NYU Seminar In Advanced Rheumatology

NEW YORK – Evidence for the use of biologics such as rituximab and abatacept to treat refractory lupus nephritis has been hampered by varying definitions of the condition and design differences in clinical trials, according to Dr. Brad H. Rovin.

Evidence of the benefit to using rituximab 1 g every 2 weeks for refractory lupus nephritis, as suggested by the American College of Rheumatology’s guidelines (Arthritis Care Res. 2012;64:797-808), is hard to confirm with the available data, Dr. Rovin said at a meeting sponsored by New York University.

"The rituximab studies are very difficult to interpret due to small sample size, aggressive concomitant therapies, variable dosing regimens, and nonuniform definitions of refractory," said Dr. Rovin, professor of nephrology and pathology and director of the division of nephrology at Ohio State University in Columbus. "Nonetheless, this collection of data has prompted the idea that rituximab is effective for refractory lupus nephritis."

Although pooled data suggest that rituximab might be helpful in refractory lupus nephritis (Autoimmun. Rev. 2012:11:357-64), only a true randomized controlled trial with sufficient power that is designed to overcome these criticisms will settle the issue, he noted. The European RING (Rituximab for Lupus Nephritis With Remission as a Goal) trial, which started in November 2012, will initially ask whether rituximab can be a useful salvage therapy once a patient still has active disease after 6 months of standard-of-care treatment. However, in Dr. Rovin’s opinion, the patients being recruited for the trial are not truly refractory because the failure of two inductiontype regimens before beginning rituximab is not required.

Examining the LUNAR trial failure

The randomized, double-blind, placebo-controlled phase III LUNAR (Lupus Nephritis Assessment With Rituximab) trial – one of the most anticipated clinical trials of lupus nephritis treatment – failed to reach its primary endpoint (Arthritis Rheum. 2012;64:1215-26), said Dr. Rovin, who was the lead author of the report. In fact, in the last few years, none of the trials of novel therapeutics for lupus nephritis have achieved their primary endpoints.

The primary endpoint of renal response (complete and partial) at week 52 was similar in patients who received rituximab or placebo (56.0% vs. 45.8%, respectively), although improvements were seen with rituximab in serum C3 and C4 and anti–double-stranded DNA antibodies. The trial involved 144 patients with class III or IV lupus nephritis treated with rituximab (1,000 mg) or placebo added on to mycophenolate mofetil and corticosteroids. Patients received rituximab or placebo on days 1, 15, 168, and 182.

Did LUNAR fail because it was added on to an already effective therapy? Dr. Rovin asked. He pointed to data from studies of other current therapies, including intravenous cyclophosphamide, which showed relatively high partial responses (63%) but low complete responses (12%-31%). "Current therapies are only modestly effective, and there is plenty of room for improvement. Evaluating add-on therapies to the standard of care is an acceptable trial design for what we can accomplish now," Dr. Rovin said.

The LUNAR trial was powered to detect complete renal remissions, and its failure to detect a difference between treatment groups does not mean that the trial should have been powered to favor partial remissions, Dr. Rovin said. In a study in which he participated that was presented last year at the American Society of Nephrology, Dr. Rovin and his colleagues found that over a period of 4.5 years, patients who have acute kidney injury as evidenced by renal flares were at heightened risk of developing new chronic kidney disease (CKD) or progression of established kidney disease. Patients with new CKD had a significantly greater frequency of new renal flares than did those without CKD (0.72 per year vs. 0.14 per year; P = .001) as well as a greater duration of time spent in flare (20 months vs. 0 months; P = .0003). These results show that "we should not be satisfied with partial remissions as an endpoint, because unresolved kidney inflammation and injury predispose these patients to CKD," he said.

The issue has also been raised as to whether LUNAR failed because its endpoint of 1 year was too short. There may have been better separation between rituximab and placebo with a 2-year endpoint, but Dr. Rovin’s own findings with repeat biopsies following good clinical responses after the first 6 months of conventional therapy (mycophenolate mofetil or intravenous cyclophosphamide for 6 months) have shown evidence of progressive renal scarring despite significant reductions in creatinine and proteinuria. These data suggest that the goal of therapy should be to decrease the time to response as much as possible and thereby perhaps decrease kidney scarring because scarring and damage to the kidney tubulointerstitium are what determine the renal prognosis. "We should not be satisfied with taking a year or more to achieve remissions," he said.

Failure of abatacept lupus nephritis trial

The failure of another recent trial to show any benefit of abatacept in treating refractory lupus nephritis could also be related to the problem of inconsistent trial endpoints making it difficult to compare therapies (Arthritis Rheum. 2012;64:3660-5). For instance, urine protein-creatinine ratios (UPCRs) are subject to individual variability but the criteria for UPCRs have varied from 0.2 to 0.5 in different lupus nephritis trials, including this abatacept trial, the LUNAR trial, the Aspreva Lupus Management Study (ALMS), and the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) trial, as well as in the ACR’s recommendations for lupus nephritis.

Estimated glomerular filtration rate (eGFR) criteria also are inconsistent, and endpoints that refer to "normal" eGFRs are hard to interpret, Dr. Rovin said, because it is unclear what is normal for creatine "unless the patient’s true serum creatinine before SLE is known."

"We need uniform, reasonable and consistent response criteria for lupus nephritis clinical trials, and these responses should be associated with long-term outcomes," said Dr. Rovin, who noted that he is involved in preparing a white paper on clinical trial design for lupus nephritis.

Dr. Rovin has served as a consultant to Bristol-Myers Squibb, which markets abatacept, as well as Biogen Idec and Genentech, which comarket rituximab in the United States. He has also received honoraria from Biogen Idec and Genentech and research funding from Roche, Genentech’s parent company.

NEW YORK – Evidence for the use of biologics such as rituximab and abatacept to treat refractory lupus nephritis has been hampered by varying definitions of the condition and design differences in clinical trials, according to Dr. Brad H. Rovin.

Evidence of the benefit to using rituximab 1 g every 2 weeks for refractory lupus nephritis, as suggested by the American College of Rheumatology’s guidelines (Arthritis Care Res. 2012;64:797-808), is hard to confirm with the available data, Dr. Rovin said at a meeting sponsored by New York University.

"The rituximab studies are very difficult to interpret due to small sample size, aggressive concomitant therapies, variable dosing regimens, and nonuniform definitions of refractory," said Dr. Rovin, professor of nephrology and pathology and director of the division of nephrology at Ohio State University in Columbus. "Nonetheless, this collection of data has prompted the idea that rituximab is effective for refractory lupus nephritis."

Although pooled data suggest that rituximab might be helpful in refractory lupus nephritis (Autoimmun. Rev. 2012:11:357-64), only a true randomized controlled trial with sufficient power that is designed to overcome these criticisms will settle the issue, he noted. The European RING (Rituximab for Lupus Nephritis With Remission as a Goal) trial, which started in November 2012, will initially ask whether rituximab can be a useful salvage therapy once a patient still has active disease after 6 months of standard-of-care treatment. However, in Dr. Rovin’s opinion, the patients being recruited for the trial are not truly refractory because the failure of two inductiontype regimens before beginning rituximab is not required.

Examining the LUNAR trial failure

The randomized, double-blind, placebo-controlled phase III LUNAR (Lupus Nephritis Assessment With Rituximab) trial – one of the most anticipated clinical trials of lupus nephritis treatment – failed to reach its primary endpoint (Arthritis Rheum. 2012;64:1215-26), said Dr. Rovin, who was the lead author of the report. In fact, in the last few years, none of the trials of novel therapeutics for lupus nephritis have achieved their primary endpoints.

The primary endpoint of renal response (complete and partial) at week 52 was similar in patients who received rituximab or placebo (56.0% vs. 45.8%, respectively), although improvements were seen with rituximab in serum C3 and C4 and anti–double-stranded DNA antibodies. The trial involved 144 patients with class III or IV lupus nephritis treated with rituximab (1,000 mg) or placebo added on to mycophenolate mofetil and corticosteroids. Patients received rituximab or placebo on days 1, 15, 168, and 182.

Did LUNAR fail because it was added on to an already effective therapy? Dr. Rovin asked. He pointed to data from studies of other current therapies, including intravenous cyclophosphamide, which showed relatively high partial responses (63%) but low complete responses (12%-31%). "Current therapies are only modestly effective, and there is plenty of room for improvement. Evaluating add-on therapies to the standard of care is an acceptable trial design for what we can accomplish now," Dr. Rovin said.

The LUNAR trial was powered to detect complete renal remissions, and its failure to detect a difference between treatment groups does not mean that the trial should have been powered to favor partial remissions, Dr. Rovin said. In a study in which he participated that was presented last year at the American Society of Nephrology, Dr. Rovin and his colleagues found that over a period of 4.5 years, patients who have acute kidney injury as evidenced by renal flares were at heightened risk of developing new chronic kidney disease (CKD) or progression of established kidney disease. Patients with new CKD had a significantly greater frequency of new renal flares than did those without CKD (0.72 per year vs. 0.14 per year; P = .001) as well as a greater duration of time spent in flare (20 months vs. 0 months; P = .0003). These results show that "we should not be satisfied with partial remissions as an endpoint, because unresolved kidney inflammation and injury predispose these patients to CKD," he said.

The issue has also been raised as to whether LUNAR failed because its endpoint of 1 year was too short. There may have been better separation between rituximab and placebo with a 2-year endpoint, but Dr. Rovin’s own findings with repeat biopsies following good clinical responses after the first 6 months of conventional therapy (mycophenolate mofetil or intravenous cyclophosphamide for 6 months) have shown evidence of progressive renal scarring despite significant reductions in creatinine and proteinuria. These data suggest that the goal of therapy should be to decrease the time to response as much as possible and thereby perhaps decrease kidney scarring because scarring and damage to the kidney tubulointerstitium are what determine the renal prognosis. "We should not be satisfied with taking a year or more to achieve remissions," he said.

Failure of abatacept lupus nephritis trial

The failure of another recent trial to show any benefit of abatacept in treating refractory lupus nephritis could also be related to the problem of inconsistent trial endpoints making it difficult to compare therapies (Arthritis Rheum. 2012;64:3660-5). For instance, urine protein-creatinine ratios (UPCRs) are subject to individual variability but the criteria for UPCRs have varied from 0.2 to 0.5 in different lupus nephritis trials, including this abatacept trial, the LUNAR trial, the Aspreva Lupus Management Study (ALMS), and the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) trial, as well as in the ACR’s recommendations for lupus nephritis.

Estimated glomerular filtration rate (eGFR) criteria also are inconsistent, and endpoints that refer to "normal" eGFRs are hard to interpret, Dr. Rovin said, because it is unclear what is normal for creatine "unless the patient’s true serum creatinine before SLE is known."

"We need uniform, reasonable and consistent response criteria for lupus nephritis clinical trials, and these responses should be associated with long-term outcomes," said Dr. Rovin, who noted that he is involved in preparing a white paper on clinical trial design for lupus nephritis.

Dr. Rovin has served as a consultant to Bristol-Myers Squibb, which markets abatacept, as well as Biogen Idec and Genentech, which comarket rituximab in the United States. He has also received honoraria from Biogen Idec and Genentech and research funding from Roche, Genentech’s parent company.

NEW YORK – Evidence for the use of biologics such as rituximab and abatacept to treat refractory lupus nephritis has been hampered by varying definitions of the condition and design differences in clinical trials, according to Dr. Brad H. Rovin.

Evidence of the benefit to using rituximab 1 g every 2 weeks for refractory lupus nephritis, as suggested by the American College of Rheumatology’s guidelines (Arthritis Care Res. 2012;64:797-808), is hard to confirm with the available data, Dr. Rovin said at a meeting sponsored by New York University.

"The rituximab studies are very difficult to interpret due to small sample size, aggressive concomitant therapies, variable dosing regimens, and nonuniform definitions of refractory," said Dr. Rovin, professor of nephrology and pathology and director of the division of nephrology at Ohio State University in Columbus. "Nonetheless, this collection of data has prompted the idea that rituximab is effective for refractory lupus nephritis."

Although pooled data suggest that rituximab might be helpful in refractory lupus nephritis (Autoimmun. Rev. 2012:11:357-64), only a true randomized controlled trial with sufficient power that is designed to overcome these criticisms will settle the issue, he noted. The European RING (Rituximab for Lupus Nephritis With Remission as a Goal) trial, which started in November 2012, will initially ask whether rituximab can be a useful salvage therapy once a patient still has active disease after 6 months of standard-of-care treatment. However, in Dr. Rovin’s opinion, the patients being recruited for the trial are not truly refractory because the failure of two inductiontype regimens before beginning rituximab is not required.

Examining the LUNAR trial failure

The randomized, double-blind, placebo-controlled phase III LUNAR (Lupus Nephritis Assessment With Rituximab) trial – one of the most anticipated clinical trials of lupus nephritis treatment – failed to reach its primary endpoint (Arthritis Rheum. 2012;64:1215-26), said Dr. Rovin, who was the lead author of the report. In fact, in the last few years, none of the trials of novel therapeutics for lupus nephritis have achieved their primary endpoints.

The primary endpoint of renal response (complete and partial) at week 52 was similar in patients who received rituximab or placebo (56.0% vs. 45.8%, respectively), although improvements were seen with rituximab in serum C3 and C4 and anti–double-stranded DNA antibodies. The trial involved 144 patients with class III or IV lupus nephritis treated with rituximab (1,000 mg) or placebo added on to mycophenolate mofetil and corticosteroids. Patients received rituximab or placebo on days 1, 15, 168, and 182.

Did LUNAR fail because it was added on to an already effective therapy? Dr. Rovin asked. He pointed to data from studies of other current therapies, including intravenous cyclophosphamide, which showed relatively high partial responses (63%) but low complete responses (12%-31%). "Current therapies are only modestly effective, and there is plenty of room for improvement. Evaluating add-on therapies to the standard of care is an acceptable trial design for what we can accomplish now," Dr. Rovin said.

The LUNAR trial was powered to detect complete renal remissions, and its failure to detect a difference between treatment groups does not mean that the trial should have been powered to favor partial remissions, Dr. Rovin said. In a study in which he participated that was presented last year at the American Society of Nephrology, Dr. Rovin and his colleagues found that over a period of 4.5 years, patients who have acute kidney injury as evidenced by renal flares were at heightened risk of developing new chronic kidney disease (CKD) or progression of established kidney disease. Patients with new CKD had a significantly greater frequency of new renal flares than did those without CKD (0.72 per year vs. 0.14 per year; P = .001) as well as a greater duration of time spent in flare (20 months vs. 0 months; P = .0003). These results show that "we should not be satisfied with partial remissions as an endpoint, because unresolved kidney inflammation and injury predispose these patients to CKD," he said.

The issue has also been raised as to whether LUNAR failed because its endpoint of 1 year was too short. There may have been better separation between rituximab and placebo with a 2-year endpoint, but Dr. Rovin’s own findings with repeat biopsies following good clinical responses after the first 6 months of conventional therapy (mycophenolate mofetil or intravenous cyclophosphamide for 6 months) have shown evidence of progressive renal scarring despite significant reductions in creatinine and proteinuria. These data suggest that the goal of therapy should be to decrease the time to response as much as possible and thereby perhaps decrease kidney scarring because scarring and damage to the kidney tubulointerstitium are what determine the renal prognosis. "We should not be satisfied with taking a year or more to achieve remissions," he said.

Failure of abatacept lupus nephritis trial

The failure of another recent trial to show any benefit of abatacept in treating refractory lupus nephritis could also be related to the problem of inconsistent trial endpoints making it difficult to compare therapies (Arthritis Rheum. 2012;64:3660-5). For instance, urine protein-creatinine ratios (UPCRs) are subject to individual variability but the criteria for UPCRs have varied from 0.2 to 0.5 in different lupus nephritis trials, including this abatacept trial, the LUNAR trial, the Aspreva Lupus Management Study (ALMS), and the Abatacept and Cyclophosphamide Combination Therapy for Lupus Nephritis (ACCESS) trial, as well as in the ACR’s recommendations for lupus nephritis.

Estimated glomerular filtration rate (eGFR) criteria also are inconsistent, and endpoints that refer to "normal" eGFRs are hard to interpret, Dr. Rovin said, because it is unclear what is normal for creatine "unless the patient’s true serum creatinine before SLE is known."

"We need uniform, reasonable and consistent response criteria for lupus nephritis clinical trials, and these responses should be associated with long-term outcomes," said Dr. Rovin, who noted that he is involved in preparing a white paper on clinical trial design for lupus nephritis.

Dr. Rovin has served as a consultant to Bristol-Myers Squibb, which markets abatacept, as well as Biogen Idec and Genentech, which comarket rituximab in the United States. He has also received honoraria from Biogen Idec and Genentech and research funding from Roche, Genentech’s parent company.

NEW YORK – Evidence has accumulated in recent years that IL-1-beta-mediated inflammation and a dysregulation of the innate immune system is common to many autoinflammatory disorders that involve bouts of seemingly unprovoked recurrent inflammation and no indication of malignancy or infection, according to Dr. Jonathan Samuels.

These findings have opened up new therapeutic targets for these disorders, and some recent clinical studies suggest that investigators are on the right track, said Dr. Samuels, a rheumatologist affiliated with the Center for Musculoskeletal Care at NYU Langone Medical Center, New York.

The term "autoinflammation" was coined in 1999 following the discovery of the genes responsible for Familial Mediterranean Fever (FMF), a disease characterized by recurrent episodes of fever and abdominal pain, along with pleurisy, arthritis, and other symptoms. Patients feel normal between bouts and are unresponsive to corticosteroids. Like other patients with autoinflammatory diseases, FMF patients show no evidence of autoantibodies or antigen-specific T-cell reactivity, suggesting instead disordered regulation of the innate immune system, Dr. Samuels said at a meeting sponsored by New York University.

IL-1 has been identified as one of the most potent proinflammatory cytokines of the innate immune system, and is being recognized as a likely therapeutic target. "Many molecular cascades from various autoinflammatory diseases converge at IL-1, with oversecretion (as in the case of neonatal-onset multisystem inflammatory disease or NOMID) or uninhibited signaling (as in the case of deficiency of the interleukin-1-receptor antagonist or DIRA)," Dr. Samuels said.

For example, while colchicine has been shown to prevent acute attacks of FMF by 75% and decrease symptoms in 95%, there are no proven alternative therapies for patients with FMF who are resistant or intolerant to colchicine. Dr. Samuels was a coinvestigator of a recent randomized, double-blind placebo-controlled trial in which 14 patients with FMF who were colchicine resistant or intolerant were treated with the IL-1 antagonist rilonacept (2.2 mg/kg, maximum 160 mg) given by weekly subcutaneous injection for two 3-month courses. Rilonacept resulted in a significant reduction in the number of attacks per month (0.77 vs. 2.00, P = .027) and there were more treatment courses without attacks with rilonacept, compared with placebo. Rilonacept did not affect the duration of attacks (Ann. Intern. Med. 2012;157:533-41).

The cryopyrin-associated periodic syndromes, commonly known as CAPS, are a group of autosomal dominant autoinflammatory diseases that have been linked to mutations in the same gene. All three cryopyrinopathies have an early onset and present with urticarial rash and fever, although they span a spectrum of severity, according to Dr. Samuels. The mildest form is familial cold autoinflammatory syndrome (FCAS), which involves episodes generally lasting less than 24 hours, and is accompanied by headache and polyarthralgia. Muckle-Wells syndrome lasts 24-48 hours, and may cause deafness, optic disk edema, oligoarthritis, and polyarthralgia, as well as abdominal pain. Patients with NOMID are the most severely affected, with almost-continuous episodes, chronic meningitis, mental retardation, deafness, blindness, epiphyseal/patellar overgrowth, and intermittent chronic arthritis.

All three CAPS syndromes have been shown to respond to anti-IL-1 agents, according to Dr. Samuels. For example, in 2012, researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases found in an open-label cohort study of 26 patients with NOMID that the IL-1 inhibitor anakinra yielded long-term improvements in measures such as global scores of disease activity, pain, CNS inflammation, and hearing for up to 5 years as long as escalating doses were used (Arthritis Rheum. 2012;64:2375-86).

Treatment with anakinra also has been beneficial for neonates with DIRA, which involves an autosomal recessive mutation on chromosome 2q that leads to uncontrolled IL-1 binding and causes crusting, erythema, pustulosis, and osteolytic lesions.

"This is a very complex group of disorders," Dr. Samuels said. Diagnosis should take into account ethnicity, inheritance pattern, cytokines, attack duration, treatment response, age of onset, triggers, and amyloid frequency. He referred audience members to a helpful diagnostic algorithm (Cleveland Clinic J. Med. 2012;79:569-81).

Dr. Samuels reported no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – Evidence has accumulated in recent years that IL-1-beta-mediated inflammation and a dysregulation of the innate immune system is common to many autoinflammatory disorders that involve bouts of seemingly unprovoked recurrent inflammation and no indication of malignancy or infection, according to Dr. Jonathan Samuels.

These findings have opened up new therapeutic targets for these disorders, and some recent clinical studies suggest that investigators are on the right track, said Dr. Samuels, a rheumatologist affiliated with the Center for Musculoskeletal Care at NYU Langone Medical Center, New York.

The term "autoinflammation" was coined in 1999 following the discovery of the genes responsible for Familial Mediterranean Fever (FMF), a disease characterized by recurrent episodes of fever and abdominal pain, along with pleurisy, arthritis, and other symptoms. Patients feel normal between bouts and are unresponsive to corticosteroids. Like other patients with autoinflammatory diseases, FMF patients show no evidence of autoantibodies or antigen-specific T-cell reactivity, suggesting instead disordered regulation of the innate immune system, Dr. Samuels said at a meeting sponsored by New York University.

IL-1 has been identified as one of the most potent proinflammatory cytokines of the innate immune system, and is being recognized as a likely therapeutic target. "Many molecular cascades from various autoinflammatory diseases converge at IL-1, with oversecretion (as in the case of neonatal-onset multisystem inflammatory disease or NOMID) or uninhibited signaling (as in the case of deficiency of the interleukin-1-receptor antagonist or DIRA)," Dr. Samuels said.

For example, while colchicine has been shown to prevent acute attacks of FMF by 75% and decrease symptoms in 95%, there are no proven alternative therapies for patients with FMF who are resistant or intolerant to colchicine. Dr. Samuels was a coinvestigator of a recent randomized, double-blind placebo-controlled trial in which 14 patients with FMF who were colchicine resistant or intolerant were treated with the IL-1 antagonist rilonacept (2.2 mg/kg, maximum 160 mg) given by weekly subcutaneous injection for two 3-month courses. Rilonacept resulted in a significant reduction in the number of attacks per month (0.77 vs. 2.00, P = .027) and there were more treatment courses without attacks with rilonacept, compared with placebo. Rilonacept did not affect the duration of attacks (Ann. Intern. Med. 2012;157:533-41).

The cryopyrin-associated periodic syndromes, commonly known as CAPS, are a group of autosomal dominant autoinflammatory diseases that have been linked to mutations in the same gene. All three cryopyrinopathies have an early onset and present with urticarial rash and fever, although they span a spectrum of severity, according to Dr. Samuels. The mildest form is familial cold autoinflammatory syndrome (FCAS), which involves episodes generally lasting less than 24 hours, and is accompanied by headache and polyarthralgia. Muckle-Wells syndrome lasts 24-48 hours, and may cause deafness, optic disk edema, oligoarthritis, and polyarthralgia, as well as abdominal pain. Patients with NOMID are the most severely affected, with almost-continuous episodes, chronic meningitis, mental retardation, deafness, blindness, epiphyseal/patellar overgrowth, and intermittent chronic arthritis.

All three CAPS syndromes have been shown to respond to anti-IL-1 agents, according to Dr. Samuels. For example, in 2012, researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases found in an open-label cohort study of 26 patients with NOMID that the IL-1 inhibitor anakinra yielded long-term improvements in measures such as global scores of disease activity, pain, CNS inflammation, and hearing for up to 5 years as long as escalating doses were used (Arthritis Rheum. 2012;64:2375-86).

Treatment with anakinra also has been beneficial for neonates with DIRA, which involves an autosomal recessive mutation on chromosome 2q that leads to uncontrolled IL-1 binding and causes crusting, erythema, pustulosis, and osteolytic lesions.

"This is a very complex group of disorders," Dr. Samuels said. Diagnosis should take into account ethnicity, inheritance pattern, cytokines, attack duration, treatment response, age of onset, triggers, and amyloid frequency. He referred audience members to a helpful diagnostic algorithm (Cleveland Clinic J. Med. 2012;79:569-81).

Dr. Samuels reported no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – Evidence has accumulated in recent years that IL-1-beta-mediated inflammation and a dysregulation of the innate immune system is common to many autoinflammatory disorders that involve bouts of seemingly unprovoked recurrent inflammation and no indication of malignancy or infection, according to Dr. Jonathan Samuels.

These findings have opened up new therapeutic targets for these disorders, and some recent clinical studies suggest that investigators are on the right track, said Dr. Samuels, a rheumatologist affiliated with the Center for Musculoskeletal Care at NYU Langone Medical Center, New York.

The term "autoinflammation" was coined in 1999 following the discovery of the genes responsible for Familial Mediterranean Fever (FMF), a disease characterized by recurrent episodes of fever and abdominal pain, along with pleurisy, arthritis, and other symptoms. Patients feel normal between bouts and are unresponsive to corticosteroids. Like other patients with autoinflammatory diseases, FMF patients show no evidence of autoantibodies or antigen-specific T-cell reactivity, suggesting instead disordered regulation of the innate immune system, Dr. Samuels said at a meeting sponsored by New York University.

IL-1 has been identified as one of the most potent proinflammatory cytokines of the innate immune system, and is being recognized as a likely therapeutic target. "Many molecular cascades from various autoinflammatory diseases converge at IL-1, with oversecretion (as in the case of neonatal-onset multisystem inflammatory disease or NOMID) or uninhibited signaling (as in the case of deficiency of the interleukin-1-receptor antagonist or DIRA)," Dr. Samuels said.

For example, while colchicine has been shown to prevent acute attacks of FMF by 75% and decrease symptoms in 95%, there are no proven alternative therapies for patients with FMF who are resistant or intolerant to colchicine. Dr. Samuels was a coinvestigator of a recent randomized, double-blind placebo-controlled trial in which 14 patients with FMF who were colchicine resistant or intolerant were treated with the IL-1 antagonist rilonacept (2.2 mg/kg, maximum 160 mg) given by weekly subcutaneous injection for two 3-month courses. Rilonacept resulted in a significant reduction in the number of attacks per month (0.77 vs. 2.00, P = .027) and there were more treatment courses without attacks with rilonacept, compared with placebo. Rilonacept did not affect the duration of attacks (Ann. Intern. Med. 2012;157:533-41).

The cryopyrin-associated periodic syndromes, commonly known as CAPS, are a group of autosomal dominant autoinflammatory diseases that have been linked to mutations in the same gene. All three cryopyrinopathies have an early onset and present with urticarial rash and fever, although they span a spectrum of severity, according to Dr. Samuels. The mildest form is familial cold autoinflammatory syndrome (FCAS), which involves episodes generally lasting less than 24 hours, and is accompanied by headache and polyarthralgia. Muckle-Wells syndrome lasts 24-48 hours, and may cause deafness, optic disk edema, oligoarthritis, and polyarthralgia, as well as abdominal pain. Patients with NOMID are the most severely affected, with almost-continuous episodes, chronic meningitis, mental retardation, deafness, blindness, epiphyseal/patellar overgrowth, and intermittent chronic arthritis.

All three CAPS syndromes have been shown to respond to anti-IL-1 agents, according to Dr. Samuels. For example, in 2012, researchers from the National Institute of Arthritis and Musculoskeletal and Skin Diseases found in an open-label cohort study of 26 patients with NOMID that the IL-1 inhibitor anakinra yielded long-term improvements in measures such as global scores of disease activity, pain, CNS inflammation, and hearing for up to 5 years as long as escalating doses were used (Arthritis Rheum. 2012;64:2375-86).

Treatment with anakinra also has been beneficial for neonates with DIRA, which involves an autosomal recessive mutation on chromosome 2q that leads to uncontrolled IL-1 binding and causes crusting, erythema, pustulosis, and osteolytic lesions.

"This is a very complex group of disorders," Dr. Samuels said. Diagnosis should take into account ethnicity, inheritance pattern, cytokines, attack duration, treatment response, age of onset, triggers, and amyloid frequency. He referred audience members to a helpful diagnostic algorithm (Cleveland Clinic J. Med. 2012;79:569-81).

Dr. Samuels reported no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – While nowadays there is less likelihood that the hepatitis B virus causes rheumatic disease, major changes in epidemiology and drug therapy, especially the use of immunosuppressives, have made reactivation of the virus during the course of rheumatic disease treatment a major public health concern, according to Dr. Leonard H. Calabrese.

"HBV reactivation has been well known in cancer and transplantation but is now really coming to the fore in autoimmune and autoinflammatory diseases. It may be mild (asymptomatic viremia) or severe (fulminant liver failure and death) and has been observed in patients with both chronic infection or resolved disease. While it is largely preventable, unfortunately many physicians who regularly prescribe immunosuppressive therapies – including rheumatologists, oncologists, gastroenterologists, and dermatologists – do not recognize this potential," Dr. Calabrese said at a meeting sponsored by New York University.

The major risk of HBV is not during but after immunosuppression, when reactivation leading to severe or fatal hepatitis can occur. Reactivations have been reported rarely with low-dose prednisone and methotrexate, as well as all tumor necrosis factor (TNF) inhibitors, rituximab, abatacept, and infliximab, prompting a black box warning for many biologics, said Dr. Calabrese, director of the Fasenmyer Center for Clinical Immunology at the Cleveland Clinic.

In a retrospective study of 257 patients with positive HBV markers who were treated with TNF-targeted therapies, 39% with chronic infections (as indicated by the presence of HB surface antigens) developed HBV reactivation. Five developed acute liver failure, and four died (Medicine 2011;90:359-71). "This is not a trivial risk," Dr. Calabrese said.

Yet many rheumatologists do not screen for HBV prior to prescribing immunosuppressive therapy, he said. Dr. Calabrese cited a 2010 survey of rheumatologists that found that only 42% routinely screen for HBV before a patient begins nonbiologic disease-modifying antirheumatic drug therapy and 69% screen before prescribing a biologic DMARD. Seven percent of rheumatologists reported witnessing a reactivation event (Arthritis Care Res. 2010;62:704-11).

Of the three serologic markers for HBV (the hepatitis B surface antigen [HBsAg], the total hepatitis B core antibody [anti-HBc]), and the hepatitis B surface antibody (anti-HBsAb), Dr. Calabrese said he prefers HBsAg. "If you remember anything from this talk, remember that all patients with hepatitis B surface antigen need to be tended to before beginning any rheumatic therapy," he said. All positive tests should be followed up with HBV DNA testing.

Although all patients with a history of HBV are at some risk for HBV reactivation, with or without the presence of serologic markers, Dr. Calabrese outlined the relative risks of HBV reactivation as indicated by serologic findings. Those at highest risk are patients with chronic HBV infection (HBsAg positive, high level of HBV DNA), followed by inactive carriers (HBsAg positive, some HBV DNA) and those with resolved HBV (HBsAg negative, anti-HBc positive, anti-HBsAb positive). Those at lowest risk have resolved HBV (anti-HBc alone).

Rheumatologists should also be aware of the increased chance of HBV reactivation in high-risk populations. While in urban areas HBV is known to be associated with drug abuse, there is also a heightened risk in immigrants, especially those from Asia. Asian Americans are 2.7 times more likely to develop hepatocellular carcinoma. According to Dr. Calabrese, in mainland China there are an estimated 1 million people with rheumatologic problems who manifest chronic HBsAg positivity. "This is a global health problem," he noted.

Dr. Calabrese recommended that preemptive therapeutic measures be taken for all HBsAg-positive and HBV DNA–positive patients, including possible lifelong antiviral medication, and then these patients can be treated for their rheumatologic issues. Those who test positive for anti-HBc should be carefully monitored. "There should not be a patient with spondylitis, rheumatoid arthritis, lupus, or vasculitis who is getting less than effective therapy because they have chronic HBV," he said.

Dr. Calabrese reported no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – While nowadays there is less likelihood that the hepatitis B virus causes rheumatic disease, major changes in epidemiology and drug therapy, especially the use of immunosuppressives, have made reactivation of the virus during the course of rheumatic disease treatment a major public health concern, according to Dr. Leonard H. Calabrese.

"HBV reactivation has been well known in cancer and transplantation but is now really coming to the fore in autoimmune and autoinflammatory diseases. It may be mild (asymptomatic viremia) or severe (fulminant liver failure and death) and has been observed in patients with both chronic infection or resolved disease. While it is largely preventable, unfortunately many physicians who regularly prescribe immunosuppressive therapies – including rheumatologists, oncologists, gastroenterologists, and dermatologists – do not recognize this potential," Dr. Calabrese said at a meeting sponsored by New York University.

The major risk of HBV is not during but after immunosuppression, when reactivation leading to severe or fatal hepatitis can occur. Reactivations have been reported rarely with low-dose prednisone and methotrexate, as well as all tumor necrosis factor (TNF) inhibitors, rituximab, abatacept, and infliximab, prompting a black box warning for many biologics, said Dr. Calabrese, director of the Fasenmyer Center for Clinical Immunology at the Cleveland Clinic.

In a retrospective study of 257 patients with positive HBV markers who were treated with TNF-targeted therapies, 39% with chronic infections (as indicated by the presence of HB surface antigens) developed HBV reactivation. Five developed acute liver failure, and four died (Medicine 2011;90:359-71). "This is not a trivial risk," Dr. Calabrese said.

Yet many rheumatologists do not screen for HBV prior to prescribing immunosuppressive therapy, he said. Dr. Calabrese cited a 2010 survey of rheumatologists that found that only 42% routinely screen for HBV before a patient begins nonbiologic disease-modifying antirheumatic drug therapy and 69% screen before prescribing a biologic DMARD. Seven percent of rheumatologists reported witnessing a reactivation event (Arthritis Care Res. 2010;62:704-11).

Of the three serologic markers for HBV (the hepatitis B surface antigen [HBsAg], the total hepatitis B core antibody [anti-HBc]), and the hepatitis B surface antibody (anti-HBsAb), Dr. Calabrese said he prefers HBsAg. "If you remember anything from this talk, remember that all patients with hepatitis B surface antigen need to be tended to before beginning any rheumatic therapy," he said. All positive tests should be followed up with HBV DNA testing.

Although all patients with a history of HBV are at some risk for HBV reactivation, with or without the presence of serologic markers, Dr. Calabrese outlined the relative risks of HBV reactivation as indicated by serologic findings. Those at highest risk are patients with chronic HBV infection (HBsAg positive, high level of HBV DNA), followed by inactive carriers (HBsAg positive, some HBV DNA) and those with resolved HBV (HBsAg negative, anti-HBc positive, anti-HBsAb positive). Those at lowest risk have resolved HBV (anti-HBc alone).

Rheumatologists should also be aware of the increased chance of HBV reactivation in high-risk populations. While in urban areas HBV is known to be associated with drug abuse, there is also a heightened risk in immigrants, especially those from Asia. Asian Americans are 2.7 times more likely to develop hepatocellular carcinoma. According to Dr. Calabrese, in mainland China there are an estimated 1 million people with rheumatologic problems who manifest chronic HBsAg positivity. "This is a global health problem," he noted.

Dr. Calabrese recommended that preemptive therapeutic measures be taken for all HBsAg-positive and HBV DNA–positive patients, including possible lifelong antiviral medication, and then these patients can be treated for their rheumatologic issues. Those who test positive for anti-HBc should be carefully monitored. "There should not be a patient with spondylitis, rheumatoid arthritis, lupus, or vasculitis who is getting less than effective therapy because they have chronic HBV," he said.

Dr. Calabrese reported no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – While nowadays there is less likelihood that the hepatitis B virus causes rheumatic disease, major changes in epidemiology and drug therapy, especially the use of immunosuppressives, have made reactivation of the virus during the course of rheumatic disease treatment a major public health concern, according to Dr. Leonard H. Calabrese.

"HBV reactivation has been well known in cancer and transplantation but is now really coming to the fore in autoimmune and autoinflammatory diseases. It may be mild (asymptomatic viremia) or severe (fulminant liver failure and death) and has been observed in patients with both chronic infection or resolved disease. While it is largely preventable, unfortunately many physicians who regularly prescribe immunosuppressive therapies – including rheumatologists, oncologists, gastroenterologists, and dermatologists – do not recognize this potential," Dr. Calabrese said at a meeting sponsored by New York University.

The major risk of HBV is not during but after immunosuppression, when reactivation leading to severe or fatal hepatitis can occur. Reactivations have been reported rarely with low-dose prednisone and methotrexate, as well as all tumor necrosis factor (TNF) inhibitors, rituximab, abatacept, and infliximab, prompting a black box warning for many biologics, said Dr. Calabrese, director of the Fasenmyer Center for Clinical Immunology at the Cleveland Clinic.

In a retrospective study of 257 patients with positive HBV markers who were treated with TNF-targeted therapies, 39% with chronic infections (as indicated by the presence of HB surface antigens) developed HBV reactivation. Five developed acute liver failure, and four died (Medicine 2011;90:359-71). "This is not a trivial risk," Dr. Calabrese said.

Yet many rheumatologists do not screen for HBV prior to prescribing immunosuppressive therapy, he said. Dr. Calabrese cited a 2010 survey of rheumatologists that found that only 42% routinely screen for HBV before a patient begins nonbiologic disease-modifying antirheumatic drug therapy and 69% screen before prescribing a biologic DMARD. Seven percent of rheumatologists reported witnessing a reactivation event (Arthritis Care Res. 2010;62:704-11).

Of the three serologic markers for HBV (the hepatitis B surface antigen [HBsAg], the total hepatitis B core antibody [anti-HBc]), and the hepatitis B surface antibody (anti-HBsAb), Dr. Calabrese said he prefers HBsAg. "If you remember anything from this talk, remember that all patients with hepatitis B surface antigen need to be tended to before beginning any rheumatic therapy," he said. All positive tests should be followed up with HBV DNA testing.

Although all patients with a history of HBV are at some risk for HBV reactivation, with or without the presence of serologic markers, Dr. Calabrese outlined the relative risks of HBV reactivation as indicated by serologic findings. Those at highest risk are patients with chronic HBV infection (HBsAg positive, high level of HBV DNA), followed by inactive carriers (HBsAg positive, some HBV DNA) and those with resolved HBV (HBsAg negative, anti-HBc positive, anti-HBsAb positive). Those at lowest risk have resolved HBV (anti-HBc alone).

Rheumatologists should also be aware of the increased chance of HBV reactivation in high-risk populations. While in urban areas HBV is known to be associated with drug abuse, there is also a heightened risk in immigrants, especially those from Asia. Asian Americans are 2.7 times more likely to develop hepatocellular carcinoma. According to Dr. Calabrese, in mainland China there are an estimated 1 million people with rheumatologic problems who manifest chronic HBsAg positivity. "This is a global health problem," he noted.

Dr. Calabrese recommended that preemptive therapeutic measures be taken for all HBsAg-positive and HBV DNA–positive patients, including possible lifelong antiviral medication, and then these patients can be treated for their rheumatologic issues. Those who test positive for anti-HBc should be carefully monitored. "There should not be a patient with spondylitis, rheumatoid arthritis, lupus, or vasculitis who is getting less than effective therapy because they have chronic HBV," he said.

Dr. Calabrese reported no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – Positive signs from the nearly completed first stage of a prospective prevention trial for cardiac neonatal lupus are giving investigators hope that hydroxychloroquine can reduce the risk of fetal heart block if given during pregnancy to women with systemic lupus erythematosus who have previously had a child with the condition.

The first stage of the PATCH (Preventive Approach to Congenital Heart Block With Hydroxychloroquine) study has enrolled all of its intended 19 pregnant women with systemic lupus erythematosus (SLE) and anti-SSA/Ro and anti-SSB/La antibodies who had a previous child with cardiac neonatal lupus (CNL). So far, cardiac abnormalities have been found in only 1 of 17 completed pregnancies in women who began taking 400-mg hydroxychloroquine (HCQ) before 10 weeks’ gestation. The study will go on to a second stage if fewer than three cases of second- or third-degree heart block occur. Enrollment of an additional 35 women is planned for the second stage, Dr. Jill P. Buyon said at the New York University Seminar in Advanced Rheumatology. She is director of the New York University Lupus Center, a professor in the division of rheumatology at New York University, and the principal investigator of the open-label PATCH study.

HCQ treatment will be considered efficacious if fewer than 6 mothers of the 54 total have a child with advanced congenital heart block. With this design, the study has 90% power to conclude that HCQ is preventive if the true recurrence rate with the treatment is 5%. In addition, the probability of rejecting the treatment for further study is 95% if the true recurrence rate is 18%, according to Dr. Buyon and her colleagues.

Women in the trial are given weekly serial fetal echocardiograms and blood tests for potential biomarkers of efficacy and compliance. The results of the study are expected to become an integral part of the counseling of women with anti-Ro/La antibodies who are considering pregnancy, according to the investigators.

"We need prophylactic treatment for autoimmune-associated congenital heart block because of the significant morbidity and mortality. The fibrosis is immutable, and there is no sustained reversal of complete heart block," Dr. Buyon said at the meeting sponsored by NYU. In previous work, Dr. Buyon reported a 17.5% mortality rate of neonates with cardiac neonatal lupus (CNL), 30% in utero (Circulation 2011;124:1927-35).

Congenital atrioventricular block and cardiomyopathy are the two major manifestations of CNL. The risk of CNL is approximately 2% in women with SLE who have given birth to an unaffected child, but the recurrence rate is 17.4% in those who have previously given birth to a baby with CNL. Mechanistically, HCQ’s inhibitory effect on toll-like receptors is thought to interfere with the pathophysiologic cascade underlying CNL.

Research leading up to the PATCH study indicated that HCQ might reduce the risk of CNL by 65% when pregnant mothers with SLE took HCQ throughout their pregnancy, Dr. Buyon said.

She and her colleagues analyzed a historical cohort gathered from three international databases (the Research Registry for Neonatal Lupus, the PRIDE study, and the PROMISSE study). In total, 257 pregnancies of anti-SSA/Ro–positive mothers with SLE who had previously given birth to a child with CNL were identified. Forty of the women were exposed throughout their pregnancies (starting before 10 weeks of gestation) to HCQ and 217 were not exposed to HCQ during pregnancy (Circulation 2012;126:76-82).

Significantly more fetuses in the unexposed group developed CNL (46 [21%] of 217) than in the exposed group (3 [8%] of 40 fetuses) (P = .05). The overall case fatality rate of the CNL fetuses in the unexposed group was 22%, compared with no deaths in the exposed group. No reduction in CNL recurrence was found for prednisone, dexamethasone, or fluorinated steroids.

Dr. Buyon reported having no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – Positive signs from the nearly completed first stage of a prospective prevention trial for cardiac neonatal lupus are giving investigators hope that hydroxychloroquine can reduce the risk of fetal heart block if given during pregnancy to women with systemic lupus erythematosus who have previously had a child with the condition.

The first stage of the PATCH (Preventive Approach to Congenital Heart Block With Hydroxychloroquine) study has enrolled all of its intended 19 pregnant women with systemic lupus erythematosus (SLE) and anti-SSA/Ro and anti-SSB/La antibodies who had a previous child with cardiac neonatal lupus (CNL). So far, cardiac abnormalities have been found in only 1 of 17 completed pregnancies in women who began taking 400-mg hydroxychloroquine (HCQ) before 10 weeks’ gestation. The study will go on to a second stage if fewer than three cases of second- or third-degree heart block occur. Enrollment of an additional 35 women is planned for the second stage, Dr. Jill P. Buyon said at the New York University Seminar in Advanced Rheumatology. She is director of the New York University Lupus Center, a professor in the division of rheumatology at New York University, and the principal investigator of the open-label PATCH study.

HCQ treatment will be considered efficacious if fewer than 6 mothers of the 54 total have a child with advanced congenital heart block. With this design, the study has 90% power to conclude that HCQ is preventive if the true recurrence rate with the treatment is 5%. In addition, the probability of rejecting the treatment for further study is 95% if the true recurrence rate is 18%, according to Dr. Buyon and her colleagues.

Women in the trial are given weekly serial fetal echocardiograms and blood tests for potential biomarkers of efficacy and compliance. The results of the study are expected to become an integral part of the counseling of women with anti-Ro/La antibodies who are considering pregnancy, according to the investigators.

"We need prophylactic treatment for autoimmune-associated congenital heart block because of the significant morbidity and mortality. The fibrosis is immutable, and there is no sustained reversal of complete heart block," Dr. Buyon said at the meeting sponsored by NYU. In previous work, Dr. Buyon reported a 17.5% mortality rate of neonates with cardiac neonatal lupus (CNL), 30% in utero (Circulation 2011;124:1927-35).

Congenital atrioventricular block and cardiomyopathy are the two major manifestations of CNL. The risk of CNL is approximately 2% in women with SLE who have given birth to an unaffected child, but the recurrence rate is 17.4% in those who have previously given birth to a baby with CNL. Mechanistically, HCQ’s inhibitory effect on toll-like receptors is thought to interfere with the pathophysiologic cascade underlying CNL.

Research leading up to the PATCH study indicated that HCQ might reduce the risk of CNL by 65% when pregnant mothers with SLE took HCQ throughout their pregnancy, Dr. Buyon said.

She and her colleagues analyzed a historical cohort gathered from three international databases (the Research Registry for Neonatal Lupus, the PRIDE study, and the PROMISSE study). In total, 257 pregnancies of anti-SSA/Ro–positive mothers with SLE who had previously given birth to a child with CNL were identified. Forty of the women were exposed throughout their pregnancies (starting before 10 weeks of gestation) to HCQ and 217 were not exposed to HCQ during pregnancy (Circulation 2012;126:76-82).

Significantly more fetuses in the unexposed group developed CNL (46 [21%] of 217) than in the exposed group (3 [8%] of 40 fetuses) (P = .05). The overall case fatality rate of the CNL fetuses in the unexposed group was 22%, compared with no deaths in the exposed group. No reduction in CNL recurrence was found for prednisone, dexamethasone, or fluorinated steroids.

Dr. Buyon reported having no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – Positive signs from the nearly completed first stage of a prospective prevention trial for cardiac neonatal lupus are giving investigators hope that hydroxychloroquine can reduce the risk of fetal heart block if given during pregnancy to women with systemic lupus erythematosus who have previously had a child with the condition.

The first stage of the PATCH (Preventive Approach to Congenital Heart Block With Hydroxychloroquine) study has enrolled all of its intended 19 pregnant women with systemic lupus erythematosus (SLE) and anti-SSA/Ro and anti-SSB/La antibodies who had a previous child with cardiac neonatal lupus (CNL). So far, cardiac abnormalities have been found in only 1 of 17 completed pregnancies in women who began taking 400-mg hydroxychloroquine (HCQ) before 10 weeks’ gestation. The study will go on to a second stage if fewer than three cases of second- or third-degree heart block occur. Enrollment of an additional 35 women is planned for the second stage, Dr. Jill P. Buyon said at the New York University Seminar in Advanced Rheumatology. She is director of the New York University Lupus Center, a professor in the division of rheumatology at New York University, and the principal investigator of the open-label PATCH study.

HCQ treatment will be considered efficacious if fewer than 6 mothers of the 54 total have a child with advanced congenital heart block. With this design, the study has 90% power to conclude that HCQ is preventive if the true recurrence rate with the treatment is 5%. In addition, the probability of rejecting the treatment for further study is 95% if the true recurrence rate is 18%, according to Dr. Buyon and her colleagues.

Women in the trial are given weekly serial fetal echocardiograms and blood tests for potential biomarkers of efficacy and compliance. The results of the study are expected to become an integral part of the counseling of women with anti-Ro/La antibodies who are considering pregnancy, according to the investigators.

"We need prophylactic treatment for autoimmune-associated congenital heart block because of the significant morbidity and mortality. The fibrosis is immutable, and there is no sustained reversal of complete heart block," Dr. Buyon said at the meeting sponsored by NYU. In previous work, Dr. Buyon reported a 17.5% mortality rate of neonates with cardiac neonatal lupus (CNL), 30% in utero (Circulation 2011;124:1927-35).

Congenital atrioventricular block and cardiomyopathy are the two major manifestations of CNL. The risk of CNL is approximately 2% in women with SLE who have given birth to an unaffected child, but the recurrence rate is 17.4% in those who have previously given birth to a baby with CNL. Mechanistically, HCQ’s inhibitory effect on toll-like receptors is thought to interfere with the pathophysiologic cascade underlying CNL.

Research leading up to the PATCH study indicated that HCQ might reduce the risk of CNL by 65% when pregnant mothers with SLE took HCQ throughout their pregnancy, Dr. Buyon said.

She and her colleagues analyzed a historical cohort gathered from three international databases (the Research Registry for Neonatal Lupus, the PRIDE study, and the PROMISSE study). In total, 257 pregnancies of anti-SSA/Ro–positive mothers with SLE who had previously given birth to a child with CNL were identified. Forty of the women were exposed throughout their pregnancies (starting before 10 weeks of gestation) to HCQ and 217 were not exposed to HCQ during pregnancy (Circulation 2012;126:76-82).

Significantly more fetuses in the unexposed group developed CNL (46 [21%] of 217) than in the exposed group (3 [8%] of 40 fetuses) (P = .05). The overall case fatality rate of the CNL fetuses in the unexposed group was 22%, compared with no deaths in the exposed group. No reduction in CNL recurrence was found for prednisone, dexamethasone, or fluorinated steroids.

Dr. Buyon reported having no relevant financial disclosures.

rhnews@frontlinemedcom.com

NEW YORK – What you screen and where you send your samples can have a tremendous impact on the usefulness of biomarkers to predict adverse pregnancy outcomes in patients with antiphospholipid syndrome, according to Dr. Michael D. Lockshin.

Women who have antiphospholipid antibodies are at high risk of developing adverse pregnancy outcomes (APOs), including preeclampsia, restricted fetal growth, prematurity, and fetal neonatal death. Antiphospholipid syndrome (APS) is defined by a clinical event (either thrombosis and/or recurrent pregnancy loss) plus the presence of an antiphospholipid antibody (either IgG or IgM anticardiolipin [aCL] and/or beta-2-glycoprotein I [beta-2 GPI]).

To see which serologic variables associated with APS may best identify women at highest risk of APO, researchers enrolled 144 pregnant patients with antiphospholipid antibodies (aPL) between 2003 and 2011 in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) study. Twenty-eight (19%) had an APO. The results showed that 39% of the patients with lupus anticoagulant (LAC) had an APO, compared with 3% who did not have LAC (P = .0001).

A small percentage (5%) of women who were LAC negative but had high titers of IgG aCL antibody (at least 40 units/mL) had APOs. IgM aCL, IgG anti-beta-2 GPI, and IgM anti-beta-2 GPI were not predictive of APOs, according to Dr. Lockshin and his colleagues (Arthritis Rheum. 2012;64:2311-8).

Among women with high titers of IgG aCL, 8% of those who were LAC negative had an APO, compared with 43% who were LAC positive (P = .002).

"The only tests that made a difference in predicting APOs were lupus anticoagulant and IgG aCL," said Dr. Lockshin, director of the Barbara Volcker Center for Women and Rheumatic Disease and professor of medicine and of obstetrics and gynecology at Weill Cornell Medical College, New York.

Similar patterns were seen in women with lupus who also had APS. In that population, 55% of those who were LAC positive and 12% who were LAC negative/high titer IgG aCL had an APO.

Dr. Lockshin then asked whether LAC screening methods differed in predicting the risk of APOs. He compared the positive and negative predictive values of the dilute prothrombin time test (dPT), the dilute Russell viper venom test (dRVVT), and the activated partial thromboplastin time test (APTT), as well as all tests combined, and found that using the results of all three tests together yielded the highest positive predictive value (all, 0.926; dPT, 0.808; dRVVT, 0.560; aPTT, 0.630). The test with the best negative predictive value was the dRVVT (0.910).

Making appropriate risk assessments for women with APS depends on accurate serological measurement. Dr. Lockshin reported that in a group of 610 women who were referred for SLE and/or aPL, 279 were found to be aPL positive by a referral laboratory. Upon reanalysis of the samples by a core laboratory, 147 of those deemed aPL positive by the referral laboratory were deemed to be aPL negative, yielding a 52% false positive rate. In a group of 196 referred as healthy controls, 2 were found to be aPL positive by the core lab, meaning that 2% of the controls were false negative for aPL. "Don’t just casually accept a commercial laboratory’s determination," Dr. Lockshin said at the meeting, sponsored by New York University.

In multivariate analysis, having SLE significantly increased the risk of having an APO (23% vs. 17%). Patients with prior thrombosis also were more likely to have an APO than were those without prior thrombosis (52% vs. 13%, P = .00005). Age, race, or prior pregnancy loss were not determinants of pregnancy problems.

Dr. Lockshin also addressed the question as to whether heparin mitigates the risk of an APO. He found that in patients who were LAC positive, there was no difference in the number of APOs in those given heparin (49%), compared with those not treated with heparin (50%). The rate of APOs was actually higher in women who were LAC negative but treated with heparin, compared with those who did not receive heparin (29% vs. 18%, no significant difference). Aspirin did reduce the occurrence of APOs (14% vs. 30%, P = .04), but neither hydroxychloroquine nor steroids had any protective effects.

At the meeting, Dr. Lockshin also reported the results of a pilot 12-month open-label phase II trial of rituximab for the noncriteria manifestations of APS (thrombocytopenia, cardiac valve disease, skin ulcers, aPL nephropathy, and/or cognitive dysfunction). After two doses of rituximab (1,000 mg) on days 1 and 15, dramatic improvements in leg ulcers were seen, and, for the first time ever, possible improvement in cognitive function, said Dr. Lockshin. No changes were noted in serology, cardiac valves, or abnormal imaging findings (Arthritis Rheum. 2013;65:464-471).

To encourage further investigation of APS, an international research network has been launched to organize well-designed, large-scale, multicenter clinical trials in aPL-positive patients, said Dr. Lockshin. The AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) has initiated two collaborative projects, one looking into the use of hydroxychloroquine for primary thrombosis prevention and the other a web-based registry of aPL-positive patients with or without systemic autoimmune diseases. For more information, go to www.apsaction.org.

Dr. Lockshin reported no financial disclosures.

NEW YORK – What you screen and where you send your samples can have a tremendous impact on the usefulness of biomarkers to predict adverse pregnancy outcomes in patients with antiphospholipid syndrome, according to Dr. Michael D. Lockshin.

Women who have antiphospholipid antibodies are at high risk of developing adverse pregnancy outcomes (APOs), including preeclampsia, restricted fetal growth, prematurity, and fetal neonatal death. Antiphospholipid syndrome (APS) is defined by a clinical event (either thrombosis and/or recurrent pregnancy loss) plus the presence of an antiphospholipid antibody (either IgG or IgM anticardiolipin [aCL] and/or beta-2-glycoprotein I [beta-2 GPI]).

To see which serologic variables associated with APS may best identify women at highest risk of APO, researchers enrolled 144 pregnant patients with antiphospholipid antibodies (aPL) between 2003 and 2011 in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) study. Twenty-eight (19%) had an APO. The results showed that 39% of the patients with lupus anticoagulant (LAC) had an APO, compared with 3% who did not have LAC (P = .0001).

A small percentage (5%) of women who were LAC negative but had high titers of IgG aCL antibody (at least 40 units/mL) had APOs. IgM aCL, IgG anti-beta-2 GPI, and IgM anti-beta-2 GPI were not predictive of APOs, according to Dr. Lockshin and his colleagues (Arthritis Rheum. 2012;64:2311-8).

Among women with high titers of IgG aCL, 8% of those who were LAC negative had an APO, compared with 43% who were LAC positive (P = .002).

"The only tests that made a difference in predicting APOs were lupus anticoagulant and IgG aCL," said Dr. Lockshin, director of the Barbara Volcker Center for Women and Rheumatic Disease and professor of medicine and of obstetrics and gynecology at Weill Cornell Medical College, New York.

Similar patterns were seen in women with lupus who also had APS. In that population, 55% of those who were LAC positive and 12% who were LAC negative/high titer IgG aCL had an APO.

Dr. Lockshin then asked whether LAC screening methods differed in predicting the risk of APOs. He compared the positive and negative predictive values of the dilute prothrombin time test (dPT), the dilute Russell viper venom test (dRVVT), and the activated partial thromboplastin time test (APTT), as well as all tests combined, and found that using the results of all three tests together yielded the highest positive predictive value (all, 0.926; dPT, 0.808; dRVVT, 0.560; aPTT, 0.630). The test with the best negative predictive value was the dRVVT (0.910).

Making appropriate risk assessments for women with APS depends on accurate serological measurement. Dr. Lockshin reported that in a group of 610 women who were referred for SLE and/or aPL, 279 were found to be aPL positive by a referral laboratory. Upon reanalysis of the samples by a core laboratory, 147 of those deemed aPL positive by the referral laboratory were deemed to be aPL negative, yielding a 52% false positive rate. In a group of 196 referred as healthy controls, 2 were found to be aPL positive by the core lab, meaning that 2% of the controls were false negative for aPL. "Don’t just casually accept a commercial laboratory’s determination," Dr. Lockshin said at the meeting, sponsored by New York University.

In multivariate analysis, having SLE significantly increased the risk of having an APO (23% vs. 17%). Patients with prior thrombosis also were more likely to have an APO than were those without prior thrombosis (52% vs. 13%, P = .00005). Age, race, or prior pregnancy loss were not determinants of pregnancy problems.

Dr. Lockshin also addressed the question as to whether heparin mitigates the risk of an APO. He found that in patients who were LAC positive, there was no difference in the number of APOs in those given heparin (49%), compared with those not treated with heparin (50%). The rate of APOs was actually higher in women who were LAC negative but treated with heparin, compared with those who did not receive heparin (29% vs. 18%, no significant difference). Aspirin did reduce the occurrence of APOs (14% vs. 30%, P = .04), but neither hydroxychloroquine nor steroids had any protective effects.

At the meeting, Dr. Lockshin also reported the results of a pilot 12-month open-label phase II trial of rituximab for the noncriteria manifestations of APS (thrombocytopenia, cardiac valve disease, skin ulcers, aPL nephropathy, and/or cognitive dysfunction). After two doses of rituximab (1,000 mg) on days 1 and 15, dramatic improvements in leg ulcers were seen, and, for the first time ever, possible improvement in cognitive function, said Dr. Lockshin. No changes were noted in serology, cardiac valves, or abnormal imaging findings (Arthritis Rheum. 2013;65:464-471).

To encourage further investigation of APS, an international research network has been launched to organize well-designed, large-scale, multicenter clinical trials in aPL-positive patients, said Dr. Lockshin. The AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) has initiated two collaborative projects, one looking into the use of hydroxychloroquine for primary thrombosis prevention and the other a web-based registry of aPL-positive patients with or without systemic autoimmune diseases. For more information, go to www.apsaction.org.

Dr. Lockshin reported no financial disclosures.

NEW YORK – What you screen and where you send your samples can have a tremendous impact on the usefulness of biomarkers to predict adverse pregnancy outcomes in patients with antiphospholipid syndrome, according to Dr. Michael D. Lockshin.

Women who have antiphospholipid antibodies are at high risk of developing adverse pregnancy outcomes (APOs), including preeclampsia, restricted fetal growth, prematurity, and fetal neonatal death. Antiphospholipid syndrome (APS) is defined by a clinical event (either thrombosis and/or recurrent pregnancy loss) plus the presence of an antiphospholipid antibody (either IgG or IgM anticardiolipin [aCL] and/or beta-2-glycoprotein I [beta-2 GPI]).

To see which serologic variables associated with APS may best identify women at highest risk of APO, researchers enrolled 144 pregnant patients with antiphospholipid antibodies (aPL) between 2003 and 2011 in the PROMISSE (Predictors of Pregnancy Outcome: Biomarkers in Antiphospholipid Syndrome and Systemic Lupus Erythematosus) study. Twenty-eight (19%) had an APO. The results showed that 39% of the patients with lupus anticoagulant (LAC) had an APO, compared with 3% who did not have LAC (P = .0001).

A small percentage (5%) of women who were LAC negative but had high titers of IgG aCL antibody (at least 40 units/mL) had APOs. IgM aCL, IgG anti-beta-2 GPI, and IgM anti-beta-2 GPI were not predictive of APOs, according to Dr. Lockshin and his colleagues (Arthritis Rheum. 2012;64:2311-8).

Among women with high titers of IgG aCL, 8% of those who were LAC negative had an APO, compared with 43% who were LAC positive (P = .002).

"The only tests that made a difference in predicting APOs were lupus anticoagulant and IgG aCL," said Dr. Lockshin, director of the Barbara Volcker Center for Women and Rheumatic Disease and professor of medicine and of obstetrics and gynecology at Weill Cornell Medical College, New York.

Similar patterns were seen in women with lupus who also had APS. In that population, 55% of those who were LAC positive and 12% who were LAC negative/high titer IgG aCL had an APO.

Dr. Lockshin then asked whether LAC screening methods differed in predicting the risk of APOs. He compared the positive and negative predictive values of the dilute prothrombin time test (dPT), the dilute Russell viper venom test (dRVVT), and the activated partial thromboplastin time test (APTT), as well as all tests combined, and found that using the results of all three tests together yielded the highest positive predictive value (all, 0.926; dPT, 0.808; dRVVT, 0.560; aPTT, 0.630). The test with the best negative predictive value was the dRVVT (0.910).

Making appropriate risk assessments for women with APS depends on accurate serological measurement. Dr. Lockshin reported that in a group of 610 women who were referred for SLE and/or aPL, 279 were found to be aPL positive by a referral laboratory. Upon reanalysis of the samples by a core laboratory, 147 of those deemed aPL positive by the referral laboratory were deemed to be aPL negative, yielding a 52% false positive rate. In a group of 196 referred as healthy controls, 2 were found to be aPL positive by the core lab, meaning that 2% of the controls were false negative for aPL. "Don’t just casually accept a commercial laboratory’s determination," Dr. Lockshin said at the meeting, sponsored by New York University.

In multivariate analysis, having SLE significantly increased the risk of having an APO (23% vs. 17%). Patients with prior thrombosis also were more likely to have an APO than were those without prior thrombosis (52% vs. 13%, P = .00005). Age, race, or prior pregnancy loss were not determinants of pregnancy problems.

Dr. Lockshin also addressed the question as to whether heparin mitigates the risk of an APO. He found that in patients who were LAC positive, there was no difference in the number of APOs in those given heparin (49%), compared with those not treated with heparin (50%). The rate of APOs was actually higher in women who were LAC negative but treated with heparin, compared with those who did not receive heparin (29% vs. 18%, no significant difference). Aspirin did reduce the occurrence of APOs (14% vs. 30%, P = .04), but neither hydroxychloroquine nor steroids had any protective effects.

At the meeting, Dr. Lockshin also reported the results of a pilot 12-month open-label phase II trial of rituximab for the noncriteria manifestations of APS (thrombocytopenia, cardiac valve disease, skin ulcers, aPL nephropathy, and/or cognitive dysfunction). After two doses of rituximab (1,000 mg) on days 1 and 15, dramatic improvements in leg ulcers were seen, and, for the first time ever, possible improvement in cognitive function, said Dr. Lockshin. No changes were noted in serology, cardiac valves, or abnormal imaging findings (Arthritis Rheum. 2013;65:464-471).

To encourage further investigation of APS, an international research network has been launched to organize well-designed, large-scale, multicenter clinical trials in aPL-positive patients, said Dr. Lockshin. The AntiPhospholipid Syndrome Alliance for Clinical Trials and International Networking (APS ACTION) has initiated two collaborative projects, one looking into the use of hydroxychloroquine for primary thrombosis prevention and the other a web-based registry of aPL-positive patients with or without systemic autoimmune diseases. For more information, go to www.apsaction.org.

Dr. Lockshin reported no financial disclosures.

NEW YORK – Current use of prednisone above 10 mg/day more than doubles the risk of cardiovascular events in patients with systemic lupus erythematosus, according to a study conducted by Dr. Michelle Petri and her colleagues.

"Do everything you can to keep patients with lupus below the 10-mg/day cutoff for prednisone," said Dr. Petri, director of the Lupus Center at Johns Hopkins Hospital, Baltimore. She presented the results of her work at a meeting sponsored by New York University.

In an observational cohort study that explored factors that might increase the risk of cardiovascular events (CVEs) in people with systemic lupus erythematosus (SLE), Dr. Petri analyzed data from 1,874 SLE patients in the Hopkins Lupus Cohort who were seen quarterly at a single clinical center for more than 23 years (April 1987 to June 2010). In patients who took 1-9 mg/day of prednisone, 32 CVEs occurred, which was not significantly different from what would be expected in the general population. But once 10 mg/day was exceeded, the risk of having a CVE increased significantly in the 10- to 19-mg/day prednisone group (relative risk 2.4, P = .002), equivalent to a rate of 20.2/1,000 person-years). A more than a fivefold increase in risk was noted in those who took 20 mg or more per day (P less than .001), which was equivalent to 35.4/1,000 person-years (Am. J. Epidemiol. 2012;176:708-19).

After adjustment for age, CVE rates were not associated with disease duration, but were associated with average past levels of lupus disease activity and recent levels of circulating anti–double-stranded DNA. Past use of corticosteroids in the absence of current use did not affect CVE rates, although a cumulative past dose of 36,500 mg or more (equivalent to 10 or more years of prednisone 10 mg/day or equivalent) more than doubled the CVE rate (P = .0066).

To reduce cardiovascular risk in patients with SLE, Dr. Petri suggested assessing and treating traditional cardiovascular risk factors (hypertension, obesity, hyperlipidemia, smoking, and a sedentary lifestyle). Clinical trials in children and adults have shown that statins do not prevent accelerated atherosclerosis in SLE, so they are not helpful. "They don’t even work in mice!" said Dr. Petri, a professor in the division of rheumatology at Johns Hopkins University School of Medicine, Baltimore.

One possible treatment might be mycophenolate mofetil (MMF), which has not been approved by the Food and Drug Administration for use in SLE. Although there is some evidence that MMF slows progression of atherosclerosis in renal transplant patients and in mice, no clinical studies have been done to support its use in SLE. But Dr. Petri discouraged treating patients with MMF because of warnings associated with its use (infection, lymphoma and malignancies, pregnancy loss and congenital malformations, neutropenia and red cell aplasia, and interference with oral contraceptives).

NSAIDs have also been associated with a 66% increased risk of cardiovascular damage in SLE, Dr. Petri said. "These findings are a driving factor behind our need for new therapies for lupus. We need to avoid steroids as well as NSAIDs."

Dr. Petri is a consultant to GlaxoSmithKline.

NEW YORK – Current use of prednisone above 10 mg/day more than doubles the risk of cardiovascular events in patients with systemic lupus erythematosus, according to a study conducted by Dr. Michelle Petri and her colleagues.

"Do everything you can to keep patients with lupus below the 10-mg/day cutoff for prednisone," said Dr. Petri, director of the Lupus Center at Johns Hopkins Hospital, Baltimore. She presented the results of her work at a meeting sponsored by New York University.

In an observational cohort study that explored factors that might increase the risk of cardiovascular events (CVEs) in people with systemic lupus erythematosus (SLE), Dr. Petri analyzed data from 1,874 SLE patients in the Hopkins Lupus Cohort who were seen quarterly at a single clinical center for more than 23 years (April 1987 to June 2010). In patients who took 1-9 mg/day of prednisone, 32 CVEs occurred, which was not significantly different from what would be expected in the general population. But once 10 mg/day was exceeded, the risk of having a CVE increased significantly in the 10- to 19-mg/day prednisone group (relative risk 2.4, P = .002), equivalent to a rate of 20.2/1,000 person-years). A more than a fivefold increase in risk was noted in those who took 20 mg or more per day (P less than .001), which was equivalent to 35.4/1,000 person-years (Am. J. Epidemiol. 2012;176:708-19).

After adjustment for age, CVE rates were not associated with disease duration, but were associated with average past levels of lupus disease activity and recent levels of circulating anti–double-stranded DNA. Past use of corticosteroids in the absence of current use did not affect CVE rates, although a cumulative past dose of 36,500 mg or more (equivalent to 10 or more years of prednisone 10 mg/day or equivalent) more than doubled the CVE rate (P = .0066).

To reduce cardiovascular risk in patients with SLE, Dr. Petri suggested assessing and treating traditional cardiovascular risk factors (hypertension, obesity, hyperlipidemia, smoking, and a sedentary lifestyle). Clinical trials in children and adults have shown that statins do not prevent accelerated atherosclerosis in SLE, so they are not helpful. "They don’t even work in mice!" said Dr. Petri, a professor in the division of rheumatology at Johns Hopkins University School of Medicine, Baltimore.

One possible treatment might be mycophenolate mofetil (MMF), which has not been approved by the Food and Drug Administration for use in SLE. Although there is some evidence that MMF slows progression of atherosclerosis in renal transplant patients and in mice, no clinical studies have been done to support its use in SLE. But Dr. Petri discouraged treating patients with MMF because of warnings associated with its use (infection, lymphoma and malignancies, pregnancy loss and congenital malformations, neutropenia and red cell aplasia, and interference with oral contraceptives).

NSAIDs have also been associated with a 66% increased risk of cardiovascular damage in SLE, Dr. Petri said. "These findings are a driving factor behind our need for new therapies for lupus. We need to avoid steroids as well as NSAIDs."

Dr. Petri is a consultant to GlaxoSmithKline.

NEW YORK – Current use of prednisone above 10 mg/day more than doubles the risk of cardiovascular events in patients with systemic lupus erythematosus, according to a study conducted by Dr. Michelle Petri and her colleagues.

"Do everything you can to keep patients with lupus below the 10-mg/day cutoff for prednisone," said Dr. Petri, director of the Lupus Center at Johns Hopkins Hospital, Baltimore. She presented the results of her work at a meeting sponsored by New York University.

In an observational cohort study that explored factors that might increase the risk of cardiovascular events (CVEs) in people with systemic lupus erythematosus (SLE), Dr. Petri analyzed data from 1,874 SLE patients in the Hopkins Lupus Cohort who were seen quarterly at a single clinical center for more than 23 years (April 1987 to June 2010). In patients who took 1-9 mg/day of prednisone, 32 CVEs occurred, which was not significantly different from what would be expected in the general population. But once 10 mg/day was exceeded, the risk of having a CVE increased significantly in the 10- to 19-mg/day prednisone group (relative risk 2.4, P = .002), equivalent to a rate of 20.2/1,000 person-years). A more than a fivefold increase in risk was noted in those who took 20 mg or more per day (P less than .001), which was equivalent to 35.4/1,000 person-years (Am. J. Epidemiol. 2012;176:708-19).

After adjustment for age, CVE rates were not associated with disease duration, but were associated with average past levels of lupus disease activity and recent levels of circulating anti–double-stranded DNA. Past use of corticosteroids in the absence of current use did not affect CVE rates, although a cumulative past dose of 36,500 mg or more (equivalent to 10 or more years of prednisone 10 mg/day or equivalent) more than doubled the CVE rate (P = .0066).

To reduce cardiovascular risk in patients with SLE, Dr. Petri suggested assessing and treating traditional cardiovascular risk factors (hypertension, obesity, hyperlipidemia, smoking, and a sedentary lifestyle). Clinical trials in children and adults have shown that statins do not prevent accelerated atherosclerosis in SLE, so they are not helpful. "They don’t even work in mice!" said Dr. Petri, a professor in the division of rheumatology at Johns Hopkins University School of Medicine, Baltimore.

One possible treatment might be mycophenolate mofetil (MMF), which has not been approved by the Food and Drug Administration for use in SLE. Although there is some evidence that MMF slows progression of atherosclerosis in renal transplant patients and in mice, no clinical studies have been done to support its use in SLE. But Dr. Petri discouraged treating patients with MMF because of warnings associated with its use (infection, lymphoma and malignancies, pregnancy loss and congenital malformations, neutropenia and red cell aplasia, and interference with oral contraceptives).

NSAIDs have also been associated with a 66% increased risk of cardiovascular damage in SLE, Dr. Petri said. "These findings are a driving factor behind our need for new therapies for lupus. We need to avoid steroids as well as NSAIDs."

Dr. Petri is a consultant to GlaxoSmithKline.

NEW YORK – Obesity appears to reduce response to anti–tumor necrosis factor–alpha treatment in individuals with psoriatic arthritis, but weight loss can improve it, according to a review of two studies by Dr. Christopher T. Ritchlin.

"These data convincingly show that if we talk to our patients and tell them to lose weight, it can have an impact on how their PsA [psoriatic arthritis] therapies are going to work," Dr. Ritchlin, director of the Translational Immunology Research Center at the University of Rochester (N.Y.), said at a meeting sponsored by New York University.

Dr. Ritchlin said these results fit in with previous epidemiologic studies that show that as body mass index goes up, so does the risk for both psoriasis and PsA (Arch. Intern. Med. 2009;167:1670-5 and Ann. Rheum. Dis. 2012;71:1273-7).

These data support a link between obesity-related chronic tissue inflammation and development of some rheumatic diseases, such as arthritis in psoriatic patients. These same inflammatory processes may also interfere with good clinical response to biologic agents.

In a study published by Dr. Matteo Nicola di Minno of Federico II University in Naples, Italy, and his colleagues, individuals with a BMI in the 30-35 kg/m² range with PsA had a nearly fourfold increased risk of not responding well to treatment with tumor necrosis factor–alpha inhibitors (TNFis). The risk of a poor response rose more than fivefold for those whose BMIs greater than 35 kg/m² (Arthritis Care Res. 2013;65:141-7).

The study prospectively followed PsA patients with active disease for 24 months who were starting TNFi therapy (30% adalimumab, 41% etanercept, 29% infliximab). The group comprised 135 obese patients (BMI greater than 30 kg/m²) and 135 controls of normal weight. The primary outcome was achievement of minimal disease activity (MDA), which meant they fulfilled five of seven outcome measures: one or fewer tender joints, one or fewer swollen joints, a score of 1 or less on the Psoriasis Area and Severity Index or body surface area = 3, a score of 15 or less on a visual analog scale (VAS) for pain, a score of 20 or less on a patient global disease severity VAS score, a score on the Health Assessment Questionnaire of 0.5 or less, or one or fewer tender entheseal points.

After 12 months, only 98 (36%) of the total group reached MDA. "What the results showed was that the odds of not achieving MDA were directly related to increased BMI," Dr. Ritchlin said.

Significantly more of the patients who did not achieve MDA were obese (64% vs. 25.5%, P less than .001). After adjustment for other variables, obesity was found to incur a nearly fivefold risk of poor response to therapy (hazard ratio 4.90, 95% confidence interval [CI] 3.04-7.87). The hazard ratios were 3.98 for those with BMI of 30-35 kg/m² and 5.4 for those with BMI greater than 35 kg/m² (both P less than .001). Among the 98 PsA patients who had achieved MDA by 12 months, those who were obese had a poor probability of sustaining MDA when tested at 24 months, according to Dr. di Minno.

In a follow-up study presented at the 2012 EULAR meeting (Ann. Rheum. Dis. 2012;71[Suppl. 3]:109), Dr. di Minno addressed the question of whether weight loss in obese PsA patients would improve treatment response. In this study, 138 obese PsA patients were divided into two groups of 69 patients each. One group received a hypocaloric diet and the controls followed a normal diet.

After 6 months, those who lost 10% of their BMI or more were almost five times more likely to achieve MDA (HR 4.79, P = .002). Those who lost 5%-10% of their BMI were twice as likely as were controls to reach MDA.

Dr. Ritchlin said that he had no relevant disclosures.

NEW YORK – Obesity appears to reduce response to anti–tumor necrosis factor–alpha treatment in individuals with psoriatic arthritis, but weight loss can improve it, according to a review of two studies by Dr. Christopher T. Ritchlin.

"These data convincingly show that if we talk to our patients and tell them to lose weight, it can have an impact on how their PsA [psoriatic arthritis] therapies are going to work," Dr. Ritchlin, director of the Translational Immunology Research Center at the University of Rochester (N.Y.), said at a meeting sponsored by New York University.

Dr. Ritchlin said these results fit in with previous epidemiologic studies that show that as body mass index goes up, so does the risk for both psoriasis and PsA (Arch. Intern. Med. 2009;167:1670-5 and Ann. Rheum. Dis. 2012;71:1273-7).

These data support a link between obesity-related chronic tissue inflammation and development of some rheumatic diseases, such as arthritis in psoriatic patients. These same inflammatory processes may also interfere with good clinical response to biologic agents.

In a study published by Dr. Matteo Nicola di Minno of Federico II University in Naples, Italy, and his colleagues, individuals with a BMI in the 30-35 kg/m² range with PsA had a nearly fourfold increased risk of not responding well to treatment with tumor necrosis factor–alpha inhibitors (TNFis). The risk of a poor response rose more than fivefold for those whose BMIs greater than 35 kg/m² (Arthritis Care Res. 2013;65:141-7).

The study prospectively followed PsA patients with active disease for 24 months who were starting TNFi therapy (30% adalimumab, 41% etanercept, 29% infliximab). The group comprised 135 obese patients (BMI greater than 30 kg/m²) and 135 controls of normal weight. The primary outcome was achievement of minimal disease activity (MDA), which meant they fulfilled five of seven outcome measures: one or fewer tender joints, one or fewer swollen joints, a score of 1 or less on the Psoriasis Area and Severity Index or body surface area = 3, a score of 15 or less on a visual analog scale (VAS) for pain, a score of 20 or less on a patient global disease severity VAS score, a score on the Health Assessment Questionnaire of 0.5 or less, or one or fewer tender entheseal points.

After 12 months, only 98 (36%) of the total group reached MDA. "What the results showed was that the odds of not achieving MDA were directly related to increased BMI," Dr. Ritchlin said.

Significantly more of the patients who did not achieve MDA were obese (64% vs. 25.5%, P less than .001). After adjustment for other variables, obesity was found to incur a nearly fivefold risk of poor response to therapy (hazard ratio 4.90, 95% confidence interval [CI] 3.04-7.87). The hazard ratios were 3.98 for those with BMI of 30-35 kg/m² and 5.4 for those with BMI greater than 35 kg/m² (both P less than .001). Among the 98 PsA patients who had achieved MDA by 12 months, those who were obese had a poor probability of sustaining MDA when tested at 24 months, according to Dr. di Minno.

In a follow-up study presented at the 2012 EULAR meeting (Ann. Rheum. Dis. 2012;71[Suppl. 3]:109), Dr. di Minno addressed the question of whether weight loss in obese PsA patients would improve treatment response. In this study, 138 obese PsA patients were divided into two groups of 69 patients each. One group received a hypocaloric diet and the controls followed a normal diet.

After 6 months, those who lost 10% of their BMI or more were almost five times more likely to achieve MDA (HR 4.79, P = .002). Those who lost 5%-10% of their BMI were twice as likely as were controls to reach MDA.

Dr. Ritchlin said that he had no relevant disclosures.

NEW YORK – Obesity appears to reduce response to anti–tumor necrosis factor–alpha treatment in individuals with psoriatic arthritis, but weight loss can improve it, according to a review of two studies by Dr. Christopher T. Ritchlin.

"These data convincingly show that if we talk to our patients and tell them to lose weight, it can have an impact on how their PsA [psoriatic arthritis] therapies are going to work," Dr. Ritchlin, director of the Translational Immunology Research Center at the University of Rochester (N.Y.), said at a meeting sponsored by New York University.

Dr. Ritchlin said these results fit in with previous epidemiologic studies that show that as body mass index goes up, so does the risk for both psoriasis and PsA (Arch. Intern. Med. 2009;167:1670-5 and Ann. Rheum. Dis. 2012;71:1273-7).

These data support a link between obesity-related chronic tissue inflammation and development of some rheumatic diseases, such as arthritis in psoriatic patients. These same inflammatory processes may also interfere with good clinical response to biologic agents.

In a study published by Dr. Matteo Nicola di Minno of Federico II University in Naples, Italy, and his colleagues, individuals with a BMI in the 30-35 kg/m² range with PsA had a nearly fourfold increased risk of not responding well to treatment with tumor necrosis factor–alpha inhibitors (TNFis). The risk of a poor response rose more than fivefold for those whose BMIs greater than 35 kg/m² (Arthritis Care Res. 2013;65:141-7).

The study prospectively followed PsA patients with active disease for 24 months who were starting TNFi therapy (30% adalimumab, 41% etanercept, 29% infliximab). The group comprised 135 obese patients (BMI greater than 30 kg/m²) and 135 controls of normal weight. The primary outcome was achievement of minimal disease activity (MDA), which meant they fulfilled five of seven outcome measures: one or fewer tender joints, one or fewer swollen joints, a score of 1 or less on the Psoriasis Area and Severity Index or body surface area = 3, a score of 15 or less on a visual analog scale (VAS) for pain, a score of 20 or less on a patient global disease severity VAS score, a score on the Health Assessment Questionnaire of 0.5 or less, or one or fewer tender entheseal points.

After 12 months, only 98 (36%) of the total group reached MDA. "What the results showed was that the odds of not achieving MDA were directly related to increased BMI," Dr. Ritchlin said.

Significantly more of the patients who did not achieve MDA were obese (64% vs. 25.5%, P less than .001). After adjustment for other variables, obesity was found to incur a nearly fivefold risk of poor response to therapy (hazard ratio 4.90, 95% confidence interval [CI] 3.04-7.87). The hazard ratios were 3.98 for those with BMI of 30-35 kg/m² and 5.4 for those with BMI greater than 35 kg/m² (both P less than .001). Among the 98 PsA patients who had achieved MDA by 12 months, those who were obese had a poor probability of sustaining MDA when tested at 24 months, according to Dr. di Minno.

In a follow-up study presented at the 2012 EULAR meeting (Ann. Rheum. Dis. 2012;71[Suppl. 3]:109), Dr. di Minno addressed the question of whether weight loss in obese PsA patients would improve treatment response. In this study, 138 obese PsA patients were divided into two groups of 69 patients each. One group received a hypocaloric diet and the controls followed a normal diet.

After 6 months, those who lost 10% of their BMI or more were almost five times more likely to achieve MDA (HR 4.79, P = .002). Those who lost 5%-10% of their BMI were twice as likely as were controls to reach MDA.

Dr. Ritchlin said that he had no relevant disclosures.

NEW YORK – Patients with rheumatoid arthritis had significantly greater aortic wall inflammation than did control patients with coronary artery disease but without autoimmune disease in an 18- fluorodeoxyglucose PET imaging study. No differences in carotid artery wall inflammation were found between the groups.

"These results suggest that part of the risk of cardiovascular disease in rheumatoid arthritis patients may not only be from systemic inflammation but truly localized inflammation that is causing plaques to become more vulnerable, less stable, and more likely to rupture," said Dr. Jeffrey D. Greenberg, who presented the results of the cross-sectional comparison at the NYU Seminar in Advanced Rheumatology, sponsored by New York University.

It has been known for some time that rheumatoid arthritis (RA) patients have systemic inflammation as well as vascular inflammation and have an increased risk of cardiovascular-related death, according to Dr. Greenberg, associate director of clinical translational sciences in the division of rheumatology at New York University Langone Medical Center and the NYU Hospital for Joint Diseases. He cited multifactorial mechanisms by which RA patients may incur heightened cardiovascular risk, including traditional cardiovascular risk factors (altered lipid balance, impaired insulin sensitivity), abnormal endothelial function, and increased plaque vulnerability. He said that the results of this study demonstrate another factor – localized inflammation causing subclinical vasculitis in the aorta and perhaps coronary vessels.

Dr. Greenberg and his associates used a 10 mCi injection of 18-fluorodeoxyglucose (18-FDG) and PET imaging in two separate cohorts of patients, one consisting of 27 RA patients (aged 35-64 years) and another of 70 controls with coronary artery disease but without autoimmune disease (aged 41-76 years). The investigators determined vascular 18-FDG uptake by calculating target to background ratios (TBRs) that served as proxies for macrophage activity and inflammation in the vessel walls.

RA patients had significantly higher TBR scores than did controls for the aorta mean TBR (1.46 vs. 1.25; P less than .0001), aorta maximum TBR (2.08 vs. 1.75; P less than .0001) and the TBR of the most diseased segment of aorta (2.23 vs. 1.87; P = .0004). These values were adjusted for differences in age, gender, and body mass index between the groups in multivariate regression models. RA patients had mean disease duration of about 11 years and mean DAS28 of 4.6, with no history of coronary artery disease, myocardial infarction, or stroke.

The results of the study were presented previously at the 2012 ACR Annual Meeting.

Dr. Greenberg serves as a consultant to the Consortium of Rheumatology Researchers of North America Inc. (CORRONA) and Pfizer and holds an ownership interest in CORRONA. He also receives grant support from the American College of Rheumatology, the Arthritis National Research Foundation, the Agency for Healthcare Research and Quality, the National Institute for Arthritis, and Musculoskeletal and Skin Diseases, and the NYU Clinical and Translational Science Institute.

NEW YORK – Patients with rheumatoid arthritis had significantly greater aortic wall inflammation than did control patients with coronary artery disease but without autoimmune disease in an 18- fluorodeoxyglucose PET imaging study. No differences in carotid artery wall inflammation were found between the groups.

"These results suggest that part of the risk of cardiovascular disease in rheumatoid arthritis patients may not only be from systemic inflammation but truly localized inflammation that is causing plaques to become more vulnerable, less stable, and more likely to rupture," said Dr. Jeffrey D. Greenberg, who presented the results of the cross-sectional comparison at the NYU Seminar in Advanced Rheumatology, sponsored by New York University.

It has been known for some time that rheumatoid arthritis (RA) patients have systemic inflammation as well as vascular inflammation and have an increased risk of cardiovascular-related death, according to Dr. Greenberg, associate director of clinical translational sciences in the division of rheumatology at New York University Langone Medical Center and the NYU Hospital for Joint Diseases. He cited multifactorial mechanisms by which RA patients may incur heightened cardiovascular risk, including traditional cardiovascular risk factors (altered lipid balance, impaired insulin sensitivity), abnormal endothelial function, and increased plaque vulnerability. He said that the results of this study demonstrate another factor – localized inflammation causing subclinical vasculitis in the aorta and perhaps coronary vessels.

Dr. Greenberg and his associates used a 10 mCi injection of 18-fluorodeoxyglucose (18-FDG) and PET imaging in two separate cohorts of patients, one consisting of 27 RA patients (aged 35-64 years) and another of 70 controls with coronary artery disease but without autoimmune disease (aged 41-76 years). The investigators determined vascular 18-FDG uptake by calculating target to background ratios (TBRs) that served as proxies for macrophage activity and inflammation in the vessel walls.

RA patients had significantly higher TBR scores than did controls for the aorta mean TBR (1.46 vs. 1.25; P less than .0001), aorta maximum TBR (2.08 vs. 1.75; P less than .0001) and the TBR of the most diseased segment of aorta (2.23 vs. 1.87; P = .0004). These values were adjusted for differences in age, gender, and body mass index between the groups in multivariate regression models. RA patients had mean disease duration of about 11 years and mean DAS28 of 4.6, with no history of coronary artery disease, myocardial infarction, or stroke.

The results of the study were presented previously at the 2012 ACR Annual Meeting.

Dr. Greenberg serves as a consultant to the Consortium of Rheumatology Researchers of North America Inc. (CORRONA) and Pfizer and holds an ownership interest in CORRONA. He also receives grant support from the American College of Rheumatology, the Arthritis National Research Foundation, the Agency for Healthcare Research and Quality, the National Institute for Arthritis, and Musculoskeletal and Skin Diseases, and the NYU Clinical and Translational Science Institute.

NEW YORK – Patients with rheumatoid arthritis had significantly greater aortic wall inflammation than did control patients with coronary artery disease but without autoimmune disease in an 18- fluorodeoxyglucose PET imaging study. No differences in carotid artery wall inflammation were found between the groups.

"These results suggest that part of the risk of cardiovascular disease in rheumatoid arthritis patients may not only be from systemic inflammation but truly localized inflammation that is causing plaques to become more vulnerable, less stable, and more likely to rupture," said Dr. Jeffrey D. Greenberg, who presented the results of the cross-sectional comparison at the NYU Seminar in Advanced Rheumatology, sponsored by New York University.

It has been known for some time that rheumatoid arthritis (RA) patients have systemic inflammation as well as vascular inflammation and have an increased risk of cardiovascular-related death, according to Dr. Greenberg, associate director of clinical translational sciences in the division of rheumatology at New York University Langone Medical Center and the NYU Hospital for Joint Diseases. He cited multifactorial mechanisms by which RA patients may incur heightened cardiovascular risk, including traditional cardiovascular risk factors (altered lipid balance, impaired insulin sensitivity), abnormal endothelial function, and increased plaque vulnerability. He said that the results of this study demonstrate another factor – localized inflammation causing subclinical vasculitis in the aorta and perhaps coronary vessels.

Dr. Greenberg and his associates used a 10 mCi injection of 18-fluorodeoxyglucose (18-FDG) and PET imaging in two separate cohorts of patients, one consisting of 27 RA patients (aged 35-64 years) and another of 70 controls with coronary artery disease but without autoimmune disease (aged 41-76 years). The investigators determined vascular 18-FDG uptake by calculating target to background ratios (TBRs) that served as proxies for macrophage activity and inflammation in the vessel walls.

RA patients had significantly higher TBR scores than did controls for the aorta mean TBR (1.46 vs. 1.25; P less than .0001), aorta maximum TBR (2.08 vs. 1.75; P less than .0001) and the TBR of the most diseased segment of aorta (2.23 vs. 1.87; P = .0004). These values were adjusted for differences in age, gender, and body mass index between the groups in multivariate regression models. RA patients had mean disease duration of about 11 years and mean DAS28 of 4.6, with no history of coronary artery disease, myocardial infarction, or stroke.

The results of the study were presented previously at the 2012 ACR Annual Meeting.

Dr. Greenberg serves as a consultant to the Consortium of Rheumatology Researchers of North America Inc. (CORRONA) and Pfizer and holds an ownership interest in CORRONA. He also receives grant support from the American College of Rheumatology, the Arthritis National Research Foundation, the Agency for Healthcare Research and Quality, the National Institute for Arthritis, and Musculoskeletal and Skin Diseases, and the NYU Clinical and Translational Science Institute.