Annette Hansen

Direct comparison of treatment responses, remission rates, and drug adherence in patients with rheumatoid arthritis treated with adalimumab, etanercept, or infliximab: Results from eight years of surveillance of clinical practice in the nationwide Danish DANBIO registry

OBJECTIVE To compare tumor necrosis factor alpha inhibitors directly regarding the rates of treatment response, remission, and the drug survival rate in patients with rheumatoid arthritis (RA), and to identify clinical prognostic factors for response. METHODS The nationwide DANBIO registry collects data on rheumatology patients receiving routine care. For the present study, we included patients from DANBIO who had RA (n = 2,326) in whom the first biologic treatment was initiated (29% received adalimumab, 22% received etanercept, and 49% received infliximab). Baseline predictors of treatment response were identified. The odds ratios (ORs) for clinical responses and remission and hazard ratios (HRs) for drug withdrawal were calculated, corrected for age, disease duration, the Disease Activity Score in 28 joints (DAS28), seropositivity, concomitant methotrexate and prednisolone, number of previous disease-modifying drugs, center, and functional status (Health Assessment Questionnaire score). RESULTS Seventy percent improvement according to the American College of Rheumatology criteria (an ACR70 response) was achieved in 19% of patients after 6 months. Older age, concomitant prednisolone treatment, and low functional status at baseline were negative predictors. The ORs (95% confidence intervals [95% CIs]) for an ACR70 response were 2.05 (95% CI 1.52-2.76) for adalimumab versus infliximab, 1.78 (95% CI 1.28-2.50) for etanercept versus infliximab, and 1.15 (95% CI 0.82-1.60) for adalimumab versus etanercept. Similar predictors and ORs were observed for a good response according to the European League Against Rheumatism criteria, DAS28 remission, and Clinical Disease Activity Index remission. At 48 months, the HRs for drug withdrawal were 1.98 for infliximab versus etanercept (95% 1.63-2.40), 1.35 for infliximab versus adalimumab (95% CI 1.15-1.58), and 1.47 for adalimumab versus etanercept (95% CI 1.20-1.80). CONCLUSION Older age, low functional status, and concomitant prednisolone treatment were negative predictors of a clinical response and remission. Infliximab had the lowest rates of treatment response, disease remission, and drug adherence, adalimumab had the highest rates of treatment response and disease remission, and etanercept had the longest drug survival rates. These findings were consistent after correction for confounders and sensitivity analyses and across outcome measures and followup times.

Symptom‐giving pelvic girdle relaxation in pregnancy, I: Prevalence and risk factors

BACKGROUND Previous studies concerning symptom-giving pelvic girdle relaxation in pregnancy have to our knowledge been retrospective. We wanted to 1) determine the incidence during pregnancy and the prevalence two, six, and twelve months post partum, 2) identify possible predisposing factors, and 3) determine the frequency and duration of sicklisting, prospectively. MATERIAL AND METHODS A cohort of 1600 consecutive pregnant women filled in a questionnaire. At the routine prenatal examinations they were asked about pelvic pain. Those who fulfilled the inclusion criteria were examined by a rheumatologist to confirm the diagnosis. The affected women were seen again two, six, and twelve months post partum. All participants were asked about sicklisting in pregnancy. RESULTS The incidence during pregnancy was 14%, the prevalence two, six, and twelve months post partum were 5%, 4%, and 2% respectively. Multivariate analysis indicates that the most important predisposing factor is pelvic pain in a previous pregnancy. Other factors were uncomfortable working conditions, lack of exercise, and previous low back pain and low abdominal pain. At least 37% of the women with symptom-giving pelvic girdle relaxation had been sicklisted in pregnancy due to pelvic pain, on average for twelve weeks. CONCLUSION Symptom-giving pelvic girdle relaxation is a considerable problem both in pregnancy and post partum. The occupational risk can possibly be prevented. The syndrome has a great social impact because of the frequent sicklisting.

No overall progression and occasional repair of erosions despite persistent inflammation in adalimumab-treated rheumatoid arthritis patients: results from a longitudinal comparative MRI, ultrasonography, CT and radiography study

Aim To monitor joint inflammation and destruction in rheumatoid arthritis (RA) patients receiving adalimumab/methotrexate combination therapy using MRI and ultrasonography. To assess the predictive value of MRI and ultrasonography for erosive progression on CT and compare MRI/ultrasonography/radiography for erosion detection/monitoring. Methods Fifty-two erosive biological-naive RA patients were followed with repeated MRI/ultrasonography/radiography (0/6/12 months) and clinical/biochemical assessments during adalimumab/methotrexate combination therapy. Results No overall erosion progression or repair was observed at 6 or 12 months (Wilcoxon; p>0.05), but erosion progressors and regressors were observed using the smallest detectable change cut-off. Scores of MRI synovitis, grey-scale synovitis (GSS) and power Doppler ultrasonography decreased after 6 and 12 months (p<0.05), as did DAS28, HAQ and tender and swollen joint counts (p<0.001). Patients with progression on CT had higher baseline MRI bone oedema scores. The RR for CT progression in bones with versus without baseline MRI bone oedema was 3.8 (95% CI 1.5 to 9.3) and time-integrated MRI bone oedema, power Doppler and GSS scores were higher in bones/joints with CT progression (Mann–Whitney; p<0.05). With CT as the reference method, sensitivities/specificities for erosion in metacarpophalangeal joints were 68%/92%, 44%/95% and 26%/98% for MRI, ultrasonography and radiography, respectively. Median intraobserver correlation coefficient was 0.95 (range 0.44–0.99). Conclusion During adalimumab/methotrexate combination therapy, no overall erosive progression or repair occurred, whereas repair of individual erosions was documented on MRI, and MRI and ultrasonography synovitis decreased. Inflammation on MRI and ultrasonography, especially MRI bone oedema, was predictive for erosive progression on CT, at bone/joint level and MRI bone oedema also at patient level.

Do rheumatoid arthritis patients in clinical practice benefit from switching from infliximab to a second tumor necrosis factor alpha inhibitor

Objective: To investigate the efficacy of switching to a second biological drug in rheumatoid arthritis (RA) patients. Methods: Since 2000, Danish RA patients (n  =  1021) receiving biological therapy have been registered in the nationwide DANBIO database. The first and second treatment series of patients, who switched therapy before 2005 (n  =  235), were analysed for their reasons for switching, Disease Activity Score 28 (DAS28), DAS28 improvement, European League against Rheumatology (EULAR) response and drug survival. Most patients switched from infliximab to etanercept or adalimumab. Results: Median survivals for switchers’ first/second treatment were 37/92 weeks (all patients’ first treatment 119 weeks). Reasons for switching were lack of efficacy (LOE; 109 patients), adverse events (AE; 72), other reasons (54). If patients experienced AE to the first drug, 15% had AE to the second. Median DAS28 improvements in first/second treatment at 3 months were: LOE switchers 1.1/1.6; AE switchers 1.5/0.8. In LOE switchers, a good/moderate EULAR response was more prevalent during the second treatment course than during the first (63% versus 54%, p  =  0.02). AE switchers achieved similar EULAR responses to both treatments (59% versus 50%, p  =  0.38). Conclusion: LOE switchers had a better clinical response to the second treatment. AE switchers responded equally well to both treatments, with a low risk of discontinuing the second drug as a result of AE. Drug survival of the switchers’ second biological therapy was higher than of the first, but lower than that of non-switchers. No difference between various sequences of drugs were found. Danish post-marketing data thus support that RA patients may benefit from switching biological therapy.

Efficacy of abatacept and tocilizumab in patients with rheumatoid arthritis treated in clinical practice: results from the nationwide Danish DANBIO registry

Objectives To describe drug survival, disease activity and clinical response in patients with rheumatoid arthritis (RA) treated with abatacept or tocilizumab in routine care, based on prospectively registered observational data from the nationwide Danish DANBIO registry. Methods 150 Patients with RA treated with abatacept and 178 treated with tocilizumab were identified. Drug survival was investigated. Response data were available in 104 and 97 patients, respectively. Changes in 28-joint Disease Activity Score (DAS28) based on C-reactive protein (CRP) and European League Against Rheumatism (EULAR) response after 24 and 48 weeks were investigated. No direct comparison of drugs was made. Results Median (IQR) disease duration was 8.5 (3–14)/9 (3–12) years (abatacept/tocilizumab). 95%/93% of patients had previously received one or more tumour necrosis factor inhibitor (TNFi). After 48 weeks, 54%/64% of patients (abatacept/tocilizumab) maintained treatment. Among patients with available response data, DAS28 was 5.3 (4.7–6.1), 3.4 (2.7–4.9) and 3.3 (2.5–4.3) at baseline, weeks 24 and 48, respectively, in the abatacept group and 5.4 (4.7–6.2), 2.9 (2.3–4.0) and 2.5 (1.9–4.5) in the tocilizumab group. At weeks 24 and 48, the remission rates for abatacept/tocilizumab were 19%/39% and 26%/58%, respectively. EULAR good-or-moderate response rates were 70%/88% and 77%/84%, respectively. The decline in DAS28 variables over time appeared similar between drugs, except for CRP, which seemed to decline more rapidly among tocilizumab-treated patients. Conclusions In patients with RA (≥90% TNFi failures), a good-or-moderate EULAR response was achieved in ≥70% of patients treated with abatacept or tocilizumab for 24 weeks in routine care. Apparent declines in DAS28 variables over time were similar between drugs, except for the more rapid CRP decline among tocilizumab-treated patients, directly caused by interleukin 6 inhibition.

Symptom-giving pelvic girdle relaxation in pregnancy, II: Symptoms and clinical signs

BACKGROUND Pelvic pain in pregnancy appears to be a problem that is increasing. This study was undertaken to describe and analyze the relationship between subjective symptoms, daily disability, and clinical findings in women with symptom-giving pelvic girdle relaxation in pregnancy MATERIALS AND METHODS Out of 1600 pregnant women 238 had pelvic pain. After a clinical examination 11 women were excluded due to low back pain. The rest, 227 women, was considered having symptom-giving pelvic girdle relaxation during pregnancy. RESULTS Symptom-giving pelvic girdle relaxation in pregnancy seriously interferes with many activities of daily living such as housekeeping, walking, working, and sexual life. The womens statements of pelvic pain are well correlated to the number of positive clinical tests. CONCLUSION Symptom-giving pelvic girdle relaxation in pregnancy causes considerable disabilities concerning daily activities.

Do changes in prescription practice in patients with rheumatoid arthritis treated with biological agents affect treatment response and adherence to therapy? Results from the nationwide Danish DANBIO Registry

Background: Prescription practice for tumour necrosis factor α (TNFα) inhibitors has changed towards treating patients with lower disease activity. Objective: To determine the trend in treatment response in cohorts of patients with rheumatoid arthritis who started TNFα inhibitor treatment between 2000 and 2005. Methods: 1813 patients with RA starting treatment with biological agents in 2000–5 were registered prospectively in the nationwide DANBIO Registry. Baseline disease activity and 12 months’ treatment responses were determined in cohorts based on start year (2000/1; 2002; 2003; 2004; 2005). Results: Despite decreasing baseline disease activity from the 2000/2001 cohort to 2005 cohort (28-joint count Disease Activity Score (DAS28): from 5.9 to 5.3 (p<0.001)), the 12 months’ DAS improvement increased from 1.8 units (2000/2001 cohort) to 2.2 units (2005 cohort) (p<0.001). The fraction with good EULAR response increased from 28% (2000/2001 cohort) to 50% (2005 cohort); the fraction with no response decreased from 29% (2000/2001 cohort) to 16% (2005 cohort). ACR20/50/70 response rates increased from 53%/31%/13% (2000/2001 cohort) to 69%/51%/30% (2005 cohort). After correction for withdrawals, treatment responses were lower, but patterns unchanged. One-year drug survival was for the 2000/2001 cohort: 73%, 2002: 62%, 2003: 67%, 2004: 70%, 2005: 69%. Conclusion: From 2000 to 2005, significantly improved treatment responses to TNF inhibitors were seen in clinical practice despite decreasing baseline disease activity levels. This lends support to the less stringent prescription practice towards treating patients with lower disease activity that has been observed in several countries.

ASDAS, BASDAI and different treatment responses and their relation to biomarkers of inflammation, cartilage and bone turnover in patients with axial spondyloarthritis treated with TNFα inhibitors

Objectives To investigate the relation between ankylosing spondylitis disease activity score (ASDAS), Bath ankylosing spondylitis disease activity index (BASDAI) and treatment response and biomarkers of inflammation (C-reactive protein (CRP), interleukin-6 (IL-6), YKL-40), angiogenesis (vascular endothelial growth factor (VEGF)), cartilage (C-terminal crosslinking telopeptide of type II collagen (CTX-II), matrix metalloproteinase-3 (MMP-3), total aggrecan, cartilage oligomeric matrix protein) and bone (C-terminal crosslinking telopeptide of type I collagen, osteocalcin) turnover in 60 patients with axial spondyloarthritis initiating tumour necrosis factor alpha (TNFα) inhibitor therapy. Methods ASDAS (CRP-based), BASDAI and biomarkers were determined before and seven times during 46 weeks of TNFα inhibitor therapy. Results Very high ASDAS were associated with high levels of inflammatory biomarkers, while high BASDAI were not related to any biomarkers. Mixed modeling demonstrated significant longitudinal associations between ASDAS and IL-6, VEGF, MMP-3 and osteocalcin and between BASDAI and CRP, IL-6 and VEGF. Major improvement in ASDAS was associated with larger percentage decreases in biomarkers of inflammation, angiogenesis, MMP-3 and increases in aggrecan and osteocalcin. BASDAI response was associated with larger decreases in CRP and IL-6. Biomarkers with moderate/high differences in responsiveness for major versus no/clinically important improvement in ASDAS were CRP, IL-6, VEGF, aggrecan and osteocalcin, and VEGF and CTX-II for BASDAI response versus non-response. Conclusion Levels and changes of 10 biomarkers in patients with axial spondyloarthritis during anti-TNFα therapy were documented. Construct validity and responsiveness of IL-6, VEGF, MMP-3, total aggrecan and osteocalcin were demonstrated. ASDAS was more associated with these biomarkers than BASDAI, and may better reflect the inflammatory disease processes. ClinicalTrials.gov identifier NCT00133315.

Erosive progression is minimal, but erosion healing rare, in patients with rheumatoid arthritis treated with adalimumab. A 1 year investigator-initiated follow-up study using high-resolution computed tomography as the primary outcome measure

Objective: With computed tomography (CT) and radiography, to investigate if repair of bone erosions, defined as regression of erosion scores, occurs during adalimumab treatment of patients with rheumatoid arthritis (RA). Methods: Fifty-two patients with RA, naïve to biological agents, with at least two low-grade radiographic erosions in the wrist or metacarpophalangeal (MCP) joints in the same (index) hand, initiated adalimumab 40 mg subcutaneously every other week. Thirty-five patients completed the study (median age 61 years (interquartile range 46–68), disease duration 8 years (3–15)). CT of the index wrist and MCP joints 2–5 and radiographs of hands and forefeet were obtained at baseline, 6 and 12 months. Images were evaluated by investigators blinded to chronology and clinical data, and assessed according to Sharp/van der Heijde (radiographs) and OMERACT RA MRI scoring (CT) methods. Results: Disease activity score, C-reactive protein, tender and swollen joints count and Health Assessment Questionnaire score had all decreased at 6 and 12 months (wilcoxon signed-ranks test p<0.001). No significant change in any imaging parameters of joint destruction was observed at 6 and 12 months. High intrareader agreements were reached (mean intraobserver intraclass coefficients: 0.96 (CT) and 0.97 (radiography)). The number of patients with change scores exceeding the smallest detectable change (SDC) was comparable on CT and radiography, as were the proportions of patients progressing/regressing. Decreased erosion scores at 12 months were registered in 1.6% and 1.8% of sites assessed on CT and radiography, respectively. Conclusion: Repair of erosions in adalimumab-treated patients with RA is rare, but erosive regression, exceeding the SDC, on CT and radiography occurred. The very limited overall erosive progression supports the view that joint destruction is minimal during adalimumab treatment of patients with RA.

Relaxin is not related to symptom‐giving pelvic girdle relaxation in pregnant women

Background The pregnancy associated hormone relaxin induces loosening of the pelvic ligaments in several species. This study was undertaken to evaluate whether pregnant women with symptom‐giving pelvic girdle relaxation had increased serum relaxin concentrations during pregnancy.