Psoriasis

Patients taking anti-tumor necrosis factor-? medications show somewhat impaired antibody response to influenza vaccination, but there is no decrease in the proportion of patients achieving a protective titer, according to the results of a recent study.

The study, by Dr. L.B.S. Gelinck of Leiden (the Netherlands) University Medical Center and colleagues, compared immunologic responses to the influenza vaccine in 64 patients taking anti-tumor necrosis factor-? (anti-TNF-?) medications for various autoimmune diseases with 48 patients with autoimmune diseases who were not taking those drugs. There were 18 healthy controls.

All three groups achieved about an 80% rate of protection to each of the three components of the vaccine (Ann. Rheum. Dis. 2007;[doi:10.1136/ard.2007.077552]).

Guidelines issued by the Centers for Disease Control and Prevention recommend annual vaccination for patients at risk of complications of influenza, including those who are treated with anti-TNF-? agents such as infliximab, etanercept, and adalimumab. On the other hand, findings from earlier studies on the effect of influenza vaccination on these patients were conflicting.

Patients with several autoimmune diseases were represented in the study, including those with gastroenterologic disease, rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, spondyloarthropathy, and inflammatory bowel disease. Their mean age was 49 years (range 18-85 years). Patients in the anti-TNF group had been using the agents for an average of 24 months, with a range of 0.5-78 months.

All study participants were vaccinated in the fall or winter of 2003 with a commercially available trivalent subunit influenza vaccine. Four weeks after vaccination, patients taking an anti-TNF-? agent had significantly lower geometric mean titers to two out of the three vaccine components, compared with patients not taking an anti-TNF-? agent and with healthy controls.

Nevertheless, more than 80% of the patients in each of the three groups achieved titers high enough to protect them against infection; there were no significant differences among the groups on this measure.

When tested separately, infliximab, etanercept, and adalimumab all had similar effects on the patients' response to vaccination.

None of the patients reported major side effects, and none experienced any deterioration in an underlying condition that was attributed to the influenza vaccine. About 20% of the patients in all groups reported minor side effects following immunization, such as local pain or tenderness at the vaccine injection site, but there were no significant differences among the groups. Similarly, about 14% of all patients experienced systemic reactions such as fever, myalgia, or headache during the 4 weeks after vaccination.

Patients taking anti-tumor necrosis factor-? medications show somewhat impaired antibody response to influenza vaccination, but there is no decrease in the proportion of patients achieving a protective titer, according to the results of a recent study.

The study, by Dr. L.B.S. Gelinck of Leiden (the Netherlands) University Medical Center and colleagues, compared immunologic responses to the influenza vaccine in 64 patients taking anti-tumor necrosis factor-? (anti-TNF-?) medications for various autoimmune diseases with 48 patients with autoimmune diseases who were not taking those drugs. There were 18 healthy controls.

All three groups achieved about an 80% rate of protection to each of the three components of the vaccine (Ann. Rheum. Dis. 2007;[doi:10.1136/ard.2007.077552]).

Guidelines issued by the Centers for Disease Control and Prevention recommend annual vaccination for patients at risk of complications of influenza, including those who are treated with anti-TNF-? agents such as infliximab, etanercept, and adalimumab. On the other hand, findings from earlier studies on the effect of influenza vaccination on these patients were conflicting.

Patients with several autoimmune diseases were represented in the study, including those with gastroenterologic disease, rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, spondyloarthropathy, and inflammatory bowel disease. Their mean age was 49 years (range 18-85 years). Patients in the anti-TNF group had been using the agents for an average of 24 months, with a range of 0.5-78 months.

All study participants were vaccinated in the fall or winter of 2003 with a commercially available trivalent subunit influenza vaccine. Four weeks after vaccination, patients taking an anti-TNF-? agent had significantly lower geometric mean titers to two out of the three vaccine components, compared with patients not taking an anti-TNF-? agent and with healthy controls.

Nevertheless, more than 80% of the patients in each of the three groups achieved titers high enough to protect them against infection; there were no significant differences among the groups on this measure.

When tested separately, infliximab, etanercept, and adalimumab all had similar effects on the patients' response to vaccination.

None of the patients reported major side effects, and none experienced any deterioration in an underlying condition that was attributed to the influenza vaccine. About 20% of the patients in all groups reported minor side effects following immunization, such as local pain or tenderness at the vaccine injection site, but there were no significant differences among the groups. Similarly, about 14% of all patients experienced systemic reactions such as fever, myalgia, or headache during the 4 weeks after vaccination.

Patients taking anti-tumor necrosis factor-? medications show somewhat impaired antibody response to influenza vaccination, but there is no decrease in the proportion of patients achieving a protective titer, according to the results of a recent study.

The study, by Dr. L.B.S. Gelinck of Leiden (the Netherlands) University Medical Center and colleagues, compared immunologic responses to the influenza vaccine in 64 patients taking anti-tumor necrosis factor-? (anti-TNF-?) medications for various autoimmune diseases with 48 patients with autoimmune diseases who were not taking those drugs. There were 18 healthy controls.

All three groups achieved about an 80% rate of protection to each of the three components of the vaccine (Ann. Rheum. Dis. 2007;[doi:10.1136/ard.2007.077552]).

Guidelines issued by the Centers for Disease Control and Prevention recommend annual vaccination for patients at risk of complications of influenza, including those who are treated with anti-TNF-? agents such as infliximab, etanercept, and adalimumab. On the other hand, findings from earlier studies on the effect of influenza vaccination on these patients were conflicting.

Patients with several autoimmune diseases were represented in the study, including those with gastroenterologic disease, rheumatoid arthritis, juvenile chronic arthritis, psoriatic arthritis, spondyloarthropathy, and inflammatory bowel disease. Their mean age was 49 years (range 18-85 years). Patients in the anti-TNF group had been using the agents for an average of 24 months, with a range of 0.5-78 months.

All study participants were vaccinated in the fall or winter of 2003 with a commercially available trivalent subunit influenza vaccine. Four weeks after vaccination, patients taking an anti-TNF-? agent had significantly lower geometric mean titers to two out of the three vaccine components, compared with patients not taking an anti-TNF-? agent and with healthy controls.

Nevertheless, more than 80% of the patients in each of the three groups achieved titers high enough to protect them against infection; there were no significant differences among the groups on this measure.

When tested separately, infliximab, etanercept, and adalimumab all had similar effects on the patients' response to vaccination.

None of the patients reported major side effects, and none experienced any deterioration in an underlying condition that was attributed to the influenza vaccine. About 20% of the patients in all groups reported minor side effects following immunization, such as local pain or tenderness at the vaccine injection site, but there were no significant differences among the groups. Similarly, about 14% of all patients experienced systemic reactions such as fever, myalgia, or headache during the 4 weeks after vaccination.

BIRMINGHAM, ENGLAND — A direct relationship between gadodiamide—a chelate used regularly to identify renal artery stenosis in patients who are potential transplant recipients—and the activation of fibroblasts in nephrogenic systemic fibrosis has been identified, Dr. Susie Mukherjee reported at the annual meeting of the British Association of Dermatologists.

The origin of nephrogenic systemic fibrosis (NSF) has long intrigued the radiologic, renal, and dermatologic worlds because of the paucity of cases, said Dr. Mukherjee. Although NSF was initially thought to be a cutaneous condition, two recent case reports have indicated that it is in fact systemic.

Dr. Mukherjee, a dermatologist at Glasgow University, and her colleagues examined the levels of hyaluronan and collagen—both key components of the extracellular matrix—of six female patients with end-stage renal failure and biopsy proven NSF. Their median duration of dialysis was 4.8 years and the mean time to developing NSF symptoms after receiving gadodiamide was 1 month.

The investigators obtained 20 mL of blood from the patients and compared the blood with that of controls. Punch biopsies were used to establish fibroblast activity.

Serum samples from the NSF patients stimulated up to a 7-fold increase in hyaluronan synthesis and a 3.3-fold increase in collagen; both increases were statistically significant when compared with control patient samples, she said. Histology samples showed thickened collagen bundles signified by strong alcian blue staining on slides, she said.

Dr. Mukherjee also found that it only takes tiny concentrations of gadolinium to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis, "which is still quite a small level compared to what patients are exposed to," she said. "So really from these simple in vitro experiments we can suggest that NSF lesional fibroblasts synthesize excess hyaluronan and collagen, which increases after prolonged exposure to gadodiamide," explained Dr. Mukherjee. "These are the first experiments to demonstrate a direct relation between gadodiamide and activation of fibroblasts."

Evidence for a link between NSF and gadolinium was first described in a case series of 13 patients, all of whom developed NSF after being exposed to gadolinium (J. Am. Soc. Nephrol. 2006;17:2359-62).

Early symptoms of NSF include swelling, pruritus, and muscle pain of the limbs. Later changes include flexion contractures and grossly thickened indurated skin.

Further work should assess the effect of gadolinium on circulating fibrocytes and their ability to migrate into skin, according to Dr. Mukherjee.

BIRMINGHAM, ENGLAND — A direct relationship between gadodiamide—a chelate used regularly to identify renal artery stenosis in patients who are potential transplant recipients—and the activation of fibroblasts in nephrogenic systemic fibrosis has been identified, Dr. Susie Mukherjee reported at the annual meeting of the British Association of Dermatologists.

The origin of nephrogenic systemic fibrosis (NSF) has long intrigued the radiologic, renal, and dermatologic worlds because of the paucity of cases, said Dr. Mukherjee. Although NSF was initially thought to be a cutaneous condition, two recent case reports have indicated that it is in fact systemic.

Dr. Mukherjee, a dermatologist at Glasgow University, and her colleagues examined the levels of hyaluronan and collagen—both key components of the extracellular matrix—of six female patients with end-stage renal failure and biopsy proven NSF. Their median duration of dialysis was 4.8 years and the mean time to developing NSF symptoms after receiving gadodiamide was 1 month.

The investigators obtained 20 mL of blood from the patients and compared the blood with that of controls. Punch biopsies were used to establish fibroblast activity.

Serum samples from the NSF patients stimulated up to a 7-fold increase in hyaluronan synthesis and a 3.3-fold increase in collagen; both increases were statistically significant when compared with control patient samples, she said. Histology samples showed thickened collagen bundles signified by strong alcian blue staining on slides, she said.

Dr. Mukherjee also found that it only takes tiny concentrations of gadolinium to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis, "which is still quite a small level compared to what patients are exposed to," she said. "So really from these simple in vitro experiments we can suggest that NSF lesional fibroblasts synthesize excess hyaluronan and collagen, which increases after prolonged exposure to gadodiamide," explained Dr. Mukherjee. "These are the first experiments to demonstrate a direct relation between gadodiamide and activation of fibroblasts."

Evidence for a link between NSF and gadolinium was first described in a case series of 13 patients, all of whom developed NSF after being exposed to gadolinium (J. Am. Soc. Nephrol. 2006;17:2359-62).

Early symptoms of NSF include swelling, pruritus, and muscle pain of the limbs. Later changes include flexion contractures and grossly thickened indurated skin.

Further work should assess the effect of gadolinium on circulating fibrocytes and their ability to migrate into skin, according to Dr. Mukherjee.

BIRMINGHAM, ENGLAND — A direct relationship between gadodiamide—a chelate used regularly to identify renal artery stenosis in patients who are potential transplant recipients—and the activation of fibroblasts in nephrogenic systemic fibrosis has been identified, Dr. Susie Mukherjee reported at the annual meeting of the British Association of Dermatologists.

The origin of nephrogenic systemic fibrosis (NSF) has long intrigued the radiologic, renal, and dermatologic worlds because of the paucity of cases, said Dr. Mukherjee. Although NSF was initially thought to be a cutaneous condition, two recent case reports have indicated that it is in fact systemic.

Dr. Mukherjee, a dermatologist at Glasgow University, and her colleagues examined the levels of hyaluronan and collagen—both key components of the extracellular matrix—of six female patients with end-stage renal failure and biopsy proven NSF. Their median duration of dialysis was 4.8 years and the mean time to developing NSF symptoms after receiving gadodiamide was 1 month.

The investigators obtained 20 mL of blood from the patients and compared the blood with that of controls. Punch biopsies were used to establish fibroblast activity.

Serum samples from the NSF patients stimulated up to a 7-fold increase in hyaluronan synthesis and a 3.3-fold increase in collagen; both increases were statistically significant when compared with control patient samples, she said. Histology samples showed thickened collagen bundles signified by strong alcian blue staining on slides, she said.

Dr. Mukherjee also found that it only takes tiny concentrations of gadolinium to stimulate hyaluronan synthesis by fibroblasts. Both 10-mmol/L and 1-mmol/L concentrations of gadolinium caused a 2.3-fold increase in hyaluronan synthesis, "which is still quite a small level compared to what patients are exposed to," she said. "So really from these simple in vitro experiments we can suggest that NSF lesional fibroblasts synthesize excess hyaluronan and collagen, which increases after prolonged exposure to gadodiamide," explained Dr. Mukherjee. "These are the first experiments to demonstrate a direct relation between gadodiamide and activation of fibroblasts."

Evidence for a link between NSF and gadolinium was first described in a case series of 13 patients, all of whom developed NSF after being exposed to gadolinium (J. Am. Soc. Nephrol. 2006;17:2359-62).

Early symptoms of NSF include swelling, pruritus, and muscle pain of the limbs. Later changes include flexion contractures and grossly thickened indurated skin.

Further work should assess the effect of gadolinium on circulating fibrocytes and their ability to migrate into skin, according to Dr. Mukherjee.

NEW YORK — Dr. Whitney A. High is into heavy metal and skin, but if you think he's a biker with a leather vest and a Black Sabbath tattoo, you've got it wrong.

Dr. High, of the University of Colorado, Denver, is a clean-cut young dermatopathologist with a soft spot for geology and physics, and his interests in heavy metal involve titanium and vanadium, not Metallica and Megadeath.

His unique set of interests—skin disease, metals, and physics—has landed him in the center of the growing controversy around gadolinium contrast agents and their role in nephrogenic systemic fibrosis.

Dr. High is part of an elite team of investigators trying to determine whether the gadolinium agents in MRI contrast media play a causative role in this devastating, largely untreatable skin disorder. Their answer could have major medicolegal and clinical implications.

Nephrogenic systemic fibrosis (NSF) is characterized by excessive fibrosis in the skin and other soft tissues that leads to disfigurement, tissue constriction, and in some cases, respiratory failure, ocular damage, and cardiac problems. It was first reported as "scleromyxedema-like disease" in renal dialysis patients in 1997. In the last decade, hundreds of cases have emerged worldwide, primarily, if not exclusively in people with end-stage renal disease (ESRD). Other than that, there were few clues as to what caused the distinctive skin and soft tissue changes.

"For a long time, we could not figure out what was going on," Dr. High said at the American Academy of Dermatology's Summer Academy 2007. The first break came in January 2006, when Austrian researchers described nine patients with ESRD, five of whom had developed NSF, with all five having undergone imaging procedures with gadolinium contrast agents. These five patients developed signs and symptoms consistent with the disorder within about 4 weeks of exposure to gadolinium-based contrast used in magnetic angiography.

Further damning evidence emerged late last summer, when Danish investigators reported that 13 of 13 ESRD patients with NSF had received gadodiamide, a commonly used gadolinium contrast agent. There were no other shared risk factors among the 13 cases.

Is there a gadolinium smoking gun in the tissues of NSF patients? That's the question Dr. High is seeking to answer.

"I had previously reported on a granulomatous reaction to titanium alloy in a patient with ear piercings. That's how people knew I was interested in metals and skin disorders, and that's why I got called in on this gadolinium issue," he said.

There are five gadolinium contrast agents currently in use around the world. The two most common are Magnevist (gadopentetate) and Omniscan (gadodiamide). Manufacturers of the products, already reeling from the Food and Drug Administration's recent issuance of a black box warning about the potential risk of NSF, are hoping that gadolinium will be judged an innocent victim of circumstance.

Malpractice lawyers, of course, hope for the opposite.

So far, the findings seem to be favoring the lawyers. Using a technique called energy dispersive spectroscopy (EDS), investigators are able to detect metals such as titanium, vanadium, and gadolinium in human tissues, said Dr. High. He has detected gadolinium in the skin of four of seven NSF patients he has studied (J. Am. Acad. Dermatol. 2007;56:21-6).

He stressed, however, that EDS is "a semiquantitative technique, not a mass-based technique, and it should not be used as such." EDS can tell whether certain metals are present in the tissue, but it cannot be used to determine how much is present, except in a relative type of way.

That type of determination requires a technique like mass spectrometry. This method, too, showed significantly elevated levels of gadolinium in all NSF patients of Dr. High's original series.

Dr. High and his colleagues have used mass spectrometry to analyze a range of different tissues. Infant foreskin samples, predictably, show no gadolinium. Multiple sclerosis patients without renal problems who had undergone semiannual MRIs showed no gadolinium. Tissue samples from Mohs surgery for skin cancer? Also clear, as were skin samples from ESRD patients who have not had gadolinium-based scans. ESRD patients who had undergone imaging with gadolinium contrast, however, did show traces of the metal albeit at much lower levels than the patients with NSF.

Circumstantial? Unlikely. "If you have gadolinium in your tissues, you got it from somewhere. There is no regularly encountered source of gadolinium in this form in nature. So unless you happen to be a gadolinium miner, you got it from a doctor," said Dr. High.

But Dr. High seems reluctant to pin blame for NSF exclusively on gadolinium contrast agents. Bear in mind that nearly all NSF patients have ESRD, meaning that their ability to filter and eliminate toxins such as metals is sorely impaired. "Renal failure patients are a toxic soup of metals—calcium, iron, zinc, copper, aluminum—all sorts of metals," Dr. High said, adding that he believes NSF results from "a collusion of coconspirators. Gadolinium alone may not be the only prerequisite exposure, and other metals may be involved in its deposition or in disease evolution." Only time will tell.

Case in point, the prevailing model for how gadolinium ends up in the skin involves a hypothetical process called "transmetallation," in which other metals, such as iron or calcium present in the tissue, knock the gadolinium off the chelator to which it is normally bound.

"Transmetallation is just a theory at this point. It hasn't yet been irrefutably proven to occur in the body. Electron microscopy cannot detect what a metal is bound to, but a special kind of subatomic particle accelerator can."

To that end, Dr. High will soon be the first dermatopathologist to gain access to such an instrument. By the time this article is published, he will have been engaged in particle accelerator experiments designed to prove whether gadolinium in tissue is no longer bound to its chelators, as the transmetallation theory suggests. "There will likely be other information coming out to show that other metals may contribute to gadolinium deposition and perhaps to NSF itself," he said.

Even if gadolinium is not the only cause of NSF, it certainly appears a strong trigger in susceptible individuals. Estimates indicate that 3%-5% of patients with ESRD may be at risk for NSF. It appears that, in addition to ESRD, predisposition to thrombosis and inflammation may be involved. The risk is also likely proportional to the number of scans a person receives during renal failure.

For those who develop the disorder, there's little physicians can do. "I see about 10-12 patients with NSF at the University of Colorado. We've tried everything—photopheresis, plasmapheresis, renal transplant. No single treatment works uniformly well for all patients. And there are no formal studies comparing modalities."

Dr. High predicted that the current controversy about gadolinium will prompt a surge of interest in "medical geology" and the study of how elemental metals affect human health. Currently, Dr. High is working on a rapid, noninvasive screening device to detect metals such as gadolinium in human tissue.

Gadolinium conglomerations in a fibrohistiocytic cell from the skin of an NSF patient are shown above. Courtesy Dr. Whitney A. High

NEW YORK — Dr. Whitney A. High is into heavy metal and skin, but if you think he's a biker with a leather vest and a Black Sabbath tattoo, you've got it wrong.

Dr. High, of the University of Colorado, Denver, is a clean-cut young dermatopathologist with a soft spot for geology and physics, and his interests in heavy metal involve titanium and vanadium, not Metallica and Megadeath.

His unique set of interests—skin disease, metals, and physics—has landed him in the center of the growing controversy around gadolinium contrast agents and their role in nephrogenic systemic fibrosis.

Dr. High is part of an elite team of investigators trying to determine whether the gadolinium agents in MRI contrast media play a causative role in this devastating, largely untreatable skin disorder. Their answer could have major medicolegal and clinical implications.

Nephrogenic systemic fibrosis (NSF) is characterized by excessive fibrosis in the skin and other soft tissues that leads to disfigurement, tissue constriction, and in some cases, respiratory failure, ocular damage, and cardiac problems. It was first reported as "scleromyxedema-like disease" in renal dialysis patients in 1997. In the last decade, hundreds of cases have emerged worldwide, primarily, if not exclusively in people with end-stage renal disease (ESRD). Other than that, there were few clues as to what caused the distinctive skin and soft tissue changes.

"For a long time, we could not figure out what was going on," Dr. High said at the American Academy of Dermatology's Summer Academy 2007. The first break came in January 2006, when Austrian researchers described nine patients with ESRD, five of whom had developed NSF, with all five having undergone imaging procedures with gadolinium contrast agents. These five patients developed signs and symptoms consistent with the disorder within about 4 weeks of exposure to gadolinium-based contrast used in magnetic angiography.

Further damning evidence emerged late last summer, when Danish investigators reported that 13 of 13 ESRD patients with NSF had received gadodiamide, a commonly used gadolinium contrast agent. There were no other shared risk factors among the 13 cases.

Is there a gadolinium smoking gun in the tissues of NSF patients? That's the question Dr. High is seeking to answer.

"I had previously reported on a granulomatous reaction to titanium alloy in a patient with ear piercings. That's how people knew I was interested in metals and skin disorders, and that's why I got called in on this gadolinium issue," he said.

There are five gadolinium contrast agents currently in use around the world. The two most common are Magnevist (gadopentetate) and Omniscan (gadodiamide). Manufacturers of the products, already reeling from the Food and Drug Administration's recent issuance of a black box warning about the potential risk of NSF, are hoping that gadolinium will be judged an innocent victim of circumstance.

Malpractice lawyers, of course, hope for the opposite.

So far, the findings seem to be favoring the lawyers. Using a technique called energy dispersive spectroscopy (EDS), investigators are able to detect metals such as titanium, vanadium, and gadolinium in human tissues, said Dr. High. He has detected gadolinium in the skin of four of seven NSF patients he has studied (J. Am. Acad. Dermatol. 2007;56:21-6).

He stressed, however, that EDS is "a semiquantitative technique, not a mass-based technique, and it should not be used as such." EDS can tell whether certain metals are present in the tissue, but it cannot be used to determine how much is present, except in a relative type of way.

That type of determination requires a technique like mass spectrometry. This method, too, showed significantly elevated levels of gadolinium in all NSF patients of Dr. High's original series.

Dr. High and his colleagues have used mass spectrometry to analyze a range of different tissues. Infant foreskin samples, predictably, show no gadolinium. Multiple sclerosis patients without renal problems who had undergone semiannual MRIs showed no gadolinium. Tissue samples from Mohs surgery for skin cancer? Also clear, as were skin samples from ESRD patients who have not had gadolinium-based scans. ESRD patients who had undergone imaging with gadolinium contrast, however, did show traces of the metal albeit at much lower levels than the patients with NSF.

Circumstantial? Unlikely. "If you have gadolinium in your tissues, you got it from somewhere. There is no regularly encountered source of gadolinium in this form in nature. So unless you happen to be a gadolinium miner, you got it from a doctor," said Dr. High.

But Dr. High seems reluctant to pin blame for NSF exclusively on gadolinium contrast agents. Bear in mind that nearly all NSF patients have ESRD, meaning that their ability to filter and eliminate toxins such as metals is sorely impaired. "Renal failure patients are a toxic soup of metals—calcium, iron, zinc, copper, aluminum—all sorts of metals," Dr. High said, adding that he believes NSF results from "a collusion of coconspirators. Gadolinium alone may not be the only prerequisite exposure, and other metals may be involved in its deposition or in disease evolution." Only time will tell.

Case in point, the prevailing model for how gadolinium ends up in the skin involves a hypothetical process called "transmetallation," in which other metals, such as iron or calcium present in the tissue, knock the gadolinium off the chelator to which it is normally bound.

"Transmetallation is just a theory at this point. It hasn't yet been irrefutably proven to occur in the body. Electron microscopy cannot detect what a metal is bound to, but a special kind of subatomic particle accelerator can."

To that end, Dr. High will soon be the first dermatopathologist to gain access to such an instrument. By the time this article is published, he will have been engaged in particle accelerator experiments designed to prove whether gadolinium in tissue is no longer bound to its chelators, as the transmetallation theory suggests. "There will likely be other information coming out to show that other metals may contribute to gadolinium deposition and perhaps to NSF itself," he said.

Even if gadolinium is not the only cause of NSF, it certainly appears a strong trigger in susceptible individuals. Estimates indicate that 3%-5% of patients with ESRD may be at risk for NSF. It appears that, in addition to ESRD, predisposition to thrombosis and inflammation may be involved. The risk is also likely proportional to the number of scans a person receives during renal failure.

For those who develop the disorder, there's little physicians can do. "I see about 10-12 patients with NSF at the University of Colorado. We've tried everything—photopheresis, plasmapheresis, renal transplant. No single treatment works uniformly well for all patients. And there are no formal studies comparing modalities."

Dr. High predicted that the current controversy about gadolinium will prompt a surge of interest in "medical geology" and the study of how elemental metals affect human health. Currently, Dr. High is working on a rapid, noninvasive screening device to detect metals such as gadolinium in human tissue.

Gadolinium conglomerations in a fibrohistiocytic cell from the skin of an NSF patient are shown above. Courtesy Dr. Whitney A. High

NEW YORK — Dr. Whitney A. High is into heavy metal and skin, but if you think he's a biker with a leather vest and a Black Sabbath tattoo, you've got it wrong.

Dr. High, of the University of Colorado, Denver, is a clean-cut young dermatopathologist with a soft spot for geology and physics, and his interests in heavy metal involve titanium and vanadium, not Metallica and Megadeath.

His unique set of interests—skin disease, metals, and physics—has landed him in the center of the growing controversy around gadolinium contrast agents and their role in nephrogenic systemic fibrosis.

Dr. High is part of an elite team of investigators trying to determine whether the gadolinium agents in MRI contrast media play a causative role in this devastating, largely untreatable skin disorder. Their answer could have major medicolegal and clinical implications.

Nephrogenic systemic fibrosis (NSF) is characterized by excessive fibrosis in the skin and other soft tissues that leads to disfigurement, tissue constriction, and in some cases, respiratory failure, ocular damage, and cardiac problems. It was first reported as "scleromyxedema-like disease" in renal dialysis patients in 1997. In the last decade, hundreds of cases have emerged worldwide, primarily, if not exclusively in people with end-stage renal disease (ESRD). Other than that, there were few clues as to what caused the distinctive skin and soft tissue changes.

"For a long time, we could not figure out what was going on," Dr. High said at the American Academy of Dermatology's Summer Academy 2007. The first break came in January 2006, when Austrian researchers described nine patients with ESRD, five of whom had developed NSF, with all five having undergone imaging procedures with gadolinium contrast agents. These five patients developed signs and symptoms consistent with the disorder within about 4 weeks of exposure to gadolinium-based contrast used in magnetic angiography.

Further damning evidence emerged late last summer, when Danish investigators reported that 13 of 13 ESRD patients with NSF had received gadodiamide, a commonly used gadolinium contrast agent. There were no other shared risk factors among the 13 cases.

Is there a gadolinium smoking gun in the tissues of NSF patients? That's the question Dr. High is seeking to answer.

"I had previously reported on a granulomatous reaction to titanium alloy in a patient with ear piercings. That's how people knew I was interested in metals and skin disorders, and that's why I got called in on this gadolinium issue," he said.

There are five gadolinium contrast agents currently in use around the world. The two most common are Magnevist (gadopentetate) and Omniscan (gadodiamide). Manufacturers of the products, already reeling from the Food and Drug Administration's recent issuance of a black box warning about the potential risk of NSF, are hoping that gadolinium will be judged an innocent victim of circumstance.

Malpractice lawyers, of course, hope for the opposite.

So far, the findings seem to be favoring the lawyers. Using a technique called energy dispersive spectroscopy (EDS), investigators are able to detect metals such as titanium, vanadium, and gadolinium in human tissues, said Dr. High. He has detected gadolinium in the skin of four of seven NSF patients he has studied (J. Am. Acad. Dermatol. 2007;56:21-6).

He stressed, however, that EDS is "a semiquantitative technique, not a mass-based technique, and it should not be used as such." EDS can tell whether certain metals are present in the tissue, but it cannot be used to determine how much is present, except in a relative type of way.

That type of determination requires a technique like mass spectrometry. This method, too, showed significantly elevated levels of gadolinium in all NSF patients of Dr. High's original series.

Dr. High and his colleagues have used mass spectrometry to analyze a range of different tissues. Infant foreskin samples, predictably, show no gadolinium. Multiple sclerosis patients without renal problems who had undergone semiannual MRIs showed no gadolinium. Tissue samples from Mohs surgery for skin cancer? Also clear, as were skin samples from ESRD patients who have not had gadolinium-based scans. ESRD patients who had undergone imaging with gadolinium contrast, however, did show traces of the metal albeit at much lower levels than the patients with NSF.

Circumstantial? Unlikely. "If you have gadolinium in your tissues, you got it from somewhere. There is no regularly encountered source of gadolinium in this form in nature. So unless you happen to be a gadolinium miner, you got it from a doctor," said Dr. High.

But Dr. High seems reluctant to pin blame for NSF exclusively on gadolinium contrast agents. Bear in mind that nearly all NSF patients have ESRD, meaning that their ability to filter and eliminate toxins such as metals is sorely impaired. "Renal failure patients are a toxic soup of metals—calcium, iron, zinc, copper, aluminum—all sorts of metals," Dr. High said, adding that he believes NSF results from "a collusion of coconspirators. Gadolinium alone may not be the only prerequisite exposure, and other metals may be involved in its deposition or in disease evolution." Only time will tell.

Case in point, the prevailing model for how gadolinium ends up in the skin involves a hypothetical process called "transmetallation," in which other metals, such as iron or calcium present in the tissue, knock the gadolinium off the chelator to which it is normally bound.

"Transmetallation is just a theory at this point. It hasn't yet been irrefutably proven to occur in the body. Electron microscopy cannot detect what a metal is bound to, but a special kind of subatomic particle accelerator can."

To that end, Dr. High will soon be the first dermatopathologist to gain access to such an instrument. By the time this article is published, he will have been engaged in particle accelerator experiments designed to prove whether gadolinium in tissue is no longer bound to its chelators, as the transmetallation theory suggests. "There will likely be other information coming out to show that other metals may contribute to gadolinium deposition and perhaps to NSF itself," he said.

Even if gadolinium is not the only cause of NSF, it certainly appears a strong trigger in susceptible individuals. Estimates indicate that 3%-5% of patients with ESRD may be at risk for NSF. It appears that, in addition to ESRD, predisposition to thrombosis and inflammation may be involved. The risk is also likely proportional to the number of scans a person receives during renal failure.

For those who develop the disorder, there's little physicians can do. "I see about 10-12 patients with NSF at the University of Colorado. We've tried everything—photopheresis, plasmapheresis, renal transplant. No single treatment works uniformly well for all patients. And there are no formal studies comparing modalities."

Dr. High predicted that the current controversy about gadolinium will prompt a surge of interest in "medical geology" and the study of how elemental metals affect human health. Currently, Dr. High is working on a rapid, noninvasive screening device to detect metals such as gadolinium in human tissue.

Gadolinium conglomerations in a fibrohistiocytic cell from the skin of an NSF patient are shown above. Courtesy Dr. Whitney A. High

BARCELONA — Clinical improvement in a small series of patients with inflammatory myopathies treated with rituximab suggests that B-cell depletion may prove useful in these disorders, according to Dr. Marlies Blom of the department of rheumatology, Radboud University Nijmegen (the Netherlands) Medical Centre.

Among seven patients with dermatomyositis, polymyositis, or antisynthetase syndrome, two infusions of 1,000 mg rituximab 2 weeks apart resulted in a mean 30% increase in muscle strength at 3 months, Dr. Blom reported in a poster session at the annual European Congress of Rheumatology.

Patients' subjective reports of improvement in muscle strength were confirmed by handheld dynamometry.

The patients ranged in age from 38 to 58 years, and the duration of their disease ranged from 3 to 16 years. Four of the seven were female.

Previous treatments included oral and intravenous prednisone, methotrexate, azathioprine, cyclophosphamide, interferon, etanercept, and intravenous immunoglobulin.

A mean 13% improvement was reported on Health Assessment Questionnaire (HAQ) scores, and improvements also were seen in levels of creatine phosphokinase, a marker of disease activity.

In one patient, a muscle biopsy taken 4 months after treatment showed a total absence of CD20+ B cells. This patient's Disease Activity Score-28 (DAS28) score fell from 6.8 to 4.5 after 3 months, according to Dr. Blom.

After initial good response, three patients required retreatment for exacerbations of myositis at about 6 months.

No serious adverse events were observed and immunoglobulin levels remained within normal levels.

These results suggest that B cells play an important role in the pathogenesis of inflammatory myopathies, Dr. Blom noted.

Another recent report suggested that a possible rationale for considering B-cell depletion as a therapeutic strategy in dermatomyositis was that treatment with rituximab had previously been shown to result in improvements in muscle strength in humorally mediated autoimmune peripheral neuropathies (Arthritis Rheum. 2005;52:601-7).

The importance of humoral immunity in dermatomyositis also is suggested by the observation that perifascicular endothelial immunoglobulin and complement deposition are thought to result in the muscle ischemia and atrophy (J. Rheumatol. 2006;33:1021-6).

Furthermore, the observation that there are antibodies specific for myositis also supports the concept of B-cell-mediated humoral abnormality in dermatomyositis (Medicine [Baltimore] 1991;70:360-74).

BARCELONA — Clinical improvement in a small series of patients with inflammatory myopathies treated with rituximab suggests that B-cell depletion may prove useful in these disorders, according to Dr. Marlies Blom of the department of rheumatology, Radboud University Nijmegen (the Netherlands) Medical Centre.

Among seven patients with dermatomyositis, polymyositis, or antisynthetase syndrome, two infusions of 1,000 mg rituximab 2 weeks apart resulted in a mean 30% increase in muscle strength at 3 months, Dr. Blom reported in a poster session at the annual European Congress of Rheumatology.

Patients' subjective reports of improvement in muscle strength were confirmed by handheld dynamometry.

The patients ranged in age from 38 to 58 years, and the duration of their disease ranged from 3 to 16 years. Four of the seven were female.

Previous treatments included oral and intravenous prednisone, methotrexate, azathioprine, cyclophosphamide, interferon, etanercept, and intravenous immunoglobulin.

A mean 13% improvement was reported on Health Assessment Questionnaire (HAQ) scores, and improvements also were seen in levels of creatine phosphokinase, a marker of disease activity.

In one patient, a muscle biopsy taken 4 months after treatment showed a total absence of CD20+ B cells. This patient's Disease Activity Score-28 (DAS28) score fell from 6.8 to 4.5 after 3 months, according to Dr. Blom.

After initial good response, three patients required retreatment for exacerbations of myositis at about 6 months.

No serious adverse events were observed and immunoglobulin levels remained within normal levels.

These results suggest that B cells play an important role in the pathogenesis of inflammatory myopathies, Dr. Blom noted.

Another recent report suggested that a possible rationale for considering B-cell depletion as a therapeutic strategy in dermatomyositis was that treatment with rituximab had previously been shown to result in improvements in muscle strength in humorally mediated autoimmune peripheral neuropathies (Arthritis Rheum. 2005;52:601-7).

The importance of humoral immunity in dermatomyositis also is suggested by the observation that perifascicular endothelial immunoglobulin and complement deposition are thought to result in the muscle ischemia and atrophy (J. Rheumatol. 2006;33:1021-6).

Furthermore, the observation that there are antibodies specific for myositis also supports the concept of B-cell-mediated humoral abnormality in dermatomyositis (Medicine [Baltimore] 1991;70:360-74).

BARCELONA — Clinical improvement in a small series of patients with inflammatory myopathies treated with rituximab suggests that B-cell depletion may prove useful in these disorders, according to Dr. Marlies Blom of the department of rheumatology, Radboud University Nijmegen (the Netherlands) Medical Centre.

Among seven patients with dermatomyositis, polymyositis, or antisynthetase syndrome, two infusions of 1,000 mg rituximab 2 weeks apart resulted in a mean 30% increase in muscle strength at 3 months, Dr. Blom reported in a poster session at the annual European Congress of Rheumatology.

Patients' subjective reports of improvement in muscle strength were confirmed by handheld dynamometry.

The patients ranged in age from 38 to 58 years, and the duration of their disease ranged from 3 to 16 years. Four of the seven were female.

Previous treatments included oral and intravenous prednisone, methotrexate, azathioprine, cyclophosphamide, interferon, etanercept, and intravenous immunoglobulin.

A mean 13% improvement was reported on Health Assessment Questionnaire (HAQ) scores, and improvements also were seen in levels of creatine phosphokinase, a marker of disease activity.

In one patient, a muscle biopsy taken 4 months after treatment showed a total absence of CD20+ B cells. This patient's Disease Activity Score-28 (DAS28) score fell from 6.8 to 4.5 after 3 months, according to Dr. Blom.

After initial good response, three patients required retreatment for exacerbations of myositis at about 6 months.

No serious adverse events were observed and immunoglobulin levels remained within normal levels.

These results suggest that B cells play an important role in the pathogenesis of inflammatory myopathies, Dr. Blom noted.

Another recent report suggested that a possible rationale for considering B-cell depletion as a therapeutic strategy in dermatomyositis was that treatment with rituximab had previously been shown to result in improvements in muscle strength in humorally mediated autoimmune peripheral neuropathies (Arthritis Rheum. 2005;52:601-7).

The importance of humoral immunity in dermatomyositis also is suggested by the observation that perifascicular endothelial immunoglobulin and complement deposition are thought to result in the muscle ischemia and atrophy (J. Rheumatol. 2006;33:1021-6).

Furthermore, the observation that there are antibodies specific for myositis also supports the concept of B-cell-mediated humoral abnormality in dermatomyositis (Medicine [Baltimore] 1991;70:360-74).

BARCELONA — Factors that were predictive of relapse in lupus nephritis after induction therapy were persistence of proteinuria and abnormal C4 levels, and patients having received cyclophosphamide for less than 2 years, Dr. Eva Salgado reported at the annual European Congress of Rheumatology.

Considerable variability is seen in the clinical course and response to therapy in patients with systemic lupus erythematosus (SLE) who develop nephritis, and it would be useful to identify factors that are associated with relapse so that more aggressive treatment could be used from the outset, explained Dr. Salgado of Hospital 12 de Octubre, Madrid.

A study was therefore conducted that included all 128 patients diagnosed with SLE and nephritis in the rheumatology department of Dr. Salgado's hospital between 1977 and 2007.

A total of 114 of the patients were women, and more than 95% were white. Mean age at the appearance of nephritis was 30 years, and mean time from the diagnosis of SLE was 2 years.

Renal biopsy at the time of diagnosis of nephritis showed minimal changes in 2%, mesangial glomerulonephritis in 18%, focal proliferative glomerulonephritis in 12%, diffuse proliferative glomerulonephritis in 55%, and membranous glomerulonephritis in 13%.

At the time of initiation of induction therapy, 29 patients had some degree of creatinine increase, Dr. Salgado reported in a poster presentation.

Induction therapies included corticosteroids alone in 23% of patients, corticosteroids plus cyclophosphamide in 65%, azathioprine in 10%, and mycophenolate mofetil in 2%. Mean duration of induction therapy was 27 months.

A total of 71% of patients showed a complete response to induction therapy, while 24% had a partial response and 5% did not respond.

After the initial response, 59% received maintenance therapy with antimalarial drugs, azathioprine, or both.

During a mean of 13 years of follow-up, 34 patients experienced renal relapse, at a mean of 51 months after the end of induction therapy.

Multivariate analysis found that relapse was independently associated with persistence of abnormal C4 levels or residual proteinuria greater than 0.5 g/day after the completion of induction therapy, and duration of cyclophosphamide therapy for less than 2 years, according to Dr. Salgado.

Factors that were not predictive of relapse included histologic findings, age at SLE or nephritis diagnosis, delay in induction therapy, use of maintenance therapy, or other clinical characteristics.

Six patients developed end-stage renal failure and 14 died. Relapse was predictive of long-term renal failure but was not associated with increased mortality in this group of patients, Dr. Salgado observed.

BARCELONA — Factors that were predictive of relapse in lupus nephritis after induction therapy were persistence of proteinuria and abnormal C4 levels, and patients having received cyclophosphamide for less than 2 years, Dr. Eva Salgado reported at the annual European Congress of Rheumatology.

Considerable variability is seen in the clinical course and response to therapy in patients with systemic lupus erythematosus (SLE) who develop nephritis, and it would be useful to identify factors that are associated with relapse so that more aggressive treatment could be used from the outset, explained Dr. Salgado of Hospital 12 de Octubre, Madrid.

A study was therefore conducted that included all 128 patients diagnosed with SLE and nephritis in the rheumatology department of Dr. Salgado's hospital between 1977 and 2007.

A total of 114 of the patients were women, and more than 95% were white. Mean age at the appearance of nephritis was 30 years, and mean time from the diagnosis of SLE was 2 years.

Renal biopsy at the time of diagnosis of nephritis showed minimal changes in 2%, mesangial glomerulonephritis in 18%, focal proliferative glomerulonephritis in 12%, diffuse proliferative glomerulonephritis in 55%, and membranous glomerulonephritis in 13%.

At the time of initiation of induction therapy, 29 patients had some degree of creatinine increase, Dr. Salgado reported in a poster presentation.

Induction therapies included corticosteroids alone in 23% of patients, corticosteroids plus cyclophosphamide in 65%, azathioprine in 10%, and mycophenolate mofetil in 2%. Mean duration of induction therapy was 27 months.

A total of 71% of patients showed a complete response to induction therapy, while 24% had a partial response and 5% did not respond.

After the initial response, 59% received maintenance therapy with antimalarial drugs, azathioprine, or both.

During a mean of 13 years of follow-up, 34 patients experienced renal relapse, at a mean of 51 months after the end of induction therapy.

Multivariate analysis found that relapse was independently associated with persistence of abnormal C4 levels or residual proteinuria greater than 0.5 g/day after the completion of induction therapy, and duration of cyclophosphamide therapy for less than 2 years, according to Dr. Salgado.

Factors that were not predictive of relapse included histologic findings, age at SLE or nephritis diagnosis, delay in induction therapy, use of maintenance therapy, or other clinical characteristics.

Six patients developed end-stage renal failure and 14 died. Relapse was predictive of long-term renal failure but was not associated with increased mortality in this group of patients, Dr. Salgado observed.

BARCELONA — Factors that were predictive of relapse in lupus nephritis after induction therapy were persistence of proteinuria and abnormal C4 levels, and patients having received cyclophosphamide for less than 2 years, Dr. Eva Salgado reported at the annual European Congress of Rheumatology.

Considerable variability is seen in the clinical course and response to therapy in patients with systemic lupus erythematosus (SLE) who develop nephritis, and it would be useful to identify factors that are associated with relapse so that more aggressive treatment could be used from the outset, explained Dr. Salgado of Hospital 12 de Octubre, Madrid.

A study was therefore conducted that included all 128 patients diagnosed with SLE and nephritis in the rheumatology department of Dr. Salgado's hospital between 1977 and 2007.

A total of 114 of the patients were women, and more than 95% were white. Mean age at the appearance of nephritis was 30 years, and mean time from the diagnosis of SLE was 2 years.

Renal biopsy at the time of diagnosis of nephritis showed minimal changes in 2%, mesangial glomerulonephritis in 18%, focal proliferative glomerulonephritis in 12%, diffuse proliferative glomerulonephritis in 55%, and membranous glomerulonephritis in 13%.

At the time of initiation of induction therapy, 29 patients had some degree of creatinine increase, Dr. Salgado reported in a poster presentation.

Induction therapies included corticosteroids alone in 23% of patients, corticosteroids plus cyclophosphamide in 65%, azathioprine in 10%, and mycophenolate mofetil in 2%. Mean duration of induction therapy was 27 months.

A total of 71% of patients showed a complete response to induction therapy, while 24% had a partial response and 5% did not respond.

After the initial response, 59% received maintenance therapy with antimalarial drugs, azathioprine, or both.

During a mean of 13 years of follow-up, 34 patients experienced renal relapse, at a mean of 51 months after the end of induction therapy.

Multivariate analysis found that relapse was independently associated with persistence of abnormal C4 levels or residual proteinuria greater than 0.5 g/day after the completion of induction therapy, and duration of cyclophosphamide therapy for less than 2 years, according to Dr. Salgado.

Factors that were not predictive of relapse included histologic findings, age at SLE or nephritis diagnosis, delay in induction therapy, use of maintenance therapy, or other clinical characteristics.

Six patients developed end-stage renal failure and 14 died. Relapse was predictive of long-term renal failure but was not associated with increased mortality in this group of patients, Dr. Salgado observed.

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus.

"The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response," Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks.

The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear anti-body of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[suppl. 9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

"Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo," said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

"This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment," she said.

The studies are being sponsored by Human Genome Sciences, Inc., manufacturer of LymphoStat-B, and GlaxoSmithKline. Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus.

"The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response," Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks.

The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear anti-body of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[suppl. 9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

"Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo," said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

"This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment," she said.

The studies are being sponsored by Human Genome Sciences, Inc., manufacturer of LymphoStat-B, and GlaxoSmithKline. Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER

BARCELONA — Significant improvements in disease activity were observed among lupus patients treated with belimumab in a new analysis of data from an earlier study using a combined response end point, Dr. Ellen Ginzler said at the annual European Congress of Rheumatology.

The analysis used an evidence-based combined response end point that has been developed to improve the assessment of responses to drug intervention in clinical trials for systemic lupus erythematosus.

"The heterogeneity of lupus disease manifestations contributes to the difficulty of using a single index to adequately assess therapeutic response," Dr. Ginzler explained.

Belimumab (LymphoStat-B) is a monoclonal antibody that binds with high specificity to B lymphocyte stimulator (BLyS), which, being a potent costimulator of B cells, is thought to play a role in B-cell-mediated autoimmunity.

In the original analysis of the study results, the primary end point—reduction in disease activity as measured by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) as modified for the Safety of Estrogens in Lupus Erythematosus National Assessment (SELENA) at 24 weeks—was not met.

The study included 449 patients with lupus who were randomized to receive placebo or belimumab in doses of 1, 4, or 10 mg/kg on days 0, 14, 28, and then monthly for 52 weeks.

The study continued in open-label fashion through week 76.

A subsequent analysis, however, determined that significant benefits were seen at 52 weeks among the 72% of patients who were serologically active at baseline, with titers of antinuclear anti-body of 1:80 or greater and/or titers of anti-double-stranded (ds) DNA of 30 IU or greater (Arthritis Rheum. 2006;54[suppl. 9]:S258).

Responses among this cohort have now been analyzed according to the new combined response end point, which defines efficacy as an improvement in SELENA-SLEDAI of four points or more and a British Isles Lupus Assessment Group (BILAG) score that reflects the number and severity of organ system flares.

The combined end point also reflects physician's global assessment and patient health-related quality of life as evaluated on the Short Form (SF)-36.

"Using this combined outcome efficacy measure, the response to belimumab therapy among patients who were serologically active at baseline was 46%, which is highly statistically significant at 52 weeks compared to a response rate of 29% with placebo," said Dr. Ginzler, who is professor of medicine and chief of rheumatology, State University of New York, Brooklyn.

By week 76 the response rate had risen to 56%.

At baseline, the mean SELANA-SLEDAI score was 9.6. Patients in the active treatment groups had 29% and 38% reductions in SELENA-SLEDAI scores at weeks 52 and 76, respectively.

At week 52 the belimumab-treated patients had fewer shifts to worse scores in three of the eight BILAG organ systems: musculoskeletal, neurologic, and cardiovascular-respiratory.

Patients who were classified as responders on the composite end point also had greater reductions in activated B cells and anti-ds DNA antibodies, along with greater improvements in the SF-36.

Combining multiple disease activity measures into a response end point improved the assessment of variable disease activity and was predictive of biomarker and quality of life improvements, Dr. Ginzler said.

"This combined end point has now been accepted by regulatory authorities and is being used in two global phase III studies of belimumab that have recently begun enrollment," she said.

The studies are being sponsored by Human Genome Sciences, Inc., manufacturer of LymphoStat-B, and GlaxoSmithKline. Dr. Ginzler has previously disclosed receiving research grants from Human Genome Sciences.

A single index cannot adequately assess treatment response in this heterogeneous disease. DR. GINZLER