexate; along with separate statin, glucocorticoid and hydroxychloroquine (yes/no) variables. Time-varying Cox proportional hazard models were used to adjust for age, sex, socioeconomic status, comorbidities, body mass index and RA severity measures. RESULTS: During a median (IQR) 4.6 (2.5-8.8) years of follow-up in 13 669 patients with RA, 1139 incident DM cases were observed. The standardised incidence ratio (95% CI) of DM in patients with RA (1.37, (1.29 to 1.45)) was increased compared with US adult population. Adjusted HR (95% CI) for DM were 0.67 (0.57 to 0.80) for hydroxychloroquine, 0.52 (0.31 to 0.89) for abatacept (compared with methotrexate monotherapy), 1.31 (1.15 to 1.49) for glucocorticoids and 1.56 (1.36 to 1.78) for statins. Other synthetic/biological DMARDs were not associated with any risk change. Concomitant use of glucocorticoids did not alter DM risk reduction with hydroxychloroquine (HR 0.69 (0.51 to 0.93)). CONCLUSIONS: In RA, incidence of DM is increased. Hydroxychloroquine and abatacept were associated with decreased risk of DM, and glucocorticoids and statins with increased risk.

Th17-Inducing Conditions Lead to in vitro Activation of Both Th17 and Th1 Responses in Behcet's Disease.

OBJECTIVES: Interleukin-17 (IL-17) has been associated with the pathogenesis of various autoimmune/inflammatory diseases. The aim of this study was to investigate the expression of Th17-related immunity in an innate immunity-dominated vasculitis, namely Behcet's disease (BD). METHODS: Peripheral blood mononuclear cells from 37 patients (age: 38.5 ± 9.8 years) with BD, and 25 healthy controls (HC) (age: 39.1 ± 9.3 years), were cultured in Th17-inducing conditions (IL-6, Phytohemagglutinin (PHA), IL-1ß, and IL-23) for 6 days. Cultured cells were stained with CD4, CD8, CD3, TCR gamma/delta, CD19, interferon-γ (IFN-γ), and IL-17 antibodies to determine the intracellular cytokine secretion by flow cytometry. RESULTS: IL-17 expression by CD8+ and γδ+ T cells was higher in BD compared to HC (p = 0.004, p = 0.003, respectively). No differences were observed between the groups in the IL-17 production by B cells. Under Th17-inducing conditions, production of IFN-γ by CD4+, CD8+, and γδ+ T cells was also higher in BD compared to HC (p < 0.05 in all). CONCLUSION: Our results suggest that under Th17-stimulating conditions, T cells express both IL-17 and IFN-γ in BD. More prominent IL-17 and IFN-γ production by all lymphocyte subsets in BD might be associated with the increased innate responses, early tissue neutrophil infiltrations and late adaptive immunity in BD.

Increased stiffness of median nerve in systemic sclerosis.

BACKGROUND: Systemic sclerosis can affect peripheral nerves, but the extent and the nature of this involvement are not well defined. The aim of this study is to compare the sonoelastrographic measurements of median nerves in systemic sclerosis (SSC), idiopathic carpal tunnel syndrome (CTS) and healthy individuals. METHODS: The clinical, electrophysiological and ultrasonographic assessments were done. Patients with SSC and CTS were assessed with nerve conduction studies. The measurements of cross sectional areas (CSA) were performed at psiform and forearm level from axial US images. The elastic ratio is the ratio of strain distribution in two selected region of interests (ROI) done via comparing the median nerve to flexor digitorum superfcialis tendon. The ROIs were fixed to 2 mm. RESULTS: The study was completed with 47 hands of 24 patients with SSC, 53 hands of 27 patients with CTS and 38 hands of health controls. The CSA of CTS group was significantly higher than systemic sclerosis and control groups. The elastic ratio at psiform level and forearm levels of systemic sclerosis group were significantly higher than the CTS and control groups. CONCLUSION: Median nerves lose the elasticity while the CSA's are in the normal range in patients with SSC. These results suggested that the increased peripheral nerve involvement in SSC is about the increased stiffness of the nerves.

The 2013 ACC/AHA 10-year atherosclerotic cardiovascular disease risk index is better than SCORE and QRisk II in rheumatoid arthritis: is it enough?

OBJECTIVE: To determine the ability of the new American College of Cardiology and American Heart Association (ACC/AHA) 10-year atherosclerotic cardiovascular disease (ASCVD) risk algorithm in detecting high cardiovascular (CV) risk, RA patients identified by carotid ultrasonography (US) were compared with Systematic Coronary Risk Evaluation (SCORE) and QRisk II algorithms. METHODS: SCORE, QRisk II, 2013 ACC/AHA 10-year ASCVD risk and EULAR recommended modified versions were calculated in 216 RA patients. In sonographic evaluation, carotid intima-media thickness >0.90 mm and/or carotid plaques were used as the gold standard test for subclinical atherosclerosis and high CV risk (US+). RESULTS: Eleven (5.1%), 15 (6.9%) and 44 (20.4%) patients were defined as having high CV risk according to SCORE, QRisk II and ACC/AHA 10-year ASCVD risk, respectively. Fifty-two (24.1%) patients were US + and of those, 8 (15.4%), 7 (13.5%) and 23 (44.2%) patients were classified as high CV risk according to SCORE, QRisk II and ACC/AHA 10-year ASCVD risk, respectively. The ACC/AHA 10-year ASCVD risk index better identified US + patients than SCORE and QRisk II (P < 0.0001). With EULAR modification, reclassification from moderate to high risk occurred only in two, five and seven patients according to SCORE, QRisk II and ACC/AHA 10-year ASCVD risk, respectively. CONCLUSION: The 2013 ACC/AHA 10-year ASCVD risk estimator was better than the SCORE and QRisk II indices in RA, but still failed to identify 55% of high risk patients. Furthermore adjustment of threshold and EULAR modification did not work well.

An unusual case with vasculo-Behçet's disease: peripheral arterial aneurysm in an elderly woman.

Behçet's disease (BD) is a chronic, multi-systemic disorder that can affect all sizes of arteries and veins. Vascular involvement of BD is generally observed in young men and is an important cause of morbidity and mortality. Arterial lesions can appear as aneurysms, stenosis and occlusions in BD. We, here, present the case of a woman who developed a peripheral arterial aneurysm in her sixth decade, 20 years after disease onset. BD patients with aneurysms should be consulted at any age for pre- and post-operative assessment for immunosuppressive treatment to reduce recurrences, complications and disease activation.

Regional myocardial dysfunction assessed by two-dimensional speckle tracking echocardiography in systemic sclerosis patients with fragmented QRS complexes.

BACKGROUND: The aim of the study was to explore the relation between regional myocardial dysfunction and fragmented QRS (fQRS) complexes in systemic sclerosis (SSc). METHODS: Fifty-three SSc patients and 26 controls were included. All subjects underwent speckle tracking echocardiography for evaluation of left ventricular (LV) function and ECG to check for fQRS complexes. RESULTS: SSc patients had significantly lower LV global longitudinal, radial and circumferential strain and twist compared to controls. Thirteen SSc patients had fQRS (DII, DIII, aVF leads in eleven patients and V1 to V5 leads in two patients) and they had significantly lower global longitudinal and circumferencial strain compared to SSc patients with normal QRS. The SSc patients with fQRS in DII, DIII, and aVF leads had impaired longitudinal strain and delay in time to peak longitudinal strain in inferior LV segments compared to those with normal QRS. CONCLUSION: fQRS is associated with lower strain measures in SSc patients indicating impairment in LV function.

Reduction of Cardiovascular Disease and Mortality Versus Risk of New-Onset Diabetes Mellitus With Statin Use in Patients With Rheumatoid Arthritis.

OBJECTIVE: To assess the effect of statin use on the risk of cardiovascular disease (CVD), all-cause mortality, and type 2 diabetes mellitus (DM) in patients with rheumatoid arthritis (RA). METHODS: We identified a cohort of patients with RA between 1989 and 2018, within the UK Clinical Practice Research Datalink. We employed a prevalent new-user cohort design by which patients initiating statins were each matched to 2 concurrent nonusers by the time-conditional propensity score (TCPS). Patients were followed until the occurrence of the composite end point of myocardial infarction, stroke, hospitalized heart failure or CVD mortality, all-cause mortality, and incident type 2 DM. The Cox proportional hazards model was used to estimate the hazard ratio (HR) of each outcome associated with as-treated statin use, with adjustment for TCPS deciles and imbalanced covariables. RESULTS: Among 1,768 statin initiators and 3,528 nonusers, 63 versus 340 CVD (3.0 per 100 person-years versus 2.7 per 100 person-years) and 62 versus 525 deaths (2.8 per 100 person-years versus 4.1 per 100 person-years) occurred. Incident type 2 DM was noted in 128 of 3,608 statin initiators (3.0 per 100 person-years) and 518 of 7,208 nonusers (2.0 per 100 person-years). Statin initiation was associated with 32% (HR 0.68 [95% confidence interval (95% CI) 0.51-0.90]) reduction in CVD, 54% (HR 0.46 [95% CI 0.35-0.60]) reduction in all-cause mortality, and 33% increase in type 2 DM (HR 1.33 [95% CI 1.09-1.63]). The number needed to treat/number needed to harm to prevent a CVD or all-cause mortality or to cause type 2 DM in 1 year was 102, 42, and 127, respectively. CONCLUSION: Statins are associated with important reductions in CVD and mortality that outweigh the modest increase in type 2 DM risk in RA patients.

Physical Activity Habits Among Older Adults Living With Rheumatic Disease.

OBJECTIVE: To describe levels of physical activity (PA) in older adults with rheumatic and musculoskeletal diseases (RMDs) and study the association between PA level and patient-reported outcomes. METHODS: Using data from FORWARD, a cross-sectional analysis was performed among adults aged 65 years and older with RMDs to assess the levels of PA. PA was categorized as high (vigorously active for at least 30 minutes, 3 times per week), moderate (moderately active for at least 3 times per week) or low (seldom active). We assessed the self-reported levels of PA among patients with different types of RMDs and assessed the association between levels of PA and PROs, including the 29-item Patient Reported Outcomes Measurement Information System (PROMIS-29) assessment. RESULTS: Among the 3343 eligible participants, rheumatoid arthritis (68%) was the most common RMD. High PA was reported by 457 (13.6%) participants, and 1820 (54.4%) reported moderate activity. Overall, participants reported a median of 7 (IQR 0-15) days of moderate to vigorous level of PA for ≥ 30 min per month. Obese participants were significantly more likely to report low levels of activity (44% of obese compared to 25% of nonobese individuals). Participants with low PA levels had higher (worse) pain scores, higher (worse) Health Assessment Questionnaire-Disability Index scores, higher depression rates, and worse PROMIS-29 scores related to pain, sleep and fatigue. CONCLUSION: Among patients with RMDs, levels of high PA were relatively low among older patients. These observations, though descriptive, support a relationship between physical inactivity and obesity, depression, poor sleep, and fatigue in patients with RMDs.

Vitamin D levels in patients with small and medium vessel vasculitis.

OBJECTIVES: To determine the prevalence of vitamin D deficiency in patients with small and medium vessel systemic vasculitis. METHODS: In this cross-sectional study, 25-hydroxy (OH) vitamin D3 levels were measured in adult patients with systemic small and medium vessel vasculitis including antineutrophil cytoplasmic antibody-associated vasculitis (AAV), cryoglobulinaemic vasculitis (CryV), IgA vasculitis (IgAV) and polyarteritis nodosa (PAN), and age- and sex-matched healthy subjects (HS) and patients with rheumatoid arthritis (RA) as control groups. 25OH vitamin D3 levels<30ng/ml and <20ng/ml were regarded as insufficiency and deficiency, respectively. RESULTS: Fifty-seven patients (42 AAV, 2 CryV, 8 IgA vasculitis, 5 PAN) with systemic vasculitis, 101 HS, and 111 RA patients were included. The mean 25OH vitamin D3 level was 21.8±14.2ng/mL in patients with vasculitis, 42.7±27.6ng/mL in HS (p<.001) and 20.1±18.47ng/mL in patients with RA (p=.54). Vitamin D insufficiency and deficiency were significantly higher in patients with systemic vasculitis compared to HS (75.4% vs 33.7%, p<.001; %50 vs 21.8%, p<.001, respectively). Vitamin D status was not different in patients with systemic vasculitis compared to RA. There was a negative correlation between vitamin D status and CRP levels (=-.364, p=.007). The multivariate logistic regression analysis showed that renal involvement was significantly associated with vitamin D deficiency/insufficiency in patients with vasculitis (OR 22.5 [95% CI 1.6-128.9]. CONCLUSION: Vitamin D deficiency and insufficiency are more frequent in patients with systemic small and medium vessel vasculitis and RA than HS. Renal involvement is one of the factors associated with vitamin D deficiency/insufficiency in patients with vasculitis.

The Risk of Cardiovascular Events Associated With Disease-modifying Antirheumatic Drugs in Rheumatoid Arthritis.

OBJECTIVE: To examine the comparative effects of biologic disease-modifying antirheumatic drugs (bDMARD) and tofacitinib against conventional synthetic DMARD (csDMARD) on incident cardiovascular disease (CVD) in patients with rheumatoid arthritis (RA). METHODS: RA patients with ≥ 1 year of participation in the FORWARD study, from 1998 through 2017, were assessed for incident composite CVD events (myocardial infarction, stroke, heart failure, and CVD-related death validated from hospital/death records). DMARD were categorized into 7 mutually exclusive groups: (1) csDMARD-referent; (2) tumor necrosis factor-α inhibitor (TNFi); (3) abatacept (ABA); (4) rituximab; (5) tocilizumab; (6) anakinra; and (7) tofacitinib. Glucocorticoids (GC) were assessed using a weighted cumulative exposure model, which combines information about duration, intensity, and timing of exposure into a summary measure by using the weighted sum of past oral doses (prednisolone equivalent). Cox proportional hazard models were used to adjust for confounders. RESULTS: During median (IQR) 4.0 (1.7-8.0) years of follow-up, 1801 CVD events were identified in 18,754 RA patients. The adjusted model showed CVD risk reduction with TNFi (HR 0.81, 95% CI 0.71-0.93) and ABA (HR 0.50, 95% CI 0.30-0.83) compared to csDMARD. While higher GC exposure as weighted cumulative exposure was associated with increased CVD risk (HR 1.15, 95% CI 1.11-1.19), methotrexate (MTX) use was associated with CVD risk reduction [use vs nonuse HR 0.82, 95% CI 0.74-0.90, and high dose (> 15 mg/week) vs low dose (≤ 15 mg/week) HR 0.83, 95% CI 0.70-0.99]. CONCLUSION: ABA and TNFi were associated with decreased risk of CVD compared to csDMARD. Minimizing GC use and optimizing MTX dose may improve cardiovascular outcomes in patients with RA.

Risk factors for venous thromboembolism and atherosclerotic cardiovascular disease: do they differ in patients with rheumatoid arthritis?

OBJECTIVE: Venous thromboembolism (VTE) is an increasing concern in rheumatoid arthritis (RA) with little known about risk factors. We aimed to compare risk factors for unprovoked VTE and atherosclerotic cardiovascular disease (ASCVD) in patients with RA and to assess subsequent ASCVD risk after an unprovoked VTE. METHODS: People with RA participating in a US-wide longitudinal observational registry from 1998 to 2018 were assessed for incident unprovoked VTE (deep venous thrombosis and pulmonary emboli not associated with cancer, recent surgery, hospitalisation, fracture and pregnancy) and ASCVD (myocardial infarction and stroke) validated from hospital/death records. Risk factors for VTE and ASCVD and the risk of ASCVD after an unprovoked VTE were determined using Cox proportional hazards models. RESULTS: During median (IQR) 4 (1.5-7) years of follow-up in 31 366 patients with RA, 539 unprovoked VTE and 1648 ASCVD events were identified. The adjusted models showed increased VTE and ASCVD risk with older age, male sex, comorbidities, prior fracture, worse disability, higher disease activity and glucocorticoids. Traditional cardiovascular disease risk factors were common in both ASCVD and VTE but only increased ASCVD risk with obesity as the exception (VTE HR (95% CI), 1.46 (1.13-1.87)) and ASCVD, 0.58 (0.50-0.68)). ASCVD risk doubled after an unprovoked VTE (HR (95% CI), 2.05 (1.43-2.95)). CONCLUSION: Our findings suggest that unprovoked VTE is mediated by inflammation of RA and may be considered a spectrum of pan-cardiovascular syndrome.

Vitamin D Levels in Patients With Small and Medium Vessel Vasculitis.

OBJECTIVES: To determine the prevalence of vitamin D deficiency in patients with small and medium vessel systemic vasculitis. METHODS: In this cross-sectional study, 25-hydroxy (OH) vitamin D3 levels were measured in adult patients with systemic small and medium vessel vasculitis including antineutrophil cytoplasmic antibody-associated vasculitis (AAV), cryoglobulinaemic vasculitis (CryV), IgA vasculitis (IgAV) and polyarteritis nodosa (PAN), and age- and sex-matched healthy subjects (HS) and patients with rheumatoid arthritis (RA) as control groups. 25OH vitamin D3 levels<30ng/ml and <20ng/ml were regarded as insufficiency and deficiency, respectively. RESULTS: Fifty-seven patients (42 AAV, 2 CryV, 8 IgA vasculitis, 5 PAN) with systemic vasculitis, 101 HS, and 111 RA patients were included. The mean 25OH vitamin D3 level was 21.8±14.2ng/mL in patients with vasculitis, 42.7±27.6ng/mL in HS (p<.001) and 20.1±18.47ng/mL in patients with RA (p=.54). Vitamin D insufficiency and deficiency were significantly higher in patients with systemic vasculitis compared to HS (75.4% vs 33.7%, p<.001; %50 vs 21.8%, p<.001, respectively). Vitamin D status was not different in patients with systemic vasculitis compared to RA. There was a negative correlation between vitamin D status and CRP levels (=-.364, p=.007). The multivariate logistic regression analysis showed that renal involvement was significantly associated with vitamin D deficiency/insufficiency in patients with vasculitis (OR 22.5 [95% CI 1.6-128.9]. CONCLUSION: Vitamin D deficiency and insufficiency are more frequent in patients with systemic small and medium vessel vasculitis and RA than HS. Renal involvement is one of the factors associated with vitamin D deficiency/insufficiency in patients with vasculitis.

Ocular Posterior Segment Involvement in Patients with Antiphospholipid Syndrome and Systemic Lupus Erythematosus.

Purpose: To describe posterior segment findings of antiphospholipid syndrome (APS) and compare them with systemic lupus erythematosus (SLE).Methods: A total of 11 patients with primary APS, 29 secondary APS patients, and 29 SLE patients without APS were included. All patients were referred from rheumatology clinic for detailed ophthalmologic examination. When patients had suspicious lesions, fundus fluorescein angiography was performed (n = 56).Results: The most common retinal examination finding was peripheral venous tortuosity (17.5%) in APS, which was not observed in SLE group. Common FFA findings were pigment epithelial window defects (10%) and vascular filling delays (7.5%) in APS, which were observed in 27.5% and 3.5% of patients with SLE consecutively.Conclusion: Venous tortuosity was significantly more in patients with APS. There was no significant difference for other ocular findings between the groups. Ocular complication rate was lower compared to earlier reports, probably due to better management of disease activity with current treatment protocols.