Objective Evidence that the type I interferon (IFN) pathway plays an important role in the pathogenesis of systemic lupus erythematosus (SLE) has been mounting over the last several decades. After IFN’s discovery in 1957, we grew to appreciate that it was a vital component of our host defense against viral infections. It wasn’t until 1979 that its role in inflammatory diseases was subsequently recognized. In that year, investigators at the National Institutes of Health noted that approximately 71% of patients with active SLE had elevated IFN concentrations in their blood. Additional links between IFN and SLE came in the form of isolated case reports; that is, patients treated with IFN for malignancy developed illnesses that resembled SLE. A major milestone occurred in 2003 with the publication by several groups of the IFN Gene Signature (IFNGS). As the measurement of IFN blood levels was quite challenging at the time, this technology advanced both basic and clinical research.

With a link materializing between IFN pathway activation and SLE, it was only natural that this pathway be the target of therapeutic interventions in SLE. Although rontalizumab and sifalimumab, the first two monoclonal antibodies directed against interferon alpha to be evaluated in clinical trials, yielded negative and modest clinical trial results, respectively, other pursuits were undertaken that proved more fruitful. The success of anifrolumab, a monoclonal antibody directed against the type I IFN receptor (IFN alpha receptor), was attributed to the fact that all five type I IFN subtypes signal through the same receptor. The prediction was that the administration of anifrolumab would therefore result in greater inhibition of the IFN pathway compared to its predecessor, sifalimumab, which inhibited only alpha IFN and left the four other type I IFN subtypes available to interact with the receptor. In fact, IFNGS inhibition was approximately 90% with anifrolumab compared to approximately 25% with sifalimumab. The next step was to determine whether greater inhibition of the IFN pathway would translate into greater clinical responses than what was observed with sifalimumab in phase 2.

The phase 2 SLE clinical trial of anifrolumab yielded robust results and served as the foundation for the phase 3 program. While there were some hiccups in the phase 3 program, robust clinical trial outcomes in the TULIP-2 phase 3 study provided solid evidence of the effectiveness of IFN inhibition.

The anifrolumab program reaffirmed the clinical significance of type I IFN in SLE and boosted confidence that other approaches to inhibit type I IFN would prove efficacious. This presentation will review various strategies being pursued in order to block the interferon pathway in SLE and lupus nephritis.