Longterm Drug Survival of Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis.

OBJECTIVE: To evaluate longterm drug survival (proportion of patients still receiving treatment) and discontinuation of etanercept (ETN), infliximab (IFX), adalimumab (ADA), certolizumab pegol (CZP), and golimumab (GOL) using observational data from patients with rheumatoid arthritis (RA). METHODS: Following a systematic literature review, drug survival at 12 and 12-24 months of followup was estimated by summing proportions of patients continuing treatment and dividing by number of studies. Drug survival at ≥ 36 months of followup was estimated through Metaprop. RESULTS: There were 170 publications included. In the first-line setting, drug survival at 12 months with ETN, IFX, or ADA was 71%, 69%, and 70%, respectively, while at 12-24 months the corresponding rates were 63%, 57%, and 59%. In the second-line setting, drug survival at 12 months with ETN, IFX, or ADA was 61%, 69%, and 55%, respectively, while at 12-24 months the corresponding rates were 53%, 39%, and 43%. Drug survival at ≥ 36 months with ETN, IFX, or ADA in the first-line setting was 59% (95% CI 46-72%), 49% (95% CI 43-54%), and 51% (95% CI 41-60%), respectively, while in the second-line setting the corresponding rates were 56% (95% CI 52-61%), 48% (95% CI 40-55%), and 41% (95% CI 36-47%). Discontinuation of ETN, IFX, and ADA at 36 months of followup was 38-48%, 42-62%, and 38-59%, respectively. Data on CZP and GOL were scarce. CONCLUSION: After > 12 months of followup, more patients with RA receiving ETN remain on treatment compared with other tumor necrosis factor inhibitors.

Health outcomes and unmet needs in patients with long-standing rheumatoid arthritis attending tertiary care in Greece: a cohort study.

BACKGROUND: No previous studies have characterized a patient's experience of rheumatoid arthritis (RA) management in Greece and unmet needs may exist despite a broad range of available treatments. Therefore, we assessed quality of life (QoL), functional ability, and healthcare resource utilization in patients with established RA and receiving treatment in a tertiary care setting in Greece. METHODS: This was a prospective, observational cohort of patients aged ≥18 years, receiving any type of treatment for RA, and followed for 12 months at 7 rheumatology referral centers across mainland Greece (NCT01001182). Patient data were collected at the initial visit and 3, 6, and 9 months. QoL was evaluated using the Euro Quality of Life-5 dimensions questionnaire (EQ-5D) and functional ability was evaluated using the Health Assessment Questionnaire (HAQ). RESULTS: A total of 210 patients with RA were enrolled (76.7% women, mean ± standard deviation [SD] age: 59.1 ± 12.6 years, median [interquartile range] disease duration: 11.9 [5.0-16.0] years). Baseline mean ± SD EQ-5D and HAQ scores were 0.57 ± 0.32 and 0.75 ± 0.63, respectively, and remained largely unchanged throughout the study. Post-hoc comparison showed that patients receiving non-biologic disease-modifying antirheumatic drugs (non-bDMARDs) had significantly higher EQ-5D and lower HAQ-DI scores compared with those receiving biologic DMARDs. A majority of patients reported having difficulty doing housework or other duties (61.4 and 61.9%, respectively), and 55.2% reported needing external support for these tasks. Positive correlation was observed between QoL and functional ability. Hospitalization at least once during the study occurred in 9.5% of the patients, and 12.5% of these cases were due to exacerbation of RA. At baseline, 52.4% of the patients were retired, with 38.5% of retirees having retired early due to RA. Among the patients who were retired at baseline, the mean ± SD period from actual retirement to expected retirement age was 12.1 ± 8.1 years. CONCLUSION: QoL and functional ability were positively correlated in patients with long-standing RA, with a large proportion showing impairments in both. Timely, target-oriented treatment initiated as soon as possible after diagnosis may help to improve patient-reported outcomes and limit the burden of RA. TRIAL REGISTRATION: ClinicalTrials.gov NCT01001182 . Registered 23 October 2009.

Fatigue independently predicts different work disability dimensions in etanercept-treated rheumatoid arthritis and ankylosing spondylitis patients.

BACKGROUND: Work disability remains a significant problem in ankylosing spondylitis (AS) and rheumatoid arthritis (RA), despite biological therapy. This study aimed to test the hypothesis that the prevalent symptom of fatigue longitudinally predicts work disability among RA and AS patients commencing etanercept. METHODS: Two observational studies, comprising RA and AS etanercept commencers, respectively, were analysed. Both provided data on work disability over 1 year and a comprehensive set of putative predictors, including fatigue. A series of repeated measures models were conducted, including baseline variables, visit (6/12 months), and the interaction between visit and each of the explanatory variables. RESULTS: A total of 1003 AS and 1747 RA patients were assessed. For AS, fatigue was significantly associated with presenteeism (linear mixed model coefficient 3.75, 95% confidence interval (CI) 2.14 to 5.36) and activity impairment (2.62, 1.26 to 3.98), but not with work productivity loss (1.81, -0.40 to 4.02) or absenteeism (generalised linear mixed model odds ratio (OR) 1.18, 95% CI 0.92 to 1.51). In RA, fatigue was associated with presenteeism (coefficient 3.44, 95% CI 2.17 to 4.70), activity impairment (1.52, 0.79 to 2.26), work productivity loss (4.16, 2.47 to 5.85), and absenteeism (OR 1.23, 95% CI 1.02 to 1.49). The lack of significant interactions between fatigue and visit supported a consistent effect of baseline fatigue over time. CONCLUSIONS: Among patients beginning etanercept therapy, fatigue has a significant and independent effect on absenteeism, presenteeism, productivity loss, and activity impairment for RA patients and a significant but dimension-selective effect on work disability among AS patients. TRIAL REGISTRATION: ClinicalTrials.gov, NCT00544557 . Registered on 16 October 2007. ClinicalTrials.gov, NCT00488475 . Registered on 20 June 2006.

The comparative immunogenicity of biologic therapy and its clinical relevance in psoriatic arthritis: a systematic review of the literature.

INTRODUCTION: Biologic agents have demonstrated efficacy in treating patients with psoriatic arthritis (PsA). Biologic agents also have an intrinsic capacity to induce an immune response in patients that could result in unwanted adverse events and/or treatment failure. AREAS COVERED: In this systematic literature review, the authors document the incidence of immune responses, primarily anti-drug antibodies (ADA), to the biologic therapeutic agents currently in clinical practice for the treatment of PsA. The authors discuss the importance of these responses with respect to clinical practice. EXPERT OPINION: Our evaluation of the published literature shows that the immune responses to the various biologic therapeutic agents currently being used to treat PsA are similar to those observed for these agents in other rheumatic diseases. Moreover, similar to observations in other rheumatic diseases, the incidence of ADA formation to biologic agents in patients with PsA is often decreased when patients are given concomitant treatment with disease-modifying anti-rheumatic drugs. These data strongly suggest that the immune response is a characteristic of the biologic agent. Using therapeutic drug monitoring may be an approach to assess the immune response to the agent and to mitigate the potential impact on efficacy and safety, and consequently optimize treatment.

First identification of resident and circulating fibrocytes in Dupuytren's disease shown to be inhibited by serum amyloid P and Xiapex.

Dupuytren's disease (DD) is a common progressive fibroproliferative disorder causing permanent digital contracture. Proliferative myofibroblasts are thought to be the cells responsible for DD initiation and recurrence, although their source remains unknown. DD tissue has also been shown to harbor mesenchymal and hematopoietic stem cells. Fibrocytes are circulating cells that show characteristics of fibroblasts and they express surface markers for both hematopoietic and mesenchymal stromal cells. Fibrocytes differentiate from peripheral CD14+ mononuclear cells, which can be inhibited by serum amyloid P (SAP). In this study we have demonstrated the presence of fibrocytes in DD blood and tissue, moreover we have evaluated the effects of SAP and Xiapex (Collagenase Clostridium histolyticum) on fibrocytes derived from DD. H&E staining showed typical Spindle shaped morphology of fibrocytes. FACS analysis based on a unique combination of 3 markers, revealed the increased presence of fibrocytes in blood and tissue of DD patients. Additionally, immunohistology of DD nodule and cord tissue showed the presence of collagen 1+/CD34+ cells. No difference in plasma SAP levels was observed between DD and control. Higher concentrations of SAP significantly inhibited fibrocytes differentiated from DD derived monocytes compared to control. DD fascia derived fibrocytes showed resistance to growth inhibition by SAP, particularly nodule derived fibrocytes showed robust growth even at higher SAP concentrations compared to control. DD derived fibrocytes were positive for typical fibrocyte dual markers, i.e. Collagen 1/LSP-1 and collagen 1/CD34. Xiapex was more effective in inhibiting the growth of nodule derived cells compared to commercially available collagenase A. Our results show for the first time the increased presence of fibrocytes in DD patient's blood and disease tissue compared to control tissue. Additionally, we evaluate the response of these fibrocytes to SAP and Xiapex therapy.

The efficacy and safety of collagenase clostridium histolyticum in the treatment of patients with moderate Dupuytren's contracture.

OBJECTIVE: The efficacy and safety of collagenase clostridium histolyticum (CCH) in patients with Dupuytren's contracture (DC) was demonstrated in a program including two pivotal phase 3 clinical trials (CORD I and II) which included patients with a broad range of disease severity. This analysis assessed the efficacy and safety of CCH in the subpopulation of DC patients with up to two joints affected and moderate disease according to British Society of Surgery of the Hand classification. This was in support of a resubmission to the Scottish Medicines Consortium. RESEARCH DESIGN AND METHODS: A post-hoc analysis that included data from patients with up to two joints affected and moderate disease treated with CCH during the randomized and open-label phases of CORD I and II. RESULTS: Of 362 patients who received CCH during the two trials, 58 had one or two joints affected and moderate disease. Sixty-seven joints were treated; 49 patients received treatment for one joint, and 9 patients received treatment for two joints. Each patient received an average of 1.62 injections of CCH per joint. Of 65 evaluable joints, 82% met the primary endpoint of clinical success (reduction in contracture to ≤5° of full extension 30 days after the last injection). This was similar if only primary joints were considered (81% achieved clinical success). Recurrence at 12 months (increase in joint contracture to ≥20° in the presence of a palpable cord in joints that had attained clinical success) was observed in 3.8% of joints. Reported adverse events were mild to moderate in intensity; none resulted in discontinuation. CONCLUSIONS: CORD I and II show that CCH is well tolerated and effective in the treatment of DC in a broad population. The present analysis suggests that CCH has particular value in patients with moderate severity disease and up to two joints affected. STUDY LIMITATIONS: This analysis used data from both the randomized and open-label phases of CORD I and II; therefore, it is not possible to present comparative data for this subpopulation. As this was a post-hoc analysis in a relatively small patient subpopulation, statistical comparisons with the full population were not considered appropriate. Furthermore, the small sample size means that additional subgroup analyses, for example of patients by previous treatment or number of injections administered, are not appropriate. Nevertheless, the data presented demonstrate that CCH is both well tolerated and effective in this population when managed by appropriately trained individuals.

Eliciting health state utilities for Dupuytren's contracture using a discrete choice experiment.

BACKGROUND AND PURPOSE: An internet-based discrete choice experiment (DCE) was conducted to elicit preferences for a wide range of Dupuytren's contracture (DC)-related health states. An algorithm was subsequently developed to convert these preferences into health state utilities that can be used to assess DC's impact on quality of life and the value of its treatments. METHODS: Health state preferences for varying levels of DC hand severity were elicited via an internet survey from a sample of the UK adult population. Severity levels were defined using a combination of contractures (0, 45, or 90 degrees) in 8 proximal interphalangeal and metacarpophalangeal joints of the index, middle, ring, and little fingers. Right-handed, left-handed, and ambidextrous respondents indicated which hand was preferable in each of the 10 randomly-selected hand-pairings comparing different DC severity levels. For consistency across comparisons, anatomically precise digital hand drawings were used. To anchor preferences onto the traditional 0-1 utility scale used in health economic evaluations, unaffected hands were assigned a utility of 1.0 whereas the utility for a maximally affected hand (i.e., all 8 joints set at 90 degrees of contracture) was derived by asking respondents to indicate what combination of attributes and levels of the EQ-5D-5L profile most accurately reflects the impact of living with such hand. Conditional logistic models were used to estimate indirect utilities, then rescaled to the anchor points on the EQ-5D-5L. RESULTS: Estimated utilities based on the responses of 1,745 qualified respondents were 0.49, 0.57, and 0.63 for completely affected dominant hands, non-dominant hands, or ambidextrous hands, respectively. Utility for a dominant hand with 90-degree contracture in t h e metacarpophalangeal joints of the ring and little fingers was estimated to be 0.89. Separately, reducing the contracture of metacarpophalangeal joint for a little finger from 50 to 12 degrees would improve utility by 0.02. INTERPRETATION: DC is associated with substantial utility decrements. The algorithms presented herein provide a robust and flexible framework to assess utility for varying degrees of DC severity.

Isolated and spontaneous correction of proximal interphalangeal joint contractures in Dupuytren's disease: an exploratory analysis of the efficacy and safety of collagenase Clostridium histolyticum.

BACKGROUND AND OBJECTIVE: Dupuytren's contractures affecting proximal interphalangeal (PIP) joints are challenging to treat. We explored the effects of collagenase Clostridium histolyticum (CCH) on PIP joint contractures after injection of an affected metacarpophalangeal (MP) joint in the same finger and after injection of an isolated PIP joint contracture. METHODS: Two patient subsets were evaluated: those with MP/PIP joints contractures in the same finger, but only the MP joint contractures were treated (Group A); and those with isolated PIP joint contractures that were treated (Group B). Endpoints included correction and improvement in contracture. Fixed-flexion contracture (FFC) and range of motion (ROM) were also assessed; adverse events (AEs) were monitored. RESULTS: In Group A, 28 and 43 % of PIP contractures spontaneously corrected after the first and last injection of CCH, respectively, for MP contractures; 40 and 63 %, respectively, improved. In Group B, 31 and 39 % of PIP joint contractures corrected after the first and last injection of CCH, respectively, 56 and 66 %, respectively, improved. In Groups A and B, FFC improvements were largest after the last injection; ROM improvements were largest after the last injection in Group A and third injection in Group B. For 46 and 44 % of patients in Groups A and B, respectively, the first injection was the last injection. In Group B, the median (minimum, maximum) injections/joint was 1.0 (1.0, 4.0). Nearly all patients (98 %) experienced ≥1 AE; most were injection-site reactions. CONCLUSIONS: The efficacy of CCH for improving PIP joint contracture was similar whether treated in isolation or after treatment of an MP joint contracture.

Recognition, diagnosis and referral of patients with Dupuytren's disease: a review of current concepts for general practitioners in Europe.

BACKGROUND: Dupuytren's disease (DD) is a fairly prevalent yet under-recognised disorder of the palmar fascia, resulting in fixed-flexion contractures of joints in the hand. Numerous population-based studies have been conducted in countries around the world, and published prevalence estimates vary widely. Nevertheless, most studies have shown that the prevalence of DD increases with age. Because the global population is aging, the prevalence of DD will also continue to increase. SCOPE: Patients with DD typically present to a variety of physicians, generalists and specialists alike. Thus, it is critical that providers have clear guidance on the early recognition of signs and symptoms, comprehensive evaluation of potential risk factors, differential diagnosis and when to refer a patient for treatment. Treatment options range from minimally invasive injections with collagenase to surgery. FINDINGS: Results from a large-scale study of the surgical management of DD in Europe indicate that most DD diagnoses and referrals are made by general practitioners, but there is much inter-country variation. Different patient- and physician-based factors affect diagnosis rates and referral pathways. Different healthcare systems and regulations are also influential. A simple management algorithm is provided herein and explained. CONCLUSION: It is important for generalists to understand the natural history of DD and the potential benefits of early referral and treatment. General practitioners should diagnose and/or refer patients with DD to a specialist as early as possible to optimise disease management and treatment outcomes.

Efficacy of collagenase in patients who did and did not have previous hand surgery for Dupuytren's contracture.

Collagenase Clostridium histolyticum (CCH) is a non-surgical, efficacious therapy for Dupuytren's contracture (DC). This study evaluated the efficacy and safety of CCH in patients with previous DC surgery. Data from 12 CCH clinical trials were pooled. At screening, patients provided details about the type/date of previous DC surgery. Reviewers coded descriptions to the Operated Hand, finger, and joint. Of 1082 patients, 422 (39%) had previous DC surgery. For these patients with previous surgery, the CCH treatment was coded on the Operated (n = 206) or Non-operated Hand (n = 196). End-points included changes in fixed-flexion contracture (FFC) and range of motion (ROM). Adverse events (AEs) were monitored. After treatment with CCH, FFC at metacarpophalangeal joints was reduced by 75% in previously Operated Hands and by 80% for Non-operated Hands (p = 0.6). Improvements in ROM were 32° and 32°, respectively (p = 0.9). For proximal inter-phalangeal joints, the reductions in FFC for the Operated and Non-operated Hands were 52% and 50%, respectively (p = 0.6); improvements in ROM were 24° and 26°, respectively (p = 0.3). Some AE rates were significantly higher in the Operated vs Non-operated Hand groups, but were not clinically relevant. There were no between-group significant differences in AE duration (p > 0.08). Previous surgery for DC does not affect efficacy or safety of CCH, suggesting CCH is an option in patients with recurring DC. Some AE rates were significantly higher, but not clinically relevant.

Current trends in the surgical management of Dupuytren's disease in Europe: the surgeon's perspective.

INTRODUCTION: Dupuytren's disease (DD), commonly affecting European men, is generally treated with surgery. METHODS: Orthopaedic and plastic surgeons who had been practicing for >3 and <30 years and operated on ≥5 patients with DD between September and December 2008 were surveyed in 12 European countries (Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, The Netherlands, Poland, Spain, Sweden and UK). The survey assessed procedures performed, factors influencing choice of procedure, use of physical therapy and recurrence. Descriptive statistics are reported. RESULTS: A total of 687 surgeons participated, including 579 orthopaedic and 108 plastic surgeons; 383 (56%) were hand surgeons. About 37% of surgeons performed percutaneous needle fasciotomy (PNF), 77% fasciotomy, 95% fasciectomy and 40% dermofasciectomy (DF). Surgeons' choice of procedure was influenced by patient preferences, age, degree of contracture and recurrent disease. The percentage of surgeons prescribing physical therapy and the mean (standard deviation [SD]) duration of therapy increased with procedure complexity: PNF = 82%, 5.2 (3.9) weeks; fasciotomy = 94%, 5.3 (3.6); fasciectomy = 97%, 6.7 (5.1); and DF = 99%, 8.5 (6.4). Using survey responses, mean (SD) estimated recurrence rates decreased and estimated time to recurrence increased with procedure complexity-PNF = 44% (27%), 17 (15) months; fasciotomy = 30% (24%), 20 (18); fasciectomy = 20% (17%), 29 (23); and DF = 20% (19%), 33 (27). CONCLUSIONS: Across Europe, patient and surgical factors influence the intention to use a surgical procedure. Fasciectomy was the most commonly performed procedure type and was associated with lower recurrence than PNF or fasciotomy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12570-012-0091-0) contains supplementary material, which is available to authorized users.

Current trends in the surgical management of Dupuytren's disease in Europe: an analysis of patient charts.

INTRODUCTION: Dupuytren's disease (DD) causes progressive digital flexion contracture and is more common in men of European descent. METHODS: Orthopaedic and plastic surgeons in 12 European countries (the Czech Republic, Denmark, Finland, France, Germany, Hungary, Italy, The Netherlands, Poland, Spain, Sweden and the UK) with >3 and <30 years experience reviewed the medical charts of five consecutive patients they had treated surgically for DD in 2008. Descriptive statistics are reported. RESULTS: In total, 3,357 patient charts were reviewed. Mean (standard deviation) patient age was 61.9 (10.2) years; 81% were men. At the time of the procedure, 11% of patients were at Tubiana stage Ia (0-20° total flexion); 30%, stage Ib (21-45°); 34%, stage II (46-90°); 17%, stage III (91-135°); and 5%, stage IV (>135°). Percutaneous needle fasciotomy was performed in 10%, fasciotomy in 13%, fasciectomy in 69% and dermofasciectomy (DF) in 6% of patients. After surgery, fingers improved a mean of 1.9 Tubiana stages, and 54% of patients had no nodules or contracture. The rate of reported complications during the procedure was 4% overall (11% in patients undergoing DF). The most common postoperative complications reported were haematoma (8%), wound healing complications (6%) and pain (6%). No postoperative complications were reported in 77% of patients. CONCLUSIONS: In this European study of more than 3,000 patients with DD, most patients were diagnosed at Tubiana stage I or II, the majority received fasciectomy and more than half had no nodules or contracture remaining after surgery. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s12570-012-0092-z) contains supplementary material, which is available to authorized users.