Jonas K Eriksson

Drug survival on TNF inhibitors in patients with rheumatoid arthritis comparison of adalimumab, etanercept and infliximab

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.

Distribution of P2X3 receptors in the rat trigeminal ganglion after inferior alveolar nerve injury.

The ATP-gated cation channel receptor P2X3 is associated with nociceptive primary sensory neurons. We have, using immunohistochemistry, examined the expression of P2X3 in rat trigeminal ganglia 4-22 days after ligation/section or chronic constriction of the mandibular inferior alveolar nerve. In the normal trigeminal ganglion the anti-P2X3 receptor antibody labeled 37-58% of all neurons. Double labeling demonstrated that about 70-95% of the small neurons that bind the isolectin I-B4 displayed P2X3-immunoreactivity, and that about 40% of larger RT97-positive nerve cells were P2X3 receptor-immunoreactive. At 4 and 10 days after inferior alveolar nerve injury, the proportion of P2X3-immunoreactive neurons had increased to about 65% (range 52-78%). Examinations at the injury sites showed an intense P2X3 receptor-immunoreactivity in nerve endings. At longer survival stages the proportion of P2X3 receptor-positive sensory neurons had returned to control values. These results show that the P2X3 receptor is transiently upregulated and anterogradely transported in trigeminal primary sensory neurons after nerve injury. Since the receptor is accumulated in injured nerve endings, it may be associated with abnormal impulse propagation from these sites.

Incidence of Rheumatoid Arthritis in Sweden: A Nationwide Population-Based Assessment of Incidence, Its Determinants, and Treatment Penetration

To estimate the nationwide incidence of rheumatoid arthritis (RA) in Sweden, including its variation across age, sex, geography, and demography, and to describe the sensitivity of register‐based incidence estimates to different RA case definitions.

Risk of Venous Thromboembolism in Patients With Rheumatoid Arthritis and Association With Disease Duration and Hospitalization

CONTEXT Recent reports suggest that rheumatoid arthritis (RA) may be a risk factor for venous thromboembolism (VTE), particularly in conjunction with hospitalization. Using hospitalization data to identify RA and VTE may identify patients when they are at elevated risk for other reasons, obscuring the incompletely understood underlying association between RA and VTE and leading to inappropriate institution or timing of interventions. OBJECTIVE To estimate risks for VTE in patients with RA, including the relation of these risks to disease duration and hospitalization. DESIGN, SETTING, AND PATIENTS Prospective, population-based cohort study of 1 prevalent RA cohort (n = 37,856), 1 incident RA cohort (n = 7904), and matched general population comparison cohorts, all from Sweden, with follow-up from 1997 through 2010. MAIN OUTCOME MEASURE First-time VTE. RESULTS Patients with prevalent RA were at greater risk of VTE than the general population (rate, 5.9 [95% CI, 5.1-6.6] vs 2.8 [95% CI, 2.6-3.1] per 1000 person-years (adjusted hazard ratio [HR], 2.0 [95% CI, 1.9-2.2]; P < .001). By the time of RA symptom onset, there was no statistically significant association between a history of VTE and RA (odds ratio, 1.2 [95% CI, 1.0-1.4]; P = .08; 150 events in the RA cohort vs 587 in the comparison cohort). Counting from RA diagnosis, an increased rate in the RA cohort vs the comparison cohort (3.8 [95% CI, 2.5-5.2] vs 2.4 [95% CI, 1.9-2.9] per 1000 person-years; HR, 1.6 [95% CI, 1.1-2.5]; P = .02) was detected within the first year and did not increase further during the first decade. Although rates for VTE following hospitalization were higher, the 1-year rate of VTE per 1000 person-years was not higher in the RA cohort than in the comparison cohort after hospital discharge (11.8 [95% CI, 8.6-15.1] vs 13.1 [11.3-14.8]; HR, 1.0 [95% CI, 0.7-1.4]; P = .90). The rates of VTE increased with age but were largely similar across sex and rheumatoid factor status, as were the HRs for VTE across age, sex, and rheumatoid factor status. CONCLUSIONS Compared with the general population, Swedish patients with RA had an elevated risk for VTE that was stable over the first 10 years after diagnosis. Although hospitalization was a risk factor for VTE the first year after discharge, the excess risk was not greater in patients with RA than in the general population.

Weight loss and dropout during a commercial weight-loss program including a very-low-calorie diet, a low-calorie diet, or restricted normal food: observational cohort study

Background: The effectiveness of commercial weight-loss programs consisting of very-low-calorie diets (VLCDs) and low-calorie diets (LCDs) is unclear. Objective: The aim of the study was to quantify weight loss and dropout during a commercial weight-loss program in Sweden (Itrim; cost:

Behavioral changes and trigeminal ganglion sodium channel regulation in an orofacial neuropathic pain model

1300/€1000; all participants paid their own fee). Design: This observational cohort study linked commercial weight-loss data with National Health Care Registers. Weight loss was induced with a 500-kcal liquid-formula VLCD [n = 3773; BMI (in kg/m2): 34 ± 5 (mean ± SD); 80% women; 45 ± 12 y of age (mean ± SD)], a 1200–1500-kcal formula and food-combination LCD (n = 4588; BMI: 30 ± 4; 86% women; 50 ± 11 y of age), and a 1500–1800-kcal/d restricted normal-food diet (n = 676; BMI: 29 ± 5; 81% women; 51 ± 12 y of age). Maintenance strategies included exercise and a calorie-restricted diet. Weight loss was analyzed by using an intention-to-treat analysis (baseline substitution). Results: After 1 y, mean (±SD) weight changes were −11.4 ± 9.1 kg with the VLCD (18% dropout), −6.8 ± 6.4 kg with the LCD (23% dropout), and −5.1 ± 5.9 kg with the restricted normal-food diet (26% dropout). In an adjusted analysis, the VLCD group lost 2.8 kg (95% CI: 2.5, 3.2) and 3.8 kg (95% CI: 3.2, 4.5) more than did the LCD and restricted normal-food groups, respectively. A high baseline BMI and rapid initial weight loss were both independently associated with greater 1-y weight loss (P < 0.001). Younger age and low initial weight loss predicted an increased dropout rate (P < 0.001). Treatment of depression (OR: 1.4; 95% CI: 1.1, 1.9) and psychosis (OR: 2.6; 95% CI: 1.1, 6.3) were associated with an increased dropout rate in the VLCD group. Conclusion: A commercial weight-loss program, particularly one using a VLCD, was effective at reducing body weight in self-selected, self-paying adults.

Effectiveness of TNF inhibitor switch in RA: results from the national Swedish register

Abstract We used a photochemical method to generate a partial ischemic injury to the infraorbital branch of the trigeminal nerve in rats. Following injury, rats developed a bilateral persistent hypersensitivity to mechanical stimulation in the territory innervated by the infraorbital nerve. In addition, spread of mechanical hypersensitivity beyond the facial region was noted. Heat hypersensitivity was also present, although to a lesser extent and of a shorter duration. In some rats, excessive facial grooming/scratching were observed. Morphological examination revealed a graded damage to the irradiated portion of the infraorbital nerve that was related to the duration of laser irradiation. Investigations of gene expression changes in injured trigeminal ganglion neurons of animals with behavioral signs of neuropathic pain demonstrated that the sodium channel α‐subunit Nav1.3—absent in sham‐operated animals—was expressed to a limited extent. mRNAs for Nav1.8 and Nav1.9 were reduced both with respect to proportions of expressing neurons and to intensities, whereas the β3 subunit was markedly upregulated. mRNA levels of p11, a regulatory factor that facilitates the surface expression of Nav1.8, were unchanged. Previous findings have shown that injury to the trigeminal nerve branches may elicit responses that differ from those of segmental spinal nerves. Despite this we conclude that the key sodium channel regulations that are reported as consequences of nerve damage in the dorsal root ganglia seem to appear also in the trigeminal ganglion. Thus, novel analgesic drugs designed to target the sodium channel subtypes involved could be of use for the treatment of orofacial pain.

Mortality in chronic kidney disease and renal replacement therapy: a population-based cohort study

Background Switching to a second tumour necrosis factor inhibitor (TNFi) after discontinuation of a first in rheumatoid arthritis (RA) is a common strategy. The reason for the switch from the first TNFi could potentially influence the response to therapy. Data on direct comparisons between TNFi after switching are limited. Methods The national Swedish register was used. RA patients who switched to a second TNFi (infliximab, etanercept or adalimumab) after failure of a TNFi as first-ever biologic were identified. Effectiveness of treatment was compared across the three drugs according to the first TNFi used, the reason for discontinuing and the drug survival. Drug survival across TNFi used as second biologic was compared. Results Half of all patients starting infliximab, adalimumab or etanercept during the period 2005–2012 discontinued treatment for various reasons. Of these patients, a third switched within 2 months to a second TNFi (infliximab, etanercept or adalimumab). Around 35% of all patients achieved low disease activity or remission at 6 months. Regarding the switching strategy, best results were observed among patients who switched from infliximab to etanercept because of (secondary) inefficacy. Etanercept as second TNFi was associated with longer drug survival compared with infliximab. Conclusions Switching to a second TNFi after the failure of the first may lead to good clinical results. The inter-drug differences in drug survival on the second TNFi mirror those reported previously for the first TNFi, suggesting that these differences are not solely due to channelling bias.

Cost-effectiveness of infliximab versus conventional combination treatment in methotrexate-refractory early rheumatoid arthritis: 2-year results of the register-enriched randomised controlled SWEFOT trial

Objective To compare mortality in chronic kidney disease (CKD) stages 4 and 5 (estimated glomerular filtration rate <30 mL/min/1.73 m2), peritoneal dialysis, haemodialysis and transplanted patients. Design Population-based cohort study. Setting Swedish national healthcare system. Participants Swedish adult patients with CKD stages 4 and 5 (n=3040; mean age 66 years), peritoneal dialysis (n=725; 60 years), haemodialysis (n=1791; 62 years) and renal transplantation (n=606; 48 years) were identified in Stockholm County clinical quality registers for renal disease between 1999 and 2010. Five general population controls were matched to each patient by age, sex and index year. Exposure CKD status (stage 4 or 5/peritoneal dialysis/haemodialysis/transplanted). Primary outcome All-cause mortality was ascertained from the Swedish Causes of Death Register. Mortality HRs were estimated using Cox regression conditioned on age, sex, diabetes status, education level and index year. Results During 6553 person-years, 766 patients with CKD stages 4 and 5 died (deaths/100 person-years 12, 95% CI 11 to 13) compared with 186 deaths during 1113 person-years in peritoneal dialysis (17, 95% CI 15 to 19), 924 deaths during 3680 person-years in haemodialysis (25, 95% CI 23 to 27) and 53 deaths during 2935 person-years in transplanted patients (1.8, 95% CI 1.4 to 2.4). Against matched general population controls, the mortality HR was 3.6 (95% CI 3.2 to 4.0) for CKD, 5.6 (95% CI 3.5 to 8.9) for transplanted patients, 9.2 (95% CI 6.6 to 12.7) for peritoneal dialysis and 12.6 (95% CI 10.8 to 14.6) for haemodialysis. In direct comparison versus CKD, the mortality HR was 1.7 (95% CI 1.4 to 2.1) for peritoneal dialysis, 2.6 (95% CI 2.3 to 2.9) for haemodialysis and 0.5 (95% CI 0.3 to 0.7) for transplanted patients. Conclusions We did not find support for mortality in CKD to be similar to dialysis mortality. The patients with CKD stages 4 and 5 had considerably lower mortality risk than dialysis patients, and considerably higher risk than transplanted patients and matched general population controls.

Biological vs Conventional Combination Treatment and Work Loss in Early Rheumatoid Arthritis A Randomized Trial

Objective To estimate the incremental cost-effectiveness of infliximab versus conventional combination treatment over 21 months in patients with methotrexate-refractory early rheumatoid arthritis. Methods In this multicentre, two-arm, parallel, randomised, active-controlled, open-label trial, rheumatoid arthritis patients with <1 year symptom duration were recruited from 15 rheumatology clinics in Sweden between October 2002 and December 2005. After 3–4 months of methotrexate monotherapy, patients not achieving low disease activity were randomised to addition of infliximab or sulfasalazine+hydroxychloroquine (conventional treatment group). Costs of drugs, healthcare use, and productivity losses were retrieved from nationwide registers, while EuroQol 5-Dimensions utility was collected quarterly. Results Of 487 patients initially enrolled, 128 and 130 were randomised to infliximab and conventional treatment, respectively. The infliximab group accumulated higher drug and healthcare costs (€27 487 vs €10 364; adjusted mean difference €16 956 (95% CI 14 647 to 19 162)), while productivity losses did not differ (€33 804 vs €29 220; €3961 (95% CI −3986 to 11 850)), resulting in higher societal cost compared to the conventional group (€61 291 vs €39 584; €20 916 (95% CI 12 800 to 28 660)). Mean accumulated quality-adjusted life-years (QALYs) did not differ (1.10 vs 1.12; adjusted mean difference favouring infliximab treatment 0.01 (95% CI −0.07 to 0.08)). The incremental cost-effectiveness ratios for the infliximab versus conventional treatment strategy were €2 404 197/QALY from the societal perspective and €1 948 919/QALY from the healthcare perspective. Conclusions In early, methotrexate-refractory rheumatoid arthritis, a treatment strategy commencing with addition of infliximab, as compared to sulfasalazine+hydroxychloroquine, was not cost-effective over 21 months at willingness to pay levels generally considered acceptable. Trial registration number: NCT00764725.