IgA2 anti-DNA antibodies as a biomarker of organ involvement and response to belimumab after rituximab in systemic lupus erythematosus

Systemic lupus erythematosus (SLE) is an autoimmune disease associated with profound immune abnormalities and inflammation in different organs, such as the kidneys and skin.

Patients can have very different patterns of organ involvement which likely explains the disappointingly wide variation in response to the advanced (targeted) therapies.

Treatment of SLE frequently relies on steroids, with all their associated side effects, and substantial morbidity and mortality remain.

Access to newer therapies in the UK is restricted to only those patients with the worst disease uncontrolled by conventional therapy.

We have recently reported encouraging results from the academic led BEAT-Lupus clinical trial, funded by VersusArthritis in a collaboration with GSK, which tested the effectiveness of two advanced therapies in combination: belimumab and rituximab, in patients whose disease did not respond adequately to conventional therapy.

Rituximab and belimumab are both targeted therapies used to treat lupus; the former depletes B cells and the latter binds to a molecule (BAFF) that activates B cells and causes autoimmunity.

The BEAT-Lupus trial demonstrated that patients treated with belimumab after rituximab had lower serum IgG anti-dsDNA antibodies, a routinely used laboratory blood test of disease activity, and significantly fewer severe disease flares over the 52 weeks of the trial compared to patients that received rituximab alone.

But like many lupus trials there was a wide variation in responsiveness between patients.

We have collected serum, cells and RNA (molecules that convert genetic information into proteins) from the blood of participants in the BEAT-lupus trial to identify biomarkers of response to B cell targeted therapy.

Preliminary analysis of this unique sample collection identified a type of anti-dsDNA antibody, not usually tested in patients, (IgA2) that predicted how well patients responded to belimumab after rituximab compared to rituximab alone.

IgA2 anti-dsDNA antibodies were also associated with renal disease, whereas IgA1 anti-dsDNA antibodies were associated with skin disease, but did not predict outcome in the BEAT-lupus trial.

IgA2 anti-dsDNA antibody serum levels at baseline outperformed IgG anti-dsDNA antibody levels in predicting response to therapy.

We now propose a comprehensive analysis of IgA autoantibody subclasses tested against a number of lupus autoantigens, using samples not only from the BEAT-lupus trial, but also from lupus patients recruited for other trials (including a paediatric trial) as part of a collaboration with GSK, to determine: (a) their ability to identify patients who will respond to belimumab, with or without rituximab, (b) their utility as a marker of specific organ disease activity, (c) the mechanisms underlying their role in lupus.

We will use cellular and genetic approaches to address whether targeting B cells using rituximab with or without belimumab affects the range of IgA autoantibody subclasses produced.

These analyses will not only confirm whether IgA subclasses can be used as an indicator (biomarker) of response to belimumab after rituximab, and possibly belimumab alone, but also as an indicator of organ disease activity, and to improve our understanding of lupus. These results may lead to improved access to B cell targeted therapies for patients with SLE.