Marie Holmqvist

Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden

Objectives To investigate the potential association between tumour necrosis factor (TNF) inhibitor treatment and malignant melanomas in rheumatoid arthritis, melanoma risks in rheumatoid arthritis patients not treated with biological drugs, and risk of all site cancer with TNF inhibitors as used in rheumatoid arthritis. Design Population based cohort study. Setting Prospectively recorded data from national clinical, health, and demographic registers in Sweden 2001-10. Patients with rheumatoid arthritis treated (n=10 878) or not (n=42 198) with TNF inhibitors and matched general population comparators (n=162 743). Main outcome measures The primary outcome was first invasive melanoma in people without any history of invasive cancer of any type. Hazard ratios were estimated using Cox regression, comparing non-biological drug treated rheumatoid arthritis patients with the general population comparator and TNF inhibitor treated rheumatoid arthritis patients with those not treated with biological drugs. Secondary outcomes included in situ melanomas, second primary melanomas, and all site cancer. Results 113 first invasive melanomas occurred in rheumatoid arthritis patients not treated with biological drugs, and 393 occurred in the general population comparator cohort. Rheumatoid arthritis patients not treated with biological drugs were not at significantly increased risk of melanoma compared with the general population (hazard ratio 1.2, 95% confidence interval 0.9 to 1.5). 38 first invasive melanomas occurred in rheumatoid arthritis patients treated with TNF inhibitors; these patients had an increased risk of melanoma compared with rheumatoid arthritis patients not treated with biological drugs (hazard ratio 1.5, 1.0 to 2.2; 20 additional cases per 100 000 person years). The risk of a second primary melanoma was non-significantly increased (hazard ratio 3.2, 0.8 to 13.1; n=3 v 10) in rheumatoid arthritis patients treated with TNF inhibitors compared with those not treated with biological drugs. Conclusion Overall, patients with rheumatoid arthritis who have not been treated with biological drugs are not at increased risk of invasive melanoma compared with the general population. Rheumatoid arthritis patients selected for TNF inhibitor treatment are not at increased overall risk for cancer but have a 50% increased relative risk of invasive melanoma. Given the small increase in absolute risk, these finding may not markedly shift the overall risk-benefit balance of TNF inhibitors as used in clinical practice but might do so in patients at high risk of melanoma for other reasons.

Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006

Abstract.  Holmqvist ME, Wedrén S, Jacobsson LTH, Klareskog L, Nyberg F, Rantapää‐Dahlqvist S, Alfredsson L, Askling J (Institute of Environmental Medicine, Karolinska Institutet, Stockholm; Karolinska Institutet/Karolinska Hospital, Stockholm; Malmö University Hospital, Malmö; AstraZeneca R&D, Mölndal; and Umeå University Hospital, Umeå, Sweden) Rapid increase in myocardial infarction risk following diagnosis of rheumatoid arthritis amongst patients diagnosed between 1995 and 2006. J Intern Med 2010; 268: 578–585.

Familial Risks and Heritability of Rheumatoid Arthritis: Role of Rheumatoid Factor/Anti–Citrullinated Protein Antibody Status, Number and Type of Affected Relatives, Sex, and Age

OBJECTIVE To estimate familial aggregation of rheumatoid arthritis (RA) in 3 large population-representative samples and to test if familial aggregation is affected by rheumatoid factor (RF)/anti-citrullinated protein antibody (ACPA) status, type of relative, sex, and age at onset of RA. METHODS A register-based nested case-control study was performed in the Swedish total population. Data on patients with RA were ascertained through the nationwide Swedish Patient Register (n = 88,639), the clinical Swedish Rheumatology Quality Register (n = 11,519), and the Epidemiological Investigation of Rheumatoid Arthritis case-control study (n = 2,871). Data on first- and second-degree relatives were obtained through the Swedish Multigeneration Register. Familial risks were calculated using conditional logistic regression. RESULTS Consistent across data sources, the familial odds ratio for RA was ∼3 in first-degree relatives of RA patients and 2 in second-degree relatives. Familial risks were similar among siblings, parents, and offspring. Familial aggregation was not modified by sex, but was higher in RA patients with early-onset disease and in RF/ACPA-positive RA patients. The observed familial risks were consistent with a heritability of ∼50% for ACPA-positive RA and ∼20% for ACPA-negative RA. CONCLUSION The pattern of risks suggests that familial factors influence RA in men and women equally and that these factors are of less importance for late-onset RA. Familial factors are more important for seropositive RA, but there is significant familial overlap between seropositive RA and seronegative RA. Even if the familial risk is assumed to be completely due to genetics, the observed risks suggest that heritability of RA is lower than previously reported, in particular for ACPA-negative RA.

No increased occurrence of ischemic heart disease prior to the onset of rheumatoid arthritis : results from two Swedish population-based rheumatoid arthritis cohorts.

OBJECTIVE To investigate the relative importance of shared etiologies for rheumatoid arthritis (RA) and ischemic heart disease (IHD) in terms of the well-known increased risk of IHD in patients with RA, by assessing the occurrence of IHD up until the time of the onset of the first symptoms of RA. METHODS We assessed the prevalence of a history of IHD, myocardial infarction (MI), and angina pectoris before the onset of RA symptoms in 2 large population-based case-control studies. Patients with newly diagnosed RA according to the criteria of the American College of Rheumatology were included as cases. We used data from the Swedish Early Arthritis Register study and the Swedish Epidemiologic Investigation of Rheumatoid Arthritis case-control study and from general population controls. Information on IHD, MI, and angina pectoris was obtained from the nationwide Hospital Discharge Register and from self reports. We calculated odds ratios (ORs) and 95% confidence intervals (95% CIs) to compare the prevalence of a history of IHD/MI/angina pectoris among patients with RA with that among population controls. RESULTS We could not detect any increased occurrence of IHD, MI, or angina pectoris before the onset of symptoms of RA, regardless of whether data on IHD were obtained from the Hospital Discharge Register or were self reported. As detected in the Hospital Discharge Register, the OR for IHD overall was 1.0 (95% CI 0.9-1.1), the OR for MI was 1.0 (95% CI 0.9-1.1), and the OR for angina pectoris was 1.0 (95% CI 0.9-1.2). CONCLUSION Shared risk factors or susceptibilities for RA and IHD are likely to contribute less than RA-related factors to the increased occurrence of IHD in patients with manifest RA. Nonetheless, the existence of shared factors associated with longer latency until the occurrence of IHD cannot be excluded.

Risk of Venous Thromboembolism in Patients With Rheumatoid Arthritis and Association With Disease Duration and Hospitalization

CONTEXT Recent reports suggest that rheumatoid arthritis (RA) may be a risk factor for venous thromboembolism (VTE), particularly in conjunction with hospitalization. Using hospitalization data to identify RA and VTE may identify patients when they are at elevated risk for other reasons, obscuring the incompletely understood underlying association between RA and VTE and leading to inappropriate institution or timing of interventions. OBJECTIVE To estimate risks for VTE in patients with RA, including the relation of these risks to disease duration and hospitalization. DESIGN, SETTING, AND PATIENTS Prospective, population-based cohort study of 1 prevalent RA cohort (n = 37,856), 1 incident RA cohort (n = 7904), and matched general population comparison cohorts, all from Sweden, with follow-up from 1997 through 2010. MAIN OUTCOME MEASURE First-time VTE. RESULTS Patients with prevalent RA were at greater risk of VTE than the general population (rate, 5.9 [95% CI, 5.1-6.6] vs 2.8 [95% CI, 2.6-3.1] per 1000 person-years (adjusted hazard ratio [HR], 2.0 [95% CI, 1.9-2.2]; P < .001). By the time of RA symptom onset, there was no statistically significant association between a history of VTE and RA (odds ratio, 1.2 [95% CI, 1.0-1.4]; P = .08; 150 events in the RA cohort vs 587 in the comparison cohort). Counting from RA diagnosis, an increased rate in the RA cohort vs the comparison cohort (3.8 [95% CI, 2.5-5.2] vs 2.4 [95% CI, 1.9-2.9] per 1000 person-years; HR, 1.6 [95% CI, 1.1-2.5]; P = .02) was detected within the first year and did not increase further during the first decade. Although rates for VTE following hospitalization were higher, the 1-year rate of VTE per 1000 person-years was not higher in the RA cohort than in the comparison cohort after hospital discharge (11.8 [95% CI, 8.6-15.1] vs 13.1 [11.3-14.8]; HR, 1.0 [95% CI, 0.7-1.4]; P = .90). The rates of VTE increased with age but were largely similar across sex and rheumatoid factor status, as were the HRs for VTE across age, sex, and rheumatoid factor status. CONCLUSIONS Compared with the general population, Swedish patients with RA had an elevated risk for VTE that was stable over the first 10 years after diagnosis. Although hospitalization was a risk factor for VTE the first year after discharge, the excess risk was not greater in patients with RA than in the general population.

Ambient air pollution exposures and risk of rheumatoid arthritis: results from the Swedish EIRA case–control study

Objective Environmental factors may play a role in the development of rheumatoid arthritis (RA). We examined whether long-term exposures to air pollution were associated with the risk of RA in the Swedish Epidemiological Investigation of Rheumatoid Arthritis Study. Methods We studied 1497 incident RA cases and 2536 controls. Local levels of particulate matter (PM10) and gaseous pollutants (sulphur dioxide (SO2) and nitrogen dioxide (NO2)) from traffic and home heating were predicted for all residential addresses. We examined the association of an IQR increase (2 µg/m3 for PM10, 8 µg/m3 for SO2 and 9 µg/m3 for NO2) in each pollutant at different time points before symptom onset and average exposure with the risk of all RA and the risk of the rheumatoid factor and anti-citrullinated protein antibody (ACPA) RA phenotypes. Results There was no evidence of an increased risk of RA with PM10. Total RA risks were modestly elevated for the gaseous pollutants, but were not statistically significant after adjustment for smoking and education (OR 1.18, 95% CI 0.97 to 1.43 and OR 1.09, 95% CI 0.99 to 1.19 for SO2 and NO2 in the 10th year before onset). Stronger elevated risks were observed for individuals with less than a university education and with the ACPA-negative RA phenotype. Conclusions No consistent overall associations between air pollution in the Stockholm area and the risk of RA were observed. However, there was a suggestion of increased risks of RA incidence with increases in NO2 from local traffic and SO2 from home heating sources with stronger associations for the ACPA-negative phenotype.

Occurrence and relative risk of stroke in incident and prevalent contemporary rheumatoid arthritis

Objective In contrast with the wealth of data on ischaemic heart disease in rheumatoid arthritis (RA), data on stroke are scarce and contradictory. Despite the high clinical and aetiological relevance, there is no data regarding when (if ever) after RA diagnosis there is an increased risk. Our objective was to assess the risk of stroke (by subtype) in contemporary patients with RA, particularly in relation to time since RA diagnosis. Methods One incident RA cohort diagnosed between 1997 and 2009 (n=8077) and one nationwide prevalent RA cohort followed at Swedish rheumatology clinics between 2005 and 2009 ((n=39 065) were assembled). Each cohort member was matched to a general population comparator. Information on first-time hospitalisations for stroke up to 2009 was retrieved from the Swedish Patient Register. HR and 95% CI were estimated using Cox models. Results In prevalent unselected RA, the HR of ischaemic stroke was 1.29 (95% CI 1.18 to 1.41). In the incident RA cohort, the overall risk increase was small and non-significant (overall HR 1.11, 95% CI 0.95 to 1.30). When stratified by RA disease duration, an increased risk of ischaemic stroke was indeed detectable but only after 10 or more years since RA diagnosis (HR>10 years: 2.33, 95% CI 1.25 to 4.34). Risk of haemorrhagic stroke was increased in prevalent but not in incident RA. Conclusion The magnitude of stroke risk is lower than for ischaemic heart disease in RA, and the evolvement of this risk from RA diagnosis may be slower. This suggests different driving forces behind these two RA co-morbidities and has implications for the clinical follow-up of patients with RA.

Rheumatoid arthritis is associated with a more severe presentation of acute coronary syndrome and worse short-term outcome

AIMS Despite a wealth of studies describing an increased incidence of acute coronary syndromes (ACSs) in rheumatoid arthritis (RA), considerably less is known about the clinical characteristics and their association with short-term outcome of such ACS. The aims of this study were therefore to investigate clinical characteristics and case-fatality rates following ACS in patients with RA. METHODS AND RESULTS We compared the clinical presentation of incident ACS between 2007 and 2010 and their short-term mortality in a cohort of 1135 subjects with prevalent RA and in a cohort of 3184 matched general population comparators. Rheumatoid arthritis subjects more frequently presented with sudden cardiac death, ST-segment elevation myocardial infarctions, had higher levels of troponin and higher frequencies of in-hospital complications compared with the general population comparators. Furthermore, the short-term mortality was higher among RA-associated ACS (7-day hazard ratio (HR) = 1.65 [95% CI 1.32-2.08]; 30-day HR = 1.57 [95% CI 1.30-1.89]), which were somewhat attenuated but remained statistically significantly increased following adjustment for previous comorbidities, demographics, and educational level (7-day HR = 1.50 [95% CI 1.19-1.90]; 30-day HR = 1.43 [95% CI 1.18-1.72]), and for ACS type (7-day HR = 1.44 [95% CI 1.14-1.82]; 30-day HR = 1.36 [95% CI 1.13-1.64]). CONCLUSION Patients with prevalent RA suffer more severe ACSs compared with the general population and also have poorer outcomes after the events, which can only partly be explained by increased event severity.

Stroke in systemic lupus erythematosus: a meta-analysis of population-based cohort studies.

Previous studies of stroke in systemic lupus erythematosus (SLE) have had limited statistical power, combined stroke subtypes into composite outcomes, and lacked a reference population estimate. Therefore, we conducted a systematic review and meta-analysis of cohort studies to summarise the stroke subtype-specific risk in patients with SLE compared to the general population. A systematic search of MEDLINE and EMBASE was performed for cohort studies examining the risk of stroke in SLE and including a general population comparator. Random effects models were used to pool the risk ratio (RR) for stroke. Subgroup analyses were carried out to investigate potential sources of heterogeneity. 10 studies were included which reported RRs for overall stroke (n=5), ischaemic stroke (n=6), intracerebral haemorrhage (n=3) and subarachnoid haemorrhage (n=3). The pooled RR for overall stroke was 2.53 (95% CI 1.96 to 3.26), ischaemic stroke 2.10 (95% CI 1.68 to 2.62), intracerebral haemorrhage 2.72 (95% CI 2.15 to 3.44) and subarachnoid haemorrhage 3.85 (95% CI 3.20 to 4.64). Significant heterogeneity among studies for ischaemic stroke was detected (p=0.002). Relative risk of stroke was highest among individuals younger than 50 years of age. Individuals with SLE have a twofold higher risk of ischaemic stroke, a threefold higher risk of intracerebral haemorrhage, and an almost fourfold higher risk of subarachnoid haemorrhage compared to the general population. Future studies should focus on whether comorbidity and disease flares are related to stroke, when individuals are at the highest risk, and how the targeting of specific groups of patients with SLE may reduce this risk.

Parity and the risk of developing rheumatoid arthritis: results from the Swedish Epidemiological Investigation of Rheumatoid Arthritis study

Objective To study the impact of parity history on the risk of antibodies to citrullinated peptide antigens (ACPA) positive and ACPA-negative rheumatoid arthritis (RA), in different age-groups. Method Data from a population-based case-control study of female incident RA cases were analysed (2035 cases and 2911 controls, aged 18–70 years ). Parity history was assessed through a questionnaire. Parous women were compared with nulliparous, by calculating odds ratios (ORs) with 95% confidence interval (CI). Results Parity was associated with an increased risk of ACPA-negative RA in women aged 18–44 years (OR=2.1, 95% CI 1.4 to 3.2), but not in those aged 45–70 years (OR=0.9, 95% CI 0.7 to 1.3). Among young women, an increased risk of ACPA-negative RA was found in those who gave birth during the year of symptom onset (OR=2.6, 95% CI 1.4 to 4.8) and who were at a young age at first birth (<23) (OR=2.5, 95% CI 1.5 to 4.1). Parity and the postpartum period were not associated with ACPA-positive RA, but older age at first birth was weakly associated with a decreased risk. Conclusions The increased risk of ACPA-negative RA in parous women of reproductive age seemed to be associated with an increased postpartum risk and with young age at first birth. Further research is needed to explore the biological mechanisms behind our findings.