ANCA Vasculitis News recently reported findings published in the journal Arthritis and Reumatology on the study “Efficacy and Safety of Belimumab and Azathioprine for Maintenance of Remission in ANCA‐Associated Vasculitis: A Randomized Controlled Study.”
A goal of the study was to test whether it was possible to delay relapse in AAV patients by adding belimumab to standard doses of glucocorticoids.
About ANCA-Associated Vasculitis (AAV)
AAV is a disorder of small vessel inflammation. It is caused by the production of abnormal autoantibodies (ANCAs – Anti-neutrophil cytoplasmic autoantibody vasculitis.) The ANCAs attack the patient’s own immune cells.
This process involves white blood cells called B lymphocytes. B lymphocytes produce antibodies that attack another type of white blood cell called the neutrophil.
Neutrophils, when attacked by ANCAs, make holes in the walls of small blood vessels, which causes scarring, weakening, narrowing and thickening of the blood vessel walls. The range of symptoms that ANCA affects is broad because neutrophils are capable of attacking anywhere in the body.
There are several types of ANCA vasculitis so patients may display various symptoms, depending on which organs are affected or the severity of blood vessel inflammation.
Common symptoms include skin rash, fatigue, fever, headache, abdominal pain, joint pain, muscle soreness, seizures, kidney failure, weight loss and loss of appetite and nerve damage.
Typically two treatments are required to treat AAV. In the first treatment, patients receive Rituxan or cyclophosphamide to induce disease remission. This is followed by maintenance treatment with low-dose glucocorticoids in combination with either azathioprine, methotrexate, mycophenolate mophetil, or Rituxan is given to prevent the disease from returning.
The investigators commented that even with these therapies, relapse is still a major clinical problem.
ANCA vasculitis may be short term or chronic and incurable. One in 50,000 people, mostly middle-aged, are affected by ANCA. In the majority of cases, patients can lead a reasonably normal life with proper treatment.,
About the Phase 3 BREVAS Clinical Trial (NCT01663623)
The study involved 105 patients with either granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) which are AAV subtypes. The patients, who were from 15 countries in Central and North America, Australia and Europe, were in remission at the onset of the study.
The participants randomly received belimumab or a placebo plus either azathioprine or methotrexate (immunosuppressants that lower or prevent the body’s immune response) in the event of sensitivity to the medication. In addition, they were given low-dose anti-inflammatory medication (glucocorticoids).
Determining the time to the first relapse was the primary goal of the trial. This is defined by a Birmingham Vasculitis Activity Score (BVAS) which is a measure of disease activity such as:
- A score of six or higher
- A predefined BVAS major item, or
- The receipt of medications not allowed by study protocol.
Time to a major relapse was a secondary measure. The only measure that was used in this case was: ‘a predefined BVAS major item only’.
According to the researchers’ analysis, the median time to the first vasculitis relapse during the study was 251 days for the belimumab arm (11.3% of participating patients) and 105 days for patients on placebo (15.4% of participating patients). However, these results were not statistically significant.
Adverse events were experienced by more patients on the belimumab arm (92.5%) than on the placebo arm (82.7%). However, serious adverse events across the two arms were similar.
There were a limited number of patients who experienced a major relapse. Therefore belimumab’s benefits could not be determined in relation to the placebo for purposes of this study.
The patients receiving belimumab had a higher rate of adverse events than the patients receiving a placebo (92.5% versus 82.7%.) However, there was no difference between either group in serious adverse events.
The final analysis of the Phase 3 clinical trial is that there is no benefit to adding belimumab to the standard maintenance treatment in ANCA-associated vasculitis patients in order to delay relapse.
Belimumab is an antibody and a product of GlaxoSmithKline. It is marketed as Benlysta for certain lupus patients. Belimumab binds the B lyphocyte stimulator (BLyS) which is a protein that activates B-cells so that they develop into antibody-producing cells.
It was B-cell stimulation that prompted researchers to design a test to determine whether adding belimumab together with azathioprine and low-dose glucocorticoids to the standard maintenance treatment would delay relapse in AAV patients.
An Unexpected Discovery
The investigators observed that the number of relapses in the placebo group using induction (the initial) treatments such as Rituxan and cyclophosphamide was similar across the different treatments and produced PR3-ANCAs. PR3 is the most common antigen target of ANCA and is known to be associated with vascular necrosis (cell death.)
Based on these results, the investigators believe that patients taking Rituxan at induction might then benefit from belimumab maintenance since Rituxan raises the levels of BLyS, the protein that activates B cells.
The findings appear to be similar to the data from preclinical models and case studies that suggest the dual B-cell-targeted immunotherapy (rituximab) plus BLyS blockade (belimumab) may possibly be more effective than either of the therapys prescribed as single agents.
The investigators concluded that “The addition of belimumab to azathioprine and low dose glucocorticoids for the maintenance of remission in AAV did not reduce the risk of … vasculitis relapse. However, patients with rituximab-induced remission who were subsequently treated with belimumab exhibited no vasculitis relapses. This observation warrants further investigation.”