Giant-Cell Arteritis May Underlie New Headache

OJAI, CA—Headache specialists may play an important role in diagnosing giant-cell arteritis, a vasculitis of large and medium vessels, because new headache is the initial symptom in about a third of cases, according to a lecture provided at the Ninth Annual Headache Cooperative of the Pacific Winter Conference. Early treatment with corticosteroids can help prevent permanent visual loss in this disorder. “If you strongly suspect the diagnosis, start prednisone and then proceed, in terms of trying to confirm the diagnosis,” said Jerry W. Swanson, MD, Professor of Neurology at the Mayo Clinic College of Medicine in Rochester, Minnesota. “If there have been any ischemic complications, which most commonly would affect the eye, therapy should be started immediately.”

Diagnosing giant-cell arteritis without sufficient evidence, however, can subject patients to the risks of long-term steroid use unnecessarily, he noted.

A Feared Complication

In the United States, an estimated 1% of women and 0.5% of men develop giant-cell arteritis. Prevalence is estimated to be one in 500 individuals over age 50, and peak incidence is in the 70s. “You virtually never see this before the age of 50,” said Dr. Swanson. The disorder has a genetic component and is most common in individuals of Scandinavian descent.

Research indicates that giant-cell arteritis “is an immunologic, not an infectious, problem,” said Dr. Swanson. The pathophysiology of the disease appears to involve dendritic cells in the vessel wall, which initiate a cascade of events that involves two major immune-response networks and leads to lumen-obstructive intimal hyperplasia and remodeling of the arterial wall.

Permanent visual loss is the most frequent and feared complication. It occurs in about 20% of patients. Transient monocular, and rarely binocular, vision loss can be an early manifestation of the disorder. This transient visual loss may soon be followed by permanent visual loss. The usual mechanism of visual loss is anterior ischemic optic neuropathy.

Headache Features Have Limited Use

The diagnosis of giant-cell arteritis should be considered in a patient age 50 or older with new headaches, abrupt onset of visual disturbances, symptoms of polymyalgia rheumatica, or jaw claudication. Systemic symptoms such as low-grade fever and anemia may arise, as well as high erythrocyte sedimentation rate or high serum C-reactive protein.

Headache is the most common symptom, occurring in almost three-quarters of patients. The headaches typically are acute or subacute and are associated with scalp tenderness near the temporal or occipital arteries. The headache features otherwise are not particularly helpful. “The headaches have been described as persistent or remittent, and they can resemble primary headache disorders just as cardiac cephalalgia can,” said Dr. Swanson. Features similar to migraine, cluster headache, or idiopathic stabbing headache have been described.

Jaw claudication is highly specific for giant-cell arteritis. Persistent dry cough and manifestations such as sore throat, tongue pain, trismus, and choking also have been described. Audiovestibular manifestations are fairly common, and polymyalgia rheumatica is present in 40% to 50% of patients with giant-cell arteritis.

Ophthalmologic exam can be normal, although some patients have cotton wool spots in the retina, suggesting retinal ischemia. Physicians should carefully examine the superficial temporal arteries for tenderness, absent pulsations, or marked prominence of the arteries.

Screening Test of Choice

Elevated erythrocyte sedimentation rate is one of the major hallmarks of giant-cell arteritis and “the screening test of choice,” said Dr. Swanson. In a series of more than 940 biopsy-proven cases, only 4% of patients had a normal sedimentation rate. “If the [sedimentation] rate is normal, still consider the diagnosis if clinical features are present, but it’s much less likely,” he said.

Although imperfect, temporal artery biopsy is the gold standard for diagnosing giant-cell arteritis. “Unfortunately, attempts to develop an algorithm that would say, ‘If they have a certain score, for instance, then do a biopsy or not,’ have failed,” he said. “You have to take the entire picture and then develop some sort of index of suspicion.”

Of all patients suspected of giant-cell arteritis, about a third of biopsies are positive. Positive yield increases if biopsies are 2 cm or longer. There is no clear consensus on whether to biopsy the temporal artery on one or both sides. At the Mayo Clinic, surgical pathologists often biopsy the side that is more symptomatic. Surgeons have the patient remain and may biopsy the other side if the first biopsy is negative and there is a high index of suspicion. “I realize that may not be possible at most institutions, but it seems to be a prudent approach,” Dr. Swanson said.

Younge et al found that certain factors and combinations of factors could be highly predictive of temporal artery biopsy results, including jaw claudication, new headache, scalp tenderness, and decreased vision.

In one series, approximately 9% of patients with negative biopsy subsequently were diagnosed with giant-cell arteritis, “so that unfortunately can occur.” One variant of giant-cell arteritis tends to affect the large vessels leaving the aorta and to spare the temporal arteries, which could lead to a negative biopsy. The most common cause of a negative biopsy, however, is that “it is a different diagnosis.”

“If the biopsy is negative, but you suspect this [disorder] very, very strongly, then continue the treatment because then there should be a marked improvement in symptoms within a week.” As this is an autoimmune disorder, consultation with a rheumatologist is usually helpful.

Imaging studies are not part of routine testing, but FDG PET may be useful in making the diagnosis.

Old and New Therapies

The FDA has not approved medications specifically for giant-cell arteritis. The mainstay of treatment is corticosteroids. Rheumatologists principally treat giant-cell arteritis, and neurologists should involve them early in the process, Dr. Swanson said.

Low-dose aspirin is frequently added for its antiplatelet effect, and this practice is supported by observational studies. Follow-up includes monitoring and treating the effects of glucocorticoids. Once glucocorticoid therapy is initiated, the risk of blindness is estimated to be about 1%.

To avoid corticosteroid or glucocorticoid adverse effects, such as osteopenia and bone fracture, methotrexate has been used. Three studies using methotrexate have shown reductions in the cumulative dose of glucocorticoid over 48 weeks and a reduced risk of relapse after prednisone is stopped. It takes 24 to 36 weeks for methotrexate to have its full anti-immune effect, Dr. Swanson noted.

Several case series have reported that tocilizumab, a humanized monoclonal antibody that targets interleukin 6, may be effective in patients in whom it has been difficult to taper glucocorticoids to an acceptable level or who have had refractory or relapsing disease. Controlled trials of this drug are under way, and “it will be important to have those results to know if this [drug] is in fact worthwhile,” Dr. Swanson said.

Results from a randomized, double-blind, placebo-controlled trial of tocilizumab in giant-cell arteritis were published online ahead of print March 4 in Lancet. In the phase II trial, 20 patients received IV tocilizumab and 10 patients received placebo infusions at four-week intervals for a year. Both groups received oral prednisolone. At 12 weeks, 85% of patients in the tocilizumab group achieved complete remission of disease, compared with 40% of patients in the placebo group. By 52 weeks, 85% of patients in the tocilizumab group achieved relapse-free survival, compared with 20% in the placebo group. The mean cumulative prednisolone dose was 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group. Rates of serious adverse events were higher in the placebo group than in the active treatment group. These preliminary results suggest that tocilizumab may become an important new management tool, Dr. Swanson said.

Cyclophosphamide has been used in patients at high risk of glucocorticoid-related adverse effects who have not responded adequately to other agents. In a meta-analysis of 88 cases, 84% of patients responded to cyclophosphamide, but 19% relapsed and 2.5% discontinued the therapy because of adverse effects.

Several other potential treatments may be on the horizon, including abatacept, a novel fusion protein that consists of cytotoxic T lymphocyte antigen (CTLA) linked to a modified heavy-chain constant region of human immunoglobulin G1; anakinra, which blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting IL-1 binding to the IL-1 type I receptor; and gevokizumab, a humanized anti-IL-1β monoclonal antibody. Randomized trials have found that tumor necrosis factor inhibition therapies, including infliximab, etanercept, and adalimumab, are not effective in giant-cell arteritis.

—Jake Remaly

OJAI, CA—Headache specialists may play an important role in diagnosing giant-cell arteritis, a vasculitis of large and medium vessels, because new headache is the initial symptom in about a third of cases, according to a lecture provided at the Ninth Annual Headache Cooperative of the Pacific Winter Conference. Early treatment with corticosteroids can help prevent permanent visual loss in this disorder. “If you strongly suspect the diagnosis, start prednisone and then proceed, in terms of trying to confirm the diagnosis,” said Jerry W. Swanson, MD, Professor of Neurology at the Mayo Clinic College of Medicine in Rochester, Minnesota. “If there have been any ischemic complications, which most commonly would affect the eye, therapy should be started immediately.”

Diagnosing giant-cell arteritis without sufficient evidence, however, can subject patients to the risks of long-term steroid use unnecessarily, he noted.

A Feared Complication

In the United States, an estimated 1% of women and 0.5% of men develop giant-cell arteritis. Prevalence is estimated to be one in 500 individuals over age 50, and peak incidence is in the 70s. “You virtually never see this before the age of 50,” said Dr. Swanson. The disorder has a genetic component and is most common in individuals of Scandinavian descent.

Research indicates that giant-cell arteritis “is an immunologic, not an infectious, problem,” said Dr. Swanson. The pathophysiology of the disease appears to involve dendritic cells in the vessel wall, which initiate a cascade of events that involves two major immune-response networks and leads to lumen-obstructive intimal hyperplasia and remodeling of the arterial wall.

Permanent visual loss is the most frequent and feared complication. It occurs in about 20% of patients. Transient monocular, and rarely binocular, vision loss can be an early manifestation of the disorder. This transient visual loss may soon be followed by permanent visual loss. The usual mechanism of visual loss is anterior ischemic optic neuropathy.

Headache Features Have Limited Use

The diagnosis of giant-cell arteritis should be considered in a patient age 50 or older with new headaches, abrupt onset of visual disturbances, symptoms of polymyalgia rheumatica, or jaw claudication. Systemic symptoms such as low-grade fever and anemia may arise, as well as high erythrocyte sedimentation rate or high serum C-reactive protein.

Headache is the most common symptom, occurring in almost three-quarters of patients. The headaches typically are acute or subacute and are associated with scalp tenderness near the temporal or occipital arteries. The headache features otherwise are not particularly helpful. “The headaches have been described as persistent or remittent, and they can resemble primary headache disorders just as cardiac cephalalgia can,” said Dr. Swanson. Features similar to migraine, cluster headache, or idiopathic stabbing headache have been described.

Jaw claudication is highly specific for giant-cell arteritis. Persistent dry cough and manifestations such as sore throat, tongue pain, trismus, and choking also have been described. Audiovestibular manifestations are fairly common, and polymyalgia rheumatica is present in 40% to 50% of patients with giant-cell arteritis.

Ophthalmologic exam can be normal, although some patients have cotton wool spots in the retina, suggesting retinal ischemia. Physicians should carefully examine the superficial temporal arteries for tenderness, absent pulsations, or marked prominence of the arteries.

Screening Test of Choice

Elevated erythrocyte sedimentation rate is one of the major hallmarks of giant-cell arteritis and “the screening test of choice,” said Dr. Swanson. In a series of more than 940 biopsy-proven cases, only 4% of patients had a normal sedimentation rate. “If the [sedimentation] rate is normal, still consider the diagnosis if clinical features are present, but it’s much less likely,” he said.

Although imperfect, temporal artery biopsy is the gold standard for diagnosing giant-cell arteritis. “Unfortunately, attempts to develop an algorithm that would say, ‘If they have a certain score, for instance, then do a biopsy or not,’ have failed,” he said. “You have to take the entire picture and then develop some sort of index of suspicion.”

Of all patients suspected of giant-cell arteritis, about a third of biopsies are positive. Positive yield increases if biopsies are 2 cm or longer. There is no clear consensus on whether to biopsy the temporal artery on one or both sides. At the Mayo Clinic, surgical pathologists often biopsy the side that is more symptomatic. Surgeons have the patient remain and may biopsy the other side if the first biopsy is negative and there is a high index of suspicion. “I realize that may not be possible at most institutions, but it seems to be a prudent approach,” Dr. Swanson said.

Younge et al found that certain factors and combinations of factors could be highly predictive of temporal artery biopsy results, including jaw claudication, new headache, scalp tenderness, and decreased vision.

In one series, approximately 9% of patients with negative biopsy subsequently were diagnosed with giant-cell arteritis, “so that unfortunately can occur.” One variant of giant-cell arteritis tends to affect the large vessels leaving the aorta and to spare the temporal arteries, which could lead to a negative biopsy. The most common cause of a negative biopsy, however, is that “it is a different diagnosis.”

“If the biopsy is negative, but you suspect this [disorder] very, very strongly, then continue the treatment because then there should be a marked improvement in symptoms within a week.” As this is an autoimmune disorder, consultation with a rheumatologist is usually helpful.

Imaging studies are not part of routine testing, but FDG PET may be useful in making the diagnosis.

Old and New Therapies

The FDA has not approved medications specifically for giant-cell arteritis. The mainstay of treatment is corticosteroids. Rheumatologists principally treat giant-cell arteritis, and neurologists should involve them early in the process, Dr. Swanson said.

Low-dose aspirin is frequently added for its antiplatelet effect, and this practice is supported by observational studies. Follow-up includes monitoring and treating the effects of glucocorticoids. Once glucocorticoid therapy is initiated, the risk of blindness is estimated to be about 1%.

To avoid corticosteroid or glucocorticoid adverse effects, such as osteopenia and bone fracture, methotrexate has been used. Three studies using methotrexate have shown reductions in the cumulative dose of glucocorticoid over 48 weeks and a reduced risk of relapse after prednisone is stopped. It takes 24 to 36 weeks for methotrexate to have its full anti-immune effect, Dr. Swanson noted.

Several case series have reported that tocilizumab, a humanized monoclonal antibody that targets interleukin 6, may be effective in patients in whom it has been difficult to taper glucocorticoids to an acceptable level or who have had refractory or relapsing disease. Controlled trials of this drug are under way, and “it will be important to have those results to know if this [drug] is in fact worthwhile,” Dr. Swanson said.

Results from a randomized, double-blind, placebo-controlled trial of tocilizumab in giant-cell arteritis were published online ahead of print March 4 in Lancet. In the phase II trial, 20 patients received IV tocilizumab and 10 patients received placebo infusions at four-week intervals for a year. Both groups received oral prednisolone. At 12 weeks, 85% of patients in the tocilizumab group achieved complete remission of disease, compared with 40% of patients in the placebo group. By 52 weeks, 85% of patients in the tocilizumab group achieved relapse-free survival, compared with 20% in the placebo group. The mean cumulative prednisolone dose was 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group. Rates of serious adverse events were higher in the placebo group than in the active treatment group. These preliminary results suggest that tocilizumab may become an important new management tool, Dr. Swanson said.

Cyclophosphamide has been used in patients at high risk of glucocorticoid-related adverse effects who have not responded adequately to other agents. In a meta-analysis of 88 cases, 84% of patients responded to cyclophosphamide, but 19% relapsed and 2.5% discontinued the therapy because of adverse effects.

Several other potential treatments may be on the horizon, including abatacept, a novel fusion protein that consists of cytotoxic T lymphocyte antigen (CTLA) linked to a modified heavy-chain constant region of human immunoglobulin G1; anakinra, which blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting IL-1 binding to the IL-1 type I receptor; and gevokizumab, a humanized anti-IL-1β monoclonal antibody. Randomized trials have found that tumor necrosis factor inhibition therapies, including infliximab, etanercept, and adalimumab, are not effective in giant-cell arteritis.

—Jake Remaly

OJAI, CA—Headache specialists may play an important role in diagnosing giant-cell arteritis, a vasculitis of large and medium vessels, because new headache is the initial symptom in about a third of cases, according to a lecture provided at the Ninth Annual Headache Cooperative of the Pacific Winter Conference. Early treatment with corticosteroids can help prevent permanent visual loss in this disorder. “If you strongly suspect the diagnosis, start prednisone and then proceed, in terms of trying to confirm the diagnosis,” said Jerry W. Swanson, MD, Professor of Neurology at the Mayo Clinic College of Medicine in Rochester, Minnesota. “If there have been any ischemic complications, which most commonly would affect the eye, therapy should be started immediately.”

Diagnosing giant-cell arteritis without sufficient evidence, however, can subject patients to the risks of long-term steroid use unnecessarily, he noted.

A Feared Complication

In the United States, an estimated 1% of women and 0.5% of men develop giant-cell arteritis. Prevalence is estimated to be one in 500 individuals over age 50, and peak incidence is in the 70s. “You virtually never see this before the age of 50,” said Dr. Swanson. The disorder has a genetic component and is most common in individuals of Scandinavian descent.

Research indicates that giant-cell arteritis “is an immunologic, not an infectious, problem,” said Dr. Swanson. The pathophysiology of the disease appears to involve dendritic cells in the vessel wall, which initiate a cascade of events that involves two major immune-response networks and leads to lumen-obstructive intimal hyperplasia and remodeling of the arterial wall.

Permanent visual loss is the most frequent and feared complication. It occurs in about 20% of patients. Transient monocular, and rarely binocular, vision loss can be an early manifestation of the disorder. This transient visual loss may soon be followed by permanent visual loss. The usual mechanism of visual loss is anterior ischemic optic neuropathy.

Headache Features Have Limited Use

The diagnosis of giant-cell arteritis should be considered in a patient age 50 or older with new headaches, abrupt onset of visual disturbances, symptoms of polymyalgia rheumatica, or jaw claudication. Systemic symptoms such as low-grade fever and anemia may arise, as well as high erythrocyte sedimentation rate or high serum C-reactive protein.

Headache is the most common symptom, occurring in almost three-quarters of patients. The headaches typically are acute or subacute and are associated with scalp tenderness near the temporal or occipital arteries. The headache features otherwise are not particularly helpful. “The headaches have been described as persistent or remittent, and they can resemble primary headache disorders just as cardiac cephalalgia can,” said Dr. Swanson. Features similar to migraine, cluster headache, or idiopathic stabbing headache have been described.

Jaw claudication is highly specific for giant-cell arteritis. Persistent dry cough and manifestations such as sore throat, tongue pain, trismus, and choking also have been described. Audiovestibular manifestations are fairly common, and polymyalgia rheumatica is present in 40% to 50% of patients with giant-cell arteritis.

Ophthalmologic exam can be normal, although some patients have cotton wool spots in the retina, suggesting retinal ischemia. Physicians should carefully examine the superficial temporal arteries for tenderness, absent pulsations, or marked prominence of the arteries.

Screening Test of Choice

Elevated erythrocyte sedimentation rate is one of the major hallmarks of giant-cell arteritis and “the screening test of choice,” said Dr. Swanson. In a series of more than 940 biopsy-proven cases, only 4% of patients had a normal sedimentation rate. “If the [sedimentation] rate is normal, still consider the diagnosis if clinical features are present, but it’s much less likely,” he said.

Although imperfect, temporal artery biopsy is the gold standard for diagnosing giant-cell arteritis. “Unfortunately, attempts to develop an algorithm that would say, ‘If they have a certain score, for instance, then do a biopsy or not,’ have failed,” he said. “You have to take the entire picture and then develop some sort of index of suspicion.”

Of all patients suspected of giant-cell arteritis, about a third of biopsies are positive. Positive yield increases if biopsies are 2 cm or longer. There is no clear consensus on whether to biopsy the temporal artery on one or both sides. At the Mayo Clinic, surgical pathologists often biopsy the side that is more symptomatic. Surgeons have the patient remain and may biopsy the other side if the first biopsy is negative and there is a high index of suspicion. “I realize that may not be possible at most institutions, but it seems to be a prudent approach,” Dr. Swanson said.

Younge et al found that certain factors and combinations of factors could be highly predictive of temporal artery biopsy results, including jaw claudication, new headache, scalp tenderness, and decreased vision.

In one series, approximately 9% of patients with negative biopsy subsequently were diagnosed with giant-cell arteritis, “so that unfortunately can occur.” One variant of giant-cell arteritis tends to affect the large vessels leaving the aorta and to spare the temporal arteries, which could lead to a negative biopsy. The most common cause of a negative biopsy, however, is that “it is a different diagnosis.”

“If the biopsy is negative, but you suspect this [disorder] very, very strongly, then continue the treatment because then there should be a marked improvement in symptoms within a week.” As this is an autoimmune disorder, consultation with a rheumatologist is usually helpful.

Imaging studies are not part of routine testing, but FDG PET may be useful in making the diagnosis.

Old and New Therapies

The FDA has not approved medications specifically for giant-cell arteritis. The mainstay of treatment is corticosteroids. Rheumatologists principally treat giant-cell arteritis, and neurologists should involve them early in the process, Dr. Swanson said.

Low-dose aspirin is frequently added for its antiplatelet effect, and this practice is supported by observational studies. Follow-up includes monitoring and treating the effects of glucocorticoids. Once glucocorticoid therapy is initiated, the risk of blindness is estimated to be about 1%.

To avoid corticosteroid or glucocorticoid adverse effects, such as osteopenia and bone fracture, methotrexate has been used. Three studies using methotrexate have shown reductions in the cumulative dose of glucocorticoid over 48 weeks and a reduced risk of relapse after prednisone is stopped. It takes 24 to 36 weeks for methotrexate to have its full anti-immune effect, Dr. Swanson noted.

Several case series have reported that tocilizumab, a humanized monoclonal antibody that targets interleukin 6, may be effective in patients in whom it has been difficult to taper glucocorticoids to an acceptable level or who have had refractory or relapsing disease. Controlled trials of this drug are under way, and “it will be important to have those results to know if this [drug] is in fact worthwhile,” Dr. Swanson said.

Results from a randomized, double-blind, placebo-controlled trial of tocilizumab in giant-cell arteritis were published online ahead of print March 4 in Lancet. In the phase II trial, 20 patients received IV tocilizumab and 10 patients received placebo infusions at four-week intervals for a year. Both groups received oral prednisolone. At 12 weeks, 85% of patients in the tocilizumab group achieved complete remission of disease, compared with 40% of patients in the placebo group. By 52 weeks, 85% of patients in the tocilizumab group achieved relapse-free survival, compared with 20% in the placebo group. The mean cumulative prednisolone dose was 43 mg/kg in the tocilizumab group versus 110 mg/kg in the placebo group. Rates of serious adverse events were higher in the placebo group than in the active treatment group. These preliminary results suggest that tocilizumab may become an important new management tool, Dr. Swanson said.

Cyclophosphamide has been used in patients at high risk of glucocorticoid-related adverse effects who have not responded adequately to other agents. In a meta-analysis of 88 cases, 84% of patients responded to cyclophosphamide, but 19% relapsed and 2.5% discontinued the therapy because of adverse effects.

Several other potential treatments may be on the horizon, including abatacept, a novel fusion protein that consists of cytotoxic T lymphocyte antigen (CTLA) linked to a modified heavy-chain constant region of human immunoglobulin G1; anakinra, which blocks the biologic activity of interleukin-1 (IL-1) by competitively inhibiting IL-1 binding to the IL-1 type I receptor; and gevokizumab, a humanized anti-IL-1β monoclonal antibody. Randomized trials have found that tumor necrosis factor inhibition therapies, including infliximab, etanercept, and adalimumab, are not effective in giant-cell arteritis.

—Jake Remaly