The risk benefit ratio of glucocorticoids in SLE: have things changed over the past 40 years?

PURPOSE OF REVIEW: Glucocorticoids have been the mainstay of treatment in systemic lupus erythematosus for more than half a century. Despite advancements in knowledge concerning the pathophysiology of systemic lupus, the genomic/non-genomic actions of glucocorticoids, and the use of novel therapeutic agents in SLE, the burden of toxicity from glucocorticoid use remains unchanged. RECENT FINDINGS: SLE patients receiving long-term prednisone therapy are at significant risk of morbidity due to permanent organ damage and prednisone daily dosages above 6 mg have been shown to increase the risk of future organ damage by 50%. Glucocorticoid use carries a higher risk of opportunistic infections, iatrogenic osteoporosis and avascular necrosis, an increase in risk of cardiovascular events, cataracts and glaucoma, as well as psychiatric adverse effects like psychosis and manic episodes. There are limited data regarding the relative efficacy of the different glucocorticoid formulations or dosing regimens. SUMMARY: The use and dosing of glucocorticoids in SLE remains more art than science, although our knowledge regarding their complex genomic and non-genomic effects, as well as the resultant adverse effects, has greatly expanded over the past half a century.

Anti-C1q in systemic lupus erythematosus.

C1q is the first component of the classical complement pathway. Both clinically validated in-house ELISA assays as well as commercial ELISA kits are used for detection of anti-C1q antibodies. Anti-C1q autoantibodies can be detected in a wide range of autoimmune diseases and are highly sensitive for hypocomplementemic uticarial vasculitis. In SLE, anti-C1q are strongly associated with proliferative lupus nephritis, and their absence carries a negative predictive value for development of lupus nephritis of close to 100%. Anti-C1q in combination with anti-dsDNA and low complement has the strongest serological association with renal involvement. The anti-C1q titers correlate with global disease activity scores in patients with renal involvement, and higher titers seem to precede renal flares. After the successful treatment of a renal flare, anti-C1q has the tendency to decrease or even become undetectable. The main obstacle to the inclusion of anti-C1q in the classification criteria and clinical management of SLE is the lack of standardized laboratory assays.

Erythrocyte sedimentation rate is a predictor of renal and overall SLE disease activity.

OBJECTIVE: Our aim was to assess whether erythrocyte sedimentation rate (ESR) levels correlate with the level of disease activity at each visit and whether a change in ESR could be useful in predicting changes in disease activity. METHODS: Thousands of visits in a prospective systemic lupus erythematosus (SLE) cohort were analyzed to assess the association of ESR and level of disease activity. We explored whether ESR was cross-sectionally associated with disease activity, whether changes in ESR were associated with changes in disease activity, and whether changes in ESR predicted future changes in disease activity. Visits when patients had cancer, infection, pregnancy or were in renal failure were excluded. RESULTS: After adjusting for confounding factors, mild (25-50 mm/h), moderate (51-75 mm/h), and marked (>75 mm/h) elevations in ESR levels at a given visit correlated with the SELENA-SLEDAI, the Physician Global Assessment (PGA), fatigue, renal, joint, rash, serositis, hematological visual analogue scale (VAS), hematuria and proteinuria (p<0.0001) levels at that visit. A change in ESR between two visits was highly correlated with a concurrent change in PGA, renal, fatigue and joint VAS (p<0.0001). There was no statistically significant correlation between change in ESR between two visits and change in disease activity at a future visit. The subgroup analysis of patients who do not have anti-dsDNA and low complement levels as a feature of their disease showed ESR to be positively associated with SLEDAI, PGA, renal and joint VAS at that visit (p<0.0001), but there were few significant associations between changes in ESR and changes in disease activity. CONCLUSION: ESR is associated with disease activity in SLE measured by the SELENA-SLEDAI, the PGA, and with organ-specific activity including serositis, rash, joint, renal and hematological VAS. Grouping baseline ESR into four levels does associate with both global and organ-specific disease activity. A change in ESR between two visits was highly correlated with a change in PGA, renal, fatigue and joint VAS. In patients without anti-dsDNA and low complement levels, ESR was positively associated with SLEDAI, PGA, renal and joint VAS at the same visit. Until more specific biomarkers are validated, serial ESR does have some utility in following disease activity in SLE.

Regulation of selectivity and translocation of aquaporins: an update.

All living beings need to solve the problem of controlled transport of water. To this purpose, a special group of integral membrane proteins called aquaporins has evolved. There are 13 known members of this family that act as channels for water and small solutes, such as glycerol and urea. Although they allow large flux of water, they successfully prevent passage of protons. Here, we present the review of the data from the literature on the selectivity mechanism of aquaporins. The regulation of aquaporin activity occurs through regulation of expression of their genes, changing the localization of the already existing proteins in the cells and direct regulation of the activity in situ. We present the review of new data on the mechanisms of direct regulation. Special emphasis is on the advances in comprehension of aquaporin-2 translocation in collecting tubule cells of the kidney. Four elements of this process are described: 1) the role of protein kinase A and phosphorylation of serine 256 on aquaporin-2, 2) the transport of vesicles along the microtubules toward the apical membrane, 3), the removal of cytoskeletal subapical obstruction and the role of Rho GTPase and ezrin-radixin-moesin proteins in this, and 4) elevation of the cytosolic Ca2+ concentration, the fusion of the vesicle with the apical membrane and the role of SNARE proteins in exocytosis.