Bente Glintborg

Predictors of treatment response and drug continuation in 842 patients with ankylosing spondylitis treated with anti-tumour necrosis factor: results from 8 years' surveillance in the Danish nationwide DANBIO registry

Objectives To use prospectively registered data from the Danish nationwide rheumatological database (DANBIO) to describe disease activity, clinical response, treatment duration and predictors of drug survival (ie, number of days individual patients maintained treatment) and clinical response among patients with ankylosing spondylitis (AS) receiving their first treatment series with a tumour necrosis factor α (TNFα) inhibitor. Methods 842 TNFα inhibitor naive patients with AS were identified in DANBIO. Clinical response, drug survival and predictors thereof were investigated. ‘Clinical response’ was defined as a 50% or 20 mm reduction in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) within 6 months compared with baseline. Achievement of a BASDAI <40 mm within 6 months was used as a second response parameter. Results 603 patients (72%) were men, disease duration 5 (1–13) years (median (IQR), age 41 (32–50) years. 445 (53%) received infliximab, 247 (29%) adalimumab and 150 (18%) etanercept. Parameters at baseline/1-year follow-up were: C-reactive protein (CRP): 14 (7–27)/5 (2–10) mg/l, BASDAI 59 (44–72)/21 (8–39) mm, Bath Ankylosing Spondylitis Functional Index (BASFI) 50 (34–67)/24 (9–45) mm, Bath Ankylosing Spondylitis Metrology Index 40 (20–50)/20 (10–40) mm. Within 6 months, 407/644 patients (63%) achieved a clinical response. Median drug survival was 4.3 years. One- and 2-year survival rates were 74% and 63%, respectively. Baseline characteristics associated with longer drug survival were male gender, CRP >14 mg/l and low visual analogue scale fatigue (Cox regression analysis). Age, TNFα inhibitor and methotrexate use were insignificant. CRP >14 mg/l, lower BASFI and younger age at baseline was associated with clinical response and achievement of a BASDAI <40 mm (logistic regression analysis). Conclusion TNFα inhibitors provide a rapid and sustained decrease of disease activity among patients with AS in clinical practice. Factors associated with continued treatment, clinical response and achievement of a BASDAI <40 mm were identified.

Clinical Response, Drug Survival, and Predictors Thereof Among 548 Patients With Psoriatic Arthritis Who Switched Tumor Necrosis Factor α Inhibitor Therapy: Results from the Danish Nationwide DANBIO Registry

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.

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.

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.

Cancer risk in patients with spondyloarthritis treated with TNF inhibitors: a collaborative study from the ARTIS and DANBIO registers

Background Safety data on cancer risks following tumour necrosis factor α inhibitors (TNFi) in patients with spondyloarthritis (SpA) (here defined as ankylosing spondylitis (AS), undifferentiated spondarthropaties (SpA UNS), psoriatic arthritis (PsA)) are scarce. Our objective was to assess risks for cancer overall and for common subtypes in patients with SpA treated with TNFi compared with TNFi-naïve patients with SpA and to the general population. Methods From the Swedish (Anti-Rheumatic Therapy in Sweden (ARTIS)) and Danish (DANBIO) biologics registers, we assembled 8703 (ARTIS=5448, DANBIO=3255) patients with SpA initiating a first TNFi 2001–2011. From the Swedish National Patient and Population Registers we assembled a TNFi-naïve SpA cohort (n=28,164) and a Swedish age-matched and sex-matched general population comparator cohort (n=131 687). We identified incident cancers by linkage with the nationwide Swedish and Danish Cancer Registers 2001–2011, and calculated age-standardised and sex-standardised incidence ratios as measures of relative risk (RR). Results Based on 1188 cancers among the TNFi-naïve patients with SpA, RR of cancer overall was 1.1 (95% CI 1.0 to 1.2). Based on 147 cancers among TNFi initiators with SpA, RR versus TNFi-naïve was 0.8 (95% CI 0.7 to 1.0) and results were similar for AS and PsA when analysed separately. Site-specific cancer RRs: prostate 0.5 (95% CI 0.3 to 0.8), lung 0.6 (95% CI 0.3 to 1.3), colorectal 1.0 (95% CI 0.5 to 2.0), breast 1.3 (95% CI 0.9 to 2.0), lymphoma 0.8 (95% CI 0.4 to 1.8) and melanoma 1.4 (95% CI 0.7 to 2.6). Conclusions In patients with SpA, treatment with TNFi was not associated with increased risks of cancer, neither overall nor for the six most common cancer types.

Association between tobacco smoking and response to tumour necrosis factor α inhibitor treatment in psoriatic arthritis: results from the DANBIO registry

Objectives To investigate the association between tobacco smoking and disease activity, treatment adherence and treatment responses among patients with psoriatic arthritis (PsA) initiating the first tumour necrosis factor α inhibitor therapy (TNFi) in routine care. Methods Observational cohort study based on the Danish nationwide DANBIO registry. Kaplan–Meier plots, logistic and Cox regression analyses by smoking status (current/previous/never smoker) were calculated for treatment adherence, ACR20/50/70-responses and EULAR-good-response. Additional stratified analyses were performed according to gender and TNFi-subtype (adalimumab/etanercept/infliximab). Results Among 1388 PsA patients included in the study, 1148 (83%) had known smoking status (33% current, 41% never and 26% previous smokers). Median follow-up time was 1.22 years (IQR 0.44–2.96). At baseline, current smokers had lower Body Mass Index (27 kg/m2 (23–30)/28 kg/m2 (24–31)) (median (IQR)), shorter disease duration (3 years (1–8)/5 years (2–10)), lower swollen joint count (2 (0–5)/3 (1–6)), higher visual-analogue-scale (VAS) patient global (72 mm (54–87)/68 mm (50–80)), VAS fatigue (72 mm (51–86)/63 mm (40–77)) and Health Assessment Questionnaire (HAQ) score (1.1 (0.7 to 1.5)/1.0 (0.5 to 1.5)) than never smokers (all p<0.05). Current smokers had shorter treatment adherence than never smokers (1.56 years (0.97 to 2.15)/2.43 years (1.88 to 2.97), (median (95% CI)), log rank p=0.02) and poorer 6 months’ EULAR-good-response rates (23%/34%), ACR20 (24%/33%) and ACR50 response rates (17%/24%) (all p<0.05), most pronounced in men. In current smokers, the treatment adherence was poorer for infliximab (HR) 1.62, 95% CI 1.06 to 2.48) and etanercept (HR 1.74, 1.14 to 2.66) compared to never smokers, but not for adalimumab (HR 0.80, 0.52 to 1.23). Conclusion In PsA, smokers had worse baseline patient-reported outcomes, shorter treatment adherence and poorer response to TNFis compared to non-smokers. This was most pronounced in men and in patients treated with infliximab or etanercept.

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.

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.