Nancy Walsh

Older depressed patients with diabetes who were treated in primary care practices using a depression care management program had lower 5-year all-cause mortality than did those treated with usual care, a study has found.

Depression and diabetes are closely linked, with depression being a risk factor for diabetes while also contributing to poor glucose control as well being associated with micro- and macrovascular complications.

Previous investigations have suggested that depression increases the risk of death among patients with diabetes, but the potential effects of an intervention to modify this risk have not previously been evaluated.

Using data from the randomized PROSPECT (Prevention of Suicide in Primary Care Elderly: Collaborative Trial) and the National Death Index, Dr. Hillary R. Bogner of the department of family medicine and community health at the University of Pennsylvania, Philadelphia, and colleagues investigated the effects on mortality of a primary care-based intervention in depressed patients with diabetes.

PROSPECT included 20 primary care practices from New York, Philadelphia, and Pittsburgh. Depression care managers worked with 10 of the practices, providing guideline-based treatment recommendations to physicians, helping patients with adherence, and providing follow-up care. Citalopram (Celexa) and interpersonal psychotherapy were provided at no cost.

In the other 10 practices, the primary care physicians were given informational materials and treatment guidelines on geriatric depression, but no specific management recommendations were provided.

The analysis included 584 depressed patients with a mean age of 70.3 years. Among this cohort, 72.3% were women, 69.7% were white, and 21.2% reported a history of diabetes.

After 5 years, 110 patients had died. The mortality rate among depressed patients with diabetes in the intervention group was 68.2/1,000 person-years, whereas the rate in depressed patients with diabetes in the usual care group was 103.4/1,000 person-years (Diabetes Care, Aug. 23 [Epub ahead of print]).

Depressed patients without diabetes in both groups had similar mortality rates, with those in the intervention group having a mortality rate of 36/1,000 person-years and those in the usual care group having a rate of 38.2/1,000 patient-years.

After adjusting for multiple factors, which included baseline imbalances in age, gender, education, and number of medical conditions, the investigators found that depressed patients with diabetes in the intervention group were significantly less likely to have died during the 5-year follow-up period than were depressed patients with diabetes in the usual care group. The adjusted hazard ratio was 0.49.

In contrast, depressed patients without diabetes in the intervention group were not at decreased risk, compared with depressed patients without diabetes in the usual care group.

According to the investigators, these findings suggest that “the intervention attenuates the influence of diabetes on mortality risk among older adults with depression.”

They concluded that a depression care management intervention can significantly reduce all-cause mortality among depressed patients with diabetes, and that models of care that integrate depression management into the care of diabetes should be developed and more widely implemented.

The investigation was provided funding by the National Institute of Mental Health.

Older depressed patients with diabetes who were treated in primary care practices using a depression care management program had lower 5-year all-cause mortality than did those treated with usual care, a study has found.

Depression and diabetes are closely linked, with depression being a risk factor for diabetes while also contributing to poor glucose control as well being associated with micro- and macrovascular complications.

Previous investigations have suggested that depression increases the risk of death among patients with diabetes, but the potential effects of an intervention to modify this risk have not previously been evaluated.

Using data from the randomized PROSPECT (Prevention of Suicide in Primary Care Elderly: Collaborative Trial) and the National Death Index, Dr. Hillary R. Bogner of the department of family medicine and community health at the University of Pennsylvania, Philadelphia, and colleagues investigated the effects on mortality of a primary care-based intervention in depressed patients with diabetes.

PROSPECT included 20 primary care practices from New York, Philadelphia, and Pittsburgh. Depression care managers worked with 10 of the practices, providing guideline-based treatment recommendations to physicians, helping patients with adherence, and providing follow-up care. Citalopram (Celexa) and interpersonal psychotherapy were provided at no cost.

In the other 10 practices, the primary care physicians were given informational materials and treatment guidelines on geriatric depression, but no specific management recommendations were provided.

The analysis included 584 depressed patients with a mean age of 70.3 years. Among this cohort, 72.3% were women, 69.7% were white, and 21.2% reported a history of diabetes.

After 5 years, 110 patients had died. The mortality rate among depressed patients with diabetes in the intervention group was 68.2/1,000 person-years, whereas the rate in depressed patients with diabetes in the usual care group was 103.4/1,000 person-years (Diabetes Care, Aug. 23 [Epub ahead of print]).

Depressed patients without diabetes in both groups had similar mortality rates, with those in the intervention group having a mortality rate of 36/1,000 person-years and those in the usual care group having a rate of 38.2/1,000 patient-years.

After adjusting for multiple factors, which included baseline imbalances in age, gender, education, and number of medical conditions, the investigators found that depressed patients with diabetes in the intervention group were significantly less likely to have died during the 5-year follow-up period than were depressed patients with diabetes in the usual care group. The adjusted hazard ratio was 0.49.

In contrast, depressed patients without diabetes in the intervention group were not at decreased risk, compared with depressed patients without diabetes in the usual care group.

According to the investigators, these findings suggest that “the intervention attenuates the influence of diabetes on mortality risk among older adults with depression.”

They concluded that a depression care management intervention can significantly reduce all-cause mortality among depressed patients with diabetes, and that models of care that integrate depression management into the care of diabetes should be developed and more widely implemented.

The investigation was provided funding by the National Institute of Mental Health.

Older depressed patients with diabetes who were treated in primary care practices using a depression care management program had lower 5-year all-cause mortality than did those treated with usual care, a study has found.

Depression and diabetes are closely linked, with depression being a risk factor for diabetes while also contributing to poor glucose control as well being associated with micro- and macrovascular complications.

Previous investigations have suggested that depression increases the risk of death among patients with diabetes, but the potential effects of an intervention to modify this risk have not previously been evaluated.

Using data from the randomized PROSPECT (Prevention of Suicide in Primary Care Elderly: Collaborative Trial) and the National Death Index, Dr. Hillary R. Bogner of the department of family medicine and community health at the University of Pennsylvania, Philadelphia, and colleagues investigated the effects on mortality of a primary care-based intervention in depressed patients with diabetes.

PROSPECT included 20 primary care practices from New York, Philadelphia, and Pittsburgh. Depression care managers worked with 10 of the practices, providing guideline-based treatment recommendations to physicians, helping patients with adherence, and providing follow-up care. Citalopram (Celexa) and interpersonal psychotherapy were provided at no cost.

In the other 10 practices, the primary care physicians were given informational materials and treatment guidelines on geriatric depression, but no specific management recommendations were provided.

The analysis included 584 depressed patients with a mean age of 70.3 years. Among this cohort, 72.3% were women, 69.7% were white, and 21.2% reported a history of diabetes.

After 5 years, 110 patients had died. The mortality rate among depressed patients with diabetes in the intervention group was 68.2/1,000 person-years, whereas the rate in depressed patients with diabetes in the usual care group was 103.4/1,000 person-years (Diabetes Care, Aug. 23 [Epub ahead of print]).

Depressed patients without diabetes in both groups had similar mortality rates, with those in the intervention group having a mortality rate of 36/1,000 person-years and those in the usual care group having a rate of 38.2/1,000 patient-years.

After adjusting for multiple factors, which included baseline imbalances in age, gender, education, and number of medical conditions, the investigators found that depressed patients with diabetes in the intervention group were significantly less likely to have died during the 5-year follow-up period than were depressed patients with diabetes in the usual care group. The adjusted hazard ratio was 0.49.

In contrast, depressed patients without diabetes in the intervention group were not at decreased risk, compared with depressed patients without diabetes in the usual care group.

According to the investigators, these findings suggest that “the intervention attenuates the influence of diabetes on mortality risk among older adults with depression.”

They concluded that a depression care management intervention can significantly reduce all-cause mortality among depressed patients with diabetes, and that models of care that integrate depression management into the care of diabetes should be developed and more widely implemented.

The investigation was provided funding by the National Institute of Mental Health.

BARCELONA — Clinical improvement in a small series of patients with inflammatory myopathies treated with rituximab suggests that B-cell depletion may prove useful in these disorders, according to Dr. Marlies Blom of the department of rheumatology, Radboud University Nijmegen Medical Centre (the Netherlands).

Among seven patients who had either dermatomyositis, polymyositis, or antisynthetase syndrome, two infusions of 1,000 mg rituximab 2 weeks apart resulted in a mean 30% increase in muscle strength at 3 months, Dr. Blom reported in a poster session at the annual European Congress of Rheumatology.

The patients' subjective reports of improvement in muscle strength were later confirmed by using handheld dynamometry.

The patients ranged in age from 38 to 58 years, and the duration of their disease ranged from 3 to 16 years. Four of the seven were female.

Previous treatments included oral and intravenous prednisone, methotrexate, azathioprine, cyclophosphamide, interferon, etanercept, and intravenous immunoglobulin.

A mean 13% improvement was reported on Health Assessment Questionnaire (HAQ) scores, and improvements also were also seen in levels of creatine phosphokinase, a marker of disease activity.

In one patient, a muscle biopsy taken 4 months after treatment showed a total absence of CD20+ B cells. This patient's Disease Activity Score-28 (DAS28) score fell from 6.83 to 4.46 after 3 months, according to Dr. Blom.

After initial good response, three patients required retreatment for exacerbations of myositis at about 6 months.

No serious adverse events were observed and immunoglobulin levels remained within normal ranges.

These results suggest that B cells play an important role in the pathogenesis of inflammatory myopathies, Dr. Blom noted.

Another recent report suggested that a possible rationale for considering B-cell depletion as a therapeutic strategy in dermatomyositis was that treatment with rituximab had previously been shown to result in improvements in muscle strength in humorally mediated autoimmune peripheral neuropathies (Arthritis Rheum. 2005;52:601-7).

The importance of humoral immunity in dermatomyositis also is suggested by the observation that perifascicular endothelial immunoglobulin and complement deposition are thought to result in the muscle ischemia and atrophy (J. Rheumatol. 2006;33:1021-6).

Furthermore, the observation that there are antibodies specific for myositis also supports the concept of B-cell-mediated humoral abnormality in dermatomyositis (Medicine [Baltimore]. 1991;70:360-74).

BARCELONA — Clinical improvement in a small series of patients with inflammatory myopathies treated with rituximab suggests that B-cell depletion may prove useful in these disorders, according to Dr. Marlies Blom of the department of rheumatology, Radboud University Nijmegen Medical Centre (the Netherlands).

Among seven patients who had either dermatomyositis, polymyositis, or antisynthetase syndrome, two infusions of 1,000 mg rituximab 2 weeks apart resulted in a mean 30% increase in muscle strength at 3 months, Dr. Blom reported in a poster session at the annual European Congress of Rheumatology.

The patients' subjective reports of improvement in muscle strength were later confirmed by using handheld dynamometry.

The patients ranged in age from 38 to 58 years, and the duration of their disease ranged from 3 to 16 years. Four of the seven were female.

Previous treatments included oral and intravenous prednisone, methotrexate, azathioprine, cyclophosphamide, interferon, etanercept, and intravenous immunoglobulin.

A mean 13% improvement was reported on Health Assessment Questionnaire (HAQ) scores, and improvements also were also seen in levels of creatine phosphokinase, a marker of disease activity.

In one patient, a muscle biopsy taken 4 months after treatment showed a total absence of CD20+ B cells. This patient's Disease Activity Score-28 (DAS28) score fell from 6.83 to 4.46 after 3 months, according to Dr. Blom.

After initial good response, three patients required retreatment for exacerbations of myositis at about 6 months.

No serious adverse events were observed and immunoglobulin levels remained within normal ranges.

These results suggest that B cells play an important role in the pathogenesis of inflammatory myopathies, Dr. Blom noted.

Another recent report suggested that a possible rationale for considering B-cell depletion as a therapeutic strategy in dermatomyositis was that treatment with rituximab had previously been shown to result in improvements in muscle strength in humorally mediated autoimmune peripheral neuropathies (Arthritis Rheum. 2005;52:601-7).

The importance of humoral immunity in dermatomyositis also is suggested by the observation that perifascicular endothelial immunoglobulin and complement deposition are thought to result in the muscle ischemia and atrophy (J. Rheumatol. 2006;33:1021-6).

Furthermore, the observation that there are antibodies specific for myositis also supports the concept of B-cell-mediated humoral abnormality in dermatomyositis (Medicine [Baltimore]. 1991;70:360-74).

BARCELONA — Clinical improvement in a small series of patients with inflammatory myopathies treated with rituximab suggests that B-cell depletion may prove useful in these disorders, according to Dr. Marlies Blom of the department of rheumatology, Radboud University Nijmegen Medical Centre (the Netherlands).

Among seven patients who had either dermatomyositis, polymyositis, or antisynthetase syndrome, two infusions of 1,000 mg rituximab 2 weeks apart resulted in a mean 30% increase in muscle strength at 3 months, Dr. Blom reported in a poster session at the annual European Congress of Rheumatology.

The patients' subjective reports of improvement in muscle strength were later confirmed by using handheld dynamometry.

The patients ranged in age from 38 to 58 years, and the duration of their disease ranged from 3 to 16 years. Four of the seven were female.

Previous treatments included oral and intravenous prednisone, methotrexate, azathioprine, cyclophosphamide, interferon, etanercept, and intravenous immunoglobulin.

A mean 13% improvement was reported on Health Assessment Questionnaire (HAQ) scores, and improvements also were also seen in levels of creatine phosphokinase, a marker of disease activity.

In one patient, a muscle biopsy taken 4 months after treatment showed a total absence of CD20+ B cells. This patient's Disease Activity Score-28 (DAS28) score fell from 6.83 to 4.46 after 3 months, according to Dr. Blom.

After initial good response, three patients required retreatment for exacerbations of myositis at about 6 months.

No serious adverse events were observed and immunoglobulin levels remained within normal ranges.

These results suggest that B cells play an important role in the pathogenesis of inflammatory myopathies, Dr. Blom noted.

Another recent report suggested that a possible rationale for considering B-cell depletion as a therapeutic strategy in dermatomyositis was that treatment with rituximab had previously been shown to result in improvements in muscle strength in humorally mediated autoimmune peripheral neuropathies (Arthritis Rheum. 2005;52:601-7).

The importance of humoral immunity in dermatomyositis also is suggested by the observation that perifascicular endothelial immunoglobulin and complement deposition are thought to result in the muscle ischemia and atrophy (J. Rheumatol. 2006;33:1021-6).

Furthermore, the observation that there are antibodies specific for myositis also supports the concept of B-cell-mediated humoral abnormality in dermatomyositis (Medicine [Baltimore]. 1991;70:360-74).

NEW YORK — Optimal management of bronchiolitis involves rational use of adrenergic drugs and avoidance of unnecessary tests and treatments, Dr. Howard M. Corneli said at a meeting sponsored by the American College of Emergency Physicians.

“We are spending over $700 million annually in hospital charges for this condition, and there is a paucity of evidence as to what works for it. And what little evidence we do have, we don't put into practice,”Dr. Corneli said.

An example of this is the use of x-rays. There is no evidence supporting the routine practice of obtaining x-rays in bronchiolitis, and no experts have ever recommended it, he said. They add considerable cost and are associated with a significant delay in care. And because multiple infiltrates often are seen, patients can be misdiagnosed as having pneumonia, which leads to inappropriate, ineffective antibiotic use.

In a systematic review that evaluated chest film data from 17 trials, abnormalities were seen on 20%-96% of films, yet there was no evidence that the x-rays helped differentiate bacterial from viral disease (Arch. Pediatr. Adolesc. Med. 2004;158:119-26).

Emergency department treatment of bronchiolitis is not systematic. In a study of 601 inpatients from 10 U.S. children's centers, 92% were given bronchodilators (Pediatrics 2001;108:851-5). Nebulized albuterol eases symptoms for some patients, but the response must be evaluated objectively and treatment continued only if benefits are seen—which is often not the case.

“In a study [at my institution] of 68 patients who received albuterol in the ED, 52% had no documented effect, yet 94% had written orders on admission to continue the drug,” said Dr. Corneli, professor of pediatrics, University of Utah, and ED medical director for transport at Primary Children's Medical Center, both in Salt Lake City.

It's also important to keep in mind that the effects of albuterol are only temporary, and there is no evidence that treatment changes the course of disease. Moreover, it can actually worsen symptoms in 20%–30% of patients, he said.

Racemic epinephrine has more potent effects on airway edema than does albuterol, and studies have found that just one treatment is needed and fewer patients worsen when treated with it. But it is potentially toxic, and there are case reports of babies having myocardial infarctions after repeated epinephrine inhalations, he said.

The rational use of epinephrine, therefore, involves a one-time trial in patients with moderate to severe bronchiolitis, an avoidance of repeated doses, and observation for at least 60 minutes. It can be used as rescue therapy for patients who worsen with albuterol, he noted.

Systemic corticosteroids also have been widely used, and it makes sense that their anti-inflammatory properties would be beneficial, he said. Many of the small early studies were negative, but firm conclusions could not be drawn because inconsistent disease definitions and outcomes were used.

However, in a small but well-conducted trial, 70 patients with moderate to severe disease were randomized to 1 mg/kg oral dexamethasone or placebo, Dr. Corneli said. At 4 hours, respiratory assessment change scores improved more in the steroid group, and admission rates were much lower, at 19%, compared with 44% in placebo patients (J. Pediatr. 2002;140:27-32).

Experts thought that this single-center trial's data could not yet be considered conclusive, so in a trial under the auspices of the Pediatric Emergency Care Applied Research Network, some 600 patients were enrolled over 3 years in 20 centers, and the effects of corticosteroids were analyzed. “The data remain under publication embargo, but in general we found insignificant differences in respiratory assessment change scores, later outcomes, or risk for admission with the use of steroids,” Dr. Corneli said.

Emerging evidence suggests that corticosteroids may not help in alleviating the airway inflammation associated with bronchiolitis because corticosteroid therapy may actually increase replication of the respiratory syncytial virus. There also is evidence that inflammation may be beneficial in slowing the spread of the virus out of the nasopharynx down into the bronchi and bronchioles, Dr. Corneli said.

Simple measures, such as suction, stimulation, and positioning of the child, along with the use of mist and fluids, can also help in the ED management of bronchiolitis.

NEW YORK — Optimal management of bronchiolitis involves rational use of adrenergic drugs and avoidance of unnecessary tests and treatments, Dr. Howard M. Corneli said at a meeting sponsored by the American College of Emergency Physicians.

“We are spending over $700 million annually in hospital charges for this condition, and there is a paucity of evidence as to what works for it. And what little evidence we do have, we don't put into practice,”Dr. Corneli said.

An example of this is the use of x-rays. There is no evidence supporting the routine practice of obtaining x-rays in bronchiolitis, and no experts have ever recommended it, he said. They add considerable cost and are associated with a significant delay in care. And because multiple infiltrates often are seen, patients can be misdiagnosed as having pneumonia, which leads to inappropriate, ineffective antibiotic use.

In a systematic review that evaluated chest film data from 17 trials, abnormalities were seen on 20%-96% of films, yet there was no evidence that the x-rays helped differentiate bacterial from viral disease (Arch. Pediatr. Adolesc. Med. 2004;158:119-26).

Emergency department treatment of bronchiolitis is not systematic. In a study of 601 inpatients from 10 U.S. children's centers, 92% were given bronchodilators (Pediatrics 2001;108:851-5). Nebulized albuterol eases symptoms for some patients, but the response must be evaluated objectively and treatment continued only if benefits are seen—which is often not the case.

“In a study [at my institution] of 68 patients who received albuterol in the ED, 52% had no documented effect, yet 94% had written orders on admission to continue the drug,” said Dr. Corneli, professor of pediatrics, University of Utah, and ED medical director for transport at Primary Children's Medical Center, both in Salt Lake City.

It's also important to keep in mind that the effects of albuterol are only temporary, and there is no evidence that treatment changes the course of disease. Moreover, it can actually worsen symptoms in 20%–30% of patients, he said.

Racemic epinephrine has more potent effects on airway edema than does albuterol, and studies have found that just one treatment is needed and fewer patients worsen when treated with it. But it is potentially toxic, and there are case reports of babies having myocardial infarctions after repeated epinephrine inhalations, he said.

The rational use of epinephrine, therefore, involves a one-time trial in patients with moderate to severe bronchiolitis, an avoidance of repeated doses, and observation for at least 60 minutes. It can be used as rescue therapy for patients who worsen with albuterol, he noted.

Systemic corticosteroids also have been widely used, and it makes sense that their anti-inflammatory properties would be beneficial, he said. Many of the small early studies were negative, but firm conclusions could not be drawn because inconsistent disease definitions and outcomes were used.

However, in a small but well-conducted trial, 70 patients with moderate to severe disease were randomized to 1 mg/kg oral dexamethasone or placebo, Dr. Corneli said. At 4 hours, respiratory assessment change scores improved more in the steroid group, and admission rates were much lower, at 19%, compared with 44% in placebo patients (J. Pediatr. 2002;140:27-32).

Experts thought that this single-center trial's data could not yet be considered conclusive, so in a trial under the auspices of the Pediatric Emergency Care Applied Research Network, some 600 patients were enrolled over 3 years in 20 centers, and the effects of corticosteroids were analyzed. “The data remain under publication embargo, but in general we found insignificant differences in respiratory assessment change scores, later outcomes, or risk for admission with the use of steroids,” Dr. Corneli said.

Emerging evidence suggests that corticosteroids may not help in alleviating the airway inflammation associated with bronchiolitis because corticosteroid therapy may actually increase replication of the respiratory syncytial virus. There also is evidence that inflammation may be beneficial in slowing the spread of the virus out of the nasopharynx down into the bronchi and bronchioles, Dr. Corneli said.

Simple measures, such as suction, stimulation, and positioning of the child, along with the use of mist and fluids, can also help in the ED management of bronchiolitis.

NEW YORK — Optimal management of bronchiolitis involves rational use of adrenergic drugs and avoidance of unnecessary tests and treatments, Dr. Howard M. Corneli said at a meeting sponsored by the American College of Emergency Physicians.

“We are spending over $700 million annually in hospital charges for this condition, and there is a paucity of evidence as to what works for it. And what little evidence we do have, we don't put into practice,”Dr. Corneli said.

An example of this is the use of x-rays. There is no evidence supporting the routine practice of obtaining x-rays in bronchiolitis, and no experts have ever recommended it, he said. They add considerable cost and are associated with a significant delay in care. And because multiple infiltrates often are seen, patients can be misdiagnosed as having pneumonia, which leads to inappropriate, ineffective antibiotic use.

In a systematic review that evaluated chest film data from 17 trials, abnormalities were seen on 20%-96% of films, yet there was no evidence that the x-rays helped differentiate bacterial from viral disease (Arch. Pediatr. Adolesc. Med. 2004;158:119-26).

Emergency department treatment of bronchiolitis is not systematic. In a study of 601 inpatients from 10 U.S. children's centers, 92% were given bronchodilators (Pediatrics 2001;108:851-5). Nebulized albuterol eases symptoms for some patients, but the response must be evaluated objectively and treatment continued only if benefits are seen—which is often not the case.

“In a study [at my institution] of 68 patients who received albuterol in the ED, 52% had no documented effect, yet 94% had written orders on admission to continue the drug,” said Dr. Corneli, professor of pediatrics, University of Utah, and ED medical director for transport at Primary Children's Medical Center, both in Salt Lake City.

It's also important to keep in mind that the effects of albuterol are only temporary, and there is no evidence that treatment changes the course of disease. Moreover, it can actually worsen symptoms in 20%–30% of patients, he said.

Racemic epinephrine has more potent effects on airway edema than does albuterol, and studies have found that just one treatment is needed and fewer patients worsen when treated with it. But it is potentially toxic, and there are case reports of babies having myocardial infarctions after repeated epinephrine inhalations, he said.

The rational use of epinephrine, therefore, involves a one-time trial in patients with moderate to severe bronchiolitis, an avoidance of repeated doses, and observation for at least 60 minutes. It can be used as rescue therapy for patients who worsen with albuterol, he noted.

Systemic corticosteroids also have been widely used, and it makes sense that their anti-inflammatory properties would be beneficial, he said. Many of the small early studies were negative, but firm conclusions could not be drawn because inconsistent disease definitions and outcomes were used.

However, in a small but well-conducted trial, 70 patients with moderate to severe disease were randomized to 1 mg/kg oral dexamethasone or placebo, Dr. Corneli said. At 4 hours, respiratory assessment change scores improved more in the steroid group, and admission rates were much lower, at 19%, compared with 44% in placebo patients (J. Pediatr. 2002;140:27-32).

Experts thought that this single-center trial's data could not yet be considered conclusive, so in a trial under the auspices of the Pediatric Emergency Care Applied Research Network, some 600 patients were enrolled over 3 years in 20 centers, and the effects of corticosteroids were analyzed. “The data remain under publication embargo, but in general we found insignificant differences in respiratory assessment change scores, later outcomes, or risk for admission with the use of steroids,” Dr. Corneli said.

Emerging evidence suggests that corticosteroids may not help in alleviating the airway inflammation associated with bronchiolitis because corticosteroid therapy may actually increase replication of the respiratory syncytial virus. There also is evidence that inflammation may be beneficial in slowing the spread of the virus out of the nasopharynx down into the bronchi and bronchioles, Dr. Corneli said.

Simple measures, such as suction, stimulation, and positioning of the child, along with the use of mist and fluids, can also help in the ED management of bronchiolitis.

VIENNA — The triad of high fever, rash, and organ involvement occurring in a patient who has recently begun a new drug treatment may signal drug hypersensitivity syndrome, Dr. Nikolai Tsankov said at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition is a severe idiosyncratic reaction to certain medications that can cause skin, liver, kidney, lung, and hematologic disturbances. The skin eruption typically is a red maculopapular rash, but can also manifest as bullae, pustules, and even as toxic epidermal necrolysis (TEN).

Mortality has been estimated at 8%, increasing to 18%-40% when hepatic involvement is present, said Dr. Tsankov of the department of dermatology and venereology, Sofia Medical University (Bulgaria). This reaction is most commonly seen with the anticonvulsants phenytoin, phenobarbital, and carbamazepine, but has also been seen with minocycline, sulfonamides, and various other medications.

Immediate withdrawal of all suspected medicines is the first rule of management, said Dr. Tsankov. He described three patients with drug hypersensitivity syndrome and TEN whom he has treated, all with good outcomes.

The first patient was a 32-year-old man with epilepsy who had been taking valproic acid, but switched to lamotrigine. After 8 days he developed symptoms including fever up to 104 degrees, painful lymph nodes, tachycardia, and positive Nikolsky's sign. His liver enzyme and creatinine phosphate levels also were increased.

The second patient was a 20-year-old man with a 10-year history of alcohol abuse who began treatment with carbamazepine and diazepam, and 3 days later developed weakness, joint pain, fever, and a widespread red maculopapular rash as well as hemorrhagic bullae on his soles and palms. He also developed tachycardia, tachypnea, and wet crepitations, as well as elevations in liver enzyme and eosinophilia levels.

The third patient was a 32-year-old man with hemorrhagic colitis who began treatment with sulfasalazine. After 13 days, a papular rash appeared on sun-exposed areas of the skin, followed by hemorrhagic crusts and blisters. Nikolsky's sign was positive. His erythrocyte sedimentation rate was elevated, and leukocytosis and eosinophilia were present.

Following the cessation of the culprit, the three patients received intensive supportive care, broad spectrum antibiotics, and corticosteroids. Within approximately 4 weeks, all three men showed resolution of symptoms and reepithelialization.

The use of corticosteroids in this situation is controversial; some suggest that systemic corticosteroids should be contraindicated in TEN. Although they do appear to arrest the progression of TEN, the immunosuppressive effects of these drugs also increase the risk of infection, which is often associated with a lethal outcome (Am. J. Clin. Dermatol. 2000;1:349-60).

On the other hand, Dr. Tsankov said in an interview, drug hypersensitivity syndrome is not only a toxic but also an immunologic reaction. "As immune response modifiers, systemic corticosteroids could ameliorate the symptoms of drug hypersensitivity syndrome, especially with severe systemic involvement," he said.

It's important to note that cross reactivity can occur among the three main aromatic anticonvulsants, so a patient who experiences a hypersensitivity reaction to one must avoid all three, he said. Moreover, first degree relatives also should be cautioned because they may be susceptible.

Drug hypersensitivity syndrome can manifest in severe widespread rashes. Courtesy Dr. Nikolai Tsankov

VIENNA — The triad of high fever, rash, and organ involvement occurring in a patient who has recently begun a new drug treatment may signal drug hypersensitivity syndrome, Dr. Nikolai Tsankov said at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition is a severe idiosyncratic reaction to certain medications that can cause skin, liver, kidney, lung, and hematologic disturbances. The skin eruption typically is a red maculopapular rash, but can also manifest as bullae, pustules, and even as toxic epidermal necrolysis (TEN).

Mortality has been estimated at 8%, increasing to 18%-40% when hepatic involvement is present, said Dr. Tsankov of the department of dermatology and venereology, Sofia Medical University (Bulgaria). This reaction is most commonly seen with the anticonvulsants phenytoin, phenobarbital, and carbamazepine, but has also been seen with minocycline, sulfonamides, and various other medications.

Immediate withdrawal of all suspected medicines is the first rule of management, said Dr. Tsankov. He described three patients with drug hypersensitivity syndrome and TEN whom he has treated, all with good outcomes.

The first patient was a 32-year-old man with epilepsy who had been taking valproic acid, but switched to lamotrigine. After 8 days he developed symptoms including fever up to 104 degrees, painful lymph nodes, tachycardia, and positive Nikolsky's sign. His liver enzyme and creatinine phosphate levels also were increased.

The second patient was a 20-year-old man with a 10-year history of alcohol abuse who began treatment with carbamazepine and diazepam, and 3 days later developed weakness, joint pain, fever, and a widespread red maculopapular rash as well as hemorrhagic bullae on his soles and palms. He also developed tachycardia, tachypnea, and wet crepitations, as well as elevations in liver enzyme and eosinophilia levels.

The third patient was a 32-year-old man with hemorrhagic colitis who began treatment with sulfasalazine. After 13 days, a papular rash appeared on sun-exposed areas of the skin, followed by hemorrhagic crusts and blisters. Nikolsky's sign was positive. His erythrocyte sedimentation rate was elevated, and leukocytosis and eosinophilia were present.

Following the cessation of the culprit, the three patients received intensive supportive care, broad spectrum antibiotics, and corticosteroids. Within approximately 4 weeks, all three men showed resolution of symptoms and reepithelialization.

The use of corticosteroids in this situation is controversial; some suggest that systemic corticosteroids should be contraindicated in TEN. Although they do appear to arrest the progression of TEN, the immunosuppressive effects of these drugs also increase the risk of infection, which is often associated with a lethal outcome (Am. J. Clin. Dermatol. 2000;1:349-60).

On the other hand, Dr. Tsankov said in an interview, drug hypersensitivity syndrome is not only a toxic but also an immunologic reaction. "As immune response modifiers, systemic corticosteroids could ameliorate the symptoms of drug hypersensitivity syndrome, especially with severe systemic involvement," he said.

It's important to note that cross reactivity can occur among the three main aromatic anticonvulsants, so a patient who experiences a hypersensitivity reaction to one must avoid all three, he said. Moreover, first degree relatives also should be cautioned because they may be susceptible.

Drug hypersensitivity syndrome can manifest in severe widespread rashes. Courtesy Dr. Nikolai Tsankov

VIENNA — The triad of high fever, rash, and organ involvement occurring in a patient who has recently begun a new drug treatment may signal drug hypersensitivity syndrome, Dr. Nikolai Tsankov said at the 16th Congress of the European Academy of Dermatology and Venereology.

This condition is a severe idiosyncratic reaction to certain medications that can cause skin, liver, kidney, lung, and hematologic disturbances. The skin eruption typically is a red maculopapular rash, but can also manifest as bullae, pustules, and even as toxic epidermal necrolysis (TEN).

Mortality has been estimated at 8%, increasing to 18%-40% when hepatic involvement is present, said Dr. Tsankov of the department of dermatology and venereology, Sofia Medical University (Bulgaria). This reaction is most commonly seen with the anticonvulsants phenytoin, phenobarbital, and carbamazepine, but has also been seen with minocycline, sulfonamides, and various other medications.

Immediate withdrawal of all suspected medicines is the first rule of management, said Dr. Tsankov. He described three patients with drug hypersensitivity syndrome and TEN whom he has treated, all with good outcomes.

The first patient was a 32-year-old man with epilepsy who had been taking valproic acid, but switched to lamotrigine. After 8 days he developed symptoms including fever up to 104 degrees, painful lymph nodes, tachycardia, and positive Nikolsky's sign. His liver enzyme and creatinine phosphate levels also were increased.

The second patient was a 20-year-old man with a 10-year history of alcohol abuse who began treatment with carbamazepine and diazepam, and 3 days later developed weakness, joint pain, fever, and a widespread red maculopapular rash as well as hemorrhagic bullae on his soles and palms. He also developed tachycardia, tachypnea, and wet crepitations, as well as elevations in liver enzyme and eosinophilia levels.

The third patient was a 32-year-old man with hemorrhagic colitis who began treatment with sulfasalazine. After 13 days, a papular rash appeared on sun-exposed areas of the skin, followed by hemorrhagic crusts and blisters. Nikolsky's sign was positive. His erythrocyte sedimentation rate was elevated, and leukocytosis and eosinophilia were present.

Following the cessation of the culprit, the three patients received intensive supportive care, broad spectrum antibiotics, and corticosteroids. Within approximately 4 weeks, all three men showed resolution of symptoms and reepithelialization.

The use of corticosteroids in this situation is controversial; some suggest that systemic corticosteroids should be contraindicated in TEN. Although they do appear to arrest the progression of TEN, the immunosuppressive effects of these drugs also increase the risk of infection, which is often associated with a lethal outcome (Am. J. Clin. Dermatol. 2000;1:349-60).

On the other hand, Dr. Tsankov said in an interview, drug hypersensitivity syndrome is not only a toxic but also an immunologic reaction. "As immune response modifiers, systemic corticosteroids could ameliorate the symptoms of drug hypersensitivity syndrome, especially with severe systemic involvement," he said.

It's important to note that cross reactivity can occur among the three main aromatic anticonvulsants, so a patient who experiences a hypersensitivity reaction to one must avoid all three, he said. Moreover, first degree relatives also should be cautioned because they may be susceptible.

Drug hypersensitivity syndrome can manifest in severe widespread rashes. Courtesy Dr. Nikolai Tsankov

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by the presence of antibodies directed against tRNA synthetase. The most common antibody is anti-Jo-1, which is found in 80% of cases.

Other antibodies sometimes found include anti-SSA, anti-PL-7, and anti-PL-12.

Clinical manifestations of the disease include interstitial lung disease, which can be severe, arthritis, Raynaud phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years, and in one-third of the group, the disease onset was before age 40. Two-thirds of the patients were women.

Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL.

Muscular manifestations rarely caused significant patient disability and were present at the onset of disease in only six of the cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren syndrome, were detected in 50% but only rarely were they associated with dry eyes and mouth, Dr. Palm wrote in a poster session.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent slowly developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received treatment with immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab.

Four patients died, two having type I pulmonary involvement. "While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted," he concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by the presence of antibodies directed against tRNA synthetase. The most common antibody is anti-Jo-1, which is found in 80% of cases.

Other antibodies sometimes found include anti-SSA, anti-PL-7, and anti-PL-12.

Clinical manifestations of the disease include interstitial lung disease, which can be severe, arthritis, Raynaud phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years, and in one-third of the group, the disease onset was before age 40. Two-thirds of the patients were women.

Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL.

Muscular manifestations rarely caused significant patient disability and were present at the onset of disease in only six of the cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren syndrome, were detected in 50% but only rarely were they associated with dry eyes and mouth, Dr. Palm wrote in a poster session.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent slowly developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received treatment with immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab.

Four patients died, two having type I pulmonary involvement. "While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted," he concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — A review of 30 patients with antisynthetase syndrome found that only half survived 10 years after diagnosis, Dr. Oyvind Palm reported at the annual European Congress of Rheumatology.

This idiopathic inflammatory myopathy is characterized by the presence of antibodies directed against tRNA synthetase. The most common antibody is anti-Jo-1, which is found in 80% of cases.

Other antibodies sometimes found include anti-SSA, anti-PL-7, and anti-PL-12.

Clinical manifestations of the disease include interstitial lung disease, which can be severe, arthritis, Raynaud phenomenon, and the hyperkeratotic rash known as mechanic's hands, according to Dr. Palm of the department of rheumatology, Rikshospitalet-Radiumhospitalet Medical Center, Oslo.

With the aim of characterizing the disease's clinical and serologic features, researchers reviewed all hospital records of patients diagnosed with an inflammatory myopathy and analyzed the charts of those who had antisynthetase antibodies and pulmonary disease.

The mean age of these 30 patients was 45.5 years, and in one-third of the group, the disease onset was before age 40. Two-thirds of the patients were women.

Most patients had histologic evidence of inflammatory myopathy and elevated serum creatine kinase, but only four had elevations of creatine kinase exceeding 3,000 IU/mL.

Muscular manifestations rarely caused significant patient disability and were present at the onset of disease in only six of the cases.

Anti-Jo-1 antibodies were detected in 90%. Anti-SSA autoantibodies, commonly found in patients with Sjögren syndrome, were detected in 50% but only rarely were they associated with dry eyes and mouth, Dr. Palm wrote in a poster session.

Pulmonary involvement was classified as follows:

▸ Type I (acute): Found in 24%; rapid onset of dyspnea or cough with development of hypoxemia within 1 month after the onset of disease.

▸ Type II (subacute): Found in 64%; gradual onset of pulmonary symptoms.

▸ Type III (asymptomatic): Found in 12%; coincidentally detected pulmonary abnormalities on x-ray or CT scan with subsequent slowly developing pulmonary symptoms.

Honeycombing with end-stage pulmonary disease was found in 30.4%.

All but one patient had received treatment with immunosuppressive drugs including corticosteroids, cyclophosphamide, and rituximab.

Four patients died, two having type I pulmonary involvement. "While approximately 90% survive the first 3 years of disease, thereafter the mortality increases sharply, and new treatment strategies are clearly warranted," he concluded.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Etanercept was well tolerated and clinical improvements maintained for up to 3 years in children with polyarticular or systemic juvenile idiopathic arthritis enrolled in an ongoing registry, Edward H. Giannini, Dr.P.H., said at the annual European Congress of Rheumatology.

The multicenter, nonrandomized registry included 601 patients between 2 and 18 years assigned to etanercept, methotrexate, or a both based on condition at enrollment. About 75% were female. Mean age was 10 years; 74% were white; 59% had polyarticular onset arthritis. Overall, 198 patients received methotrexate, 105 received etanercept, and 298 were treated with both.

Etanercept was given subcutaneously twice weekly in doses of 0.4 mg/kg, to a maximum of 25 mg, or 0.8 mg/kg once weekly to, at most, 50 mg. Methotrexate was given in doses of at least 10 mg/m

Patients given methotrexate could switch to etanercept or the combination and reenroll, but those taking etanercept who switched to methotrexate could not. To date, the numbers of patients who've completed the study in the methotrexate, etanercept, and combination groups are 55 (28%), 25 (24%), and 79 (27%), respectively, said Dr. Giannini of Cincinnati Children's Hospital Medical Center.

Patients discontinued the study for reasons including remission and inadequate therapeutic effect (see chart). Thirty-four patients initially taking methotrexate were switched to one of the etanercept groups.

Rates of serious adverse events per 100 patient-years were 5.25, 8.36, and 5.78 for patients on methotrexate, etanercept, or the combination, respectively, he wrote in a poster. Serious events included arthritis flare, headache, viral infection, and asthma.

Rates of medically important infections per 100 patient-years were 0.95, 1.97, and 1.98 for the methotrexate, etanercept, and combination groups, respectively. One case of sepsis was reported in a patient on methotrexate and another in a patient on the combination. Five opportunistic infections were reported, two in the methotrexate and three in the combination group. There were no cases of tuberculosis, lymphoma, or other malignancies. New autoimmune features were seen in all groups. One case of lupus was reported.

Active joint counts in the methotrexate, etanercept, and combination groups fell from a mean of 6, 5, and 6 at baseline to 0, 0, and 1 at year 3. Physician global assessment fell from 4, 3, and 4 to 1 for all groups. “However, comparisons between treatment arms are limited by the inherent bias associated with nonrandomized patient assignment and early dropout of nonresponders,” Dr. Giannini noted.

Polyarticular JIA can lead to symmetric arthritis of both large and small joints. ©Cassidy JT, Petty RE: Textbook of Pediatric Rheumatology. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1995

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Etanercept was well tolerated and clinical improvements maintained for up to 3 years in children with polyarticular or systemic juvenile idiopathic arthritis enrolled in an ongoing registry, Edward H. Giannini, Dr.P.H., said at the annual European Congress of Rheumatology.

The multicenter, nonrandomized registry included 601 patients between 2 and 18 years assigned to etanercept, methotrexate, or a both based on condition at enrollment. About 75% were female. Mean age was 10 years; 74% were white; 59% had polyarticular onset arthritis. Overall, 198 patients received methotrexate, 105 received etanercept, and 298 were treated with both.

Etanercept was given subcutaneously twice weekly in doses of 0.4 mg/kg, to a maximum of 25 mg, or 0.8 mg/kg once weekly to, at most, 50 mg. Methotrexate was given in doses of at least 10 mg/m

Patients given methotrexate could switch to etanercept or the combination and reenroll, but those taking etanercept who switched to methotrexate could not. To date, the numbers of patients who've completed the study in the methotrexate, etanercept, and combination groups are 55 (28%), 25 (24%), and 79 (27%), respectively, said Dr. Giannini of Cincinnati Children's Hospital Medical Center.

Patients discontinued the study for reasons including remission and inadequate therapeutic effect (see chart). Thirty-four patients initially taking methotrexate were switched to one of the etanercept groups.

Rates of serious adverse events per 100 patient-years were 5.25, 8.36, and 5.78 for patients on methotrexate, etanercept, or the combination, respectively, he wrote in a poster. Serious events included arthritis flare, headache, viral infection, and asthma.

Rates of medically important infections per 100 patient-years were 0.95, 1.97, and 1.98 for the methotrexate, etanercept, and combination groups, respectively. One case of sepsis was reported in a patient on methotrexate and another in a patient on the combination. Five opportunistic infections were reported, two in the methotrexate and three in the combination group. There were no cases of tuberculosis, lymphoma, or other malignancies. New autoimmune features were seen in all groups. One case of lupus was reported.

Active joint counts in the methotrexate, etanercept, and combination groups fell from a mean of 6, 5, and 6 at baseline to 0, 0, and 1 at year 3. Physician global assessment fell from 4, 3, and 4 to 1 for all groups. “However, comparisons between treatment arms are limited by the inherent bias associated with nonrandomized patient assignment and early dropout of nonresponders,” Dr. Giannini noted.

Polyarticular JIA can lead to symmetric arthritis of both large and small joints. ©Cassidy JT, Petty RE: Textbook of Pediatric Rheumatology. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1995

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Etanercept was well tolerated and clinical improvements maintained for up to 3 years in children with polyarticular or systemic juvenile idiopathic arthritis enrolled in an ongoing registry, Edward H. Giannini, Dr.P.H., said at the annual European Congress of Rheumatology.

The multicenter, nonrandomized registry included 601 patients between 2 and 18 years assigned to etanercept, methotrexate, or a both based on condition at enrollment. About 75% were female. Mean age was 10 years; 74% were white; 59% had polyarticular onset arthritis. Overall, 198 patients received methotrexate, 105 received etanercept, and 298 were treated with both.

Etanercept was given subcutaneously twice weekly in doses of 0.4 mg/kg, to a maximum of 25 mg, or 0.8 mg/kg once weekly to, at most, 50 mg. Methotrexate was given in doses of at least 10 mg/m

Patients given methotrexate could switch to etanercept or the combination and reenroll, but those taking etanercept who switched to methotrexate could not. To date, the numbers of patients who've completed the study in the methotrexate, etanercept, and combination groups are 55 (28%), 25 (24%), and 79 (27%), respectively, said Dr. Giannini of Cincinnati Children's Hospital Medical Center.

Patients discontinued the study for reasons including remission and inadequate therapeutic effect (see chart). Thirty-four patients initially taking methotrexate were switched to one of the etanercept groups.

Rates of serious adverse events per 100 patient-years were 5.25, 8.36, and 5.78 for patients on methotrexate, etanercept, or the combination, respectively, he wrote in a poster. Serious events included arthritis flare, headache, viral infection, and asthma.

Rates of medically important infections per 100 patient-years were 0.95, 1.97, and 1.98 for the methotrexate, etanercept, and combination groups, respectively. One case of sepsis was reported in a patient on methotrexate and another in a patient on the combination. Five opportunistic infections were reported, two in the methotrexate and three in the combination group. There were no cases of tuberculosis, lymphoma, or other malignancies. New autoimmune features were seen in all groups. One case of lupus was reported.

Active joint counts in the methotrexate, etanercept, and combination groups fell from a mean of 6, 5, and 6 at baseline to 0, 0, and 1 at year 3. Physician global assessment fell from 4, 3, and 4 to 1 for all groups. “However, comparisons between treatment arms are limited by the inherent bias associated with nonrandomized patient assignment and early dropout of nonresponders,” Dr. Giannini noted.

Polyarticular JIA can lead to symmetric arthritis of both large and small joints. ©Cassidy JT, Petty RE: Textbook of Pediatric Rheumatology. 3rd ed. Philadelphia, Pa: WB Saunders Co; 1995

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Combining the anticlotting agent dipyridamole with low-dose prednisone led to a rapid decrease in rheumatoid arthritis disease activity, according to Dr. John R. Kirwan, speaking at the annual European Congress of Rheumatology.

The effects of glucocorticoids on inflammatory cells in rheumatoid arthritis (RA) include alterations in the expression of certain genes and intracellular metabolic pathways, said Dr. Kirwan, professor of rheumatic diseases at the Bristol Royal Infirmary (England).

“However, they do not affect all the genes involved in inflammation, they do not work completely, and they also upregulate some genes that cause side effects,” Dr. Kirwan explained in an interview.

This weak interaction becomes stronger in the presence of dipyridamole, amplifying the anti-inflammatory effects. Because the prednisone dose is low, fewer side effects would be expected, he said.

The double-blind study included 59 patients with Disease Activity Scores (DAS28) greater than 4.5 and C-reactive protein (CRP) levels of 2.2 mg/L or higher. Participants' mean age was 59 years, three-quarters were women, and almost all were white. Stable background methotrexate and nonsteroidal anti-inflammatory drugs were allowed, but no oral glucocorticoids were allowed for at least a month prior to enrollment.

Patients were randomized to receive the combination, known as CRx-102, or placebo for 6 weeks. The combination regimen is 2 mg prednisone with 200 mg dipyridamole at 8 a.m. and 1 mg prednisone plus 200 mg dipyridamole at 1 p.m. At day 42, 63% of patients receiving CRx-102 achieved an American College of Rheumatology (ACR) 20 response rate, as did 30% of patients receiving placebo. The difference was statistically significant.

Significant differences between the groups also were seen on DAS28, patient and physician global assessments, pain, and Health Assessment Questionnaire score, Dr. Kirwan wrote in a poster.

CRP levels fell significantly, decreasing by 50% by day seven. The most common adverse events, headache and gastrointestinal disturbances, were reported by 15% of patients receiving the active therapy.

“CRx-102 produced a clinically meaningful and rapid decrease in disease activity as assessed by DAS28, ACR 20, and CRP. These data suggest that this is a well-tolerated oral therapy that can be safely added to disease-modifying antirheumatic drugs in RA,” he concluded.

Dr. Kirwan was principal investigator on this study, which was sponsored by CombinatoRx Inc., Cambridge, Mass.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Combining the anticlotting agent dipyridamole with low-dose prednisone led to a rapid decrease in rheumatoid arthritis disease activity, according to Dr. John R. Kirwan, speaking at the annual European Congress of Rheumatology.

The effects of glucocorticoids on inflammatory cells in rheumatoid arthritis (RA) include alterations in the expression of certain genes and intracellular metabolic pathways, said Dr. Kirwan, professor of rheumatic diseases at the Bristol Royal Infirmary (England).

“However, they do not affect all the genes involved in inflammation, they do not work completely, and they also upregulate some genes that cause side effects,” Dr. Kirwan explained in an interview.

This weak interaction becomes stronger in the presence of dipyridamole, amplifying the anti-inflammatory effects. Because the prednisone dose is low, fewer side effects would be expected, he said.

The double-blind study included 59 patients with Disease Activity Scores (DAS28) greater than 4.5 and C-reactive protein (CRP) levels of 2.2 mg/L or higher. Participants' mean age was 59 years, three-quarters were women, and almost all were white. Stable background methotrexate and nonsteroidal anti-inflammatory drugs were allowed, but no oral glucocorticoids were allowed for at least a month prior to enrollment.

Patients were randomized to receive the combination, known as CRx-102, or placebo for 6 weeks. The combination regimen is 2 mg prednisone with 200 mg dipyridamole at 8 a.m. and 1 mg prednisone plus 200 mg dipyridamole at 1 p.m. At day 42, 63% of patients receiving CRx-102 achieved an American College of Rheumatology (ACR) 20 response rate, as did 30% of patients receiving placebo. The difference was statistically significant.

Significant differences between the groups also were seen on DAS28, patient and physician global assessments, pain, and Health Assessment Questionnaire score, Dr. Kirwan wrote in a poster.

CRP levels fell significantly, decreasing by 50% by day seven. The most common adverse events, headache and gastrointestinal disturbances, were reported by 15% of patients receiving the active therapy.

“CRx-102 produced a clinically meaningful and rapid decrease in disease activity as assessed by DAS28, ACR 20, and CRP. These data suggest that this is a well-tolerated oral therapy that can be safely added to disease-modifying antirheumatic drugs in RA,” he concluded.

Dr. Kirwan was principal investigator on this study, which was sponsored by CombinatoRx Inc., Cambridge, Mass.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Combining the anticlotting agent dipyridamole with low-dose prednisone led to a rapid decrease in rheumatoid arthritis disease activity, according to Dr. John R. Kirwan, speaking at the annual European Congress of Rheumatology.

The effects of glucocorticoids on inflammatory cells in rheumatoid arthritis (RA) include alterations in the expression of certain genes and intracellular metabolic pathways, said Dr. Kirwan, professor of rheumatic diseases at the Bristol Royal Infirmary (England).

“However, they do not affect all the genes involved in inflammation, they do not work completely, and they also upregulate some genes that cause side effects,” Dr. Kirwan explained in an interview.

This weak interaction becomes stronger in the presence of dipyridamole, amplifying the anti-inflammatory effects. Because the prednisone dose is low, fewer side effects would be expected, he said.

The double-blind study included 59 patients with Disease Activity Scores (DAS28) greater than 4.5 and C-reactive protein (CRP) levels of 2.2 mg/L or higher. Participants' mean age was 59 years, three-quarters were women, and almost all were white. Stable background methotrexate and nonsteroidal anti-inflammatory drugs were allowed, but no oral glucocorticoids were allowed for at least a month prior to enrollment.

Patients were randomized to receive the combination, known as CRx-102, or placebo for 6 weeks. The combination regimen is 2 mg prednisone with 200 mg dipyridamole at 8 a.m. and 1 mg prednisone plus 200 mg dipyridamole at 1 p.m. At day 42, 63% of patients receiving CRx-102 achieved an American College of Rheumatology (ACR) 20 response rate, as did 30% of patients receiving placebo. The difference was statistically significant.

Significant differences between the groups also were seen on DAS28, patient and physician global assessments, pain, and Health Assessment Questionnaire score, Dr. Kirwan wrote in a poster.

CRP levels fell significantly, decreasing by 50% by day seven. The most common adverse events, headache and gastrointestinal disturbances, were reported by 15% of patients receiving the active therapy.

“CRx-102 produced a clinically meaningful and rapid decrease in disease activity as assessed by DAS28, ACR 20, and CRP. These data suggest that this is a well-tolerated oral therapy that can be safely added to disease-modifying antirheumatic drugs in RA,” he concluded.

Dr. Kirwan was principal investigator on this study, which was sponsored by CombinatoRx Inc., Cambridge, Mass.

ELSEVIER GLOBAL MEDICAL NEWS

BARCELONA — Patients with rheumatoid arthritis who are undergoing repeat courses of treatment with rituximab should begin re-treatment promptly once symptoms begin to recur, Dr. Philip J. Mease said at the annual European Congress of Rheumatology.

This conclusion emerged from analysis of the open-label extension phase of the Randomized Evaluation of Long-Term Efficacy of Rituximab in Rheumatoid Arthritis (REFLEX) trial, a double-blind, placebo-controlled multicenter study in which 298 patient initially received the active drug treatment.

All patients had failed at least one tumor necrosis factor blocker prior to beginning treatment with the B-cell-depleting agent. Those randomized to active treatment received two doses of rituximab, 1,000 mg, 2 weeks apart, plus stable doses of methotrexate.

Patients who achieved a 20% or greater improvement in swollen and tender joint counts during the 24-week blinded phase of the study were eligible to enter the open-label phase; 168 did so and had adequate follow-up for analysis 24 weeks after the second course of rituximab.

The four components of the 28-joint disease activity score (DAS28)—swollen joint count, tender joint count, erythrocyte sedimentation rate, and patient's global assessment—were assessed before each course of rituximab treatment, and every 4–8 weeks thereafter.

Mean DAS28 was 6.89 before the first course of rituximab and 6.12 before the second course, Dr. Mease wrote in a poster. The second course was administered at a median time of 43 weeks after the first course.

A generalized linear mixed model fit to all visits after the second course was used to evaluate the effects of various variables on DAS28, including pretrial patient and disease characteristics, DAS28 and Health Assessment Questionnaire at various times, and peripheral CD19+ B cell count before courses.

According to the model, DAS28 after the second course of treatment was independently increased by three factors: DAS28 before the second course, DAS28 at trial week 20, and Health Assessment Questionnaire at week 16.

Every 1 point that DAS28 was allowed to worsen before the second course of rituximab resulted in a 0.32-point higher DAS28 after the second course, according to Dr. Mease, who is a rheumatologist in Seattle.

Equally significant in the model but with the opposite effect on DAS28 was the peripheral CD19+ B-cell count before the second course: A count of at least 80 u 103/mL before the second course resulted in a 0.47-point lower DAS28 after the second course.

“The take-home message from this analysis is that in order to achieve the best DAS with a repeat course of rituximab, the preferable time for re-treatment is when the patient is starting to have resurgent symptoms,” Dr. Mease commented in an interview.

“On average, patient response lasts 6 months and at that point clinicians should start monitoring more diligently, looking for signs of disease activity. If the patient waits until 8 months for re-treatment, the resulting DAS won't be as good,” Dr. Mease added.

REFLEX was supported by Genentech, Biogen, and Roche. Dr. Mease has previously disclosed receiving consulting fees from Genentech and Biogen.

Symptom resurgence usually occurs about 6 months after ending the first course. DR. MEASE

BARCELONA — Patients with rheumatoid arthritis who are undergoing repeat courses of treatment with rituximab should begin re-treatment promptly once symptoms begin to recur, Dr. Philip J. Mease said at the annual European Congress of Rheumatology.

This conclusion emerged from analysis of the open-label extension phase of the Randomized Evaluation of Long-Term Efficacy of Rituximab in Rheumatoid Arthritis (REFLEX) trial, a double-blind, placebo-controlled multicenter study in which 298 patient initially received the active drug treatment.

All patients had failed at least one tumor necrosis factor blocker prior to beginning treatment with the B-cell-depleting agent. Those randomized to active treatment received two doses of rituximab, 1,000 mg, 2 weeks apart, plus stable doses of methotrexate.

Patients who achieved a 20% or greater improvement in swollen and tender joint counts during the 24-week blinded phase of the study were eligible to enter the open-label phase; 168 did so and had adequate follow-up for analysis 24 weeks after the second course of rituximab.

The four components of the 28-joint disease activity score (DAS28)—swollen joint count, tender joint count, erythrocyte sedimentation rate, and patient's global assessment—were assessed before each course of rituximab treatment, and every 4–8 weeks thereafter.

Mean DAS28 was 6.89 before the first course of rituximab and 6.12 before the second course, Dr. Mease wrote in a poster. The second course was administered at a median time of 43 weeks after the first course.

A generalized linear mixed model fit to all visits after the second course was used to evaluate the effects of various variables on DAS28, including pretrial patient and disease characteristics, DAS28 and Health Assessment Questionnaire at various times, and peripheral CD19+ B cell count before courses.

According to the model, DAS28 after the second course of treatment was independently increased by three factors: DAS28 before the second course, DAS28 at trial week 20, and Health Assessment Questionnaire at week 16.

Every 1 point that DAS28 was allowed to worsen before the second course of rituximab resulted in a 0.32-point higher DAS28 after the second course, according to Dr. Mease, who is a rheumatologist in Seattle.

Equally significant in the model but with the opposite effect on DAS28 was the peripheral CD19+ B-cell count before the second course: A count of at least 80 u 103/mL before the second course resulted in a 0.47-point lower DAS28 after the second course.

“The take-home message from this analysis is that in order to achieve the best DAS with a repeat course of rituximab, the preferable time for re-treatment is when the patient is starting to have resurgent symptoms,” Dr. Mease commented in an interview.

“On average, patient response lasts 6 months and at that point clinicians should start monitoring more diligently, looking for signs of disease activity. If the patient waits until 8 months for re-treatment, the resulting DAS won't be as good,” Dr. Mease added.

REFLEX was supported by Genentech, Biogen, and Roche. Dr. Mease has previously disclosed receiving consulting fees from Genentech and Biogen.

Symptom resurgence usually occurs about 6 months after ending the first course. DR. MEASE

BARCELONA — Patients with rheumatoid arthritis who are undergoing repeat courses of treatment with rituximab should begin re-treatment promptly once symptoms begin to recur, Dr. Philip J. Mease said at the annual European Congress of Rheumatology.

This conclusion emerged from analysis of the open-label extension phase of the Randomized Evaluation of Long-Term Efficacy of Rituximab in Rheumatoid Arthritis (REFLEX) trial, a double-blind, placebo-controlled multicenter study in which 298 patient initially received the active drug treatment.

All patients had failed at least one tumor necrosis factor blocker prior to beginning treatment with the B-cell-depleting agent. Those randomized to active treatment received two doses of rituximab, 1,000 mg, 2 weeks apart, plus stable doses of methotrexate.

Patients who achieved a 20% or greater improvement in swollen and tender joint counts during the 24-week blinded phase of the study were eligible to enter the open-label phase; 168 did so and had adequate follow-up for analysis 24 weeks after the second course of rituximab.

The four components of the 28-joint disease activity score (DAS28)—swollen joint count, tender joint count, erythrocyte sedimentation rate, and patient's global assessment—were assessed before each course of rituximab treatment, and every 4–8 weeks thereafter.

Mean DAS28 was 6.89 before the first course of rituximab and 6.12 before the second course, Dr. Mease wrote in a poster. The second course was administered at a median time of 43 weeks after the first course.

A generalized linear mixed model fit to all visits after the second course was used to evaluate the effects of various variables on DAS28, including pretrial patient and disease characteristics, DAS28 and Health Assessment Questionnaire at various times, and peripheral CD19+ B cell count before courses.

According to the model, DAS28 after the second course of treatment was independently increased by three factors: DAS28 before the second course, DAS28 at trial week 20, and Health Assessment Questionnaire at week 16.

Every 1 point that DAS28 was allowed to worsen before the second course of rituximab resulted in a 0.32-point higher DAS28 after the second course, according to Dr. Mease, who is a rheumatologist in Seattle.

Equally significant in the model but with the opposite effect on DAS28 was the peripheral CD19+ B-cell count before the second course: A count of at least 80 u 103/mL before the second course resulted in a 0.47-point lower DAS28 after the second course.

“The take-home message from this analysis is that in order to achieve the best DAS with a repeat course of rituximab, the preferable time for re-treatment is when the patient is starting to have resurgent symptoms,” Dr. Mease commented in an interview.

“On average, patient response lasts 6 months and at that point clinicians should start monitoring more diligently, looking for signs of disease activity. If the patient waits until 8 months for re-treatment, the resulting DAS won't be as good,” Dr. Mease added.

REFLEX was supported by Genentech, Biogen, and Roche. Dr. Mease has previously disclosed receiving consulting fees from Genentech and Biogen.

Symptom resurgence usually occurs about 6 months after ending the first course. DR. MEASE

BARCELONA — Evidence from placebo-controlled trials now exists confirming that both oral and intravenous cyclophosphamide are beneficial in the treatment of scleroderma lung disease.

However, there are no head-to-head data identifying which route of administration is more effective or less toxic, so to address this question Dr. Daniel E. Furst reviewed the data for both in a presentation at the annual European Congress of Rheumatology.

Oral cyclophosphamide was evaluated in a double-blind study at 13 clinical centers throughout the United States. “We asked very simple questions: Would oral cyclophosphamide work in the lung and would it be worth the side effects of such a drug?” said Dr. Furst, who is Carl M. Pearson Professor in Rheumatology, University of California at Los Angeles, and who was one of the study investigators.

A total of 158 patients with diffuse or limited scleroderma were enrolled and randomized to receive oral cyclophosphamide, 2 mg/kg or less per day, or placebo for 1 year.

The primary end point was the percentage of predicted value of forced vital capacity (FVC) at 12 months.

At 1 year, the adjusted mean absolute difference in FVC between the cyclophosphamide and placebo groups was 2.53%, favoring cyclophosphamide (N. Engl. J. Med. 2006;354:2655–66).

The difference was significant but quite modest, the investigators pointed out. “These are very small changes, and all we can say about this outcome is that there is a statistical difference but not necessarily a clinical difference,” Dr. Furst said.

Greater differences were seen on a secondary end point, the transitional dyspnea index. Scores improved by 1.4 points in the cyclophosphamide group and worsened by 1.5 points in the placebo group, which was quite significant and a large enough difference to be clinically important, he said. Favorable effects also were seen on total lung capacity, functional ability, and Rodnan skin scores.

More adverse events were seen in the active treatment group, with leukopenia being the principal one. There were no statistical difference in numbers of serious adverse events between the two groups, and those that are attributable to cyclophosphamide also occurred in the placebo group, Dr. Furst said.

No information is available yet on possible long-term adverse events such as bladder cancer.

“We are following these patients but we have no answers yet,” he said.

Intravenous cyclophosphamide was evaluated in the Fibrosing Alveolitis in Scleroderma trial (FAST), which included 45 patients from five centers in the United Kingdom. They were randomized to receive low-dose prednisone plus placebo or cyclophosphamide, approximately 1,000 mg/month for 6 months, and then oral azathioprine in doses of 2.5 mg/kg per day as maintenance therapy.

The FVC decreased about 5% in the placebo group and was stable in the cyclophosphamide group. The difference in change in FVC between the groups trended toward, but did not achieve, statistical significance (Arthritis Rheum. 2006;54:3962–70).

However, only about 60% of patients completed the trial. “And with such small numbers, it would have been a great surprise to see statistical differences,” Dr. Furst said.

“In this case, you have to think differently—if it comes close that's very encouraging,” he said.

The FAST investigators wrote, “We would suggest that a trend for improvement, intuitively better than a trend for decline, is hugely encouraging for the patient, and this must not be ignored.”

They also noted that many patients with severe or deteriorating disease were excluded from the trial and that the small therapeutic effects they saw in patients with milder disease might be greater in more progressive disease.

Adverse events associated with the active treatment were few, resulting in withdrawal in only two cases. There were no cases of hemorrhagic cystitis or bone marrow suppression.

“So you can see that both drugs work, but data from lupus and Wegener's trials tell us that, in general, if the intravenous administration is handled carefully, it is a little safer than the oral drug. So, for my patients, if they can tolerate the intravenous drug, I tend to go with that,” Dr. Furst said.

It's important to provide clear instructions about increased fluid intake, to be cognizant of the potential for cardiovascular toxicity, and not to treat for too long, he said.

With regard to the duration of treatment, Dr. Furst said in response to a question from the audience that he tends to treat for about 6 months to 1 year and then give the patient a rest period for about 6–8 months.

“But in real life, sometimes patients only begin to respond at 3–6 months, and you might be reluctant to stop. If you go longer than a year, you have to discuss it with the patient, because of the possibility that 5 years down the road they may have a serious problem,” he said.

Dr. Douglas J. Veale of University College Dublin, who was involved in FAST, offered a closing comment.

“I think you would agree that if we thought 10 years ago that we would be sitting in a room this big talking to this many people about any drug trial in systemic sclerosis, we would have been very excited. I think to have two trials showing benefits for patients is a remarkable achievement. The greatest need now is close collaboration from both sides of the Atlantic in designing similar studies with sufficient power,” he said.

“I could not possibly agree more,” Dr. Furst replied.

BARCELONA — Evidence from placebo-controlled trials now exists confirming that both oral and intravenous cyclophosphamide are beneficial in the treatment of scleroderma lung disease.

However, there are no head-to-head data identifying which route of administration is more effective or less toxic, so to address this question Dr. Daniel E. Furst reviewed the data for both in a presentation at the annual European Congress of Rheumatology.

Oral cyclophosphamide was evaluated in a double-blind study at 13 clinical centers throughout the United States. “We asked very simple questions: Would oral cyclophosphamide work in the lung and would it be worth the side effects of such a drug?” said Dr. Furst, who is Carl M. Pearson Professor in Rheumatology, University of California at Los Angeles, and who was one of the study investigators.

A total of 158 patients with diffuse or limited scleroderma were enrolled and randomized to receive oral cyclophosphamide, 2 mg/kg or less per day, or placebo for 1 year.

The primary end point was the percentage of predicted value of forced vital capacity (FVC) at 12 months.

At 1 year, the adjusted mean absolute difference in FVC between the cyclophosphamide and placebo groups was 2.53%, favoring cyclophosphamide (N. Engl. J. Med. 2006;354:2655–66).

The difference was significant but quite modest, the investigators pointed out. “These are very small changes, and all we can say about this outcome is that there is a statistical difference but not necessarily a clinical difference,” Dr. Furst said.

Greater differences were seen on a secondary end point, the transitional dyspnea index. Scores improved by 1.4 points in the cyclophosphamide group and worsened by 1.5 points in the placebo group, which was quite significant and a large enough difference to be clinically important, he said. Favorable effects also were seen on total lung capacity, functional ability, and Rodnan skin scores.

More adverse events were seen in the active treatment group, with leukopenia being the principal one. There were no statistical difference in numbers of serious adverse events between the two groups, and those that are attributable to cyclophosphamide also occurred in the placebo group, Dr. Furst said.

No information is available yet on possible long-term adverse events such as bladder cancer.

“We are following these patients but we have no answers yet,” he said.

Intravenous cyclophosphamide was evaluated in the Fibrosing Alveolitis in Scleroderma trial (FAST), which included 45 patients from five centers in the United Kingdom. They were randomized to receive low-dose prednisone plus placebo or cyclophosphamide, approximately 1,000 mg/month for 6 months, and then oral azathioprine in doses of 2.5 mg/kg per day as maintenance therapy.

The FVC decreased about 5% in the placebo group and was stable in the cyclophosphamide group. The difference in change in FVC between the groups trended toward, but did not achieve, statistical significance (Arthritis Rheum. 2006;54:3962–70).

However, only about 60% of patients completed the trial. “And with such small numbers, it would have been a great surprise to see statistical differences,” Dr. Furst said.

“In this case, you have to think differently—if it comes close that's very encouraging,” he said.

The FAST investigators wrote, “We would suggest that a trend for improvement, intuitively better than a trend for decline, is hugely encouraging for the patient, and this must not be ignored.”

They also noted that many patients with severe or deteriorating disease were excluded from the trial and that the small therapeutic effects they saw in patients with milder disease might be greater in more progressive disease.

Adverse events associated with the active treatment were few, resulting in withdrawal in only two cases. There were no cases of hemorrhagic cystitis or bone marrow suppression.

“So you can see that both drugs work, but data from lupus and Wegener's trials tell us that, in general, if the intravenous administration is handled carefully, it is a little safer than the oral drug. So, for my patients, if they can tolerate the intravenous drug, I tend to go with that,” Dr. Furst said.

It's important to provide clear instructions about increased fluid intake, to be cognizant of the potential for cardiovascular toxicity, and not to treat for too long, he said.

With regard to the duration of treatment, Dr. Furst said in response to a question from the audience that he tends to treat for about 6 months to 1 year and then give the patient a rest period for about 6–8 months.

“But in real life, sometimes patients only begin to respond at 3–6 months, and you might be reluctant to stop. If you go longer than a year, you have to discuss it with the patient, because of the possibility that 5 years down the road they may have a serious problem,” he said.

Dr. Douglas J. Veale of University College Dublin, who was involved in FAST, offered a closing comment.

“I think you would agree that if we thought 10 years ago that we would be sitting in a room this big talking to this many people about any drug trial in systemic sclerosis, we would have been very excited. I think to have two trials showing benefits for patients is a remarkable achievement. The greatest need now is close collaboration from both sides of the Atlantic in designing similar studies with sufficient power,” he said.

“I could not possibly agree more,” Dr. Furst replied.

BARCELONA — Evidence from placebo-controlled trials now exists confirming that both oral and intravenous cyclophosphamide are beneficial in the treatment of scleroderma lung disease.

However, there are no head-to-head data identifying which route of administration is more effective or less toxic, so to address this question Dr. Daniel E. Furst reviewed the data for both in a presentation at the annual European Congress of Rheumatology.

Oral cyclophosphamide was evaluated in a double-blind study at 13 clinical centers throughout the United States. “We asked very simple questions: Would oral cyclophosphamide work in the lung and would it be worth the side effects of such a drug?” said Dr. Furst, who is Carl M. Pearson Professor in Rheumatology, University of California at Los Angeles, and who was one of the study investigators.

A total of 158 patients with diffuse or limited scleroderma were enrolled and randomized to receive oral cyclophosphamide, 2 mg/kg or less per day, or placebo for 1 year.

The primary end point was the percentage of predicted value of forced vital capacity (FVC) at 12 months.

At 1 year, the adjusted mean absolute difference in FVC between the cyclophosphamide and placebo groups was 2.53%, favoring cyclophosphamide (N. Engl. J. Med. 2006;354:2655–66).

The difference was significant but quite modest, the investigators pointed out. “These are very small changes, and all we can say about this outcome is that there is a statistical difference but not necessarily a clinical difference,” Dr. Furst said.

Greater differences were seen on a secondary end point, the transitional dyspnea index. Scores improved by 1.4 points in the cyclophosphamide group and worsened by 1.5 points in the placebo group, which was quite significant and a large enough difference to be clinically important, he said. Favorable effects also were seen on total lung capacity, functional ability, and Rodnan skin scores.

More adverse events were seen in the active treatment group, with leukopenia being the principal one. There were no statistical difference in numbers of serious adverse events between the two groups, and those that are attributable to cyclophosphamide also occurred in the placebo group, Dr. Furst said.

No information is available yet on possible long-term adverse events such as bladder cancer.

“We are following these patients but we have no answers yet,” he said.

Intravenous cyclophosphamide was evaluated in the Fibrosing Alveolitis in Scleroderma trial (FAST), which included 45 patients from five centers in the United Kingdom. They were randomized to receive low-dose prednisone plus placebo or cyclophosphamide, approximately 1,000 mg/month for 6 months, and then oral azathioprine in doses of 2.5 mg/kg per day as maintenance therapy.

The FVC decreased about 5% in the placebo group and was stable in the cyclophosphamide group. The difference in change in FVC between the groups trended toward, but did not achieve, statistical significance (Arthritis Rheum. 2006;54:3962–70).

However, only about 60% of patients completed the trial. “And with such small numbers, it would have been a great surprise to see statistical differences,” Dr. Furst said.

“In this case, you have to think differently—if it comes close that's very encouraging,” he said.

The FAST investigators wrote, “We would suggest that a trend for improvement, intuitively better than a trend for decline, is hugely encouraging for the patient, and this must not be ignored.”

They also noted that many patients with severe or deteriorating disease were excluded from the trial and that the small therapeutic effects they saw in patients with milder disease might be greater in more progressive disease.

Adverse events associated with the active treatment were few, resulting in withdrawal in only two cases. There were no cases of hemorrhagic cystitis or bone marrow suppression.

“So you can see that both drugs work, but data from lupus and Wegener's trials tell us that, in general, if the intravenous administration is handled carefully, it is a little safer than the oral drug. So, for my patients, if they can tolerate the intravenous drug, I tend to go with that,” Dr. Furst said.

It's important to provide clear instructions about increased fluid intake, to be cognizant of the potential for cardiovascular toxicity, and not to treat for too long, he said.

With regard to the duration of treatment, Dr. Furst said in response to a question from the audience that he tends to treat for about 6 months to 1 year and then give the patient a rest period for about 6–8 months.

“But in real life, sometimes patients only begin to respond at 3–6 months, and you might be reluctant to stop. If you go longer than a year, you have to discuss it with the patient, because of the possibility that 5 years down the road they may have a serious problem,” he said.

Dr. Douglas J. Veale of University College Dublin, who was involved in FAST, offered a closing comment.

“I think you would agree that if we thought 10 years ago that we would be sitting in a room this big talking to this many people about any drug trial in systemic sclerosis, we would have been very excited. I think to have two trials showing benefits for patients is a remarkable achievement. The greatest need now is close collaboration from both sides of the Atlantic in designing similar studies with sufficient power,” he said.

“I could not possibly agree more,” Dr. Furst replied.

BARCELONA — Factors that were predictive of relapse in lupus nephritis after induction therapy were persistence of proteinuria and abnormal C4 levels, and patients having received cyclophosphamide for less than 2 years, Dr. Eva Salgado reported at the annual European Congress of Rheumatology.

Considerable variability is seen in the clinical course and response to therapy in patients with systemic lupus erythematosus (SLE) who develop nephritis, and it would be useful to identify factors that are associated with relapse so that more aggressive treatment could be used from the outset, explained Dr. Salgado of Hospital 12 de Octubre, Madrid.

A study was therefore conducted that included all 128 patients diagnosed with SLE and nephritis in the rheumatology department of Dr. Salgado's hospital between 1977 and 2007.

A total of 114 of the patients were women, and more than 95% were white. Mean age at the appearance of nephritis was 30 years, and mean time from the diagnosis of SLE was 2 years.

Renal biopsy at the time of diagnosis of nephritis showed minimal changes in 2% of the patients, mesangial glomerulonephritis in 18%, focal proliferative glomerulonephritis in 12%, diffuse proliferative glomerulonephritis in 55%, and membranous glomerulonephritis in 13%.

At the time of initiation of induction therapy, 29 patients had some degree of creatinine increase, Dr. Salgado wrote in a poster session.

Induction therapies included corticosteroids alone in 23% of patients, corticosteroids plus cyclophosphamide in 65%, azathioprine in 10%, and mycophenolate mofetil in 2%. Mean duration of induction therapy was 27 months.

A total of 71% of patients showed a complete response to induction therapy, while 24% had a partial response and 5% did not respond.

After the initial response, 59% received maintenance therapy with antimalarial drugs, azathioprine, or both.

During a mean of 13 years of follow-up, 34 patients experienced renal relapse, at a mean of 51 months after the end of induction therapy.

Multivariate analysis found that relapse was independently associated with persistence of abnormal C4 levels or residual proteinuria greater than 0.5 g/day after the completion of induction therapy, and duration of cyclophosphamide therapy for less than 2 years, according to Dr. Salgado.

Factors that were not predictive of relapse included histologic findings, age at SLE or nephritis diagnosis, delay in induction therapy, use of maintenance therapy, or other clinical characteristics.

Six patients developed end-stage renal failure and 14 died.

Relapse was predictive of long term renal failure but was not associated with increased mortality in this group of patients, Dr. Salgado observed.

BARCELONA — Factors that were predictive of relapse in lupus nephritis after induction therapy were persistence of proteinuria and abnormal C4 levels, and patients having received cyclophosphamide for less than 2 years, Dr. Eva Salgado reported at the annual European Congress of Rheumatology.

Considerable variability is seen in the clinical course and response to therapy in patients with systemic lupus erythematosus (SLE) who develop nephritis, and it would be useful to identify factors that are associated with relapse so that more aggressive treatment could be used from the outset, explained Dr. Salgado of Hospital 12 de Octubre, Madrid.

A study was therefore conducted that included all 128 patients diagnosed with SLE and nephritis in the rheumatology department of Dr. Salgado's hospital between 1977 and 2007.

A total of 114 of the patients were women, and more than 95% were white. Mean age at the appearance of nephritis was 30 years, and mean time from the diagnosis of SLE was 2 years.

Renal biopsy at the time of diagnosis of nephritis showed minimal changes in 2% of the patients, mesangial glomerulonephritis in 18%, focal proliferative glomerulonephritis in 12%, diffuse proliferative glomerulonephritis in 55%, and membranous glomerulonephritis in 13%.

At the time of initiation of induction therapy, 29 patients had some degree of creatinine increase, Dr. Salgado wrote in a poster session.

Induction therapies included corticosteroids alone in 23% of patients, corticosteroids plus cyclophosphamide in 65%, azathioprine in 10%, and mycophenolate mofetil in 2%. Mean duration of induction therapy was 27 months.

A total of 71% of patients showed a complete response to induction therapy, while 24% had a partial response and 5% did not respond.

After the initial response, 59% received maintenance therapy with antimalarial drugs, azathioprine, or both.

During a mean of 13 years of follow-up, 34 patients experienced renal relapse, at a mean of 51 months after the end of induction therapy.

Multivariate analysis found that relapse was independently associated with persistence of abnormal C4 levels or residual proteinuria greater than 0.5 g/day after the completion of induction therapy, and duration of cyclophosphamide therapy for less than 2 years, according to Dr. Salgado.

Factors that were not predictive of relapse included histologic findings, age at SLE or nephritis diagnosis, delay in induction therapy, use of maintenance therapy, or other clinical characteristics.

Six patients developed end-stage renal failure and 14 died.

Relapse was predictive of long term renal failure but was not associated with increased mortality in this group of patients, Dr. Salgado observed.

BARCELONA — Factors that were predictive of relapse in lupus nephritis after induction therapy were persistence of proteinuria and abnormal C4 levels, and patients having received cyclophosphamide for less than 2 years, Dr. Eva Salgado reported at the annual European Congress of Rheumatology.

Considerable variability is seen in the clinical course and response to therapy in patients with systemic lupus erythematosus (SLE) who develop nephritis, and it would be useful to identify factors that are associated with relapse so that more aggressive treatment could be used from the outset, explained Dr. Salgado of Hospital 12 de Octubre, Madrid.

A study was therefore conducted that included all 128 patients diagnosed with SLE and nephritis in the rheumatology department of Dr. Salgado's hospital between 1977 and 2007.

A total of 114 of the patients were women, and more than 95% were white. Mean age at the appearance of nephritis was 30 years, and mean time from the diagnosis of SLE was 2 years.

Renal biopsy at the time of diagnosis of nephritis showed minimal changes in 2% of the patients, mesangial glomerulonephritis in 18%, focal proliferative glomerulonephritis in 12%, diffuse proliferative glomerulonephritis in 55%, and membranous glomerulonephritis in 13%.

At the time of initiation of induction therapy, 29 patients had some degree of creatinine increase, Dr. Salgado wrote in a poster session.

Induction therapies included corticosteroids alone in 23% of patients, corticosteroids plus cyclophosphamide in 65%, azathioprine in 10%, and mycophenolate mofetil in 2%. Mean duration of induction therapy was 27 months.

A total of 71% of patients showed a complete response to induction therapy, while 24% had a partial response and 5% did not respond.

After the initial response, 59% received maintenance therapy with antimalarial drugs, azathioprine, or both.

During a mean of 13 years of follow-up, 34 patients experienced renal relapse, at a mean of 51 months after the end of induction therapy.

Multivariate analysis found that relapse was independently associated with persistence of abnormal C4 levels or residual proteinuria greater than 0.5 g/day after the completion of induction therapy, and duration of cyclophosphamide therapy for less than 2 years, according to Dr. Salgado.

Factors that were not predictive of relapse included histologic findings, age at SLE or nephritis diagnosis, delay in induction therapy, use of maintenance therapy, or other clinical characteristics.

Six patients developed end-stage renal failure and 14 died.

Relapse was predictive of long term renal failure but was not associated with increased mortality in this group of patients, Dr. Salgado observed.