Psoriasis

VIENNA — The triad of high fever, rash, and organ involvement occurring in a patient who has recently begun a new drug treatment may signal drug hypersensitivity syndrome, Dr. Nikolai Tsankov said at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition is a severe idiosyncratic reaction to certain medications that can cause skin, liver, kidney, lung, and hematologic disturbances. The skin eruption typically is a red maculopapular rash, but can also manifest as bullae, pustules, and even as toxic epidermal necrolysis (TEN).

Mortality has been estimated at 8%, increasing to 18%-40% when hepatic involvement is present, said Dr. Tsankov of the department of dermatology and venereology, Sofia Medical University (Bulgaria). This reaction is most commonly seen with the anticonvulsants phenytoin, phenobarbital, and carbamazepine, but has also been seen with minocycline, sulfonamides, and various other medications.

Immediate withdrawal of all suspected medicines is the first rule of management, said Dr. Tsankov. He described three patients with drug hypersensitivity syndrome and TEN whom he has treated, all with good outcomes.

The first patient was a 32-year-old man with epilepsy who had been taking valproic acid, but switched to lamotrigine. After 8 days he developed symptoms including fever up to 104 degrees, painful lymph nodes, tachycardia, and positive Nikolsky's sign. His liver enzyme and creatinine phosphate levels also were increased.

The second patient was a 20-year-old man with a 10-year history of alcohol abuse who began treatment with carbamazepine and diazepam, and 3 days later developed weakness, joint pain, fever, and a widespread red maculopapular rash as well as hemorrhagic bullae on his soles and palms. He also developed tachycardia, tachypnea, and wet crepitations, as well as elevations in liver enzyme and eosinophilia levels.

The third patient was a 32-year-old man with hemorrhagic colitis who began treatment with sulfasalazine. After 13 days, a papular rash appeared on sun-exposed areas of the skin, followed by hemorrhagic crusts and blisters. Nikolsky's sign was positive. His erythrocyte sedimentation rate was elevated, and leukocytosis and eosinophilia were present.

Following the cessation of the culprit, the three patients received intensive supportive care, broad spectrum antibiotics, and corticosteroids. Within approximately 4 weeks, all three men showed resolution of symptoms and reepithelialization.

The use of corticosteroids in this situation is controversial; some suggest that systemic corticosteroids should be contraindicated in TEN. Although they do appear to arrest the progression of TEN, the immunosuppressive effects of these drugs also increase the risk of infection, which is often associated with a lethal outcome (Am. J. Clin. Dermatol. 2000;1:349-60).

On the other hand, Dr. Tsankov said in an interview, drug hypersensitivity syndrome is not only a toxic but also an immunologic reaction. "As immune response modifiers, systemic corticosteroids could ameliorate the symptoms of drug hypersensitivity syndrome, especially with severe systemic involvement," he said.

It's important to note that cross reactivity can occur among the three main aromatic anticonvulsants, so a patient who experiences a hypersensitivity reaction to one must avoid all three, he said. Moreover, first degree relatives also should be cautioned because they may be susceptible.

Drug hypersensitivity syndrome can manifest in severe widespread rashes. Courtesy Dr. Nikolai Tsankov

VIENNA — The triad of high fever, rash, and organ involvement occurring in a patient who has recently begun a new drug treatment may signal drug hypersensitivity syndrome, Dr. Nikolai Tsankov said at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition is a severe idiosyncratic reaction to certain medications that can cause skin, liver, kidney, lung, and hematologic disturbances. The skin eruption typically is a red maculopapular rash, but can also manifest as bullae, pustules, and even as toxic epidermal necrolysis (TEN).

Mortality has been estimated at 8%, increasing to 18%-40% when hepatic involvement is present, said Dr. Tsankov of the department of dermatology and venereology, Sofia Medical University (Bulgaria). This reaction is most commonly seen with the anticonvulsants phenytoin, phenobarbital, and carbamazepine, but has also been seen with minocycline, sulfonamides, and various other medications.

Immediate withdrawal of all suspected medicines is the first rule of management, said Dr. Tsankov. He described three patients with drug hypersensitivity syndrome and TEN whom he has treated, all with good outcomes.

The first patient was a 32-year-old man with epilepsy who had been taking valproic acid, but switched to lamotrigine. After 8 days he developed symptoms including fever up to 104 degrees, painful lymph nodes, tachycardia, and positive Nikolsky's sign. His liver enzyme and creatinine phosphate levels also were increased.

The second patient was a 20-year-old man with a 10-year history of alcohol abuse who began treatment with carbamazepine and diazepam, and 3 days later developed weakness, joint pain, fever, and a widespread red maculopapular rash as well as hemorrhagic bullae on his soles and palms. He also developed tachycardia, tachypnea, and wet crepitations, as well as elevations in liver enzyme and eosinophilia levels.

The third patient was a 32-year-old man with hemorrhagic colitis who began treatment with sulfasalazine. After 13 days, a papular rash appeared on sun-exposed areas of the skin, followed by hemorrhagic crusts and blisters. Nikolsky's sign was positive. His erythrocyte sedimentation rate was elevated, and leukocytosis and eosinophilia were present.

Following the cessation of the culprit, the three patients received intensive supportive care, broad spectrum antibiotics, and corticosteroids. Within approximately 4 weeks, all three men showed resolution of symptoms and reepithelialization.

The use of corticosteroids in this situation is controversial; some suggest that systemic corticosteroids should be contraindicated in TEN. Although they do appear to arrest the progression of TEN, the immunosuppressive effects of these drugs also increase the risk of infection, which is often associated with a lethal outcome (Am. J. Clin. Dermatol. 2000;1:349-60).

On the other hand, Dr. Tsankov said in an interview, drug hypersensitivity syndrome is not only a toxic but also an immunologic reaction. "As immune response modifiers, systemic corticosteroids could ameliorate the symptoms of drug hypersensitivity syndrome, especially with severe systemic involvement," he said.

It's important to note that cross reactivity can occur among the three main aromatic anticonvulsants, so a patient who experiences a hypersensitivity reaction to one must avoid all three, he said. Moreover, first degree relatives also should be cautioned because they may be susceptible.

Drug hypersensitivity syndrome can manifest in severe widespread rashes. Courtesy Dr. Nikolai Tsankov

VIENNA — The triad of high fever, rash, and organ involvement occurring in a patient who has recently begun a new drug treatment may signal drug hypersensitivity syndrome, Dr. Nikolai Tsankov said at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition is a severe idiosyncratic reaction to certain medications that can cause skin, liver, kidney, lung, and hematologic disturbances. The skin eruption typically is a red maculopapular rash, but can also manifest as bullae, pustules, and even as toxic epidermal necrolysis (TEN).

Mortality has been estimated at 8%, increasing to 18%-40% when hepatic involvement is present, said Dr. Tsankov of the department of dermatology and venereology, Sofia Medical University (Bulgaria). This reaction is most commonly seen with the anticonvulsants phenytoin, phenobarbital, and carbamazepine, but has also been seen with minocycline, sulfonamides, and various other medications.

Immediate withdrawal of all suspected medicines is the first rule of management, said Dr. Tsankov. He described three patients with drug hypersensitivity syndrome and TEN whom he has treated, all with good outcomes.

The first patient was a 32-year-old man with epilepsy who had been taking valproic acid, but switched to lamotrigine. After 8 days he developed symptoms including fever up to 104 degrees, painful lymph nodes, tachycardia, and positive Nikolsky's sign. His liver enzyme and creatinine phosphate levels also were increased.

The second patient was a 20-year-old man with a 10-year history of alcohol abuse who began treatment with carbamazepine and diazepam, and 3 days later developed weakness, joint pain, fever, and a widespread red maculopapular rash as well as hemorrhagic bullae on his soles and palms. He also developed tachycardia, tachypnea, and wet crepitations, as well as elevations in liver enzyme and eosinophilia levels.

The third patient was a 32-year-old man with hemorrhagic colitis who began treatment with sulfasalazine. After 13 days, a papular rash appeared on sun-exposed areas of the skin, followed by hemorrhagic crusts and blisters. Nikolsky's sign was positive. His erythrocyte sedimentation rate was elevated, and leukocytosis and eosinophilia were present.

Following the cessation of the culprit, the three patients received intensive supportive care, broad spectrum antibiotics, and corticosteroids. Within approximately 4 weeks, all three men showed resolution of symptoms and reepithelialization.

The use of corticosteroids in this situation is controversial; some suggest that systemic corticosteroids should be contraindicated in TEN. Although they do appear to arrest the progression of TEN, the immunosuppressive effects of these drugs also increase the risk of infection, which is often associated with a lethal outcome (Am. J. Clin. Dermatol. 2000;1:349-60).

On the other hand, Dr. Tsankov said in an interview, drug hypersensitivity syndrome is not only a toxic but also an immunologic reaction. "As immune response modifiers, systemic corticosteroids could ameliorate the symptoms of drug hypersensitivity syndrome, especially with severe systemic involvement," he said.

It's important to note that cross reactivity can occur among the three main aromatic anticonvulsants, so a patient who experiences a hypersensitivity reaction to one must avoid all three, he said. Moreover, first degree relatives also should be cautioned because they may be susceptible.

Drug hypersensitivity syndrome can manifest in severe widespread rashes. Courtesy Dr. Nikolai Tsankov

CHICAGO — Radiologic professional associations and governmental regulatory agencies in the United States and Europe are in the midst of grappling with how best to deal with nephrogenic systemic fibrosis, a severe scleroderma-like syndrome that may arise in patients with poor kidney function after receiving gadolinium-based contrast agents administered during magnetic resonance imaging.

This problem necessitates practice changes, including restrictions on contrast magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) in patients with moderate- to end-stage renal disease, attention to new, stricter screening recommendations, and foregoing sensitive studies that rely on high doses of contrast agents, according to Dr. Emanuel Kanal, who spoke at the American Society of Neuroradiology meeting.

"This has taken the world by storm," said Dr. Kanal, a neuroradiologist at the University of Pittsburgh, who has received hundreds of e-mails from concerned physicians. New developments are occurring almost daily. For instance, on June 22, the American College of Radiology Committees on Drugs and Contrast Media and MR Safety discussed recommendations for screening patients before contrast-enhanced MRI that go beyond verbal questioning.

Although final recommendations have not yet been issued, it is expected that plasma blood screening to assess glomerular filtration rates (GFRs) will be recommended before contrast-enhanced MRI for patients at risk.

Within the same week, on June 26:

▸ A European regulatory body representing 31 members of the European Union (the European Pharmacovigilance Working Party of the Committee for Medicinal Products for Human Use) added the gadolinium-based contrast agent Magnevist to the list of contraindicated drugs for patients with severe and end-stage renal disease.

▸ The Chairman of the Commission on Human Medicines in the United Kingdom, Sir Gordon Duff, released a "Dear Colleague" letter with similar content.

▸ The European Update issued a statement that "a review of the available data does not suggest that the risk of NSF in patients with advanced renal impairment is the same for all gadolinium-based contrast agents"–the first time any formal society or agency other than the American College of Radiology has arrived at that conclusion, Dr. Kanal said.

Nephrogenic systemic fibrosis (NSF) is a scleroderma/myxoderma-like condition that causes painful scarring, tightening, thickening, and discoloration of the skin. It also affects the lungs, myocardium, diaphragm, and striated muscle.

NSF can be debilitating and fulminant in about 5% of cases and can lead to immobility and death within weeks to months. There is no known cure, with occasional improvement noted following renal transplantation.

In 2006, Dr. Thomas Grobner, a nephrologist at the General Hospital of Wiener Neustadt, Austria, made the first association between gadolinium and NSF (Nephrol. Dial. Transplant. 2006 Oct. 11;E-pub ahead of print). Since then, more than 240 confirmed cases have been included in a registry maintained by Dr. Shawn Cowper, a dermatopathologist at Yale University, New Haven, Conn., who found that all affected patients had received gadolinium contrast agents within a few months before diagnosis.

Of the over 230 cases of NSF that have been reported to the Food and Drug Administration's MedWatch up until April 17 of this year, 160 were related to Omniscan and 73 to Magnevist, with 3 associated with isolated prior Optimark administration.

Gadolinium concentrations in the biopsies of NSF patients were 35 to 150 times higher than those found in normal volunteers who received contrast material, Dr. Kanal said. Although the half-life of gadolinium is 70-90 minutes in those with normal renal function, gadolinium has been detected in tissue biopsy specimens of NSF patients as long as 11 months after administration.

Clinical data suggest several associations that impact clinical practice:

▸ The higher the dose of contrast, the greater the chance of developing NSF.

▸ The greater the severity of renal disease, the greater the chance of developing NSF.

▸ Cumulative doses of contrast seem to increase the incidence of NSF.

These findings can have a significant impact on clinical practice. For instance, MRI studies that use double or triple doses of contrast, such as contrast dynamic bolus MRA, may no longer be an option for patients with severely impaired renal function. Alternatively, the radiologist may modify the study to minimize the administered dose of gadolinium-based contrast agent.

The spike in NSF cases in recent years is directly related to the more common use of high-dose contrast studies since the proliferation of especially non-neuroradiologic contrast bolus dynamic MR angiography in the mid-1990s, Dr. Kanal suggested.

"With iodinated contrast-related [contrast-induced nephropathy] concerns for CT and NSF-related concerns for gadolinium-based MR contrast agents in MRI, this is becoming a problem for neurologists and other referring physicians, as the number of imaging tests available for patients with severe renal disease that can sensitively evaluate problems is decreasing," he said.

Patients with stage III kidney disease or worse should not routinely be administered standard doses of gadolinium-based MR contrast agents, he recommended. This can have serious implications for the 35 million U.S. adults over age 65 years who have stage III or IV renal disease, many of whom require access to diagnostic MR services, Dr. Kanal said.

Exacerbating the problem is poor patient awareness of renal disease. According to Dr. Kanal, 97% of women and 82% of men with stage III chronic kidney disease are unaware that they have it. Thus asking patients whether they have renal disease may no longer be a sufficient screening method.

It is anticipated that a subset of patients at risk for renal disease (over age 60 years, history of hypertension, diabetes, renal disease or severe hepatic disease) will be required to have their glomerular filtration rates assessed before receiving gadolinium-based MR contrast agents. Since the risk of NSF may increase with cumulative dosing, neurologists should carefully consider the potential risk of serial contrast-enhanced scans when following patients.

While the FDA has applied black box warnings to all five MR contrast agents available in the United States, "the available data 'screams' that [the risk of NSF] is not equal for all the five FDA-approved MR contrast agents, and appears to be higher or far higher for Omniscan," he said, estimating that roughly 3%-7% of patients with end-stage renal disease receiving high-dose Omniscan will develop NSF.

"In my opinion, the present data are sufficiently compelling to avoid Omniscan administration in patients with any significant level of renal disease," he added.

For gadolinium to be tolerated by humans, it must be chelated to a ligand molecule, he said. The likelihood of the ligand dissociating from the gadolinium ion (leaving the toxic free Gd+3) is far from equal among these five agents, being far greater in Omniscan and Optimark than in Magnevist, Multihance, or Prohance, judging from findings from in vitro and some in vivo studies. Because nonionic Omniscan and Optimark have a far lower conditional stability constant than do Magnevist, Multihance, and Prohance at normal body pH, it is possible that this may be related to the perceived greater incidence of NSF in patients who received Omniscan, Dr. Kanal said.

Elevated levels of calcium, phosphate, copper, iron, and zinc, which can compete with the gadolinium ion for coupling with the ligand molecule, may also exacerbate the risk of toxicity.

"You need a radiologist who knows what she or he is doing in this area to help design the study in a manner that will decrease dosing yet still be as diagnostic as possible. Trust your radiologist and then follow his feedback and guidance," he commented.

If a dialysis patient must have a contrast MRI, the American College of Radiology guidelines recommend that the patient be taken to hemodialysis immediately following the completion of the MR examination in which the gadolinium-based MR contrast agent had been administered. Radiologists should compile a database of all patients with stage III or more severe kidney disease who have had contrast-enhanced MRIs and follow them to ensure that they do not develop NSF, Dr. Kanal recommended.

"It used to be that patients with renal failure would specifically be sent to MR because the contrast agents were not directly nephrotoxic at the doses used, whereas giving iodine to patients with renal disease could cause iodine-induced nephropathy. Now we have something else to worry about for patients with renal disease: NSF," Dr. Kanal said.

Patients with stage IIIkidney disease or worse shouldn't be routinely given standard doses of gadolinium-based agents. DR. KANAL

The skin on the arm of a patient with contrast agent-induced nephrogenic systemic fibrosis shows scleroderma-like changes, including scarring (which is usually painful), tightening, thickening, and discoloration. Nephrogenic systemic fibrosis is fulminant in about 5% of cases and can prove to be fatal within weeks. Courtesy Dr. Shawn Cowper

CHICAGO — Radiologic professional associations and governmental regulatory agencies in the United States and Europe are in the midst of grappling with how best to deal with nephrogenic systemic fibrosis, a severe scleroderma-like syndrome that may arise in patients with poor kidney function after receiving gadolinium-based contrast agents administered during magnetic resonance imaging.

This problem necessitates practice changes, including restrictions on contrast magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) in patients with moderate- to end-stage renal disease, attention to new, stricter screening recommendations, and foregoing sensitive studies that rely on high doses of contrast agents, according to Dr. Emanuel Kanal, who spoke at the American Society of Neuroradiology meeting.

"This has taken the world by storm," said Dr. Kanal, a neuroradiologist at the University of Pittsburgh, who has received hundreds of e-mails from concerned physicians. New developments are occurring almost daily. For instance, on June 22, the American College of Radiology Committees on Drugs and Contrast Media and MR Safety discussed recommendations for screening patients before contrast-enhanced MRI that go beyond verbal questioning.

Although final recommendations have not yet been issued, it is expected that plasma blood screening to assess glomerular filtration rates (GFRs) will be recommended before contrast-enhanced MRI for patients at risk.

Within the same week, on June 26:

▸ A European regulatory body representing 31 members of the European Union (the European Pharmacovigilance Working Party of the Committee for Medicinal Products for Human Use) added the gadolinium-based contrast agent Magnevist to the list of contraindicated drugs for patients with severe and end-stage renal disease.

▸ The Chairman of the Commission on Human Medicines in the United Kingdom, Sir Gordon Duff, released a "Dear Colleague" letter with similar content.

▸ The European Update issued a statement that "a review of the available data does not suggest that the risk of NSF in patients with advanced renal impairment is the same for all gadolinium-based contrast agents"–the first time any formal society or agency other than the American College of Radiology has arrived at that conclusion, Dr. Kanal said.

Nephrogenic systemic fibrosis (NSF) is a scleroderma/myxoderma-like condition that causes painful scarring, tightening, thickening, and discoloration of the skin. It also affects the lungs, myocardium, diaphragm, and striated muscle.

NSF can be debilitating and fulminant in about 5% of cases and can lead to immobility and death within weeks to months. There is no known cure, with occasional improvement noted following renal transplantation.

In 2006, Dr. Thomas Grobner, a nephrologist at the General Hospital of Wiener Neustadt, Austria, made the first association between gadolinium and NSF (Nephrol. Dial. Transplant. 2006 Oct. 11;E-pub ahead of print). Since then, more than 240 confirmed cases have been included in a registry maintained by Dr. Shawn Cowper, a dermatopathologist at Yale University, New Haven, Conn., who found that all affected patients had received gadolinium contrast agents within a few months before diagnosis.

Of the over 230 cases of NSF that have been reported to the Food and Drug Administration's MedWatch up until April 17 of this year, 160 were related to Omniscan and 73 to Magnevist, with 3 associated with isolated prior Optimark administration.

Gadolinium concentrations in the biopsies of NSF patients were 35 to 150 times higher than those found in normal volunteers who received contrast material, Dr. Kanal said. Although the half-life of gadolinium is 70-90 minutes in those with normal renal function, gadolinium has been detected in tissue biopsy specimens of NSF patients as long as 11 months after administration.

Clinical data suggest several associations that impact clinical practice:

▸ The higher the dose of contrast, the greater the chance of developing NSF.

▸ The greater the severity of renal disease, the greater the chance of developing NSF.

▸ Cumulative doses of contrast seem to increase the incidence of NSF.

These findings can have a significant impact on clinical practice. For instance, MRI studies that use double or triple doses of contrast, such as contrast dynamic bolus MRA, may no longer be an option for patients with severely impaired renal function. Alternatively, the radiologist may modify the study to minimize the administered dose of gadolinium-based contrast agent.

The spike in NSF cases in recent years is directly related to the more common use of high-dose contrast studies since the proliferation of especially non-neuroradiologic contrast bolus dynamic MR angiography in the mid-1990s, Dr. Kanal suggested.

"With iodinated contrast-related [contrast-induced nephropathy] concerns for CT and NSF-related concerns for gadolinium-based MR contrast agents in MRI, this is becoming a problem for neurologists and other referring physicians, as the number of imaging tests available for patients with severe renal disease that can sensitively evaluate problems is decreasing," he said.

Patients with stage III kidney disease or worse should not routinely be administered standard doses of gadolinium-based MR contrast agents, he recommended. This can have serious implications for the 35 million U.S. adults over age 65 years who have stage III or IV renal disease, many of whom require access to diagnostic MR services, Dr. Kanal said.

Exacerbating the problem is poor patient awareness of renal disease. According to Dr. Kanal, 97% of women and 82% of men with stage III chronic kidney disease are unaware that they have it. Thus asking patients whether they have renal disease may no longer be a sufficient screening method.

It is anticipated that a subset of patients at risk for renal disease (over age 60 years, history of hypertension, diabetes, renal disease or severe hepatic disease) will be required to have their glomerular filtration rates assessed before receiving gadolinium-based MR contrast agents. Since the risk of NSF may increase with cumulative dosing, neurologists should carefully consider the potential risk of serial contrast-enhanced scans when following patients.

While the FDA has applied black box warnings to all five MR contrast agents available in the United States, "the available data 'screams' that [the risk of NSF] is not equal for all the five FDA-approved MR contrast agents, and appears to be higher or far higher for Omniscan," he said, estimating that roughly 3%-7% of patients with end-stage renal disease receiving high-dose Omniscan will develop NSF.

"In my opinion, the present data are sufficiently compelling to avoid Omniscan administration in patients with any significant level of renal disease," he added.

For gadolinium to be tolerated by humans, it must be chelated to a ligand molecule, he said. The likelihood of the ligand dissociating from the gadolinium ion (leaving the toxic free Gd+3) is far from equal among these five agents, being far greater in Omniscan and Optimark than in Magnevist, Multihance, or Prohance, judging from findings from in vitro and some in vivo studies. Because nonionic Omniscan and Optimark have a far lower conditional stability constant than do Magnevist, Multihance, and Prohance at normal body pH, it is possible that this may be related to the perceived greater incidence of NSF in patients who received Omniscan, Dr. Kanal said.

Elevated levels of calcium, phosphate, copper, iron, and zinc, which can compete with the gadolinium ion for coupling with the ligand molecule, may also exacerbate the risk of toxicity.

"You need a radiologist who knows what she or he is doing in this area to help design the study in a manner that will decrease dosing yet still be as diagnostic as possible. Trust your radiologist and then follow his feedback and guidance," he commented.

If a dialysis patient must have a contrast MRI, the American College of Radiology guidelines recommend that the patient be taken to hemodialysis immediately following the completion of the MR examination in which the gadolinium-based MR contrast agent had been administered. Radiologists should compile a database of all patients with stage III or more severe kidney disease who have had contrast-enhanced MRIs and follow them to ensure that they do not develop NSF, Dr. Kanal recommended.

"It used to be that patients with renal failure would specifically be sent to MR because the contrast agents were not directly nephrotoxic at the doses used, whereas giving iodine to patients with renal disease could cause iodine-induced nephropathy. Now we have something else to worry about for patients with renal disease: NSF," Dr. Kanal said.

Patients with stage IIIkidney disease or worse shouldn't be routinely given standard doses of gadolinium-based agents. DR. KANAL

The skin on the arm of a patient with contrast agent-induced nephrogenic systemic fibrosis shows scleroderma-like changes, including scarring (which is usually painful), tightening, thickening, and discoloration. Nephrogenic systemic fibrosis is fulminant in about 5% of cases and can prove to be fatal within weeks. Courtesy Dr. Shawn Cowper

CHICAGO — Radiologic professional associations and governmental regulatory agencies in the United States and Europe are in the midst of grappling with how best to deal with nephrogenic systemic fibrosis, a severe scleroderma-like syndrome that may arise in patients with poor kidney function after receiving gadolinium-based contrast agents administered during magnetic resonance imaging.

This problem necessitates practice changes, including restrictions on contrast magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) in patients with moderate- to end-stage renal disease, attention to new, stricter screening recommendations, and foregoing sensitive studies that rely on high doses of contrast agents, according to Dr. Emanuel Kanal, who spoke at the American Society of Neuroradiology meeting.

"This has taken the world by storm," said Dr. Kanal, a neuroradiologist at the University of Pittsburgh, who has received hundreds of e-mails from concerned physicians. New developments are occurring almost daily. For instance, on June 22, the American College of Radiology Committees on Drugs and Contrast Media and MR Safety discussed recommendations for screening patients before contrast-enhanced MRI that go beyond verbal questioning.

Although final recommendations have not yet been issued, it is expected that plasma blood screening to assess glomerular filtration rates (GFRs) will be recommended before contrast-enhanced MRI for patients at risk.

Within the same week, on June 26:

▸ A European regulatory body representing 31 members of the European Union (the European Pharmacovigilance Working Party of the Committee for Medicinal Products for Human Use) added the gadolinium-based contrast agent Magnevist to the list of contraindicated drugs for patients with severe and end-stage renal disease.

▸ The Chairman of the Commission on Human Medicines in the United Kingdom, Sir Gordon Duff, released a "Dear Colleague" letter with similar content.

▸ The European Update issued a statement that "a review of the available data does not suggest that the risk of NSF in patients with advanced renal impairment is the same for all gadolinium-based contrast agents"–the first time any formal society or agency other than the American College of Radiology has arrived at that conclusion, Dr. Kanal said.

Nephrogenic systemic fibrosis (NSF) is a scleroderma/myxoderma-like condition that causes painful scarring, tightening, thickening, and discoloration of the skin. It also affects the lungs, myocardium, diaphragm, and striated muscle.

NSF can be debilitating and fulminant in about 5% of cases and can lead to immobility and death within weeks to months. There is no known cure, with occasional improvement noted following renal transplantation.

In 2006, Dr. Thomas Grobner, a nephrologist at the General Hospital of Wiener Neustadt, Austria, made the first association between gadolinium and NSF (Nephrol. Dial. Transplant. 2006 Oct. 11;E-pub ahead of print). Since then, more than 240 confirmed cases have been included in a registry maintained by Dr. Shawn Cowper, a dermatopathologist at Yale University, New Haven, Conn., who found that all affected patients had received gadolinium contrast agents within a few months before diagnosis.

Of the over 230 cases of NSF that have been reported to the Food and Drug Administration's MedWatch up until April 17 of this year, 160 were related to Omniscan and 73 to Magnevist, with 3 associated with isolated prior Optimark administration.

Gadolinium concentrations in the biopsies of NSF patients were 35 to 150 times higher than those found in normal volunteers who received contrast material, Dr. Kanal said. Although the half-life of gadolinium is 70-90 minutes in those with normal renal function, gadolinium has been detected in tissue biopsy specimens of NSF patients as long as 11 months after administration.

Clinical data suggest several associations that impact clinical practice:

▸ The higher the dose of contrast, the greater the chance of developing NSF.

▸ The greater the severity of renal disease, the greater the chance of developing NSF.

▸ Cumulative doses of contrast seem to increase the incidence of NSF.

These findings can have a significant impact on clinical practice. For instance, MRI studies that use double or triple doses of contrast, such as contrast dynamic bolus MRA, may no longer be an option for patients with severely impaired renal function. Alternatively, the radiologist may modify the study to minimize the administered dose of gadolinium-based contrast agent.

The spike in NSF cases in recent years is directly related to the more common use of high-dose contrast studies since the proliferation of especially non-neuroradiologic contrast bolus dynamic MR angiography in the mid-1990s, Dr. Kanal suggested.

"With iodinated contrast-related [contrast-induced nephropathy] concerns for CT and NSF-related concerns for gadolinium-based MR contrast agents in MRI, this is becoming a problem for neurologists and other referring physicians, as the number of imaging tests available for patients with severe renal disease that can sensitively evaluate problems is decreasing," he said.

Patients with stage III kidney disease or worse should not routinely be administered standard doses of gadolinium-based MR contrast agents, he recommended. This can have serious implications for the 35 million U.S. adults over age 65 years who have stage III or IV renal disease, many of whom require access to diagnostic MR services, Dr. Kanal said.

Exacerbating the problem is poor patient awareness of renal disease. According to Dr. Kanal, 97% of women and 82% of men with stage III chronic kidney disease are unaware that they have it. Thus asking patients whether they have renal disease may no longer be a sufficient screening method.

It is anticipated that a subset of patients at risk for renal disease (over age 60 years, history of hypertension, diabetes, renal disease or severe hepatic disease) will be required to have their glomerular filtration rates assessed before receiving gadolinium-based MR contrast agents. Since the risk of NSF may increase with cumulative dosing, neurologists should carefully consider the potential risk of serial contrast-enhanced scans when following patients.

While the FDA has applied black box warnings to all five MR contrast agents available in the United States, "the available data 'screams' that [the risk of NSF] is not equal for all the five FDA-approved MR contrast agents, and appears to be higher or far higher for Omniscan," he said, estimating that roughly 3%-7% of patients with end-stage renal disease receiving high-dose Omniscan will develop NSF.

"In my opinion, the present data are sufficiently compelling to avoid Omniscan administration in patients with any significant level of renal disease," he added.

For gadolinium to be tolerated by humans, it must be chelated to a ligand molecule, he said. The likelihood of the ligand dissociating from the gadolinium ion (leaving the toxic free Gd+3) is far from equal among these five agents, being far greater in Omniscan and Optimark than in Magnevist, Multihance, or Prohance, judging from findings from in vitro and some in vivo studies. Because nonionic Omniscan and Optimark have a far lower conditional stability constant than do Magnevist, Multihance, and Prohance at normal body pH, it is possible that this may be related to the perceived greater incidence of NSF in patients who received Omniscan, Dr. Kanal said.

Elevated levels of calcium, phosphate, copper, iron, and zinc, which can compete with the gadolinium ion for coupling with the ligand molecule, may also exacerbate the risk of toxicity.

"You need a radiologist who knows what she or he is doing in this area to help design the study in a manner that will decrease dosing yet still be as diagnostic as possible. Trust your radiologist and then follow his feedback and guidance," he commented.

If a dialysis patient must have a contrast MRI, the American College of Radiology guidelines recommend that the patient be taken to hemodialysis immediately following the completion of the MR examination in which the gadolinium-based MR contrast agent had been administered. Radiologists should compile a database of all patients with stage III or more severe kidney disease who have had contrast-enhanced MRIs and follow them to ensure that they do not develop NSF, Dr. Kanal recommended.

"It used to be that patients with renal failure would specifically be sent to MR because the contrast agents were not directly nephrotoxic at the doses used, whereas giving iodine to patients with renal disease could cause iodine-induced nephropathy. Now we have something else to worry about for patients with renal disease: NSF," Dr. Kanal said.

Patients with stage IIIkidney disease or worse shouldn't be routinely given standard doses of gadolinium-based agents. DR. KANAL

The skin on the arm of a patient with contrast agent-induced nephrogenic systemic fibrosis shows scleroderma-like changes, including scarring (which is usually painful), tightening, thickening, and discoloration. Nephrogenic systemic fibrosis is fulminant in about 5% of cases and can prove to be fatal within weeks. Courtesy Dr. Shawn Cowper

The first attempt to develop "comprehensive management guidelines" for systemic lupus erythematosus resulted in 12 recommendations—some potentially controversial—from a European task force.

A European League Against Rheumatism (EULAR) task force composed of 19 rheumatology specialists and one clinical epidemiologist based the guidelines on its review of over 8,000 articles. "These recommendations should facilitate the medical care of lupus patients without restricting the autonomy of the provider physicians," wrote the authors, adding the "remarkable heterogeneity" of lupus makes it especially challenging to cover all aspects of the disease.

As such, the authors did not cover some systemic lupus erythematosus (SLE) diagnostic criteria, such as the potential usefulness of the American College of Rheumatology 1999 classification criteria for diagnosing SLE at early stages. Nor did they delve into detailed management guidelines for cutaneous lupus. "These issues will be addressed in future sessions," they wrote.

Dr. Virginia D. Steen, professor of rheumatology at Georgetown University, Washington, noted the lack of differential diagnostic criteria in the guidelines. "Some of the biggest problems in lupus are things like separating infection from active lupus, determining whether 'CNS' disease is actually a manifestation of lupus … distinguishing drug toxicity from disease manifestations. These may not be things that are apropos to these types of guidelines, but they would be more helpful."

The members of the EULAR task force noted that in selecting studies to consider, "Retrieved items from electronic searches were screened for eligibility based on their title, abstract, and/or full content. Animal studies, narrative review articles, commentaries, conference abstracts or statements, expert opinion statements, and guidelines were excluded."

In assessing the prognosis, diagnosis, etiology, or comorbidities associated with SLE, studies were eligible if they had at least 50 patients. Randomized studies of therapy that included at least five patients were also included (Ann. Rheum. Dis. 2007 July 5 [Epub doi: 10.1136/ard.2007.070367

"For nontherapy questions of specific organ manifestations (e.g., nephritis, neuropsychiatric lupus), or specific problems (pregnancy, APS [antiphospholipid syndrome]), studies were eligible if they had studied at least 20 SLE patients with the relevant manifestation," the authors wrote.

Dr. Robert Lahita, who helped compile the ACR's SLE classification criteria in 1999, noted that some of the recommendations touch on divisive issues, such as the contention that "pregnancy may increase lupus disease activity, but these flares are usually mild."

"A lot of people say pregnancy makes lupus worse," said Dr. Lahita, a professor at Mount Sinai School of Medicine, New York, and chairman of medicine at Jersey City (N.J.) Medical Center.

Another controversial aspect of the EULAR guidelines is the task force's recommendation that "in patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss."

The recommendations of the EULAR task force include the following:

▸ Prognosis. In SLE patients, new clinical signs (e.g., rashes, arthritis, serositis); routine laboratory tests (CBC, serum creatinine, proteinuria, and urinary sediment); and immunologic tests (e.g., serum C3, anti-ds DNA) may offer information about the outcome in general and in potential organ involvement. Confirmation by imaging (brain MRI) and pathology (renal biopsy) may add to this in selected patients.

▸ Monitoring. New manifestations such as number and type of skin lesions, neurologic manifestations (seizures/psychosis), and validated global activity indices may be used to monitor lupus patients.

▸ Comorbidities. SLE patients are at high risk for infections (urinary tract infections, among others), atherosclerosis, hypertension, dyslipidemias, diabetes, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin's lymphoma). Minimize additional risk factors, harbor a high index of suspicion, and practice prompt evaluation and follow-up.

▸ Treatment of nonmajor organ involvement. In SLE without major organ involvement, antimalarials and/or glucocorticoids may be used. NSAIDs may be used judiciously in patients at low risk for complications. In nonresponsive patients or patients unable to cut steroid doses to levels acceptable for chronic use, immunosuppressives (azathioprine, mycophenolate mofetil, methotrexate) may be considered.

▸ Adjunctive therapy. Photoprotection should be considered in patients with skin manifestations. Lifestyle modifications (smoking cessation, weight control, exercise) should be encouraged. On a case-by-case basis, low-dose aspirin, calcium/vitamin D, bisphosphonates, statins, and antihypertensives, including angiotensin-converting enzyme inhibitors, may be considered. Estrogens may be used, but risks must be assessed.

▸ Diagnosis of neuropsychiatric lupus. The diagnostic work-up (clinical, laboratory, neuropsychological, and imaging tests) of neuropsychiatric manifestations should be similar to that of a work-up for someone in the general population presenting with the same symptoms.

▸ Treatment of severe, inflammatory neuropsychiatric lupus. Patients with major neuropsychiatric manifestations of inflammatory origin (optic neuritis, acute confusional state/coma, cranial or peripheral neuropathy, psychosis, and transverse myelitis/myelopathy) may benefit from immunosuppressives.

▸ Pregnancy in lupus. There is no significant difference in fertility in lupus patients. Pregnancy may increase disease activity, but flares are usually mild. Lupus nephritis patients and patients with antiphospholipid antibodies are at increased risk of developing preeclampsia. SLE may affect the fetus, especially if the mother has a history of lupus nephritis and antiphospholipid, anti-Ro, and/or anti-La antibodies. These conditions are associated with an increased risk of miscarriage, stillbirth, premature delivery, intrauterine growth restriction, and fetal heart block. Prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin may be used in lupus pregnancies. Mycophenolate mofetil, cyclophosphamide, and methotrexate must all be avoided.

▸ Antiphospholipid syndrome in lupus. In patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss. Other risk factors should be assessed; estrogen-containing drugs raise thrombosis risk. In nonpregnant patients with SLE and APS-associated thrombosis, long-term anticoagulation with oral anticoagulants is effective for secondary thrombosis prevention. In pregnant patients with SLE and antiphospholipid syndrome, combined unfractionated or low molecular weight heparin and aspirin cut pregnancy loss and thrombosis.

▸ Lupus nephritis: diagnosis and disease monitoring. Renal biopsy, urine sediment analysis, proteinuria, and kidney function may have independent predictive ability for clinical outcome in therapy of lupus nephritis but need to be interpreted in conjunction with each other. Changes in immunologic tests (anti-ds DNA, serum C3) have only a limited ability to predict patient response to treatment and should be used only supplementally.

▸ Lupus nephritis: treatment. In patients with proliferative lupus nephritis, glucocorticoids plus immunosuppressive agents are effective against progression to end-stage renal disease. Long-term efficacy has been demonstrated only for cyclophosphamide-based regimens, which have considerable adverse effects. In short- and medium-term trials, mycophenolate mofetil has demonstrated at least similar efficacy, compared with pulse cyclophosphamide, and has a more favorable toxicity profile. Failure to respond by 6 months should evoke discussions for intensification of therapy. Flares following remission are not uncommon and require diligent follow-up.

▸ End-stage renal disease. Dialysis and transplantation in SLE have comparable rates for long-term patient and graft survival as those observed in nondiabetic non-SLE patients.

Despite the many manifestations of lupus, the new guidelines lack differential diagnostic criteria. DR. STEEN

Additional Lupus Research Is Needed

The EULAR task force that authored the new SLE guidelines has proposed a research agenda to correct for the current dearth of randomized controlled trials establishing optimal management of lupus. Areas that the task force highlighted for future investigation included:

▸ The validity of renal biopsy, urinary sediment analysis, tests for proteinuria, and immunologic tests as surrogate markers in the treatment of lupus nephritis.

▸ The relative impact on disease susceptibility and severity of environmental factors like sun exposure, smoking, diet, and genetics.

▸ Mechanisms by which to identify patients at higher risk for SLE.

▸ Diagnostic criteria with improved sensitivity and specificity as well as criteria to identify distinct SLE subpopulations.

▸ Reliable diagnostic algorithms for neuropsychiatric lupus.

▸ The indications and optimal targets for autologous stem cell therapy in SLE, as well as the major indications for biologic therapies like B-cell depletion, inhibition of B-cell differentiation, costimulation blockade, and toleragens.

▸ Treatment options for resistant disease that involve major and nonmajor organs.

▸ The mechanisms of a lupus flare, along with the best way to manage flares.

▸ The epidemiology, management, and long-term outcome of geriatric, pediatric, and adolescent SLE.

The first attempt to develop "comprehensive management guidelines" for systemic lupus erythematosus resulted in 12 recommendations—some potentially controversial—from a European task force.

A European League Against Rheumatism (EULAR) task force composed of 19 rheumatology specialists and one clinical epidemiologist based the guidelines on its review of over 8,000 articles. "These recommendations should facilitate the medical care of lupus patients without restricting the autonomy of the provider physicians," wrote the authors, adding the "remarkable heterogeneity" of lupus makes it especially challenging to cover all aspects of the disease.

As such, the authors did not cover some systemic lupus erythematosus (SLE) diagnostic criteria, such as the potential usefulness of the American College of Rheumatology 1999 classification criteria for diagnosing SLE at early stages. Nor did they delve into detailed management guidelines for cutaneous lupus. "These issues will be addressed in future sessions," they wrote.

Dr. Virginia D. Steen, professor of rheumatology at Georgetown University, Washington, noted the lack of differential diagnostic criteria in the guidelines. "Some of the biggest problems in lupus are things like separating infection from active lupus, determining whether 'CNS' disease is actually a manifestation of lupus … distinguishing drug toxicity from disease manifestations. These may not be things that are apropos to these types of guidelines, but they would be more helpful."

The members of the EULAR task force noted that in selecting studies to consider, "Retrieved items from electronic searches were screened for eligibility based on their title, abstract, and/or full content. Animal studies, narrative review articles, commentaries, conference abstracts or statements, expert opinion statements, and guidelines were excluded."

In assessing the prognosis, diagnosis, etiology, or comorbidities associated with SLE, studies were eligible if they had at least 50 patients. Randomized studies of therapy that included at least five patients were also included (Ann. Rheum. Dis. 2007 July 5 [Epub doi: 10.1136/ard.2007.070367

"For nontherapy questions of specific organ manifestations (e.g., nephritis, neuropsychiatric lupus), or specific problems (pregnancy, APS [antiphospholipid syndrome]), studies were eligible if they had studied at least 20 SLE patients with the relevant manifestation," the authors wrote.

Dr. Robert Lahita, who helped compile the ACR's SLE classification criteria in 1999, noted that some of the recommendations touch on divisive issues, such as the contention that "pregnancy may increase lupus disease activity, but these flares are usually mild."

"A lot of people say pregnancy makes lupus worse," said Dr. Lahita, a professor at Mount Sinai School of Medicine, New York, and chairman of medicine at Jersey City (N.J.) Medical Center.

Another controversial aspect of the EULAR guidelines is the task force's recommendation that "in patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss."

The recommendations of the EULAR task force include the following:

▸ Prognosis. In SLE patients, new clinical signs (e.g., rashes, arthritis, serositis); routine laboratory tests (CBC, serum creatinine, proteinuria, and urinary sediment); and immunologic tests (e.g., serum C3, anti-ds DNA) may offer information about the outcome in general and in potential organ involvement. Confirmation by imaging (brain MRI) and pathology (renal biopsy) may add to this in selected patients.

▸ Monitoring. New manifestations such as number and type of skin lesions, neurologic manifestations (seizures/psychosis), and validated global activity indices may be used to monitor lupus patients.

▸ Comorbidities. SLE patients are at high risk for infections (urinary tract infections, among others), atherosclerosis, hypertension, dyslipidemias, diabetes, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin's lymphoma). Minimize additional risk factors, harbor a high index of suspicion, and practice prompt evaluation and follow-up.

▸ Treatment of nonmajor organ involvement. In SLE without major organ involvement, antimalarials and/or glucocorticoids may be used. NSAIDs may be used judiciously in patients at low risk for complications. In nonresponsive patients or patients unable to cut steroid doses to levels acceptable for chronic use, immunosuppressives (azathioprine, mycophenolate mofetil, methotrexate) may be considered.

▸ Adjunctive therapy. Photoprotection should be considered in patients with skin manifestations. Lifestyle modifications (smoking cessation, weight control, exercise) should be encouraged. On a case-by-case basis, low-dose aspirin, calcium/vitamin D, bisphosphonates, statins, and antihypertensives, including angiotensin-converting enzyme inhibitors, may be considered. Estrogens may be used, but risks must be assessed.

▸ Diagnosis of neuropsychiatric lupus. The diagnostic work-up (clinical, laboratory, neuropsychological, and imaging tests) of neuropsychiatric manifestations should be similar to that of a work-up for someone in the general population presenting with the same symptoms.

▸ Treatment of severe, inflammatory neuropsychiatric lupus. Patients with major neuropsychiatric manifestations of inflammatory origin (optic neuritis, acute confusional state/coma, cranial or peripheral neuropathy, psychosis, and transverse myelitis/myelopathy) may benefit from immunosuppressives.

▸ Pregnancy in lupus. There is no significant difference in fertility in lupus patients. Pregnancy may increase disease activity, but flares are usually mild. Lupus nephritis patients and patients with antiphospholipid antibodies are at increased risk of developing preeclampsia. SLE may affect the fetus, especially if the mother has a history of lupus nephritis and antiphospholipid, anti-Ro, and/or anti-La antibodies. These conditions are associated with an increased risk of miscarriage, stillbirth, premature delivery, intrauterine growth restriction, and fetal heart block. Prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin may be used in lupus pregnancies. Mycophenolate mofetil, cyclophosphamide, and methotrexate must all be avoided.

▸ Antiphospholipid syndrome in lupus. In patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss. Other risk factors should be assessed; estrogen-containing drugs raise thrombosis risk. In nonpregnant patients with SLE and APS-associated thrombosis, long-term anticoagulation with oral anticoagulants is effective for secondary thrombosis prevention. In pregnant patients with SLE and antiphospholipid syndrome, combined unfractionated or low molecular weight heparin and aspirin cut pregnancy loss and thrombosis.

▸ Lupus nephritis: diagnosis and disease monitoring. Renal biopsy, urine sediment analysis, proteinuria, and kidney function may have independent predictive ability for clinical outcome in therapy of lupus nephritis but need to be interpreted in conjunction with each other. Changes in immunologic tests (anti-ds DNA, serum C3) have only a limited ability to predict patient response to treatment and should be used only supplementally.

▸ Lupus nephritis: treatment. In patients with proliferative lupus nephritis, glucocorticoids plus immunosuppressive agents are effective against progression to end-stage renal disease. Long-term efficacy has been demonstrated only for cyclophosphamide-based regimens, which have considerable adverse effects. In short- and medium-term trials, mycophenolate mofetil has demonstrated at least similar efficacy, compared with pulse cyclophosphamide, and has a more favorable toxicity profile. Failure to respond by 6 months should evoke discussions for intensification of therapy. Flares following remission are not uncommon and require diligent follow-up.

▸ End-stage renal disease. Dialysis and transplantation in SLE have comparable rates for long-term patient and graft survival as those observed in nondiabetic non-SLE patients.

Despite the many manifestations of lupus, the new guidelines lack differential diagnostic criteria. DR. STEEN

Additional Lupus Research Is Needed

The EULAR task force that authored the new SLE guidelines has proposed a research agenda to correct for the current dearth of randomized controlled trials establishing optimal management of lupus. Areas that the task force highlighted for future investigation included:

▸ The validity of renal biopsy, urinary sediment analysis, tests for proteinuria, and immunologic tests as surrogate markers in the treatment of lupus nephritis.

▸ The relative impact on disease susceptibility and severity of environmental factors like sun exposure, smoking, diet, and genetics.

▸ Mechanisms by which to identify patients at higher risk for SLE.

▸ Diagnostic criteria with improved sensitivity and specificity as well as criteria to identify distinct SLE subpopulations.

▸ Reliable diagnostic algorithms for neuropsychiatric lupus.

▸ The indications and optimal targets for autologous stem cell therapy in SLE, as well as the major indications for biologic therapies like B-cell depletion, inhibition of B-cell differentiation, costimulation blockade, and toleragens.

▸ Treatment options for resistant disease that involve major and nonmajor organs.

▸ The mechanisms of a lupus flare, along with the best way to manage flares.

▸ The epidemiology, management, and long-term outcome of geriatric, pediatric, and adolescent SLE.

The first attempt to develop "comprehensive management guidelines" for systemic lupus erythematosus resulted in 12 recommendations—some potentially controversial—from a European task force.

A European League Against Rheumatism (EULAR) task force composed of 19 rheumatology specialists and one clinical epidemiologist based the guidelines on its review of over 8,000 articles. "These recommendations should facilitate the medical care of lupus patients without restricting the autonomy of the provider physicians," wrote the authors, adding the "remarkable heterogeneity" of lupus makes it especially challenging to cover all aspects of the disease.

As such, the authors did not cover some systemic lupus erythematosus (SLE) diagnostic criteria, such as the potential usefulness of the American College of Rheumatology 1999 classification criteria for diagnosing SLE at early stages. Nor did they delve into detailed management guidelines for cutaneous lupus. "These issues will be addressed in future sessions," they wrote.

Dr. Virginia D. Steen, professor of rheumatology at Georgetown University, Washington, noted the lack of differential diagnostic criteria in the guidelines. "Some of the biggest problems in lupus are things like separating infection from active lupus, determining whether 'CNS' disease is actually a manifestation of lupus … distinguishing drug toxicity from disease manifestations. These may not be things that are apropos to these types of guidelines, but they would be more helpful."

The members of the EULAR task force noted that in selecting studies to consider, "Retrieved items from electronic searches were screened for eligibility based on their title, abstract, and/or full content. Animal studies, narrative review articles, commentaries, conference abstracts or statements, expert opinion statements, and guidelines were excluded."

In assessing the prognosis, diagnosis, etiology, or comorbidities associated with SLE, studies were eligible if they had at least 50 patients. Randomized studies of therapy that included at least five patients were also included (Ann. Rheum. Dis. 2007 July 5 [Epub doi: 10.1136/ard.2007.070367

"For nontherapy questions of specific organ manifestations (e.g., nephritis, neuropsychiatric lupus), or specific problems (pregnancy, APS [antiphospholipid syndrome]), studies were eligible if they had studied at least 20 SLE patients with the relevant manifestation," the authors wrote.

Dr. Robert Lahita, who helped compile the ACR's SLE classification criteria in 1999, noted that some of the recommendations touch on divisive issues, such as the contention that "pregnancy may increase lupus disease activity, but these flares are usually mild."

"A lot of people say pregnancy makes lupus worse," said Dr. Lahita, a professor at Mount Sinai School of Medicine, New York, and chairman of medicine at Jersey City (N.J.) Medical Center.

Another controversial aspect of the EULAR guidelines is the task force's recommendation that "in patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss."

The recommendations of the EULAR task force include the following:

▸ Prognosis. In SLE patients, new clinical signs (e.g., rashes, arthritis, serositis); routine laboratory tests (CBC, serum creatinine, proteinuria, and urinary sediment); and immunologic tests (e.g., serum C3, anti-ds DNA) may offer information about the outcome in general and in potential organ involvement. Confirmation by imaging (brain MRI) and pathology (renal biopsy) may add to this in selected patients.

▸ Monitoring. New manifestations such as number and type of skin lesions, neurologic manifestations (seizures/psychosis), and validated global activity indices may be used to monitor lupus patients.

▸ Comorbidities. SLE patients are at high risk for infections (urinary tract infections, among others), atherosclerosis, hypertension, dyslipidemias, diabetes, osteoporosis, avascular necrosis, and malignancies (especially non-Hodgkin's lymphoma). Minimize additional risk factors, harbor a high index of suspicion, and practice prompt evaluation and follow-up.

▸ Treatment of nonmajor organ involvement. In SLE without major organ involvement, antimalarials and/or glucocorticoids may be used. NSAIDs may be used judiciously in patients at low risk for complications. In nonresponsive patients or patients unable to cut steroid doses to levels acceptable for chronic use, immunosuppressives (azathioprine, mycophenolate mofetil, methotrexate) may be considered.

▸ Adjunctive therapy. Photoprotection should be considered in patients with skin manifestations. Lifestyle modifications (smoking cessation, weight control, exercise) should be encouraged. On a case-by-case basis, low-dose aspirin, calcium/vitamin D, bisphosphonates, statins, and antihypertensives, including angiotensin-converting enzyme inhibitors, may be considered. Estrogens may be used, but risks must be assessed.

▸ Diagnosis of neuropsychiatric lupus. The diagnostic work-up (clinical, laboratory, neuropsychological, and imaging tests) of neuropsychiatric manifestations should be similar to that of a work-up for someone in the general population presenting with the same symptoms.

▸ Treatment of severe, inflammatory neuropsychiatric lupus. Patients with major neuropsychiatric manifestations of inflammatory origin (optic neuritis, acute confusional state/coma, cranial or peripheral neuropathy, psychosis, and transverse myelitis/myelopathy) may benefit from immunosuppressives.

▸ Pregnancy in lupus. There is no significant difference in fertility in lupus patients. Pregnancy may increase disease activity, but flares are usually mild. Lupus nephritis patients and patients with antiphospholipid antibodies are at increased risk of developing preeclampsia. SLE may affect the fetus, especially if the mother has a history of lupus nephritis and antiphospholipid, anti-Ro, and/or anti-La antibodies. These conditions are associated with an increased risk of miscarriage, stillbirth, premature delivery, intrauterine growth restriction, and fetal heart block. Prednisolone, azathioprine, hydroxychloroquine, and low-dose aspirin may be used in lupus pregnancies. Mycophenolate mofetil, cyclophosphamide, and methotrexate must all be avoided.

▸ Antiphospholipid syndrome in lupus. In patients with SLE and antiphospholipid antibodies, low-dose aspirin may be considered for primary prevention of thrombosis and pregnancy loss. Other risk factors should be assessed; estrogen-containing drugs raise thrombosis risk. In nonpregnant patients with SLE and APS-associated thrombosis, long-term anticoagulation with oral anticoagulants is effective for secondary thrombosis prevention. In pregnant patients with SLE and antiphospholipid syndrome, combined unfractionated or low molecular weight heparin and aspirin cut pregnancy loss and thrombosis.

▸ Lupus nephritis: diagnosis and disease monitoring. Renal biopsy, urine sediment analysis, proteinuria, and kidney function may have independent predictive ability for clinical outcome in therapy of lupus nephritis but need to be interpreted in conjunction with each other. Changes in immunologic tests (anti-ds DNA, serum C3) have only a limited ability to predict patient response to treatment and should be used only supplementally.

▸ Lupus nephritis: treatment. In patients with proliferative lupus nephritis, glucocorticoids plus immunosuppressive agents are effective against progression to end-stage renal disease. Long-term efficacy has been demonstrated only for cyclophosphamide-based regimens, which have considerable adverse effects. In short- and medium-term trials, mycophenolate mofetil has demonstrated at least similar efficacy, compared with pulse cyclophosphamide, and has a more favorable toxicity profile. Failure to respond by 6 months should evoke discussions for intensification of therapy. Flares following remission are not uncommon and require diligent follow-up.

▸ End-stage renal disease. Dialysis and transplantation in SLE have comparable rates for long-term patient and graft survival as those observed in nondiabetic non-SLE patients.

Despite the many manifestations of lupus, the new guidelines lack differential diagnostic criteria. DR. STEEN

Additional Lupus Research Is Needed

The EULAR task force that authored the new SLE guidelines has proposed a research agenda to correct for the current dearth of randomized controlled trials establishing optimal management of lupus. Areas that the task force highlighted for future investigation included:

▸ The validity of renal biopsy, urinary sediment analysis, tests for proteinuria, and immunologic tests as surrogate markers in the treatment of lupus nephritis.

▸ The relative impact on disease susceptibility and severity of environmental factors like sun exposure, smoking, diet, and genetics.

▸ Mechanisms by which to identify patients at higher risk for SLE.

▸ Diagnostic criteria with improved sensitivity and specificity as well as criteria to identify distinct SLE subpopulations.

▸ Reliable diagnostic algorithms for neuropsychiatric lupus.

▸ The indications and optimal targets for autologous stem cell therapy in SLE, as well as the major indications for biologic therapies like B-cell depletion, inhibition of B-cell differentiation, costimulation blockade, and toleragens.

▸ Treatment options for resistant disease that involve major and nonmajor organs.

▸ The mechanisms of a lupus flare, along with the best way to manage flares.

▸ The epidemiology, management, and long-term outcome of geriatric, pediatric, and adolescent SLE.

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by the presence of antibodies directed against tRNA synthetase. The most common antibody is anti-Jo-1, which is found in 80% of cases.

Other antibodies sometimes found include anti-SSA, anti-PL-7, and anti-PL-12.

Clinical manifestations of the disease include interstitial lung disease, which can be severe, arthritis, Raynaud phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years, and in one-third of the group, the disease onset was before age 40. Two-thirds of the patients were women.

Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL.

Muscular manifestations rarely caused significant patient disability and were present at the onset of disease in only six of the cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren syndrome, were detected in 50% but only rarely were they associated with dry eyes and mouth, Dr. Palm wrote in a poster session.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent slowly developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received treatment with immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab.

Four patients died, two having type I pulmonary involvement. "While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted," he concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by the presence of antibodies directed against tRNA synthetase. The most common antibody is anti-Jo-1, which is found in 80% of cases.

Other antibodies sometimes found include anti-SSA, anti-PL-7, and anti-PL-12.

Clinical manifestations of the disease include interstitial lung disease, which can be severe, arthritis, Raynaud phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years, and in one-third of the group, the disease onset was before age 40. Two-thirds of the patients were women.

Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL.

Muscular manifestations rarely caused significant patient disability and were present at the onset of disease in only six of the cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren syndrome, were detected in 50% but only rarely were they associated with dry eyes and mouth, Dr. Palm wrote in a poster session.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent slowly developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received treatment with immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab.

Four patients died, two having type I pulmonary involvement. "While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted," he concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by the presence of antibodies directed against tRNA synthetase. The most common antibody is anti-Jo-1, which is found in 80% of cases.

Other antibodies sometimes found include anti-SSA, anti-PL-7, and anti-PL-12.

Clinical manifestations of the disease include interstitial lung disease, which can be severe, arthritis, Raynaud phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years, and in one-third of the group, the disease onset was before age 40. Two-thirds of the patients were women.

Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL.

Muscular manifestations rarely caused significant patient disability and were present at the onset of disease in only six of the cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren syndrome, were detected in 50% but only rarely were they associated with dry eyes and mouth, Dr. Palm wrote in a poster session.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent slowly developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received treatment with immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab.

Four patients died, two having type I pulmonary involvement. "While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted," he concluded.

ELSEVIER GLOBAL MEDICAL NEWS

Psoriasis is a common chronic dermatologic disease that affects approximately 3% of the US population.1 Research has implicated T-cell mediated immunity as having an increasingly important role in the pathophysiology of this disorder. The pathogenesis of psoriasis now is best linked to the antigen-based activation of Langerhans cells, which subsequently drive a T-cell inflammatory cascade.2 Along with this new understanding has come a radical shift in the approach to treating this disease. While the focus of psoriasis treatment was once on excessive keratinocyte proliferation and abnormal differentiation,3 the new target is the activated T cell. Along with the older immunomodulating agents, newer biologic agents have been designed to interrupt various stages in the inflammatory response. Despite the influx of treatments for psoriasis, clearance still is not always a realistic expectation4; therefore, the search for therapeutic options continues. One of the most promising options is the steroidal alkaloid cyclopamine (Figure), a direct inhibitor of the hedgehog (Hh) intracellular signaling pathway. Building on work demonstrating cyclopamine's success in the induction of the differentiation and apoptosis of basal cell carcinomas (BCCs),5 investigators have now provided evidence of this compound's use in the treatment of psoriasis.6

Hh Signaling
The Hh gene was first identified more than 25 years ago in Drosophila melanogaster as a critical organizer of cell-fate determination during embryogenesis and development.7,8 More recently, the Hh signaling pathway has shown saliency in regulating cellular proliferation and differentiation in a wide array of human tissues. Consequently, the pathway has been implicated in aberrant cell survival in numerous human malignancies,9 ranging from BCCs5,10 and medulloblastomas11 to small cell lung,12 gastrointestinal,13 breast,14 and prostate15 tumors. The Hh pathway has 3 main components: (1) the Hh ligand, a transmembrane receptor circuit composed of the negative regulator Patched (Ptc); (2) the activator Smoothened (Smo); and (3) a cytoplasmic complex that regulates the Gli family of transcription factors. In the normal resting state, the 7-transmembrane protein Smo's activity is suppressed by the 12-transmembrane protein Ptc. It is only with Hh ligand stimulation of the Ptc receptor that this inhibition is released, leading to Smo activation of the Gli transcriptional response.16-20 Consistent with this model, autonomous Hh signaling may result from either inactivating mutations (eg, loss of heterozygosity or truncating mutations) in the gene Ptc or activating mutations in the gene Smo.21 Abnormal activation of the Hh pathway is responsible for the pathway's tumorigenic properties, subsequently defining Ptc and Smo as a tumor suppressor and proto-oncogene, respectively.16 Characteristic of their newly discovered roles, Ptc and Smo are 2 of the newest targets in oncology. 

Cyclopamine and Hh
Even before the Hh pathway was understood, Binns et al22 reported an epidemic of cyclopia (complex birth defect characterized by the absence of median facial structure and an undivided forebrain—ie, holoprosencephaly) in sheep herds of the western United States. The etiology of this birth defect ultimately proved to be ingestion of a lily, Veratrum californicum, during gestation. The lily is common in the subalpine meadows from which the steroidal alkaloid cyclopamine was extracted.23,24 It took almost 40 years, though, to prove that cyclopamine's teratogenic effects were related to the gene family Hh. Cyclopamine's involvement in the Sonic Hh pathway was first shown in studies with chick embryos.25,26 Incardona et al²⁵ noted that Sonic Hh pathway–dependent patterning of the ventral tube is interrupted in cyclopamine-treated embryos, yielding offspring with facial malformations similar to the cyclopic sheep discovered almost 40 years prior. Although the researchers were unable to locate the exact mechanism of action, the findings suggested cyclopamine's role as a direct antagonist of Hh signal transduction. More recently, Chen et al27 used photoaffinity and fluorescent derivatives to prove that this inhibitory effect is mediated by the direct binding of cyclopamine to the heptahelical bundle of Smo. When properly understood, cyclopamine inhibits Hh signaling by antagonizing Smo, thereby interrupting the Gli-mediated transcriptional pathway. With this discovery and the knowledge that Hh overactivation is implicated in numerous human malignancies, cyclopamine has become one of the more popular compounds in recent oncology trials. Within the past 2 years, cyclopamine and the Hh signaling pathway have become new therapeutic targets for patients with breast,14 brain,28 colorectal,13 and prostate15 tumors. Cyclopamine's interruption of the Hh pathway has shown promise in the treatment of BCCs. Because most BCCs manifest loss-of-function mutations in Ptc29 (leading to unrestrained Smo and, therefore, Gli activity), Smo antagonism seems a natural vehicle to target treatment. Recently, Athar et al30 proved that cyclopamine could be used in mice to prevent UVB-induced BCCs. Athar and colleagues30 showed that Hh inhibition induced high levels of the gene Fas, which augmented tumor apoptosis. Tas and Avci5 also have recently shown cyclopamine to be effective in the treatment of human BCCs. Using histologic and immunohistochemical markers, the researchers were able to demonstrate inhibition of the proliferation and highly efficient induction of the differentiation and apoptosis of tumor cells. Because apoptotic tumor cells actually had reduced levels of p53 expression, Tas and Avci5 also concluded that cyclopamine performed its function in a nongenotoxic manner, a positive finding considering the substance's potential teratogenic side effects.

Cyclopamine and Psoriasis
Building on their success inducing epidermal differentiation in BCCs, Tas and Avci6 hypothesized that cyclopamine may have a mechanistic role in the treatment of psoriasis. In a preliminary proof-of-concept study, they treated a total of 31 psoriatic lesions in 7 patients (all with an established diagnosis of plaque or guttate psoriasis) with a cream containing cyclopamine. At least one lesion (similar in size to a cyclopamine-treated lesion) was treated with base cream alone in each patient. The researchers also conducted an assay comparing cyclopamine with a potent topical steroid, clobetasol-17-propionate. The results were extremely impressive, with clinical and histologic clearance as early as 2 days and frequency of applications ranging from 6 to 8 times per day. Although clobetasol-17-propionate added to cyclopamine's performance, the Smo antagonist was superior to the steroid alone. Histologic and immunohistochemical analysis showed signs of rapid induction of epidermal cell differentiation because there was a vigorous reappearance of the epidermal granular layer, a marked decrease in epidermal hyperplasia, return of the elongated and thickened rete ridges towards normalcy, and normalization of the thinning of the suprapapillary epidermis.6 The reappearance of granular cells in response to cyclopamine is evidence of the terminal differentiation of spinous cells, a marker associated with the cessation of proliferation. Inhibition of Hh signaling by cyclopamine, therefore, opens new doors in the treatment of psoriasis, moving the concentration away from immunomodulation and bringing the role of keratinocytes back into focus.

Conclusion
The recent study by Tas and Avci6 opens a new field for therapeutic development in psoriasis, but considerable research lies ahead before cyclopamine becomes a mainstream treatment. Most importantly, little is known about the human toxicity of cyclopamine and its metabolism into the skin. No adverse effects were seen in either of Tas and Avci's5,6 clinical studies of cyclopamine, yet the drug's role in stem cell development31 and its teratogenicity32 cautions its use in women of childbearing potential until sufficient relevant data are available. Additionally, large, prospective, randomized, controlled trials are needed to confirm cyclopamine's effectiveness. If successful, these studies will provide the optimal concentration, frequency, and mode of administration of treatment. Because the importance of Hh in epidermal hyper-proliferation and development has been demonstrated, a field recently focused on immunology must once again look at the keratinocyte as a fundamental target in the pathophysiology of psoriasis. 

Psoriasis is a common chronic dermatologic disease that affects approximately 3% of the US population.1 Research has implicated T-cell mediated immunity as having an increasingly important role in the pathophysiology of this disorder. The pathogenesis of psoriasis now is best linked to the antigen-based activation of Langerhans cells, which subsequently drive a T-cell inflammatory cascade.2 Along with this new understanding has come a radical shift in the approach to treating this disease. While the focus of psoriasis treatment was once on excessive keratinocyte proliferation and abnormal differentiation,3 the new target is the activated T cell. Along with the older immunomodulating agents, newer biologic agents have been designed to interrupt various stages in the inflammatory response. Despite the influx of treatments for psoriasis, clearance still is not always a realistic expectation4; therefore, the search for therapeutic options continues. One of the most promising options is the steroidal alkaloid cyclopamine (Figure), a direct inhibitor of the hedgehog (Hh) intracellular signaling pathway. Building on work demonstrating cyclopamine's success in the induction of the differentiation and apoptosis of basal cell carcinomas (BCCs),5 investigators have now provided evidence of this compound's use in the treatment of psoriasis.6

Hh Signaling
The Hh gene was first identified more than 25 years ago in Drosophila melanogaster as a critical organizer of cell-fate determination during embryogenesis and development.7,8 More recently, the Hh signaling pathway has shown saliency in regulating cellular proliferation and differentiation in a wide array of human tissues. Consequently, the pathway has been implicated in aberrant cell survival in numerous human malignancies,9 ranging from BCCs5,10 and medulloblastomas11 to small cell lung,12 gastrointestinal,13 breast,14 and prostate15 tumors. The Hh pathway has 3 main components: (1) the Hh ligand, a transmembrane receptor circuit composed of the negative regulator Patched (Ptc); (2) the activator Smoothened (Smo); and (3) a cytoplasmic complex that regulates the Gli family of transcription factors. In the normal resting state, the 7-transmembrane protein Smo's activity is suppressed by the 12-transmembrane protein Ptc. It is only with Hh ligand stimulation of the Ptc receptor that this inhibition is released, leading to Smo activation of the Gli transcriptional response.16-20 Consistent with this model, autonomous Hh signaling may result from either inactivating mutations (eg, loss of heterozygosity or truncating mutations) in the gene Ptc or activating mutations in the gene Smo.21 Abnormal activation of the Hh pathway is responsible for the pathway's tumorigenic properties, subsequently defining Ptc and Smo as a tumor suppressor and proto-oncogene, respectively.16 Characteristic of their newly discovered roles, Ptc and Smo are 2 of the newest targets in oncology. 

Cyclopamine and Hh
Even before the Hh pathway was understood, Binns et al22 reported an epidemic of cyclopia (complex birth defect characterized by the absence of median facial structure and an undivided forebrain—ie, holoprosencephaly) in sheep herds of the western United States. The etiology of this birth defect ultimately proved to be ingestion of a lily, Veratrum californicum, during gestation. The lily is common in the subalpine meadows from which the steroidal alkaloid cyclopamine was extracted.23,24 It took almost 40 years, though, to prove that cyclopamine's teratogenic effects were related to the gene family Hh. Cyclopamine's involvement in the Sonic Hh pathway was first shown in studies with chick embryos.25,26 Incardona et al²⁵ noted that Sonic Hh pathway–dependent patterning of the ventral tube is interrupted in cyclopamine-treated embryos, yielding offspring with facial malformations similar to the cyclopic sheep discovered almost 40 years prior. Although the researchers were unable to locate the exact mechanism of action, the findings suggested cyclopamine's role as a direct antagonist of Hh signal transduction. More recently, Chen et al27 used photoaffinity and fluorescent derivatives to prove that this inhibitory effect is mediated by the direct binding of cyclopamine to the heptahelical bundle of Smo. When properly understood, cyclopamine inhibits Hh signaling by antagonizing Smo, thereby interrupting the Gli-mediated transcriptional pathway. With this discovery and the knowledge that Hh overactivation is implicated in numerous human malignancies, cyclopamine has become one of the more popular compounds in recent oncology trials. Within the past 2 years, cyclopamine and the Hh signaling pathway have become new therapeutic targets for patients with breast,14 brain,28 colorectal,13 and prostate15 tumors. Cyclopamine's interruption of the Hh pathway has shown promise in the treatment of BCCs. Because most BCCs manifest loss-of-function mutations in Ptc29 (leading to unrestrained Smo and, therefore, Gli activity), Smo antagonism seems a natural vehicle to target treatment. Recently, Athar et al30 proved that cyclopamine could be used in mice to prevent UVB-induced BCCs. Athar and colleagues30 showed that Hh inhibition induced high levels of the gene Fas, which augmented tumor apoptosis. Tas and Avci5 also have recently shown cyclopamine to be effective in the treatment of human BCCs. Using histologic and immunohistochemical markers, the researchers were able to demonstrate inhibition of the proliferation and highly efficient induction of the differentiation and apoptosis of tumor cells. Because apoptotic tumor cells actually had reduced levels of p53 expression, Tas and Avci5 also concluded that cyclopamine performed its function in a nongenotoxic manner, a positive finding considering the substance's potential teratogenic side effects.

Cyclopamine and Psoriasis
Building on their success inducing epidermal differentiation in BCCs, Tas and Avci6 hypothesized that cyclopamine may have a mechanistic role in the treatment of psoriasis. In a preliminary proof-of-concept study, they treated a total of 31 psoriatic lesions in 7 patients (all with an established diagnosis of plaque or guttate psoriasis) with a cream containing cyclopamine. At least one lesion (similar in size to a cyclopamine-treated lesion) was treated with base cream alone in each patient. The researchers also conducted an assay comparing cyclopamine with a potent topical steroid, clobetasol-17-propionate. The results were extremely impressive, with clinical and histologic clearance as early as 2 days and frequency of applications ranging from 6 to 8 times per day. Although clobetasol-17-propionate added to cyclopamine's performance, the Smo antagonist was superior to the steroid alone. Histologic and immunohistochemical analysis showed signs of rapid induction of epidermal cell differentiation because there was a vigorous reappearance of the epidermal granular layer, a marked decrease in epidermal hyperplasia, return of the elongated and thickened rete ridges towards normalcy, and normalization of the thinning of the suprapapillary epidermis.6 The reappearance of granular cells in response to cyclopamine is evidence of the terminal differentiation of spinous cells, a marker associated with the cessation of proliferation. Inhibition of Hh signaling by cyclopamine, therefore, opens new doors in the treatment of psoriasis, moving the concentration away from immunomodulation and bringing the role of keratinocytes back into focus.

Conclusion
The recent study by Tas and Avci6 opens a new field for therapeutic development in psoriasis, but considerable research lies ahead before cyclopamine becomes a mainstream treatment. Most importantly, little is known about the human toxicity of cyclopamine and its metabolism into the skin. No adverse effects were seen in either of Tas and Avci's5,6 clinical studies of cyclopamine, yet the drug's role in stem cell development31 and its teratogenicity32 cautions its use in women of childbearing potential until sufficient relevant data are available. Additionally, large, prospective, randomized, controlled trials are needed to confirm cyclopamine's effectiveness. If successful, these studies will provide the optimal concentration, frequency, and mode of administration of treatment. Because the importance of Hh in epidermal hyper-proliferation and development has been demonstrated, a field recently focused on immunology must once again look at the keratinocyte as a fundamental target in the pathophysiology of psoriasis. 

Psoriasis is a common chronic dermatologic disease that affects approximately 3% of the US population.1 Research has implicated T-cell mediated immunity as having an increasingly important role in the pathophysiology of this disorder. The pathogenesis of psoriasis now is best linked to the antigen-based activation of Langerhans cells, which subsequently drive a T-cell inflammatory cascade.2 Along with this new understanding has come a radical shift in the approach to treating this disease. While the focus of psoriasis treatment was once on excessive keratinocyte proliferation and abnormal differentiation,3 the new target is the activated T cell. Along with the older immunomodulating agents, newer biologic agents have been designed to interrupt various stages in the inflammatory response. Despite the influx of treatments for psoriasis, clearance still is not always a realistic expectation4; therefore, the search for therapeutic options continues. One of the most promising options is the steroidal alkaloid cyclopamine (Figure), a direct inhibitor of the hedgehog (Hh) intracellular signaling pathway. Building on work demonstrating cyclopamine's success in the induction of the differentiation and apoptosis of basal cell carcinomas (BCCs),5 investigators have now provided evidence of this compound's use in the treatment of psoriasis.6

Hh Signaling
The Hh gene was first identified more than 25 years ago in Drosophila melanogaster as a critical organizer of cell-fate determination during embryogenesis and development.7,8 More recently, the Hh signaling pathway has shown saliency in regulating cellular proliferation and differentiation in a wide array of human tissues. Consequently, the pathway has been implicated in aberrant cell survival in numerous human malignancies,9 ranging from BCCs5,10 and medulloblastomas11 to small cell lung,12 gastrointestinal,13 breast,14 and prostate15 tumors. The Hh pathway has 3 main components: (1) the Hh ligand, a transmembrane receptor circuit composed of the negative regulator Patched (Ptc); (2) the activator Smoothened (Smo); and (3) a cytoplasmic complex that regulates the Gli family of transcription factors. In the normal resting state, the 7-transmembrane protein Smo's activity is suppressed by the 12-transmembrane protein Ptc. It is only with Hh ligand stimulation of the Ptc receptor that this inhibition is released, leading to Smo activation of the Gli transcriptional response.16-20 Consistent with this model, autonomous Hh signaling may result from either inactivating mutations (eg, loss of heterozygosity or truncating mutations) in the gene Ptc or activating mutations in the gene Smo.21 Abnormal activation of the Hh pathway is responsible for the pathway's tumorigenic properties, subsequently defining Ptc and Smo as a tumor suppressor and proto-oncogene, respectively.16 Characteristic of their newly discovered roles, Ptc and Smo are 2 of the newest targets in oncology. 

Cyclopamine and Hh
Even before the Hh pathway was understood, Binns et al22 reported an epidemic of cyclopia (complex birth defect characterized by the absence of median facial structure and an undivided forebrain—ie, holoprosencephaly) in sheep herds of the western United States. The etiology of this birth defect ultimately proved to be ingestion of a lily, Veratrum californicum, during gestation. The lily is common in the subalpine meadows from which the steroidal alkaloid cyclopamine was extracted.23,24 It took almost 40 years, though, to prove that cyclopamine's teratogenic effects were related to the gene family Hh. Cyclopamine's involvement in the Sonic Hh pathway was first shown in studies with chick embryos.25,26 Incardona et al²⁵ noted that Sonic Hh pathway–dependent patterning of the ventral tube is interrupted in cyclopamine-treated embryos, yielding offspring with facial malformations similar to the cyclopic sheep discovered almost 40 years prior. Although the researchers were unable to locate the exact mechanism of action, the findings suggested cyclopamine's role as a direct antagonist of Hh signal transduction. More recently, Chen et al27 used photoaffinity and fluorescent derivatives to prove that this inhibitory effect is mediated by the direct binding of cyclopamine to the heptahelical bundle of Smo. When properly understood, cyclopamine inhibits Hh signaling by antagonizing Smo, thereby interrupting the Gli-mediated transcriptional pathway. With this discovery and the knowledge that Hh overactivation is implicated in numerous human malignancies, cyclopamine has become one of the more popular compounds in recent oncology trials. Within the past 2 years, cyclopamine and the Hh signaling pathway have become new therapeutic targets for patients with breast,14 brain,28 colorectal,13 and prostate15 tumors. Cyclopamine's interruption of the Hh pathway has shown promise in the treatment of BCCs. Because most BCCs manifest loss-of-function mutations in Ptc29 (leading to unrestrained Smo and, therefore, Gli activity), Smo antagonism seems a natural vehicle to target treatment. Recently, Athar et al30 proved that cyclopamine could be used in mice to prevent UVB-induced BCCs. Athar and colleagues30 showed that Hh inhibition induced high levels of the gene Fas, which augmented tumor apoptosis. Tas and Avci5 also have recently shown cyclopamine to be effective in the treatment of human BCCs. Using histologic and immunohistochemical markers, the researchers were able to demonstrate inhibition of the proliferation and highly efficient induction of the differentiation and apoptosis of tumor cells. Because apoptotic tumor cells actually had reduced levels of p53 expression, Tas and Avci5 also concluded that cyclopamine performed its function in a nongenotoxic manner, a positive finding considering the substance's potential teratogenic side effects.

Cyclopamine and Psoriasis
Building on their success inducing epidermal differentiation in BCCs, Tas and Avci6 hypothesized that cyclopamine may have a mechanistic role in the treatment of psoriasis. In a preliminary proof-of-concept study, they treated a total of 31 psoriatic lesions in 7 patients (all with an established diagnosis of plaque or guttate psoriasis) with a cream containing cyclopamine. At least one lesion (similar in size to a cyclopamine-treated lesion) was treated with base cream alone in each patient. The researchers also conducted an assay comparing cyclopamine with a potent topical steroid, clobetasol-17-propionate. The results were extremely impressive, with clinical and histologic clearance as early as 2 days and frequency of applications ranging from 6 to 8 times per day. Although clobetasol-17-propionate added to cyclopamine's performance, the Smo antagonist was superior to the steroid alone. Histologic and immunohistochemical analysis showed signs of rapid induction of epidermal cell differentiation because there was a vigorous reappearance of the epidermal granular layer, a marked decrease in epidermal hyperplasia, return of the elongated and thickened rete ridges towards normalcy, and normalization of the thinning of the suprapapillary epidermis.6 The reappearance of granular cells in response to cyclopamine is evidence of the terminal differentiation of spinous cells, a marker associated with the cessation of proliferation. Inhibition of Hh signaling by cyclopamine, therefore, opens new doors in the treatment of psoriasis, moving the concentration away from immunomodulation and bringing the role of keratinocytes back into focus.

Conclusion
The recent study by Tas and Avci6 opens a new field for therapeutic development in psoriasis, but considerable research lies ahead before cyclopamine becomes a mainstream treatment. Most importantly, little is known about the human toxicity of cyclopamine and its metabolism into the skin. No adverse effects were seen in either of Tas and Avci's5,6 clinical studies of cyclopamine, yet the drug's role in stem cell development31 and its teratogenicity32 cautions its use in women of childbearing potential until sufficient relevant data are available. Additionally, large, prospective, randomized, controlled trials are needed to confirm cyclopamine's effectiveness. If successful, these studies will provide the optimal concentration, frequency, and mode of administration of treatment. Because the importance of Hh in epidermal hyper-proliferation and development has been demonstrated, a field recently focused on immunology must once again look at the keratinocyte as a fundamental target in the pathophysiology of psoriasis.