Robert L. Wong

Assessment of radiographic progression in the spines of patients with ankylosing spondylitis treated with adalimumab for up to 2 years

IntroductionAnkylosing spondylitis (AS) is a chronic rheumatic disease associated with spinal inflammation that subsequently leads to progression of structural damage and loss of function. The fully human anti-tumor necrosis factor (anti-TNF) antibody adalimumab reduces the signs and symptoms and improves overall quality of life in patients with active AS; these benefits have been maintained through 2 years of treatment. Our objective was to compare the progression of structural damage in the spine in patients with AS treated with adalimumab for up to 2 years versus patients who had not received TNF antagonist therapy.MethodsRadiographs from patients with AS who received adalimumab 40 mg every other week subcutaneously were pooled from the Adalimumab Trial Evaluating Long-Term Efficacy and Safety for Ankylosing Spondylitis (ATLAS) study and a Canadian AS study (M03-606). Radiographic progression from baseline to 2 years in the spine of adalimumab-treated patients from these two studies (adalimumab cohort, n = 307) was compared with an historic anti-TNF-naïve cohort (Outcome in AS International Study [OASIS], n = 169) using the modified Stoke AS Spine Score (mSASSS) method.ResultsmSASSS results were not significantly different between the adalimumab cohort and the OASIS cohort, based on baseline and 2-year radiographs. Mean changes in mSASSS from baseline to 2 years were 0.9 for the OASIS cohort and 0.8 for the adalimumab cohort (P = 0.771), indicating similar radiographic progression in both groups. When results for patients in the OASIS cohort who met the baseline disease activity criteria for the ATLAS and Canadian studies (OASIS-Eligible cohort) were analyzed, there was no significant difference in mean change in mSASSS from baseline to 2 years between OASIS-Eligible patients and adalimumab-treated patients; the mean changes in mSASSS were 0.9 for the OASIS-Eligible cohort and 0.8 for the adalimumab cohort (P = 0.744).ConclusionsTwo years of treatment with adalimumab did not slow radiographic progression in patients with AS, as assessed by the mSASSS scoring system, when compared with radiographic data from patients naïve to TNF antagonist therapy.Trial registrationCanadian study (M03-606) ClinicalTrials.gov identifier: NCT00195819; ATLAS study (M03-607) ClinicalTrials.gov identifier: NCT00085644.

Efficacy of adalimumab in the treatment of axial spondylarthritis without radiographically defined sacroiliitis: results of a twelve-week randomized, double-blind, placebo-controlled trial followed by an open-label extension up to week fifty-two.

OBJECTIVE To evaluate the efficacy and safety of the tumor necrosis factor (TNF) antagonist adalimumab in patients with axial spondylarthritis (SpA) without radiographically defined sacroiliitis refractory to conventional treatment. METHODS Patients with active axial SpA (n = 46) were randomized to receive placebo or adalimumab at a dosage of 40 mg subcutaneously every other week for 12 weeks, followed by an open-label extension that continued up to week 52. The diagnosis of axial SpA required the presence of 3 of 6 diagnostic criteria, including 2 of the following 3 criteria: inflammatory back pain, HLA-B27 positivity, or acute inflammation of the spine or sacroiliac joints on magnetic resonance imaging, in the absence of radiographic evidence of sacroiliitis. The primary end point was a 40% response according to the improvement criteria of the Assessment of SpondyloArthritis international Society (ASAS40). RESULTS All 46 patients (22 receiving adalimumab and 24 receiving placebo) completed the 12-week trial; 38 patients completed the extension period to week 52. At week 12, an ASAS40 response was achieved by 54.5% of the adalimumab-treated patients, as compared with 12.5% of the placebo-treated patients (P = 0.004). After switching to adalimumab, a similar degree of efficacy was also achieved by the patients who were initially treated with placebo. Efficacy was maintained in all patients until week 52. Young age at study entry and an elevated C-reactive protein concentration were the best predictors of achieving an ASAS40 response. Serious adverse events occurred in 5 patients, none of which was related to the study drug. CONCLUSION Adalimumab is the first TNF antagonist to demonstrate good clinical efficacy and safety in patients with axial SpA without radiographically defined sacroiliitis.

Adalimumab effectiveness for the treatment of ankylosing spondylitis is maintained for up to 2 years: long-term results from the ATLAS trial

Objective: To determine the long-term effect of adalimumab on patients with ankylosing spondylitis (AS) who participated in the Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS), a randomised, double-blind, placebo controlled, 24-week trial. Methods: Patients received adalimumab 40 mg every other week (eow) or placebo for 24 weeks in ATLAS. At week 24, patients were switched to open-label adalimumab 40 mg eow. Efficacy measures included 20% improvement in the Assessment in SpondyloArthritis International Society (ASAS) criteria (ASAS20), ASAS40 and ASAS partial remission responses and changes in individual components of the ASAS20 response evaluations, for example, Bath AS Functional Index (BASFI) and Bath AS Disease Activity Index (BASDAI). Two-year interim data were analysed based on the total duration of adalimumab exposure, irrespective of the treatment randomisation group. Results: At 2 years, 255 (82.0%) of the original 311 ATLAS patients continued receiving adalimumab treatment. Improvements in ASAS responses observed in ATLAS were sustained during long-term treatment; 64.5% (200/310) were ASAS20 responders, 50.6% (157/310) were ASAS40 responders and 33.5% (104/310) had maintained ASAS-defined partial remission. Changes in individual ASAS response components were sustained or improved during long-term adalimumab treatment. From ATLAS baseline to 2 years of adalimumab exposure, respectively, BASDAI improved from 6.3 (SD 1.7) to 2.4 (SD 2.3) and BASFI improved from 5.2 (SD 2.4) to 2.9 (SD 2.5). Adalimumab was well tolerated. No cases of tuberculosis, congestive heart failure, lupus-like symptoms, or demyelinating disease were reported. Conclusions: Adalimumab reduced the signs and symptoms of AS and induced partial remission for up to 2 years. The long-term safety profile was similar to the short-term safety profile. Trial registration information: NCT00085644

Development and validation of the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index

Background: Enthesitis is a recommended core domain for assessment of ankylosing spondylitis (AS), but no measurement has yet been validated according to Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) criteria. Objective: The purpose of this study was to seek to validate an enthesitis index for patients with AS according to OMERACT criteria. Methods: An enthesitis index was validated in two AS patient cohorts: (1) a longitudinal cohort (n = 223) and (2) 22 patients from three Canadian sites participating in a 24-week randomised placebo-controlled trial of adalimumab in AS. Construct validity was evaluated by correlation analysis with the Bath AS Disease Activity Index (BASDAI), the Bath AS Functional Index (BASFI) and quality of life instruments. Reproducibility was assessed by intraclass correlation coefficient (ICC), and responsiveness was assessed by Guyatt’s effect size and standardised response mean. Results: The most frequently affected sites were the greater trochanter and supraspinatus insertion (∼20%). Patients with enthesitis had significantly greater scores for the BASDAI, BASFI, patient global, AS-specific quality of life index (ASQOL) and the Short Form 36 (SF-36) General Health Survey (p<0.001). The enthesitis score contributed significantly to variance in the BASDAI and BASFI. Interobserver ICCs were 0.96 in the longitudinal cohort and 0.89 and 0.77 in the adalimumab clinical trial cohort (for status and change score, respectively). Significant differences in change scores were evident for all patients after 24 weeks of adalimumab treatment, (p = 0.04), this being more significant when a subset of the most commonly affected entheses were analysed (p = 0.01). Conclusion: AS patients with enthesitis constitute a more severe subset of disease, and the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index is feasible and reliable for measurement of this condition. Discrimination requires further study in larger trials.

Impact of age, sex, physical function, health-related quality of life, and treatment with adalimumab on work status and work productivity of patients with ankylosing spondylitis.

Objective. To determine factors associated with work in patients with ankylosing spondylitis (AS). Methods. Three hundred fifteen patients with AS were enrolled in a 24-week, randomized controlled study of adalimumab with a longterm, open-label, adalimumab extension phase. Patient-reported outcome (PRO) measures included the Medical Outcome Study Short Form 36 Health Survey (SF-36), AS Quality of Life Questionnaire (ASQOL), Health Utilities Index Mark 3 (HUI-3), and Work Productivity and Activity Impairment-Specific Health Problem Questionnaire (WPAI-SHP). Multivariate logistic regression was used to analyze differences between working and nonworking patients. The relationships between PRO and WPAI-SHP scores were assessed using Pearson correlation coefficients. Multivariate modeling was applied to determine factors associated with productivity while at work. WPAI-SHP was assessed through 3 years of adalimumab exposure. Results. Younger age (p = 0.002) and male sex (p < 0.001) were significantly and independently associated with working patients with AS. The SF-36 Physical Component Summary score (p < 0.001), ASQOL score (p < 0.001), HUI-3 scores (p < 0.001), and both patient’s global assessment of disease activity (p < 0.001) and nocturnal pain (p < 0.001) scores were independently associated with working status. Work absenteeism due to AS was weakly correlated with all PRO scores. WPAI-SHP components of work presenteeism (lack of productivity at work), activity impairment, and overall work productivity loss due to AS were moderately correlated with quality of life as measured by the ASQOL, the SF-36 Physical Component Summary score, and the SF-36 Bodily Pain domain. Linear multivariate analyses indicated that work presenteeism was significantly associated with pain, functioning, and disease activity. Longterm adalimumab treatment was associated with sustained improvements in WPAI-SHP scores. Conclusions. Quality of life and the physical consequences associated with AS have a direct relationship with a patient’s ability to work. Adalimumab sustains improvements in work outcomes in patients with AS.

Adalimumab effectively reduces the signs and symptoms of active ankylosing spondylitis in patients with total spinal ankylosis.

Objective: To evaluate the long-term safety and efficacy of adalimumab in patients with ankylosing spondylitis (AS) and total spinal ankylosis (TSA). Design: Patients (n = 315) with active AS were randomised in a 2:1 ratio to receive adalimumab 40 mg every other week or placebo for 24 weeks followed by open-label adalimumab for up to 5 years. Two-year efficacy and safety data for 11 patients with investigator-defined TSA were evaluated. The primary end point was the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at Week 12. On or after Week 12, ASAS20 non-responders could switch to open-label adalimumab. Other efficacy measurements included ASAS40, ASAS 5/6, ASAS partial remission, and 50% improvement in the Bath AS Disease Activity Index (BASDAI 50). Results: 6 of 11 TSA patients were randomised to adalimumab and 5 to placebo. At Week 12, 50% of the adalimumab-treated patients achieved an ASAS20 response and 33% achieved an ASAS40, ASAS 5/6 and BASDAI 50. No placebo-treated patients achieved any response criteria at Week 12. 4 placebo- and 2 adalimumab-treated patients switched to open-label adalimumab before Week 24. After 1 year of adalimumab treatment, 8 of 11 patients achieved an ASAS20 response. After 2 years, 6 of the remaining 8 patients with TSA reported an ASAS20 response. There were no serious adverse events or adverse event-related study discontinuations. Conclusion: In patients with TSA, adalimumab treatment resulted in rapid and clinically significant improvement in the signs and symptoms of active disease. Adalimumab effectiveness and safety were sustained for at least 2 years. Trial registration number: NCT00085644.

Physical function, disease activity, and health-related quality-of-life outcomes after 3 years of adalimumab treatment in patients with ankylosing spondylitis

IntroductionWe evaluated the three-year impact of adalimumab on patient-reported physical function and health-related quality-of-life (HRQOL) outcomes in patients with active ankylosing spondylitis (AS).MethodsThe Adalimumab Trial Evaluating Long-Term Efficacy and Safety in AS (ATLAS) is an ongoing five-year study that included an initial 24-week, randomized, placebo-controlled, double-blind period, followed by open-label extension treatment with adalimumab. Clinical and HRQOL data collected for up to three years from ATLAS were used for these analyses. Patients were randomized to receive adalimumab 40 mg or placebo by subcutaneous injection every other week. Physical function was assessed by the Bath AS Functional Index (BASFI), as well as by the Short Form 36 (SF-36) Health Survey Physical Component Summary (PCS) and Physical Function subscale scores. HRQOL was assessed using the AS Quality of Life (ASQOL) questionnaire. Disease activity was assessed by the Bath AS Disease Activity Index (BASDAI).ResultsOf 315 patients enrolled in ATLAS, 288 (91%) participated in an open-label adalimumab treatment extension and 82% provided three-year outcome data. During the 24-week double-blind phase, adalimumab-treated patients experienced significant improvement compared with placebo-treated patients in the BASDAI (P < 0.001), BASFI (P < 0.001), ASQOL (P < 0.001), and both the SF-36 PCS (P < 0.001) and Physical Function subscale (P < 0.001) scores, but not the SF-36 Mental Component Summary score (P = 0.181) and Mental Health subscale scores (P = 0.551). Mean changes from baseline through three years of adalimumab treatment were statistically significant for the BASDAI (change score: -3.9, P < 0.001), BASFI (change score: -29.6, P < 0.001), SF-36 PCS (change score: 11.6, P < 0.001), and Physical Function (change score: 23.3, P < 0.001). Comparable results were observed for the other SF-36 scores and for the ASQOL (all P < 0.001).ConclusionsAdalimumab significantly improved disease activity, patient-reported physical function, and HRQOL. These benefits were maintained over three years of treatment in patients with AS.Trial registrationClinicalTrials.gov NCT00085644.

Translation and validation of non-English versions of the Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire.

BackgroundThe Ankylosing Spondylitis Quality of Life (ASQOL) questionnaire is a unidimensional, disease-specific measure developed in the UK and the Netherlands. This study describes its adaptation into other languages.MethodsThe UK English ASQOL was translated into US English; Canadian French and English; French; German; Italian; Spanish; and Swedish (dual-panel methods). Cognitive debriefing interviews were conducted with AS patients. Psychometric/scaling properties were assessed using data from two Phase III studies of adalimumab. Baseline and Week-2 data were used to assess test-retest reliability. Validity was determined by correlation of ASQOL with SF-36 and BASFI and by discriminative ability of ASQOL based on disease severity. Item response theory (Rasch model) was used to test ASQOLs scaling properties.ResultsCognitive debriefing showed the new ASQOL versions to be clear, relevant and comprehensive. Sample sizes varied, but were sufficient for: psychometric/scaling assessment for US English and Canadian English; psychometric but not scaling analyses for German; and preliminary evidence of these properties for the remaining languages. Test-retest reliability and Cronbachs alpha coefficients were high: US English (0.85, 0.85), Canadian English (0.87, 0.86), and German (0.77, 0.79). Correlations of ASQOL with SF-36 and BASFI for US English, Canadian English, and German measures were moderate, but ASQOL discriminated between patients based on perceived disease severities (p < 0.01). Results were comparable for the other languages. US English and Canadian English exhibited fit to the Rasch model (non-significant p-values: 0.54, 0.68), confirming unidimensionality.ConclusionThe ASQOL was successfully translated into all eight languages. Psychometric properties were excellent for US English, Canadian English, and German, and extremely promising for the other languages.

Inhibition of nuclear DMA synthesis by an autoantibody to proliferating cell nuclear antigen/cyclin

Proliferating cell nuclear antigen (PCNA) is expressed in the nuclei of proliferating cells, but is not detected in resting cells. The kinetics of PCNA expression suggest that it is associated with a phase preceding active DNA synthesis. DNA synthesis is under cytoplasmic control, and there is a cytoplasmic protein, ADR (activator of DNA replication), that induces DNA synthesis in isolated quiescent nuclei. We now report that a human antibody preparation monospecific for PCNA, but not two monoclonal antibodies directed against different epitopes on PCNA, can inhibit the ability of ADR to induce DNA synthesis in isolated quiescent nuclei. This effect is not due to inhibition of DNA polymerase alpha activity. Thus, the anti-PCNA antibody exerts its effect either by directly influencing the initial interaction of ADR with the nucleus, or by inhibiting subsequent synthetic events.

Adalimumab improves sleep and sleep quality in patients with active ankylosing spondylitis.

Objective. Fatigue and sleep problems are significant in patients with ankylosing spondylitis (AS). This subanalysis of the RHAPSODY study (Review of Safety and Effectiveness with Adalimumab in Patients with Active Ankylosing Spondylitis) was conducted to evaluate the effect of adalimumab on sleep in patients with active AS. Methods. All patients (n = 1250) had active AS and received adalimumab 40 mg every other week during the 12-week open-label treatment period. Sleep was assessed by the Medical Outcomes Study Sleep Scale (MOS-SS) at screening and Weeks 6, 12, and 20 (optional continuation period). Effect sizes were calculated to determine clinical significance. Paired Student t tests compared the change in the MOS-SS domains from Week 12 to baseline. Correlation coefficients were calculated to determine the relationship between change in sleep domains and other Week 12 clinical and patient-reported outcomes (Bath AS Disease Activity Index, C-reactive protein, nocturnal pain, total back pain, Bath AS Functional Index, patient’s global assessment of disease activity, morning stiffness, Short Form-36 Health Survey, and Work Productivity and Activity Impairment questionnaire components). Results. At Week 12, adalimumab significantly improved sleep in each of the MOS-SS domains (p < 0.001). Effect sizes for 3 of the 6 domains (disturbance, −0.69; adequacy, 0.55; somnolence, −0.52) and both sleep problems indices (Index I, −0.68; Index II, −0.77) were moderate, suggesting clinical significance. Change in the MOS-SS Sleep Problem Index II was moderately correlated with change in most clinical and patient-reported outcomes. Sleep improvements were similar in patients with and without radiographically advanced AS. Conclusion. Adalimumab improves overall sleep and sleep quality in patients with active AS.