Nancy Walsh

NEW YORK — A new generation of clinical trials is evaluating various ways of interrupting autoimmune β-cell destruction in type 1 diabetes, thereby preventing development of the disease, Dr. Carla J. Greenbaum said at a meeting sponsored by the American Diabetes Association.

Two studies begun in the early 1990s, the Diabetes Prevention Trial-Type 1 (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT), showed the feasibility of conducting large, well-designed, rigorously controlled clinical trials in patients at risk for diabetes. But the therapies tested—low-dose insulin injections, oral insulin, and nicotinamide—failed to delay or prevent the onset of type 1 diabetes, said Dr. Greenbaum, director of the diabetes research program at Benaroya Research Institute at Virginia Mason, Seattle.

Today, with significant advances in understanding of immune regulation and β-cell growth and development, multiple primary, secondary, and tertiary prevention trials are being conducted. These studies are needed because of the tremendous recent increase in the incidence of type 1 diabetes worldwide, including a 300% increase in type 1 incidence among children younger than 4 years, she said.

▸ Primary prevention. The goals of primary prevention studies are to identify patients who are genetically at risk because they have certain genetic mutations or because a close relative has the disease, to monitor those patients for the development of autoantibodies, and to intervene when antibodies appear.

In the randomized Trial to Reduce Insulin-Dependent Diabetes in the Genetically at Risk (TRIGR), the effects of cow's milk or soy-based formula in addition to breast-feeding is being evaluated in at-risk babies. A previous pilot study suggested that cow's milk was associated with a higher incidence of antibody development.

In the Nutritional Intervention to Prevent Diabetes (NIP) trial, anti-inflammatory omega-3 fatty acids are being given to mothers and infants to determine if this beneficial fatty acid can inhibit the initial autoimmune process.

▸ Secondary prevention. The goal in patients who already are antibody positive and in whom the autoimmune process is underway is to prevent the development of clinical disease, Dr. Greenbaum said.

ENDIT and DPT-1 were secondary prevention studies, and although unsuccessful, they provided data that have proved useful in the newer generation of prevention trials. In DPT-1, for example, although oral insulin was not effective overall, it was beneficial in a subset of patients who had very high levels of autoantibodies. This is now being tested again in patients considered most likely to benefit, she said.

▸ Tertiary prevention. For patients who already have clinical disease, the goal is to preserve β-cell function and thereby prevent both short- and long-term complications; of particular concern in the short term is severe hypoglycemia. Patients in the Diabetes Control and Complications Trial who had some residual β-cell function and who received intensive therapy had a 60% reduction in risk of hypoglycemia, Dr. Greenbaum said.

To prevent long-term complications and to stabilize pancreatic function, the concept of using immunotherapy is being explored. This premise was first tested in the 1980s with cyclosporine, and although the trial showed some benefit to patients, toxicity was a problem. The intention now is to find a tolerable drug or drugs that can be used for a short course that will “reset” the immune system so it stops attacking the pancreas, she said. Among the agents being evaluated are the newer immunosuppressants mycophenolate mofetil, thymoglobulin, daclizumab, and rituximab.

“We can cure diabetes in mice, but we can't yet cure it in people,” Dr. Greenbaum said. “When I think about what cure is going to look like, multiple avenues are going to be needed.” For patients who are genetically at risk, there may be dietary interventions, and for those who go on to develop autoimmunity, antigen-specific therapies may block β-cell destruction. In those who lose β-cell function, achieving a cure may involve tolerance induction, intermittent immunotherapy, and the use of β-cell growth factors and insulin sensitizers, she predicted.

Dr. Greenbaum concluded with a plea for clinicians to refer patients and relatives willing to participate in these trials. Information is available at www.diabetestrialnet.org

NEW YORK — A new generation of clinical trials is evaluating various ways of interrupting autoimmune β-cell destruction in type 1 diabetes, thereby preventing development of the disease, Dr. Carla J. Greenbaum said at a meeting sponsored by the American Diabetes Association.

Two studies begun in the early 1990s, the Diabetes Prevention Trial-Type 1 (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT), showed the feasibility of conducting large, well-designed, rigorously controlled clinical trials in patients at risk for diabetes. But the therapies tested—low-dose insulin injections, oral insulin, and nicotinamide—failed to delay or prevent the onset of type 1 diabetes, said Dr. Greenbaum, director of the diabetes research program at Benaroya Research Institute at Virginia Mason, Seattle.

Today, with significant advances in understanding of immune regulation and β-cell growth and development, multiple primary, secondary, and tertiary prevention trials are being conducted. These studies are needed because of the tremendous recent increase in the incidence of type 1 diabetes worldwide, including a 300% increase in type 1 incidence among children younger than 4 years, she said.

▸ Primary prevention. The goals of primary prevention studies are to identify patients who are genetically at risk because they have certain genetic mutations or because a close relative has the disease, to monitor those patients for the development of autoantibodies, and to intervene when antibodies appear.

In the randomized Trial to Reduce Insulin-Dependent Diabetes in the Genetically at Risk (TRIGR), the effects of cow's milk or soy-based formula in addition to breast-feeding is being evaluated in at-risk babies. A previous pilot study suggested that cow's milk was associated with a higher incidence of antibody development.

In the Nutritional Intervention to Prevent Diabetes (NIP) trial, anti-inflammatory omega-3 fatty acids are being given to mothers and infants to determine if this beneficial fatty acid can inhibit the initial autoimmune process.

▸ Secondary prevention. The goal in patients who already are antibody positive and in whom the autoimmune process is underway is to prevent the development of clinical disease, Dr. Greenbaum said.

ENDIT and DPT-1 were secondary prevention studies, and although unsuccessful, they provided data that have proved useful in the newer generation of prevention trials. In DPT-1, for example, although oral insulin was not effective overall, it was beneficial in a subset of patients who had very high levels of autoantibodies. This is now being tested again in patients considered most likely to benefit, she said.

▸ Tertiary prevention. For patients who already have clinical disease, the goal is to preserve β-cell function and thereby prevent both short- and long-term complications; of particular concern in the short term is severe hypoglycemia. Patients in the Diabetes Control and Complications Trial who had some residual β-cell function and who received intensive therapy had a 60% reduction in risk of hypoglycemia, Dr. Greenbaum said.

To prevent long-term complications and to stabilize pancreatic function, the concept of using immunotherapy is being explored. This premise was first tested in the 1980s with cyclosporine, and although the trial showed some benefit to patients, toxicity was a problem. The intention now is to find a tolerable drug or drugs that can be used for a short course that will “reset” the immune system so it stops attacking the pancreas, she said. Among the agents being evaluated are the newer immunosuppressants mycophenolate mofetil, thymoglobulin, daclizumab, and rituximab.

“We can cure diabetes in mice, but we can't yet cure it in people,” Dr. Greenbaum said. “When I think about what cure is going to look like, multiple avenues are going to be needed.” For patients who are genetically at risk, there may be dietary interventions, and for those who go on to develop autoimmunity, antigen-specific therapies may block β-cell destruction. In those who lose β-cell function, achieving a cure may involve tolerance induction, intermittent immunotherapy, and the use of β-cell growth factors and insulin sensitizers, she predicted.

Dr. Greenbaum concluded with a plea for clinicians to refer patients and relatives willing to participate in these trials. Information is available at www.diabetestrialnet.org

NEW YORK — A new generation of clinical trials is evaluating various ways of interrupting autoimmune β-cell destruction in type 1 diabetes, thereby preventing development of the disease, Dr. Carla J. Greenbaum said at a meeting sponsored by the American Diabetes Association.

Two studies begun in the early 1990s, the Diabetes Prevention Trial-Type 1 (DPT-1) and the European Nicotinamide Diabetes Intervention Trial (ENDIT), showed the feasibility of conducting large, well-designed, rigorously controlled clinical trials in patients at risk for diabetes. But the therapies tested—low-dose insulin injections, oral insulin, and nicotinamide—failed to delay or prevent the onset of type 1 diabetes, said Dr. Greenbaum, director of the diabetes research program at Benaroya Research Institute at Virginia Mason, Seattle.

Today, with significant advances in understanding of immune regulation and β-cell growth and development, multiple primary, secondary, and tertiary prevention trials are being conducted. These studies are needed because of the tremendous recent increase in the incidence of type 1 diabetes worldwide, including a 300% increase in type 1 incidence among children younger than 4 years, she said.

▸ Primary prevention. The goals of primary prevention studies are to identify patients who are genetically at risk because they have certain genetic mutations or because a close relative has the disease, to monitor those patients for the development of autoantibodies, and to intervene when antibodies appear.

In the randomized Trial to Reduce Insulin-Dependent Diabetes in the Genetically at Risk (TRIGR), the effects of cow's milk or soy-based formula in addition to breast-feeding is being evaluated in at-risk babies. A previous pilot study suggested that cow's milk was associated with a higher incidence of antibody development.

In the Nutritional Intervention to Prevent Diabetes (NIP) trial, anti-inflammatory omega-3 fatty acids are being given to mothers and infants to determine if this beneficial fatty acid can inhibit the initial autoimmune process.

▸ Secondary prevention. The goal in patients who already are antibody positive and in whom the autoimmune process is underway is to prevent the development of clinical disease, Dr. Greenbaum said.

ENDIT and DPT-1 were secondary prevention studies, and although unsuccessful, they provided data that have proved useful in the newer generation of prevention trials. In DPT-1, for example, although oral insulin was not effective overall, it was beneficial in a subset of patients who had very high levels of autoantibodies. This is now being tested again in patients considered most likely to benefit, she said.

▸ Tertiary prevention. For patients who already have clinical disease, the goal is to preserve β-cell function and thereby prevent both short- and long-term complications; of particular concern in the short term is severe hypoglycemia. Patients in the Diabetes Control and Complications Trial who had some residual β-cell function and who received intensive therapy had a 60% reduction in risk of hypoglycemia, Dr. Greenbaum said.

To prevent long-term complications and to stabilize pancreatic function, the concept of using immunotherapy is being explored. This premise was first tested in the 1980s with cyclosporine, and although the trial showed some benefit to patients, toxicity was a problem. The intention now is to find a tolerable drug or drugs that can be used for a short course that will “reset” the immune system so it stops attacking the pancreas, she said. Among the agents being evaluated are the newer immunosuppressants mycophenolate mofetil, thymoglobulin, daclizumab, and rituximab.

“We can cure diabetes in mice, but we can't yet cure it in people,” Dr. Greenbaum said. “When I think about what cure is going to look like, multiple avenues are going to be needed.” For patients who are genetically at risk, there may be dietary interventions, and for those who go on to develop autoimmunity, antigen-specific therapies may block β-cell destruction. In those who lose β-cell function, achieving a cure may involve tolerance induction, intermittent immunotherapy, and the use of β-cell growth factors and insulin sensitizers, she predicted.

Dr. Greenbaum concluded with a plea for clinicians to refer patients and relatives willing to participate in these trials. Information is available at www.diabetestrialnet.org

Long-term outcomes of uveitis associated with juvenile idiopathic arthritis were excellent in a large, single-center study in which there was a low incidence of resulting blindness, Dr. Rotraud K. Saurenmann and colleagues reported.

Dr. Saurenmann and her associates at the Hospital for Sick Children and the University of Toronto analyzed data from an inception cohort of 1,081 children with juvenile idiopathic arthritis (JIA) who were followed for a median of 6.9 years; uveitis developed in 142 (13%).

At the last follow-up visit, with best corrected visual acuity assessment available for 108 patients, 10 had become legally blind, 4 had impaired vision, and the remaining 94 had good visual acuity, the researchers reported (Arthritis Rheum. 2007;56:647–57).

Chronic anterior uveitis was the most common type, developing in 97 of the 142 patients (68%). Acute anterior uveitis was seen in 23 patients (16%), anterior recurrent uveitis in 17 (12%), and anterior uveitis with vitritis in 5 (4%).

The study also identified risk factors for the development of uveitis. These included age younger than 6 years at diagnosis, antinuclear antibody (ANA) positivity, and oligoarticular disease.

The highest rate of uveitis (21%) occurred in the subgroup of patients with oligoarticular disease, a finding that is in line with other reports, according to Dr. Saurenmann, who is currently in the department of pediatrics, University Children's Hospital, Zürich.

Among patients with rheumatoid factor (RF)-negative polyarticular JIA, 32 (14%) developed uveitis, but none of the patients with polyarticular RF-positive JIA developed the ocular condition. Only one patient with systemic JIA developed uveitis, and that was during the onset of systemic disease during a period of severe systemic inflammation. The symptoms responded promptly to topical treatment.

Previous studies have found a higher prevalence of uveitis among girls than among boys with JIA. In this investigation, however, gender did not remain a significant predictive factor after Cox regression analysis. “This result suggests that the increased prevalence of uveitis in females with JIA is a result of the female predominance in young-onset oligoarticular JIA and of a higher percentage of females with ANA positivity,” the investigators wrote.

The relative contribution of risk factors to the development of uveitis in the different subtypes of JIA also was analyzed. ANA positivity was associated with a risk of uveitis in patients with RF-negative polyarticular disease, enthesitis-related arthritis, and persistent oligoarthritis. The association was not seen in patients with psoriatic or extended oligoarticular JIA. This latter condition refers to oligoarticular disease that evolves into polyarticular disease after 6 months, according to current classification by the International League of Associations for Rheumatology.

The uveitis was mild and self-limited, requiring no topical treatment, in 11 (8%) of patients. Two of these patients were receiving systemic medications, one with methotrexate and the other with corticosteroids. Topical corticosteroids were prescribed for 129 patients (91%), mydriatics for 86 (61%), and topical nonsteroidal anti-inflammatory drugs (NSAIDs) for 33 (23%). Systemic medications included NSAIDs in 139 patients (98%), methotrexate in 63 (44%), corticosteroids in 39 (28%), and tumor necrosis factor-α blockers in 16 (11%).

Combination therapy was needed to control severe articular disease in 10 patients, refractory uveitis in 7 patients, and both articular and ocular disease in 3.

Complications of uveitis developed in 53 (37%) patients. These included cataracts, synechiae, glaucoma, band keratopathy, and macular edema.

The authors recommended that aggressive immunosuppressive treatment be instituted early in these patients to prevent prolonged ocular inflammation.

Immunosuppression should start early in JIAto prevent prolonged ocular inflammation. American College of Rheumatology

Long-term outcomes of uveitis associated with juvenile idiopathic arthritis were excellent in a large, single-center study in which there was a low incidence of resulting blindness, Dr. Rotraud K. Saurenmann and colleagues reported.

Dr. Saurenmann and her associates at the Hospital for Sick Children and the University of Toronto analyzed data from an inception cohort of 1,081 children with juvenile idiopathic arthritis (JIA) who were followed for a median of 6.9 years; uveitis developed in 142 (13%).

At the last follow-up visit, with best corrected visual acuity assessment available for 108 patients, 10 had become legally blind, 4 had impaired vision, and the remaining 94 had good visual acuity, the researchers reported (Arthritis Rheum. 2007;56:647–57).

Chronic anterior uveitis was the most common type, developing in 97 of the 142 patients (68%). Acute anterior uveitis was seen in 23 patients (16%), anterior recurrent uveitis in 17 (12%), and anterior uveitis with vitritis in 5 (4%).

The study also identified risk factors for the development of uveitis. These included age younger than 6 years at diagnosis, antinuclear antibody (ANA) positivity, and oligoarticular disease.

The highest rate of uveitis (21%) occurred in the subgroup of patients with oligoarticular disease, a finding that is in line with other reports, according to Dr. Saurenmann, who is currently in the department of pediatrics, University Children's Hospital, Zürich.

Among patients with rheumatoid factor (RF)-negative polyarticular JIA, 32 (14%) developed uveitis, but none of the patients with polyarticular RF-positive JIA developed the ocular condition. Only one patient with systemic JIA developed uveitis, and that was during the onset of systemic disease during a period of severe systemic inflammation. The symptoms responded promptly to topical treatment.

Previous studies have found a higher prevalence of uveitis among girls than among boys with JIA. In this investigation, however, gender did not remain a significant predictive factor after Cox regression analysis. “This result suggests that the increased prevalence of uveitis in females with JIA is a result of the female predominance in young-onset oligoarticular JIA and of a higher percentage of females with ANA positivity,” the investigators wrote.

The relative contribution of risk factors to the development of uveitis in the different subtypes of JIA also was analyzed. ANA positivity was associated with a risk of uveitis in patients with RF-negative polyarticular disease, enthesitis-related arthritis, and persistent oligoarthritis. The association was not seen in patients with psoriatic or extended oligoarticular JIA. This latter condition refers to oligoarticular disease that evolves into polyarticular disease after 6 months, according to current classification by the International League of Associations for Rheumatology.

The uveitis was mild and self-limited, requiring no topical treatment, in 11 (8%) of patients. Two of these patients were receiving systemic medications, one with methotrexate and the other with corticosteroids. Topical corticosteroids were prescribed for 129 patients (91%), mydriatics for 86 (61%), and topical nonsteroidal anti-inflammatory drugs (NSAIDs) for 33 (23%). Systemic medications included NSAIDs in 139 patients (98%), methotrexate in 63 (44%), corticosteroids in 39 (28%), and tumor necrosis factor-α blockers in 16 (11%).

Combination therapy was needed to control severe articular disease in 10 patients, refractory uveitis in 7 patients, and both articular and ocular disease in 3.

Complications of uveitis developed in 53 (37%) patients. These included cataracts, synechiae, glaucoma, band keratopathy, and macular edema.

The authors recommended that aggressive immunosuppressive treatment be instituted early in these patients to prevent prolonged ocular inflammation.

Immunosuppression should start early in JIAto prevent prolonged ocular inflammation. American College of Rheumatology

Long-term outcomes of uveitis associated with juvenile idiopathic arthritis were excellent in a large, single-center study in which there was a low incidence of resulting blindness, Dr. Rotraud K. Saurenmann and colleagues reported.

Dr. Saurenmann and her associates at the Hospital for Sick Children and the University of Toronto analyzed data from an inception cohort of 1,081 children with juvenile idiopathic arthritis (JIA) who were followed for a median of 6.9 years; uveitis developed in 142 (13%).

At the last follow-up visit, with best corrected visual acuity assessment available for 108 patients, 10 had become legally blind, 4 had impaired vision, and the remaining 94 had good visual acuity, the researchers reported (Arthritis Rheum. 2007;56:647–57).

Chronic anterior uveitis was the most common type, developing in 97 of the 142 patients (68%). Acute anterior uveitis was seen in 23 patients (16%), anterior recurrent uveitis in 17 (12%), and anterior uveitis with vitritis in 5 (4%).

The study also identified risk factors for the development of uveitis. These included age younger than 6 years at diagnosis, antinuclear antibody (ANA) positivity, and oligoarticular disease.

The highest rate of uveitis (21%) occurred in the subgroup of patients with oligoarticular disease, a finding that is in line with other reports, according to Dr. Saurenmann, who is currently in the department of pediatrics, University Children's Hospital, Zürich.

Among patients with rheumatoid factor (RF)-negative polyarticular JIA, 32 (14%) developed uveitis, but none of the patients with polyarticular RF-positive JIA developed the ocular condition. Only one patient with systemic JIA developed uveitis, and that was during the onset of systemic disease during a period of severe systemic inflammation. The symptoms responded promptly to topical treatment.

Previous studies have found a higher prevalence of uveitis among girls than among boys with JIA. In this investigation, however, gender did not remain a significant predictive factor after Cox regression analysis. “This result suggests that the increased prevalence of uveitis in females with JIA is a result of the female predominance in young-onset oligoarticular JIA and of a higher percentage of females with ANA positivity,” the investigators wrote.

The relative contribution of risk factors to the development of uveitis in the different subtypes of JIA also was analyzed. ANA positivity was associated with a risk of uveitis in patients with RF-negative polyarticular disease, enthesitis-related arthritis, and persistent oligoarthritis. The association was not seen in patients with psoriatic or extended oligoarticular JIA. This latter condition refers to oligoarticular disease that evolves into polyarticular disease after 6 months, according to current classification by the International League of Associations for Rheumatology.

The uveitis was mild and self-limited, requiring no topical treatment, in 11 (8%) of patients. Two of these patients were receiving systemic medications, one with methotrexate and the other with corticosteroids. Topical corticosteroids were prescribed for 129 patients (91%), mydriatics for 86 (61%), and topical nonsteroidal anti-inflammatory drugs (NSAIDs) for 33 (23%). Systemic medications included NSAIDs in 139 patients (98%), methotrexate in 63 (44%), corticosteroids in 39 (28%), and tumor necrosis factor-α blockers in 16 (11%).

Combination therapy was needed to control severe articular disease in 10 patients, refractory uveitis in 7 patients, and both articular and ocular disease in 3.

Complications of uveitis developed in 53 (37%) patients. These included cataracts, synechiae, glaucoma, band keratopathy, and macular edema.

The authors recommended that aggressive immunosuppressive treatment be instituted early in these patients to prevent prolonged ocular inflammation.

Immunosuppression should start early in JIAto prevent prolonged ocular inflammation. American College of Rheumatology

WASHINGTON — Among the clinical benefits associated with tumor necrosis factor-α inhibition in patients with rheumatoid arthritis are improvements in hemoglobin levels, Dr. Mittie Doyle said in a poster session at the annual meeting of the American College of Rheumatology.

Anemia associated with chronic inflammation is common in rheumatoid arthritis (RA), with an estimated prevalence of 50%, and contributes to the fatigue and impaired quality of life associated with the disease.

Some evidence suggests that the proinflammatory cytokine TNF-α has an inhibitory effect on erythropoiesis in chronic inflammatory disease, according to Dr. Doyle. Therefore, to determine if blocking TNF-α would improve hemoglobin levels, a post hoc analysis of data from three randomized trials was undertaken.

In ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis With Concomitant Therapy), 428 patients with active RA despite methotrexate therapy got either placebo or infliximab (3 or 10 mg/kg) at weeks 0, 2, and 6, and every 4 or 8 weeks thereafter.

In ASPIRE (Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset), 1,049 methotrexate-naive patients with RA of 3 years' duration or less received methotrexate and placebo, or methotrexate and infliximab (3 or 6 mg/ kg) at weeks 0, 2, and 6 and every 8 weeks thereafter, reported Dr. Doyle.

In START (Safety Trial for Rheumatoid Arthritis With Remicade Therapy), 1,084 patients receiving methotrexate were randomized to one of three regimens: placebo through week 14 followed by infliximab (3 mg/kg) at weeks 22, 26, 30, 38, and 46; infliximab (3 mg/kg) at weeks 0, 2, and 6 and every 8 weeks through week 48, with dosage escalations up to 9 mg/kg permitted after week 22; or infliximab (10 mg/kg) at weeks 0, 2, and 6 and every 8 weeks through week 48.

Anemia was defined as hemoglobin below 12 g/dL and improvement as an increase in hemoglobin of 1 g/dL or more.

In all three studies, the proportion of patients with improvements in anemia was greater among the infliximab plus methotrexate groups than among the methotrexate plus placebo groups, according to Dr. Doyle of Centocor Research and Development Inc., Horsham, Pa.

In ATTRACT, 35.6% of patients receiving infliximab had an increase in hemoglobin of 1 g/dL or more by week 22, compared with 7.1% of those receiving placebo plus methotrexate.

In ASPIRE, 45.4% and 45.9% of patients receiving infliximab 3 mg/kg and 6 mg/kg, respectively, showed an increase in hemoglobin of 1 g/dL or more by week 22. Among patients receiving placebo plus methotrexate, 29.7% patients showed this degree of improvement.

In START, 22.3% and 23.9% of patients receiving infliximab 3 mg/kg and 10 mg/kg, respectively, had an increase in hemoglobin of 1 g/dL or more by week 22, as did 7.2% of those receiving placebo plus methotrexate.

“The study showed that treatment with combination therapy with infliximab and methotrexate resulted in larger improvements in hemoglobin than treatment with methotrexate alone,” coinvestigator Dr. Joan Bathon, professor of medicine and director of the arthritis center at Johns Hopkins University, Baltimore, said in an interview. “Whether these changes will translate into clinically meaningful results, remains to be determined.”

The pathogenesis of anemia of chronic inflammation has been linked to the impaired delivery and use of iron by erythroid precursors, according to Dr. Doyle. Elevated levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and TNF-α have been shown to play an important role in the development of anemia of chronic inflammation through mechanisms that include shortened red blood cell survival, enhanced apoptosis of marrow erythroid progenitors, and suppression of erythropoietin production.

More recently, hepcidin has been identified as the acute phase protein that may link iron metabolism and red blood cell production to the type II acute phase response. IL-6 is the primary mediator of hepcidin production, and TNF-α likely influences hepcidin production indirectly via IL-6 induction, said Dr. Doyle in an interview.

The study was supported by Centocor Research and Development Inc.

WASHINGTON — Among the clinical benefits associated with tumor necrosis factor-α inhibition in patients with rheumatoid arthritis are improvements in hemoglobin levels, Dr. Mittie Doyle said in a poster session at the annual meeting of the American College of Rheumatology.

Anemia associated with chronic inflammation is common in rheumatoid arthritis (RA), with an estimated prevalence of 50%, and contributes to the fatigue and impaired quality of life associated with the disease.

Some evidence suggests that the proinflammatory cytokine TNF-α has an inhibitory effect on erythropoiesis in chronic inflammatory disease, according to Dr. Doyle. Therefore, to determine if blocking TNF-α would improve hemoglobin levels, a post hoc analysis of data from three randomized trials was undertaken.

In ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis With Concomitant Therapy), 428 patients with active RA despite methotrexate therapy got either placebo or infliximab (3 or 10 mg/kg) at weeks 0, 2, and 6, and every 4 or 8 weeks thereafter.

In ASPIRE (Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset), 1,049 methotrexate-naive patients with RA of 3 years' duration or less received methotrexate and placebo, or methotrexate and infliximab (3 or 6 mg/ kg) at weeks 0, 2, and 6 and every 8 weeks thereafter, reported Dr. Doyle.

In START (Safety Trial for Rheumatoid Arthritis With Remicade Therapy), 1,084 patients receiving methotrexate were randomized to one of three regimens: placebo through week 14 followed by infliximab (3 mg/kg) at weeks 22, 26, 30, 38, and 46; infliximab (3 mg/kg) at weeks 0, 2, and 6 and every 8 weeks through week 48, with dosage escalations up to 9 mg/kg permitted after week 22; or infliximab (10 mg/kg) at weeks 0, 2, and 6 and every 8 weeks through week 48.

Anemia was defined as hemoglobin below 12 g/dL and improvement as an increase in hemoglobin of 1 g/dL or more.

In all three studies, the proportion of patients with improvements in anemia was greater among the infliximab plus methotrexate groups than among the methotrexate plus placebo groups, according to Dr. Doyle of Centocor Research and Development Inc., Horsham, Pa.

In ATTRACT, 35.6% of patients receiving infliximab had an increase in hemoglobin of 1 g/dL or more by week 22, compared with 7.1% of those receiving placebo plus methotrexate.

In ASPIRE, 45.4% and 45.9% of patients receiving infliximab 3 mg/kg and 6 mg/kg, respectively, showed an increase in hemoglobin of 1 g/dL or more by week 22. Among patients receiving placebo plus methotrexate, 29.7% patients showed this degree of improvement.

In START, 22.3% and 23.9% of patients receiving infliximab 3 mg/kg and 10 mg/kg, respectively, had an increase in hemoglobin of 1 g/dL or more by week 22, as did 7.2% of those receiving placebo plus methotrexate.

“The study showed that treatment with combination therapy with infliximab and methotrexate resulted in larger improvements in hemoglobin than treatment with methotrexate alone,” coinvestigator Dr. Joan Bathon, professor of medicine and director of the arthritis center at Johns Hopkins University, Baltimore, said in an interview. “Whether these changes will translate into clinically meaningful results, remains to be determined.”

The pathogenesis of anemia of chronic inflammation has been linked to the impaired delivery and use of iron by erythroid precursors, according to Dr. Doyle. Elevated levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and TNF-α have been shown to play an important role in the development of anemia of chronic inflammation through mechanisms that include shortened red blood cell survival, enhanced apoptosis of marrow erythroid progenitors, and suppression of erythropoietin production.

More recently, hepcidin has been identified as the acute phase protein that may link iron metabolism and red blood cell production to the type II acute phase response. IL-6 is the primary mediator of hepcidin production, and TNF-α likely influences hepcidin production indirectly via IL-6 induction, said Dr. Doyle in an interview.

The study was supported by Centocor Research and Development Inc.

WASHINGTON — Among the clinical benefits associated with tumor necrosis factor-α inhibition in patients with rheumatoid arthritis are improvements in hemoglobin levels, Dr. Mittie Doyle said in a poster session at the annual meeting of the American College of Rheumatology.

Anemia associated with chronic inflammation is common in rheumatoid arthritis (RA), with an estimated prevalence of 50%, and contributes to the fatigue and impaired quality of life associated with the disease.

Some evidence suggests that the proinflammatory cytokine TNF-α has an inhibitory effect on erythropoiesis in chronic inflammatory disease, according to Dr. Doyle. Therefore, to determine if blocking TNF-α would improve hemoglobin levels, a post hoc analysis of data from three randomized trials was undertaken.

In ATTRACT (Anti-TNF Trial in Rheumatoid Arthritis With Concomitant Therapy), 428 patients with active RA despite methotrexate therapy got either placebo or infliximab (3 or 10 mg/kg) at weeks 0, 2, and 6, and every 4 or 8 weeks thereafter.

In ASPIRE (Active Controlled Study of Patients Receiving Infliximab for Treatment of Rheumatoid Arthritis of Early Onset), 1,049 methotrexate-naive patients with RA of 3 years' duration or less received methotrexate and placebo, or methotrexate and infliximab (3 or 6 mg/ kg) at weeks 0, 2, and 6 and every 8 weeks thereafter, reported Dr. Doyle.

In START (Safety Trial for Rheumatoid Arthritis With Remicade Therapy), 1,084 patients receiving methotrexate were randomized to one of three regimens: placebo through week 14 followed by infliximab (3 mg/kg) at weeks 22, 26, 30, 38, and 46; infliximab (3 mg/kg) at weeks 0, 2, and 6 and every 8 weeks through week 48, with dosage escalations up to 9 mg/kg permitted after week 22; or infliximab (10 mg/kg) at weeks 0, 2, and 6 and every 8 weeks through week 48.

Anemia was defined as hemoglobin below 12 g/dL and improvement as an increase in hemoglobin of 1 g/dL or more.

In all three studies, the proportion of patients with improvements in anemia was greater among the infliximab plus methotrexate groups than among the methotrexate plus placebo groups, according to Dr. Doyle of Centocor Research and Development Inc., Horsham, Pa.

In ATTRACT, 35.6% of patients receiving infliximab had an increase in hemoglobin of 1 g/dL or more by week 22, compared with 7.1% of those receiving placebo plus methotrexate.

In ASPIRE, 45.4% and 45.9% of patients receiving infliximab 3 mg/kg and 6 mg/kg, respectively, showed an increase in hemoglobin of 1 g/dL or more by week 22. Among patients receiving placebo plus methotrexate, 29.7% patients showed this degree of improvement.

In START, 22.3% and 23.9% of patients receiving infliximab 3 mg/kg and 10 mg/kg, respectively, had an increase in hemoglobin of 1 g/dL or more by week 22, as did 7.2% of those receiving placebo plus methotrexate.

“The study showed that treatment with combination therapy with infliximab and methotrexate resulted in larger improvements in hemoglobin than treatment with methotrexate alone,” coinvestigator Dr. Joan Bathon, professor of medicine and director of the arthritis center at Johns Hopkins University, Baltimore, said in an interview. “Whether these changes will translate into clinically meaningful results, remains to be determined.”

The pathogenesis of anemia of chronic inflammation has been linked to the impaired delivery and use of iron by erythroid precursors, according to Dr. Doyle. Elevated levels of proinflammatory cytokines, such as interleukin-6 (IL-6) and TNF-α have been shown to play an important role in the development of anemia of chronic inflammation through mechanisms that include shortened red blood cell survival, enhanced apoptosis of marrow erythroid progenitors, and suppression of erythropoietin production.

More recently, hepcidin has been identified as the acute phase protein that may link iron metabolism and red blood cell production to the type II acute phase response. IL-6 is the primary mediator of hepcidin production, and TNF-α likely influences hepcidin production indirectly via IL-6 induction, said Dr. Doyle in an interview.

The study was supported by Centocor Research and Development Inc.

CHICAGO — Needle biopsy of an incidentally discovered adrenal mass is unlikely to be informative, diagnostic, or of assistance in clinical decision making, according to Dr. Frank J. Quayle.

Nonetheless, the procedure continues to be done, and at considerable risk to patients, Dr. Quayle said at the annual meeting of the Central Surgical Association.

In a chart review of 347 patients referred to the endocrine surgery service, 22 had undergone fine-needle aspiration biopsy before referral, said Dr. Quayle of Washington University, St. Louis.

Fifteen of these 22 patients had been referred for incidentally discovered adrenal masses, or incidentalomas, four for suspected metastases, and three for symptomatic masses.

Of particular concern was the fact that 10 of the biopsies were performed before biochemical testing was done to exclude pheochromocytoma, despite the existence of well-established guidelines on biochemical evaluation for this potentially lethal tumor, Dr. Quayle said.

Biopsy results were either nondiagnostic or noninformative in 17 patients, or 77% of the cohort, including 13 of the 15 referred for incidentalomas.

Following resection and pathologic analysis, six of the incidentalomas were found to be adenomas and four were pheochromocytomas, with the remainder having various diagnoses including paragangliomas and organizing hematomas.

In three of the incidentalomas the biopsy results were discordant with the final pathology, showing normal tissues where the final diagnosis was pheochromocytoma in two and organizing hematoma in one.

Two of the four patients with suspected metastases had noninformative biopsies, while in one the biopsy was diagnostic for metastatic melanoma and one was diagnostic for renal cell carcinoma. All four of these patients underwent resection, and in the patients whose biopsies had been nondiagnostic the final diagnoses were renal cell metastasis and organizing hematoma, he said.

Two of the three biopsies for patients with symptomatic masses were nondiagnostic, with the third demonstrating a poorly differentiated malignant neoplasm.

Biopsy-related complications that required hospitalization—such as hemothorax—occurred in three patients. There were no hemodynamic complications, although these have been described in the literature, Dr. Quayle said.

In the operating room, resection had to be converted to an open procedure in one patient, with a key factor being inflammation relating to the biopsy, he said.

“Perhaps the most important finding was that biopsy results did not change clinical management in any of the patients,” he said.

All of the incidentalomas had biochemical and imaging findings that directed management, and all those with symptomatic masses and suspected metastases were candidates for resection regardless of biopsy results, he said.

“We therefore conclude that the risk-benefit ratio for adrenal biopsy in incidentally discovered adrenal masses is unacceptably high. The decision to perform a biopsy should be made by specialists who understand the limitations of the procedure and exactly how the results will be used to direct patient care,” Dr. Quayle said.

After Dr. Quayle's presentation, a member of the audience, Dr. Herbert Chen, said that often, “we are asked [as surgeons] to evaluate patients with incidentally discovered masses, and we generally do not consider an invasive biopsy unless it will change our management. Unfortunately this is not the case among nonsurgeons.”

“It was all risk with no benefit for these patients,” added Dr. Chen, of the University of Wisconsin, Madison.

Another member of the audience, Dr. Christopher McHenry of MetroHealth Medical Center, Cleveland, said that it is also important to emphasize that microscopic features cannot be used to distinguish benign from malignant tumors.

“Our pathologists can't make the diagnosis of malignancy even if they have the entire tumor,” he said.

“It's the presence of local invasion and metastases, either lymph node or systemic, that makes these diagnoses,” Dr. McHenry said.

CHICAGO — Needle biopsy of an incidentally discovered adrenal mass is unlikely to be informative, diagnostic, or of assistance in clinical decision making, according to Dr. Frank J. Quayle.

Nonetheless, the procedure continues to be done, and at considerable risk to patients, Dr. Quayle said at the annual meeting of the Central Surgical Association.

In a chart review of 347 patients referred to the endocrine surgery service, 22 had undergone fine-needle aspiration biopsy before referral, said Dr. Quayle of Washington University, St. Louis.

Fifteen of these 22 patients had been referred for incidentally discovered adrenal masses, or incidentalomas, four for suspected metastases, and three for symptomatic masses.

Of particular concern was the fact that 10 of the biopsies were performed before biochemical testing was done to exclude pheochromocytoma, despite the existence of well-established guidelines on biochemical evaluation for this potentially lethal tumor, Dr. Quayle said.

Biopsy results were either nondiagnostic or noninformative in 17 patients, or 77% of the cohort, including 13 of the 15 referred for incidentalomas.

Following resection and pathologic analysis, six of the incidentalomas were found to be adenomas and four were pheochromocytomas, with the remainder having various diagnoses including paragangliomas and organizing hematomas.

In three of the incidentalomas the biopsy results were discordant with the final pathology, showing normal tissues where the final diagnosis was pheochromocytoma in two and organizing hematoma in one.

Two of the four patients with suspected metastases had noninformative biopsies, while in one the biopsy was diagnostic for metastatic melanoma and one was diagnostic for renal cell carcinoma. All four of these patients underwent resection, and in the patients whose biopsies had been nondiagnostic the final diagnoses were renal cell metastasis and organizing hematoma, he said.

Two of the three biopsies for patients with symptomatic masses were nondiagnostic, with the third demonstrating a poorly differentiated malignant neoplasm.

Biopsy-related complications that required hospitalization—such as hemothorax—occurred in three patients. There were no hemodynamic complications, although these have been described in the literature, Dr. Quayle said.

In the operating room, resection had to be converted to an open procedure in one patient, with a key factor being inflammation relating to the biopsy, he said.

“Perhaps the most important finding was that biopsy results did not change clinical management in any of the patients,” he said.

All of the incidentalomas had biochemical and imaging findings that directed management, and all those with symptomatic masses and suspected metastases were candidates for resection regardless of biopsy results, he said.

“We therefore conclude that the risk-benefit ratio for adrenal biopsy in incidentally discovered adrenal masses is unacceptably high. The decision to perform a biopsy should be made by specialists who understand the limitations of the procedure and exactly how the results will be used to direct patient care,” Dr. Quayle said.

After Dr. Quayle's presentation, a member of the audience, Dr. Herbert Chen, said that often, “we are asked [as surgeons] to evaluate patients with incidentally discovered masses, and we generally do not consider an invasive biopsy unless it will change our management. Unfortunately this is not the case among nonsurgeons.”

“It was all risk with no benefit for these patients,” added Dr. Chen, of the University of Wisconsin, Madison.

Another member of the audience, Dr. Christopher McHenry of MetroHealth Medical Center, Cleveland, said that it is also important to emphasize that microscopic features cannot be used to distinguish benign from malignant tumors.

“Our pathologists can't make the diagnosis of malignancy even if they have the entire tumor,” he said.

“It's the presence of local invasion and metastases, either lymph node or systemic, that makes these diagnoses,” Dr. McHenry said.

CHICAGO — Needle biopsy of an incidentally discovered adrenal mass is unlikely to be informative, diagnostic, or of assistance in clinical decision making, according to Dr. Frank J. Quayle.

Nonetheless, the procedure continues to be done, and at considerable risk to patients, Dr. Quayle said at the annual meeting of the Central Surgical Association.

In a chart review of 347 patients referred to the endocrine surgery service, 22 had undergone fine-needle aspiration biopsy before referral, said Dr. Quayle of Washington University, St. Louis.

Fifteen of these 22 patients had been referred for incidentally discovered adrenal masses, or incidentalomas, four for suspected metastases, and three for symptomatic masses.

Of particular concern was the fact that 10 of the biopsies were performed before biochemical testing was done to exclude pheochromocytoma, despite the existence of well-established guidelines on biochemical evaluation for this potentially lethal tumor, Dr. Quayle said.

Biopsy results were either nondiagnostic or noninformative in 17 patients, or 77% of the cohort, including 13 of the 15 referred for incidentalomas.

Following resection and pathologic analysis, six of the incidentalomas were found to be adenomas and four were pheochromocytomas, with the remainder having various diagnoses including paragangliomas and organizing hematomas.

In three of the incidentalomas the biopsy results were discordant with the final pathology, showing normal tissues where the final diagnosis was pheochromocytoma in two and organizing hematoma in one.

Two of the four patients with suspected metastases had noninformative biopsies, while in one the biopsy was diagnostic for metastatic melanoma and one was diagnostic for renal cell carcinoma. All four of these patients underwent resection, and in the patients whose biopsies had been nondiagnostic the final diagnoses were renal cell metastasis and organizing hematoma, he said.

Two of the three biopsies for patients with symptomatic masses were nondiagnostic, with the third demonstrating a poorly differentiated malignant neoplasm.

Biopsy-related complications that required hospitalization—such as hemothorax—occurred in three patients. There were no hemodynamic complications, although these have been described in the literature, Dr. Quayle said.

In the operating room, resection had to be converted to an open procedure in one patient, with a key factor being inflammation relating to the biopsy, he said.

“Perhaps the most important finding was that biopsy results did not change clinical management in any of the patients,” he said.

All of the incidentalomas had biochemical and imaging findings that directed management, and all those with symptomatic masses and suspected metastases were candidates for resection regardless of biopsy results, he said.

“We therefore conclude that the risk-benefit ratio for adrenal biopsy in incidentally discovered adrenal masses is unacceptably high. The decision to perform a biopsy should be made by specialists who understand the limitations of the procedure and exactly how the results will be used to direct patient care,” Dr. Quayle said.

After Dr. Quayle's presentation, a member of the audience, Dr. Herbert Chen, said that often, “we are asked [as surgeons] to evaluate patients with incidentally discovered masses, and we generally do not consider an invasive biopsy unless it will change our management. Unfortunately this is not the case among nonsurgeons.”

“It was all risk with no benefit for these patients,” added Dr. Chen, of the University of Wisconsin, Madison.

Another member of the audience, Dr. Christopher McHenry of MetroHealth Medical Center, Cleveland, said that it is also important to emphasize that microscopic features cannot be used to distinguish benign from malignant tumors.

“Our pathologists can't make the diagnosis of malignancy even if they have the entire tumor,” he said.

“It's the presence of local invasion and metastases, either lymph node or systemic, that makes these diagnoses,” Dr. McHenry said.

MONTREAL — Hypogonadism should be considered a risk factor for cardiovascular disease in older men, Dr. Andre T. Guay said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

He based that conclusion on an analysis of testosterone levels in 154 men (average age of 53.5) seen at the erectile dysfunction (ED) clinic of the Lahey Clinic Medical Center, Peabody, Mass., where Dr. Guay is an endocrinologist.

Overall, 25% of the men had hypogonadism, defined as a free testosterone level below 10 pg/mL. Among men with low testosterone, 92.3% had insulin resistance, compared with 25.2% of those without low testosterone levels. High rates of metabolic syndrome also were seen among hypogonadal men, using both the National Cholesterol Education Program (NCEP) criteria and the more stringent World Health Organization criteria for metabolic syndrome. (See box.)

In a previous study, 91% of the cohort of men seen in the ED clinic had cardiac risk factors. A total of 43% had hypertension, 73% had dyslipidemia, and 85% had a body mass index greater than 25 kg/m

Also, 43% of the men had metabolic syndrome, according to the NCEP criteria, compared with 24% of the general population. Insulin resistance was found in 79%, compared with a 25% incidence in the general population. These findings suggest that ED may be an early warning sign of cardiac disease, he said.

The new findings on hypogonadism go beyond this link to suggest that low testosterone also may be associated with underlying cardiovascular disease, according to Dr. Guay.

Several large reviews have indicated that men with low testosterone have increased cardiovascular risks, with a high incidence of metabolic syndrome and insulin resistance. “There are associations, but that doesn't necessarily prove cause and effect,” Dr. Guay said in an interview. “However, we know that testosterone can positively affect endothelial function, increasing blood flow, and we know that even acute stimulation of testosterone can decrease insulin resistance, which is the basis of the metabolic syndrome and many chronic diseases. Testosterone must therefore have a protective effect on the vascular lining where atherosclerosis begins.”

The study findings suggest that “when patients present with ED, you should immediately look for major cardiac risks and either treat or refer for treatment. It also may be that we should be checking the testosterone level in every man with ED,” he said at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

ELSEVIER GLOBAL MEDICAL NEWS

MONTREAL — Hypogonadism should be considered a risk factor for cardiovascular disease in older men, Dr. Andre T. Guay said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

He based that conclusion on an analysis of testosterone levels in 154 men (average age of 53.5) seen at the erectile dysfunction (ED) clinic of the Lahey Clinic Medical Center, Peabody, Mass., where Dr. Guay is an endocrinologist.

Overall, 25% of the men had hypogonadism, defined as a free testosterone level below 10 pg/mL. Among men with low testosterone, 92.3% had insulin resistance, compared with 25.2% of those without low testosterone levels. High rates of metabolic syndrome also were seen among hypogonadal men, using both the National Cholesterol Education Program (NCEP) criteria and the more stringent World Health Organization criteria for metabolic syndrome. (See box.)

In a previous study, 91% of the cohort of men seen in the ED clinic had cardiac risk factors. A total of 43% had hypertension, 73% had dyslipidemia, and 85% had a body mass index greater than 25 kg/m

Also, 43% of the men had metabolic syndrome, according to the NCEP criteria, compared with 24% of the general population. Insulin resistance was found in 79%, compared with a 25% incidence in the general population. These findings suggest that ED may be an early warning sign of cardiac disease, he said.

The new findings on hypogonadism go beyond this link to suggest that low testosterone also may be associated with underlying cardiovascular disease, according to Dr. Guay.

Several large reviews have indicated that men with low testosterone have increased cardiovascular risks, with a high incidence of metabolic syndrome and insulin resistance. “There are associations, but that doesn't necessarily prove cause and effect,” Dr. Guay said in an interview. “However, we know that testosterone can positively affect endothelial function, increasing blood flow, and we know that even acute stimulation of testosterone can decrease insulin resistance, which is the basis of the metabolic syndrome and many chronic diseases. Testosterone must therefore have a protective effect on the vascular lining where atherosclerosis begins.”

The study findings suggest that “when patients present with ED, you should immediately look for major cardiac risks and either treat or refer for treatment. It also may be that we should be checking the testosterone level in every man with ED,” he said at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

ELSEVIER GLOBAL MEDICAL NEWS

MONTREAL — Hypogonadism should be considered a risk factor for cardiovascular disease in older men, Dr. Andre T. Guay said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

He based that conclusion on an analysis of testosterone levels in 154 men (average age of 53.5) seen at the erectile dysfunction (ED) clinic of the Lahey Clinic Medical Center, Peabody, Mass., where Dr. Guay is an endocrinologist.

Overall, 25% of the men had hypogonadism, defined as a free testosterone level below 10 pg/mL. Among men with low testosterone, 92.3% had insulin resistance, compared with 25.2% of those without low testosterone levels. High rates of metabolic syndrome also were seen among hypogonadal men, using both the National Cholesterol Education Program (NCEP) criteria and the more stringent World Health Organization criteria for metabolic syndrome. (See box.)

In a previous study, 91% of the cohort of men seen in the ED clinic had cardiac risk factors. A total of 43% had hypertension, 73% had dyslipidemia, and 85% had a body mass index greater than 25 kg/m

Also, 43% of the men had metabolic syndrome, according to the NCEP criteria, compared with 24% of the general population. Insulin resistance was found in 79%, compared with a 25% incidence in the general population. These findings suggest that ED may be an early warning sign of cardiac disease, he said.

The new findings on hypogonadism go beyond this link to suggest that low testosterone also may be associated with underlying cardiovascular disease, according to Dr. Guay.

Several large reviews have indicated that men with low testosterone have increased cardiovascular risks, with a high incidence of metabolic syndrome and insulin resistance. “There are associations, but that doesn't necessarily prove cause and effect,” Dr. Guay said in an interview. “However, we know that testosterone can positively affect endothelial function, increasing blood flow, and we know that even acute stimulation of testosterone can decrease insulin resistance, which is the basis of the metabolic syndrome and many chronic diseases. Testosterone must therefore have a protective effect on the vascular lining where atherosclerosis begins.”

The study findings suggest that “when patients present with ED, you should immediately look for major cardiac risks and either treat or refer for treatment. It also may be that we should be checking the testosterone level in every man with ED,” he said at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

ELSEVIER GLOBAL MEDICAL NEWS

LA JOLLA, CALIF. — The newly enacted Dietary Supplement and Nonprescription Drug Consumer Protection Act mandates for the first time the reporting of serious adverse events associated with dietary supplements and over-the-counter products.

The law, passed by Congress in December, is the first revision of the regulation of dietary supplements since the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994, Peter Reinecke said at a symposium on natural supplements sponsored by the Scripps Center for Integrative Medicine.

DSHEA authorized the Food and Drug Administration (FDA) to seize adulterated or misbranded products and to remove from the market products that present significant or unreasonable risk of injury or illness or pose an imminent hazard to public health or safety. It made no provision for the same type of reporting of adverse events required for pharmaceutical drugs.

But when the new law goes into effect on December 22, 2007, all manufacturers, packers, and distributors of supplements will be required to report serious adverse events to the FDA within 15 business days through the MedWatch program.

Serious adverse events are defined as those that result in death, a life-threatening experience, inpatient hospitalization, persistent or significant disability or incapacity, or a congenital abnormality or birth defect; or that require, based on reasonable medical judgment, a medical or surgical intervention to prevent one of these outcomes.

If a consumer reports that he or she has experienced a serious adverse event, the manufacturer must report it— regardless of whether proof is provided, medical care was sought, or the company disagrees with the claim.

“The intent of the new law is clearly to err on the side of over-reporting to give the FDA the ability to spot trends that are out there, not to overanalyze any single event,” said Mr. Reinecke, principal of Reinecke Strategic Solutions, Bethesda, Md.

The labeling of dietary supplements will be required to include an address or telephone number consumers can use to contact the manufacturer or other responsible party, should an adverse event occur. Any product without this information on the label will be considered misbranded, Mr. Reinecke said at the meeting, which was cosponsored by the University of California, San Diego.

Manufacturers, packers, and distributors will be required to maintain for 6 years all records relating to adverse- event reports. Falsification of records will be illegal, and could lead to an injunction or criminal penalties.

The recent change of leadership in Congress is likely to result in greater efforts to ensure the safety of supplements, particularly by implementing and making final the DSHEA provision that establishes good manufacturing practices governing the preparation, packing, and holding of these products, said Mr. Reinecke, who was one of the Capitol Hill staffers involved in writing DSHEA.

“The coming year also is likely to see the biggest effort in Washington in the 20-something years I've been there to get the FDA some much-needed resources. This will be difficult given the fiscal situation in which we find ourselves, but there is strong support for this in industry and consumer groups,” he said.

LA JOLLA, CALIF. — The newly enacted Dietary Supplement and Nonprescription Drug Consumer Protection Act mandates for the first time the reporting of serious adverse events associated with dietary supplements and over-the-counter products.

The law, passed by Congress in December, is the first revision of the regulation of dietary supplements since the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994, Peter Reinecke said at a symposium on natural supplements sponsored by the Scripps Center for Integrative Medicine.

DSHEA authorized the Food and Drug Administration (FDA) to seize adulterated or misbranded products and to remove from the market products that present significant or unreasonable risk of injury or illness or pose an imminent hazard to public health or safety. It made no provision for the same type of reporting of adverse events required for pharmaceutical drugs.

But when the new law goes into effect on December 22, 2007, all manufacturers, packers, and distributors of supplements will be required to report serious adverse events to the FDA within 15 business days through the MedWatch program.

Serious adverse events are defined as those that result in death, a life-threatening experience, inpatient hospitalization, persistent or significant disability or incapacity, or a congenital abnormality or birth defect; or that require, based on reasonable medical judgment, a medical or surgical intervention to prevent one of these outcomes.

If a consumer reports that he or she has experienced a serious adverse event, the manufacturer must report it— regardless of whether proof is provided, medical care was sought, or the company disagrees with the claim.

“The intent of the new law is clearly to err on the side of over-reporting to give the FDA the ability to spot trends that are out there, not to overanalyze any single event,” said Mr. Reinecke, principal of Reinecke Strategic Solutions, Bethesda, Md.

The labeling of dietary supplements will be required to include an address or telephone number consumers can use to contact the manufacturer or other responsible party, should an adverse event occur. Any product without this information on the label will be considered misbranded, Mr. Reinecke said at the meeting, which was cosponsored by the University of California, San Diego.

Manufacturers, packers, and distributors will be required to maintain for 6 years all records relating to adverse- event reports. Falsification of records will be illegal, and could lead to an injunction or criminal penalties.

The recent change of leadership in Congress is likely to result in greater efforts to ensure the safety of supplements, particularly by implementing and making final the DSHEA provision that establishes good manufacturing practices governing the preparation, packing, and holding of these products, said Mr. Reinecke, who was one of the Capitol Hill staffers involved in writing DSHEA.

“The coming year also is likely to see the biggest effort in Washington in the 20-something years I've been there to get the FDA some much-needed resources. This will be difficult given the fiscal situation in which we find ourselves, but there is strong support for this in industry and consumer groups,” he said.

LA JOLLA, CALIF. — The newly enacted Dietary Supplement and Nonprescription Drug Consumer Protection Act mandates for the first time the reporting of serious adverse events associated with dietary supplements and over-the-counter products.

The law, passed by Congress in December, is the first revision of the regulation of dietary supplements since the passage of the Dietary Supplement Health and Education Act (DSHEA) of 1994, Peter Reinecke said at a symposium on natural supplements sponsored by the Scripps Center for Integrative Medicine.

DSHEA authorized the Food and Drug Administration (FDA) to seize adulterated or misbranded products and to remove from the market products that present significant or unreasonable risk of injury or illness or pose an imminent hazard to public health or safety. It made no provision for the same type of reporting of adverse events required for pharmaceutical drugs.

But when the new law goes into effect on December 22, 2007, all manufacturers, packers, and distributors of supplements will be required to report serious adverse events to the FDA within 15 business days through the MedWatch program.

Serious adverse events are defined as those that result in death, a life-threatening experience, inpatient hospitalization, persistent or significant disability or incapacity, or a congenital abnormality or birth defect; or that require, based on reasonable medical judgment, a medical or surgical intervention to prevent one of these outcomes.

If a consumer reports that he or she has experienced a serious adverse event, the manufacturer must report it— regardless of whether proof is provided, medical care was sought, or the company disagrees with the claim.

“The intent of the new law is clearly to err on the side of over-reporting to give the FDA the ability to spot trends that are out there, not to overanalyze any single event,” said Mr. Reinecke, principal of Reinecke Strategic Solutions, Bethesda, Md.

The labeling of dietary supplements will be required to include an address or telephone number consumers can use to contact the manufacturer or other responsible party, should an adverse event occur. Any product without this information on the label will be considered misbranded, Mr. Reinecke said at the meeting, which was cosponsored by the University of California, San Diego.

Manufacturers, packers, and distributors will be required to maintain for 6 years all records relating to adverse- event reports. Falsification of records will be illegal, and could lead to an injunction or criminal penalties.

The recent change of leadership in Congress is likely to result in greater efforts to ensure the safety of supplements, particularly by implementing and making final the DSHEA provision that establishes good manufacturing practices governing the preparation, packing, and holding of these products, said Mr. Reinecke, who was one of the Capitol Hill staffers involved in writing DSHEA.

“The coming year also is likely to see the biggest effort in Washington in the 20-something years I've been there to get the FDA some much-needed resources. This will be difficult given the fiscal situation in which we find ourselves, but there is strong support for this in industry and consumer groups,” he said.

MONTREAL — Hypogonadism should be considered a risk factor for cardiovascular disease in older men, Dr. Andre T. Guay said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

He based that conclusion on an analysis of testosterone levels in 154 men with an average age of 53.5 who were seen at the erectile dysfunction (ED) clinic of the Lahey Clinic Medical Center, Peabody, Mass., where Dr. Guay is an endocrinologist.

Overall, 25% of the men had hypogonadism, defined as a free testosterone level below 10 pg/mL. Among men with low testosterone, 92.3% had insulin resistance, compared with 25.2% of those without low testosterone levels. High rates of metabolic syndrome also were seen among hypogonadal men, using both the NCEP criteria and the more stringent World Health Organization criteria for metabolic syndrome. (See box.)

In a previous study, 91% of the cohort of men seen in the ED clinic had cardiac risk factors. A total of 43% had hypertension, 73% had dyslipidemia, and 85% had a body mass index greater than 25 kg/m

Additionally, 43% of the men had metabolic syndrome, according to the National Cholesterol Education Program (NCEP) criteria, compared with 24% of the general population. Insulin resistance was found in 79%, compared with a 25% incidence in the general population.

These findings suggest that ED may be an early warning sign of cardiac disease, he said.

The new findings on hypogonadism go beyond the link between ED and cardiac risk, suggesting that low testosterone also may be associated with cardiovascular disease, according to Dr. Guay.

Several large reviews have indicated that men with low testosterone have increased cardiovascular risks, with a high incidence of metabolic syndrome and insulin resistance.

“There are associations, but that doesn't necessarily prove cause and effect,” Dr. Guay said in an interview. “However, we know that testosterone can positively affect endothelial function, increasing blood flow, and we know that even acute stimulation of testosterone can decrease insulin resistance, which is the basis of the metabolic syndrome and many chronic diseases. Testosterone must therefore have a protective effect on the vascular lining where atherosclerosis begins.”

The study findings suggest that “when patients present with ED, you should immediately look for major cardiac risks and either treat or refer for treatment. It also may be that we should be checking the testosterone level in every man with ED,” he said at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

ELSEVIER GLOBAL MEDICAL NEWS

MONTREAL — Hypogonadism should be considered a risk factor for cardiovascular disease in older men, Dr. Andre T. Guay said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

He based that conclusion on an analysis of testosterone levels in 154 men with an average age of 53.5 who were seen at the erectile dysfunction (ED) clinic of the Lahey Clinic Medical Center, Peabody, Mass., where Dr. Guay is an endocrinologist.

Overall, 25% of the men had hypogonadism, defined as a free testosterone level below 10 pg/mL. Among men with low testosterone, 92.3% had insulin resistance, compared with 25.2% of those without low testosterone levels. High rates of metabolic syndrome also were seen among hypogonadal men, using both the NCEP criteria and the more stringent World Health Organization criteria for metabolic syndrome. (See box.)

In a previous study, 91% of the cohort of men seen in the ED clinic had cardiac risk factors. A total of 43% had hypertension, 73% had dyslipidemia, and 85% had a body mass index greater than 25 kg/m

Additionally, 43% of the men had metabolic syndrome, according to the National Cholesterol Education Program (NCEP) criteria, compared with 24% of the general population. Insulin resistance was found in 79%, compared with a 25% incidence in the general population.

These findings suggest that ED may be an early warning sign of cardiac disease, he said.

The new findings on hypogonadism go beyond the link between ED and cardiac risk, suggesting that low testosterone also may be associated with cardiovascular disease, according to Dr. Guay.

Several large reviews have indicated that men with low testosterone have increased cardiovascular risks, with a high incidence of metabolic syndrome and insulin resistance.

“There are associations, but that doesn't necessarily prove cause and effect,” Dr. Guay said in an interview. “However, we know that testosterone can positively affect endothelial function, increasing blood flow, and we know that even acute stimulation of testosterone can decrease insulin resistance, which is the basis of the metabolic syndrome and many chronic diseases. Testosterone must therefore have a protective effect on the vascular lining where atherosclerosis begins.”

The study findings suggest that “when patients present with ED, you should immediately look for major cardiac risks and either treat or refer for treatment. It also may be that we should be checking the testosterone level in every man with ED,” he said at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

ELSEVIER GLOBAL MEDICAL NEWS

MONTREAL — Hypogonadism should be considered a risk factor for cardiovascular disease in older men, Dr. Andre T. Guay said at a congress sponsored by the Canadian Society for the Study of the Aging Male.

He based that conclusion on an analysis of testosterone levels in 154 men with an average age of 53.5 who were seen at the erectile dysfunction (ED) clinic of the Lahey Clinic Medical Center, Peabody, Mass., where Dr. Guay is an endocrinologist.

Overall, 25% of the men had hypogonadism, defined as a free testosterone level below 10 pg/mL. Among men with low testosterone, 92.3% had insulin resistance, compared with 25.2% of those without low testosterone levels. High rates of metabolic syndrome also were seen among hypogonadal men, using both the NCEP criteria and the more stringent World Health Organization criteria for metabolic syndrome. (See box.)

In a previous study, 91% of the cohort of men seen in the ED clinic had cardiac risk factors. A total of 43% had hypertension, 73% had dyslipidemia, and 85% had a body mass index greater than 25 kg/m

Additionally, 43% of the men had metabolic syndrome, according to the National Cholesterol Education Program (NCEP) criteria, compared with 24% of the general population. Insulin resistance was found in 79%, compared with a 25% incidence in the general population.

These findings suggest that ED may be an early warning sign of cardiac disease, he said.

The new findings on hypogonadism go beyond the link between ED and cardiac risk, suggesting that low testosterone also may be associated with cardiovascular disease, according to Dr. Guay.

Several large reviews have indicated that men with low testosterone have increased cardiovascular risks, with a high incidence of metabolic syndrome and insulin resistance.

“There are associations, but that doesn't necessarily prove cause and effect,” Dr. Guay said in an interview. “However, we know that testosterone can positively affect endothelial function, increasing blood flow, and we know that even acute stimulation of testosterone can decrease insulin resistance, which is the basis of the metabolic syndrome and many chronic diseases. Testosterone must therefore have a protective effect on the vascular lining where atherosclerosis begins.”

The study findings suggest that “when patients present with ED, you should immediately look for major cardiac risks and either treat or refer for treatment. It also may be that we should be checking the testosterone level in every man with ED,” he said at the meeting, which was cosponsored by the International Society for the Study of the Aging Male.

ELSEVIER GLOBAL MEDICAL NEWS

WASHINGTON — Women with lupus are at increased risk for thrombosis, infection, hematologic disorders, and death during pregnancy, according to data from the large National Inpatient Survey, Dr. Megan E.B. Clowse reported at the annual meeting of the American College of Rheumatology.

The National Inpatient Survey (NIS), which is administered by the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, contains data from 1,000 hospitals nationwide.

Out of more than 18.3 million pregnancy-related hospital admissions between 2000 and 2002 in the United States, 17,262 (0.01%) involved women with systemic lupus erythematosus (SLE), according to Dr. Clowse, a rheumatologist at Duke University, Durham, N.C.

Analysis of data from the NIS revealed that women with SLE who become pregnant were significantly more likely also to have other underlying medical conditions that are associated with adverse outcomes, including renal failure (odds ratio 35.8), antiphospholipid syndrome (odds ratio 31.9), hypertension (odds ratio 6.4), and diabetes (odds ratio 1.6), according to Dr. Clowse.

They were also more likely to experience complications during pregnancy (see table).

More than one-third had cesarean births, and preeclampsia was three times higher among the SLE patients than among non-SLE women, at 23%. Eclampsia developed in only a small percentage of lupus patients (0.5%), but this was still four times more common than in nonaffected women.

Moreover, women in the survey with SLE had demographic factors that may predispose them to more medical problems during pregnancy. They were older, with a mean age of 30 years, compared with 27.5 years in the general pregnancy population, and more were African American (20%) than in the general pregnancy population (14%).

The observation that pregnancy poses risks to women with SLE is not surprising, Dr. Clowse wrote in a poster session. After all, lupus itself increases the risk of death in women of reproductive age by up to 12 times, regardless of pregnancy, and also heightens the risk of infection, thrombosis, and hematologic complications.

But the absolute risk of death during pregnancy remains low, at 0.3%, while the annual mortality among SLE patients ranges from 0.8% to 3%.

“The risk of death during pregnancy may actually be lower than during nonpregnancy for SLE patients, because the sickest patients do not get pregnant,” Dr. Clowse observed.

Nonetheless, pregnancy does carry risk for patients with lupus, and they should be followed closely by a rheumatologist and an obstetrician who specializes in high-risk pregnancies.

Also, because of the risk of thrombosis, consideration should be given for all pregnant SLE patients to have prophylaxis with low-dose aspirin, she noted.

Dr. Clowse disclosed that she had no conflicts of interest.

ELSEVIER GLOBAL MEDICAL NEWS

WASHINGTON — Women with lupus are at increased risk for thrombosis, infection, hematologic disorders, and death during pregnancy, according to data from the large National Inpatient Survey, Dr. Megan E.B. Clowse reported at the annual meeting of the American College of Rheumatology.

The National Inpatient Survey (NIS), which is administered by the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, contains data from 1,000 hospitals nationwide.

Out of more than 18.3 million pregnancy-related hospital admissions between 2000 and 2002 in the United States, 17,262 (0.01%) involved women with systemic lupus erythematosus (SLE), according to Dr. Clowse, a rheumatologist at Duke University, Durham, N.C.

Analysis of data from the NIS revealed that women with SLE who become pregnant were significantly more likely also to have other underlying medical conditions that are associated with adverse outcomes, including renal failure (odds ratio 35.8), antiphospholipid syndrome (odds ratio 31.9), hypertension (odds ratio 6.4), and diabetes (odds ratio 1.6), according to Dr. Clowse.

They were also more likely to experience complications during pregnancy (see table).

More than one-third had cesarean births, and preeclampsia was three times higher among the SLE patients than among non-SLE women, at 23%. Eclampsia developed in only a small percentage of lupus patients (0.5%), but this was still four times more common than in nonaffected women.

Moreover, women in the survey with SLE had demographic factors that may predispose them to more medical problems during pregnancy. They were older, with a mean age of 30 years, compared with 27.5 years in the general pregnancy population, and more were African American (20%) than in the general pregnancy population (14%).

The observation that pregnancy poses risks to women with SLE is not surprising, Dr. Clowse wrote in a poster session. After all, lupus itself increases the risk of death in women of reproductive age by up to 12 times, regardless of pregnancy, and also heightens the risk of infection, thrombosis, and hematologic complications.

But the absolute risk of death during pregnancy remains low, at 0.3%, while the annual mortality among SLE patients ranges from 0.8% to 3%.

“The risk of death during pregnancy may actually be lower than during nonpregnancy for SLE patients, because the sickest patients do not get pregnant,” Dr. Clowse observed.

Nonetheless, pregnancy does carry risk for patients with lupus, and they should be followed closely by a rheumatologist and an obstetrician who specializes in high-risk pregnancies.

Also, because of the risk of thrombosis, consideration should be given for all pregnant SLE patients to have prophylaxis with low-dose aspirin, she noted.

Dr. Clowse disclosed that she had no conflicts of interest.

ELSEVIER GLOBAL MEDICAL NEWS

WASHINGTON — Women with lupus are at increased risk for thrombosis, infection, hematologic disorders, and death during pregnancy, according to data from the large National Inpatient Survey, Dr. Megan E.B. Clowse reported at the annual meeting of the American College of Rheumatology.

The National Inpatient Survey (NIS), which is administered by the Healthcare Cost and Utilization Project of the Agency for Healthcare Research and Quality, contains data from 1,000 hospitals nationwide.

Out of more than 18.3 million pregnancy-related hospital admissions between 2000 and 2002 in the United States, 17,262 (0.01%) involved women with systemic lupus erythematosus (SLE), according to Dr. Clowse, a rheumatologist at Duke University, Durham, N.C.

Analysis of data from the NIS revealed that women with SLE who become pregnant were significantly more likely also to have other underlying medical conditions that are associated with adverse outcomes, including renal failure (odds ratio 35.8), antiphospholipid syndrome (odds ratio 31.9), hypertension (odds ratio 6.4), and diabetes (odds ratio 1.6), according to Dr. Clowse.

They were also more likely to experience complications during pregnancy (see table).

More than one-third had cesarean births, and preeclampsia was three times higher among the SLE patients than among non-SLE women, at 23%. Eclampsia developed in only a small percentage of lupus patients (0.5%), but this was still four times more common than in nonaffected women.

Moreover, women in the survey with SLE had demographic factors that may predispose them to more medical problems during pregnancy. They were older, with a mean age of 30 years, compared with 27.5 years in the general pregnancy population, and more were African American (20%) than in the general pregnancy population (14%).

The observation that pregnancy poses risks to women with SLE is not surprising, Dr. Clowse wrote in a poster session. After all, lupus itself increases the risk of death in women of reproductive age by up to 12 times, regardless of pregnancy, and also heightens the risk of infection, thrombosis, and hematologic complications.

But the absolute risk of death during pregnancy remains low, at 0.3%, while the annual mortality among SLE patients ranges from 0.8% to 3%.

“The risk of death during pregnancy may actually be lower than during nonpregnancy for SLE patients, because the sickest patients do not get pregnant,” Dr. Clowse observed.

Nonetheless, pregnancy does carry risk for patients with lupus, and they should be followed closely by a rheumatologist and an obstetrician who specializes in high-risk pregnancies.

Also, because of the risk of thrombosis, consideration should be given for all pregnant SLE patients to have prophylaxis with low-dose aspirin, she noted.

Dr. Clowse disclosed that she had no conflicts of interest.

ELSEVIER GLOBAL MEDICAL NEWS

GLASGOW, SCOTLAND — Because the presenting symptoms of systemic lupus erythematosus are manifold, may mimic other disorders, and can evolve over time, assembling the diagnostic puzzle sometimes requires digging into the patient's past, according to Dr. Hala Y. Sadik.

This is particularly the case when the onset is acute, as happened in a case seen by Dr. Sadik of the University of Liverpool Academic Rheumatology Unit, University Hospital Aintree, Liverpool, England.

In August 2005, a 57-year-old woman presented with hypothermia, bradycardia, confusion, a low score on the Glasgow coma scale, and hyponatremia. Plasma sodium was low, at 120 mmol/L; plasma osmolality was low, at 235 mosmol/kg; and urinary sodium and osmolality were high. The diagnosis of syndrome of inappropriate antidiuretic hormone secretion was made, Dr. Sadik wrote in a poster session at the annual meeting of the British Society for Rheumatology. Initial management included fluid restriction and administration of double-strength normal saline, which normalized the plasma sodium level.

Initial MRI of the head raised the possibility of neurosarcoidosis, but serum angiotensin-converting enzyme levels and chest x-ray were normal.

A repeat MRI with gadolinium suggested demyelinating disease or systemic lupus erythematosus. Immunology profile findings included positive antinuclear antibody (ANA) and double-stranded DNA antibody. Thrombocytopenia and lymphopenia also were present.

At this point, her previous case records were located at another hospital. These revealed that she had been admitted in 1992 with a 2-week history of arthralgias, Raynaud's phenomenon, thrombocytopenia, lymphopenia, and positive ANA.

A diagnosis of lupus had been considered at that time, and she was followed for several years as an outpatient, but ANA remained weakly positive and double-stranded DNA was persistently negative, so the diagnosis had been dismissed, Dr. Sadik wrote.

With improvements on the Glasgow coma scale during her current admission, it became apparent that the patient was profoundly depressed, so she was treated with mirtazapine. Following a diagnosis of neuropsychiatric lupus, she began treatment with intravenous methylprednisolone and cyclophosphamide.

Significant improvements were seen in her disabling depression, and her hematologic parameters normalized, according to Dr. Sadik.

This case highlights the necessity for careful review of medical history and investigation results in any case where acute nonspecific symptoms might represent neuropsychiatric lupus, she said.

GLASGOW, SCOTLAND — Because the presenting symptoms of systemic lupus erythematosus are manifold, may mimic other disorders, and can evolve over time, assembling the diagnostic puzzle sometimes requires digging into the patient's past, according to Dr. Hala Y. Sadik.

This is particularly the case when the onset is acute, as happened in a case seen by Dr. Sadik of the University of Liverpool Academic Rheumatology Unit, University Hospital Aintree, Liverpool, England.

In August 2005, a 57-year-old woman presented with hypothermia, bradycardia, confusion, a low score on the Glasgow coma scale, and hyponatremia. Plasma sodium was low, at 120 mmol/L; plasma osmolality was low, at 235 mosmol/kg; and urinary sodium and osmolality were high. The diagnosis of syndrome of inappropriate antidiuretic hormone secretion was made, Dr. Sadik wrote in a poster session at the annual meeting of the British Society for Rheumatology. Initial management included fluid restriction and administration of double-strength normal saline, which normalized the plasma sodium level.

Initial MRI of the head raised the possibility of neurosarcoidosis, but serum angiotensin-converting enzyme levels and chest x-ray were normal.

A repeat MRI with gadolinium suggested demyelinating disease or systemic lupus erythematosus. Immunology profile findings included positive antinuclear antibody (ANA) and double-stranded DNA antibody. Thrombocytopenia and lymphopenia also were present.

At this point, her previous case records were located at another hospital. These revealed that she had been admitted in 1992 with a 2-week history of arthralgias, Raynaud's phenomenon, thrombocytopenia, lymphopenia, and positive ANA.

A diagnosis of lupus had been considered at that time, and she was followed for several years as an outpatient, but ANA remained weakly positive and double-stranded DNA was persistently negative, so the diagnosis had been dismissed, Dr. Sadik wrote.

With improvements on the Glasgow coma scale during her current admission, it became apparent that the patient was profoundly depressed, so she was treated with mirtazapine. Following a diagnosis of neuropsychiatric lupus, she began treatment with intravenous methylprednisolone and cyclophosphamide.

Significant improvements were seen in her disabling depression, and her hematologic parameters normalized, according to Dr. Sadik.

This case highlights the necessity for careful review of medical history and investigation results in any case where acute nonspecific symptoms might represent neuropsychiatric lupus, she said.

GLASGOW, SCOTLAND — Because the presenting symptoms of systemic lupus erythematosus are manifold, may mimic other disorders, and can evolve over time, assembling the diagnostic puzzle sometimes requires digging into the patient's past, according to Dr. Hala Y. Sadik.

This is particularly the case when the onset is acute, as happened in a case seen by Dr. Sadik of the University of Liverpool Academic Rheumatology Unit, University Hospital Aintree, Liverpool, England.

In August 2005, a 57-year-old woman presented with hypothermia, bradycardia, confusion, a low score on the Glasgow coma scale, and hyponatremia. Plasma sodium was low, at 120 mmol/L; plasma osmolality was low, at 235 mosmol/kg; and urinary sodium and osmolality were high. The diagnosis of syndrome of inappropriate antidiuretic hormone secretion was made, Dr. Sadik wrote in a poster session at the annual meeting of the British Society for Rheumatology. Initial management included fluid restriction and administration of double-strength normal saline, which normalized the plasma sodium level.

Initial MRI of the head raised the possibility of neurosarcoidosis, but serum angiotensin-converting enzyme levels and chest x-ray were normal.

A repeat MRI with gadolinium suggested demyelinating disease or systemic lupus erythematosus. Immunology profile findings included positive antinuclear antibody (ANA) and double-stranded DNA antibody. Thrombocytopenia and lymphopenia also were present.

At this point, her previous case records were located at another hospital. These revealed that she had been admitted in 1992 with a 2-week history of arthralgias, Raynaud's phenomenon, thrombocytopenia, lymphopenia, and positive ANA.

A diagnosis of lupus had been considered at that time, and she was followed for several years as an outpatient, but ANA remained weakly positive and double-stranded DNA was persistently negative, so the diagnosis had been dismissed, Dr. Sadik wrote.

With improvements on the Glasgow coma scale during her current admission, it became apparent that the patient was profoundly depressed, so she was treated with mirtazapine. Following a diagnosis of neuropsychiatric lupus, she began treatment with intravenous methylprednisolone and cyclophosphamide.

Significant improvements were seen in her disabling depression, and her hematologic parameters normalized, according to Dr. Sadik.

This case highlights the necessity for careful review of medical history and investigation results in any case where acute nonspecific symptoms might represent neuropsychiatric lupus, she said.

The world's largest database on scleroderma, which now includes 5,500 patients from more than 100 centers on five continents, has begun to yield data that may more clearly delineate the evolution and variability of the disease and help assess risk for systemic organ involvement.

Currently, systemic sclerosis (SSc) is classified into diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) subsets according to degree and severity of skin involvement. This classification is inadequate, however, for predicting organ involvement, which is now crucial with the availability of targeted therapies that can alter outcomes, according to Dr. Ulrich A. Walker of the department of rheumatology, Basel University, Switzerland, and his colleagues.

With the goal of developing a more comprehensive disease classification system that better reflects the vascular, immunologic, and fibrotic processes that result in organ damage in SSc, the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) database was formed in 2004. The group has now published its initial report, analyzing the association of various demographic, clinical, and laboratory factors with systemic organ involvement (Ann. Rheum. Dis. 2007 Feb. 1 [Epub doi:10.1136/ard.2006.062901]).

At the data cutoff point for this first report in April 2006, 3,656 patients had been enrolled. A total of 1,349 (40%) were classified as dcSSc, with skin thickening extending proximal to the elbows and knees or with involvement of the trunk, and 2,101 (58%) as lcSSc, with skin involvement limited to the distal extremities and face.

The remaining 206 (6%) had scleroderma in combination with another connective tissue disease, according to the investigators. Among the SSc-associated autoantibodies detected were Scl70 autoantibodies in 1,330 patients and anticentromere autoantibodies (ACA) in 1,106, according to database findings reported by Dr. Walker and his associates.

Patients with dcSSc and those with lcSSc had the same mean age of onset of Raynaud's phenomenon, at 43 years, the investigators reported. The age of the first non-Raynaud's manifestation differed, however, being 45 years in dcSSc and 48 years in lcSSc. The mean modified Rodnan's skin score was 19 in the dcSSc group and 8.1 in the lcSSc group. Onset of disease was earlier in women, and early onset was associated with a decreased prevalence of severe organ involvement such as pulmonary fibrosis and pulmonary arterial hypertension, they noted.

Upon multivariate analysis, disease subset, antibody status, and age at onset of Raynaud's phenomenon all were independently associated with organ manifestations, but autoantibody status was associated with 15 organ manifestations and clinical subtype was associated with only 11 organ complications.

“The most important finding in this analysis was that antibody status is more predictive of individual disease presentation than is the disease subtype,” said Dr. Walker in an interview.

Other findings that emerged from the analysis included the observation that 88.7% of patients who were positive for ACA had lcSSc, as did 36.1% of those who were anti-Scl70 positive.

Although there was no difference in mean age of onset of Raynaud's phenomenon between patients who were ACA positive and those who were anti-Scl70 positive, those with ACA had a longer mean lag period of 6.5 years before the onset of non-Raynaud's manifestations than did those with antiScl70, whose mean lag period was 2.4 years.

The database does not yet contain information on treatment and outcomes. This will be included when the database goes online, which is expected in approximately 6 months, Dr. Walker said.

The majority of participating clinics are in Europe, but three centers in the United States have enrolled patients, he added.

The world's largest database on scleroderma, which now includes 5,500 patients from more than 100 centers on five continents, has begun to yield data that may more clearly delineate the evolution and variability of the disease and help assess risk for systemic organ involvement.

Currently, systemic sclerosis (SSc) is classified into diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) subsets according to degree and severity of skin involvement. This classification is inadequate, however, for predicting organ involvement, which is now crucial with the availability of targeted therapies that can alter outcomes, according to Dr. Ulrich A. Walker of the department of rheumatology, Basel University, Switzerland, and his colleagues.

With the goal of developing a more comprehensive disease classification system that better reflects the vascular, immunologic, and fibrotic processes that result in organ damage in SSc, the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) database was formed in 2004. The group has now published its initial report, analyzing the association of various demographic, clinical, and laboratory factors with systemic organ involvement (Ann. Rheum. Dis. 2007 Feb. 1 [Epub doi:10.1136/ard.2006.062901]).

At the data cutoff point for this first report in April 2006, 3,656 patients had been enrolled. A total of 1,349 (40%) were classified as dcSSc, with skin thickening extending proximal to the elbows and knees or with involvement of the trunk, and 2,101 (58%) as lcSSc, with skin involvement limited to the distal extremities and face.

The remaining 206 (6%) had scleroderma in combination with another connective tissue disease, according to the investigators. Among the SSc-associated autoantibodies detected were Scl70 autoantibodies in 1,330 patients and anticentromere autoantibodies (ACA) in 1,106, according to database findings reported by Dr. Walker and his associates.

Patients with dcSSc and those with lcSSc had the same mean age of onset of Raynaud's phenomenon, at 43 years, the investigators reported. The age of the first non-Raynaud's manifestation differed, however, being 45 years in dcSSc and 48 years in lcSSc. The mean modified Rodnan's skin score was 19 in the dcSSc group and 8.1 in the lcSSc group. Onset of disease was earlier in women, and early onset was associated with a decreased prevalence of severe organ involvement such as pulmonary fibrosis and pulmonary arterial hypertension, they noted.

Upon multivariate analysis, disease subset, antibody status, and age at onset of Raynaud's phenomenon all were independently associated with organ manifestations, but autoantibody status was associated with 15 organ manifestations and clinical subtype was associated with only 11 organ complications.

“The most important finding in this analysis was that antibody status is more predictive of individual disease presentation than is the disease subtype,” said Dr. Walker in an interview.

Other findings that emerged from the analysis included the observation that 88.7% of patients who were positive for ACA had lcSSc, as did 36.1% of those who were anti-Scl70 positive.

Although there was no difference in mean age of onset of Raynaud's phenomenon between patients who were ACA positive and those who were anti-Scl70 positive, those with ACA had a longer mean lag period of 6.5 years before the onset of non-Raynaud's manifestations than did those with antiScl70, whose mean lag period was 2.4 years.

The database does not yet contain information on treatment and outcomes. This will be included when the database goes online, which is expected in approximately 6 months, Dr. Walker said.

The majority of participating clinics are in Europe, but three centers in the United States have enrolled patients, he added.

The world's largest database on scleroderma, which now includes 5,500 patients from more than 100 centers on five continents, has begun to yield data that may more clearly delineate the evolution and variability of the disease and help assess risk for systemic organ involvement.

Currently, systemic sclerosis (SSc) is classified into diffuse cutaneous (dcSSc) and limited cutaneous (lcSSc) subsets according to degree and severity of skin involvement. This classification is inadequate, however, for predicting organ involvement, which is now crucial with the availability of targeted therapies that can alter outcomes, according to Dr. Ulrich A. Walker of the department of rheumatology, Basel University, Switzerland, and his colleagues.

With the goal of developing a more comprehensive disease classification system that better reflects the vascular, immunologic, and fibrotic processes that result in organ damage in SSc, the European League Against Rheumatism (EULAR) Scleroderma Trials and Research (EUSTAR) database was formed in 2004. The group has now published its initial report, analyzing the association of various demographic, clinical, and laboratory factors with systemic organ involvement (Ann. Rheum. Dis. 2007 Feb. 1 [Epub doi:10.1136/ard.2006.062901]).

At the data cutoff point for this first report in April 2006, 3,656 patients had been enrolled. A total of 1,349 (40%) were classified as dcSSc, with skin thickening extending proximal to the elbows and knees or with involvement of the trunk, and 2,101 (58%) as lcSSc, with skin involvement limited to the distal extremities and face.

The remaining 206 (6%) had scleroderma in combination with another connective tissue disease, according to the investigators. Among the SSc-associated autoantibodies detected were Scl70 autoantibodies in 1,330 patients and anticentromere autoantibodies (ACA) in 1,106, according to database findings reported by Dr. Walker and his associates.

Patients with dcSSc and those with lcSSc had the same mean age of onset of Raynaud's phenomenon, at 43 years, the investigators reported. The age of the first non-Raynaud's manifestation differed, however, being 45 years in dcSSc and 48 years in lcSSc. The mean modified Rodnan's skin score was 19 in the dcSSc group and 8.1 in the lcSSc group. Onset of disease was earlier in women, and early onset was associated with a decreased prevalence of severe organ involvement such as pulmonary fibrosis and pulmonary arterial hypertension, they noted.

Upon multivariate analysis, disease subset, antibody status, and age at onset of Raynaud's phenomenon all were independently associated with organ manifestations, but autoantibody status was associated with 15 organ manifestations and clinical subtype was associated with only 11 organ complications.

“The most important finding in this analysis was that antibody status is more predictive of individual disease presentation than is the disease subtype,” said Dr. Walker in an interview.

Other findings that emerged from the analysis included the observation that 88.7% of patients who were positive for ACA had lcSSc, as did 36.1% of those who were anti-Scl70 positive.

Although there was no difference in mean age of onset of Raynaud's phenomenon between patients who were ACA positive and those who were anti-Scl70 positive, those with ACA had a longer mean lag period of 6.5 years before the onset of non-Raynaud's manifestations than did those with antiScl70, whose mean lag period was 2.4 years.

The database does not yet contain information on treatment and outcomes. This will be included when the database goes online, which is expected in approximately 6 months, Dr. Walker said.

The majority of participating clinics are in Europe, but three centers in the United States have enrolled patients, he added.