Greater role discussed for current biologics in lupus

BUENOS AIRES – Approved biologic therapies for systematic lupus erythematosus have so far been limited to belimumab, and there has been little compelling trial evidence to date for the effectiveness of abatacept or rituximab in either SLE or lupus nephritis.

Nonetheless, investigators presenting at an international congress on systemic lupus erythematosus gave clinicians reasons to be optimistic about these three biologics currently in clinical use, both on and off label.

Reinterpretation of randomized controlled trial data even from trials that did not meet their primary or secondary endpoints, new registry data, clinical observation, and ongoing trials with better-defined endpoints are producing insights into how and which SLE and lupus nephritis patients might benefit from rituximab, abatacept, or belimumab.

Dr. Ronald F. van Vollenhoven of the Karolinska Institute in Stockholm discussed findings from a yet-unpublished registry study of biologics in lupus, to be presented in June at the EULAR annual meeting in Madrid. Dr. van Vollenhoven and colleagues found that rituximab, which had not succeeded in the 2012 LUNAR trial in lupus nephritis patients (Arthritis Rheum. 2012;64:1215-26), was the most frequently used off-label biologic being used in lupus in European countries, with about 1% of lupus patients receiving it. "These are more severe disease patients with more damage who have failed other therapies – it seems to be an option of last resort," Dr. van Vollenhoven said.

Dr. Elizabeth Lightstone, a nephrologist at Imperial College London, argued for a role for rituximab beyond rescue therapy in lupus nephritis. "I think most of us think that rituximab does work," Dr. Lightstone told the conference, and described soon-to-be published results from an observational cohort study (n = 50) of new or relapsed lupus nephritis patients receiving rituximab as a first-line treatment protocol along with mycophenolate mofetil (MMF), with a median follow-up of 163 weeks.

By 12 weeks, 18% of patients saw a complete renal response, which increased to 32% at 26 weeks and 50% at 52 weeks, Dr. Lightstone said. Remarkably, 43 patients who started on this regimen have been managed successfully without oral steroids. Dr. Lightstone said that her U.K.-based nephrology group was about to begin recruiting for a randomized, controlled trial that would compare this rituximab-based regimen with MMF and steroids in 252 lupus nephritis patients.

Dr. Lightstone described the failed LUNAR study as having set the bar too high in its definition of complete renal remission, and having gone too short at only 1 year. "There were a lot of positives in that trial," she said. "The serology normalized significantly; in the exploratory endpoints there was at least a 50% reduction in proteinuria significant in the rituximab group at 78 weeks, so there was divergence beyond one year. The need for immunosuppression was significantly different in week 52 and week 78, and there was a reduction in steroids. And black patients responded better – the trial wasn’t powered to show that as significant, but it looks tantalizing."

She also pointed to a randomized, controlled trial of rituximab vs. standard of care, led by Dr. Frédéric Houssiau of the Université Catholique de Louvain in Brussels that may better define the role of rituximab in lupus nephritis. This trial, which aims to recruit 194 patients and is scheduled to end in 2016, is double the duration of the LUNAR trial, at 104 weeks, and defines complete response as a protein/creatinine ratio of 0.5 or less (compared with 0.2 or less in the LUNAR trial).

Dr. van Vollenhoven told the conference that abatacept was being used very rarely in clinical practice in Europe in either SLE or lupus nephritis. He noted, however, that in a negative trial of abatacept in SLE (Arthritis Rheum. 2010;62:3077-87), patients with polyarthritis were seen to benefit most, and though this did not reach statistical significance, it indicated that abatacept might be appropriate for off-label use in such patients. A post hoc analysis of one failed trial of abatacept in lupus nephritis argued that better-defined response criteria would have shown significant differences between the control and placebo groups (Arthritis Rheum. 2012;64:3660-5); company report PDF. "And there are several interesting trials going on with abatacept suggesting that it could work in combination with cyclophosphamide for lupus nephritis," Dr. van Vollenhoven said. "I don’t think the book is completely closed on this."

While belimumab has been the success story among biologics in SLE, as the first biologic developed and licensed to treat the disease, Dr. van Vollenhoven argued that even belimumab may be given short shrift. In the phase III trial of belimumab in SLE (n = 867), belimumab at 10 mg/kg was associated with significant improvement over placebo in standard lupus disease activity scores (Lancet 2011;377:721-31).

"But with just a 10% difference effect size between the two arms, people say this is a weak effect, making all patients a little better," Dr. van Vollenhoven said. "But there could be at least two other explanations. One is that this is a very good medication, but only for some patients. In practice we would have to figure out who these patients are and that they should be getting this treatment. Another is that in these huge trials there is a lot of static – if you’re measuring with an instrument that’s not very good, you won’t get a strong signal."

Dr. van Vollenhoven said that in his clinical practice, "we have found that the patient who has low complement and anti-DNA antibodies plus active disease and are on steroids have a pretty good likelihood of benefiting from belimumab, and that’s how we have been using it in our practice. And we are seeing good results."

Dr. van Vollenhoven has served as an adviser or consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, and UCB Pharma. Dr. Lightstone has received support from Genentech, Roche, Biogen Idec, Aspreva, and GlaxoSmithKline.

BUENOS AIRES – Approved biologic therapies for systematic lupus erythematosus have so far been limited to belimumab, and there has been little compelling trial evidence to date for the effectiveness of abatacept or rituximab in either SLE or lupus nephritis.

Nonetheless, investigators presenting at an international congress on systemic lupus erythematosus gave clinicians reasons to be optimistic about these three biologics currently in clinical use, both on and off label.

Reinterpretation of randomized controlled trial data even from trials that did not meet their primary or secondary endpoints, new registry data, clinical observation, and ongoing trials with better-defined endpoints are producing insights into how and which SLE and lupus nephritis patients might benefit from rituximab, abatacept, or belimumab.

Dr. Ronald F. van Vollenhoven of the Karolinska Institute in Stockholm discussed findings from a yet-unpublished registry study of biologics in lupus, to be presented in June at the EULAR annual meeting in Madrid. Dr. van Vollenhoven and colleagues found that rituximab, which had not succeeded in the 2012 LUNAR trial in lupus nephritis patients (Arthritis Rheum. 2012;64:1215-26), was the most frequently used off-label biologic being used in lupus in European countries, with about 1% of lupus patients receiving it. "These are more severe disease patients with more damage who have failed other therapies – it seems to be an option of last resort," Dr. van Vollenhoven said.

Dr. Elizabeth Lightstone, a nephrologist at Imperial College London, argued for a role for rituximab beyond rescue therapy in lupus nephritis. "I think most of us think that rituximab does work," Dr. Lightstone told the conference, and described soon-to-be published results from an observational cohort study (n = 50) of new or relapsed lupus nephritis patients receiving rituximab as a first-line treatment protocol along with mycophenolate mofetil (MMF), with a median follow-up of 163 weeks.

By 12 weeks, 18% of patients saw a complete renal response, which increased to 32% at 26 weeks and 50% at 52 weeks, Dr. Lightstone said. Remarkably, 43 patients who started on this regimen have been managed successfully without oral steroids. Dr. Lightstone said that her U.K.-based nephrology group was about to begin recruiting for a randomized, controlled trial that would compare this rituximab-based regimen with MMF and steroids in 252 lupus nephritis patients.

Dr. Lightstone described the failed LUNAR study as having set the bar too high in its definition of complete renal remission, and having gone too short at only 1 year. "There were a lot of positives in that trial," she said. "The serology normalized significantly; in the exploratory endpoints there was at least a 50% reduction in proteinuria significant in the rituximab group at 78 weeks, so there was divergence beyond one year. The need for immunosuppression was significantly different in week 52 and week 78, and there was a reduction in steroids. And black patients responded better – the trial wasn’t powered to show that as significant, but it looks tantalizing."

She also pointed to a randomized, controlled trial of rituximab vs. standard of care, led by Dr. Frédéric Houssiau of the Université Catholique de Louvain in Brussels that may better define the role of rituximab in lupus nephritis. This trial, which aims to recruit 194 patients and is scheduled to end in 2016, is double the duration of the LUNAR trial, at 104 weeks, and defines complete response as a protein/creatinine ratio of 0.5 or less (compared with 0.2 or less in the LUNAR trial).

Dr. van Vollenhoven told the conference that abatacept was being used very rarely in clinical practice in Europe in either SLE or lupus nephritis. He noted, however, that in a negative trial of abatacept in SLE (Arthritis Rheum. 2010;62:3077-87), patients with polyarthritis were seen to benefit most, and though this did not reach statistical significance, it indicated that abatacept might be appropriate for off-label use in such patients. A post hoc analysis of one failed trial of abatacept in lupus nephritis argued that better-defined response criteria would have shown significant differences between the control and placebo groups (Arthritis Rheum. 2012;64:3660-5); company report PDF. "And there are several interesting trials going on with abatacept suggesting that it could work in combination with cyclophosphamide for lupus nephritis," Dr. van Vollenhoven said. "I don’t think the book is completely closed on this."

While belimumab has been the success story among biologics in SLE, as the first biologic developed and licensed to treat the disease, Dr. van Vollenhoven argued that even belimumab may be given short shrift. In the phase III trial of belimumab in SLE (n = 867), belimumab at 10 mg/kg was associated with significant improvement over placebo in standard lupus disease activity scores (Lancet 2011;377:721-31).

"But with just a 10% difference effect size between the two arms, people say this is a weak effect, making all patients a little better," Dr. van Vollenhoven said. "But there could be at least two other explanations. One is that this is a very good medication, but only for some patients. In practice we would have to figure out who these patients are and that they should be getting this treatment. Another is that in these huge trials there is a lot of static – if you’re measuring with an instrument that’s not very good, you won’t get a strong signal."

Dr. van Vollenhoven said that in his clinical practice, "we have found that the patient who has low complement and anti-DNA antibodies plus active disease and are on steroids have a pretty good likelihood of benefiting from belimumab, and that’s how we have been using it in our practice. And we are seeing good results."

Dr. van Vollenhoven has served as an adviser or consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, and UCB Pharma. Dr. Lightstone has received support from Genentech, Roche, Biogen Idec, Aspreva, and GlaxoSmithKline.

BUENOS AIRES – Approved biologic therapies for systematic lupus erythematosus have so far been limited to belimumab, and there has been little compelling trial evidence to date for the effectiveness of abatacept or rituximab in either SLE or lupus nephritis.

Nonetheless, investigators presenting at an international congress on systemic lupus erythematosus gave clinicians reasons to be optimistic about these three biologics currently in clinical use, both on and off label.

Reinterpretation of randomized controlled trial data even from trials that did not meet their primary or secondary endpoints, new registry data, clinical observation, and ongoing trials with better-defined endpoints are producing insights into how and which SLE and lupus nephritis patients might benefit from rituximab, abatacept, or belimumab.

Dr. Ronald F. van Vollenhoven of the Karolinska Institute in Stockholm discussed findings from a yet-unpublished registry study of biologics in lupus, to be presented in June at the EULAR annual meeting in Madrid. Dr. van Vollenhoven and colleagues found that rituximab, which had not succeeded in the 2012 LUNAR trial in lupus nephritis patients (Arthritis Rheum. 2012;64:1215-26), was the most frequently used off-label biologic being used in lupus in European countries, with about 1% of lupus patients receiving it. "These are more severe disease patients with more damage who have failed other therapies – it seems to be an option of last resort," Dr. van Vollenhoven said.

Dr. Elizabeth Lightstone, a nephrologist at Imperial College London, argued for a role for rituximab beyond rescue therapy in lupus nephritis. "I think most of us think that rituximab does work," Dr. Lightstone told the conference, and described soon-to-be published results from an observational cohort study (n = 50) of new or relapsed lupus nephritis patients receiving rituximab as a first-line treatment protocol along with mycophenolate mofetil (MMF), with a median follow-up of 163 weeks.

By 12 weeks, 18% of patients saw a complete renal response, which increased to 32% at 26 weeks and 50% at 52 weeks, Dr. Lightstone said. Remarkably, 43 patients who started on this regimen have been managed successfully without oral steroids. Dr. Lightstone said that her U.K.-based nephrology group was about to begin recruiting for a randomized, controlled trial that would compare this rituximab-based regimen with MMF and steroids in 252 lupus nephritis patients.

Dr. Lightstone described the failed LUNAR study as having set the bar too high in its definition of complete renal remission, and having gone too short at only 1 year. "There were a lot of positives in that trial," she said. "The serology normalized significantly; in the exploratory endpoints there was at least a 50% reduction in proteinuria significant in the rituximab group at 78 weeks, so there was divergence beyond one year. The need for immunosuppression was significantly different in week 52 and week 78, and there was a reduction in steroids. And black patients responded better – the trial wasn’t powered to show that as significant, but it looks tantalizing."

She also pointed to a randomized, controlled trial of rituximab vs. standard of care, led by Dr. Frédéric Houssiau of the Université Catholique de Louvain in Brussels that may better define the role of rituximab in lupus nephritis. This trial, which aims to recruit 194 patients and is scheduled to end in 2016, is double the duration of the LUNAR trial, at 104 weeks, and defines complete response as a protein/creatinine ratio of 0.5 or less (compared with 0.2 or less in the LUNAR trial).

Dr. van Vollenhoven told the conference that abatacept was being used very rarely in clinical practice in Europe in either SLE or lupus nephritis. He noted, however, that in a negative trial of abatacept in SLE (Arthritis Rheum. 2010;62:3077-87), patients with polyarthritis were seen to benefit most, and though this did not reach statistical significance, it indicated that abatacept might be appropriate for off-label use in such patients. A post hoc analysis of one failed trial of abatacept in lupus nephritis argued that better-defined response criteria would have shown significant differences between the control and placebo groups (Arthritis Rheum. 2012;64:3660-5); company report PDF. "And there are several interesting trials going on with abatacept suggesting that it could work in combination with cyclophosphamide for lupus nephritis," Dr. van Vollenhoven said. "I don’t think the book is completely closed on this."

While belimumab has been the success story among biologics in SLE, as the first biologic developed and licensed to treat the disease, Dr. van Vollenhoven argued that even belimumab may be given short shrift. In the phase III trial of belimumab in SLE (n = 867), belimumab at 10 mg/kg was associated with significant improvement over placebo in standard lupus disease activity scores (Lancet 2011;377:721-31).

"But with just a 10% difference effect size between the two arms, people say this is a weak effect, making all patients a little better," Dr. van Vollenhoven said. "But there could be at least two other explanations. One is that this is a very good medication, but only for some patients. In practice we would have to figure out who these patients are and that they should be getting this treatment. Another is that in these huge trials there is a lot of static – if you’re measuring with an instrument that’s not very good, you won’t get a strong signal."

Dr. van Vollenhoven said that in his clinical practice, "we have found that the patient who has low complement and anti-DNA antibodies plus active disease and are on steroids have a pretty good likelihood of benefiting from belimumab, and that’s how we have been using it in our practice. And we are seeing good results."

Dr. van Vollenhoven has served as an adviser or consultant for Abbott, Bristol-Myers Squibb, GlaxoSmithKline, Merck Sharp & Dohme, Pfizer, Roche, and UCB Pharma. Dr. Lightstone has received support from Genentech, Roche, Biogen Idec, Aspreva, and GlaxoSmithKline.