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author:("cease, Philip")
1.  Systematic literature review of domains assessed in psoriatic arthritis to inform the update of the psoriatic arthritis core domain set 
RMD Open  2016;2(1):e000217.
The objectives of this systematic literature review (SLR) were to identify domains and outcome measures used in psoriatic arthritis (PsA) studies in the past 5 years, and to compare the measurement of the Outcome Measures in Rheumatology (OMERACT) 2006 PsA Core Domain Set in studies published in 2010–2015 vs those published in 2006–2010. We performed a systematic literature search in two databases, PubMed and Embase, to identify randomised controlled trials (RCTs) in PsA. We also identified PsA longitudinal observational studies (LOS). Three patient research partners provided input into study conception, and data collection and interpretation. We identified 41 studies representing 22 unique RCTs, 27 LOS and 12 registries. Across all studies, we identified 24 domains and 169 outcome measures. In addition to the PsA Core Domain Set (6 domains), the following domains were also assessed in more than 30% of RCTs: acute phase reactants, dactylitis, enthesitis, fatigue and work productivity. We identified a range of 1–15 outcome measures per domain with a mean (SD) of 7 (4.7) per domain. The complete PsA Core Domain Set was assessed in 59% of RCTs in 2010–2015 compared to 23.5% RCTs in 2006–2010. There has been increased measurement of the PsA Core Domain Set in RCTs and LOS in the past 5 years. Numerous additional outcomes were also measured. The PsA Core Domain Set needs an update to standardise PsA outcome assessments. This SLR will inform the development of an updated PsA Core Domain Set with patient research partner input.
doi:10.1136/rmdopen-2015-000217
PMCID: PMC4780312  PMID: 26966554
Psoriatic Arthritis; Outcomes research; Health services research
2.  Comparative effectiveness of biologic monotherapy versus combination therapy for patients with psoriatic arthritis: results from the Corrona registry 
RMD Open  2015;1(1):e000181.
Objectives
To characterise the comparative effectiveness of combination therapy (a tumour necrosis factor inhibitor (TNFi) and a conventional synthetic disease-modifying antirheumatic drug (csDMARD) such as methotrexate) and monotherapy (TNFi only) for psoriatic arthritis (PsA) from a large US registry.
Methods
The analysis included adult patients with PsA who were enrolled in the Corrona database (ClinicalTrials.gov, NCT01402661), had initiated a TNFi, were biologic naïve, and had a follow-up visit ≥90 days after drug initiation. The endpoints of the analysis were TNFi persistence (drug survival) and time to Clinical Disease Activity Index (CDAI) remission. All analyses were performed using propensity scoring, which were estimated using CDAI and patient sex, to control for channelling bias.
Results
Of 519 patients meeting the inclusion criteria (318 with combination therapy and 201 with monotherapy), the analysis population was 497 for TNFi persistence and 380 for time to remission. The difference between combination therapy (TNFi+methotrexate, 91% of patients; TNFi+other csDMARD, 9%) and monotherapy was not statistically significant for TNFi persistence (32 and 31 months, p=0.73) and time to remission (21 and 25 months, p=0.56). Predictors of TNFi persistence included Hispanic ethnicity (longer persistence), PsA duration (longer persistence), history of methotrexate use (shorter persistence), body mass index (shorter persistence) and disease activity (shorter persistence).
Conclusions
Patients with PsA from a large US registry experienced similar TNFi persistence on combination therapy and monotherapy. Prospective, randomised clinical trials evaluating the efficacy of combination therapy versus monotherapy would provide much-needed clarity on treatment options for patients with PsA.
Trial registration number
NCT01402661.
doi:10.1136/rmdopen-2015-000181
PMCID: PMC4716450  PMID: 26819748
Anti-TNF; Psoriatic Arthritis; DMARDs (biologic)
3.  Randomized Controlled Trial of Adalimumab in Patients With Nonpsoriatic Peripheral Spondyloarthritis 
Objective
To evaluate the efficacy and safety of adalimumab in patients with active nonpsoriatic peripheral spondyloarthritis (SpA).
Methods
ABILITY-2 is an ongoing phase III, multicenter study of adalimumab treatment. Eligible patients age ≥18 years fulfilled the Assessment of SpondyloArthritis international Society (ASAS) classification criteria for peripheral SpA, did not have a prior diagnosis of psoriasis, psoriatic arthritis (PsA), or ankylosing spondylitis (AS), and had an inadequate response or intolerance to nonsteroidal antiinflammatory drugs (NSAIDs). Patients were randomized 1:1 to receive adalimumab 40 mg every other week or matching placebo for 12 weeks, followed by a 144-week open-label period. The primary end point was the proportion of patients achieving 40% improvement in disease activity according to the Peripheral SpA Response Criteria (PSpARC40) at week 12. This was defined as ≥40% improvement from baseline (≥20-mm absolute improvement on a visual analog scale) in patient's global assessments of disease activity and pain, and ≥40% improvement in at least one of the following features: swollen joint and tender joint counts, total enthesitis count, or dactylitis count. Adverse events were recorded throughout the study.
Results
In total, 165 patients were randomized to a treatment group, of whom 81 were randomized to receive placebo and 84 to receive adalimumab. Baseline demographics and disease characteristics were generally similar between the 2 groups. At week 12, a greater proportion of patients receiving adalimumab achieved a PSpARC40 response compared to patients receiving placebo (39% versus 20%; P = 0.006). Overall, improvement in other outcomes was greater in the adalimumab group compared to the placebo group. The rates of adverse events were similar in both treatment groups.
Conclusion
Treatment with adalimumab ameliorated the signs and symptoms of disease and improved physical function in patients with active nonpsoriatic peripheral SpA who exhibited an inadequate response or intolerance to NSAIDs, with a safety profile consistent with that observed in patients with AS, PsA, or other immune-mediated diseases.
doi:10.1002/art.39008
PMCID: PMC4409087  PMID: 25545240
4.  Efficacy of long-term milnacipran treatment in patients meeting different thresholds of clinically relevant pain relief: subgroup analysis of a randomized, double-blind, placebo-controlled withdrawal study 
Journal of Pain Research  2014;7:679-687.
Background
Fibromyalgia patients from a long-term, open-label study of milnacipran (50–200 mg/day) were eligible to participate in a 12-week, randomized, placebo-controlled withdrawal study. The withdrawal study evaluated loss of therapeutic response in patients who achieved ≥50% pain improvements after receiving up to 3.25 years of milnacipran. This post-hoc analysis investigated whether patients who met lower thresholds of pain improvement also experienced worsening of fibromyalgia symptoms upon treatment withdrawal.
Method
Among patients who received milnacipran ≥100 mg/day during the long-term study, three subgroups were identified based on percentage of pain reduction at randomization: ≥50% (protocol-defined “responders”; n=150); ≥30% to <50% (patients with clinically meaningful pain improvement; n=61); and <30% (n=110). Efficacy assessments included the visual analog scale (VAS) for pain, Fibromyalgia Impact Questionnaire-Revised (FIQR), 36-Item Short-Form Health Survey Physical Component Summary (SF-36 PCS), and Beck Depression Inventory (BDI).
Results
In the ≥30 to <50% subgroup, significant worsening in pain was detected after treatment withdrawal. The difference between placebo and milnacipran in mean VAS score changes for this subgroup (+9.0, P<0.05) was similar to the difference in protocol-defined responders (+9.4, P<0.05). In the <30% subgroup, no worsening in pain was observed in either treatment arm. However, patients in this subgroup experienced significant worsening in FIQR scores after treatment withdrawal (placebo, +6.9; milnacipran, −2.8; P<0.001), as well as worsening in SF-36 PCS and BDI scores.
Conclusion
Patients who experienced ≥30% to <50% pain reduction with long-term milnacipran had significant worsening of fibromyalgia symptoms after treatment withdrawal. These results suggest that the conventional ≥30% pain responder cutoff may be adequate to demonstrate efficacy in randomized withdrawal studies of fibromyalgia. Patients in the <30% pain reduction subgroup had worsening scores on the FIQR and other multidimensional measures after treatment withdrawal, indicating the importance of identifying and managing the multiple symptoms of fibromyalgia.
doi:10.2147/JPR.S70200
PMCID: PMC4247140  PMID: 25473309
fibromyalgia; responders; post-hoc analysis; symptoms
5.  Updating the OMERACT Filter: Implications for imaging and soluble biomarkers 
The Journal of rheumatology  2014;41(5):1016-1024.
Objective
The OMERACT Filter provides a framework for the validation of outcome measures for use in rheumatology clinical research. However, imaging and biochemical measures may face additional validation challenges due to their technical nature. The Imaging and Soluble Biomarker Session at OMERACT 11 aimed to provide a guide for the iterative development of an imaging or biochemical measurement instrument so it can be used in therapeutic assessment.
Methods
A hierarchical structure was proposed, reflecting 3 dimensions needed for validating an imaging or biochemical measurement instrument: outcome domain(s), study setting and performance of the instrument. Movement along the axes in any dimension reflects increasing validation. For a given test instrument, the 3-axis structure assesses the extent to which the instrument is a validated measure for the chosen domain, whether it assesses a patient or disease centred-variable, and whether its technical performance is adequate in the context of its application. Some currently used imaging and soluble biomarkers for rheumatoid arthritis, spondyloarthritis and knee osteoarthritis were then evaluated using the original OMERACT filter and the newly proposed structure. Break-out groups critically reviewed the extent to which the candidate biomarkers complied with the proposed step-wise approach, as a way of examining the utility of the proposed 3 dimensional structure.
Results
Although there was a broad acceptance of the value of the proposed structure in general, some areas for improvement were suggested including clarification of criteria for achieving a certain level of validation and how to deal with extension of the structure to areas beyond clinical trials.
Conclusion
General support was obtained for a proposed tri-axis structure to assess validation of imaging and soluble biomarkers; nevertheless, additional work is required to better evaluate its place within the OMERACT Filter 2.0.
doi:10.3899/jrheum.131313
PMCID: PMC4223089  PMID: 24584916
biomarkers; imaging; OMERACT filter; validation framework
6.  Updating the OMERACT Filter: Core Areas as a basis for defining core outcome sets 
The Journal of rheumatology  2014;41(5):994-999.
Objective
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter pre-supposes an explicit framework for identifying the relevant core outcomes that are universal to all studies of the effects of intervention effects. There is no published outline for instrument choice or development that is aimed at measuring outcome, was derived from broad consensus over its underlying philosophy, or includes a structured and documented critique. Therefore, a new proposal for defining core areas of measurement (“Filter 2.0 Core Areas of Measurement”) was presented at OMERACT 11 to explore areas of consensus and consider whether already endorsed core outcome sets fit in to this newly proposed framework.
Method
Discussion groups critically reviewed the extent to which case studies of current OMERACT Working Groups complied with or negated the proposed framework, whether these observations had a more general application, and what issues remained to be resolved.
Result
Although there was a broad acceptance of the framework in general, several important areas of construction, presentation and clarity of the framework were questioned. The discussion groups and subsequent feedback highlighted 20 such issues.
Conclusion
These issues will require resolution in order to reach consensus on accepting the proposed Filter 2.0 framework of Core Areas as the basis for the selection of Core Outcome Domains and hence appropriate Core Outcome Sets for clinical trials.
doi:10.3899/jrheum.131309
PMCID: PMC4217644  PMID: 24634204
7.  Updating the OMERACT Filter: Implications of Filter 2.0 to select outcome instruments through assessment of ‘Truth’: content, face and construct validity 
The Journal of rheumatology  2014;41(5):1000-1004.
Objective
The OMERACT Filter provides guidelines for the development and validation of outcome measures for use in clinical research. The ‘Truth’ section of the OMERACT Filter requires that criteria be met to demonstrate that the outcome instrument meets the criteria for content, face and construct validity.
Method
Discussion groups critically reviewed the variety of ways in which case studies of current OMERACT Working Groups complied with the ‘Truth’ component of the Filter and what issues remained to be resolved.
Results
The case studies showed that there is broad agreement on criteria for meeting the ‘Truth’ criteria through demonstration of content, face and construct validity; however several issues were identified that the Filter Working Group will need to address.
Conclusion
These issues will require resolution in order to reach consensus on how ‘Truth’ will be assessed for the proposed Filter 2.0 framework, for instruments to be endorsed by OMERACT.
doi:10.3899/jrheum.131310
PMCID: PMC4212637  PMID: 24692531
9.  Managing Patients with Psoriatic Disease: The Diagnosis and Pharmacologic Treatment of Psoriatic Arthritis in Patients with Psoriasis 
Drugs  2014;74(4):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
10.  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
11.  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
12.  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
13.  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
14.  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
15.  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
16.  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
17.  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
18.  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
19.  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
20.  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
21.  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
22.  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
23.  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
24.  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
25.  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

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