SLE International Congress

BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.

It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.

Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.

At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.

Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.

"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"

HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).

In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.

The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.

Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).

Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).

Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."

A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).

Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."

Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."

Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.

Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.

"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.

Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.

The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."

One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."

Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.

Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."

None of the investigators mentioned have financial disclosures related to HCQ.

BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.

It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.

Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.

At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.

Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.

"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"

HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).

In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.

The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.

Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).

Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).

Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."

A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).

Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."

Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."

Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.

Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.

"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.

Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.

The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."

One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."

Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.

Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."

None of the investigators mentioned have financial disclosures related to HCQ.

BUENOS AIRES – The antimalarial drug hydroxychloroquine is now standard first-line therapy in systemic lupus erythematosus, with most SLE patients taking it indefinitely alone or in addition to other medications.

It was not always this way. The past 15 years have seen what was long regarded as a mild drug, one commonly withdrawn after evidence of disease improvement, become more often compared to a miracle drug. Hydroxychloroquine (HCQ) is now considered indispensible in lupus, and is thought to confer a host of previously unrecognized benefits, with new ones being discovered every year.

Prospective and retrospective observational studies have found HCQ use associated with the prevention of lupus flares, less damage accrual, prolonged survival, less vascular damage, fewer thrombolic and cardiovascular events, better renal outcomes, and skin and joint improvement (J. Rheumatol. 2012;39:1769-71). One team of investigators has hypothesized that HCQ decreases cancer risk in people with lupus (Ann. Rheum. Dis. 2007;66:815-17). But other researchers have challenged some of these studies as potentially biased and not in keeping with observed clinical outcomes.

At the international congress on systemic lupus erythematosus, researchers discussed the latest findings related to HCQ in lupus, and shared thoughts on their implications for clinical practice.

Dr. Murray Urowitz, a senior scientist at the Toronto Western Research Institute, referred to results from a large multicenter cohort study (n = 1,631) that showed SLE patients taking antimalarial drugs in the absence of immunosuppressant medicines had significantly lower risk of seizures (Ann. Rheum. Dis. 2012;71:1502-9), possibly because HCQ is protective against flares, and seizures are thought to be caused by active neuropsychiatric lupus.

"We’ve heard this antimalarials story over and over again," Dr. Urowitz said, in commenting on the seizure findings. "Why aren’t all of our patients on antimalarials?"

HCQ use was seen as protective against cardiovascular disease (odds ratio 0.34, 95% confidence interval 0.16-0.71; P = .003) in a cohort of 306 SLE patients in Turkey, according to findings presented at the conference by Dr. Murat Inanc of Istanbul University (Lupus 2013;22[Suppl.]:O07).

In a separate presentation, Dr. Jill Buyon, director of the Lupus Center at New York University, reported encouraging preliminary data from a small, open-label study (n = 19) of HCQ in pregnant women with anti-SSA/Ro antibodies who previously had a child with cardiac manifestations of neonatal lupus, or cardiac-NL.

The major manifestation of cardiac-NL is heart block, an abnormality in which the heart beats too slowly. It is seen in about 2% of pregnancies in mothers with anti-SSA/Ro and anti-SSB/La serology, and the risk is 17.4% for those who have previously given birth to a child with cardiac-NL. Thus far, third degree heart block has been seen in only 1 of 17 pregnancies in women with a previous child with cardiac-NL taking 400 mg hydroxychloroquine daily, Dr. Buyon reported, suggesting a protective effect.

Dr. Bevra Hahn, chief of rheumatology at UCLA David Geffen School of Medicine, Los Angeles, discussed her own approach to HCQ in the clinic. When faced with patients whose serology or symptoms are suggestive of lupus yet insufficient to fulfill criteria for a lupus diagnosis, Dr. Hahn said she initiates treatment with HCQ. "Can we prevent, delay, or make disease milder with [HCQ]? My answer to that is yes, and we do it a lot," Dr. Hahn said, citing a retrospective study that showed lupus onset to be delayed in people treated with HCQ (Lupus 2007;16:401-9).

Another recent case-control study (n = 481) bolstered the case for early use of HCQ. Investigators found that prompt use of HCQ after SLE diagnosis protected against cumulative damage after 3 years (J. Rheumatol. 2013 April 15 [doi:10.3899/jrheum.120572]).

Dr. Guillermo Ruiz-Irastorza of the University of the Basque Country, Barakaldo, Spain, gave an update at the congress on current approaches to antimalarials. "I am absolutely convinced that HCQ has a very wide range of good effects in lupus, and that the longer it is used, the better it works," he said in a later interview. "Our patients are now almost 100% on HCQ, and the outcome of most of them is amazing – obviously not only because of HCQ, but I am sure it plays a main role. We have seen very severe flares in patients stopping HCQ monotherapy. HCQ is also a crucial part of therapy in renal disease – along with lower prednisone doses, pulse methylprednisolone, and low-dose cyclophosphamide. That is our protocol, with excellent results."

A better understanding of the way HCQ works in lupus has only increased the perception of its clinical importance. In recent years, HCQ was found to have activity against antiphospholipid antibodies (Lupus 2010;19:460-9), which helps to explain its protective effect against pregnancy loss and thrombosis in SLE. More recently, HCQ has been found to antagonize toll-like receptors (TLR) 7 and 9, which are components of innate immunity erroneously activated in lupus. They are a target for new drug development in SLE (Curr. Allergy Asthma Rep. 2012;12:1-7).

Dr. David Pisetsky, professor of immunology at Duke University, Durham, N.C., discussed the implications of HCQ’s anti-TLR activity at the congress. "This relatively benign drug has powerful immunological effects, even though we don’t really think of it that way," he said. "When we’re talking about strategies to block TLR, we’ve already been probably doing it unbeknownst to us rather effectively."

Dr. Buyon, who was moderating Dr. Pisetsky’s talk, noted: "Maybe we’re really underselling ourselves [with HCQ]. Most of us confine ourselves to 6.5 mg/kg," she said, referring to the well-known risk of ocular toxicity and retinal changes associated with long-term HCQ treatment, requiring patients on HCQ to get eye exams yearly. Dr. Pisetsky agreed: "To me it would seem very worthwhile to push the dose to get more out of it."

Dr. Pisetsky and Dr. Buyon both expressed hope that manufacturers would seek to create an HCQ-like compound without the ocular risk, allowing the administration of higher doses with presumably more clinical effect. "But so far there’s been a very limited effort," Dr. Pisetsky said.

Another lupus researcher, rheumatologist and epidemiologist Dr. Sasha Bernatsky of McGill University, Montreal, expressed cautious optimism about some of the recent findings. Like Dr. Urowitz, Dr. Inanc, Dr. Buyon, Dr. Ruiz-Irastorz, and many other international scientists, Dr. Bernatsky is a member of the Systemic Lupus International Collaborating Clinics research group, which studies long-term outcomes in SLE.

"The exact possibilities, in terms of disease modification, remain a matter for further study," Dr. Bernatsky said in an interview, adding that while she strongly endorses HCQ for its many benefits, and recommends the drug in almost all SLE patients, she doesn’t fully understand the extremely strong effects that recent studies have suggested, related to nephritis, central nervous system manifestations, cancer, and overall survival.

Dr. Bernatsky struggles with the findings of a study that found HCQ associated with a 70% reduction in renal damage in lupus patients (Arthritis Rheum. 2009;61:830-9; Arthritis Rheum. 2009;61:1614-5). "I am amazed by that degree of disease-modifying effect in terms of active kidney disease, with [HCQ]," she said.

The recent finding of reduced seizures in lupus patients taking HCQ also surprised her. "A hazards ratio of 0.07 suggests that antimalarials reduce 93% of the risk of seizures, which is an incredibly large effect size."

One area of particular debate in HCQ and lupus concerns cancer risk. While Dr. Ruiz-Irastorza and his colleagues found a protective effect associated with HCQ in a cohort study of 235 patients (Ann. Rheum. Dis. 2007;66:815-7), "I did not believe the results at first," Dr. Ruiz-Irastorza said. "However, after discovering several papers showing biological plausibility for such an effect, I changed my mind. It seems to work by a number of different mechanisms, including inhibition of autophagy and sensitization of tumor cells to chemotherapy."

Dr. Bernatsky and SLICC investigators have studied malignancy risk and medication exposures in a large cohort (n = 16,409) of SLE patients (J. Autoimmun. 2013;42:130-5) without finding a protective effect associated with HCQ. "While I would not rule out some beneficial effects for cancer risk in the rheumatic diseases, I think the jury is still out," she said.

Nonetheless, Dr. Bernatsky said, "At our clinic, we keep most of our patients on antimalarials for years, and I hope it is similar in the United States and Europe. I’m happy for almost all SLE patients to be on HCQ because I think it’s a great drug."

None of the investigators mentioned have financial disclosures related to HCQ.

BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.

Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.

"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."

Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.

Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.

Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.

Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).

"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.

Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.

In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."

The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.

Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."

The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.

BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.

Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.

"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."

Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.

Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.

Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.

Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).

"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.

Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.

In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."

The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.

Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."

The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.

BUENOS AIRES – Clinicians facing cases of severe refractory cutaneous lupus erythematosus – including in patients who smoke – have several treatment options, according to a prominent CLE researcher.

Dr. Victoria P. Werth, professor of dermatology at the Hospital of the University of Pennsylvania, Philadelphia, and chief of dermatology at the Philadelphia Veterans Affairs Medical Center, shared clinical strategies for treating CLE that is resistant to topical or intralesional treatments, and even systemic therapy with antimalarials.

"In terms of systemic therapy there are very few randomized placebo-controlled trials, and recommendations are based on expert opinion and retrospective case series. However, this is beginning to change," Dr. Werth said at an international congress on systemic lupus erythematosus. With the validated CLASI (CLE Disease Area and Severity Index) measure, which Dr. Werth and her colleagues introduced in 2005, "it’s been possible to prospectively follow patients who are being put on treatment."

Antimalarials are the established first-line systemic treatment for CLE, with studies showing hydroxychloroquine to be effective in 50%-70% of patients (Curr. Rheumatol. Rep. 2011;13: 300-7). "It’s worth it to give antimalarials to smokers," Dr. Werth said, citing findings from a prospective cohort study she coauthored (n = 218). She and her colleagues found that even though smoking was associated with more severe disease activity, current smokers requiring treatment with antimalarial agents alone actually improved more than nonsmokers treated with only these agents (Arch. Dermatol. 2012;148:317-21). When skin disease was refractory to antimalarials, the smokers responded less well than nonsmokers to additional therapies such as immunosuppressants.

Dr. Werth noted that patients who do not respond to hydroxychloroquine tend to be those with generalized discoid lupus. In her clinic, she said, patients are started with hydroxychloroquine at less than 6.5 mg/kg per day and given 6-8 weeks to respond. If they do not, quinacrine 100 mg/day is added. At another 6-8 weeks, if no improvement is seen, "stop the hydroxychloroquine and consider starting chloroquine at a dose of less than 3.5 mg/kg per day," Dr. Werth advised, noting that chloroquine has more eye toxicity than hydroxychloroquine.

Immunosuppressants are the usual next step after treatment failure with antimalarials; mycophenolate mofetil (MMF) has been shown in small, uncontrolled studies to be effective in CLE. Dr. Werth discussed a yet-unpublished open-label study (n = 13) that her group conducted in which azathioprine tended to be less effective than MMF in patients who had failed antimalarials.

Thalidomide is effective for refractory CLE, Dr. Werth noted, citing a Spanish study (n = 60) in which nearly all patients treated with 100 mg daily achieved a clinical response, as assessed by CLASI scores, with a complete response seen in 85% (Br. J. Dermatol. 2012;166:616-23).

"Many patients not responsive to antimalarials do respond to thalidomide, and sometimes a lower maintenance dose – as much as 25-50 mg/day or even once a week – can be helpful," she said. Patients, particularly those with discoid forms of CLE, can relapse when taken off thalidomide, but do respond when started again, she said, and kept on low-dose aspirin or hydroxychloroquine to prevent thrombotic events.

Thalidomide is used cautiously in CLE because of its serious adverse effect profile, which includes teratogenicity, amenorrhea, stroke, and peripheral neuropathy. And about 10% of patients, mostly smokers, prove refractory to immunosuppressives and/or thalidomide. For severely refractory patients, the thalidomide analog lenalidomide may have a role.

In Dr. Werth and her colleagues’ case series of lenalidomide in five severely refractory CLE patients, four improved, but one developed systemic lupus erythematosus, leading to speculation that the drug could activate T cells and trigger systemic disease (J. Am. Acad. Dermatol. 2012;66:571-82). In a Spanish open-label study evaluating 5-10 mg/day of lenalidomide in 15 patients, a complete response occurred in 12, and there were no reports of systemic lupus developing after a mean 15 months’ follow-up (Arthritis Res. Ther. 2012;14:R265). Dr. Werth called the lenalidomide findings "encouraging," but warned that the thalidomide derivatives "have complex mechanisms that need to be studied."

The biologic agents belimumab and rituximab offer other options for patients who fail thalidomide. Post-hoc analyses of randomized clinical trials of belimumab "showed that there seemed to be dose-dependent improvement in rash in patients relative to baseline – so there’s hope that further study will demonstrate that skin may benefit from treatment with belimumab," Dr. Werth said.

Rituximab also may be indicated for patients with bullous lupus that is unresponsive to treatment with dapsone or steroids. "It would make sense because this is clearly an autoantibody-driven process," Dr. Werth said. "There have been a number of reports of rituximab helping patients with refractory bullous lupus."

The CLASI copyright is owned by the University of Pennsylvania, Dr. Werth’s institution. Dr. Werth disclosed financial relationships with Pfizer, Novartis, Cephalon, Rigel, and Medimmune, and grant support from Celgene and Amgen.

BUENOS AIRES – A group of new studies on juvenile-onset systemic lupus erythematosus suggests that investigators are gaining a foothold on noninvasively monitoring renal disease, making more accurate diagnoses, and determining the prevalence of hippocampal atrophy in adolescents with the condition.

One of the three reports presented at the international congress on systemic lupus erythematosus (SLE) involved research from U.K. investigators on novel noninvasive biomarkers that can predict the course of renal disease in juvenile SLE, potentially allowing for earlier intervention, fewer kidney biopsies, and more accurate drug titration.

Researchers from Argentina revealed that new classification criteria for SLE, published in 2012, were more sensitive and specific in juvenile lupus patients than the widely used American College of Rheumatology criteria, which were last revised in 1997.

A third report from Brazil-based investigators found that atrophy of the hippocampus, the part of the brain associated with memory and learning, occurred in nearly two-thirds of a cohort of juvenile SLE patients.

Urine biomarkers for lupus nephritis

Dr. Louise Watson of Alder Hey Children’s NHS Hospital, Liverpool, England, presented findings on novel urine biomarkers from a multicenter, prospective cohort study of 64 SLE patients aged 16 years and younger. "We were keen to look for better ways to monitor the disease through biomarkers, and to move from a more reactive to a more proactive approach," Dr. Watson said at the meeting.

Rather than wait until the onset of proteinuria to start treatment, reliable noninvasive biomarkers "could allow disease to be detected at a much earlier time point, and hopefully help us try and prevent some of the irreversible kidney damage that we might see" associated with juvenile-onset SLE.

Dr. Watson and her colleagues looked at both standard and novel biomarkers in the cohort, and found that two novel ones – monocyte chemoattractant protein 1 (MCP1) and neutrophil gelatinase associated lipocalin (NGAL) – predicted changes in the course of renal disease over a 2-year period. MCP1 was highly predictive of disease improvement, and NGAL of disease progression.

MCP1 at a concentration of 343 pg/mL was a significant predictor of improvement in renal disease (P = .013; specificity 71%, sensitivity 70%), the researchers found. Meanwhile, NGAL at 30 ng/mL predicted worsening renal disease (P = .04; specificity 60%, sensitivity 61%).

Urine MCP1 and NGAL changed as subsequent renal disease changed (MCP1, P = .015; NGAL, P = .038), while standard biomarkers (erythrocyte sedimentation rate, anti-double stranded DNA, urine albumin to creatinine ratio, creatinine, complement 3, complement 4, and lymphocytes) did not predict disease activity changes. MCP1 and C3 were seen in a multivariate analysis as independent variables (P less than .001) for active renal disease (Lupus 2013;22 [Suppl.]:O13).

The fact that MCP1 and NGAL are so specific, Dr. Watson said, "may be because they’re expressed directly from the kidney cells. Perhaps we need to begin to validate some of these and move them towards commercialization so we can look towards earlier intervention and monitoring to try and improve the outcome in our patients."

New disease criteria perform better than old

In a separate talk at the congress (Lupus 2013;22[Suppl.]:O12), Dr. Marìa M. Katsicas of the Hospital de Pediatría Prof. Dr. Juan P. Garrahan, in Buenos Aires, presented results from a study comparing the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, published last year (Arthritis Rheum. 2012;64:2677-86), with the revised American College of Rheumatology criteria for SLE (Arthritis Rheum. 1997;40:1725) in a cohort of juvenile patients.

"The ACR criteria have not been completely evaluated in pediatric patients," Dr. Katsicas explained. "Only one publication describes sensitivity and specificity in Brazilian children" (Clin. Exp. Rheumatol. 1994;12:83-7).

For Dr. Katsicas and her colleagues’ study, experienced pediatric rheumatologists reviewed medical records and prospective data for 107 patients with juvenile-onset SLE, and 124 controls with juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune hepatitis, juvenile systemic sclerosis, ANCA-associated vasculitis, or Henoch-Schönlein purpura.

Using the SLICC SLE criteria, all of the SLE cases were correctly identified, while under the ACR 1997 criteria, six cases were missed. Sensitivity for the new criteria was 100%, compared with 86% for the ACR criteria, while specificity was 98% and 96% respectively. "It is very important to note that six patients were correctly identified by SLICC and not ACR," Dr. Katsicas said.

Many patients develop hippocampal atrophy

Dr. Simone Appenzeller of the State University of Campinas, São Paulo, Brazil, and her colleagues reported finding MRI evidence of hippocampal atrophy (in one or both lobes) in 24 of 40 juvenile SLE patients, compared with only 1 of 40 controls.

"Studies have suggested that in the hippocampus, which is the brain area important to memory and learning, [there] may be a specific target for some autoantibodies in neuropsychiatric SLE," Dr. Appenzeller told the congress.

"We have previously shown in adults that there is hippocampal atrophy associated with the total dose of corticosteroids," Dr. Appenzeller said (Ann. Rheum. Dis. 2006;65:1585-9), noting that the association was found once again in the current study (P = .019). Atrophy was also associated with anticardiolipin antibodies (P = .009), vasculitis (P = .042), disease duration (P = .001), cognitive impairment (P = .005), age of disease onset (P = .008) and current age (P = .013). However, disease activity and damage scores were not associated with hippocampal atrophy.

Patients that may have hippocampal atrophy should be followed more closely with MRI and cognitive evaluation, Dr. Appenzeller advised, adding that the findings "could allow us to develop strategies to prevent its occurrence" (Lupus 2013;22[Suppl.]:O15)

Neither Dr. Katsicas nor Dr. Appenzeller reported conflicts of interest. Dr. Watson disclosed that Abbott Laboratories provided the NGAL assay for her group’s study at no cost.

BUENOS AIRES – A group of new studies on juvenile-onset systemic lupus erythematosus suggests that investigators are gaining a foothold on noninvasively monitoring renal disease, making more accurate diagnoses, and determining the prevalence of hippocampal atrophy in adolescents with the condition.

One of the three reports presented at the international congress on systemic lupus erythematosus (SLE) involved research from U.K. investigators on novel noninvasive biomarkers that can predict the course of renal disease in juvenile SLE, potentially allowing for earlier intervention, fewer kidney biopsies, and more accurate drug titration.

Researchers from Argentina revealed that new classification criteria for SLE, published in 2012, were more sensitive and specific in juvenile lupus patients than the widely used American College of Rheumatology criteria, which were last revised in 1997.

A third report from Brazil-based investigators found that atrophy of the hippocampus, the part of the brain associated with memory and learning, occurred in nearly two-thirds of a cohort of juvenile SLE patients.

Urine biomarkers for lupus nephritis

Dr. Louise Watson of Alder Hey Children’s NHS Hospital, Liverpool, England, presented findings on novel urine biomarkers from a multicenter, prospective cohort study of 64 SLE patients aged 16 years and younger. "We were keen to look for better ways to monitor the disease through biomarkers, and to move from a more reactive to a more proactive approach," Dr. Watson said at the meeting.

Rather than wait until the onset of proteinuria to start treatment, reliable noninvasive biomarkers "could allow disease to be detected at a much earlier time point, and hopefully help us try and prevent some of the irreversible kidney damage that we might see" associated with juvenile-onset SLE.

Dr. Watson and her colleagues looked at both standard and novel biomarkers in the cohort, and found that two novel ones – monocyte chemoattractant protein 1 (MCP1) and neutrophil gelatinase associated lipocalin (NGAL) – predicted changes in the course of renal disease over a 2-year period. MCP1 was highly predictive of disease improvement, and NGAL of disease progression.

MCP1 at a concentration of 343 pg/mL was a significant predictor of improvement in renal disease (P = .013; specificity 71%, sensitivity 70%), the researchers found. Meanwhile, NGAL at 30 ng/mL predicted worsening renal disease (P = .04; specificity 60%, sensitivity 61%).

Urine MCP1 and NGAL changed as subsequent renal disease changed (MCP1, P = .015; NGAL, P = .038), while standard biomarkers (erythrocyte sedimentation rate, anti-double stranded DNA, urine albumin to creatinine ratio, creatinine, complement 3, complement 4, and lymphocytes) did not predict disease activity changes. MCP1 and C3 were seen in a multivariate analysis as independent variables (P less than .001) for active renal disease (Lupus 2013;22 [Suppl.]:O13).

The fact that MCP1 and NGAL are so specific, Dr. Watson said, "may be because they’re expressed directly from the kidney cells. Perhaps we need to begin to validate some of these and move them towards commercialization so we can look towards earlier intervention and monitoring to try and improve the outcome in our patients."

New disease criteria perform better than old

In a separate talk at the congress (Lupus 2013;22[Suppl.]:O12), Dr. Marìa M. Katsicas of the Hospital de Pediatría Prof. Dr. Juan P. Garrahan, in Buenos Aires, presented results from a study comparing the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, published last year (Arthritis Rheum. 2012;64:2677-86), with the revised American College of Rheumatology criteria for SLE (Arthritis Rheum. 1997;40:1725) in a cohort of juvenile patients.

"The ACR criteria have not been completely evaluated in pediatric patients," Dr. Katsicas explained. "Only one publication describes sensitivity and specificity in Brazilian children" (Clin. Exp. Rheumatol. 1994;12:83-7).

For Dr. Katsicas and her colleagues’ study, experienced pediatric rheumatologists reviewed medical records and prospective data for 107 patients with juvenile-onset SLE, and 124 controls with juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune hepatitis, juvenile systemic sclerosis, ANCA-associated vasculitis, or Henoch-Schönlein purpura.

Using the SLICC SLE criteria, all of the SLE cases were correctly identified, while under the ACR 1997 criteria, six cases were missed. Sensitivity for the new criteria was 100%, compared with 86% for the ACR criteria, while specificity was 98% and 96% respectively. "It is very important to note that six patients were correctly identified by SLICC and not ACR," Dr. Katsicas said.

Many patients develop hippocampal atrophy

Dr. Simone Appenzeller of the State University of Campinas, São Paulo, Brazil, and her colleagues reported finding MRI evidence of hippocampal atrophy (in one or both lobes) in 24 of 40 juvenile SLE patients, compared with only 1 of 40 controls.

"Studies have suggested that in the hippocampus, which is the brain area important to memory and learning, [there] may be a specific target for some autoantibodies in neuropsychiatric SLE," Dr. Appenzeller told the congress.

"We have previously shown in adults that there is hippocampal atrophy associated with the total dose of corticosteroids," Dr. Appenzeller said (Ann. Rheum. Dis. 2006;65:1585-9), noting that the association was found once again in the current study (P = .019). Atrophy was also associated with anticardiolipin antibodies (P = .009), vasculitis (P = .042), disease duration (P = .001), cognitive impairment (P = .005), age of disease onset (P = .008) and current age (P = .013). However, disease activity and damage scores were not associated with hippocampal atrophy.

Patients that may have hippocampal atrophy should be followed more closely with MRI and cognitive evaluation, Dr. Appenzeller advised, adding that the findings "could allow us to develop strategies to prevent its occurrence" (Lupus 2013;22[Suppl.]:O15)

Neither Dr. Katsicas nor Dr. Appenzeller reported conflicts of interest. Dr. Watson disclosed that Abbott Laboratories provided the NGAL assay for her group’s study at no cost.

BUENOS AIRES – A group of new studies on juvenile-onset systemic lupus erythematosus suggests that investigators are gaining a foothold on noninvasively monitoring renal disease, making more accurate diagnoses, and determining the prevalence of hippocampal atrophy in adolescents with the condition.

One of the three reports presented at the international congress on systemic lupus erythematosus (SLE) involved research from U.K. investigators on novel noninvasive biomarkers that can predict the course of renal disease in juvenile SLE, potentially allowing for earlier intervention, fewer kidney biopsies, and more accurate drug titration.

Researchers from Argentina revealed that new classification criteria for SLE, published in 2012, were more sensitive and specific in juvenile lupus patients than the widely used American College of Rheumatology criteria, which were last revised in 1997.

A third report from Brazil-based investigators found that atrophy of the hippocampus, the part of the brain associated with memory and learning, occurred in nearly two-thirds of a cohort of juvenile SLE patients.

Urine biomarkers for lupus nephritis

Dr. Louise Watson of Alder Hey Children’s NHS Hospital, Liverpool, England, presented findings on novel urine biomarkers from a multicenter, prospective cohort study of 64 SLE patients aged 16 years and younger. "We were keen to look for better ways to monitor the disease through biomarkers, and to move from a more reactive to a more proactive approach," Dr. Watson said at the meeting.

Rather than wait until the onset of proteinuria to start treatment, reliable noninvasive biomarkers "could allow disease to be detected at a much earlier time point, and hopefully help us try and prevent some of the irreversible kidney damage that we might see" associated with juvenile-onset SLE.

Dr. Watson and her colleagues looked at both standard and novel biomarkers in the cohort, and found that two novel ones – monocyte chemoattractant protein 1 (MCP1) and neutrophil gelatinase associated lipocalin (NGAL) – predicted changes in the course of renal disease over a 2-year period. MCP1 was highly predictive of disease improvement, and NGAL of disease progression.

MCP1 at a concentration of 343 pg/mL was a significant predictor of improvement in renal disease (P = .013; specificity 71%, sensitivity 70%), the researchers found. Meanwhile, NGAL at 30 ng/mL predicted worsening renal disease (P = .04; specificity 60%, sensitivity 61%).

Urine MCP1 and NGAL changed as subsequent renal disease changed (MCP1, P = .015; NGAL, P = .038), while standard biomarkers (erythrocyte sedimentation rate, anti-double stranded DNA, urine albumin to creatinine ratio, creatinine, complement 3, complement 4, and lymphocytes) did not predict disease activity changes. MCP1 and C3 were seen in a multivariate analysis as independent variables (P less than .001) for active renal disease (Lupus 2013;22 [Suppl.]:O13).

The fact that MCP1 and NGAL are so specific, Dr. Watson said, "may be because they’re expressed directly from the kidney cells. Perhaps we need to begin to validate some of these and move them towards commercialization so we can look towards earlier intervention and monitoring to try and improve the outcome in our patients."

New disease criteria perform better than old

In a separate talk at the congress (Lupus 2013;22[Suppl.]:O12), Dr. Marìa M. Katsicas of the Hospital de Pediatría Prof. Dr. Juan P. Garrahan, in Buenos Aires, presented results from a study comparing the Systemic Lupus International Collaborating Clinics (SLICC) classification criteria for SLE, published last year (Arthritis Rheum. 2012;64:2677-86), with the revised American College of Rheumatology criteria for SLE (Arthritis Rheum. 1997;40:1725) in a cohort of juvenile patients.

"The ACR criteria have not been completely evaluated in pediatric patients," Dr. Katsicas explained. "Only one publication describes sensitivity and specificity in Brazilian children" (Clin. Exp. Rheumatol. 1994;12:83-7).

For Dr. Katsicas and her colleagues’ study, experienced pediatric rheumatologists reviewed medical records and prospective data for 107 patients with juvenile-onset SLE, and 124 controls with juvenile idiopathic arthritis, juvenile dermatomyositis, autoimmune hepatitis, juvenile systemic sclerosis, ANCA-associated vasculitis, or Henoch-Schönlein purpura.

Using the SLICC SLE criteria, all of the SLE cases were correctly identified, while under the ACR 1997 criteria, six cases were missed. Sensitivity for the new criteria was 100%, compared with 86% for the ACR criteria, while specificity was 98% and 96% respectively. "It is very important to note that six patients were correctly identified by SLICC and not ACR," Dr. Katsicas said.

Many patients develop hippocampal atrophy

Dr. Simone Appenzeller of the State University of Campinas, São Paulo, Brazil, and her colleagues reported finding MRI evidence of hippocampal atrophy (in one or both lobes) in 24 of 40 juvenile SLE patients, compared with only 1 of 40 controls.

"Studies have suggested that in the hippocampus, which is the brain area important to memory and learning, [there] may be a specific target for some autoantibodies in neuropsychiatric SLE," Dr. Appenzeller told the congress.

"We have previously shown in adults that there is hippocampal atrophy associated with the total dose of corticosteroids," Dr. Appenzeller said (Ann. Rheum. Dis. 2006;65:1585-9), noting that the association was found once again in the current study (P = .019). Atrophy was also associated with anticardiolipin antibodies (P = .009), vasculitis (P = .042), disease duration (P = .001), cognitive impairment (P = .005), age of disease onset (P = .008) and current age (P = .013). However, disease activity and damage scores were not associated with hippocampal atrophy.

Patients that may have hippocampal atrophy should be followed more closely with MRI and cognitive evaluation, Dr. Appenzeller advised, adding that the findings "could allow us to develop strategies to prevent its occurrence" (Lupus 2013;22[Suppl.]:O15)

Neither Dr. Katsicas nor Dr. Appenzeller reported conflicts of interest. Dr. Watson disclosed that Abbott Laboratories provided the NGAL assay for her group’s study at no cost.

BUENOS AIRES – Traditional tools such as the Framingham risk score have long been known to underestimate cardiovascular risk in people with systemic lupus erythematosus.

At the international congress on systemic lupus erythematosus, Dr. Michelle Petri of Johns Hopkins University, Baltimore, presented data in support of a novel risk-assessment formula to calculate the 10-year risk of a cardiovascular event (CVE). The tool combines the traditional cardiovascular disease risk factors of age, sex, high blood pressure, high cholesterol, smoking, diabetes, and body mass index (BMI), with three lupus-specific factors: a SLEDAI (SLE Disease Activity Index) score of 2 or higher, lupus anticoagulant, and a low mean complement 3 (C3) level.

Under both this and the Framingham algorithms, a 50-year old woman with SLE with a BMI of 23 kg/m², systolic blood pressure of 150 mm Hg, and high cholesterol has about an 8% 10-year risk of a CVE. However, if she also has lupus anticoagulant, high disease activity, or a low C3 level, her risk rises to 15%-18% under the SLE-specific system, whereas her Framingham score, which does not measure these, would remain at 8%.

Courtesy of Keith Weller/Johns Hopkins Medicine

Dr. Petri told the conference that with rheumatoid arthritis, the advice has been to multiply an existing risk score by 1.5 when the patient has certain evidence of disease. "I thought we could do better than that in lupus, because we could derive a formula using actual data," she said.

"We know that traditional CV risk factors do predict actual events and also predict the progression of subclinical atherosclerosis. Even after we adjust, though, for every traditional cardiovascular risk factor, lupus patients still have a twofold increase in coronary calcium over controls – so obviously lupus-specific factors must be in the formula as well."

The data used to derive the new scoring system came from a cohort of 1,342 lupus patients (93% female) treated at the Johns Hopkins Lupus Center. None had a history of CVEs during the first 2 years of follow-up. Over the study period, 109 incident CVEs occurred in the cohort, including 52 strokes and 26 myocardial infarctions.

Dr. Petri and her colleagues used Cox proportional hazards models to determine the baseline variables affecting the risk of a subsequent CVE. Using the results, they derived a formula to calculate the 10-year risk of a CVE. For each of the risk factors, they investigators converted the hazard ratio into a simple integer score to simplify calculation in clinical practice. By adding up the integers and using a slide rule that stands in for the exponential equation, clinicians can translate the integer score into a risk percentage.

Dr. Petri acknowledged as limitations of the study its single-site design; the fact that the Johns Hopkins Lupus Center does not routinely perform cholesterol screening; and that the study reflects care from 1988 onward, where more recent data could reflect a better standard of care. "This needs to be independently validated," she said.

In another multivariate analysis of cardiovascular disease (CVD) risk factors in lupus, a cohort of 306 consecutive SLE patients at a clinic in Istanbul, Turkey, revealed pericarditis, lymphopenia, thrombocytopenia, and psychosis to be significantly associated with nonfatal CVD.

Dr. Murat Inanc of Istanbul University, the lead author of the study, said that 15.2% of the cohort (mean age, 40.2 years; 89% female) had clinical evidence of CVD. Many of them also had traditional risk factors. "The usual suspects are there – hypertension, high cholesterol, metabolic syndrome – but we also found disease-specific features more present in patients with CV involvement," Dr. Inanc said.

Patients with evidence of CVD were older and had longer disease duration, significantly more organ damage, and a higher number of American College of Rheumatology criteria for SLE. "We think disease severity takes almost equal importance with traditional risk factors in this population," he said. Treatment with cyclophosphamide was also seen as a risk factor, although it is likely related to disease severity, he told the congress.

Dr. Inanc noted that the conclusions that can be drawn from the study are limited by its single-site design and lack of data on subclinical CVD. Cumulative corticosteroid use was not investigated, and investigators did not have information on immunosuppressive use in the cohort.

Dr. Murray Urowitz, of the Toronto Western Research Institute, presented findings from an international, multicenter inception cohort of 1,401 SLE patients. The goal of the study was to determine factors at diagnosis that are predictive of the development of premature atherosclerosis. Dr. Urowitz and his colleagues looked at age, sex, diabetes, smoking, obesity, low-density lipoprotein cholesterol, and creatinine. A multivariate analysis showed that only age and male sex were significant risk factors for atherosclerotic vascular events after a mean 5 years’ follow-up. "The implication here is these risk factors take more time to have their maximum effect, and in the first decade it’s hard to have more than age and sex," Dr. Urowitz told the congress.

Also at the congress, Dr. Maureen McMahon of the University of California, Los Angeles, gave a presentation on a panel of biomarkers found to be predictive of current, progressive, or acquired carotid plaque in a cohort of SLE patients.

For their research, Dr. McMahon and her colleagues looked at 210 female SLE patients and 100 age-matched controls who underwent ultrasound imaging of their carotid arteries at baseline and after a mean 29 months of follow-up. Nearly a third of SLE patients had evidence of plaque on follow-up.

The researchers found that three or more of the following factors at baseline were 94% predictive of plaque: age 48 or older, evidence of proinflammatory high-density lipoprotein cholesterol, plasma leptin of 34 ng/dL or greater, homocysteine of 12 mmol/L or greater, and plasma levels of sTWEAK (soluble tumor necrosis factor–like weak inducer of apoptosis) of 373 pg/mL or greater. Any one of these factors plus diabetes was also predictive. Patients with at least three indicators (or one plus diabetes) saw a 28-fold increased odds for the longitudinal presence of carotid plaque (95% confidence interval, 10.6-72.7; P less than .001) and a significantly increased rate of progression of both plaque and intima-media thickness.

None of the investigators disclosed financial relationships related to these studies.

BUENOS AIRES – Traditional tools such as the Framingham risk score have long been known to underestimate cardiovascular risk in people with systemic lupus erythematosus.

At the international congress on systemic lupus erythematosus, Dr. Michelle Petri of Johns Hopkins University, Baltimore, presented data in support of a novel risk-assessment formula to calculate the 10-year risk of a cardiovascular event (CVE). The tool combines the traditional cardiovascular disease risk factors of age, sex, high blood pressure, high cholesterol, smoking, diabetes, and body mass index (BMI), with three lupus-specific factors: a SLEDAI (SLE Disease Activity Index) score of 2 or higher, lupus anticoagulant, and a low mean complement 3 (C3) level.

Under both this and the Framingham algorithms, a 50-year old woman with SLE with a BMI of 23 kg/m², systolic blood pressure of 150 mm Hg, and high cholesterol has about an 8% 10-year risk of a CVE. However, if she also has lupus anticoagulant, high disease activity, or a low C3 level, her risk rises to 15%-18% under the SLE-specific system, whereas her Framingham score, which does not measure these, would remain at 8%.

Courtesy of Keith Weller/Johns Hopkins Medicine

Dr. Petri told the conference that with rheumatoid arthritis, the advice has been to multiply an existing risk score by 1.5 when the patient has certain evidence of disease. "I thought we could do better than that in lupus, because we could derive a formula using actual data," she said.

"We know that traditional CV risk factors do predict actual events and also predict the progression of subclinical atherosclerosis. Even after we adjust, though, for every traditional cardiovascular risk factor, lupus patients still have a twofold increase in coronary calcium over controls – so obviously lupus-specific factors must be in the formula as well."

The data used to derive the new scoring system came from a cohort of 1,342 lupus patients (93% female) treated at the Johns Hopkins Lupus Center. None had a history of CVEs during the first 2 years of follow-up. Over the study period, 109 incident CVEs occurred in the cohort, including 52 strokes and 26 myocardial infarctions.

Dr. Petri and her colleagues used Cox proportional hazards models to determine the baseline variables affecting the risk of a subsequent CVE. Using the results, they derived a formula to calculate the 10-year risk of a CVE. For each of the risk factors, they investigators converted the hazard ratio into a simple integer score to simplify calculation in clinical practice. By adding up the integers and using a slide rule that stands in for the exponential equation, clinicians can translate the integer score into a risk percentage.

Dr. Petri acknowledged as limitations of the study its single-site design; the fact that the Johns Hopkins Lupus Center does not routinely perform cholesterol screening; and that the study reflects care from 1988 onward, where more recent data could reflect a better standard of care. "This needs to be independently validated," she said.

In another multivariate analysis of cardiovascular disease (CVD) risk factors in lupus, a cohort of 306 consecutive SLE patients at a clinic in Istanbul, Turkey, revealed pericarditis, lymphopenia, thrombocytopenia, and psychosis to be significantly associated with nonfatal CVD.

Dr. Murat Inanc of Istanbul University, the lead author of the study, said that 15.2% of the cohort (mean age, 40.2 years; 89% female) had clinical evidence of CVD. Many of them also had traditional risk factors. "The usual suspects are there – hypertension, high cholesterol, metabolic syndrome – but we also found disease-specific features more present in patients with CV involvement," Dr. Inanc said.

Patients with evidence of CVD were older and had longer disease duration, significantly more organ damage, and a higher number of American College of Rheumatology criteria for SLE. "We think disease severity takes almost equal importance with traditional risk factors in this population," he said. Treatment with cyclophosphamide was also seen as a risk factor, although it is likely related to disease severity, he told the congress.

Dr. Inanc noted that the conclusions that can be drawn from the study are limited by its single-site design and lack of data on subclinical CVD. Cumulative corticosteroid use was not investigated, and investigators did not have information on immunosuppressive use in the cohort.

Dr. Murray Urowitz, of the Toronto Western Research Institute, presented findings from an international, multicenter inception cohort of 1,401 SLE patients. The goal of the study was to determine factors at diagnosis that are predictive of the development of premature atherosclerosis. Dr. Urowitz and his colleagues looked at age, sex, diabetes, smoking, obesity, low-density lipoprotein cholesterol, and creatinine. A multivariate analysis showed that only age and male sex were significant risk factors for atherosclerotic vascular events after a mean 5 years’ follow-up. "The implication here is these risk factors take more time to have their maximum effect, and in the first decade it’s hard to have more than age and sex," Dr. Urowitz told the congress.

Also at the congress, Dr. Maureen McMahon of the University of California, Los Angeles, gave a presentation on a panel of biomarkers found to be predictive of current, progressive, or acquired carotid plaque in a cohort of SLE patients.

For their research, Dr. McMahon and her colleagues looked at 210 female SLE patients and 100 age-matched controls who underwent ultrasound imaging of their carotid arteries at baseline and after a mean 29 months of follow-up. Nearly a third of SLE patients had evidence of plaque on follow-up.

The researchers found that three or more of the following factors at baseline were 94% predictive of plaque: age 48 or older, evidence of proinflammatory high-density lipoprotein cholesterol, plasma leptin of 34 ng/dL or greater, homocysteine of 12 mmol/L or greater, and plasma levels of sTWEAK (soluble tumor necrosis factor–like weak inducer of apoptosis) of 373 pg/mL or greater. Any one of these factors plus diabetes was also predictive. Patients with at least three indicators (or one plus diabetes) saw a 28-fold increased odds for the longitudinal presence of carotid plaque (95% confidence interval, 10.6-72.7; P less than .001) and a significantly increased rate of progression of both plaque and intima-media thickness.

None of the investigators disclosed financial relationships related to these studies.

BUENOS AIRES – Traditional tools such as the Framingham risk score have long been known to underestimate cardiovascular risk in people with systemic lupus erythematosus.

At the international congress on systemic lupus erythematosus, Dr. Michelle Petri of Johns Hopkins University, Baltimore, presented data in support of a novel risk-assessment formula to calculate the 10-year risk of a cardiovascular event (CVE). The tool combines the traditional cardiovascular disease risk factors of age, sex, high blood pressure, high cholesterol, smoking, diabetes, and body mass index (BMI), with three lupus-specific factors: a SLEDAI (SLE Disease Activity Index) score of 2 or higher, lupus anticoagulant, and a low mean complement 3 (C3) level.

Under both this and the Framingham algorithms, a 50-year old woman with SLE with a BMI of 23 kg/m², systolic blood pressure of 150 mm Hg, and high cholesterol has about an 8% 10-year risk of a CVE. However, if she also has lupus anticoagulant, high disease activity, or a low C3 level, her risk rises to 15%-18% under the SLE-specific system, whereas her Framingham score, which does not measure these, would remain at 8%.

Courtesy of Keith Weller/Johns Hopkins Medicine

Dr. Petri told the conference that with rheumatoid arthritis, the advice has been to multiply an existing risk score by 1.5 when the patient has certain evidence of disease. "I thought we could do better than that in lupus, because we could derive a formula using actual data," she said.

"We know that traditional CV risk factors do predict actual events and also predict the progression of subclinical atherosclerosis. Even after we adjust, though, for every traditional cardiovascular risk factor, lupus patients still have a twofold increase in coronary calcium over controls – so obviously lupus-specific factors must be in the formula as well."

The data used to derive the new scoring system came from a cohort of 1,342 lupus patients (93% female) treated at the Johns Hopkins Lupus Center. None had a history of CVEs during the first 2 years of follow-up. Over the study period, 109 incident CVEs occurred in the cohort, including 52 strokes and 26 myocardial infarctions.

Dr. Petri and her colleagues used Cox proportional hazards models to determine the baseline variables affecting the risk of a subsequent CVE. Using the results, they derived a formula to calculate the 10-year risk of a CVE. For each of the risk factors, they investigators converted the hazard ratio into a simple integer score to simplify calculation in clinical practice. By adding up the integers and using a slide rule that stands in for the exponential equation, clinicians can translate the integer score into a risk percentage.

Dr. Petri acknowledged as limitations of the study its single-site design; the fact that the Johns Hopkins Lupus Center does not routinely perform cholesterol screening; and that the study reflects care from 1988 onward, where more recent data could reflect a better standard of care. "This needs to be independently validated," she said.

In another multivariate analysis of cardiovascular disease (CVD) risk factors in lupus, a cohort of 306 consecutive SLE patients at a clinic in Istanbul, Turkey, revealed pericarditis, lymphopenia, thrombocytopenia, and psychosis to be significantly associated with nonfatal CVD.

Dr. Murat Inanc of Istanbul University, the lead author of the study, said that 15.2% of the cohort (mean age, 40.2 years; 89% female) had clinical evidence of CVD. Many of them also had traditional risk factors. "The usual suspects are there – hypertension, high cholesterol, metabolic syndrome – but we also found disease-specific features more present in patients with CV involvement," Dr. Inanc said.

Patients with evidence of CVD were older and had longer disease duration, significantly more organ damage, and a higher number of American College of Rheumatology criteria for SLE. "We think disease severity takes almost equal importance with traditional risk factors in this population," he said. Treatment with cyclophosphamide was also seen as a risk factor, although it is likely related to disease severity, he told the congress.

Dr. Inanc noted that the conclusions that can be drawn from the study are limited by its single-site design and lack of data on subclinical CVD. Cumulative corticosteroid use was not investigated, and investigators did not have information on immunosuppressive use in the cohort.

Dr. Murray Urowitz, of the Toronto Western Research Institute, presented findings from an international, multicenter inception cohort of 1,401 SLE patients. The goal of the study was to determine factors at diagnosis that are predictive of the development of premature atherosclerosis. Dr. Urowitz and his colleagues looked at age, sex, diabetes, smoking, obesity, low-density lipoprotein cholesterol, and creatinine. A multivariate analysis showed that only age and male sex were significant risk factors for atherosclerotic vascular events after a mean 5 years’ follow-up. "The implication here is these risk factors take more time to have their maximum effect, and in the first decade it’s hard to have more than age and sex," Dr. Urowitz told the congress.

Also at the congress, Dr. Maureen McMahon of the University of California, Los Angeles, gave a presentation on a panel of biomarkers found to be predictive of current, progressive, or acquired carotid plaque in a cohort of SLE patients.

For their research, Dr. McMahon and her colleagues looked at 210 female SLE patients and 100 age-matched controls who underwent ultrasound imaging of their carotid arteries at baseline and after a mean 29 months of follow-up. Nearly a third of SLE patients had evidence of plaque on follow-up.

The researchers found that three or more of the following factors at baseline were 94% predictive of plaque: age 48 or older, evidence of proinflammatory high-density lipoprotein cholesterol, plasma leptin of 34 ng/dL or greater, homocysteine of 12 mmol/L or greater, and plasma levels of sTWEAK (soluble tumor necrosis factor–like weak inducer of apoptosis) of 373 pg/mL or greater. Any one of these factors plus diabetes was also predictive. Patients with at least three indicators (or one plus diabetes) saw a 28-fold increased odds for the longitudinal presence of carotid plaque (95% confidence interval, 10.6-72.7; P less than .001) and a significantly increased rate of progression of both plaque and intima-media thickness.

None of the investigators disclosed financial relationships related to these studies.

BUENOS AIRES – Incidences of certain cancers, particularly lymphomas, have been shown to be higher in people with systemic lupus erythematosus, while hormone-influenced breast, ovarian, and endometrial cancers have recently been found to occur less often in SLE patients than in the general population.

At the 10th International Congress on SLE, the researchers responsible for these findings discussed their implications for clinical practice.

Dr. Ann Clarke of McGill University, Montreal, coauthor of a large case-cohort study that found neither immunosuppressant drug use nor disease activity correlated with lymphoma risk as hypothesized (Ann. Rheum. Dis. 2013 Jan. 8 [doi:10.1136/annrheumdis-2012-202099]), said that clinicians should nonetheless consider a history of malignancies when deciding whether to prescribe immunosuppressants.

The study by Dr. Clarke and her colleagues, led by Dr. Sasha Bernatsky of McGill, enrolled 75 SLE patients with lymphoma and 4,961 cancer-free controls with SLE, seeking to determine associations between lymphoma risk and exposures to cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarials, or steroids. The team also looked at Sjögren’s syndrome, disease duration, and disease activity as potential indicators of risk.

Although cyclophosphamide use was seen more frequently among the lymphoma cases (20%) than in the controls (16.8%), this difference did not reach statistical significance. "There isn’t a strong signal that the drugs are responsible," Dr. Clarke said, but she nonetheless argued for caution in the clinic.

"If there is a remote history of malignancy – more than 5 years, certainly more than 10 – I would proceed [with immunosuppressants]," she said. "If there is a recent history, I would try to avoid them, using rituximab or belimumab as appropriate."

Dr. Clarke’s team, again led by Dr. Bernatsky, also conducted research that examined the incidence of specific cancers in an international cohort of 16,409 patients with SLE (J. Autoimmun. 2013 Feb. 11 [doi:10.1016/j.jaut.2012.12.009]).

This study showed that lupus patients had a threefold higher risk for hematological cancers, especially non-Hodgkin’s lymphoma, and a slightly elevated risk for cancer overall, but saw fewer hormone-sensitive cancers than expected, with the standardized incidence ratio of 0.73 for breast cancers (95% confidence interval [CI], 0.61-0.88), 0.44 for endometrial cancers (95% CI, 0.23-0.77), and 0.64 for ovarian cancers (95% CI, 0.34-1.10).

"There certainly seems to be a convincing signal that female hormone-sensitive cancers appear to be decreased in patients with lupus," said Dr. Clarke, who is also codirector of the lupus clinic at Montreal General Hospital. She said that there are various hypotheses as to why, including animal models that suggest that anti-DNA antibodies could have antitumor effects against certain cancer cell lines (Sci. Transl. Med. 2012;4:157ra142).

"I don’t think this should give us a false sense of reassurance," Dr. Clarke said of the findings, noting that vulvar cancers, likely resulting from HPV infection, were seen as increased in lupus patients and that cervical dysplasia was known to be increased as well.

"I think we still have to screen for breast cancer. And I think that this risk for dysplasia calls us to be even more vigilant than current recommendations," she said.

In a related talk, Dr. Murray B. Urowitz, director of the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Research Institute and a coauthor on both studies, praised Dr. Clarke and colleagues’ malignancy findings as "very important."

"The expected numbers of malignancy in this tremendous number of patients was 561," Dr. Urowitz said at the meeting, referring to the large cohort study. "And the observed number was 644, with the driver being hematologic malignancies." He noted that only age and male gender were found to be predictive factors.

The lower-than expected incidence of hormone-sensitive cancers in the same cohort study, Dr. Urowitz said, was yet another mystery. "Is there a hormonal factor favoring the lupus patient – less total estrogen over her lifetime, less likely to get hormone replacement? Maybe, but the decreased risk seen in SLE is evident in both pre- and postmenopausal lupus. Could it be genetic? It’s unclear. There [are] some very exciting data that anti-DNA antibody may actually be protective, but that’s still in the very early phases."

Dr. Urowitz, Dr. Clarke, and Dr. Bernatsky did not disclose financial relationships bearing on their studies.

BUENOS AIRES – Incidences of certain cancers, particularly lymphomas, have been shown to be higher in people with systemic lupus erythematosus, while hormone-influenced breast, ovarian, and endometrial cancers have recently been found to occur less often in SLE patients than in the general population.

At the 10th International Congress on SLE, the researchers responsible for these findings discussed their implications for clinical practice.

Dr. Ann Clarke of McGill University, Montreal, coauthor of a large case-cohort study that found neither immunosuppressant drug use nor disease activity correlated with lymphoma risk as hypothesized (Ann. Rheum. Dis. 2013 Jan. 8 [doi:10.1136/annrheumdis-2012-202099]), said that clinicians should nonetheless consider a history of malignancies when deciding whether to prescribe immunosuppressants.

The study by Dr. Clarke and her colleagues, led by Dr. Sasha Bernatsky of McGill, enrolled 75 SLE patients with lymphoma and 4,961 cancer-free controls with SLE, seeking to determine associations between lymphoma risk and exposures to cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarials, or steroids. The team also looked at Sjögren’s syndrome, disease duration, and disease activity as potential indicators of risk.

Although cyclophosphamide use was seen more frequently among the lymphoma cases (20%) than in the controls (16.8%), this difference did not reach statistical significance. "There isn’t a strong signal that the drugs are responsible," Dr. Clarke said, but she nonetheless argued for caution in the clinic.

"If there is a remote history of malignancy – more than 5 years, certainly more than 10 – I would proceed [with immunosuppressants]," she said. "If there is a recent history, I would try to avoid them, using rituximab or belimumab as appropriate."

Dr. Clarke’s team, again led by Dr. Bernatsky, also conducted research that examined the incidence of specific cancers in an international cohort of 16,409 patients with SLE (J. Autoimmun. 2013 Feb. 11 [doi:10.1016/j.jaut.2012.12.009]).

This study showed that lupus patients had a threefold higher risk for hematological cancers, especially non-Hodgkin’s lymphoma, and a slightly elevated risk for cancer overall, but saw fewer hormone-sensitive cancers than expected, with the standardized incidence ratio of 0.73 for breast cancers (95% confidence interval [CI], 0.61-0.88), 0.44 for endometrial cancers (95% CI, 0.23-0.77), and 0.64 for ovarian cancers (95% CI, 0.34-1.10).

"There certainly seems to be a convincing signal that female hormone-sensitive cancers appear to be decreased in patients with lupus," said Dr. Clarke, who is also codirector of the lupus clinic at Montreal General Hospital. She said that there are various hypotheses as to why, including animal models that suggest that anti-DNA antibodies could have antitumor effects against certain cancer cell lines (Sci. Transl. Med. 2012;4:157ra142).

"I don’t think this should give us a false sense of reassurance," Dr. Clarke said of the findings, noting that vulvar cancers, likely resulting from HPV infection, were seen as increased in lupus patients and that cervical dysplasia was known to be increased as well.

"I think we still have to screen for breast cancer. And I think that this risk for dysplasia calls us to be even more vigilant than current recommendations," she said.

In a related talk, Dr. Murray B. Urowitz, director of the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Research Institute and a coauthor on both studies, praised Dr. Clarke and colleagues’ malignancy findings as "very important."

"The expected numbers of malignancy in this tremendous number of patients was 561," Dr. Urowitz said at the meeting, referring to the large cohort study. "And the observed number was 644, with the driver being hematologic malignancies." He noted that only age and male gender were found to be predictive factors.

The lower-than expected incidence of hormone-sensitive cancers in the same cohort study, Dr. Urowitz said, was yet another mystery. "Is there a hormonal factor favoring the lupus patient – less total estrogen over her lifetime, less likely to get hormone replacement? Maybe, but the decreased risk seen in SLE is evident in both pre- and postmenopausal lupus. Could it be genetic? It’s unclear. There [are] some very exciting data that anti-DNA antibody may actually be protective, but that’s still in the very early phases."

Dr. Urowitz, Dr. Clarke, and Dr. Bernatsky did not disclose financial relationships bearing on their studies.

BUENOS AIRES – Incidences of certain cancers, particularly lymphomas, have been shown to be higher in people with systemic lupus erythematosus, while hormone-influenced breast, ovarian, and endometrial cancers have recently been found to occur less often in SLE patients than in the general population.

At the 10th International Congress on SLE, the researchers responsible for these findings discussed their implications for clinical practice.

Dr. Ann Clarke of McGill University, Montreal, coauthor of a large case-cohort study that found neither immunosuppressant drug use nor disease activity correlated with lymphoma risk as hypothesized (Ann. Rheum. Dis. 2013 Jan. 8 [doi:10.1136/annrheumdis-2012-202099]), said that clinicians should nonetheless consider a history of malignancies when deciding whether to prescribe immunosuppressants.

The study by Dr. Clarke and her colleagues, led by Dr. Sasha Bernatsky of McGill, enrolled 75 SLE patients with lymphoma and 4,961 cancer-free controls with SLE, seeking to determine associations between lymphoma risk and exposures to cyclophosphamide, azathioprine, methotrexate, mycophenolate, antimalarials, or steroids. The team also looked at Sjögren’s syndrome, disease duration, and disease activity as potential indicators of risk.

Although cyclophosphamide use was seen more frequently among the lymphoma cases (20%) than in the controls (16.8%), this difference did not reach statistical significance. "There isn’t a strong signal that the drugs are responsible," Dr. Clarke said, but she nonetheless argued for caution in the clinic.

"If there is a remote history of malignancy – more than 5 years, certainly more than 10 – I would proceed [with immunosuppressants]," she said. "If there is a recent history, I would try to avoid them, using rituximab or belimumab as appropriate."

Dr. Clarke’s team, again led by Dr. Bernatsky, also conducted research that examined the incidence of specific cancers in an international cohort of 16,409 patients with SLE (J. Autoimmun. 2013 Feb. 11 [doi:10.1016/j.jaut.2012.12.009]).

This study showed that lupus patients had a threefold higher risk for hematological cancers, especially non-Hodgkin’s lymphoma, and a slightly elevated risk for cancer overall, but saw fewer hormone-sensitive cancers than expected, with the standardized incidence ratio of 0.73 for breast cancers (95% confidence interval [CI], 0.61-0.88), 0.44 for endometrial cancers (95% CI, 0.23-0.77), and 0.64 for ovarian cancers (95% CI, 0.34-1.10).

"There certainly seems to be a convincing signal that female hormone-sensitive cancers appear to be decreased in patients with lupus," said Dr. Clarke, who is also codirector of the lupus clinic at Montreal General Hospital. She said that there are various hypotheses as to why, including animal models that suggest that anti-DNA antibodies could have antitumor effects against certain cancer cell lines (Sci. Transl. Med. 2012;4:157ra142).

"I don’t think this should give us a false sense of reassurance," Dr. Clarke said of the findings, noting that vulvar cancers, likely resulting from HPV infection, were seen as increased in lupus patients and that cervical dysplasia was known to be increased as well.

"I think we still have to screen for breast cancer. And I think that this risk for dysplasia calls us to be even more vigilant than current recommendations," she said.

In a related talk, Dr. Murray B. Urowitz, director of the Centre for Prognosis Studies in the Rheumatic Diseases at Toronto Western Research Institute and a coauthor on both studies, praised Dr. Clarke and colleagues’ malignancy findings as "very important."

"The expected numbers of malignancy in this tremendous number of patients was 561," Dr. Urowitz said at the meeting, referring to the large cohort study. "And the observed number was 644, with the driver being hematologic malignancies." He noted that only age and male gender were found to be predictive factors.

The lower-than expected incidence of hormone-sensitive cancers in the same cohort study, Dr. Urowitz said, was yet another mystery. "Is there a hormonal factor favoring the lupus patient – less total estrogen over her lifetime, less likely to get hormone replacement? Maybe, but the decreased risk seen in SLE is evident in both pre- and postmenopausal lupus. Could it be genetic? It’s unclear. There [are] some very exciting data that anti-DNA antibody may actually be protective, but that’s still in the very early phases."

Dr. Urowitz, Dr. Clarke, and Dr. Bernatsky did not disclose financial relationships bearing on their studies.

BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.

At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.

Biomarker-driven response to rontalizumab

Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.

Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.

Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).

Limiting background medications in trials

Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.

Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."

Targeting CD22 antigen on B cells

Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).

Phase II data on blisibimod

Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).

Improving on past trial missteps

One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."

Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.

Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.

BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.

At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.

Biomarker-driven response to rontalizumab

Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.

Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.

Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).

Limiting background medications in trials

Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.

Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."

Targeting CD22 antigen on B cells

Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).

Phase II data on blisibimod

Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).

Improving on past trial missteps

One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."

Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.

Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.

BUENOS AIRES – Despite some early letdowns in clinical trials, biologic therapies targeting nearly every point in the pathway of the known pathogenesis of systemic lupus erythematosus are currently in the pipeline.

At the International Congress on Systemic Lupus Erythematosus, investigators presented promising new data on several experimental biologics. And in the shadow of some costly failures, they also discussed ways to refine endpoints, inclusion criteria, and the use of background medicines to make trial results for these agents clearer.

Biomarker-driven response to rontalizumab

Rontalizumab, a humanized antibody against anti-interferon-alpha, was shown in a phase II randomized controlled trial of 159 patients with moderate to severe SLE to improve signs and symptoms, flare rates, and need for steroids at 24 weeks in the subset of patients who had low interferon signature gene expression metric (ISM), an emerging biomarker in SLE, at baseline.

Although whether patients are classified as ISM high or low makes little difference in terms of measurable disease activity, it does appear to affect how treatments work. "No matter what drug you look at, the impact differs depending on whether the patients are ISM high or low," said Dr. Joan T. Merrill, one of the coauthors of the rontalizumab study, which was presented at the meeting by Dr. William Kennedy, senior medical director of Genentech.

Rontalizumab was associated with improvement in the ISM-low subgroup in the trial, which compared both intravenous and subcutaneous forms of rontalizumab with placebo. In ISM-low patients, a quarter of the total enrolled, IV rontalizumab vs. placebo SLE Responder Index (SRI) response rates were 75% vs. 18%. Treatment groups saw a nearly 40% reduced risk of disease flare based on SELENA-SLEDAI (Safety of Estrogens in Lupus Erythematosus National Assessment-SLE Disease Activity Index) flare rates, compared with placebo (hazard ratio 0.61 [90% confidence interval 0.46-0.81; P = .0040]), driven by ISM-low patients. Also, 91% of ISM-low patients in the treatment groups achieved prednisone reduction (10 mg/day) by week 24, compared with 67% of placebo subjects (Lupus 2013;22[Suppl.]:O22).

Limiting background medications in trials

Background immunosuppressants were not used in the rontalizumab study, and steroids were limited. Dr. Merrill, of the University of Oklahoma Health Sciences Center, Oklahoma City, discussed some of the thinking behind this. Limiting background medications "can lead to more interpretable results," she said. While many investigators have argued that only the sickest and most refractory patients should be enrolled in SLE clinical trials as a way to discern a clearer differences between treatment and placebo, Dr. Merrill instead championed recruiting less-sick patients for whom it is safer to withdraw or minimize background medicines.

Patients without severe disease will still die early and accumulate increasing damage over time, Dr. Merrill said. "They represent a huge unmet need. So if we could do trials with these patients and limit the background noise caused by their medications, perhaps we could also see a difference between treatment and placebo. Trials would be easier to recruit, we would see fewer infections, and most importantly, there would be a bigger market for pharma companies to pursue."

Targeting CD22 antigen on B cells

Two randomized, placebo-controlled trials of epratuzumab, a monoclonal antibody targeting CD22 antigen on B cells, had to be terminated when drug supply was interrupted. However, the early findings had shown clinically meaningful improvements in disease activity and corticosteroid sparing. Final results from an open-label extension study for SLE patients previously enrolled in these trials (n = 429), sponsored by UCB Pharma, showed that continued administration of epratuzumab resulted in sustained improvements after a mean four years of treatment, with no new safety signals (Lupus 2013;22[Suppl.]:O25).

Phase II data on blisibimod

Blisibimod, a biologic injected subcutaneously that inhibits B-cell activating factor, or BAFF, was investigated in a phase IIb manufacturer-sponsored trial of 547 patients with anti-dsDNA or anti-nuclear antibodies and SELENA-SLEDAI score of 6 or higher at baseline. Dr. Morton Scheinberg of Rheumatology Hospital Abreu Sodre Pesquisa Clínica, São Paulo, Brazil, led the trial, sponsored by Anthera Pharmaceuticals, in which patients were randomized to one of three doses or placebo. The composite primary endpoint, SRI-5 (defined as a 5-point improvement in SELENA-SLEDAI, no new BILAG A or 2B organ domain scores, and no worsening in Physician’s Global Assessment) was not met because efficacy was not shown in the lower doses. However, more subjects who received the highest dose (200 mg once weekly) met the response criteria starting in week 16 (8%, P = .14), through week 24 (8.2%, P = .15), reaching statistical significance at week 20 (Lupus 2013;22[Suppl.]:O21).

Improving on past trial missteps

One of the coinvestigators on the blisibimod trial, Dr. Richard A. Furie, discussed missteps in the design of earlier studies. "Trials of new biologic therapies have taught us to be humble and logical, and to persevere – we’ve made a lot of mistakes over last 20 years," he told the conference, pointing to a handful of trials in which subjects did not have serologic evidence of disease at baseline. "In my book, if someone is clinically active they should have autoantibodies," he said. "So the rules for entry were changed for all trials."

Dr. Furie, chief of the division of rheumatology and allergy-clinical immunology in the North Shore–LIJ Health System and professor of medicine at Hofstra University, Hempstead, N.Y., said that while inclusion criteria had improved, investigators of biologic agents still had far to go in refining SLE trial endpoints. "No two endpoints are the same – we’ve customized the endpoints and are struggling with extrarenal trials whether it should be a single or composite endpoint, whether it should be based on SLEDAI or BILAG alone or should we use SRI – there is no consensus." Echoing Dr. Merrill, he stressed that background medications were another area in need of increased scrutiny and consensus. "Each trial has handled steroids and immunosuppressants differently," he said.

Dr. Merrill has received support from Genentech. Dr. Furie has received support from Anthera, Genentech, and UCB Pharma. Both rheumatologists have received support from many other companies involved in lupus research and therapy.

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.