Becky McCall

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

In recent months, the discovery of the C9ORF72 mutation has added fresh insight into the causes of frontotemporal dementia and amyotrophic lateral sclerosis. Now, a series of new studies describes the frequency of the mutation and how the mutation reveals itself clinically in a spectrum of phenotypes in patients with either disease.

The series of studies found that the mutation most often is associated with behavioral variant frontotemporal dementia (FTD), and occurred in 2%-5% of patients with sporadic FTD and 15%-48% of patients with familial FTD. For amyotrophic lateral sclerosis (ALS) patients, the mutation occurred in 4%-7% of sporadic cases and 22%-43% of familial cases. Another 20%-40% of patients who show symptoms of both diseases had the mutation; the rate reached almost 50% among these patients with a family history of ALS or FTD. Some studies reported finding the mutation in 0%-28% of patients who present with the progressive nonfluent aphasia variant of FTD.

The eventual clinical impact of identifying the C9ORF72 mutation is the availability of a population of at-risk carriers of the mutation to aid research into the preclinical phase of disease, said Dr. Kevin Talbot, professor of motor neuron biology at the University of Oxford, England. "Rather than work in the phase of established disease, which may be intractable to disease-modifying therapy, this provides a new departure to ‘fill in’ a phase in the natural history of ALS which has hitherto not been amenable to study." Dr. Talbot was a coauthor on a study that screened 4,448 patients with ALS and 1,425 patients with FTD for the mutation (Lancet Neurol. 2012 March 9 [doi:10.1016/S1474-4422(12)70043-1]).

The discovery of the mutation and the subsequent characterization among patients who have FTD, ALS, both FTD and ALS, or primary progressive aphasia are just the first steps of many before treatments can be based on the new knowledge, said Dr. Paul Schulz of the department of neurology at the University of Texas, Houston, where his lab examines the mechanisms underlying normal cognition and neurodegenerative disorders.

To illustrate his point, Dr. Schulz cited how the genes for myotonic dystrophy and Huntington’s disease were discovered in 1992 and 1994, respectively, but researchers still know little about them. "We don’t know what they do, how the mutations cause problems, and how to replace them."

Preliminary findings underpinning the discovery of C9ORF72 were made in 2006 when investigators discovered that either FTD and ALS or a combination of both diseases were linked to a region on chromosome 9p21 in members of some families with the diseases. The big step came in September 2011 when two research groups independently identified the precise nature of the long-sought-after mutation (Neuron 2011;72:245-56; 257-68). It proved to be a GGGGCC hexanucleotide repeat in the noncoding region of the C9ORF72 gene.

Originally, no mutation had been found even after repeated sequencing of the investigational region on chromosome 9p21, but eventually, the two research groups examined the pattern of inheritance and noticed that only the good gene appeared to be inherited rather than one gene from each parent.

"After various experiments, it was realized that the abnormal gene was invisible to gene sequencing because the hexanucleotide bound to itself," related Dr. Schulz. "As a result, it was impenetrable by normal PCR [polymerase chain reaction] amplification. Now that this mechanism of mutation is known, I’m sure gene hunters are looking for others that are also ‘silent.’ "

Mutation Screening in FTD and ALS

In the Lancet Neurology study of 4,448 ALS patients and 1,425 FTD patients from the United States, Europe, and Australia, researchers found the C9ORF79 mutation in 7% of sporadic ALS in white patients and 4.1% of black patients. It was present in 6% of white patients with sporadic FTD. The results of those with familial FTD or ALS were more surprising, with the expansion present in 38% of all patients with familial ALS and 25% in white patients with familial FTD.

A series of four papers published in Brain by groups from the Netherlands; Manchester, England; London, England; and the Mayo Clinic in Rochester, Minn., and Jacksonville, Fla., reported the results of screening large cohorts of patients with FTD totaling nearly 1,200 cases. Overall, 7%-12% of the cohorts were found to have the mutation (Brain 2012;135:693-708; 723-35; 736-50; 765-83).

Another two papers and the same Mayo Clinic paper reported on the frequency of the mutation in patients with ALS. In 563 ALS patients from northern England, including 63 with a family history of ALS, the C9ORF72 expansion was found in 11%, but it occurred more often among patients with familial disease (43%) than with sporadic (7%) disease (Brain 2012;135:751-64).

Among patients with familial ALS, the mutation occurred in 38% of 141 Italian cases (including 57% in 21 Sardinian cases) and in 22% of 41 German cases (Brain 2012;135:784-93).

Mayo Clinic researchers detected the mutation in 7% of 229 ALS patients and in 24% of 34 patients with familial ALS, parkinsonism, or dementia. Only 4% of sporadic ALS cases had the mutation. Among patients with a clinical phenotype of FTD and ALS, the prevalence of the mutation was 22%, but it approached 50% among those with a positive family history (Brain 2012;135:765-83).

Another study that will be reported April 25 at the annual meeting of the American Academy of Neurology focused on 1,488 patients (1,082 with FTD, 328 with ALS, and 78 with both) in the European Early-Onset Dementia consortium. In patients with a family history of dementia or ALS, the relative contribution of C9ORF72 was 10% in the FTD patients, 42% in the ALS patients, and 48% in the FTD-ALS patients.

"All of these statistics mean that this hexameric repeat is fairly common amongst those with familial FTD or ALS, or especially FTD with ALS," according to Dr. Schulz. But familial FTD was present in only 40% of those with FTD, and familial ALS was present in only 5% of ALS patients, he noted.

"This means that most sporadic FTD, ALS, or FTD-ALS patients are not accounted for. In sporadic FTD, which is more common than familial FTD, then the rate of C9ORF72 mutations appears to be between 2% and 5%," Dr. Schulz said.

Effect of Other FTD/ALS Mutations

The new C9ORF72 expansion joins two other mutations found in patients with FTD and/or ALS, namely those affecting the genes for microtubulin-associated protein tau (MAPT) and progranulin (GRN). In a commentary on the studies featured in Brain, Dr. John Hodges of Neuroscience Research Australia and the University of New South Wales in Sydney, NSW, Australia, noted that the results of the London-based group (Brain 2012;135:736-50) provide some insight into how likely it is that a patient would have a C9ORF72 mutation and whether this likelihood could be predicted based upon family history and clinical features.

The researchers found that the prevalences of the three mutations were roughly equal in their sample. They also found – based on their Goldman scoring method for quantifying family history – that 88% of patients with a score of 1 (representing an autosomal dominant family history of FTD or ALS) had a mutation in one of those three genes.

However, the Mayo Clinic samples suggest that the C9ORF72 mutation is the most common FTD mutation, present in one-third of people with a family history.

Links Between FTD and ALS

The C9ORF72 mutation may also provide some insight on the links between FTD and ALS. In all cohorts, the prevalence of C9ORF72 was highest in those with FTD/ALS at 20%-40%, and approached 50% among FTD/ALS cases with a positive family history. Dr. Brad Dickerson, director of the frontotemporal dementia unit and laboratory of neuroimaging at Massachusetts General Hospital in Boston, Mass., said that linking FTD and ALS through this gene was especially important because it would likely lead to research that sheds light on what causes cells in different parts of the brain to be vulnerable in both of these diseases.

"This once again underscores the value that studying one neurodegenerative disease can have for other neurodegenerative disease," he said. "In the case of this gene, advances in understanding its role in FTD will have direct implications for understanding its role in ALS, and vice versa."

Dr. Marsel Mesulam, director of the cognitive neurology and Alzheimer’s disease center at Northwestern University in Chicago, said that "exactly how the hopes raised by the C9ORF72 finding will be realized is currently unclear, since we do not yet fully understand the function of C9ORF72." He added that the discovery also generates new puzzles. "Why does the same type of mutation cause ALS in some patients, behavioral FTD in others, and PPA [primary progressive aphasia] in still others?"

Behavioral Variant FTD Most Common

The behavioral variant of FTD was the most common clinical phenotype associated with the C9ORF72 expansion, and was often accompanied by features of ALS as the disease progressed.

Some studies showed that patients with the C9ORF72 mutation also presented with progressive nonfluent aphasia, Dr. Hodges noted in his commentary. Major psychiatric symptoms also were very common, but more details are needed, he wrote. "It appears, therefore, that the majority of patients have the behavioral variant of FTD, although a pattern of progressive [nonfluent aphasia] should not mitigate against screening for the mutation in patients with a strong family history or concurrent features of ALS."

Who Should Undergo Screening?

Given that some patients had the C9ORF72 mutation even without a strong family history, "the most important immediate clinical implication is that we will likely begin screening patients for this mutation once a standard laboratory test for this gene becomes available," Dr. Dickerson said.

In a commentary, Rosa Rademakers, Ph.D., of the Mayo Clinic in Jacksonville, Fla., argued that the use of a clinical screening algorithm to decide whether to test for the C9ORF72 mutation in a patient with a family history of ALS or FTD – or when a patient is behaviorally impaired – may not work, because detailed information about family history is often unavailable. Instead, it should be considered in all patients, particularly because 6%-7% of whites with sporadic disease in the Lancet Neurology paper had the mutation, and the clinical phenotype associated with the C9ORF72 expansion extends beyond FTD and ALS. At the moment, however, caution is advised on testing because "our present understanding of the disease penetrance and range of clinical phenotypes associated with this mutation is poor and the smallest repeat size needed for pathogenicity is unknown," Dr. Rademakers wrote.

The sources interviewed for this article did not have any relevant financial disclosures. Dr. Rademakers disclosed that she has a patent pending on the discovery of the hexanucleotide repeat expansion in the C9ORF72 gene.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

Joint replacement surgery continues to become less common in patients with rheumatoid arthritis, probably reflecting the widespread adoption of disease modifying antirheumatic drugs, judging from findings of a population-based study published in this month’s Journal of Rheumatology.

Previous studies have found a trend for declining rates of joint surgery in patients with RA since 1985. In this study, "we examined whether the prior sex differences and use trends in reduced surgical intervention for RA persist in patients diagnosed after 1995, and evaluated the effect of RA surgery on survival in these patients," wrote Dr. Courtney A. Shourt and her associates from the Mayo Clinic in Rochester, Minn. (J. Rheumatol. 2012 Jan. 15 [doi:10.3899/jrheum.111056]).

"The possible contribution of RA-related joint surgery to excess mortality in patients with RA is largely unexplored," they pointed out.

A retrospective medical record review was performed using data from the Rochester Epidemiology Project (www.rochesterproject.org). The researchers reviewed records from a population-based cohort of 813 adult residents of Olmsted County, Minn., who had incident RA between Jan. 1, 1980, and Dec. 31, 2007. All cases were followed longitudinally until Dec. 31, 2008; death; or migration out of the county.

All joint surgeries were marginally associated with mortality (hazard ratio, 1.3; 95% confidence interval, 0.96-1.8; P = .09), but joint reconstructive procedures (JRPs) showed a significant association with mortality, adjusted for known RA mortality risk factors, compared with findings in patients not requiring JRP (HR, 2.8; 95% CI, 1.9-4.1; P less than .001). "The need for joint replacement surgery is still a marker of bad disease," commented Dr. Eric L. Matteson, professor of medicine and chair of rheumatology at the Mayo Clinic, in an interview.

The proportion of patients undergoing RA-related surgeries dropped between the two time periods of 1980-94 and 1995-2007. Of the 813 Olmsted County residents in the analysis, 189 underwent at least one surgical procedure involving joints, during a mean follow up of 9.6 years. The cumulative incidence of any joint surgery at 10 years after RA incidence for the 1980-94 cohort was 27.3%, compared with 19.5% for the 1995-2007 cohort (P = 0.08), which was not statistically significant.

More aggressive use of effective DMARDs with a reduction in the progression of radiographic joint damage was suggested as a possible reason for the decline in surgical procedures. "These findings reveal that modern medical management strategy has had markedly beneficial effects on the disease course," with less damage to the target small- and medium-size joints such as the hands, wrists, and feet than in past decades, noted Dr. Matteson, one of the report’s authors.

The greatest reduction in surgeries was seen in soft tissue procedures (synovectomy, tendon repair, tendon transfer, meniscus repair, ligament release, and/or cartilage repair). These decreased from 12% in 1980-94 to 6% in 1995-2007 at 10 years after RA incidence (P = .012).

No differences were found in the cumulative incidence of total hip arthroplasty (P = .77) or total knee arthroplasty (P = .18) between the time periods, reported the authors. Addressing the continued need for surgery on weight-bearing joints, particularly total knee and total hip arthroplasties, Dr. Matteson added, "in this respect patients are beginning to be more like people from the general population who have hip and knee replacements for osteoarthritis."

Study coinvestigator Cynthia Crowson of the Mayo Clinic’s biostatistics division noted in an interview that "persons with RA are requiring fewer surgeries, which may indicate [that] current management strategies are leading to less disability among patients who have developed RA since 1995" compared with previous times.

The study was supported by a grant from the National Institutes of Health, and was made possible by the Rochester Epidemiology Project. The authors reported having no financial disclosures.

The incidence of total knee arthroplasties increased from 0.5 operations per 100,000 inhabitants to 65 operations per 100,000 inhabitants aged 30-59 years during 1980-2006 in patients with primary knee osteoarthritis, according to a Finnish study.

Patients born shortly after World War II showed the most dramatic increases.

Incidences of unicondylar or partial knee arthroplasties (UKAs) were also found to grow from 0.2 operations per 100,000 inhabitants to 10 operations per 100,000 inhabitants over the same period in the same Finnish patient age group.

"This phenomenon has been especially strong during the 21st century. There is no single explanatory factor for this growth. Some of the increase in incidence can be explained by hospital volume," wrote Dr. Jarkko Leskinen, Consultant Orthopedic Surgeon, Peijas Hospital, Helsinki University Central Hospital, who was lead author of the study published in the January issue of Arthritis & Rheumatism (Arthritis Rheum. 2012;64:423-8).

"The demand for primary TKA [total knee arthroplasty] has been estimated to grow by 673 percent to 3.48 million procedures in the United States by the year 2030," reported Dr. Leskinen. Previous studies reported increases in the incidence of TKA in younger patients in Australia and the United States in the 1980s and 1990s. This study aimed to analyze the changes in age group as well as the sex-standardized incidence of UKAs and TKAs in Finland between the years 1980 and 2006.

Patient data were drawn from the Finnish Arthroplasty Registry, and population data were obtained from Statistics Finland. A total of 8,961 knee arthroplasties were performed for primary osteoarthritis in patients under age 60 during 1980-2006. In addition to evaluating the effects of age and gender on the incidences of knee arthroplasties, Dr. Leskinen and his colleagues evaluated the effects of hospital volume.

Overall, the incidence rate ratio (IRR) for the annual increase in general incidence of UKAs was lower than that of TKAs, with an IRR of 1.26 for UKAs (95% confidence interval, 1.24-1.28; P less than .001) and 6.92 for TKAs (95% CI, 6.50-7.36; P less than .001).

In particular, the study found that the TKA incidence rose sharply from 18 per 100,000 in 2001 to 65 per 100,000 in 2006. TKAs were performed more often in women than men, with a 1.6- to 2.4-fold higher incidence in women than men during the past 10 years. Since 2000, a greater number of UKAs also were performed in women than men. Most of the increased incidence in TKAs and UKAs was in women aged 50-59 years.

Regarding the incidence of TKAs by age group, patients aged 50-59 years showed the largest increase, from 1.5 TKAs per 100,000 in 1980 to 160 per 100,000 in 2006. Incidences of UKAs by age group showed a similar pattern to TKAs, with the most marked growth in patients aged 50-59 years, increasing from 0.5 to 24 operations per 100,000. Growth was most rapid after the year 2000.

"Possible explanations for this phenomenon include the high functional and quality of life demands of younger patients aged less than 60 years," the authors wrote. "Another reason could be that the baby boomers may opt for elective operations at an earlier stage with milder symptoms, than the situation that was faced by earlier generations."

Hospitals were divided into low-, intermediate-, and high-volume centers, according to the number of TKAs performed in all the hospitals in Finland in 2006. The incidence of TKAs grew more rapidly in low- and intermediate-volume hospitals, while the incidence of UKAs grew in low-volume hospitals. The IRR for TKAs was 1.23 in both comparisons of low- to high-volume centers (95% CI, 1.13-1.34; P less than .001), and intermediate- to high-volume centers (95%CI, 1.16-1.31; P less than .001).

The authors warned against the widespread use of TKAs in younger patients. "Long-term results in young patients may differ from those reported in older patients, and risk for revision may be higher," they concluded.

Dr. Leskinen and his colleagues reported having no financial disclosures.

The incidence of total knee arthroplasties increased from 0.5 operations per 100,000 inhabitants to 65 operations per 100,000 inhabitants aged 30-59 years during 1980-2006 in patients with primary knee osteoarthritis, according to a Finnish study.

Patients born shortly after World War II showed the most dramatic increases.

Incidences of unicondylar or partial knee arthroplasties (UKAs) were also found to grow from 0.2 operations per 100,000 inhabitants to 10 operations per 100,000 inhabitants over the same period in the same Finnish patient age group.

"This phenomenon has been especially strong during the 21st century. There is no single explanatory factor for this growth. Some of the increase in incidence can be explained by hospital volume," wrote Dr. Jarkko Leskinen, Consultant Orthopedic Surgeon, Peijas Hospital, Helsinki University Central Hospital, who was lead author of the study published in the January issue of Arthritis & Rheumatism (Arthritis Rheum. 2012;64:423-8).

"The demand for primary TKA [total knee arthroplasty] has been estimated to grow by 673 percent to 3.48 million procedures in the United States by the year 2030," reported Dr. Leskinen. Previous studies reported increases in the incidence of TKA in younger patients in Australia and the United States in the 1980s and 1990s. This study aimed to analyze the changes in age group as well as the sex-standardized incidence of UKAs and TKAs in Finland between the years 1980 and 2006.

Patient data were drawn from the Finnish Arthroplasty Registry, and population data were obtained from Statistics Finland. A total of 8,961 knee arthroplasties were performed for primary osteoarthritis in patients under age 60 during 1980-2006. In addition to evaluating the effects of age and gender on the incidences of knee arthroplasties, Dr. Leskinen and his colleagues evaluated the effects of hospital volume.

Overall, the incidence rate ratio (IRR) for the annual increase in general incidence of UKAs was lower than that of TKAs, with an IRR of 1.26 for UKAs (95% confidence interval, 1.24-1.28; P less than .001) and 6.92 for TKAs (95% CI, 6.50-7.36; P less than .001).

In particular, the study found that the TKA incidence rose sharply from 18 per 100,000 in 2001 to 65 per 100,000 in 2006. TKAs were performed more often in women than men, with a 1.6- to 2.4-fold higher incidence in women than men during the past 10 years. Since 2000, a greater number of UKAs also were performed in women than men. Most of the increased incidence in TKAs and UKAs was in women aged 50-59 years.

Regarding the incidence of TKAs by age group, patients aged 50-59 years showed the largest increase, from 1.5 TKAs per 100,000 in 1980 to 160 per 100,000 in 2006. Incidences of UKAs by age group showed a similar pattern to TKAs, with the most marked growth in patients aged 50-59 years, increasing from 0.5 to 24 operations per 100,000. Growth was most rapid after the year 2000.

"Possible explanations for this phenomenon include the high functional and quality of life demands of younger patients aged less than 60 years," the authors wrote. "Another reason could be that the baby boomers may opt for elective operations at an earlier stage with milder symptoms, than the situation that was faced by earlier generations."

Hospitals were divided into low-, intermediate-, and high-volume centers, according to the number of TKAs performed in all the hospitals in Finland in 2006. The incidence of TKAs grew more rapidly in low- and intermediate-volume hospitals, while the incidence of UKAs grew in low-volume hospitals. The IRR for TKAs was 1.23 in both comparisons of low- to high-volume centers (95% CI, 1.13-1.34; P less than .001), and intermediate- to high-volume centers (95%CI, 1.16-1.31; P less than .001).

The authors warned against the widespread use of TKAs in younger patients. "Long-term results in young patients may differ from those reported in older patients, and risk for revision may be higher," they concluded.

Dr. Leskinen and his colleagues reported having no financial disclosures.

The incidence of total knee arthroplasties increased from 0.5 operations per 100,000 inhabitants to 65 operations per 100,000 inhabitants aged 30-59 years during 1980-2006 in patients with primary knee osteoarthritis, according to a Finnish study.

Patients born shortly after World War II showed the most dramatic increases.

Incidences of unicondylar or partial knee arthroplasties (UKAs) were also found to grow from 0.2 operations per 100,000 inhabitants to 10 operations per 100,000 inhabitants over the same period in the same Finnish patient age group.

"This phenomenon has been especially strong during the 21st century. There is no single explanatory factor for this growth. Some of the increase in incidence can be explained by hospital volume," wrote Dr. Jarkko Leskinen, Consultant Orthopedic Surgeon, Peijas Hospital, Helsinki University Central Hospital, who was lead author of the study published in the January issue of Arthritis & Rheumatism (Arthritis Rheum. 2012;64:423-8).

"The demand for primary TKA [total knee arthroplasty] has been estimated to grow by 673 percent to 3.48 million procedures in the United States by the year 2030," reported Dr. Leskinen. Previous studies reported increases in the incidence of TKA in younger patients in Australia and the United States in the 1980s and 1990s. This study aimed to analyze the changes in age group as well as the sex-standardized incidence of UKAs and TKAs in Finland between the years 1980 and 2006.

Patient data were drawn from the Finnish Arthroplasty Registry, and population data were obtained from Statistics Finland. A total of 8,961 knee arthroplasties were performed for primary osteoarthritis in patients under age 60 during 1980-2006. In addition to evaluating the effects of age and gender on the incidences of knee arthroplasties, Dr. Leskinen and his colleagues evaluated the effects of hospital volume.

Overall, the incidence rate ratio (IRR) for the annual increase in general incidence of UKAs was lower than that of TKAs, with an IRR of 1.26 for UKAs (95% confidence interval, 1.24-1.28; P less than .001) and 6.92 for TKAs (95% CI, 6.50-7.36; P less than .001).

In particular, the study found that the TKA incidence rose sharply from 18 per 100,000 in 2001 to 65 per 100,000 in 2006. TKAs were performed more often in women than men, with a 1.6- to 2.4-fold higher incidence in women than men during the past 10 years. Since 2000, a greater number of UKAs also were performed in women than men. Most of the increased incidence in TKAs and UKAs was in women aged 50-59 years.

Regarding the incidence of TKAs by age group, patients aged 50-59 years showed the largest increase, from 1.5 TKAs per 100,000 in 1980 to 160 per 100,000 in 2006. Incidences of UKAs by age group showed a similar pattern to TKAs, with the most marked growth in patients aged 50-59 years, increasing from 0.5 to 24 operations per 100,000. Growth was most rapid after the year 2000.

"Possible explanations for this phenomenon include the high functional and quality of life demands of younger patients aged less than 60 years," the authors wrote. "Another reason could be that the baby boomers may opt for elective operations at an earlier stage with milder symptoms, than the situation that was faced by earlier generations."

Hospitals were divided into low-, intermediate-, and high-volume centers, according to the number of TKAs performed in all the hospitals in Finland in 2006. The incidence of TKAs grew more rapidly in low- and intermediate-volume hospitals, while the incidence of UKAs grew in low-volume hospitals. The IRR for TKAs was 1.23 in both comparisons of low- to high-volume centers (95% CI, 1.13-1.34; P less than .001), and intermediate- to high-volume centers (95%CI, 1.16-1.31; P less than .001).

The authors warned against the widespread use of TKAs in younger patients. "Long-term results in young patients may differ from those reported in older patients, and risk for revision may be higher," they concluded.

Dr. Leskinen and his colleagues reported having no financial disclosures.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.

Oral glucocorticoid therapy increases the risk of serious infection in elderly patients with rheumatoid arthritis, even when the drugs were stopped as long as 2.5 years earlier, according to findings from a recently published study.

The researchers used a novel, weighted cumulative dose model to assess serious infection risk associated with glucocorticoid exposure, providing greater accuracy over conventional models.

Conducted in Quebec, the case-control analysis assessed the infection risk in 16,207 patients who were at least 65 years of age and who had rheumatoid arthritis (RA). The findings showed that taking a 5 mg/day dose of prednisolone for 12 months increases risk of serious infection by 55%, compared to non-users. Furthermore, this risk was found to increase cumulatively to 100% (odds ratio, 2.00; 95% confidence interval, 1.69 to 2.26) in patients who took prednisolone for 3 years (Ann. Rheum. Dis. 2012 Jan. 12 [doi:10.1136/annrheumdis-2011-200702]).

"This is important as many physicians consider a 5 mg [daily prednisolone equivalent dosage] a ‘physiological dose’ that may not have important harms," according to Dr. William G. Dixon, Medical Research Council Clinician Scientist at the University of Manchester (England).

The investigators noted that 1,927 patients developed a first serious infection after an average 3.8 years of follow up. Patients who are currently or recently taking glucocorticoid therapy had the greatest risk of serious infection. The analysis showed that a current user on 5 mg/day prednisolone had an increased risk over non-users of 11% (OR, 1.11), 30% (OR, 1.30), and 55% (OR, 1.46) after 1 month, 3 months, and 12 months of use respectively.

"The risk associated with 5 mg prednisolone taken for the last 3 years was similar to that associated with 30 mg taken for the last month," noted Dr. Dixon and his associates.

The impact of discontinuation of glucocorticoid therapy was also investigated. Discontinuing a 2-year course of a 10-mg daily dose of prednisolone for 6 months was found to halve risk compared to continued use (OR, 1.87; CI, 1.32 to 2.63).

Dr. Dixon used a weighted, cumulative-dose model to assess the risk of serious infection associated with glucocorticoid exposure. This enabled doses to be given a weighting determined by how recently the patient took that dose. The authors note that this model "provides a far superior fit than all conventional models."

Dr. Jeffrey Curtis commented in an interview that the weighted cumulative dose model represents an advance. "The advance here is that there may be preferable ways to model steroid dose that allow for different estimations of risk, and presumably more accurate estimations. In the model used here, the researchers take into account the patients’ history of steroid therapy."

However, the study did not resolve the issue of confounding by indication, in which the effects of more active and severe disease can be difficult to disentangle from the effects of drugs, noted Dr. Curtis, who is director of the Arthritis Clinical Intervention Program Division of Clinical Immunology and Rheumatology at the University of Alabama at Birmingham.

"I think the risks with steroid therapy may produce different estimations of risk depending on the data source used, and the pattern of use in any particular disease. Analysis needs to be done by disease."

Addressing the issue of whether serious infection risk in patients with autoimmune diseases was associated with glucocorticoids, biologics, or non-biologic treatments, Dr. Curtis referred to a recently published paper he coauthored (JAMA 2011;306:2331-9). "We found a significantly increased risk of serious infection for steroid therapy but no greater risk overall for tumor necrosis factor (TNF)–alpha antagonists compared to patients receiving non-biologic treatments in a range of autoimmune diseases."

The study was funded by the Canadian Institutes of Health Research and the Canadian Foundation for Innovation. The lead author received support from a Medical Research Council Clinician Scientist Fellowship. The authors did not report having any other financial disclosures. Dr. Curtis is a consultant to various pharmaceutical companies that manufacture biologic therapies but he has no disclosures of relevance to glucocorticoids.