Publications

BACKGROUND

Although one study showed minimal progression of erosions in patients with rheumatoid arthritis (RA) one year after TNFα inhibition therapy, no studies have investigated very early bone changes after initiation of anti-TNFα treatment. We investigated the effects of 3-month anti-TNFα treatment on bone erosion progression and bone microarchitecture in RA patients using high-resolution peripheral quantitative computed tomography (HR-pQCT).

METHODS

Patients with RA (n = 27) (17 in the anti-TNFα and 10 in the MTX-only group) underwent assessment of disease activity score in 28 joints (DAS-28), radiographs, 3-T magnetic resonance imaging (MRI) and HR-pQCT of metacarpophalangeal and wrist joints at baseline and 3 months. HR-pQCT-derived erosion volume, joint volume/width and bone microarchitecture were computed and joint destruction was assessed using Sharp and RAMRIS scorings on radiographs and MRI, respectively.

RESULTS

Overall, 73 erosions were identified by HR-pQCT at baseline. Over 3 months, the anti-TNFα group had decreased mean erosion volume; increased erosion volume was observed in one clinical non-responder. The MTX-only group in contrast, trended toward increasing erosion volume despite low disease activity. In the anti-TNFα group, joint-space width and volume of MCP joints decreased significantly and was positively correlated with erosion volume changes (R  = 0.311, p = 0.013; R  = 0.527, p = 0.003, respectively). In addition, erosion volume changes were significantly negatively correlated with changes in trabecular bone mineral density (R  = 0.353, p = 0.020) in this group. We observed significant correlation between percentage change in erosion volume and change in DAS-28 erythrocyte sedimentation rate and C-reactive protein CRP scores (R  = 0.558, p < 0.001; R  = 0.745, p < 0.001, respectively) in all patients.

CONCLUSIONS

Using HR-pQCT, our data suggest that anti-TNFα treatment prevents erosion progression and deterioration of bone microarchitecture within the first 3 months of treatment, one patient not responding to treatment, had significant progression of bone erosions within this short time period. Patients with low disease activity scores (<3.2) can have continuous HR-pQCT-detectable progression of erosive disease with MTX treatment only. HR-pQCT can be a sensitive, powerful tool to quantify bone changes and monitor RA treatment short term (such as 3 months).

BACKGROUND

Early detection of adverse effects of novel therapies and understanding of their mechanisms could improve the safety and efficiency of drug development. We have retrospectively applied large-scale proteomics to blood samples from ILLUMINATE (Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events), a trial of torcetrapib (a cholesterol ester transfer protein inhibitor), that involved 15 067 participants at high cardiovascular risk. ILLUMINATE was terminated at a median of 550 days because of significant absolute increases of 1.2% in cardiovascular events and 0.4% in mortality with torcetrapib. The aims of our analysis were to determine whether a proteomic analysis might reveal biological mechanisms responsible for these harmful effects and whether harmful effects of torcetrapib could have been detected early in the ILLUMINATE trial with proteomics.

METHODS

A nested case-control analysis of paired plasma samples at baseline and at 3 months was performed in 249 participants assigned to torcetrapib plus atorvastatin and 223 participants assigned to atorvastatin only. Within each treatment arm, cases with events were matched to controls 1:1. Main outcomes were a survey of 1129 proteins for discovery of biological pathways altered by torcetrapib and a 9-protein risk score validated to predict myocardial infarction, stroke, heart failure, or death.

RESULTS

Plasma concentrations of 200 proteins changed significantly with torcetrapib. Their pathway analysis revealed unexpected and widespread changes in immune and inflammatory functions, as well as changes in endocrine systems, including in aldosterone function and glycemic control. At baseline, 9-protein risk scores were similar in the 2 treatment arms and higher in participants with subsequent events. At 3 months, the absolute 9-protein derived risk increased in the torcetrapib plus atorvastatin arm compared with the atorvastatin-only arm by 1.08% (=0.0004). Thirty-seven proteins changed in the direction of increased risk of 49 proteins previously associated with cardiovascular and mortality risk.

CONCLUSIONS

Heretofore unknown effects of torcetrapib were revealed in immune and inflammatory functions. A protein-based risk score predicted harm from torcetrapib within just 3 months. A protein-based risk assessment embedded within a large proteomic survey may prove to be useful in the evaluation of therapies to prevent harm to patients.

CLINICAL TRIAL REGISTRATION

URL: https://www.clinicaltrials.gov. Unique identifier: NCT00134264.

OBJECTIVE

A prior study established that concurrent poverty, persistent poverty, and exiting poverty were associated with the subsequent extent of damage accumulation in systemic lupus erythematosus (SLE). In this study, we examined whether concurrent poverty affects mortality after taking extent of damage accumulation into account.

METHODS

Analyses were conducted on 807 persons with SLE participating in the University of California-San Francisco Lupus Outcomes Study in 2009, stratified by whether they lived in households with incomes ≤125% of the federal poverty level in that year. We used Cox proportional hazards regression to estimate the risk of mortality as a function of poverty status, with and without adjustment for demographics; lupus status, including extent of disease damage; overall health status; health behaviors; and health care characteristics.

RESULTS

Among 807 individuals interviewed in 2009, 71 (8.8%) had died by 2015, 57 (8.3%) among the nonpoor and 14 (12.1%) among the poor (P = 0.18). With adjustment only for age, poverty in 2009 was associated with an increased risk of mortality (hazard ratio [HR] 2.14 [95% confidence interval (95% CI) 1.18-3.88]) through 2015. However, after adjustment for extent of damage and age, poverty was no longer associated with an increased risk of mortality (HR 1.68 [95% CI 0.91-3.10]). Among those who died, those who were poor lived 13.9 fewer years (95% CI 6.9-20.8; P < 0.0001).

CONCLUSION

The principal way that poverty results in higher mortality in SLE is by increasing the extent of damage accumulation.