Objective. To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with active ankylosing spondylitis (AS).Methods. This phase III, multicenter, double... Show moreObjective. To evaluate the efficacy and safety of apremilast, an oral phosphodiesterase 4 inhibitor, in patients with active ankylosing spondylitis (AS).Methods. This phase III, multicenter, double-blind, placebo-controlled study (ClinicalTrials.gov: NCT01583374) randomized patients with active AS (1:1:1) to placebo, apremilast 20 mg twice daily, or apremilast 30 mg twice daily for 24 weeks, followed by a long-term extension phase (up to 5 yrs). The primary endpoint was Assessment of the Spondyloarthritis international Society 20 (ASAS20) response at Week 16. The effect of treatment on radiographic outcomes after 104 weeks was assessed using the modified Stoke Ankylosing Spondylitis Spine Score (mSASSS).Results. In total, 490 patients with active AS were randomized in the study (placebo: n = 164; apremilast 20 mg twice daily: n = 163; apremilast 30 mg twice daily: n = 163). The primary endpoint of ASAS20 response at Week 16 was not met (placebo: 37%; apremilast 20 mg twice daily: 35%; apremilast 30 mg twice daily: 33%; P = 0.44 vs placebo). At Week 104, mean (SD) changes from baseline in mSASSS were 0.83 (3.6), 0.98 (2.2), and 0.57 (1.9) in patients initially randomized to placebo, apremilast 20 mg twice daily, and apremilast 30 mg twice daily, respectively. The most frequently reported adverse events through Week 104 were diarrhea, nasopharyngitis, upper respiratory infection, and nausea.Conclusion. No clinical benefit was observed with apremilast treatment in patients with active AS. The safety and tolerability of apremilast were consistent with its known profile. Show less
Objective. Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases.... Show moreObjective. Autoreactive antibody responses, including the use of several isotypes of autoantibodies, have been shown to be associated with clinical outcome in several rheumatic autoimmune diseases. The goals of this study were to evaluate whether (1) anticentrornere antibody (ACA)- and antitopoisomerase antibody (ATA)-specific isotype expression, and (2) organ involvement are associated with the degree of microangiopathy in systemic sclerosis (SSc).Methods. ACA and MA IgG, IgM, and IgA levels were measured in baseline serum samples of ACA IgG-positive (+) and ATA IgG+ patients with SSc. The degree of microangiopathy was determined based on nailfold videocapillaroscopy (NVC) images collected at the same point in time. Logistic regression analyses with autoantibodies, clinical characteristics, isotype expression, and ACA and ATA IgG, IgM, and IgA levels as independent variables, and NVC pattern as the dependent variable were performed.Results. In 164 patients, isotype levels and degree of microangiopathy were evaluated. Logistic regression confirmed the association of the degree of microangiopathy with the presence of digital ulcers (OR 3.07, 95% CI 1.43-6.60), interstitial lung disease (OR 3.41, 95% CI 1.11-10.61), and pulmonary arterial hypertension (OR 5.58, 95% CI 2.05-17.81). ATA positivity was associated with more severe microangiopathy (OR 2.09, 95% CI 1.05-4.13). Patients who expressed solely ACA IgG showed a trend towards less severe microangiopathy compared to patients also expressing ACA IgM and/or IgA. Levels of ACA IgG and ATA IgM were found to be associated with microangiopathy severity.Conclusion. We observed an association between ACA and ATA responses and the degree of microangiopathy in SSc. These findings might indicate that the breadth of the autoimmune response, as reflected by autoantibody production and microvascular damage, interacts in the pathophysiology of SSc. Show less
Lunteren, M. van; Landewe, R.; Fongen, C.; Ramonda, R.; Heijde, D. van der; Gaalen, F.A. van 2020
Objective. It is unknown if in axial spondyloarthritis (axSpA) patients' illness perceptions and coping strategies change when disease activity changes.Methods. Patients diagnosed with axSpA and... Show moreObjective. It is unknown if in axial spondyloarthritis (axSpA) patients' illness perceptions and coping strategies change when disease activity changes.Methods. Patients diagnosed with axSpA and with 1 or more follow-up visits (1 and/or 2 yrs in the SPACE cohort) were included. Mixed linear models were used for illness perceptions (range 1-5), coping (range 1-4), back pain (numeric rating scale range 0-10), health-related quality of life (range 0-100), physical and mental component summary (PCS and MCS; range 0-100), work productivity loss (WPL; range 0-100), and activity impairment (AI; range 0-100%), separately, to test if they changed over time.Results. At baseline, 150 axSpA patients (mean age 30.4 yrs, 51% female, 65% HLA-B27+) had a mean (SD) numeric rating scale back pain of 4.0 (2.5), PCS of 28.8 (14.0), MCS of 47.8 (12.4), WPL of 34.1% (29.8), and AI of 38.7% (27.9). Over 2 years, clinically and statistically significant improvements were seen in the proportion of patients with an Ankylosing Spondylitis Disease Activity Score (ASDAS) of low disease activity (from 39% at baseline to 68% at 2 years), back pain (-1.5, SD 2.2), AI (-14.4%, SD 27.2), PCS (11.1, SD 13.3), and WPL (-15.3%, SD 28.7), but MCS did not change (0.7, SD 13.9; P = 0.201). In contrast, illness perceptions and coping strategies did not change over a period of 2 years. For example, at 2 years patients believed that their illness had severe "consequences" (2.8, SD 0.9) and they had negative emotions (e.g., feeling upset or fear) towards their illness ["emotional representation", 2.5 (0.8)]. Patients most often coped with their pain by putting pain into perspective ["comforting cognitions", 2.8 (0.6)] and tended to cope with limitations by being optimistic ["optimism", 2.9 (0.7)].Conclusion. While back pain, disease activity, and health outcomes clearly improved over 2 years, illness perceptions and coping strategies remained remarkably stable. Show less
Bentum, R.E. van; Vodnizza, S.E.I.; Fuente, M.P.P. de la; Aldridge, F.V.; Navarro-Compan, V.; Rusman, T.R.; ... ; Horst-Bruinsma, I.E. van der 2020
Objective. Physical function in patients with axial spondyloarthritis (axSpA) is currently evaluated through questionnaires. The Ankylosing Spondylitis Performance Index (ASPI) is a performance... Show moreObjective. Physical function in patients with axial spondyloarthritis (axSpA) is currently evaluated through questionnaires. The Ankylosing Spondylitis Performance Index (ASPI) is a performance-based measure for physical functioning, which has been validated in Dutch patients with radiographic (r-) axSpA. The interrater reliability has not yet been determined. To our knowledge, this study is the first to evaluate the validity, reliability, and feasibility of the ASPI in another patient population, including both r- and nonradiographic (nr-) axSpA patients.Methods. Patients with axSpA were recruited from rheumatology clinics in Santiago, Chile. Dutch instructions were translated to Spanish by a forward-backward procedure. Study visits were performed at baseline and 1-4 weeks later. Four ASPI observers were involved, measuring the performance times of the 3 ASPI tests. Validity was assessed through a patient questionnaire (numeric rating scale 0-10: >= 6 sufficient). For reliability, intraclass correlation coefficients (ICC) were calculated (with 95% CI). Correlations between the ASPI and disease variables were tested with regression analyses.Results. Sixty-eight patients were included (57% male, 52% r-axSpA). All patients understood the Spanish instructions and considered the ASPI to reach its aim (84%) and representativeness (85%) for physical functioning. The overall interrater (n = 62) and test-retest (n = 39) reliability (ICC) of the 3 tests combined were 0.93 (0.88-0.96) and 0.94 (0.87-0.97), respectively. Eighty-two percent of the patients completed all tests and 94% finished in < 15 min (feasibility).Conclusion. This study demonstrated a high validity and feasibility in an entirely different population, with both r-axSpA and nr- axSpA. The interrater and test-retest reliability was excellent. The ASPI instructions are now available for Spanish-speaking patients. Show less
Loef, M.; Damman, W.; Mutsert, R. de; Rosendaal, F.R.; Kloppenburg, M. 2020
Objective. To investigate the association of hand osteoarthritis (OA) and concurrent hand and knee OA with health-related quality of life (HRQOL) in the general population, and in patients... Show moreObjective. To investigate the association of hand osteoarthritis (OA) and concurrent hand and knee OA with health-related quality of life (HRQOL) in the general population, and in patients consulting a rheumatology outpatient clinic.Methods. In the population-based Netherlands Epidemiology of Obesity (NEO) study, participants were recruited from the greater area of Leiden, the Netherlands. In the Hand OSTeoArthritis in Secondary care (HOSTAS) study, patients with a rheumatologist's diagnosis of hand OA were recruited from a Leiden-based hospital. In both cohorts, hand and knee OA were defined by the American College of Rheumatology clinical criteria. In NEO, self-reported hospital-based specialist consultation for OA was recorded. Physical and mental HRQOL was assessed with normalized Medical Outcomes Study Short Form-36 scores. Associations were analyzed using linear regression, adjusted for age, sex, education, ethnicity, and body mass index.Results. Hand OA alone and concurrent hand and knee OA was present in 8% and 4% of 6334 NEO participants, and in 57% and 32% of 538 HOSTAS patients. In NEO, hand OA alone, and concurrent hand and knee OA, were associated with lower physical component summary (PCS) scores [mean difference -2.4 (95% CI -3.6, -1.3) and -7.7 (95% CI -9.3, -6.2), respectively] compared with no OA. Consulting a specialist was associated with worse PCS scores. In the HOSTAS cohort, mean PCS scores were lower than norm values (-3.5 and -7.9 for hand OA and combined OA, respectively). Mental HRQOL was not clinically relevantly associated in either cohort.Conclusion. Hand OA was associated with reduced physical, but not mental, HRQOL in the general population and hospital patients. Physical HRQOL was further reduced in hospital care, and with concurrent knee OA. Show less
Vries-Bouwstra, J.K. de; Allanore, Y.; Matucci-Cerinic, M.; Balbir-Gurman, A. 2020
Objective. To evaluate agreement of the updated European League Against Rheumatism and European Scleroderma Trials and Research group (EUSTAR) recommendations for treatment of systemic sclerosis ... Show moreObjective. To evaluate agreement of the updated European League Against Rheumatism and European Scleroderma Trials and Research group (EUSTAR) recommendations for treatment of systemic sclerosis (SSc) among international experts. In addition, to determine factors that might influence agreement.Methods. Level of agreement (10-point scale: 0 = not at all, 10 = completely agree) and local drug availability (yes/no) were assessed using an online survey. The Web link to the survey was shared with 481 unique e-mail addresses and SSc networks (Scleroderma Clinical Trials Consortium, Australian Scleroderma Interest Group, International Systemic Sclerosis Inception Cohort). Level of agreement was compared between subgroups stratified for participant characteristics.Results. In total, 263 experts participated, of whom n = 209 (79%) completed each single item. The majority were rheumatologists (n = 200, 76%) working in Europe (n = 185; 71%); 59% (n = 156) were EUSTAR members; and 57% (n = 151) had > 10 years of clinical experience. Overall level of agreement was high (mean 8.0, SD 2.5). The 3 highest mean agreements included (1) angiotensin-converting enzyme inhibitors for scleroderma renal crisis (9.2, SD 2.1); (2) blood pressure control in SSc-patients treated with corticosteroids (9.0, SD 2.2); (3) proton pump inhibitors to prevent reflux complications (9.0, SD 2.2). The 3 lowest mean agreements included (1) fluoxetine for Raynaud phenomenon (RP; 4.6, SD 2.8); (2) hematopoietic stem cell transplantation (HSCT) for severe SSc (7.1, SD 2.9); (3) phosphodiesterase inhibitors 5 for RP (7.3, SD 2.7). Agreement differed between Europe and non-Europe for the use of iloprost, bosentan, methotrexate, HSCT, and cyclophosphamide. Treatment availability could partially explain differential agreement for iloprost, bosentan, and HSCT.Conclusion. In general, worldwide expert agreement on updated recommendations for treatment of SSc is high, supporting their value. Differences in agreement are partially explained by geographical area and treatment availability. Show less
Heijde, D. van der; Gladman, D.D.; FitzGerald, O.; Kavanaugh, A.; Graham, D.; Wang, C.S.; Fallon, L. 2019
Objective. To update the 1997 OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) core domain set for clinical trials in hip and/or knee osteoarthritis ... Show moreObjective. To update the 1997 OMERACT-OARSI (Outcome Measures in Rheumatology-Osteoarthritis Research Society International) core domain set for clinical trials in hip and/or knee osteoarthritis (OA).Methods. An initial review of the COMET database of core outcome sets (COS) was undertaken to identify all domains reported in previous COS including individuals with hip and/or knee OA. These were presented during 5 patient and health professionals/researcher meetings in 3 continents (Europe, Australasia, North America). A 3-round international Delphi survey was then undertaken among patients, healthcare professionals, researchers, and industry representatives to gain consensus on key domains to be included in a core domain set for hip and/or knee OA. Findings were presented and discussed in small groups at OMERACT 2018, where consensus was obtained in the final plenary.Results. Four previous COS were identified. Using these, and the patient and health professionals/researcher meetings, 50 potential domains formed the Delphi survey. There were 426 individuals from 25 different countries who contributed to the Delphi exercise. OMERACT 2018 delegates (n = 129) voted on candidate domains. Six domains gained agreement as mandatory to be measured and reported in all hip and/or knee OA clinical trials: pain, physical function, quality of life, and patient's global assessment of the target joint, in addition to the mandated core domain of adverse events including mortality. Joint structure was agreed as mandatory in specific circumstances, i.e., depending on the intervention.Conclusion. The updated core domain set for hip and/or knee OA has been agreed upon. Work will commence to determine which outcome measurement instrument should be recommended to cover each core domain. Show less
Objective. Cardiac involvement is a main cause of mortality in systemic sclerosis (SSc). Its detection remains challenging using conventional echocardiography and little is known about its... Show moreObjective. Cardiac involvement is a main cause of mortality in systemic sclerosis (SSc). Its detection remains challenging using conventional echocardiography and little is known about its potential progression. This study assessed changes in cardiac performance over time in a prospective cohort of patients with SSc, including echocardiographic speckle-tracking strain analysis.Methods. The study included 234 patients with SSc [196 women, age 52 +/- 14 yrs, 165 limited SSc, time since diagnosis 5.2 yrs, interquartile range (IQR) 2.9-11.3]. Clinical variables, laboratory tests, pulmonary function tests, and echocardiographic measures were recorded at baseline and followup (median 2.3 yrs, IQR 1.3-3.9). Additionally, left ventricular (LV) systolic function was assessed with global longitudinal strain (GLS) by echocardiographic speckle-tracking analysis.Results. At followup, GLS had significantly worsened (-21% +/- 2 vs -19% +/- 2, p < 0.001) while LV ejection fraction had not changed (62% +/- 7 vs 61% +/- 8, p = 0.124). In particular, 39 patients showed a significant deterioration of GLS as defined by a >= 15% decrease, which was accompanied by a concomitant worsening of proximal muscle weakness, lung fibrosis, renal function, LV diastolic function, and right ventricular systolic function. Baseline variables associated with >= 15% deterioration in GLS were proximal muscle weakness (OR 3.437, 95% CI 1.13-10.43, p = 0.020), decreased DLCO (OR 3.621, 95% CI 1.25-10.51, p = 0.049), and LV diastolic dysfunction (OR 2.378, 95% CI 1.07-5.27, p = 0.033).Conclusion. In patients with SSc, progression of LV systolic dysfunction was demonstrated by GLS but not by LV ejection fraction. Proximal muscle weakness, DLCO, and LV diastolic dysfunction may identify patients at risk for progressive LV systolic dysfunction and in need of closer cardiac monitoring. Show less
