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1.  Managing Patients with Psoriatic Disease: The Diagnosis and Pharmacologic Treatment of Psoriatic Arthritis in Patients with Psoriasis 
Drugs  2014;74:423-441.
Psoriatic arthritis (PsA) is a chronic, systemic inflammatory disease. Up to 40 % of patients with psoriasis will go on to develop PsA, usually within 5–10 years of cutaneous disease onset. Both conditions share common pathogenic mechanisms involving genetic and environmental factors. Because psoriasis is typically present for years before PsA-related joint symptoms emerge, dermatologists are in a unique position to detect PsA earlier in the disease process through regular, routine screening of psoriasis patients. Distinguishing clinical features of PsA include co-occurrence of psoriatic skin lesions and nail dystrophy, as well as dactylitis and enthesitis. Patients with PsA are usually seronegative for rheumatoid factor, and radiographs may reveal unique features such as juxta-articular new bone formation and pencil-in-cup deformity. Early treatment of PsA with disease-modifying anti-rheumatic drugs has the potential to slow disease progression and maintain patient quality of life. Optimally, a single therapeutic agent will control both the skin and joint psoriatic symptoms. A number of traditional treatments used to manage psoriasis, such as methotrexate and cyclosporine, are also effective for PsA, but these agents are often inadequately effective, temporary in benefit and associated with significant safety concerns. Biologic anti-tumour necrosis factor agents, such as etanercept, infliximab and adalimumab, are effective for treating patients who have both psoriasis and PsA. However, a substantial number of patients may lose efficacy, have adverse effects or find intravenous or subcutaneous administration inconvenient. Emerging oral treatments, including phosphodiesterase 4 inhibitors, such as apremilast, and new biologics targeting interleukin-17, such as secukinumab, brodalumab and ixekizumab, have shown encouraging clinical results in the treatment of psoriasis and/or PsA. Active and regular collaboration of dermatologists with rheumatologists in managing patients who have psoriasis and PsA is likely to yield more optimal control of psoriatic dermal and joint symptoms, and improve long-term patient outcomes.
doi:10.1007/s40265-014-0191-y
PMCID: PMC3958815  PMID: 24566842
2.  Continuing efficacy of milnacipran following long-term treatment in fibromyalgia: a randomized trial 
Introduction
Previous studies of long-term treatment response in fibromyalgia and other chronic pain states have generally been limited to approximately one year, leaving questions about the longer-term durability of response. The purpose of this study was to demonstrate continuing efficacy of milnacipran by characterizing changes in pain and other fibromyalgia symptoms after discontinuing long-term treatment. The mean length of milnacipran treatment at the time of randomized withdrawal was 36.1 months from initial exposure to milnacipran (range, 17.9 to 54.4 months).
Methods
After completing a long-term, open-label, lead-in study of milnacipran (which followed varying periods of exposure in previous studies), adult patients with fibromyalgia entered the four-week open-label period of the current study for evaluation of ongoing treatment response. After the four-week period to confirm new baseline status, 151 patients taking milnacipran ≥100 mg/day and reporting ≥50% improvement from pre-milnacipran exposure in Visual Analogue Scale (VAS) pain scores were classified as responders. These responders entered the 12-week, double-blind withdrawal period in which they were randomized 2:1 to continue milnacipran or switched to placebo. The prespecified primary parameter was loss of therapeutic response (LTR), defined as increase in VAS pain score to <30% reduction from pre-milnacipran exposure or worsening of fibromyalgia requiring alternative treatment. Adverse events and vital signs were also monitored.
Results
Time to LTR was shorter in patients randomized to placebo than in patients continuing milnacipran (P < 0.001). Median time to LTR was 56 days with placebo and was not calculable for milnacipran, because less than half of the latter group of patients lost therapeutic response by study end. Additionally, 81% of patients continuing on milnacipran maintained clinically meaningful pain response (≥30% improvement from pre-milnacipran exposure), compared with 58% of patients switched to placebo (sensitivity analysis II; P < 0.001). The incidences of treatment-emergent adverse events were 58% and 47% for placebo and milnacipran, respectively. Mean decreases in blood pressure and heart rate were found in both groups, with greater decreases for patients switched to placebo.
Conclusions
Continuing efficacy of milnacipran was demonstrated by the loss of effect following withdrawal of treatment in patients who received an average of three years of milnacipran treatment.
Trial registration
ClinicalTrials.gov: NCT01014585
doi:10.1186/ar4268
PMCID: PMC3978750  PMID: 23953493
3.  Milnacipran combined with pregabalin in fibromyalgia: a randomized, open-label study evaluating the safety and efficacy of adding milnacipran in patients with incomplete response to pregabalin 
Objective:
To evaluate the safety, tolerability, and efficacy of adding milnacipran to pregabalin in patients with fibromyalgia who have experienced an incomplete response to pregabalin.
Methods:
In this randomized, multicenter, open-label study, patients received pregabalin 300 or 450 mg/day during a 4- to 12-week run-in period. Patients with weekly recall visual analog scale (VAS) pain score of at least 40 and up to 90, Patient Global Impression of Severity score of at least 4, and Patient Global Impression of Change (PGIC) score of at least 3 were classified as incomplete responders and randomized to continue pregabalin alone (n = 180) or receive milnacipran 100 mg/day added to pregabalin (n = 184). The primary efficacy parameter was responder status based on PGIC score of up to 2. The secondary efficacy parameter was change from randomization in weekly recall VAS pain score. Safety parameters included adverse events (AEs), vital signs, and clinical laboratory tests.
Results:
The percentage of PGIC responders was significantly higher with milnacipran added to pregabalin (46.4%) than with pregabalin alone (20.8%; p < 0.001). Mean improvement from randomization in weekly recall VAS pain scores was greater in patients receiving milnacipran added to pregabalin (−20.77) than in patients receiving pregabalin alone (−6.43; p < 0.001). During the run-in period, the most common treatment-emergent AEs with pregabalin were dizziness (22.8%), somnolence (17.3%), and fatigue (9.1%). During the randomized period, the most common treatment-emergent AEs with milnacipran added to pregabalin were nausea (12.5%), fatigue (10.3%), and constipation (9.8%).
Conclusions:
In this exploratory, open-label study, adding milnacipran to pregabalin improved global status, pain, and other symptoms in patients with fibromyalgia with an incomplete response to pregabalin treatment.
doi:10.1177/1759720X13483894
PMCID: PMC3707344  PMID: 23858335
clinical trials; fibromyalgia; milnacipran; pain; pregabalin
4.  Development of Responder Definitions for Fibromyalgia Clinical Trials 
Arthritis and Rheumatism  2012;64(3):885-894.
Objective
To develop responder definitions for fibromyalgia clinical trials using key symptom and functional domains.
Methods
24 candidate responder definitions were developed by expert consensus and evaluated in 12 randomized, placebo-controlled fibromyalgia trials of 4 medications. For each definition, treatment effects of the medication compared with placebo were analyzed using the Cochran-Mantel-Haenszel test or Chi Square test. A meta-analysis of the pooled results for the 4 medications established risk ratios to determine the definitions that best favored medication over placebo.
Results
Two definitions performed best in the analyses. Both definitions included ≥ 30% reduction in pain and ≥ 10% improvement in physical function. They differed in that one (FM30 short version) included ≥ 30% improvement in sleep or fatigue, and the other (FM30 long version) required ≥ 30% improvement in 2 of the following symptoms: sleep, fatigue, depression, anxiety, or cognition. In the analysis of both versions, the response rate was ≥ 15% for each medication and significantly greater than placebo. The risk ratio favoring drug over placebo (95% CI) in the pooled analysis for the FM30 short version was 1.50 (1.24, 1.82), P ≤ 0.0001; the FM30 long version was 1.60 (1.31, 1.96), P ≤ 0.00001.
Conclusion
Among the 24 responder definitions tested, 2 were identified as most sensitive in identifying response to treatment. The identification of responder definitions for fibromyalgia clinical trials that include assessments of key symptom and functional domains may improve the sensitivity of clinical trials to identify meaningful improvements, leading to improved management of fibromyalgia.
doi:10.1002/art.33360
PMCID: PMC3252491  PMID: 21953205
5.  Fibromyalgia Syndrome Module at OMERACT 9 
The Journal of rheumatology  2009;36(10):2318-2329.
Objectives
(1) Establish a core domain set for fibromyalgia (FM) assessment in clinical trials and practice, (2) review outcome measures’ performance characteristics, (3) discuss development of a responder index for the assessment of FM in clinical trials, (4) review objective markers, (5) review the domain of cognitive dysfunction, (6) establish a research agenda for work regarding outcomes research.
Methods
(1) Results of univariate and multivariate analysis of 10 different FM clinical trials of four different drugs, mapping key domains identified in previously presented patient focus group: Delphi exercises and a clinician/researcher Delphi exercise, breakout discussions to vote on possible essential domains and reliable measures. (2) Updates presented regarding outcome measures’ status. (3) Presented update on objective markers to measure FM disease state. 4) The issue of cognitive dysfunction (dyscognition) in FM was reviewed.
Results
(1) Greater than 70% of OMERACT participants agreed that pain, tenderness, fatigue, patient global, multidimensional function and sleep disturbance domains should be measured in all FM clinical trials, dyscognition and depression in some trial, and domains of research interest include stiffness, anxiety, functional imaging, and cerebrospinal fluid biomarkers. (2) FM domains’ outcome measures have generally proven to be reliable, discriminative, and feasible. More sophisticated and comprehensive measures are in development, as is a responder index for FM. (3) Increasing number of objective markers are being developed for FM assessment. (4) Cognitive dysfunction assessment by self-assessed and applied outcome measures is being developed.
Conclusions
A multidimensional symptom core set is proposed for the evaluation of FM in clinical trials. There is ongoing research on improved measures of single domains and composite measures.
doi:10.3899/jrheum.090367
PMCID: PMC3419373  PMID: 19820221
Fibromyalgia; OMERACT; outcome measures; clinical trials
6.  Content and Criterion Validity of The Preliminary Core Dataset for Clinical Trials in Fibromyalgia Syndrome 
The Journal of rheumatology  2009;36(10):2330-2334.
Increasing research interest and emerging new therapies for treatment of fibromyalgia (FM) have led to a need to develop a consensus on a core set of outcome measures that should be assessed and reported in all clinical trials, to facilitate interpretation of the data and understanding of the disease. This aligns with the key objective of the Outcome Measures in Rheumatology (OMERACT) initiative to improve outcome measurement through a data driven, interactive consensus process. Through patient focus groups and Delphi processes, working groups at previous OMERACT meetings identified potential domains to be included in the core data set. A systematic review has shown that instruments measuring these domains are available and at least moderately sensitive to change. Most of instruments have been validated in multiple languages. This pooled analysis study aims to develop the core data set by analysing data from 10 randomised controlled trials (RCTs) in FM. Results from this study provide support for the inclusion of the following in the core data set: pain, tenderness, fatigue, sleep, patient global assessment and multi-dimensional function/health related quality of life. Construct validity was demonstrated with outcome instruments showing convergent and divergent validity. Content and criterion validity were confirmed by multivariate analysis showing R square values between 0.4 and 0.6. Low R square value is associated with studies in which one or more domains were not assessed. The core data set was supported by high consensus among attendees at OMERACT 9. Establishing an international standard for RCTs in FM should facilitate future meta-analyses and indirect comparisons.
doi:10.3899/jrheum.090368
PMCID: PMC3412585  PMID: 19820222
Fibromyalgia; OMERACT; outcome measures; clinical trials; core data set
7.  Retreatment with rituximab based on a treatment-to-target approach provides better disease control than treatment as needed in patients with rheumatoid arthritis: a retrospective pooled analysis 
Rheumatology (Oxford, England)  2011;50(12):2223-2232.
Objective. To assess the efficacy and safety profiles of two different rituximab retreatment regimens in patients with RA.
Methods. Four hundred and ninety-three RA patients with an inadequate response to MTX recruited into rituximab Phase II/III studies received further courses of open-label rituximab based on two approaches: (i) treatment to target (TT): patients assessed 24 weeks after each course and retreated if not in remission [DAS in 28 joints based on ESR (DAS-28-ESR) ≥ 2.6]; (ii) treatment as needed (PRN): patients retreated at the physician’s discretion ≥24 weeks following the first course and ≥16 weeks following further courses, if both swollen and tender joint counts were ≥8. All courses consisted of i.v. rituximab 2 × 1000 mg 2 weeks apart plus MTX. Observed data were analysed according to treatment strategy.
Results. Multiple courses of rituximab maintained or improved responses irrespective of regimen. TT provided tighter control of disease activity with significantly greater improvements in DAS-28-ESR and lower HAQ-disability index scores vs PRN. TT resulted in significantly more patients achieving major clinical response. PRN resulted in recurrence of disease symptoms between courses, with TT significantly reducing the incidence of RA flares. Despite more frequent retreatment with TT compared with PRN, the rates of serious adverse events and serious infections were comparable between regimens.
Conclusions. Retreatment with rituximab based on 24-week evaluations and to a target of DAS-28-ESR remission leads to improved efficacy and tighter control of disease activity compared with PRN without a compromised safety profile. TT may be the preferable rituximab treatment regimen for patients with RA.
doi:10.1093/rheumatology/ker253
PMCID: PMC3222846  PMID: 21926153
Methotrexate-inadequate responder; Treatment to target; Treatment as needed; Retreatment; Rituximab; Treatment strategy
8.  The 2010 American College of Rheumatology/European League Against Rheumatism Classification Criteria for Rheumatoid Arthritis 
Arthritis and rheumatism  2010;62(9):2582-2591.
Objective
The American College of Rheumatology and the European League Against Rheumatism have developed new classification criteria for rheumatoid arthritis (RA). The aim of Phase 2 of the development process was to achieve expert consensus on the clinical and laboratory variables that should contribute to the final criteria set.
Methods
Twenty-four expert RA clinicians (12 from Europe and 12 from North America) participated in Phase 2. A consensus-based decision analysis approach was used to identify factors (and their relative weights) that influence the probability of “developing RA,” complemented by data from the Phase 1 study. Patient case scenarios were used to identify and reach consensus on factors important in determining the probability of RA development. Decision analytic software was used to derive the relative weights for each of the factors and their categories, using choice-based conjoint analysis.
Results
The expert panel agreed that the new classification criteria should be applied to individuals with undifferentiated inflammatory arthritis in whom at least 1 joint is deemed by an expert assessor to be swollen, indicating definite synovitis. In this clinical setting, they identified 4 additional criteria as being important: number of joints involved and site of involvement, serologic abnormality, acute-phase response, and duration of symptoms in the involved joints. These criteria were consistent with those identified in the Phase 1 data-driven approach.
Conclusion
The consensus-based, decision analysis approach used in Phase 2 complemented the Phase 1 efforts. The 4 criteria and their relative weights form the basis of the final criteria set.
doi:10.1002/art.27580
PMCID: PMC3077961  PMID: 20872596
9.  Certolizumab pegol plus methotrexate provides broad relief from the burden of rheumatoid arthritis: analysis of patient-reported outcomes from the RAPID 2 trial 
Annals of the Rheumatic Diseases  2011;70(6):996-1002.
Objective
To assess the impact of certolizumab pegol (CZP) on patient-reported outcomes (PROs) in rheumatoid arthritis (RA), and to interpret these results using number needed to treat (NNT), and associations between PRO responses and longer term outcomes.
Methods
A total of 619 patients with active RA were randomised to CZP 200 or 400 mg, or placebo plus methotrexate (MTX). PROs assessed included pain, patient's global assessment of disease activity (PtGA), physical function, fatigue and health-related quality of life. Treatment impact on PROs, NNT to achieve simultaneous improvements in multiple PROs and correlations between PROs were calculated. Times to onset of improvements greater than or equal to minimum clinically important differences (MCIDs) in pain as a determinant of clinical outcomes at week 24 were compared between week 6 and 12 responders, and in patients with improvements in pain ≥MCID at week 12 (week 12 responders/non-responders).
Results
CZP 200 and 400 mg plus MTX were associated with rapid, clinically meaningful improvements in all PROs. The NNT for subjects to report changes ≥MCID in up to five PROs was two to three, and five for all six PROs (pain, PtGA, physical function, fatigue and short-form 36-item Physical and Mental Component Summary Scores). More patients with improvements ≥MCID in pain at week 6 than those at week 12 had lower disease activity at week 24. Week 12 pain responders had better clinical outcomes at week 24 than non-responders.
Conclusions
The data demonstrate that CZP provides broad relief from the burden of RA.
Trial registration number
NCT00160602.
doi:10.1136/ard.2010.143586
PMCID: PMC3086050  PMID: 21415050
10.  Certolizumab pegol in the treatment of rheumatoid arthritis: a comprehensive review of its clinical efficacy and safety 
Rheumatology (Oxford, England)  2010;50(2):261-270.
Biological agents, including TNF inhibitors, have revolutionized the treatment of RA in recent years. Certolizumab pegol (CZP) is a novel pegylated anti-TNF approved for the treatment of adult patients with moderately to severely active RA. This article provides an overview of three published clinical trials of CZP in RA in patients with active disease who have shown an inadequate response to DMARDs, including MTX: RA prevention of structural damage (RAPID) 1 and 2, which evaluated the efficacy and safety of CZP added to MTX when dosed every 2 weeks, and efficacy and safety of CZP – 4 weekly dosage in rheumatoid arthritis (FAST4WARD), which evaluated CZP monotherapy when dosed every 4 weeks. In the trials, CZP plus MTX or as monotherapy significantly improved the signs and symptoms of RA and RA disease activity, and CZP plus MTX significantly inhibited the progression of radiographic joint damage as early as Week 16 of the treatment. In addition, CZP treatment significantly improved patient-reported outcome measures, providing significant reductions in pain and fatigue and improvements in physical function as early as Week 1 of treatment; improvements in health-related quality of life were evident at the first assessment at Week 12. CZP treatment improved productivity at work, significantly reducing the number of days of missed work as well as the number of days with reduced productivity, and also increased productivity within the home and improved participation in family, social and leisure activities. CZP was generally well tolerated when used either as monotherapy or added to MTX; most adverse events were mild or moderate. Taken together, the results of these trials suggest that CZP is an effective new option for the treatment of RA.
doi:10.1093/rheumatology/keq285
PMCID: PMC3021948  PMID: 20871129
Certolizumab pegol; Methotrexate; Monotherapy; Rheumatoid arthritis; TNF-α inhibitor
11.  Fatigue in fibromyalgia: a conceptual model informed by patient interviews 
Background
Fatigue is increasingly recognized as an important symptom in fibromyalgia (FM). Unknown however is how fatigue is experienced by individuals in the context of FM. We conducted qualitative research in order to better understand aspects of fatigue that might be unique to FM as well as the impact it has on patients' lives. The data obtained informed the development of a conceptual model of fatigue in FM.
Methods
Open-ended interviews were conducted with 40 individuals with FM (US [n = 20], Germany [n = 10] and France [n = 10]). Transcripts were analyzed using qualitative methods based upon grounded theory to identify key themes and concepts.
Results
Participants were mostly female (70%) with a mean age of 48.7 years (range: 25-79). Thirty-one individuals (i.e., 77.5%) spontaneously described experiencing tiredness/lack of energy/fatigue due to FM. Participants discussed FM fatigue as being more severe, constant/persistent and unpredictable than normal tiredness. The conceptual model depicts the key elements of fatigue in FM from a patient perspective. This includes: an overwhelming feeling of tiredness (n = 17, 42.5%), not relieved by resting/sleeping (n = 15, 37.5%), not proportional to effort exerted (n = 25, 62.5%), associated with a feeling of weakness/heaviness (n = 20, 50%), interferes with motivation (n = 22, 55%), interferes with desired activities (n = 27, 67.5%), prolongs tasks (n = 15, 37.5%), and makes it difficult to concentrate (n = 21, 52.5%), think clearly (n = 12, 30%) or remember things (n = 9, 22.5%).
Conclusion
The majority of individuals with FM who participated in this study experience fatigue and describe it as more severe than normal tiredness.
doi:10.1186/1471-2474-11-216
PMCID: PMC2946273  PMID: 20854680
12.  Physical function improvements and relief from fatigue and pain are associated with increased productivity at work and at home in rheumatoid arthritis patients treated with certolizumab pegol 
Rheumatology (Oxford, England)  2010;49(10):1900-1910.
Objectives. To evaluate the association between improvements in physical function, fatigue and pain and improvements in productivity at work and at home in patients treated with certolizumab pegol (CZP) in combination with MTX.
Methods. Physical function, fatigue and pain were assessed in two CZP clinical trials (Rheumatoid Arthritis PreventIon of structural Damage 1 and 2) using the HAQ-Disability Index (HAQ-DI), Fatigue Assessment Scale (FAS) and Patient Assessment of Pain, with minimal clinically important differences (MCIDs) defined as ≥0.22, ≥1 and ≥10 points, respectively. Work and home productivity were evaluated using the RA-specific Work Productivity Survey (WPS-RA). The odds of achieving an HAQ-DI, FAS or pain ‘response’ at Week 12, defined as improvements ≥MCID, were compared between CZP and control groups. Improvements in productivity at Week 12 were compared between CZP-treated HAQ-DI, FAS or pain responders and non-responders.
Results. The odds of achieving improvements ≥MCID were five times higher for pain, and two to three times higher for physical function and fatigue, in patients receiving CZP vs control. Per month, responders reported significantly greater improvements in productivity at work and reduced interference of RA with their work productivity than non-responders. Responders also reported significantly greater improvements in productivity at home and participation in family, social and leisure activities.
Conclusions. This study demonstrated a clear association between patient-reported improvements in physical function, fatigue and pain, and improvements in productivity both at work and home.
doi:10.1093/rheumatology/keq109
PMCID: PMC2936945  PMID: 20547658
Rheumatoid arthritis; Certolizumab pegol; Physical function; Fatigue; Pain; TNF; Work productivity; Household productivity; Daily activities
13.  Risk factors for radiographic progression in psoriatic arthritis: subanalysis of the randomized controlled trial ADEPT 
Arthritis Research & Therapy  2010;12(3):R113.
Introduction
To identify independent predictors of radiographic progression in psoriatic arthritis (PsA) for patients treated with adalimumab or placebo in the Adalimumab Effectiveness in PsA Trial (ADEPT).
Methods
Univariate analyses and multivariate linear regression analyses assessed risk for radiographic progression (change in modified total Sharp score, ΔmTSS > 0.5) from baseline to week 24 for C-reactive protein (CRP) and other baseline variables, and for 24-week time-averaged CRP (univariate analysis only). Subanalyses determined mean ΔmTSS for CRP subgroups. Analyses were post hoc, with observed data.
Results
One hundred and forty-four adalimumab-treated patients and 152 placebo-treated patients were assessed. Mean CRP was 64% lower by week 2 with adalimumab and essentially unchanged with placebo. Univariate analyses indicated that elevated CRP at baseline and time-averaged CRP were strongly associated with radiographic progression for placebo-treated patients but not for adalimumab-treated patients. Multivariate analysis confirmed that elevated baseline CRP was the only strong independent risk factor for radiographic progression (for CRP ≥1.0 mg/dl: odds ratio = 3.28, 95% confidence interval = 1.66 to 6.51, P < 0.001). Adalimumab treatment reduced risk of progression approximately fivefold. The difference between mean ΔmTSS for adalimumab versus placebo was greatest for patients with baseline CRP ≥2.0 mg/dl (-0.5 vs. 2.6).
Conclusions
Systemic inflammation in PsA, as indicated by elevated baseline CRP, was the only strong independent predictor of radiographic progression. This association was observed predominantly for placebo-treated patients. Adalimumab treatment substantially reduced the overall risk of radiographic progression, and provided greatest radiographic benefit for patients with the greatest CRP concentrations at baseline.
Trial Registration
Trial registration: NCT00195689.
doi:10.1186/ar3049
PMCID: PMC2911906  PMID: 20537151
14.  Rapid and sustained improvements in health-related quality of life, fatigue, and other patient-reported outcomes in rheumatoid arthritis patients treated with certolizumab pegol plus methotrexate over 1 year: results from the RAPID 1 randomized controlled trial 
Arthritis Research & Therapy  2009;11(6):R170.
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.
doi:10.1186/ar2859
PMCID: PMC3003523  PMID: 19909548
15.  Patient Perspectives on the Impact of Fibromyalgia 
Patient education and counseling  2008;73(1):114-120.
Objective
The objective of this study was to elicit and assess important symptom domains and the impact of fibromyalgia on patients’ quality of life and functioning from a patient’s perspective. The intention was to collect this information as part of an overall effort to overcome shortcomings of existing outcome measures in fibromyalgia.
Methods
This was a qualitative study in which six focus group sessions with 48 women diagnosed with fibromyalgia were conducted to elicit concepts and ideas to assess the impact of fibromyalgia on their lives.
Results
The focus groups conducted with fibromyalgia patients identified symptom domains that had the greatest impact on their quality of life including pain, sleep disturbance, fatigue depression, anxiety, and cognitive impairment. Fibromyalgia had a substantial negative impact on social and occupational function. Patients reported disrupted relationships with family and friends, social isolation, reduced activities of daily living and leisure activities, avoidance of physical activity, and loss of career or inability to advance in careers or education.
Conclusion
The findings from the focus groups revealed that fibromyalgia has a substantial negative impact on patients’ lives.
Practice Implications
A comprehensive assessment of the multiple symptoms domains associated with fibromyalgia and the impact of fibromyalgia on multidimensional aspects of function should be a routine part of the care of fibromyalgia patients.
doi:10.1016/j.pec.2008.06.005
PMCID: PMC2564867  PMID: 18640807
fibromyalgia; patient focus group; symptom domains; quality of life
16.  Safety and tolerability of duloxetine in the treatment of patients with fibromyalgia: pooled analysis of data from five clinical trials 
Clinical Rheumatology  2009;28(9):1035-1044.
The purpose of this report is to describe the overall safety profile of both short- and longer-term duloxetine treatment of fibromyalgia. Data from four double-blind, randomized, placebo-controlled studies (two with 6-month open-label extension phases) and a 1-year, open-label safety study were included. Safety measures included treatment-emergent adverse events (TEAEs), adverse events leading to discontinuation, serious adverse events (SAEs), clinical laboratory tests, vital signs, and electrocardiograms. The most common TEAEs for short-term treatment with duloxetine were nausea (29.3%), headache (20.0%), dry mouth (18.2%), insomnia (14.5%), fatigue (13.5%), constipation (14.5%), diarrhea (11.6%), and dizziness (11.0%; all p < 0.05 vs. placebo). Most TEAEs emerged early and were mild to moderate in severity. The profile of adverse events in patients enrolled at least 6 months, and for patients in the 1-year study, was similar to that found in the short-term treatment studies, with no new adverse events emerging at a notable rate. About 20% of patients discontinued due to adverse events in the short-term treatment studies and in the 1-year study. SAEs were uncommon, and none occurred at a significantly higher frequency for duloxetine compared with placebo. Mean changes in vital signs and weight were small. Rates of treatment-emergent potentially clinically significant (PCS) vital sign, laboratory, and electrocardiogram measures were low, with only PCS rates of alanine aminotransferase being significantly higher for duloxetine compared with placebo in the placebo-controlled treatment studies. In the 1-year study, four patients (1.1%) had suicide-related behavior. The data provided here summarize short- and long-term safety from five clinical studies in patients treated with duloxetine for fibromyalgia. In addition, postmarketing surveillance continues for adverse events reported with duloxetine in fibromyalgia, as in other indications.
doi:10.1007/s10067-009-1203-2
PMCID: PMC2721139  PMID: 19533210
Adverse events; Duloxetine; Fibromyalgia; Safety
17.  Adalimumab in the treatment of arthritis 
Tumor necrosis factor (TNF) has been implicated in a number of arthritic disease states, including rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis. Adalimumab is the first fully human, high-affinity, recombinant immunoglobulin G1 (IgG1) anti-TNF monoclonal antibody. Adalimumab in combination with methotrexate or standard antirheumatic therapies, or as monotherapy, is effective in the treatment of adults with active rheumatoid arthritis who have had an inadequate response to disease-modifying antirheumatic drugs. Adalimumab is also effective in the treatment of patients with moderately to severely active psoriatic arthritis, improving both joint and skin manifestations of the disease as well as disability due to joint damage. In the Adalimumab Trial Evaluating Long-term Efficacy and Safety in Ankylosing Spondylitis (ATLAS), adalimumab significantly reduced the signs and symptoms of active ankylosing spondylitis and established a sustained clinical response in patients who had an inadequate response or intolerance to nonsteroidal antiinflammatory drug therapy. Overall, across these indications, adalimumab demonstrated a rapid onset of action, sustained efficacy with long-term treatment, and was well-tolerated, with few patients discontinuing treatment because of adverse events. The safety profile was similar to other TNF antagonists. Inhibition of TNF activity by adalimumab also significantly improved physical functioning and quality of life measures.
PMCID: PMC1936294  PMID: 18360621
Adalimumab; TNF antagonists; rheumatoid arthritis; psoriatic arthritis; ankylosing spondylitis
18.  Infliximab (Remicade) in the treatment of psoriatic arthritis 
Elucidation of the cellular immunopathology and cytokine profile of psoriatic arthritis (PsA), a chronic inflammatory disease associated with psoriasis, has resulted in the development of a number of novel biologic therapies. Among these biologics, tumor necrosis factor-alpha (TNF-α) inhibitors have been used successfully to treat patients suffering from rheumatoid arthritis or psoriasis. The pivotal role of TNF-α in the pathogenesis and progression of PsA suggested that anti-TNF-α agents could be effective in controlling PsA. The results from two large, randomized, double-blind, placebo-controlled trials in patients with moderate to severe PsA indicated that the anti-TNF-inhibitor, infliximab, can control both the joint and skin manifestations of the disease. This review focuses on the clinical development of infliximab as a treatment for PsA. The development of other anti-TNF-α biologics is also discussed.
PMCID: PMC1936360  PMID: 18360651
psoriatic arthritis; psoriasis; spondyloarthropathies; TNF inhibition; biologics
19.  Markers of inflammation and bone remodelling associated with improvement in clinical response measures in psoriatic arthritis patients treated with golimumab 
Objective
To determine serum biomarker associations with clinical response to golimumab treatment in patients with psoriatic arthritis (PsA).
Methods
GO–REVEAL was a randomised, placebo-controlled study of golimumab in patients with active PsA. Samples were collected from 100 patients at baseline, week 4 and week 14, and analysed for serum-based biomarkers and protein profiling (total 92 markers); data were correlated with clinical measures at week 14.
Results
Serum levels of a subset of proteins (apolipoprotein C III, ENRAGE, IL-16, myeloperoxidase, vascular endothelial growth factor, pyridinoline, matrix metalloproteinase 3, C-reactive protein (CRP), carcinoembryonic antigen, intercellular adhesion molecule 1 and macrophage inflammatory protein 1α) at baseline or week 4 were strongly associated with American College of Rheumatology 20% improvement (ACR20) response and/or disease activity score in 28 joints (DAS28) at week 14. A smaller subset of proteins was significantly associated with a 75% improvement in the psoriasis area and severity index score (PASI75) at week 14, (adiponectin, apolipoprotein CIII, serum glutamic oxaloacetic transaminase, and tumour necrosis factor α). Subsets of proteins were identified as potentially predictive of clinical response for each of the clinical measures, and the power of these biomarker panels to predict clinical response to golimumab treatment was stronger than for CRP alone.
Conclusions
This analysis provides insight into several panels of markers that may have utility in identifying PsA patients likely to have ACR20, DAS28, or PASI75 responses following golimumab treatment.
doi:10.1136/annrheumdis-2012-201697
PMCID: PMC3551220  PMID: 22975755
Psoriatic Arthritis; Anti-TNF; TNF-alpha
20.  Efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis: results of a randomised placebo-controlled trial (ABILITY-1) 
Annals of the Rheumatic Diseases  2012;72(6):815-822.
Purpose
To evaluate the efficacy and safety of adalimumab in patients with non-radiographic axial spondyloarthritis (nr-axSpA).
Methods
Patients fulfilled Assessment of Spondyloarthritis international Society (ASAS) criteria for axial spondyloarthritis, had a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) score of ≥ 4, total back pain score of ≥ 4 (10 cm visual analogue scale) and inadequate response, intolerance or contraindication to non-steroidal anti-inflammatory drugs (NSAIDs); patients fulfilling modified New York criteria for ankylosing spondylitis were excluded. Patients were randomised to adalimumab (N=91) or placebo (N=94). The primary endpoint was the percentage of patients achieving ASAS40 at week 12. Efficacy assessments included BASDAI and Ankylosing Spondylitis Disease Activity Score (ASDAS). MRI was performed at baseline and week 12 and scored using the Spondyloarthritis Research Consortium of Canada (SPARCC) index.
Results
Significantly more patients in the adalimumab group achieved ASAS40 at week 12 compared with patients in the placebo group (36% vs 15%, p<0.001). Significant clinical improvements based on other ASAS responses, ASDAS and BASDAI were also detected at week 12 with adalimumab treatment, as were improvements in quality of life measures. Inflammation in the spine and sacroiliac joints on MRI significantly decreased after 12 weeks of adalimumab treatment. Shorter disease duration, younger age, elevated baseline C-reactive protein or higher SPARCC MRI sacroiliac joint scores were associated with better week 12 responses to adalimumab. The safety profile was consistent with what is known for adalimumab in ankylosing spondylitis and other diseases.
Conclusions
In patients with nr-axSpA, adalimumab treatment resulted in effective control of disease activity, decreased inflammation and improved quality of life compared with placebo. Results from ABILITY-1 suggest that adalimumab has a positive benefit–risk profile in active nr-axSpA patients with inadequate response to NSAIDs.
doi:10.1136/annrheumdis-2012-201766
PMCID: PMC3664374  PMID: 22772328
21.  Clinical efficacy, radiographic and safety findings through 2 years of golimumab treatment in patients with active psoriatic arthritis: results from a long-term extension of the randomised, placebo-controlled GO-REVEAL study 
Annals of the Rheumatic Diseases  2012;72(11):1777-1785.
Objectives
To assess long-term golimumab efficacy/safety in patients with active psoriatic arthritis (PsA).
Methods
Adult PsA patients (≥3 swollen, ≥3 tender joints, active psoriasis) were randomly assigned to subcutaneous injections of placebo, golimumab 50 mg or 100 mg every 4 weeks (q4wks) through week 20. All patients received golimumab 50 or 100 mg beginning week 24. Findings through 2 years are reported. Efficacy evaluations included ≥20% improvement in American College of Rheumatology (ACR20) response, good/moderate response in Disease Activity Scores incorporating 28 joints and C-reactive protein (DAS28-CRP), ≥75% improvement in Psoriasis Area and Severity Index (PASI75) and changes in PsA-modified Sharp/van der Heijde scores (SHS).
Results
Golimumab treatment through 2 years was effective in maintaining clinical response (response rates: ACR20 63%–70%, DAS28-CRP 77%–86%, PASI75 56%–72%) and inhibiting radiographic progression (mean change in PsA-modified SHS in golimumab-treated patients: −0.36), with no clear difference between doses. No new safety signals were identified through 2 years. With the study's tuberculosis screening and prophylactic measures, no patient developed active tuberculosis through 2 years.
Conclusions
Golimumab 50 and 100 mg for up to 2 years yielded sustained clinical and radiographic efficacy when administered to patients with active PsA. Increasing the golimumab dose from 50 to 100 mg q4wks added limited benefit. Golimumab safety through up to 2 years was consistent with other antitumour necrosis factor α agents used to treat PsA. Treatment of patients with latent tuberculosis identified at baseline appeared to be effective in inhibiting the development of active tuberculosis.
doi:10.1136/annrheumdis-2012-202035
PMCID: PMC3812864  PMID: 23161902
Psoriatic Arthritis; Anti-TNF; Spondyloarthritis
22.  Treating spondyloarthritis, including ankylosing spondylitis and psoriatic arthritis, to target: recommendations of an international task force 
Background
Therapeutic targets have been defined for diseases like diabetes, hypertension or rheumatoid arthritis and adhering to them has improved outcomes. Such targets are just emerging for spondyloarthritis (SpA).
Objective
To define the treatment target for SpA including ankylosing spondylitis and psoriatic arthritis (PsA) and develop recommendations for achieving the target, including a treat-to-target management strategy.
Methods
Based on results of a systematic literature review and expert opinion, a task force of expert physicians and patients developed recommendations which were broadly discussed and voted upon in a Delphi-like process. Level of evidence, grade and strength of the recommendations were derived by respective means. The commonalities between axial SpA, peripheral SpA and PsA were discussed in detail.
Results
Although the literature review did not reveal trials comparing a treat-to-target approach with another or no strategy, it provided indirect evidence regarding an optimised approach to therapy that facilitated the development of recommendations. The group agreed on 5 overarching principles and 11 recommendations; 9 of these recommendations related commonly to the whole spectrum of SpA and PsA, and only 2 were designed separately for axial SpA, peripheral SpA and PsA. The main treatment target, which should be based on a shared decision with the patient, was defined as remission, with the alternative target of low disease activity. Follow-up examinations at regular intervals that depend on the patient's status should safeguard the evolution of disease activity towards the targeted goal. Additional recommendations relate to extra-articular and extramusculoskeletal aspects and other important factors, such as comorbidity. While the level of evidence was generally quite low, the mean strength of recommendation was 9–10 (10: maximum agreement) for all recommendations. A research agenda was formulated.
Conclusions
The task force defined the treatment target as remission or, alternatively, low disease activity, being aware that the evidence base is not strong and needs to be expanded by future research. These recommendations can inform the various stakeholders about expert opinion that aims for reaching optimal outcomes of SpA.
doi:10.1136/annrheumdis-2013-203419
PMCID: PMC3888616  PMID: 23749611
Treat-to-target; spondyloarthritis; ankylosing spondylitis; psoriatic arthritis; therapy

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