Lars Cöster

Haematopoietic malignancies in rheumatoid arthritis: lymphoma risk and characteristics after exposure to tumour necrosis factor antagonists

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.

Risks of solid cancers in patients with rheumatoid arthritis and after treatment with tumour necrosis factor antagonists

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.

Time-dependent increase in risk of hospitalisation with infection among Swedish RA patients treated with TNF antagonists

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.

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.

Anti-tumour necrosis factor therapy in rheumatoid arthritis and risk of malignant lymphomas: relative risks and time trends in the Swedish Biologics Register

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.

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.

Chronic widespread musculoskeletal pain - a comparison of those who meet criteria for fibromyalgia and those who do not.

Fibromyalgia is currently classified as chronic widespread pain with widespread allodynia to pressure pain. There are few data describing pain characteristics, quality of life, consequences for daily living, and psychosocial status in patients who meet the classification criteria for fibromyalgia proposed by the American College of Rheumatology compared with patients with chronic widespread pain but not widespread allodynia.

Prevalence of widespread pain and associations with work status: a population study

BackgroundThis population study based on a representative sample from a Swedish county investigates the prevalence, duration, and determinants of widespread pain (WSP) in the population using two constructs and estimates how WSP affects work status. In addition, this study investigates the prevalence of widespread pain and its relationship to pain intensity, gender, age, income, work status, citizenship, civil status, urban residence, and health care seeking.MethodsA cross-sectional survey using a postal questionnaire was sent to a representative sample (n = 9952) of the target population (284,073 people, 18–74 years) in a county (Östergötland) in the southern Sweden. The questionnaire was mailed and followed by two postal reminders when necessary.ResultsThe participation rate was 76.7% (n = 7637); the non-participants were on the average younger, earned less money, and male. Women had higher prevalences of pain in 10 different predetermined anatomical regions. WSP was generally chronic (90–94%) and depending on definition of WSP the prevalence varied between 4.8–7.4% in the population. Women had significantly higher prevalence of WSP than men and the age effect appeared to be stronger in women than in men. WSP was a significant negative factor – together with age 50–64 years, low annual income, and non-Nordic citizen – for work status in the community and in the group with chronic pain. Chronic pain but not the spreading of pain was related to health care seeking in the population.ConclusionThis study confirms earlier studies that report high prevalences of widespread pain in the population and especially among females and with increasing age. Widespread pain is associated with prominent effects on work status.

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.

Influence of FCGR3A genotype on the therapeutic response to rituximab in rheumatoid arthritis: an observational cohort study

Objectives To determine whether a polymorphism in the Fcγ receptor type IIIA (FCGR3A-F158V), influencing immunoglobulin G binding affinity, relates to the therapeutic efficacy of rituximab in rheumatoid arthritis (RA) patients. Design Observational cohort study. Setting Three university hospital rheumatology units in Sweden. Participants Patients with established RA (n=177; 145 females and 32 males) who started rituximab (Mabthera) as part of routine care. Primary outcome measures Response to rituximab therapy in relation to FCGR3A genotype, including stratification for sex. Results The frequency of responders differed significantly across FCGR3A genotypes (p=0.017 in a 3×2 contingency table). Heterozygous patients showed the highest response rate at 83%, as compared with patients carrying 158FF (68%) or 158VV (56%) (p=0.028 and 0.016, respectively). Among 158VV patients, response rates differed between male and female patients (p=0.036), but not among 158FF or 158VF patients (p=0.72 and 0.46, respectively). Conclusions Therapeutic efficacy of rituximab in RA patients is influenced by FCGR3A genotype, with the highest response rates found among heterozygous patients. This may suggest that different rituximab mechanisms of action in RA are optimally balanced in FCGR3A-158VF patients. Similar to the previously described associations with RA susceptibility and disease course, the impact of 158VV on rituximab response may be influenced by sex.