Rheumatoid Arthritis: Askling J

Askling J, Dixon W. · Department of Medicine Solna, Clinical Epidemiology Unit, Karolinska University Hospital and Karolinska Institutet, Solna, Stockholm, Sweden. · Curr Opin Rheumatol. · Pubmed #18349742 No free full text.

Abstract: PURPOSE OF REVIEW: Anti-tumour necrosis factor therapy has proven effective as treatment against a series of autoimmune inflammatory diseases, and has displayed a rapidly increasing market penetration. The safety profile of these drugs is, however, both uncertain and debated, in particular with respect to infections and malignancy. Lack of uniform definitions and methods of analysis makes it difficult to directly compare data from randomized controlled trials, meta-analyses of trials, open-label extensions, data from spontaneous reporting, and particularly, observational cohort studies. RECENT FINDINGS: In this review, we provide a summary of currently published data on infection, malignancy, cardiovascular disease, interstitial lung disease, and death in relation to treatment of rheumatoid arthritis with anti-tumour necrosis factor agents. SUMMARY: Superficially contradictory data on infection display a more or less coherent pattern of an increased risk shortly after treatment starts. Available data on malignancy, cardiovascular disease, interstitial lung disease, and death do not exclude clinically important increased risks, nor do they refute beneficial effects. Harmonized methods of reporting safety data would greatly improve the interpretation and comparison of class and drug-specific risks.

Askling J. · Clinical Epidemiology Unit M9:01, Department of Medicine Solna, Karolinska University Hospital Solna, SE-171 76 Stockholm, Sweden. · Curr Rheumatol Rep. · Pubmed #17915099 No free full text.

Abstract: The occurrence of cancer is not an infrequent event in patients with rheumatoid arthritis (RA). Indeed, following diagnosis of RA at a typical age (55 years), one in five patients will be diagnosed with cancer. In the vast majority of such cases, the cancer has nothing to do with RA or its treatment; rather, it represents the "background" risk applicable to all humans. In some cases, the cancer occurs as a result of factors also associated with the risk of developing RA (eg, smoking), even though no direct link exists between the cancer and the RA. In a fraction of cases, however, the cancer is causally associated with the RA disease or its treatments. This review summarizes our current understanding of the occurrence of cancer in RA, possible links to RA disease and to traditional and newer RA treatments.

Smedby KE, Baecklund E, Askling J. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, S-171 77 Stockholm, Sweden. · Cancer Epidemiol Biomarkers Prev. · Pubmed #17119030 links to  free full text

Abstract: Certain autoimmune and chronic inflammatory conditions, such as Sjögren's syndrome and rheumatoid arthritis (RA), have consistently been associated with an increased risk of malignant lymphomas, but it is unclear whether elevated lymphoma risk is a phenomenon that accompanies inflammatory conditions in general. Likewise, it is debated whether the increased risk identified in association with some disorders pertains equally to all individuals or whether it varies among groups of patients with different phenotypic or treatment-related characteristics. It is similarly unclear to what extent the increased lymphoma occurrence is mediated through specific lymphoma subtypes. This update reviews the many findings on risks, risk levels, and lymphoma characteristics that have been presented recently in relation to a broad range of chronic inflammatory, including autoimmune, conditions. Recent results clearly indicate an association between severity of chronic inflammation and lymphoma risk in RA and Sjögren's syndrome. Thus, the average risk of lymphoma in RA may be composed of a markedly increased risk in those with most severe disease and little or no increase in those with mild or moderate disease. The roles of immunosuppressive therapy and EBV infection seem to be limited. Furthermore, RA, Sjögren's syndrome, systemic lupus erythematosus, and possibly celiac disease may share an association with risk of diffuse large B-cell lymphoma, in addition to well-established links of Sjögren's syndrome with risk of mucosa-associated lymphoid tissue lymphoma and of celiac disease with risk of small intestinal lymphoma. However, there is also obvious heterogeneity in risk and risk mediators among different inflammatory diseases.

Askling J, Fored CM, Geborek P, Jacobsson LT, van Vollenhoven R, Feltelius N, Lindblad S, Klareskog L. · Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institutet, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #16414975 links to  free full text

Abstract: Data from several different monitoring systems are examined. The potential for registers based on data obtained from clinical practice, and linkage of such data to national health and population registers, is discussed. The approach described is a possible prototype for long term surveillance systems needed for the safe introduction of new treatments.

Baecklund E, Askling J, Rosenquist R, Ekbom A, Klareskog L. · Department of Rheumatology, Uppsala University Hospital, SE-751 85 Uppsala, Sweden. · Curr Opin Rheumatol. · Pubmed #15103253 No free full text.

Abstract: PURPOSE OF REVIEW: The reason for the increased lymphoma risk in patients with rheumatoid arthritis (RA) has remained unclear. Reports of lymphomas in patients treated with TNF-blockers have brought renewed interest in this issue. This review summarizes data on possible associations between RA and lymphomas, including different treatments and RA disease related risk factors. RECENT FINDINGS: Some recent studies reported increased lymphoma risks linked to RA disease activity. The hypothesis that disease-modifying drugs, and in particular methotrexate, would increase the lymphoma risk receives little support. Observation times for the TNF-blocking therapies are still short, but so far no clear increased risk for lymphoma has been observed. Presence of Epstein-Barr virus, as analyzed with EBER in situ hybridization, appears to be uncommon in RA related lymphomas. Hypothetically, an increased proliferative drive caused by self or non-self antigens may play a role in lymphoma development in RA patients, but this has to be further studied. SUMMARY: Rheumatologists need to be aware of the increased lymphoma risk in their RA patients. The reason for the increased lymphoma risk in RA patients is still unclear, but available studies rather support the hypothesis of a link between RA disease severity and the risk of lymphoma than increased risks associated with specific treatment regimens. To facilitate the future evaluation of lymphoma risks in connection with treatment, we suggest that patients treated with new drugs should be subject to structured surveillance. Collected information should include data about RA disease activity and severity.

Liao KP, Gunnarsson M, Källberg H, Ding B, Plenge RM, Padyukov L, Karlson EW, Klareskog L, Askling J, Alfredsson L. · Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, Boston, MA 02114, USA. · Arthritis Rheum. · Pubmed #19248096 No free full text.

Abstract: OBJECTIVE: The co-occurrence of autoimmune diseases such as rheumatoid arthritis (RA) and type 1 diabetes mellitus (DM) has been reported in individuals and families. In this study, the strength and nature of this association were investigated at the population level in a Swedish case-control cohort. METHODS: For this case-control study, 1,419 patients with incident RA diagnosed between 1996 and 2003 were recruited from university, public, and private rheumatology units throughout Sweden; 1,674 matched control subjects were recruited from the Swedish national population registry. Sera from the subjects were tested for the presence of antibodies to cyclic citrullinated peptide (anti-CCP), rheumatoid factor (RF), and the 620W PTPN22 allele. Information on a history of diabetes was obtained by questionnaire, telephone interview, and/or medical record review. The prevalence of type 1 DM and type 2 DM was compared between patients with incident RA and control subjects and further stratified for the presence of anti-CCP, RF, and the PTPN22 risk allele. RESULTS: Type 1 DM was associated with an increased risk of RA (odds ratio [OR] 4.9, 95% confidence interval [95% CI] 1.8-13.1), and this association was specific for anti-CCP-positive RA (OR 7.3, 95% CI 2.7-20.0), but not anti-CCP-negative RA. Further adjustment for the presence of PTPN22 attenuated the risk of anti-CCP-positive RA in patients with type 1 DM to an OR of 5.3 (95% CI 1.5-18.7). No association between RA and type 2 DM was observed. CONCLUSION: The association between type 1 DM and RA is specific for a particular RA subset, anti-CCP-positive RA. The risk of developing RA later in life in patients with type 1 DM may be attributed, in part, to the presence of the 620W PTPN22 allele, suggesting that this risk factor may represent a common pathway for the pathogenesis of these 2 diseases.

Carlens C, Jacobsson L, Brandt L, Cnattingius S, Stephansson O, Askling J. · Department of Medicine, Karolinska University Hospital and Institute, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #18957482 No free full text.

Abstract: OBJECTIVES: To investigate the importance of birth characteristics and early life infections on the risk of later rheumatoid arthritis (RA) and juvenile idiopathic arthritis (JIA). METHODS: A nationwide register-based case-control study was performed based on prospectively recorded data on individuals born in 1973 or later. Using the Swedish inpatient register and the early arthritis register, cases with RA aged 16 years or above (n = 333) and JIA (n = 3334) were identified. From the Swedish medical birth register (MBR), four controls per case, matched by sex, year and delivery unit were randomly selected. Through linkage to the MBR and to the Swedish inpatient register information on maternal, pregnancy and birth characteristics and infections during the first year of life was identified. Univariate and multivariate odds ratios (OR) were calculated using conditional logistic regression. RESULTS: Overall, infections during the first year of life were associated with increased risks for seronegative (OR 2.6, 95% CI 1.0 to 7.0) but not seropositive (OR 1.2) RA and for JIA (OR 1.9, 95% CI 1.7 to 2.1). Low birth weight (OR 0.7) and being small for gestational age (OR 0.5) were associated with reduced risks of RA of borderline statistical significance. Preterm birth (gestational age < or =258 days) was associated with a non-significantly decreased risk of RA (OR 0.6). Large for gestational age (OR 1.6) and having more than three older siblings (OR 1.4) were non-significantly associated with the risk of RA. CONCLUSION: Infections during the first year of life, and possibly also factors related to fetal growth and timing of birth, may be important in the aetiologies of adult RA and JIA.

Askling J, Baecklund E, Granath F, Geborek P, Fored M, Backlin C, Bertilsson L, Cöster L, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, van Vollenhoven R, Klareskog L, Feltelius N. · Department of Medicine, Clinical Epidemiology Unit, Karolinska Institutet at Karolinska University Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #18467516 No free full text.

Abstract: BACKGROUND: Tumour necrosis factor (TNF) antagonists have proved effective as treatment against rheumatoid arthritis (RA), but the unresolved issue of whether the use of anti-TNF therapy increases the already elevated risk of lymphoma in RA remains a concern. METHODS: Using the Swedish Biologics Register (ARTIS), the Swedish Cancer Register, pre-existing RA cohorts and cross-linkage with other national health and census registers, a national RA cohort (n = 67,743) was assembled and patients who started anti-TNF therapy between 1998 and July 2006 (n = 6604) were identified. A general population comparator (n = 471,024) was also assembled and the incidence of lymphomas from 1999 to 31 December 2006 was assessed and compared in these individuals. RESULTS: Among the 6604 anti-TNF-treated RA patients, 26 malignant lymphomas were observed during 26,981 person-years of follow-up, which corresponded to a relative risk (RR) of 1.35 (95% CI 0.82 to 2.11) versus anti-TNF-naive RA patients (336 lymphomas during 365,026 person-years) and 2.72 (95% CI 1.82 to 4.08) versus the general population comparator (1568 lymphomas during 3,355,849 person-years). RA patients starting anti-TNF therapy in 1998-2001 accounted for the entire increase in lymphoma risk versus the two comparators. By contrast, RR did not vary significantly by time since start of first treatment or with the accumulated duration of treatment, nor with the type of anti-TNF agent. CONCLUSION: Overall and as used in routine care against RA, TNF antagonists are not associated with any major further increase in the already elevated lymphoma occurrence in RA. Changes in the selection of patients for treatment may influence the observed risk.

Askling J, Bongartz T. · Department of Medicine, Clinical Epidemiology Unit, Karolinska University Hospital and Karolinska Institute, Sweden. · Curr Opin Rheumatol. · Pubmed #18388527 No free full text.

Abstract: PURPOSE OF REVIEW: Owing to the complex functions of the inflammatory response systems--potentially or clearly of importance in human carcinogenesis--that biological therapies interfere with uncertainty regarding their safety profile for malignancy is more or less expected. This uncertainty has been further sparked by the apparent discordance between trial data and observational studies of anti-TNF agents, and the methodological challenges inherent in addressing the safety profile of new drugs for delayed and multifactorial events like cancer. RECENT FINDINGS: This review provides a summary of the pattern of cancer seen in patients with rheumatoid arthritis not treated with biologics, and the currently published data on cancer risk following treatment with biologics in patients with rheumatoid arthritis, primarily anti-TNF therapy. SUMMARY: Published data currently do not exclude clinically important increased risks, nor do they refute beneficial effects. As per definition, much of the currently available safety data from trials or clinical practice do not capture the impact of either any effect that biological therapy might have on early events in carcinogenesis, or of sustained exposure to biologics. Beyond the risk of de-novo cancer development, several other clinically important aspects of cancer safety remain to be addressed, including issues of prognosis, progression, and relapse.

Baecklund E, Natkunam Y, Backlin C, Iliadou A, Askling J, Ekbom A, Feltelius N, Klareskog L, Enblad G, Lossos IS, Levy R, Sundström C, Rosenquist R. · Department of Rheumatology, University Hospital, Uppsala, Sweden. · Br J Haematol. · Pubmed #18324968 No free full text.

Abstract: Diffuse large B-cell lymphomas (DLBCL) can be subdivided into germinal centre (GC)-like and non-GC-like subtypes by CD10, BCL6 and MUM1/IRF4 status. We previously reported that patients with severe rheumatoid arthritis (RA) are at increased risk of non-GC DLBCL. This study examined a new GC-marker, human germinal-centre-associated lymphoma (HGAL) protein, in RA-DLBCL. Of 111, 38 (34%) DLBCL were HGAL-positive and showed less disseminated disease and a tendency toward improved overall survival compared to HGAL-negative cases. This supports that a majority of RA-DLBCL are of non-GC origin, indicating a specific role for activated peripheral B cells in the pathogenesis of RA-DLBCL.

Knight A, Sandin S, Askling J. · Uppsala University Hospital, Uppsala, Sweden. · Arthritis Rheum. · Pubmed #18163522 links to  free full text

Abstract: OBJECTIVE: The etiology of Wegener's granulomatosis (WG) supposedly involves interplay between genetic susceptibility and environmental triggers. However, little is known about whether WG actually clusters in families. Information on the degree of familial aggregation in WG is of clinical relevance, because patients with WG often want to know whether their diagnosis puts their closest relatives at increased risk of the disease. The aim of this study was to investigate the risk of WG in relatives of patients with WG. METHODS: Using Swedish nationwide registers on morbidity, family structure, and vital status, we compared the occurrence of WG (register-based plus chart review) among 6,670 first-degree relatives and 428 spouses of 1,944 Swedish patients with WG with the occurrence among 68,994 first-degree relatives and 4,812 spouses of 19,655 control subjects from the general population. Relative risks were estimated using the Cox proportional hazards regression model. RESULTS: Two of the 6,670 first-degree relatives of patients with WG and 13 of the 68,994 first-degree relatives of their population controls had WG, resulting in a relative risk of 1.56 (95% confidence interval 0.35-6.90). None of the 428 spouses of patients had WG. CONCLUSION: In absolute terms, the occurrence of WG among close biologic and nonbiologic relatives of patients with WG is low. In terms of relative risk, our results provide strong evidence against a pronounced increase in familial risk such as that noted for systemic lupus erythematosus, irritable bowel disease, and multiple sclerosis but are compatible with familial aggregation of a magnitude similar to that for rheumatoid arthritis.

Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, Cöster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, van Vollenhoven RF, Klareskog L. · Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #17261532 No free full text.

Abstract: OBJECTIVES: The degree to which treatment with tumour necrosis factor (TNF) antagonists may be associated with increased risks for serious infections is unclear. An observational cohort study was performed using prospectively collected data from the Swedish Biologics Register (ARTIS) and other national Swedish registers. METHODS: First, in the ARTIS, all 4167 rheumatoid arthritis (RA) patients starting TNF antagonist treatment between 1999 and 2003 were identified. Secondly, in the Swedish Inpatient Register, all individuals hospitalised for any reason and who also carried a diagnosis of RA, between 1964 and 2003 (n = 44 946 of whom 2692 also occurred in ARTIS), were identified. Thirdly, in the Swedish Inpatient Register, all hospitalisations listing an infection between 1999 and 2003 were identified. By cross-referencing these three data sets, RRs for hospitalisation with infection associated with TNF antagonist treatment were calculated within the cohort of 44 946 RA patients, using Cox regression taking sex, age, geography, co-morbidity and use of inpatient care into account. RESULTS: Among the 4167 patients treated with TNF antagonists, 367 hospitalisations with infections occurred during 7776 person-years. Within the cohort of 44 496 RA patients, the RR for infection associated with TNF antagonists was 1.43 (95% CI 1.18 to 1.73) during the first year of treatment, 1.15 (95% CI 0.88 to 1.51) during the second year of treatment, and 0.82 (95% CI 0.62 to 1.08) for subjects remaining on their first TNF antagonist treatment after 2 years. CONCLUSION: Treatment with TNF antagonists may be associated with a small to moderate increase in risk of hospitalisation with infection, which disappears with increasing treatment duration.

Baecklund E, Backlin C, Iliadou A, Granath F, Ekbom A, Amini RM, Feltelius N, Enblad G, Sundström C, Klareskog L, Askling J, Rosenquist R. · Department of Rheumatology, Akademiska Hospital, Uppsala, Sweden. · Arthritis Rheum. · Pubmed #17133544 links to  free full text

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, with a correlation between RA disease severity and lymphoma risk, most pronounced for diffuse large B cell lymphomas (DLBCLs), which also constitute the majority of RA-associated lymphomas. DLBCLs can be further subdivided into germinal center (GC)-like and non-GC-like subtypes, with different cellular origins and prognoses. This study was undertaken to investigate whether RA displays a specific association with any of the DLBCL subtypes. METHODS: We identified 139 patients with DLBCLs within a population-based case-control study of 378 RA patients with lymphoma. The DLBCLs were examined for CD10, Bcl-6, and interferon regulatory factor 4 expression patterns, subclassified into GC and non-GC subtypes, and then correlated with clinical parameters. RESULTS: We found a statistically significant predominance of the non-GC subtype (97 patients; 70% of all DLBCLs). These patients more often had an advanced stage of lymphoma at diagnosis and had a worse 5-year overall survival rate (16% versus 33%) compared with patients with the GC subtype. There was a strong association with RA disease activity in both subtypes, with >70% of the GC and non-GC cases occurring in RA patients with the highest overall disease activity scores. CONCLUSION: These findings suggest that severe RA is particularly associated with the non-GC subtype of DLBCL, and indicate a critical role of activated peripheral B cells as the cells of origin in these lymphomas.

Carlens C, Brandt L, Klareskog L, Lampa J, Askling J. · Rheumatology Unit, Department of Medicine, Karolinska University Hospital and Institute, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #16877531 No free full text.

Abstract: Recent data suggest remarkable effects of vagus stimulation (reduction) and vagotomy (exacerbation) on acute inflammation in rats, the so-called "inflammatory reflex". Its role in humans remains unknown. Therefore, the aim was to explore whether surgical vagotomy in humans would affect the risk of a prototype inflammatory disease, rheumatoid arthritis. This was a case-control study. Assessment of the relative risk (RR) of developing rheumatoid arthritis after surgical vagotomy during 1964-2001 in 63,092 prevalent rheumatoid arthritis cases versus 125,404 matched controls from the general population and in 2548 incident rheumatoid arthritis cases versus 24,357 matched controls from the general population, respectively, was done. For comparison, we assessed RRs for hospitalisation for gastric disorders not including vagotomy. Data on exposures and rheumatoid arthritis were retrieved from population-based and prospectively recorded Swedish registers. A pre-rheumatoid arthritis vagotomy was not significantly associated with an increased risk for rheumatoid arthritis (RR = 1.17, 95% CI 0.97 to 1.40). RRs in the same range were observed for several other pre-rheumatoid arthritis gastric conditions that do not include vagotomy (eg, gastric ulcer RR = 1.21, 95% 1.11 to 1.33). Vagotomy has no specific effect on the risk of developing rheumatoid arthritis in humans. Gastroduodenal ulcers occur more often than expected even before the occurrence of rheumatoid arthritis.

Baecklund E, Iliadou A, Askling J, Ekbom A, Backlin C, Granath F, Catrina AI, Rosenquist R, Feltelius N, Sundström C, Klareskog L. · Department of Rheumatology, Akademiska Hospital, Uppsala, Sweden. · Arthritis Rheum. · Pubmed #16508929 links to  free full text

Abstract: OBJECTIVE: Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective. METHODS: We performed a matched case-control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population-based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein-Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments. RESULTS: The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1-28.0], OR tenth decile 61.6 [95% confidence interval 21.0-181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas. CONCLUSION: Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.

Smedby KE, Hjalgrim H, Askling J, Chang ET, Gregersen H, Porwit-MacDonald A, Sundström C, Akerman M, Melbye M, Glimelius B, Adami HO. · Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden. · J Natl Cancer Inst. · Pubmed #16391371 links to  free full text

Abstract: BACKGROUND: Some autoimmune and chronic inflammatory disorders are associated with increased risks of non-Hodgkin lymphoma (NHL). Because different NHL subtypes develop at different stages of lymphocyte differentiation, associations of autoimmune and inflammatory disorders with specific NHL subtypes could lead to a better understanding of lymphomagenic mechanisms. METHODS: In a population-based case-control study in Denmark and Sweden, 3055 NHL patients and 3187 matched control subjects were asked about their history of autoimmune and chronic inflammatory disorders, markers of severity, and treatment. Logistic regression with adjustment for study matching factors was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for NHL overall and for NHL subtypes. RESULTS: Risks of all NHL were increased in association with rheumatoid arthritis (OR = 1.5, 95% CI = 1.1 to 1.9), primary Sjögren syndrome (OR = 6.1, 95% CI = 1.4 to 27), systemic lupus erythematosus (OR = 4.6, 95% CI = 1.0 to 22), and celiac disease (OR = 2.1, 95% CI = 1.0 to 4.8). All of these conditions were also associated with diffuse large B-cell lymphoma, and some were associated with marginal zone, lymphoplasmacytic, or T-cell lymphoma. Ever use of nonsteroidal anti-inflammatory drugs, systemic corticosteroids, and selected immunosuppressants was associated with risk of NHL in rheumatoid arthritis patients but not in subjects without rheumatoid arthritis. Also, multivariable adjustment for treatment had little impact on risk estimates. Psoriasis, sarcoidosis, and inflammatory bowel disorders were not associated with increased risk of NHL overall or of any NHL subtype. CONCLUSIONS: Our results confirm the associations between certain autoimmune disorders and risk of NHL and suggest that the associations may not be general but rather mediated through specific NHL subtypes. These NHL subtypes develop during postantigen exposure stages of lymphocyte differentiation, consistent with a role of antigenic drive in autoimmunity-related lymphomagenesis.

van Vollenhoven RF, Askling J. · Rheumatology Unit, Karolinska University Hospital and Karolinska Institute, Stockholm, Sweden. · Clin Exp Rheumatol. · Pubmed #16273807 No free full text.

Abstract: Patient registries provide valuable contributions to the field of rheumatology for both quality control and scientific purposes. With respect to the latter, patient registries are among the most important datasets used for longitudinal observational studies in rheumatic diseases, which are in turn an essential complement to data obtained from randomized, controlled trials. In Sweden a number of registries are available for such studies, ranging from general medical registries such as the in-patient registry, to rheumatoid arthritis (RA)-specific inception cohorts and biologics registries focusing on a specific patient population defined by a group of treatments. In recent years it has become particularly clear that questions regarding new therapies, their use in practice and their long-term safety, as well as aspects such as pharmacoeconomics, cannot fully be assessed using the data from clinical trials, and that registries are indispensible to obtain accurate answers to such questions. In this review we describe the Swedish rheumatology registries, including the Swedish RA registry and the Swedish biologics registries ARTIS (Antirheumatic Therapies Iin Sweden), SSATG (Southern Sweden Antirheumatic Therapy Group), and STURE (Stockholm Tumor Necrosis Factor-a Follow-up Registry). Data obtained from analyses based on these registries are reviewed. It is concluded that rheumatology registries are excellent tools for improving our knowledge base regarding rheumatic diseases.

Björnådal L, Brandt L, Klareskog L, Askling J. · Rheumatology Unit, Department of Medicine, Karolinska University Hospital Solna, and Karolinska Institutet, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #16249229 links to  free full text

Abstract: BACKGROUND: Patients with rheumatoid arthritis are at increased risk of death from cardiovascular disease (CVD). This risk is influenced by the inflammatory activity of the rheumatoid arthritis as well as by traditional risk factors for CVD. However, little is known about whether or to what extent hereditary factors for CVD contribute additional risk in patients with rheumatoid arthritis. OBJECTIVE: To assess the clinical impact of a parental history of CVD in patients with rheumatoid arthritis. METHODS: Population based cohort study of 10,805 Swedish patients with rheumatoid arthritis aged 16-67 years during follow up (1990-2000). Parents, and cardiovascular deaths among patients and parents, were identified through register linkages. Relative risk of death v the general population was assessed using standardised mortality ratios (SMR), which were compared by Poisson regression. RESULTS: Rheumatoid patients with a parental history of fatal CVD had an SMR of death from CVD of 2.9 (95% confidence interval, 2.5 to 3.4). By contrast, rheumatoid patients without a parental history of fatal CVD had an SMR of 1.7 (1.2 to 2.3). A parental death from CVD was associated with a 70% increase in the risk of fatal CVD in rheumatoid arthritis (SMR ratio = 1.7 (1.2 to 2.4), and an increase in the 10 year mortality from CVD from 5% to 10% in men and from 2% to 4% in women aged 50 to 67 years. CONCLUSIONS: Parental history of death from CVD is an important (and easily assessable) risk factor for fatal CVD in rheumatoid arthritis.

Landgren O, Björkholm M, Montgomery SM, Hjalgrim H, Sjöberg J, Goldin LR, Askling J. · Division of Hematology, Karolinska Hospital and Institutet, Stockholm, Sweden. · Int J Cancer. · Pubmed #16049983 No free full text.

Abstract: Young-adult-onset (15-44 years of age) Hodgkin lymphoma (HL) is believed to arise as a consequence of late primary infection in susceptible individuals. The properties of this susceptibility remain little understood. We have previously reported an increased occurrence of HL in patients with rheumatoid arthritis and among their offspring, suggesting that susceptibility to autoimmunity might be of importance also in the pathogenesis of HL. To explore this hypothesis, we assessed the association of personal and family history of diabetes mellitus, with risk of subsequent HL in a population-based case-control study, including as cases all individuals diagnosed with HL above 15 years of age 1964-1999 (n = 6,873) in Sweden, and matched population controls (n = 12,565). First-degree relatives of cases and controls were identified through linkage with the Multi-generation Register. We identified discharges listing diabetes mellitus through linkage with the Inpatient Register (1964-2000). We used odds ratios (OR) as measures of relative risk. Cases with young-adult-onset HL were less likely to have a personal (OR =0.5, 95% CI 0.2-1.1) or family (OR =0.7, 95% CI 0.6-0.8) history of diabetes mellitus. In contrast, HL diagnosed at older ages was neither associated with a personal (OR =1.0) nor family (OR =1.0) history of diabetes mellitus. These findings suggests that characteristics of the immune system associated with conditions such as diabetes mellitus type I are of importance in the pathogenesis of young-adult-onset HL.

Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Cöster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, Romanus V, Klareskog L, Feltelius N. · Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital Solna, Karolinska Institute, Stockholm, Sweden. · Arthritis Rheum. · Pubmed #15986370 links to  free full text

Abstract: OBJECTIVE: Because treatment with tumor necrosis factor (TNF) antagonists may increase the risk of tuberculosis (TB), and because knowledge of the risk of TB in rheumatoid arthritis (RA) not treated with biologics is scarce and of uncertain generalizability to low-risk populations, this study sought to determine the risk of TB among Swedish patients with RA. METHODS: Using data from Swedish nationwide and population-based registers and data from an ongoing monitoring program of TNF antagonists, the relative risks of TB in patients with RA (versus the general population) and of TB associated with TNF antagonists (versus RA patients not treated with biologics) were determined by comparing the incidence of hospitalization for TB in 3 RA cohorts and 2 general population cohorts from 1999 to 2001. We also reviewed the characteristics of all reported cases of TB in RA patients treated with TNF antagonists in Sweden and calculated the incidence of TB per type of TNF antagonist between 1999 and 2004. RESULTS: During 1999-2001, RA patients who were not treated with TNF antagonists were at increased risk of TB versus the general population (relative risk 2.0, 95% confidence interval [95% CI] 1.2-3.4). RA patients treated with TNF antagonists had a 4-fold increased risk of TB (relative risk 4.0, 95% CI 1.3-12) versus RA patients not treated with TNF antagonists. The reported TB cases during 1999-2004 in RA patients exposed to TNF antagonists (9 infliximab, 4 etanercept, 2 both) were predominantly pulmonary. TB occurred up to 3 years following the start of treatment. CONCLUSION: Irrespective of whether TNF antagonists are administered, Swedish patients with RA are at increased risk of TB. During 1999-2001, TNF antagonists were associated with an increased risk of TB, up to 4-fold in magnitude. This increased risk may persist over time during treatment and is related to both infliximab and etanercept.

Askling J, Fored CM, Baecklund E, Brandt L, Backlin C, Ekbom A, Sundström C, Bertilsson L, Cöster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, Klareskog L, Feltelius N. · Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #15843454 links to  free full text

Abstract: BACKGROUND: Patients with rheumatoid arthritis (RA) are at increased risk of malignant lymphomas, and maybe also of leukaemia and multiple myeloma. The effect of tumour necrosis factor (TNF) antagonists on lymphoma risk and characteristics is unclear. OBJECTIVE: To assess expected rates and relative risks of haematopoietic malignancies, especially those associated with TNF antagonists, in large population based cohorts of patients with RA. METHODS: A population based cohort study was performed of patients with RA (one prevalent cohort (n = 53,067), one incident cohort (n = 3703), and one TNF antagonist treated cohort 1999 through 2003 (n = 4160)), who were linked with the Swedish Cancer Register. Additionally, the lymphoma specimens for the 12 lymphomas occurring in patients with RA exposed to TNF antagonists in Sweden 1999 through 2004 were reviewed. RESULTS: Study of almost 500 observed haematopoietic malignancies showed that prevalent and incident patients with RA were at increased risk of lymphoma (SIR = 1.9 and 2.0, respectively) and leukaemia (SIR = 2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIR = 2.9) compared with the general population. After adjustment for sex, age, and disease duration, the lymphoma risk after exposure to TNF antagonists was no higher than in the other RA cohorts. Lymphomas associated with TNF antagonists had characteristics similar to those of other RA lymphomas. CONCLUSION: Overall, patients with RA are at equally increased risks for lymphomas and leukaemias. Patients with RA treated with TNF antagonists did not have higher lymphoma risks than other patients with RA. Prolonged observation is needed to determine the long term effects of TNF antagonists on lymphoma risk.

Askling J, Fored CM, Brandt L, Baecklund E, Bertilsson L, Feltelius N, Cöster L, Geborek P, Jacobsson LT, Lindblad S, Lysholm J, Rantapää-Dahlqvist S, Saxne T, Klareskog L. · Clinical Epidemiology Unit, Department of Medicine, Karolinska University Hospital, Stockholm, Sweden. · Ann Rheum Dis. · Pubmed #15829572 links to  free full text

Abstract: BACKGROUND: Existing studies of solid cancers in rheumatoid arthritis (RA) reflect cancer morbidity up until the early 1990s in prevalent cohorts admitted to hospital during the 1980s. OBJECTIVE: To depict the cancer pattern of contemporary patients with RA, from updated risk data from prevalent and incident RA populations. To understand the risk of solid cancer after tumour necrosis factor (TNF) treatment by obtaining cancer data from cohorts treated in routine care rather than trials. METHODS: A population based study of three RA cohorts (one prevalent, admitted to hospital 1990-2003 (n = 53,067), one incident, diagnosed 1995-2003 (n = 3703), and one treated with TNF antagonists 1999-2003 (n = 4160)), which were linked with Swedish nationwide cancer and census registers and followed up for cancer occurrence through 2003. RESULTS: With 3379 observed cancers, the prevalent RA cohort was at marginally increased overall risk of solid cancer, with 20-50% increased risks for smoke related cancers and +70% increased risk for non-melanoma skin cancer, but decreased risk for breast (-20%) and colorectal cancer (-25%). With 138 cancers, the incident RA cohort displayed a similar cancer pattern apart from non-decreased risks for colorectal cancer. TNF antagonist treated patients displayed solid cancer (n = 67) risks largely similar to those of other patients with RA. CONCLUSION: The cancer pattern in patients treated with TNF antagonists mirrors those of other contemporary as well as historic RA cohorts. The consistent increase in smoking associated cancers in patients with RA emphasises the potential for smoking cessation as a cancer preventive measure in RA.

Peters U, Askling J, Gridley G, Ekbom A, Linet M. · Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, Bethesda, MD 20892-7273, USA. · Arch Intern Med. · Pubmed #12860579 links to  free full text

Abstract: BACKGROUND: Patients with celiac disease have an increased risk of death from gastrointestinal malignancies and lymphomas, but little is known about mortality from other causes and few studies have assessed long-term outcomes. METHODS: Nationwide data on 10 032 Swedish patients hospitalized from January 1, 1964, through December 31, 1993, with celiac disease and surviving at least 12 months were linked with the national mortality register. Mortality risks were computed as standardized mortality ratios (SMRs), comparing mortality rates of patients with celiac disease with rates in the general Swedish population. RESULTS: A total of 828 patients with celiac disease died during the follow-up period (1965-1994). For all causes of death combined, mortality risks were significantly elevated: 2.0-fold (95% confidence interval [CI], 1.8-2.1) among all patients with celiac disease and 1.4-fold (95% CI, 1.2-1.6) among patients with celiac disease with no other discharge diagnoses at initial hospitalization. The overall SMR did not differ by sex or calendar year of initial hospitalization, whereas mortality risk in patients hospitalized with celiac disease before the age of 2 years was significantly lower by 60% (95% CI, 0.2-0.8) compared with the same age group of the general population. Mortality risks were elevated for a wide array of diseases, including non-Hodgkin lymphoma (SMR, 11.4), cancer of the small intestine (SMR, 17.3), autoimmune diseases (including rheumatoid arthritis [SMR, 7.3] and diffuse diseases of connective tissue [SMR, 17.0]), allergic disorders (such as asthma [SMR, 2.8]), inflammatory bowel diseases (including ulcerative colitis and Crohn disease [SMR, 70.9]), diabetes mellitus (SMR, 3.0), disorders of immune deficiency (SMR, 20.9), tuberculosis (SMR, 5.9), pneumonia (SMR, 2.9), and nephritis (SMR, 5.4). CONCLUSION: The elevated mortality risk for all causes of death combined reflected, for the most part, disorders characterized by immune dysfunction.

Jacobsson LT, Jacobsson ME, Askling J, Knowler WC. · Department of Rheumatology, Malmö University Hospital, Sweden. · BMJ. · Pubmed #12750209 links to  free full text

This publication has no abstract.

Ekström K, Hjalgrim H, Brandt L, Baecklund E, Klareskog L, Ekbom A, Askling J. · Karolinska Institutet, Stockholm, Sweden. · Arthritis Rheum. · Pubmed #12687538 links to  free full text

Abstract: OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk for malignant lymphomas. Both conditions display a familial aggregation, and there are reports of RA and malignant lymphomas occurring in the same families. This study was undertaken to determine the risk of malignant lymphomas in first-degree relatives of RA patients, in order to investigate whether the increased risk of malignant lymphomas in RA could be due to genetic or environmental risk factors common to both conditions, rather than being a consequence of the rheumatic disease. METHODS: Using Swedish nationwide and population-based registers, we identified 76,527 patients hospitalized with RA in 1964-1999 and 70,290 first-degree relatives of a subset of these patients. These subjects were followed up for more than 3 decades, and information on cancer occurrence was recorded. RESULTS: Patients with RA had a significantly increased risk of malignant lymphomas (535 cases; standardized incidence ratio [SIR] 2.00, 95% confidence interval [95% CI] 1.83-2.17), which was apparent for up to 2 decades of followup. Among the first-degree relatives without RA, no increased risk of malignant lymphomas was found overall, although modest and nonsignificantly elevated risk estimates were observed in subgroups. With respect to childhood cancer (0-14 years of age), we observed an increased risk of Hodgkin's lymphoma (5 cases; SIR 3.18, 95% CI 1.03-7.42). CONCLUSION: Patients with RA are at a markedly, but possibly time-limited, increased risk for malignant lymphomas. There is little to suggest a prominent role for coinherited or common environmental risk factors in malignant lymphomas arising in the context of RA. Instead, lymphomas complicating RA appear to be a direct consequence of the inflammation or its treatment.