Introduction of the second-generation direct-acting antivirals (DAAs) in chronic hepatitis C: a register-based study in Sweden.

PURPOSE: Introduction of the direct-acting antivirals (DAAs) for treatment of chronic hepatitis C (CHC) infection has been challenging in all health systems. In Sweden, a national protocol for managed introduction was developed. It was optional, but all county councils agreed to implement and follow it. The purpose of this study was to study (a) cure rates among all patients initiated on treatment in 2014-2015, (b) prescribers' adherence to the drug recommendations and treatment eligibility criteria in the protocol, and (c) introduction rate in the six Swedish healthcare regions. METHOD: A cross-sectional study where national data from the Prescribed Drug Register and the quality register InfCare Hepatitis defined the study population, and clinical data from the Patient Register and InfCare Hepatitis were used to monitor outcomes. Descriptive statistics were used. RESULTS: A total of 3447 patients were initiated on treatment during 2014-2015. The overall cure rate, based on data from 85% of the cohort, was 96%, with variation between genotypes. Adherence to drug recommendations increased over time and varied between 43.2 and 94.2%. Adherence to the treatment eligibility criteria was initially 80% and increased to 87% when treatment restrictions were widened. The introduction rate differed initially between the regions and reached stable levels 15-18 months after the launch of the first DAA. CONCLUSION: The estimated overall cure rate was 96%, with some variations between genotypes. A high level of adherence to the introduction protocol as well as similar introduction rates in the health care regions indicate that the introduction protocol, alongside with other measures taken, contributed considerably to a rapid uptake and equal distribution of DAAs in Sweden.

The immunogenetics of narcolepsy associated with A(H1N1)pdm09 vaccination (Pandemrix) supports a potent gene-environment interaction.

The influenza A(H1N1)pdm09 vaccination campaign from 2009 to 2010 was associated with a sudden increase in the incidence of narcolepsy in several countries. Narcolepsy with cataplexy is strongly associated with the human leukocyte antigen (HLA) class II DQB1*06:02 allele, and protective associations with the DQB1*06:03 allele have been reported. Several non-HLA gene loci are also associated, such as common variants of the T-cell receptor-α (TRA), the purinergic receptor P2RY11, cathepsin H (CTSH) and TNFSF4/OX40L/CD252. In this retrospective multicenter study, we investigated if these predisposing gene loci were also involved in vaccination-associated narcolepsy. We compared HLA- along with single-nucleotide polymorphism genotypes for non-HLA regions between 42 Pandemrix-vaccinated narcolepsy cases and 1990 population-based controls. The class II gene loci associations supported previous findings. Nominal association (P-value<0.05) with TRA as well as suggestive (P-value<0.1) associations with P2RY11 and CTSH were found. These associations suggest a very strong gene-environment interaction, in which the influenza A(H1N1)pdm09 strain or Pandemrix vaccine can act as potent environmental triggers.

A coordinated cross-disciplinary research initiative to address an increased incidence of narcolepsy following the 2009-2010 Pandemrix vaccination programme in Sweden.

In response to the 2009-2010 influenza A(H1N1)pdm09 pandemic, a mass vaccination programme with the AS03-adjuvanted influenza A(H1N1) vaccine Pandemrix was initiated in Sweden. Unexpectedly, there were a number of narcolepsy cases amongst vaccinated children and adolescents reported. In this review, we summarize the results of a joint cross-disciplinary national research effort to investigate the adverse reaction signal from the spontaneous reporting system and to better understand possible causative mechanisms. A three- to fourfold increased risk of narcolepsy in vaccinated children and adolescents was verified by epidemiological studies. Of importance, no risk increase was observed for the other neurological and autoimmune diseases studied. Genetic studies confirmed the association with the allele HLA-DQB1*06:02, which is known to be related to sporadic narcolepsy. Furthermore, a number of studies using cellular and molecular experimental models investigated possible links between influenza vaccination and narcolepsy. Serum analysis, using a peptide microarray platform, showed that individuals who received Pandemrix exhibited a different epitope reactivity pattern to neuraminidase and haemagglutinin, as compared to individuals who were infected with H1N1. Patients with narcolepsy were also found to have increased levels of interferon-gamma production in response to streptococcus-associated antigens. The chain of patient-related events and the study results emerging over time were subjected to intense nationwide media attention. The importance of transparent communication and collaboration with patient representatives to maintain public trust in vaccination programmes is also discussed in the review. Organizational challenges due to this unexpected event delayed the initiation of some of the research projects, still the main objectives of this joint, cross-disciplinary research effort were reached, and important insights were acquired for future, similar situations in which a fast and effective task force may be required to evaluate vaccination-related adverse events.

Ankylosing spondylitis, psoriatic arthritis, and risk of malignant lymphoma: a cohort study based on nationwide prospectively recorded data from Sweden.

OBJECTIVE: Data on lymphoma risk in ankylosing spondylitis (AS) and psoriatic arthritis (PsA) are scarce. This study was undertaken to assess the risk of lymphoma in AS and PsA overall and in relation to therapies, including tumor necrosis factor inhibitor (TNFi), for which lymphoma risks are a concern. METHODS: Through the Swedish National Patient Register we assembled nationwide prevalence cohorts of patients with AS (n = 8,707) and patients with PsA (n = 19,283) for whom data were obtained between 2001 and 2010. Each cohort member was matched to 5 population comparator subjects. Linkage with the nationwide Cancer Register identified all lymphomas recorded from 2001 to 2010. Through the Swedish Biologics Register (Anti-Rheumatic Therapy in Sweden [ARTIS]), we identified patients exposed to TNFi in the AS cohort (n = 1,908) and the PsA cohort (n = 2,605) before lymphoma diagnosis. Hazard ratios (HRs) for lymphoma were estimated by Cox regression. Crude incidences of lymphoma in TNFi-exposed and TNFi-naive patients were compared. RESULTS: For AS patients, the HR of having lymphoma versus the general population was 0.9 (95% confidence interval [95% CI] 0.5-1.6) (14 lymphomas). For PsA patients, the corresponding HR was 1.2 (95% CI 0.9-1.7) (45 lymphomas). For PsA patients treated with methotrexate and/or sulfasalazine, the HR of having lymphoma was 1.7 (95% CI 1.0-3.1). The numbers and incidence of lymphoma were not materially different in TNFi-exposed versus TNFi-naive AS and PsA patients, although the numbers of lymphomas were small. CONCLUSION: In contrast to rheumatoid arthritis, the average risks of lymphoma in AS or PsA are not elevated, although increased risks in a subset of PsA patients cannot be excluded. Our findings indicate that TNFi does not affect the risk of lymphoma in AS or in PsA.

Risks of neurological and immune-related diseases, including narcolepsy, after vaccination with Pandemrix: a population- and registry-based cohort study with over 2 years of follow-up.

OBJECTIVES: To investigate the association between vaccination with Pandemrix and risk of selected neurological and immune-related diseases including narcolepsy. DESIGN: Population-based prospective cohort study using data from regional vaccination registries and national health registries. SETTING: Seven healthcare regions in Sweden comprising 61% of the Swedish population. SUBJECTS: Study population of 3,347,467 vaccinated and 2,497,572 nonvaccinated individuals (vaccination coverage ≈ 60%) followed between 2009 and 2011 for 6.9 million person-years after exposure and 6.0 million person-years without exposure. MAIN OUTCOME MEASURE AND ANALYSIS: First recorded diagnosis of neurological and immune-related diseases. Relative risks [hazard ratios (HRs) with 95% confidence intervals (CIs)] assessed using Cox regression, adjusted for covariates. RESULTS: For all selected neurological and immune-related outcomes under study, other than allergic vaccine reactions (for which we verified an expected increase in risk) and narcolepsy, HRs were close to 1.0 and always below 1.3. We observed a three-fold increased risk of a diagnosis of narcolepsy (HR: 2.92, 95% CI: 1.78-4.79; that is, four additional cases per 100,000 person-years) in individuals ≤ 20 years of age at vaccination and a two-fold increase (HR: 2.18, 95% CI: 1.00-4.75) amongst young adults between 21 and 30 years of age. The excess risk declined successively with increasing age at vaccination; no increase in risk was seen after 40 years of age. CONCLUSIONS: For a large number of selected neurological and immune-related diseases, we could neither confirm any causal association with Pandemrix nor refute entirely a small excess risk. We confirmed an increased risk for a diagnosis of narcolepsy in individuals ≤ 20 years of age and observed a trend towards an increased risk also amongst young adults between 21 and 30 years.

Small-area variations in sales of TNF inhibitors in Sweden between 2000 and 2009.

OBJECTIVE: To measure small-area variations in sales per capita of tumour necrosis factor (TNF) inhibitors. METHODS: For 2000-2009, sales data on etanercept, infliximab, and adalimumab were retrieved from the Swedish National Corporation of Pharmacies, which keeps data on drugs dispensed in ambulatory care and hospitals. As points of reference, data were retrieved on all drugs, non-biologic treatments for chronic inflammatory disorders (sulfasalazine, methotrexate, azathioprine), and for a biologic used in a different therapeutic area (trastuzumab). As a corollary measure to sales per capita, penetration of biologics in the rheumatoid arthritis (RA) population was calculated using nationwide registers. Small areas were defined as the 21 counties of Sweden. RESULTS: From 2000 to 2009, annual TNF inhibitor sales increased 9-fold from 195 to 1779 million SEK (0.7-5.0% of total drug expenditure). The county variation in sales per capita, initially 6.2-fold (coefficient of variation 42%), decreased to 2.3-fold in 2009 (24%). During the same period, total drug expenditure per capita remained at a 1.2-fold county variation (4-6%). Sales per capita variations of non-biologic treatments against chronic inflammatory diseases ranged from 1.5 to 1.8 (12-16%). For trastuzumab, a 3.2-fold variation (30%) was observed in 2009. At the patient level, there was a 2-fold county variation (from 10% to 21%) in biologic penetration in RA. County-specific sales per capita were associated with mean RA duration (r = -0.52, p = 0.015) and C-reactive protein at treatment initiation (r = -0.49, p = 0.025), while pain was borderline significant (r = -0.43, p = 0.055). CONCLUSIONS: Despite universal access to treatment, substantial but decreasing small-area variations were observed. Although geographic variations are anticipated initially, their persistence calls for investigation of patient equity and treatment appropriateness as counties seem to have different initiation thresholds.

Generalisability of clinical registers used for drug safety and comparative effectiveness research: coverage of the Swedish Biologics Register.

OBJECTIVE: To determine coverage and generalisability of data in the Swedish Biologics Register ARTIS. METHODS: Patients with adult onset rheumatoid arthritis (RA) were identified in the National Patient Register and the Swedish Rheumatology Quality Register, including the ARTIS cohort of patients exposed to biological agents. Exposure to etanercept and adalimumab between 2006 and 2008 was determined by register linkage to the Prescribed Drug Register which contains patient-level data on >99% of all etanercept and adalimumab use in Sweden. RESULTS: Of 62 897 patients with RA, 6510 had received treatment with etanercept or adalimumab according to the Prescribed Drug Register. Of these, 5673 were also registered in ARTIS, resulting in a national coverage of 87%. The regional variation was small with >85% coverage in 18 of 21 counties. In multivariable analysis, ARTIS-registered and non-registered patients did not differ by age (p=0.62), sex (p=0.84) or education level (p=0.24). CONCLUSION: Nationwide drug dispensing and demographic data may function as quality metrics for coverage and generalisability assessments. Using such data, the coverage of ARTIS was estimated at 87% with no indications of compromised external generalisability regarding demography.

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.

Risk for malignant lymphoma in ankylosing spondylitis: a nationwide Swedish case-control study.

BACKGROUND: Several inflammatory conditions are associated with an increased risk of lymphoma. The specific features of inflammation that mediate this risk are unknown. There are few studies on whether ankylosing spondylitis increases the risk of lymphoma. Besides inflammation-lymphoma aetiology, information on risk of lymphoma in ankylosing spondylitis is particularly important as a benchmark in the evaluation of, for example, tumour necrosis factor inhibitors. METHODS: The association between ankylosing spondylitis and malignant lymphomas overall, and separately for non-Hodgkin's lymphoma, Hodgkin's lymphoma and chronic lymphocytic leukaemia, was assessed in a nationwide, population-based case-control study of 50 615 cases of lymphoma and 92 928 matched controls by using prospectively recorded data on lymphomas from the Swedish Cancer Register (1964-2000) and data on pre-lymphoma hospitalisations for ankylosing spondylitis from the Swedish Inpatient Register (1964-2000). The odds ratios (ORs) associated with pre-lymphoma hospitalisation for ankylosing spondylitis were calculated using conditional logistic regression. RESULTS: 23 (0.05%) patients with lymphoma and 41 (0.05%) controls had a pre-lymphoma hospitalisation listing ankylosing spondylitis, relative risk = 1.0 (95% confidence interval (CI) 0.6 to 1.7). The number of discharges and the mean latency between ankylosing spondylitis and lymphoma were similar in patients and controls. Analyses restricted to lymphomas diagnosed during the 1990s showed similar results (OR = 1.3, 95% CI 0.6 to 2.5, number of exposed cases/controls = 14/21). CONCLUSIONS: On average and in the absence of tumour necrosis factor inhibitors, patients hospitalised with ankylosing spondylitis do not appreciably show an increased risk of lymphoma.

Swedish registers to examine drug safety and clinical issues in RA.

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.

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.

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.

Results from a nationwide postmarketing cohort study of patients in Sweden treated with etanercept.

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.

Cancer incidence among patients with ankylosing spondylitis in Sweden 1965-95: a population based cohort study.

BACKGROUND: Ankylosing spondylitis (AS) is a chronic inflammatory joint disease which may lead to extra-articular complications. The disease associated cancer risk has been poorly explored. Recently, tumour necrosis factor alpha blockers have been found to be efficacious in AS, but their long term risk is unknown. OBJECTIVE: To analyse a large national cohort of patients with AS to determine the overall cancer risk in AS as a background to the future introduction of new treatments. METHODS: All patients with AS admitted to Swedish hospitals 1965-95 were linked through individual national registration numbers to the Swedish Cancer Register and National Death Register. Standardised incidence ratio (SIR) of cancer risk was calculated in 6621 people, monitored during 67 885 person-years. RESULTS: No overall increase in cancer risk was found (SIR 1.05, 95% CI 0.94 to 1.17). Rectal cancer was less common (SIR 0.41, 95% CI 0.15 to 0.89) while unspecified kidney cancer was more common (SIR 5.90, 95% CI 1.61 to 15.1). Risks for colon, renal parenchymal, and renal pelvic cancer were not significantly increased. Laryngeal cancer was more common than expected, while lung cancer was not. Risks of haematopoietic malignancies were not increased. CONCLUSIONS: No overall increase in cancer risk was found. The decreased risk of rectal cancer might be due to local application of NSAIDs, and the increased risk of unspecified kidney cancer to frequent radiological pelvic examinations. If information on disease characteristics, including HLA-B27, was available for individual patients with cancer, risk-benefit analysis of long term effects of new immunomodulation treatment might be improved.

A 10-year survey of inflammatory bowel diseases-drug therapy, costs and adverse reactions.

BACKGROUND: Drug therapy for Crohn's disease and ulcerative colitis is based on anti-inflammatory and immunodulating drugs, nutritional support and surgical resection. Recently, new drugs have been introduced. AIM: To report drug prescriptions, costs and adverse reactions among inflammatory bowel disease patients in Sweden between 1988 and 1997. METHODS: Drug use was calculated from the national Diagnosis and therapy survey and drug costs from prescriptions and drug sales. Adverse drug reactions were obtained from the Medical Products Agency's National Pharmacovigilance system. RESULTS: The annual drug exposure for Crohn's disease was 0.55 million daily doses per million population, mainly supplementation and aminosalicylic acids. Mesalazine and olsalazine had 61% within this group. For ulcerative colitis patients, drug exposure was 0.61 million daily doses per million per year and aminosalicylic acids fell from 70% to 65%. For inflammatory bowel disease patients, corticosteroids and nutritional supplementation were common. The annual average cost for inflammatory bowel disease drugs was 7.0 million US dollars. Annually, 32 adverse drug reactions were reported, mainly haematological reactions such as agranulocytosis and pancytopenia (60%), followed by skin reactions. Only two deaths were reported. Aminosalicylic acids were the most commonly reported compounds. CONCLUSIONS: Drug use for inflammatory bowel disease in the pre-biologic agent era rested on aminosalicylic acid drugs and corticosteroids with stable levels, proportions and costs. The level of adverse drug reactions was low but haematological reactions support the monitoring of inflammatory bowel disease patients.

[New drugs require nw follow-up surveillance]. / Nya läkemedel kräver nya former för uppföljning.

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.

Self-reported symptoms among women after cosmetic breast implant and breast reduction surgery.

A retrospective cohort study was performed in Sweden to evaluate the possibility that an individual symptom or constellation of illness symptoms related to silicone occurs in women after breast implant surgery. A random sample (n = 2500) of all women in the Swedish national implant registry who underwent breast augmentation surgery with alloplastic breast implants during the years 1965 through 1993 was compared with a sample (n = 3500) of women who underwent breast reduction surgery during the same period, frequency matched to the implant patients for age and calendar year at the time of surgery. In total, 65 percent of the breast implant patients (n = 1546) and 72 percent of the breast reduction patients (n = 2496) completed a self-administered questionnaire covering 28 rheumatologic and other symptoms and lifestyle and demographic factors. Practically all of the 28 symptoms inquired about were reported more often by women in the breast implant cohort, with 16 (57 percent) significantly more common in breast implant recipients. In contrast, few significant differences or consistent patterns were observed in the length of time since the implant and in the type (silicone or saline) or volume of the implant. Although women with breast implants report a multitude of symptoms more often than women who have breast reduction surgery, the lack of specificity and absence of dose-response relationships suggest that the excess of reported symptoms is not causally related to cosmetic implants.

Rheumatoid arthritis in Sweden. Drug prescriptions, costs, and adverse drug reactions.

OBJECTIVE: Many patients with rheumatoid arthritis (RA) need continuous medication, bringing considerable costs for drugs and a need for monitoring adverse drug reactions. We studied drug exposure, drug costs, and adverse drug reactions in patients with RA in Sweden from 1987 to 1997. METHODS: Prescription patterns, drug costs, and adverse drug reactions, and their distributions and trends were analyzed by cross sectional annual data. Drug exposures and costs were assessed from the National Diagnosis and Therapy Survey. All costs were recalculated to the 1997 level using the drug price index. Information on adverse drug reactions was obtained from the national pharmacovigilance system. RESULTS: The drug prescription level was, on average, 2 defined daily doses (DDD) throughout the study period. Nonsteroidal antiinflammatory drugs (NSAID) accounted for > 40% of the drugs prescribed, methotrexate (MTX) 10%, corticosteroids 10%, and sulfasalazine 5%. Analgesics and opioids made up 14% of prescriptions - a low estimate considering the availability of over-the-counter preparations. Disease modifying antirheumatic drugs (DMARD) increased their proportion from 28.5 to 39.3%. Total costs were stable at $16 million US annually. NSAID costs decreased, while those of sulfasalazine, MTX, and cyclosporine increased. On average, 91 adverse drug reactions were reported annually. Hematological reactions (agranulocytosis, thrombocytopenia, leukopenia, pancytopenia) predominated, constituting 21% of reported reactions. Skin and gastrointestinal reactions, mainly mild, accounted for 15 and 14%, respectively. Deaths from adverse drug reactions were uncommon, about 3 per year, and were mainly attributed to hematological reactions. CONCLUSION: The total volume as well as the total cost of drug consumption for RA in Sweden was relatively constant during our 11 year observation period, despite a notable increase in the use of DMARD. This was mainly due to a decrease in costs per DDD of NSAID, and an increased use of cyclosporine. Drug related adverse reactions were dominated by hematological reactions, and fatal events were few. This emphasizes the need for an extended evaluation of which safety procedures are most cost effective for monitoring the drugs used for RA.