Europe has now approved the use of Benlysta to treat children with lupus

By Dr. Robert Katz

Europe has now approved the use of Benlysta to treat children with lupus. Benlysta has the generic name belimumab. The “mab” at the end indicates it is a monoclonal antibody. That means it is a special antibody that is manufactured to antagonize some substance, and in this case it is called B-lymphocyte stimulator or B-cell activating factor. So Benlysta works against this B-lymphocyte stimulator protein.

B-lymphocyte stimulator is a substance that is present in lymphocyte white blood cells called B-cells that participate in the production of autoimmune antibodies associated with lupus. Autoimmune means that the immune system is working against the body rather than just supporting it like most antibodies do against infection, etc. By binding to B-lymphocyte stimulator, Benlysta suppresses the survival of these specific B-cell lymphocytes and the differentiation of these B-cell lymphocytes into antibody-producing cells that make the autoimmune factors causing lupus.

Benlysta is the only biologic approved for lupus at this point, though others are under study, but the fact that it is now approved in Europe for young lupus patients is a new development.

The United States Food and Drug Administration (FDA) has given a special designation of “breakthrough therapy” to a monoclonal antibody by the name of Gazyva. The generic name for Gazyva is obinutuzumab. The “mab” at the end means it is a monoclonal antibody, and it is directed against a specific protein in the body.

Gazyva is for the treatment of patients with significant lupus kidney disease (lupus nephritis). The drug binds CD20, a protein found on the surface of certain B-lymphocyte cells. It may be useful to prevent excessive inflammation associated with lupus. So the breakthrough designation is given to medications to try to accelerate their development and approval. It is not yet approved for lupus nephritis, but is on a fast track.

A medication called aldesleukin was well tolerated and lessened disease activity in patients with refractory systemic lupus, in an early trial. The different trial phases included phase I, where safety and efficacy are determined in a very small group of patients. Then there is phase II, a larger trial, and phase III is a very large national and international trial, on which the FDA (Food and Drug Administration) approval is based. This is only a phase I/IIA trial, so it is quite early, but this treatment of a low dose interleukin-2 therapy was successful in this small group of patients. Whether it will be finally FDA approved is unclear. It is given by subcutaneous (under the skin) injection.

SELENA-SLEDAI is a tool of assessment of lupus activity. Another lupus activity index is called the BILAG. That stands for British Isles Lupus Activity Group. Both of these scales are used in clinical research trials to measure how active lupus is.

In a recently published study, nearly one in three adults with lupus use prescription opioids to treat pain despite the lack of evidence that opioids effectively reduce pain in lupus and that they can lead to dependency. It is also important to be sure these patients with lupus do not also have fibromyalgia with widespread muscle and joint pain, poor sleep, fatigue, and concentration difficulties.

In this study, 462 patients with lupus from the Michigan Lupus Epidemiology and Surveillance Cohort versus 192 people without lupus, the data show that nearly one-third of the lupus patients were using prescription opioids during the study period of 2014-2015, compared with 8 percent of people without lupus.

It is a much lower percentage now because of all the publicity about the danger of opioid therapy and physicians are reluctant to prescribe it. Nonetheless, this study did show much greater use of opioids in this lupus population.

In a recent study, adding anifrolumab to lupus treatment led to a significant reduction in lupus activity at the one-year mark. This is a phase III study, which means it is an advanced clinical trial. We will see if this drug receives FDA approval. The medication is a monoclonal antibody against type 1 interferon receptor. So, it antagonizes/neutralizes this protein. A monoclonal antibody is a specially produced antibody to bind a specific substance in the body. Anifrolumab is given by intravenous infusion every four weeks.

An imaging technology advance called functional magnetic resonance imaging or 3D arterial spin labeling measures blood flow in the brain and may help with the early detection of lupus affecting the brain. In a study entitled, “Cerebral blood flow abnormalities in neuropsychiatric systemic lupus erythematosus,” published in the Journal of Lupus, there is research support for this new technology, but it is not yet widely available.

Many women with lupus stop taking their medications when they become pregnant, but prednisone is an acceptable therapy based on clinical experience, if needed. Plaquenil (or the generic name hydroxychloroquine) has also been determined to be safe during pregnancy, though some lupus patients would prefer to withhold all medications when they are pregnant and their lupus is not active.

An article in the Journal of Neuroscience entitled, “Neuronal BC RNA transport impairments caused by systemic lupus erythematosus autoantibodies,” found that autoantibodies targeting different types of RNA (ribonucleoprotein) molecules are associated with neuropsychiatric lupus. Brain RNA controls the production of proteins that regulate the activity of brain communication between nerve cells. These anti-brain cytoplasmic RNA autoantibodies were present only in lupus patients in this study and may suggest that at least these antibodies could be at the root cause of some of the symptoms of neuropsychiatric lupus.

In the Journal of Rheumatology, an article on “Persistent disease activity remains a burden for patients with systemic lupus erythematosus,” the study found that higher disease activity at the entrance of patients in this study was associated with frequent persistence of active disease in patients with long-standing disease. Thus, if the disease is more active at the entry of a five-year study, it tended to remain a significant predictor of higher disease activity in later years.

In the study in the Journal Arthritis Care and Research in June 2019, patients receiving belimumab (Benlysta) given intravenously or(Rituxan) rituximab, also given intravenously, showed an improvement in the clinical findings of systemic lupus, but not always improvement in all parameters such as social functioning and mental health. The effects on the quality of life may be different than the effects on specific lupus activity.

In another study in Arthritis Care and Research, prolonged clinical remission of lupus activity was demonstrated in 18 percent of patients in that study. So, prolonged clinical remission is certainly a possible outcome in lupus patients.

In a study in Arthritis Care and Research, long-term control of lupus disease activity with belimumab (Benlysta) intravenously every month translated into meaningful improvements in patient-reported fatigue and quality of life. Belimumab is the only biologic currently approved for the treatment of systemic lupus. It is an anti-B-lymphocyte cell therapy. These B-lymphocytes differentiate into cells that produce antibodies, including autoimmune antibodies in lupus patients, so suppressing their activity in lupus can be clinically beneficial.

In a study in the Journal of Lupus, poor adherence to drug treatment is associated with a worse prognosis of lupus kidney disease. This is especially true after kidney transplantation. Identifying lupus patients at risk for nonadherence to medication therapy is a challenge, but is important, especially in those with lupus kidney disease who might then go on to kidney failure.

In a study in Arthritis and Rheumatology July 2019, researchers found that the safety and efficacy of Benlysta plus standard therapy for up to 13 years in patients with systemic lupus were quite successful. Benlysta was well tolerated with no new safety concerns, and efficacy was maintained in the patients who continued in this study. For patients who initially receive a good response to Benlysta, the treatment continues to be well tolerated and provides long-term disease control. Benlysta is an anti-B-lymphocyte therapy, and these B-lymphocytes differentiate into other white blood cells that produce autoimmune antibodies some of which are responsible for the symptoms of lupus.

In a small study in an early phase of a trial of omalizumab, a monoclonal antibody against immunoglobulin E, the drug improved lupus activity. This is a study of only 16 patients with lupus with active disease, but this medication is another potential new therapy for systemic lupus. It will require further testing and then later FDA approval to be used in lupus patients.

In a study in the journal Arthritis and Rheumatology, fracture risk was increased in lupus patients, compared to non-lupus patients. The fracture incidence rate was highest among lupus patients with kidney disease. They had an approximately two-fold higher fracture risk. Part of this may be due to corticosteroids used mainly prednisone. Thus, it is important to identify high risk patients with lupus for fracture prevention using bone density studies.

Robert S. Katz, M.D.

October, 2019