KEP: Chronic Inflammatory Diseases

Targets in clinical epidemiology

The overarching aim of our work is to better understand the etiology, clinical course, treatment effects, outcome and costs of Rheumatoid Arthritis (RA) and other chronic inflammatory diseases.

To this end, we use combinations of data from clinical quality registers, from linkages to national health- and demographics registers, clinical research databases including biobanks, and have developed methods to work with large-scale linkage data.

Much of our work is performed in close co-operation with other research groups within the Clinical Epidemiology Unit (KEP), other researchers in the inflammatory disease research network at Karolinska Institutet, and at the department of Rheumatology at Karolinska University Hospital, colleagues in rheumatology research from Lund, Göteborg, Umeå, and Uppsala, including the Swedish Society for Rheumatology quality register, and as part of international research collaborations.

Group Members

Johan Askling, MD, PhD (Group Leader) 

Elizabeth Arkema, ScD 

Thomas Bergman, PhD 

Gustaf Bruze, PhD

Katharina Büsch, MSc

Thomas Frisell, PhD 

Karin Hellgren, MD, PhD

Marie Holmqvist, MD, PhD

Kari Johansson, PhD

Lotta Ljung, MD, PhD

Ängla Mantel, MD

Martin Neovius, PhD

Ola Olén, MD, PhD

Carl-Martin Pethrus, PhD-Student

Pauline Raaschou, MD, PhD

Marios Rossides, MSc

John Svensson, MSc, PhD-Student

Hjalmar Wadström, PhD-student

Kristin Waldenlind, MD, PhD-Student



Study Summaries

Prevalence of RA in Sweden

Using Swedish nationwide health care registers, nearly 60,000 adult patients with at least one RA diagnosis were identified. This corresponded to a prevalence in 2008 of 0.6-0.8% depending on definition (Figure).

The well-known sex gradient varied with age, decreasing from a 4:1 women to men ratio in the youngest to 2:1 in the oldest.

A strong age gradient was also observed for biologic treatment, with much greater penetration in younger than older patients.

Publication: Nationwide prevalence of rheumatoid arthritis and penetration of disease-modifying drugs in Sweden.
Neovius M, Simard J, Askling J,
Ann. Rheum. Dis. 2011 Apr;70(4):624-9


Familial aggregation of RA

By linking the Swedish Rheumatology Quality register (SRQ) to the EIRA case-control study and several national registers we were able to provide the most precise estimates of the familial risk for RA to date, while also being able to study the influence of several clinical features. 

The pattern of risks suggested 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 a significant familial overlap between seropositive and seronegative RA. Even if the familial risk is assumed to be completely due to genetics, the observed risks suggest a heritability of RA lower than previously reported, in particular for ACPA-negative RA.

Publication: 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.
Frisell T, Holmqvist M, Källberg H, Klareskog L, Alfredsson L, Askling J
Arthritis Rheum. 2013 Nov;65(11):2773-82


Cancer survival in RA-patients treated with TNF-inhibitors

TNF-inhibitor treatment may affect tumor initiation and spread. In a national cohort of patients with rheumatoid arthritis (RA), we studied the clinical presentation and outcome of cancers that developed during or after TNF-inhibitor therapy.

We found that cancers that occur following TNF-inhibitor treatment in RA routine care do not display any markedly altered stage at presentation or altered post-cancer survival rates.

Publication: Does cancer that occurs during or after anti-tumor necrosis factor therapy have a worse prognosis? A national assessment of overall and site-specific cancer survival in rheumatoid arthritis patients treated with biologic agents.
Raaschou P, Simard J, Neovius M, Askling J,
Arthritis Rheum. 2011 Jul;63(7):1812-22


Malignant melanoma in RA treated with anti-TNF therapy

TNF-inhibitor treatment may increase the risk of cancer, in particular malignant melanomas which are considered “immunogenic” tumors. We investigated the risk of invasive and in situ melanomas in a national cohort of patients with rheumatoid arthritis (RA), and the general population.

We found that patients selected for TNF-inhibitor treatment have a 50% increased relative risk of invasive melanoma, compared to RA-patients never treated with TNF-inhibitors. RA-patients never treated with TNF-inhibitors were not at an increased risk of melanoma compared to the general population.

Publication: Rheumatoid arthritis, anti-tumour necrosis factor therapy, and risk of malignant melanoma: nationwide population based prospective cohort study from Sweden.
Raaschou P, Simard J, Holmqvist M, Askling J,
BMJ 2013 Apr;346():f1939


Tuberculosis in RA and the role of treatment

The extent to which increased awareness and targeted pre-treatment screening over the past decade have reduced tuberculosis (TB) risk with anti-TNFs is unclear. In a prospective population-based cohort study (2002-2011) using data from Swedish national population registers, we estimated the rate of incident TB in the general population and in a cohort of individuals with rheumatoid arthritis (RA). Compared to the general population, RA patients not exposed to biologicals had a 4-fold increased risk of TB, which did not decline over calendar time. When we comparing the risk of TB in biological-exposed RA to biological naïve, the risk was 8-fold higher from 2002-2006 but decreased to 2-fold from 2007-2011. Most cases of TB in RA occur in biological-naïve RA patients, underscoring the elevated risk also in these patients.

Publication: Are patients with rheumatoid arthritis still at an increased risk of tuberculosis and what is the role of biological treatments?
Arkema E, Jonsson J, Baecklund E, Bruchfeld J, Feltelius N, Askling J, et al
Ann. Rheum. Dis. 2015 Jun;74(6):1212-7

Work loss in relation to RA diagnosis

Using data from the Swedish Rheumatology Quality Register and work loss data from the Social Insurance Office, we investigated the trajectory of days of sick leave and disability pension before and after RA diagnosis.

We found that one year before diagnosis, future RA patients did not differ in work loss compared to general population comparators matched by age, sex, education level and place of residence. At diagnosis, the mean monthly work loss in patients with RA was more than three times that in comparators (Figure).

The level decreased during the first year, but remained considerably higher than both the pre-diagnosis level and versus comparators for the four years of follow-up investigated.

Publication: How large are the productivity losses in contemporary patients with RA, and how soon in relation to diagnosis do they develop?
Neovius M, Simard J, Askling J,
Ann. Rheum. Dis. 2011 Jun;70(6):1010-5


A biobank for RA patients coupled with the Swedish Rheumatology Quality register

A biobank sample collection of patients newly diagnosed with RA or prevalent RA patients recently started on biologics treatment have been established. A growing number of Swedish rheumatology clinics are participating in recruitment and sampling of RA patients. A novel decision support system integrated with the SRQ application has been developed, that suggests patients suitable for sampling during visits to a rheumatologist. The availability of patients biobank samples (plasma, serum and DNA) are presented in the SRQ register on-line.


Bergman T, Baecklund E, Gjertsson I, Rantapää Dahlqvist S, Skogh T, Turesson C och Askling J.

Reumadagarna 2014, Örebro



The randomized Swefot trial  

The investigator-initiated randomized Swefot trial aimed to compare the intensive treatment alternatives of adding conventional DMARDs (hydroxychloroquine+sulfasalazine) or a TNFi (infliximab) in the common clinical situation of patients with early RA that have failed their initial treatment with methotrexate monotherapy. After 1 year, a difference in disease activity measured by DAS28 favouring the infliximab treatment strategy was detected, but no difference in DAS28 could be detected after 2 years, while the infliximab strategy showed superior radiological outcomes compared to conventional combination therapy.

In the following two studies, the aims were to investigate whether this radiological superiority translates into better work loss outcomes, and to estimate the incremental cost-effectiveness of infliximab versus conventional treatment.

In the first study, the mean changes in work loss at 21 months were -4.9 days/month in the infliximab and -6.2 days/month in the conventional treatment group (adjusted mean difference 1.6 days/month; 95% CI -1.2 to 4.4).

Publication: Biological vs. conventional combination treatment and work loss in early rheumatoid arthritis: a randomized trial.
Eriksson J, Neovius M, Bratt J, Petersson I, van Vollenhoven R, Geborek P, et al
JAMA Intern Med 2013 Aug;173(15):1407-14

In the cost-effectiveness analysis, the incremental cost-effectiveness ratios for the infliximab versus conventional treatment strategy were €2 400 000/QALY from the societal perspective and €1 900 000/QALY from the healthcare perspective.

Publication: Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial.
Eriksson J, Karlsson J, Bratt J, Petersson I, van Vollenhoven R, Ernestam S, et al
Ann. Rheum. Dis. 2015 Jun;74(6):1094-101

To summarize, in methotrexate-refractory early RA followed over 21 months, the radiological superiority of a strategy adding infliximab versus adding further conventional DMARDs did not translate into better work loss outcomes, and was not cost-effective at willingness to pay levels generally considered acceptable.



Our work has received funding from several public funding bodies, including The Swedish Research Council (VR), The Swedish Foundation for Strategic Research (SSF), The Swedish Cancer Society (CF), Stockholm County Council (ALF), from EU IMI (BTCure). Our post-marketing surveillance of anti-rheumatic therapies based on data from the Swedish Quality of Care Register, and run in collaboration with the Swedish Rheumatology Association (the ARTIS group) has received funding from AstraZeneca, Pfizer, Merck, Abbvie, BMS, SOBI, UCB, and Roche.