Hypogammaglobulinemia And Infection Risk Clarified In MS Patients On Anti-CD20 Agents

By Bruce Jancin

Monitoring immunoglobulin levels regularly has become an imperative in patients with multiple sclerosis (MS) on anti-CD20 agents in light of consistent findings from long-term, open-label studies of rituximab and ocrelizumab presented at the annual congress of the European Committee for Treatment and Research in Multiple Sclerosis. The results offer years of additional carefully monitored experience beyond the narrow window provided by double-blind phase 3 randomized trials.


Rituximab has previously been associated with significantly increased risks of hypogammaglobulinemia and infections in patients treated for rheumatoid arthritis and other autoimmune diseases. But what about in MS, where rituximab is widely prescribed off label? Susanna Hallberg, MD, presented the results of a Swedish NEURO Registry study of 1,933 MS patients at three academic medical centers followed for a mean of 2.6 years on the biologic. Rituximab, she explained, is a very popular off-label treatment for MS in Sweden because of its high efficacy and tolerability. Indeed, she added, 45% of Swedish MS patients are currently on rituximab.

“We found that the risk of hypogammaglobulinemia is an important side effect of long-term rituximab therapy in MS, which is also consistent with treatment of other autoimmune diseases. So you really do need to think about this when you start treatment,” according to Dr. Hallberg, a PhD candidate at the Karolinska Institute in Stockholm.

The key findings from the Swedish registry study were the following: With an average 3,500-mg cumulative dose of rituximab, typically dosed at 500-1,000 mg IV every 6-12 months, 9.0% of MS patients developed hypogammaglobulinemia, as defined by a serum IgG level less than 6.7 g/L. The IgG level dropped in a dose-dependent fashion, with a mean decrease of 0.2 g/L per 1,000 mg. The rate of decrease was significantly greater in women, at 0.24 g/L per 1,000 mg, than in men, most likely because of differences in body weight, although this is conjecture because the registry does not contain information on body weight.

Credit: Dr P. Marazzi/Science Source

Risk of hypogammaglobulinemia in long-term treatment with rituximab in multiple sclerosis
credit: 2019 © European Committee for Treatment and Research in Multiple Sclerosis
The main predictors of a treatment-induced drop in IgG, in addition to cumulative dose of rituximab, were treatment duration and a patient’s pretreatment IgG level. Also, prior immunomodulatory therapy was associated with a lower baseline IgG level at the start of rituximab. The average IgG reductions in pretreated patients, compared with those on no immunomodulatory therapy prior to rituximab, ranged from 0.5 g/L for dimethyl fumarate to 1.3 g/L for teriflunomide, with natalizumab and fingolimod falling in between. In contrast, patients who had been on interferons or glatiramer acetate prior to rituximab did not have a lower baseline IgG level than treatment-naive individuals.

“We do not know yet if this rituximab-induced hypogammaglobulinemia is reversible or not,” Dr. Hallberg cautioned. “And even after stopping the rituximab you need to follow the IgG levels because sometimes they will continue to drop.”

She and her coinvestigators suggest that when IgG drops below 7 g/L, it is time to shift to longer intervals between doses of rituximab or to dose reduction.

“We’re shifting to lower doses because of the problems we’ve seen. Instead of giving 1,000 mg yearly, after 3 years give 500 mg yearly. This is being addressed in an ongoing clinical trial,” she said. Alternatively, it is reasonable to discontinue rituximab altogether and monitor patients clinically and by MRI, switching to non–CD20-inhibitor forms of disease-modifying therapy if the disease is active. Dr. Hallberg and her colleagues administer intravenous immunoglobulin in patients whose IgG falls below 4 g/L, or if the level is simply below the lower threshold of normal in the presence of increased susceptibility to infection.

The Swedish group is preparing to perform an analysis of the rate of serious infections in rituximab-treated MS patients with hypogammaglobulinemia.

Serum immunoglobulin levels and risk of serious infections in the pivotal Phase III trials of ocrelizumab in multiple sclerosis and their open-label extensions
credit: 2019 © European Committee for Treatment and Research in Multiple Sclerosis

Dr. Tobias Derfuss
Image credit: Bruce Jancin/MDedge News


Tobias Derfuss, MD, provided data on infection rates in the pivotal phase 3 OPERA and ORATIO double-blind clinical trials combined with their long-term, open-label extensions totaling 288 weeks, or nearly 6 years, of follow-up. Serum IgG levels fell at a rate of about 3% per year, a trajectory that meant roughly 93% of patients remained within normal range throughout the study period. In contrast, IgM levels dropped sharply during the first year of treatment with ocrelizumab, followed by a slower decline. At 288 weeks, 31% of patients were below the lower limit of normal for serum IgM.

A low IgG was strongly associated with an increased risk of serious infections: The rate was 5.48 per 100 person-years in ocrelizumab-treated patients whose IgG was below the lower limit of normal, compared with 2.14/100 person-years in those within normal range. In terms of absolute numbers of serious infections, however, there were only 14 such infections in patients with IgG below the lower limit of normal, versus 208 in patients with a normal-range level.

“So you can say that low IgG is a risk factor, but most of the infections occurred in patients that are still in normal levels,” observed Dr. Derfuss, professor of neurology at the University of Basel in Switzerland.

The most common serious infections associated with low IgG were urinary tract infections, cellulitis, and pneumonia. Sixty-nine percent were grade 3. No opportunistic or fatal infections occurred during the nearly 6-year study. Ninety-three percent of the serious infections resolved without sequelae in response to standard appropriate antibiotics. Seventy-nine percent of infections lasted less than 28 days. No change in ocrelizumab therapy occurred in 88% of patients with serious infections.

Overall, the rate of serious infections during 6 years of ocrelizumab therapy was low and consistent with the experience of the general MS population in real-world registries maintained in Canada and the U.S. Veterans Affairs database, Dr. Derfuss said.

However, audience member Annette Langer-Gould, MD, PhD, took issue with the findings.

“In your pooled clinical trials data, most patients had relapsing-remitting MS, and patients who were wheelchair bound were excluded. Those are the patients at highest risk of MS-related infection. Just to be clear: The data that you are showing for your comparators in the Canadian and VA databases include a lot of patients in wheelchairs or with higher-level disability. I think it is disingenuous to say that your rates are in line with those in natural history settings,” said Dr. Langer-Gould, regional lead for Clinical and Translational Neuroscience for the Southern California Permanente Medical Group in Los Angeles.

Dr. Derfuss conceded the point, noting, “This is a clinical trial population. It is not the patients you see every day in clinical practice. It might be that we underestimate the infection risk when we look at this population. Over time the IgG levels keep decreasing, so I think over time we have to think about adapting the dose in patients where it drops lower, either by decreasing the dose or extending the intervals. But we need to do studies of this because we need to see if we keep the efficacy of the drug.”

He observed that the ocrelizumab long-term extension study differs importantly from the Swedish rituximab registry study in that many Swedish patients were pretreated with other disease-modifying therapies, which pushed their IgG level lower before they embarked on anti-CD20 therapy. In contrast, participants in OPERA and ORATIO were often previously untreated or had received interferons, which actually drive up IgG levels, he added.

Top image credit: KATERYNA KON/Science Source

The ocrelizumab long-term extension study was funded by F. Hoffmann-La Roche. Dr. Derfuss reported having financial relationships with Actelion, Biogen, Celgene, Genzyme, GeNeuro, Merck, Mitsubishi Pharma, and MedDay.

The Swiss registry study was free of commercial support. Dr. Hallberg reported serving on advisory boards for Merck and Biogen.

SOURCE: Hallberg S et al. ECTRIMS 2019, Abstract 64; Derfuss T et al. ECTRIMS 2019, Abstract 65.