Rituximab-Induced Low IgG Linked to Infections

NEW YORK – The low levels of immunoglobulin G seen in a group of patients receiving rituximab for rheumatoid arthritis were associated with a twofold increased risk of serious infections, judging from the results of a 5-year prospective French register of 2,000 patients, according to Dr. Yusuf Yazici.

“These results give us one piece of evidence to support what investigators have long suspected: Low IgG levels may increase risk of infections,” said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the New York University Hospital for Joint Diseases.*

Of the risk factors investigated by Dr. Jacques-Eric Gottenberg of the Strasbourg (France) University Hospital and his associates, only low serum IgG levels – not gamma globulin or immunoglobulin M (IgM) levels – were associated with serious infections in rheumatoid arthritis (RA) patients treated with rituximab, according to Dr. Yazici. This finding suggests that serum IgG levels in particular should be checked before each new cycle of rituximab and that the risk/benefit ratio of rituximab should be carefully assessed for those with low IgG levels. A therapy other than rituximab should be considered for patients with low immunoglobulin G (IgG) levels who already have a severe infection or severe comorbidities, according to Dr. Gottenberg’s findings.

The French AIR (Autoimmunity and Rituximab) Registry is a 5-year, prospective, multicenter study begun in 2006 that prospectively collects data on patients treated with rituximab on and off label for refractory arthritides. It is thought to be the largest prospective study, based on a national registry, focusing on severe infections in RA patients treated with rituximab in a clinical setting. Many patients have comorbidities, such as cancer, chronic lung disease, cardiac insufficiency, or diabetes. A nationwide initiative, most patients were registered from rheumatology departments while less than 10% originated from internal medicine departments. The 88 centers who participated in the register write more than 85% of all rituximab prescriptions in France for nonhematologic, nononcologic indications.

"You can’t suppress IgG levels forever without expecting some increase in infections."

Since this was a noninterventional study, no laboratory exams were required either at baseline or after rituximab treatment. Even though immunoglobulin levels are not routinely assessed during rituximab therapy, of the 2000 patients with RA included in the AIR Registry, gamma globulin, IgM, or IgG levels after rituximab treatment had been collected in almost 60% of enrolled patients. Of those who had undergone these analyses, 15.5% had low levels of serum gamma globulin less than 6 g/L), 26.6% had low levels of IgM less than 0.5 g/L) and 12.1% had low IgG levels (less than 6 g/L).

The authors looked at the rates of serious infections (defined as an infection occurring during the 12 months following each infusion of rituximab that required hospitalization and/or intravenous antibiotics and/or resulted in death) in patients with normal and low levels of gamma globulin, IgM, or IgG. Univariate analysis adjusted according to follow-up duration revealed that only low IgG levels after rituximab were associated with a significantly increased risk of serious infections, with almost a twofold increase in risk (odds ratio, 1.99; 95% confidence interval, 1.2-3.3; P = .008). No significant effects were found for low levels of gamma globulin (OR, 1.5; 95% CI, 0.9-2.5; P = .09) or IgM (OR, 1.5; 95% CI, 0.9-2.3; P = .08).

In a multivariate analysis, when the researchers adjusted for older age, previous cancer, or serious or recurrent infections, only low IgG after rituximab remained associated with serious infections. In published work, Dr. Gottenberg reported that chronic lung disease and/or cardiac insufficiency and extraarticular involvement also rendered RA patients treated with rituximab more prone to severe infections (Arthritis Rheum. 2010;62[9]:2625-32).

For all measures serious infections were more frequent in those with lower levels of immunologic indices. For instance, 13.5% of patients with low gamma globulin levels after rituximab had serious infections, compared with 8.8% of those with normal gamma globulin levels. Rates of serious infection, as indicated by the ratio of low to normal levels for IgM, were 11.8%:8.1% while the rates for IgG were 15.1%:8.2%.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Gottenberg reported a relevant financial relationship with Roche.

* Clarification: This story was updated on 12/12/2011.

NEW YORK – The low levels of immunoglobulin G seen in a group of patients receiving rituximab for rheumatoid arthritis were associated with a twofold increased risk of serious infections, judging from the results of a 5-year prospective French register of 2,000 patients, according to Dr. Yusuf Yazici.

“These results give us one piece of evidence to support what investigators have long suspected: Low IgG levels may increase risk of infections,” said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the New York University Hospital for Joint Diseases.*

Of the risk factors investigated by Dr. Jacques-Eric Gottenberg of the Strasbourg (France) University Hospital and his associates, only low serum IgG levels – not gamma globulin or immunoglobulin M (IgM) levels – were associated with serious infections in rheumatoid arthritis (RA) patients treated with rituximab, according to Dr. Yazici. This finding suggests that serum IgG levels in particular should be checked before each new cycle of rituximab and that the risk/benefit ratio of rituximab should be carefully assessed for those with low IgG levels. A therapy other than rituximab should be considered for patients with low immunoglobulin G (IgG) levels who already have a severe infection or severe comorbidities, according to Dr. Gottenberg’s findings.

The French AIR (Autoimmunity and Rituximab) Registry is a 5-year, prospective, multicenter study begun in 2006 that prospectively collects data on patients treated with rituximab on and off label for refractory arthritides. It is thought to be the largest prospective study, based on a national registry, focusing on severe infections in RA patients treated with rituximab in a clinical setting. Many patients have comorbidities, such as cancer, chronic lung disease, cardiac insufficiency, or diabetes. A nationwide initiative, most patients were registered from rheumatology departments while less than 10% originated from internal medicine departments. The 88 centers who participated in the register write more than 85% of all rituximab prescriptions in France for nonhematologic, nononcologic indications.

"You can’t suppress IgG levels forever without expecting some increase in infections."

Since this was a noninterventional study, no laboratory exams were required either at baseline or after rituximab treatment. Even though immunoglobulin levels are not routinely assessed during rituximab therapy, of the 2000 patients with RA included in the AIR Registry, gamma globulin, IgM, or IgG levels after rituximab treatment had been collected in almost 60% of enrolled patients. Of those who had undergone these analyses, 15.5% had low levels of serum gamma globulin less than 6 g/L), 26.6% had low levels of IgM less than 0.5 g/L) and 12.1% had low IgG levels (less than 6 g/L).

The authors looked at the rates of serious infections (defined as an infection occurring during the 12 months following each infusion of rituximab that required hospitalization and/or intravenous antibiotics and/or resulted in death) in patients with normal and low levels of gamma globulin, IgM, or IgG. Univariate analysis adjusted according to follow-up duration revealed that only low IgG levels after rituximab were associated with a significantly increased risk of serious infections, with almost a twofold increase in risk (odds ratio, 1.99; 95% confidence interval, 1.2-3.3; P = .008). No significant effects were found for low levels of gamma globulin (OR, 1.5; 95% CI, 0.9-2.5; P = .09) or IgM (OR, 1.5; 95% CI, 0.9-2.3; P = .08).

In a multivariate analysis, when the researchers adjusted for older age, previous cancer, or serious or recurrent infections, only low IgG after rituximab remained associated with serious infections. In published work, Dr. Gottenberg reported that chronic lung disease and/or cardiac insufficiency and extraarticular involvement also rendered RA patients treated with rituximab more prone to severe infections (Arthritis Rheum. 2010;62[9]:2625-32).

For all measures serious infections were more frequent in those with lower levels of immunologic indices. For instance, 13.5% of patients with low gamma globulin levels after rituximab had serious infections, compared with 8.8% of those with normal gamma globulin levels. Rates of serious infection, as indicated by the ratio of low to normal levels for IgM, were 11.8%:8.1% while the rates for IgG were 15.1%:8.2%.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Gottenberg reported a relevant financial relationship with Roche.

* Clarification: This story was updated on 12/12/2011.

NEW YORK – The low levels of immunoglobulin G seen in a group of patients receiving rituximab for rheumatoid arthritis were associated with a twofold increased risk of serious infections, judging from the results of a 5-year prospective French register of 2,000 patients, according to Dr. Yusuf Yazici.

“These results give us one piece of evidence to support what investigators have long suspected: Low IgG levels may increase risk of infections,” said Dr. Yazici, director of the Seligman Center for Advanced Therapeutics and Behçet’s Syndrome Evaluation, Treatment, and Research Center at the New York University Hospital for Joint Diseases.*

Of the risk factors investigated by Dr. Jacques-Eric Gottenberg of the Strasbourg (France) University Hospital and his associates, only low serum IgG levels – not gamma globulin or immunoglobulin M (IgM) levels – were associated with serious infections in rheumatoid arthritis (RA) patients treated with rituximab, according to Dr. Yazici. This finding suggests that serum IgG levels in particular should be checked before each new cycle of rituximab and that the risk/benefit ratio of rituximab should be carefully assessed for those with low IgG levels. A therapy other than rituximab should be considered for patients with low immunoglobulin G (IgG) levels who already have a severe infection or severe comorbidities, according to Dr. Gottenberg’s findings.

The French AIR (Autoimmunity and Rituximab) Registry is a 5-year, prospective, multicenter study begun in 2006 that prospectively collects data on patients treated with rituximab on and off label for refractory arthritides. It is thought to be the largest prospective study, based on a national registry, focusing on severe infections in RA patients treated with rituximab in a clinical setting. Many patients have comorbidities, such as cancer, chronic lung disease, cardiac insufficiency, or diabetes. A nationwide initiative, most patients were registered from rheumatology departments while less than 10% originated from internal medicine departments. The 88 centers who participated in the register write more than 85% of all rituximab prescriptions in France for nonhematologic, nononcologic indications.

"You can’t suppress IgG levels forever without expecting some increase in infections."

Since this was a noninterventional study, no laboratory exams were required either at baseline or after rituximab treatment. Even though immunoglobulin levels are not routinely assessed during rituximab therapy, of the 2000 patients with RA included in the AIR Registry, gamma globulin, IgM, or IgG levels after rituximab treatment had been collected in almost 60% of enrolled patients. Of those who had undergone these analyses, 15.5% had low levels of serum gamma globulin less than 6 g/L), 26.6% had low levels of IgM less than 0.5 g/L) and 12.1% had low IgG levels (less than 6 g/L).

The authors looked at the rates of serious infections (defined as an infection occurring during the 12 months following each infusion of rituximab that required hospitalization and/or intravenous antibiotics and/or resulted in death) in patients with normal and low levels of gamma globulin, IgM, or IgG. Univariate analysis adjusted according to follow-up duration revealed that only low IgG levels after rituximab were associated with a significantly increased risk of serious infections, with almost a twofold increase in risk (odds ratio, 1.99; 95% confidence interval, 1.2-3.3; P = .008). No significant effects were found for low levels of gamma globulin (OR, 1.5; 95% CI, 0.9-2.5; P = .09) or IgM (OR, 1.5; 95% CI, 0.9-2.3; P = .08).

In a multivariate analysis, when the researchers adjusted for older age, previous cancer, or serious or recurrent infections, only low IgG after rituximab remained associated with serious infections. In published work, Dr. Gottenberg reported that chronic lung disease and/or cardiac insufficiency and extraarticular involvement also rendered RA patients treated with rituximab more prone to severe infections (Arthritis Rheum. 2010;62[9]:2625-32).

For all measures serious infections were more frequent in those with lower levels of immunologic indices. For instance, 13.5% of patients with low gamma globulin levels after rituximab had serious infections, compared with 8.8% of those with normal gamma globulin levels. Rates of serious infection, as indicated by the ratio of low to normal levels for IgM, were 11.8%:8.1% while the rates for IgG were 15.1%:8.2%.

Dr. Yazici serves as a consultant to Bristol-Myers Squibb and Genentech. Dr. Gottenberg reported a relevant financial relationship with Roche.

* Clarification: This story was updated on 12/12/2011.