Management of refractory lupus nephritis: rationale to consider tacrolimus

We read with great interest the review article by Mejia-Vilet et al. about the management of lupus nephritis (LN). 1 Mejia-Vilet J.M. Malvar A. Arazi A. Rovin B.H. The lupus nephritis management renaissance. Kidney Int. 2022; 101: 242-255 Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar The authors mentioned that few uncontrolled studies had evaluated tacrolimus in combination with mycophenolate mofetil for LN. 1 Mejia-Vilet J.M. Malvar A. Arazi A. Rovin B.H. The lupus nephritis management renaissance. Kidney Int. 2022; 101: 242-255 Abstract Full Text Full Text PDF PubMed Scopus (35) Google Scholar In a recent prospective observational study from our group, similar proportions of patients with refractory LN treated with tacrolimus (n = 12) or treatment-naïve LN treated with cyclophosphamide (Euro-Lupus Nephritis Trial protocol; n = 16) attained at least partial kidney response at 3 months of therapy (risk ratio for refractory vs. treatment-naïve LN, 1.07; 95% confidence interval, 0.61–1.85). 2 Edavalath S, Rai MK, Gupta V, et al. Tacrolimus induces remission in refractory and relapsing lupus nephritis by decreasing P-glycoprotein expression and function on peripheral blood lymphocytes. Rheumatol Int. Published online January 7, 2022. https://doi.org/10.1007/s00296-021-05057-1 Google Scholar Moreover, tacrolimus significantly reduced P-glycoprotein expression and function on peripheral blood mononuclear cells in refractory LN 3 months after treatment. 2 Edavalath S, Rai MK, Gupta V, et al. Tacrolimus induces remission in refractory and relapsing lupus nephritis by decreasing P-glycoprotein expression and function on peripheral blood lymphocytes. Rheumatol Int. Published online January 7, 2022. https://doi.org/10.1007/s00296-021-05057-1 Google Scholar A subset of T helper cell 17 (Th17) lymphocytes expressing both interleukin-17A and interferon-γ (Th17.1 lymphocytes) has been recently identified in LN and other immune-mediated inflammatory diseases. 3 Zhong W. Jiang Y. Ma H. et al. Elevated levels of CCR6(+) T helper 22 cells correlate with skin and renal impairment in systemic lupus erythematosus. Sci Rep. 2017; 7: 12962 Crossref PubMed Scopus (28) Google Scholar ,4 Singh K. Rathore U. Rai M.K. et al. Novel Th17 lymphocyte populations, Th17.1 and PD1+Th17, are increased in Takayasu arteritis, and both Th17 and Th17.1 sub-populations associate with active disease. J Inflamm Res. 2022; 15: 1521-1541 Crossref PubMed Scopus (20) Google Scholar Th17.1 lymphocytes are refractory to corticosteroids due to P-glycoprotein expression. Tacrolimus might be useful in a subset of refractory LN by blocking P-glycoprotein on T lymphocytes, including possibly Th17.1 lymphocytes. 2 Edavalath S, Rai MK, Gupta V, et al. Tacrolimus induces remission in refractory and relapsing lupus nephritis by decreasing P-glycoprotein expression and function on peripheral blood lymphocytes. Rheumatol Int. Published online January 7, 2022. https://doi.org/10.1007/s00296-021-05057-1 Google Scholar Therefore, we suggest the exploration of tacrolimus or other calcineurin inhibitors, such as voclosporin, in refractory LN. Future studies might also prospectively evaluate tacrolimus or voclosporin on Th17.1 lymphocyte frequency and P-glycoprotein expression in LN. The lupus nephritis management renaissanceKidney InternationalVol. 101Issue 2PreviewOver the past year, and for the first time ever, the US Food and Drug Administration approved 2 drugs specifically for the treatment of lupus nephritis (LN). As the lupus community works toward understanding how to best use these new therapies, it is also an ideal time to begin to rethink the overall management strategy of LN. In addition to new drugs, this must include how to use kidney biopsies for management and not just diagnosis, how molecular technologies can be applied to interrogate biopsies and how such data can impact management, and how to incorporate LN biomarkers into management paradigms. Full-Text PDF