Lotta Ljung

Addition of infliximab compared with addition of sulfasalazine and hydroxychloroquine to methotrexate in patients with early rheumatoid arthritis (Swefot trial): 1-year results of a randomised trial

BACKGROUND New treatment strategies for early rheumatoid arthritis are evolving rapidly. We aimed to compare addition of conventional disease-modifying antirheumatic drugs (sulfasalazine and hydroxychloroquine) with addition of a tumour necrosis factor antagonist (infliximab) to methotrexate in patients with early rheumatoid arthritis. METHODS We undertook a randomised trial in 15 rheumatology units in Sweden. We enrolled patients with early rheumatoid arthritis (symptom duration <1 year) and administered methotrexate (up to 20 mg per week). After 3-4 months, those who had not achieved low disease activity but who could tolerate methotrexate were randomly allocated by computer addition of either sulfasalazine and hydroxychloroquine or infliximab. Primary outcome was achievement of a good response according to European League Against Rheumatism (EULAR) criteria at 12 months. Patients were followed up to 24 months; here, we present findings at 12 months. Analysis was by intention to treat and we used non-responder imputation. The Swefot (Swedish Pharmacotherapy) study is registered in the WHO database at the Karolinska University Hospital, number CT20080004. FINDINGS 487 patients were initially enrolled. Of 258 who had not achieved low disease activity with methotrexate, 130 were allocated sulfasalazine and hydroxychloroquine and 128 were assigned infliximab. 32 of 130 (25%) patients allocated sulfasalazine and hydroxychloroquine achieved the primary outcome compared with 50 of 128 (39%) assigned infliximab (risk ratio 1.59 [95% CI 1.10-2.30], p=0.0160). Adverse events were balanced fairly well between the two groups and accorded with known adverse events of the drugs used. No deaths occurred in either group. INTERPRETATION In patients with early rheumatoid arthritis in whom methotrexate treatment failed, addition of a tumour necrosis factor antagonist to methotrexate monotherapy is clinically superior to addition of conventional disease-modifying antirheumatic drugs. FUNDING Swedish Rheumatism Association, Schering-Plough.

Cardiovascular events in early RA are a result of inflammatory burden and traditional risk factors: a five year prospective study

IntroductionCo-morbidity and mortality due to cardiovascular disease (CVD) are increased in patients with rheumatoid arthritis (RA). Most published studies in this field are retrospective or cross sectional. We investigated the presence of traditional and disease related risk factors for CVD at the onset of RA and during the first five years following diagnosis. We also evaluated their potential for predicting a new cardiovascular event (CVE) during the five-year follow-up period and the modulatory effect of pharmacological treatment.MethodsAll patients from the four northern-most counties of Sweden with early RA are, since December 1995, consecutively recruited at diagnosis (T0) into a large survey on the progress of the disease. Information regarding cardiovascular co-morbidity and related predictors was collected from clinical records and supplemented with questionnaires. By April 2008, 700 patients had been included of whom 442 patients had reached the five-year follow-up (T5).ResultsAmong the 442 patients who reached T5 during the follow-up period, treatment for hypertension increased from 24.5 to 37.4% (P < 0.001)), diagnosis of diabetes mellitus (DM) from 7.1 to 9.5% (P < 0.01) whilst smoking decreased from 29.8 to 22.4% (P < 0.001) and the BMI from 26.3 to 25.8 (P < 0.05), respectively. By T5, 48 patients had suffered a new CVE of which 12 were fatal. A total of 23 patients died during the follow-up period. Age at disease onset, male sex, a previous CVE, DM, treatment for hypertension, triglyceride level, cumulative disease activity (area under the curve (AUC) disease activity score (DAS28)), extra-articular disease, corticosteroid use, shorter duration of treatment with disease modifying anti-rheumatic drugs (DMARDs) and use of COX-2 inhibitors increased the hazard rate for a new CVE. A raised erythrocyte sedimentation rate (ESR) at inclusion and AUC DAS28 at six months increased the hazard rate of CVE independently whilst DMARD treatment was protective in multiple Cox extended models adjusted for sex and CV risk factors. The risk of a CVE due to inflammation was potentiated by traditional CV risk factors.ConclusionsThe occurrence of new CV events in very early RA was explained by traditional CV risk factors and was potentiated by high disease activity. Treatment with DMARDs decreased the risk. The results may have implications for cardio-protective strategies in RA.

Beneficial Effect of Interleukin 1 Inhibition with Anakinra in Adult-onset Still's Disease. An Open, Randomized, Multicenter Study

Objective. To study the efficacy of anakinra versus disease-modifying antirheumatic drugs (DMARD) in refractory adult-onset Still’s disease (AOSD). Methods. In a 24-week study, 22 patients with AOSD taking prednisolone ≥ 10 mg/day received anakinra (n = 12) or DMARD (n = 10). The primary endpoint was achievement of remission. Results. At 8 and 24 weeks, 7/12 and 6/12 receiving anakinra and 5/10 and 2/10 receiving DMARD achieved remission. Anakinra induced greater improvement in physical health measured by Medical Outcomes Study Short-Form 36 (SF-36; p < 0.011). During an open-label extension (OLE) of 28 weeks, 7/14 patients taking anakinra and 2/3 taking DMARD were in remission. Conclusion. Anakinra induced more beneficial responses than DMARD in patients with AOSD and was favored in the OLE phase. (ClinicalTrials.gov Protocol Registration NCT01033656).

Treatment with tumor necrosis factor inhibitors and the risk of acute coronary syndromes in early rheumatoid arthritis

OBJECTIVE Rheumatoid arthritis (RA) is associated with an increased risk of ischemic heart disease, in both early and established RA. Data on the risk of ischemic heart disease in relation to therapy with tumor necrosis factor (TNF) antagonists (anti-TNF) are conflicting in patients with established RA and essentially lacking in those with early RA. In established RA, the risk of myocardial infarction has been linked to the response to anti-TNF therapies. The aim of this study was to determine the risk of acute coronary syndromes (ACS) in patients with early RA in relation to treatment with, and response to, anti-TNF. METHODS A cohort consisting of patients in whom RA was diagnosed between 1999 and 2007 was identified from the Swedish Rheumatology Register (n=6,000), from which information on disease activity and pharmacologic treatments was extracted. In a cohort study, the risk of first occurrence of an ACS was compared between patients treated with anti-TNF and those without exposure to anti-TNF, using hazard ratios (HRs). In a nested case-control study, the relationship between response to anti-TNF according to the European League Against Rheumatism (EULAR) response criteria and the risk of ACS was investigated. RESULTS In the cohort study, treatment with anti-TNF was not related to any statistically significant alteration in the risk of ACS (HR 0.80, 95% confidence interval [95% CI] 0.52-1.24). In the nested case-control study, a good or moderate EULAR treatment response at 3 months and at 6 months was not associated with a risk of ACS (odds ratio [OR] 1.7, 95% CI 0.5-5.1 and OR 1.5, 95% CI 0.3-6.9, respectively), when adjusted for disease activity before treatment start. CONCLUSION In this study of patients treated with anti-TNF within the first years of RA, neither treatment with, nor response to, anti-TNF therapy could be linked to any statistically significant decrease in the risk of ACS.

Age at onset determines severity and choice of treatment in early rheumatoid arthritis: a prospective study

IntroductionDisease activity, severity and comorbidity contribute to increased mortality in patients with rheumatoid arthritis (RA). We evaluated the impact of age at disease onset on prognostic risk factors and treatment in patients with early disease.MethodsIn this study, 950 RA patients were followed regularly from the time of inclusion (<12 months from symptom onset) for disease activity (erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), tender and/or swollen joints, Visual Analogue Scale pain and global scores, and Disease Activity Score in 28 joints (DAS28)) and function (Health Assessment Questionnaire (HAQ)). Disease severity, measured on the basis of radiographs of the hands and feet (erosions based on Larsen score), extraarticular disease, nodules, and comorbidities and treatment (disease-modifying antirheumatic drugs (DMARDs), corticosteroids, biologics and nonsteroidal anti-inflammatory drugs) were recorded at the time of inclusion and at 5 years. Autoantibodies (rheumatoid factor, antinuclear antibodies and antibodies against cyclic citrullinated peptides (ACPAs)) and genetic markers (human leucocyte antibody (HLA) shared epitope and protein tyrosine phosphatase nonreceptor type 22 (PTPN22)) were analysed at the time of inclusion. Data were stratified as young-onset RA (YORA) and late-onset RA (LORA), which were defined as being below or above the median age at the time of onset of RA (58 years).ResultsLORA was associated with lower frequency of ACPA (P < 0.05) and carriage of PTPN22-T variant (P < 0.01), but with greater disease activity at the time of inclusion measured on the basis of ESR (P < 0.001), CRP (P < 0.01) and accumulated disease activity (area under the curve for DAS28 score) at 6 months (P < 0.01), 12 months (P < 0.01) and 24 months (P < 0.05), as well as a higher HAQ score (P < 0.01) compared with YORA patients. At baseline and 24 months, LORA was more often associated with erosions (P < 0.01 for both) and higher Larsen scores (P < 0.001 for both). LORA was more often treated with corticosteroids (P < 0.01) and less often with methotrexate (P < 0.001) and biologics (P < 0.001). YORA was more often associated with early DMARD treatment (P < 0.001). The results of multiple regression analyses supported our findings regarding the impact of age on chosen treatment.ConclusionYORA patients were more frequently ACPA-positive than LORA patients. LORA was more often associated with erosions, higher Larsen scores, higher disease activity and higher HAQ scores at baseline. Nevertheless, YORA was treated earlier with DMARDs, whilst LORA was more often treated with corticosteroids and less often with DMARDs in early-stage disease. These findings could have implications for the development of comorbidities.

Response to biological treatment and subsequent risk of coronary events in rheumatoid arthritis

Objectives Whether the increased risk of comorbidities, such as cardiovascular disease, in rheumatoid arthritis (RA) can be reverted by particular antirheumatic therapies, or response to these, is unclear but of critical clinical importance. We wanted to investigate whether response to tumour necrosis factor inhibitors (TNFi) translates into a reduced risk for acute coronary syndrome (ACS). Methods A cohort of patients with RA initiating a first TNFi 2001–2012 was identified in the Swedish Biologics Register. The association between European League Against Rheumatism (EULAR) response after 3–8 months of treatment (assessed using the first, the best and the measurement closest to 5 months, respectively), and the risk of incident ACS during the subsequent year was analysed in Cox regression models. Adjustments included cardiovascular risk factors, joint surgery, RA duration, education and work disability. Results During 6592 person-years among TNFi initiators (n=6864, mean age 55 years, 77% women), 47 ACS occurred. The adjusted HRs (95% CI), which were similar to the crude HRs, of the 1-year risk of ACS among EULAR good responders compared with non-responders were 0.5 (0.2 to 1.4), 0.4 (0.2 to 0.9) and 0.5 (0.2 to 1.2), for the first, the best and the evaluation closest to 5 months, respectively. EULAR moderate responders had equal risk to that of EULAR non-responders, who, compared with the general population referents (n=34 229), had a more than twice the risk of ACS. For good responders, there was no statistically significant difference in risk versus the general population. Conclusions Optimised RA disease control has the potential to revert otherwise increased risks for ACS in RA.

Mortality following new-onset Rheumatoid Arthritis : has modern Rheumatology had an impact?

Objective To investigate if, and when, patients diagnosed with rheumatoid arthritis (RA) in recent years are at increased risk of death. Methods Using an extensive register linkage, we designed a population-based nationwide cohort study in Sweden. Patients with new-onset RA from the Swedish Rheumatology Quality Register, and individually matched comparators from the general population were followed with respect to death, as captured by the total population register. Results 17 512 patients with new-onset RA between 1 January 1997 and 31 December 2014, and 78 847 matched general population comparator subjects were followed from RA diagnosis until death, emigration or 31 December 2015. There was a steady decrease in absolute mortality rates over calendar time, both in the RA cohort and in the general population. Although the relative risk of death in the RA cohort was not increased (HR=1.01, 95% CI 0.96 to 1.06), an excess mortality in the RA cohort was present 5 years after RA diagnosis (HR after 10 years since RA diagnosis=1.43 (95% CI 1.28 to 1.59)), across all calendar periods of RA diagnosis. Taking RA disease duration into account, there was no clear trend towards lower excess mortality for patients diagnosed more recently. Conclusions Despite decreasing mortality rates, RA continues to be linked to an increased risk of death. Thus, despite advancements in RA management during recent years, increased efforts to prevent disease progression and comorbidity, from disease onset, are needed.

Acute coronary syndrome in new-onset rheumatoid arthritis: a population-based nationwide cohort study of time trends in risks and excess risks

Background Acute coronary syndrome (ACS) and other cardiovascular diseases are the main drivers of the increased morbidity and preterm mortality in rheumatoid arthritis (RA). ACS in RA has been linked to inflammation and RA severity. During recent years and with new therapeutic options and treat-to-target strategies, increasing efforts have been made to reach RA remission as soon as possible after diagnosis, and the average level of RA disease activity has declined. Whether this has resulted in declining excess risks for RA comorbidities remains unclear. Methods We performed a nationwide population-based cohort study of patients with new-onset RA from 1997 to 2014, and matched general population comparators. In the Swedish healthcare system, all residents have equal access to healthcare services. Healthcare is monitored using high-quality population-based registers that can be linked together. 15 744 patients with new-onset RA, identified from the Swedish Rheumatology Quality Register, and 70 899 general population comparator subjects were included. Results Seven hundred and seventy two patients with RA developed an ACS during 103 835 person-years of follow-up (crude incidence, 7.4 per 1000), corresponding to an overall HR versus the general population of 1.41 (95% CI 1.29 to 1.54). Whereas the ACS incidence declined over calendar time in both the RA and the general population cohort, the excess and the relative risks of ACS remained the same. Conclusions Despite improved disease control in new-onset RA, the elevated risk of ACS in RA remains a concern.

SAT0140 The risk of acute coronary syndromes in RA in relation to TNF inhibitors and risks in the general population: A national cohort study

Background A positive impact on the increased risk for ischemic coronary events in rheumatoid arthritis (RA) could be expected by control of inflammation. Anti-rheumatic drugs might also directly improve risks for ischemic events. In a previous study based on the Swedish Rheumatology Register we reported a relative risk of 0.80 (95% CI 0.52-1.24) for acute coronary syndromes (ACS) comparing early RA patients starting TNF inhibitor therapy (TNFi) to patients with early RA treated otherwise. Objectives To evaluate the role of TNFi on the risk of ACS in a larger population-based cohort including both incident and prevalent RA cases. Methods In the Swedish Biologics Register, a national cohort of patients with RA who started their first TNFi between 2001 and 2009 (n=9,869) was identified. For each TNFi exposed patient, three matched referents were randomly selected from the underlying national cohort of all individuals with two or more outpatients visits listing RA (one of which at a dept. of rheumatology/internal medicine) as identified in the National Patient Register. Furthermore, for each TNFi-exposed patient, five matched referents from the general population were identified in the Population Register. Individuals with previous ischemic or congestive heart disease were excluded. Following matching and exclusions, 7,185 patients starting TNFi treatment, 17,702 matched biologics naïve RA referents, and 32,161 matched general population referents remained. Information on any previous diagnoses of hypertension, diabetes mellitus, chronic pulmonary diseases, infections and joint surgery was extracted from the Patient Register. Data on level of education and work disability was extracted from Statistics Sweden. The outcome, first ever ACS, was defined as a discharge diagnosis of myocardial infarction (ICD10: I21) or unstable angina (ICD10: I20.0) during follow-up. Results We observed 85 ACS (crude incidence 4.8 per 1000 person-yrs) among the TNFi exposed patients, 280 ACS (5.1 per 1000) among the matched RA comparators, and 284 ACS (2.2 per 1000) among the matched general population subjects. Kaplan-Meier curves displayed no differences in event-free survival between RA patients starting TNFi and their matched comparators, but a lower event-free survival in both these cohorts compared with the general population comparator. The age- and sex- adjusted hazard ratios (HR; 95% CI) for TNFi compared with matched, biologics-naïve RA patients was 0.98 (0.78-1.23), and for TNFi vs. general population 2.13 (1.69-2.68). When further adjusted for level of education, work disability, disease duration, cardiovascular risk factors, joint surgery, chronic pulmonary disease and previous infections the RR for TNFi vs. matched biologics-naive RA remained close to 1 (HR 1.12, 95% CI 0.84-1.48). Conclusions In this nation-wide, population-based, matched cohort study, no association between treatment with TNFi and the risk of ACS in RA was seen. Compared with the general population a doubled risk for ACS was noted among the patients with RA. The lack of risk reduction vs. the general population through TNFi could be due to lack of a true protective effect, residual confounding or channelling, or an insufficient level of RA disease control whether obtained through TNFi or alternative therapies. Disclosure of Interest None Declared

THU0144 Performance of the ers-ra cardiovascular risk prediction tool: external validation in a large swedish cohort with ra

Background Risk prediction tools developed for the general population tend to underestimate the risk of cardiovascular (CV) disease in patients with RA1. An accurate and RA-specific CV risk prediction tool would ideally be integrated as a routine part of clinical practice in rheumatology, to identify patients with increased CV risks. For example, 10 year CV risks above 7.5%, or 10%, could warrant specific preventive measures2,3. The ERS-RA was derived and internally validated in the US Corrona RA registry4. ERS-RA estimates the 10 year CV risk using dichotomous clinical variables, and includes variables on RA disease severity and activity. Objectives To assess the external validity of the ERS-RA in Swedish cohorts of patients with RA, with focus on the risk intervals of main clinical interest. Methods We identified two cohorts of patients with RA: (i) an “incident 2006 cohort” with RA patients in the Swedish Rheumatology Register from Jan 1, 2006 – Dec 31, 2011 who were also in the EIRA case-control study (n=2047, mean age 55±13 years, 72% women), and (ii) a “prevalent 2012 cohort” that included all RA patients in the Swedish Rheumatology Register between Jan 1, 2012 – Dec 31, 2015 (n=14485, mean age 61±14 years, 74% women). The 10 year CV risk was estimated using ERS-RA. Patients with a history of myocardial infarction or stroke were excluded. All patients were followed for the first of any of the following: a CV event (myocardial infarction, stroke, cardiovascular death), death, 10 years of follow-up, or Dec 31, 2015. Ten-year CV rates were expressed using the Kaplan-Meier method. In the prevalent 2012 cohort, the 10 year event rates were extrapolated from the observed (maximally four-year) rates.5 The C-statistic was estimated to assess discrimination. A measure of model calibration, the observed event rates were compared with the mean predicted 10 year risks. Results The C-statistic was 0.75 for both cohorts. Most patients had an estimated CV risk <5% or of >10% (See table 1). An accurate risk prediction was observed for estimated risks in the intervals<5%, and 5.0 to <7.5%. ERS-RA underestimated risk in the interval 7.5 to <10% (see table 1 and figure 1).Abstract THU0144 – table 1 and figure 1. Comparisons of the mean estimated and the observed 10-year CV risks within groups of estimated risk levels. Groups of estimated10 year risk N patients (%) Mean estimated10 year risk (%) Observed10 year rate (%) Difference Observed rate – Mean estimated risk Incident2006 Cohort <5% 884 (48) 2.5 2.3 −0.2 5.0 to<7.5% 282 (15) 6.2 5.7 −0.5 7.5 to<10% 43 (2) 8.6 13.4 4.8 ≥10.0% 638 (35) 18.3 18.3 0 Prevalent 2012 Cohort <5% 4691 (32) 2.7 1.9 −0.8 5.0 to<7.5% 1604 (11) 6.2 4.0 −2.2 7.5 to<10% 1485 (10) 8.6 12.0 3.4 ≥10.0% 6705 (46) 22.2 24.5 2.3 Conclusions In a Swedish population with RA, ERS-RA performed well in identifying patients with a very low and very high CV 10 year CV risk. In clinical routine practice, ERS-RA could be used to identify low and high risk individuals, who might be considered for additional CV risk factor evaluation and subsequent intervention. References [1] Crowson CS, et al. Ann Rheum Dis. 2018. [2] Stone NJ, et al. Circulation. 2014. [3] https://www.nice.org.uk [4] Solomon DH, et al. Arthritis Rheum. 2015. [5] Cook NR, Ridker PM. JAMA Intern Med. 2014. Disclosure of Interest None declared