CHICAGO — An apparent defect in Ras signaling in lupus patients' T cells contributes to sustained expression of CD40 ligand and may provide a target to suppress disease activity, Dilrukshie Cooray, M.D., reported at the combined annual meeting of the Central Society for Clinical Research and the Midwestern section of the American Federation for Medical Research.

Previous evidence suggested that a defect in the downregulation of the Ras pathway in lupus T cells led to the failure to develop anergy and to an abnormally prolonged expression of CD40 ligand (CD40L) (Arthritis Rheum. 2001;44:397–407).

Working on that hypothesis, Dr. Cooray and colleagues performed immunocytochemistry to test freshly isolated lymphocytes from patients with SLE and healthy controls before and after inactivation of Ras with the Ras inhibitor S-farnesylthiosalicylic acid.

They found that Ras inactivation markedly decreased the level of CD40L in T cells obtained from patients with lupus but not from healthy subjects.

“Our preliminary results support the hypothesis that there is an intrinsic defect in Ras signaling in lupus patients' T cells that contributes to sustained expression of CD40L,” reported Dr. Cooray of the rheumatology department at Loma Linda (Calif.) University. “By suppressing levels of CD40L, we think we are able to suppress disease activity.”

Because the researchers tested only six patients, it's not clear what level of CD40L is necessary for suppression of disease activity.

CHICAGO — An apparent defect in Ras signaling in lupus patients' T cells contributes to sustained expression of CD40 ligand and may provide a target to suppress disease activity, Dilrukshie Cooray, M.D., reported at the combined annual meeting of the Central Society for Clinical Research and the Midwestern section of the American Federation for Medical Research.

Previous evidence suggested that a defect in the downregulation of the Ras pathway in lupus T cells led to the failure to develop anergy and to an abnormally prolonged expression of CD40 ligand (CD40L) (Arthritis Rheum. 2001;44:397–407).

Working on that hypothesis, Dr. Cooray and colleagues performed immunocytochemistry to test freshly isolated lymphocytes from patients with SLE and healthy controls before and after inactivation of Ras with the Ras inhibitor S-farnesylthiosalicylic acid.

They found that Ras inactivation markedly decreased the level of CD40L in T cells obtained from patients with lupus but not from healthy subjects.

“Our preliminary results support the hypothesis that there is an intrinsic defect in Ras signaling in lupus patients' T cells that contributes to sustained expression of CD40L,” reported Dr. Cooray of the rheumatology department at Loma Linda (Calif.) University. “By suppressing levels of CD40L, we think we are able to suppress disease activity.”

Because the researchers tested only six patients, it's not clear what level of CD40L is necessary for suppression of disease activity.

CHICAGO — An apparent defect in Ras signaling in lupus patients' T cells contributes to sustained expression of CD40 ligand and may provide a target to suppress disease activity, Dilrukshie Cooray, M.D., reported at the combined annual meeting of the Central Society for Clinical Research and the Midwestern section of the American Federation for Medical Research.

Previous evidence suggested that a defect in the downregulation of the Ras pathway in lupus T cells led to the failure to develop anergy and to an abnormally prolonged expression of CD40 ligand (CD40L) (Arthritis Rheum. 2001;44:397–407).

Working on that hypothesis, Dr. Cooray and colleagues performed immunocytochemistry to test freshly isolated lymphocytes from patients with SLE and healthy controls before and after inactivation of Ras with the Ras inhibitor S-farnesylthiosalicylic acid.

They found that Ras inactivation markedly decreased the level of CD40L in T cells obtained from patients with lupus but not from healthy subjects.

“Our preliminary results support the hypothesis that there is an intrinsic defect in Ras signaling in lupus patients' T cells that contributes to sustained expression of CD40L,” reported Dr. Cooray of the rheumatology department at Loma Linda (Calif.) University. “By suppressing levels of CD40L, we think we are able to suppress disease activity.”

Because the researchers tested only six patients, it's not clear what level of CD40L is necessary for suppression of disease activity.

BIRMINGHAM, ENGLAND — Increased understanding of the molecular mechanisms of glucocorticoids may eventually lead to the development of new agents that provide the clinical benefits without the attendant side effects that currently hamper the use of these drugs in rheumatic diseases.

It is now known that the anti-inflammatory and immunosuppressive effects of glucocorticoids primarily function via a process of negative regulation of gene expression, or transrepression, Frank Buttgereit, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

“Glucocorticoids are very lipophilic molecules and are able to penetrate the cell membrane and bind to the cytosolic glucocorticoid receptor complex, which becomes activated and moves into the nucleus where it binds to specific DNA sites,” he explained. The result is upregulation of anti-inflammatory proteins and downregulation of inflammatory molecules such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, he said.

An example of glucocorticoid transrepression is the effect on bone metabolism. “We currently think that TNF-α and IL-1 are able to induce osteoclasts and T cells to produce RANK ligand, which binds to the RANK receptor on osteoclast precursor cells and to the RANK receptor of the osteoclast,” he said. This results in an induced maturation of precursor cells into mature, very aggressive osteoclasts responsible for bone erosion and progression of osteoporosis. Downregulation of the TNF-α and IL-1 through transrepression retards these effects, he said.

While the benefits of these drugs stem from the genomic effects of transrepression, many of the unwanted cardiovascular, endocrine, and metabolic effects are mediated by a separate genomic process known as transactivation, said Dr. Buttgereit of the department of rheumatology and clinical immunology, University Hospital of Humboldt University, Berlin. Certain enzymes involved in the development of diabetes, for example, are activated at the genomic level by glucocorticoids, and an ongoing research effort is intended to create designer glucocorticoids that preferentially induce transrepression and have little or no transactivating activity—obtaining the benefit without the adverse effects.

These agents, several of which have been developed, are known as selective glucocorticoid receptor agonists (SEGRAs). One of these compounds, AK 216348, has been shown in animal studies to have anti-inflammatory effects equivalent to those of prednisone but with fewer transactivating effects, Dr. Buttgereit said.

Drugs of a second type of compound that has been developed are known as nitric oxide glucocorticoids or nitrosteroids. These not only bind to the glucocorticoid receptor but also slowly release nitric oxide, resulting in synergistic anti-inflammatory effects. In vitro studies of a prototype nitrosteroid, NCX-1015, have suggested that, unlike prednisone, it does not activate unwanted osteoclast activity (Rheum. Dis. Clin. North. Am. 2005;31:1–17).

Further preclinical work and then clinical trials will be needed to determine if these preliminary findings hold up, Dr. Buttgereit said.

BIRMINGHAM, ENGLAND — Increased understanding of the molecular mechanisms of glucocorticoids may eventually lead to the development of new agents that provide the clinical benefits without the attendant side effects that currently hamper the use of these drugs in rheumatic diseases.

It is now known that the anti-inflammatory and immunosuppressive effects of glucocorticoids primarily function via a process of negative regulation of gene expression, or transrepression, Frank Buttgereit, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

“Glucocorticoids are very lipophilic molecules and are able to penetrate the cell membrane and bind to the cytosolic glucocorticoid receptor complex, which becomes activated and moves into the nucleus where it binds to specific DNA sites,” he explained. The result is upregulation of anti-inflammatory proteins and downregulation of inflammatory molecules such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, he said.

An example of glucocorticoid transrepression is the effect on bone metabolism. “We currently think that TNF-α and IL-1 are able to induce osteoclasts and T cells to produce RANK ligand, which binds to the RANK receptor on osteoclast precursor cells and to the RANK receptor of the osteoclast,” he said. This results in an induced maturation of precursor cells into mature, very aggressive osteoclasts responsible for bone erosion and progression of osteoporosis. Downregulation of the TNF-α and IL-1 through transrepression retards these effects, he said.

While the benefits of these drugs stem from the genomic effects of transrepression, many of the unwanted cardiovascular, endocrine, and metabolic effects are mediated by a separate genomic process known as transactivation, said Dr. Buttgereit of the department of rheumatology and clinical immunology, University Hospital of Humboldt University, Berlin. Certain enzymes involved in the development of diabetes, for example, are activated at the genomic level by glucocorticoids, and an ongoing research effort is intended to create designer glucocorticoids that preferentially induce transrepression and have little or no transactivating activity—obtaining the benefit without the adverse effects.

These agents, several of which have been developed, are known as selective glucocorticoid receptor agonists (SEGRAs). One of these compounds, AK 216348, has been shown in animal studies to have anti-inflammatory effects equivalent to those of prednisone but with fewer transactivating effects, Dr. Buttgereit said.

Drugs of a second type of compound that has been developed are known as nitric oxide glucocorticoids or nitrosteroids. These not only bind to the glucocorticoid receptor but also slowly release nitric oxide, resulting in synergistic anti-inflammatory effects. In vitro studies of a prototype nitrosteroid, NCX-1015, have suggested that, unlike prednisone, it does not activate unwanted osteoclast activity (Rheum. Dis. Clin. North. Am. 2005;31:1–17).

Further preclinical work and then clinical trials will be needed to determine if these preliminary findings hold up, Dr. Buttgereit said.

BIRMINGHAM, ENGLAND — Increased understanding of the molecular mechanisms of glucocorticoids may eventually lead to the development of new agents that provide the clinical benefits without the attendant side effects that currently hamper the use of these drugs in rheumatic diseases.

It is now known that the anti-inflammatory and immunosuppressive effects of glucocorticoids primarily function via a process of negative regulation of gene expression, or transrepression, Frank Buttgereit, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

“Glucocorticoids are very lipophilic molecules and are able to penetrate the cell membrane and bind to the cytosolic glucocorticoid receptor complex, which becomes activated and moves into the nucleus where it binds to specific DNA sites,” he explained. The result is upregulation of anti-inflammatory proteins and downregulation of inflammatory molecules such as interleukin (IL)-1 and tumor necrosis factor (TNF)-α, he said.

An example of glucocorticoid transrepression is the effect on bone metabolism. “We currently think that TNF-α and IL-1 are able to induce osteoclasts and T cells to produce RANK ligand, which binds to the RANK receptor on osteoclast precursor cells and to the RANK receptor of the osteoclast,” he said. This results in an induced maturation of precursor cells into mature, very aggressive osteoclasts responsible for bone erosion and progression of osteoporosis. Downregulation of the TNF-α and IL-1 through transrepression retards these effects, he said.

While the benefits of these drugs stem from the genomic effects of transrepression, many of the unwanted cardiovascular, endocrine, and metabolic effects are mediated by a separate genomic process known as transactivation, said Dr. Buttgereit of the department of rheumatology and clinical immunology, University Hospital of Humboldt University, Berlin. Certain enzymes involved in the development of diabetes, for example, are activated at the genomic level by glucocorticoids, and an ongoing research effort is intended to create designer glucocorticoids that preferentially induce transrepression and have little or no transactivating activity—obtaining the benefit without the adverse effects.

These agents, several of which have been developed, are known as selective glucocorticoid receptor agonists (SEGRAs). One of these compounds, AK 216348, has been shown in animal studies to have anti-inflammatory effects equivalent to those of prednisone but with fewer transactivating effects, Dr. Buttgereit said.

Drugs of a second type of compound that has been developed are known as nitric oxide glucocorticoids or nitrosteroids. These not only bind to the glucocorticoid receptor but also slowly release nitric oxide, resulting in synergistic anti-inflammatory effects. In vitro studies of a prototype nitrosteroid, NCX-1015, have suggested that, unlike prednisone, it does not activate unwanted osteoclast activity (Rheum. Dis. Clin. North. Am. 2005;31:1–17).

Further preclinical work and then clinical trials will be needed to determine if these preliminary findings hold up, Dr. Buttgereit said.

MIAMI BEACH — The off-label use of immunosuppressive agents for myasthenia gravis can significantly decrease the need for steroids, while improving symptoms.

However, compared with prednisone, other immunosuppressants are much more expensive and carry their own risks of adverse events, so their use should be carefully evaluated on a case-by-case basis, Gil Wolfe, M.D., said at the annual meeting of the American Academy of Neurology.

Since acetylcholinesterase inhibitor monotherapy controls the symptoms of no more than 40% of myasthenia gravis (MG) patients, most patients will end up taking prednisone or other immunosuppressive agents, either alone or in combination, said Dr. Wolfe, a neurologist and codirector of the Muscular Dystrophy Association clinic at the University of Texas Southwestern Medical Center in Dallas.

▸ Prednisone—started low and slowly titrated, and tapered down very slowly after symptom improvement—is the most commonly used regimen. But few patients will be able to taper off prednisone completely; the rest will require long-term, low-dose therapy. Other immunosuppressants may be added to prednisone to act as steroid-sparing agents and to assist in successful prednisone discontinuation, Dr. Wolfe said.

▸ Azathioprine is used as a steroid-sparing agent for patients who relapse during a prednisone taper and for those who have adverse events during long-term steroid use. “Up to 90% of patients respond well to [azathioprine], if they can tolerate it,” he said. “In those who can, it can reduce steroid consumption by up to 80% by 2 years.” One small study concluded that 63% of those who took azathioprine for 36 months had completely tapered off prednisone, compared with 20% of those who took prednisone alone.

The major cause for discontinuation is a flulike reaction, seen in 10%–20% of patients. The drug also has a long onset of action—maximum benefit may not be seen for up to 2 years.

▸ Cyclosporine works more rapidly, with maximum benefit seen by 3 months. Patients who are refractory to other agents may respond to cyclosporine; this drug is as effective as azathioprine in symptom improvement, judging from the findings of a recent study. However, cyclosporine is less well tolerated than azathioprine, and some studies suggest that about half of patients discontinue the medication because of adverse events.

“It's important not to mix different cyclosporine preparations, because the different brands are not bioequivalent,” Dr. Wolfe added.

▸ Mycophenolate mofetil has shown promise as the newest immunosuppressive agent commonly used for MG, he said. A recent open-label study showed that 73% of patients achieved pharmacologic remission, minimal manifestation status, or symptom improvement with mycophenolate. The drug has a rapid onset of action, with improvement seen in 9–11 weeks and maximum effect by 6 months. “You may be able to decrease steroids by up to 50% in most patients with this drug,” Dr. Wolfe said.

Mycophenolate is well tolerated. Its main adverse events are diarrhea, vomiting, increased risk of infection, and rarely, leukopenia; only about 6% of patients discontinue the drug because of an adverse event. Switching to dosing three times daily may decrease the incidence of diarrhea.

▸ Cyclophosphamide is used mainly for refractory MG patients. “This drug has a lot of potential for adverse events,” Dr. Wolfe said. “But IV pulse therapy looks like it could be safer than daily oral therapy, because there is a lower cumulative dose.” However, cyclophosphamide should be considered a third-line therapy.

▸ Intravenous gamma globulin is employed as a lower-risk alternative to plasma exchange. An analysis of eight retrospective studies indicated that 73% of patients responded well to intravenous gamma globulin, and did so very quickly—in about 4–5 days. The beneficial effects can last up to several months. “IV gamma globulin is a particularly attractive alternative to plasma exchange for patients with poor venous access, hemodynamic instability, or other contraindications to plasmapheresis,” he said.

▸ Investigational agents include tacrolimus, rituximab, and monarsen. Tacrolimus has demonstrated efficacy as a monotherapy or in combination with corticosteroids, in a few recent open trials. It has a similar mechanism of action to cyclosporine but appears less nephrotoxic. However, hyperglycemia may occur. Rituximab has been reported in just a few MG cases and was associated with substantial clinical improvement at 4 weeks and with no complications or adverse events. Monarsen is being investigated in preliminary MG studies. In an open trial of 16 patients, 15 who discontinued the antiacetylcholinesterase pyridostigmine demonstrated improvement while using monarsen.

MIAMI BEACH — The off-label use of immunosuppressive agents for myasthenia gravis can significantly decrease the need for steroids, while improving symptoms.

However, compared with prednisone, other immunosuppressants are much more expensive and carry their own risks of adverse events, so their use should be carefully evaluated on a case-by-case basis, Gil Wolfe, M.D., said at the annual meeting of the American Academy of Neurology.

Since acetylcholinesterase inhibitor monotherapy controls the symptoms of no more than 40% of myasthenia gravis (MG) patients, most patients will end up taking prednisone or other immunosuppressive agents, either alone or in combination, said Dr. Wolfe, a neurologist and codirector of the Muscular Dystrophy Association clinic at the University of Texas Southwestern Medical Center in Dallas.

▸ Prednisone—started low and slowly titrated, and tapered down very slowly after symptom improvement—is the most commonly used regimen. But few patients will be able to taper off prednisone completely; the rest will require long-term, low-dose therapy. Other immunosuppressants may be added to prednisone to act as steroid-sparing agents and to assist in successful prednisone discontinuation, Dr. Wolfe said.

▸ Azathioprine is used as a steroid-sparing agent for patients who relapse during a prednisone taper and for those who have adverse events during long-term steroid use. “Up to 90% of patients respond well to [azathioprine], if they can tolerate it,” he said. “In those who can, it can reduce steroid consumption by up to 80% by 2 years.” One small study concluded that 63% of those who took azathioprine for 36 months had completely tapered off prednisone, compared with 20% of those who took prednisone alone.

The major cause for discontinuation is a flulike reaction, seen in 10%–20% of patients. The drug also has a long onset of action—maximum benefit may not be seen for up to 2 years.

▸ Cyclosporine works more rapidly, with maximum benefit seen by 3 months. Patients who are refractory to other agents may respond to cyclosporine; this drug is as effective as azathioprine in symptom improvement, judging from the findings of a recent study. However, cyclosporine is less well tolerated than azathioprine, and some studies suggest that about half of patients discontinue the medication because of adverse events.

“It's important not to mix different cyclosporine preparations, because the different brands are not bioequivalent,” Dr. Wolfe added.

▸ Mycophenolate mofetil has shown promise as the newest immunosuppressive agent commonly used for MG, he said. A recent open-label study showed that 73% of patients achieved pharmacologic remission, minimal manifestation status, or symptom improvement with mycophenolate. The drug has a rapid onset of action, with improvement seen in 9–11 weeks and maximum effect by 6 months. “You may be able to decrease steroids by up to 50% in most patients with this drug,” Dr. Wolfe said.

Mycophenolate is well tolerated. Its main adverse events are diarrhea, vomiting, increased risk of infection, and rarely, leukopenia; only about 6% of patients discontinue the drug because of an adverse event. Switching to dosing three times daily may decrease the incidence of diarrhea.

▸ Cyclophosphamide is used mainly for refractory MG patients. “This drug has a lot of potential for adverse events,” Dr. Wolfe said. “But IV pulse therapy looks like it could be safer than daily oral therapy, because there is a lower cumulative dose.” However, cyclophosphamide should be considered a third-line therapy.

▸ Intravenous gamma globulin is employed as a lower-risk alternative to plasma exchange. An analysis of eight retrospective studies indicated that 73% of patients responded well to intravenous gamma globulin, and did so very quickly—in about 4–5 days. The beneficial effects can last up to several months. “IV gamma globulin is a particularly attractive alternative to plasma exchange for patients with poor venous access, hemodynamic instability, or other contraindications to plasmapheresis,” he said.

▸ Investigational agents include tacrolimus, rituximab, and monarsen. Tacrolimus has demonstrated efficacy as a monotherapy or in combination with corticosteroids, in a few recent open trials. It has a similar mechanism of action to cyclosporine but appears less nephrotoxic. However, hyperglycemia may occur. Rituximab has been reported in just a few MG cases and was associated with substantial clinical improvement at 4 weeks and with no complications or adverse events. Monarsen is being investigated in preliminary MG studies. In an open trial of 16 patients, 15 who discontinued the antiacetylcholinesterase pyridostigmine demonstrated improvement while using monarsen.

MIAMI BEACH — The off-label use of immunosuppressive agents for myasthenia gravis can significantly decrease the need for steroids, while improving symptoms.

However, compared with prednisone, other immunosuppressants are much more expensive and carry their own risks of adverse events, so their use should be carefully evaluated on a case-by-case basis, Gil Wolfe, M.D., said at the annual meeting of the American Academy of Neurology.

Since acetylcholinesterase inhibitor monotherapy controls the symptoms of no more than 40% of myasthenia gravis (MG) patients, most patients will end up taking prednisone or other immunosuppressive agents, either alone or in combination, said Dr. Wolfe, a neurologist and codirector of the Muscular Dystrophy Association clinic at the University of Texas Southwestern Medical Center in Dallas.

▸ Prednisone—started low and slowly titrated, and tapered down very slowly after symptom improvement—is the most commonly used regimen. But few patients will be able to taper off prednisone completely; the rest will require long-term, low-dose therapy. Other immunosuppressants may be added to prednisone to act as steroid-sparing agents and to assist in successful prednisone discontinuation, Dr. Wolfe said.

▸ Azathioprine is used as a steroid-sparing agent for patients who relapse during a prednisone taper and for those who have adverse events during long-term steroid use. “Up to 90% of patients respond well to [azathioprine], if they can tolerate it,” he said. “In those who can, it can reduce steroid consumption by up to 80% by 2 years.” One small study concluded that 63% of those who took azathioprine for 36 months had completely tapered off prednisone, compared with 20% of those who took prednisone alone.

The major cause for discontinuation is a flulike reaction, seen in 10%–20% of patients. The drug also has a long onset of action—maximum benefit may not be seen for up to 2 years.

▸ Cyclosporine works more rapidly, with maximum benefit seen by 3 months. Patients who are refractory to other agents may respond to cyclosporine; this drug is as effective as azathioprine in symptom improvement, judging from the findings of a recent study. However, cyclosporine is less well tolerated than azathioprine, and some studies suggest that about half of patients discontinue the medication because of adverse events.

“It's important not to mix different cyclosporine preparations, because the different brands are not bioequivalent,” Dr. Wolfe added.

▸ Mycophenolate mofetil has shown promise as the newest immunosuppressive agent commonly used for MG, he said. A recent open-label study showed that 73% of patients achieved pharmacologic remission, minimal manifestation status, or symptom improvement with mycophenolate. The drug has a rapid onset of action, with improvement seen in 9–11 weeks and maximum effect by 6 months. “You may be able to decrease steroids by up to 50% in most patients with this drug,” Dr. Wolfe said.

Mycophenolate is well tolerated. Its main adverse events are diarrhea, vomiting, increased risk of infection, and rarely, leukopenia; only about 6% of patients discontinue the drug because of an adverse event. Switching to dosing three times daily may decrease the incidence of diarrhea.

▸ Cyclophosphamide is used mainly for refractory MG patients. “This drug has a lot of potential for adverse events,” Dr. Wolfe said. “But IV pulse therapy looks like it could be safer than daily oral therapy, because there is a lower cumulative dose.” However, cyclophosphamide should be considered a third-line therapy.

▸ Intravenous gamma globulin is employed as a lower-risk alternative to plasma exchange. An analysis of eight retrospective studies indicated that 73% of patients responded well to intravenous gamma globulin, and did so very quickly—in about 4–5 days. The beneficial effects can last up to several months. “IV gamma globulin is a particularly attractive alternative to plasma exchange for patients with poor venous access, hemodynamic instability, or other contraindications to plasmapheresis,” he said.

▸ Investigational agents include tacrolimus, rituximab, and monarsen. Tacrolimus has demonstrated efficacy as a monotherapy or in combination with corticosteroids, in a few recent open trials. It has a similar mechanism of action to cyclosporine but appears less nephrotoxic. However, hyperglycemia may occur. Rituximab has been reported in just a few MG cases and was associated with substantial clinical improvement at 4 weeks and with no complications or adverse events. Monarsen is being investigated in preliminary MG studies. In an open trial of 16 patients, 15 who discontinued the antiacetylcholinesterase pyridostigmine demonstrated improvement while using monarsen.

KEY BISCAYNE, FLA. — Although antimalarial agents are first-line treatment for cutaneous sarcoidosis, infliximab and leflunomide are showing promise and may be appropriate for refractory patients, Theodore Rosen, M.D., said at the annual meeting of the Noah Worcester Dermatological Society.

Corticosteroids and/or methotrexate are generally second-line therapy for patients who fail to respond to chloroquine or hydroxychloroquine. There are few data, however, to support the use of other drugs that researchers have considered—pentoxifylline, tetracyclines, or isotretinoin, “which we can barely give right now,” Dr. Rosen said.

Sarcoidosis occurs 10–20 times more often in black patients, particularly women, and is associated with a mortality rate 15 times greater in blacks than in whites. The condition is rare in patients younger than 4 years, and the peak incidence is between age 20 and 40 years. When there is skin involvement, it suggests a chronic condition with lung and bone involvement. Sarcoidosis is fatal in 5%–10% of cases.

Diagnosis can be challenging. Skin presentations are polymorphic, and include lesions that are lupus pernio, annular, psoriasiform, ichthyosis-like, verrucous, ulcerative, hypopigmented, nodular, or micropapular. “Any skin lesion not otherwise diagnosed should suggest sarcoidosis,” said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

Treatments are aimed at interrupting the immunopathogenesis at various stages. For example, 4 mg/kg per day of chloroquine or 6.5 mg/kg per day of hydroxychloroquine can inhibit antigen presentation. Topical or oral corticosteroids, including 40–80 mg/day of oral prednisone, can suppress granuloma formation. An immunosuppressive agent, such as methotrexate, 30 mg weekly, is another option.

Tumor necrosis factor α (TNF-α) agents also suppress granuloma formation. Infliximab [Remicade] is “where I'm putting my money,” Dr. Rosen said. Infliximab appears to offer excellent control, but there are risk and cost considerations, he said. The Food and Drug Administration approved the TNF-α antibody for Crohn's disease and rheumatoid arthritis. For sarcoidosis, Dr. Rosen suggested a dosing regimen of 3–10 mg/kg per dose delivered by intravenous infusion at 0, 2, and 6 weeks, and then as dictated.

Several studies have shown that infliximab provides a “dramatic and rapid response” for cutaneous lesions, Dr. Rosen said (J. Am. Acad. Dermatol. 2003;48:290–3; J. Drugs Dermatol. 2003;2:413–4; Chest 2003;124:2028–31; and Arthritis Rheum. 2003;48:3542–3).

He also cited a woman he treated for cutaneous sarcoidosis. She failed treatment with chloroquine and hydroxychloroquine at maximal doses. She also failed treatment with prednisone as well as methotrexate; nor did she show any response to potent topical steroids. Intralesional steroids provided minimal improvement. She tried pentoxifylline and tetracycline regimens, again with no clinical improvement. However, after receiving infliximab 5 mg/kg IV at 0, 2, and 6 weeks, the prominent lesions on her face disappeared.

Long-term safety, possible induction of lymphoma, and risk of infection are concerns with infliximab. Dr. Rosen stressed that physicians must ensure the diagnosis is sarcoidosis and not TB. Cost is another factor with infliximab. He estimated the cost per infusion is $4,500–$9,000.

Leflunomide (Arava) appears promising for sarcoidosis, Dr. Rosen said. The FDA approved the agent for RA. The drug may work for this condition because it inhibits pyrimidine synthesis, decreases TNF-α response, and inhibits monocyte activation by proliferating T cells. A case series of 32 patients with skin, eye, and/or lung involvement showed 80% responded to leflunomide (Sarcoidosis Vasc. Diffuse Lung Dis. 2004;21:43–8). Nausea, headache, hypersensitivity reactions, and hepatic injury are concerns with leflunomide (Dermatology 2003;207:386–9).

KEY BISCAYNE, FLA. — Although antimalarial agents are first-line treatment for cutaneous sarcoidosis, infliximab and leflunomide are showing promise and may be appropriate for refractory patients, Theodore Rosen, M.D., said at the annual meeting of the Noah Worcester Dermatological Society.

Corticosteroids and/or methotrexate are generally second-line therapy for patients who fail to respond to chloroquine or hydroxychloroquine. There are few data, however, to support the use of other drugs that researchers have considered—pentoxifylline, tetracyclines, or isotretinoin, “which we can barely give right now,” Dr. Rosen said.

Sarcoidosis occurs 10–20 times more often in black patients, particularly women, and is associated with a mortality rate 15 times greater in blacks than in whites. The condition is rare in patients younger than 4 years, and the peak incidence is between age 20 and 40 years. When there is skin involvement, it suggests a chronic condition with lung and bone involvement. Sarcoidosis is fatal in 5%–10% of cases.

Diagnosis can be challenging. Skin presentations are polymorphic, and include lesions that are lupus pernio, annular, psoriasiform, ichthyosis-like, verrucous, ulcerative, hypopigmented, nodular, or micropapular. “Any skin lesion not otherwise diagnosed should suggest sarcoidosis,” said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

Treatments are aimed at interrupting the immunopathogenesis at various stages. For example, 4 mg/kg per day of chloroquine or 6.5 mg/kg per day of hydroxychloroquine can inhibit antigen presentation. Topical or oral corticosteroids, including 40–80 mg/day of oral prednisone, can suppress granuloma formation. An immunosuppressive agent, such as methotrexate, 30 mg weekly, is another option.

Tumor necrosis factor α (TNF-α) agents also suppress granuloma formation. Infliximab [Remicade] is “where I'm putting my money,” Dr. Rosen said. Infliximab appears to offer excellent control, but there are risk and cost considerations, he said. The Food and Drug Administration approved the TNF-α antibody for Crohn's disease and rheumatoid arthritis. For sarcoidosis, Dr. Rosen suggested a dosing regimen of 3–10 mg/kg per dose delivered by intravenous infusion at 0, 2, and 6 weeks, and then as dictated.

Several studies have shown that infliximab provides a “dramatic and rapid response” for cutaneous lesions, Dr. Rosen said (J. Am. Acad. Dermatol. 2003;48:290–3; J. Drugs Dermatol. 2003;2:413–4; Chest 2003;124:2028–31; and Arthritis Rheum. 2003;48:3542–3).

He also cited a woman he treated for cutaneous sarcoidosis. She failed treatment with chloroquine and hydroxychloroquine at maximal doses. She also failed treatment with prednisone as well as methotrexate; nor did she show any response to potent topical steroids. Intralesional steroids provided minimal improvement. She tried pentoxifylline and tetracycline regimens, again with no clinical improvement. However, after receiving infliximab 5 mg/kg IV at 0, 2, and 6 weeks, the prominent lesions on her face disappeared.

Long-term safety, possible induction of lymphoma, and risk of infection are concerns with infliximab. Dr. Rosen stressed that physicians must ensure the diagnosis is sarcoidosis and not TB. Cost is another factor with infliximab. He estimated the cost per infusion is $4,500–$9,000.

Leflunomide (Arava) appears promising for sarcoidosis, Dr. Rosen said. The FDA approved the agent for RA. The drug may work for this condition because it inhibits pyrimidine synthesis, decreases TNF-α response, and inhibits monocyte activation by proliferating T cells. A case series of 32 patients with skin, eye, and/or lung involvement showed 80% responded to leflunomide (Sarcoidosis Vasc. Diffuse Lung Dis. 2004;21:43–8). Nausea, headache, hypersensitivity reactions, and hepatic injury are concerns with leflunomide (Dermatology 2003;207:386–9).

KEY BISCAYNE, FLA. — Although antimalarial agents are first-line treatment for cutaneous sarcoidosis, infliximab and leflunomide are showing promise and may be appropriate for refractory patients, Theodore Rosen, M.D., said at the annual meeting of the Noah Worcester Dermatological Society.

Corticosteroids and/or methotrexate are generally second-line therapy for patients who fail to respond to chloroquine or hydroxychloroquine. There are few data, however, to support the use of other drugs that researchers have considered—pentoxifylline, tetracyclines, or isotretinoin, “which we can barely give right now,” Dr. Rosen said.

Sarcoidosis occurs 10–20 times more often in black patients, particularly women, and is associated with a mortality rate 15 times greater in blacks than in whites. The condition is rare in patients younger than 4 years, and the peak incidence is between age 20 and 40 years. When there is skin involvement, it suggests a chronic condition with lung and bone involvement. Sarcoidosis is fatal in 5%–10% of cases.

Diagnosis can be challenging. Skin presentations are polymorphic, and include lesions that are lupus pernio, annular, psoriasiform, ichthyosis-like, verrucous, ulcerative, hypopigmented, nodular, or micropapular. “Any skin lesion not otherwise diagnosed should suggest sarcoidosis,” said Dr. Rosen, professor of dermatology at Baylor College of Medicine, Houston.

Treatments are aimed at interrupting the immunopathogenesis at various stages. For example, 4 mg/kg per day of chloroquine or 6.5 mg/kg per day of hydroxychloroquine can inhibit antigen presentation. Topical or oral corticosteroids, including 40–80 mg/day of oral prednisone, can suppress granuloma formation. An immunosuppressive agent, such as methotrexate, 30 mg weekly, is another option.

Tumor necrosis factor α (TNF-α) agents also suppress granuloma formation. Infliximab [Remicade] is “where I'm putting my money,” Dr. Rosen said. Infliximab appears to offer excellent control, but there are risk and cost considerations, he said. The Food and Drug Administration approved the TNF-α antibody for Crohn's disease and rheumatoid arthritis. For sarcoidosis, Dr. Rosen suggested a dosing regimen of 3–10 mg/kg per dose delivered by intravenous infusion at 0, 2, and 6 weeks, and then as dictated.

Several studies have shown that infliximab provides a “dramatic and rapid response” for cutaneous lesions, Dr. Rosen said (J. Am. Acad. Dermatol. 2003;48:290–3; J. Drugs Dermatol. 2003;2:413–4; Chest 2003;124:2028–31; and Arthritis Rheum. 2003;48:3542–3).

He also cited a woman he treated for cutaneous sarcoidosis. She failed treatment with chloroquine and hydroxychloroquine at maximal doses. She also failed treatment with prednisone as well as methotrexate; nor did she show any response to potent topical steroids. Intralesional steroids provided minimal improvement. She tried pentoxifylline and tetracycline regimens, again with no clinical improvement. However, after receiving infliximab 5 mg/kg IV at 0, 2, and 6 weeks, the prominent lesions on her face disappeared.

Long-term safety, possible induction of lymphoma, and risk of infection are concerns with infliximab. Dr. Rosen stressed that physicians must ensure the diagnosis is sarcoidosis and not TB. Cost is another factor with infliximab. He estimated the cost per infusion is $4,500–$9,000.

Leflunomide (Arava) appears promising for sarcoidosis, Dr. Rosen said. The FDA approved the agent for RA. The drug may work for this condition because it inhibits pyrimidine synthesis, decreases TNF-α response, and inhibits monocyte activation by proliferating T cells. A case series of 32 patients with skin, eye, and/or lung involvement showed 80% responded to leflunomide (Sarcoidosis Vasc. Diffuse Lung Dis. 2004;21:43–8). Nausea, headache, hypersensitivity reactions, and hepatic injury are concerns with leflunomide (Dermatology 2003;207:386–9).

BIRMINGHAM, ENGLAND — Patients with lupus who have high levels of proinflammatory high-density lipoprotein may be at particular risk for atherosclerosis and therefore could be suitable candidates for prophylactic treatment, Bevra Hahn, M.D., said at a joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

Recognition of the prevalence and lethality of atherosclerosis in systemic lupus erythematosus (SLE) has led to increased interest in strategies to prevent its onset and progression, such as with statin therapy.

“We know that 30%–40% of lupus patients have carotid plaque, coronary artery calcifications, or some other manifestation of atherosclerosis, but we found that only 15% of patients in our cohort had any lipid abnormalities, so it didn't seem very reasonable to just put them all on statins,” said Dr. Hahn, professor of medicine and chief of rheumatology, at the University of California, Los Angeles.

Caution also is needed because the statin drugs have been reported to induce lupus-like syndromes with the development of antinuclear antibodies in an increasing number of patients. Statins also might aggravate lupus itself, possibly through enhancing the shift from a Th1 to Th2 immune response, which heightens B cell reactivity and increases the production of pathogenic autoantibodies (Lupus 2005;14:192–6).

So Dr. Hahn and her colleagues began looking for a new biomarker that might provide a more targeted population for statin therapy. “We reasoned that people with a chronic inflammatory disease like lupus might have a lot of proinflammatory HDL. That turned out to be right,” Dr. Hahn said.

Proinflammatory HDL particles contain inadequate amounts of antioxidant enzymes such as paraoxonase. These components are replaced by serum amyloid and oxidation products, rendering the HDL particle incapable of its vital function of protecting LDL particles from becoming oxidized. Once oxidized, LDL contributes to the early development of carotid plaque.

In a study at her center that included 153 patients with lupus, 45% were found to have proinflammatory HDL, as did 21% of a group of 44 patients with rheumatoid arthritis.

Fewer than 5% of a healthy control group had the abnormal HDL, Dr. Hahn said.

On multivariate analysis, the presence of proinflammatory HDL was highly correlated with increases in oxidized LDL, and was also correlated with coronary artery events, hypertension, and high erythrocyte sedimentation rate (ESR).

“So it looks like we might have one biomarker that would tell us which people are predisposed to atherosclerosis and should be treated for it,” she said.

The next question is what that treatment should be. In patients who have had a myocardial infarction and have high levels of proinflammatory HDL, statins do lower the levels, but not even close to the normal range, Dr. Hahnsaid.

“My personal opinion is that statins may be helpful but, if we are right about what is important in lupus atherogenesis, they won't be enough. I think the most effective therapy will be one that actually suppresses SLE activity,” she said.

BIRMINGHAM, ENGLAND — Patients with lupus who have high levels of proinflammatory high-density lipoprotein may be at particular risk for atherosclerosis and therefore could be suitable candidates for prophylactic treatment, Bevra Hahn, M.D., said at a joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

Recognition of the prevalence and lethality of atherosclerosis in systemic lupus erythematosus (SLE) has led to increased interest in strategies to prevent its onset and progression, such as with statin therapy.

“We know that 30%–40% of lupus patients have carotid plaque, coronary artery calcifications, or some other manifestation of atherosclerosis, but we found that only 15% of patients in our cohort had any lipid abnormalities, so it didn't seem very reasonable to just put them all on statins,” said Dr. Hahn, professor of medicine and chief of rheumatology, at the University of California, Los Angeles.

Caution also is needed because the statin drugs have been reported to induce lupus-like syndromes with the development of antinuclear antibodies in an increasing number of patients. Statins also might aggravate lupus itself, possibly through enhancing the shift from a Th1 to Th2 immune response, which heightens B cell reactivity and increases the production of pathogenic autoantibodies (Lupus 2005;14:192–6).

So Dr. Hahn and her colleagues began looking for a new biomarker that might provide a more targeted population for statin therapy. “We reasoned that people with a chronic inflammatory disease like lupus might have a lot of proinflammatory HDL. That turned out to be right,” Dr. Hahn said.

Proinflammatory HDL particles contain inadequate amounts of antioxidant enzymes such as paraoxonase. These components are replaced by serum amyloid and oxidation products, rendering the HDL particle incapable of its vital function of protecting LDL particles from becoming oxidized. Once oxidized, LDL contributes to the early development of carotid plaque.

In a study at her center that included 153 patients with lupus, 45% were found to have proinflammatory HDL, as did 21% of a group of 44 patients with rheumatoid arthritis.

Fewer than 5% of a healthy control group had the abnormal HDL, Dr. Hahn said.

On multivariate analysis, the presence of proinflammatory HDL was highly correlated with increases in oxidized LDL, and was also correlated with coronary artery events, hypertension, and high erythrocyte sedimentation rate (ESR).

“So it looks like we might have one biomarker that would tell us which people are predisposed to atherosclerosis and should be treated for it,” she said.

The next question is what that treatment should be. In patients who have had a myocardial infarction and have high levels of proinflammatory HDL, statins do lower the levels, but not even close to the normal range, Dr. Hahnsaid.

“My personal opinion is that statins may be helpful but, if we are right about what is important in lupus atherogenesis, they won't be enough. I think the most effective therapy will be one that actually suppresses SLE activity,” she said.

BIRMINGHAM, ENGLAND — Patients with lupus who have high levels of proinflammatory high-density lipoprotein may be at particular risk for atherosclerosis and therefore could be suitable candidates for prophylactic treatment, Bevra Hahn, M.D., said at a joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.

Recognition of the prevalence and lethality of atherosclerosis in systemic lupus erythematosus (SLE) has led to increased interest in strategies to prevent its onset and progression, such as with statin therapy.

“We know that 30%–40% of lupus patients have carotid plaque, coronary artery calcifications, or some other manifestation of atherosclerosis, but we found that only 15% of patients in our cohort had any lipid abnormalities, so it didn't seem very reasonable to just put them all on statins,” said Dr. Hahn, professor of medicine and chief of rheumatology, at the University of California, Los Angeles.

Caution also is needed because the statin drugs have been reported to induce lupus-like syndromes with the development of antinuclear antibodies in an increasing number of patients. Statins also might aggravate lupus itself, possibly through enhancing the shift from a Th1 to Th2 immune response, which heightens B cell reactivity and increases the production of pathogenic autoantibodies (Lupus 2005;14:192–6).

So Dr. Hahn and her colleagues began looking for a new biomarker that might provide a more targeted population for statin therapy. “We reasoned that people with a chronic inflammatory disease like lupus might have a lot of proinflammatory HDL. That turned out to be right,” Dr. Hahn said.

Proinflammatory HDL particles contain inadequate amounts of antioxidant enzymes such as paraoxonase. These components are replaced by serum amyloid and oxidation products, rendering the HDL particle incapable of its vital function of protecting LDL particles from becoming oxidized. Once oxidized, LDL contributes to the early development of carotid plaque.

In a study at her center that included 153 patients with lupus, 45% were found to have proinflammatory HDL, as did 21% of a group of 44 patients with rheumatoid arthritis.

Fewer than 5% of a healthy control group had the abnormal HDL, Dr. Hahn said.

On multivariate analysis, the presence of proinflammatory HDL was highly correlated with increases in oxidized LDL, and was also correlated with coronary artery events, hypertension, and high erythrocyte sedimentation rate (ESR).

“So it looks like we might have one biomarker that would tell us which people are predisposed to atherosclerosis and should be treated for it,” she said.

The next question is what that treatment should be. In patients who have had a myocardial infarction and have high levels of proinflammatory HDL, statins do lower the levels, but not even close to the normal range, Dr. Hahnsaid.

“My personal opinion is that statins may be helpful but, if we are right about what is important in lupus atherogenesis, they won't be enough. I think the most effective therapy will be one that actually suppresses SLE activity,” she said.

BIRMINGHAM, ENGLAND — Tumor necrosis factor blockade may offer a successful therapeutic alternative to high-dose corticosteroids in the rare, potentially life-threatening occlusive vasculitis known as Takayasu's arteritis.

This large-vessel vasculitis typically involves the aorta and its main branches, causing stenosis or even obstruction. It occurs most commonly in young women.

In a case report presented at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology by Lucy E. Coates, M.D., of the Royal National Hospital for Rheumatic Diseases in Bath, England, a 17-year-old female patient developed severe left-sided facial pain that radiated into her neck and left arm.

Initially, the symptoms were thought to be musculoskeletal in origin, and she was treated with physiotherapy, analgesics, and tricyclic antidepressants.

Subsequent investigations, however, revealed the presence of markedly elevated inflammatory markers, including a plasma viscosity of 2.41 millipascal seconds (normal range 1.50–1.70 mPa·s).

She also had microcytic anemia, and levels of immunoglobulins were raised, with IgG at 17.4 g/L, IgA at 4.2 g/L, and IgM at 3.8 g/L. Various imaging studies were done, including MRI of the brain and cervical spine and CT of the abdomen and pelvis, without result.

Two years later, a lump was discovered in her neck. On examination, she was found to have bilateral carotid bruits. Magnetic resonance angiography (MRA) results showed thickening in the wall of the right brachiocephalic artery, narrowing the vessel. The subclavian artery was narrowed at its origin and underfilled distal to its origin. This was suggestive of a proximal stenosis such as is seen in Takayasu's arteritis, Dr. Coates said.

The patient was started on prednisone and azathioprine, but 1 year later her symptoms had worsened, as had the imaging findings on repeat MRA. The decision was made to institute more aggressive therapy because of concerns that the blood vessels supplying her brain were being affected, Dr. Coates said in a poster session.

Infliximab treatment was begun, with infusions of 5 mg/kg at weeks 0, 2, 6, and 10 and then every 6 weeks.

She also continued to take azathioprine (100 mg/day) and prednisone (20 mg/day). Symptomatic improvement was immediate, and another MRA the following year showed significant improvement in the caliber and appearance of the aortic arch vessels.

“Anti-TNF therapy appears to offer a promising alternative in Takayasu's arteritis, particularly if other forms of immunosuppression fail to control progression,” Dr. Coates said in her poster presentation.

Her findings support those seen in another recent series in which 14 of 15 patients with the condition responded and 10 experienced sustained remission and were able to discontinue glucocorticoid therapy (Arthritis Rheum. 2004;50:2296–304).

BIRMINGHAM, ENGLAND — Tumor necrosis factor blockade may offer a successful therapeutic alternative to high-dose corticosteroids in the rare, potentially life-threatening occlusive vasculitis known as Takayasu's arteritis.

This large-vessel vasculitis typically involves the aorta and its main branches, causing stenosis or even obstruction. It occurs most commonly in young women.

In a case report presented at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology by Lucy E. Coates, M.D., of the Royal National Hospital for Rheumatic Diseases in Bath, England, a 17-year-old female patient developed severe left-sided facial pain that radiated into her neck and left arm.

Initially, the symptoms were thought to be musculoskeletal in origin, and she was treated with physiotherapy, analgesics, and tricyclic antidepressants.

Subsequent investigations, however, revealed the presence of markedly elevated inflammatory markers, including a plasma viscosity of 2.41 millipascal seconds (normal range 1.50–1.70 mPa·s).

She also had microcytic anemia, and levels of immunoglobulins were raised, with IgG at 17.4 g/L, IgA at 4.2 g/L, and IgM at 3.8 g/L. Various imaging studies were done, including MRI of the brain and cervical spine and CT of the abdomen and pelvis, without result.

Two years later, a lump was discovered in her neck. On examination, she was found to have bilateral carotid bruits. Magnetic resonance angiography (MRA) results showed thickening in the wall of the right brachiocephalic artery, narrowing the vessel. The subclavian artery was narrowed at its origin and underfilled distal to its origin. This was suggestive of a proximal stenosis such as is seen in Takayasu's arteritis, Dr. Coates said.

The patient was started on prednisone and azathioprine, but 1 year later her symptoms had worsened, as had the imaging findings on repeat MRA. The decision was made to institute more aggressive therapy because of concerns that the blood vessels supplying her brain were being affected, Dr. Coates said in a poster session.

Infliximab treatment was begun, with infusions of 5 mg/kg at weeks 0, 2, 6, and 10 and then every 6 weeks.

She also continued to take azathioprine (100 mg/day) and prednisone (20 mg/day). Symptomatic improvement was immediate, and another MRA the following year showed significant improvement in the caliber and appearance of the aortic arch vessels.

“Anti-TNF therapy appears to offer a promising alternative in Takayasu's arteritis, particularly if other forms of immunosuppression fail to control progression,” Dr. Coates said in her poster presentation.

Her findings support those seen in another recent series in which 14 of 15 patients with the condition responded and 10 experienced sustained remission and were able to discontinue glucocorticoid therapy (Arthritis Rheum. 2004;50:2296–304).

BIRMINGHAM, ENGLAND — Tumor necrosis factor blockade may offer a successful therapeutic alternative to high-dose corticosteroids in the rare, potentially life-threatening occlusive vasculitis known as Takayasu's arteritis.

This large-vessel vasculitis typically involves the aorta and its main branches, causing stenosis or even obstruction. It occurs most commonly in young women.

In a case report presented at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology by Lucy E. Coates, M.D., of the Royal National Hospital for Rheumatic Diseases in Bath, England, a 17-year-old female patient developed severe left-sided facial pain that radiated into her neck and left arm.

Initially, the symptoms were thought to be musculoskeletal in origin, and she was treated with physiotherapy, analgesics, and tricyclic antidepressants.

Subsequent investigations, however, revealed the presence of markedly elevated inflammatory markers, including a plasma viscosity of 2.41 millipascal seconds (normal range 1.50–1.70 mPa·s).

She also had microcytic anemia, and levels of immunoglobulins were raised, with IgG at 17.4 g/L, IgA at 4.2 g/L, and IgM at 3.8 g/L. Various imaging studies were done, including MRI of the brain and cervical spine and CT of the abdomen and pelvis, without result.

Two years later, a lump was discovered in her neck. On examination, she was found to have bilateral carotid bruits. Magnetic resonance angiography (MRA) results showed thickening in the wall of the right brachiocephalic artery, narrowing the vessel. The subclavian artery was narrowed at its origin and underfilled distal to its origin. This was suggestive of a proximal stenosis such as is seen in Takayasu's arteritis, Dr. Coates said.

The patient was started on prednisone and azathioprine, but 1 year later her symptoms had worsened, as had the imaging findings on repeat MRA. The decision was made to institute more aggressive therapy because of concerns that the blood vessels supplying her brain were being affected, Dr. Coates said in a poster session.

Infliximab treatment was begun, with infusions of 5 mg/kg at weeks 0, 2, 6, and 10 and then every 6 weeks.

She also continued to take azathioprine (100 mg/day) and prednisone (20 mg/day). Symptomatic improvement was immediate, and another MRA the following year showed significant improvement in the caliber and appearance of the aortic arch vessels.

“Anti-TNF therapy appears to offer a promising alternative in Takayasu's arteritis, particularly if other forms of immunosuppression fail to control progression,” Dr. Coates said in her poster presentation.

Her findings support those seen in another recent series in which 14 of 15 patients with the condition responded and 10 experienced sustained remission and were able to discontinue glucocorticoid therapy (Arthritis Rheum. 2004;50:2296–304).

Activation of the interferon-α pathway identifies a subgroup of lupus erythematosus patients with distinct serologic features and more active disease, according to Kyriakos A. Kirou, M.D.

There is no consensus in the current literature regarding the most useful or accurate marker of lupus disease activity, thus the use of increased interferon-inducible gene expression as a potential biomarker of active disease could prove valuable to clinicians and researchers.

The investigators subjected freshly isolated peripheral blood mononuclear cells from 77 patients with systemic lupus erythematosus (SLE), 22 disease controls with either rheumatoid arthritis or inflammatory uveitis, and 28 healthy donors to real-time polymerase chain reaction for three genes (PRKR, IFIT1, and IF144) that are preferentially induced by interferon-α. The results were used to determine an IFN-α score for all participants.

SLE patients with a high IFN-α score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did patients with a low IFN-α score (Arthritis Rheum. 2005;52:1491–503).

Patients with high IFN-α scores also showed increased disease activity, as measured by lower serum C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score.

“Our most striking data, and that which may provide us new clues regarding underlying disease mechanisms, came from analysis of the serologic profiles of the SLE patients,” wrote Dr. Kirou and colleagues at the Hospital for Special Surgery in New York.

The investigators found that the presence of antibodies specific for RNA-binding protein (RBP), including Ro, U1 ribonucleoprotein (RNP), and Sm, was significantly associated with a high IFN-α score.

Logistic regression analysis confirmed that the presence of renal disease, low complement levels, autoantibodies specific for RBP (but not anti-dsDNA or antiphospholipid autoantibodies), and higher SDI scores, all independently increased the likelihood of having a high IFN-α score.

“Activation of the IFN-α pathway could be an important mediator of the immune system alterations that confer tissue damage in SLE,” the authors wrote.

Additionally, activation of the IFN-α pathway may also contribute to production of pathogenic autoantibodies by direct and indirect effects on B cells, resulting in differentiation and Ig class switching to IgG and IgA isotypes.

Prospective longitudinal studies are needed to assess the role of interferon-inducible genes in monitoring disease activity, they concluded.

Activation of the interferon-α pathway identifies a subgroup of lupus erythematosus patients with distinct serologic features and more active disease, according to Kyriakos A. Kirou, M.D.

There is no consensus in the current literature regarding the most useful or accurate marker of lupus disease activity, thus the use of increased interferon-inducible gene expression as a potential biomarker of active disease could prove valuable to clinicians and researchers.

The investigators subjected freshly isolated peripheral blood mononuclear cells from 77 patients with systemic lupus erythematosus (SLE), 22 disease controls with either rheumatoid arthritis or inflammatory uveitis, and 28 healthy donors to real-time polymerase chain reaction for three genes (PRKR, IFIT1, and IF144) that are preferentially induced by interferon-α. The results were used to determine an IFN-α score for all participants.

SLE patients with a high IFN-α score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did patients with a low IFN-α score (Arthritis Rheum. 2005;52:1491–503).

Patients with high IFN-α scores also showed increased disease activity, as measured by lower serum C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score.

“Our most striking data, and that which may provide us new clues regarding underlying disease mechanisms, came from analysis of the serologic profiles of the SLE patients,” wrote Dr. Kirou and colleagues at the Hospital for Special Surgery in New York.

The investigators found that the presence of antibodies specific for RNA-binding protein (RBP), including Ro, U1 ribonucleoprotein (RNP), and Sm, was significantly associated with a high IFN-α score.

Logistic regression analysis confirmed that the presence of renal disease, low complement levels, autoantibodies specific for RBP (but not anti-dsDNA or antiphospholipid autoantibodies), and higher SDI scores, all independently increased the likelihood of having a high IFN-α score.

“Activation of the IFN-α pathway could be an important mediator of the immune system alterations that confer tissue damage in SLE,” the authors wrote.

Additionally, activation of the IFN-α pathway may also contribute to production of pathogenic autoantibodies by direct and indirect effects on B cells, resulting in differentiation and Ig class switching to IgG and IgA isotypes.

Prospective longitudinal studies are needed to assess the role of interferon-inducible genes in monitoring disease activity, they concluded.

Activation of the interferon-α pathway identifies a subgroup of lupus erythematosus patients with distinct serologic features and more active disease, according to Kyriakos A. Kirou, M.D.

There is no consensus in the current literature regarding the most useful or accurate marker of lupus disease activity, thus the use of increased interferon-inducible gene expression as a potential biomarker of active disease could prove valuable to clinicians and researchers.

The investigators subjected freshly isolated peripheral blood mononuclear cells from 77 patients with systemic lupus erythematosus (SLE), 22 disease controls with either rheumatoid arthritis or inflammatory uveitis, and 28 healthy donors to real-time polymerase chain reaction for three genes (PRKR, IFIT1, and IF144) that are preferentially induced by interferon-α. The results were used to determine an IFN-α score for all participants.

SLE patients with a high IFN-α score had a significantly higher prevalence of renal disease, a greater number of American College of Rheumatology criteria for SLE, and a higher Systemic Lupus International Collaborating Clinics damage index (SDI) score than did patients with a low IFN-α score (Arthritis Rheum. 2005;52:1491–503).

Patients with high IFN-α scores also showed increased disease activity, as measured by lower serum C3 levels, hemoglobin levels, absolute lymphocyte counts, and albumin levels, and a higher anti-double-stranded DNA (dsDNA) titer, erythrocyte sedimentation rate, and SLE Disease Activity Index 2000 score.

“Our most striking data, and that which may provide us new clues regarding underlying disease mechanisms, came from analysis of the serologic profiles of the SLE patients,” wrote Dr. Kirou and colleagues at the Hospital for Special Surgery in New York.

The investigators found that the presence of antibodies specific for RNA-binding protein (RBP), including Ro, U1 ribonucleoprotein (RNP), and Sm, was significantly associated with a high IFN-α score.

Logistic regression analysis confirmed that the presence of renal disease, low complement levels, autoantibodies specific for RBP (but not anti-dsDNA or antiphospholipid autoantibodies), and higher SDI scores, all independently increased the likelihood of having a high IFN-α score.

“Activation of the IFN-α pathway could be an important mediator of the immune system alterations that confer tissue damage in SLE,” the authors wrote.

Additionally, activation of the IFN-α pathway may also contribute to production of pathogenic autoantibodies by direct and indirect effects on B cells, resulting in differentiation and Ig class switching to IgG and IgA isotypes.

Prospective longitudinal studies are needed to assess the role of interferon-inducible genes in monitoring disease activity, they concluded.

WASHINGTON — By the first few months of this year, drug-eluting coronary stents had become more cost effective than ever before.

Based on the price of drug-eluting stents, the average number of stents used per patient, and their efficacy at cutting the rate of restenosis, drug-eluting stents are now cost effective in any patient who would have a risk of restenosis of 10% or more if treated with bare-metal stents, David J. Cohen, M.D., said at a meeting sponsored by the Cardiovascular Research Institute of the Washington Hospital Center.

In contrast, based on last year's averages, drug-eluting stents were cost effective whenever the restenosis rate with bare-metal stents was 12% or greater (CARDIOLOGY NEWS, March 2005, p. 7).

The upshot is that drug-eluting stents now make economic sense in wider coronary arteries and in vessels with shorter lesions. It is reasonable from an economic standpoint to use drug-eluting stents in most patients with coronary artery disease, said Dr. Cohen, associate director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston.

By early 2005, the two types of drug-eluting stents sold in the United States (sirolimus-eluting and paclitaxel-eluting) cost an average of $2,300 per stent, down from an average of $2,700 last year and $3,100 in 2003. In early 2005, the difference in cost of a drug-eluting coronary stent over a comparable bare-metal stent had dropped to $1,600, down by $300 from the year before.

At Dr. Cohen's center, patients who had drug-eluting coronary stents placed in late 2004 received an average of 1.6 stents each. And the most current data from studies that compared drug-eluting stents with bare-metal stents showed that drug-eluting stents cut the need for target vessel revascularization by about 82%.

One additional issue for a cost-effectiveness calculation is that patients who receive drug-eluting stents require daily treatment with clopidogrel for several months, a regimen that costs about $120 per month.

Crunching all of these cost-adding and -saving numbers together yields the estimate that placement of a drug-eluting stent adds no incremental cost when used in patients with an expected restenosis rate with bare-metal stents of at least 10%, he said.

Based on an analysis done by Dr. Cohen and his associates in the late 1990s, virtually all patients with diabetes have a restenosis rate of 10% or greater with bare-metal stents. The only exceptions are patients with lesions that are less than 30 mm in length that are in coronary arteries that are at least 4.0 mm in diameter. Among patients without diabetes, a restenosis rate of less than 10% with bare-metal stents occurs in all coronary arteries that are 4.0 mm in diameter or greater, regardless of lesion length, and in vessels that are 3.5 mm in diameter or greater if the lesion length is less than 25 mm.

WASHINGTON — By the first few months of this year, drug-eluting coronary stents had become more cost effective than ever before.

Based on the price of drug-eluting stents, the average number of stents used per patient, and their efficacy at cutting the rate of restenosis, drug-eluting stents are now cost effective in any patient who would have a risk of restenosis of 10% or more if treated with bare-metal stents, David J. Cohen, M.D., said at a meeting sponsored by the Cardiovascular Research Institute of the Washington Hospital Center.

In contrast, based on last year's averages, drug-eluting stents were cost effective whenever the restenosis rate with bare-metal stents was 12% or greater (CARDIOLOGY NEWS, March 2005, p. 7).

The upshot is that drug-eluting stents now make economic sense in wider coronary arteries and in vessels with shorter lesions. It is reasonable from an economic standpoint to use drug-eluting stents in most patients with coronary artery disease, said Dr. Cohen, associate director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston.

By early 2005, the two types of drug-eluting stents sold in the United States (sirolimus-eluting and paclitaxel-eluting) cost an average of $2,300 per stent, down from an average of $2,700 last year and $3,100 in 2003. In early 2005, the difference in cost of a drug-eluting coronary stent over a comparable bare-metal stent had dropped to $1,600, down by $300 from the year before.

At Dr. Cohen's center, patients who had drug-eluting coronary stents placed in late 2004 received an average of 1.6 stents each. And the most current data from studies that compared drug-eluting stents with bare-metal stents showed that drug-eluting stents cut the need for target vessel revascularization by about 82%.

One additional issue for a cost-effectiveness calculation is that patients who receive drug-eluting stents require daily treatment with clopidogrel for several months, a regimen that costs about $120 per month.

Crunching all of these cost-adding and -saving numbers together yields the estimate that placement of a drug-eluting stent adds no incremental cost when used in patients with an expected restenosis rate with bare-metal stents of at least 10%, he said.

Based on an analysis done by Dr. Cohen and his associates in the late 1990s, virtually all patients with diabetes have a restenosis rate of 10% or greater with bare-metal stents. The only exceptions are patients with lesions that are less than 30 mm in length that are in coronary arteries that are at least 4.0 mm in diameter. Among patients without diabetes, a restenosis rate of less than 10% with bare-metal stents occurs in all coronary arteries that are 4.0 mm in diameter or greater, regardless of lesion length, and in vessels that are 3.5 mm in diameter or greater if the lesion length is less than 25 mm.

WASHINGTON — By the first few months of this year, drug-eluting coronary stents had become more cost effective than ever before.

Based on the price of drug-eluting stents, the average number of stents used per patient, and their efficacy at cutting the rate of restenosis, drug-eluting stents are now cost effective in any patient who would have a risk of restenosis of 10% or more if treated with bare-metal stents, David J. Cohen, M.D., said at a meeting sponsored by the Cardiovascular Research Institute of the Washington Hospital Center.

In contrast, based on last year's averages, drug-eluting stents were cost effective whenever the restenosis rate with bare-metal stents was 12% or greater (CARDIOLOGY NEWS, March 2005, p. 7).

The upshot is that drug-eluting stents now make economic sense in wider coronary arteries and in vessels with shorter lesions. It is reasonable from an economic standpoint to use drug-eluting stents in most patients with coronary artery disease, said Dr. Cohen, associate director of interventional cardiology at Beth Israel Deaconess Medical Center in Boston.

By early 2005, the two types of drug-eluting stents sold in the United States (sirolimus-eluting and paclitaxel-eluting) cost an average of $2,300 per stent, down from an average of $2,700 last year and $3,100 in 2003. In early 2005, the difference in cost of a drug-eluting coronary stent over a comparable bare-metal stent had dropped to $1,600, down by $300 from the year before.

At Dr. Cohen's center, patients who had drug-eluting coronary stents placed in late 2004 received an average of 1.6 stents each. And the most current data from studies that compared drug-eluting stents with bare-metal stents showed that drug-eluting stents cut the need for target vessel revascularization by about 82%.

One additional issue for a cost-effectiveness calculation is that patients who receive drug-eluting stents require daily treatment with clopidogrel for several months, a regimen that costs about $120 per month.

Crunching all of these cost-adding and -saving numbers together yields the estimate that placement of a drug-eluting stent adds no incremental cost when used in patients with an expected restenosis rate with bare-metal stents of at least 10%, he said.

Based on an analysis done by Dr. Cohen and his associates in the late 1990s, virtually all patients with diabetes have a restenosis rate of 10% or greater with bare-metal stents. The only exceptions are patients with lesions that are less than 30 mm in length that are in coronary arteries that are at least 4.0 mm in diameter. Among patients without diabetes, a restenosis rate of less than 10% with bare-metal stents occurs in all coronary arteries that are 4.0 mm in diameter or greater, regardless of lesion length, and in vessels that are 3.5 mm in diameter or greater if the lesion length is less than 25 mm.

ORLANDO, FLA. — A new type of drug-eluting coronary stent was safe and effective in its first phase III clinical trial, compared with a similar bare-metal stent in about 1,200 patients.

But the results also raised novel issues on how effective drug-eluting stents must be at stopping the growth of coronary artery endothelium in order to prevent restenosis and the need for revascularization. That's because the new stent, brand named Endeavor and coated with a sirolimus-like drug called ABT-578, was successful at capping the target-lesion revascularization rate at 4.6% after 9 months, despite allowing a surprisingly high average late lumen loss of 0.62 mm within stented coronary arteries.

“The current paradigm is that inflating a balloon leads to a vascular response to injury that then produces intimal proliferation, restenosis, and [cardiac] events; but it didn't work that way” in this study, commented Lloyd W. Klein, M.D., at the annual meeting of the American College of Cardiology. “It makes you wonder if we have the right paradigm. Patients don't care about their intimal thickness; they care about whether they need to come back to the cath lab,” said Dr. Klein of Gottlieb Memorial Hospital in Melrose, Ill.

In the study, named ENDEAVOR II, 1,197 patients were enrolled at 72 centers in Europe, Asia, and Oceania. About 20% of patients had diabetes.

The study's primary end point was the composite incidence of cardiac death, nonfatal myocardial infarction, or need for target-vessel revascularization during 9 months of follow-up. The incidence of this composite end point was 8.1% in patients who received the drug-eluting stent and 15.4% in patients who received a comparable bare-metal stent (Driver), reported William Wijns, M.D., codirector of the Cardiovascular Centre at OLV Hospital in Aalst, Belgium. The study was sponsored by Medtronic Inc., which makes both the Endeavor and Driver stents.

Two other studies, both funded by Medtronic and now in progress, are comparing the Endeavor stent with the two competing drug-eluting stents on the U.S. market. One study matches the Endeavor and sirolimus-eluting (Cypher) stents; the other matches the Endeavor and paclitaxel-eluting (Taxus) stents. Medtronic will not seek U.S. marketing approval for the Endeavor stent until results from these studies are in.

In the current study, the ABT-578-eluting stent also looked good by other clinical end points: the 4.6% rate of target-lesion revascularization with the drug-eluting stent, compared with a 12.1% rate with the bare-metal stent; and the 0.5% rate of stent thrombosis during 9 months with the drug-eluting stent, compared with 1.2% with the bare-metal stent.

But this drug-eluting stent was less successful by the angiographic measures that were collected in 89% of the first 600 patients enrolled in the study. Although the mean late loss of 0.62 mm in the drug-eluting stents improved on the 1.03-mm rate of late loss with the bare-metal stent, it's a higher rate than has been seen in prior studies with other types of drug-eluting stents. Similarly, the in-stent binary restenosis rate of 9.5% with Endeavor in this study improved on the 32.7% rate with bare-metal stents, and was a higher restenosis rate than in earlier studies with other brands of drug-eluting stents.

In recent pivotal studies, the late-loss rate following coronary artery stenting averaged 0.17 mm with the sirolimus-eluting stent and 0.39 mm with the paclitaxel-eluting stent, said Gregg W. Stone, M.D., of Columbia University in New York. When compared with the 0.62-mm late loss with the ABT-578-eluting stent, these findings show “a striking difference in biologic potency” between the three drug-eluting stents.

But it's a different story for the target-lesion revascularization rates, the “purest surrogate measure of efficacy for drug-eluting stents.” These rates were 4.1% with the sirolimus-eluting stent and 3.0% with the paclitaxel-eluting stent, not substantially better than the 4.6% rate with the ABT-578-eluting stent in the new study.

“We go from a marked difference in biologic response to no difference in clinical results,” said Dr. Stone, although he also warned that these data were collected in three different studies, and comparisons across studies must be done cautiously.

What explains this apparent paradox? He hypothesized that the difference in late-loss rates may stem from differences in drug-elution rates. “You wouldn't expect such a difference in biologic responses based on any difference in the drugs.” But 75% of the sirolimus on a Cypher stent elutes in 10 days, and it takes 30 days for all of the drug to come off. In contrast, 75% of ABT-578 is off the Endeavor stent within 2 days after a stent is placed in a coronary artery, and 100% is off within 10 days. “It's plausible that the difference in elution rates at least partially explains the difference in vascular effects between the two stents,” he said.

When it comes to their clinical effect, “we know that most patients can accommodate a certain amount of stenosis before it overwhelms their coronary flow reserve,” said Dr. Stone. “The target lesion revascularization rate is only 7% when late loss is 0.70 mm. A 0.62-mm late-loss rate would not be expected to cause much target-lesion revascularization,” he said.

“Late loss is significantly greater [with the Endeavor stent] than with other drug-eluting stents, but it is still low enough to produce excellent freedom from restenosis,” Dr. Stone concluded.

Another factor is that the ENDEAVOR II study mostly used patients with a low relative risk for target-lesion restenosis. If the stent is tested in higher-risk patients or in higher-risk lesions, such as those in narrow coronary arteries, it's possible that the higher rate of late loss will make a clinical difference, commented Laura Mauri, M.D., a cardiologist at Brigham and Women's Hospital in Boston.

Nonetheless, the Endeavor stent may have other attributes that make it an attractive option. The Driver bare-metal stent that's the platform for the ABT-578-eluting stent is widely regarded as easy to use. Plus, the Endeavor stent uses a biocompatible phosphorylcholine coating that binds the drug layer to the metal stent. The sirolimus- and paclitaxel-eluting stents use a polymer coating. The phosphorylcholine coating may explain why the rate of late thrombosis in the ENDEAVOR II study was so low, 0.5%. The polymer coats on the other drug-eluting stents may, in part, be why they have led to some problems with late thrombosis, Dr. Mauri said. But a study designed to definitively show whether these stents differ in their rate of late thrombosis would require several thousand patients.

ORLANDO, FLA. — A new type of drug-eluting coronary stent was safe and effective in its first phase III clinical trial, compared with a similar bare-metal stent in about 1,200 patients.

But the results also raised novel issues on how effective drug-eluting stents must be at stopping the growth of coronary artery endothelium in order to prevent restenosis and the need for revascularization. That's because the new stent, brand named Endeavor and coated with a sirolimus-like drug called ABT-578, was successful at capping the target-lesion revascularization rate at 4.6% after 9 months, despite allowing a surprisingly high average late lumen loss of 0.62 mm within stented coronary arteries.

“The current paradigm is that inflating a balloon leads to a vascular response to injury that then produces intimal proliferation, restenosis, and [cardiac] events; but it didn't work that way” in this study, commented Lloyd W. Klein, M.D., at the annual meeting of the American College of Cardiology. “It makes you wonder if we have the right paradigm. Patients don't care about their intimal thickness; they care about whether they need to come back to the cath lab,” said Dr. Klein of Gottlieb Memorial Hospital in Melrose, Ill.

In the study, named ENDEAVOR II, 1,197 patients were enrolled at 72 centers in Europe, Asia, and Oceania. About 20% of patients had diabetes.

The study's primary end point was the composite incidence of cardiac death, nonfatal myocardial infarction, or need for target-vessel revascularization during 9 months of follow-up. The incidence of this composite end point was 8.1% in patients who received the drug-eluting stent and 15.4% in patients who received a comparable bare-metal stent (Driver), reported William Wijns, M.D., codirector of the Cardiovascular Centre at OLV Hospital in Aalst, Belgium. The study was sponsored by Medtronic Inc., which makes both the Endeavor and Driver stents.

Two other studies, both funded by Medtronic and now in progress, are comparing the Endeavor stent with the two competing drug-eluting stents on the U.S. market. One study matches the Endeavor and sirolimus-eluting (Cypher) stents; the other matches the Endeavor and paclitaxel-eluting (Taxus) stents. Medtronic will not seek U.S. marketing approval for the Endeavor stent until results from these studies are in.

In the current study, the ABT-578-eluting stent also looked good by other clinical end points: the 4.6% rate of target-lesion revascularization with the drug-eluting stent, compared with a 12.1% rate with the bare-metal stent; and the 0.5% rate of stent thrombosis during 9 months with the drug-eluting stent, compared with 1.2% with the bare-metal stent.

But this drug-eluting stent was less successful by the angiographic measures that were collected in 89% of the first 600 patients enrolled in the study. Although the mean late loss of 0.62 mm in the drug-eluting stents improved on the 1.03-mm rate of late loss with the bare-metal stent, it's a higher rate than has been seen in prior studies with other types of drug-eluting stents. Similarly, the in-stent binary restenosis rate of 9.5% with Endeavor in this study improved on the 32.7% rate with bare-metal stents, and was a higher restenosis rate than in earlier studies with other brands of drug-eluting stents.

In recent pivotal studies, the late-loss rate following coronary artery stenting averaged 0.17 mm with the sirolimus-eluting stent and 0.39 mm with the paclitaxel-eluting stent, said Gregg W. Stone, M.D., of Columbia University in New York. When compared with the 0.62-mm late loss with the ABT-578-eluting stent, these findings show “a striking difference in biologic potency” between the three drug-eluting stents.

But it's a different story for the target-lesion revascularization rates, the “purest surrogate measure of efficacy for drug-eluting stents.” These rates were 4.1% with the sirolimus-eluting stent and 3.0% with the paclitaxel-eluting stent, not substantially better than the 4.6% rate with the ABT-578-eluting stent in the new study.

“We go from a marked difference in biologic response to no difference in clinical results,” said Dr. Stone, although he also warned that these data were collected in three different studies, and comparisons across studies must be done cautiously.

What explains this apparent paradox? He hypothesized that the difference in late-loss rates may stem from differences in drug-elution rates. “You wouldn't expect such a difference in biologic responses based on any difference in the drugs.” But 75% of the sirolimus on a Cypher stent elutes in 10 days, and it takes 30 days for all of the drug to come off. In contrast, 75% of ABT-578 is off the Endeavor stent within 2 days after a stent is placed in a coronary artery, and 100% is off within 10 days. “It's plausible that the difference in elution rates at least partially explains the difference in vascular effects between the two stents,” he said.

When it comes to their clinical effect, “we know that most patients can accommodate a certain amount of stenosis before it overwhelms their coronary flow reserve,” said Dr. Stone. “The target lesion revascularization rate is only 7% when late loss is 0.70 mm. A 0.62-mm late-loss rate would not be expected to cause much target-lesion revascularization,” he said.

“Late loss is significantly greater [with the Endeavor stent] than with other drug-eluting stents, but it is still low enough to produce excellent freedom from restenosis,” Dr. Stone concluded.

Another factor is that the ENDEAVOR II study mostly used patients with a low relative risk for target-lesion restenosis. If the stent is tested in higher-risk patients or in higher-risk lesions, such as those in narrow coronary arteries, it's possible that the higher rate of late loss will make a clinical difference, commented Laura Mauri, M.D., a cardiologist at Brigham and Women's Hospital in Boston.

Nonetheless, the Endeavor stent may have other attributes that make it an attractive option. The Driver bare-metal stent that's the platform for the ABT-578-eluting stent is widely regarded as easy to use. Plus, the Endeavor stent uses a biocompatible phosphorylcholine coating that binds the drug layer to the metal stent. The sirolimus- and paclitaxel-eluting stents use a polymer coating. The phosphorylcholine coating may explain why the rate of late thrombosis in the ENDEAVOR II study was so low, 0.5%. The polymer coats on the other drug-eluting stents may, in part, be why they have led to some problems with late thrombosis, Dr. Mauri said. But a study designed to definitively show whether these stents differ in their rate of late thrombosis would require several thousand patients.

ORLANDO, FLA. — A new type of drug-eluting coronary stent was safe and effective in its first phase III clinical trial, compared with a similar bare-metal stent in about 1,200 patients.

But the results also raised novel issues on how effective drug-eluting stents must be at stopping the growth of coronary artery endothelium in order to prevent restenosis and the need for revascularization. That's because the new stent, brand named Endeavor and coated with a sirolimus-like drug called ABT-578, was successful at capping the target-lesion revascularization rate at 4.6% after 9 months, despite allowing a surprisingly high average late lumen loss of 0.62 mm within stented coronary arteries.

“The current paradigm is that inflating a balloon leads to a vascular response to injury that then produces intimal proliferation, restenosis, and [cardiac] events; but it didn't work that way” in this study, commented Lloyd W. Klein, M.D., at the annual meeting of the American College of Cardiology. “It makes you wonder if we have the right paradigm. Patients don't care about their intimal thickness; they care about whether they need to come back to the cath lab,” said Dr. Klein of Gottlieb Memorial Hospital in Melrose, Ill.

In the study, named ENDEAVOR II, 1,197 patients were enrolled at 72 centers in Europe, Asia, and Oceania. About 20% of patients had diabetes.

The study's primary end point was the composite incidence of cardiac death, nonfatal myocardial infarction, or need for target-vessel revascularization during 9 months of follow-up. The incidence of this composite end point was 8.1% in patients who received the drug-eluting stent and 15.4% in patients who received a comparable bare-metal stent (Driver), reported William Wijns, M.D., codirector of the Cardiovascular Centre at OLV Hospital in Aalst, Belgium. The study was sponsored by Medtronic Inc., which makes both the Endeavor and Driver stents.

Two other studies, both funded by Medtronic and now in progress, are comparing the Endeavor stent with the two competing drug-eluting stents on the U.S. market. One study matches the Endeavor and sirolimus-eluting (Cypher) stents; the other matches the Endeavor and paclitaxel-eluting (Taxus) stents. Medtronic will not seek U.S. marketing approval for the Endeavor stent until results from these studies are in.

In the current study, the ABT-578-eluting stent also looked good by other clinical end points: the 4.6% rate of target-lesion revascularization with the drug-eluting stent, compared with a 12.1% rate with the bare-metal stent; and the 0.5% rate of stent thrombosis during 9 months with the drug-eluting stent, compared with 1.2% with the bare-metal stent.

But this drug-eluting stent was less successful by the angiographic measures that were collected in 89% of the first 600 patients enrolled in the study. Although the mean late loss of 0.62 mm in the drug-eluting stents improved on the 1.03-mm rate of late loss with the bare-metal stent, it's a higher rate than has been seen in prior studies with other types of drug-eluting stents. Similarly, the in-stent binary restenosis rate of 9.5% with Endeavor in this study improved on the 32.7% rate with bare-metal stents, and was a higher restenosis rate than in earlier studies with other brands of drug-eluting stents.

In recent pivotal studies, the late-loss rate following coronary artery stenting averaged 0.17 mm with the sirolimus-eluting stent and 0.39 mm with the paclitaxel-eluting stent, said Gregg W. Stone, M.D., of Columbia University in New York. When compared with the 0.62-mm late loss with the ABT-578-eluting stent, these findings show “a striking difference in biologic potency” between the three drug-eluting stents.

But it's a different story for the target-lesion revascularization rates, the “purest surrogate measure of efficacy for drug-eluting stents.” These rates were 4.1% with the sirolimus-eluting stent and 3.0% with the paclitaxel-eluting stent, not substantially better than the 4.6% rate with the ABT-578-eluting stent in the new study.

“We go from a marked difference in biologic response to no difference in clinical results,” said Dr. Stone, although he also warned that these data were collected in three different studies, and comparisons across studies must be done cautiously.

What explains this apparent paradox? He hypothesized that the difference in late-loss rates may stem from differences in drug-elution rates. “You wouldn't expect such a difference in biologic responses based on any difference in the drugs.” But 75% of the sirolimus on a Cypher stent elutes in 10 days, and it takes 30 days for all of the drug to come off. In contrast, 75% of ABT-578 is off the Endeavor stent within 2 days after a stent is placed in a coronary artery, and 100% is off within 10 days. “It's plausible that the difference in elution rates at least partially explains the difference in vascular effects between the two stents,” he said.

When it comes to their clinical effect, “we know that most patients can accommodate a certain amount of stenosis before it overwhelms their coronary flow reserve,” said Dr. Stone. “The target lesion revascularization rate is only 7% when late loss is 0.70 mm. A 0.62-mm late-loss rate would not be expected to cause much target-lesion revascularization,” he said.

“Late loss is significantly greater [with the Endeavor stent] than with other drug-eluting stents, but it is still low enough to produce excellent freedom from restenosis,” Dr. Stone concluded.

Another factor is that the ENDEAVOR II study mostly used patients with a low relative risk for target-lesion restenosis. If the stent is tested in higher-risk patients or in higher-risk lesions, such as those in narrow coronary arteries, it's possible that the higher rate of late loss will make a clinical difference, commented Laura Mauri, M.D., a cardiologist at Brigham and Women's Hospital in Boston.

Nonetheless, the Endeavor stent may have other attributes that make it an attractive option. The Driver bare-metal stent that's the platform for the ABT-578-eluting stent is widely regarded as easy to use. Plus, the Endeavor stent uses a biocompatible phosphorylcholine coating that binds the drug layer to the metal stent. The sirolimus- and paclitaxel-eluting stents use a polymer coating. The phosphorylcholine coating may explain why the rate of late thrombosis in the ENDEAVOR II study was so low, 0.5%. The polymer coats on the other drug-eluting stents may, in part, be why they have led to some problems with late thrombosis, Dr. Mauri said. But a study designed to definitively show whether these stents differ in their rate of late thrombosis would require several thousand patients.

SAN FRANCISCO — Use of the Gore TAG thoracic endograft markedly reduced morbidity and mortality, compared with open repair through 2 years of follow-up, R. Scott Mitchell, M.D., said at the annual meeting of the American Association for Thoracic Surgery.

Earlier this year, the catheter-delivered Gore TAG device was approved as the first stent graft for treating descending thoracic aortic aneurysms. It consists of a Teflon tube covered by a nitinol exoskeleton. Although several endovascular devices for treatment of abdominal aortic aneurysms are on the market, endoprostheses for the less frequent thoracic aortic aneurysms has been slower to develop. The Gore TAG was the first such device to enter clinical trials, which were halted for 2 years upon discovery that it was prone to asymptomatic stent fractures along the graft spine.

The 17-center prospective nonrandomized trial compared outcomes in 140 patients with endovascular repair using the Gore TAG and a historical control group of 94 patients with a conventional open repair.

Mean estimated procedural blood loss was 472 mL in the Gore TAG group vs. 2,402 mL with open surgery. Temporary or permanent paraplegia occurred within 30 days in 3% of the Gore TAG group and 14% of controls. Early mortality in the Gore TAG group was 2%, compared with 6% in controls. The 3.5% perioperative stroke rate in the Gore TAG group was significantly lower than in controls. Rates of renal dysfunction and cardiac complications were also lower. ICU time and hospital length of stay were markedly shorter in the Gore TAG patients, who were able to return to normal activities in an average of 30 days, vs. 78 days in the open-surgery patients.

The rate of 2-year freedom from aneurysm-related mortality was 98% in the stent group and 91% in controls. However, all-cause mortality was similar in the two groups, at about 25%, according to Dr. Mitchell, professor of cardiovascular surgery at Stanford (Calif.) University and co-principal investigator in the trial.

Over 2 years of follow-up, 15% of Gore TAG-treated patients had an endoleak, for which four underwent endovascular revision; one required an open conversion.

During follow-up, the aneurysm sac decreased in size by more than 5 mm in 24 patients and grew by more than 5 mm in 11 patients. There have been no late aneurysm ruptures.

“I think these complications will be ongoing. Hopefully they'll be decreasing with time. But we don't know that, so these patients will require lifelong follow-up,” the surgeon stressed.

The device is not for everyone. It requires access vessels that allow passage of a 20–24 French sheath. The patient must have a minimum 2-cm landing zone of normal thoracic aorta free of thrombus or calcification proximal and distal to the aneurysm. Patients with Marfan syndrome and other connective tissue disorders were excluded from the trial, and Dr. Mitchell urged that the same policy be followed in clinical practice because the device is unlikely to be effective in that population.

Roughly 10,000–15,000 thoracic aortic aneurysms are diagnosed annually, often in elderly patients who are not good surgical candidates. The Gore TAG device, which spares patients the large chest incision and prolonged aortic clamping entailed in open surgery, could expand the pool of patients who can undergo repair.

Recognizing this, discussant Joseph S. Coselli, M.D., of Baylor College of Medicine in Houston, predicted, “this technology will forever alter how we approach descending thoracic aortic aneurysm pathology.” He added, however, that many participants in the control group for this trial were retrospectively acquired.

“It's not the best control group. We admit that,” said Dr. Mitchell. “But I think all of us are aware of the difficulties in trying to get a very aware public to enroll in a randomized trial.”

He is a consultant to W.L. Gore & Associates Inc., the study sponsor.

SAN FRANCISCO — Use of the Gore TAG thoracic endograft markedly reduced morbidity and mortality, compared with open repair through 2 years of follow-up, R. Scott Mitchell, M.D., said at the annual meeting of the American Association for Thoracic Surgery.

Earlier this year, the catheter-delivered Gore TAG device was approved as the first stent graft for treating descending thoracic aortic aneurysms. It consists of a Teflon tube covered by a nitinol exoskeleton. Although several endovascular devices for treatment of abdominal aortic aneurysms are on the market, endoprostheses for the less frequent thoracic aortic aneurysms has been slower to develop. The Gore TAG was the first such device to enter clinical trials, which were halted for 2 years upon discovery that it was prone to asymptomatic stent fractures along the graft spine.

The 17-center prospective nonrandomized trial compared outcomes in 140 patients with endovascular repair using the Gore TAG and a historical control group of 94 patients with a conventional open repair.

Mean estimated procedural blood loss was 472 mL in the Gore TAG group vs. 2,402 mL with open surgery. Temporary or permanent paraplegia occurred within 30 days in 3% of the Gore TAG group and 14% of controls. Early mortality in the Gore TAG group was 2%, compared with 6% in controls. The 3.5% perioperative stroke rate in the Gore TAG group was significantly lower than in controls. Rates of renal dysfunction and cardiac complications were also lower. ICU time and hospital length of stay were markedly shorter in the Gore TAG patients, who were able to return to normal activities in an average of 30 days, vs. 78 days in the open-surgery patients.

The rate of 2-year freedom from aneurysm-related mortality was 98% in the stent group and 91% in controls. However, all-cause mortality was similar in the two groups, at about 25%, according to Dr. Mitchell, professor of cardiovascular surgery at Stanford (Calif.) University and co-principal investigator in the trial.

Over 2 years of follow-up, 15% of Gore TAG-treated patients had an endoleak, for which four underwent endovascular revision; one required an open conversion.

During follow-up, the aneurysm sac decreased in size by more than 5 mm in 24 patients and grew by more than 5 mm in 11 patients. There have been no late aneurysm ruptures.

“I think these complications will be ongoing. Hopefully they'll be decreasing with time. But we don't know that, so these patients will require lifelong follow-up,” the surgeon stressed.

The device is not for everyone. It requires access vessels that allow passage of a 20–24 French sheath. The patient must have a minimum 2-cm landing zone of normal thoracic aorta free of thrombus or calcification proximal and distal to the aneurysm. Patients with Marfan syndrome and other connective tissue disorders were excluded from the trial, and Dr. Mitchell urged that the same policy be followed in clinical practice because the device is unlikely to be effective in that population.

Roughly 10,000–15,000 thoracic aortic aneurysms are diagnosed annually, often in elderly patients who are not good surgical candidates. The Gore TAG device, which spares patients the large chest incision and prolonged aortic clamping entailed in open surgery, could expand the pool of patients who can undergo repair.

Recognizing this, discussant Joseph S. Coselli, M.D., of Baylor College of Medicine in Houston, predicted, “this technology will forever alter how we approach descending thoracic aortic aneurysm pathology.” He added, however, that many participants in the control group for this trial were retrospectively acquired.

“It's not the best control group. We admit that,” said Dr. Mitchell. “But I think all of us are aware of the difficulties in trying to get a very aware public to enroll in a randomized trial.”

He is a consultant to W.L. Gore & Associates Inc., the study sponsor.

SAN FRANCISCO — Use of the Gore TAG thoracic endograft markedly reduced morbidity and mortality, compared with open repair through 2 years of follow-up, R. Scott Mitchell, M.D., said at the annual meeting of the American Association for Thoracic Surgery.

Earlier this year, the catheter-delivered Gore TAG device was approved as the first stent graft for treating descending thoracic aortic aneurysms. It consists of a Teflon tube covered by a nitinol exoskeleton. Although several endovascular devices for treatment of abdominal aortic aneurysms are on the market, endoprostheses for the less frequent thoracic aortic aneurysms has been slower to develop. The Gore TAG was the first such device to enter clinical trials, which were halted for 2 years upon discovery that it was prone to asymptomatic stent fractures along the graft spine.

The 17-center prospective nonrandomized trial compared outcomes in 140 patients with endovascular repair using the Gore TAG and a historical control group of 94 patients with a conventional open repair.

Mean estimated procedural blood loss was 472 mL in the Gore TAG group vs. 2,402 mL with open surgery. Temporary or permanent paraplegia occurred within 30 days in 3% of the Gore TAG group and 14% of controls. Early mortality in the Gore TAG group was 2%, compared with 6% in controls. The 3.5% perioperative stroke rate in the Gore TAG group was significantly lower than in controls. Rates of renal dysfunction and cardiac complications were also lower. ICU time and hospital length of stay were markedly shorter in the Gore TAG patients, who were able to return to normal activities in an average of 30 days, vs. 78 days in the open-surgery patients.

The rate of 2-year freedom from aneurysm-related mortality was 98% in the stent group and 91% in controls. However, all-cause mortality was similar in the two groups, at about 25%, according to Dr. Mitchell, professor of cardiovascular surgery at Stanford (Calif.) University and co-principal investigator in the trial.

Over 2 years of follow-up, 15% of Gore TAG-treated patients had an endoleak, for which four underwent endovascular revision; one required an open conversion.

During follow-up, the aneurysm sac decreased in size by more than 5 mm in 24 patients and grew by more than 5 mm in 11 patients. There have been no late aneurysm ruptures.

“I think these complications will be ongoing. Hopefully they'll be decreasing with time. But we don't know that, so these patients will require lifelong follow-up,” the surgeon stressed.

The device is not for everyone. It requires access vessels that allow passage of a 20–24 French sheath. The patient must have a minimum 2-cm landing zone of normal thoracic aorta free of thrombus or calcification proximal and distal to the aneurysm. Patients with Marfan syndrome and other connective tissue disorders were excluded from the trial, and Dr. Mitchell urged that the same policy be followed in clinical practice because the device is unlikely to be effective in that population.

Roughly 10,000–15,000 thoracic aortic aneurysms are diagnosed annually, often in elderly patients who are not good surgical candidates. The Gore TAG device, which spares patients the large chest incision and prolonged aortic clamping entailed in open surgery, could expand the pool of patients who can undergo repair.

Recognizing this, discussant Joseph S. Coselli, M.D., of Baylor College of Medicine in Houston, predicted, “this technology will forever alter how we approach descending thoracic aortic aneurysm pathology.” He added, however, that many participants in the control group for this trial were retrospectively acquired.

“It's not the best control group. We admit that,” said Dr. Mitchell. “But I think all of us are aware of the difficulties in trying to get a very aware public to enroll in a randomized trial.”

He is a consultant to W.L. Gore & Associates Inc., the study sponsor.