Rheumatoid Arthritis

The newly formed American Board of Addiction Medicine has certified more than 1,600 physicians as specialists in addiction medicine so far this year, including more than 200 internists. Physicians from multiple disciplines who meet expertise criteria are taking advantage of the opportunity to be “grandfathered in” to the nascent specialty by taking a special 6-hour certifying examination.

Dr. Kevin B. Kunz, president of the American Board of Addiction Medicine (ABAM), said in an interview that the 15 physicians on the ABAM board of directors will create a new examination to certify physicians after the grandfathering option ends in December. Previously, only psychiatrists could claim addiction-related board certification.

Official recognition of addiction expertise is being expanded to include internists, family physicians, emergency physicians, ob.gyns., surgeons, pediatricians, preventive medicine physicians, and neurologists.

“There are already folks out there toiling in relative obscurity in addiction medicine,” internist Peter D. Friedmann said in an interview. “Creation of the ABAM was driven by the need for better recognition within medicine.” The American Society of Addiction Medicine provided a certification exam for years, “but it was not accorded the same respect and gravitas as fields that have their own subspecialty boards.” Dr. Friedmann of Brown University in Providence, R.I., is one of the internists who took advantage of the grandfathering option.

Criteria for certification grandfathering include at least 1,950 hours over the past decade providing addiction-related care, research, and/or education; 50 hours of CME related to addiction medicine in the past 2 years; letters of recommendation supporting proficiency in this area; and successful completion of the examination.

Primary care physicians will continue to play a large role in addiction care because “there will never be enough ABAM-certified specialists to treat everyone,” Dr. Friedmann said. “It would be like expecting everyone with hypertension to be treated by a cardiologist.”

“So many of the more than 120 million emergency department visits each year are due to substance abuse,” said Dr. Gail D'Onofrio of the ABAM board of directors and section chief of emergency medicine at Yale University in New Haven, Conn. Dr. D'Onofrio cited a statewide survey of seven Tennessee EDs showing that 31% of screened patients tested positive for substance abuse and 27% were assessed as needing substance abuse treatment.

Unfortunately, emergency physicians identified only 1% as having a diagnosis or problem related to substance abuse (Ann. Emerg. Med. 2003;41:802-13). ABAM plans to establish addiction medicine residency programs and get them recognized by the Accreditation Council for Graduate Medical Education (ACGME). “We expect these programs to be in place by 2011, after which time we will add a residency requirement to ABAM certification, as well as a maintenance-of-certification program,” Dr. Kunz said.

There is a core content shared among all specialties treating addiction, and therefore one examination, but individual specialties could add their own content to fellowship programs, Dr. D'Onofrio noted.

Once these requirements are in place, ABAM will seek recognition from the American Board of Medical Specialties (ABMS), which may take another 4-6 years. “We want addiction prevention, screening, intervention, and treatment to become routine aspects of medical care, available virtually any place health care is provided,” noted Dr. Jeffrey H. Samet, ABAM president-elect and professor of medicine at Boston University.

Reimbursement for addiction-related services remains a challenge. “These are difficult patients who take time and for whom there has been little reimbursement,” Dr. Kunz said. Although reimbursement codes for addiction screening and brief intervention in addiction are recognized by Medicare, some states, and some private insurers, “reimbursement for doing this work is still quite low,” Dr. Friedmann said. Better financial incentives are needed to encourage physicians to get into this field and make it a career, he added.

The codes for screening and intervention “are very important. You can't get doctors to do something they won't get paid to do,” Dr. Sokol said.

The next ABAM examination is scheduled for Dec. 11, 2010. Application deadlines are Oct. 31, 2009; Jan. 31, 2010; and April 30, 2010. More information is available at www.asam.org/ABAM.html

The newly formed American Board of Addiction Medicine has certified more than 1,600 physicians as specialists in addiction medicine so far this year, including more than 200 internists. Physicians from multiple disciplines who meet expertise criteria are taking advantage of the opportunity to be “grandfathered in” to the nascent specialty by taking a special 6-hour certifying examination.

Dr. Kevin B. Kunz, president of the American Board of Addiction Medicine (ABAM), said in an interview that the 15 physicians on the ABAM board of directors will create a new examination to certify physicians after the grandfathering option ends in December. Previously, only psychiatrists could claim addiction-related board certification.

Official recognition of addiction expertise is being expanded to include internists, family physicians, emergency physicians, ob.gyns., surgeons, pediatricians, preventive medicine physicians, and neurologists.

“There are already folks out there toiling in relative obscurity in addiction medicine,” internist Peter D. Friedmann said in an interview. “Creation of the ABAM was driven by the need for better recognition within medicine.” The American Society of Addiction Medicine provided a certification exam for years, “but it was not accorded the same respect and gravitas as fields that have their own subspecialty boards.” Dr. Friedmann of Brown University in Providence, R.I., is one of the internists who took advantage of the grandfathering option.

Criteria for certification grandfathering include at least 1,950 hours over the past decade providing addiction-related care, research, and/or education; 50 hours of CME related to addiction medicine in the past 2 years; letters of recommendation supporting proficiency in this area; and successful completion of the examination.

Primary care physicians will continue to play a large role in addiction care because “there will never be enough ABAM-certified specialists to treat everyone,” Dr. Friedmann said. “It would be like expecting everyone with hypertension to be treated by a cardiologist.”

“So many of the more than 120 million emergency department visits each year are due to substance abuse,” said Dr. Gail D'Onofrio of the ABAM board of directors and section chief of emergency medicine at Yale University in New Haven, Conn. Dr. D'Onofrio cited a statewide survey of seven Tennessee EDs showing that 31% of screened patients tested positive for substance abuse and 27% were assessed as needing substance abuse treatment.

Unfortunately, emergency physicians identified only 1% as having a diagnosis or problem related to substance abuse (Ann. Emerg. Med. 2003;41:802-13). ABAM plans to establish addiction medicine residency programs and get them recognized by the Accreditation Council for Graduate Medical Education (ACGME). “We expect these programs to be in place by 2011, after which time we will add a residency requirement to ABAM certification, as well as a maintenance-of-certification program,” Dr. Kunz said.

There is a core content shared among all specialties treating addiction, and therefore one examination, but individual specialties could add their own content to fellowship programs, Dr. D'Onofrio noted.

Once these requirements are in place, ABAM will seek recognition from the American Board of Medical Specialties (ABMS), which may take another 4-6 years. “We want addiction prevention, screening, intervention, and treatment to become routine aspects of medical care, available virtually any place health care is provided,” noted Dr. Jeffrey H. Samet, ABAM president-elect and professor of medicine at Boston University.

Reimbursement for addiction-related services remains a challenge. “These are difficult patients who take time and for whom there has been little reimbursement,” Dr. Kunz said. Although reimbursement codes for addiction screening and brief intervention in addiction are recognized by Medicare, some states, and some private insurers, “reimbursement for doing this work is still quite low,” Dr. Friedmann said. Better financial incentives are needed to encourage physicians to get into this field and make it a career, he added.

The codes for screening and intervention “are very important. You can't get doctors to do something they won't get paid to do,” Dr. Sokol said.

The next ABAM examination is scheduled for Dec. 11, 2010. Application deadlines are Oct. 31, 2009; Jan. 31, 2010; and April 30, 2010. More information is available at www.asam.org/ABAM.html

The newly formed American Board of Addiction Medicine has certified more than 1,600 physicians as specialists in addiction medicine so far this year, including more than 200 internists. Physicians from multiple disciplines who meet expertise criteria are taking advantage of the opportunity to be “grandfathered in” to the nascent specialty by taking a special 6-hour certifying examination.

Dr. Kevin B. Kunz, president of the American Board of Addiction Medicine (ABAM), said in an interview that the 15 physicians on the ABAM board of directors will create a new examination to certify physicians after the grandfathering option ends in December. Previously, only psychiatrists could claim addiction-related board certification.

Official recognition of addiction expertise is being expanded to include internists, family physicians, emergency physicians, ob.gyns., surgeons, pediatricians, preventive medicine physicians, and neurologists.

“There are already folks out there toiling in relative obscurity in addiction medicine,” internist Peter D. Friedmann said in an interview. “Creation of the ABAM was driven by the need for better recognition within medicine.” The American Society of Addiction Medicine provided a certification exam for years, “but it was not accorded the same respect and gravitas as fields that have their own subspecialty boards.” Dr. Friedmann of Brown University in Providence, R.I., is one of the internists who took advantage of the grandfathering option.

Criteria for certification grandfathering include at least 1,950 hours over the past decade providing addiction-related care, research, and/or education; 50 hours of CME related to addiction medicine in the past 2 years; letters of recommendation supporting proficiency in this area; and successful completion of the examination.

Primary care physicians will continue to play a large role in addiction care because “there will never be enough ABAM-certified specialists to treat everyone,” Dr. Friedmann said. “It would be like expecting everyone with hypertension to be treated by a cardiologist.”

“So many of the more than 120 million emergency department visits each year are due to substance abuse,” said Dr. Gail D'Onofrio of the ABAM board of directors and section chief of emergency medicine at Yale University in New Haven, Conn. Dr. D'Onofrio cited a statewide survey of seven Tennessee EDs showing that 31% of screened patients tested positive for substance abuse and 27% were assessed as needing substance abuse treatment.

Unfortunately, emergency physicians identified only 1% as having a diagnosis or problem related to substance abuse (Ann. Emerg. Med. 2003;41:802-13). ABAM plans to establish addiction medicine residency programs and get them recognized by the Accreditation Council for Graduate Medical Education (ACGME). “We expect these programs to be in place by 2011, after which time we will add a residency requirement to ABAM certification, as well as a maintenance-of-certification program,” Dr. Kunz said.

There is a core content shared among all specialties treating addiction, and therefore one examination, but individual specialties could add their own content to fellowship programs, Dr. D'Onofrio noted.

Once these requirements are in place, ABAM will seek recognition from the American Board of Medical Specialties (ABMS), which may take another 4-6 years. “We want addiction prevention, screening, intervention, and treatment to become routine aspects of medical care, available virtually any place health care is provided,” noted Dr. Jeffrey H. Samet, ABAM president-elect and professor of medicine at Boston University.

Reimbursement for addiction-related services remains a challenge. “These are difficult patients who take time and for whom there has been little reimbursement,” Dr. Kunz said. Although reimbursement codes for addiction screening and brief intervention in addiction are recognized by Medicare, some states, and some private insurers, “reimbursement for doing this work is still quite low,” Dr. Friedmann said. Better financial incentives are needed to encourage physicians to get into this field and make it a career, he added.

The codes for screening and intervention “are very important. You can't get doctors to do something they won't get paid to do,” Dr. Sokol said.

The next ABAM examination is scheduled for Dec. 11, 2010. Application deadlines are Oct. 31, 2009; Jan. 31, 2010; and April 30, 2010. More information is available at www.asam.org/ABAM.html

COPENHAGEN — Rheumatoid arthritis patients can safely undergo multiple courses of retreatment with the anti-CD20 monoclonal antibody rituximab without increasing their risk of serious adverse events, Dr. Ronald F. van Vollenhoven reported at the annual European Congress of Rheumatology.

Presenting the results of a pooled analysis of safety data representing 5,964 patient-years of rituximab exposure from retreatment populations in RA clinical trials, Dr. van Vollenhoven reported that rituximab remains well tolerated with a stable safety profile after up to five treatment courses. Specifically, “the rates of adverse events, serious adverse events, and infections remained stable following each course of treatment,” he said. The findings are particularly important because multiple courses of treatment are often needed to sustain the efficacy of rituximab, which is often used as a treatment of last resort after the failure of other therapies.

The pooled analysis, which included safety data from phase IIA, IIB, and III studies, included 2,579 RA patients who received multiple courses of rituximab. Of these, 1,926 patients received two or more treatment courses, 1,228 patients received three or more courses, 794 patients received four or more, and 282 received at least five courses, said Dr. van Vollenhoven, a rheumatologist at the Karolinska University Hospital in Stockholm. Of the 2,579 patients, 2,417 were followed for more than 1 year from start of treatment, whereas 1,198, 743, 564, and 109, respectively, were followed for more than 2, 3, 4, and 5 years, and 138 withdrew from the trials because of adverse events.

Based on the pooled analysis, the rates of any adverse event (reported per 100 patient-years) after treatment courses one through five, respectively, were 379, 313, 319, 329, and 330, and the respective rates per 100 patient-years of any serious adverse events were 18.3, 17.4, 16.6, 12.0, and 13.4.

“The most frequent adverse events were infusion-related reactions, which occurred in 25% of the patients for the first infusion of the first course, and decreased for subsequent infusions,” Dr. van Vollenhoven said. In all, “15 events in 14 patients were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring in courses one through five, respectively.”

Although the proportion of patients with below-normal IgM or IgG levels increased with the number of treatment courses, there were no significant differences by course in the rates of infections or serious infections, said Dr. van Vollenhoven. The overall serious infection rate per 100 patient-years was 4.26, which is consistent with observations in other RA cohorts, and there were no cases of tuberculosis, he noted.

“There was one case of progressive multifocal leukoencephalopathy [PML] reported in a patient who had previously received chemotherapy for oropharyngeal cancer,” Dr. van Vollenhoven said, but like other cases of PML that have been reported in the RA treatment literature, it is unclear whether the occurrence of the fatal reactivation of the JC virus in the central nervous system was related to the rituximab, to other drugs, to the prior cancer treatment, or to the patient's existing impaired immune response.

With respect to malignancy, the analysis showed rates comparable to malignancy rates observed in the general RA population, and there was no increased risk of malignancy with additional courses of treatment, he said.

“These [data], showing the same basic safety profile with retreatment that has been shown in clinical treatment trials, are important. We pride ourselves on the use of biologics and the ability to reach specific targets with treatment, but B-cell therapies, for all their effectiveness, may have long-term consequences that are hard to predict,” said Dr. van Vollenhoven. “It's important to have a good long-term safety system to evaluate retreatment with these drugs.”

Dr. van Vollenhoven disclosed having received financial support for research from Roche.

COPENHAGEN — Rheumatoid arthritis patients can safely undergo multiple courses of retreatment with the anti-CD20 monoclonal antibody rituximab without increasing their risk of serious adverse events, Dr. Ronald F. van Vollenhoven reported at the annual European Congress of Rheumatology.

Presenting the results of a pooled analysis of safety data representing 5,964 patient-years of rituximab exposure from retreatment populations in RA clinical trials, Dr. van Vollenhoven reported that rituximab remains well tolerated with a stable safety profile after up to five treatment courses. Specifically, “the rates of adverse events, serious adverse events, and infections remained stable following each course of treatment,” he said. The findings are particularly important because multiple courses of treatment are often needed to sustain the efficacy of rituximab, which is often used as a treatment of last resort after the failure of other therapies.

The pooled analysis, which included safety data from phase IIA, IIB, and III studies, included 2,579 RA patients who received multiple courses of rituximab. Of these, 1,926 patients received two or more treatment courses, 1,228 patients received three or more courses, 794 patients received four or more, and 282 received at least five courses, said Dr. van Vollenhoven, a rheumatologist at the Karolinska University Hospital in Stockholm. Of the 2,579 patients, 2,417 were followed for more than 1 year from start of treatment, whereas 1,198, 743, 564, and 109, respectively, were followed for more than 2, 3, 4, and 5 years, and 138 withdrew from the trials because of adverse events.

Based on the pooled analysis, the rates of any adverse event (reported per 100 patient-years) after treatment courses one through five, respectively, were 379, 313, 319, 329, and 330, and the respective rates per 100 patient-years of any serious adverse events were 18.3, 17.4, 16.6, 12.0, and 13.4.

“The most frequent adverse events were infusion-related reactions, which occurred in 25% of the patients for the first infusion of the first course, and decreased for subsequent infusions,” Dr. van Vollenhoven said. In all, “15 events in 14 patients were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring in courses one through five, respectively.”

Although the proportion of patients with below-normal IgM or IgG levels increased with the number of treatment courses, there were no significant differences by course in the rates of infections or serious infections, said Dr. van Vollenhoven. The overall serious infection rate per 100 patient-years was 4.26, which is consistent with observations in other RA cohorts, and there were no cases of tuberculosis, he noted.

“There was one case of progressive multifocal leukoencephalopathy [PML] reported in a patient who had previously received chemotherapy for oropharyngeal cancer,” Dr. van Vollenhoven said, but like other cases of PML that have been reported in the RA treatment literature, it is unclear whether the occurrence of the fatal reactivation of the JC virus in the central nervous system was related to the rituximab, to other drugs, to the prior cancer treatment, or to the patient's existing impaired immune response.

With respect to malignancy, the analysis showed rates comparable to malignancy rates observed in the general RA population, and there was no increased risk of malignancy with additional courses of treatment, he said.

“These [data], showing the same basic safety profile with retreatment that has been shown in clinical treatment trials, are important. We pride ourselves on the use of biologics and the ability to reach specific targets with treatment, but B-cell therapies, for all their effectiveness, may have long-term consequences that are hard to predict,” said Dr. van Vollenhoven. “It's important to have a good long-term safety system to evaluate retreatment with these drugs.”

Dr. van Vollenhoven disclosed having received financial support for research from Roche.

COPENHAGEN — Rheumatoid arthritis patients can safely undergo multiple courses of retreatment with the anti-CD20 monoclonal antibody rituximab without increasing their risk of serious adverse events, Dr. Ronald F. van Vollenhoven reported at the annual European Congress of Rheumatology.

Presenting the results of a pooled analysis of safety data representing 5,964 patient-years of rituximab exposure from retreatment populations in RA clinical trials, Dr. van Vollenhoven reported that rituximab remains well tolerated with a stable safety profile after up to five treatment courses. Specifically, “the rates of adverse events, serious adverse events, and infections remained stable following each course of treatment,” he said. The findings are particularly important because multiple courses of treatment are often needed to sustain the efficacy of rituximab, which is often used as a treatment of last resort after the failure of other therapies.

The pooled analysis, which included safety data from phase IIA, IIB, and III studies, included 2,579 RA patients who received multiple courses of rituximab. Of these, 1,926 patients received two or more treatment courses, 1,228 patients received three or more courses, 794 patients received four or more, and 282 received at least five courses, said Dr. van Vollenhoven, a rheumatologist at the Karolinska University Hospital in Stockholm. Of the 2,579 patients, 2,417 were followed for more than 1 year from start of treatment, whereas 1,198, 743, 564, and 109, respectively, were followed for more than 2, 3, 4, and 5 years, and 138 withdrew from the trials because of adverse events.

Based on the pooled analysis, the rates of any adverse event (reported per 100 patient-years) after treatment courses one through five, respectively, were 379, 313, 319, 329, and 330, and the respective rates per 100 patient-years of any serious adverse events were 18.3, 17.4, 16.6, 12.0, and 13.4.

“The most frequent adverse events were infusion-related reactions, which occurred in 25% of the patients for the first infusion of the first course, and decreased for subsequent infusions,” Dr. van Vollenhoven said. In all, “15 events in 14 patients were considered serious infusion-related reactions, with 10, 4, 0, 1, and 0 events occurring in courses one through five, respectively.”

Although the proportion of patients with below-normal IgM or IgG levels increased with the number of treatment courses, there were no significant differences by course in the rates of infections or serious infections, said Dr. van Vollenhoven. The overall serious infection rate per 100 patient-years was 4.26, which is consistent with observations in other RA cohorts, and there were no cases of tuberculosis, he noted.

“There was one case of progressive multifocal leukoencephalopathy [PML] reported in a patient who had previously received chemotherapy for oropharyngeal cancer,” Dr. van Vollenhoven said, but like other cases of PML that have been reported in the RA treatment literature, it is unclear whether the occurrence of the fatal reactivation of the JC virus in the central nervous system was related to the rituximab, to other drugs, to the prior cancer treatment, or to the patient's existing impaired immune response.

With respect to malignancy, the analysis showed rates comparable to malignancy rates observed in the general RA population, and there was no increased risk of malignancy with additional courses of treatment, he said.

“These [data], showing the same basic safety profile with retreatment that has been shown in clinical treatment trials, are important. We pride ourselves on the use of biologics and the ability to reach specific targets with treatment, but B-cell therapies, for all their effectiveness, may have long-term consequences that are hard to predict,” said Dr. van Vollenhoven. “It's important to have a good long-term safety system to evaluate retreatment with these drugs.”

Dr. van Vollenhoven disclosed having received financial support for research from Roche.

Conventional measures of disease activity, such as swollen joints, do not appear to be associated with fatigue in rheumatoid arthritis, according to a study that examined fatigue assessments from more than 16,000 rheumatoid arthritis patients in the U.S.

Reports of fatigue were closely associated with patient-measures of pain. But fatigue was weakly associated with clinical measures of inflammation such as sedimentation rate, joint swelling, joint tenderness, and physician-reported global assessment, Dr. Martin J. Bergman said at the annual European Congress of Rheumatology.

The results are not meant to downplay the impact of fatigue in RA patients, he said. Fatigue is a common and devastating complaint for many patients with RA, said Dr. Bergman, a Philadelphia-area rheumatologist.

In addition to examining levels of fatigue among RA patients, the researchers collected data on reported fatigue from about 3,500 patients with fibromyalgia and 4,600 patients with osteoarthritis. As with the patients with RA, these other patients were asked to rate their problems with “unusual fatigue” over the past week on a scale of 0-10.

The findings show that fatigue was common not only in fibromyalgia and rheumatoid arthritis but also in patients with osteoarthritis.

Conventional measures of disease activity, such as swollen joints, do not appear to be associated with fatigue in rheumatoid arthritis, according to a study that examined fatigue assessments from more than 16,000 rheumatoid arthritis patients in the U.S.

Reports of fatigue were closely associated with patient-measures of pain. But fatigue was weakly associated with clinical measures of inflammation such as sedimentation rate, joint swelling, joint tenderness, and physician-reported global assessment, Dr. Martin J. Bergman said at the annual European Congress of Rheumatology.

The results are not meant to downplay the impact of fatigue in RA patients, he said. Fatigue is a common and devastating complaint for many patients with RA, said Dr. Bergman, a Philadelphia-area rheumatologist.

In addition to examining levels of fatigue among RA patients, the researchers collected data on reported fatigue from about 3,500 patients with fibromyalgia and 4,600 patients with osteoarthritis. As with the patients with RA, these other patients were asked to rate their problems with “unusual fatigue” over the past week on a scale of 0-10.

The findings show that fatigue was common not only in fibromyalgia and rheumatoid arthritis but also in patients with osteoarthritis.

Conventional measures of disease activity, such as swollen joints, do not appear to be associated with fatigue in rheumatoid arthritis, according to a study that examined fatigue assessments from more than 16,000 rheumatoid arthritis patients in the U.S.

Reports of fatigue were closely associated with patient-measures of pain. But fatigue was weakly associated with clinical measures of inflammation such as sedimentation rate, joint swelling, joint tenderness, and physician-reported global assessment, Dr. Martin J. Bergman said at the annual European Congress of Rheumatology.

The results are not meant to downplay the impact of fatigue in RA patients, he said. Fatigue is a common and devastating complaint for many patients with RA, said Dr. Bergman, a Philadelphia-area rheumatologist.

In addition to examining levels of fatigue among RA patients, the researchers collected data on reported fatigue from about 3,500 patients with fibromyalgia and 4,600 patients with osteoarthritis. As with the patients with RA, these other patients were asked to rate their problems with “unusual fatigue” over the past week on a scale of 0-10.

The findings show that fatigue was common not only in fibromyalgia and rheumatoid arthritis but also in patients with osteoarthritis.

COPENHAGEN — Patients with rheumatoid arthritis have a substantially higher prevalence of peripheral artery disease than do similar people without RA, based on a case-control study with 101 subjects.

PAD “should not be overlooked in rheumatoid arthritis patients,” Dr. Suzan Abou-Raya said at the annual meeting of the European Congress of Rheumatology. RA patients “should be regularly screened [for PAD] to help reduce their incidence of cardiovascular morbidity and mortality,” said Dr. Abou-Raya, a researcher in the geriatric unit at the University of Alexandria (Egypt).

The study enrolled 64 consecutive RA patients (38 women and 26 men), with an average age of 55 years and an average RA duration of 12 years. The patients had no history of cardiovascular disease. Dr. Abou-Raya and her associates also enrolled 37 healthy controls without RA or cardiovascular disease who were matched with the cases by age, sex, body mass index, and their conventional cardiovascular-disease risk factors. All the cases and controls were nonsmokers. The average total cholesterol level was about 190 mg/dL. The researchers assessed PAD by the ankle brachial index (ABI). They measured arterial pressure with a Doppler ultrasound velocity detector at two ankle sites: posterior tibial and dorsalis pedis. An ABI ratio of 0.9 or less in an artery meant it was obstructed; a ratio of 1.0 to less than 1.3 was normal, and a ratio of 1.3 or greater meant an incompressible artery (a marker of significant calcification). Abnormal ABIs, either obstructed or incompressible, existed in 19 RA patients (30%) and in two controls (5%), a statistically significant difference. In a total of 256 arteries examined in the 64 RA patients, 10 (4%) were obstructed and 20 (8%) were incompressible. That's significantly higher than in 148 arteries examined in the 37 controls, with two obstructed (1%) and one incompressible (1%).

In a multivariate analysis, clinical characteristics of the RA patients that significantly correlated with an abnormal ABI were RA disease duration, serum level of C-reactive protein, and a worse score on the Health Assessment Questionnaire (HAQ).

Dr. Abou-Raya said that she and her associates had no financial disclosures.

COPENHAGEN — Patients with rheumatoid arthritis have a substantially higher prevalence of peripheral artery disease than do similar people without RA, based on a case-control study with 101 subjects.

PAD “should not be overlooked in rheumatoid arthritis patients,” Dr. Suzan Abou-Raya said at the annual meeting of the European Congress of Rheumatology. RA patients “should be regularly screened [for PAD] to help reduce their incidence of cardiovascular morbidity and mortality,” said Dr. Abou-Raya, a researcher in the geriatric unit at the University of Alexandria (Egypt).

The study enrolled 64 consecutive RA patients (38 women and 26 men), with an average age of 55 years and an average RA duration of 12 years. The patients had no history of cardiovascular disease. Dr. Abou-Raya and her associates also enrolled 37 healthy controls without RA or cardiovascular disease who were matched with the cases by age, sex, body mass index, and their conventional cardiovascular-disease risk factors. All the cases and controls were nonsmokers. The average total cholesterol level was about 190 mg/dL. The researchers assessed PAD by the ankle brachial index (ABI). They measured arterial pressure with a Doppler ultrasound velocity detector at two ankle sites: posterior tibial and dorsalis pedis. An ABI ratio of 0.9 or less in an artery meant it was obstructed; a ratio of 1.0 to less than 1.3 was normal, and a ratio of 1.3 or greater meant an incompressible artery (a marker of significant calcification). Abnormal ABIs, either obstructed or incompressible, existed in 19 RA patients (30%) and in two controls (5%), a statistically significant difference. In a total of 256 arteries examined in the 64 RA patients, 10 (4%) were obstructed and 20 (8%) were incompressible. That's significantly higher than in 148 arteries examined in the 37 controls, with two obstructed (1%) and one incompressible (1%).

In a multivariate analysis, clinical characteristics of the RA patients that significantly correlated with an abnormal ABI were RA disease duration, serum level of C-reactive protein, and a worse score on the Health Assessment Questionnaire (HAQ).

Dr. Abou-Raya said that she and her associates had no financial disclosures.

COPENHAGEN — Patients with rheumatoid arthritis have a substantially higher prevalence of peripheral artery disease than do similar people without RA, based on a case-control study with 101 subjects.

PAD “should not be overlooked in rheumatoid arthritis patients,” Dr. Suzan Abou-Raya said at the annual meeting of the European Congress of Rheumatology. RA patients “should be regularly screened [for PAD] to help reduce their incidence of cardiovascular morbidity and mortality,” said Dr. Abou-Raya, a researcher in the geriatric unit at the University of Alexandria (Egypt).

The study enrolled 64 consecutive RA patients (38 women and 26 men), with an average age of 55 years and an average RA duration of 12 years. The patients had no history of cardiovascular disease. Dr. Abou-Raya and her associates also enrolled 37 healthy controls without RA or cardiovascular disease who were matched with the cases by age, sex, body mass index, and their conventional cardiovascular-disease risk factors. All the cases and controls were nonsmokers. The average total cholesterol level was about 190 mg/dL. The researchers assessed PAD by the ankle brachial index (ABI). They measured arterial pressure with a Doppler ultrasound velocity detector at two ankle sites: posterior tibial and dorsalis pedis. An ABI ratio of 0.9 or less in an artery meant it was obstructed; a ratio of 1.0 to less than 1.3 was normal, and a ratio of 1.3 or greater meant an incompressible artery (a marker of significant calcification). Abnormal ABIs, either obstructed or incompressible, existed in 19 RA patients (30%) and in two controls (5%), a statistically significant difference. In a total of 256 arteries examined in the 64 RA patients, 10 (4%) were obstructed and 20 (8%) were incompressible. That's significantly higher than in 148 arteries examined in the 37 controls, with two obstructed (1%) and one incompressible (1%).

In a multivariate analysis, clinical characteristics of the RA patients that significantly correlated with an abnormal ABI were RA disease duration, serum level of C-reactive protein, and a worse score on the Health Assessment Questionnaire (HAQ).

Dr. Abou-Raya said that she and her associates had no financial disclosures.

COPENHAGEN — Reduced responses to pneumococcal polysaccharide and neoantigen vaccination in rheumatoid arthritis patients who were treated with rituximab and methotrexate suggest that polysaccharide and primary immunizations should be administered before rituximab infusions to maximize their efficacy, Dr. Clifton O. Bingham III said at the annual European Congress of Rheumatology.

Presenting data from SIERRA (Study Investigating the Effects of Rituximab on Rheumatoid Arthritis Patients), Dr. Bingham, director of the rheumatology clinics at Johns Hopkins University in Baltimore, reported that relative to patients treated with methotrexate only, patients who were given rituximab plus methotrexate mount a comparable recall response to tetanus toxoid, a measure of retained immunity. Patients on combination therapy also showed preserved delayed-type hypersensitivity (DTH) responses to the Candida albicans skin test.

However, patients on combination therapy showed decreased responses to both the 23-valent pneumococcal polysaccharide vaccine (PPV23), which measures T cell-independent humoral responses, and the neoantigen keyhole limpet hemocyanin (KLH), which tests T cell-dependent primary humoral responses.

The multicenter trial included 103 patients with active RA who were stratified by age and randomized 2:1 to receive two 1,000-mg infusions of rituximab 14 days apart plus methotrexate, or methotrexate alone. Patients aged 18-65 years were included in the study if they had at least four swollen and five tender joints and had been on stable doses of methotrexate for more than 4 weeks, Dr. Bingham explained. Additionally, background corticosteroids were permitted “as long as the dose was less than 10 mg per day and stable for more than 4 weeks,” he said.

Individuals older than 65 years were excluded from the study “because of the known effect of aging on immune responses,” Dr. Bingham stated. Patients who received the pneumococcal vaccine within the previous 3 years, or the tetanus vaccine within the previous 5 years, and those with other uncontrolled concomitant medical illnesses or concurrent use of other disease-modifying antirheumatic drugs or biologics were also excluded, he said.

The methotrexate-only patients received the tetanus toxoid-adsorbed vaccine on day 1, the PPV23 at week 4, and KLH at weeks 8 and 9, whereas the rituximab group received the same vaccines in the same intervals beginning at week 24, Dr. Bingham said.

The C. albicans skin test was administered on day 1 to both groups and then again at week 12 in the methotrexate-only group and at week 24 in the rituximab group.

The study's primary end point was the proportion of patients with a fourfold increase in antitetanus IgG from prevaccination levels, measured 4 weeks after immunization, Dr. Bingham stated. Secondary end points included a twofold increase in tetanus toxoid titer; a twofold increase or an increase of more than one mcg/mL from prevaccination levels in immune response to the PPV23; postvaccination KLH titers; and postvaccination DTH reactions, based on a C. albicans skin test with a cutoff of 5 mm of induration, he said.

With respect to baseline demographics, the patients in both groups were similarly matched except for baseline steroid use and positive skin test at baseline, Dr. Bingham noted. Baseline steroid use was higher in the rituximab group (42%), compared with 19% in the methotrexate-only group, whereas the proportion of patients with a positive skin test was lower in the rituximab group (48%), compared with 71% in the methotrexate-only population, he said.

An evaluation of B cells in the rituximab group at the time of vaccine administration showed that “peripheral B-cell depletion was as expected,” Dr. Bingham said.

“At 24 weeks, when the tetanus toxoid was administered, 92% of the patients remained B cell depleted; at 28 weeks, when the pneumococcus vaccine was given, 89% were B cell depleted; and at 36 weeks, when the KLH was given, 76% of the patients were B cell depleted.”

Regarding the study end points, there was no significant difference between the methotrexate-only patients and the rituximab patients in their responses to the tetanus vaccine at either the fourfold or twofold titer increase thresholds, Dr. Bingham stated.

“What was striking, actually, is that even in patients treated with methotrexate only, the tetanus responses were somewhat low, with only 39% of the rituximab-treated group and 42% of the methotrexate-only group demonstrating a fourfold titer rise.”

Significantly fewer of the rituximab patients responded to at least one pneumococcal serotype of the PPV23 (57% vs. 82% of the methotrexate-only group) and to KLH (47% vs. 93%), said Dr. Bingham. “The mean titers were also lower in the rituximab-treated patients.”

Although many patients in the rituximab group were able to mount an immune response to the vaccinations, “it did appear that neoantigen responses to KLH and T cell-independent responses to pneumococcal polysaccharide vaccination were decreased,” according to Dr. Bingham.

The only significant predictor of vaccine response was IgG2 level at the time of immunization for tetanus, PPV23, and KLH vaccines, he said, noting that “age, methotrexate dose, concomitant corticosteroid use, diagnosis of diabetes mellitus, skin test anergy [less than 5-mm induration], IgM, IgA, total IgG, and IgG1, IgG3, and IgG4 subsets were not predictors of immunization response, nor did rituximab affect total IgG or IgG2 levels.”

Dr. Bingham has served as a consultant to Genentech Inc. and to Roche.

COPENHAGEN — Reduced responses to pneumococcal polysaccharide and neoantigen vaccination in rheumatoid arthritis patients who were treated with rituximab and methotrexate suggest that polysaccharide and primary immunizations should be administered before rituximab infusions to maximize their efficacy, Dr. Clifton O. Bingham III said at the annual European Congress of Rheumatology.

Presenting data from SIERRA (Study Investigating the Effects of Rituximab on Rheumatoid Arthritis Patients), Dr. Bingham, director of the rheumatology clinics at Johns Hopkins University in Baltimore, reported that relative to patients treated with methotrexate only, patients who were given rituximab plus methotrexate mount a comparable recall response to tetanus toxoid, a measure of retained immunity. Patients on combination therapy also showed preserved delayed-type hypersensitivity (DTH) responses to the Candida albicans skin test.

However, patients on combination therapy showed decreased responses to both the 23-valent pneumococcal polysaccharide vaccine (PPV23), which measures T cell-independent humoral responses, and the neoantigen keyhole limpet hemocyanin (KLH), which tests T cell-dependent primary humoral responses.

The multicenter trial included 103 patients with active RA who were stratified by age and randomized 2:1 to receive two 1,000-mg infusions of rituximab 14 days apart plus methotrexate, or methotrexate alone. Patients aged 18-65 years were included in the study if they had at least four swollen and five tender joints and had been on stable doses of methotrexate for more than 4 weeks, Dr. Bingham explained. Additionally, background corticosteroids were permitted “as long as the dose was less than 10 mg per day and stable for more than 4 weeks,” he said.

Individuals older than 65 years were excluded from the study “because of the known effect of aging on immune responses,” Dr. Bingham stated. Patients who received the pneumococcal vaccine within the previous 3 years, or the tetanus vaccine within the previous 5 years, and those with other uncontrolled concomitant medical illnesses or concurrent use of other disease-modifying antirheumatic drugs or biologics were also excluded, he said.

The methotrexate-only patients received the tetanus toxoid-adsorbed vaccine on day 1, the PPV23 at week 4, and KLH at weeks 8 and 9, whereas the rituximab group received the same vaccines in the same intervals beginning at week 24, Dr. Bingham said.

The C. albicans skin test was administered on day 1 to both groups and then again at week 12 in the methotrexate-only group and at week 24 in the rituximab group.

The study's primary end point was the proportion of patients with a fourfold increase in antitetanus IgG from prevaccination levels, measured 4 weeks after immunization, Dr. Bingham stated. Secondary end points included a twofold increase in tetanus toxoid titer; a twofold increase or an increase of more than one mcg/mL from prevaccination levels in immune response to the PPV23; postvaccination KLH titers; and postvaccination DTH reactions, based on a C. albicans skin test with a cutoff of 5 mm of induration, he said.

With respect to baseline demographics, the patients in both groups were similarly matched except for baseline steroid use and positive skin test at baseline, Dr. Bingham noted. Baseline steroid use was higher in the rituximab group (42%), compared with 19% in the methotrexate-only group, whereas the proportion of patients with a positive skin test was lower in the rituximab group (48%), compared with 71% in the methotrexate-only population, he said.

An evaluation of B cells in the rituximab group at the time of vaccine administration showed that “peripheral B-cell depletion was as expected,” Dr. Bingham said.

“At 24 weeks, when the tetanus toxoid was administered, 92% of the patients remained B cell depleted; at 28 weeks, when the pneumococcus vaccine was given, 89% were B cell depleted; and at 36 weeks, when the KLH was given, 76% of the patients were B cell depleted.”

Regarding the study end points, there was no significant difference between the methotrexate-only patients and the rituximab patients in their responses to the tetanus vaccine at either the fourfold or twofold titer increase thresholds, Dr. Bingham stated.

“What was striking, actually, is that even in patients treated with methotrexate only, the tetanus responses were somewhat low, with only 39% of the rituximab-treated group and 42% of the methotrexate-only group demonstrating a fourfold titer rise.”

Significantly fewer of the rituximab patients responded to at least one pneumococcal serotype of the PPV23 (57% vs. 82% of the methotrexate-only group) and to KLH (47% vs. 93%), said Dr. Bingham. “The mean titers were also lower in the rituximab-treated patients.”

Although many patients in the rituximab group were able to mount an immune response to the vaccinations, “it did appear that neoantigen responses to KLH and T cell-independent responses to pneumococcal polysaccharide vaccination were decreased,” according to Dr. Bingham.

The only significant predictor of vaccine response was IgG2 level at the time of immunization for tetanus, PPV23, and KLH vaccines, he said, noting that “age, methotrexate dose, concomitant corticosteroid use, diagnosis of diabetes mellitus, skin test anergy [less than 5-mm induration], IgM, IgA, total IgG, and IgG1, IgG3, and IgG4 subsets were not predictors of immunization response, nor did rituximab affect total IgG or IgG2 levels.”

Dr. Bingham has served as a consultant to Genentech Inc. and to Roche.

COPENHAGEN — Reduced responses to pneumococcal polysaccharide and neoantigen vaccination in rheumatoid arthritis patients who were treated with rituximab and methotrexate suggest that polysaccharide and primary immunizations should be administered before rituximab infusions to maximize their efficacy, Dr. Clifton O. Bingham III said at the annual European Congress of Rheumatology.

Presenting data from SIERRA (Study Investigating the Effects of Rituximab on Rheumatoid Arthritis Patients), Dr. Bingham, director of the rheumatology clinics at Johns Hopkins University in Baltimore, reported that relative to patients treated with methotrexate only, patients who were given rituximab plus methotrexate mount a comparable recall response to tetanus toxoid, a measure of retained immunity. Patients on combination therapy also showed preserved delayed-type hypersensitivity (DTH) responses to the Candida albicans skin test.

However, patients on combination therapy showed decreased responses to both the 23-valent pneumococcal polysaccharide vaccine (PPV23), which measures T cell-independent humoral responses, and the neoantigen keyhole limpet hemocyanin (KLH), which tests T cell-dependent primary humoral responses.

The multicenter trial included 103 patients with active RA who were stratified by age and randomized 2:1 to receive two 1,000-mg infusions of rituximab 14 days apart plus methotrexate, or methotrexate alone. Patients aged 18-65 years were included in the study if they had at least four swollen and five tender joints and had been on stable doses of methotrexate for more than 4 weeks, Dr. Bingham explained. Additionally, background corticosteroids were permitted “as long as the dose was less than 10 mg per day and stable for more than 4 weeks,” he said.

Individuals older than 65 years were excluded from the study “because of the known effect of aging on immune responses,” Dr. Bingham stated. Patients who received the pneumococcal vaccine within the previous 3 years, or the tetanus vaccine within the previous 5 years, and those with other uncontrolled concomitant medical illnesses or concurrent use of other disease-modifying antirheumatic drugs or biologics were also excluded, he said.

The methotrexate-only patients received the tetanus toxoid-adsorbed vaccine on day 1, the PPV23 at week 4, and KLH at weeks 8 and 9, whereas the rituximab group received the same vaccines in the same intervals beginning at week 24, Dr. Bingham said.

The C. albicans skin test was administered on day 1 to both groups and then again at week 12 in the methotrexate-only group and at week 24 in the rituximab group.

The study's primary end point was the proportion of patients with a fourfold increase in antitetanus IgG from prevaccination levels, measured 4 weeks after immunization, Dr. Bingham stated. Secondary end points included a twofold increase in tetanus toxoid titer; a twofold increase or an increase of more than one mcg/mL from prevaccination levels in immune response to the PPV23; postvaccination KLH titers; and postvaccination DTH reactions, based on a C. albicans skin test with a cutoff of 5 mm of induration, he said.

With respect to baseline demographics, the patients in both groups were similarly matched except for baseline steroid use and positive skin test at baseline, Dr. Bingham noted. Baseline steroid use was higher in the rituximab group (42%), compared with 19% in the methotrexate-only group, whereas the proportion of patients with a positive skin test was lower in the rituximab group (48%), compared with 71% in the methotrexate-only population, he said.

An evaluation of B cells in the rituximab group at the time of vaccine administration showed that “peripheral B-cell depletion was as expected,” Dr. Bingham said.

“At 24 weeks, when the tetanus toxoid was administered, 92% of the patients remained B cell depleted; at 28 weeks, when the pneumococcus vaccine was given, 89% were B cell depleted; and at 36 weeks, when the KLH was given, 76% of the patients were B cell depleted.”

Regarding the study end points, there was no significant difference between the methotrexate-only patients and the rituximab patients in their responses to the tetanus vaccine at either the fourfold or twofold titer increase thresholds, Dr. Bingham stated.

“What was striking, actually, is that even in patients treated with methotrexate only, the tetanus responses were somewhat low, with only 39% of the rituximab-treated group and 42% of the methotrexate-only group demonstrating a fourfold titer rise.”

Significantly fewer of the rituximab patients responded to at least one pneumococcal serotype of the PPV23 (57% vs. 82% of the methotrexate-only group) and to KLH (47% vs. 93%), said Dr. Bingham. “The mean titers were also lower in the rituximab-treated patients.”

Although many patients in the rituximab group were able to mount an immune response to the vaccinations, “it did appear that neoantigen responses to KLH and T cell-independent responses to pneumococcal polysaccharide vaccination were decreased,” according to Dr. Bingham.

The only significant predictor of vaccine response was IgG2 level at the time of immunization for tetanus, PPV23, and KLH vaccines, he said, noting that “age, methotrexate dose, concomitant corticosteroid use, diagnosis of diabetes mellitus, skin test anergy [less than 5-mm induration], IgM, IgA, total IgG, and IgG1, IgG3, and IgG4 subsets were not predictors of immunization response, nor did rituximab affect total IgG or IgG2 levels.”

Dr. Bingham has served as a consultant to Genentech Inc. and to Roche.

COPENHAGEN — An investigational oral drug showed safety and efficacy as monotherapy in patients with rheumatoid arthritis in a phase II study with 384 patients.

The new drug is CP-690550, a selective inhibitor of Janus kinase (JAK), which is an enzyme involved in cytokine signaling. The agent is “clearly effective,” and so far the adverse effects profile seems manageable, Dr. Roy M. Fleischmann said at the annual European Congress of Rheumatology.

Because CP-690550 is a small molecule and an oral drug, it should be cheaper to make than biologic agents, and it has the potential to be easier and less expensive to use than tumor necrosis factor inhibitors, said Dr. Fleischmann, a rheumatologist at the University of Texas Southwestern Medical Center in Dallas.

“This drug has the potential to be very significant” for treating patients with rheumatoid arthritis (RA), Dr. Fleischmann said.

The study was funded by Pfizer Inc., which is developing CP-690550. Dr. Fleischmann said that he has received research support from and has been a consultant to Pfizer in developing this drug.

The study randomized patients who had active RA despite treatment with a disease-modifying antirheumatic drug either to monotherapy with one of five different dosage regimens of the JAK inhibitor (1, 3, 5, 10, or 15 mg b.i.d.), to the tumor necrosis factor inhibitor adalimumab (Humira) administered at 40 mg subcutaneously once every other week, or to placebo.

About 50 patients formed each treatment group. The primary efficacy end point was ACR 20 response after 12 weeks of treatment using a nonresponder imputation analysis. (Dropouts were considered to be nonresponders.)

ACR 20 response rates in patients who received 3, 5, 10, and 15 mg b.i.d. were all significantly increased over the placebo rate. Response rates were about 25% with placebo, 40% with adalimumab, and 45%-70% in patients on 3-15 mg b.i.d. of CP-690550. Response rates among patients on the JAK inhibitor rose in a dose-dependent way.

Patients who were placed on higher doses of the investigational drug also had significant improvements in their HAQ-DI (Health Assessment Questionnaire-Disability Index) and DAS28 (Disease Activity Score 28).

In the safety analysis, the new drug didn't produce a significant decline in hemoglobin, a significant change in blood pressure, a significant increase in serum creatinine, or any serious or opportunistic infections. The 3- to 15-mg dosages were linked with statistically significant drops in neutrophil counts. Average neutrophil levels did not fall below the normal range, however; average levels in patients on the highest doses were about 4,000/mm

Average levels of LDL cholesterol rose by 25 mg/dL in patients who were given 10-mg or 15-mg b.i.d. dosages. Serum levels of HDL cholesterol also rose by an average of 10 mg/dL in the highest-dosage groups.

Cholesterol levels don't increase in everyone, but everyone should be monitored, and those with elevated levels should be treated, Dr. Fleischmann said in an interview. “Treatment with a statin should control it.” Serum cholesterol levels in all RA patients already need monitoring because cardiovascular disease is such an important comorbidity, he added.

Based on these results and on findings in other phase I and II studies with the drug, Pfizer began a large phase III study last February, according to a company-written statement. The best candidate dosages for phase III testing are 5 mg and 10 mg b.i.d., Dr. Fleischmann said.

A flaw in the study was that the active comparator group was “suboptimal,” using adalimumab monotherapy instead of its usual combination with methotrexate, commented Dr. Ferdinand C. Breedveld, professor of rheumatology at Leiden (the Netherlands) University.

Dr. Fleischmann defended the choice, pointing out that the study was designed to test monotherapy, and that adalimumab is licensed for monotherapy by the Food and Drug Administration. He also noted that a phase III study will likely compare adalimumab plus methotrexate to CP-690550 and methotrexate in RA patients.

But Dr. Breedveld also saw potential for the JAK inhibitor if it can be proved safe and even comparable in efficacy to tumor necrosis factor inhibitors like adalimumab. “It would be easy to use and should save cost. It would be a major step in RA treatment.” Dr. Breedveld has been a consultant to Pfizer and other drug companies.

To watch a video interview with Dr. Fleischmann, go to: www.youtube.com/watch?v=g00XHsjhFS0

CP-690550 is expected to be cheaper and easier to use than TNF inhibitors, with a manageable adverse event profile, according to Dr. Roy M. Fleischmann

Source Mitchel L. Zoler/Elsevier Global Medical News

COPENHAGEN — An investigational oral drug showed safety and efficacy as monotherapy in patients with rheumatoid arthritis in a phase II study with 384 patients.

The new drug is CP-690550, a selective inhibitor of Janus kinase (JAK), which is an enzyme involved in cytokine signaling. The agent is “clearly effective,” and so far the adverse effects profile seems manageable, Dr. Roy M. Fleischmann said at the annual European Congress of Rheumatology.

Because CP-690550 is a small molecule and an oral drug, it should be cheaper to make than biologic agents, and it has the potential to be easier and less expensive to use than tumor necrosis factor inhibitors, said Dr. Fleischmann, a rheumatologist at the University of Texas Southwestern Medical Center in Dallas.

“This drug has the potential to be very significant” for treating patients with rheumatoid arthritis (RA), Dr. Fleischmann said.

The study was funded by Pfizer Inc., which is developing CP-690550. Dr. Fleischmann said that he has received research support from and has been a consultant to Pfizer in developing this drug.

The study randomized patients who had active RA despite treatment with a disease-modifying antirheumatic drug either to monotherapy with one of five different dosage regimens of the JAK inhibitor (1, 3, 5, 10, or 15 mg b.i.d.), to the tumor necrosis factor inhibitor adalimumab (Humira) administered at 40 mg subcutaneously once every other week, or to placebo.

About 50 patients formed each treatment group. The primary efficacy end point was ACR 20 response after 12 weeks of treatment using a nonresponder imputation analysis. (Dropouts were considered to be nonresponders.)

ACR 20 response rates in patients who received 3, 5, 10, and 15 mg b.i.d. were all significantly increased over the placebo rate. Response rates were about 25% with placebo, 40% with adalimumab, and 45%-70% in patients on 3-15 mg b.i.d. of CP-690550. Response rates among patients on the JAK inhibitor rose in a dose-dependent way.

Patients who were placed on higher doses of the investigational drug also had significant improvements in their HAQ-DI (Health Assessment Questionnaire-Disability Index) and DAS28 (Disease Activity Score 28).

In the safety analysis, the new drug didn't produce a significant decline in hemoglobin, a significant change in blood pressure, a significant increase in serum creatinine, or any serious or opportunistic infections. The 3- to 15-mg dosages were linked with statistically significant drops in neutrophil counts. Average neutrophil levels did not fall below the normal range, however; average levels in patients on the highest doses were about 4,000/mm

Average levels of LDL cholesterol rose by 25 mg/dL in patients who were given 10-mg or 15-mg b.i.d. dosages. Serum levels of HDL cholesterol also rose by an average of 10 mg/dL in the highest-dosage groups.

Cholesterol levels don't increase in everyone, but everyone should be monitored, and those with elevated levels should be treated, Dr. Fleischmann said in an interview. “Treatment with a statin should control it.” Serum cholesterol levels in all RA patients already need monitoring because cardiovascular disease is such an important comorbidity, he added.

Based on these results and on findings in other phase I and II studies with the drug, Pfizer began a large phase III study last February, according to a company-written statement. The best candidate dosages for phase III testing are 5 mg and 10 mg b.i.d., Dr. Fleischmann said.

A flaw in the study was that the active comparator group was “suboptimal,” using adalimumab monotherapy instead of its usual combination with methotrexate, commented Dr. Ferdinand C. Breedveld, professor of rheumatology at Leiden (the Netherlands) University.

Dr. Fleischmann defended the choice, pointing out that the study was designed to test monotherapy, and that adalimumab is licensed for monotherapy by the Food and Drug Administration. He also noted that a phase III study will likely compare adalimumab plus methotrexate to CP-690550 and methotrexate in RA patients.

But Dr. Breedveld also saw potential for the JAK inhibitor if it can be proved safe and even comparable in efficacy to tumor necrosis factor inhibitors like adalimumab. “It would be easy to use and should save cost. It would be a major step in RA treatment.” Dr. Breedveld has been a consultant to Pfizer and other drug companies.

To watch a video interview with Dr. Fleischmann, go to: www.youtube.com/watch?v=g00XHsjhFS0

CP-690550 is expected to be cheaper and easier to use than TNF inhibitors, with a manageable adverse event profile, according to Dr. Roy M. Fleischmann

Source Mitchel L. Zoler/Elsevier Global Medical News

COPENHAGEN — An investigational oral drug showed safety and efficacy as monotherapy in patients with rheumatoid arthritis in a phase II study with 384 patients.

The new drug is CP-690550, a selective inhibitor of Janus kinase (JAK), which is an enzyme involved in cytokine signaling. The agent is “clearly effective,” and so far the adverse effects profile seems manageable, Dr. Roy M. Fleischmann said at the annual European Congress of Rheumatology.

Because CP-690550 is a small molecule and an oral drug, it should be cheaper to make than biologic agents, and it has the potential to be easier and less expensive to use than tumor necrosis factor inhibitors, said Dr. Fleischmann, a rheumatologist at the University of Texas Southwestern Medical Center in Dallas.

“This drug has the potential to be very significant” for treating patients with rheumatoid arthritis (RA), Dr. Fleischmann said.

The study was funded by Pfizer Inc., which is developing CP-690550. Dr. Fleischmann said that he has received research support from and has been a consultant to Pfizer in developing this drug.

The study randomized patients who had active RA despite treatment with a disease-modifying antirheumatic drug either to monotherapy with one of five different dosage regimens of the JAK inhibitor (1, 3, 5, 10, or 15 mg b.i.d.), to the tumor necrosis factor inhibitor adalimumab (Humira) administered at 40 mg subcutaneously once every other week, or to placebo.

About 50 patients formed each treatment group. The primary efficacy end point was ACR 20 response after 12 weeks of treatment using a nonresponder imputation analysis. (Dropouts were considered to be nonresponders.)

ACR 20 response rates in patients who received 3, 5, 10, and 15 mg b.i.d. were all significantly increased over the placebo rate. Response rates were about 25% with placebo, 40% with adalimumab, and 45%-70% in patients on 3-15 mg b.i.d. of CP-690550. Response rates among patients on the JAK inhibitor rose in a dose-dependent way.

Patients who were placed on higher doses of the investigational drug also had significant improvements in their HAQ-DI (Health Assessment Questionnaire-Disability Index) and DAS28 (Disease Activity Score 28).

In the safety analysis, the new drug didn't produce a significant decline in hemoglobin, a significant change in blood pressure, a significant increase in serum creatinine, or any serious or opportunistic infections. The 3- to 15-mg dosages were linked with statistically significant drops in neutrophil counts. Average neutrophil levels did not fall below the normal range, however; average levels in patients on the highest doses were about 4,000/mm

Average levels of LDL cholesterol rose by 25 mg/dL in patients who were given 10-mg or 15-mg b.i.d. dosages. Serum levels of HDL cholesterol also rose by an average of 10 mg/dL in the highest-dosage groups.

Cholesterol levels don't increase in everyone, but everyone should be monitored, and those with elevated levels should be treated, Dr. Fleischmann said in an interview. “Treatment with a statin should control it.” Serum cholesterol levels in all RA patients already need monitoring because cardiovascular disease is such an important comorbidity, he added.

Based on these results and on findings in other phase I and II studies with the drug, Pfizer began a large phase III study last February, according to a company-written statement. The best candidate dosages for phase III testing are 5 mg and 10 mg b.i.d., Dr. Fleischmann said.

A flaw in the study was that the active comparator group was “suboptimal,” using adalimumab monotherapy instead of its usual combination with methotrexate, commented Dr. Ferdinand C. Breedveld, professor of rheumatology at Leiden (the Netherlands) University.

Dr. Fleischmann defended the choice, pointing out that the study was designed to test monotherapy, and that adalimumab is licensed for monotherapy by the Food and Drug Administration. He also noted that a phase III study will likely compare adalimumab plus methotrexate to CP-690550 and methotrexate in RA patients.

But Dr. Breedveld also saw potential for the JAK inhibitor if it can be proved safe and even comparable in efficacy to tumor necrosis factor inhibitors like adalimumab. “It would be easy to use and should save cost. It would be a major step in RA treatment.” Dr. Breedveld has been a consultant to Pfizer and other drug companies.

To watch a video interview with Dr. Fleischmann, go to: www.youtube.com/watch?v=g00XHsjhFS0

CP-690550 is expected to be cheaper and easier to use than TNF inhibitors, with a manageable adverse event profile, according to Dr. Roy M. Fleischmann

Source Mitchel L. Zoler/Elsevier Global Medical News

COPENHAGEN — Rheumatoid arthritis patients with higher disease severity and longer disease duration had the highest risk for developing cardiovascular disease during 15 years of follow-up in a small study.

Rheumatoid arthritis (RA) patients with a higher level of inflammation, as indicated by elevated serum levels of C-reactive protein (CRP) early in the course of their RA, had the greatest risk for developing arterial stiffness during follow-up, Dr. Sella Aarrestad Provan said at the annual European Congress of Rheumatology.

Because the study enrolled RA patients who had been diagnosed within the prior 4 years, the findings “support the importance of early, active disease management in patients with RA,” said Dr. Provan of the department of rheumatology at Diakonhjemmet Hospital in Oslo. The study involved 238 patients enrolled in the EURIDISS (European Research on Incapacitating Disease and Social Support) cohort in 1992. Average age at enrollment was 52 years, and three-quarters were women. Dr. Provan conducted the research as part of her ongoing doctoral studies.

At 15 years after enrollment, 107 of these patients underwent a follow-up examination. During follow-up, 44 of the 107 self-reported having cardiovascular disease. Also at 15 years, 102 patients had an applanation tonometry assessment that determined their central arterial stiffness. The analysis correlated these two end points with patients' clinical characteristics at entry.

Patients who developed cardiovascular disease had significantly longer disease duration at entry than did patients who remained free of cardiovascular disease, although none of the patients entered the study having had RA for more than 4 years. Other significant correlates of cardiovascular disease risk were a high CRP level at entry, a high score on the Stanford HAQ (Health Assessment Questionnaire), and a high score on the Ritchie index. In a logistic regression model that also controlled for age, sex, diabetes, and smoking status, the only entry measures that remained significant were disease duration and HAQ score, she said.

The only significant baseline predictor of high central arterial stiffness (augmentation index) at 15 years was a high CRP level.

Dr. Provan said that she and her associates had no financial relationships to disclose.

COPENHAGEN — Rheumatoid arthritis patients with higher disease severity and longer disease duration had the highest risk for developing cardiovascular disease during 15 years of follow-up in a small study.

Rheumatoid arthritis (RA) patients with a higher level of inflammation, as indicated by elevated serum levels of C-reactive protein (CRP) early in the course of their RA, had the greatest risk for developing arterial stiffness during follow-up, Dr. Sella Aarrestad Provan said at the annual European Congress of Rheumatology.

Because the study enrolled RA patients who had been diagnosed within the prior 4 years, the findings “support the importance of early, active disease management in patients with RA,” said Dr. Provan of the department of rheumatology at Diakonhjemmet Hospital in Oslo. The study involved 238 patients enrolled in the EURIDISS (European Research on Incapacitating Disease and Social Support) cohort in 1992. Average age at enrollment was 52 years, and three-quarters were women. Dr. Provan conducted the research as part of her ongoing doctoral studies.

At 15 years after enrollment, 107 of these patients underwent a follow-up examination. During follow-up, 44 of the 107 self-reported having cardiovascular disease. Also at 15 years, 102 patients had an applanation tonometry assessment that determined their central arterial stiffness. The analysis correlated these two end points with patients' clinical characteristics at entry.

Patients who developed cardiovascular disease had significantly longer disease duration at entry than did patients who remained free of cardiovascular disease, although none of the patients entered the study having had RA for more than 4 years. Other significant correlates of cardiovascular disease risk were a high CRP level at entry, a high score on the Stanford HAQ (Health Assessment Questionnaire), and a high score on the Ritchie index. In a logistic regression model that also controlled for age, sex, diabetes, and smoking status, the only entry measures that remained significant were disease duration and HAQ score, she said.

The only significant baseline predictor of high central arterial stiffness (augmentation index) at 15 years was a high CRP level.

Dr. Provan said that she and her associates had no financial relationships to disclose.

COPENHAGEN — Rheumatoid arthritis patients with higher disease severity and longer disease duration had the highest risk for developing cardiovascular disease during 15 years of follow-up in a small study.

Rheumatoid arthritis (RA) patients with a higher level of inflammation, as indicated by elevated serum levels of C-reactive protein (CRP) early in the course of their RA, had the greatest risk for developing arterial stiffness during follow-up, Dr. Sella Aarrestad Provan said at the annual European Congress of Rheumatology.

Because the study enrolled RA patients who had been diagnosed within the prior 4 years, the findings “support the importance of early, active disease management in patients with RA,” said Dr. Provan of the department of rheumatology at Diakonhjemmet Hospital in Oslo. The study involved 238 patients enrolled in the EURIDISS (European Research on Incapacitating Disease and Social Support) cohort in 1992. Average age at enrollment was 52 years, and three-quarters were women. Dr. Provan conducted the research as part of her ongoing doctoral studies.

At 15 years after enrollment, 107 of these patients underwent a follow-up examination. During follow-up, 44 of the 107 self-reported having cardiovascular disease. Also at 15 years, 102 patients had an applanation tonometry assessment that determined their central arterial stiffness. The analysis correlated these two end points with patients' clinical characteristics at entry.

Patients who developed cardiovascular disease had significantly longer disease duration at entry than did patients who remained free of cardiovascular disease, although none of the patients entered the study having had RA for more than 4 years. Other significant correlates of cardiovascular disease risk were a high CRP level at entry, a high score on the Stanford HAQ (Health Assessment Questionnaire), and a high score on the Ritchie index. In a logistic regression model that also controlled for age, sex, diabetes, and smoking status, the only entry measures that remained significant were disease duration and HAQ score, she said.

The only significant baseline predictor of high central arterial stiffness (augmentation index) at 15 years was a high CRP level.

Dr. Provan said that she and her associates had no financial relationships to disclose.

COPENHAGEN — Patients who develop rheumatoid arthritis undergo an unexplained drop in their serum cholesterol level during the years immediately preceding their diagnosis, based on a study of more than 500 patients.

Dr. Elena Myasoedova said at the annual European Congress of Rheumatolog that serum levels of LDL cholesterol fell before—as well as following—RA diagnosis, whereas serum levels of HDL cholesterol rose both before and after RA diagnosis.

This overall pattern of lipid changes resulting in a less-atherogenic profile in RA patients is a surprise, as it's been clearly documented in results from several studies that RA increases the risk for both atherosclerosis and cardiovascular disease.

The study involved 577 residents of Olmsted County, Minn., who were at least 18 years old and were diagnosed with RA during 1988-2008.

During the 5 years before diagnosis, their serum levels of both LDL cholesterol and total cholesterol fell significantly, by an average of 24 mg/dL for LDL cholesterol and an average of 23 mg/dL for total cholesterol. During the same period, HDL cholesterol levels rose by 3 mg/dL, said Dr. Myasoedova, who did her research while she was a Fulbright scholar at the Mayo Clinic in Rochester, Minn.

In the 5 years after RA diagnosis, their total and LDL cholesterol levels underwent a smaller decline, with LDL cholesterol levels dropping by an average of another 8 mg/dL. HDL cholesterol increased by an additional 5 mg/dL after the diagnosis.

To better assess the relationship of these changes to RA, the researchers ran a similar analysis on 540 control residents of Olmsted County who were matched to the RA patients based on their sex, age during the calendar year of RA diagnosis in the cases, and length of their medical history in Olmsted County and with the Mayo Clinic. The average age of the RA patients and controls was 57 years.

The comparison showed that people who were never diagnosed with RA also had a drop in their total and LDL cholesterol levels over the same period, likely because of an increased prevalence of treatment for hypercholesterolemia in the United States during 1988-2008, Dr. Myasoedova said. The extent of the cholesterol reduction was substantially steeper among those who eventually developed RA.

Treatment with lipid-lowering drugs of any kind, treatment specifically with a statin, and body mass index did not seem to be factors, as these parameters were similar in both RA patients and controls.

The study was funded in part with a grant from Roche Laboratories, Dr. Myasoedova said.

COPENHAGEN — Patients who develop rheumatoid arthritis undergo an unexplained drop in their serum cholesterol level during the years immediately preceding their diagnosis, based on a study of more than 500 patients.

Dr. Elena Myasoedova said at the annual European Congress of Rheumatolog that serum levels of LDL cholesterol fell before—as well as following—RA diagnosis, whereas serum levels of HDL cholesterol rose both before and after RA diagnosis.

This overall pattern of lipid changes resulting in a less-atherogenic profile in RA patients is a surprise, as it's been clearly documented in results from several studies that RA increases the risk for both atherosclerosis and cardiovascular disease.

The study involved 577 residents of Olmsted County, Minn., who were at least 18 years old and were diagnosed with RA during 1988-2008.

During the 5 years before diagnosis, their serum levels of both LDL cholesterol and total cholesterol fell significantly, by an average of 24 mg/dL for LDL cholesterol and an average of 23 mg/dL for total cholesterol. During the same period, HDL cholesterol levels rose by 3 mg/dL, said Dr. Myasoedova, who did her research while she was a Fulbright scholar at the Mayo Clinic in Rochester, Minn.

In the 5 years after RA diagnosis, their total and LDL cholesterol levels underwent a smaller decline, with LDL cholesterol levels dropping by an average of another 8 mg/dL. HDL cholesterol increased by an additional 5 mg/dL after the diagnosis.

To better assess the relationship of these changes to RA, the researchers ran a similar analysis on 540 control residents of Olmsted County who were matched to the RA patients based on their sex, age during the calendar year of RA diagnosis in the cases, and length of their medical history in Olmsted County and with the Mayo Clinic. The average age of the RA patients and controls was 57 years.

The comparison showed that people who were never diagnosed with RA also had a drop in their total and LDL cholesterol levels over the same period, likely because of an increased prevalence of treatment for hypercholesterolemia in the United States during 1988-2008, Dr. Myasoedova said. The extent of the cholesterol reduction was substantially steeper among those who eventually developed RA.

Treatment with lipid-lowering drugs of any kind, treatment specifically with a statin, and body mass index did not seem to be factors, as these parameters were similar in both RA patients and controls.

The study was funded in part with a grant from Roche Laboratories, Dr. Myasoedova said.

COPENHAGEN — Patients who develop rheumatoid arthritis undergo an unexplained drop in their serum cholesterol level during the years immediately preceding their diagnosis, based on a study of more than 500 patients.

Dr. Elena Myasoedova said at the annual European Congress of Rheumatolog that serum levels of LDL cholesterol fell before—as well as following—RA diagnosis, whereas serum levels of HDL cholesterol rose both before and after RA diagnosis.

This overall pattern of lipid changes resulting in a less-atherogenic profile in RA patients is a surprise, as it's been clearly documented in results from several studies that RA increases the risk for both atherosclerosis and cardiovascular disease.

The study involved 577 residents of Olmsted County, Minn., who were at least 18 years old and were diagnosed with RA during 1988-2008.

During the 5 years before diagnosis, their serum levels of both LDL cholesterol and total cholesterol fell significantly, by an average of 24 mg/dL for LDL cholesterol and an average of 23 mg/dL for total cholesterol. During the same period, HDL cholesterol levels rose by 3 mg/dL, said Dr. Myasoedova, who did her research while she was a Fulbright scholar at the Mayo Clinic in Rochester, Minn.

In the 5 years after RA diagnosis, their total and LDL cholesterol levels underwent a smaller decline, with LDL cholesterol levels dropping by an average of another 8 mg/dL. HDL cholesterol increased by an additional 5 mg/dL after the diagnosis.

To better assess the relationship of these changes to RA, the researchers ran a similar analysis on 540 control residents of Olmsted County who were matched to the RA patients based on their sex, age during the calendar year of RA diagnosis in the cases, and length of their medical history in Olmsted County and with the Mayo Clinic. The average age of the RA patients and controls was 57 years.

The comparison showed that people who were never diagnosed with RA also had a drop in their total and LDL cholesterol levels over the same period, likely because of an increased prevalence of treatment for hypercholesterolemia in the United States during 1988-2008, Dr. Myasoedova said. The extent of the cholesterol reduction was substantially steeper among those who eventually developed RA.

Treatment with lipid-lowering drugs of any kind, treatment specifically with a statin, and body mass index did not seem to be factors, as these parameters were similar in both RA patients and controls.

The study was funded in part with a grant from Roche Laboratories, Dr. Myasoedova said.

Histiocytoid Sweet Syndrome

At first glance, it appeared that a straightforward diagnosis was in order, said Dr. Paul A. Krusinski at the annual meeting of the Noah Worcester Dermatological Society.

“We thought it looked pretty good for Sweet syndrome,” he said, referencing the patient's characteristic fever and joint pain. “Often, Sweet syndrome has a prodrome associated with it and she had her—quote—sinus infection,” he said.

A second differential diagnosis was drug hypersensitivity reaction, noted Dr. Krusinski, professor and director of the division of dermatology at the University of Vermont, Burlington.

Histologically, edema could be seen in the upper papillary dermis. A perivascular infiltrate was evident in the dermis. At higher power, however, the Sweet syndrome diagnosis seemed less likely. “When you get a little closer, you say, 'Where are the polys [polymorphonuclear neutrophils]? Where are the neutrophils?'” he said. In their place appeared to be large histiocytes.

A dermatopathology report on an initial biopsy specimen identified “a moderately dense dermal inflammatory infiltrate that is of mixed composition but predominated by mononuclear cells,” and went on to note that “only rare neutrophils are present, thus militating against Sweet syndrome.” Immunostaining was positive for CD68 and myeloid precursors.

Classic Sweet syndrome, first described in 1964, is characterized by its female predominance, abrupt onset, fever, painful erythematous plaques or nodules, and abnormal laboratory values such as elevated erythrocyte sedimentation rate and positive C-reactive protein, just as in this case.

Neutrophilic infiltrate conventionally heralds classic Sweet syndrome, either in the absence of vasculitis or, rarely, with secondary vasculitis. Three subtypes are classically described, including idiopathic Sweet syndrome associated with other inflammatory diseases, cases related to hematologic malignancies, and cases associated with solid malignant neoplasms.

A literature review revealed a study from Spanish researchers detailing 41 cases of a previously undescribed entity: histiocytoid Sweet syndrome. In this series, 26 women and 15 men aged 29–79 years had lesions typical of Sweet syndrome but failed to meet conventional histopathologic criteria for the disease (Arch. Dermatol. 2005;141:834–42).

Biopsies showed dense, bandlike infiltrate in the superficial dermis and mid-dermis that was predominated by large mononuclear cells with “eccentric” nuclei and irregular contours. Few neutrophils, lymphocytes, or small histiocytes were present. Moderate to intense superficial dermal edema was present and there was no appreciable vasculitis.

Findings align with the monocytic histiocytic lineage, with positive staining for CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme.

The authors of a recent article detailing six clinically and microscopically diverse cases thought to be Sweet syndrome, drug eruptions, erythema nodosum, or Wells's syndrome hypothesized that histiocytoid neutrophilic dermatoses and panniculitides are “variations on a theme” and proposed three new disease classifications: Sweetlike neutrophilic dermatoses, histiocytoid; subcutaneous Sweet syndrome, histiocytoid; and histiocytoid neutrophilic dermatosis, unspecified (Am. J. Dermatopathol. 2007;29:334–41).

The case patient had age-appropriate cancer screening, with negative results, and responded well to prednisone 40 mg daily followed by a tapering of the drug.

Dr. Kathryn Schwarzenberger was the physician at the University of Vermont who made the diagnosis.

Histology shows dense dermal inflam-matory infiltrate of mononuclear cells. Courtesy Dr. Paul A. Krusinski

Histiocytoid Sweet Syndrome

At first glance, it appeared that a straightforward diagnosis was in order, said Dr. Paul A. Krusinski at the annual meeting of the Noah Worcester Dermatological Society.

“We thought it looked pretty good for Sweet syndrome,” he said, referencing the patient's characteristic fever and joint pain. “Often, Sweet syndrome has a prodrome associated with it and she had her—quote—sinus infection,” he said.

A second differential diagnosis was drug hypersensitivity reaction, noted Dr. Krusinski, professor and director of the division of dermatology at the University of Vermont, Burlington.

Histologically, edema could be seen in the upper papillary dermis. A perivascular infiltrate was evident in the dermis. At higher power, however, the Sweet syndrome diagnosis seemed less likely. “When you get a little closer, you say, 'Where are the polys [polymorphonuclear neutrophils]? Where are the neutrophils?'” he said. In their place appeared to be large histiocytes.

A dermatopathology report on an initial biopsy specimen identified “a moderately dense dermal inflammatory infiltrate that is of mixed composition but predominated by mononuclear cells,” and went on to note that “only rare neutrophils are present, thus militating against Sweet syndrome.” Immunostaining was positive for CD68 and myeloid precursors.

Classic Sweet syndrome, first described in 1964, is characterized by its female predominance, abrupt onset, fever, painful erythematous plaques or nodules, and abnormal laboratory values such as elevated erythrocyte sedimentation rate and positive C-reactive protein, just as in this case.

Neutrophilic infiltrate conventionally heralds classic Sweet syndrome, either in the absence of vasculitis or, rarely, with secondary vasculitis. Three subtypes are classically described, including idiopathic Sweet syndrome associated with other inflammatory diseases, cases related to hematologic malignancies, and cases associated with solid malignant neoplasms.

A literature review revealed a study from Spanish researchers detailing 41 cases of a previously undescribed entity: histiocytoid Sweet syndrome. In this series, 26 women and 15 men aged 29–79 years had lesions typical of Sweet syndrome but failed to meet conventional histopathologic criteria for the disease (Arch. Dermatol. 2005;141:834–42).

Biopsies showed dense, bandlike infiltrate in the superficial dermis and mid-dermis that was predominated by large mononuclear cells with “eccentric” nuclei and irregular contours. Few neutrophils, lymphocytes, or small histiocytes were present. Moderate to intense superficial dermal edema was present and there was no appreciable vasculitis.

Findings align with the monocytic histiocytic lineage, with positive staining for CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme.

The authors of a recent article detailing six clinically and microscopically diverse cases thought to be Sweet syndrome, drug eruptions, erythema nodosum, or Wells's syndrome hypothesized that histiocytoid neutrophilic dermatoses and panniculitides are “variations on a theme” and proposed three new disease classifications: Sweetlike neutrophilic dermatoses, histiocytoid; subcutaneous Sweet syndrome, histiocytoid; and histiocytoid neutrophilic dermatosis, unspecified (Am. J. Dermatopathol. 2007;29:334–41).

The case patient had age-appropriate cancer screening, with negative results, and responded well to prednisone 40 mg daily followed by a tapering of the drug.

Dr. Kathryn Schwarzenberger was the physician at the University of Vermont who made the diagnosis.

Histology shows dense dermal inflam-matory infiltrate of mononuclear cells. Courtesy Dr. Paul A. Krusinski

Histiocytoid Sweet Syndrome

At first glance, it appeared that a straightforward diagnosis was in order, said Dr. Paul A. Krusinski at the annual meeting of the Noah Worcester Dermatological Society.

“We thought it looked pretty good for Sweet syndrome,” he said, referencing the patient's characteristic fever and joint pain. “Often, Sweet syndrome has a prodrome associated with it and she had her—quote—sinus infection,” he said.

A second differential diagnosis was drug hypersensitivity reaction, noted Dr. Krusinski, professor and director of the division of dermatology at the University of Vermont, Burlington.

Histologically, edema could be seen in the upper papillary dermis. A perivascular infiltrate was evident in the dermis. At higher power, however, the Sweet syndrome diagnosis seemed less likely. “When you get a little closer, you say, 'Where are the polys [polymorphonuclear neutrophils]? Where are the neutrophils?'” he said. In their place appeared to be large histiocytes.

A dermatopathology report on an initial biopsy specimen identified “a moderately dense dermal inflammatory infiltrate that is of mixed composition but predominated by mononuclear cells,” and went on to note that “only rare neutrophils are present, thus militating against Sweet syndrome.” Immunostaining was positive for CD68 and myeloid precursors.

Classic Sweet syndrome, first described in 1964, is characterized by its female predominance, abrupt onset, fever, painful erythematous plaques or nodules, and abnormal laboratory values such as elevated erythrocyte sedimentation rate and positive C-reactive protein, just as in this case.

Neutrophilic infiltrate conventionally heralds classic Sweet syndrome, either in the absence of vasculitis or, rarely, with secondary vasculitis. Three subtypes are classically described, including idiopathic Sweet syndrome associated with other inflammatory diseases, cases related to hematologic malignancies, and cases associated with solid malignant neoplasms.

A literature review revealed a study from Spanish researchers detailing 41 cases of a previously undescribed entity: histiocytoid Sweet syndrome. In this series, 26 women and 15 men aged 29–79 years had lesions typical of Sweet syndrome but failed to meet conventional histopathologic criteria for the disease (Arch. Dermatol. 2005;141:834–42).

Biopsies showed dense, bandlike infiltrate in the superficial dermis and mid-dermis that was predominated by large mononuclear cells with “eccentric” nuclei and irregular contours. Few neutrophils, lymphocytes, or small histiocytes were present. Moderate to intense superficial dermal edema was present and there was no appreciable vasculitis.

Findings align with the monocytic histiocytic lineage, with positive staining for CD15, CD43, CD45, CD68, MAC-386, HAM56, and lysozyme.

The authors of a recent article detailing six clinically and microscopically diverse cases thought to be Sweet syndrome, drug eruptions, erythema nodosum, or Wells's syndrome hypothesized that histiocytoid neutrophilic dermatoses and panniculitides are “variations on a theme” and proposed three new disease classifications: Sweetlike neutrophilic dermatoses, histiocytoid; subcutaneous Sweet syndrome, histiocytoid; and histiocytoid neutrophilic dermatosis, unspecified (Am. J. Dermatopathol. 2007;29:334–41).

The case patient had age-appropriate cancer screening, with negative results, and responded well to prednisone 40 mg daily followed by a tapering of the drug.

Dr. Kathryn Schwarzenberger was the physician at the University of Vermont who made the diagnosis.

Histology shows dense dermal inflam-matory infiltrate of mononuclear cells. Courtesy Dr. Paul A. Krusinski

COPENHAGEN — Rheumatoid arthritis patients who do not respond to initial treatment with rituximab can be re-treated successfully with a second course of the B-cell-depleting, monoclonal anti-CD20 antibody after 6 months, Dr. Edward Vital reported at the European Congress of Rheumatology.

The findings are particularly important because rituximab is often used as a treatment of last resort after the failure of other therapies, such as anti-tumor necrosis factor agents and methotrexate, “and approximately one-third of patients fail to achieve an adequate response to initial treatment with the drug,” said Dr. Vital of the Leeds Institute of Molecular Medicine at the University of Leeds (England).

Although it had previously been presumed that RA patients who failed initial rituximab therapy had B-cell-independent disease, the new data suggest that is not the case, said Dr. Vital.

To determine whether nonresponders to initial rituximab therapy might have disease that is potentially still amenable to B-cell-depletion therapy, and to assess the impact of re-treatment, Dr. Vital and his colleagues assessed the B-cell status and treatment response of 104 RA patients treated with standard doses of rituximab. All of the patients were positive for rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies. Of the 104 patients, 38 did not respond to initial therapy, based on change in clinical status as measured by Disease Activity Score 28 and EULAR criteria.

A comparison of baseline blood and synovial B-cell parameters showed no difference in erythrocyte sedimentation rates or C reactive protein levels between nonresponders and responders. But nonresponders had significantly higher numbers of memory and pre-plasma cells at baseline, along with more synovial B cells, Dr. Vital reported. Additionally, using highly sensitive rare-event fluorescence-activated cell sorting (RE-FACS), the investigators identified incomplete B-cell depletion in 90% of the treatment nonresponders, he said.

Of the nonresponders, 25 underwent re-treatment 6 months later, “when their B-cell numbers were significantly lower than they were at baseline of their first treatment cycle,” Dr. Vital reported. Among the re-treated patients, 72% responded clinically (defined as a moderate or better EULAR response) to the therapy at 6 months. Of these, 32% had a good response and 16% were in remission—response rates that are comparable to those observed among treatment-naive patients, he said.

The findings have had an immediate impact on clinical practice at the Leeds Teaching Hospitals. “From these results, we have immediately changed our practice regarding how we treat these patients. Now all patients who fail the first cycle of rituximab get a second cycle of treatment,” Dr. Vital said.

“The next question to consider is whether patients who have predictors of poor response could be treated more intensively from the outset, possibly with a different dose of rituximab, which is something we are currently investigating,” he noted. Dr. Vital disclosed a financial relationship with Roche, which provided free study drugs for 45 patients. The study was funded by the U.K. National Institute for Health Research.

To watch an interview of Dr. Vital, go to www.youtube.com/watch?v=YfEX2UxSlps

COPENHAGEN — Rheumatoid arthritis patients who do not respond to initial treatment with rituximab can be re-treated successfully with a second course of the B-cell-depleting, monoclonal anti-CD20 antibody after 6 months, Dr. Edward Vital reported at the European Congress of Rheumatology.

The findings are particularly important because rituximab is often used as a treatment of last resort after the failure of other therapies, such as anti-tumor necrosis factor agents and methotrexate, “and approximately one-third of patients fail to achieve an adequate response to initial treatment with the drug,” said Dr. Vital of the Leeds Institute of Molecular Medicine at the University of Leeds (England).

Although it had previously been presumed that RA patients who failed initial rituximab therapy had B-cell-independent disease, the new data suggest that is not the case, said Dr. Vital.

To determine whether nonresponders to initial rituximab therapy might have disease that is potentially still amenable to B-cell-depletion therapy, and to assess the impact of re-treatment, Dr. Vital and his colleagues assessed the B-cell status and treatment response of 104 RA patients treated with standard doses of rituximab. All of the patients were positive for rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies. Of the 104 patients, 38 did not respond to initial therapy, based on change in clinical status as measured by Disease Activity Score 28 and EULAR criteria.

A comparison of baseline blood and synovial B-cell parameters showed no difference in erythrocyte sedimentation rates or C reactive protein levels between nonresponders and responders. But nonresponders had significantly higher numbers of memory and pre-plasma cells at baseline, along with more synovial B cells, Dr. Vital reported. Additionally, using highly sensitive rare-event fluorescence-activated cell sorting (RE-FACS), the investigators identified incomplete B-cell depletion in 90% of the treatment nonresponders, he said.

Of the nonresponders, 25 underwent re-treatment 6 months later, “when their B-cell numbers were significantly lower than they were at baseline of their first treatment cycle,” Dr. Vital reported. Among the re-treated patients, 72% responded clinically (defined as a moderate or better EULAR response) to the therapy at 6 months. Of these, 32% had a good response and 16% were in remission—response rates that are comparable to those observed among treatment-naive patients, he said.

The findings have had an immediate impact on clinical practice at the Leeds Teaching Hospitals. “From these results, we have immediately changed our practice regarding how we treat these patients. Now all patients who fail the first cycle of rituximab get a second cycle of treatment,” Dr. Vital said.

“The next question to consider is whether patients who have predictors of poor response could be treated more intensively from the outset, possibly with a different dose of rituximab, which is something we are currently investigating,” he noted. Dr. Vital disclosed a financial relationship with Roche, which provided free study drugs for 45 patients. The study was funded by the U.K. National Institute for Health Research.

To watch an interview of Dr. Vital, go to www.youtube.com/watch?v=YfEX2UxSlps

COPENHAGEN — Rheumatoid arthritis patients who do not respond to initial treatment with rituximab can be re-treated successfully with a second course of the B-cell-depleting, monoclonal anti-CD20 antibody after 6 months, Dr. Edward Vital reported at the European Congress of Rheumatology.

The findings are particularly important because rituximab is often used as a treatment of last resort after the failure of other therapies, such as anti-tumor necrosis factor agents and methotrexate, “and approximately one-third of patients fail to achieve an adequate response to initial treatment with the drug,” said Dr. Vital of the Leeds Institute of Molecular Medicine at the University of Leeds (England).

Although it had previously been presumed that RA patients who failed initial rituximab therapy had B-cell-independent disease, the new data suggest that is not the case, said Dr. Vital.

To determine whether nonresponders to initial rituximab therapy might have disease that is potentially still amenable to B-cell-depletion therapy, and to assess the impact of re-treatment, Dr. Vital and his colleagues assessed the B-cell status and treatment response of 104 RA patients treated with standard doses of rituximab. All of the patients were positive for rheumatoid factor and/or anti-cyclic citrullinated peptide antibodies. Of the 104 patients, 38 did not respond to initial therapy, based on change in clinical status as measured by Disease Activity Score 28 and EULAR criteria.

A comparison of baseline blood and synovial B-cell parameters showed no difference in erythrocyte sedimentation rates or C reactive protein levels between nonresponders and responders. But nonresponders had significantly higher numbers of memory and pre-plasma cells at baseline, along with more synovial B cells, Dr. Vital reported. Additionally, using highly sensitive rare-event fluorescence-activated cell sorting (RE-FACS), the investigators identified incomplete B-cell depletion in 90% of the treatment nonresponders, he said.

Of the nonresponders, 25 underwent re-treatment 6 months later, “when their B-cell numbers were significantly lower than they were at baseline of their first treatment cycle,” Dr. Vital reported. Among the re-treated patients, 72% responded clinically (defined as a moderate or better EULAR response) to the therapy at 6 months. Of these, 32% had a good response and 16% were in remission—response rates that are comparable to those observed among treatment-naive patients, he said.

The findings have had an immediate impact on clinical practice at the Leeds Teaching Hospitals. “From these results, we have immediately changed our practice regarding how we treat these patients. Now all patients who fail the first cycle of rituximab get a second cycle of treatment,” Dr. Vital said.

“The next question to consider is whether patients who have predictors of poor response could be treated more intensively from the outset, possibly with a different dose of rituximab, which is something we are currently investigating,” he noted. Dr. Vital disclosed a financial relationship with Roche, which provided free study drugs for 45 patients. The study was funded by the U.K. National Institute for Health Research.

To watch an interview of Dr. Vital, go to www.youtube.com/watch?v=YfEX2UxSlps