Lennart Jacobsson

Cancer risk in patients with rheumatoid arthritis treated with anti-tumor necrosis factor alpha therapies: does the risk change with the time since start of treatment?

OBJECTIVE To determine the short-term and medium-term risks of cancer in patients receiving anti-tumor necrosis factor alpha (anti-TNFalpha) therapies that have proven effective in the treatment of chronic inflammatory conditions. METHODS By linking together data from the Swedish Biologics Register, Swedish registers of RA, and the Swedish Cancer Register, we identified and analyzed for cancer occurrence a national cohort of 6,366 patients with RA who first started anti-TNF therapy between January 1999 and July 2006. As comparators, we used a national biologics-naive RA cohort (n = 61,160), a cohort of RA patients newly starting methotrexate (n = 5,989), a cohort of RA patients newly starting disease-modifying antirheumatic drug combination therapy (n = 1,838), and the general population of Sweden. Relative risks (RRs) were estimated using Cox regression analyses, examining overall RR as well as RR by time since the first start of anti-TNF therapy, by the duration of active anti-TNF therapy, and by the anti-TNF agent received. RESULTS During 25,693 person-years of followup in 6,366 patients newly starting anti-TNF, 240 first cancers occurred, yielding an RR of 1.00 (95% confidence interval 0.86-1.15) versus the biologics-naive RA cohort, and similar RRs versus the other 2 RA comparators. RRs did not increase with increasing time since the start of anti-TNF therapy, nor with the cumulative duration of active anti-TNF therapy. During the first year following the first treatment start, but not thereafter, dissimilar cancer risks for adalimumab, etanercept, and infliximab were observed. CONCLUSION During the first 6 years after the start of anti-TNF therapy in routine care, no overall elevation of cancer risk and no increase with followup time were observed.

Incidence and survival rates in Wegener's granulomatosis, microscopic polyangiitis, Churg–Strauss syndrome and polyarteritis nodosa

OBJECTIVE To estimate the incidence of and survival rates for WG, microscopic polyangiitis (MPA), Churg-Strauss syndrome (CSS) and PAN within a defined population in southern Sweden. METHODS Cases were retrieved using hospital records and a serology database. All new cases of WG, MPA, CSS and PAN between 1997 and 2006 were included, provided they met pre-defined criteria, and were followed until 30 June 2008. The study area comprised two health care districts with a total population of 641 000. The standardized mortality ratio (SMR) was estimated using Swedish population data as a reference. RESULTS A total of 140 (WG, 63; MPA 65; CSS 6; and PAN 6) cases (52% women) with a median age of 67.6 (range 20-96) years fulfilled the inclusion criteria. The annual incidence per million of the population (95% CI) was estimated to be 9.8 (7.4-12.2) for WG, 10.1 (7.7-12.6) for MPA and 0.9 (0-1.7) for both CSS and PAN. The highest incidence was found in patients aged >or=75 years (79.1/million). The 1- and 5-year survival rates were 87.8 and 71.6% for all patients, but lower for MPA (80 and 55%) compared with WG (95 and 83%; P = 0.001), although the difference was not significant in the multivariate analysis. The SMR was 2.77 (95% CI 2.02, 3.71) for all patients. CONCLUSIONS The incidence of WG and MPA was equal in our district, but there was a difference in survival rates related to age and renal function. A progressive increase in age-specific incidence rates was observed.

Prevalence and incidence of rheumatoid arthritis in southern Sweden 2008 and their relation to prescribed biologics

OBJECTIVES To gain updated estimates of prevalence and incidence of RA and proportion on biological treatment in southern Sweden. METHODS Inpatient and outpatient health care provided to residents in the southernmost county of Sweden (1.2 million inhabitants) is registered in the Skåne Health Care Register (SHCR). We identified residents aged > or = 20 years who had received a diagnosis of RA at least twice during 2003-08. Valid point prevalence estimates by 31 December 2008 were obtained by linkage to the Swedish population register, and information on biological treatment was obtained from the South Swedish Arthritis Treatment Group register. We also tested our estimates of RA occurrence in a series of sensitivity analyses to investigate the effect of altered case criteria and the uncertainty generated by clinical visits without diagnoses. RESULTS The prevalence of RA in adults was estimated to 0.66% (women = 0.94%, men = 0.37%). The prevalence peaked at age 70-79 years (women = 2.1%, men = 1.1%) before dropping in those aged > or = 80 years. Of prevalent cases, 20% had ongoing biological treatment, a percentage that was highest in women aged 40-49 years (36%). The incidence of RA in 2008 was estimated as 50/100,000 (women = 68/100,000, men = 32/100,000). CONCLUSIONS When compared with a previous report from southern Sweden, the prevalence of RA seems not to have declined in the last decade. The proportion of patients with ongoing biological treatment was slightly higher in women than men. SHCR data are promising additions to other methods to gain frequency estimates of clinically important disease in a timely and cost-efficient manner.

The impact of HLA-DRB1 genes on extra-articular disease manifestations in rheumatoid arthritis

The objective of this study was to examine HLA-DRB1 and HLA-DQB1 genotypes in patients with severe extra-articular rheumatoid arthritis (ExRA) and to compare them with the genotypes of rheumatoid arthritis (RA) patients without extra-articular manifestations. Patients with severe ExRA were recruited from a large research database of patients with RA, from two cohorts of prevalent RA cases, and from a regional multicenter early RA cohort. Cases with ExRA manifestations (n = 159) were classified according to predefined criteria. Controls (n = 178) with RA but no ExRA were selected from the same sources. Cases and controls were matched for duration of RA and for clinical center. PCR based HLA-DRB1 and HLA-DQB1 genotyping was performed using the Biotest SSP kit, with additional sequencing in order to distinguish DRB1*04 subtypes. Associations between alleles and disease phenotypes were tested using multiple simulations of random distributions of alleles. There was no difference in global distribution of HLA-DRB1 and HLA-DQB1 alleles between patients with ExRA and controls. DRB1*0401 (P = 0.003) and 0401/0401 homozygosity (P = 0.002) were more frequent in Feltys syndrome than in controls. The presence of two HLA-DRB1*04 alleles encoding the shared epitope (SE) was associated with ExRA (overall odds ratio 1.79, 95% confidence interval 1.04–3.08) and with rheumatoid vasculitis (odds ratio 2.44, 95% confidence interval 1.22–4.89). In this large sample of patients with ExRA, Feltys syndrome was the only manifestation that was clearly associated with HLA-DRB1*0401. Other ExRA manifestations were not associated with individual alleles but with DRB1*04 SE double dose genotypes. This confirms that SE genes contribute to RA disease severity and ExRA. Other genetic and environmental factors may have a more specific impact on individual ExRA manifestations.

Relationship of Sjögren's Syndrome to Other Connective Tissue and Autoimmune Disorders

Sjögrens syndrome is a systemic autoimmune disease that frequently presents concomitantly with other systemic connective tissue or organ-specific autoimmune diseases. This association is well described for systemic lupus erythematosus and rheumatoid arthritis. The presence of Sjögrens syndrome influences the expression of the other autoimmune disease to some degree, for instance by increasing fatigue and lymphoma risk. The etiopathogenic mechanism for the simultaneous or sequential development of multiple autoimmune diseases in one individual is not well understood. Common genetic backgrounds and additional immunogenetic, environmental, or hormonal factors may be responsible for the formation of subsets of autoimmune disease clustering. While the most currently accepted classification criteria (American European Consensus Criteria) designate these cases as secondary Sjögrens syndrome, the terms overlapping or associated Sjögrens syndrome are frequently used in the literature to describe these cases.

Joint swelling as a predictor of death from cardiovascular disease in a population study of Pima Indians

OBJECTIVE Markers of inflammation have recently been shown to be predictive of cardiovascular disease (CVD). Furthermore, the excess mortality in rheumatoid arthritis (RA), a disease characterized by chronic polyarthritis, is chiefly due to death from CVD. With this background, we studied the effect of inflammation, as reflected by the number of joints with soft tissue swelling, and rheumatoid factor (RF) seropositivity on CVD-related mortality. METHODS Mortality rates and rate ratios for all-cause and CVD-related deaths were computed in a longitudinal, population-based cohort of Pima Indians in Arizona from 1965 through 1994. Repeated health examinations were performed, involving systematic assessment of the features of RA, cardiovascular risk factors, serum titers of RF, as well as mortality. The cohort comprised 4,120 subjects (1,861 men, 2,259 women) who were examined an average of 3.5 times during a mean followup of 14 years. RESULTS During the followup period, 182 CVD-related deaths ocurred. The age- and sex-adjusted CVD-related mortality rates increased significantly with the presence of a higher number of joints with soft tissue swelling (Ptrend = 0.04), and were 2.07 (95% confidence interval [95% CI] 1.30-3.31) times as high in those subjects who had 2 or more swollen joints as in those who had none. There were no significant additional effects on CVD-related mortality when seropositivity for RF or a previous diagnosis of RA were considered. In age- and sex-adjusted proportional hazards analyses, which were controlled for possible confounders, the effect of swollen joints remained significant (mortality rate ratio 1.33, 95% CI 1.04-1.71 per category increase [no swollen joints, 1 swollen joint, at least 2 swollen joints]). CONCLUSION Joint swelling is a significant risk factor for CVD-related death, independent of other known risk factors including a diagnosis of RA. This finding supports the hypothesis that inflammatory mechanisms are important for the development of CVD.

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.

Ten years with biologics: to whom do data on effectiveness and safety apply?

OBJECTIVES During the past decade, the position of biologics in the therapeutic armamentarium, the number of approved indications and the number of available biologics have changed. Available data on (long-term) safety might thus pertain to patient populations not comparable with contemporary patients. The aim of this study was to assess the extent to which contemporary patients who start or switch biologic therapies are comparable with those patients who gave rise to the currently available data on effectiveness and safety. METHODS We identified all adult patients with RA (n=9612), PsA (n=1417) and other SpA (n=1652) initiating a first biologic therapy between 1 January 1999 and 31 December 2008, registered in the Swedish Biologics Register (ARTIS), including information on demographics, disease characteristics and 1-year risk of first-line treatment discontinuation. RESULTS Over calendar time, measures of disease activity at start declined substantially for all indications, and diminished between first-, second- and third-line therapy starts. One-year risks of first-line therapy discontinuation increased. Switchers to anti-TNF and non-TNF biologics had different comorbidities. Despite <50% drug retention at 5 years, most patients remained exposed to some biologic. CONCLUSIONS The trends in baseline characteristics and drug retention underscores that any effects of biologics, including comparison between different biologics, must be interpreted in light of the characteristics of the population treated. The observed differences further call for continued vigilance to properly evaluate the safety profiles of biologic treatments as they are currently used. Exposure to multiple biologics presents a challenge for attribution of long-term effects.

Improved outcome in Wegener's granulomatosis and microscopic polyangiitis? A retrospective analysis of 95 cases in two cohorts

Objectives.  Mortality rates for Wegener’s granulomatosis (WG) and microscopic polyangiitis (MPA) have decreased after the introduction of cyclophosphamide. Standardized mortality ratio (SMR) expresses the overall mortality of patients compared with the general population. The aims of this study were to compare survival in an old and a recent cohort of patients with WG and MPA using SMR and to determine predictors for death in both groups combined.

High disease activity disability burden and smoking predict severe extra-articular manifestations in early rheumatoid arthritis

OBJECTIVES To identify patients with severe extra-articular RA (ExRA) in an early RA cohort and to investigate potential risk factors. METHODS From a cohort (n = 2900) in a structured programme for newly diagnosed RA, 40 patients with severe ExRA after RA diagnosis were identified. Disease activity score (DAS28), functional disability (HAQ) and treatment with glucocorticosteroids (GCs) and DMARDs were assessed regularly. Cases with ExRA were compared with RA controls from the same cohort matched for age, sex and duration of symptoms at inclusion. RESULTS Patients who developed severe ExRA were more often current smokers and had higher mean DAS28, HAQ and CRP at baseline. Among the ExRA cases, 93% had a positive RF vs 59% of the controls. The area under the curve (AUC) of DAS28 odds ratio (OR) 7.79/S.D.; 95% CI 3.04, 19.95, HAQ (OR 2.30/S.D.; 95% CI 1.37, 3.88) and CRP (OR 3.05/S.D.; 95% CI 1.77, 5.26) during the first 2 years of follow-up were strong predictors of subsequent development of ExRA. The most frequently used DMARDs were MTX and SSZ, with similar frequency and duration of treatment among cases and controls. The cases were treated with GC before onset of ExRA more frequently (73 vs 47%; P = 0.005) and with higher mean cumulative dose (3667 vs 2037 mg, P = 0.015). CONCLUSIONS High levels of disease activity and disability during the first 2 years after RA diagnosis, smoking and RF predict the development of severe extra-articular RA.