Aggrecanolysis and in vitro matrix degradation in the immature bovine meniscus: mechanisms and functional implications

Introduction

The objective of this study was to assess the impact of certolizumab pegol (CZP) treatment on health-related quality of life (HRQoL), fatigue and other patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA).

Methods

Patients with active RA (N = 982) were randomized 2:2:1 to subcutaneous CZP (400 mg at weeks 0, 2 and 4; followed by CZP 200 mg or 400 mg) plus methotrexate (MTX) every other week, or placebo (PBO) plus MTX. PRO assessments included HRQoL, fatigue, physical function, arthritis pain and disease activity. Adjusted mean changes from baseline in all PROs were obtained using analysis of covariance (ANCOVA) applying last observation carried forward (LOCF) imputation. The proportion of patients achieving clinically meaningful improvements in each PRO was obtained using logistic regression and by applying non-responder imputation to missing values after rescue medication or withdrawal. The correlations between PRO responses and clinical responses were also assessed by tetrachoric correlation using non-responder imputation.

Results

Patients treated with CZP plus MTX reported significant (P < 0.001), clinically meaningful improvements in HRQoL at the first assessment (week 12); reductions in fatigue, disease activity and pain and improvements in physical function were reported at week 1. In particular, CZP-treated patients reported improvements in mental health. Mean changes from baseline in the SF-36 Mental Component Summary (MCS) at week 52 for CZP 200 mg and 400 mg plus MTX, and PBO plus MTX were 6.4, 6.4 and 2.1, respectively (P < 0.001). In addition, mental health and vitality scores in CZP-treated patients approached age- and gender-adjusted US population norms. Improvements in all PROs were sustained. Similar benefits were reported with both CZP doses. Changes in SF-36 MCS scores had the lowest correlation with disease activity scores (DAS28) and American College of Rheumatology 20% improvement (ACR20) response rates, while improvements in pain showed the highest correlation.

Conclusions

Treatment with CZP plus MTX resulted in rapid and sustained improvements in all PROs, indicating that the benefits of CZP extend beyond clinical efficacy endpoints into areas that are more relevant and meaningful for patients on a daily basis.

Trial Registration

ClinicalTrials.gov NCT00152386.     

Use of a baseline risk score to identify the risk of serious infectious events in patients with rheumatoid arthritis during certolizumab pegol treatment

Background

The risk of serious infectious events (SIEs) is increased in patients with rheumatoid arthritis (RA). The aim of this study was to develop an age-adjusted comorbidity index (AACI) to predict, using baseline characteristics, the SIE risk in patients with RA treated with certolizumab pegol (CZP).

Methods

Data of CZP-treated patients with RA were pooled from the RAPID1/RAPID2 randomized controlled trials (RCT CZP) and their open-label extensions (All CZP). Predictors of the first SIE were examined using multivariate Cox models. The AACI was developed by assigning specific weights to patient age and comorbidities on the basis of relative SIE risk. SIE rates were predicted using AACI score and baseline glucocorticoid use, and they were compared with observed rates. The percentage of patients in each SIE risk group achieving low disease activity (LDA)/remission was examined at 1 year of treatment.

Results

Among 1224 RCT CZP patients, 40 reported ≥?1 SIE (incidence rate [IR] 5.09/100 patient-years [PY]), and 201 of 1506 All CZP patients reported ≥?1 SIE (IR 3.66/100 PY). Age ≥?70 years, diabetes mellitus, and chronic obstructive pulmonary disease/asthma made the greatest contributions to AACI score. SIE rates predicted using AACI and glucocorticoid use at baseline showed good agreement with observed SIE rates across low-risk and high-risk groups. At 1 year, more high-risk All CZP patients than low-risk All CZP patients reported SIEs (IR 8.4/100 PY vs. IR 3.4/100 PY). Rates of LDA/remission were similar between groups.

Conclusions

AACI and glucocorticoid use were strong baseline predictors of SIE risk in CZP-treated patients with RA. Predicted SIE risk was not associated with patients’ likelihood of clinical response. This SIE risk score may provide a valuable tool for clinicians when considering the risk of infection in individual patients with RA.

Trial registration

ClinicalTrials.gov, NCT00152386 (registered 7 September 2005); NCT00160602 (registered 8 September 2005); NCT00175877 (registered 9 September 2005); and NCT00160641 (registered 8 September 2005).

     

Health-related quality of life and functional ability in patients with early arthritis during remission steered treatment: results of the IMPROVED study

Introduction

The aim of this study was to investigate patient reported outcomes (PROs) of functional ability and health related quality of life (HRQoL) in patients with early (rheumatoid) arthritis during one year of remission steered treatment.

Methods

In this study, 610 patients with early rheumatoid arthritis (RA) or undifferentiated arthritis (UA) were treated with methotrexate (MTX) and tapered high dose of prednisone. Patients in early remission (Disease Activity Score (DAS) <1.6 after 4 months) tapered prednisone to zero and when in persistent remission, also tapered MTX. Patients not in early remission were randomized to either MTX + hydroxychloroquine + sulphasalazine + prednisone (arm 1) or to MTX + adalimumab (arm 2). Every 4 months, patients filled out the Health Assessment Questionnaire (HAQ) and the McMaster Toronto Arthritis Patient Preference Questionnaire (MACTAR), the Short Form 36 (SF-36) and visual analogue scales (VAS). Change scores were compared between treatment groups. The association with achieving remission was analyzed using linear mixed models.

Results

During year 1, patients who achieved early remission had the most improvement in PROs with scores comparable to the general population. Patients in the randomization arms showed less improvement. Scores were comparable between the arms. There was a significant association between achieving remission and scores of HAQ, MACTAR and physical HRQoL.

Conclusions

In early arthritis, PROs of functional ability and HRQoL after one year of remission steered treatment reach normal values in patients who achieved early remission. In patients not in early remission, who were randomized to two strategy arms, PROs improved less, with similar scores in both treatment arms.

Trial registrations

ISRCTN11916566 and EudraCT2006-006186-16     

Certolizumab pegol plus methotrexate 5-year results from the rheumatoid arthritis prevention of structural damage (RAPID) 2 randomized controlled trial and long-term extension in rheumatoid arthritis patients

IntroductionAs patients with rheumatoid arthritis (RA) receive treatment with anti-tumour necrosis factors over several years, it is important to evaluate their long-term safety and efficacy. The objective of this study was to examine the safety and benefits of certolizumab pegol (CZP)+methotrexate (MTX) treatment for almost 5 years in patients with RA.MethodsPatients who completed the 24-week Rheumatoid Arthritis Prevention of Structural Damage (RAPID) 2 randomized controlled trial (RCT; {"type":"clinical-trial","attrs":{"text":"NCT00160602","term_id":"NCT00160602"}}NCT00160602), or who were American College of Rheumatology (ACR) 20 non-responders at Week 16, entered the open-label extension (OLE; {"type":"clinical-trial","attrs":{"text":"NCT00160641","term_id":"NCT00160641"}}NCT00160641). After ≥6 months treatment with CZP 400 mg every two weeks (Q2W), dose was reduced to 200 mg Q2W, the approved maintenance dose. Safety data are presented from all patients who received ≥1 dose CZP (Safety population, n=612). Efficacy data are presented to Week 232 for the intent-to-treat (ITT, n=492) and Week 24 CZP RCT Completer (n=342) populations, and through 192 weeks of dose-reduction for the Dose-reduction population (patients whose CZP dose was reduced to 200 mg, n=369). Radiographic progression (modified total Sharp score change from RCT baseline >0.5) to Week 128 is reported for the Week 24 CZP Completers.ResultsIn the RCT, 619 patients were randomized to CZP+MTX (n=492) or placebo+MTX (n=127). Overall, 567 patients (91.6%) entered the OLE: 447 CZP and 120 placebo patients. Of all randomized patients, 358 (57.8%) were ongoing at Week 232. Annual drop-out rates during the first four years ranged from 8.4–15.0%. Event rates per 100 patient-years were 163.0 for adverse events (AEs) and 15.7 for serious AEs. Nineteen patients (3.1%) had fatal AEs (incidence rate=0.8). Clinical improvements in the RCT were maintained to Week 232 in the CZP Completers: mean Disease Activity Score 28 (Erythrocyte Sedimentation Rate) change from baseline was −3.4 and ACR20/50/70 responses 68.4%/47.1%/25.1% (non-responder imputation). Similar improvements observed in the ITT were maintained following dose-reduction. 73.2% of CZP Completers had no radiographic progression at Week 128.ConclusionsIn patients with active RA despite MTX therapy, CZP was well tolerated, with no new safety signals identified. CZP provided sustained improvements in clinical outcomes for almost 5 years.

Trial registration

ClinicalTrials.gov, {"type":"clinical-trial","attrs":{"text":"NCT00160602","term_id":"NCT00160602"}}NCT00160602 and {"type":"clinical-trial","attrs":{"text":"NCT00160641","term_id":"NCT00160641"}}NCT00160641. Registered 8 September 2005.

Electronic supplementary material

The online version of this article (doi:10.1186/s13075-015-0767-2) contains supplementary material, which is available to authorized users.     

The Outcomes of a 12-Week Internet Intervention Aimed at Improving Fitness and Health-Related Quality of Life in Overweight Adolescents: The Young & Active Controlled Trial

Background

Overweight and obesity among adolescents may have consequences, with potentially lasting effects on health and health-related quality of life (HRQoL). Excess weight is also associated with decreases in physical activity and cardiorespiratory fitness. The aim of the current study was to investigate the short-term effects of a 12-week Internet intervention in a primary care setting intended to increase cardiorespiratory fitness and HRQoL among overweight and obese adolescents.

Methods

In this controlled trial, participants (13–15 years) were non-randomly allocated to an intervention- or a control group. The intervention group received 12-weeks access to an online program providing tailored physical activity counseling based on principles from Self-determination Theory and Motivational Interviewing. The control group received standard follow-up by the school nurses. The primary outcome measure of cardiorespiratory fitness was determined using a shuttle run test. The secondary outcomes: HRQoL, leisure time exercise, body image and self-determined motivation for physical activity and exercise, were assessed by self-report measures. Age- and gender-adjusted body mass index (BMI) was calculated based on measurements of height and weight. To compare pre-to post intervention differences within groups, a paired samples t-test was used while crude differences between groups were analyzed with an independent samples t-test.

Results

Of the 120 participants, 108 completed the study, 75 in the intervention group and 33 in the control group. Exposure to the intervention had a small effect on cardiorespiratory fitness (0.14; 95% CI [0.01;0.28]; P = 0.04), and a moderate effect on HRQoL (5.22; 95% CI [0.90; 9.53]; P = 0.02). Moreover, the control group increased significantly in BMI, yielding a moderate preventive effect on BMI (−0.39; 95% CI [−0.74;−0.03]; P = 0.03) for the intervention group.

Conclusion

The results suggest that the Internet intervention with tailored physical activity counseling can have beneficial short-term effect on cardiorespiratory fitness, HRQoL and BMI among adolescents with overweight and obesity.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01700309","term_id":"NCT01700309"}}NCT01700309     

The effect of smoking and alcohol consumption on markers of systemic inflammation,immunoglobulin levels and immune response following pneumococcal vaccination in patients with arthritis

Introduction

The purpose of this research was to study the influence of cigarette smoking and alcohol consumption on immune response to heptavalent pneumococcal conjugate vaccine, immunoglobulin levels (Ig) and markers of systemic inflammation in patients with rheumatoid arthritis (RA) or spondylarthropathy (SpA).

Methods

In total, 505 patients were vaccinated. Six pre-specified groups were enrolled: RA on methotrexate (MTX) treatment in some cases other disease-modifying antirheumatic drugs (DMARDs) (I); RA on anti-tumour necrosis factor (TNF) as monotherapy (II); RA on anti-TNF+MTX+ possibly other DMARDs (III); SpA on anti-TNF as monotherapy (IV); SpA on anti-TNF+MTX+ possibly other DMARDs (V); and SpA on nonsteroidal anti-inflammatory drugs (NSAIDs) and/or analgesics (VI). Smoking (pack-years) and alcohol consumption (g/week) were calculated from patient questionnaires. Ig, C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR) were determined at vaccination. IgG antibodies against serotypes 23F and 6B were measured at vaccination and after four to six weeks using standard ELISA. Immune response (ratio between post- and pre-vaccination antibodies; immune response (IR)) and positive immune response (≥2-fold increase in pre-vaccination antibodies; posIR) were calculated.

Results

Eighty-eight patients (17.4%) were current smokers. Smokers had higher CRP and ESR, lower IgG and lower IR for both serotypes (P between 0.012 and 0.045). RA patients on MTX who smoked ≥1pack-year had lower posIR for both serotypes (P = 0.021; OR 0.29; CI 0.1 to 0.7) compared to never-smokers. Alcohol consumption was associated with lower CRP (P = 0.05) and ESR (P = 0.003) but did not influence IR or Ig levels.

Conclusion

Smoking predicted impaired immune response to pneumococcal conjugate vaccine in RA patients on MTX. Smokers with arthritis had higher inflammatory markers and lower IgG regardless of diagnosis and treatment. Low to moderate alcohol consumption was related to lower levels of inflammation markers but had no impact on immune response.

Trial registration

EudraCT EU 2007-006539-29 and NCT00828997     

Botulinum Toxin to Improve Results in Cleft Lip Repair: A Double-Blinded,Randomized, Vehicle-Controlled Clinical Trial

Background

Most patients with facial scarring would value even a slight improvement in scar quality. Botulinum toxin A is widely used to alleviate facial dynamic rhytides but is also believed to improve scar quality by reducing wound tension during healing. The main objective was to assess the effect of Botulinum toxin on scars resultant from standardized upper lip wounds.

Methods

In this double-blinded, randomized, vehicle-controlled, prospective clinical trial, 60 consecutive consenting adults undergoing cleft lip scar revision (CLSR) surgery between July 2010 and March 2012 were randomized to receive botulinum toxin A (n = 30) or vehicle (normal saline; n = 30) injections into the subjacent orbicularis oris muscle immediately after wound closure. Scars were independently assessed at 6-months follow-up in blinded fashion using: Vancouver Scar Scale (VSS), Visual Analogue Scale (VAS) and photographic plus ultrasound measurements of scar widths.

Results

58 patients completed the trial. All scar assessment modalities revealed statistically significantly better scars in the experimental than the vehicle-control group.

Conclusion

Quality of surgical upper lip scars, which are oriented perpendicular to the direction of pull of the underlying orbicularis oris muscle, is significantly improved by its temporary paralysis during wound healing.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01429402","term_id":"NCT01429402"}}NCT01429402     

Quality of Life,Safety and Efficacy Profile of Thermostable Flolan in Pulmonary Arterial Hypertension

Background

Flolan (epoprostenol sodium) is most commonly prescribed to patients with severe pulmonary arterial hypertension (PAH) owing to the requirement that the drug be delivered by continuous intravenous infusion and the reconstituted solution may only be administered up to 24 hours when it is maintained between a temperature of 2°C and 8°C. The aim of this single-arm, open label study was to describe the effects of the new thermostable formulation of Flolan on health-related quality of life (HRQoL) and ease of administration in subjects switching from the currently marketed Flolan to the reformulated product.

Methods

Following a 4-week run-in period and after 4 weeks of treatment with the reformulated product, patients completed the SF-36 HRQoL questionnaire and a study-specific questionnaire evaluating ease of administration, along with World Health Organization (WHO) functional class, six-minute walked distance (6MWD) and N-terminal-pro B-type natriuretic peptide (NT-proBNP) assessment.

Results

16 participants completed the study. The SF-36 scores remained unchanged from baseline to Week 4. Conversely, there were small improvements for the majority of the study-specific questionnaire items and 14 (88%) subjects preferred the reformulated product to the currently marketed Flolan. There was no significant change in the dose of reformulated product, 6MWD, Borg dyspnoea index, WHO functional class and mean NT-proBNP levels. No significant changes in haemodynamic parameters were seen from baseline to 2 hours post transition in a subset of patients undergoing catheterization.

Conclusion

The reformulated product was not associated with significant improvement in HRQoL compared with the currently marketed Flolan as measured by the SF-36. However, most subjects preferred the reformulated product to the currently marketed Flolan. Moreover, the 2 formulations of Flolan had similar safety and efficacy profiles.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01462565","term_id":"NCT01462565"}}NCT01462565     

Improved patient-reported outcomes in patients with psoriatic arthritis treated with abatacept: results from a phase 3 trial

Background

To explore the effect of abatacept treatment on patient-reported outcomes (PROs) in psoriatic arthritis (PsA).

Methods

Patients with PsA were randomised (1:1) to subcutaneous abatacept 125?mg weekly/placebo for 24?weeks with early escape (EE) to open-label abatacept (week 16). Adjusted mean changes from baseline to weeks 16 (all patients) and 24 (non-EE responders) in Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36; physical and mental component summary and domains), Dermatology Life Quality Index and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) were evaluated. Subpopulations were analysed by baseline C-reactive protein (CRP) level (> vs?≤?upper limit of normal [ULN]) and prior tumour necrosis factor inhibitor (TNFi) exposure. Proportions of patients reporting improvements ≥ minimal clinically important differences (MCIDs) and?≥?normative values (NVs) in HAQ-DI, SF-36 and FACIT-F (week 16 before EE) were analysed.

Results

In total population, numerically higher improvements in most PROs were reported with abatacept (n?=?213) versus placebo (n?=?211) at both time points (P?>?0.05). Higher proportions of abatacept versus placebo patients reported PRO improvements ≥ MCID and?≥?NV at week 16. At week 16, all PRO improvements were numerically greater (P?>?0.05) in patients with baseline CRP?>?ULN versus CRP?≤?ULN (all significant [95% confidence interval] for abatacept vs placebo); improvements in SF-36 component summaries and FACIT-F were greater in TNFi-naïve versus TNFi-exposed patients (abatacept > placebo). Week 24 subgroup data were difficult to interpret due to low patient numbers.

Conclusions

Abatacept treatment improved PROs in patients with PsA versus placebo, with better results in elevated baseline CRP and TNFi-naïve subpopulations.

Trial registration

ClinicalTrials.gov number, NCT01860976 (funded by Bristol-Myers Squibb); date of registration: 23 May 2013.

     

A Randomised Trial to Compare the Safety,Tolerability and Efficacy of Three Drug Combinations for Intermittent Preventive Treatment in Children

Background

Results from trials of intermittent preventive treatment (IPT) in infants and children have shown that IPT provides significant protection against clinical malaria. Sulfadoxine-pyrimethamine (SP) given alone or in combination with other drugs has been used for most IPT programmes. However, SP resistance is increasing in many parts of Africa. Thus, we have investigated whether SP plus AQ, SP plus piperaquine (PQ) and dihydroartemisinin (DHA) plus PQ might be equally safe and effective when used for IPT in children in an area of seasonal transmission.

Methods

During the 2007 malaria transmission season, 1008 Gambian children were individually randomized to receive SP plus amodiaquine (AQ), SP plus piperaquine (PQ) or dihydroartemisinin (DHA) plus PQ at monthly intervals on three occasions during the peak malaria transmission season. To determine the risk of side effects following drug administration, participants in each treatment group were visited at home three days after the start of each round of drug administration and a side effects questionnaire completed. To help establish whether adverse events were drug related, the same questionnaire was administered to 286 age matched control children recruited from adjacent villages. Morbidity was monitored throughout the malaria transmission season and study children were seen at the end of the malaria transmission season.

Results

All three treatment regimens showed good safety profiles. No severe adverse event related to IPT was reported. The most frequent adverse events reported were coughing, diarrhoea, vomiting, abdominal pain and loss of appetite. Cough was present in 15.2%, 15.4% and 18.7% of study subjects who received SP plus AQ, DHA plus PQ or SP plus PQ respectively, compared to 19.2% in a control group. The incidence of malaria in the DHA plus PQ, SP plus AQ and SP plus PQ groups were 0.10 cases per child year (95% CI: 0.05, 0.22), 0.06 (95% CI: 0.022, 0.16) and 0.06 (95% CI: 0.02, 0.15) respectively. The incidence of malaria in the control group was 0.79 cases per child year (0.58, 1.08).

Conclusion

All the three regimens of IPT in children were safe and highly efficacious

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00561899","term_id":"NCT00561899"}}NCT00561899     

Cost-effectiveness of peer-delivered interventions for cocaine and alcohol abuse among women: a randomized controlled trial

Aims

To determine whether the additional interventions to standard care are cost-effective in addressing cocaine and alcohol abuse at 4 months (4 M) and 12 months (12 M) from baseline.

Method

We conducted a cost-effectiveness analysis of a randomized controlled trial with three arms: (1) NIDA''s Standard intervention (SI); (2) SI plus a Well Woman Exam (WWE); and, (3) SI, WWE, plus four Educational Sessions (4ES).

Results

To obtain an additional cocaine abstainer, WWE compared to SI cost $7,223 at 4 M and $3,611 at 12 M. Per additional alcohol abstainer, WWE compared to SI cost $3,611 and $7,223 at 4 M and 12 M, respectively. At 12 M, 4ES was dominated (more costly and less effective) by WWE for abstinence outcomes.

Conclusions

To our knowledge, this is the first cost-effectiveness analysis simultaneously examining cocaine and alcohol abuse in women. Depending on primary outcomes sought and priorities of policy makers, peer-delivered interventions can be a cost-effective way to address the needs of this growing, underserved population.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01235091","term_id":"NCT01235091"}}NCT01235091     

Rituximab and abatacept but not tocilizumab impair antibody response to pneumococcal conjugate vaccine in patients with rheumatoid arthritis

Introduction

The objective of the study was to investigate the impact of newer biologic treatments including rituximab, abatacept and tocilizumab on antibody response following pneumococcal vaccination using a 7-valent conjugate vaccine in patients with established rheumatoid arthritis (RA).

Methods

Patients with RA receiving rituximab, abatacept or tocilizumab as monotherapy or combined with methotrexate (MTX) participated in the study. Specific IgG antibodies against 23F and 6B serotypes were measured at vaccination and 4 to 6 weeks after vaccination using standardised ELISA. Geometric mean antibody levels (GML) were calculated. Antibody response (AR) was defined as the ratio between post- and pre-vaccination antibody levels and a positive antibody response (posAR) was AR ≥2.

Results

In total, 88 patients were enrolled in the study. Of 55 patients treated with rituximab, 26 (46%) were on concomitant MTX. Of patients receiving abatacept (n = 17) and tocilizumab (n = 16) biologic treatment was given in combination with MTX in 13 (76%) and 9 (56%) patients, respectively. Patients treated with rituximab had significantly lower AR compared to those on tocilizumab, as well as compared to previously reported RA patients on MTX and controls (spondylarthropathy patients treated with NSAIDs and/or analgesics). In total, 10.3% of patients on rituximab monotherapy and no patient on rituximab + MTX had posAR for both serotypes. For abatacept and tocilizumab the corresponding figures were 17.6% and 50%.

Conclusion

In this cohort of patients with established RA, treatment with rituximab and abatacept was associated with diminished antibody response but this was most pronounced for rituximab. Pneumococcal conjugate vaccine administrated during ongoing tocilizumab treatment seems to be associated with sufficient antibody response. Pneumococcal vaccination should preferably be encouraged before initiation of rituximab or abatacept treatment.

Trial registration

NCT00828997 and EudraCT EU 2007-006539-29.     

Discriminant validity,responsiveness and reliability of the arthritis-specific Work Productivity Survey assessing workplace and household productivity in patients with psoriatic arthritis

Introduction

The novel arthritis-specific Work Productivity Survey (WPS) was developed to estimate patient productivity limitations associated with arthritis within and outside the home, which is an unmet need in psoriatic arthritis (PsA). The WPS has been validated in rheumatoid arthritis. This report assesses the discriminant validity, responsiveness and reliability of the WPS in adult-onset PsA.

Methods

Psychometric properties were assessed using data from the RAPID-PsA trial ({"type":"clinical-trial","attrs":{"text":"NCT01087788","term_id":"NCT01087788"}}NCT01087788) investigating certolizumab pegol (CZP) efficacy and safety in PsA. WPS was completed at baseline and every 4 weeks until Week 24. Validity was evaluated at baseline via known-groups defined using first and third quartiles of patients’ Disease Activity Score 28 based on C-reactive protein (DAS28(CRP)), Health Assessment Questionnaire-Disability Index (HAQ-DI), Short Form-36 (SF-36) items and PsA Quality of Life (PsAQoL) scores. Responsiveness and reliability were assessed by comparing WPS mean changes at Week 12 in American College of Rheumatology 20% improvement criteria (ACR20) or HAQ-DI Minimal Clinically Important Difference (MCID) 0.3 responders versus non-responders, as well as using standardized response means (SRM). All comparisons were conducted on the observed cases in the Randomized Set, regardless of the randomization group, using a non-parametric bootstrap-t method.

Results

Compared with patients with a better health state, patients with a worse health state had on average 2 to 6 times more household work days lost, more days with reduced household productivity, more days missed of family/social/leisure activities, more days with outside help hired and a significantly higher interference of arthritis per month. Among employed patients, those with a worse health state had 2 to 4 times more workplace days lost, more days with patient workplace productivity reduced, and a significantly higher interference of arthritis on patient workplace productivity versus patients with a better health state. WPS was also responsive to clinical changes, with responders having significantly larger improvements at Week 12 in WPS scores versus non-responders. The effect sizes for changes in productivity in ACR20 or HAQ-DI MCID responders were moderate (0.5 < SRM < 0.8) or small.

Conclusions

These analyses demonstrate the validity, responsiveness and reliability of the WPS, as an instrument for the measurement of patient productivity within and outside the home in an adult-onset PsA population.     

Good correlation between changes in objective and subjective signs of inflammation in patients with short- but not long duration of axial spondyloarthritis treated with tumor necrosis factor-blockers

Introduction

The aim of this study was to investigate the influence of symptom duration on treatment response and on the correlation between improvements in patient reported outcomes (PRO) and objective inflammation in patients with axial spondylarthritis (SpA) treated with etanercept (ETA) or adalimumab (ADA).

Methods

Data from 112 patients with axial SpA originally enrolled in two randomized controlled clinical trials were pooled and analyzed after one year of treatment with ETA (n = 66) or ADA (n = 46). Patients with <4 years and ≥4 years of disease were compared for improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS), C-reactive protein (CRP) and magnetic resonance imaging (MRI) score for sacroiliac joints (SIJ).

Results

Patients with <4 years of disease showed a significantly better improvement than longer diseased patients in BASDAI (3.2 (95% confidence interval (CI): 2.7 to 3.7) vs. 1.7 (1.1 to 2.2)), BASFI, BASMI and ASDAS (1.6 (1.4 to 1.8) vs. 0.9 (0.7 to 1.1)). The change in BASDAI showed a significant correlation with the change in SIJ score (Spearman’s rank correlation coefficient (rho) = 0.37, P = 0.01) and the change in CRP (rho = 0.45, P = 0.001) in patients with <4 years of disease. For long diseased patients this correlation was poor and did not achieve statistical significance (rho = 0.13, P = 0.46; rho = 0.22, P = 0.13 respectively).

Conclusion

The low correlation between change of PROs and change of objective signs of inflammation seen in axial SpA patients with longer symptom duration treated with tumor necrosis factor-blocker seems to indicate that inflammation is not the only cause of the patients’ symptoms, while inflammation seems to be the major cause in short diseased patients.

Trial registration

Clinical Trials.gov NCT00844142 (Trial 1); NCT00235105 (Trial 2)     

A Cluster Randomized Trial of Routine HIV-1 Viral Load Monitoring in Zambia: Study Design,Implementation, and Baseline Cohort Characteristics

Background

The benefit of routine HIV-1 viral load (VL) monitoring of patients on antiretroviral therapy (ART) in resource-constrained settings is uncertain because of the high costs associated with the test and the limited treatment options. We designed a cluster randomized controlled trial to compare the use of routine VL testing at ART-initiation and at 3, 6, 12, and 18 months, versus our local standard of care (which uses immunological and clinical criteria to diagnose treatment failure, with discretionary VL testing when the two do not agree).

Methodology

Dedicated study personnel were integrated into public-sector ART clinics. We collected participant information in a dedicated research database. Twelve ART clinics in Lusaka, Zambia constituted the units of randomization. Study clinics were stratified into pairs according to matching criteria (historical mortality rate, size, and duration of operation) to limit the effect of clustering, and independently randomized to the intervention and control arms. The study was powered to detect a 36% reduction in mortality at 18 months.

Principal Findings

From December 2006 to May 2008, we completed enrollment of 1973 participants. Measured baseline characteristics did not differ significantly between the study arms. Enrollment was staggered by clinic pair and truncated at two matched sites.

Conclusions

A large clinical trial of routing VL monitoring was successfully implemented in a dynamic and rapidly growing national ART program. Close collaboration with local health authorities and adequate reserve staff were critical to success. Randomized controlled trials such as this will likely prove valuable in determining long-term outcomes in resource-constrained settings.

Trial Registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT00929604","term_id":"NCT00929604"}}NCT00929604     

Prevalence of methotrexate intolerance in rheumatoid arthritis and psoriatic arthritis

Introduction

The aim of this study was to determine the prevalence of gastrointestinal and behavioural symptoms occurring before (anticipatory/associative) and after methotrexate (MTX) administration, termed MTX intolerance, in rheumatoid (RA) and psoriatic arthritis (PsA).

Methods

Methotrexate Intolerance Severity Score (MISS), previously validated in juvenile idiopathic arthritis patients, was used to determine MTX intolerance prevalence in 291 RA/PsA patients. The MISS consisted of four domains: abdominal pain, nausea, vomiting and behavioural symptoms, occurring upon, prior to (anticipatory) and when thinking of MTX (associative). MTX intolerance was defined as ≥6 on the MISS with ≥1 point on anticipatory and/or associative and/or behavioural items.

Results

A total of 123 patients (42.3%) experienced at least one gastrointestinal adverse effect. The prevalence of MTX intolerance was 11%. MTX intolerance prevalence was higher in patients on parenteral (20.6%) than on oral MTX (6.2%) (p < 0.001).

Conclusion

Besides well-known gastrointestinal symptoms after MTX, RA and PsA patients experienced these symptoms also before MTX intake. RA and PsA patients on MTX should be closely monitored with the MISS for early detection of MTX intolerance, in order to intervene timely and avoid discontinuation of an effective treatment.     

A phasing and imputation method for pedigreed populations that results in a single-stage genomic evaluation

Background

Efficient, robust, and accurate genotype imputation algorithms make large-scale application of genomic selection cost effective. An algorithm that imputes alleles or allele probabilities for all animals in the pedigree and for all genotyped single nucleotide polymorphisms (SNP) provides a framework to combine all pedigree, genomic, and phenotypic information into a single-stage genomic evaluation.

Methods

An algorithm was developed for imputation of genotypes in pedigreed populations that allows imputation for completely ungenotyped animals and for low-density genotyped animals, accommodates a wide variety of pedigree structures for genotyped animals, imputes unmapped SNP, and works for large datasets. The method involves simple phasing rules, long-range phasing and haplotype library imputation and segregation analysis.

Results

Imputation accuracy was high and computational cost was feasible for datasets with pedigrees of up to 25 000 animals. The resulting single-stage genomic evaluation increased the accuracy of estimated genomic breeding values compared to a scenario in which phenotypes on relatives that were not genotyped were ignored.

Conclusions

The developed imputation algorithm and software and the resulting single-stage genomic evaluation method provide powerful new ways to exploit imputation and to obtain more accurate genetic evaluations.     

Quality of Life after Diet or Exercise-Induced Weight Loss in Overweight to Obese Postmenopausal Women: The SHAPE-2 Randomised Controlled Trial

Introduction

This study investigates the effect of a modest weight loss either by a calorie restricted diet or mainly by increased physical exercise on health related quality of life (HRQoL) in overweight-to-obese and inactive postmenopausal women. We hypothesize that HRQoL improves with weight loss, and that exercise-induced weight loss is more effective for this than diet-induced weight loss.

Methods

The SHAPE-2 trial was primarily designed to evaluate any additional effect of weight loss by exercise compared with a comparable amount of weight loss by diet on biomarkers relevant for breast cancer risk. In the present analysis we focus on HRQoL. We randomly assigned 243 eligible women to a diet (n = 97), exercise (n = 98), or control group (n = 48). Both interventions aimed for 5–6 kg weight loss. HRQoL was measured at baseline and after 16 weeks by the SF-36 questionnaire.

Results

Data of 214 women were available for analysis. Weight loss was 4.9 kg (6.1%) and 5.5 kg (6.9%) with diet and exercise, respectively. Scores of the SF-36 domain ‘health change’ increased significantly by 8.8 points (95% CI 1.6;16.1) with diet, and by 20.5 points (95% CI 13.2;27.7) with exercise when compared with control. Direct comparison of diet and exercise showed a statistically significantly stronger improvement with exercise. Both intervention groups showed a tendency towards improvements in most other domains, which were more pronounced in the exercise group, but not statistically different from control or each other.

Conclusion

In a randomized trial in overweight-to-obese and inactive postmenopausal women a comparable 6%-7% weight loss was achieved by diet-only or mainly by exercise and showed improvements in physical and mental HRQoL domains, but results were not statistically significant in either the diet or exercise group. However, a modest weight loss does lead to a positive change in self-perceived health status. This effect was significantly larger with exercise-induced weight loss than with comparable diet-induced weight loss.

Trial Registration

ClinicalTrials.gov NCT01511276     

Two-year home-based nocturnal noninvasive ventilation added to rehabilitation in chronic obstructive pulmonary disease patients: A randomized controlled trial

Background

The use of noninvasive intermittent positive pressure ventilation (NIPPV) in chronic obstructive pulmonary disease (COPD) patients with chronic hypercapnic respiratory failure remains controversial as long-term data are almost lacking.The aim was to compare the outcome of 2-year home-based nocturnal NIPPV in addition to rehabilitation (NIPPV + PR) with rehabilitation alone (PR) in COPD patients with chronic hypercapnic respiratory failure.

Methods

Sixty-six patients could be analyzed for the two-year home-based follow-up period. Differences in change between the NIPPV + PR and PR group were assessed by a linear mixed effects model with a random effect on the intercept, and adjustment for baseline values. The primary outcome was health-related quality of life (HRQoL); secondary outcomes were mood state, dyspnea, gas exchange, functional status, pulmonary function, and exacerbation frequency.

Results

Although the addition of NIPPV did not significantly improve the Chronic Respiratory Questionnaire compared to rehabilitation alone (mean difference in change between groups -1.3 points (95% CI: -9.7 to 7.4)), the addition of NIPPV did improve HRQoL assessed with the Maugeri Respiratory Failure questionnaire (-13.4% (-22.7 to -4.2; p = 0.005)), mood state (Hospital Anxiety and Depression scale -4.0 points (-7.8 to 0.0; p = 0.05)), dyspnea (Medical Research Council -0.4 points (-0.8 to -0.0; p = 0.05)), daytime arterial blood gases (PaCO₂ -0.4 kPa (-0.8 to -0.2; p = 0.01); PaO₂ 0.8 kPa (0.0 to 1.5; p = 0.03)), 6-minute walking distance (77.3 m (46.4 to 108.0; p < 0.001)), Groningen Activity and Restriction scale (-3.8 points (-7.4 to -0.4; p = 0.03)), and forced expiratory volume in 1 second (115 ml (19 to 211; p = 0.019)). Exacerbation frequency was not changed.

Conclusions

The addition of NIPPV to pulmonary rehabilitation for 2 years in severe COPD patients with chronic hypercapnic respiratory failure improves HRQoL, mood, dyspnea, gas exchange, exercise tolerance and lung function decline. The benefits increase further with time.

Trial registration

ClinicalTrials.Gov (ID NCT00135538).