René Cordtz

Predictors of revision, prosthetic joint infection and mortality following total hip or total knee arthroplasty in patients with rheumatoid arthritis: a nationwide cohort study using Danish healthcare registers

Objectives To investigate predictors of 10-year risk of revision and 1-year risk of prosthetic joint infection (PJI) and death following total hip/total knee arthroplasty (THA/TKA) in (1) patients with rheumatoid arthritis (RA) compared with patients with osteoarthritis (OA); and (2) patients with RA treated with biological disease-modifying antirheumatic drugs (bDMARD) within 90 days preceding surgery compared with non-treated. Methods Register-based cohort study using the Danish National Patient Register, the DANBIO rheumatology register (RA-specific confounders and treatment episodes) and the Danish Hip and Knee Arthroplasty Registers. Survival analyses were used to calculate confounder-adjusted sub-HRs (SHR) and HRs. Results In total, 3913 patients with RA with THA/TKA were compared with 120 499 patients with OA. Patients with RA had decreased risk of revision (SHR 0.71 (0.57–0.89)), but increased risk of PJI (SHR=1.46 (1.13–1.88)) and death (HR=1.25 (1.01–1.55)). In DANBIO, 345 of 1946 patients with RA with THA/TKA had received bDMARD treatment within 90 days preceding surgery. bDMARD-treated patients did not have a statistically significant increased risk of revision (SHR=1.49 (0.65–3.40)), PJI (SHR=1.61 (0.70–3.69)) nor death (HR=0.75 (0.24–2.33)) compared with non-treated. Glucocorticoid exposure (HR=2.87 (1.12–7.34)) and increasing DAS28 (HR=1.49 (1.01–2.20)) were risk factors for mortality. Conclusion Patients with RA had a decreased 10-year risk of revision while the risk of death and PJI was increased compared with patients with OA following THA/TKA. bDMARD exposure was not associated with statistically significant increased risk of neither PJI nor death in this study. Glucocorticoid exposure and increased disease activity were associated with an increased risk of death.

Spectrum of lymphomas across different drug treatment groups in rheumatoid arthritis: a European registries collaborative project

Background Lymphomas comprise a heterogeneous group of malignant diseases with highly variable prognosis. Rheumatoid arthritis (RA) is associated with a twofold increased risk of both Hodgkin’s lymphoma (HL) and non-Hodgkin’s lymphoma (NHL). It is unknown whether treatment with biologic disease-modifying antirheumatic drugs (bDMARDs) affect the risk of specific lymphoma subtypes. Methods Patients never exposed to (bionaïve) or ever treated with bDMARDs from 12 European biologic registers were followed prospectively for the occurrence of first ever histologically confirmed lymphoma. Patients were considered exposed to a bDMARD after having received the first dose. Lymphomas were attributed to the most recently received bDMARD. Results Among 124 997 patients (mean age 59 years; 73.7% female), 533 lymphomas were reported. Of these, 9.5% were HL, 83.8% B-cell NHL and 6.8% T-cell NHL. No cases of hepatosplenic T-cell lymphoma were observed. Diffuse large B-cell lymphoma (DLBCL) was the most frequent B-cell NHL subtype (55.8% of all B-cell NHLs). The subtype distributions were similar between bionaïve patients and those treated with tumour necrosis factor inhibitors (TNFi). For other bDMARDs, the numbers of cases were too small to draw any conclusions. Patients with RA developed more DLBCLs and less chronic lymphocytic leukaemia compared with the general population. Conclusion This large collaborative analysis of European registries has successfully collated subtype information on 533 lymphomas. While the subtype distribution differs between RA and the general population, there was no evidence of any modification of the distribution of lymphoma subtypes in patients with RA treated with TNFi compared with bionaïve patients.

Malignant progression of precancerous lesions of the uterine cervix following biological DMARD therapy in patients with arthritis

Patients with rheumatoid arthritis (RA) are more frequent chronic carriers of high-risk human papilloma virus (HPV) strains compared with the background population—an important risk factor for developing cervical cancer—and patients with RA have an increased risk of high-grade cervical dysplasia (CD) and cervical cancer.1–3 Little is known about the safety of biological disease-modifying antirheumatic drug (bDMARD) treatment in arthritis patients with a history of premalignant lesions. We aimed to investigate how often female patients with inflammatory arthritis (RA, ankylosing spondylitis, psoriatic arthritis or other) and a history of premalignant lesions of the uterine cervix developed cervical cancer or another HPV-associated cancer according to ever versus never exposure to bDMARDs. The nationwide Danish DANBIO Registry started in 2000 and covers >90% of adults with rheumatological disease treated with bDMARDs in routine care.4 Since 2005, patients not treated with bDMARDs have also been registered. We linked 15 238 female patients identified in DANBIO …

Risk of multiple sclerosis during tumour necrosis factor inhibitor treatment for arthritis: a population-based study from DANBIO and the Danish Multiple Sclerosis Registry

Multiple sclerosis (MS) is a chronic inflammatory neurological disease with multifactorial aetiology.1 Evidence of tumour necrosis factor (TNF)-α as an important factor in the pathogenesis of MS has emerged.2 However, attempts of treating MS with TNF-inhibitors (TNFi) have increased disease activity.3 Several case reports have indicated that demyelinating diseases could be a serious adverse event following TNFi treatment while data from the Spanish Registry of biological therapies in rheumatic diseases did not bring clarification.4 ,5 Some, but not all, studies have suggested a negative association between rheumatoid arthritis (RA) and MS.6 ,7 We aimed to investigate whether TNFi treatment in patients with arthritis is associated with an increased risk of developing MS and whether RA is associated with a decreased risk compared with the general population. The nationwide Danish DANBIO Registry started in 2000 and covers >90% of adults with rheumatological disease treated with TNFi in routine care.8 Since 2005, patients not treated with …

Incidence of hip and knee replacement in patients with rheumatoid arthritis following the introduction of biological DMARDs: an interrupted time-series analysis using nationwide Danish healthcare registers

Objectives To study the impact of the introduction of biological disease-modifying anti-rheumatic drugs (bDMARDs) and associated rheumatoid arthritis (RA) management guidelines on the incidence of total hip (THR) and knee replacements (TKR) in Denmark. Methods Nationwide register-based cohort and interrupted time-series analysis. Patients with incident RA between 1996 and 2011 were identified in the Danish National Patient Register. Patients with RA were matched on age, sex and municipality with up to 10 general population comparators (GPCs). Standardised 5-year incidence rates of THR and TKR per 1000 person-years were calculated for patients with RA and GPCs in 6-month periods. Levels and trends in the pre-bDMARD (1996–2001) were compared with the bDMARD era (2003–2016) using segmented linear regression interrupted by a 1-year lag period (2002). Results We identified 30 404 patients with incident RA and 297 916 GPCs. In 1996, the incidence rate of THR and TKR was 8.72 and 5.87, respectively, among patients with RA, and 2.89 and 0.42 in GPCs. From 1996 to 2016, the incidence rate of THR decreased among patients with RA, but increased among GPCs. Among patients with RA, the incidence rate of TKR increased from 1996 to 2001, but started to decrease from 2003 and throughout the bDMARD era. The incidence of TKR increased among GPCs from 1996 to 2016. Conclusion We report that the incidence rate of THR and TKR was 3-fold and 14-fold higher, respectively among patients with RA compared with GPCs in 1996. In patients with RA, introduction of bDMARDs was associated with a decreasing incidence rate of TKR, whereas the incidence of THR had started to decrease before bDMARD introduction.

Association between NICE guidance on biologic therapies with rates of hip and knee replacement among rheumatoid arthritis patients in England and Wales: An interrupted time-series analysis

OBJECTIVE To estimate the impact of NICE approval of tumor necrosis factor inhibitor (TNFi) therapies on the incidence of total hip replacement (THR) and total knee replacement (TKR) among rheumatoid arthritis (RA) patients in England and Wales. METHODS Primary care data [Clinical Practice Research Datalink (CPRD)] for the study period (1995-2014) were used to identify incident adult RA patients. The age and sex-standardised 5-year incidence of THR and TKR was calculated separately for RA patients diagnosed in each six-months between 1995-2009. We took a natural experimental approach, using segmented linear regression to estimate changes in level and trend following the publication of NICE TA 36 in March 2002, incorporating a 1-year lag. Regression coefficients were used to calculate average change in rates, adjusted for prior level and trend. RESULTS We identified 17,505 incident RA patients of whom 465 and 650 underwent THR and TKR surgery, respectively. The modeled average incidence of THR and TKR over the biologic-era was 6.57/1000 person years (PYs) and 8.51/1000 PYs, respectively, with projected (had pre-NICE TA 36 level and trend continued uninterrupted) figures of 5.63/1000 PYs and 12.92 PYs, respectively. NICE guidance was associated with a significant average decrease in TKR incidence of -4.41/1000 PYs (95% C.I. -6.88 to -1.94), equating to a relative 34% reduction. Overall, no effect was seen on THR rates. CONCLUSIONS Among incident RA patients in England and Wales, NICE guidance on TNFi therapies for RA management was temporally associated with reduced rates of TKR but not THR.

Risk of virus-associated cancer in female arthritis patients treated with biological DMARDs—a cohort study

OBJECTIVE To investigate the risk of virus-associated cancer in female arthritis patients ever treated with biological DMARDs (bDMARDs) compared with never bDMARD-treated patients and ever and never treated with bDMARD compared with the general population. METHODS This was a cohort study that included 13 905 female patients with RA (72%), PsA (12%), AS (4%) or other arthritides (12%) identified in the DANBIO registry. Ever (n = 5647) and never (n = 10 331) bDMARD-treated patients were followed for virus-associated cancers during 2000-11 by linkage to the Danish Cancer Registry. Hazard ratios and standardized incidence ratios (SIRs) were calculated. RESULTS In total, 24 and 32 virus-associated cancers were identified among ever and never bDMARD users, respectively (hazard ratio = 0.9, 95% CI: 0.7, 1.2). Oropharyngeal (n = 3, SIR = 4.0, 95% CI: 1.3, 12.4) and anal (n = 2, SIR = 2.5, 95% CI: 0.6, 10.0) cancer only occurred among bDMARD-treated patients. SIR was not increased for cervical cancer, either in ever or never bDMARD-treated patients. SIRs for Hodgkins and non-Hodgkins lymphomas were increased in never bDMARD-treated patients (SIR = 2.5, 95% CI: 1.5, 4.0). CONCLUSION bDMARD therapy was not associated with an overall excess of virus-associated cancers in female arthritis patients. The observed increased occurrence of oropharyngeal cancer needs further investigation. Lymphoma incidence was increased in patients unexposed to bDMARD treatment.

The impact of comorbidities on tumor necrosis factor inhibitor therapy in psoriatic arthritis: A population-based cohort study

The objective of this population‐based cohort study was to investigate the impact of comorbidities on disease activity, treatment response, and persistence with the first‐tried tumor necrosis factor inhibitor (TNFi) in patients with psoriatic arthritis (PsA).

Risk of second malignant neoplasm and mortality in patients with rheumatoid arthritis treated with biological DMARDs: a Danish population-based cohort study

Objective To study the risk of a second malignant neoplasm (SMN) and mortality in patients with rheumatoid arthritis (RA) with a history of a primary cancer diagnosis and treated with biological disease-modifying antirheumatic drugs (bDMARD). Methods Among patients with RA (n=15 286) registered in the DANBIO Register during 2000–2011, 1678 had a primary cancer according to the Danish Cancer Registry. HRs for SMN and death were calculated. Results During follow-up there were 279 patients with RA contributing person-years to the bDMARDs use before their primary cancer diagnosis, 220 to the only after, 92 to the both before and after, while 1203 patients with RA contributed to the non-use strata. Ever use of bDMARDs was associated with a HR of 1.11 (95% CI 0.74 to 1.67) for developing a SMN compared with non-use (cancer site adjusted). The HR for death associated with bDMARD use before the primary cancer diagnosis was increased 1.53 (95% CI 1.13 to 2.09). After further adjustment for extent of the primary cancer, the HR for death was 1.20 (95% CI 0.88 to 1.63) for bDMARDs use before cancer, 1.36 (95% CI 0.78 to 2.39) for bDMARD use only after cancer and 1.22 (95% CI 0.70 to 2.13) for use both before and after the cancer. Conclusions Among patients with RA with a history of cancer, treatment with bDMARDs was not associated with increased risk of SMN. No clear conclusion can be drawn regarding mortality in bDMARD-treated patients with RA.

Gender differences in biologic treatment outcomes-a study of 1750 patients with psoriatic arthritis using Danish Health Care Registers

Objective We aimed to investigate gender differences in disease manifestations, patient-reported outcomes, comorbidities and treatment effectiveness among patients with PsA treated with their first TNFα inhibitor (TNFI). Methods In this observational cohort study, the DANBIO register provided prospectively collected data on PsA patients who initiated their first TNFI in 2000-15. Comorbidity information was achieved from the Danish Nationwide Patient Register. Response to treatment was assessed according to EULAR and ACR criteria at 3 and 6 months. Cox and logistic regression models analysed the impact of gender on TNFI persistence and response, respectively, while adjusting for a priori selected confounders including clinical-, laboratory- and patient-reported factors, comorbidities and lifestyle characteristics. Results A total of 1750 PsA patients (935 women) were included. At baseline, women were older (49 years/47 years), more often smokers (32%/26%), had worse patient-reported scores (e.g. global score 71 mm/65 mm) and higher frequencies of hospital-diagnosed anxiety or depression (7%/4%) and chronic pulmonary disease (7%/3%) than men (all P < 0.01). Median TNFI persistence was 3.8 years (95% CI: 3.0, 5.7) in men vs 1.4 (1.1, 1.8) in women (P < 0.001). Men had higher odds of achieving response after 3 and 6 months, for example, adjusted odds ratio = 3.2 (1.6, 6.1) for EULAR good/moderate response (vs women) at 6 months. Conclusion Male gender was strongly associated with greater TNFI treatment effectiveness. Adjustment for baseline risk factors including patient-reported outcomes, disease activity, comorbidities and lifestyle factors did not influence this relationship, which suggests a role of biological factors.