Sytemic lupus erythematosus: pathogenesis and treatment advances

Resumen

The    pathogenesis    of    systemic    lupus erythematosus (SLE) is being unraveled and successfully translated   into  therapeutics   for patients. Nuclear autoimmunity remains a unifying concept. The route to and from nuclear autoimmunity can be divided into nucleic acid waste clearance, nucleic acid sensing and interferon signaling, and lymphocyte activation and autoantibody production. Recent evidence has revealed increased nucleic acid waste generation in patients with SLE via increased NETosis of low-density granulocytes (LDGs) and retained mitochondria within erythrocytes. The detection of this waste via the toll-like receptors (TLRs) 7 and 9 or activation of the cyclic GMP- AMP synthase respectively results in increased production of type I interferon. All forms of type I interferon share a heterodimer receptor of interferon receptor (IFNAR) 1 and IFNAR2 that utilizes Janus kinase 1 (JAK1) and non-receptor tyrosine protein kinase 2 (TYK2) for intracellular signaling. The effect of type I interferon varies by cell line but includes increased production of antibodies by plasmablasts and plasma cells. Recent therapeutic advances include the blockade of IFNAR1 with anifrolumab in patients with SLE and the inhibition of B-cell activation factor (BAFF) with belimumab in patients with lupus nephritis (LN). Additional therapeutic success in phase 2 trials include JAK inhibition with baricitinib and B cell depletion with obinutuzumab.