VIENNA, Austria-Adding to the emerging body of evidence for the role of B-cell depletion in many autoimmune conditions, new research suggests that rituximab (RituxanR) improves symptoms of central nervous system neuropsychiatric systemic lupus erythematosus (CNS-NPSLE) within 2 to 4 weeks of the first infusion. The findings were presented here at the Annual European Congress of Rheumatology of the European League Against Rheumatism (EULAR).1

Looking forward, "I think [rituximab] will be a very good option as there hasn't been a new drug for lupus in 40 years, and this is the first agent I have seen that makes a difference in people with more severe disease," lead researcher Michael Neuwelt, MD, clinical professor of medicine at the University of California, San Francisco, tells CIAOMed. "One of the big advantages of rituximab is that it is a kinder, gentler drug with much fewer side effects than intravenous cyclophosphamide, and it avoids the line infections of plasmapheresis."

To date, Dr. Neuwelt has treated 37 CNS-NPSLE patients with rituximab or a combination of agents including rituximab. At EULAR, he presented data on 22 of these patients.

Of the initial 22 patients, 72% improved, 9% stabilized, and 19% progressed. All patients preferred rituximab over intravenous cyclophosphamide (IV-CYC) and plasmapheresis due to the favorable side-effect profile of the B-cell-depleting agent, including a lack of nausea, hair loss, amenorrhea, and the indwelling catheter complications with plasmapheresis.

The results from the other 15 patients are "very, very similar," Dr. Neuwelt says. "There is a good response rate of 72% and clearly, out of all 37, if you asked them which treatment they prefer against IV-CYC, they prefer rituximab because of the decrease in side effects." More than half of the study patients received rituximab monotherapy, while others received it in combination with steroids and one-third received it with chemotherapy and cyclophosphamide.

In the study, patients were assessed via MRI, cerebrospinal fluid, neuropsychological testing, and SLE disease indices including the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), the Systemic Lupus Activity Measure (SLAM), and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) scores, and the health assessment questionnaire-disability index (HAQ-DI).

 

Index patient shows dramatic improvement

In his presentation, Dr. Neuwelt focused primarily on one index patient who had been followed for 18 months and achieved the most pronounced responses to treatment. This patient switched to rituximab, but after flaring, IV-CYC was reintroduced. According to Dr. Neuwelt, this patient showed dramatic improvements in IQ, quality of life and number of visible lesions as seen on MRI.

 

Long-term safety issues remain

While there have been some concerns regarding the safety of B-cell depletion, "it's safe because it doesn't deplete the immature B cells in bone marrow or the plasma cells, which make gammaglobulin and immunoglobulin that fight off infections," he says. "[But] since lupus is a chromic disease, we need to study the safety of longer-term depletion."

In the future, studies will need to compare rituximab to cyclophosphamide in CNS-NPSLE and to compare rituximab alone to the combination of rituximab plus IV-CYC, he says.

"Some patients respond to combination, but not to either drug alone," Dr. Neuwelt explains. "Trials in general lupus are just beginning to start. Trials in CNS lupus, where it's hard to find many patients, will probably continue to be patient-related outcome case series, rather than controlled studies."

When (and if) the drug receives federal Food and Drug Administration approval for rheumatoid arthritis (RA), "it will open [ritximab] up to a lot of other lupus patients," he says.

 

Biomarkers needed

Like in RA, "earlier treatment in SLE is important," Dr. Neuwelt says. However, "lupus is a complex disease and we don't have markers like kidney biopsy results for the brain, so a lot is left to clinical judgment," he says. "If we could find specific markers in cerebrospinal fluid that we can prove we are removing by depleting B cells, it would be beneficial, but unfortunately there haven't been any definite markers that have stood out clearly."

The new work is an extension of research conducted by Betty Diamond, MD, immunologist and rheumatologist at the Albert Einstein College of Medicine in the Bronx, New York. Reporting her findings in the journal Immunity,2 Dr. Diamond demonstrated that in mice, autoantibodies can and do cross the blood-brain barrier; causing some of the cognitive problems associated with lupus. Her work showed that these antibodies react with, and destroy N-methyl-D-aspartate (NMDA) receptors on the surface of nerve cells in the cerebral cortex.

But in the same study, injection of the Alzheimer's drug memantine into brains of mice after forcing open the blood-brain barrier protected neurons from certain death by filling the receptors so that the autoantibodies could not enter the cells to destroy them. Currently, Dr. Diamond and colleagues are conducting a similar study in approximately 200 patients with lupus to see if the findings are consistent with the results of this animal model.

"This drug shows a promising outlook for SLE patients with mild cognitive impairment," Dr. Neuwelt says, noting that his own work is looking at severe, early-onset cognitive impairment in younger patients.

But "the two agents may be used together in the future, including the possibility of more aggressive therapy with Rituxan to slow down the progress and then using memantine to improve thinking ability," he says.

 

Rituximab may have role in primary Sjögren's syndrome

In related research also presented at EULAR, rituximab resulted in an "acute and complete" CD20 depletion in sera of 16 primary Sjogren's syndrome patients.3 Moreover, low-dose infusions were well-tolerated without concomitant steroids in these patients. In addition, patients in this open-label trial had statistically significant improvement in fatigue and dryness (P <0.05).

"I think it will also be helpful in antineutrophilic cytoplasmic antibody-associated vasculitis, idiopathic thrombocytopenic purpura, refractive autoimmune hemolytic anemia, and dermatomyositis," Dr. Neuwelt says.

References:

1. Neuwelt CM, Young RG, McGhee RA, Freeman J. Role of rituximab in the treatment of severe central nervous system neuropsychiatric systemic lupus erythematosus as monotherapy or in combination therapy. Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract OP0004.
2. Kowal C, DeGiorgio LA, Nakaoka T, et al. Cognition and immunity; antibody impairs memory. Immunity. 2004;21:179-188.
3. Devauchelle-Pensec V, Morvan J, Pennec Y, et al. Rituximab (anti-CD20) in the treatment of primary Sjögren's syndrome: results of an open label study (PHRC Brest 2003). Presented at: Annual European Congress of Rheumatology of EULAR; June 8-11, 2005; Vienna, Austria. Abstract FRI0175.