Henrik Nordin

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.

Clinical response, drug survival, and predictors thereof among 548 patients with psoriatic arthritis who switched tumor necrosis factor α inhibitor therapy

OBJECTIVE To describe the frequency of treatment switching and outcomes among patients with psoriatic arthritis (PsA) who switched tumor necrosis factor α inhibitor (TNFi) agents in routine care. METHODS We conducted an observational cohort study based on the Danish nationwide DANBIO registry. Treatment outcomes were evaluated using the American College of Rheumatology criteria for 20% improvement (ACR20)/ACR50/ACR70, European League Against Rheumatism (EULAR) response criteria for good response, and the 28-joint count Disease Activity Score (DAS28) (remission). Kaplan-Meier and regression analyses were used for drug survival analyses and to identify predictors of outcome after treatment switching. RESULTS Of 1,422 patients starting TNFi agents, 548 patients (39%) switched to a second biologic drug during up to 10 years of followup. Median followup was 2.3 years (interquartile range [IQR] 1.0-4.3 years). Switchers were more frequently women (56% versus 45%), had a shorter disease duration (3 versus 4 years), a higher median Health Assessment Questionnaire (HAQ) score (1.1 [IQR 0.6-1.6] versus 0.9 [IQR 0.5-1.4]), DAS28 (4.8 [4.0-5.7] versus 4.4 [3.6-5.2]), pain score on a visual analog scale (VAS) (65 mm [46-77] versus 62 mm [40-75]), and fatigue score on a VAS (69 mm [50-83] versus 64 mm [42-80] mm) (all P < 0.05 at start of first TNFi). During the first and second treatment, HAQ, DAS28, and VAS scores and C-reactive protein levels had decreased after 6 months (all P < 0.05), and median drug survival was 2.2 versus 1.3 years (P < 0.001). Lower fatigue score increased survival of the second TNFi. After switching, the proportions of patients achieving a sustained ACR20, ACR50, ACR70, EULAR good response, and DAS28 remission after 3-6 months were 22% (number needed to treat [NNT] 4.5), 13% (NNT 7.9), 5% (NNT 20), 19% (NNT 5.3), and 34% (NNT 2.9), respectively. Response rates were lower during the second treatment (all P < 0.01 versus first TNFi). At the 2-year visit, 47% of switchers had achieved an ACR20 response. No differences between drug-drug combinations were found. CONCLUSION Thirty-nine percent of the patients with PsA switched TNFi agents. Response rates and drug survival were lower after switching; however, half of the switchers had an ACR20 response 2 years after starting the first TNFi.

A nationwide non-medical switch from originator infliximab to biosimilar CT-P13 in 802 patients with inflammatory arthritis: 1-year clinical outcomes from the DANBIO registry

Objectives According to guidelines, a nationwide non-medical switch from originator (INX, Remicade) to biosimilar infliximab (Remsima, CT-P13) was conducted in Danish patients with rheumatoid arthritis (RA), psoriatic arthritis (PsA) and axial spondyloarthritis (AxSpA). We investigated disease activity before/after switching and retention rates in the DANBIO registry. Methods Disease activities 3 months before and after switch and changes over time were calculated. Flare was defined as change in 28 Joint Disease Activity Score (∆DAS28) ≥1.2 (RA/PsA) or Ankylosing Spondylitis Disease Activity Score (∆ASDAS) ≥1.3 (AxSpA). Crude and adjusted retention rates were compared with a historic cohort of INX-treated patients. Results Eight hundred and two patients switched (403 RA/120 PsA/279 AxSpA; 51% women, age (median (IQR): 55 (44-66)) years). Follow-up was 413 (339–442) days. Prior INX treatment duration was 6.8 (4.3–9.5) years. Disease activities were similar 3 months before/after switch. Crude 1-year CT-P13 retention rate (84.1 (95% CI 81.3 to 86.5)) was similar to the historic IFX cohort (86.2 (95% CI 84.0 to 88.0), p=0.22). The adjusted absolute retention rates were 83.4 (95% CI 80.8 to 86.2) and 86.8% (95% CI 84.8 to 88.8), respectively (p=0.03). In total 132 patients withdrew (lack of effect: 71/132=54%, adverse events: 37/132=28%). Patients with previous INX treatment duration >5 years had longer CT-P13 retention. Conclusion In 802 arthritis patients treated with INX for median >6 years, a nationwide non-medical switch to CT-P13 had no negative impact on disease activity. Adjusted 1-year CT-P13 retention rate was slightly lower than for INX in a historic cohort.

Microalbuminuria in patients with rheumatoid arthritis.

OBJECTIVES--To assess (a) the prevalence of microalbuminuria in patients with rheumatoid arthritis, (b) the association between urinary albumin excretion and disease activity as estimated by the erythrocyte sedimentation rate and C reactive protein (CRP), and (c) the association between urinary albumin excretion and treatment with antirheumatic drugs. METHODS--Sixty five patients with rheumatoid arthritis attending two rheumatology clinics were compared with 51 control subjects matched by age and sex. The controls consisted of 20 healthy subjects, 16 patients with osteoarthritis and 15 with non-articular rheumatism. Patients with hypertension, diabetes mellitus, or evidence of previous renal disease were not included. Urinary albumin was assayed by immunoturbidimetry in random urine samples on two occasions within seven months. The results were expressed as the ratio of urinary albumin to urinary creatinine ratio. Disease activity was assessed by the erythrocyte sedimentation rate and CRP. A drug history for the year before entry to the study was obtained for each patient. RESULTS--Urinary albumin to creatinine ratio in patients with rheumatoid arthritis was significantly greater than in controls (p < 0.01). Microalbuminuria (urinary albumin to creatinine ratio 3-30 mg/mmol in either or both urine samples) was present in 27.7% of patients with rheumatoid arthritis and 7.8% of the control subjects. A significant relation was noted between urinary albumin to creatinine ratio and CRP, and the duration of disease. The number of patients treated with either gold or penicillamine was significantly greater in patients with microalbuminuria than in patients with normoalbuminuria. CONCLUSIONS--Microalbuminuria is frequently present in patients with rheumatoid arthritis. Treatment with gold and penicillamine seems to increase the risk of developing microalbuminuria. Urinary albumin measured by immunochemical methods is a simple and sensitive test to detect early subclinical renal dysfunction and drug induced renal damage in rheumatoid arthritis. Urinary albumin excretion was found to be significantly correlated with CRP and may be a sensitive indicator of disease activity in patients with rheumatoid arthritis.

Discordance of Global Assessments by Patient and Physician Is Higher in Female than in Male Patients Regardless of the Physician's Sex: Data on Patients with Rheumatoid Arthritis, Axial Spondyloarthritis, and Psoriatic Arthritis from the DANBIO Registry.

Objective. To assess the frequency of discordance in patient’s (PtGA) and physician’s (PGA) global assessment, and to investigate whether higher discordance in female patients compared with male patients is associated with the physician’s sex in patients with rheumatoid arthritis (RA), axial spondyloarthritis (axSpA), and psoriatic arthritis (PsA). Methods. PtGA, PGA, and other patient-related variables were retrieved from the Danish DANBIO registry, used nationwide to monitor patients with RA, axSpA, and PsA. A questionnaire was sent to all physicians registering in DANBIO (n = 265) regarding individual physician characteristics including sex and age. Discordance was defined as PtGA > 20 mm higher (or lower) than PGA. First encounters between patients and physicians were analyzed using descriptive statistics and mixed model regression analysis. Results. Ninety physicians (34%) returned the questionnaire and were pairwise matched with 10,282 first patient encounters (8300 patients with RA, 524 axSpA, and 1458 PsA). The frequency of discordant (PtGA > PGA) encounters (not including PGA > PtGA seen in < 2%) in RA, axSpA, and PsA was 49.0%, 48.3%, and 56.5%, respectively. Discordance was more common in female patients with high scores on functional disability, pain, and fatigue across the 3 diseases, whereas it was independent of the physician’s sex. Conclusion. In this study on Danish patients with RA, axSpA, and PsA, the PtGA was > 20 mm higher than the PGA in about half of the encounters, and more common in female patients of both female and male physicians. This finding highlights one of the challenges in shared decision making.

Impact of different infliximab dose regimens on treatment response and drug survival in 462 patients with psoriatic arthritis: results from the nationwide registries DANBIO and ICEBIO

OBJECTIVE The aim of this study was to describe dose regimens, dose escalation and clinical outcomes in TNF-α inhibitor (TNFi)-naive patients with PsA treated with infliximab in routine rheumatology care. METHODS We conducted an observational cohort study based on the nationwide Danish Rheumatologic Database (DANBIO) and Center for Rheumatology Research (ICEBIO) registries. Stratified by country, characteristics of patients treated with ≤3 mg infliximab/kg body weight, 3-5 mg/kg or ≥5 mg/kg every 8 weeks were described. Outcomes were evaluated by ACR 20%, 50% and 70% (ACR20/50/70) responses and European League Against Rheumatism good response after 6 months, disease activity after 12 months, Kaplan-Meier plots and regression analyses. RESULTS Four hundred and sixty-two patients (376 Danish, 86 Icelandic) received treatment with infliximab. In Danish patients, the starting dose was ≤3 mg/kg in 110 patients (29%), 3-5 mg/kg in 157 (42%), ≥5 mg/kg in 38 (10%) and unregistered in 71 (19%). In Icelandic patients, corresponding numbers were 64 (74%), 17 (27%), 0 (0%) and 5 (6%). Patients with a higher body weight received lower doses per kilogram. Danish patients received higher doses than Icelandic patients at baseline [median 3.1 (interquartile range 3.0-3.8) vs 2.3 (2.1-2.9) mg/kg, P < 0.05] and after 12 months [3.3 (3.0-4.5) vs 2.9 (2.2-3.5) mg/kg, P < 0.0001]. After 12 months, 58% of Danish and 66% of Icelandic patients maintained treatment. Danish patients had shorter drug survival than Icelandic patients (1183 vs 483 days). In univariate analyses stratified by country, time until dose escalation, response rates, drug survival and 1-years disease activity were independent of starting dose. Drug survival was shorter among patients not receiving concomitant MTX. CONCLUSION In clinical practice, > 70% of Icelandic and Danish PsA patients treated with infliximab received sustained doses below the 5 mg/kg every 8 weeks recommended in international guidelines. Lower starting doses did not affect drug survival or response.

Ankylosing Spondylitis versus Nonradiographic Axial Spondyloarthritis: Comparison of Tumor Necrosis Factor Inhibitor Effectiveness and Effect of HLA-B27 Status. An Observational Cohort Study from the Nationwide DANBIO Registry

Objective. To compare baseline disease activity and treatment effectiveness in biologic-naive patients with nonradiographic axial spondyloarthritis (nr-axSpA) and ankylosing spondylitis (AS) who initiate tumor necrosis factor inhibitor (TNFi) treatment and to study the role of potential confounders (e.g., HLA-B27 status). Methods. Observational cohort study based on prospectively registered data in the nationwide DANBIO registry. We used Kaplan-Meier plots, Cox, and logistic regression analyses to study the effect of diagnosis (nr-axSpA vs AS) and potential confounders (sex/age/start yr/HLA-B27/disease duration/TNFi-type/smoking/baseline disease activity) on TNFi adherence and response [e.g., Bath Ankylosing Spondylitis Activity Index (BASDAI) 50%/20 mm]. Results. The study included 1250 TNFi-naive patients with axSpA (29% nr-axSpA, 50% AS, 21% lacked radiographs of sacroiliac joints). Patients with nr-axSpA were more frequently women (50%/27%) and HLA-B27–negative (85/338 = 25%), compared to AS (81/476 = 17%; p < 0.01). At TNFi start patients with nr-axSpA had higher visual analog scale scores [median (quartiles)] for pain: 72 mm (55–84)/65 mm (48–77); global: 76 mm (62–88)/68 mm (50–80); fatigue: 74 mm (55–85)/67 mm (50–80); and BASDAI: 64 (54–77)/59 (46–71); all p < 0.01. However, patients with nr-axSpA had lower C-reactive protein: 7 mg/l (3–17)/11 mg/l (5–22); and BAS Metrology Index: 20 (10–40)/40 (20–50); all p < 0.01. Median (95% CI) treatment adherence was poorer in nr-axSpA than in AS: 1.59 years (1.15–2.02) versus 3.67 years (2.86–4.49), p < 0.0001; but only in univariate and not confounder-adjusted analyses (p > 0.05). Response rates were similar in AS and nr-axSpA (p > 0.05). HLA-B27 negativity was associated with poorer treatment adherence [HLA-B27 negative/positive, nr-axSpA: HR 1.74 (1.29–2.36), AS: HR 2.04 (1.53–2.71), both p < 0.0001]; and lower response rates (nr-axSpA: 18/61 = 30% vs 93/168 = 55%; AS: 17/59 = 29% vs 157/291 = 54%, both p < 0.05). Conclusion. In this nationwide cohort, patients with nr-axSpA had higher subjective disease activity at start of first TNFi treatment, but similar outcomes to patients with AS after confounder adjustment. HLA-B27 positivity was associated with better outcomes irrespective of axSpA subdiagnosis.

Validity and completeness of rheumatoid arthritis diagnoses in the nationwide DANBIO clinical register and the Danish National Patient Registry

Objectives In Denmark, patients with rheumatoid arthritis (RA) are registered in the nationwide clinical DANBIO quality register and the Danish National Patient Registry (DNPR). The aim was to study the validity of the RA diagnosis and to estimate the completeness of relevant RA cases in each registry. Study design and setting Patients registered for the first time in 2011 with a diagnosis of RA were identified in DANBIO and DNPR in January 2013. For DNPR, filters were applied to reduce false-positive cases. The diagnosis was verified by a review of patient records. We calculated the positive predictive values (PPVs) of the RA diagnosis registrations in DANBIO and DNPR, and estimated the registry completeness of relevant RA cases for both DANBIO and DNPR. Updated data from 2011 to 2015 from DANBIO were retrieved to identify patients with delayed registration, and the registry completeness and PPV was recalculated. Results We identified 1,678 unique patients in DANBIO or in DNPR. The PPV (2013 dataset) was 92% in DANBIO and 79% in DNPR. PPV for DANBIO on the 2015 update was 96%. The registry completeness of relevant RA cases was 43% in DANBIO, increasing to 91% in the 2015 update and 90% in DNPR. Conclusion DANBIO held a high proportion of true RA cases (96%) and was found to be superior to the DNPR (79%) with regard to the validity of the diagnosis. Both registries were estimated to have a high completeness of RA cases treated in hospital care (~90%).

Drug concentrations and anti-drug antibodies during treatment with biosimilar infliximab (CT-P13) in routine care

The Danish Rheumatologic Biobank, the DANBIO Registry and Copenhagen Center for Arthritis Research (COPECARE), Center for Rheumatology and Spine Diseases, Centre of Head and Orthopaedics, Rigshospitalet, Glostrup, Denmark Department of Rheumatology, Gentofte and Herlev Hospital, Copenhagen University Hospital, Gentofte, Denmark The Danish Rheumatologic Biobank, Department of Pathology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Oslo, Norway Department of Rheumatology, Zealand University Hospital, Køge, Denmark Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark Department of Rheumatology, Aarhus University Hospital, Aarhus, Denmark King Christian X’s Hospital for Rheumatic Diseases, Graasten, Denmark Department of Rheumatology, Odense University Hospital, Svendborg Hospital, Svendborg, Denmark Department of Rheumatology, North Denmark Regional Hospital, Hjørring, Denmark Department of Rheumatology, Aalborg University Hospital, Aalborg, Denmark Department of Rheumatology, Odense University Hospital, Odense, Denmark Department of Rheumatology, Diakonhjemmet Hospital, Oslo, Norway The Danish Rheumatologic Biobank, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark Department of Medical Biochemistry, Oslo University Hospital, Radiumhospitalet, Norway Center for Rheumatology and Spine Diseases, Institute for Inflammation Research (IIR), Rigshospitalet, Copenhagen University Hospital, Glostrup, Denmark Zitelab, Copenhagen, Denmark Department of Medicine and Oncology, Herlev and Gentofte Hospital, Copenhagen University Hospital, Herlev, Denmark

Variations in blood viscosity in patients with acute cardiogenic pulmonary oedema treated with frusemide

In 10 patients with acute cardiogenic pulmonary oedema, treatment with large doses of intravenous frusemide (mean dose 156 mg) induced no signs of haemoconcentration. On the contrary, during an observation period of 2 h after start of treatment we registered a significant reduction of mean blood viscosity and mean haematocrit, indicating haemodilution. All the patients also received a basic treatment of intravenous pethidine and nasal oxygen and the conclusion is therefore that large doses of intravenous frusemide in treatment of acute cardiogenic pulmonary oedema can be given without risk of haemoconcentration when combined with intravenous pethidine and nasal oxygen.