Annette Schlemmer

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.

Circadian variation in the serum concentration of C-terminal telopeptide of type I collagen (serum CTx): effects of gender, age, menopausal status, posture, daylight, serum cortisol, and fasting.

We examined the diurnal variation in serum concentration of C-terminal telopeptide of type I collagen (serum CrossLaps, sCTx) under various conditions. The studies included a total of 100 individuals. Blood samples were collected every 3 h over 27 h. sCTx levels varied over the 24 h with a maximum at about 05:00 in the morning and a minimum of about 14:00 in the afternoon. The variation had a magnitude of about +/-40% around the 24 h mean and was similar in premenopausal and early and late postmenopausal women with normal and low bone mass. Furthermore, it was not affected by 5 days of bed-rest, by absence of a normal diurnal variation in cortisol production, or by absence of a normal light cycle (blindness). Nasal salmon calcitonin, an antiresorptive drug used for treatment of osteoporosis, was not able to break the circadian pattern whether the treatment was administered in the morning or the evening. The only parameter that showed a pronounced influence on the circadian variation was fasting, which reduced the variation significantly to about one fourth. From a practical point of view the results of this study demonstrate that samples for sCTx should be taken in the fasting state.

Incidences of overall and site specific cancers in TNFα inhibitor treated patients with rheumatoid arthritis and other arthritides – a follow-up study from the DANBIO Registry

Objectives To investigate the incidence of cancer in arthritis patients treated with or without TNFα inhibitors (TNF-I). Methods Arthritis patients from the DANBIO database were followed-up for cancer in the Danish Cancer Registry during 2000–2008. Results Hazard ratio for cancer overall was 1.02 (95% confidence interval (CI) 0.80-1.30) in 3347 TNF-I-treated RA patients compared to non-treated. Excess among TNF-I-treated was found for colon cancer (HR 3.52 (95%CI 1.11-11.15), whereas 6 and 0 ovarian cancer cases were observed in treated and non-treated patients, respectively. Compared to the general population, TNF-I-treated RA patients had increased risk for cancer overall, cancer in lymphatic-haematopoietic tissue and non-melanoma skin cancer, while non-RA patients had no increase in overall cancer risk. Conclusions Our results suggest that TNF-I therapy in routine care is not associated with an overall excess of cancer in arthritis patients, but observed increased risks of colon and ovarian cancer need further investigation.

The effect of growth hormone (GH) therapy on urinary pyridinoline cross‐links in GH‐deficient adults

objective The aim was to study the effect of growth hormone (GH) on new markers of bone resorption (fasting urinary excretion of pyridinium cross‐links (pyridinoline and deoxypyrWlnoline)) in GH‐deficient adults

Adalimumab added to a treat-to-target strategy with methotrexate and intra-articular triamcinolone in early rheumatoid arthritis increased remission rates, function and quality of life. The OPERA Study: an investigator-initiated, randomised, double-blind, parallel-group, placebo-controlled trial

Objectives An investigator-initiated, double-blinded, placebo-controlled, treat-to-target protocol (Clinical Trials:NCT00660647) studied whether adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment in early rheumatoid arthritis (ERA) increased the frequency of low disease activity (DAS28CRP<3.2) at 12 months. Methods In 14 Danish hospital-based clinics, 180 disease-modifying anti-rheumatic drugs (DMARD)-naïve ERA patients (<6 months duration) received methotrexate 7.5 mg/week (increased to 20 mg/week within 2 months) plus adalimumab 40 mg every other week (adalimumab-group, n=89) or methotrexate+placebo-adalimumab (placebo-group, n=91). At all visits, triamcinolone was injected into swollen joints (max. four joints/visit). If low disease activity was not achieved, sulfasalazine 2 g/day and hydroxychloroquine 200 mg/day were added after 3 months, and open-label biologics after 6–9 months. Efficacy was assessed primarily on the proportion of patients who reached treatment target (DAS28CRP<3.2). Secondary endpoints included DAS28CRP, remission, Health Assessment Questionnaire (HAQ), EQ-5D and SF-12. Analysis was by intention-to-treat with last observation carried forward. Results Baseline characteristics were similar between groups. In the adalimumab group/placebo group the 12-month cumulative triamcinolone doses were 5.4/7.0 ml (p=0.08). Triple therapy was applied in 18/27 patients (p=0.17). At 12 months, DAS28CRP<3.2 was reached in 80%/76% (p=0.65) and DAS28CRP was 2.0 (1.7–5.2) (medians (5th/95th percentile ranges)), versus 2.6 (1.7–4.7) (p=0.009). Remission rates were: DAS28CRP<2.6: 74%/49%, Clinical Disease Activity Index≤2.8: 61%/41%, Simplified Disease Activity Index<3.3: 57%/37%, European League Against Rheumatism/American College of Rheumatology Boolean: 48%/30% (0.0008<p<0.014, number-needed-to-treat: 4.0–5.4). Twelve months HAQ, SF12PCS and EQ-5D improvements were most pronounced in the adalimumab group. Treatments were well tolerated. Conclusions Adalimumab added to methotrexate and intra-articular triamcinolone as first-line treatment did not increase the proportion of patients who reached the DAS28CRP<3.2 treatment target, but improved DAS28CRP, remission rates, function and quality of life in DMARD-naïve ERA.

Influence of smoking, body fat distribution, and alcohol consumption on serum lipids, lipoproteins, and apolipoproteins in early postmenopausal women

The impact of smoking, alcohol consumption, obesity, and body fat distribution (measured either directly by dual photon absorptiometry as abdominal fat% (AF%) or as the waist-to-hip ratio (WTH] on serum lipids, lipoproteins, and apolipoproteins was investigated in 148 early postmenopausal women. All the women were healthy and none were taking medication known to influence the parameters studied. Smokers had significantly higher levels of triglycerides, low density lipoprotein cholesterol (LDL-C), and apolipoprotein B (P less than 0.05), and higher ratios of LDL-C/HDL-C and apolipoprotein B/A-I (P less than 0.01), but lower levels of high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (P less than 0.01). Moderate alcohol consumption was positively associated with HDL-C and apolipoprotein A-I (P less than 0.001). Body weight and body mass index (BMI) tended to be positively associated with an atherogenic lipoprotein and apolipoprotein profile. However, body fat distribution parameters (AF% and WTH) were stronger predictors of lipoproteins and apolipoproteins than were body weight and BMI, which did not seem to be independent predictors of lipoproteins and apolipoproteins. We conclude that cigarette smoking and a central fat distribution have a significant, independent, negative influence on lipids, lipoproteins, and apolipoproteins, whereas moderate alcohol consumption has a positive effect on these parameters in early postmenopausal women.

Circadian variation in bone resorption is not related to serum cortisol

Serum osteocalcin, serum procollagen type I carboxyterminal propeptide (sPICP), and the urinary excretion of pyridinium crosslinks (biochemical markers of bone formation and resorption) all exhibit a circadian variation with a peak during the night. This study was performed to investigate the influence of the endogenous circadian rhythm in cortisol on the biochemical markers of bone turnover. Participants included 11 patients substituted with hydrocortisone due to either hypopituitarism (n = 7) or bilateral adrenalectomy (n = 4). Their daily tablet intake of hydrocortisone was divided in four equal doses in order to abrogate the known circadian variation in cortisol. 24 healthy postmenopausal women served as controls. The study design was performed over 24 h, with blood samples taken every 3 h, and urine collected in 3 h aliquots. Urinary pyridinium crosslinks (Pyr/ Cr, D-Pyr/Cr), serum osteocalcin (sOC), and serum PICP were measured. Patients without a circadian variation in cortisol had normal circadian variation in the urinary excretion of pyridinium crosslinks and sPICP, but no circadian rhythm in serum osteocalcin. We conclude that the etiology of the circadian rhythm in the biochemical markers of bone turnover is still unknown. This study indicates that the circadian variation in sOC can be controlled by the endogenous circadian variation in serum cortisol, whereas this hormone does not control the circadian variation in either the serum PICP or the urinary excretion in pyridinium crosslinks.

A treat-to-target strategy with methotrexate and intra-articular triamcinolone with or without adalimumab effectively reduces MRI synovitis, osteitis and tenosynovitis and halts structural damage progression in early rheumatoid arthritis: results from the OPERA randomised controlled trial

Objectives To investigate whether a treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid injections suppresses MRI inflammation and halts structural damage progression in patients with early rheumatoid arthritis (ERA), and whether adalimumab provides an additional effect. Methods In a double-blind, placebo-controlled trial, 85 disease-modifying antirheumatic drug-naïve patients with ERA were randomised to receive methotrexate, intra-articular glucocorticosteroid injections and placebo/adalimumab (43/42). Contrast-enhanced MRI of the right hand was performed at months 0, 6 and 12. Synovitis, osteitis, tenosynovitis, MRI bone erosion and joint space narrowing (JSN) were scored with validated methods. Dynamic contrast-enhanced MRI (DCE-MRI) was carried out in 14 patients. Results Synovitis, osteitis and tenosynovitis scores decreased highly significantly (p<0.0001) during the 12-months’ follow-up, with mean change scores of −3.7 (median −3.0), −2.2 (−1) and −5.3 (−4.0), respectively. No overall change in MRI bone erosion and JSN scores was seen, with change scores of 0.1 (0) and 0.2 (0). The tenosynovitis score at month 6 was significantly lower in the adalimumab group, 1.3 (0), than in the placebo group, 3.9 (2), Mann–Whitney: p<0.035. Furthermore, the osteitis score decreased significantly during the 12-months’ follow-up in the adalimumab group, but not in the placebo group, Wilcoxon: p=0.001–0.002 and p=0.062–0.146. DCE-MRI parameters correlated closely with conventional MRI inflammatory parameters. Clinical measures decreased highly significantly during follow-up. Conclusions A treat-to-target strategy with methotrexate and intra-articular glucocorticosteroid in patients with ERA effectively decreased synovitis, osteitis and tenosynovitis and halted structural damage progression as judged by MRI. The findings suggest that addition of adalimumab is associated with further suppression of osteitis and tenosynovitis.

Urinary excretion of pyridinium cross‐links in healthy women; the long‐term effects of menopause and oestrogen/progesterone therapy

OBJECTIVES We investigated the effect of the menopause when followed longitudinally for a decade to evaluate whether women with an increased bone loss continue to have elevated urinary excretion of pyridinium cross‐links later in menopause. Furthermore, we investigated the effect of oestrogen/progesterone therapy on the urinary excretion of pyridinium cross‐links.

Changes in the carboxyl terminal propeptide of type I procollagen and other markers of bone formation upon five days of bed rest

This study was performed in order to investigate the influence of skeletal unloading on the serum concentration of the carboxyl-terminal propeptide of type I procollagen (sPICP) and other markers of bone formation. Blood samples were taken every third hour from nine healthy premenopausal women (22-29 years) in two 24 h studies, before and at the end of five days of bed rest. Furthermore, a set of samples were taken 12 h apart after three days of bed rest. We measured sPICP, the serum concentration of intact and N-terminal-Mid fragment osteocalcin (sOC), and the serum concentration of alkaline phosphatase (sAP). During the five days of bed rest a gradual increase in sOC was observed, while sPICP gradually decreased. sAP was unchanged. Five days of best rest resulted in the following overall changes in the 24 h mean values: sPICP: -14% (p = 0.002); sOC: +9% (p = 0.009); sAP: -1% (not significant). The circadian patterns did not change significantly after bed rest. It is puzzling that the changes in the bone formation markers are of different magnitude, and for sPICP and sOC even in opposite directions. The increase in sOC may be caused by an increase in OC secretion by the osteoblasts or a release of bone-incorporated OC from resorbing sites; the accompanying decrease in sPICP may indicate that bone formation is actually transiently decreased after short term bed rest.