Gina Kollerup

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.

Pre-analytical and biological variability in circulating interleukin 6 in healthy subjects and patients with rheumatoid arthritis

Abstract Interleukin (IL)-6, a key player in the inflammatory response, may be a useful biomarker in rheumatoid arthritis (RA). The aim was to determine analytical variability, a reference interval in healthy subjects, and long- and short-term variation in serum and plasma IL-6 in healthy subjects and RA patients. An enzyme-linked immunosorbent assay from R&D was used for determination of serum and plasma IL-6. The IL-6 concentration did not depend on the type of anticoagulant used or the 3-h time delay between sampling and processing or repeated freeze–thaw cycles. The median plasma and serum IL-6 in 318 healthy subjects were 1.3 pg ml−1 (range 0.33–26) and 1.4 pg ml−1 (range 0.25–23), respectively. The median coefficient of variation in plasma IL-6 in 27 healthy subjects during 1 month, and repeated after 6 and 12 months were 27%, 31% and 26%, respectively. No significant long-term changes were observed in serum IL-6 over a 3-year period (14%, p=0.33). Exercise (cycling) increased serum IL-6 in healthy subjects but not in RA patients. In conclusion, circulating IL-6 is stable regarding sample handling and shows little variation over time. Changes in IL-6 concentrations >60% (2 times the biological variation) are likely to reflect changes in disease activity and not only pre-analytical or normal biological variability.

Bone Metabolism in Patients with Systemic Lupus Erythematosus: Effect of disease activity and glucocorticoid treatment

The bone metabolism in patients with systemic lupus erythematosus (SLE) has previously been examined, but the results are conflicting. In the present study the bone mineral density (BMD) of the axial and the appendicular skeleton was examined by means of dual energy x-ray absorptiometry. The bone turnover was evaluated by means of biochemical markers in serum and urine in a prospective cohort consisting of 36 female and male SLE patients. Repeated measurements of BMD were performed for up to two years. The BMD was decreased in the hand and in the femoral neck but normal in the spine and in the distal forearm. A weak correlation was found between the BMD of the femoral neck and the total consumption of glucocorticoids. Apart from this finding the BMD was uninfluenced by treatment with glucocorticoids and cyclophosphamide. No significant changes of BMD were found during the follow-up period. The serum concentration of the carboxyterminal cross-linked telopeptide of type I collagen was increased in almost all patients, but no other biochemical markers of bone metabolism were abnormal.

Impact of tumour necrosis factor inhibitor treatment on radiographic progression in rheumatoid arthritis patients in clinical practice: results from the nationwide Danish DANBIO registry

Objectives To compare radiographic progression during treatment with disease-modifying antirheumatic drugs (DMARD) and subsequent treatment with tumour necrosis factor α inhibitors (TNF-I) in rheumatoid arthritis (RA) patients in clinical practice. Methods Conventional radiographs (x-rays) of hands and wrists were obtained ∼2 years before start (prebaseline), at baseline and ∼2 years after start (follow-up) of TNF-I. Clinical data were obtained from the DANBIO registry and the patient files. x-Rays were scored blinded to chronology according to the Sharp/van der Heijde method. Annual radiographic progression rates during the DMARD (prebaseline to baseline x-ray) and TNF-I (baseline to follow-up x-ray) periods were calculated. Results 517 RA patients (76% women, 80% IgM rheumatoid factor positive, 65% anticyclic citrullinated peptide positive, 40% current smokers, age 54 years (range 21–86), median disease duration 5 years (range 0–57)) were included. Patients were treated with infliximab (61%), etanercept (15%) or adalimumab (24%). During the DMARD period 85% of patients received methotrexate, 51% sulphasalazine and 78% prednisolone. The median DMARD period was 733 days (IQR 484–1002) and the median TNF-I period was 562 days (IQR 405–766). The median radiographic progression rate decreased from 0.7 (IQR 0–2.9) total Sharp score units/year (dTSS) in the DMARD period to 0 (0–0.9) units/year in the TNF-I period (p<0.0001, Wilcoxon). Corresponding mean dTSS values were 2.1 (SD 3.7) versus 0.7 (SD 2.3) units/year (p<0.0001, paired t test). 305 patients progressed (dTSS >0) in the DMARD period compared with 158 patients in the TNF-I period (p<0.0001, χ2). Conclusion This nationwide observational study of RA patients documented significantly reduced radiographic progression during TNF-I treatment compared with the previous period of DMARD treatment.

Acute effects of nasal salmon calcitonin on calcium and bone metabolism

SummaryEffects of a single dose of 200 IU of nasal salmon calcitonin (SCT) on calcium metabolism and biochemical markers of bone turnover were investigated in 12 healthy male volunteers in a randomized, placebo-controlled, crossover design. The nasal spray was given in the morning, and subsequently blood and urine samples were collected for 26 hours. There was a significant decrease in serum ionized calcium with a nadir 4 hours after administration of nasal SCT accompanied by a significant increase in serum parathyroid hormone (P = 0.01) and serum calcitriol (P = 0.04). Nasal SCT did not reduce urinary hydroxyproline/creatinine. Urinary deoxypyridinoline/creatinine was lowered significantly 2 hours after administration of nasal SCT and throughout the first 24 hours, but remained unchanged for the last 2 hours. On a 24-hour basis, urinary deoxypyridinoline/creatinine decreased from 14.1 (3.5) nmol/mmol to 11.7 (3.2) nmol/mmol after nasal SCT (P = 0.04). Nasal SCT did not change the serum levels of alkaline phosphatase, osteocalcin, and the carboxyterminal propeptide of type 1 procollagen. The results indicate that nasal SCT given as a single dose provokes a modest decrease in bone resorption lasting several hours, but leaves bone formation unaffected.

Which Factors Influence Radiographic Progression During Treatment with Tumor Necrosis Factor Inhibitors in Clinical Practice? Results from 930 Patients with Rheumatoid Arthritis in the Nationwide Danish DANBIO Registry

Objective. To investigate baseline characteristics associated with radiographic progression and the effect of disease activity, drug, switching, and withdrawal on radiographic progression in tumor necrosis factor (TNF) inhibitor-naive patients with rheumatoid arthritis (RA) followed for about 2 years after anti-TNF initiation in clinical practice. Methods. DANBIO-registered patients with RA who had available radiographs (anti-TNF initiation and ∼2 yrs followup) were included. Radiographs were scored, blinded to chronology with the Sharp/van der Heijde method and linked with DANBIO data. Baseline characteristics were investigated with univariate regression and significant variables included in a multivariable logistic regression analysis with ± radiographic progression [Δ total Sharp score (TSS) > 0] as dependent variable. Effect of time-averaged C-reactive protein (CRP), 28-joint Disease Activity Score with CRP (DAS28-CRP), and treatment status at followup were investigated with univariate regression analysis. Results. The study included 930 patients. They were 75% women, 79% positive for IgM-rheumatoid factor (IgM-RF), median age was 57 yrs (range 19–88), disease duration 9 yrs (1–59), DAS28-CRP 5.0 (1.4–7.8), TSS median 15 [3–45 interquartile range (IQR)] and mean 31 (SD 40). Patients started treatment with infliximab (59%), etanercept (18%), or adalimumab (23%). At followup (median 526 days, IQR 392–735), 61% were treated with the initial anti-TNF, 29% had switched TNF inhibitor, and 10% had withdrawn. Twenty-seven percent of patients had progressed radiographically. ΔTSS was median 0.0 [0.0–0.5 IQR/mean 0.6 (SD 2.4)] units/year. Higher TSS, older age, positive IgM-RF, and concomitant prednisolone at baseline were associated with radiographic progression. Time-averaged DAS28-CRP and time-averaged CRP, but not type of TNF inhibitor, were associated with radiographic progression. Patients who stopped/switched during followup progressed more than patients who continued treatment. Conclusion. High TSS, older age, IgM-RF positivity, and concomitant prednisolone were associated with radiographic progression during 2 years of followup of 930 anti-TNF–treated patients with RA in clinical practice. High disease activity and switching/stopping anti-TNF treatment were associated with radiographic progression.

Establishment of age- and sex-adjusted reference data for hand bone mass and investigation of hand bone loss in patients with rheumatoid arthritis treated in clinical practice: an observational study from the DANBIO registry and the Copenhagen Osteoarthritis Study.

BackgroundRheumatoid arthritis is characterised by progressive joint destruction and loss of periarticular bone mass. Hand bone loss (HBL) has therefore been proposed as an outcome measure for treatment efficacy. A definition of increased HBL adjusted for age- and sex-related bone loss is lacking. In this study, we aimed to: 1) establish reference values for normal hand bone mass (bone mineral density measured by digital x-ray radiogrammetry (DXR-BMD)); and 2) examine whether HBL is normalised in rheumatoid arthritis patients during treatment with tumour necrosis factor alpha inhibitors (TNFI).MethodsDXR-BMD was measured from hand x-rays in a reference cohort (1485 men/2541 women) without arthritis randomly selected from an urban Danish population. Sex- and age-related HBL/year was estimated. DXR-BMD was measured in rheumatoid arthritis patients (n = 350: at start of TNFI, and ~2 years after TNFI start), of which 135 patients had three x-rays (~2 years prior to TNFI, at start of TNFI, and ~2 years after TNFI start). Individual HBL/year prior to and during TNFI was calculated and compared to reference values.ResultsEstimated HBL/year varied strongly with age and sex. Compared to the reference values, 75 % of 135 patients had increased HBL prior to TNFI treatment and 59 % had increased HBL during TNFI treatment (p = 0.17, Chi-squared). In 38 % (38/101) of patients with increased HBL, HBL was normalised during TNFI treatment, whereas 47 % (16/34) of patients with normal HBL prior to TNFI had increased HBL during TNFI treatment. In the 350 patients, increased HBL during TNFI was associated with time-averaged 28-joint disease activity score (odds ratio 1.69 (95 % Confidence Interval 1.34-2.15)/unit increase, p < 0.001), and patients in time-averaged remission had lower HBL than patients without remission (0.0032 vs. 0.0058 g/cm2/year; p < 0.001, Mann-Whitney).ConclusionsWe established age- and sex-specific reference values for DXR-BMD in a large cohort without arthritis. HBL was increased in the majority of rheumatoid arthritis patients initiating TNFI in clinical practice, and only normalised in a minority during TNFI.

Lack of effect of nasal salmon calcitonin on cell-mediated immunity

The calcium lowering hormone, calcitonin, also affects the immune system. The effect of nasal salmon calcitonin on lymphocyte transformation tests and on serum-ionised calcium was investigated in a randomised, double-blind and placebo-controlled study including 24 healthy adult volunteers. The participants received a single dose of either 200 IU of nasal salmon calcitonin or nasal placebo in the morning and measurements were done before and 3 h after administration of the spray. Nasal salmon calcitonin exerted a significant hypocalcemic effect, but did not interfere with antigen- or mitogen-induced expansion of T-lymphocytes. It is unlikely that nasal salmon calcitonin affects cell-mediated immunity in healthy subjects.

SAT0079 Tumour Necrosis Factor Alpha Inhibitor Treatment Normalises Hand Bone Loss in a Minority of Rheumatoid Arthritis Patients Treated in Clinical Practice. Results from the Copenhagen Osteoarthritis Study and the Danbio Registry

Background Rheumatoid arthritis (RA) is characterised by progressive joint destruction and loss of periarticular bone mass. Hand bone loss (HBL) is measured by Digital X-ray Radiogrammetry (DXR) which has been proposed as an outcome measure for treatment effect in RA. A definition of increased HBL adjusted for age- and gender-related bone loss is lacking. Furthermore, it is unknown to which extent HBL is normalised in RA patients during treatment with tumour necrosis factor alpha inhibitors (TNF-I). Objectives To establish a reference material for HBL and to investigate whether HBL normalises in RA patients during TNF-I treatment in clinical practice. Methods Hand bone mass (DXR-BMD) was measured with DXR, a computerised method of estimating cortical bone mineral density in the diaphysis of the 2nd – 4th metacarpal bone in a reference population and a patient cohort. The reference population consisted of 1,533 men and 2618 women randomly selected from the urban county of Østerbro in Denmark who had hand x-rays performed in the cross-sectional Copenhagen Osteoarthritis Study. Linear regression analyses were used to calculate normal HBL (defined as the 95% Confidence Interval (95%CI) for the age-related mean changes in DXR-BMD between subsequent age-groups). The patient cohort was 135 patients from the DANBIO registry with hand x-rays obtained ∼2 years before start of TNF-I (pre-baseline, all patients treated with conventional synthethic Disease-Modifying Anti-Rheumatic Drugs (csDMARD)), at start of TNF-I (baseline) and ∼ 2 years after start of TNF-I (follow-up). Annual HBL during csDMARD and TNF-I treatment were calculated in individual patients and compared with the lower 95%CI of mean DXR-BMD change in the gender- and age-matched reference group to assess if increased HBL was present. Results Table 1 presents the HBL reference material. The 135 RA patients (85% women, 71% IgM-RF positive, median age 55 (range 23-84) years; median disease duration 5 (range 1-53) years) had a pre-baseline median DAS28 of 4.3 (range 1.6-6.9) and a baseline DAS28 of 5.3 (1.4-8.2). TNF-I treatment was infliximab (74%), etanercept (13%) or adalimumab (13%). At follow-up (DAS28 3.1 (1.4-7.7) 59% received the initial TNF-I, 27% had switched to another biological drug and 14% had withdrawn. Compared to the reference population, 84 (62%) patients had increased HBL during csDMARD treatment and 60 (44%) had during TNF-I treatment (p=0.10,Chi-Sq). In 42 patients who had elevated HBL during csDMARD treatment HBL was normalised during TNF-I. Eighteen patients had normal HBL during csDMARD treatment but increased HBL during treatment with TNF-I. Conclusions We have established a reference material for HBL in the general population and found significant age-related decreases in DXR-BMD in both men and women. Increased HBL was present in the majority of RA patients initiating TNF-I treatment in clinical practice and was normalised in only a minority of patients during treatment. Disclosure of Interest None declared