Psoriasis

SNOWMASS, Colo. – Hereditary periodic fever syndromes can be distinguished by the nature of the associated rash and the duration of attacks, according to Dr. Daniel Kastner.

These syndromes are characterized by recurrent episodes of fever with dramatic, seemingly unprovoked inflammation – both local and systemic – without evidence of autoimmunity or infection. Hereditary periodic fever syndromes result from inherited abnormalities in innate immunity. They are classified as systemic autoinflammatory diseases distinguished by inflammation in the absence of major involvement of the adaptive immune system.

These disorders include the tumor necrosis factor receptor–associated periodic syndrome (TRAPS), familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), and the cryopyrin-associated periodic syndromes (CAPS), Dr. Kastner said at a symposium sponsored by the American College of Rheumatology.

One of the world’s preeminent authorities on the hereditary periodic fever syndromes, Dr. Kastner and his coworkers at the National Institutes of Health have identified the causative genes in several of these disorders. Their discoveries led directly to novel and highly effective therapies.

TRAPS was known as Hibernian fever until Dr. Kastner and his colleagues discovered the causative mutations. "We wanted a name that was short and snappy, easy to remember," recalled Dr. Kastner, scientific director of the National Human Genome Research Institute in Bethesda, Md.

Here's what Dr. Kastner thinks physicians need to know about these syndromes:

TRAPS. The rash in TRAPS is usually migratory. It often begins proximally on a limb, for example on the thigh. The next day the rash might be on the knee but no longer on the thigh. The following day it might appear on the calf, while the knee is clear. Marked periorbital edema with conjunctivitis is another distinguishing feature. Renal amyloidosis can occur in severely affected patients.

TRAPS is associated with fever and rash, often with serositis and/or arthritis. Unlike other hereditary period fever syndromes, an episode of TRAPS may last for weeks. On MRI, the inflammation is fasciitis, not myositis.

Onset is usually in childhood, but TRAPS often goes undiagnosed until adulthood. TRAPS is caused by autosomal dominant mutations in the tumor necrosis factor RSF1A gene, which encodes the p55 TNF receptor. The resultant protein misfolding is the mechanism underlying the disease.

Colchicine is generally not effective in TRAPS. Corticosteroids are, but the side effects are often limiting. Dr. Kastner and his colleagues showed that the anti-TNF biologic etanercept (Enbrel) can be quite effective. Surprisingly, however, the anti-TNF monoclonal antibodies infliximab and adalimumab have actually been shown to cause TRAPS flares.

Familial Mediterranean fever. The rash of FMF is usually stationary. Sometimes called erysipeloid erythema, the rash is reddish, raised, usually well demarcated, and sometimes painful. It often occurs on the dorsum of the foot, ankle, or lower leg.

The attacks typically last 1-3 days and occur on a monthly basis. These attacks are characterized by fever and rash accompanied by various kinds of inflammation, including pleural inflammation with effusion; massive joint effusions; and a nonerosive, nondeforming, monoarticular arthritis.

"Many of these patients have such severe abdominal pain during attacks that early in their disease they’re mistaken for appendicitis and undergo at least one exploratory laparotomy," according to Dr. Kastner.

Histologically, huge numbers of polymorphonuclear cells are evident in the synovial fluid during a joint attack. It's comparable to what would be seen in a septic joint, except nothing can be cultured.

This disorder is seen predominantly in individuals of Arab, Armenian, Jewish, Turkish, or Italian origin. Dr. Kastner and his coworkers discovered that the disease is caused by recessive mutations in the Mediterranean fever gene, which encodes the pyrin protein, figuring prominently in a pathway of inflammation.

Onset of FMF is usually in childhood, but the disorder is often not diagnosed until adulthood because of a lack of awareness of the disease.

The treatment for FMF is daily colchicine, an inexpensive drug with a good track record for efficacy and a good safety profile. Systemic AA amyloidosis has become less common as a long-term complication of FMF since colchicine became the treatment of choice.

Occasionally a patient cannot take colchicine because of either side effects or lack of response. In such cases there is a highly effective alternative which came about through studies by Dr. Kastner's group. First the investigators showed in animals that the inflammation in FMF is interleukin-1 dependent, and then they pioneered the use of high-dose anakinra (Kinaret), the IL-1 receptor antagonist, as an effective therapy.

HIDS. The rash of hyperimmunoglobulinemia D with periodic fever syndrome is diffuse and maculopapular, and is most typically located on the palms and soles. Pronounced cervical lymphadenopathy is a distinctive feature in this syndrome.

The febrile episodes in HIDS typically last 3-7 days, intermediate in duration between those of FMF and TRAPS. The fever episodes are accompanied by the maculopapular rash, abdominal pain, and arthralgias. Onset is almost always within the first year of life. Episodes are often triggered by childhood immunizations. HIDS is seen mainly in people of northern European ancestry, particularly the Dutch. Renal amyloidosis occurs only rarely.

HIDS is caused by recessive mutations in the mevalonate kinase gene, resulting in reduced production of geranylgeranyl pyrophosphate. HIDS is something of a misnomer in that some affected patients with mevalonate kinase mutations have normal IgD levels.

As yet there's no consensus on the treatment of HIDS, Dr. Kastner said.

CAPS. The cryopyrin-associated periodic syndromes consist of three diseases caused by dominant mutations in one gene, NLRP3, which encodes the cryopyrin protein involved in interleukin-1beta activation. The three cryopyrinopathies are neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, and familial cold autoinflammatory syndrome (FCAS).

What these three diseases have in common is fever, urticarial rash, and excessive production of IL-1beta. Patients with NOMID experience fever nearly every day, while in those with FCAS the fever and hives-like rash develop within a couple of hours after exposure to cold.

Cryopyrin is a central component of the inflammasome, a macromolecular scaffold promoting activation of caspase-1.

"The inflammasome is something that if you were taking a recertification exam or the boards for the first time, you might very well need to know about," the rheumatologist said. "You need to know that cryopyrin is part of the inflammasome, and the inflammasome activates IL-1beta. Patients with these three diseases have activating mutations in cryopyrin, which activates the inflammasome. You need to know that if you’re going to take tests."

NOMID is characterized by bony overgrowth, conjunctivitis, and aseptic meningitis, in addition to fever and urticarial rash. Roughly 40% of NOMID patients lack the cryopyrin mutations and have an as-yet unknown cause for their disease.

Dr. Kastner and his coworkers pioneered anti-IL-1 therapy with anakinra in CAPS patients. "I's quite a dramatic and remarkable response," he said. Other investigators have subsequently reported treatment success using canakinumab and rilonacept.

Dr. Kastner declared having no relevant financial interests.

SNOWMASS, Colo. – Hereditary periodic fever syndromes can be distinguished by the nature of the associated rash and the duration of attacks, according to Dr. Daniel Kastner.

These syndromes are characterized by recurrent episodes of fever with dramatic, seemingly unprovoked inflammation – both local and systemic – without evidence of autoimmunity or infection. Hereditary periodic fever syndromes result from inherited abnormalities in innate immunity. They are classified as systemic autoinflammatory diseases distinguished by inflammation in the absence of major involvement of the adaptive immune system.

These disorders include the tumor necrosis factor receptor–associated periodic syndrome (TRAPS), familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), and the cryopyrin-associated periodic syndromes (CAPS), Dr. Kastner said at a symposium sponsored by the American College of Rheumatology.

One of the world’s preeminent authorities on the hereditary periodic fever syndromes, Dr. Kastner and his coworkers at the National Institutes of Health have identified the causative genes in several of these disorders. Their discoveries led directly to novel and highly effective therapies.

TRAPS was known as Hibernian fever until Dr. Kastner and his colleagues discovered the causative mutations. "We wanted a name that was short and snappy, easy to remember," recalled Dr. Kastner, scientific director of the National Human Genome Research Institute in Bethesda, Md.

Here's what Dr. Kastner thinks physicians need to know about these syndromes:

TRAPS. The rash in TRAPS is usually migratory. It often begins proximally on a limb, for example on the thigh. The next day the rash might be on the knee but no longer on the thigh. The following day it might appear on the calf, while the knee is clear. Marked periorbital edema with conjunctivitis is another distinguishing feature. Renal amyloidosis can occur in severely affected patients.

TRAPS is associated with fever and rash, often with serositis and/or arthritis. Unlike other hereditary period fever syndromes, an episode of TRAPS may last for weeks. On MRI, the inflammation is fasciitis, not myositis.

Onset is usually in childhood, but TRAPS often goes undiagnosed until adulthood. TRAPS is caused by autosomal dominant mutations in the tumor necrosis factor RSF1A gene, which encodes the p55 TNF receptor. The resultant protein misfolding is the mechanism underlying the disease.

Colchicine is generally not effective in TRAPS. Corticosteroids are, but the side effects are often limiting. Dr. Kastner and his colleagues showed that the anti-TNF biologic etanercept (Enbrel) can be quite effective. Surprisingly, however, the anti-TNF monoclonal antibodies infliximab and adalimumab have actually been shown to cause TRAPS flares.

Familial Mediterranean fever. The rash of FMF is usually stationary. Sometimes called erysipeloid erythema, the rash is reddish, raised, usually well demarcated, and sometimes painful. It often occurs on the dorsum of the foot, ankle, or lower leg.

The attacks typically last 1-3 days and occur on a monthly basis. These attacks are characterized by fever and rash accompanied by various kinds of inflammation, including pleural inflammation with effusion; massive joint effusions; and a nonerosive, nondeforming, monoarticular arthritis.

"Many of these patients have such severe abdominal pain during attacks that early in their disease they’re mistaken for appendicitis and undergo at least one exploratory laparotomy," according to Dr. Kastner.

Histologically, huge numbers of polymorphonuclear cells are evident in the synovial fluid during a joint attack. It's comparable to what would be seen in a septic joint, except nothing can be cultured.

This disorder is seen predominantly in individuals of Arab, Armenian, Jewish, Turkish, or Italian origin. Dr. Kastner and his coworkers discovered that the disease is caused by recessive mutations in the Mediterranean fever gene, which encodes the pyrin protein, figuring prominently in a pathway of inflammation.

Onset of FMF is usually in childhood, but the disorder is often not diagnosed until adulthood because of a lack of awareness of the disease.

The treatment for FMF is daily colchicine, an inexpensive drug with a good track record for efficacy and a good safety profile. Systemic AA amyloidosis has become less common as a long-term complication of FMF since colchicine became the treatment of choice.

Occasionally a patient cannot take colchicine because of either side effects or lack of response. In such cases there is a highly effective alternative which came about through studies by Dr. Kastner's group. First the investigators showed in animals that the inflammation in FMF is interleukin-1 dependent, and then they pioneered the use of high-dose anakinra (Kinaret), the IL-1 receptor antagonist, as an effective therapy.

HIDS. The rash of hyperimmunoglobulinemia D with periodic fever syndrome is diffuse and maculopapular, and is most typically located on the palms and soles. Pronounced cervical lymphadenopathy is a distinctive feature in this syndrome.

The febrile episodes in HIDS typically last 3-7 days, intermediate in duration between those of FMF and TRAPS. The fever episodes are accompanied by the maculopapular rash, abdominal pain, and arthralgias. Onset is almost always within the first year of life. Episodes are often triggered by childhood immunizations. HIDS is seen mainly in people of northern European ancestry, particularly the Dutch. Renal amyloidosis occurs only rarely.

HIDS is caused by recessive mutations in the mevalonate kinase gene, resulting in reduced production of geranylgeranyl pyrophosphate. HIDS is something of a misnomer in that some affected patients with mevalonate kinase mutations have normal IgD levels.

As yet there's no consensus on the treatment of HIDS, Dr. Kastner said.

CAPS. The cryopyrin-associated periodic syndromes consist of three diseases caused by dominant mutations in one gene, NLRP3, which encodes the cryopyrin protein involved in interleukin-1beta activation. The three cryopyrinopathies are neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, and familial cold autoinflammatory syndrome (FCAS).

What these three diseases have in common is fever, urticarial rash, and excessive production of IL-1beta. Patients with NOMID experience fever nearly every day, while in those with FCAS the fever and hives-like rash develop within a couple of hours after exposure to cold.

Cryopyrin is a central component of the inflammasome, a macromolecular scaffold promoting activation of caspase-1.

"The inflammasome is something that if you were taking a recertification exam or the boards for the first time, you might very well need to know about," the rheumatologist said. "You need to know that cryopyrin is part of the inflammasome, and the inflammasome activates IL-1beta. Patients with these three diseases have activating mutations in cryopyrin, which activates the inflammasome. You need to know that if you’re going to take tests."

NOMID is characterized by bony overgrowth, conjunctivitis, and aseptic meningitis, in addition to fever and urticarial rash. Roughly 40% of NOMID patients lack the cryopyrin mutations and have an as-yet unknown cause for their disease.

Dr. Kastner and his coworkers pioneered anti-IL-1 therapy with anakinra in CAPS patients. "I's quite a dramatic and remarkable response," he said. Other investigators have subsequently reported treatment success using canakinumab and rilonacept.

Dr. Kastner declared having no relevant financial interests.

SNOWMASS, Colo. – Hereditary periodic fever syndromes can be distinguished by the nature of the associated rash and the duration of attacks, according to Dr. Daniel Kastner.

These syndromes are characterized by recurrent episodes of fever with dramatic, seemingly unprovoked inflammation – both local and systemic – without evidence of autoimmunity or infection. Hereditary periodic fever syndromes result from inherited abnormalities in innate immunity. They are classified as systemic autoinflammatory diseases distinguished by inflammation in the absence of major involvement of the adaptive immune system.

These disorders include the tumor necrosis factor receptor–associated periodic syndrome (TRAPS), familial Mediterranean fever, hyperimmunoglobulinemia D with periodic fever syndrome (HIDS), and the cryopyrin-associated periodic syndromes (CAPS), Dr. Kastner said at a symposium sponsored by the American College of Rheumatology.

One of the world’s preeminent authorities on the hereditary periodic fever syndromes, Dr. Kastner and his coworkers at the National Institutes of Health have identified the causative genes in several of these disorders. Their discoveries led directly to novel and highly effective therapies.

TRAPS was known as Hibernian fever until Dr. Kastner and his colleagues discovered the causative mutations. "We wanted a name that was short and snappy, easy to remember," recalled Dr. Kastner, scientific director of the National Human Genome Research Institute in Bethesda, Md.

Here's what Dr. Kastner thinks physicians need to know about these syndromes:

TRAPS. The rash in TRAPS is usually migratory. It often begins proximally on a limb, for example on the thigh. The next day the rash might be on the knee but no longer on the thigh. The following day it might appear on the calf, while the knee is clear. Marked periorbital edema with conjunctivitis is another distinguishing feature. Renal amyloidosis can occur in severely affected patients.

TRAPS is associated with fever and rash, often with serositis and/or arthritis. Unlike other hereditary period fever syndromes, an episode of TRAPS may last for weeks. On MRI, the inflammation is fasciitis, not myositis.

Onset is usually in childhood, but TRAPS often goes undiagnosed until adulthood. TRAPS is caused by autosomal dominant mutations in the tumor necrosis factor RSF1A gene, which encodes the p55 TNF receptor. The resultant protein misfolding is the mechanism underlying the disease.

Colchicine is generally not effective in TRAPS. Corticosteroids are, but the side effects are often limiting. Dr. Kastner and his colleagues showed that the anti-TNF biologic etanercept (Enbrel) can be quite effective. Surprisingly, however, the anti-TNF monoclonal antibodies infliximab and adalimumab have actually been shown to cause TRAPS flares.

Familial Mediterranean fever. The rash of FMF is usually stationary. Sometimes called erysipeloid erythema, the rash is reddish, raised, usually well demarcated, and sometimes painful. It often occurs on the dorsum of the foot, ankle, or lower leg.

The attacks typically last 1-3 days and occur on a monthly basis. These attacks are characterized by fever and rash accompanied by various kinds of inflammation, including pleural inflammation with effusion; massive joint effusions; and a nonerosive, nondeforming, monoarticular arthritis.

"Many of these patients have such severe abdominal pain during attacks that early in their disease they’re mistaken for appendicitis and undergo at least one exploratory laparotomy," according to Dr. Kastner.

Histologically, huge numbers of polymorphonuclear cells are evident in the synovial fluid during a joint attack. It's comparable to what would be seen in a septic joint, except nothing can be cultured.

This disorder is seen predominantly in individuals of Arab, Armenian, Jewish, Turkish, or Italian origin. Dr. Kastner and his coworkers discovered that the disease is caused by recessive mutations in the Mediterranean fever gene, which encodes the pyrin protein, figuring prominently in a pathway of inflammation.

Onset of FMF is usually in childhood, but the disorder is often not diagnosed until adulthood because of a lack of awareness of the disease.

The treatment for FMF is daily colchicine, an inexpensive drug with a good track record for efficacy and a good safety profile. Systemic AA amyloidosis has become less common as a long-term complication of FMF since colchicine became the treatment of choice.

Occasionally a patient cannot take colchicine because of either side effects or lack of response. In such cases there is a highly effective alternative which came about through studies by Dr. Kastner's group. First the investigators showed in animals that the inflammation in FMF is interleukin-1 dependent, and then they pioneered the use of high-dose anakinra (Kinaret), the IL-1 receptor antagonist, as an effective therapy.

HIDS. The rash of hyperimmunoglobulinemia D with periodic fever syndrome is diffuse and maculopapular, and is most typically located on the palms and soles. Pronounced cervical lymphadenopathy is a distinctive feature in this syndrome.

The febrile episodes in HIDS typically last 3-7 days, intermediate in duration between those of FMF and TRAPS. The fever episodes are accompanied by the maculopapular rash, abdominal pain, and arthralgias. Onset is almost always within the first year of life. Episodes are often triggered by childhood immunizations. HIDS is seen mainly in people of northern European ancestry, particularly the Dutch. Renal amyloidosis occurs only rarely.

HIDS is caused by recessive mutations in the mevalonate kinase gene, resulting in reduced production of geranylgeranyl pyrophosphate. HIDS is something of a misnomer in that some affected patients with mevalonate kinase mutations have normal IgD levels.

As yet there's no consensus on the treatment of HIDS, Dr. Kastner said.

CAPS. The cryopyrin-associated periodic syndromes consist of three diseases caused by dominant mutations in one gene, NLRP3, which encodes the cryopyrin protein involved in interleukin-1beta activation. The three cryopyrinopathies are neonatal-onset multisystem inflammatory disease (NOMID), Muckle-Wells syndrome, and familial cold autoinflammatory syndrome (FCAS).

What these three diseases have in common is fever, urticarial rash, and excessive production of IL-1beta. Patients with NOMID experience fever nearly every day, while in those with FCAS the fever and hives-like rash develop within a couple of hours after exposure to cold.

Cryopyrin is a central component of the inflammasome, a macromolecular scaffold promoting activation of caspase-1.

"The inflammasome is something that if you were taking a recertification exam or the boards for the first time, you might very well need to know about," the rheumatologist said. "You need to know that cryopyrin is part of the inflammasome, and the inflammasome activates IL-1beta. Patients with these three diseases have activating mutations in cryopyrin, which activates the inflammasome. You need to know that if you’re going to take tests."

NOMID is characterized by bony overgrowth, conjunctivitis, and aseptic meningitis, in addition to fever and urticarial rash. Roughly 40% of NOMID patients lack the cryopyrin mutations and have an as-yet unknown cause for their disease.

Dr. Kastner and his coworkers pioneered anti-IL-1 therapy with anakinra in CAPS patients. "I's quite a dramatic and remarkable response," he said. Other investigators have subsequently reported treatment success using canakinumab and rilonacept.

Dr. Kastner declared having no relevant financial interests.

NEW ORLEANS - Thalidomide is an effective and, when used judiciously, a reasonably safe second-line therapy for cutaneous lupus erythematosus, according to Dr. Jeffrey P. Callen, professor of medicine and chief of dermatology at the University of Louisville (Ky.).

"Thalidomide works regularly," Dr. Callen said at the annual meeting of the American Academy of Dermatology.

Hydroxychloroquine has to be considered first-line therapy for cutaneous LE because the antimalarials are disease modifying; their early use can prevent progression from strictly cutaneous disease to systemic lupus.

In contrast, thalidomide (Thalomid) doesn't modify the disease process. Once patients discontinue the drug, they relapse. And thalidomide doesn't have a marked effect on concomitant SLE. But upon readministration of thalidomide after a break, physicians can expect a clinical response similar to that seen earlier, he said.

Dr. Callen added that in patients who can't tolerate or don't respond to antimalarials, his next thought is thalidomide – ahead of immunosuppressive agents including methotrexate, azathioprine, and mycophenolate mofetil. Systemic corticosteroids are reserved for last-ditch therapy in his therapeutic algorithm.

Because of thalidomide's notorious teratogenicity, participation in the Food and Drug Administration–mandated System for Thalidomide Education and Prescribing Safety is required.

"Once you've selected an appropriate patient, the major issue then becomes, are they going to develop a neuropathy? I think with very low doses used every other night, you can get away with long-term therapy without developing neuropathy," he said. "I personally do not get nerve conduction studies. I follow the patients, and if they tell me they have symptoms that sound like sensory neuropathy, I stop the drug whether their nerve conduction study is positive or not."

In numerous published series, the majority of cutaneous LE patients placed on thalidomide achieved a complete response, with another 15%-20% attaining a partial response, and 15%-20% being nonresponders or encountering unacceptable toxicity, according to the dermatologist.

The clinical response to thalidomide begins quickly, within about 2 weeks at a dose of 100 mg/day. A full clinical response is achieved in 2-3 months. At that point the patient can shift to maintenance therapy, which might range from 50 mg/day to 25 mg every second or third day.

To place thalidomide in context, Dr. Callen said that the very first thing he does in managing cutaneous LE is remove any exacerbating factors. Topping the list is sunlight, which he addresses by means of daily use of a broad-spectrum sunscreen, sun avoidance, and sun-protective clothing.

In smokers with any form of lupus, the response to medications, especially antimalarials, is significantly improved by quitting the habit.

"It has been shown that smoking doesn't affect blood levels of antimalarials [Ann. Rheum. Dis. 2007;66:1547-8], so I think that the effect of smoking is probably to worsen the disease rather than in some way impede the antimalarial," Dr. Callen said.

A careful drug history is important, especially in patients with subacute cutaneous LE, whose lesions turn out to be drug related in about 20% of new cases.

The treatment goals in patients with cutaneous LE are to halt formation of new lesions in order to prevent scarring, atrophy, and dyspigmentation. New patients can be reassured that it's likely their disease will remain limited to the skin. "It doesn't mean it's not possible they have systemic disease, but they generally don't," the dermatologist said.

Dr. Callen said he had no relevant financial disclosures.

NEW ORLEANS - Thalidomide is an effective and, when used judiciously, a reasonably safe second-line therapy for cutaneous lupus erythematosus, according to Dr. Jeffrey P. Callen, professor of medicine and chief of dermatology at the University of Louisville (Ky.).

"Thalidomide works regularly," Dr. Callen said at the annual meeting of the American Academy of Dermatology.

Hydroxychloroquine has to be considered first-line therapy for cutaneous LE because the antimalarials are disease modifying; their early use can prevent progression from strictly cutaneous disease to systemic lupus.

In contrast, thalidomide (Thalomid) doesn't modify the disease process. Once patients discontinue the drug, they relapse. And thalidomide doesn't have a marked effect on concomitant SLE. But upon readministration of thalidomide after a break, physicians can expect a clinical response similar to that seen earlier, he said.

Dr. Callen added that in patients who can't tolerate or don't respond to antimalarials, his next thought is thalidomide – ahead of immunosuppressive agents including methotrexate, azathioprine, and mycophenolate mofetil. Systemic corticosteroids are reserved for last-ditch therapy in his therapeutic algorithm.

Because of thalidomide's notorious teratogenicity, participation in the Food and Drug Administration–mandated System for Thalidomide Education and Prescribing Safety is required.

"Once you've selected an appropriate patient, the major issue then becomes, are they going to develop a neuropathy? I think with very low doses used every other night, you can get away with long-term therapy without developing neuropathy," he said. "I personally do not get nerve conduction studies. I follow the patients, and if they tell me they have symptoms that sound like sensory neuropathy, I stop the drug whether their nerve conduction study is positive or not."

In numerous published series, the majority of cutaneous LE patients placed on thalidomide achieved a complete response, with another 15%-20% attaining a partial response, and 15%-20% being nonresponders or encountering unacceptable toxicity, according to the dermatologist.

The clinical response to thalidomide begins quickly, within about 2 weeks at a dose of 100 mg/day. A full clinical response is achieved in 2-3 months. At that point the patient can shift to maintenance therapy, which might range from 50 mg/day to 25 mg every second or third day.

To place thalidomide in context, Dr. Callen said that the very first thing he does in managing cutaneous LE is remove any exacerbating factors. Topping the list is sunlight, which he addresses by means of daily use of a broad-spectrum sunscreen, sun avoidance, and sun-protective clothing.

In smokers with any form of lupus, the response to medications, especially antimalarials, is significantly improved by quitting the habit.

"It has been shown that smoking doesn't affect blood levels of antimalarials [Ann. Rheum. Dis. 2007;66:1547-8], so I think that the effect of smoking is probably to worsen the disease rather than in some way impede the antimalarial," Dr. Callen said.

A careful drug history is important, especially in patients with subacute cutaneous LE, whose lesions turn out to be drug related in about 20% of new cases.

The treatment goals in patients with cutaneous LE are to halt formation of new lesions in order to prevent scarring, atrophy, and dyspigmentation. New patients can be reassured that it's likely their disease will remain limited to the skin. "It doesn't mean it's not possible they have systemic disease, but they generally don't," the dermatologist said.

Dr. Callen said he had no relevant financial disclosures.

NEW ORLEANS - Thalidomide is an effective and, when used judiciously, a reasonably safe second-line therapy for cutaneous lupus erythematosus, according to Dr. Jeffrey P. Callen, professor of medicine and chief of dermatology at the University of Louisville (Ky.).

"Thalidomide works regularly," Dr. Callen said at the annual meeting of the American Academy of Dermatology.

Hydroxychloroquine has to be considered first-line therapy for cutaneous LE because the antimalarials are disease modifying; their early use can prevent progression from strictly cutaneous disease to systemic lupus.

In contrast, thalidomide (Thalomid) doesn't modify the disease process. Once patients discontinue the drug, they relapse. And thalidomide doesn't have a marked effect on concomitant SLE. But upon readministration of thalidomide after a break, physicians can expect a clinical response similar to that seen earlier, he said.

Dr. Callen added that in patients who can't tolerate or don't respond to antimalarials, his next thought is thalidomide – ahead of immunosuppressive agents including methotrexate, azathioprine, and mycophenolate mofetil. Systemic corticosteroids are reserved for last-ditch therapy in his therapeutic algorithm.

Because of thalidomide's notorious teratogenicity, participation in the Food and Drug Administration–mandated System for Thalidomide Education and Prescribing Safety is required.

"Once you've selected an appropriate patient, the major issue then becomes, are they going to develop a neuropathy? I think with very low doses used every other night, you can get away with long-term therapy without developing neuropathy," he said. "I personally do not get nerve conduction studies. I follow the patients, and if they tell me they have symptoms that sound like sensory neuropathy, I stop the drug whether their nerve conduction study is positive or not."

In numerous published series, the majority of cutaneous LE patients placed on thalidomide achieved a complete response, with another 15%-20% attaining a partial response, and 15%-20% being nonresponders or encountering unacceptable toxicity, according to the dermatologist.

The clinical response to thalidomide begins quickly, within about 2 weeks at a dose of 100 mg/day. A full clinical response is achieved in 2-3 months. At that point the patient can shift to maintenance therapy, which might range from 50 mg/day to 25 mg every second or third day.

To place thalidomide in context, Dr. Callen said that the very first thing he does in managing cutaneous LE is remove any exacerbating factors. Topping the list is sunlight, which he addresses by means of daily use of a broad-spectrum sunscreen, sun avoidance, and sun-protective clothing.

In smokers with any form of lupus, the response to medications, especially antimalarials, is significantly improved by quitting the habit.

"It has been shown that smoking doesn't affect blood levels of antimalarials [Ann. Rheum. Dis. 2007;66:1547-8], so I think that the effect of smoking is probably to worsen the disease rather than in some way impede the antimalarial," Dr. Callen said.

A careful drug history is important, especially in patients with subacute cutaneous LE, whose lesions turn out to be drug related in about 20% of new cases.

The treatment goals in patients with cutaneous LE are to halt formation of new lesions in order to prevent scarring, atrophy, and dyspigmentation. New patients can be reassured that it's likely their disease will remain limited to the skin. "It doesn't mean it's not possible they have systemic disease, but they generally don't," the dermatologist said.

Dr. Callen said he had no relevant financial disclosures.

SNOWMASS, COLO. - Abnormal findings on nailfold capillary microscopy and the presence of scleroderma-specific autoantibodies in patients presenting with new-onset Raynaud’s phenomenon without overt connective tissue disease are powerful independent predictors of progression to definite scleroderma.

A landmark Canadian prospective study in 586 consecutive patients presenting with isolated Raynaud’s phenomenon showed that 13% of them developed scleroderma during 3,197 person-years of follow-up. Another 1% developed other connective tissue diseases. Fewer than 2% of those with normal nailfold capillaries and no scleroderma-specific antibodies went on to develop definite scleroderma during 15-20 years, and the majority who did progress to scleroderma did so within the first year or two, noted Dr. Fredrick M. Wigley at a symposium sponsored by the American College of Rheumatology.

In contrast, 80% of patients with baseline evidence of microvascular damage on nailfold microscopy together with one or more scleroderma-specific autoantibodies developed scleroderma. Two-thirds of patients with these baseline findings in the University of Montreal study (Arthritis Rheum. 2008;58:3902-12) progressed to definite scleroderma within the first 5 years of follow-up, added Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.

Raynaud’s patients with one or more scleroderma-specific autoantibodies but no nailfold capillary abnormalities had a 35% rate of progression to scleroderma, with 60% of cases being diagnosed within the first 5 years. Patients with nailfold capillary abnormalities but no scleroderma-specific autoantibodies had a 26% long-term rate of progression to scleroderma, with roughly 90% of cases occurring within 5 years.

Nailfold microscopy is a simple matter. It can be carried out using a drop of immersion oil and an ophthalmoscope set at diopter 40. The microvascular damage that portends subsequent definite scleroderma follows a characteristic chronologic sequence consisting of enlarged capillary loops, followed by capillary loss, and capillary telangiectasias, Dr. Wigley explained.

The scleroderma-specific autoantibodies that proved predictive in the large Canadian study were anticentromere (anti-CENP-B) anti-TH/To, anti-topoisomerase I, and anti-RNA polymerase III.

The findings in the Canadian study, which was the first large prospective study of predictors of scleroderma in patients with Raynaud’s phenomenon, were remarkably consistent with those obtained earlier through a literature search by investigators at Dartmouth-Hitchcock Medical Center, Lebanon, N.H. They analyzed 10 published articles including 639 patients with primary Raynaud’s phenomenon, and determined that 12.6% of them developed a connective tissue disease during 2,531 person-years of follow-up, compared with 13.6% of patients in the Montreal study. Scleroderma accounted for the great majority of the cases of connective tissue disease in the Dartmouth-Hitchcock analysis, Dr. Wigley noted.

The mean rate of transition from isolated Raynaud's to scleroderma or another connective tissue disease in this series was 3.2 cases per 100 person-years. The best predictors were abnormal nailfold capillaries and the presence of antinuclear antibodies (Arch. Intern. Med. 1998;158:595-600).

Dr. Wigley declared that he receives consulting fees and/or research grants from Actelion, Amira, KineMed, MedImmune, Novartis, Orion, Pfizer, and United Therapeutics.

********* UNDERSET  

SNOWMASS, COLO. - Abnormal findings on nailfold capillary microscopy and the presence of scleroderma-specific autoantibodies in patients presenting with new-onset Raynaud’s phenomenon without overt connective tissue disease are powerful independent predictors of progression to definite scleroderma.

A landmark Canadian prospective study in 586 consecutive patients presenting with isolated Raynaud’s phenomenon showed that 13% of them developed scleroderma during 3,197 person-years of follow-up. Another 1% developed other connective tissue diseases. Fewer than 2% of those with normal nailfold capillaries and no scleroderma-specific antibodies went on to develop definite scleroderma during 15-20 years, and the majority who did progress to scleroderma did so within the first year or two, noted Dr. Fredrick M. Wigley at a symposium sponsored by the American College of Rheumatology.

In contrast, 80% of patients with baseline evidence of microvascular damage on nailfold microscopy together with one or more scleroderma-specific autoantibodies developed scleroderma. Two-thirds of patients with these baseline findings in the University of Montreal study (Arthritis Rheum. 2008;58:3902-12) progressed to definite scleroderma within the first 5 years of follow-up, added Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.

Raynaud’s patients with one or more scleroderma-specific autoantibodies but no nailfold capillary abnormalities had a 35% rate of progression to scleroderma, with 60% of cases being diagnosed within the first 5 years. Patients with nailfold capillary abnormalities but no scleroderma-specific autoantibodies had a 26% long-term rate of progression to scleroderma, with roughly 90% of cases occurring within 5 years.

Nailfold microscopy is a simple matter. It can be carried out using a drop of immersion oil and an ophthalmoscope set at diopter 40. The microvascular damage that portends subsequent definite scleroderma follows a characteristic chronologic sequence consisting of enlarged capillary loops, followed by capillary loss, and capillary telangiectasias, Dr. Wigley explained.

The scleroderma-specific autoantibodies that proved predictive in the large Canadian study were anticentromere (anti-CENP-B) anti-TH/To, anti-topoisomerase I, and anti-RNA polymerase III.

The findings in the Canadian study, which was the first large prospective study of predictors of scleroderma in patients with Raynaud’s phenomenon, were remarkably consistent with those obtained earlier through a literature search by investigators at Dartmouth-Hitchcock Medical Center, Lebanon, N.H. They analyzed 10 published articles including 639 patients with primary Raynaud’s phenomenon, and determined that 12.6% of them developed a connective tissue disease during 2,531 person-years of follow-up, compared with 13.6% of patients in the Montreal study. Scleroderma accounted for the great majority of the cases of connective tissue disease in the Dartmouth-Hitchcock analysis, Dr. Wigley noted.

The mean rate of transition from isolated Raynaud's to scleroderma or another connective tissue disease in this series was 3.2 cases per 100 person-years. The best predictors were abnormal nailfold capillaries and the presence of antinuclear antibodies (Arch. Intern. Med. 1998;158:595-600).

Dr. Wigley declared that he receives consulting fees and/or research grants from Actelion, Amira, KineMed, MedImmune, Novartis, Orion, Pfizer, and United Therapeutics.

********* UNDERSET  

SNOWMASS, COLO. - Abnormal findings on nailfold capillary microscopy and the presence of scleroderma-specific autoantibodies in patients presenting with new-onset Raynaud’s phenomenon without overt connective tissue disease are powerful independent predictors of progression to definite scleroderma.

A landmark Canadian prospective study in 586 consecutive patients presenting with isolated Raynaud’s phenomenon showed that 13% of them developed scleroderma during 3,197 person-years of follow-up. Another 1% developed other connective tissue diseases. Fewer than 2% of those with normal nailfold capillaries and no scleroderma-specific antibodies went on to develop definite scleroderma during 15-20 years, and the majority who did progress to scleroderma did so within the first year or two, noted Dr. Fredrick M. Wigley at a symposium sponsored by the American College of Rheumatology.

In contrast, 80% of patients with baseline evidence of microvascular damage on nailfold microscopy together with one or more scleroderma-specific autoantibodies developed scleroderma. Two-thirds of patients with these baseline findings in the University of Montreal study (Arthritis Rheum. 2008;58:3902-12) progressed to definite scleroderma within the first 5 years of follow-up, added Dr. Wigley, professor of medicine and director of the scleroderma center at Johns Hopkins University, Baltimore.

Raynaud’s patients with one or more scleroderma-specific autoantibodies but no nailfold capillary abnormalities had a 35% rate of progression to scleroderma, with 60% of cases being diagnosed within the first 5 years. Patients with nailfold capillary abnormalities but no scleroderma-specific autoantibodies had a 26% long-term rate of progression to scleroderma, with roughly 90% of cases occurring within 5 years.

Nailfold microscopy is a simple matter. It can be carried out using a drop of immersion oil and an ophthalmoscope set at diopter 40. The microvascular damage that portends subsequent definite scleroderma follows a characteristic chronologic sequence consisting of enlarged capillary loops, followed by capillary loss, and capillary telangiectasias, Dr. Wigley explained.

The scleroderma-specific autoantibodies that proved predictive in the large Canadian study were anticentromere (anti-CENP-B) anti-TH/To, anti-topoisomerase I, and anti-RNA polymerase III.

The findings in the Canadian study, which was the first large prospective study of predictors of scleroderma in patients with Raynaud’s phenomenon, were remarkably consistent with those obtained earlier through a literature search by investigators at Dartmouth-Hitchcock Medical Center, Lebanon, N.H. They analyzed 10 published articles including 639 patients with primary Raynaud’s phenomenon, and determined that 12.6% of them developed a connective tissue disease during 2,531 person-years of follow-up, compared with 13.6% of patients in the Montreal study. Scleroderma accounted for the great majority of the cases of connective tissue disease in the Dartmouth-Hitchcock analysis, Dr. Wigley noted.

The mean rate of transition from isolated Raynaud's to scleroderma or another connective tissue disease in this series was 3.2 cases per 100 person-years. The best predictors were abnormal nailfold capillaries and the presence of antinuclear antibodies (Arch. Intern. Med. 1998;158:595-600).

Dr. Wigley declared that he receives consulting fees and/or research grants from Actelion, Amira, KineMed, MedImmune, Novartis, Orion, Pfizer, and United Therapeutics.

********* UNDERSET  

SNOWMASS, COLO. -  Persistent pain and nonreversible digital discoloration in a patient with Raynaud's phenomenon are indicators of critical ischemia constituting a medical emergency.

"Raynaud's patients will often say, 'My fingers are uncomfortable. I feel pins and needles.' But when they say it actually hurts, you're in trouble. Particularly if they say, 'It hurts beyond my finger, it hurts in the palm of my hand and radiates up in my arm, I have to hang my hand off the edge of the bed to get relief, it’s worse at nighttime,' then you’ve reached the point of critical ischemia and if you don't react you're going to have big trouble," Dr. Fredrick M. Wigley said at a symposium sponsored by the American College of Rheumatology.

Although pain is the key feature marking a critical ischemic event, nonreversible discoloration is another indication. Affected digits will have well-demarcated pale-blue areas, and upon pressing down and then releasing the finger, no blood reflow is seen, explained Dr. Wigley, professor of medicine and head of the scleroderma center at Johns Hopkins University, Baltimore.

In contrast, reversibility is the hallmark of uncomplicated Raynaud's. One of the most common triggers is reaching into the frozen foods section at the supermarket. But 15 minutes after rewarming, the discoloration is reversed. Uncomplicated Raynaud's involves all the digits; the thumb is less often involved than the fingers, but it is not spared.

An acute ischemic crisis requires urgent care. Dr. Wigley's management approach begins with rest and warming of the affected hand, followed quickly by a local digital block. He injects 2% lidocaine into the web at the base of the affected finger, placing the needle tip close to the digital nerve. This accomplishes two things: It brings immediate pain relief, and it lets him see whether acute vasodilation occurs in response to the injection, an encouraging finding.

If the patient isn't already on oral vasodilator therapy with a long-acting oral calcium channel blocker, he starts amlodipine immediately. In an acute ischemic crisis, Dr. Wigley resorts to low-dose epoprostenol infused into a peripheral vein at 0.5-2.0 ng/kg per minute continuously for 3 or more days. To avoid hospitalization, he allows patients to undergo the prostacyclin infusions on an outpatient basis and go home at the end of each treatment day.

Although it's not a well-studied intervention, 48 hours of anticoagulation with unfractionated heparin or low-molecular-weight heparin makes sense in a patient with acute, rapidly advancing digital ischemia who is at risk of losing a digit, he said.

Dr. Wigley disclosed that he has received consulting fees and/or research grants from Actelion, Amira, KineMed, MedImmune, Novartis, Orion, Pfizer, and United Therapeutics.

SNOWMASS, COLO. -  Persistent pain and nonreversible digital discoloration in a patient with Raynaud's phenomenon are indicators of critical ischemia constituting a medical emergency.

"Raynaud's patients will often say, 'My fingers are uncomfortable. I feel pins and needles.' But when they say it actually hurts, you're in trouble. Particularly if they say, 'It hurts beyond my finger, it hurts in the palm of my hand and radiates up in my arm, I have to hang my hand off the edge of the bed to get relief, it’s worse at nighttime,' then you’ve reached the point of critical ischemia and if you don't react you're going to have big trouble," Dr. Fredrick M. Wigley said at a symposium sponsored by the American College of Rheumatology.

Although pain is the key feature marking a critical ischemic event, nonreversible discoloration is another indication. Affected digits will have well-demarcated pale-blue areas, and upon pressing down and then releasing the finger, no blood reflow is seen, explained Dr. Wigley, professor of medicine and head of the scleroderma center at Johns Hopkins University, Baltimore.

In contrast, reversibility is the hallmark of uncomplicated Raynaud's. One of the most common triggers is reaching into the frozen foods section at the supermarket. But 15 minutes after rewarming, the discoloration is reversed. Uncomplicated Raynaud's involves all the digits; the thumb is less often involved than the fingers, but it is not spared.

An acute ischemic crisis requires urgent care. Dr. Wigley's management approach begins with rest and warming of the affected hand, followed quickly by a local digital block. He injects 2% lidocaine into the web at the base of the affected finger, placing the needle tip close to the digital nerve. This accomplishes two things: It brings immediate pain relief, and it lets him see whether acute vasodilation occurs in response to the injection, an encouraging finding.

If the patient isn't already on oral vasodilator therapy with a long-acting oral calcium channel blocker, he starts amlodipine immediately. In an acute ischemic crisis, Dr. Wigley resorts to low-dose epoprostenol infused into a peripheral vein at 0.5-2.0 ng/kg per minute continuously for 3 or more days. To avoid hospitalization, he allows patients to undergo the prostacyclin infusions on an outpatient basis and go home at the end of each treatment day.

Although it's not a well-studied intervention, 48 hours of anticoagulation with unfractionated heparin or low-molecular-weight heparin makes sense in a patient with acute, rapidly advancing digital ischemia who is at risk of losing a digit, he said.

Dr. Wigley disclosed that he has received consulting fees and/or research grants from Actelion, Amira, KineMed, MedImmune, Novartis, Orion, Pfizer, and United Therapeutics.

SNOWMASS, COLO. -  Persistent pain and nonreversible digital discoloration in a patient with Raynaud's phenomenon are indicators of critical ischemia constituting a medical emergency.

"Raynaud's patients will often say, 'My fingers are uncomfortable. I feel pins and needles.' But when they say it actually hurts, you're in trouble. Particularly if they say, 'It hurts beyond my finger, it hurts in the palm of my hand and radiates up in my arm, I have to hang my hand off the edge of the bed to get relief, it’s worse at nighttime,' then you’ve reached the point of critical ischemia and if you don't react you're going to have big trouble," Dr. Fredrick M. Wigley said at a symposium sponsored by the American College of Rheumatology.

Although pain is the key feature marking a critical ischemic event, nonreversible discoloration is another indication. Affected digits will have well-demarcated pale-blue areas, and upon pressing down and then releasing the finger, no blood reflow is seen, explained Dr. Wigley, professor of medicine and head of the scleroderma center at Johns Hopkins University, Baltimore.

In contrast, reversibility is the hallmark of uncomplicated Raynaud's. One of the most common triggers is reaching into the frozen foods section at the supermarket. But 15 minutes after rewarming, the discoloration is reversed. Uncomplicated Raynaud's involves all the digits; the thumb is less often involved than the fingers, but it is not spared.

An acute ischemic crisis requires urgent care. Dr. Wigley's management approach begins with rest and warming of the affected hand, followed quickly by a local digital block. He injects 2% lidocaine into the web at the base of the affected finger, placing the needle tip close to the digital nerve. This accomplishes two things: It brings immediate pain relief, and it lets him see whether acute vasodilation occurs in response to the injection, an encouraging finding.

If the patient isn't already on oral vasodilator therapy with a long-acting oral calcium channel blocker, he starts amlodipine immediately. In an acute ischemic crisis, Dr. Wigley resorts to low-dose epoprostenol infused into a peripheral vein at 0.5-2.0 ng/kg per minute continuously for 3 or more days. To avoid hospitalization, he allows patients to undergo the prostacyclin infusions on an outpatient basis and go home at the end of each treatment day.

Although it's not a well-studied intervention, 48 hours of anticoagulation with unfractionated heparin or low-molecular-weight heparin makes sense in a patient with acute, rapidly advancing digital ischemia who is at risk of losing a digit, he said.

Dr. Wigley disclosed that he has received consulting fees and/or research grants from Actelion, Amira, KineMed, MedImmune, Novartis, Orion, Pfizer, and United Therapeutics.

PALM BEACH, ARUBA – Calcineurin inhibitors – used largely off-label for dermatologic conditions – should become a better-known part of the armamentarium, said Dr. Charles Ellis.

Calcineurin inhibitors work by preventing T-cell activation by blocking calcineurin through its inhibitor immunophilin, said Dr. Ellis, of the University of Michigan, Ann Arbor. Among the drugs in this class are cyclosporine, pimecrolimus, tacrolimus, and a therapy in development, voclosporin. Only pimecrolimus and tacrolimus are available in topical forms.

In the United States, oral cyclosporine is approved for psoriasis but is generally not marketed for the indication, he said. All of the other therapies are used off label, although oral tacrolimus and oral pimecrolimus have been shown to be effective against psoriasis in small studies. The drugs have proved useful for atopic dermatitis, pyoderma gangrenosum, lichen planus, and alopecia areata.

Cyclosporine should not be used for longer than 1 year because it can cause kidney dysfunction, so it is not recommended for psoriasis. And in alopecia, it usually stops working, so he said he generally will not start patients on the drug for this condition.

Voclosporin is being developed for psoriasis by the Canadian company Isotechnika. A phase III trial showed about a 50% improvement in Psoriasis Area and Severity Index (PASI-75) score by week 12; the effect continued through week 24 (Lancet 2008;371:1337-42).

However, patients taking voclosporin had double the rate of headache and gastrointestinal problems as did those on placebo, said Dr. Ellis.

The drug was to be reviewed by a Food and Drug Administration advisory panel in 2010, but the agency cancelled the meeting. In the United States, Isotechnika is seeking approval to treat infectious uveitis; the psoriasis indication is being pursued in Canada. The drug is also in development for prevention of kidney transplant rejection.

Topical calcineurin inhibitors offer a distinct advantage because they do not have the same systemic side effects seen with the oral formulations, said Dr. Ellis.

Pimecrolimus cream and tacrolimus ointment are approved as second-line therapies for short-term chronic treatment of moderate to severe dermatitis in nonimmunocompromised adults and children. They can be used in a standard regimen, with applications up to a week after clearing, or in a proactive regimen, using the topicals until there is clearance, and then applying twice weekly to all affected areas for a year.

Topical calcineurin inhibitors were initially embraced as a potentially safe alternative to topical steroids. But animal data has linked high exposure to lymphoma.

There are no human data to support this as a potential risk, but the FDA, in 2006, added a boxed warning for rare cases of malignancy, he said. "It's a theoretical problem," but has nonetheless dampened enthusiasm for the drugs, said Dr. Ellis.

Even so, he said, in his practice, topical calcineurin inhibitors are not considered anathema. He uses them off label for psoriasis of the face, groin, and genitals; seborrheic dermatitis; pyoderma gangrenosum; mucosal lichen planus; and vitiligo, among other conditions.

When considering use, weigh the potency, the cost, and how long it takes to discuss the potential risks with patients, said Dr. Ellis.

Astellas Pharma, which markets tacrolimus ointment (Protopic) in the United States, is conducting a very long-term safety study of the therapy in children with atopic dermatitis, which might provide answers on the cancer risk, he said.

He disclosed serving as a consultant to Allergan and Ferndale Laboratories.

PALM BEACH, ARUBA – Calcineurin inhibitors – used largely off-label for dermatologic conditions – should become a better-known part of the armamentarium, said Dr. Charles Ellis.

Calcineurin inhibitors work by preventing T-cell activation by blocking calcineurin through its inhibitor immunophilin, said Dr. Ellis, of the University of Michigan, Ann Arbor. Among the drugs in this class are cyclosporine, pimecrolimus, tacrolimus, and a therapy in development, voclosporin. Only pimecrolimus and tacrolimus are available in topical forms.

In the United States, oral cyclosporine is approved for psoriasis but is generally not marketed for the indication, he said. All of the other therapies are used off label, although oral tacrolimus and oral pimecrolimus have been shown to be effective against psoriasis in small studies. The drugs have proved useful for atopic dermatitis, pyoderma gangrenosum, lichen planus, and alopecia areata.

Cyclosporine should not be used for longer than 1 year because it can cause kidney dysfunction, so it is not recommended for psoriasis. And in alopecia, it usually stops working, so he said he generally will not start patients on the drug for this condition.

Voclosporin is being developed for psoriasis by the Canadian company Isotechnika. A phase III trial showed about a 50% improvement in Psoriasis Area and Severity Index (PASI-75) score by week 12; the effect continued through week 24 (Lancet 2008;371:1337-42).

However, patients taking voclosporin had double the rate of headache and gastrointestinal problems as did those on placebo, said Dr. Ellis.

The drug was to be reviewed by a Food and Drug Administration advisory panel in 2010, but the agency cancelled the meeting. In the United States, Isotechnika is seeking approval to treat infectious uveitis; the psoriasis indication is being pursued in Canada. The drug is also in development for prevention of kidney transplant rejection.

Topical calcineurin inhibitors offer a distinct advantage because they do not have the same systemic side effects seen with the oral formulations, said Dr. Ellis.

Pimecrolimus cream and tacrolimus ointment are approved as second-line therapies for short-term chronic treatment of moderate to severe dermatitis in nonimmunocompromised adults and children. They can be used in a standard regimen, with applications up to a week after clearing, or in a proactive regimen, using the topicals until there is clearance, and then applying twice weekly to all affected areas for a year.

Topical calcineurin inhibitors were initially embraced as a potentially safe alternative to topical steroids. But animal data has linked high exposure to lymphoma.

There are no human data to support this as a potential risk, but the FDA, in 2006, added a boxed warning for rare cases of malignancy, he said. "It's a theoretical problem," but has nonetheless dampened enthusiasm for the drugs, said Dr. Ellis.

Even so, he said, in his practice, topical calcineurin inhibitors are not considered anathema. He uses them off label for psoriasis of the face, groin, and genitals; seborrheic dermatitis; pyoderma gangrenosum; mucosal lichen planus; and vitiligo, among other conditions.

When considering use, weigh the potency, the cost, and how long it takes to discuss the potential risks with patients, said Dr. Ellis.

Astellas Pharma, which markets tacrolimus ointment (Protopic) in the United States, is conducting a very long-term safety study of the therapy in children with atopic dermatitis, which might provide answers on the cancer risk, he said.

He disclosed serving as a consultant to Allergan and Ferndale Laboratories.

PALM BEACH, ARUBA – Calcineurin inhibitors – used largely off-label for dermatologic conditions – should become a better-known part of the armamentarium, said Dr. Charles Ellis.

Calcineurin inhibitors work by preventing T-cell activation by blocking calcineurin through its inhibitor immunophilin, said Dr. Ellis, of the University of Michigan, Ann Arbor. Among the drugs in this class are cyclosporine, pimecrolimus, tacrolimus, and a therapy in development, voclosporin. Only pimecrolimus and tacrolimus are available in topical forms.

In the United States, oral cyclosporine is approved for psoriasis but is generally not marketed for the indication, he said. All of the other therapies are used off label, although oral tacrolimus and oral pimecrolimus have been shown to be effective against psoriasis in small studies. The drugs have proved useful for atopic dermatitis, pyoderma gangrenosum, lichen planus, and alopecia areata.

Cyclosporine should not be used for longer than 1 year because it can cause kidney dysfunction, so it is not recommended for psoriasis. And in alopecia, it usually stops working, so he said he generally will not start patients on the drug for this condition.

Voclosporin is being developed for psoriasis by the Canadian company Isotechnika. A phase III trial showed about a 50% improvement in Psoriasis Area and Severity Index (PASI-75) score by week 12; the effect continued through week 24 (Lancet 2008;371:1337-42).

However, patients taking voclosporin had double the rate of headache and gastrointestinal problems as did those on placebo, said Dr. Ellis.

The drug was to be reviewed by a Food and Drug Administration advisory panel in 2010, but the agency cancelled the meeting. In the United States, Isotechnika is seeking approval to treat infectious uveitis; the psoriasis indication is being pursued in Canada. The drug is also in development for prevention of kidney transplant rejection.

Topical calcineurin inhibitors offer a distinct advantage because they do not have the same systemic side effects seen with the oral formulations, said Dr. Ellis.

Pimecrolimus cream and tacrolimus ointment are approved as second-line therapies for short-term chronic treatment of moderate to severe dermatitis in nonimmunocompromised adults and children. They can be used in a standard regimen, with applications up to a week after clearing, or in a proactive regimen, using the topicals until there is clearance, and then applying twice weekly to all affected areas for a year.

Topical calcineurin inhibitors were initially embraced as a potentially safe alternative to topical steroids. But animal data has linked high exposure to lymphoma.

There are no human data to support this as a potential risk, but the FDA, in 2006, added a boxed warning for rare cases of malignancy, he said. "It's a theoretical problem," but has nonetheless dampened enthusiasm for the drugs, said Dr. Ellis.

Even so, he said, in his practice, topical calcineurin inhibitors are not considered anathema. He uses them off label for psoriasis of the face, groin, and genitals; seborrheic dermatitis; pyoderma gangrenosum; mucosal lichen planus; and vitiligo, among other conditions.

When considering use, weigh the potency, the cost, and how long it takes to discuss the potential risks with patients, said Dr. Ellis.

Astellas Pharma, which markets tacrolimus ointment (Protopic) in the United States, is conducting a very long-term safety study of the therapy in children with atopic dermatitis, which might provide answers on the cancer risk, he said.

He disclosed serving as a consultant to Allergan and Ferndale Laboratories.

ORLANDO – The photodynamic therapy protocol that works best on the face is not necessarily the best protocol for the scalp, according to Dr. Amy Forman Taub of Northwestern University in Chicago.

The main indications for PDT are actinic keratoses, acne, and photorejuvenation, but other indications include psoriasis, vulvar neoplasia, methicillin-resistant Staphylococcus aureus, and onychomycosis.

"For long-term cosmesis, nothing stands up like PDT," said Dr. Taub at the Orlando Dermatology Aesthetic and Clinical Conference. She explained her protocols for using PDT for actinic keratoses on different parts of the body.

• Scalp. To treat actinic keratoses on the scalp, Dr. Taub recommended incubation for 60-90 minutes with 5-aminolevulinic acid (5-ALA), followed by exposure to blue light at 2-4 inches for 20 minutes. Next, prescribe emollients for morning use and fluticasone for nighttime use. Check the scalp at 4 weeks. Repeat the PDT protocol after 8 weeks. Check the patient again in 12-16 weeks and biopsy any residual lesions, Dr. Taub said.

• Face. For severe actinic keratoses on the face, Dr. Taub recommended incubation with 5-ALA for 1 hour, followed by exposure to blue light for 16 minutes. Next, instruct the patient to apply zinc oxide sunscreen on top of topical emollients in the morning, and to use topical emollients at night. If 20% or fewer lesions remain at a 4-week follow-up visit, use an alternate therapy. But if more than 20% of the lesions remain, repeat the PDT with 90 minutes of incubation and 1 minute of blue light, Dr. Taub advised.

• Arms and hands. Be sure to elevate the arms so they are 2-4 inches from the light source, Dr. Taub said. She recommended using the push-up handles sold at sporting goods stores to elevate a patient’s arms for more effective PDT. Her preferred protocol for treatment of the arms and hands is to incubate with 5-ALA for 2 hours using Saran Wrap and gloves for occlusion, followed by exposure to blue light for 20 minutes. Repeat the procedure in 4-8 weeks, then examine the patient 12 weeks later and biopsy any residual lesions.

• Legs and feet. When planning PDT for the legs, remove or biopsy any lesions 4 weeks before PDT, said Dr. Taub. She recommended dividing the legs into four quadrants that each take one stick of ALA: upper, lower, anterior, and posterior. Perform the PDT on each quadrant separately, she said. Incubate the area for 2-3 hours, ideally after 1 week of 5-fluorouracil treatment. Next, expose the quadrant to blue light for 20 minutes. Repeat the protocol 8 weeks later, and re-evaluate the patient 12 weeks after the second treatment, she said.

Tricky areas such as the arms, legs, and chest can respond especially well to intense pulsed light (IPL)-PDT, Dr. Taub noted. The cost to the patient is higher, but she has seen dramatic improvements. Another option is to do one IPL-PDT treatment and follow with a blue light treatment if necessary, she said.

Dr. Taub disclosed serving as a consultant and speaker for, and receiving research funding from, DUSA Pharmaceuticals and Syneron.

ORLANDO – The photodynamic therapy protocol that works best on the face is not necessarily the best protocol for the scalp, according to Dr. Amy Forman Taub of Northwestern University in Chicago.

The main indications for PDT are actinic keratoses, acne, and photorejuvenation, but other indications include psoriasis, vulvar neoplasia, methicillin-resistant Staphylococcus aureus, and onychomycosis.

"For long-term cosmesis, nothing stands up like PDT," said Dr. Taub at the Orlando Dermatology Aesthetic and Clinical Conference. She explained her protocols for using PDT for actinic keratoses on different parts of the body.

• Scalp. To treat actinic keratoses on the scalp, Dr. Taub recommended incubation for 60-90 minutes with 5-aminolevulinic acid (5-ALA), followed by exposure to blue light at 2-4 inches for 20 minutes. Next, prescribe emollients for morning use and fluticasone for nighttime use. Check the scalp at 4 weeks. Repeat the PDT protocol after 8 weeks. Check the patient again in 12-16 weeks and biopsy any residual lesions, Dr. Taub said.

• Face. For severe actinic keratoses on the face, Dr. Taub recommended incubation with 5-ALA for 1 hour, followed by exposure to blue light for 16 minutes. Next, instruct the patient to apply zinc oxide sunscreen on top of topical emollients in the morning, and to use topical emollients at night. If 20% or fewer lesions remain at a 4-week follow-up visit, use an alternate therapy. But if more than 20% of the lesions remain, repeat the PDT with 90 minutes of incubation and 1 minute of blue light, Dr. Taub advised.

• Arms and hands. Be sure to elevate the arms so they are 2-4 inches from the light source, Dr. Taub said. She recommended using the push-up handles sold at sporting goods stores to elevate a patient’s arms for more effective PDT. Her preferred protocol for treatment of the arms and hands is to incubate with 5-ALA for 2 hours using Saran Wrap and gloves for occlusion, followed by exposure to blue light for 20 minutes. Repeat the procedure in 4-8 weeks, then examine the patient 12 weeks later and biopsy any residual lesions.

• Legs and feet. When planning PDT for the legs, remove or biopsy any lesions 4 weeks before PDT, said Dr. Taub. She recommended dividing the legs into four quadrants that each take one stick of ALA: upper, lower, anterior, and posterior. Perform the PDT on each quadrant separately, she said. Incubate the area for 2-3 hours, ideally after 1 week of 5-fluorouracil treatment. Next, expose the quadrant to blue light for 20 minutes. Repeat the protocol 8 weeks later, and re-evaluate the patient 12 weeks after the second treatment, she said.

Tricky areas such as the arms, legs, and chest can respond especially well to intense pulsed light (IPL)-PDT, Dr. Taub noted. The cost to the patient is higher, but she has seen dramatic improvements. Another option is to do one IPL-PDT treatment and follow with a blue light treatment if necessary, she said.

Dr. Taub disclosed serving as a consultant and speaker for, and receiving research funding from, DUSA Pharmaceuticals and Syneron.

ORLANDO – The photodynamic therapy protocol that works best on the face is not necessarily the best protocol for the scalp, according to Dr. Amy Forman Taub of Northwestern University in Chicago.

The main indications for PDT are actinic keratoses, acne, and photorejuvenation, but other indications include psoriasis, vulvar neoplasia, methicillin-resistant Staphylococcus aureus, and onychomycosis.

"For long-term cosmesis, nothing stands up like PDT," said Dr. Taub at the Orlando Dermatology Aesthetic and Clinical Conference. She explained her protocols for using PDT for actinic keratoses on different parts of the body.

• Scalp. To treat actinic keratoses on the scalp, Dr. Taub recommended incubation for 60-90 minutes with 5-aminolevulinic acid (5-ALA), followed by exposure to blue light at 2-4 inches for 20 minutes. Next, prescribe emollients for morning use and fluticasone for nighttime use. Check the scalp at 4 weeks. Repeat the PDT protocol after 8 weeks. Check the patient again in 12-16 weeks and biopsy any residual lesions, Dr. Taub said.

• Face. For severe actinic keratoses on the face, Dr. Taub recommended incubation with 5-ALA for 1 hour, followed by exposure to blue light for 16 minutes. Next, instruct the patient to apply zinc oxide sunscreen on top of topical emollients in the morning, and to use topical emollients at night. If 20% or fewer lesions remain at a 4-week follow-up visit, use an alternate therapy. But if more than 20% of the lesions remain, repeat the PDT with 90 minutes of incubation and 1 minute of blue light, Dr. Taub advised.

• Arms and hands. Be sure to elevate the arms so they are 2-4 inches from the light source, Dr. Taub said. She recommended using the push-up handles sold at sporting goods stores to elevate a patient’s arms for more effective PDT. Her preferred protocol for treatment of the arms and hands is to incubate with 5-ALA for 2 hours using Saran Wrap and gloves for occlusion, followed by exposure to blue light for 20 minutes. Repeat the procedure in 4-8 weeks, then examine the patient 12 weeks later and biopsy any residual lesions.

• Legs and feet. When planning PDT for the legs, remove or biopsy any lesions 4 weeks before PDT, said Dr. Taub. She recommended dividing the legs into four quadrants that each take one stick of ALA: upper, lower, anterior, and posterior. Perform the PDT on each quadrant separately, she said. Incubate the area for 2-3 hours, ideally after 1 week of 5-fluorouracil treatment. Next, expose the quadrant to blue light for 20 minutes. Repeat the protocol 8 weeks later, and re-evaluate the patient 12 weeks after the second treatment, she said.

Tricky areas such as the arms, legs, and chest can respond especially well to intense pulsed light (IPL)-PDT, Dr. Taub noted. The cost to the patient is higher, but she has seen dramatic improvements. Another option is to do one IPL-PDT treatment and follow with a blue light treatment if necessary, she said.

Dr. Taub disclosed serving as a consultant and speaker for, and receiving research funding from, DUSA Pharmaceuticals and Syneron.

NEW ORLEANS - The use of tumor necrosis factor inhibitors in psoriasis patients is independently associated with nearly a 50% reduction in MI risk, compared with that of patients not on the biologic agents, a large retrospective cohort study has shown.

In this study of 24,081 psoriasis patients belonging to Kaiser Permanente Southern California, those on TNF inhibitors had an adjusted 48% reduction in the risk of MI during 4 years of follow-up, compared with patients on other therapies. This was the case in a multivariate analysis controlling for traditional cardiovascular risk factors as well as use of statins, beta-blockers, and other medications known to reduce cardiovascular risk, Dr. Jashin J. Wu reported at the annual meeting of the American Academy of Dermatology.

Photo credit: Shane Sato/Elsevier Global Medical News

Previous studies by other investigators have shown that psoriasis is associated with an increased cardiovascular event rate, and that the risk is greatest in those patients having severe skin disease. But in the Kaiser Permanente study, patients on TNF inhibitors had a 44% lower MI risk than patients with mild psoriasis in the multivariate analysis, noted Dr. Wu, a dermatologist at Kaiser Permanente Los Angeles Medical Center.

At baseline, more than half of all the Kaiser psoriasis patients had dyslipidemia, more than half were hypertensive, and 22% had type 2 diabetes. Fully 48% of the 1,877 patients on TNF inhibitors had psoriatic arthritis, as did 21.5% of patients on methotrexate or other oral drugs or phototherapy, and 2.9% of those with mild psoriasis not on these other therapies.

In the multivariate analysis, psoriatic arthritis was independently associated with a 58% increased risk for MI compared with that of psoriasis patients without joint symptoms.

There were 26 MIs in the TNF inhibitor group, 54 in those on oral agents or phototherapy, and 397 in patients with mild psoriasis. This translated into an MI incidence of 268 cases per 100,000 person-years in patients on TNF inhibitors, 373/100,000 in those on oral therapy or phototherapy, and 481/100,000 person-years in patients with mild psoriasis.

Methotrexate has previously been shown to reduce cardiovascular risk. Of note, in this study the use of TNF inhibitors was associated with a significant 41% reduction in MI risk compared with that of methotrexate-treated patients.

Dr. Wu said the likely mechanism of benefit for anti-TNF therapy in terms of reduced MIs in psoriasis patients involves the marked reduction in systemic inflammation achieved with these agents. He noted that etanercept, the most prescribed TNF inhibitor in the Kaiser cohort, has been shown to reduce the elevated C-reactive protein levels present in patients with moderate to severe psoriasis (Br. J. Dermatol. 2008;159:322-30).

Because of its retrospective nature, the Kaiser study doesn't prove causality, Dr. Wu observed. But he added that the results do raise several intriguing questions. For example, if the reduced risk of MI with anti-TNF therapy seen in this large study is real, does the use of these agents in psoriasis patients also reduce their risk of other cardiovascular end points, such as stroke, heart failure, and cardiac death? And do the various TNF inhibitors vary in the degree of cardiovascular risk protection they provide?

The Kaiser study is ongoing, with continuing patient enrollment and follow-up, and further reports are expected in the future.

Dr. Wu disclosed that he has received research funds from Abbott Laboratories and Amgen; however, the Kaiser psoriasis project is wholly funded by Kaiser Permanente.

NEW ORLEANS - The use of tumor necrosis factor inhibitors in psoriasis patients is independently associated with nearly a 50% reduction in MI risk, compared with that of patients not on the biologic agents, a large retrospective cohort study has shown.

In this study of 24,081 psoriasis patients belonging to Kaiser Permanente Southern California, those on TNF inhibitors had an adjusted 48% reduction in the risk of MI during 4 years of follow-up, compared with patients on other therapies. This was the case in a multivariate analysis controlling for traditional cardiovascular risk factors as well as use of statins, beta-blockers, and other medications known to reduce cardiovascular risk, Dr. Jashin J. Wu reported at the annual meeting of the American Academy of Dermatology.

Photo credit: Shane Sato/Elsevier Global Medical News

Previous studies by other investigators have shown that psoriasis is associated with an increased cardiovascular event rate, and that the risk is greatest in those patients having severe skin disease. But in the Kaiser Permanente study, patients on TNF inhibitors had a 44% lower MI risk than patients with mild psoriasis in the multivariate analysis, noted Dr. Wu, a dermatologist at Kaiser Permanente Los Angeles Medical Center.

At baseline, more than half of all the Kaiser psoriasis patients had dyslipidemia, more than half were hypertensive, and 22% had type 2 diabetes. Fully 48% of the 1,877 patients on TNF inhibitors had psoriatic arthritis, as did 21.5% of patients on methotrexate or other oral drugs or phototherapy, and 2.9% of those with mild psoriasis not on these other therapies.

In the multivariate analysis, psoriatic arthritis was independently associated with a 58% increased risk for MI compared with that of psoriasis patients without joint symptoms.

There were 26 MIs in the TNF inhibitor group, 54 in those on oral agents or phototherapy, and 397 in patients with mild psoriasis. This translated into an MI incidence of 268 cases per 100,000 person-years in patients on TNF inhibitors, 373/100,000 in those on oral therapy or phototherapy, and 481/100,000 person-years in patients with mild psoriasis.

Methotrexate has previously been shown to reduce cardiovascular risk. Of note, in this study the use of TNF inhibitors was associated with a significant 41% reduction in MI risk compared with that of methotrexate-treated patients.

Dr. Wu said the likely mechanism of benefit for anti-TNF therapy in terms of reduced MIs in psoriasis patients involves the marked reduction in systemic inflammation achieved with these agents. He noted that etanercept, the most prescribed TNF inhibitor in the Kaiser cohort, has been shown to reduce the elevated C-reactive protein levels present in patients with moderate to severe psoriasis (Br. J. Dermatol. 2008;159:322-30).

Because of its retrospective nature, the Kaiser study doesn't prove causality, Dr. Wu observed. But he added that the results do raise several intriguing questions. For example, if the reduced risk of MI with anti-TNF therapy seen in this large study is real, does the use of these agents in psoriasis patients also reduce their risk of other cardiovascular end points, such as stroke, heart failure, and cardiac death? And do the various TNF inhibitors vary in the degree of cardiovascular risk protection they provide?

The Kaiser study is ongoing, with continuing patient enrollment and follow-up, and further reports are expected in the future.

Dr. Wu disclosed that he has received research funds from Abbott Laboratories and Amgen; however, the Kaiser psoriasis project is wholly funded by Kaiser Permanente.

NEW ORLEANS - The use of tumor necrosis factor inhibitors in psoriasis patients is independently associated with nearly a 50% reduction in MI risk, compared with that of patients not on the biologic agents, a large retrospective cohort study has shown.

In this study of 24,081 psoriasis patients belonging to Kaiser Permanente Southern California, those on TNF inhibitors had an adjusted 48% reduction in the risk of MI during 4 years of follow-up, compared with patients on other therapies. This was the case in a multivariate analysis controlling for traditional cardiovascular risk factors as well as use of statins, beta-blockers, and other medications known to reduce cardiovascular risk, Dr. Jashin J. Wu reported at the annual meeting of the American Academy of Dermatology.

Photo credit: Shane Sato/Elsevier Global Medical News

Previous studies by other investigators have shown that psoriasis is associated with an increased cardiovascular event rate, and that the risk is greatest in those patients having severe skin disease. But in the Kaiser Permanente study, patients on TNF inhibitors had a 44% lower MI risk than patients with mild psoriasis in the multivariate analysis, noted Dr. Wu, a dermatologist at Kaiser Permanente Los Angeles Medical Center.

At baseline, more than half of all the Kaiser psoriasis patients had dyslipidemia, more than half were hypertensive, and 22% had type 2 diabetes. Fully 48% of the 1,877 patients on TNF inhibitors had psoriatic arthritis, as did 21.5% of patients on methotrexate or other oral drugs or phototherapy, and 2.9% of those with mild psoriasis not on these other therapies.

In the multivariate analysis, psoriatic arthritis was independently associated with a 58% increased risk for MI compared with that of psoriasis patients without joint symptoms.

There were 26 MIs in the TNF inhibitor group, 54 in those on oral agents or phototherapy, and 397 in patients with mild psoriasis. This translated into an MI incidence of 268 cases per 100,000 person-years in patients on TNF inhibitors, 373/100,000 in those on oral therapy or phototherapy, and 481/100,000 person-years in patients with mild psoriasis.

Methotrexate has previously been shown to reduce cardiovascular risk. Of note, in this study the use of TNF inhibitors was associated with a significant 41% reduction in MI risk compared with that of methotrexate-treated patients.

Dr. Wu said the likely mechanism of benefit for anti-TNF therapy in terms of reduced MIs in psoriasis patients involves the marked reduction in systemic inflammation achieved with these agents. He noted that etanercept, the most prescribed TNF inhibitor in the Kaiser cohort, has been shown to reduce the elevated C-reactive protein levels present in patients with moderate to severe psoriasis (Br. J. Dermatol. 2008;159:322-30).

Because of its retrospective nature, the Kaiser study doesn't prove causality, Dr. Wu observed. But he added that the results do raise several intriguing questions. For example, if the reduced risk of MI with anti-TNF therapy seen in this large study is real, does the use of these agents in psoriasis patients also reduce their risk of other cardiovascular end points, such as stroke, heart failure, and cardiac death? And do the various TNF inhibitors vary in the degree of cardiovascular risk protection they provide?

The Kaiser study is ongoing, with continuing patient enrollment and follow-up, and further reports are expected in the future.

Dr. Wu disclosed that he has received research funds from Abbott Laboratories and Amgen; however, the Kaiser psoriasis project is wholly funded by Kaiser Permanente.

LAS VEGAS – There are so many psoriasis medications that have been approved or are in the experimental pipeline that it can be hard to track them all.

"I can't even keep them straight," Dr. Craig L. Leonardi said. "It's an amazing time right now."

He mapped out the major trends in psoriasis medications for physicians at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

The armamentarium started off with T-cell inhibitors, the main one being alefacept, said Dr. Leonardi of St. Louis University. "I'm not aware of any other T-cell inhibitors that are in development right now. This seems to be a strategy that has been pushed off to the side for now."

On the other hand, psoriasis drugs involving cytokines and cytokine inhibitors are booming. A few other anti-inflammatory strategies also are being tested, including activation of the sirtuin 1 (SIRT1) protein, an oral phospholipid analog, an oral phosphodiesterase inhibitor, and a drug that inhibits Janus kinase (JAK) 1 and 3.

Cytokines: "Cytokines and cytokine inhibitors are exploding," Dr. Leonardi said. The five approved tumor necrosis factor (TNF) antagonists – adalimumab, certolizumab, etanercept, infliximab, and golimumab – "have great utility," he said.

There are two drugs that block both interleukins (IL) 12 and 23. Ustekinumab is approved, and Abbott Laboratories in January 2011 withdrew its biologics license application for briakinumab to perform additional studies at the request of regulators. These two drugs seem to have a "class effect" associated with increased risk of major cardiovascular events, Dr. Leonardi said.

Two other experimental drugs inhibit just IL-23. "These drugs are not interacting with IL-12 at all. If the cardiovascular signal we have seen with briakinumab and with ustekinumab is real, maybe it has to do with IL-12 more than IL-23. Maybe we'll see an improved safety profile for targeting just IL-23," he said.

Trials are underway of three drugs that inhibit IL-17 and one that targets the IL-17 receptor.

"The IL-23 drugs, IL-17 drugs, and IL-17 receptor blocker drug have a lot of briakinumab/ustekinumab feel in terms of efficacy," Dr. Leonardi said. The studies are blinded, so he doesn't know which patients are getting drug or placebo, but he's noticed that in some patients "amazing things are happening to skin and they're happening fast. This is going to be a great moment for many psoriasis sufferers" if these drugs fulfill the promises he thinks he's glimpsed.

Another trial is studying an IL-22 blocking agent.

In other categories, the novel agents being studied are oral medications, "That's a good thing for those that like that approach, but when you use oral medication, you lose a lot of the specificity that we've come to really expect with our biologic agents," he said.

Resveratrol: This compound is believed to activate SIRT1, which may have anti-inflammatory properties. Preliminary trials are underway.

VB-201: The first drug in its class, VB-201 by Vascular Biogenics is an oral phospholipid analog that downregulates production of proinflammatory cytokines by mature dendritic cells. It inhibits the shared p40 subunit of IL-12 and IL-23, and is in preliminary trials for psoriasis.

Apremilast: An oral inhibitor of type 4 phosphodiesterase (PDE4), apremilast inhibits production of inflammatory cytokines. Its mechanism of action on psoriasis is unclear. "Is it a floor wax or is it a milk shake? I can't decide. How does this drug work?" Dr. Leonardi asked.

Reports from a phase II trial by Celgene, which is developing the drug, suggest that it has multiple effects including reducing TNF-alpha, IL-2, interferon-gamma, and several leukotrienes, he said. In the trial of 260 patients, 24% of patients on a 20-mg b.i.d. dosage achieved a 75% improvement in their Psoriasis Area and Severity Index (PASI 75) score at 12 weeks, compared with 10% of patients on either a 20-mg/day dosage or placebo.

Tasocitinib: Also known as CP-690,550, this is a relatively selective inhibitor of JAK1 and JAK3. In early trials for rheumatoid arthritis, the oral drug appears to decrease inflammatory cytokines and chemokines, and decrease the influx of inflammatory cells, "so that provides a rationale for using it in psoriasis," Dr. Leonardi said.

In a phase II trial, 67% of patients on 15 mg b.i.d. achieved a PASI 75 score at 12 weeks, compared with 41% on 5 mg b.i.d., 25% on 2 mg b.i.d., and 2% on placebo. There were signals of potential safety issues with the drug, however, with a total of five major adverse events, some decreases in hemoglobin levels, transient decreases in polymorphonuclear leukocytes, and dose-related increases in lipids.

"Whether or not these are going to be significant, we'll have to wait and see," Dr. Leonardi said. "At least it showed some promise."

SDEF and this news organization are owned by Elsevier.

Dr. Leonardi declared having potential conflicts of interest with Pfizer (which is developing tasocitinib), Celgene (apremilast), Abbott (briakinumab and adalimumab), Centocor (ustekinumab, infliximab, and golimumab), Amgen (etanercept), Abgenix, Allergan, Alza, Biogen-IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, MedImmune, Miravant, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – There are so many psoriasis medications that have been approved or are in the experimental pipeline that it can be hard to track them all.

"I can't even keep them straight," Dr. Craig L. Leonardi said. "It's an amazing time right now."

He mapped out the major trends in psoriasis medications for physicians at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

The armamentarium started off with T-cell inhibitors, the main one being alefacept, said Dr. Leonardi of St. Louis University. "I'm not aware of any other T-cell inhibitors that are in development right now. This seems to be a strategy that has been pushed off to the side for now."

On the other hand, psoriasis drugs involving cytokines and cytokine inhibitors are booming. A few other anti-inflammatory strategies also are being tested, including activation of the sirtuin 1 (SIRT1) protein, an oral phospholipid analog, an oral phosphodiesterase inhibitor, and a drug that inhibits Janus kinase (JAK) 1 and 3.

Cytokines: "Cytokines and cytokine inhibitors are exploding," Dr. Leonardi said. The five approved tumor necrosis factor (TNF) antagonists – adalimumab, certolizumab, etanercept, infliximab, and golimumab – "have great utility," he said.

There are two drugs that block both interleukins (IL) 12 and 23. Ustekinumab is approved, and Abbott Laboratories in January 2011 withdrew its biologics license application for briakinumab to perform additional studies at the request of regulators. These two drugs seem to have a "class effect" associated with increased risk of major cardiovascular events, Dr. Leonardi said.

Two other experimental drugs inhibit just IL-23. "These drugs are not interacting with IL-12 at all. If the cardiovascular signal we have seen with briakinumab and with ustekinumab is real, maybe it has to do with IL-12 more than IL-23. Maybe we'll see an improved safety profile for targeting just IL-23," he said.

Trials are underway of three drugs that inhibit IL-17 and one that targets the IL-17 receptor.

"The IL-23 drugs, IL-17 drugs, and IL-17 receptor blocker drug have a lot of briakinumab/ustekinumab feel in terms of efficacy," Dr. Leonardi said. The studies are blinded, so he doesn't know which patients are getting drug or placebo, but he's noticed that in some patients "amazing things are happening to skin and they're happening fast. This is going to be a great moment for many psoriasis sufferers" if these drugs fulfill the promises he thinks he's glimpsed.

Another trial is studying an IL-22 blocking agent.

In other categories, the novel agents being studied are oral medications, "That's a good thing for those that like that approach, but when you use oral medication, you lose a lot of the specificity that we've come to really expect with our biologic agents," he said.

Resveratrol: This compound is believed to activate SIRT1, which may have anti-inflammatory properties. Preliminary trials are underway.

VB-201: The first drug in its class, VB-201 by Vascular Biogenics is an oral phospholipid analog that downregulates production of proinflammatory cytokines by mature dendritic cells. It inhibits the shared p40 subunit of IL-12 and IL-23, and is in preliminary trials for psoriasis.

Apremilast: An oral inhibitor of type 4 phosphodiesterase (PDE4), apremilast inhibits production of inflammatory cytokines. Its mechanism of action on psoriasis is unclear. "Is it a floor wax or is it a milk shake? I can't decide. How does this drug work?" Dr. Leonardi asked.

Reports from a phase II trial by Celgene, which is developing the drug, suggest that it has multiple effects including reducing TNF-alpha, IL-2, interferon-gamma, and several leukotrienes, he said. In the trial of 260 patients, 24% of patients on a 20-mg b.i.d. dosage achieved a 75% improvement in their Psoriasis Area and Severity Index (PASI 75) score at 12 weeks, compared with 10% of patients on either a 20-mg/day dosage or placebo.

Tasocitinib: Also known as CP-690,550, this is a relatively selective inhibitor of JAK1 and JAK3. In early trials for rheumatoid arthritis, the oral drug appears to decrease inflammatory cytokines and chemokines, and decrease the influx of inflammatory cells, "so that provides a rationale for using it in psoriasis," Dr. Leonardi said.

In a phase II trial, 67% of patients on 15 mg b.i.d. achieved a PASI 75 score at 12 weeks, compared with 41% on 5 mg b.i.d., 25% on 2 mg b.i.d., and 2% on placebo. There were signals of potential safety issues with the drug, however, with a total of five major adverse events, some decreases in hemoglobin levels, transient decreases in polymorphonuclear leukocytes, and dose-related increases in lipids.

"Whether or not these are going to be significant, we'll have to wait and see," Dr. Leonardi said. "At least it showed some promise."

SDEF and this news organization are owned by Elsevier.

Dr. Leonardi declared having potential conflicts of interest with Pfizer (which is developing tasocitinib), Celgene (apremilast), Abbott (briakinumab and adalimumab), Centocor (ustekinumab, infliximab, and golimumab), Amgen (etanercept), Abgenix, Allergan, Alza, Biogen-IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, MedImmune, Miravant, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – There are so many psoriasis medications that have been approved or are in the experimental pipeline that it can be hard to track them all.

"I can't even keep them straight," Dr. Craig L. Leonardi said. "It's an amazing time right now."

He mapped out the major trends in psoriasis medications for physicians at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

The armamentarium started off with T-cell inhibitors, the main one being alefacept, said Dr. Leonardi of St. Louis University. "I'm not aware of any other T-cell inhibitors that are in development right now. This seems to be a strategy that has been pushed off to the side for now."

On the other hand, psoriasis drugs involving cytokines and cytokine inhibitors are booming. A few other anti-inflammatory strategies also are being tested, including activation of the sirtuin 1 (SIRT1) protein, an oral phospholipid analog, an oral phosphodiesterase inhibitor, and a drug that inhibits Janus kinase (JAK) 1 and 3.

Cytokines: "Cytokines and cytokine inhibitors are exploding," Dr. Leonardi said. The five approved tumor necrosis factor (TNF) antagonists – adalimumab, certolizumab, etanercept, infliximab, and golimumab – "have great utility," he said.

There are two drugs that block both interleukins (IL) 12 and 23. Ustekinumab is approved, and Abbott Laboratories in January 2011 withdrew its biologics license application for briakinumab to perform additional studies at the request of regulators. These two drugs seem to have a "class effect" associated with increased risk of major cardiovascular events, Dr. Leonardi said.

Two other experimental drugs inhibit just IL-23. "These drugs are not interacting with IL-12 at all. If the cardiovascular signal we have seen with briakinumab and with ustekinumab is real, maybe it has to do with IL-12 more than IL-23. Maybe we'll see an improved safety profile for targeting just IL-23," he said.

Trials are underway of three drugs that inhibit IL-17 and one that targets the IL-17 receptor.

"The IL-23 drugs, IL-17 drugs, and IL-17 receptor blocker drug have a lot of briakinumab/ustekinumab feel in terms of efficacy," Dr. Leonardi said. The studies are blinded, so he doesn't know which patients are getting drug or placebo, but he's noticed that in some patients "amazing things are happening to skin and they're happening fast. This is going to be a great moment for many psoriasis sufferers" if these drugs fulfill the promises he thinks he's glimpsed.

Another trial is studying an IL-22 blocking agent.

In other categories, the novel agents being studied are oral medications, "That's a good thing for those that like that approach, but when you use oral medication, you lose a lot of the specificity that we've come to really expect with our biologic agents," he said.

Resveratrol: This compound is believed to activate SIRT1, which may have anti-inflammatory properties. Preliminary trials are underway.

VB-201: The first drug in its class, VB-201 by Vascular Biogenics is an oral phospholipid analog that downregulates production of proinflammatory cytokines by mature dendritic cells. It inhibits the shared p40 subunit of IL-12 and IL-23, and is in preliminary trials for psoriasis.

Apremilast: An oral inhibitor of type 4 phosphodiesterase (PDE4), apremilast inhibits production of inflammatory cytokines. Its mechanism of action on psoriasis is unclear. "Is it a floor wax or is it a milk shake? I can't decide. How does this drug work?" Dr. Leonardi asked.

Reports from a phase II trial by Celgene, which is developing the drug, suggest that it has multiple effects including reducing TNF-alpha, IL-2, interferon-gamma, and several leukotrienes, he said. In the trial of 260 patients, 24% of patients on a 20-mg b.i.d. dosage achieved a 75% improvement in their Psoriasis Area and Severity Index (PASI 75) score at 12 weeks, compared with 10% of patients on either a 20-mg/day dosage or placebo.

Tasocitinib: Also known as CP-690,550, this is a relatively selective inhibitor of JAK1 and JAK3. In early trials for rheumatoid arthritis, the oral drug appears to decrease inflammatory cytokines and chemokines, and decrease the influx of inflammatory cells, "so that provides a rationale for using it in psoriasis," Dr. Leonardi said.

In a phase II trial, 67% of patients on 15 mg b.i.d. achieved a PASI 75 score at 12 weeks, compared with 41% on 5 mg b.i.d., 25% on 2 mg b.i.d., and 2% on placebo. There were signals of potential safety issues with the drug, however, with a total of five major adverse events, some decreases in hemoglobin levels, transient decreases in polymorphonuclear leukocytes, and dose-related increases in lipids.

"Whether or not these are going to be significant, we'll have to wait and see," Dr. Leonardi said. "At least it showed some promise."

SDEF and this news organization are owned by Elsevier.

Dr. Leonardi declared having potential conflicts of interest with Pfizer (which is developing tasocitinib), Celgene (apremilast), Abbott (briakinumab and adalimumab), Centocor (ustekinumab, infliximab, and golimumab), Amgen (etanercept), Abgenix, Allergan, Alza, Biogen-IDEC, Boehringer-Ingelheim, Bristol-Myers Squibb, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, MedImmune, Miravant, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.

LAS VEGAS – Increased risk for major cardiovascular events may be a "class effect" associated with two monoclonal antibody therapies for psoriasis, Dr. Craig Leonardi said.

"I used to give them a pass on this, but no more. I'm going to point out a few things that bother me," he said at a dermatology seminar sponsored by Skin Disease Education Foundation (SDEF).

Ustekinumab, which is approved to treat adults with moderate to severe plaque psoriasis, and the investigational psoriasis drug briakinumab inhibit interleukin 12 (IL-12) and IL-23 proteins linked to inflammation. Conventional thought holds that reducing systemic inflammation should decrease cardiovascular risk, but ustekinumab and briakinumab have been associated with an increase in major cardiovascular events in clinical trials, said Dr. Leonardi, a dermatologist and psoriasis specialist at St. Louis University.

(Abbott Laboratories pulled briakinumab from the drug approval process in the United States and Europe in a financial filing on Jan. 14.)

He recently conducted a meta-analysis summarizing major cardiovascular events during the placebo-controlled portions of 19 trials encompassing all the biologic therapies for psoriasis. Only one patient on placebo developed a major cardiovascular event in a study of etanercept. Five patients on ustekinumab, five on briakinumab, and one on adalimumab developed major cardiovascular events.

In a separate look at Phase III trials data on ustekinumab, adverse events included chest pain in one patient on placebo, a case of angina, and a case of stroke in patients on low-dose therapy (45 mg). On high-dose therapy (90 mg) one patient developed congestive cardiomyopathy and died and another required a coronary artery bypass graft, he noted.

"I think there's a bit of an imbalance when I look at these data" in major cardiovascular events, he said.

In data on 3,117 patients followed for 3 years or less, the risk for major cardiovascular events (MI, stroke, or death from cardiovascular causes) seemed to be higher on ustekinumab during the initial 12-week placebo-controlled portions of the study but the risk leveled out between groups over time, Dr. Leonardi said.

During the controlled period, the incidence of major cardiovascular events was 0 per 100 patient-years in the placebo group, 0.98/100 patient-years on low-dose ustekinumab, and 1.47/100 patient-years on high-dose ustekinumab. Over the 3-year period, the incidence was 0.55, 0.41, and 0.35 per 100 patient-years, respectively.

Even in Phase II trial data on ustekinumab there was a potential "signal" of increased risk for major cardiovascular events, Dr. Leonardi added. Looking at data from all trials of ustekinumab for any indication (not just psoriasis), there's a "flurry" of major cardiovascular events early in treatment that then settles down and becomes comparable to the placebo group over time.

"The statisticians will say that there's no statistically significant difference between the treated versus the placebo" in major cardiovascular events, "but I don't think we have to be a rocket scientist to see that there’s something very different going on" between groups, Dr. Leonardi said.

Safety data from the placebo-controlled periods in phase III data on briakinumab suggest even greater problems. "The news here, quite frankly, is not good," he said.

There were three MIs, one cardiac arrest, and a stroke in 981 patients on briakinumab, compared with none in 484 patients on placebo. In addition, five patients on briakinumab and one on placebo developed serious infections requiring hospitalization and IV antibiotics. Six patients on briakinumab and none on placebo developed malignancies, all of them squamous cell carcinomas of the skin, lung, or nasopharynx.

"Cancers usually take months or years to show up, and yet these showed up in the first 12 weeks" on treatment," he noted.

The combination of increased risks for major cardiovascular events, malignancies, and infections with briakinumab is "unprecedented," he said. "We should pay close attention to this data."

Both drugs can boast "impressive" efficacy in treating plaque psoriasis, but the potential risks need to be carefully considered, Dr. Leonardi said.

He recommends considering all options when selecting a biologic treatment for psoriasis, even if patients request the treatment they only have to get every 3 months. Remember that patients with psoriasis typically have multiple cardiac risk factors. If ustekinumab is used, start with a low dose regardless of the patient’s weight, Dr. Leonardi advised.

"Consider adding low-dose aspirin, 81 mg per day," he added. "That's what I’m doing."

Analyses underway by the Food and Drug Administration and the drug companies should provide further insights into the potential risks and benefits of these drugs.

"Remember that all new drugs are new," Dr. Leonardi cautioned. "We don't know everything we need to know about new drugs, especially when there's a new mechanism of action."

He speculated that the monoclonal antibody therapies increase major cardiovascular events by increasing delivery of IL-12 and IL-23 to atherosclerotic plaques, or perhaps the p40 subunits of IL-12 and IL-23 form dimers that become bioactive. Or, some unknown biologic activity could be at play.

SDEF and this news organization are owned by Elsevier. Dr. Leonardi declared having potential conflicts of interest with Abbott and Centocor, which manufacture briakinumab and ustekinumab, and with Abgenix, Allergan, Alza, Amgen, Biogen-IDEC, Boehringer-Ingelheim, Bristol Myers Squibb, Celgene, Connetics, Corixa, Fujisawa, Galderma, Genentech, Genzyme, GSK, Incyte, Isis, Lilly, Medimmune, Miravant, Pfizer, Schering Plough, Serono, Synta, Wyeth, and Xoma.