Miriam E. Tucker

BALTIMORE — Intravenous immunoglobulin appears to be a safe and effective treatment for scleromyxedema, Dr. Francesco Boin said at a conference on rheumatic diseases sponsored by the Johns Hopkins University.

Scleromyxedema is a rare—though probably underrecognized—disorder that mimics scleroderma. It is characterized by widespread thickened skin and multisystem disease caused by mucinous deposition in the skin and internal organs. It has been described worldwide, with males and females equally affected, and both black and white patients reported in the United States. Mean age of diagnosis is about 55 years, ranging from 30 to 80.

Patients typically present with waxy, bumpy skin, initially in patches but later becoming confluent and generalized and eventually thickened and pendulous. Skin changes behind the ears are almost always present. “The buzzword is the ear … It's a very important spot to check if you're suspicious for this entity,” said Dr. Boin, of the division of rheumatology at Johns Hopkins.

The patient's face will often have a “leonine” appearance. The hands may appear scleroderma-like, with flexion contractures of the fingers. Some patients have microstomia.

Findings from an incisional biopsy will show a distinct infiltrative process with massive amounts of mucin deposition. Patients will have a low-level monoclonal gammopathy, with no specific distribution of subtype. As with most fibrosing skin disorders, punch biopsy is not generally helpful in the diagnosis and is often not necessary.

Aside from the skin, scleromyxedema affects the neurologic, hematologic, gastrointestinal, and cardiopulmonary systems. Neurologic symptoms may include encephalopathy, seizures, stroke, psychosis, aphasia, gait disturbance, vertigo, and tinnitus. Cardiopulmonary involvement includes pulmonary hypertension in approximately 50% of patients, as well as pericardial effusion. Gastrointestinal symptoms can include dysphagia and esophageal dysmotility, Dr. Boin said.

Less commonly, some scleromyxedema patients will experience proximal muscle weakness or frank myopathy, with biopsy showing inflammation, atrophy, necrosis, and mucin deposition.

Without treatment, progressive disease and a poor prognosis are typical. Currently, there is no consistent therapeutic approach and few available long-term data. Treatments that have been investigated in small studies include thalidomide, cyclosporine, autologous stem cell transplants, prednisone, isotretinoin, intravenous immunoglobulin (IVIG), dermabrasion, extracorporeal phototherapy, radiation therapy, plasmapheresis, and psoralen-ultraviolet-light therapy.

Findings from a review of nine scleromyxedema patients who were referred to The Scleroderma Center at Johns Hopkins between 1996 and 2005 showed the mean patient age at diagnosis was 53.6 years (range 33–74), and the mean disease duration prior to referral was 2.1 years (range 0–6). Eight of the patients were white, and one African American. The majority (seven of nine) were female. Monoclonal gammopathy was present in eight patients, but none had evidence of multiple myeloma.

Clinical manifestations mimicking scleroderma included Raynaud's phenomenon in five (another had “cold sensitivity”), sclerodactyly (five), pulmonary hypertension (three), and gastroesophageal reflux disease (two). Encephalopathy was present in one patient, dysphagia in four, elevated creatine phosphokinase in two, and rhabdomyolysis in one. The only autoantibody detected was an antinuclear autoantibody in two patients, Dr. Boin's Hopkins associates Dr. Laura K. Hummers and Dr. Frederick M. Wigley reported in a poster at the 2005 American College of Rheumatology meeting.

Four of the patients with severe symptomatic skin involvement were treated with IVIG at a dose of 2 g/kg daily for 5 days. All patients tolerated the full course of IVIG, and all experienced dramatic improvement in their papular mucinosis skin lesions. Of those four, one also experienced rapid resolution of severe neurologic involvement after just one IVIG course, and another received six monthly treatments and continued without flare 4 months later.

The other two patients, followed for 31 and 34 months, respectively, postinitial treatment, both responded to six monthly treatments, reflared after 4 months, and are now continuing to respond to low-dose infusions at regular intervals—every 4–6 weeks in one patient, every 8 weeks in the other—to maintain control. Indeed, while IVIG appears to produce dramatic and rapid response, with “a softening in a matter of days,” it may be necessary to continue therapy long term, he noted.

One scleromyxedema patient received IVIG 2 g/kg once monthly for 6 months and then every 8 weeks for 1 year. Photos courtesy Dr. Laura Hummers

BALTIMORE — Intravenous immunoglobulin appears to be a safe and effective treatment for scleromyxedema, Dr. Francesco Boin said at a conference on rheumatic diseases sponsored by the Johns Hopkins University.

Scleromyxedema is a rare—though probably underrecognized—disorder that mimics scleroderma. It is characterized by widespread thickened skin and multisystem disease caused by mucinous deposition in the skin and internal organs. It has been described worldwide, with males and females equally affected, and both black and white patients reported in the United States. Mean age of diagnosis is about 55 years, ranging from 30 to 80.

Patients typically present with waxy, bumpy skin, initially in patches but later becoming confluent and generalized and eventually thickened and pendulous. Skin changes behind the ears are almost always present. “The buzzword is the ear … It's a very important spot to check if you're suspicious for this entity,” said Dr. Boin, of the division of rheumatology at Johns Hopkins.

The patient's face will often have a “leonine” appearance. The hands may appear scleroderma-like, with flexion contractures of the fingers. Some patients have microstomia.

Findings from an incisional biopsy will show a distinct infiltrative process with massive amounts of mucin deposition. Patients will have a low-level monoclonal gammopathy, with no specific distribution of subtype. As with most fibrosing skin disorders, punch biopsy is not generally helpful in the diagnosis and is often not necessary.

Aside from the skin, scleromyxedema affects the neurologic, hematologic, gastrointestinal, and cardiopulmonary systems. Neurologic symptoms may include encephalopathy, seizures, stroke, psychosis, aphasia, gait disturbance, vertigo, and tinnitus. Cardiopulmonary involvement includes pulmonary hypertension in approximately 50% of patients, as well as pericardial effusion. Gastrointestinal symptoms can include dysphagia and esophageal dysmotility, Dr. Boin said.

Less commonly, some scleromyxedema patients will experience proximal muscle weakness or frank myopathy, with biopsy showing inflammation, atrophy, necrosis, and mucin deposition.

Without treatment, progressive disease and a poor prognosis are typical. Currently, there is no consistent therapeutic approach and few available long-term data. Treatments that have been investigated in small studies include thalidomide, cyclosporine, autologous stem cell transplants, prednisone, isotretinoin, intravenous immunoglobulin (IVIG), dermabrasion, extracorporeal phototherapy, radiation therapy, plasmapheresis, and psoralen-ultraviolet-light therapy.

Findings from a review of nine scleromyxedema patients who were referred to The Scleroderma Center at Johns Hopkins between 1996 and 2005 showed the mean patient age at diagnosis was 53.6 years (range 33–74), and the mean disease duration prior to referral was 2.1 years (range 0–6). Eight of the patients were white, and one African American. The majority (seven of nine) were female. Monoclonal gammopathy was present in eight patients, but none had evidence of multiple myeloma.

Clinical manifestations mimicking scleroderma included Raynaud's phenomenon in five (another had “cold sensitivity”), sclerodactyly (five), pulmonary hypertension (three), and gastroesophageal reflux disease (two). Encephalopathy was present in one patient, dysphagia in four, elevated creatine phosphokinase in two, and rhabdomyolysis in one. The only autoantibody detected was an antinuclear autoantibody in two patients, Dr. Boin's Hopkins associates Dr. Laura K. Hummers and Dr. Frederick M. Wigley reported in a poster at the 2005 American College of Rheumatology meeting.

Four of the patients with severe symptomatic skin involvement were treated with IVIG at a dose of 2 g/kg daily for 5 days. All patients tolerated the full course of IVIG, and all experienced dramatic improvement in their papular mucinosis skin lesions. Of those four, one also experienced rapid resolution of severe neurologic involvement after just one IVIG course, and another received six monthly treatments and continued without flare 4 months later.

The other two patients, followed for 31 and 34 months, respectively, postinitial treatment, both responded to six monthly treatments, reflared after 4 months, and are now continuing to respond to low-dose infusions at regular intervals—every 4–6 weeks in one patient, every 8 weeks in the other—to maintain control. Indeed, while IVIG appears to produce dramatic and rapid response, with “a softening in a matter of days,” it may be necessary to continue therapy long term, he noted.

One scleromyxedema patient received IVIG 2 g/kg once monthly for 6 months and then every 8 weeks for 1 year. Photos courtesy Dr. Laura Hummers

BALTIMORE — Intravenous immunoglobulin appears to be a safe and effective treatment for scleromyxedema, Dr. Francesco Boin said at a conference on rheumatic diseases sponsored by the Johns Hopkins University.

Scleromyxedema is a rare—though probably underrecognized—disorder that mimics scleroderma. It is characterized by widespread thickened skin and multisystem disease caused by mucinous deposition in the skin and internal organs. It has been described worldwide, with males and females equally affected, and both black and white patients reported in the United States. Mean age of diagnosis is about 55 years, ranging from 30 to 80.

Patients typically present with waxy, bumpy skin, initially in patches but later becoming confluent and generalized and eventually thickened and pendulous. Skin changes behind the ears are almost always present. “The buzzword is the ear … It's a very important spot to check if you're suspicious for this entity,” said Dr. Boin, of the division of rheumatology at Johns Hopkins.

The patient's face will often have a “leonine” appearance. The hands may appear scleroderma-like, with flexion contractures of the fingers. Some patients have microstomia.

Findings from an incisional biopsy will show a distinct infiltrative process with massive amounts of mucin deposition. Patients will have a low-level monoclonal gammopathy, with no specific distribution of subtype. As with most fibrosing skin disorders, punch biopsy is not generally helpful in the diagnosis and is often not necessary.

Aside from the skin, scleromyxedema affects the neurologic, hematologic, gastrointestinal, and cardiopulmonary systems. Neurologic symptoms may include encephalopathy, seizures, stroke, psychosis, aphasia, gait disturbance, vertigo, and tinnitus. Cardiopulmonary involvement includes pulmonary hypertension in approximately 50% of patients, as well as pericardial effusion. Gastrointestinal symptoms can include dysphagia and esophageal dysmotility, Dr. Boin said.

Less commonly, some scleromyxedema patients will experience proximal muscle weakness or frank myopathy, with biopsy showing inflammation, atrophy, necrosis, and mucin deposition.

Without treatment, progressive disease and a poor prognosis are typical. Currently, there is no consistent therapeutic approach and few available long-term data. Treatments that have been investigated in small studies include thalidomide, cyclosporine, autologous stem cell transplants, prednisone, isotretinoin, intravenous immunoglobulin (IVIG), dermabrasion, extracorporeal phototherapy, radiation therapy, plasmapheresis, and psoralen-ultraviolet-light therapy.

Findings from a review of nine scleromyxedema patients who were referred to The Scleroderma Center at Johns Hopkins between 1996 and 2005 showed the mean patient age at diagnosis was 53.6 years (range 33–74), and the mean disease duration prior to referral was 2.1 years (range 0–6). Eight of the patients were white, and one African American. The majority (seven of nine) were female. Monoclonal gammopathy was present in eight patients, but none had evidence of multiple myeloma.

Clinical manifestations mimicking scleroderma included Raynaud's phenomenon in five (another had “cold sensitivity”), sclerodactyly (five), pulmonary hypertension (three), and gastroesophageal reflux disease (two). Encephalopathy was present in one patient, dysphagia in four, elevated creatine phosphokinase in two, and rhabdomyolysis in one. The only autoantibody detected was an antinuclear autoantibody in two patients, Dr. Boin's Hopkins associates Dr. Laura K. Hummers and Dr. Frederick M. Wigley reported in a poster at the 2005 American College of Rheumatology meeting.

Four of the patients with severe symptomatic skin involvement were treated with IVIG at a dose of 2 g/kg daily for 5 days. All patients tolerated the full course of IVIG, and all experienced dramatic improvement in their papular mucinosis skin lesions. Of those four, one also experienced rapid resolution of severe neurologic involvement after just one IVIG course, and another received six monthly treatments and continued without flare 4 months later.

The other two patients, followed for 31 and 34 months, respectively, postinitial treatment, both responded to six monthly treatments, reflared after 4 months, and are now continuing to respond to low-dose infusions at regular intervals—every 4–6 weeks in one patient, every 8 weeks in the other—to maintain control. Indeed, while IVIG appears to produce dramatic and rapid response, with “a softening in a matter of days,” it may be necessary to continue therapy long term, he noted.

One scleromyxedema patient received IVIG 2 g/kg once monthly for 6 months and then every 8 weeks for 1 year. Photos courtesy Dr. Laura Hummers

BALTIMORE — Scleroderma patients should have yearly screening for pulmonary arterial hypertension, Dr. Kwas Huston said at a conference on rheumatic diseases sponsored by Johns Hopkins University.

At Johns Hopkins' Scleroderma Center, all patients undergo annual screening for pulmonary arterial hypertension (PAH) with pulmonary function testing (PFT) and two-dimensional echocardiography. Asymptomatic patients with mild changes and right ventricular systolic pressure (RVSP) less than 40 mm Hg are rescreened at 6 months. Symptomatic patients with signs and/or abnormal two-dimensional echocardiography (RVSP greater than 40 mm Hg) undergo right heart catheterization to confirm the diagnosis.

“We now have treatments we didn't have 5 or 10 years ago. … The evaluation is important to identify pulmonary hypertension and for prognosis,” said Dr. Huston, of the division of rheumatology at Johns Hopkins.

In the UNCOVER study published by Dr. Huston's group, 122 of 791 patients with scleroderma and mixed connective tissue disease seen in 50 community rheumatology practices had an existing diagnosis of PAH. But when the remaining 669 patients without a diagnosis of PAH subsequently underwent echocardiography, 89 had previously unrecognized PAH, for a total prevalence of 27% (Arthritis Rheum. 2005;52;2125–32).

Increased age at the onset of scleroderma is a major risk factor for PAH. Data from one study suggest that PAH risk increases 52% for every 10 years of age at disease onset, and that patients aged 60 and older have over twice the risk of younger patients (Chest 2003;124:2098–104). Other risk factors include severe Raynaud's phenomenon, low pulmonary diffusing capacity, calcinosis, Raynaud's disease, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome, he said.

PFT is useful for identifying PAH and for determining prognosis. In 71 scleroderma patients followed for a mean of 5 years, those with a carbon monoxide diffusing capacity (DLCO) of 40% or less had a 9% survival at 5 years, versus 75% among those with DLCO above 40% (Am. J. Med. 1984;77:1027–34). Pulmonary pressures were not measured in that study, but mortality is thought to be attributed to PAH, Dr. Huston noted.

The DLCO is also a useful predictor of who will develop PAH. In a retrospective case-control study of 212 scleroderma patients, the mean DLCO among the 106 with PAH was 52% of predicted 4.5 years prior to the PAH diagnosis, compared with 80% of predicted among the other 106 scleroderma patients who did not develop PAH (Arthritis Rheum. 2003;48:516–22).

Echocardiography is a useful companion screening tool. It had a sensitivity of 90% and specificity of 75% for identifying patients who had PAH on catheterization in a study of 33 scleroderma patients in whom clinical assessment, including ECG, chest x-ray, pulmonary function tests, and high-resolution computed tomography, raised suspicion of PAH (Br. J. Rheumatol. 1997;36:239–43). Echocardiography missed just two patients, both with pulmonary arterial systolic pressures (PASP) in the 30s. All patients with PASP above 40 mm Hg by echocardiography had abnormal pressures on catheterization.

As with PFT, echocardiography adds prognostic value. Increased mortality was tied to higher initial reading and with rising pressures in a study of 930 scleroderma patients, in whom mortality was 20% at 20 months among those with a single pressure of 30 mm Hg or greater. Rapid rises occurred more frequently in limited than in diffuse scleroderma (Rheumatology [Oxford]:2001;40:453–9).

In a study of 794 patients followed for 4 years, 3-year survival was inversely proportionate to mean PASP, from 75% among those with PASP under 32 mm Hg to 61% for 32–44 mm Hg, to 33% for pressures above 45 mm Hg (Ann. Rheum. Dis. 2003;62:1088–93).

Data support echocardiography and PFT for screening scleroderma, but Dr. Huston said areas of uncertainty include the role of exercise echocardiography in identifying patients with elevated right heart pressures on exercise but normal at rest, and the significance of a low-normal RVSP or low DLCO with normal echocardiography.

Flawed Drugs Still Give Hope

While five of the approved medications for treating pulmonary arterial hypertension offer patients hope that was unavailable a few years ago, each has drawbacks, Dr. Huston cautioned. (For the newest approval, see story below.)

The five medications are three prostanoids (epoprostenol, treprostinil, and inhaled lipoprost), an endothelin antagonist (bosentan) and the phosphodiesterase inhibitor sildenafil. Each was approved by the Food and Drug Administration after short-term randomized controlled trials, usually lasting 12–16 weeks. “We don't know what to expect in the long term,” Dr. Huston said.

The only drug to show a survival benefit was epoprostenol. Trials for the other drugs did not include enough patients to assess the drug's effect on mortality, and instead, used surrogate end points, like results of the 6-minute walk test or dyspnea questionnaires. Moreover, the large trials included patients with multiple causes of PAH, including scleroderma and lupus, groups that may not be comparable.

Epoprostenol requires a central intravenous line, the invasive nature of which carries an infection risk. The drug has a short half-life, which can lead to pump failure and disease worsening. Treprostinil can be infused subcutaneously and has a longer half-life, but a majority of patients experience pain at the infusion site. Inhaled lipoprost requires six to nine inhalations a day, and 10 minutes per inhalation, a process that patients find “a little cumbersome,” Dr. Huston said.

Bosentan has the advantage of oral administration but is associated with abnormal elevations on liver function tests, and it interacts with several common drugs. It is contraindicated with cyclosporine and glyburide, for example. Sildenafil, called Revatio instead of Viagra when used to treat PAH, can potentiate hypotension when used with nitroglycerin. It also interacts with bosentan.

It is not clear which agent is best, or if combination therapy might help patients further, said Dr. Huston, who added he had no financial conflicts of interest to disclose.

BALTIMORE — Scleroderma patients should have yearly screening for pulmonary arterial hypertension, Dr. Kwas Huston said at a conference on rheumatic diseases sponsored by Johns Hopkins University.

At Johns Hopkins' Scleroderma Center, all patients undergo annual screening for pulmonary arterial hypertension (PAH) with pulmonary function testing (PFT) and two-dimensional echocardiography. Asymptomatic patients with mild changes and right ventricular systolic pressure (RVSP) less than 40 mm Hg are rescreened at 6 months. Symptomatic patients with signs and/or abnormal two-dimensional echocardiography (RVSP greater than 40 mm Hg) undergo right heart catheterization to confirm the diagnosis.

“We now have treatments we didn't have 5 or 10 years ago. … The evaluation is important to identify pulmonary hypertension and for prognosis,” said Dr. Huston, of the division of rheumatology at Johns Hopkins.

In the UNCOVER study published by Dr. Huston's group, 122 of 791 patients with scleroderma and mixed connective tissue disease seen in 50 community rheumatology practices had an existing diagnosis of PAH. But when the remaining 669 patients without a diagnosis of PAH subsequently underwent echocardiography, 89 had previously unrecognized PAH, for a total prevalence of 27% (Arthritis Rheum. 2005;52;2125–32).

Increased age at the onset of scleroderma is a major risk factor for PAH. Data from one study suggest that PAH risk increases 52% for every 10 years of age at disease onset, and that patients aged 60 and older have over twice the risk of younger patients (Chest 2003;124:2098–104). Other risk factors include severe Raynaud's phenomenon, low pulmonary diffusing capacity, calcinosis, Raynaud's disease, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome, he said.

PFT is useful for identifying PAH and for determining prognosis. In 71 scleroderma patients followed for a mean of 5 years, those with a carbon monoxide diffusing capacity (DLCO) of 40% or less had a 9% survival at 5 years, versus 75% among those with DLCO above 40% (Am. J. Med. 1984;77:1027–34). Pulmonary pressures were not measured in that study, but mortality is thought to be attributed to PAH, Dr. Huston noted.

The DLCO is also a useful predictor of who will develop PAH. In a retrospective case-control study of 212 scleroderma patients, the mean DLCO among the 106 with PAH was 52% of predicted 4.5 years prior to the PAH diagnosis, compared with 80% of predicted among the other 106 scleroderma patients who did not develop PAH (Arthritis Rheum. 2003;48:516–22).

Echocardiography is a useful companion screening tool. It had a sensitivity of 90% and specificity of 75% for identifying patients who had PAH on catheterization in a study of 33 scleroderma patients in whom clinical assessment, including ECG, chest x-ray, pulmonary function tests, and high-resolution computed tomography, raised suspicion of PAH (Br. J. Rheumatol. 1997;36:239–43). Echocardiography missed just two patients, both with pulmonary arterial systolic pressures (PASP) in the 30s. All patients with PASP above 40 mm Hg by echocardiography had abnormal pressures on catheterization.

As with PFT, echocardiography adds prognostic value. Increased mortality was tied to higher initial reading and with rising pressures in a study of 930 scleroderma patients, in whom mortality was 20% at 20 months among those with a single pressure of 30 mm Hg or greater. Rapid rises occurred more frequently in limited than in diffuse scleroderma (Rheumatology [Oxford]:2001;40:453–9).

In a study of 794 patients followed for 4 years, 3-year survival was inversely proportionate to mean PASP, from 75% among those with PASP under 32 mm Hg to 61% for 32–44 mm Hg, to 33% for pressures above 45 mm Hg (Ann. Rheum. Dis. 2003;62:1088–93).

Data support echocardiography and PFT for screening scleroderma, but Dr. Huston said areas of uncertainty include the role of exercise echocardiography in identifying patients with elevated right heart pressures on exercise but normal at rest, and the significance of a low-normal RVSP or low DLCO with normal echocardiography.

Flawed Drugs Still Give Hope

While five of the approved medications for treating pulmonary arterial hypertension offer patients hope that was unavailable a few years ago, each has drawbacks, Dr. Huston cautioned. (For the newest approval, see story below.)

The five medications are three prostanoids (epoprostenol, treprostinil, and inhaled lipoprost), an endothelin antagonist (bosentan) and the phosphodiesterase inhibitor sildenafil. Each was approved by the Food and Drug Administration after short-term randomized controlled trials, usually lasting 12–16 weeks. “We don't know what to expect in the long term,” Dr. Huston said.

The only drug to show a survival benefit was epoprostenol. Trials for the other drugs did not include enough patients to assess the drug's effect on mortality, and instead, used surrogate end points, like results of the 6-minute walk test or dyspnea questionnaires. Moreover, the large trials included patients with multiple causes of PAH, including scleroderma and lupus, groups that may not be comparable.

Epoprostenol requires a central intravenous line, the invasive nature of which carries an infection risk. The drug has a short half-life, which can lead to pump failure and disease worsening. Treprostinil can be infused subcutaneously and has a longer half-life, but a majority of patients experience pain at the infusion site. Inhaled lipoprost requires six to nine inhalations a day, and 10 minutes per inhalation, a process that patients find “a little cumbersome,” Dr. Huston said.

Bosentan has the advantage of oral administration but is associated with abnormal elevations on liver function tests, and it interacts with several common drugs. It is contraindicated with cyclosporine and glyburide, for example. Sildenafil, called Revatio instead of Viagra when used to treat PAH, can potentiate hypotension when used with nitroglycerin. It also interacts with bosentan.

It is not clear which agent is best, or if combination therapy might help patients further, said Dr. Huston, who added he had no financial conflicts of interest to disclose.

BALTIMORE — Scleroderma patients should have yearly screening for pulmonary arterial hypertension, Dr. Kwas Huston said at a conference on rheumatic diseases sponsored by Johns Hopkins University.

At Johns Hopkins' Scleroderma Center, all patients undergo annual screening for pulmonary arterial hypertension (PAH) with pulmonary function testing (PFT) and two-dimensional echocardiography. Asymptomatic patients with mild changes and right ventricular systolic pressure (RVSP) less than 40 mm Hg are rescreened at 6 months. Symptomatic patients with signs and/or abnormal two-dimensional echocardiography (RVSP greater than 40 mm Hg) undergo right heart catheterization to confirm the diagnosis.

“We now have treatments we didn't have 5 or 10 years ago. … The evaluation is important to identify pulmonary hypertension and for prognosis,” said Dr. Huston, of the division of rheumatology at Johns Hopkins.

In the UNCOVER study published by Dr. Huston's group, 122 of 791 patients with scleroderma and mixed connective tissue disease seen in 50 community rheumatology practices had an existing diagnosis of PAH. But when the remaining 669 patients without a diagnosis of PAH subsequently underwent echocardiography, 89 had previously unrecognized PAH, for a total prevalence of 27% (Arthritis Rheum. 2005;52;2125–32).

Increased age at the onset of scleroderma is a major risk factor for PAH. Data from one study suggest that PAH risk increases 52% for every 10 years of age at disease onset, and that patients aged 60 and older have over twice the risk of younger patients (Chest 2003;124:2098–104). Other risk factors include severe Raynaud's phenomenon, low pulmonary diffusing capacity, calcinosis, Raynaud's disease, esophageal dysmotility, sclerodactyly, and telangiectasia (CREST) syndrome, he said.

PFT is useful for identifying PAH and for determining prognosis. In 71 scleroderma patients followed for a mean of 5 years, those with a carbon monoxide diffusing capacity (DLCO) of 40% or less had a 9% survival at 5 years, versus 75% among those with DLCO above 40% (Am. J. Med. 1984;77:1027–34). Pulmonary pressures were not measured in that study, but mortality is thought to be attributed to PAH, Dr. Huston noted.

The DLCO is also a useful predictor of who will develop PAH. In a retrospective case-control study of 212 scleroderma patients, the mean DLCO among the 106 with PAH was 52% of predicted 4.5 years prior to the PAH diagnosis, compared with 80% of predicted among the other 106 scleroderma patients who did not develop PAH (Arthritis Rheum. 2003;48:516–22).

Echocardiography is a useful companion screening tool. It had a sensitivity of 90% and specificity of 75% for identifying patients who had PAH on catheterization in a study of 33 scleroderma patients in whom clinical assessment, including ECG, chest x-ray, pulmonary function tests, and high-resolution computed tomography, raised suspicion of PAH (Br. J. Rheumatol. 1997;36:239–43). Echocardiography missed just two patients, both with pulmonary arterial systolic pressures (PASP) in the 30s. All patients with PASP above 40 mm Hg by echocardiography had abnormal pressures on catheterization.

As with PFT, echocardiography adds prognostic value. Increased mortality was tied to higher initial reading and with rising pressures in a study of 930 scleroderma patients, in whom mortality was 20% at 20 months among those with a single pressure of 30 mm Hg or greater. Rapid rises occurred more frequently in limited than in diffuse scleroderma (Rheumatology [Oxford]:2001;40:453–9).

In a study of 794 patients followed for 4 years, 3-year survival was inversely proportionate to mean PASP, from 75% among those with PASP under 32 mm Hg to 61% for 32–44 mm Hg, to 33% for pressures above 45 mm Hg (Ann. Rheum. Dis. 2003;62:1088–93).

Data support echocardiography and PFT for screening scleroderma, but Dr. Huston said areas of uncertainty include the role of exercise echocardiography in identifying patients with elevated right heart pressures on exercise but normal at rest, and the significance of a low-normal RVSP or low DLCO with normal echocardiography.

Flawed Drugs Still Give Hope

While five of the approved medications for treating pulmonary arterial hypertension offer patients hope that was unavailable a few years ago, each has drawbacks, Dr. Huston cautioned. (For the newest approval, see story below.)

The five medications are three prostanoids (epoprostenol, treprostinil, and inhaled lipoprost), an endothelin antagonist (bosentan) and the phosphodiesterase inhibitor sildenafil. Each was approved by the Food and Drug Administration after short-term randomized controlled trials, usually lasting 12–16 weeks. “We don't know what to expect in the long term,” Dr. Huston said.

The only drug to show a survival benefit was epoprostenol. Trials for the other drugs did not include enough patients to assess the drug's effect on mortality, and instead, used surrogate end points, like results of the 6-minute walk test or dyspnea questionnaires. Moreover, the large trials included patients with multiple causes of PAH, including scleroderma and lupus, groups that may not be comparable.

Epoprostenol requires a central intravenous line, the invasive nature of which carries an infection risk. The drug has a short half-life, which can lead to pump failure and disease worsening. Treprostinil can be infused subcutaneously and has a longer half-life, but a majority of patients experience pain at the infusion site. Inhaled lipoprost requires six to nine inhalations a day, and 10 minutes per inhalation, a process that patients find “a little cumbersome,” Dr. Huston said.

Bosentan has the advantage of oral administration but is associated with abnormal elevations on liver function tests, and it interacts with several common drugs. It is contraindicated with cyclosporine and glyburide, for example. Sildenafil, called Revatio instead of Viagra when used to treat PAH, can potentiate hypotension when used with nitroglycerin. It also interacts with bosentan.

It is not clear which agent is best, or if combination therapy might help patients further, said Dr. Huston, who added he had no financial conflicts of interest to disclose.

BALTIMORE — The hepatitis B vaccine does not appear to be associated with an increased risk for rheumatoid arthritis, Dr. Roger P. Baxter and his associates reported at a vaccine research conference sponsored by the National Foundation for Infectious Diseases.

Both acute and chronic arthropathies have been reported in adults vaccinated with the tetanus-diphtheria (Td), hepatitis B (HepB), and measles-mumps-rubella (MMR) vaccines. However, most of the evidence to support or refute a causal relationship between the Td or HepB vaccine and chronic arthritis has come from isolated case reports, uncontrolled observational studies, or studies that lacked sufficient statistical power, said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif., and his associates.

A case-control analysis designed to overcome the shortcomings of the previous studies included a cohort of continuous enrollees in Northern California Kaiser Permanente's health plan from Jan. 1, 1995, through Dec. 31, 1999, who were aged 15–59 years during Jan. 1, 1997-Dec. 31, 1999. Individuals who had made clinic visits for rheumatoid arthritis (RA) and other inflammatory conditions prior to their follow-up start date were excluded.

A total of 416 incident cases of RA were identified (based on definitive diagnosis at the time or subsequent assessment by a rheumatologist), and each was matched with three controls based on age and the number of clinic visits made during the year prior to the onset date. Rates of hepatitis B vaccination among the RA patients were compared with those of controls, with adjustment for sex, age, and exact number of clinic visits. Similar comparisons were made for the tetanus and influenza vaccines.

No statistically significant risk of RA was found for any of the three vaccines. Only 1% of RA patients versus 0.6% of controls had been exposed to the hepatitis B vaccine within 1–90 days of onset of RA symptoms, for an adjusted odds ratio of 1.48.

Within 1–180 days, the percentages were 1.9% with RA versus 0.9% of controls, giving a still insignificant odds ratio of 2.01. Within 1 year, 2.4% of RA cases and 1.6% of controls had been exposed to the vaccine, again insignificant at 1.42.

In all, only 10 of the 416 RA patients had received the HepB vaccine within 1 year of symptom onset, suggesting that “If there is an association, these data would imply that hepatitis B vaccine would only contribute to a small minority of cases,” Dr. Baxter and his associates said in their poster.

Results for the other two vaccines were also not significant, with adjusted odds ratios of 0.77–1.06 for tetanus and 0.66–1.11 for influenza.

Health care utilization was higher among those with RA, which was a slight confounder in this study despite the attempt to control for number of visits: Even after adjustment, there was still a significant residual effect for number of visits, with an odds ratio of 1.15.

“Basically, people who get vaccines of all kinds are different from those who don't, and underlying differences may confound the relationship with things like RA. We try to control for these factors by matching and analyses, but still we think there are differences. … People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines than people who don't utilize the system as much,” Dr. Baxter said in a follow-up interview.

However, he added, although the difference in utilization was statistically significant, it probably wasn't that different clinically. “We thought initially this was an important confounder. But in the end we found that although they were different, in reality we could adjust for the vast majority of the difference.”

'People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines.' DR. BAXTER

BALTIMORE — The hepatitis B vaccine does not appear to be associated with an increased risk for rheumatoid arthritis, Dr. Roger P. Baxter and his associates reported at a vaccine research conference sponsored by the National Foundation for Infectious Diseases.

Both acute and chronic arthropathies have been reported in adults vaccinated with the tetanus-diphtheria (Td), hepatitis B (HepB), and measles-mumps-rubella (MMR) vaccines. However, most of the evidence to support or refute a causal relationship between the Td or HepB vaccine and chronic arthritis has come from isolated case reports, uncontrolled observational studies, or studies that lacked sufficient statistical power, said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif., and his associates.

A case-control analysis designed to overcome the shortcomings of the previous studies included a cohort of continuous enrollees in Northern California Kaiser Permanente's health plan from Jan. 1, 1995, through Dec. 31, 1999, who were aged 15–59 years during Jan. 1, 1997-Dec. 31, 1999. Individuals who had made clinic visits for rheumatoid arthritis (RA) and other inflammatory conditions prior to their follow-up start date were excluded.

A total of 416 incident cases of RA were identified (based on definitive diagnosis at the time or subsequent assessment by a rheumatologist), and each was matched with three controls based on age and the number of clinic visits made during the year prior to the onset date. Rates of hepatitis B vaccination among the RA patients were compared with those of controls, with adjustment for sex, age, and exact number of clinic visits. Similar comparisons were made for the tetanus and influenza vaccines.

No statistically significant risk of RA was found for any of the three vaccines. Only 1% of RA patients versus 0.6% of controls had been exposed to the hepatitis B vaccine within 1–90 days of onset of RA symptoms, for an adjusted odds ratio of 1.48.

Within 1–180 days, the percentages were 1.9% with RA versus 0.9% of controls, giving a still insignificant odds ratio of 2.01. Within 1 year, 2.4% of RA cases and 1.6% of controls had been exposed to the vaccine, again insignificant at 1.42.

In all, only 10 of the 416 RA patients had received the HepB vaccine within 1 year of symptom onset, suggesting that “If there is an association, these data would imply that hepatitis B vaccine would only contribute to a small minority of cases,” Dr. Baxter and his associates said in their poster.

Results for the other two vaccines were also not significant, with adjusted odds ratios of 0.77–1.06 for tetanus and 0.66–1.11 for influenza.

Health care utilization was higher among those with RA, which was a slight confounder in this study despite the attempt to control for number of visits: Even after adjustment, there was still a significant residual effect for number of visits, with an odds ratio of 1.15.

“Basically, people who get vaccines of all kinds are different from those who don't, and underlying differences may confound the relationship with things like RA. We try to control for these factors by matching and analyses, but still we think there are differences. … People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines than people who don't utilize the system as much,” Dr. Baxter said in a follow-up interview.

However, he added, although the difference in utilization was statistically significant, it probably wasn't that different clinically. “We thought initially this was an important confounder. But in the end we found that although they were different, in reality we could adjust for the vast majority of the difference.”

'People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines.' DR. BAXTER

BALTIMORE — The hepatitis B vaccine does not appear to be associated with an increased risk for rheumatoid arthritis, Dr. Roger P. Baxter and his associates reported at a vaccine research conference sponsored by the National Foundation for Infectious Diseases.

Both acute and chronic arthropathies have been reported in adults vaccinated with the tetanus-diphtheria (Td), hepatitis B (HepB), and measles-mumps-rubella (MMR) vaccines. However, most of the evidence to support or refute a causal relationship between the Td or HepB vaccine and chronic arthritis has come from isolated case reports, uncontrolled observational studies, or studies that lacked sufficient statistical power, said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif., and his associates.

A case-control analysis designed to overcome the shortcomings of the previous studies included a cohort of continuous enrollees in Northern California Kaiser Permanente's health plan from Jan. 1, 1995, through Dec. 31, 1999, who were aged 15–59 years during Jan. 1, 1997-Dec. 31, 1999. Individuals who had made clinic visits for rheumatoid arthritis (RA) and other inflammatory conditions prior to their follow-up start date were excluded.

A total of 416 incident cases of RA were identified (based on definitive diagnosis at the time or subsequent assessment by a rheumatologist), and each was matched with three controls based on age and the number of clinic visits made during the year prior to the onset date. Rates of hepatitis B vaccination among the RA patients were compared with those of controls, with adjustment for sex, age, and exact number of clinic visits. Similar comparisons were made for the tetanus and influenza vaccines.

No statistically significant risk of RA was found for any of the three vaccines. Only 1% of RA patients versus 0.6% of controls had been exposed to the hepatitis B vaccine within 1–90 days of onset of RA symptoms, for an adjusted odds ratio of 1.48.

Within 1–180 days, the percentages were 1.9% with RA versus 0.9% of controls, giving a still insignificant odds ratio of 2.01. Within 1 year, 2.4% of RA cases and 1.6% of controls had been exposed to the vaccine, again insignificant at 1.42.

In all, only 10 of the 416 RA patients had received the HepB vaccine within 1 year of symptom onset, suggesting that “If there is an association, these data would imply that hepatitis B vaccine would only contribute to a small minority of cases,” Dr. Baxter and his associates said in their poster.

Results for the other two vaccines were also not significant, with adjusted odds ratios of 0.77–1.06 for tetanus and 0.66–1.11 for influenza.

Health care utilization was higher among those with RA, which was a slight confounder in this study despite the attempt to control for number of visits: Even after adjustment, there was still a significant residual effect for number of visits, with an odds ratio of 1.15.

“Basically, people who get vaccines of all kinds are different from those who don't, and underlying differences may confound the relationship with things like RA. We try to control for these factors by matching and analyses, but still we think there are differences. … People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines than people who don't utilize the system as much,” Dr. Baxter said in a follow-up interview.

However, he added, although the difference in utilization was statistically significant, it probably wasn't that different clinically. “We thought initially this was an important confounder. But in the end we found that although they were different, in reality we could adjust for the vast majority of the difference.”

'People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines.' DR. BAXTER

BALTIMORE — Immunity to hepatitis B might wane 15 years after vaccination among those who received the vaccine series beginning at birth, Dr. Stephanie R. Bialek said at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Data from long-term follow-up studies have established that people who received the three-dose hepatitis B vaccine series beginning after 6 months of age have long-term protection against chronic hepatitis B infection and do not need booster shots. In that population, breakthrough infections occur in only about 0%–7% of individuals more than 20 years after vaccination, and most of those are asymptomatic.

Chronic hepatitis B infection is extremely rare, occurring in fewer than 1%, said Dr. Bialek, a medical officer in the division of viral hepatitis at the Centers for Disease Control and Prevention.

However, it is not known whether the same is true for those who begin the vaccine series at birth, a practice that was first recommended in the United States in 1992.

Thus far, 10-year data in that population suggest that breakthrough infections are rare, occurring in 0%–6%, and there have been no reports of chronic infections among vaccine responders.

On the other hand, protective concentrations of antibody to hepatitis B surface antigen (anti-HBs), defined as levels greater than 10 mIU/mL, are present in fewer than 20% at 10 years, compared with more than 50% at 7–22 years among those vaccinated beginning after 6 months of age, Dr. Bialek noted.

Now, new data from an investigation conducted in Micronesia suggest that protection in those vaccinated as newborns may begin to subside at around 15 years.

The Federated States of Micronesia, a U.S.-affiliated jurisdiction in the western Pacific where hepatitis B virus infection had historically been endemic, implemented hepatitis B vaccination beginning at birth in 1989.

Micronesian adolescents who had received three doses of recombinant hepatitis B vaccine (at birth, 2 months, and 6 months of age) and who had tested negative for antibody to hepatitis B core antigen (anti-HBc) 2 years after the primary vaccination were followed for 15 years after the primary vaccination. Recombivax had been given in doses of 5 mcg at birth, followed by doses of 2.5 mcg at 2 and 6 months. Today, 5 mcg is recommended for all three doses, she noted.

In 2006, investigators were able to track down 105 of the 238 children who had received three doses of hepatitis B vaccine, were anti-HBc-negative, and had been tested for anti-HBs at 35 months. By then, they had a median age of 15.8 years, with a median of 15.1 years since completion of the vaccine series. A total of eight (7.6%) were anti-HBc-positive, but none was HBsAg-positive.

Booster doses of vaccine were given to the 96 who were anti-HBc-negative in 2006. Of these, only 7 (7%) had anti-HBs concentrations greater than 10 mIU/mL at the time they were given the booster, and only about half (45, or 47%) had anamnestic anti-HBs responses at 14 days after the booster (defined as an increase in anti-HBs concentration greater than 10 mIU/mL). Absence of an anamnestic response might indicate waning immunity, Dr. Bialek said at the meeting.

Limitations of this study include the fact that maternal HBsAg status was not known, postvaccination testing had not been performed (some of the participants may have been nonresponders), and the vaccine dose used for the second and third doses was half of the currently recommended dose. And importantly, “Just because they didn't boost doesn't mean they're not protected,” Dr. Bialek said in an interview following her presentation. At least two ongoing studies are investigating this issue further, she added.

BALTIMORE — Immunity to hepatitis B might wane 15 years after vaccination among those who received the vaccine series beginning at birth, Dr. Stephanie R. Bialek said at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Data from long-term follow-up studies have established that people who received the three-dose hepatitis B vaccine series beginning after 6 months of age have long-term protection against chronic hepatitis B infection and do not need booster shots. In that population, breakthrough infections occur in only about 0%–7% of individuals more than 20 years after vaccination, and most of those are asymptomatic.

Chronic hepatitis B infection is extremely rare, occurring in fewer than 1%, said Dr. Bialek, a medical officer in the division of viral hepatitis at the Centers for Disease Control and Prevention.

However, it is not known whether the same is true for those who begin the vaccine series at birth, a practice that was first recommended in the United States in 1992.

Thus far, 10-year data in that population suggest that breakthrough infections are rare, occurring in 0%–6%, and there have been no reports of chronic infections among vaccine responders.

On the other hand, protective concentrations of antibody to hepatitis B surface antigen (anti-HBs), defined as levels greater than 10 mIU/mL, are present in fewer than 20% at 10 years, compared with more than 50% at 7–22 years among those vaccinated beginning after 6 months of age, Dr. Bialek noted.

Now, new data from an investigation conducted in Micronesia suggest that protection in those vaccinated as newborns may begin to subside at around 15 years.

The Federated States of Micronesia, a U.S.-affiliated jurisdiction in the western Pacific where hepatitis B virus infection had historically been endemic, implemented hepatitis B vaccination beginning at birth in 1989.

Micronesian adolescents who had received three doses of recombinant hepatitis B vaccine (at birth, 2 months, and 6 months of age) and who had tested negative for antibody to hepatitis B core antigen (anti-HBc) 2 years after the primary vaccination were followed for 15 years after the primary vaccination. Recombivax had been given in doses of 5 mcg at birth, followed by doses of 2.5 mcg at 2 and 6 months. Today, 5 mcg is recommended for all three doses, she noted.

In 2006, investigators were able to track down 105 of the 238 children who had received three doses of hepatitis B vaccine, were anti-HBc-negative, and had been tested for anti-HBs at 35 months. By then, they had a median age of 15.8 years, with a median of 15.1 years since completion of the vaccine series. A total of eight (7.6%) were anti-HBc-positive, but none was HBsAg-positive.

Booster doses of vaccine were given to the 96 who were anti-HBc-negative in 2006. Of these, only 7 (7%) had anti-HBs concentrations greater than 10 mIU/mL at the time they were given the booster, and only about half (45, or 47%) had anamnestic anti-HBs responses at 14 days after the booster (defined as an increase in anti-HBs concentration greater than 10 mIU/mL). Absence of an anamnestic response might indicate waning immunity, Dr. Bialek said at the meeting.

Limitations of this study include the fact that maternal HBsAg status was not known, postvaccination testing had not been performed (some of the participants may have been nonresponders), and the vaccine dose used for the second and third doses was half of the currently recommended dose. And importantly, “Just because they didn't boost doesn't mean they're not protected,” Dr. Bialek said in an interview following her presentation. At least two ongoing studies are investigating this issue further, she added.

BALTIMORE — Immunity to hepatitis B might wane 15 years after vaccination among those who received the vaccine series beginning at birth, Dr. Stephanie R. Bialek said at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Data from long-term follow-up studies have established that people who received the three-dose hepatitis B vaccine series beginning after 6 months of age have long-term protection against chronic hepatitis B infection and do not need booster shots. In that population, breakthrough infections occur in only about 0%–7% of individuals more than 20 years after vaccination, and most of those are asymptomatic.

Chronic hepatitis B infection is extremely rare, occurring in fewer than 1%, said Dr. Bialek, a medical officer in the division of viral hepatitis at the Centers for Disease Control and Prevention.

However, it is not known whether the same is true for those who begin the vaccine series at birth, a practice that was first recommended in the United States in 1992.

Thus far, 10-year data in that population suggest that breakthrough infections are rare, occurring in 0%–6%, and there have been no reports of chronic infections among vaccine responders.

On the other hand, protective concentrations of antibody to hepatitis B surface antigen (anti-HBs), defined as levels greater than 10 mIU/mL, are present in fewer than 20% at 10 years, compared with more than 50% at 7–22 years among those vaccinated beginning after 6 months of age, Dr. Bialek noted.

Now, new data from an investigation conducted in Micronesia suggest that protection in those vaccinated as newborns may begin to subside at around 15 years.

The Federated States of Micronesia, a U.S.-affiliated jurisdiction in the western Pacific where hepatitis B virus infection had historically been endemic, implemented hepatitis B vaccination beginning at birth in 1989.

Micronesian adolescents who had received three doses of recombinant hepatitis B vaccine (at birth, 2 months, and 6 months of age) and who had tested negative for antibody to hepatitis B core antigen (anti-HBc) 2 years after the primary vaccination were followed for 15 years after the primary vaccination. Recombivax had been given in doses of 5 mcg at birth, followed by doses of 2.5 mcg at 2 and 6 months. Today, 5 mcg is recommended for all three doses, she noted.

In 2006, investigators were able to track down 105 of the 238 children who had received three doses of hepatitis B vaccine, were anti-HBc-negative, and had been tested for anti-HBs at 35 months. By then, they had a median age of 15.8 years, with a median of 15.1 years since completion of the vaccine series. A total of eight (7.6%) were anti-HBc-positive, but none was HBsAg-positive.

Booster doses of vaccine were given to the 96 who were anti-HBc-negative in 2006. Of these, only 7 (7%) had anti-HBs concentrations greater than 10 mIU/mL at the time they were given the booster, and only about half (45, or 47%) had anamnestic anti-HBs responses at 14 days after the booster (defined as an increase in anti-HBs concentration greater than 10 mIU/mL). Absence of an anamnestic response might indicate waning immunity, Dr. Bialek said at the meeting.

Limitations of this study include the fact that maternal HBsAg status was not known, postvaccination testing had not been performed (some of the participants may have been nonresponders), and the vaccine dose used for the second and third doses was half of the currently recommended dose. And importantly, “Just because they didn't boost doesn't mean they're not protected,” Dr. Bialek said in an interview following her presentation. At least two ongoing studies are investigating this issue further, she added.

AMELIA ISLAND, FLA. — Neurogenic sources should be considered in patients who have severe pruritus for which a cutaneous cause can't be found, Dr. Jeffrey D. Bernhard said at a symposium sponsored by the Dermatology Foundation.

In many of these cases, there is a nonspecific rash that is caused by the patients' repeated scratching rather than by the disease itself, which can lead to misdiagnosis.

“Patients who scratch a lot can end up with a nonspecific rash that may be eczematous in nature. Don't assume there isn't an underlying noncutaneous cause,” said Dr. Bernhard, professor of medicine and physiology in the division of dermatology at the University of Massachusetts, Worcester.

Notalgia paresthetica and brachioradial pruritus are two examples of severe itches that arise in the peripheral nervous system rather than on the skin.

Localized pruritus of the midback, called notalgia paresthetica (NP), occurs in about 10% of the population. For most people, it's simply an occasional annoying itch. But in a small number of individuals, it manifests as a severe, constant pruritus on a patch of skin in one or both of the medial scapular borders that may be accompanied by numbness, tingling, formication, burning, hyperalgesia, and tenderness.

Associated findings also may include hyperesthesia, along with reductions in pinprick sensitivity, light-touch sensation, two-point discrimination, temperature sensitivity, and sweat response. Although NP does not ordinarily produce visible skin changes, there may be hyperpigmentation over the pruritic area and sometimes a “ragged spot” on a blouse or shirt, both caused by the patients' persistent scratching and/or rubbing.

The condition is believed to result from spinal nerve impingement. In a study of 43 NP patients with 61 lesions, 34 patients had vertebral pathology—including degenerative changes and herniated nucleus pulposus—on spinal radiography. In 28 of the 34, the changes were most prominent in the vertebrae that corresponded to a lesional dermatome (J. Am. Acad. Dermatol. 2005;52:1085–7).

The authors speculated that spinal pathologies that cannot easily be diagnosed radiographically, such as cervical fibrous bands or muscle spasms, also might contribute to NP. They urged physicians who are treating the neuromuscular problems in these patients to consider pruritus in the list of signs and symptoms of spinal disease.

Another study of 12 NP cases found dorsal arthrosis or spinal static disequilibrium on spinal x-ray in 9 patients. Symptoms improved in four of six patients who underwent spinal and paraspinal ultrasound or radiation physiotherapy. Those authors noted that capsaicin has been reported to relieve symptoms in some NP patients, but only transiently (J. Eur. Acad. Dermatol. Venereol. 1999;12:215–21).

NP is an uncomfortable condition, but brachioradial pruritus (BP) can be excruciating. Patients describe BP as a “horrendous itch” that has a “tingling, prickling, sometimes burning sensation.” It also is commonly associated with abnormal pinprick and temperature sensations. In contrast to NP, in which patients may scratch and rub to alleviate the itch, patients with BP sometimes actually gouge their forearms attempting to alleviate the sensation, Dr. Bernhard noted.

As with NP, evidence suggests that BP also arises from nerve compression or damage. In a retrospective study for which Dr. Bernhard was a coinvestigator, a chart review of 22 patients with BP seen between 1993 and 2000 showed that in all 11 for whom cervical spine radiography had been performed, the cervical spine disease correlated with the location of the itching (J. Am. Acad. Dermatol. 2003;48:521–4).

In another study of seven consecutive BP patients, electrophysiologic studies of the median, ulnar, and radial nerves yielded abnormal responses diagnostic of cervical radiculopathy in four. One of those patients had polyneuropathy secondary to diabetes. Six of the seven reported sunlight as a trigger for their itch (J. Am. Acad. Dermatol. 2003;48:825–8).

Indeed, BP also has been named “solar pruritus” because of this curious sun-triggering phenomenon. One recent study attempted to determine whether BP was, in fact, caused by a nerve compression in the cervical spine or by prolonged exposure to sunlight. Skin biopsy specimens collected from itchy skin of 16 BP patients revealed cutaneous innervation visualized by antibodies against protein gene product 9.5 (general neuronal marker), by antibodies against calcitonin gene-related peptide (marker for thin sensory nerve fibers), and by antibodies against VR1-receptor (marker for capsaicin-sensitive nerve fibers).

Compared with controls, the BP patients had reductions of 23%–43% in various nerve fibers. Itching of the arms or shoulders was seasonal in all but two of the patients, occurring more often during August-December than during the rest of the year (J. Am. Acad. Dermatol. 2005;52:142–5).

“The temporal course of brachioradial pruritus and the [histologic] changes in the skin similar to those caused by ultraviolet light indicate that sunlight is an eliciting factor and that cervical spine disease can be a predisposing factor,” the authors wrote.

Another itchy condition, anogenital pruritus, also may arise from nerve pathology. In a study of 18 men and 2 women (mean age 53 years) with “idiopathic” anogenital pruritus, degenerative changes in the lower spine were found on x-ray in 16, and lumbosacral radiculopathy confirmed by nerve conduction studies in 16. Paravertebral injections of triamcinolone and lidocaine reduced the degree of pruritus and sleep disturbance but were less effective in reducing other symptoms such as burning, tingling, and pain (Am. J. Acad. Dermatol. 2005;52:61–6).

Finally, there are many references to conditions such as “neurotic excoriation,” “psychogenic pruritus,” “senile pruritus,” in the literature, all suggesting that the itch is in the patient's head. “You have to be careful about assuming people are crazy when they actually may have pathologic changes in the nervous system that are making them itch,” Dr. Bernhard said.

Localized pruritus of the midback occurs in about 10% of the population.

Patients who have brachioradial pruritus sometimes gouge their forearms to alleviate the sensation. Photos courtesy Dr. Jeffrey D. Bernhard

AMELIA ISLAND, FLA. — Neurogenic sources should be considered in patients who have severe pruritus for which a cutaneous cause can't be found, Dr. Jeffrey D. Bernhard said at a symposium sponsored by the Dermatology Foundation.

In many of these cases, there is a nonspecific rash that is caused by the patients' repeated scratching rather than by the disease itself, which can lead to misdiagnosis.

“Patients who scratch a lot can end up with a nonspecific rash that may be eczematous in nature. Don't assume there isn't an underlying noncutaneous cause,” said Dr. Bernhard, professor of medicine and physiology in the division of dermatology at the University of Massachusetts, Worcester.

Notalgia paresthetica and brachioradial pruritus are two examples of severe itches that arise in the peripheral nervous system rather than on the skin.

Localized pruritus of the midback, called notalgia paresthetica (NP), occurs in about 10% of the population. For most people, it's simply an occasional annoying itch. But in a small number of individuals, it manifests as a severe, constant pruritus on a patch of skin in one or both of the medial scapular borders that may be accompanied by numbness, tingling, formication, burning, hyperalgesia, and tenderness.

Associated findings also may include hyperesthesia, along with reductions in pinprick sensitivity, light-touch sensation, two-point discrimination, temperature sensitivity, and sweat response. Although NP does not ordinarily produce visible skin changes, there may be hyperpigmentation over the pruritic area and sometimes a “ragged spot” on a blouse or shirt, both caused by the patients' persistent scratching and/or rubbing.

The condition is believed to result from spinal nerve impingement. In a study of 43 NP patients with 61 lesions, 34 patients had vertebral pathology—including degenerative changes and herniated nucleus pulposus—on spinal radiography. In 28 of the 34, the changes were most prominent in the vertebrae that corresponded to a lesional dermatome (J. Am. Acad. Dermatol. 2005;52:1085–7).

The authors speculated that spinal pathologies that cannot easily be diagnosed radiographically, such as cervical fibrous bands or muscle spasms, also might contribute to NP. They urged physicians who are treating the neuromuscular problems in these patients to consider pruritus in the list of signs and symptoms of spinal disease.

Another study of 12 NP cases found dorsal arthrosis or spinal static disequilibrium on spinal x-ray in 9 patients. Symptoms improved in four of six patients who underwent spinal and paraspinal ultrasound or radiation physiotherapy. Those authors noted that capsaicin has been reported to relieve symptoms in some NP patients, but only transiently (J. Eur. Acad. Dermatol. Venereol. 1999;12:215–21).

NP is an uncomfortable condition, but brachioradial pruritus (BP) can be excruciating. Patients describe BP as a “horrendous itch” that has a “tingling, prickling, sometimes burning sensation.” It also is commonly associated with abnormal pinprick and temperature sensations. In contrast to NP, in which patients may scratch and rub to alleviate the itch, patients with BP sometimes actually gouge their forearms attempting to alleviate the sensation, Dr. Bernhard noted.

As with NP, evidence suggests that BP also arises from nerve compression or damage. In a retrospective study for which Dr. Bernhard was a coinvestigator, a chart review of 22 patients with BP seen between 1993 and 2000 showed that in all 11 for whom cervical spine radiography had been performed, the cervical spine disease correlated with the location of the itching (J. Am. Acad. Dermatol. 2003;48:521–4).

In another study of seven consecutive BP patients, electrophysiologic studies of the median, ulnar, and radial nerves yielded abnormal responses diagnostic of cervical radiculopathy in four. One of those patients had polyneuropathy secondary to diabetes. Six of the seven reported sunlight as a trigger for their itch (J. Am. Acad. Dermatol. 2003;48:825–8).

Indeed, BP also has been named “solar pruritus” because of this curious sun-triggering phenomenon. One recent study attempted to determine whether BP was, in fact, caused by a nerve compression in the cervical spine or by prolonged exposure to sunlight. Skin biopsy specimens collected from itchy skin of 16 BP patients revealed cutaneous innervation visualized by antibodies against protein gene product 9.5 (general neuronal marker), by antibodies against calcitonin gene-related peptide (marker for thin sensory nerve fibers), and by antibodies against VR1-receptor (marker for capsaicin-sensitive nerve fibers).

Compared with controls, the BP patients had reductions of 23%–43% in various nerve fibers. Itching of the arms or shoulders was seasonal in all but two of the patients, occurring more often during August-December than during the rest of the year (J. Am. Acad. Dermatol. 2005;52:142–5).

“The temporal course of brachioradial pruritus and the [histologic] changes in the skin similar to those caused by ultraviolet light indicate that sunlight is an eliciting factor and that cervical spine disease can be a predisposing factor,” the authors wrote.

Another itchy condition, anogenital pruritus, also may arise from nerve pathology. In a study of 18 men and 2 women (mean age 53 years) with “idiopathic” anogenital pruritus, degenerative changes in the lower spine were found on x-ray in 16, and lumbosacral radiculopathy confirmed by nerve conduction studies in 16. Paravertebral injections of triamcinolone and lidocaine reduced the degree of pruritus and sleep disturbance but were less effective in reducing other symptoms such as burning, tingling, and pain (Am. J. Acad. Dermatol. 2005;52:61–6).

Finally, there are many references to conditions such as “neurotic excoriation,” “psychogenic pruritus,” “senile pruritus,” in the literature, all suggesting that the itch is in the patient's head. “You have to be careful about assuming people are crazy when they actually may have pathologic changes in the nervous system that are making them itch,” Dr. Bernhard said.

Localized pruritus of the midback occurs in about 10% of the population.

Patients who have brachioradial pruritus sometimes gouge their forearms to alleviate the sensation. Photos courtesy Dr. Jeffrey D. Bernhard

AMELIA ISLAND, FLA. — Neurogenic sources should be considered in patients who have severe pruritus for which a cutaneous cause can't be found, Dr. Jeffrey D. Bernhard said at a symposium sponsored by the Dermatology Foundation.

In many of these cases, there is a nonspecific rash that is caused by the patients' repeated scratching rather than by the disease itself, which can lead to misdiagnosis.

“Patients who scratch a lot can end up with a nonspecific rash that may be eczematous in nature. Don't assume there isn't an underlying noncutaneous cause,” said Dr. Bernhard, professor of medicine and physiology in the division of dermatology at the University of Massachusetts, Worcester.

Notalgia paresthetica and brachioradial pruritus are two examples of severe itches that arise in the peripheral nervous system rather than on the skin.

Localized pruritus of the midback, called notalgia paresthetica (NP), occurs in about 10% of the population. For most people, it's simply an occasional annoying itch. But in a small number of individuals, it manifests as a severe, constant pruritus on a patch of skin in one or both of the medial scapular borders that may be accompanied by numbness, tingling, formication, burning, hyperalgesia, and tenderness.

Associated findings also may include hyperesthesia, along with reductions in pinprick sensitivity, light-touch sensation, two-point discrimination, temperature sensitivity, and sweat response. Although NP does not ordinarily produce visible skin changes, there may be hyperpigmentation over the pruritic area and sometimes a “ragged spot” on a blouse or shirt, both caused by the patients' persistent scratching and/or rubbing.

The condition is believed to result from spinal nerve impingement. In a study of 43 NP patients with 61 lesions, 34 patients had vertebral pathology—including degenerative changes and herniated nucleus pulposus—on spinal radiography. In 28 of the 34, the changes were most prominent in the vertebrae that corresponded to a lesional dermatome (J. Am. Acad. Dermatol. 2005;52:1085–7).

The authors speculated that spinal pathologies that cannot easily be diagnosed radiographically, such as cervical fibrous bands or muscle spasms, also might contribute to NP. They urged physicians who are treating the neuromuscular problems in these patients to consider pruritus in the list of signs and symptoms of spinal disease.

Another study of 12 NP cases found dorsal arthrosis or spinal static disequilibrium on spinal x-ray in 9 patients. Symptoms improved in four of six patients who underwent spinal and paraspinal ultrasound or radiation physiotherapy. Those authors noted that capsaicin has been reported to relieve symptoms in some NP patients, but only transiently (J. Eur. Acad. Dermatol. Venereol. 1999;12:215–21).

NP is an uncomfortable condition, but brachioradial pruritus (BP) can be excruciating. Patients describe BP as a “horrendous itch” that has a “tingling, prickling, sometimes burning sensation.” It also is commonly associated with abnormal pinprick and temperature sensations. In contrast to NP, in which patients may scratch and rub to alleviate the itch, patients with BP sometimes actually gouge their forearms attempting to alleviate the sensation, Dr. Bernhard noted.

As with NP, evidence suggests that BP also arises from nerve compression or damage. In a retrospective study for which Dr. Bernhard was a coinvestigator, a chart review of 22 patients with BP seen between 1993 and 2000 showed that in all 11 for whom cervical spine radiography had been performed, the cervical spine disease correlated with the location of the itching (J. Am. Acad. Dermatol. 2003;48:521–4).

In another study of seven consecutive BP patients, electrophysiologic studies of the median, ulnar, and radial nerves yielded abnormal responses diagnostic of cervical radiculopathy in four. One of those patients had polyneuropathy secondary to diabetes. Six of the seven reported sunlight as a trigger for their itch (J. Am. Acad. Dermatol. 2003;48:825–8).

Indeed, BP also has been named “solar pruritus” because of this curious sun-triggering phenomenon. One recent study attempted to determine whether BP was, in fact, caused by a nerve compression in the cervical spine or by prolonged exposure to sunlight. Skin biopsy specimens collected from itchy skin of 16 BP patients revealed cutaneous innervation visualized by antibodies against protein gene product 9.5 (general neuronal marker), by antibodies against calcitonin gene-related peptide (marker for thin sensory nerve fibers), and by antibodies against VR1-receptor (marker for capsaicin-sensitive nerve fibers).

Compared with controls, the BP patients had reductions of 23%–43% in various nerve fibers. Itching of the arms or shoulders was seasonal in all but two of the patients, occurring more often during August-December than during the rest of the year (J. Am. Acad. Dermatol. 2005;52:142–5).

“The temporal course of brachioradial pruritus and the [histologic] changes in the skin similar to those caused by ultraviolet light indicate that sunlight is an eliciting factor and that cervical spine disease can be a predisposing factor,” the authors wrote.

Another itchy condition, anogenital pruritus, also may arise from nerve pathology. In a study of 18 men and 2 women (mean age 53 years) with “idiopathic” anogenital pruritus, degenerative changes in the lower spine were found on x-ray in 16, and lumbosacral radiculopathy confirmed by nerve conduction studies in 16. Paravertebral injections of triamcinolone and lidocaine reduced the degree of pruritus and sleep disturbance but were less effective in reducing other symptoms such as burning, tingling, and pain (Am. J. Acad. Dermatol. 2005;52:61–6).

Finally, there are many references to conditions such as “neurotic excoriation,” “psychogenic pruritus,” “senile pruritus,” in the literature, all suggesting that the itch is in the patient's head. “You have to be careful about assuming people are crazy when they actually may have pathologic changes in the nervous system that are making them itch,” Dr. Bernhard said.

Localized pruritus of the midback occurs in about 10% of the population.

Patients who have brachioradial pruritus sometimes gouge their forearms to alleviate the sensation. Photos courtesy Dr. Jeffrey D. Bernhard

BALTIMORE — In settings with good access to care and high immunization rates, asking patients if they've received a tetanus booster in the last 10 years is a fairly accurate way to determine if they need one, Dr. M. Hassan Murad and his associates said in a poster presentation at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Patients who answer “yes” are probably right and do not need readministration of the vaccine. But those who say either “no” or “I don't know” should receive a tetanus-diphtheria (Td) booster as long as there are no contraindications, said Dr. Murad of the division of preventive medicine at the Mayo Clinic, Rochester, Minn.

Although previous studies have demonstrated poor accuracy of patients' recall of their last Td booster, this has not been evaluated previously in settings where immunization rates are high and good documentation is available. In this study, 572 patients of an employee health clinic of a large health care organization were asked whether they had a Td booster in the last 10 years. Of those, 65.6% were able to answer either “yes” or “no.”

Comparison of their responses with their charts yielded high sensitivity (92.4%) and low specificity (26.5%). Accuracy of recall did not differ by age or gender, Dr. Murad and his associates reported.

The results from this study patient population are likely generalizable to those of other working-age adults of similar education level. “Since the results rely in significant part on human memory of a rare event—a once-every-10-years shot—they probably reflect useful information. … The general characteristics of our population are they were mostly working age, education generally high school graduate or greater, and nearly all have good access to routine office care. That is probably similar to many office practices around the country,” Dr. Murad said in a follow-up interview.

The advantage to conducting this study at the Mayo Clinic is that the institution keeps exceptionally good electronic immunization records of all employees, he noted. “In addition, we believe that our results are generalizable to the newer form of the vaccine [tetanus-diphtheria-acellular pertussis] since it is given at the same interval and in similar situations.”

BALTIMORE — In settings with good access to care and high immunization rates, asking patients if they've received a tetanus booster in the last 10 years is a fairly accurate way to determine if they need one, Dr. M. Hassan Murad and his associates said in a poster presentation at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Patients who answer “yes” are probably right and do not need readministration of the vaccine. But those who say either “no” or “I don't know” should receive a tetanus-diphtheria (Td) booster as long as there are no contraindications, said Dr. Murad of the division of preventive medicine at the Mayo Clinic, Rochester, Minn.

Although previous studies have demonstrated poor accuracy of patients' recall of their last Td booster, this has not been evaluated previously in settings where immunization rates are high and good documentation is available. In this study, 572 patients of an employee health clinic of a large health care organization were asked whether they had a Td booster in the last 10 years. Of those, 65.6% were able to answer either “yes” or “no.”

Comparison of their responses with their charts yielded high sensitivity (92.4%) and low specificity (26.5%). Accuracy of recall did not differ by age or gender, Dr. Murad and his associates reported.

The results from this study patient population are likely generalizable to those of other working-age adults of similar education level. “Since the results rely in significant part on human memory of a rare event—a once-every-10-years shot—they probably reflect useful information. … The general characteristics of our population are they were mostly working age, education generally high school graduate or greater, and nearly all have good access to routine office care. That is probably similar to many office practices around the country,” Dr. Murad said in a follow-up interview.

The advantage to conducting this study at the Mayo Clinic is that the institution keeps exceptionally good electronic immunization records of all employees, he noted. “In addition, we believe that our results are generalizable to the newer form of the vaccine [tetanus-diphtheria-acellular pertussis] since it is given at the same interval and in similar situations.”

BALTIMORE — In settings with good access to care and high immunization rates, asking patients if they've received a tetanus booster in the last 10 years is a fairly accurate way to determine if they need one, Dr. M. Hassan Murad and his associates said in a poster presentation at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Patients who answer “yes” are probably right and do not need readministration of the vaccine. But those who say either “no” or “I don't know” should receive a tetanus-diphtheria (Td) booster as long as there are no contraindications, said Dr. Murad of the division of preventive medicine at the Mayo Clinic, Rochester, Minn.

Although previous studies have demonstrated poor accuracy of patients' recall of their last Td booster, this has not been evaluated previously in settings where immunization rates are high and good documentation is available. In this study, 572 patients of an employee health clinic of a large health care organization were asked whether they had a Td booster in the last 10 years. Of those, 65.6% were able to answer either “yes” or “no.”

Comparison of their responses with their charts yielded high sensitivity (92.4%) and low specificity (26.5%). Accuracy of recall did not differ by age or gender, Dr. Murad and his associates reported.

The results from this study patient population are likely generalizable to those of other working-age adults of similar education level. “Since the results rely in significant part on human memory of a rare event—a once-every-10-years shot—they probably reflect useful information. … The general characteristics of our population are they were mostly working age, education generally high school graduate or greater, and nearly all have good access to routine office care. That is probably similar to many office practices around the country,” Dr. Murad said in a follow-up interview.

The advantage to conducting this study at the Mayo Clinic is that the institution keeps exceptionally good electronic immunization records of all employees, he noted. “In addition, we believe that our results are generalizable to the newer form of the vaccine [tetanus-diphtheria-acellular pertussis] since it is given at the same interval and in similar situations.”

BALTIMORE — The hepatitis B vaccine does not appear to be associated with an increased risk for rheumatoid arthritis, Dr. Roger P. Baxter and his associates reported at a vaccine research conference sponsored by the National Foundation for Infectious Diseases.

Both acute and chronic arthropathies have been reported in adults vaccinated with the tetanus-diphtheria (Td), hepatitis B (HepB), and measles-mumps-rubella (MMR) vaccines.

However, most of the evidence to support or refute a causal relationship between the Td or HepB vaccine and chronic arthritis has come from isolated case reports, uncontrolled observational studies, or studies that lacked sufficient statistical power, said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif., and his associates.

A case-control analysis designed to overcome the shortcomings of the previous studies included a cohort of continuous enrollees in Northern California Kaiser Permanente's health plan from Jan. 1, 1995, through Dec. 31, 1999, who were aged 15–59 years during Jan. 1, 1997-Dec. 31, 1999.

Individuals who had made clinic visits for rheumatoid arthritis (RA) and other inflammatory conditions prior to their follow-up start date were excluded.

A total of 416 incident cases of RA were identified (based on definitive diagnosis at the time or subsequent assessment by a rheumatologist), and each was matched with three controls based on age and the number of clinic visits made during the year prior to the onset date.

Rates of hepatitis B vaccination among the RA patients were compared with those of controls, with adjustment for sex, age, and exact number of clinic visits. Similar comparisons were made for the tetanus and influenza vaccines.

No statistically significant risk of RA was found for any of the three vaccines. Only 1% of RA patients versus 0.6% of controls had been exposed to the hepatitis B vaccine within 1–90 days of onset of RA symptoms, for an adjusted odds ratio of 1.48.

Within 1–180 days, the percentages were 1.9% with RA versus 0.9% of controls, giving a still insignificant odds ratio of 2.01. Within 1 year, 2.4% of RA cases and 1.6% of controls had been exposed to the vaccine, again insignificant at 1.42.

In all, only 10 of the 416 RA patients had received the HepB vaccine within 1 year of symptom onset, suggesting that “if there is an association, these data would imply that hepatitis B vaccine would only contribute to a small minority of cases,” Dr. Baxter and his associates said in their poster.

Results for the other two vaccines were also not significant, with adjusted odds ratios of 0.77–1.06 for tetanus and 0.66–1.11 for influenza.

Health care utilization was higher among those with RA, which was a slight confounder in this study despite the attempt to control for number of visits: Even after adjustment, there was still a significant residual effect for number of visits, with an odds ratio of 1.15.

“Basically, people who get vaccines of all kinds are different from those who don't, and underlying differences may confound the relationship with things like RA. We try to control for these factors by matching and analyses, but still we think there are differences. … People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines than people who don't utilize the system as much,” Dr. Baxter said in a follow-up interview.

However, he added, although the difference in utilization was statistically significant, it probably wasn't that different clinically. “We thought initially this was an important confounder. But in the end we found that although they were different, in reality we could adjust for the vast majority of the difference.”

'These data would imply that hepatitis B vaccine would only contribute to a small minority of cases.' DR. BAXTER

BALTIMORE — The hepatitis B vaccine does not appear to be associated with an increased risk for rheumatoid arthritis, Dr. Roger P. Baxter and his associates reported at a vaccine research conference sponsored by the National Foundation for Infectious Diseases.

Both acute and chronic arthropathies have been reported in adults vaccinated with the tetanus-diphtheria (Td), hepatitis B (HepB), and measles-mumps-rubella (MMR) vaccines.

However, most of the evidence to support or refute a causal relationship between the Td or HepB vaccine and chronic arthritis has come from isolated case reports, uncontrolled observational studies, or studies that lacked sufficient statistical power, said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif., and his associates.

A case-control analysis designed to overcome the shortcomings of the previous studies included a cohort of continuous enrollees in Northern California Kaiser Permanente's health plan from Jan. 1, 1995, through Dec. 31, 1999, who were aged 15–59 years during Jan. 1, 1997-Dec. 31, 1999.

Individuals who had made clinic visits for rheumatoid arthritis (RA) and other inflammatory conditions prior to their follow-up start date were excluded.

A total of 416 incident cases of RA were identified (based on definitive diagnosis at the time or subsequent assessment by a rheumatologist), and each was matched with three controls based on age and the number of clinic visits made during the year prior to the onset date.

Rates of hepatitis B vaccination among the RA patients were compared with those of controls, with adjustment for sex, age, and exact number of clinic visits. Similar comparisons were made for the tetanus and influenza vaccines.

No statistically significant risk of RA was found for any of the three vaccines. Only 1% of RA patients versus 0.6% of controls had been exposed to the hepatitis B vaccine within 1–90 days of onset of RA symptoms, for an adjusted odds ratio of 1.48.

Within 1–180 days, the percentages were 1.9% with RA versus 0.9% of controls, giving a still insignificant odds ratio of 2.01. Within 1 year, 2.4% of RA cases and 1.6% of controls had been exposed to the vaccine, again insignificant at 1.42.

In all, only 10 of the 416 RA patients had received the HepB vaccine within 1 year of symptom onset, suggesting that “if there is an association, these data would imply that hepatitis B vaccine would only contribute to a small minority of cases,” Dr. Baxter and his associates said in their poster.

Results for the other two vaccines were also not significant, with adjusted odds ratios of 0.77–1.06 for tetanus and 0.66–1.11 for influenza.

Health care utilization was higher among those with RA, which was a slight confounder in this study despite the attempt to control for number of visits: Even after adjustment, there was still a significant residual effect for number of visits, with an odds ratio of 1.15.

“Basically, people who get vaccines of all kinds are different from those who don't, and underlying differences may confound the relationship with things like RA. We try to control for these factors by matching and analyses, but still we think there are differences. … People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines than people who don't utilize the system as much,” Dr. Baxter said in a follow-up interview.

However, he added, although the difference in utilization was statistically significant, it probably wasn't that different clinically. “We thought initially this was an important confounder. But in the end we found that although they were different, in reality we could adjust for the vast majority of the difference.”

'These data would imply that hepatitis B vaccine would only contribute to a small minority of cases.' DR. BAXTER

BALTIMORE — The hepatitis B vaccine does not appear to be associated with an increased risk for rheumatoid arthritis, Dr. Roger P. Baxter and his associates reported at a vaccine research conference sponsored by the National Foundation for Infectious Diseases.

Both acute and chronic arthropathies have been reported in adults vaccinated with the tetanus-diphtheria (Td), hepatitis B (HepB), and measles-mumps-rubella (MMR) vaccines.

However, most of the evidence to support or refute a causal relationship between the Td or HepB vaccine and chronic arthritis has come from isolated case reports, uncontrolled observational studies, or studies that lacked sufficient statistical power, said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif., and his associates.

A case-control analysis designed to overcome the shortcomings of the previous studies included a cohort of continuous enrollees in Northern California Kaiser Permanente's health plan from Jan. 1, 1995, through Dec. 31, 1999, who were aged 15–59 years during Jan. 1, 1997-Dec. 31, 1999.

Individuals who had made clinic visits for rheumatoid arthritis (RA) and other inflammatory conditions prior to their follow-up start date were excluded.

A total of 416 incident cases of RA were identified (based on definitive diagnosis at the time or subsequent assessment by a rheumatologist), and each was matched with three controls based on age and the number of clinic visits made during the year prior to the onset date.

Rates of hepatitis B vaccination among the RA patients were compared with those of controls, with adjustment for sex, age, and exact number of clinic visits. Similar comparisons were made for the tetanus and influenza vaccines.

No statistically significant risk of RA was found for any of the three vaccines. Only 1% of RA patients versus 0.6% of controls had been exposed to the hepatitis B vaccine within 1–90 days of onset of RA symptoms, for an adjusted odds ratio of 1.48.

Within 1–180 days, the percentages were 1.9% with RA versus 0.9% of controls, giving a still insignificant odds ratio of 2.01. Within 1 year, 2.4% of RA cases and 1.6% of controls had been exposed to the vaccine, again insignificant at 1.42.

In all, only 10 of the 416 RA patients had received the HepB vaccine within 1 year of symptom onset, suggesting that “if there is an association, these data would imply that hepatitis B vaccine would only contribute to a small minority of cases,” Dr. Baxter and his associates said in their poster.

Results for the other two vaccines were also not significant, with adjusted odds ratios of 0.77–1.06 for tetanus and 0.66–1.11 for influenza.

Health care utilization was higher among those with RA, which was a slight confounder in this study despite the attempt to control for number of visits: Even after adjustment, there was still a significant residual effect for number of visits, with an odds ratio of 1.15.

“Basically, people who get vaccines of all kinds are different from those who don't, and underlying differences may confound the relationship with things like RA. We try to control for these factors by matching and analyses, but still we think there are differences. … People who have RA are more likely to be higher utilizers and also more likely to have gotten vaccines than people who don't utilize the system as much,” Dr. Baxter said in a follow-up interview.

However, he added, although the difference in utilization was statistically significant, it probably wasn't that different clinically. “We thought initially this was an important confounder. But in the end we found that although they were different, in reality we could adjust for the vast majority of the difference.”

'These data would imply that hepatitis B vaccine would only contribute to a small minority of cases.' DR. BAXTER

BALTIMORE — Immunity to hepatitis B might wane 15 years after vaccination among those who received the vaccine series beginning at birth, Dr. Stephanie R. Bialek said at a conference on vaccine research. The conference was sponsored by the National Foundation for Infectious Diseases.

Data from long-term follow-up studies have established that people who received the three-dose hepatitis B vaccine series beginning after 6 months of age have long-term protection against chronic hepatitis B infection and do not need booster shots.

In that population, breakthrough infections occur in only 0%–7% of individuals more than 20 years after vaccination, and most of those are asymptomatic. Chronic hepatitis B infection is extremely rare, occurring in fewer than 1%, said Dr. Bialek, a medical officer in the division of viral hepatitis at the Centers for Disease Control and Prevention.

However, it is not known whether the same is true for those who begin the vaccine series at birth, a practice that was first recommended in the United States in 1992. Thus far, 10-year data in that population suggest that breakthrough infections are rare, occurring in 0%–6%, and there have been no reports of chronic infections among vaccine responders.

On the other hand, protective concentrations of antibody to hepatitis B surface antigen (anti-HBs), defined as levels greater than 10 mIU/mL, are present in fewer than 20% at 10 years, compared with more than 50% at 7–22 years among those vaccinated beginning after 6 months of age, Dr. Bialek noted.

Now, new data from a study conducted in Micronesia suggest that protection in those vaccinated as newborns may begin to subside at around 15 years. The Federated States of Micronesia, a U.S.-affiliated jurisdiction in the western Pacific where hepatitis B virus infection had historically been endemic, implemented hepatitis B vaccination beginning at birth in 1989.

Micronesian adolescents who had received three doses of recombinant hepatitis B vaccine (at birth, at the age of 2 months, and at age 6 months) and who had tested negative for antibody to hepatitis B core antigen (anti-HBc) 2 years after the primary vaccination were followed for 15 years after the primary vaccination. Recombivax had been given in doses of 5 mcg at birth, followed by doses of 2.5 mcg at 2 and 6 months. Today, 5 mcg is recommended for all three doses, she noted.

In 2006, investigators were able to track down 105 of the 238 children who had received three doses of hepatitis B vaccine, were anti-HBc negative, and had been tested for anti-HBs at 35 months. By then, they had a median age of 15.8 years, with a median of 15.1 years since completion of the vaccine series. A total of eight (7.6%) were anti-HBc positive, but none was HBsAg positive.

Booster doses of vaccine were given to the 96 who were anti-HBc negative in 2006. Of these, only 7 (7%) had anti-HBs concentrations greater than 10 mIU/mL at the time they were given the booster, and only about half (45, or 47%) had anamnestic anti-HBs responses at 14 days after the booster (defined as an increase in anti-HBs concentration greater than 10 mIU/mL). Absence of an anamnestic response might indicate waning immunity, Dr. Bialek said.

Limitations of this study include the fact that maternal HBsAg status was not known, postvaccination testing had not been performed (some of the participants may have been nonresponders), and the vaccine dose used for the second and third doses was half of the currently recommended dose.

And importantly, “Just because they didn't boost doesn't mean they're not protected,” Dr. Bialek said in an interview following her presentation. At least two ongoing studies are investigating this issue further, she added.

BALTIMORE — Immunity to hepatitis B might wane 15 years after vaccination among those who received the vaccine series beginning at birth, Dr. Stephanie R. Bialek said at a conference on vaccine research. The conference was sponsored by the National Foundation for Infectious Diseases.

Data from long-term follow-up studies have established that people who received the three-dose hepatitis B vaccine series beginning after 6 months of age have long-term protection against chronic hepatitis B infection and do not need booster shots.

In that population, breakthrough infections occur in only 0%–7% of individuals more than 20 years after vaccination, and most of those are asymptomatic. Chronic hepatitis B infection is extremely rare, occurring in fewer than 1%, said Dr. Bialek, a medical officer in the division of viral hepatitis at the Centers for Disease Control and Prevention.

However, it is not known whether the same is true for those who begin the vaccine series at birth, a practice that was first recommended in the United States in 1992. Thus far, 10-year data in that population suggest that breakthrough infections are rare, occurring in 0%–6%, and there have been no reports of chronic infections among vaccine responders.

On the other hand, protective concentrations of antibody to hepatitis B surface antigen (anti-HBs), defined as levels greater than 10 mIU/mL, are present in fewer than 20% at 10 years, compared with more than 50% at 7–22 years among those vaccinated beginning after 6 months of age, Dr. Bialek noted.

Now, new data from a study conducted in Micronesia suggest that protection in those vaccinated as newborns may begin to subside at around 15 years. The Federated States of Micronesia, a U.S.-affiliated jurisdiction in the western Pacific where hepatitis B virus infection had historically been endemic, implemented hepatitis B vaccination beginning at birth in 1989.

Micronesian adolescents who had received three doses of recombinant hepatitis B vaccine (at birth, at the age of 2 months, and at age 6 months) and who had tested negative for antibody to hepatitis B core antigen (anti-HBc) 2 years after the primary vaccination were followed for 15 years after the primary vaccination. Recombivax had been given in doses of 5 mcg at birth, followed by doses of 2.5 mcg at 2 and 6 months. Today, 5 mcg is recommended for all three doses, she noted.

In 2006, investigators were able to track down 105 of the 238 children who had received three doses of hepatitis B vaccine, were anti-HBc negative, and had been tested for anti-HBs at 35 months. By then, they had a median age of 15.8 years, with a median of 15.1 years since completion of the vaccine series. A total of eight (7.6%) were anti-HBc positive, but none was HBsAg positive.

Booster doses of vaccine were given to the 96 who were anti-HBc negative in 2006. Of these, only 7 (7%) had anti-HBs concentrations greater than 10 mIU/mL at the time they were given the booster, and only about half (45, or 47%) had anamnestic anti-HBs responses at 14 days after the booster (defined as an increase in anti-HBs concentration greater than 10 mIU/mL). Absence of an anamnestic response might indicate waning immunity, Dr. Bialek said.

Limitations of this study include the fact that maternal HBsAg status was not known, postvaccination testing had not been performed (some of the participants may have been nonresponders), and the vaccine dose used for the second and third doses was half of the currently recommended dose.

And importantly, “Just because they didn't boost doesn't mean they're not protected,” Dr. Bialek said in an interview following her presentation. At least two ongoing studies are investigating this issue further, she added.

BALTIMORE — Immunity to hepatitis B might wane 15 years after vaccination among those who received the vaccine series beginning at birth, Dr. Stephanie R. Bialek said at a conference on vaccine research. The conference was sponsored by the National Foundation for Infectious Diseases.

Data from long-term follow-up studies have established that people who received the three-dose hepatitis B vaccine series beginning after 6 months of age have long-term protection against chronic hepatitis B infection and do not need booster shots.

In that population, breakthrough infections occur in only 0%–7% of individuals more than 20 years after vaccination, and most of those are asymptomatic. Chronic hepatitis B infection is extremely rare, occurring in fewer than 1%, said Dr. Bialek, a medical officer in the division of viral hepatitis at the Centers for Disease Control and Prevention.

However, it is not known whether the same is true for those who begin the vaccine series at birth, a practice that was first recommended in the United States in 1992. Thus far, 10-year data in that population suggest that breakthrough infections are rare, occurring in 0%–6%, and there have been no reports of chronic infections among vaccine responders.

On the other hand, protective concentrations of antibody to hepatitis B surface antigen (anti-HBs), defined as levels greater than 10 mIU/mL, are present in fewer than 20% at 10 years, compared with more than 50% at 7–22 years among those vaccinated beginning after 6 months of age, Dr. Bialek noted.

Now, new data from a study conducted in Micronesia suggest that protection in those vaccinated as newborns may begin to subside at around 15 years. The Federated States of Micronesia, a U.S.-affiliated jurisdiction in the western Pacific where hepatitis B virus infection had historically been endemic, implemented hepatitis B vaccination beginning at birth in 1989.

Micronesian adolescents who had received three doses of recombinant hepatitis B vaccine (at birth, at the age of 2 months, and at age 6 months) and who had tested negative for antibody to hepatitis B core antigen (anti-HBc) 2 years after the primary vaccination were followed for 15 years after the primary vaccination. Recombivax had been given in doses of 5 mcg at birth, followed by doses of 2.5 mcg at 2 and 6 months. Today, 5 mcg is recommended for all three doses, she noted.

In 2006, investigators were able to track down 105 of the 238 children who had received three doses of hepatitis B vaccine, were anti-HBc negative, and had been tested for anti-HBs at 35 months. By then, they had a median age of 15.8 years, with a median of 15.1 years since completion of the vaccine series. A total of eight (7.6%) were anti-HBc positive, but none was HBsAg positive.

Booster doses of vaccine were given to the 96 who were anti-HBc negative in 2006. Of these, only 7 (7%) had anti-HBs concentrations greater than 10 mIU/mL at the time they were given the booster, and only about half (45, or 47%) had anamnestic anti-HBs responses at 14 days after the booster (defined as an increase in anti-HBs concentration greater than 10 mIU/mL). Absence of an anamnestic response might indicate waning immunity, Dr. Bialek said.

Limitations of this study include the fact that maternal HBsAg status was not known, postvaccination testing had not been performed (some of the participants may have been nonresponders), and the vaccine dose used for the second and third doses was half of the currently recommended dose.

And importantly, “Just because they didn't boost doesn't mean they're not protected,” Dr. Bialek said in an interview following her presentation. At least two ongoing studies are investigating this issue further, she added.

BALTIMORE — In settings with good access to care and high immunization rates, asking patients whether they've received a tetanus booster in the last 10 years is a fairly accurate way to determine if they need one, Dr. M. Hassan Murad and his associates said in a poster presentation at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Patients who answer “yes” are probably right and do not need readministration of the vaccine. But those who say either “no” or “I don't know” should receive a tetanus-diphtheria (Td) booster as long as there are no contraindications, said Dr. Murad of the preventive medicine division of the Mayo Clinic, Rochester, Minn.

Although previous studies have demonstrated poor accuracy of patients' recall of their last Td booster, this has not been evaluated previously in settings where immunization rates are high and good documentation is available. In this study, 572 patients of an employee health clinic of a large health care organization were asked whether they had a Td booster in the last 10 years. Of those, 65.6% were able to answer either “yes” or “no.”

Comparison of their responses with their charts yielded high sensitivity (92.4%) and low specificity (26.5%). Accuracy of recall did not differ by age or gender, Dr. Murad and his associates reported.

The results from this study patient population are likely generalizable to those of other working-age adults of similar education level. “Since the results rely in significant part on human memory of a rare event—a once-every-10-years shot—they probably reflect useful information. … The general characteristics of our population are they were mostly working age, education generally high school graduate or greater, and nearly all have good access to routine office care. That is probably similar to many [U.S.] office practices,” Dr. Murad said in a follow-up interview.

BALTIMORE — In settings with good access to care and high immunization rates, asking patients whether they've received a tetanus booster in the last 10 years is a fairly accurate way to determine if they need one, Dr. M. Hassan Murad and his associates said in a poster presentation at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Patients who answer “yes” are probably right and do not need readministration of the vaccine. But those who say either “no” or “I don't know” should receive a tetanus-diphtheria (Td) booster as long as there are no contraindications, said Dr. Murad of the preventive medicine division of the Mayo Clinic, Rochester, Minn.

Although previous studies have demonstrated poor accuracy of patients' recall of their last Td booster, this has not been evaluated previously in settings where immunization rates are high and good documentation is available. In this study, 572 patients of an employee health clinic of a large health care organization were asked whether they had a Td booster in the last 10 years. Of those, 65.6% were able to answer either “yes” or “no.”

Comparison of their responses with their charts yielded high sensitivity (92.4%) and low specificity (26.5%). Accuracy of recall did not differ by age or gender, Dr. Murad and his associates reported.

The results from this study patient population are likely generalizable to those of other working-age adults of similar education level. “Since the results rely in significant part on human memory of a rare event—a once-every-10-years shot—they probably reflect useful information. … The general characteristics of our population are they were mostly working age, education generally high school graduate or greater, and nearly all have good access to routine office care. That is probably similar to many [U.S.] office practices,” Dr. Murad said in a follow-up interview.

BALTIMORE — In settings with good access to care and high immunization rates, asking patients whether they've received a tetanus booster in the last 10 years is a fairly accurate way to determine if they need one, Dr. M. Hassan Murad and his associates said in a poster presentation at a conference on vaccine research sponsored by the National Foundation for Infectious Diseases.

Patients who answer “yes” are probably right and do not need readministration of the vaccine. But those who say either “no” or “I don't know” should receive a tetanus-diphtheria (Td) booster as long as there are no contraindications, said Dr. Murad of the preventive medicine division of the Mayo Clinic, Rochester, Minn.

Although previous studies have demonstrated poor accuracy of patients' recall of their last Td booster, this has not been evaluated previously in settings where immunization rates are high and good documentation is available. In this study, 572 patients of an employee health clinic of a large health care organization were asked whether they had a Td booster in the last 10 years. Of those, 65.6% were able to answer either “yes” or “no.”

Comparison of their responses with their charts yielded high sensitivity (92.4%) and low specificity (26.5%). Accuracy of recall did not differ by age or gender, Dr. Murad and his associates reported.

The results from this study patient population are likely generalizable to those of other working-age adults of similar education level. “Since the results rely in significant part on human memory of a rare event—a once-every-10-years shot—they probably reflect useful information. … The general characteristics of our population are they were mostly working age, education generally high school graduate or greater, and nearly all have good access to routine office care. That is probably similar to many [U.S.] office practices,” Dr. Murad said in a follow-up interview.

BALTIMORE — Influenza vaccination is associated with lower rates of hospitalization and outpatient visits for flulike illness, but only after statistical adjustment for the fact that people who get vaccinated are less healthy than are those who don't, Dr. Roger P. Baxter said at a vaccine research conference that was sponsored by the National Foundation for Infectious Diseases.

Raw data from Kaiser Permanente's medical records of approximately 500,000 adults aged 65 and older during each of four consecutive influenza seasons showed that hospitalization and outpatient visit rates were actually higher for those who received the influenza vaccine than for those who didn't, primarily because the population is sicker.

“People who get the flu vaccine are less healthy and utilize the medical system much more than those who don't get the vaccine. … It's a real confounder in all these studies,” said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif.

Another study confounder is the fact that the vaccine works better in some years than in others, a phenomenon believed to be caused at least in part by how good a “match” there is between the vaccine and the season's circulating strains.

Unadjusted, the rates of hospitalization per 1,000 person-years during the influenza season ranged from 169/1,000 vaccinated vs. 159/1,000 unvaccinated in 2003–2004 (risk ratio 1.06 in favor of no vaccination), to 182/1,000 vs. 150/1,000 in 2002–2003 (1.22 in favor of no vaccination).

Even after adjustment for age, gender, and three underlying diagnoses (diabetes, coronary artery disease, and heart failure), all of the values for the vaccine's effectiveness were negative, giving the counterintuitive impression that the vaccine actually causes disease. The values were −8.4% for preventing all hospital stays, −25.5% for all pneumonia and influenza outpatient visits, −21.4% for other respiratory outpatient visits, and −23.3% for all respiratory visits, all significant values.

But a second analysis that focused on health care utilization outside of the flu season suggests that “people who get the vaccine are high utilizers” year-round, Dr. Baxter said.

He and his associates compared the data during each year's influenza season with the off-season control period of June 1-Aug. 31. This level of analysis revealed that the difference in utilization between vaccinated and unvaccinated patients was even greater during the off-season than during influenza season, with a risk ratio of about 1.25 for each of the four seasons.

Dr. Baxter and his associates are further analyzing the Kaiser data to examine vaccine effectiveness in younger, healthier people, as well as adding mortality to the outcomes and looking more closely at the relationship between “good” vs. “bad” vaccine matches in the face of more or less virulent circulating influenza strains. Conducting such studies is “not easy,” he noted.

The Kaiser Permanente Vaccine Study Center receives research grants from the influenza vaccine manufacturers Sanofi-Pasteur, GlaxoSmithKline, Novartis, and MedImmune.

BALTIMORE — Influenza vaccination is associated with lower rates of hospitalization and outpatient visits for flulike illness, but only after statistical adjustment for the fact that people who get vaccinated are less healthy than are those who don't, Dr. Roger P. Baxter said at a vaccine research conference that was sponsored by the National Foundation for Infectious Diseases.

Raw data from Kaiser Permanente's medical records of approximately 500,000 adults aged 65 and older during each of four consecutive influenza seasons showed that hospitalization and outpatient visit rates were actually higher for those who received the influenza vaccine than for those who didn't, primarily because the population is sicker.

“People who get the flu vaccine are less healthy and utilize the medical system much more than those who don't get the vaccine. … It's a real confounder in all these studies,” said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif.

Another study confounder is the fact that the vaccine works better in some years than in others, a phenomenon believed to be caused at least in part by how good a “match” there is between the vaccine and the season's circulating strains.

Unadjusted, the rates of hospitalization per 1,000 person-years during the influenza season ranged from 169/1,000 vaccinated vs. 159/1,000 unvaccinated in 2003–2004 (risk ratio 1.06 in favor of no vaccination), to 182/1,000 vs. 150/1,000 in 2002–2003 (1.22 in favor of no vaccination).

Even after adjustment for age, gender, and three underlying diagnoses (diabetes, coronary artery disease, and heart failure), all of the values for the vaccine's effectiveness were negative, giving the counterintuitive impression that the vaccine actually causes disease. The values were −8.4% for preventing all hospital stays, −25.5% for all pneumonia and influenza outpatient visits, −21.4% for other respiratory outpatient visits, and −23.3% for all respiratory visits, all significant values.

But a second analysis that focused on health care utilization outside of the flu season suggests that “people who get the vaccine are high utilizers” year-round, Dr. Baxter said.

He and his associates compared the data during each year's influenza season with the off-season control period of June 1-Aug. 31. This level of analysis revealed that the difference in utilization between vaccinated and unvaccinated patients was even greater during the off-season than during influenza season, with a risk ratio of about 1.25 for each of the four seasons.

Dr. Baxter and his associates are further analyzing the Kaiser data to examine vaccine effectiveness in younger, healthier people, as well as adding mortality to the outcomes and looking more closely at the relationship between “good” vs. “bad” vaccine matches in the face of more or less virulent circulating influenza strains. Conducting such studies is “not easy,” he noted.

The Kaiser Permanente Vaccine Study Center receives research grants from the influenza vaccine manufacturers Sanofi-Pasteur, GlaxoSmithKline, Novartis, and MedImmune.

BALTIMORE — Influenza vaccination is associated with lower rates of hospitalization and outpatient visits for flulike illness, but only after statistical adjustment for the fact that people who get vaccinated are less healthy than are those who don't, Dr. Roger P. Baxter said at a vaccine research conference that was sponsored by the National Foundation for Infectious Diseases.

Raw data from Kaiser Permanente's medical records of approximately 500,000 adults aged 65 and older during each of four consecutive influenza seasons showed that hospitalization and outpatient visit rates were actually higher for those who received the influenza vaccine than for those who didn't, primarily because the population is sicker.

“People who get the flu vaccine are less healthy and utilize the medical system much more than those who don't get the vaccine. … It's a real confounder in all these studies,” said Dr. Baxter, associate director of the Vaccine Study Center at Kaiser Permanente, Oakland, Calif.

Another study confounder is the fact that the vaccine works better in some years than in others, a phenomenon believed to be caused at least in part by how good a “match” there is between the vaccine and the season's circulating strains.

Unadjusted, the rates of hospitalization per 1,000 person-years during the influenza season ranged from 169/1,000 vaccinated vs. 159/1,000 unvaccinated in 2003–2004 (risk ratio 1.06 in favor of no vaccination), to 182/1,000 vs. 150/1,000 in 2002–2003 (1.22 in favor of no vaccination).

Even after adjustment for age, gender, and three underlying diagnoses (diabetes, coronary artery disease, and heart failure), all of the values for the vaccine's effectiveness were negative, giving the counterintuitive impression that the vaccine actually causes disease. The values were −8.4% for preventing all hospital stays, −25.5% for all pneumonia and influenza outpatient visits, −21.4% for other respiratory outpatient visits, and −23.3% for all respiratory visits, all significant values.

But a second analysis that focused on health care utilization outside of the flu season suggests that “people who get the vaccine are high utilizers” year-round, Dr. Baxter said.

He and his associates compared the data during each year's influenza season with the off-season control period of June 1-Aug. 31. This level of analysis revealed that the difference in utilization between vaccinated and unvaccinated patients was even greater during the off-season than during influenza season, with a risk ratio of about 1.25 for each of the four seasons.

Dr. Baxter and his associates are further analyzing the Kaiser data to examine vaccine effectiveness in younger, healthier people, as well as adding mortality to the outcomes and looking more closely at the relationship between “good” vs. “bad” vaccine matches in the face of more or less virulent circulating influenza strains. Conducting such studies is “not easy,” he noted.

The Kaiser Permanente Vaccine Study Center receives research grants from the influenza vaccine manufacturers Sanofi-Pasteur, GlaxoSmithKline, Novartis, and MedImmune.