Ib 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.

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.

Plasma Adiponectin in Patients with Active, Early, and Chronic Rheumatoid Arthritis Who Are Steroid- and Disease -Modifying Antirheumatic Drug-Naive Compared with Patients with Osteoarthritis and Controls

Objective. Rheumatoid arthritis (RA) is a systemic chronic inflammatory joint disease, whereas osteoarthritis (OA) is a local joint disease with low-level inflammatory activity. The pathogenic role of the adipocytokine adiponectin is largely unknown in these diseases. We hypothesized (1) that plasma adiponectin concentrations differ in healthy controls and patients with early disease-modifying antirheumatic drug (DMARD)-naive RA, chronic RA, and OA; (2) that changes in adiponectin are observed during methotrexate (MTX) treatment of chronic RA; and (3) that adiponectin correlates to disease activity measures in RA. Methods. Plasma adiponectin was analyzed with a validated in-house immunoassay. We measured adiponectin in healthy controls (n = 45) and patients with early DMARD-naive RA (n = 40), chronic RA (n = 74), and OA (n = 35). In a subgroup of patients with chronic RA (n = 31), the longitudinal effect of MTX treatment on adiponectin (Week 0 vs Week 28) was investigated. Results. Adiponectin differed significantly between healthy controls (mean 4.8 ± SD 2.7 mg/l) and the 3 groups, with 8.9 ± 4.8 mg/l in early RA, 11.6 ± 5.6 mg/l in chronic RA, and 14.1 ± 6.4 mg/l in OA. Longitudinally, MTX treatment increased adiponectin significantly from 9.7 ± 4.5 mg/l at Week 0 to 11.0 ± 4.5 mg/l at Week 28 in chronic RA. No correlations to disease activity measures were found. Conclusion. Both early DMARD-naive and chronic RA were associated with higher plasma adiponectin compared to healthy controls, but lower plasma adiponectin than OA. Adiponectin increased 13% during MTX treatment. In patients with RA and OA body mass index, age, sex, and disease activity measures failed to explain the findings.

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.

Short- and long-term efficacy of intra-articular injections with betamethasone as part of a treat-to-target strategy in early rheumatoid arthritis: impact of joint area, repeated injections, MRI findings, anti-CCP, IgM-RF and CRP

Objective To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA). Methods During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan–Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested. Results 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not. Conclusion In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Outcome of Pre-hospital Antibiotic Treatment of Meningococcal Disease

OBJECTIVE To assess the effect of pre-hospital antibiotic treatment given by general practitioners to patients with meningococcal disease. DESIGN A 16-year population-based historical follow-up study based on referral letters and hospital records in the County of North Jutland, Denmark. SUBJECTS 320 patients with meningococcal disease, of whom 302 were examined by a general practitioner before admission to hospital. MAIN OUTCOME MEASURES Death. RESULTS 44 patients (14.6%) were given antibiotic treatment by the referring general practitioner. Nine of these (20.5%) died, compared with 16 (6.2%) patients who did not receive pre-hospital antibiotic treatment. The presence of skin bleeding, petechiae, and impaired consciousness were strongly associated with case fatality. Even after adjustment for these variables the odds ratio (OR) for death in patients treated with antibiotics was high (OR = 3.2; 95% CI, 0.9-10.6). In the 15 patients with skin bleeding (ecchymoses, suggillations) the case fatality rate was 100% in patients treated with antibiotics, and 50% in patients who did not receive antibiotics before hospitalization. If skin bleeding was replaced in the models by the presence of disseminated intravascular coagulation on admission, the OR for death in patients with pre-hospital antibiotic treatment was 35.9 (95% CI, 2.9-441.8) in the presence of disseminated intravascular coagulation and 1.9 (95% CI, 0.2-19.5) in its absence. CONCLUSIONS Pre-hospital treatment is mainly given to the most severe cases with expected high case fatality, and this confounding by indication was probably not fully adjusted for with the available data. The results contradict previous findings but provide reason to doubt the benefit of pre-hospital antibiotic treatment in patients with meningococcal disease.

Identification of cases of meningococcal disease: data quality in two Danish population-based information systems during a 14-year period

Meningococcal disease (MCD) is registered in two population-based information systems in Denmark because of the interest in long-term surveillance as a means of following trends, and in public health intervention such as chemoprophylaxis and vaccination. The two systems are the Notifiable System of Communicable Diseases (NSCD) and the Hospital Discharge Register for in-patients (HDR). The aim of the present study was to assess the data quality of the two systems over a 14-year period in the County of Northern Jutland, Denmark. All records of patients registered in the two systems were reviewed with respect to the criteria for the diagnosis of MCD. In addition, records from the local clinical microbiology department, where all microbiological examinations were carried out, were reviewed. The degree of completeness for the HDR system was 89.8% and for the NSCD system was 92.2%. In the in-patient HDR, 296 cases were registered, but only 254 cases (85.8%) fulfilled the criteria for MCD. In the notifiable system, 273 cases were registered, but only 261 cases (95.6%) fulfilled the criteria for MCD. A capture-recapture analysis showed that one to two cases apparently escaped registration.

Prolonged risk of specific malignancies following cyclophosphamide therapy among patients with granulomatosis with polyangiitis

OBJECTIVE The long-term cancer risk for patients treated for granulomatosis with polyangiitis (GPA) is not well characterized. We assessed the risk of early and late-occurring cancers among 293 patients diagnosed with GPA from 1973 to 1999 and followed throughout 2010. METHODS Cancer incidence in the cohort was determined by linkage with the Danish Cancer Registry and compared with that in the general population by calculation of standardized incidence ratios (SIRs). RESULTS The median duration of follow-up was 9.7 years (range 0-36). Seventy-three cancers occurred, of which 30 were non-melanoma skin cancers (NMSCs) and 11 were bladder carcinomas. A high occurrence of NMSC was observed from the second year of follow-up onwards, with a SIR of 7.0 (95% CI 2.3, 16) for cases diagnosed ≥20 years after GPA. The incidence of bladder cancer increased after 5-9, 10-14 and 15-19 years of follow-up, with SIR estimates for these latency periods of 5.3 (95% CI 1.1, 15), 14.4 (95% CI 5.3, 31) and 10.5 (95% CI 1.2, 38), respectively. The incidence of myeloid leukaemia was significantly increased during years 5-9 [SIR 23.9 (95% CI 2.7, 86)]. Increased incidence of NMSC, bladder cancer and myeloid leukaemia was observed among patients exposed to cumulative CYC doses >36 g, while the only malignancy type observed in excess among those treated with lower CYC doses was NMSC. The cancer risk among CYC-naive patients was not significantly increased. CONCLUSION GPA patients experience a greater than expected number of specific malignancies following conventional therapies. Our analyses demonstrate a substantially increased risk of very late-occurring NMSC and bladder cancer in this patient group.

Periarticular and generalised bone loss in patients with early rheumatoid arthritis: influence of alendronate and intra-articular glucocorticoid treatment. Post hoc analyses from the CIMESTRA trial

Objectives The aims of this study were to investigate the influence of alendronate and intra-articular betamethasone treatment on bone mineral density (BMD) changes in hand, lumbar spine and femoral neck during 1 year of a treat-to-target study (Cyclosporine, Methotrexate, Steroid in RA (CIMESTRA)). Patients and methods A hundred and sixty patients with early, active rheumatoid arthritis (RA) received methotrexate, intra-articular betamethasone and ciclosporin /placebo-ciclosporin. Patients with Z-score ≤0 also started alendronate 10 mg/day. BMD of the hand (digital x-ray radiogrammetry (DXR-BMDhand)), BMD of lumbar spine and femoral neck (dual x-ray absorptiometry (DXA-BMDlumbar spine and DXA-BMDfemoral neck)) and x-rays of hands, wrists and forefeet (modified Sharp-van der Heijde score) were measured at baseline and 1 year, with complete data available in 107 patients. Results The change in BMD in hand, lumbar spine and femoral neck was negatively associated with the dose of intra-articular betamethasone (p<0.01 for all), but the bone loss in hand was modest and in the axial skeleton comparable with that of healthy individuals. Alendronate did not influence changes in DXR-BMDhand, which averaged −2.8%, whereas significant changes were observed in DXA-BMDlumbar spine and DXA-BMDfemoral neck in alendronate-treated patients (1.8% and 0.8%) compared with untreated patients (–1.8% and –2.2%) (p<0.01 and 0.02). Alendronate did not affect the radiographic progression (alendronate-treated patients: 0 (range 0–19), non-alendronate: 0 (0–18)). Conclusions In early active RA, intra-articular betamethasone injections added to disease-modifying antirheumatic drug (DMARD) treatment led to minimal loss of hip and lumbar BMD, and the loss could be prevented by treatment with alendronate. Alendronate treatment did not affect radiographic progression.

Mannose-Binding Lectin Gene Polymorphisms Are Associated with Disease Activity and Physical Disability in Untreated, Anti-Cyclic Citrullinated Peptide-Positive Patients with Early Rheumatoid Arthritis

Objective. To study the association between polymorphisms in the mannose-binding lectin gene (MBL2) and disease activity, physical disability, and joint erosions in patients with newly diagnosed rheumatoid arthritis (RA). Methods. Patients with early RA (n = 158) not previously treated with disease modifying antirheumatic drugs, participating in a treatment trial (CIMESTRA study) were examined at inclusion for MBL2 pooled structural genotypes (O/O, A/O, A/A), regulatory MBL2 promoter polymorphism in position −221 (XX, XY, YY), anti-cyclic citrullinated peptide 2 antibodies (anti-CCP2), disease activity by Disease Activity Score-28 (DAS28 score), physical disability by Health Assessment Questionnaire (HAQ) score, and erosive changes in hands and feet (Sharp-van der Heijde score). Results. Eight patients were homozygous MBL2 defective (O/O), 101 belonged to an intermediate group, and 49 were MBL2 high producers (YA/YA). Anti-CCP was present in 93 patients (59%). High scores of disease activity, C-reactive protein-based DAS28 (p = 0.02), and physical disability by HAQ (p = 0.01) were associated with high MBL2 expression genotypes in a gene-dose dependent way, but only in anti-CCP-positive patients. At this early stage of the disease there was no association with erosion score from radiographs. Conclusion. The results point to a synovitis-enhancing effect of MBL in anti-CCP-positive RA, whereas such an effect was not demonstrated for joint erosions.