Rash Pattern, Duration ID Hereditary Periodic Fever Syndromes

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.