While the chronic inflammation of autoimmune conditions can be reduced by treatment with drugs known as corticosteroids – or more colloquially steroids – there are trade-offs to the treatment. Long term use of steroids can have undesired side effects. For young people especially, rheumatologists try to reduce the use of steroids whenever possible.
In a recent multi-center collaboration, HSS pediatric rheumatologists studied two non-steroid drugs – previously used in cancer therapy – to determine their effectiveness in treating systemic lupus erythematosus (SLE). The drugs are rituximab and cyclophosphamide.
The study, presented by HSS doctors at the 2012 Annual Meeting of the American College of Rheumatology, found that a carefully supervised, systematic regimen of the two drugs could significantly reduce steroid dosage while improving a patient’s lupus condition. What’s more, the improvement showed long duration.
In the study, 15 patients, ranging in age from 10 to 22, with active lupus, who had been dependent on steroids for control of the condition, received a systematic regimen of rituximab and cyclophosphamide administered at three intervals – at the start of the trial, then again at 6 months, and a third time at 18 months. All 15 patients experienced improvements in 6 standard indicators of lupus disease level in their blood tests. (Details charted below)
All patients saw improvement in their scores on the SLE Disease Activity Index, known as SLEDAI, which is a list of 24 items, including clinical markers, that is used to measure a patient’s level of active disease. The mean SLEDAI score of the patients in the study decreased from 8.929 to 1.917 after the first six months of therapy and remained low thereafter.
The steroid dosage for all the patients was able to be gradually reduced over the course of the study. (Speed of steroid reduction was at the discretion of the treating physician.) No patient experienced a disease flare requiring hospitalization.
A key test used to determine if a patient has lupus is detecting the presence of antinuclear antibodies (ANA) in the blood. Being ANA positive indicates the patient is likely to have lupus. Of the 15 patients in the study, 4 patients where shown to be ANA negative at month 36 following the initiation of treatment.
The improvement the patients experienced in their lupus condition was long lasting. The improvement was measured to still be maintaining at 42 months following the last dose of the rituximab and cyclophosphamide regimen, which was 60 months from the initiation of therapy.
The two drugs in the study work in different ways:
Rituximab targets a specific protein called CD20 that is expressed on the surface of all B cells of the immune system. Overactive B cells are prime components of the chronic inflammation of autoimmune conditions such as lupus. Rituximab destroys the B cells, which disrupts inflammation. The target protein of the drug – CD20 – is present throughout B-cell development, from earliest beginnings until maturity. Thus, targeting CD20 means being able to affect B cells over their lifespan.
Cyclophosphamide is a drug from a class known as alkylating agents that has been used in chemotherapy of cancers involving white blood cells such as lymphoma, leukemia, and even brain tumors, as well as to treat unresponsive kidney disease in children. Cyclosphosphamide is called a “pro-drug” because the patient’s liver actually changes the drug into its two active agents acrolein and phosphoramide. Those two active agents interfere with a cell’s DNA, preventing the cell from successfully reproducing itself.
Like all drugs, rituximab and cyclophosphamide are not without their own side effects. So besides assessing how well the two drugs could control lupus and reduce steroid dosage, the study was also observing the dosage, timing, and side effects of the two test drugs. In this carefully supervised study, for this particular population, the side effects were minimal, but when used in cancer therapy, the drugs have shown side effects.
It must be noted that these are powerful drugs, used in chemotherapy, and must not be administered without careful supervision from doctors familiar with the medications. The combination of cyclophosphamide and rituximab eliminates most of the patient’s B cells – and the T cells associated with them – that are driving the patient’s lupus. This lack of immune system protection leaves a patient open to infection and must be carefully monitored.
Dosage: All patients received rituximab 750 mg/m2 (max 1 gram) on day 1 and cyclophosphamide 750 mg/m2 on day 2. This regimen was repeated on days 15 and 16.
All patients received a further two doses of rituximab and cyclophosphamide at month 6 and two doses at month 18. Corticosteroid regimens for all patients were gradually reduced in all patients, but at individual rates chosen by the patient’s doctor.
Study presented by Thomas J.A. Lehman, MD, at 2012 Annual Meeting of the American College of Rheumatology in Washington, DC
Thomas J. A. Lehman, MD
Anusha Ramanathan, MD
Risa Alperin, MD
Emma J. MacDermott, MD
Alexa B. Adams, MD
Maimonides Medical Center:
Laura V. Barinstein, MD
Robert Wood Johnson-UMDNJ:
Lakshmi N. Moorthy, MD