Gastrointestinal adverse drug reaction profile of etanercept:Real world data from patients and healthcare professionals

Objective. We aimed to describe the nature and frequency of gastrointestinal adverse drug reactions (GI-ADRs) of etanercept (ETN) using patient-reported and healthcare professional (HCP)-registered data and compared this frequency with the GI-ADR frequency of the widely used tumor necrosis factor-α inhibitor adalimumab (ADA). Methods. Reported GI-ADRs of ETN for rheumatic diseases were collected from the Dutch Biologic Monitor and DREAM registries. We described the clinical course of GI-ADRs and compared the frequency with ADA in both data sources using Fisher exact test. Results. Out of 416 patients using ETN for inflammatory rheumatic diseases in the Dutch Biologic Monitor, 25 (6%) patients reported 36 GI-ADRs. In the DREAM registries 11 GI-ADRs were registered for 9 patients (2.3%), out of 399 patients using ETN, with an incidence of 7.1 per 1000 patient-years. Most GI-ADRs consisted of diarrhea, nausea, and abdominal pain. GI-ADRs led to ETN discontinuation in 1 patient (4%) and dose adjustment in 4 (16%) in the Dutch Biologic Monitor. Eight GI-ADRs (73%) led to ETN discontinuation in the DREAM registries. The frequency of GI-ADRs of ETN did not significantly differ from GI-ADRs of ADA in both data sources (Dutch Biologic Monitor: ETN 8.7% vs ADA 5.3%, P = 0.07; DREAM: ETN 2.8% vs ADA 4.7%, P = 0.16). Conclusion. Most GI-ADRs associated with ETN concerned gastrointestinal symptoms. These ADRs may lead to dose adjustment or ETN discontinuation. The frequency of ETN-associated GI-ADRs was comparable to the frequency of ADA-associated GI-ADRs. Knowledge about these previously unknown ADRs can facilitate early recognition and improve patient communication

Minimal to no transfer of certolizumab pegol into breast milk: Results from CRADLE, a prospective, postmarketing, multicentre, pharmacokinetic study

Background Women with chronic inflammatory diseases face uncertainty regarding the safety of biologics during breast feeding. CRADLE was the first industry-sponsored study to evaluate certolizumab pegol (CZP) concentrations in human breast milk and estimate average daily infant dose (ADID) of maternal CZP. Methods CRADLE (NCT02154425) was a pharmacokinetic study of lactating mothers receiving CZP. After ≥3 CZP doses, breast milk samples were collected across one dosing period (14 days for 200 mg every 2 weeks [Q2W]; 28 days for 400 mg every 4 weeks [Q4W]). Optimal analytical methods were developed to determine CZP and polyethylene glycol (PEG) levels in breast milk. ADID and relative infant dose (RID) were estimated. Safety events in mothers and infants were assessed. Results 19 CZP-Treated mothers were screened; 17 entered the sampling period: 16 on 200 mg Q2W, 1 on 400 mg Q4W. 77/137 (56%) breast milk samples had no measurable CZP. For 4/17 mothers, all samples were below the lower limit of quantification (LLOQ). Estimated ADID was 0-0.0104 mg/kg/day; median RID: 0.15%. PEG was undetectable in 134/137 samples (results could not be determined in three samples). Infants of CZP-exposed mothers had a safety profile consistent with that of unexposed similar-Age infants. Conclusion When quantifiable, CZP concentrations were <3× LLOQ (<1% plasma concentration observed with therapeutic dose), indicating no/minimal CZP transfer from plasma to breast milk. RID was 0.15% of maternal dose; <10% is considered unlikely to be of clinical concern. No PEG transfer was observed. CZP absorption by infants via breast milk is unlikely due to its low oral bioavailability and Fc-Â-free molecular structure. These findings are reassuring and support continuation of CZP treatment during breast feeding. Trial registration number NCT02154425; Results

Bone marrow edema on magnetic resonance imaging (MRI) of the sacroiliac joints is associated with development of fatty lesions on MRI over a 1-year interval in patients with early inflammatory low back pain: a 2-year followup study

To assess whether bone marrow edema (BME) detected on magnetic resonance imaging (MRI) of the sacroiliac joints (MRI-SIJ) is associated with development of structural changes on both MRI and pelvic radiographs in patients with early inflammatory back pain (IBP). Patients with IBP ≤ 2 years were followed for 2 years with annual MRI-SIJ. MRI were scored for BME and structural changes (erosions and fatty lesions). Pelvic radiographs were graded according to the modified New York (mNY) criteria. With generalized estimated equation analysis, a time trend in the structural change scores was investigated. Sixty-eight patients [38% male; mean (SD) age 34.9 (10.3) yrs] were included. During the 2-year followup, pelvic radiograph grading remained constant. On MRI, the number of erosions per patient increased significantly (mean score 2.5 at baseline and 3.5 at 2-yr followup; p = 0.05). A trend was found for an increase in the number of fatty lesions per patient (mean score 5.4 at baseline and 8.5 at 2-yr followup; p = 0.06). Overall, BME was associated with the development of fatty lesions (right SIJ: OR 3.13, 95% CI 1.06-9.20; left SIJ: OR 22.13, 95% CI 1.27-384.50), preferentially in quadrants showing resolution of BME. In contrast, BME (or the resolution thereof) was not associated with the development of erosions. BME at baseline, especially when it disappears over time, results in the development of fatty lesions, but an association with erosions could not be demonstrate

Validation and implementation of a patient-reported experience measure for patients with rheumatoid arthritis and spondyloarthritis in the Netherlands

Objectives To test the psychometric properties of the United Kingdom's Commissioning for Quality in Rheumatoid Arthritis Patient-Reported Experience Measure (CQRA-PREM) in patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA) and to implement this questionnaire in daily practice in the Netherlands. Methods After a forward-backward translation procedure into Dutch, the CQRA-PREM was tested into two quality registries in daily practice. Face validity was assessed with focus group interviews. Feasibility was evaluated through completion times and interpretability of domain scores through floor and ceiling effects. Internal consistency (Cronbach's alpha coefficients) and homogeneity (corrected item-total correlations) were determined. Divergent validity was assessed by Spearman's rank correlation coefficients (r(s)) between the average scores of domains and outcome measures. The CQRA-PREM was implemented in daily practice, and the results were used in quality improvement cycles. Results Face validity of the CQRA-PREM was good. The CQRA-PREM was completed by 282 patients with SpA and 376 with RA. Median time to complete the CQRA-PREM was 4.7 min. Ceiling effects were found in three out of seven domains. Internal consistency of nearly all domains was considered good (0.65 0.7), suggesting item redundancy. Divergent validity showed that nearly all domains of the CQRA-PREM were at most weakly correlated with outcomes measures (- 0.

Validation and implementation of a patient-reported experience measure for patients with rheumatoid arthritis and spondyloarthritis in the Netherlands

Objectives: To test the psychometric properties of the United Kingdom’s Commissioning for Quality in Rheumatoid Arthritis Patient-Reported Experience Measure (CQRA-PREM) in patients with spondyloarthritis (SpA) and rheumatoid arthritis (RA) and to implement this questionnaire in daily practice in the Netherlands. Methods: After a forward-backward translation procedure into Dutch, the CQRA-PREM was tested into two quality registries in daily practice. Face validity was assessed with focus group interviews. Feasibility was evaluated through completion times and interpretability of domain scores through floor and ceiling effects. Internal consistency (Cronbach’s α coefficients) and homogeneity (corrected item-total correlations) were determined. Divergent validity was assessed by Spearman’s rank correlation coefficients (rs) between the average scores of domains and outcome measures. The CQRA-PREM was implemented in daily practice, and the results were used in quality improvement cycles. Results: Face validity of the CQRA-PREM was good. The CQRA-PREM was completed by 282 patients with SpA and 376 with RA. Median time to complete the CQRA-PREM was 4.7 min. Ceiling effects were found in three out of seven domains. Internal consistency of nearly all domains was considered good (0.65 ≤ α ≤ 0.95). Thresholds for homogeneity were exceeded within three domains (rp > 0.7), suggesting item redundancy. Divergent validity showed that nearly all domains of the CQRA-PREM were at most weakly correlated with outcomes measures (− 0.3 ≤ rs ≤ 0.3). The CQRA-PREM could identify areas of improvement for providing patient-centered care. Conclusion: The CQRA-PREM has acceptable psychometric properties and has shown to be a useful tool in evaluating quality of care from the patients’ perspective in the Netherlands. Trial registration: SpA-Net is registered in the Netherlands Trial Registry (NTR6740). Key Points: • The Commissioning for Quality in Rheumatoid Arthritis Patient-Reported Experience Measure (CQRA-PREM) is a valid measure for assessing patient-centeredness of rheumatology care. • The Dutch version of the CQRA-PREM shows acceptable psychometric properties. • The CQRA-PREM shows to be a useful tool in Plan-Do-Check-Act quality improvement cycles in the Netherlands. • The CQRA-PREM can be used for benchmarking and quality improvement of rheumatology services

Combination therapy for pain management in inflammatory arthritis (rheumatoid arthritis, ankylosing spondylitis, psoriatic arthritis, other spondyloarthritis)

Despite optimal therapy with disease-modifying antirheumatic drugs, many people with inflammatory arthritis (IA) continue to have persistent pain that may require additional therapy. To assess the benefits and safety of combination pain therapy for people with IA (rheumatoid arthritis (RA), ankylosing spondylitis (AS), psoriatic arthritis (PsA) and other spondyloarthritis (SpA)). We planned to assess differences in effects between patients on background disease-modifying antirheumatic drug (DMARD) therapy and patients on no background therapy in subgroup analyses. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); MEDLINE; and EMBASE. We did not impose any date or language restrictions in the search. We also handsearched conference proceedings of the American College of Rheumatology and the European League against Rheumatism (2008-10). Randomised and controlled clinical trials (RCTs and CCTs) assessing combination therapy (at least two drugs from the following classes: analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), opioids, opioid-like drugs and neuromodulators (antidepressants, anticonvulsants and muscle relaxants)) compared with monotherapy, for adults with IA (RA, AS, PsA and other SpA). We speficically excluded studies that did not report pain or studies without a standardised pain scale as an outcome measure. Two review authors independently selected trials for inclusion, assessed risk of bias and extracted data. Twenty-three trials (total of 912 patients) met the inclusion criteria (22 in RA; one in a mixed population of RA and osteoarthritis); all except one were published before 1990. Most study populations were not taking DMARDs (e.g. methotrexate, sulphasalazine, hydroxychloroquine and leflunomide) and all studies were performed prior to the introduction of biologic therapies (e.g. etanercept, infliximab and adalimumab). All trials were at high risk of bias, heterogeneity precluded meta-analysis, and we were only able to report a general description of results.The majority (18 studies, 78%) found no differences between the combination and monotherapy treatments they studied, while five (22%) reported conflicting results, favouring either the combination or monotherapy arms.From the 12 trials on NSAID + analgesic vs NSAID, nine reported no significant difference between the interventions, while three did: in two, the combination therapy achieved better pain control; and the third trial compared combination therapy with two different dosages of monotherapy (NSAID alone) and reported that a high dose phenylbutazone was superior to combination therapy (paracetamol + aspirin), which was superior to low dose phenylbutazone.From the five studies on the combination of two NSAIDS vs one NSAID, four reported no significant differences between interventions, and one reported significantly better pain control with combination therapy.The single trial comparing a combination of opioid + neuromodulator vs opioid reported better pain control with monotherapy.The remaining trials (NSAID + neuromodulator vs NSAID (3 trials); opioid + NSAID vs NSAID (1 trial); and opioid + analgesic vs analgesic (1 trial)) found no significant difference between combination therapy and monotherapy.Information regarding withdrawals due to inadequate analgesia and safety was incompletely reported, but in general there were no differences between combination therapy and monotherapy.No data were available that addressed the value of combination pain therapy or monotherapy for people with IA who have optimal disease suppression. There were no studies that included patients with AS, PsA or SpA. Based on 23 trials, all at high risk of bias, there is insufficient evidence to establish the value of combination therapy over monotherapy for people with IA. Importantly, there are no studies addressing the value of combination therapy for patients with IA who have persistent pain despite optimal disease suppression. Well designed trials are needed to address this questio

Do extra-articular manifestations influence outcome in ankylosing spondylitis?: a 12 year follow-up study

Pathophysiology and treatment of rheumatic disease

BIOLOGICALS AND SWITCH IN RHEUMATOID ARTHRITIS THROUGHOUT TIME - ARE WE BEING MORE AGGRESSIVE?

Objectives: To investigate the switches performed in patients with rheumatoid arthritis under biolo-gical therapy and specifically comparing the swi-tches from earlier days with more recent switches. Patients and methods: Patients with rheumatoid arthritis under biological therapy followed at Hospi-tal Garcia de Orta, Almada, and included in the Rheumatic Diseases Portuguese Register (Reuma.Pt) were included in this study. Switches occurring before and after January 2007 were compared with respect to patients' demographic and clinical characteristics, such as disease activity and duration of biological therapy. The survival of the first biological agent was compared between patients starting biological therapy before and after 2007. EULAR response and remission rate at the last evaluation were calculated. Comparisons between groups were established using a t-test or chi--square, as appropriate. Survival curves of the first biological were compared through the logrank test. Results: In total, 123 patients were included in the analysis (mean age 57.0 ± 13.1 years and mean di-sease duration 11.7 ± 8.0 years). A total of 85 swi-tches were documented, 20% of which took place before 2007. Comparing the switches before and after 2007, the latter were registered among older patients (recent switches 56.2 ± 12.9 years vs older switches 48.9 ± 11.0 years, p=0.04) and with a shor-ter duration of the first biological agent (recent switches 461.9 ± 293.2 days vs older switches 773.7 ± 475.8 days, p=0.03). No further significant diffe-rences were found, including the disease activity. The survival of the first biological was shorter in patients starting biological therapy after 2007 (2949 days for biological onset before 2007 and 818 days for onset after 2007, p <0.001). A good EULAR res-ponse was achieved by 19% and 30% of the patients, before and after 2007, respectively (p = 0.23). Remission was achieved by 14% and 22% of the patients, before and after 2007, respectively (p = 0.30). Conclusions: Switches were more frequently performed in more recent years, in older patients and with a shorter duration of biological therapy. A trend towards a better and more targeted control of the disease could be discussed in light of our results. Although switches were more frequently performed in more recent years, in older patients and with a shorter duration of biological therapy, there is still room for improvement when aiming at remission, for example by applying a tighter therapy strategy like the "treat to target model