Correction to: Sustained improvement in work outcomes in employed patients with rheumatoid arthritis during 2 years of adalimumab therapy: an observational cohort study.

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Does concomitant methotrexate confer clinical benefits in patients treated with prior biologic therapy? Analysis of data from a noninterventional study of rheumatoid arthritis patients initiating treatment with adalimumab.

Most studies of methotrexate (MTX) in combination with tumor necrosis factor (TNF) inhibitors have focused on treatment-naive patients with early disease. The goal of this study was to evaluate whether previous biologic therapy influenced the impact of concomitant MTX in patients initiating treatment with adalimumab.We retrospectively analyzed data from 2 large noninterventional studies of German patients with active rheumatoid arthritis (RA) who initiated adalimumab therapy during routine clinical practice. Patients were seen between April 2004 and February 2013 for study 1 and between April 2003 and March 2013 for study 2. Key outcomes were Disease Activity Score-28 joints (DAS28), patient global assessment of health (PGA), and pain. Subgroup analyses by prior biologic treatment were performed on patients treated with continuous adalimumab monotherapy or adalimumab plus MTX for 12 months and 2-sample t tests were used to evaluate differences. We also assessed outcomes in subgroups in which MTX had been added or removed at 6 months and compared outcomes with 1-sample t tests.Of 2654 patients, 1911 (72%) were biologic naive and 743 (28%) had received prior biologic therapy, usually with a TNF inhibitor. All subgroups showed improvements following initiation of adalimumab therapy. In patients with no previous biologic treatment, continuous adalimumab plus MTX was associated with greater improvements in DAS28, PGA, and pain at month 12 compared with continuous adalimumab monotherapy (P = .0006, .0031, and .0032, respectively). In patients with previous biologic treatment, concomitant MTX was associated with statistically significant benefits in pain only. Adding MTX at month 6 resulted in additional benefits in patients with no prior biologic therapy, but not those with previous biologics.We conclude that concomitant MTX resulted in additional improvements in DAS28 and PGA vs adalimumab monotherapy in patients with no previous biologic therapy, but changes were not statistically significant in patients treated with prior biologics. These findings may help inform the patient/provider treatment decision during routine clinical care.

Sustained improvement in work outcomes in employed patients with rheumatoid arthritis during 2 years of adalimumab therapy: an observational cohort study.

OBJECTIVE: The goal of this study was to evaluate the long-term impact of adalimumab therapy on work-related outcomes in employed patients with rheumatoid arthritis (RA). METHOD: We utilized data from an observational cohort of German patients who initiated adalimumab treatment during routine clinical care. Analyses were based on employed patients (part-time or full-time) who continued adalimumab treatment for 24 months. Major outcomes were self-reported sick leave days in the previous 6 months, absenteeism, presenteeism, and total work productivity impairment as assessed by the Work Productivity and Activity Impairment (WPAI) questionnaire and disease activity assessments. The normal number of sick leave days was based on data from the German Federal Statistical Office. RESULTS: Of 783 patients, 72.3% were women, mean age was 47.9 years, and mean disease duration was 7.8 years. At baseline (before adalimumab initiation), 42.9% of patients had higher than normal sick leave days (> 5) in the previous 6 months. During 24 months of adalimumab treatment, 61% of patients with higher than normal sick leave days at baseline returned to normal sick leave values (≤ 5 days/6 months). Overall, mean sick leave days/6 months decreased from 14.8 days at baseline to 7.4 days at month 24. Improvements were observed in WPAI assessments and disease activity measures, although presenteeism levels remained high (32.2% at month 24). CONCLUSIONS: Adalimumab treatment was associated with strong and sustained improvements in work-related outcomes in employed patients who continued on adalimumab for 24 months. Presenteeism appears to be the work outcome most resistant to improvement during RA treatment. TRIAL REGISTRATION: NCT01076205 Key Points • Long-term adalimumab therapy was associated with sustained improvements in work outcomes in patients with rheumatoid arthritis. • Despite improvements in sick leave days and work absenteeism, presenteeism (impairment while at work) remained relatively high.

Use of a "critical difference" statistical criterion improves the predictive utility of the Health Assessment Questionnaire-Disability Index score in patients with rheumatoid arthritis.

BACKGROUND: The Health Assessment Questionnaire-Disability Index (HAQ-DI) is used to assess functional status in rheumatoid arthritis (RA), but the change required for meaningful improvements remains unclear. A minimum clinically important difference (MCID) of 0.22 is frequently used in RA trials. The aim of this study was to determine a statistically defined critical difference for HAQ-DI (HAQ-DI-dcrit) and evaluate its association with therapeutic outcomes. METHODS: We retrospectively analyzed data from adult German patients with RA enrolled in a multicenter observational trial in which they received adalimumab therapy at the decision of the treating clinician during routine clinical care. The HAQ-DI-dcrit, defined as the minimum change that can be reliably discriminated from random long-term variations in patients on stable therapy, was determined by evaluating intra-individual variation in patient scores. Other outcomes of interest included Disease Activity Score-28 joints and patient-reported pain and fatigue. RESULTS: The HAQ-DI-dcrit was calculated as an improvement (decrease) from baseline of 0.68 in a discovery cohort (N = 1645) of RA patients on stable therapy and with moderate disease activity (mean DAS28 [standard deviation] of 4.4 [1.6]). In the full patient cohort (N = 2740), 22.1% of patients achieved a HAQ-DI-dcrit improvement at month 6. Compared with patients with a small improvement in HAQ-DI (decrease of ≥0.22 to < 0.68) or no improvement (< 0.22), patients achieving a HAQ-DI-dcrit at month 6 had better therapeutic outcomes at months 12 and 24, including stable functional improvements. Change in pain was the most important predictor of HAQ-DI improvement during the first 6 months of therapy. CONCLUSIONS: A HAQ-DI-dcrit of 0.68 is a reliable measure of functional improvement. This measure may be useful in routine clinical care and clinical trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT01076205. Registered on February 26, 2010 (retrospectively registered).

Minimal disease activity is a stable measure of therapeutic response in psoriatic arthritis patients receiving treatment with adalimumab.

Objective: The aim of this study was to evaluate minimal disease activity (MDA) assessments in patients with PsA during routine clinical care. Methods: We used data from a multicentre observational study of patients with active PsA who initiated treatment with adalimumab during routine clinical practice and continued treatment for at least 6 months to evaluate achievement of MDA, individual MDA criteria (modified to conform to study assessments) and ACR responses during 24 months of therapy. Pearson correlation coefficients were used to evaluate the association between MDA and individual criteria at month 6; regression models were used to determine the influence of baseline MDA criteria on achievement of MDA at month 6. Results: A total of 1684 patients were included in these analyses; most had long-standing disease. MDA was achieved by 597 patients (35.5%) at month 6. This proportion increased to 45.5% at month 24 in patients remaining on therapy. MDA status was stable over time; >75% of patients with MDA at month 6 recorded MDA at subsequent visits. Pain was the most difficult individual criterion to achieve, and enthesitis was the least difficult. Higher functional status and fewer tender joints at baseline predicted achievement of MDA at month 6. About half of patients (51.5%) with an ACR20 response at month 6 achieved MDA. Conclusion: In this observational cohort of patients with long-standing disease, MDA provided a stable and valid assessment of clinical status over 24 months. Trial registration: Clinicaltrials.gov, https://clinicaltrials.gov, NCT01111240.

Anti-citrullinated protein antibodies are linked to erosive disease in an observational study of patients with psoriatic arthritis.

OBJECTIVE: ACPAs are associated with bone destruction in RA. The aim of this study was to evaluate the association between ACPA and bone destruction in patients with a distinct inflammatory disorder, PsA. METHODS: We used baseline data from a large observational study of PsA patients preparing to initiate treatment with adalimumab to analyse demographic and disease characteristics by ACPA status. To ensure a homogeneous PsA study population, only patients with active psoriatic skin manifestations who met Classification of Psoriatic Arthritis criteria for PsA were included in the analyses, thereby minimizing the risk of including misdiagnosed RA patients. Multiple logistic regression analyses were used to explore potential associations between ACPA seropositivity and bone destruction. RESULTS: Of 1996 PsA patients who met the strict inclusion criteria, 105 (5.3%) were positive for ACPA. ACPA-positive patients had significantly higher swollen joint counts and 28-joint DAS values than ACPA-negative patients and significantly higher rates of erosive changes and dactylitis. Multiple logistic regression analysis confirmed the association of ACPA seropositivity with a 2.8-fold increase in the risk of erosive disease. CONCLUSION: As has been previously shown for RA, ACPA is associated with bone destruction in PsA, suggesting that the osteocatabolic effect of ACPA is not confined to RA but is also detectable in the different pathogenetic context of a distinct disease entity. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01111240.

Association of Improvement in Pain With Therapeutic Response as Determined by Individual Improvement Criteria in Patients With Rheumatoid Arthritis.

OBJECTIVE: To use statistical methods to establish a threshold for individual response in patient-reported outcomes (PROs) in patients with rheumatoid arthritis. METHODS: We used an analysis of variance model in patients on stable therapy (discovery cohort) to establish critical differences (dcrit ) for the minimum change associated with a significant individual patient response (beyond normal variation) in the PRO measures of pain (0-10), fatigue (0-10), and function (Funktionsfragebogen Hannover questionnaire; 0-100). We then evaluated PRO responses in patients initiating adalimumab in a noninterventional study (treatment cohort). RESULTS: In the discovery cohort (n = 700), PROs showed excellent long-term retest reliability. The minimum change that exceeded random fluctuation was conservatively determined to be 3 points for pain, 4 points for fatigue, and 16 points for function. In the treatment cohort (n = 2,788), 1,483 patients (53.2%) achieved a significant individual therapeutic response as assessed by Disease Activity Score in 28 joints (DAS28)-dcrit (≥1.8 points) after 12 months of adalimumab treatment; 68.5% of patients with a DAS28-dcrit response achieved a significant improvement in pain, whereas approximately 40% achieved significant improvements in fatigue or function. Significant improvements in all 3 PROs occurred in 22.7% of patients; 22.8% did not have any significant PRO responses. In contrast, significant improvements in all 3 PROs occurred in only 4.4% of 1,305 patients who did not achieve a DAS28-dcrit response at month 12, and 59.1% did not achieve any significant PRO responses. CONCLUSION: The establishment of critical differences in PROs distinguishes true responses from random variation and provides insights into appropriate patient management.

Does Concomitant Methotrexate with Adalimumab Influence Treatment Outcomes in Patients with Psoriatic Arthritis? Data from a Large Observational Study.

OBJECTIVE: To examine the influence of concomitant methotrexate (MTX) with adalimumab (ADA) on outcomes in patients with psoriatic arthritis (PsA) using data from an observational study of ADA. METHODS: Data from a German noninterventional study of patients with PsA starting treatment with ADA were analyzed retrospectively for effects of concomitant MTX on key outcomes, including Disease Activity Score-28 joints, tender and swollen joint counts, skin assessments, and safety. Patients were categorized into those with symptoms of axial involvement and those with no symptoms of axial involvement as judged by the examining clinician. RESULTS: A total of 1455 patients met the study criteria, 296 with axial involvement (ADA monotherapy = 165; plus MTX = 131) and 1159 with no axial involvement (ADA monotherapy = 658; plus MTX = 501). ADA, alone or combined with MTX, resulted in strong and comparable reductions in disease activity measures in patients with and those without axial disease over 24 months of therapy. In multiple regression analyses, concomitant MTX did not affect joint or skin outcomes in either the group with axial manifestations or the group without axial disease. Neither adverse event rates nor withdrawal rates were significantly influenced by concomitant MTX. CONCLUSION: ADA is an effective treatment option for patients with PsA with or without axial involvement. Compared with ADA monotherapy, the use of concomitant MTX with ADA does not improve articular or skin outcomes in patients with PsA regardless of axial symptoms. TRIAL REGISTRATION: Clinicaltrials.gov NCT01111240.

The impact of prior biologic therapy on adalimumab response in patients with rheumatoid arthritis.

OBJECTIVES: The aim of this study is to use data from a non-interventional study of adalimumab in patients with rheumatoid arthritis (RA) during routine clinical practice to evaluate the impact of prior treatment with biologics on the effectiveness of current therapy. METHODS: Efficacy parameters were evaluated for all patients with values at baseline and month 12. Subgroup analyses were performed on patients with 0, 1, or ≥2 prior biologic agents. Key outcome measures included Disease Activity Score- 28 joints (DAS28) and Funktionsfragebogen Hannover (FFbH) functional ability score. RESULTS: A total of 4700 RA adalimumab-treated patients were included in this analysis. Baseline disease activity increased with an increasing number of prior biologic agents and therapeutic response diminished. After 12 months of adalimumab therapy, DAS28 and FFbH scores showed improvements in all groups, but the group with 0 prior biologic agents had the best outcomes, while the group with ≥2 prior biologic agents had the worst. Clinical response (EULAR and DAS28-dcrit) and remission rates showed a similar pattern. Nevertheless, 44% to 67% of patients treated with ≥2 prior biologic agents achieved a clinical response. Multiple regression analyses identified prior biologic therapy as a significant negative predictor for response to therapy. CONCLUSIONS: Treatment with adalimumab leads to decreases in disease activity and improvements in function. Improvements are most pronounced in patients with 0 or 1 prior biologic agent, but a substantial proportion of patients treated with ≥2 prior biologic agents experience significant benefit from adalimumab therapy.

Association between skin and joint involvement in patients with psoriatic arthritis treated with adalimumab: analysis of data from a German non-interventional study.

BACKGROUND: The association between skin and joint manifestations in patients with psoriatic arthritis (PsA) requires further characterization. OBJECTIVE: We evaluated the association between severity of skin disease and joint involvement and the effectiveness and safety of adalimumab in PsA patients by baseline psoriasis severity. METHODS: Descriptive statistics and regression analyses were used to evaluate data from 1,918 PsA patients starting adalimumab treatment. Subgroup analyses were conducted on patients empirically grouped by baseline target lesion score as a marker of psoriasis severity. RESULTS: Psoriasis severity was not associated with joint manifestations at baseline or after 12 months of treatment. All subgroups showed improvements in skin and joints during therapy, and adalimumab was safe and well tolerated in all subgroups. CONCLUSION: The severity of skin manifestations does not correlate with the severity of joint disease in PsA patients; even patients with mild skin disease may have extensive musculoskeletal involvement.

Development and validation of a new disease activity score in 28 joints-based treatment response criterion for rheumatoid arthritis.

OBJECTIVE: To define a valid criterion for treatment response as assessed by the Disease Activity Score in 28 joints (DAS28) that exceeds random disease activity variations in patients with rheumatoid arthritis (RA). METHODS: We utilized anonymized data sets of RA patients from multiple rheumatology centers in Germany to identify patients with stable responses to conventional or biologic disease-modifying antirheumatic drug (DMARD) therapy (discovery cohort). To evaluate fluctuations in DAS28 scores, we subjected patients' DAS28 scores at months 12, 18, and 24 to an analysis of variance model to establish a 1-sided 95% confidence interval for normal fluctuations; this value was used to define the critical difference (DAS28-dcrit ) for individual changes from baseline. The DAS28-dcrit value was then applied to analyses of therapeutic response in an adalimumab noninterventional study cohort. RESULTS: The discovery cohort included 415 patients receiving stable treatment. Values for DAS28-dcrit were comparable regardless of age, sex, disease activity, and class of therapy (DMARDs or biologic agents) and fell below 1.8 in all subgroups. We therefore conclude that DAS28 improvements of 1.8 or higher are outside the normal variation and represent a therapeutic response. When applied to data from the adalimumab noninterventional study (n = 1,874), a DAS28-dcrit response was more robust over time than a European League Against Rheumatism response and was more closely correlated with improved functional capacity. CONCLUSION: Based on our data, a DAS28-dcrit value of 1.8 signifies a positive individual therapeutic response that exceeds the threshold of random fluctuation. The DAS28-dcrit criterion may be useful in steering individual therapy and stratifying clinical trials.