Objective
Despite the pivotal role that hydroxychloroquine (HCQ) plays in treating systemic lupus erythematosus (SLE), less than 50% of patients take HCQ as prescribed. Measurement of HCQ blood levels can help clinicians distinguish nonadherence versus lack of efficacy of HCQ. Our objective was to systematically review publications and perform a meta‐analysis to examine the correlation between HCQ levels and 1) nonadherence and 2) Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores, in SLE.
Methods
A comprehensive search was performed. We included observational and interventional studies that measured HCQ levels and assessed adherence or SLEDAI scores in adults with SLE. Forest plots compared pooled estimates of correlations between HCQ levels and reported nonadherence or SLEDAI scores.
Results
Among 604 studies screened, 17 were reviewed. We found 3‐times higher odds of reported nonadherence in patients with low HCQ levels (odds ratio 2.95 [95% confidence interval (95% CI) 1.63, 5.35], P < 0.001). The mean SLEDAI score was 3.14 points higher in groups with below‐threshold HCQ levels on a priori analysis (δ = 3.14 [95% CI –0.05, 6.23], P = 0.053), and 1.4 points higher in groups with HCQ levels of <500 ng/ml (δ = 1.42 [95% CI 0.07, 2.76], P = 0.039). Among 1,223 patients, those with HCQ levels ≥750 ng/ml had a 58% lower risk of active disease, and their SLEDAI score was 3.2 points lower.
Conclusion
We found a strong association between low HCQ levels and reported nonadherence. Our results suggest that HCQ levels of ≥750 ng/ml might be a potential therapeutic target.
The negative feedback actions of corticosterone (CORT) depend on both phasic and tonic CORT secretion patterns to regulate hypothalamic pituitary adrenal (HPA) axis activity. How these two different CORT secretion pattens influence specific intracellular signal transduction pathway activity within the cellular elements of the HPA axis has not been determined. For example, it is unknown whether CORT has suppressive actions over signal transduction events within medial parvocellular paraventricular nucleus (PVN) corticotropin-releasing hormone (CRH) neurons and if these suppressive actions are responsible for alterations in PVN transcriptional processes and neurohormone secretion associated with stress. The extracellular-regulated kinase (ERK) is a stress activated intracellular signaling molecule that is potentially subject to glucocorticoid negative feedback regulation. We tested the ability of CORT to modulate levels of the active (phosphorylated) form of ERK (pERK1/2) in the PVN of rats. Acute psychological stress (restraint) produced a rapid increase in the number of PVN pERK1/2 immunopositive cells within CRH neurons. Absence of tonic CORT via adrenalectomy (ADX) produced no change in basal pERK1/2 cell counts, but augmented the increased pERK1/2 cell counts elicited by acute restraint. Treatment of ADX rats with CORT in the drinking water normalized this enhanced pERK1/2 response to stress. In contrast, treatment of ADX rats with a phasic increase in CORT 1 hour prior to restraint had no effect on pERK1/2 cell counts, despite substantially suppressing stress-induced PVN crh gene expression and ACTH secretion. This tonic CORT inhibition of stress-induced activation of ERK1/2 may involve both alteration of the activity of stress-dependent neural inputs to PVN CRH neurons and alteration within those neurons of stress-dependent intracellular signaling mechanisms associated with ERK activation.
Objectives To investigate the relationship between smoking history and pack-year exposure on the rate of end-organ damage in systemic lupus erythematosus (SLE). Methods The SLE incident cohort included patients who met American College of Rheumatology (ACR) 1997 or SLE International Collaborating Clinics (SLICC) 2012 SLE criteria and had rheumatology encounters at a US academic institution (2008–16). The primary outcome was median time to SLICC/ACR damage index (SLICC/ACR-DI) increase or death. Main explanatory variables were smoking status and pack-years. Covariates included age, sex, race, ethnicity, receipt of Medicaid, neighborhood area deprivation index, and baseline SLE damage. Damage increase-free survival was evaluated by smoking status and pack-years using Kaplan-Meier and Cox proportional hazards methods. Results Patients of Black race and Medicaid recipients were more commonly current smokers ( p’s < 0.05). Former smokers were older and more likely to have late-onset SLE (54% versus 33% of never and 29% of current smokers, p = 0.001). Median time to SLICC/ACR-DI increase or death was earlier in current or former compared to never smokers (4.5 and 3.4 versus 9.0 yrs; p = 0.002). In multivariable models, the rate of damage accumulation was twice as fast in current smokers (HR 2.18; 1.33, 3.57) and smokers with a >10 pack-year history (HR 2.35; 1.15, 3.64) versus never smokers. Conclusions In this incident SLE cohort, past or current smoking predicted new SLE damage 4-5 years earlier. After adjustment, current smokers and patients with a pack-year history of >10 years accumulated damage at twice the rate of never smokers.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.