Combo Useful in Methotrexate Failure

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.

PARIS — The combination of leflunomide and rituximab may offer an effective therapeutic option for patients with rheumatoid arthritis who can't tolerate methotrexate, a small study suggests.

The most effective therapy thus far for RA is a combination of a traditional disease-modifying antirheumatic drug (DMARD) and a biologic. While methotrexate is the most widely used DMARD, a significant number of patients are unable to tolerate this drug, said Dr. Edward M. Vital of the academic unit of musculoskeletal disease, University of Leeds (England).

Combination therapy substituting leflunomide for methotrexate has therefore been tried, first with infliximab as the biologic component. Initial experience, however, demonstrated that this combination was problematic, with a high incidence of vasculitis and 100% of patients who were on the regimen for an extended period developing antinuclear antibodies (ANA). Many also became positive for anti-double stranded (ds) DNA antibodies, Dr. Vital said at the annual European Congress of Rheumatology.

The probable reason for this induction of autoimmunity is that the removal of tumor necrosis factor (TNF) results in a shift in T cells from a predominant Th1 RA-type response to a Th2 lupus-type response, with the production of autoantibodies. “Therefore, using a strategy of B-cell depletion with rituximab seems logical and potentially synergistic in combination therapy,” he said.

Leflunomide in doses of 10–20 mg/day was administered to 15 patients with active RA in combination with rituximab, given as two infusions of 1,000 mg on days 1 and 15 following pretreatment with 100 mg methylprednisone. The primary end point was a EULAR moderate/good response at 6 months.

The mean age of the patients was 55 years and the mean disease duration was 10 years. The patients had received a mean of four previous DMARDs, and five had previously been treated with anti-TNF drugs.

All were inadequate responders to leflunomide alone.

Mean tender joint count was 18 and mean swollen joint count was 12. The mean disease activity score (DAS) was 6.8 and mean health assessment questionnaire disability index (HAQ-DI) was 2.3.

Thirteen of the patients were rheumatoid factor positive and the remaining two were positive for anticyclic citrullinated peptide (anti-CCP) antibody.

A total of 80% of patients achieved a EULAR moderate/good response with significant reductions in DAS28, said Dr. Vital, who had no financial disclosures.

ACR20, 50, and 70 responses were seen in 68%, 33%, and 20%, respectively, with significant improvements being seen in each component of the ACR core set.

Reductions were also seen in rheumatoid factor, IgM, and IgA.

At the time of Dr. Vital's presentation, eight patients had relapsed, at a mean time of 46 weeks post treatment. Four had not relapsed, with follow-up time of 62–85 weeks. Three partial responders were retreated with good results.

“Relapse-free survival has been somewhat better than expected, with one-third of responders still responding 20 months after treatment,” he said.

In contrast, mean time to retreatment among patients treated with rituximab and methotrexate is 45.5 weeks after an inadequate response to methotrexate (Arthritis Rheum. 2007;56:3896–908).

One serious adverse event, a case of gastroenteritis that required 24 hours of hospitalization, was seen. There were no infusion reactions and none of the patients developed ANA or anti-dsDNA antibodies.

“This is a potential treatment option—and a much needed one—for patients who are intolerant of methotrexate,” Dr. Vital said.