Baseline Antibodies May Help Predict Response to Rituximab in Lupus

BARCELONA — B-cell depletion with rituximab showed substantial clinical benefits in a small series of patients with active, refractory lupus, according to Dr. David A. Isenberg, professor of rheumatology, University College London.

Approximately one-third of a series of 45 patients who have undergone treatment with rituximab have remained well without needing further immunosuppressive therapy for a mean of 3 years, Dr. Isenberg reported at the annual European Congress of Rheumatology.

The regimen being used in the Bloomsbury Rheumatology Unit, University College London, involves two rituximab infusions of 500 mg, 2 weeks apart, usually in combination with cyclophosphamide and corticosteroids. Follow-up data are available for 35 patients, all of whom have failed lengthy courses of immunosuppression with cyclophosphamide, mycophenolate mofetil, azathioprine, and corticosteroids.

A total of 14 patients remained well after a single course of rituximab treatment, whereas 12 flared between 6 and 12 months after B-cell depletion, 5 flared earlier than 6 months after depletion, and 4 flared later than 12 months.

The mean time to flare was 10 months after B-cell depletion. The mean duration of depletion was 4 months. Two patients remain depleted, one for 73 months. One patient's B cells did not deplete at all, said Dr. Isenberg.

On the scoring system of the British Isles Lupus Assessment Group (BILAG), mean global scores fell from 13 to 5 at 6 months, representing “substantial benefits” in these patients, he said.

“While not all of the new biologic therapies are active against the whole panoply of lupus systems, it appeared that B-cell depletion was useful for just about every type of lupus feature—skin, renal, musculoskeletal, vascular,” he said.

Serologic effects also were pronounced, with anti-double-stranded (ds) DNA antibodies being significantly reduced after 6 months, from median titers of 203 to 74 IU/mL. Analysis of 12 patients for whom 1 year of follow-up data are available suggested the baseline antibody profile might predict which patients will respond to B-cell depletion.

Patients whose anti-dsDNA antibodies were accompanied by extractable antibodies to DNA (anti-ENA) were more likely to flare at any time after depletion, with an odds ratio of 6.

Also striking was that patients with anti-Sm or anti-La antibodies were more likely to flare, with odds ratios of 9 and 10, respectively. Anti-Sm antibodies vary with ethnicity; they are present in about 10% of Caucasians and 30% of blacks.

A low serum C3 complement level also was associated with a shorter time to flare, with a median time to flare of 12 months in those with low baseline levels. In contrast, the median time to flare among patients with normal C3 levels has not yet been reached.

Thus far, retreatment seems as effective as initial treatment. Among patients who flared, 14 were retreated, 10 for two cycles and 4 for three cycles. “Experience with rheumatoid arthritis suggests that B-cell depletion is safe for three cycles, but after the fourth infusion you do begin to see falls in total immunoglobulin levels,” he said.

Treatment was well-tolerated by most. Serious adverse events included one case of pneumococcal sepsis, one severe serum sickness-like reaction, and one case of seizures related to hyponatremia, probably tied to cyclophosphamide, Dr. Isenberg said. In addition, one patient developed fatal pancarditis related to active lupus after B-cell repopulation.

“We regard the safety profile as reasonable, given the fact that these are very active patients, often who have had years of very aggressive immunosuppression,” he said. “We found that most patients flare from 6 to 12 months after depletion if they are going to flare, and that baseline autoantibody profiles may be useful in predicting which patients may respond to this treatment.”

Dr. Isenberg disclosed no conflicts of interest in this study.

BARCELONA — B-cell depletion with rituximab showed substantial clinical benefits in a small series of patients with active, refractory lupus, according to Dr. David A. Isenberg, professor of rheumatology, University College London.

Approximately one-third of a series of 45 patients who have undergone treatment with rituximab have remained well without needing further immunosuppressive therapy for a mean of 3 years, Dr. Isenberg reported at the annual European Congress of Rheumatology.

The regimen being used in the Bloomsbury Rheumatology Unit, University College London, involves two rituximab infusions of 500 mg, 2 weeks apart, usually in combination with cyclophosphamide and corticosteroids. Follow-up data are available for 35 patients, all of whom have failed lengthy courses of immunosuppression with cyclophosphamide, mycophenolate mofetil, azathioprine, and corticosteroids.

A total of 14 patients remained well after a single course of rituximab treatment, whereas 12 flared between 6 and 12 months after B-cell depletion, 5 flared earlier than 6 months after depletion, and 4 flared later than 12 months.

The mean time to flare was 10 months after B-cell depletion. The mean duration of depletion was 4 months. Two patients remain depleted, one for 73 months. One patient's B cells did not deplete at all, said Dr. Isenberg.

On the scoring system of the British Isles Lupus Assessment Group (BILAG), mean global scores fell from 13 to 5 at 6 months, representing “substantial benefits” in these patients, he said.

“While not all of the new biologic therapies are active against the whole panoply of lupus systems, it appeared that B-cell depletion was useful for just about every type of lupus feature—skin, renal, musculoskeletal, vascular,” he said.

Serologic effects also were pronounced, with anti-double-stranded (ds) DNA antibodies being significantly reduced after 6 months, from median titers of 203 to 74 IU/mL. Analysis of 12 patients for whom 1 year of follow-up data are available suggested the baseline antibody profile might predict which patients will respond to B-cell depletion.

Patients whose anti-dsDNA antibodies were accompanied by extractable antibodies to DNA (anti-ENA) were more likely to flare at any time after depletion, with an odds ratio of 6.

Also striking was that patients with anti-Sm or anti-La antibodies were more likely to flare, with odds ratios of 9 and 10, respectively. Anti-Sm antibodies vary with ethnicity; they are present in about 10% of Caucasians and 30% of blacks.

A low serum C3 complement level also was associated with a shorter time to flare, with a median time to flare of 12 months in those with low baseline levels. In contrast, the median time to flare among patients with normal C3 levels has not yet been reached.

Thus far, retreatment seems as effective as initial treatment. Among patients who flared, 14 were retreated, 10 for two cycles and 4 for three cycles. “Experience with rheumatoid arthritis suggests that B-cell depletion is safe for three cycles, but after the fourth infusion you do begin to see falls in total immunoglobulin levels,” he said.

Treatment was well-tolerated by most. Serious adverse events included one case of pneumococcal sepsis, one severe serum sickness-like reaction, and one case of seizures related to hyponatremia, probably tied to cyclophosphamide, Dr. Isenberg said. In addition, one patient developed fatal pancarditis related to active lupus after B-cell repopulation.

“We regard the safety profile as reasonable, given the fact that these are very active patients, often who have had years of very aggressive immunosuppression,” he said. “We found that most patients flare from 6 to 12 months after depletion if they are going to flare, and that baseline autoantibody profiles may be useful in predicting which patients may respond to this treatment.”

Dr. Isenberg disclosed no conflicts of interest in this study.

BARCELONA — B-cell depletion with rituximab showed substantial clinical benefits in a small series of patients with active, refractory lupus, according to Dr. David A. Isenberg, professor of rheumatology, University College London.

Approximately one-third of a series of 45 patients who have undergone treatment with rituximab have remained well without needing further immunosuppressive therapy for a mean of 3 years, Dr. Isenberg reported at the annual European Congress of Rheumatology.

The regimen being used in the Bloomsbury Rheumatology Unit, University College London, involves two rituximab infusions of 500 mg, 2 weeks apart, usually in combination with cyclophosphamide and corticosteroids. Follow-up data are available for 35 patients, all of whom have failed lengthy courses of immunosuppression with cyclophosphamide, mycophenolate mofetil, azathioprine, and corticosteroids.

A total of 14 patients remained well after a single course of rituximab treatment, whereas 12 flared between 6 and 12 months after B-cell depletion, 5 flared earlier than 6 months after depletion, and 4 flared later than 12 months.

The mean time to flare was 10 months after B-cell depletion. The mean duration of depletion was 4 months. Two patients remain depleted, one for 73 months. One patient's B cells did not deplete at all, said Dr. Isenberg.

On the scoring system of the British Isles Lupus Assessment Group (BILAG), mean global scores fell from 13 to 5 at 6 months, representing “substantial benefits” in these patients, he said.

“While not all of the new biologic therapies are active against the whole panoply of lupus systems, it appeared that B-cell depletion was useful for just about every type of lupus feature—skin, renal, musculoskeletal, vascular,” he said.

Serologic effects also were pronounced, with anti-double-stranded (ds) DNA antibodies being significantly reduced after 6 months, from median titers of 203 to 74 IU/mL. Analysis of 12 patients for whom 1 year of follow-up data are available suggested the baseline antibody profile might predict which patients will respond to B-cell depletion.

Patients whose anti-dsDNA antibodies were accompanied by extractable antibodies to DNA (anti-ENA) were more likely to flare at any time after depletion, with an odds ratio of 6.

Also striking was that patients with anti-Sm or anti-La antibodies were more likely to flare, with odds ratios of 9 and 10, respectively. Anti-Sm antibodies vary with ethnicity; they are present in about 10% of Caucasians and 30% of blacks.

A low serum C3 complement level also was associated with a shorter time to flare, with a median time to flare of 12 months in those with low baseline levels. In contrast, the median time to flare among patients with normal C3 levels has not yet been reached.

Thus far, retreatment seems as effective as initial treatment. Among patients who flared, 14 were retreated, 10 for two cycles and 4 for three cycles. “Experience with rheumatoid arthritis suggests that B-cell depletion is safe for three cycles, but after the fourth infusion you do begin to see falls in total immunoglobulin levels,” he said.

Treatment was well-tolerated by most. Serious adverse events included one case of pneumococcal sepsis, one severe serum sickness-like reaction, and one case of seizures related to hyponatremia, probably tied to cyclophosphamide, Dr. Isenberg said. In addition, one patient developed fatal pancarditis related to active lupus after B-cell repopulation.

“We regard the safety profile as reasonable, given the fact that these are very active patients, often who have had years of very aggressive immunosuppression,” he said. “We found that most patients flare from 6 to 12 months after depletion if they are going to flare, and that baseline autoantibody profiles may be useful in predicting which patients may respond to this treatment.”

Dr. Isenberg disclosed no conflicts of interest in this study.