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Neovius M.,Karolinska Institutet | Arkema E.V.,Karolinska Institutet | Olsson H.,Karolinska Institutet | Eriksson J.K.,Karolinska Institutet | And 13 more authors.
Annals of the Rheumatic Diseases | Year: 2013

Objective: To compare drug survival on adalimumab, etanercept and infliximab in patients with rheumatoid arthritis (RA). Methods: Patients with RA (n=9139; 76% women; mean age 56 years) starting their first tumour necrosis factor (TNF) inhibitor between 2003 and 2011 were identified in the Swedish Biologics Register (ARTIS). Data were collected through 31 December 2011. Drug survival over up to 5 years of follow-up was compared overall and by period of treatment start (2003-2005/2006-2009; n=3168/4184) with adjustment for age, sex, education, period, health assessment questionnaire (HAQ), disease duration, concomitant disease modifying antirheumatic drug (DMARD) treatment and general frailty (using hospitalisation history as proxy). Results: During 20 198 person-years (mean/median 2.2/1.7 years) of follow-up, 3782 patients discontinued their first biological (19/100 person-years; 51% due to inefficacy, 36% due to adverse events). Compared with etanercept, infliximab (adjusted HR 1.63, 95% CI 1.51 to 1.77) and adalimumab initiators had higher discontinuation rates (1.26, 95% CI 1.16 to 1.37), and infliximab had a higher discontinuation rate than adalimumab (1.28, 95% CI 1.18 to 1.40). These findings were consistent across periods, but were modified by time for adalimumab versus etanercept (p<0.001; between-drug difference highest the 1st year in both periods). The discontinuation rate was higher for starters in 2006-2009 than 2003-2005 (adjusted HR 1.12, 95% CI 1.04 to 1.20). The composition of 1-year discontinuations also changed from 2003-2005 vs 2006-2009: adverse events decreased from 45% to 35%, while inefficacy increased from 43% to 53% (p<0.001). Conclusions: Discontinuation rates were higher for infliximab compared with adalimumab and etanercept initiators, and for adalimumab versus etanercept during the 1st year. Discontinuation rates increased with calendar period, as did the percentage discontinuations due to inefficacy. © 2013 BMJ Publishing Group Ltd & European League Against Rheumatism.

Mani N.,University of California at Berkeley | Murray J.,U.S. Food and Drug Administration | Gulick R.M.,Cornell University | Josephson F.,Swedish Medical Products Agency | And 5 more authors.
AIDS | Year: 2012

The resounding success of combination antiretroviral efficacy for both treatment-naïve and treatment-experienced patients - with 70-90% viral suppression rates in recent studies - has made registration trials for new agents challenging. With the inevitable specter of drug resistance, new agents must have a pathway to approval. The Forum for Collaborative HIV Research obtained input from concerned stakeholders including industry, clinical sciences, community advocacy, and regulatory sciences (Food and Drug Administration and European Medicines Agency) to discuss how safety and efficacy of new agents could be demonstrated. Recognizing the shortfalls of superiority or noninferiority trials in this environment, a new trial design for treatment-experienced patients, minimizing the risk for drug resistance but allowing full assessment of safety, was proposed. The antiviral efficacy of an active investigational drug would be assessed by comparison to placebo as an add-on to a failing regimen in a short, 10-14-day study followed by institution of an optimized background regimen (OBR) in both arms with investigational drug given to all patients. The follow-on stage would assess dose response, safety, durability of initial response, and development of resistance. Additionally, a second safety trial could be conducted comparing patients randomized to the investigational agent with a new OBR to those on a new OBR and placebo. Finally, approval decisions could consider other long-term safety endpoints. Exposing treatment-naïve patients to investigational agents remains a controversial issue; stakeholders have different interpretations of risk-benefit for trials in this population that necessitate careful consideration before initiating trials in them. © 2012 Wolters Kluwer Health | Lippincott Williams and Wilkins.

Magnusson U.,Swedish University of Agricultural Sciences | Ljungvall K.,Swedish Medical Products Agency
Reproductive Toxicology | Year: 2014

The scientific literature on altered onset of puberty predominantly involves studies on females. This paper reviews current knowledge on the role of environmental pollutants in dysregulation of male puberty in humans, laboratory rodents and farm animals. The methods used to determine the onset of puberty are well developed in humans and farm animals, and standardized across studies in humans. In laboratory rodents standardized external morphological endpoints are used. There is an increasing weight of evidence from epidemiological studies in humans, as well as from experiments in animals, indicating that environmental pollutants dysregulate puberty in males. Most data are from studies on "classical" persistent environmental pollutants. Assessing the effect of multichemical environmental pollution on dysregulation of puberty in humans is more challenging; further solid epidemiological data would likely contribute most to our understanding, especially if combined with systematically collected field-data from selected wildlife. © 2014 The Authors.

Hellgren K.,Karolinska University Hospital | Smedby K.E.,Karolinska University Hospital | Feltelius N.,Karolinska University Hospital | Feltelius N.,Swedish Medical Products Agency | And 2 more authors.
Arthritis and Rheumatism | Year: 2010

Objective. Patients with rheumatoid arthritis (RA), in particular those with the most severe disease, are at increased risk of developing malignant lymphoma. Whether this increase is entirely a consequence of the RA disease and/or its treatment or is reflective of shared susceptibility to the two diseases remains unclear. We undertook this study to assess whether patients with RA are already at increased risk of lymphoma or of other cancers before the diagnosis of RA, and if the relative risk increases with time since RA diagnosis. Methods. Patients with incident RA (symptom duration <1 year) (n = 6,745) registered in the Swedish Early Arthritis Registry from 1997 through 2006 were identified. For each patient, 5 general population controls were randomly matched by sex, age, marital status, and residence (n = 33,657). For all study subjects, inclusion in the nationwide Swedish Cancer Register in 1958-2006 was determined. Relative risks (RRs) (with 95% confidence intervals [95% CIs]) of lymphoma and of cancer overall, before and after diagnosis of RA, were estimated using conditional logistic regression and Cox regression, respectively. Results. Before diagnosis of RA, there was no observed increase in the risk of lymphoma (RR [odds ratio] 0.67 [95% CI 0.37-1.23]) or other cancers (RR 0.78 [95% CI 0.70-0.88]). During the first 10 years following diagnosis of RA, the overall RR (hazard ratio) of lymphoma development was 1.75 (95 % CI 1.04-2.96). Conclusion. These findings indicate that overall, a history of cancer, including lymphoma, does not increase the risk of subsequent RA development. Shared susceptibility to RA and lymphoma may thus be of limited importance. In contrast, increased lymphoma risks were observed within the first decade following RA diagnosis. © 2010, American College of Rheumatology.

Ottosson C.,Karolinska Institutet | Pettersson H.,Karolinska Institutet | Bergman B.,Swedish Medical Products Agency | Ponzer S.,Karolinska Institutet
Journal of Trauma - Injury, Infection and Critical Care | Year: 2010

Background: Personality disorders (PDs) have been suggested to be one of the determinants that might influence recovery after injuries but has rarely been measured. This study describes the occurrence of PDs among patients with minor traffic-related musculoskeletal injuries and relates these disorders to nonrecovery 12 months after the injury. Methods: This is a single-center, prospective, cohort study. We included patients with minor traffic-related musculoskeletal injuries at a general hospital in Stockholm, Sweden, with a catchment area of 0.6 million people. Structured Clinical Interview II screen questionnaire was used to measure PD. Outcome measure were self-reported recovery at 12 months (yes/no). Results: Fifty-one percent of all patients (102 of 200) had at least one PD, and 20% had at least two. The proportion of nonrecovered was 50% (51 of 102) among those with one or more PD compared with 39% (38 of 98) among those without any PD (p = 0.12). Patients with a Cluster A (paranoid, schizoid, and schitzotypal) or Cluster B (borderline, histrionic, narcissistic, and antisocial) PD were associated with nonrecovery. When compared with patients without any PD, patients with a Cluster A or Cluster B PD had an increased risk of nonrecovery (OR: 2.5; 95% CI: 1.0 -5.9 and OR: 2.1; 95% CI: 1.2-3.8, respectively). However, after adjusting for mental health factors at the time of the injury, these associations were no longer significant. DISCUSSION:: PDs are common among patients with minor traffic-related musculoskeletal injuries. Our study does not support the view that PDs are associated with nonrecovery. The patient's mental health status at the time of the crash seems to be more important for nonrecovery than a PD. © 2010 by Lippincott Williams & Wilkins.

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