[Show abstract][Hide abstract]ABSTRACT: Objectives:
Asymmetric dimethylarginine (ADMA) is a novel biomarker of endothelial cell dysfunction. In this proof of concept study, we sought to evaluate the role of ADMA as a screening biomarker for incident systemic sclerosis-related pulmonary arterial hypertension (SSc-PAH).
ADMA levels were measured using high performance liquid chromatography in 15 consecutive treatment-naive patients with newly-diagnosed SSc-PAH and compared with 30 SSc-controls without PAH. Logistic regression models were used to evaluate the independent association of ADMA with PAH. The optimal cut-point of ADMA for SSc-PAH screening was determined. NT-proBNP levels were previously measured in the same patients and the optimal cut-point of NT-proBNP of ≥210ng/mL was coupled with the optimal cut-point of ADMA to create a screening model that combined the two biomarkers.
The PAH group had significantly higher mean ADMA levels than the control group (0.76±0.14 μM versus 0.59±0.07 μM; p<0.0001). ADMA levels remained significantly associated with PAH after the adjustment for specific disease characteristics, cardiovascular risk factors and other SSc-related vascular complications (all p<0.01). An ADMA level ≥0.7 μM had a sensitivity of 86.7%, specificity of 90.0% and AUC of 0.86 for diagnosing PAH. A screening model that combined an NT-proBNP ≥210ng/mL and/ or ADMA ≥0.7 ng/mL resulted in a sensitivity of 100% and specificity of 90% for the detection of SSc-PAH.
In this small study, use of ADMA in combination with NT-proBNP produced excellent sensitivity and specificity for the non-invasive identification of SSc-PAH. The role of ADMA as a screening biomarker for SSc-PAH merits further evaluation.
Article · May 2016 · Clinical and experimental rheumatology
[Show abstract][Hide abstract]ABSTRACT: Objective:
Update the 2009 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) treatment recommendations for the spectrum of manifestations affecting patients with psoriatic arthritis (PsA).
GRAPPA rheumatologists, dermatologists, and PsA patients drafted overarching principles for the management of PsA patients based on consensus at face-to-face meetings and via online surveys. We published literature reviews regarding treatment for the key domains of PsA (arthritis, spondylitis, enthesitis, dactylitis, skin, and nail disease), and convened a new group to identify pertinent comorbidities and their effect on treatment. Finally, we drafted treatment recommendations for each of the clinical manifestations and assessed the level of agreement for the overarching principles and treatment recommendations among GRAPPA members, with an online questionnaire.
Six overarching principles had at least 80% agreement among both health care professionals (HCPs; n=135) and patient research partners (PRPs; n=10). We developed treatment recommendations and a schema incorporating these principles for arthritis, spondylitis, enthesitis, dactylitis, skin, and nail disease, and comorbidities in the setting of PsA, using the GRADE process. Over 80% agreement was reached for approval of the individual recommendations and the overall schema.
Herein, we present overarching principles and updated treatment recommendations for the key manifestations of PsA, including related comorbidities, based on a literature review and consensus of GRAPPA members (rheumatologists, dermatologists, other HCPs, and PRPs). Further updates are anticipated as the therapeutic landscape in PsA evolves. This article is protected by copyright. All rights reserved.
Full-text available · Article · Jan 2016 · Arthritis and Rheumatology
[Show abstract][Hide abstract]ABSTRACT: Objective:
Evaluate the safety and efficacy of golimumab through 5 years in adults with active RA who had not previously received methotrexate (MTX).
In GO-BEFORE, 637 MTX-naïve adult patients with active RA were randomized (1:1:1:1) to placebo+MTX (Group 1), golimumab 100mg+placebo (Group 2), golimumab 50mg+MTX (Group 3), or golimumab 100mg+MTX (Group 4). Inadequate responders in Groups 1, 2, and 3 entered early escape at week28 to golimumab 50mg+MTX, golimumab 100mg+MTX, or golimumab 100mg +MTX, respectively; remaining patients in Group 1 could crossover to golimumab 50mg+MTX at week52. Assessments included ACR20/50/70 response, DAS28-CRP scores, and vdH-mTSS. Efficacy was analyzed using an intent-to-treat analysis. Pharmacokinetics and immunogenicity were evaluated at selected visits.
A total of 422 patients completed golimumab treatment through week256. At week256, 72.8%, 54.6%, and 38.0% of all patients in the full ITT population (n=637) had an ACR20/50/70 response, respectively, 84.1% had a good or moderate DAS28-CRP response, and 72.7% had a clinically meaningful improvement in physical function. Radiographic progression was minimal in all treatment groups through week256, and the overall mean change from baseline in vdH-mTSS was 1.36. Serum trough golimumab concentrations were approximately dose proportional and maintained through week256. Antibodies to golimumab occurred in 9.6% of patients through week256. Infections were the most common type of AE; 204/616 patients (33.1%) had ≥1 serious AE.
Clinical efficacy with golimumab treatment was maintained through week256 of the GO-BEFORE trial of MTX-naïve RA patients. No unexpected AEs occurred; safety results through 5 years are consistent with earlier reports. This article is protected by copyright. All rights reserved.
[Show abstract][Hide abstract]ABSTRACT: Background In a phase 2 study, the inhibition of the interleukin-17A receptor improved signs and symptoms of psoriatic arthritis. We sought to evaluate the efficacy and safety of secukinumab, an anti-interleukin-17A monoclonal antibody, in such patients. Methods In this double-blind, phase 3 study, 606 patients with psoriatic arthritis were randomly assigned in a 1:1:1 ratio to receive intravenous secukinumab (at a dose of 10 mg per kilogram) at weeks 0, 2, and 4, followed by subcutaneous secukinumab at a dose of either 150 mg or 75 mg every 4 weeks, or placebo. Patients in the placebo group were switched to subcutaneous secukinumab at a dose of 150 mg or 75 mg at week 16 or 24, depending on clinical response. The primary end point was the proportion of patients with an American College of Rheumatology 20 (ACR20) response at week 24, defined as a 20% improvement from baseline in the number of tender and swollen joints and at least three other important domains. Results ACR20 response rates at week 24 were significantly higher in the group receiving secukinumab at doses of 150 mg (50.0%) and 75 mg (50.5%) than in those receiving placebo (17.3%) (P<0.001 for both comparisons with placebo). Secondary end points, including the ACR50 response and joint structural damage, were significantly better in the secukinumab groups than in the placebo group. Improvements were sustained through 52 weeks. Infections, including candida, were more common in the secukinumab groups. Throughout the study (mean secukinumab exposure, 438.5 days; mean placebo exposure, 128.5 days), four patients in the secukinumab groups had a stroke (0.6 per 100 patient-years; 95% confidence interval [CI], 0.2 to 1.5), and two had a myocardial infarction (0.3 per 100 patient-years; 95% CI, 0.0 to 1.0), as compared with no patients in the placebo group. Conclusions Secukinumab was more effective than placebo in patients with psoriatic arthritis, which validates interleukin-17A as a therapeutic target. Infections were more common in the secukinumab groups than in the placebo group. The study was neither large enough nor long enough to evaluate uncommon serious adverse events or the risks associated with long-term use. (Funded by Novartis Pharma; ClinicalTrials.gov number, NCT01392326 .).
Article · Sep 2015 · New England Journal of Medicine
[Show abstract][Hide abstract]ABSTRACT: Objectives Biological disease-modifying antirheumatic drugs (bDMARDs) have shown diminished clinical response following an inadequate response (IR) to >= 1 previous bDMARD. Here, tofacitinib was compared with placebo in patients with an IR to conventional synthetic DMARDs (csDMARDs; bDMARD-naive) and in patients with an IR to bDMARDs (bDMARD-IR). Methods Data were taken from phase II and phase III studies of tofacitinib in patients with rheumatoid arthritis (RA). Patients received tofacitinib 5 or 10 mg twice daily, or placebo, as monotherapy or with background methotrexate or other csDMARDs. Efficacy endpoints and incidence rates of adverse events (AEs) of special interest were assessed. Results 2812 bDMARD-naive and 705 bDMARD-IR patients were analysed. Baseline demographics and disease characteristics were generally similar between treatment groups within subpopulations. Across subpopulations, improvements in efficacy parameters at month 3 were generally significantly greater for both tofacitinib doses versus placebo. Clinical response was numerically greater with bDMARD-naive versus bDMARD-IR patients (overlapping 95% CIs). Rates of safety events of special interest were generally similar between tofacitinib doses and subpopulations; however, patients receiving glucocorticoids had more serious AEs, discontinuations due to AEs, serious infection events and herpes zoster. Numerically greater clinical responses and incidence rates of AEs of special interest were generally reported for tofacitinib 10 mg twice daily versus tofacitinib 5 mg twice daily (overlapping 95% CIs). Conclusions Tofacitinib demonstrated efficacy in both bDMARD-naive and bDMARD-IR patients with RA. Clinical response to tofacitinib was generally numerically greater in bDMARD-naive than bDMARD-IR patients. The safety profile appeared similar between subpopulations.
Full-text available · Article · Aug 2015 · Annals of the rheumatic diseases
[Show abstract][Hide abstract]ABSTRACT: Clinically meaningful change in systemic sclerosis (SSc) related interstitial lung (SSc-ILD) disease is unknown. The aim of this study was to quantify change in pulmonary function as a predictor of outcome in SSc-ILD.
All patients had SSc-ILD defined by HRCT chest. All PFTs during follow-up, including FVC (L), DLCO (ml/min/mmHg) and KCO (DLCO/alveolar volume ratio; DLCO/VA) (ml/min/mmHg/L) were retrieved. The rate of change over the first four years, and percentage change in the first year of follow-up were used in ROC curve analysis to determine the best cut-off points to predict adverse outcome (home oxygen, lung transplantation, or death).
Among 264 patients, there were 49 events (38 deaths, 10 supplemental oxygen, one lung transplant) over a mean (±SD) follow-up of 3.0 (±1.7) years. The rates of decline over time and percentage change over one year in each of FVC, DLCO and KCO were predictive of adverse outcome. Stable PFTs over four years gave the optimal negative predictive values (NPVs) of 88-96%. The best sensitivity-specificity trade-off was a decline in FVC of 10% and in DLCO and KCO of 15% with NPVs of 92-93%.
The course that SSc-ILD takes is evident within the first 1-4 years of follow up. Patients who have no decline in PFTs over 4 years have better outcomes. A decline within one year in DLCO or KCO of 15% or more is a poor prognostic factor, and identifies patients who should be monitored more closely and considered for therapy.
Article · Aug 2015 · Clinical and experimental rheumatology
[Show abstract][Hide abstract]ABSTRACT: A systematic literature review (SLR; 2009-2014) to compare a target-oriented approach with routine management in the treatment of rheumatoid arthritis (RA) to allow an update of the treat-to-target recommendations.
Two SLRs focused on clinical trials employing a treatment approach targeting a specific clinical outcome were performed. In addition to testing clinical, functional and/or structural changes as endpoints, comorbidities, cardiovascular risk, work productivity and education as well as patient self-assessment were investigated. The searches covered MEDLINE, EMBASE, Cochrane databases and Clinicaltrial.gov for the period between 2009 and 2012 and separately for the period of 2012 to May of 2014.
Of 8442 citations retrieved in the two SLRs, 176 articles underwent full-text review. According to predefined inclusion/exclusion criteria, six articles were included of which five showed superiority of a targeted treatment approach aiming at least at low-disease activity versus routine care; in addition, publications providing supportive evidence were also incorporated that aside from expanding the evidence provided by the above six publications allowed concluding that a target-oriented approach leads to less comorbidities and cardiovascular risk and better work productivity than conventional care.
The current study expands the evidence that targeting low-disease activity or remission in the management of RA conveys better outcomes than routine care.
Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.
Article · May 2015 · Annals of the rheumatic diseases
[Show abstract][Hide abstract]ABSTRACT: IntroductionThere is evidence that early screening for pulmonary arterial hypertension (PAH) in systemic sclerosis (SSc) improves outcomes. We compared the predictive accuracy of two recently published screening algorithms (DETECT 2013 and Australian Scleroderma Interest Group (ASIG) 2012) for SSc-associated PAH (SSc-PAH) with the commonly used European Society of Cardiology/Respiratory Society (ESC/ERS 2009) guidelines.Methods
We included 73 consecutive SSc patients with suspected PAH undergoing right heart catheterization (RHC). The three screening models were applied to each patient. For each model, contingency table analysis was used to determine sensitivity, specificity, positive (PPV) and negative predictive values (NPV) for PAH. These properties were also evaluated in an `alternate scenario analysis¿ where the prevalence of PAH was set at 10%.ResultsRHC revealed PAH in 27 (36.9%) patients. Both DETECT and ASIG algorithms performed equally in predicting PAH with sensitivity and NPV of 100%. The ESC/ERS guidelines had sensitivity of 96.3% and NPV of only 91%, missing one case of PAH; these guidelines could not be applied to three patients who had absent tricuspid regurgitant (TR) jet. The ASIG algorithm had the highest specificity of 54.5%. With PAH prevalence set at 10%, the NPV of the models was unchanged, but the PPV dropped to less than 20%.Conclusions
In this cohort, the DETECT and ASIG algorithms out-perform the ESC/ERS guidelines, detecting all patients with PAH. The ESC/ERS guidelines have limitations in the absence of a TR jet. Ultimately, the choice of SSc-PAH screening algorithm will also depend on cost and ease of application.
Full-text available · Article · Jan 2015 · Arthritis Research & Therapy
[Show abstract][Hide abstract]ABSTRACT: Axial involvement in patients with psoriatic arthritis (PsA) remains common and can be defined in terms of spinal disease alone or in combination with peripheral manifestations. Diagnosis is based upon inflammatory spinal symptoms or the presence of radiological sacroiliitis and other radiographic signs of spondylitis, or by criteria for axial spondyloarthritis (SpA) defined by ASAS (Assessment of SpondyloArthritis International Society). Although recent data are scarce for efficacy of traditional therapies for axial disease (e.g., nonsteroidal antiinflammatory drugs, methotrexate, etc.), limited data are available for targeted biologics and novel agents. We identify and evaluate the efficacy of therapeutic interventions for treatment of axial disease in PsA. This review is an update of the axial PsA section of the treatment recommendations project by the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA).
Full-text available · Article · Nov 2014 · The Journal of Rheumatology
[Show abstract][Hide abstract]ABSTRACT: IntroductionThe aim of the study was to interrogate the genetic architecture and autoimmune pleiotropy of scleroderma susceptibility in the Australian population.Methods
We genotyped individuals from a well-characterized cohort of Australian scleroderma patients with the Immunochip, a custom array enriched for single nucleotide polymorphisms (SNPs) at immune loci. Controls were taken from the 1958 British Birth Cohort. After data cleaning and adjusting for population stratification the final dataset consisted of 486 cases, 4,458 controls and 146,525 SNPs. Association analyses were conducted using logistic regression in PLINK. A replication study was performed using 833 cases and 1938 controls.ResultsA total of 8 loci with suggestive association (P <10-4.5) were identified, of which 5 showed significant association in the replication cohort (HLA-DRB1, DNASE1L3, STAT4, TNP03-IRF5 and VCAM1). The most notable findings were at the DNASE1L3 locus, previously associated with systemic lupus erythematosus, and VCAM1, a locus not previously associated with human disease. This study identified a likely functional variant influencing scleroderma susceptibility at the DNASE1L3 locus; a missense polymorphism rs35677470 in DNASE1L3, with an odds ratio of 2.35 (P¿=¿2.3¿×¿10¿10) in anti-centromere antibody (ACA) positive cases.Conclusions
This pilot study has confirmed previously reported scleroderma associations, revealed further genetic overlap between scleroderma and systemic lupus erythematosus, and identified a putative novel scleroderma susceptibility locus.
Full-text available · Article · Oct 2014 · Arthritis Research & Therapy
[Show abstract][Hide abstract]ABSTRACT: Objective
To investigate the safety of long-term subcutaneous (SC) abatacept treatment using integrated clinical trial data obtained in patients with rheumatoid arthritis refractory to traditional disease-modifying antirheumatic drugs.
Data from the double-blind and open-label phases of 5 clinical trials of SC abatacept were pooled. The overall and 6-month incidence rates were calculated as events per 100 patient-years of exposure.
This analysis included 1,879 patients with 4,214.6 patient-years of exposure to SC abatacept. The mean ± SD length of exposure was 27.3 ± 9.1 months. The reported incidence rate of serious infections was 1.79 (95% confidence interval [95% CI] 1.42–2.24); the most frequent infections were pneumonia (incidence rate 0.36 [95% CI 0.22–0.59]), urinary tract infection (incidence rate 0.14 [95% CI 0.06–0.32]), and gastroenteritis (incidence rate 0.10 [95% CI 0.04–0.25]). Tuberculosis occurred rarely (incidence rate 0.09 [95% CI 0.04–0.25]). The reported incidence rate of malignancies was 1.32 (95% CI 1.01–1.72), and the most common was solid organ malignancy (incidence rate 0.69 [95% CI 0.48–0.99]). The incidence rate of autoimmune events was 1.37 (95% CI 1.06–1.78), and the most frequent events were psoriasis (incidence rate 0.33 [95% CI 0.20–0.56]) and Sjögren's syndrome (incidence rate 0.24 [95% CI 0.13–0.44]). The reported incidence rate of local injection site reactions was 1.72 (95% CI 1.36–2.17); these events occurred primarily during the first 6 months of treatment, and almost all were of mild or moderate intensity. The incidence rates of serious infections, malignancies, autoimmune events, and injection site reactions did not increase over time.
Long-term treatment with SC abatacept was associated with low incidence rates of serious infections, malignancies, and autoimmune events and was well tolerated, with infrequent injection site reactions. These findings are consistent with those related to treatment with intravenous abatacept. Long-term treatment with SC abatacept did not lead to new safety signals over time.
Full-text available · Article · Aug 2014 · Arthritis and Rheumatology
[Show abstract][Hide abstract]ABSTRACT: Background Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). Phase (P) 2, P3, and open-label long-term extension (LTE) studies described the safety profile of tofacitinib and demonstrated that tofacitinib is effective as monotherapy and in combination with non-biologic disease-modifying antirheumatic drugs (DMARDs).
Objectives This analysis describes safety data for tofacitinib in patients (pts) from the integrated RA clinical trial database based on cumulative exposure in P2, P3, and LTE studies, with a focus on safety events of special interest according to duration of tofacitinib exposure.
Methods The analysis was performed on pts who received ≥1 dose of tofacitinib (doses pooled), as monotherapy or with background DMARDs, integrated across 6 P2, 6 P3 trials, and in 2 LTE studies (ongoing; database not locked) up to April 10, 2013. Pts switching from placebo, adalimumab or methotrexate to tofacitinib contributed data following their first dose of tofacitinib. Incidence rates (IR; events/100 patient-years [py] and 95% confidence intervals [CI]) are listed. The IR for opportunistic infections (OI) included herpes zoster (HZ) events that were described as disseminated or multidermatomal and excluded events of tuberculosis (TB), which are reported separately.
Results The analysis includes 5,671 pts and represents an overall 12,664 py of tofacitinib exposure, with a median exposure of 2.4 years. The numbers of pts receiving tofacitinib for at least 12, 24, 36 and >48 months were 4,204 (74%), 3,804 (54%), 1,948 (34%), and 555 (10%) respectively. Overall 926 (16.3%) discontinued due to adverse events (AEs). The IR for mortality (within 30 days of last dose) was 0.28 (0.20, 0.39). IRs across discrete 6-month periods of exposure for serious AEs (SAEs) and AEs of interest, were stable across time intervals (Table 1). Serious infections were the most common SAEs (IR 2.93 [2.65, 3.25]). IRs for OI and TB were 0.25 (0.18, 0.36) and 0.21 (0.14, 0.30), respectively. Of all HZ AEs (overall IR 4.22 [3.87, 4.61]), 93% were non-serious; disseminated and multidermatomal cases were rare. Rates of all malignancies, excluding non-melanoma skin cancer (NMSC), and of lymphoma/lymphoproliferative disorders, were similar across time intervals (Table 1). US Surveillance, Epidemiology, and End Results Program (SEER) standardised incidence ratios (95% CI) were 1.08 (0.89, 1.31) for malignancies excluding NMSC and 2.58 (1.24, 4.74) for lymphoma, and were comparable to those reported from cohorts of RA pts treated with tumour necrosis factor inhibitors.
Conclusions The pattern and rate of SAEs, and AEs of special interest observed following >12,000 py of overall exposure was stable across time intervals. No new risks were identified compared to previous reports. Longer term follow-up, observational research, and pharmacovigilance activities will further characterise the safety profile of tofacitinib in RA.
Acknowledgements All studies were sponsored by Pfizer Inc. Editorial support was provided by Claire Cridland, of Complete Medical Communications and funded by Pfizer Inc.
Disclosure of Interest S. Cohen Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, Y. Tanaka Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, X. Mariette Grant/research support: Pfizer Inc, J. Curtis Grant/research support: Pfizer Inc, K. Kwok Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, E. Lee Consultant for: Pfizer Inc, P. Nash Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, K. Winthrop Grant/research support: Pfizer Inc, C. Charles-Schoeman Grant/research support: Pfizer Inc, Consultant for: Pfizer Inc, K. Thirunavukkarasu Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, A. Anisfeld Shareholder of: Pfizer Inc, Consultant for: Pfizer Inc, L. Wang Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, R. Riese Shareholder of: Pfizer Inc, Employee of: Pfizer Inc, J. Wollenhaupt Grant/research support: Pfizer Inc
Article · Jun 2014 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract]ABSTRACT: Assess longterm tolerability, safety, and efficacy of subcutaneous (SC) abatacept (ABA) in methotrexate-refractory patients with rheumatoid arthritis (RA).
The phase III, multinational Abatacept Comparison of Sub[QU]cutaneous Versus Intravenous in Inadequate Responders to MethotrexatE (ACQUIRE) trial comprised a 6-month, randomized, double-blind (DB) period, in which patients received intravenous (IV) or SC ABA, plus MTX, followed by an open-label, longterm extension (LTE), in which patients received SC ABA, 125 mg/week. Safety and efficacy from the LTE (~3.5 yrs of exposure) are reported.
Patients who completed the DB period (1372/1385, 99.1%) entered the LTE; 1134 patients (82.7%) kept taking the treatment at time of reporting. Mean (SD) was 31.9 months (6.8); median (range) exposure was 33.0 (8-44) months. Patients entering the LTE had longstanding, moderate-to-severe disease [mean 7.6 (7.9) yrs and DAS28 (C-reactive protein) 6.2 (0.9)]. Incidence rates (events/100 patient-yrs) were reported for serious adverse events (8.76, 95% CI 7.71, 9.95), infections (44.80, 95% CI 41.76, 48.01), serious infections (1.72, 95% CI 1.30, 2.27), malignancies (1.19, 95% CI 0.86, 1.66), and autoimmune events (1.31, 95% CI 0.95, 1.79). Twenty-seven patients (2%) experienced injection-site reactions; all except 1 were mild. American College of Rheumatology 20, 50, and 70 responses achieved during the DB period were maintained through the LTE, and on Day 981 were 80.2% (95% CI 77.2, 83.2), 63.5% (95% CI 58.2, 68.9), and 39.5% (95% CI 34.0, 44.9) for patients who kept taking SC ABA, and 80.0% (95% CI 77.0, 83.0), 63.2% (95% CI 57.8, 68.7), and 39.2% (95% CI 33.7, 44.7) for those who switched from IV to SC ABA.
These findings support SC ABA as a well-tolerated and efficacious longterm treatment for patients with RA and inadequate response to MTX (ClinicalTrials.gov identifier NCT00559585).
Full-text available · Article · Mar 2014 · The Journal of Rheumatology
[Show abstract][Hide abstract]ABSTRACT: To determine the prevalence and correlates of antiphospholipid antibodies (APLA) in systemic sclerosis (SSc).
Nine hundred and forty SSc patients were tested for APLA using an ELISA assay at recruitment. Clinical manifestations were defined as present, if ever present from SSc diagnosis. Logistic regression analysis was used to determine the associations of APLA.
One or more types of APLA were present in 226 (24.0%) patients. Anticardiolipin (ACA) IgG (ACA-IgG) antibodies were associated with right heart catheter-diagnosed pulmonary arterial hypertension (PAH), with higher titres corresponding with a higher likelihood of PAH (moderate titre (20-39 U/ml) ACA-IgG odds ratio [OR] 1.70, 95% CI: 1.01-2.93, p=0.047; high titre (>40 U/ml) ACA-IgG OR 4.60, 95% CI:1.02-20.8, p=0.047). Both ACA-IgM (OR 2.04, 95% CI: 1.4-3.0, p<0.0001) and ACA-IgG (OR 1.84, 95% CI: 1.2-2.8, p=0.005) were associated with interstitial lung disease (ILD). Increasing ACA-IgM and IgG titres were associated with increased likelihood of ILD. ACA-IgG was a marker of coexistent pulmonary hypertension and ILD (ILD-PH) (OR 2.10, 95% CI: 1.1-4.2, p=0.036). We also found an association between ACA-IgG and digital ulcers (OR 1.76, 95% CI: 1.16-2.67, p=0.008) and ACA-IgM and Raynaud's phenomenon (OR 2.39, 95% CI: 1.08-5.27, p=0.031). There was no association between APLA and SSc disease subtype, peak skin score, presence of other autoantibodies, mortality or other disease manifestations.
The association of APLA with PAH, ILD, ILD-PH, Raynaud's phenomenon and digital ulcers suggests that endothelial abnormalities and small vessel thrombosis may be important in the pathogenesis of these disease features.
Article · Feb 2014 · Clinical and experimental rheumatology
[Show abstract][Hide abstract]ABSTRACT: Background Disease-modifying therapies for RA have proven efficacy, but selective toxicities, such as malignancy, may increase with treatment duration. Periodic re-evaluation of incidence rates (IRs) allows assessment of any cumulative or new events over time.
Objectives To investigate the long-term (LT) safety of subcutaneous (SC) and intravenous (IV) abatacept (ABA) using the largest pool of integrated clinical trial data to date.1,2
Methods Data were pooled from the cumulative (double-blind and open-label short-term [ST] and open-label LT extension) periods of 13 Phase II and III studies.1,2 IRs of safety events were calculated as the number per 100 patient-years (pt-yrs) of exposure (Poisson 95% CI). IRs for the cumulative period were compared with IRs originally estimated from the pooled ST periods of eight IV ABA clinical studies.2
Results A total of 6028 pts received IV or SC ABA during the cumulative period (total exposure of 16,670.56 pt-yrs; 1167 pts received ABA for >5 years). IRs of adverse events (AEs), serious AEs (SAEs), infections or serious infections did not increase in the cumulative relative to ST periods (Table). The most frequently reported serious infections in the cumulative period were pneumonia (IR [95% CI]: 0.43 [0.34, 0.54]) and upper respiratory tract infection (0.18 [0.12, 0.26]). There was no increase in IRs between the ST and cumulative periods for hospitalised, opportunistic or tuberculosis infections. The IRs of overall malignancy, combined lymphomas and lung cancers did not increase in the cumulative versus the ST periods; the most common malignancies in the cumulative period were basal cell carcinoma (IR [95% CI]: 0.46 [0.36, 0.58]) and squamous cell carcinoma (0.15 [0.09, 0.22]). The IR of autoimmune AEs during the cumulative period was comparable to the ST period, the most common event being psoriasis (IR [95% CI]: 0.51 [0.40, 0.63]).
Conclusions Based on the cumulative ST and LT exposure of 6028 patients to IV or SC abatacept (16,670.56 pt-yrs), the IRs and events reported with LT abatacept treatment were similar to those reported in the ST, with no increase in rate for any event with increasing exposure. These findings demonstrate that IV and SC abatacept are both well tolerated over the LT.
Disclosure of Interest R. Alten Grant/research support from: BMS, Merck Pharma GmbH, Wyeth Pharmaceuticals, Pfizer, Consultant for: Abbott Laboratories, Horizon Pharma, Merck Pharma GmbH, Nitec Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, Speakers bureau: Abbott Laboratories, BMS, Horizon Pharma, Merck Pharma GmbH, Novartis Pharmaceuticals Corporation, Roche, M. Hochberg Grant/research support from: NIH, Consultant for: Abbott Laboratories, Amgen Inc., BMS, Eli Lilly and Company, EMD Serono Inc., Genentech/Roche, Merck & Co., Inc., Novartis Pharma AG, Pfizer Inc, Speakers bureau: Bioberica SA, IBSA, Rottapharm/Madaus, R. Cohen Consultant for: Bristol-Myers Squibb, M. Weinblatt Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Abbott, J. Kaine Grant/research support from: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, UCB, E. Keystone Grant/research support from: Abbott Laboratories; Amgen Inc.; AstraZeneca Pharmaceuticals LP;, Consultant for: Abbott Laboratories; AstraZeneca Pharma, Biotest, Bristol-Myers Squibb Company; F. Hoffmann-La Roche Inc; Genentech Inc; Jannsen Inc, Lilly Pharmaceuticals; Merck, Nycomed, Pfizer Pharmaceuticals, UCB, Speakers bureau: Abbott Laboratories; Astrazeneca LP, Bristol-Myers Squibb Canada; F. Hoffmann-La Roche Inc.; Janssen Inc.; Pfizer Pharmaceuticals, UCB, Amgen, Abbott Pharmaceuticals, P. Nash Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb, Speakers bureau: Bristol-Myers Squibb, I. Delaet Shareholder of: Bristol-Myers Squibb, Employee of: Bristol-Myers Squibb, M. Genovese Grant/research support from: Bristol-Myers Squibb, Consultant for: Bristol-Myers Squibb
Article · Jan 2014 · Annals of the Rheumatic Diseases
[Show abstract][Hide abstract]ABSTRACT: To improve treatment for rheumatoid arthritis (RA), rheumatologists have embraced patient-reported outcomes; however, limited data are available on patient perceptions of treatment. Our objective was to assess the use and perceptions of methotrexate (MTX) by patients with RA (primary objective) and their rheumatologists, patient-reported adverse events (AEs) related to MTX, and patient-reported use of alcohol, folic acid and biologic agents.
Each rheumatologist completed a rheumatologist questionnaire and then asked patients with RA to complete a patient questionnaire.
Questionnaires were completed by 46/50 rheumatologists and 1313/1313 patients. Patients (72% female, 38% > 10 years RA) took oral MTX regularly (72% never miss a dose) and at therapeutic doses. Most patients (79%) were currently taking MTX, but 36% of patients were on low doses (≤ 10 mg/week) and 8% intentionally and regularly did not take MTX. Most patients had a positive perception of MTX; 82% of patients considered MTX to be important; 60% preferred to continue taking MTX. Although AEs (generally mild and gastrointestinal) occurred regularly (38%) and in some patients continuously (13%), 41% of patients did not experience an AE. Patients abstained from alcohol (46%) and took folic acid (91%, but with variable dosage regimens and doses). There were 29% of patients taking biologic agent therapy; only 70% of these patients were also taking MTX.
MTX was well used, well tolerated and well perceived. However, to ensure that MTX therapy is as effective as possible, rheumatologists should discuss MTX use with their patients and consider alternative strategies for some patients.
Article · Dec 2013 · International Journal of Rheumatic Diseases
[Show abstract][Hide abstract]ABSTRACT: Pulmonary arterial hypertension (PAH) is a major cause of mortality in systemic sclerosis (SSc). Screening guidelines for PAH recommend multiple investigations, including annual echocardiography, which together have low specificity and may not be cost-effective. We sought to evaluate the predictive accuracy of serum N-Terminal pro-brain natriuretic peptide (NT-proBNP) in combination with pulmonary function tests (PFT) ('proposed' algorithm) in a screening algorithm for SSc-PAH.
We evaluated our proposed algorithm (PFT with NTproBNP) on 49 consecutive SSc patients with suspected pulmonary hypertension undergoing right heart catherisation (RHC). The predictive accuracy of the proposed algorithm was compared with existing screening recommendations, and is presented as sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV).
Overall, 27 patients were found to have pulmonary hypertension (PH) at RHC, while 22 had no PH. The sensitivity, specificity, PPV and NPV of the proposed algorithm for PAH was 94.1%, 54.5%, 61.5% and 92.3%, respectively; current European Society of Cardiology (ESC)/European Respiratory Society (ERS) guidelines achieved a sensitivity, specificity, PPV and NPV of 94.1%, 31.8%, 51.6% and 87.5%, respectively. In an alternate case scenario analysis, estimating a PAH prevalence of 10%, the proposed algorithm achieved a sensitivity, specificity, PPV and NPV for PAH of 94.1%, 54.5%, 18.7% and 98.8% , respectively.
The combination of NT-proBNP with PFT is a sensitive, yet simple and non-invasive screening strategy for SSc-PAH. Patients with a positive screening result can be referred for echocardiography, and further confirmatory testing for PAH. In this way, it may be possible to shift the burden of routine screening away from echocardiography. The findings of this study should be confirmed in larger studies.
Full-text available · Article · Nov 2013 · Arthritis research & therapy
[Show abstract][Hide abstract]ABSTRACT: Objective
To assess 2-year golimumab efficacy/safety in patients with active rheumatoid arthritis (RA) who had never taken methotrexate (MTX). MethodsRA patients who had never taken MTX (n = 637) were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4) every 4 weeks. Nonresponders based on week 28 swollen/tender joint counts changed treatment as follows: group 1 added golimumab 50 mg, group 2 added MTX, group 3 increased golimumab to 100 mg, and group 4 had no change. Most group 1 patients (85%) initiated golimumab 50 mg + MTX at week 28 or subsequently at week 52. After the last patient completed week 52 and blinding was broken, the investigator could escalate golimumab to 100 mg and/or adjust MTX. The co–primary end points (week 24 American College of Rheumatology criteria for 50% improvement [ACR50] response and week 52 change in Sharp/van der Heijde score [SHS]) have been published previously. We now detail week 52 major secondary end points (Health Assessment Questionnaire [HAQ] disability index [DI] scores and SHS among patients with a baseline C-reactive protein [CRP] level >1.0 mg/dl) and week 104 findings. ResultsAt week 52 for combined groups 3 and 4 versus group 1, the respective proportions of patients achieving ACR20 and ACR50 responses were 63.2% versus 51.9% (P = 0.017) and 45.3% versus 35.6% (P = 0.044). Respective week 52 mean HAQ DI improvements were 0.70 versus 0.58 (P = 0.053); mean SHS changes were 0.41 versus 1.37 (P = 0.006) among all patients and 0.74 versus 2.16 (P = 0.003) in patients with a CRP level >1.0 mg/dl. Improvements were maintained through week 104. Golimumab + MTX for 2 years yielded statistically less radiographic progression than initial MTX or golimumab 100 mg monotherapy. Golimumab safety profiles through weeks 24, 52, and 104 were generally consistent with those observed in other golimumab studies. Conclusion
In RA patients who had never taken MTX, up to 2 years of golimumab + MTX yielded sustained improvements in clinical signs/symptoms, physical function, and radiographic progression.
[Show abstract][Hide abstract]ABSTRACT: Objective
To evaluate the impact of concomitant methotrexate (MTX) on subcutaneous (SC) abatacept immunogenicity, and to assess safety and efficacy. Methods
This phase III, open-label study had a 4-month short-term (ST) period and an ongoing long-term extension (LTE) period. Rheumatoid arthritis patients were stratified to receive SC abatacept (125 mg/week) with (combination) or without MTX (monotherapy), with no intravenous loading dose; patients receiving monotherapy could add MTX in the LTE period. Immunogenicity (percentage of anti-abatacept antibody–positive patients) was assessed. ST and LTE period data are reported, including efficacy through LTE month 14 and safety through LTE month 20. ResultsNinety-six of 100 enrolled patients completed the ST period; 3.9% (combination) and 4.1% of patients (monotherapy) developed transient immunogenicity, and no patients were antibody positive at month 4. Serious adverse events (SAEs) were reported in 3.9% (combination) and 6.1% of patients (monotherapy); 5.9% (combination) and 8.2% of patients (monotherapy) experienced SC injection reactions, and all were mild in intensity. Mean 28-joint Disease Activity Score (DAS28) changes were −1.67 (95% confidence interval [95% CI] −2.06, −1.28; combination) and −1.94 (95% CI −2.46, −1.42; monotherapy) at month 4. Ninety patients entered and were treated in the LTE period; 83.3% (75 of 90) remained ongoing at month 24. One LTE-treated patient (1.1%) developed immunogenicity, 14.4% of patients experienced SAEs, and no SC injection reactions were reported. For patients entering the LTE period, mean DAS28 changes from baseline were −1.84 (95% CI −2.23, −1.34; combination) and −2.86 (95% CI −3.46, −2.27; monotherapy) at month 18. ConclusionSC abatacept did not elicit immunogenicity associated with loss of safety or efficacy, either with or without MTX.