Biomedical subjects
Publications and source records attributed to S Lindblad.
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.
OBJECTIVE: To characterise temporal trends and factors associated with the prescription of disease modifying antirheumatic drugs (DMARDs) at the initial consultation in early rheumatoid arthritis (RA). METHODS: Data from 2584 patients with early RA at 19 hospitals were extracted from the Swedish Rheumatoid Arthritis Register for the period 1997-2001. Disease characteristics and DMARD prescription at first consultation with the rheumatologist were investigated using cross tabulation and logistic regression. RESULTS: DMARD prescriptions, particularly for methotrexate, increased from 1997 to 2001 independently of patient characteristics. Stratification by hospital type showed that patients in district hospitals were less likely to be prescribed DMARDs than those in university hospitals (adjusted odds ratio (OR) = 0.53 (95% confidence interval (CI) 0.40 to 0.69), p<0.001), independently of confounding factors. Association of the DAS28 with the likelihood of DMARD prescription was greater among patients attending district hospitals (OR = 1.65 (1.34 to 2.02), p<0.001) than those at university hospitals (OR = 1.23 (1.07 to 1.41), p = 0.003) and county hospitals (OR = 1.34 (1.01 to 1.63), p = 0.003). Interaction testing indicated that the difference was significant (p = 0.007). CONCLUSIONS: Temporal trends in DMARD prescription indicate an increasingly aggressive approach to disease management among Swedish rheumatologists. However, the association of hospital type with DMARD prescription suggests that the adoption of research findings in clinical care varies considerably.
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.
OBJECTIVE: To study serum levels of citrullinated protein/peptide antibodies (anti-CP) during up to 5 years' follow up of patients with early rheumatoid arthritis (RA), and to relate serum levels to disease course and to treatments in clinical practice. METHODS: 279 patients with early RA were followed up with clinical investigations, radiographs, and measurement of anti-CP at baseline and after 3 months, 1, 2, 3, and 5 years. RESULTS: 160/279 (57.3%) patients were anti-CP positive at the first visit (mean 5 months after first symptoms). During follow up only 11/279 (3.9%) of the patients changed their anti-CP status. Anti-CP levels fell significantly during the first year, and this drop correlated with the extent of sulfasalazine treatment but not with other drugs or clinical indices. Anti-CP positive and negative patients had similar disease activities at baseline, but during follow up the anti-CP positive patients had worse clinical disease and greater radiological progression, despite at least equally intensive antirheumatic treatment. CONCLUSIONS: Anti-CP are stable during the first 5 years of RA, suggesting that events before rather than after onset of clinical manifestations of disease determine this phenotype. The presence of anti-CP at diagnosis predicts a less favourable disease course and greater radiological progression despite antirheumatic treatment, but subsequent changes in antibody levels do not reflect changes in disease activity. Taken together, these observations suggest that anti-CP positive RA is a distinct clinical and pathophysiological entity.
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.
OBJECTIVES: To describe a nationwide system for postmarketing follow up of new antirheumatic drugs in Sweden, and to analyse safety and effectiveness in an etanercept treated patient cohort. METHODS: Etanercept became available in Sweden for prescribing on a named patient basis in 1999. All patients treated were included in a follow up of intensified adverse event reporting and recording of clinical outcome during 24 months, according to the EULAR core set. RESULTS: The mean (SD) disease activity score (DAS 28) value at inclusion among 820 patients recruited on a named patient basis during year 1 was 5.99 (1.19). After two years, 21% (n = 172) of these patients had discontinued the treatment. Of the remaining 648 patients, 68% (n = 442) responded to the treatment. However, in 55% of the responders, the disease activity was intermediate or high (mean DAS 28, 3.37 (1.20)). In all, 540 adverse events were reported in 421 adverse drug reaction (ADR) reports, in 294 patients. The events in 80 reports (19%) were serious. Twenty two per cent of the events were infections, of which 24% (n = 29) were serious. The incidence of serious adverse events remained constant over time. CONCLUSIONS: At start of etanercept treatment, patients had high disease activity. Activity remained high in a large proportion of the responding patients. Although serious ADRs occurred during late phases of treatment, no unexpected safety problems arose. No specific indicators of ADR risk were found. The monitoring system that was established may be useful in future postmarketing surveillance.
OBJECTIVE: To determine if intrapatient comparisons between prediagnosis and subsequent radiological progression could be used to assess effects of DMARDs in an RA inception cohort. PATIENTS AND METHODS: 149 non-randomised patients with newly diagnosed RA in four groups were analysed: patients treated with (a) methotrexate (n = 56); (b) sulfasalazine (n = 55); (c) auranofin (n = 19); and (d) controls who were poor treatment responders (n = 19). Radiographs were quantified using the Larsen erosion score. The prediagnosis radiological progression from the onset of RA symptoms to diagnosis was calculated and compared with the observed progression rate during the first year after diagnosis while receiving DMARD treatment. RESULTS: Mean (SD) disease duration from onset of symptoms until diagnosis was 6.7 (4.0) months. Mean (SD) baseline Larsen score was 13.2 (9.3), giving a mean (SD) estimated prediagnosis progression rate of 23.6 (12.4) Larsen score units/year. Control and auranofin groups showed radiological progression after diagnosis similar to the progression predicted by prediagnosis progression rates. Patients receiving methotrexate or sulfasalazine showed a marked reduction (71% and 73%, respectively; p<0.001) in radiographic progression compared with prediagnosis progression. CONCLUSIONS: Prediagnosis rates of radiological progression can be used quantitatively to obtain information on the potential efficacy of DMARDs, and indicate that methotrexate and sulfasalazine, but not auranofin, significantly retard radiographic damage in the first year after diagnosis.
OBJECTIVES: Disease-modifying anti-rheumatic drugs (DMARDs) decrease clinical signs and symptoms in rheumatoid arthritis (RA). However, radiographic changes sometimes continue to accrue despite effective suppression of clinical symptoms by therapy. The objective of this study was to identify whether successful clinical disease-control in a Swedish early RA-inception cohort of patients led to an attenuation of radiological progression. PATIENTS AND METHODS: We analysed clinical data and radiographs of 95 patients who were on a stable treatment regimen [methotrexate (MTX), sulfasalazine (SSZ), oral gold (AUR)] or who had changed between different DMARDs during the 2-year observation period [multiple therapy failures (mTF)]. Radiographs were quantified using the modified Larsen score and 'X-Ray RheumaCoach' software. RESULTS: Clinical measures improved markedly (p <0.001) from baseline to year 2 under AUR, MTX, and SSZ therapy but not in the mTF group. Similar levels of disease control were seen for each DMARD. During this period, patients treated with AUR had a deltaLarsen score (+ 14.5+/-1.3) similar to mTF patients (+ 15.8+/-1.1) but greater than patients on MTX (+8.6+/-0.8) or SSZ (+9.1+/-0.8). CONCLUSIONS: This study confirms that radiological progression occurs despite a clinically acceptable disease control, but also shows that, given the same degree of clinical disease control, radiological progression can be different for different DMARDs.
BACKGROUND: The relationship between inflammation and joint destruction in rheumatoid arthritis (RA) has not been unequivocally characterised. Joint destruction may result from the cumulative inflammatory burden over time, modified by an individual constant factor. OBJECTIVE: To test the hypothesis that the relationship between radiological progression and inflammation can mathematically be expressed as: [equation: see text] where Re is a factor that varies from person to person. METHODS: Clinical data and radiographs of 76 patients with early RA receiving different disease modifying antirheumatic drugs were analysed. Radiographs were quantified using the modified Larsen score and the "X-Ray RheumaCoach" software. The cumulative inflammatory burden was estimated by the time integrated 28 joint Disease Activity Score (DAS28), calculated as the area under the curve. RESULTS: 76 patients with early RA who started treatment with methotrexate (n = 20), sulfasalazine (n = 37), or oral gold (n = 19) monotherapy were evaluated. The mean (SEM) DAS28 decreased from 4.6 (0.1) at baseline to 2.3 (0.1) after 2 years. The mean (SEM) DeltaLarsen score from baseline to year 2 was 10.3 (1.5). Correlation between cumulative inflammation and radiographic change was poor. In contrast, when calculating a person's factor Re in year 1 ( Re 1) and year 2 ( Re 2), a strong and significant correlation (r = 0.58, p<0.000001) was seen between Re 1 and Re 2. CONCLUSIONS: Joint destruction is the result of the cumulative burden of inflammation over time, modified by an individual factor Re that remains relatively constant over the first 2 years of observation. The data support a mathematical model that expresses the interrelationship between inflammation and joint destruction.
BACKGROUND: Gymnasts practise many hours a week, and symptoms from injuries do not seem to stop them from continuing with practice. They may even compete with symptoms from injuries, which could increase the risk of reinjury, or of the occurrence of a more severe injury. OBJECTIVES: To investigate whether team gymnasts compete at high level in spite of symptoms from an injury. METHODS: 188 male and female competitors participating in the Swedish Cup for juniors and seniors answered a questionnaire about symptoms from injuries on the day of the competition. RESULTS: More than half the gymnasts (58%) competed despite having symptoms from an injury on the day of the competition. More seniors than juniors competed in spite of symptoms from an injury (p = 0.006). Two of three team gymnasts (65%) reported symptoms from the lower extremities and around one in five (22%) reported back symptoms. Fifty five per cent of the gymnasts reported recurrence of an injury at the same site (reinjury). CONCLUSIONS: There was a high prevalence of symptoms from injuries on the day of competition. This did not stop the team gymnasts from competing.
OBJECTIVE: To quantify the influence of cigarette smoking on the risk of developing rheumatoid arthritis (RA). METHODS: 679 cases and 847 controls included during May 1996-June 2000 in a case-control study, using incident cases, comprising the population aged 18-70 years of a defined area of Sweden, were investigated. A case was defined as a person from the study base who received for the first time a diagnosis of RA using the 1987 American College of Rheumatology criteria, and controls were randomly selected from the study base. Self reported smoking habits among cases and controls, and rheumatoid factor status among cases were registered. The incidence of RA in current smokers, ex-smokers, and ever-smokers, respectively, was compared with that of never-smokers. RESULTS: Current smokers, ex-smokers, and ever-smokers of both sexes had an increased risk for seropositive RA (for ever-smokers the odds ratio was 1.7 (95% confidence interval (95% CI) 1.2 to 2.3) for women, and 1.9 (95% CI 1.0 to 3.5) for men), but not for seronegative RA. The increased risk was only apparent among subjects who had smoked > or =20 years, was evident at an intensity of smoking of 6-9 cigarettes/day, and remained for up to 10-19 years after smoking cessation. The risk increased with increasing cumulative dose of smoking. CONCLUSION: Smokers of both sexes have an increased risk of developing seropositive, but not seronegative, RA. The increased risk occurs after a long duration, but merely a moderate intensity, of smoking and may remain for several years after smoking cessation.
OBJECTIVES: To define synovial apoptosis with respect to disease duration, inflammatory cell type, FLIP (FLICE-like inhibitory protein), and cytokines expression in patients with rheumatoid arthritis (RA). METHODS: Synovial biopsy specimens from 11 patients with longstanding RA (median disease duration 21 years) and eight with early RA (median disease duration five months) were investigated. Apoptosis (TUNEL method combined with morphological analysis), cell surface markers (CD3, CD68), cytokines (interleukin (IL) 1alpha, IL1beta, tumour necrosis factor alpha, and IL6), and FLIP expression were evaluated. Computer assisted image analysis was used for quantification. RESULTS: The apoptosis level in RA synovium was significantly higher in the group of patients with longstanding RA than in the patients with early RA (8.8% v 0.6%, p=0.001), while the number of macrophages and FLIP expression were higher in the group with early disease than in the group with longstanding RA (16.2% v 8.3%, p=0.02 and 31.1% v 0.2%, p=0.001 respectively). All three markers correlated significantly with disease duration (R=-0.7, p<0.001 for FLIP, R=0.6, p=0.001 for apoptosis, and R=-0.5, p<0.05 for CD68). Cytokine expression and T cell score were not significantly different in early RA from longstanding RA. No differences were seen between patients treated or not treated with corticosteroids or between patients treated or not treated with disease modifying antirheumatic drugs. CONCLUSIONS: The findings suggest that RA synovial macrophages are resistant to apoptosis in early RA and express high levels of FLIP. During natural or drug modified disease progression the apoptotic mechanism may be restored with a specific increase of synovial apoptosis in patients with longstanding arthritis.
The marketing of new drugs has been sped up considerably, partly as a consequence of the common EU regulatory system. At the time of approval the documentation concerning long-term effects and health economic outcomes of a new drug is scanty. This is of particular relevance to chronic and debilitating diseases like rheumatoid arthritis. In the field of rheumatology new, expensive, and clinically effective drugs have been marketed recently. This has lead to subsequent problems in the setting of priorities at the clinical as well as the administrative level. The demand for appropriate systems for following up of effects, toxicity and economy of these drugs has compelled the Swedish Society for Rheumatology and the Medical Products Agency to establish a surveillance system for TNF-blockers. This was implemented already in the pre-marketing phase, and is presently being continued as an observational study after approval. Experience from the development phase of this system and some preliminary results are presented.
Early active treatment with disease-modifying anti-rheumatic drugs has become standard management for patients with recent-onset rheumatoid arthritis. A number of questions, however, remain unresolved for practising clinicians, for example how early and how actively to treat and what the treatment goals should be. This chapter summarizes some recent data that have added important empirical evidence on these issues. It has thus been demonstrated that the formal organization of an early arthritis clinic shortens the referral time from primary care, that a delay in the institution of disease-modifying drug treatment leads to decreased long-term function and that early active treatment with pharmacotherapy as well as team-based care may increase occupational capacity. It is argued that adopting a day care approach in the initial encounter with specialist care may increase the possibility for patients actively to understand the disease and their own potentials to diminish and cope with its effects. The further development of care for early arthritis patients with new, potentially efficient but also expensive drugs will increase the requirement for a structured documentation of outcomes, systems for such documentation being discussed in the chapter.
Wind noise was measured in four behind-the-ear hearing instruments with different microphone openings. A silent airflow of 7 m/s was directed toward the ear of a Kemar head and the resulting wind noise was measured. The amplification was set to an insertion gain of 35 dB at 1.6 kHz. The wind noise amplitude at the position of the drum ranged from 84 to 97 dB(A). The hearing instrument with a partially covered microphone entrance proved best, whereas one with an open microphone entrance had the poorest performance. A reduction in wind noise of 6-17 dB could be achieved in all hearing instruments by using a simple windscreen made of Styrofoam. The windscreen affected the frequency response by less than 2 dB. By subtracting the insertion gain from the wind noise, an equivalent wind noise could be presented as a function of frequency. A considerable difference was found between the wind noise sensitivity in different hearing instruments. All could be improved by a windscreen without adversely affecting the frequency response.
OBJECTIVES: Assessment of the numbers and spatial distribution of cells producing interleukin 1alpha (IL1alpha), interleukin 1beta (IL1beta), tumour necrosis factor alpha (TNFalpha), and interleukin 6 (IL6) in the synovial membranes of patients with rheumatoid arthritis (RA). METHODS: Synovial tissue specimens from 40 patients with RA and eight patients with non-rheumatic disease were obtained by arthroscopy guided biopsy techniques or during joint surgery. A modified immunohistochemical method detecting cytokine producing rather than cytokine binding cells was applied to determine cytokine synthesis in fixed cryopreserved sections. Computerised image analysis methods provided comparative quantitative assessments. RESULTS: A wide variation between subjects was recorded for both quantities and profiles of expressed cytokines, despite similar macroscopic and histopathological features of inflammation. IL1alpha and IL1beta were the most abundant monokines identified, though produced at different sites. IL1alpha was predominantly seen in vascular endothelial cells, whereas IL1beta staining was mainly shown in macrophages and fibroblasts. Concordant results for the detection of TNFalpha at protein and mRNA levels were obtained with an unexpectedly low number of TNFalpha producing cells compared with IL1 expressing cells in many patients with RA. Specimens acquired arthroscopically from areas with maximum signs of macroscopic inflammation showed an increased number of TNFalpha producing cells in pannus tissue compared with that occurring in synovial villi of a given joint. This clustered distribution was not found for cells expressing any of the other studied cytokines. CONCLUSION: The recorded heterogeneous profile of proinflammatory cytokine synthesis in the synovial membrane among patients with RA may provide a clue for an understanding of the wide variation in responsiveness to different modes of antirheumatic treatment between patients.
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OBJECTIVE: The objective of this study was to quantify selected features of chronic synovial tissue inflammation by computerised image analysis and to validate the results by comparison with conventional microscopic measurements. METHODS: Synovial biopsy samples were obtained from the knee joints of patients with chronic arthritis and prepared for immunohistochemical analysis using standard techniques. Following the development of special software, four parameters of chronic synovial inflammation were evaluated: intimal layer thickness, CD3+ cell infiltration, CD8+ cell infiltration and vascularity. Intimal layer thickness was expressed in microns. The intensity of CD3+ and CD8+ cell infiltration was expressed as the percentage area of the tissue section occupied by positively stained cells. Vascularity was expressed as the percentage area occupied by blood vessels. Conventional quantitative microscopic analysis was also undertaken and the results from both methods compared. RESULTS: Seventy eight tissue sections were selected for study. Measurements of intimal layer thickness by both techniques correlated strongly: r = 0.85, p = 0.0006. Measurements of CD8+ cell infiltration, usually widely dispersed, also correlated well: r = 0.64, p = 0.005. Measurements of CD3+ cell infiltration, often densely aggregated, correlated less well: r = 0.55, p = 0.02. Measurements of vascularity demonstrated no statistically significant correlation: r = 0.41, p = 0.07. Proficiency in the use of computerised image analysis was readily acquired. CONCLUSION: Computerised image analysis was successfully applied to the measurement of some features of synovial tissue inflammation. Further software development is required to validate measurement of blood vessels of variable size.