Comparing DAPSA, DAPSA28, and DAS28-CRP in Patients With Psoriatic Arthritis Initiating a First Tumor Necrosis Factor Inhibitor Across Nine European Countries.

OBJECTIVE: Because 66/68 joint counts are not always performed in routine care, we aimed to determine which of the modified 28-joint disease activity index for psoriatic arthritis (DAPSA28) or 28-joint disease activity score with C-reactive protein (DAS28-CRP) should be preferred for monitoring disease activity in psoriatic arthritis (PsA) when the original DAPSA (66/68 joints) is not available. METHODS: Prospectively collected real-world data of European bionaive patients with PsA initiating a first tumor necrosis factor inhibitor were pooled. Remission and response status were evaluated at 6 months by remission (DAPSA ≤ 4, DAPSA28 ≤ 4, and DAS28-CRP < 2.6), response (75% improvement for DAPSA and DAPSA28), and combined EULAR good/moderate responses for DAS28-CRP. Logistic regression analyses on multiple imputed data were used to identify baseline predictors. RESULTS: Remission and response cohorts included 3,159 and 1,866 patients, respectively. The 6-month proportions achieving remission/response were DAPSA (27%/44%), DAPSA28 (28%/44%), and DAS28-CRP (59%/80%). Of 14 possible baseline predictors, 11 predicted both DAPSA and DAPSA28 remission (8 of which also predicted their response, indicated by "*"): longer disease duration*, male sex*, and higher CRP* were positive, whereas older age*, higher body mass index*, patient fatigue*, and global, physician global, health assessment questionnaire score*, and tender and swollen* joint counts were negative predictors. Eight and five of these predicted DAS28-CRP remission and response, respectively. CONCLUSION: In patients with PsA, DAPSA28 should be preferred over DAS28-CRP as a substitute for DAPSA when 66/68 joint counts are not available because of the large overlap in remission and response status and in predictors between DAPSA and DAPSA28.

Haemodynamic implications of VA-ECMO vs. VA-ECMO plus Impella CP for cardiogenic shock in a large animal model.

AIMS: Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) with profound left ventricular (LV) failure is associated with inadequate LV emptying. To unload the LV, VA-ECMO can be combined with Impella CP (ECMELLA). We hypothesized that ECMELLA improves cardiac energetics compared with VA-ECMO in a porcine model of cardiogenic shock (CS). METHODS AND RESULTS: Land-race pigs (weight 70 kg) were instrumented, including a LV conductance catheter and a carotid artery Doppler flow probe. CS was induced with embolization in the left main coronary artery. CS was defined as reduction of ≥50% in cardiac output or mixed oxygen saturation (SvO2) or a SvO2 < 30%. At CS VA-ECMO was initiated and embolization was continued until arterial pulse pressure was <10 mmHg. At this point, Impella CP was placed in the ECMELLA arm. Support was maintained for 4 h. CS was induced in 15 pigs (VA-ECMO n = 7, ECMELLA n = 8). At time of CS MAP was <45 mmHg in both groups, with no difference at 4 h (VA-ECMO 64 mmHg ± 11 vs. ECMELLA 55 mmHg ± 21, P = 0.08). Carotid blood flow and arterial lactate increased from CS and was similar in VA-ECMO and ECMELLA [239 mL/min ± 97 vs. 213 mL/min ± 133 (P = 0.6) and 5.2 ± 3.3 vs. 4.2 ± 2.9 mmol/ (P = 0.5)]. Pressure-volume area (PVA) was significantly higher with VA-ECMO compared with ECMELLA (9567 ± 1733 vs. 6921 ± 5036 mmHg × mL/min × 10-3, P = 0.014). Total diureses was found to be lower in VA-ECMO compared with ECMELLA [248 mL (179-930) vs. 506 mL (418-2190); P = 0.005]. CONCLUSIONS: In a porcine model of CS, we found lower PVA, with the ECMELLA configuration compared with VA-ECMO, indicating better cardiac energetics without compromising systemic perfusion.

Drug effectiveness of 2nd and 3rd TNF inhibitors in psoriatic arthritis - relationship with the reason for withdrawal from the previous treatment.

OBJECTIVE: To investigate real-world retention and remission rates in PsA patients initiating a 2nd or 3rd TNFi and the association with reason for discontinuation from the previous TNFi-treatment. METHODS: Prospectively collected routine care data from 12 European registries were pooled. Retention rates (Kaplan-Meier estimation) and crude/LUNDEX-adjusted rates of Disease Activity Score 28 and Disease Activity index for PSoriatic Arthritis (DAS28 and DAPSA28) remission were calculated and compared with adjusted Cox regression analyses and Chi-squared test, respectively). RESULTS: We included 5233 (2nd TNFi) and 1906 (3rd TNFi) patients. Twelve-month retention rates for the 2nd and 3rd TNFi were 68% (95%CI: 67-70%) and 66% (64-68%), respectively. Patients who stopped the previous TNFi due to AE/LOE had 12-month retention rates of 66%/65% (2nd TNFi), and 65%/63% (3rd TNFi), respectively. Patients who stopped the previous TNFi due to LOE after less vs more than 24 weeks had 12-month retention rates of 54%/69% (2nd TNFi), and 58%/65% (3rd TNFi). Six-month crude/LUNDEX-adjusted DAS28 remission rates were 48%/35% and 38%/27%, and DAPSA28 remission rates were 19%/14% and 14%/10%, for the 2nd and 3rd TNFi. CONCLUSION: Two-thirds of patients remained on TNFi at 12months for both the 2nd and 3rd TNFi, while one-third and one-quarter of patients were in DAS28 remission after 6months on the 2nd and 3rd TNFi. While drug effectiveness was similar in patients who stopped the previous TNFi due to AE compared to overall LOE, drug effectiveness was better in patients who had stopped the previous TNF due to secondary LOE compared to primary LOE.

Immediate inflammatory response to mechanical circulatory support in a porcine model of severe cardiogenic shock.

BACKGROUND: In selected cases of cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (V-A ECMO) is combined with trans valvular micro axial flow pumps (ECMELLA). Observational studies indicate that ECMELLA may reduce mortality but exposing the patient to two advanced mechanical support devices may affect the early inflammatory response. We aimed to explore inflammatory biomarkers in a porcine cardiogenic shock model managed with V-A ECMO or ECMELLA. METHODS: Fourteen landrace pigs had acute myocardial infarction-induced cardiogenic shock with minimal arterial pulsatility by microsphere embolization and were afterwards managed 1:1 with either V-A ECMO or ECMELLA for 4 h. Serial blood samples were drawn hourly and analyzed for serum concentrations of interleukin 6 (IL-6), IL-8, tumor necrosis factor alpha, and serum amyloid A (SAA). RESULTS: An increase in IL-6, IL-8, and SAA levels was observed during the experiment for both groups. At 2-4 h of support, IL-6 levels were higher in ECMELLA compared to V-A ECMO animals (difference: 1416 pg/ml, 1278 pg/ml, and 1030 pg/ml). SAA levels were higher in ECMELLA animals after 3 and 4 h of support (difference: 401 ng/ml and 524 ng/ml) and a significant treatment-by-time effect of ECMELLA on SAA was identified (p = 0.04). No statistical significant between-group differences were observed in carotid artery blood flow, urine output, and lactate levels. CONCLUSIONS: Left ventricular unloading with Impella during V-A ECMO resulted in a more extensive inflammatory reaction despite similar end-organ perfusion.

Predictors of DAPSA28 remission in patients with psoriatic arthritis initiating a first TNF inhibitor: results from 13 European registries.

OBJECTIVES: In bio-naïve patients with PsA initiating a TNF inhibitor (TNFi), we aimed to identify baseline predictors of Disease Activity index for PsA in 28 joints (DAPSA28) remission (primary objective) and DAPSA28 moderate response at 6 months, as well as drug retention at 12 months across 13 European registries. METHODS: Baseline demographic and clinical characteristics were retrieved and the three outcomes investigated per registry and in pooled data, using logistic regression analyses on multiply imputed data. In the pooled cohort, selected predictors that were either consistently positive or negative across all three outcomes were defined as common predictors. RESULTS: In the pooled cohort (n = 13 369), 6-month proportions of remission, moderate response and 12-month drug retention were 25%, 34% and 63% in patients with available data (n = 6954, n = 5275 and n = 13 369, respectively). Five common baseline predictors of remission, moderate response and 12-month drug retention were identified across all three outcomes. The odds ratios (95% CIs) for DAPSA28 remission were: age, per year: 0.97 (0.96-0.98); disease duration, years (<2 years as reference): 2-3 years: 1.20 (0.89-1.60), 4-9 years: 1.42 (1.09-1.84), ≥10 years: 1.66 (1.26-2.20); men vs women: 1.85 (1.54-2.23); CRP of >10 vs ≤10 mg/l: 1.52 (1.22-1.89) and 1 mm increase in patient fatigue score: 0.99 (0.98-0.99). CONCLUSION: Baseline predictors of remission, response and adherence to TNFi therapy were identified, of which five were common for all three outcomes, indicating that the predictors emerging from our pooled cohort may be considered generalizable from country level to disease level.

Commonalities and differences in set-up and data collection across European spondyloarthritis registries - results from the EuroSpA collaboration.

BACKGROUND: In European axial spondyloarthritis (axSpA) and psoriatic arthritis (PsA) clinical registries, we aimed to investigate commonalities and differences in (1) set-up, clinical data collection; (2) data availability and completeness; and (3) wording, recall period, and scale used for selected patient-reported outcome measures (PROMs). METHODS: Data was obtained as part of the EuroSpA Research Collaboration Network and consisted of (1) an online survey and follow-up interview, (2) upload of real-world data, and (3) selected PROMs included in the online survey. RESULTS: Fifteen registries participated, contributing 33,948 patients (axSpA: 21,330 (63%), PsA: 12,618 (37%)). The reported coverage of eligible patients ranged from 0.5 to 100%. Information on age, sex, biological/targeted synthetic disease-modifying anti-rheumatic drug treatment, disease duration, and C-reactive protein was available in all registries with data completeness between 85% and 100%. All PROMs (Bath Ankylosing Spondylitis Disease Activity and Functional Indices, Health Assessment Questionnaire, and patient global, pain and fatigue assessments) were more complete after 2015 (68-86%) compared to prior (50-79%). Patient global, pain and fatigue assessments showed heterogeneity between registries in terms of wording, recall periods, and scale. CONCLUSION: Important heterogeneity in registry design and data collection across fifteen European axSpA and PsA registries was observed. Several core measures were widely available, and an increase in data completeness of PROMs in recent years was identified. This study might serve as a basis for examining how differences in data collection across registries may impact the results of collaborative research in the future.

Second and third TNF inhibitors in European patients with axial spondyloarthritis: Effectiveness and impact of the reason for switching.

OBJECTIVE: To investigate real-world effectiveness of tumor necrosis factor inhibitors (TNFi) in patients with axial spondyloarthritis (axSpA) and the association with 1) treatment line (second and third TNFi-series) and 2) reason for withdrawal from the preceding TNFi (lack of efficacy (LOE) versus adverse events (AE)). METHODS: Prospectively collected routine care data from 12 European registries were pooled. Rates for 12-month drug retention and 6-month remission (Ankylosing Spondylitis Disease Activity Score C-reactive protein inactive disease (ASDAS-ID)) were assessed in second and third TNFi-series and stratified by withdrawal reason. RESULTS: We included 8254 s and 2939 third TNFi-series; 12-month drug retention rates were similar (71%). Six-month ASDAS-ID rates were higher for the second (23%) than third TNFi (16%). Twelve-month drug retention rates for patients withdrawing from the preceding TNFi due to AE versus LOE were similar for the second (68% and 67%) and third TNFi (both 68%), while for the second TNFi, rates were lower in primary than secondary non-responders (LOE < 26 versus ≥26 weeks) (58% versus 71%, p< 0.001). Six-month ASDAS-ID rates for the second TNFi were higher if the withdrawal reason was AE (27%) versus LOE (17%), p< 0.001, while similar for the third TNFi (19% versus 13%, p= 0.20). CONCLUSION: A similar proportion of axSpA patients remained on a second and third TNFi after one year, but with low remission rates for the third TNFi. Remission rates on the second TNFi (but not the third) were higher if the withdrawal reason from the preceding TNFi was AE versus LOE.

Predictors of ASDAS-CRP inactive disease in axial spondyloarthritis during treatment with TNF-inhibitors: Data from the EuroSpA collaboration.

OBJECTIVES: In patients with axial spondyloarthritis (axSpA) initiating their first tumor necrosis factor alpha-inhibitor (TNFi), we aimed to identify common baseline predictors of Ankylosing Spondylitis Disease Activity Score (ASDAS-CRP) inactive disease (primary objective) and clinically important improvement (CII) at 6 months, and drug retention at 12-months across 15 European registries. METHODS: Baseline demographic and clinical characteristics were collected. Outcomes were investigated per registry and in pooled data using logistic regression analyses on multiply imputed data. RESULTS: The consistency of baseline predictors in individual registries justified pooling the data. In the pooled dataset (n = 21,196), the 6-month rates for ASDAS inactive disease and ASDAS CII were 26% and 51%, and the 12-month drug retention rate 65% in patients with available data (n = 9,845, n = 6,948 and n = 21,196, respectively). Nine common baseline predictors of ASDAS inactive disease, ASDAS CII and 12-month drug retention were identified, and the odds ratios (95%-confidence interval) for ASDAS inactive disease were: age, per year: 0.97 (0.97-0.98), men vs. women: 1.88 (1.60-2.22), current vs. non-smoking: 0.76 (0.63-0.91), HLA-B27 positive vs. negative: 1.51 (1.20-1.91), TNF start year 2015-2018 vs. 2009-2014: 1.24 (1.06-1.45), CRP>10 vs. ≤10 mg/l: 1.49 (1.25-1.77), one unit increase in health assessment questionnaire (HAQ): 0.77 (0.58-1.03), one-millimeter (mm) increase in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) fatigue and spinal pain: 0.99 (0.99-1.00) and 0.99 (0.99-1.99), respectively CONCLUSION: Common baseline predictors of treatment response and adherence to TNFi could be identified across data from 15 European registries, indicating that they may be universal across different axSpA populations.

Sex differences in aortic valve calcification in severe aortic valve stenosis: association between computer tomography assessed calcification and valvular calcium concentrations.

AIMS: The aims of this study were to investigate the correlation and sex differences between total valve calcium, valve calcium concentration, and aortic valve calcification (AVC) in explanted valves from patients with severe aortic valve stenosis undergoing aortic valve replacement (AVR). METHODS AND RESULTS: Sixty-nine patients with severe aortic stenosis (AS) scheduled for elective AVR underwent echocardiography and cardiac computed tomography (CT) prior to surgery (AVCin vivo) and CT of the explanted aortic valve (AVCex vivo). Explanted valves were prepared in acid solution, sonicated, and analysed with Arsenazo III dye to estimate total valve calcium and valve calcium concentration. Median AVCex vivo was 2082 (1421-2973) AU; mean valve calcium concentration was 1.43 ± 0.42 µmol Ca2+/mg tissue; median total valve calcium 156 (111-255) mg Ca2+, and valve calcium density 52 (35-81) mg/cm2. AVC displayed a strong correlation with total valve calcium (R2 = 0.98, P < 0.001) and a moderate correlation with valve calcium concentration (R2 = 0.62, P < 0.001). Valvular calcium concentration was associated with sex, aortic valve area, and mean gradient. After adjusting for age and estimated glomerular filtration rate, sex and mean gradient remained associated with valve calcium concentrations. CONCLUSION: AVC score provides a strong estimate for total valve calcium but to a lesser degree calcium concentration in the valve tissue of patients with severe AS. Females presented lower valvular calcium concentrations than males irrespective of AS severity, adding evidence and providing support to the important point that sex differences in valvular calcium concentration in AS does not reflect valvular size.

Incidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides - a follow-up study from the DANBIO Registry.

OBJECTIVES: To investigate the incidence of cancer in arthritis patients treated with or without TNFα inhibitors (TNF-I). METHODS: Arthritis patients from the DANBIO database were followed-up for cancer in the Danish Cancer Registry during 2000-2008. RESULTS: Hazard ratio for cancer overall was 1.02 (95% confidence interval (CI) 0.80-1.30) in 3347 TNF-I-treated RA patients compared to non-treated. Excess among TNF-I-treated was found for colon cancer (HR 3.52 (95%CI 1.11-11.15), whereas 6 and 0 ovarian cancer cases were observed in treated and non-treated patients, respectively. Compared to the general population, TNF-I-treated RA patients had increased risk for cancer overall, cancer in lymphatic-haematopoietic tissue and non-melanoma skin cancer, while non-RA patients had no increase in overall cancer risk. CONCLUSIONS: Our results suggest that TNF-I therapy in routine care is not associated with an overall excess of cancer in arthritis patients, but observed increased risks of colon and ovarian cancer need further investigation.

Does clinical remission lead to normalization of EQ-5D in patients with rheumatoid arthritis and is selection of remission criteria important?

OBJECTIVE: To compare health-related quality of life (HRQOL) of patients with rheumatoid arthritis (RA) to that of the general population and to investigate the association with disease activity, focusing on different clinical remission criteria. METHODS: EQ-5D data from 3156 patients with RA from 11 Danish centers were compared with Danish EQ-5D population norms (n = 16,136). The Disease Activity Score (DAS28) and the Clinical Disease Activity Index score (CDAI) were used as definitions of disease activity and clinical remission. The score difference (DeltaEQ-5D) was calculated in each patient as the difference from the age and sex-matched general population and adjusted for age, marital status, education, body mass index, smoking, exercise habits, disease duration, IgM-rheumatoid factor status, joint surgery, extraarticular features, treatment, and comorbidity in multiple linear regression models. RESULTS: 37% vs 22% fulfilled the DAS28 and CDAI remission criteria, respectively. The DeltaEQ-5D values for women/men in clinical remission were DAS28 0.05/0.06 vs CDAI 0.01/0.02; low disease activity: DAS28 0.12/0.13 vs CDAI 0.11/0.14; moderate disease activity: DAS28 0.18/0.20 vs CDAI 0.20/0.23; and high disease activity: DAS28 0.38/0.28 vs CDAI 0.33/0.26. Adjusting for confounders reduced the DeltaEQ-5D values between 0 and 0.04 units. CONCLUSION: Patients with RA had worse EQ-5D scores than the general population, and the difference was strongly associated with disease activity. The EQ-5D score for patients in clinical remission approached that of the general population, suggesting that strict treatment goals are critical in order to achieve near-normal HRQOL in patients with RA.

Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry.

OBJECTIVE: To compare tumor necrosis factor alpha inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response. METHODS: The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease-modifying drugs, center, and functional status (Health Assessment Questionnaire score). RESULTS: Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52-2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28-2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82-1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63-2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15-1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20-1.80). CONCLUSION: Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times.