L. Jacobsson

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 (nu200a=u200a53 067), one incident cohort (nu200a=u200a3703), and one TNF antagonist treated cohort 1999 through 2003 (nu200a=u200a4160)), 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 (SIRu200a=u200a1.9 and 2.0, respectively) and leukaemia (SIRu200a=u200a2.1 and 2.2, respectively) but not of myeloma. Patients with RA treated with TNF antagonists had a tripled lymphoma risk (SIRu200a=u200a2.9) 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 (nu200a=u200a53 067), one incident, diagnosed 1995–2003 (nu200a=u200a3703), and one treated with TNF antagonists 1999–2003 (nu200a=u200a4160)), 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 (nu200a=u200a67) 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.

Health-related quality of life in primary Sjogren's syndrome, rheumatoid arthritis and fibromyalgia compared to normal population data using SF-36

Objective: To investigate the health-related quality of life in women with primary Sjögrens syndrome (prim SS) and compare with normative data and the healthrelated quality of life in women with rheumatoid arthritis (RA) and women with fibromyalgia. Methods: A questionnaire including the MOS Short-Form 36 (SF-36) was completed by 42 prim SS women, 59 RA women, and 44 women with fibromyalgia.ResultsOBJECTIVEnTo investigate the health-related quality of life in women with primary Sjogrens syndrome (prim SS) and compare with normative data and the health-related quality of life in women with rheumatoid arthritis (RA) and women with fibromyalgia.nnnMETHODSnA questionnaire including the MOS Short-Form 36 (SF-36) was completed by 42 prim SS women, 59 RA women, and 44 women with fibromyalgia.nnnRESULTSnAll three patient groups experienced a decreased quality of life level ranging from 5 to 65 % in all SF-36 scales compared to normative data. Differences between groups were seen in 7 of the 8 scales (p< or = 0.004). The prim SS patients experienced a higher quality of life level with regard to physical function than the women with RA and fibromyalgia, whereas in the psychological dimensions the quality of life level was comparable to that of the two other groups.nnnCONCLUSIONnThe health-related quality of life was significantly decreased as compared to norms in prim SS women and comparable to the levels of women with RA and fibromyalgia.

Reduced functional performance in the lower extremity predicted radiographic knee osteoarthritis five years later

Background: Reduced quadriceps strength is an early finding in subjects with knee osteoarthritis, but it is not clear whether it is a cause or a consequence of knee osteoarthritis. Objective: To determine whether reduced functional performance in the lower extremity predicts the incidence or progression of radiographic knee osteoarthritis. Design: Prospective, epidemiological, population based cohort study. Patients: 148 subjects (62 women), aged 35–54 (mean 44.8), with chronic knee pain from a population based cohort. Measurements: Predictors analysed were age, sex, body mass index, baseline knee pain, and three tests of lower extremity functional performance: maximum number of one-leg rises from sitting, time spent walking 300 m, and timed standing on one leg. Weightbearing tibiofemoral knee radiographs were obtained at baseline and after 5 years (median 5.1, range 4.2–6.1), and classified according to Kellgren and Lawrence as no osteoarthritis (Kellgren and Lawrenceu200a=u200a0, nu200a=u200a94) or prevalent osteoarthritis (Kellgren and Lawrence ⩾1, nu200a=u200a54). Results: Fewer one-leg rises (median 17 v 25) predicted incident radiographic osteoarthritis five years later (OR 2.6, 95% CI 1.1 to 6.0). The association remained significant after controlling for age, sex, body mass index, and pain. No significant predictor of radiographic progression in the group with prevalent osteoarthritis was found. Conclusion: Reduced functional performance in the lower extremity predicted development of radiographic knee osteoarthritis 5 years later among people aged 35–55 with chronic knee pain and normal radiographs at baseline. These findings suggest that a test of one-leg rises may be useful, and interventions aimed at improving functional performance may be protective against development of knee osteoarthritis.

The Commonest Rheumatic Complaints of Over Six Weeks' Duration in a Twelve-month Period in a Defined Swedish Population Prevalences and Relationships

In 900 randomly selected individuals, 50-70 years old, we examined the prevalence over the preceding 12-month period of rheumatic complaints of more than 6 weeks duration. We found them to represent a major health problem, with an overall prevalence of 37.8%, the predominant diagnoses being subacromial shoulder pain (6.7%), neck pain (6.5%), low back pain (6.3%), osteo-arthrosis (8.5%), and arthralgia (4.9%). With a prevalence of 1.0%, primary fibromyalgia was as common as rheumatoid arthritis (0.7%) and other chronic arthritides (1.1%). The prevalences of the different diagnoses were higher among participants whose data were obtained from personal investigation by a physician than among non-participants where data were obtained by interview, letter, and scrutiny of case records. The odds ratio from incurring more than one rheumatic disease was higher for subacromial shoulder pain and lowest for arthralgia and osteo-arthrosis.

Epidemiology of extra‐articular manifestations in rheumatoid arthritis

Extra‐articular RA (ExRA) includes a wide variety of disease manifestations. Although rheumatologists in general are aware that such events are clinically important, the heterogeneity of available data, including discrepancies in case definitions, has complicated constructive discussions on this aspect of the RA disease phenotype. In recent years, there has been a growing recognition of the importance of co‐morbidity in patients with RA. ExRA manifestations are not uncommon, explain excess mortality in RA and are predicted by smoking and autoantibodies. Further studies of the mechanisms underlying these associations are likely to be important in improving our understanding of the systemic nature of RA. This article discusses the methodological issues involved in the study of ExRA manifestations, presents suggested criteria that have been used in clinical studies, and reviews important surveys of the epidemiology of extra‐articular RA.

Correlation of fatty acid composition of adipose tissue lipids and serum phosphatidylcholine and serum concentrations of micronutrients with disease duration in rheumatoid arthritis.

To establish the concentrations of micronutrients in serum, fatty acid composition in serum phosphatidylcholine and in adipose tissue, and their correlation with inflammation and disease duration in rheumatoid arthritis (RA), 21 consecutive patients with recently diagnosed disease (mean duration eight months), 21 patients with longstanding disease (mean duration 15 years), and 57 controls were examined. In the patients with RA low concentrations of the essential fatty acids, linoleic acid (18:2) and linolenic (18:3) acid, and high concentrations of total saturated fatty acids, both in serum phosphatidylcholine and in adipose tissue, were found, abnormalities that increased with disease duration. The proportion of 18:2 in serum phosphatidylcholine correlated inversely with such acute phase proteins as orosomucoid and C reactive protein. It is proposed that the decreases in essential fatty acids are related to increased activity in the desaturase/elongation enzymes, increased production of eicosanoids, or metabolic changes secondary to cytokine mediated inflammatory reaction. When the micronutrients were studied it was found that serum concentrations of selenium were lower in patients than in controls, but not those of ascorbic acid, alpha-tocopherol, retinol, folic acid, or cobalamine. Ascorbic acid concentrations tended to be lower in RA, however, and correlated inversely with those of haptoglobin, orosomucoid, and C reactive protein, indicating a relation between the ascorbic acid concentration and the degree of inflammation.

Effect of education, occupation and some lifestyle factors on common rheumatic complaints in a Swedish group aged 50-70 years.

The relation between common rheumatic diseases such as osteoarthrosis, arthralgia without definite signs of osteoarthrosis, subacromial shoulder pain, different forms of tendinitis, low back pain and neck pain, and the level of formal education, occupational workload and some lifestyle factors were examined in 502 of 900 randomly selected subjects aged 50-70 years. The group with rheumatic complaints had a higher proportion of subjects with a lower level of formal education (less than or equal to eight years) by bivariate analysis. In multivariate analysis, the major risk factors were: a self rated heavy workload (odds ratio (OR) 6.4), sleep disturbance (OR 3.6), and advanced age (OR 2.0 per five year increase) for osteoarthrosis; a self rated heavy workload for subacromial shoulder pain (OR 5.4) and low back pain (OR 4.8); and a self rated heavy workload (OR 8.0) and female sex (OR 4.8) for neck pain. A self rated heavy workload was strongly correlated with a low level of formal education. A heavy workload (i.e. previous or present principal occupation) could only be confirmed in the groups with neck pain and low back pain on the basis of available occupational classification data. Neck pain was thus associated with occupations entailing repetitive tasks and awkward posture with respect to the neck, shoulders, and back. Low back pain was associated with occupations entailing awkward posture with respect to the neck, shoulders, and back, and occupations entailing exposure to vibration and heavy manual work. It is concluded that, in a cross sectional sample of an elderly population, a low level of formal education and self rated heavy physical work are associated with the occurrence of adult rheumatic complaints, though the self rated heavy workload could only be verified in the groups with neck pain and low back pain. There correlations between heavy work and low back pain, and especially neck pain, suggest that successful prevention would mean a substantial economic gain to the community. Whether the level of education is a marker of risk factors other than a heavy occupational workload needs further evaluation.

Smoking, low formal level of education, alcohol consumption, and the risk of rheumatoid arthritis.

Objective: Suggested predictors of rheumatoid arthritis (RA) include environmental exposure, such as smoking. Our purpose was to investigate potential predictors of RA in a nested case–control study based on a prospective cohort. Method: Between 1991 and 1996, 30 447 persons were included in the Malmö Diet and Cancer Study (MDCS). Individuals who developed RA after inclusion up to 31 December 2004 were identified by linking the database to different registers. Four controls were selected for every case. Data on lifestyle factors were collected in the MDCS. Results: We identified 172 incident cases of RA [36 men/136 women, mean age at diagnosis 63 years, 69% rheumatoid factor (RF) positive, median time from inclusion to diagnosis 5 (range 1–13) years]. In bivariate analyses, baseline smoking [odds ratio (OR) 2.02, 95% confidence interval (CI) 1.31–3.12] and a low level of formal education (i.e. ≤ 8 years; OR 2.42, 95% CI 1.18–4.93 vs. University degree) predicted subsequent development of RA. Infrequent baseline alcohol consumption was a predictor of RA (OR 3.47, 95% CI 1.91–6.30) compared to recent use (within the past month), and individuals with moderate baseline alcohol consumption (3.5–15.2 g/day vs. < 3.5 g/day) tended to have a reduced risk of RA (OR 0.48, 95% CI 0.22–1.05) in multivariate analyses, adjusted for smoking and level of education. Conclusions: Smoking and a low level of formal education were found to be independent predictors of RA. Moderate alcohol consumption may also be associated with a reduced risk.

MRI assessment of early response to certolizumab pegol in rheumatoid arthritis: a randomised, double-blind, placebo-controlled phase IIIb study applying MRI at weeks 0, 1, 2, 4, 8 and 16

Objectives To identify the first time point of an MRI-verified response to certolizumab pegol (CZP) therapy in patients with rheumatoid arthritis (RA). Methods Forty-one patients with active RA despite disease-modifying antirheumatic drug therapy were randomised 2:1 to CZP (CZP loading dose 400u2005mg every 2u2005weeks at weeks 0–4; CZP 200u2005mg every 2u2005weeks at weeks 6–16) or placebo→CZP (placebo at weeks 0–2; CZP loading dose at weeks 2–6; CZP 200u2005mg every 2u2005weeks at weeks 8–16). Contrast-enhanced MRI of one hand and wrist was acquired at baseline (week 0) and weeks 1, 2, 4, 8 and 16. All six time points were read simultaneously, blinded to time, using the Outcome Measures in Rheumatology Clinical Trials RA MRI scoring system. Primary outcome was change in synovitis score in the CZP group; secondary outcomes were change in bone oedema (osteitis) and erosion scores and clinical outcome measures. Results Forty patients were treated (27 CZP, 13 placebo→CZP), and 36 (24 CZP, 12 placebo→CZP) completed week 16. In the CZP group, there were significant reductions from baseline synovitis (Hodges–Lehmann estimate of median change, −1.5, p=0.049) and osteitis scores (−2.5, p=0.031) at week 16. Numerical, but statistically insignificant, MRI inflammation reductions were observed at weeks 1–2 in the CZP group. No significant change was seen in bone erosion score. Improvements across all clinical outcomes were seen in the CZP group. Conclusions CZP reduced MRI synovitis and osteitis scores at week 16, despite small sample size and the technical challenge of reading six time points simultaneously. This study provides essential information on optimal MRI timing for subsequent trials. Trial registration number ClinicalTrials.gov, NCT01235598.