Wednesday, 25 Apr 2018

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mTOR Inhibition with Sirolimus Effective in Lupus

Lancet reports that 12 months of sirolimus treatment is associated with improvement in lupus disease activity presumeably by correction of pro-inflammatory T-cell activity.

Systemic lupus erythematosus (SLE) oatients are known to have T-cell dysfunction attributed to the activation of the mammalian target of rapamycin (mTOR). Rapamycin inhibits antigen-induced T-cell proliferation and has been developed as a medication under the generic designation of sirolimus. Researchers investigated the efficacy, safety, and tolerance of sirolimus in a prospective, open-label trial.

A single-arm, open-label study of 40 active SLE patients, unresponsive or intolerant of conventional therapy were given oral sirolimus 2 mg per day, with dose adjustments to achieve a therapeutic range of 6–15 ng/mL. The primary endpoint was decrease in disease activity, assessed using the British Isles Lupus Assessment Group (BILAG) index and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI).

The study was hampered by high dropout and discontinuations. Of the 40, 11 discontinued treatment for intolerance (n=2) or noncompliance (n=9).  In the remaining 29 patients only 16 (37.5% of the original cohort) completed 12 months of therapy.

Clinical (SLEDAI and BILAG) and immunological improvements were seen over 12 months:

  • SLEDAI score decreased from 10·2 to 4·8 (p<0·001)
  • Total BILAG index score decreased from 28·4 to 17·4 (p<0·001)
  • Mean prednisone dose decreased from 23·7 mg to 7·2 mg (p<0·001)
  • Increased CD4+CD25+FoxP3+ regulatory T cells
  • Increased CD8+ memory T-cell populations
  • Inhibited interleukin-4 and interleukin-17 production by CD4+ and CD4−CD8− double-negative T cells

Safety parameters (liver function and lymphocyte counts) were largely unchanged and modest reductions in HDL-cholesterol  neutrophil counts and hemoglobin and slight increases in platelet counts were observed.

mTOR blockade with sirolimus appears to be effective in a subset of active systemic lupus erythematosus.patients. Larger studies are needed to better determine the ideal candidates or measures to improve compliance and tolerability.

Disclosures: 
The author has no conflicts of interest to disclose related to this subject

Rheumatologists' Comments

Single arm, open label, high dropout. That pretty much tells us how much trust we can put in this study. Lancet apparently continues its tradition of publishing great sounding studies of low scientific quality.

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