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Initiate Prevention of Steroid-Induced Bone Loss in SLE Early
BIRMINGHAM, ENGLAND — All patients with systemic lupus erythematosus who are taking 7.5 mg prednisone or more daily should be treated to prevent bone loss, Bevra Hahn, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Almost everyone loses bone mass at that level of steroid treatment, and relatively rapidly. “We know most bone loss occurs in the first 12 months of steroid treatment, so there isn't any point … waiting until the disease goes into remission—and lupus hardly ever goes into true remission—or waiting until they are better or their drug regimen is simpler,” she said.
Despite the fact that estrogen therapy is “out,” there are still treatment options. Calcium plus vitamin D supplementation is a typical initial approach, and has a small but measurable impact on reducing the degree of bone loss.
Another choice would be to use a vitamin D metabolite such as calcitriol. “These are more effective, but if you use a vitamin D metabolite, don't give supplemental calcium and be sure to monitor for hypercalcemia and maybe even hypercalcuria if you are practicing in an area where there are a lot of renal stones,” said Dr. Hahn, professor of medicine and chief of rheumatology, University of California, Los Angeles. Hypercalcemia is particularly hazardous when patients are acutely ill and take to bed. The drug should be stopped at that time, she said.
But there's no question in 2005 that bisphosphonate therapy is the most effective strategy to prevent bone loss in steroid-induced osteoporosis, she said. In fact, calcium plus ordinary vitamin D has been used as the placebo in a lot of the clinical trials of bisphosphonates.
“It doesn't matter which one you choose—whichever one you like. Now that Fosamax comes in a liquid I have a lot more patients who can tolerate bisphosphonate therapy,” she said. Liquid alendronate causes less esophageal irritation and gastric distress than the capsules, she said.
Another option for certain patients is treatment with the anabolic hormone PTH 1–34 (teriparatide, Forteo). This drug is useful for patients who have very low bone turnover and are continuing to fracture despite treatment with bisphosphonates, active vitamin D, and calcitonin, she said.
In some patients it isn't enough to turn the osteoclast off, which is how these drugs work. For these patients it's also necessary to turn the osteoblast on, which is what PTH does, she said.
PTH stimulates osteoblast accumulation and bone formation through receptor signals that modulate osteoblast proliferation and maturation. It also increases the lifespan and productivity of the osteoblast by preventing apoptosis (Treat. Endocrinol. 2002:1;175–90).
Unfortunately, patients don't like to take this drug because it's injectable and must be taken every day or every other day. But three other formulations, two injectable and one oral, are now in clinical trials (Expert Opin. Investig. Drugs 2005;14:251–64).
One caution is needed with using PTH in patients with lupus. “This is not recommended by anybody but me, but I think you should screen your patients for hyperparathyroidism before you start PTH. I have found elevated levels of parathyroid hormone in one-third of my lupus patients, and we shouldn't be giving PTH to people who already have primary hyperparathyroidism,” she said.
BIRMINGHAM, ENGLAND — All patients with systemic lupus erythematosus who are taking 7.5 mg prednisone or more daily should be treated to prevent bone loss, Bevra Hahn, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Almost everyone loses bone mass at that level of steroid treatment, and relatively rapidly. “We know most bone loss occurs in the first 12 months of steroid treatment, so there isn't any point … waiting until the disease goes into remission—and lupus hardly ever goes into true remission—or waiting until they are better or their drug regimen is simpler,” she said.
Despite the fact that estrogen therapy is “out,” there are still treatment options. Calcium plus vitamin D supplementation is a typical initial approach, and has a small but measurable impact on reducing the degree of bone loss.
Another choice would be to use a vitamin D metabolite such as calcitriol. “These are more effective, but if you use a vitamin D metabolite, don't give supplemental calcium and be sure to monitor for hypercalcemia and maybe even hypercalcuria if you are practicing in an area where there are a lot of renal stones,” said Dr. Hahn, professor of medicine and chief of rheumatology, University of California, Los Angeles. Hypercalcemia is particularly hazardous when patients are acutely ill and take to bed. The drug should be stopped at that time, she said.
But there's no question in 2005 that bisphosphonate therapy is the most effective strategy to prevent bone loss in steroid-induced osteoporosis, she said. In fact, calcium plus ordinary vitamin D has been used as the placebo in a lot of the clinical trials of bisphosphonates.
“It doesn't matter which one you choose—whichever one you like. Now that Fosamax comes in a liquid I have a lot more patients who can tolerate bisphosphonate therapy,” she said. Liquid alendronate causes less esophageal irritation and gastric distress than the capsules, she said.
Another option for certain patients is treatment with the anabolic hormone PTH 1–34 (teriparatide, Forteo). This drug is useful for patients who have very low bone turnover and are continuing to fracture despite treatment with bisphosphonates, active vitamin D, and calcitonin, she said.
In some patients it isn't enough to turn the osteoclast off, which is how these drugs work. For these patients it's also necessary to turn the osteoblast on, which is what PTH does, she said.
PTH stimulates osteoblast accumulation and bone formation through receptor signals that modulate osteoblast proliferation and maturation. It also increases the lifespan and productivity of the osteoblast by preventing apoptosis (Treat. Endocrinol. 2002:1;175–90).
Unfortunately, patients don't like to take this drug because it's injectable and must be taken every day or every other day. But three other formulations, two injectable and one oral, are now in clinical trials (Expert Opin. Investig. Drugs 2005;14:251–64).
One caution is needed with using PTH in patients with lupus. “This is not recommended by anybody but me, but I think you should screen your patients for hyperparathyroidism before you start PTH. I have found elevated levels of parathyroid hormone in one-third of my lupus patients, and we shouldn't be giving PTH to people who already have primary hyperparathyroidism,” she said.
BIRMINGHAM, ENGLAND — All patients with systemic lupus erythematosus who are taking 7.5 mg prednisone or more daily should be treated to prevent bone loss, Bevra Hahn, M.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Almost everyone loses bone mass at that level of steroid treatment, and relatively rapidly. “We know most bone loss occurs in the first 12 months of steroid treatment, so there isn't any point … waiting until the disease goes into remission—and lupus hardly ever goes into true remission—or waiting until they are better or their drug regimen is simpler,” she said.
Despite the fact that estrogen therapy is “out,” there are still treatment options. Calcium plus vitamin D supplementation is a typical initial approach, and has a small but measurable impact on reducing the degree of bone loss.
Another choice would be to use a vitamin D metabolite such as calcitriol. “These are more effective, but if you use a vitamin D metabolite, don't give supplemental calcium and be sure to monitor for hypercalcemia and maybe even hypercalcuria if you are practicing in an area where there are a lot of renal stones,” said Dr. Hahn, professor of medicine and chief of rheumatology, University of California, Los Angeles. Hypercalcemia is particularly hazardous when patients are acutely ill and take to bed. The drug should be stopped at that time, she said.
But there's no question in 2005 that bisphosphonate therapy is the most effective strategy to prevent bone loss in steroid-induced osteoporosis, she said. In fact, calcium plus ordinary vitamin D has been used as the placebo in a lot of the clinical trials of bisphosphonates.
“It doesn't matter which one you choose—whichever one you like. Now that Fosamax comes in a liquid I have a lot more patients who can tolerate bisphosphonate therapy,” she said. Liquid alendronate causes less esophageal irritation and gastric distress than the capsules, she said.
Another option for certain patients is treatment with the anabolic hormone PTH 1–34 (teriparatide, Forteo). This drug is useful for patients who have very low bone turnover and are continuing to fracture despite treatment with bisphosphonates, active vitamin D, and calcitonin, she said.
In some patients it isn't enough to turn the osteoclast off, which is how these drugs work. For these patients it's also necessary to turn the osteoblast on, which is what PTH does, she said.
PTH stimulates osteoblast accumulation and bone formation through receptor signals that modulate osteoblast proliferation and maturation. It also increases the lifespan and productivity of the osteoblast by preventing apoptosis (Treat. Endocrinol. 2002:1;175–90).
Unfortunately, patients don't like to take this drug because it's injectable and must be taken every day or every other day. But three other formulations, two injectable and one oral, are now in clinical trials (Expert Opin. Investig. Drugs 2005;14:251–64).
One caution is needed with using PTH in patients with lupus. “This is not recommended by anybody but me, but I think you should screen your patients for hyperparathyroidism before you start PTH. I have found elevated levels of parathyroid hormone in one-third of my lupus patients, and we shouldn't be giving PTH to people who already have primary hyperparathyroidism,” she said.
New Targets Under Investigation for Wegener's
NEW YORK — Treatment of Wegener's granulomatosis continues to challenge and evolve, as researchers investigate the complex molecular cross-talk underlying immune dysfunction, looking for new ways to target therapy, and clinicians seek new ways to balance necessarily aggressive cytotoxic treatment against the potential for serious adverse events.
Standard induction treatment for severe vasculitis associated with the presence of antineutrophil cytoplasmic antibodies (ANCA) remains cyclophosphamide plus glucocorticoids—a regimen that is lifesaving, Gary S. Hoffman, M.D., said at a rheumatology meeting sponsored by New York University.
But because of the high incidence of bladder cancer and other serious toxicities associated with long-term use of cyclophosphamide, once remission is achieved, maintenance therapy with methotrexate or azathioprine is now preferred, he said.
Relapse remains problematic, however, and a subset of patients do not respond to the most cytotoxic cyclophosphamide-based regimen.
For these patients, a potential new approach has emerged: B-cell depletion with rituximab, said Dr. Hoffman, chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic Foundation.
A group of 11 patients who had active, ANCA-positive vasculitis and either did not respond to cyclophosphamide or who had contraindications to its use were given infusions of rituximab (Rituxan) plus glucocorticoids on a compassionate use basis. Ten of the patients had Wegener's granulomatosis, and one had a related ANCA-associated vasculitis, microscopic polyangiitis.
Not only did all 11 achieve remission, but they also were able to discontinue steroids, which has not been possible before, said Dr. Hoffman, who was not involved in the study.
All patients had significant decreases in ANCA, which are thought to mediate the glomerulonephritis and small vessel vasculitis, and 8 of the 11 became ANCA negative.
B-cell depletion typically persists for months following rituximab treatment; all patients remained in remission while B cells were undetectable.
Reappearance of B cells occurred in nine patients, 4–12 months after infusion. Two patients experienced disease relapse following discontinuation of glucocorticoids but recovered after resuming the rituximab/glucocorticoid regimen. Three others whose ANCA titers began to rise were retreated preemptively with rituximab alone and have remained in remission (Arthritis Rheum. 2005;52:262–8). The remaining four patients whose B cells repopulated did not revert to ANCA positivity.
Rituximab targets the CD20 receptor on the surface of B cells, and one rationale for using the drug in Wegener's granulomatosis is that it is able to deplete CD20-expressing precursors of ANCA-producing plasma cells (Arthritis Rheum. 2005;52:1–5).
A randomized, double-blind trial, Rituximab in ANCA-Associated Vasculitis (RAVE) is underway, with the goal of addressing the issue of whether targeted therapy, rather than broad-based immunosuppression, can provide enduring remission.
Many mediators other than B cells are involved in the inflammatory process of vasculitis, including dendritic cells, macrophages, and various different cytokines that interact with one another.
A previous trial evaluated the tumor necrosis factor (TNF)-α blocking agent etanercept (Enbrel), because the evidence suggested that this cytokine plays a role.
But a randomized, placebo-controlled trial that included 174 patients from eight centers found no benefit in the addition of etanercept to standard therapy. Furthermore, six patients who were taking etanercept plus cyclophosphamide developed solid tumors (N. Engl. J. Med. 2005;352:351–61).
“We didn't see this with people who were on methotrexate plus etanercept, and it's a major concern,” said Dr. Hoffman, who was coprincipal investigator for the trial.
“The new opportunities for selective targets certainly are seductive, and we hope they will work, but we cannot dismiss what we've learned from the history of this disease, which is that it carries a very high risk of morbidity and mortality, and that although our conventional therapy has risks, it is lifesaving,” he said.
Before glucocorticoids began being used for Wegener's granulomatosis, survival was only 50% at 5 months, and most patients died within 2 years of diagnosis. Even with glucocorticoids, survival increased only slightly, to 50% at 1 year.
The addition of cyclophosphamide to the regimen, first reported by the National Institutes of Health in the early 1970s, increased survival to 80% at 8 years.
“But I think we still have a long road ahead of us. I hope the future looks great, but I view it with guarded optimism,” Dr. Hoffman said.
NEW YORK — Treatment of Wegener's granulomatosis continues to challenge and evolve, as researchers investigate the complex molecular cross-talk underlying immune dysfunction, looking for new ways to target therapy, and clinicians seek new ways to balance necessarily aggressive cytotoxic treatment against the potential for serious adverse events.
Standard induction treatment for severe vasculitis associated with the presence of antineutrophil cytoplasmic antibodies (ANCA) remains cyclophosphamide plus glucocorticoids—a regimen that is lifesaving, Gary S. Hoffman, M.D., said at a rheumatology meeting sponsored by New York University.
But because of the high incidence of bladder cancer and other serious toxicities associated with long-term use of cyclophosphamide, once remission is achieved, maintenance therapy with methotrexate or azathioprine is now preferred, he said.
Relapse remains problematic, however, and a subset of patients do not respond to the most cytotoxic cyclophosphamide-based regimen.
For these patients, a potential new approach has emerged: B-cell depletion with rituximab, said Dr. Hoffman, chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic Foundation.
A group of 11 patients who had active, ANCA-positive vasculitis and either did not respond to cyclophosphamide or who had contraindications to its use were given infusions of rituximab (Rituxan) plus glucocorticoids on a compassionate use basis. Ten of the patients had Wegener's granulomatosis, and one had a related ANCA-associated vasculitis, microscopic polyangiitis.
Not only did all 11 achieve remission, but they also were able to discontinue steroids, which has not been possible before, said Dr. Hoffman, who was not involved in the study.
All patients had significant decreases in ANCA, which are thought to mediate the glomerulonephritis and small vessel vasculitis, and 8 of the 11 became ANCA negative.
B-cell depletion typically persists for months following rituximab treatment; all patients remained in remission while B cells were undetectable.
Reappearance of B cells occurred in nine patients, 4–12 months after infusion. Two patients experienced disease relapse following discontinuation of glucocorticoids but recovered after resuming the rituximab/glucocorticoid regimen. Three others whose ANCA titers began to rise were retreated preemptively with rituximab alone and have remained in remission (Arthritis Rheum. 2005;52:262–8). The remaining four patients whose B cells repopulated did not revert to ANCA positivity.
Rituximab targets the CD20 receptor on the surface of B cells, and one rationale for using the drug in Wegener's granulomatosis is that it is able to deplete CD20-expressing precursors of ANCA-producing plasma cells (Arthritis Rheum. 2005;52:1–5).
A randomized, double-blind trial, Rituximab in ANCA-Associated Vasculitis (RAVE) is underway, with the goal of addressing the issue of whether targeted therapy, rather than broad-based immunosuppression, can provide enduring remission.
Many mediators other than B cells are involved in the inflammatory process of vasculitis, including dendritic cells, macrophages, and various different cytokines that interact with one another.
A previous trial evaluated the tumor necrosis factor (TNF)-α blocking agent etanercept (Enbrel), because the evidence suggested that this cytokine plays a role.
But a randomized, placebo-controlled trial that included 174 patients from eight centers found no benefit in the addition of etanercept to standard therapy. Furthermore, six patients who were taking etanercept plus cyclophosphamide developed solid tumors (N. Engl. J. Med. 2005;352:351–61).
“We didn't see this with people who were on methotrexate plus etanercept, and it's a major concern,” said Dr. Hoffman, who was coprincipal investigator for the trial.
“The new opportunities for selective targets certainly are seductive, and we hope they will work, but we cannot dismiss what we've learned from the history of this disease, which is that it carries a very high risk of morbidity and mortality, and that although our conventional therapy has risks, it is lifesaving,” he said.
Before glucocorticoids began being used for Wegener's granulomatosis, survival was only 50% at 5 months, and most patients died within 2 years of diagnosis. Even with glucocorticoids, survival increased only slightly, to 50% at 1 year.
The addition of cyclophosphamide to the regimen, first reported by the National Institutes of Health in the early 1970s, increased survival to 80% at 8 years.
“But I think we still have a long road ahead of us. I hope the future looks great, but I view it with guarded optimism,” Dr. Hoffman said.
NEW YORK — Treatment of Wegener's granulomatosis continues to challenge and evolve, as researchers investigate the complex molecular cross-talk underlying immune dysfunction, looking for new ways to target therapy, and clinicians seek new ways to balance necessarily aggressive cytotoxic treatment against the potential for serious adverse events.
Standard induction treatment for severe vasculitis associated with the presence of antineutrophil cytoplasmic antibodies (ANCA) remains cyclophosphamide plus glucocorticoids—a regimen that is lifesaving, Gary S. Hoffman, M.D., said at a rheumatology meeting sponsored by New York University.
But because of the high incidence of bladder cancer and other serious toxicities associated with long-term use of cyclophosphamide, once remission is achieved, maintenance therapy with methotrexate or azathioprine is now preferred, he said.
Relapse remains problematic, however, and a subset of patients do not respond to the most cytotoxic cyclophosphamide-based regimen.
For these patients, a potential new approach has emerged: B-cell depletion with rituximab, said Dr. Hoffman, chair of the department of rheumatic and immunologic diseases at the Cleveland Clinic Foundation.
A group of 11 patients who had active, ANCA-positive vasculitis and either did not respond to cyclophosphamide or who had contraindications to its use were given infusions of rituximab (Rituxan) plus glucocorticoids on a compassionate use basis. Ten of the patients had Wegener's granulomatosis, and one had a related ANCA-associated vasculitis, microscopic polyangiitis.
Not only did all 11 achieve remission, but they also were able to discontinue steroids, which has not been possible before, said Dr. Hoffman, who was not involved in the study.
All patients had significant decreases in ANCA, which are thought to mediate the glomerulonephritis and small vessel vasculitis, and 8 of the 11 became ANCA negative.
B-cell depletion typically persists for months following rituximab treatment; all patients remained in remission while B cells were undetectable.
Reappearance of B cells occurred in nine patients, 4–12 months after infusion. Two patients experienced disease relapse following discontinuation of glucocorticoids but recovered after resuming the rituximab/glucocorticoid regimen. Three others whose ANCA titers began to rise were retreated preemptively with rituximab alone and have remained in remission (Arthritis Rheum. 2005;52:262–8). The remaining four patients whose B cells repopulated did not revert to ANCA positivity.
Rituximab targets the CD20 receptor on the surface of B cells, and one rationale for using the drug in Wegener's granulomatosis is that it is able to deplete CD20-expressing precursors of ANCA-producing plasma cells (Arthritis Rheum. 2005;52:1–5).
A randomized, double-blind trial, Rituximab in ANCA-Associated Vasculitis (RAVE) is underway, with the goal of addressing the issue of whether targeted therapy, rather than broad-based immunosuppression, can provide enduring remission.
Many mediators other than B cells are involved in the inflammatory process of vasculitis, including dendritic cells, macrophages, and various different cytokines that interact with one another.
A previous trial evaluated the tumor necrosis factor (TNF)-α blocking agent etanercept (Enbrel), because the evidence suggested that this cytokine plays a role.
But a randomized, placebo-controlled trial that included 174 patients from eight centers found no benefit in the addition of etanercept to standard therapy. Furthermore, six patients who were taking etanercept plus cyclophosphamide developed solid tumors (N. Engl. J. Med. 2005;352:351–61).
“We didn't see this with people who were on methotrexate plus etanercept, and it's a major concern,” said Dr. Hoffman, who was coprincipal investigator for the trial.
“The new opportunities for selective targets certainly are seductive, and we hope they will work, but we cannot dismiss what we've learned from the history of this disease, which is that it carries a very high risk of morbidity and mortality, and that although our conventional therapy has risks, it is lifesaving,” he said.
Before glucocorticoids began being used for Wegener's granulomatosis, survival was only 50% at 5 months, and most patients died within 2 years of diagnosis. Even with glucocorticoids, survival increased only slightly, to 50% at 1 year.
The addition of cyclophosphamide to the regimen, first reported by the National Institutes of Health in the early 1970s, increased survival to 80% at 8 years.
“But I think we still have a long road ahead of us. I hope the future looks great, but I view it with guarded optimism,” Dr. Hoffman said.
Annual CV Risk Evaluation a Must In Lupus Patients
LONDON — Patients with systemic lupus erythematosus should be evaluated on an annual basis for cardiovascular risk until such time as specific recommendations are formulated, Heiko Schotte, M.D., said at the Sixth European Lupus Meeting.
Results of procedures that detect coronary insufficiency, surrogates of atherosclerotic burden, and echocardiographic findings are often abnormal in SLE, but evidence to support routine screening is not currently available. “Therefore, based on the recommendations that have been proposed for other conditions associated with cardiovascular disease, we suggest annual assessment of traditional risk factors including diabetes mellitus, dyslipidemia, hypertension, smoking, and family history of premature coronary disease,” Dr. Schotte said in a poster session at the meeting, which was sponsored by the British Society for Rheumatology.
If two or more risk factors are present, an exercise ECG should be done, he said.
SLE can involve the pericardium, myocardium, and valves—and pulmonary hypertension also often develops. Echocardiography also should be done each year to look for any of these abnormalities, even in asymptomatic patients, he said.
These recommendations must be confirmed in prospective studies, and should be enlarged to include other SLE-specific risk factors such as antiphospholipid antibodies and long-term corticosteroid therapy, said Dr. Schotte of the department of medicine, Muenster (Germany) University Hospital.
LONDON — Patients with systemic lupus erythematosus should be evaluated on an annual basis for cardiovascular risk until such time as specific recommendations are formulated, Heiko Schotte, M.D., said at the Sixth European Lupus Meeting.
Results of procedures that detect coronary insufficiency, surrogates of atherosclerotic burden, and echocardiographic findings are often abnormal in SLE, but evidence to support routine screening is not currently available. “Therefore, based on the recommendations that have been proposed for other conditions associated with cardiovascular disease, we suggest annual assessment of traditional risk factors including diabetes mellitus, dyslipidemia, hypertension, smoking, and family history of premature coronary disease,” Dr. Schotte said in a poster session at the meeting, which was sponsored by the British Society for Rheumatology.
If two or more risk factors are present, an exercise ECG should be done, he said.
SLE can involve the pericardium, myocardium, and valves—and pulmonary hypertension also often develops. Echocardiography also should be done each year to look for any of these abnormalities, even in asymptomatic patients, he said.
These recommendations must be confirmed in prospective studies, and should be enlarged to include other SLE-specific risk factors such as antiphospholipid antibodies and long-term corticosteroid therapy, said Dr. Schotte of the department of medicine, Muenster (Germany) University Hospital.
LONDON — Patients with systemic lupus erythematosus should be evaluated on an annual basis for cardiovascular risk until such time as specific recommendations are formulated, Heiko Schotte, M.D., said at the Sixth European Lupus Meeting.
Results of procedures that detect coronary insufficiency, surrogates of atherosclerotic burden, and echocardiographic findings are often abnormal in SLE, but evidence to support routine screening is not currently available. “Therefore, based on the recommendations that have been proposed for other conditions associated with cardiovascular disease, we suggest annual assessment of traditional risk factors including diabetes mellitus, dyslipidemia, hypertension, smoking, and family history of premature coronary disease,” Dr. Schotte said in a poster session at the meeting, which was sponsored by the British Society for Rheumatology.
If two or more risk factors are present, an exercise ECG should be done, he said.
SLE can involve the pericardium, myocardium, and valves—and pulmonary hypertension also often develops. Echocardiography also should be done each year to look for any of these abnormalities, even in asymptomatic patients, he said.
These recommendations must be confirmed in prospective studies, and should be enlarged to include other SLE-specific risk factors such as antiphospholipid antibodies and long-term corticosteroid therapy, said Dr. Schotte of the department of medicine, Muenster (Germany) University Hospital.
Antimalarials May Have Survival Benefit in SLE
LONDON — The list of reasons for treating patients who have lupus with antimalarial drugs now includes long-term survival benefits, according to a Spanish cohort study.
Antimalarials have proved beneficial for several aspects of systemic lupus erythematosus (SLE), such as for controlling disease activity, improving lipid profiles, and preventing thrombosis. But an analysis of 15 years' follow-up in a group of 232 patients now has shown significant differences in survival between those treated with antimalarial drugs and those never given the drugs, Guillermo Ruiz-Irastorza, M.D., said at the Sixth European Lupus Meeting.
A total of 147 of the 232 patients (64%) in the cohort received an antimalarial at some time during the course of their disease. Thus far 23 have died. The causes of death were thrombosis (seven patients), neoplasm (six patients), infection (five patients), and other (five patients).
Of the 23, there were 19 (83%) who had never received antimalarials, said Dr. Ruiz-Irastorza of the department of internal medicine at Hospital de Cruces, University of the Basque Country, Barakaldo, Spain.
Of those treated with antimalarials, 97% remain alive, he said.
Cumulative 15-year survival rates were 68% for patients not receiving antimalarials, compared with 95% for those treated with antimalarials, which was a statistically significant difference.
After adjusting for independent covariates, including renal disease, thrombosis, neoplasia, presence of irreversible damage 6 months after diagnosis, and age at diagnosis, the adjusted hazard ratio for death at 15 years for those not receiving antimalarials was found to be 3.8, he said at the meeting, sponsored by the British Society for Rheumatology.
The limitations of the study include its nonrandomized design, and the fact that it is a homogeneous population with easy access to health facilities, Dr. Ruiz-Irastorza said. The cohort consisted of 204 women and 28 men; 99% were white.
“But the protective effect is too big to reject,” he said.
These study findings suggest a beneficial effect of antimalarials on the long-term prognosis of patients with SLE. Although these results should be confirmed by randomized clinical trials, they support the routine use of antimalarials in all patients with SLE, given the drugs' safety profile, he said.
Ocular toxicity is rare at the usual dose of 200 mg/day, he noted.
LONDON — The list of reasons for treating patients who have lupus with antimalarial drugs now includes long-term survival benefits, according to a Spanish cohort study.
Antimalarials have proved beneficial for several aspects of systemic lupus erythematosus (SLE), such as for controlling disease activity, improving lipid profiles, and preventing thrombosis. But an analysis of 15 years' follow-up in a group of 232 patients now has shown significant differences in survival between those treated with antimalarial drugs and those never given the drugs, Guillermo Ruiz-Irastorza, M.D., said at the Sixth European Lupus Meeting.
A total of 147 of the 232 patients (64%) in the cohort received an antimalarial at some time during the course of their disease. Thus far 23 have died. The causes of death were thrombosis (seven patients), neoplasm (six patients), infection (five patients), and other (five patients).
Of the 23, there were 19 (83%) who had never received antimalarials, said Dr. Ruiz-Irastorza of the department of internal medicine at Hospital de Cruces, University of the Basque Country, Barakaldo, Spain.
Of those treated with antimalarials, 97% remain alive, he said.
Cumulative 15-year survival rates were 68% for patients not receiving antimalarials, compared with 95% for those treated with antimalarials, which was a statistically significant difference.
After adjusting for independent covariates, including renal disease, thrombosis, neoplasia, presence of irreversible damage 6 months after diagnosis, and age at diagnosis, the adjusted hazard ratio for death at 15 years for those not receiving antimalarials was found to be 3.8, he said at the meeting, sponsored by the British Society for Rheumatology.
The limitations of the study include its nonrandomized design, and the fact that it is a homogeneous population with easy access to health facilities, Dr. Ruiz-Irastorza said. The cohort consisted of 204 women and 28 men; 99% were white.
“But the protective effect is too big to reject,” he said.
These study findings suggest a beneficial effect of antimalarials on the long-term prognosis of patients with SLE. Although these results should be confirmed by randomized clinical trials, they support the routine use of antimalarials in all patients with SLE, given the drugs' safety profile, he said.
Ocular toxicity is rare at the usual dose of 200 mg/day, he noted.
LONDON — The list of reasons for treating patients who have lupus with antimalarial drugs now includes long-term survival benefits, according to a Spanish cohort study.
Antimalarials have proved beneficial for several aspects of systemic lupus erythematosus (SLE), such as for controlling disease activity, improving lipid profiles, and preventing thrombosis. But an analysis of 15 years' follow-up in a group of 232 patients now has shown significant differences in survival between those treated with antimalarial drugs and those never given the drugs, Guillermo Ruiz-Irastorza, M.D., said at the Sixth European Lupus Meeting.
A total of 147 of the 232 patients (64%) in the cohort received an antimalarial at some time during the course of their disease. Thus far 23 have died. The causes of death were thrombosis (seven patients), neoplasm (six patients), infection (five patients), and other (five patients).
Of the 23, there were 19 (83%) who had never received antimalarials, said Dr. Ruiz-Irastorza of the department of internal medicine at Hospital de Cruces, University of the Basque Country, Barakaldo, Spain.
Of those treated with antimalarials, 97% remain alive, he said.
Cumulative 15-year survival rates were 68% for patients not receiving antimalarials, compared with 95% for those treated with antimalarials, which was a statistically significant difference.
After adjusting for independent covariates, including renal disease, thrombosis, neoplasia, presence of irreversible damage 6 months after diagnosis, and age at diagnosis, the adjusted hazard ratio for death at 15 years for those not receiving antimalarials was found to be 3.8, he said at the meeting, sponsored by the British Society for Rheumatology.
The limitations of the study include its nonrandomized design, and the fact that it is a homogeneous population with easy access to health facilities, Dr. Ruiz-Irastorza said. The cohort consisted of 204 women and 28 men; 99% were white.
“But the protective effect is too big to reject,” he said.
These study findings suggest a beneficial effect of antimalarials on the long-term prognosis of patients with SLE. Although these results should be confirmed by randomized clinical trials, they support the routine use of antimalarials in all patients with SLE, given the drugs' safety profile, he said.
Ocular toxicity is rare at the usual dose of 200 mg/day, he noted.
Study Links Lupus to a Range of Pulmonary Complications
LONDON — Long-term follow-up of the 1,500-patient Johns Hopkins lupus cohort is providing some much needed data about the profile and natural history of pulmonary disease in patients with systemic lupus erythematosus, according to Michelle Petri, M.D.
Pleurisy is the most common pulmonary manifestation of lupus, with a prevalence of approximately 40%–60%. The majority of patients who ever experience pleurisy have their first episode within a year of their lupus diagnosis, Dr. Petri said at the Sixth European Lupus Meeting.
The condition, which can be unilateral or bilateral, is more common among African Americans and is often accompanied by fever and lymphadenopathy. Patients also typically have other manifestations of lupus such as Raynaud's phenomenon, arthritis, and cardiac murmurs, said Dr. Petri, professor in the division of rheumatology, Johns Hopkins University, Baltimore.
“Once patients develop pleurisy, our cohort database suggests they are going to have other pulmonary problems, including pneumonitis, pulmonary hypertension, and pneumonia,” she said.
With acute lupus pneumonitis—a rare but dangerous complication—patients present with fever, dyspnea, tachypnea, and hemoptysis. “Your job in the first 24 hours is to treat and rule out infection at the same time,” Dr. Petris said at the meeting, which was sponsored by the British Society for Rheumatology.
Lung biopsy is often required, and findings include a diffuse lymphocytic infiltrate, lymphoid nodules, and bronchiolitis. “There also is deposition of both immunoglobulin and complement, which proves this is an immune-complex-mediated condition,” she said.
In one early series, 50% of patients with lupus pneumonitis died (Medicine [Baltimore] 1975;54:397–409). “That has not been my experience. My patients have done well when treated aggressively with intravenous pulsed methylprednisolone therapy,” she said. If the patient does not stabilize within the first 48 hours and infection has been ruled out, usually with a bronchoscopy, intravenous cyclophosphamide is begun.
Another rare and equally dangerous manifestation is pulmonary hemorrhage, where patients present with fever, dyspnea, cough, and blood-tinged sputum. This condition is usually rapidly progressive, with a dramatic drop in hematocrit and bilateral pulmonary infiltrates. Diagnosis may require bronchoscopy, MRI, or CT, she said.
Treatment is similar to that for acute lupus pneumonitis, but with the addition of plasmapheresis in patients who do not stabilize. Prognosis is not good, with reported survival rates ranging from 50% to 75%.
“Pulmonary embolism is something we all have seen.” In addition to their tendency to develop nephrotic syndrome, their antiphospholipid antibody and homocysteine levels may also contribute to making them hypercoagulable.
“In our cohort data we found that, if lupus anticoagulant was present at the time of diagnosis, the patient had about a 50% chance of having a venous thromboembolism within the next 20 years,” she said.
Prevention is key in these patients, and includes some simple measures like avoiding oral contraceptives in patients with lupus anticoagulant at the time of diagnosis. “But prospective data from our cohort show that patients who are on hydroxychloroquine at more than 50% of their clinic visits had a remarkable reduction in venous thrombosis, with an odds ratio of 0.36,” she said.
Hydroxychloroquine may have a beneficial effect by lowering titers of antiphospholipid antibodies, and/or by reducing thrombus size.
Pulmonary hypertension is increasingly recognized as a complication of lupus. The condition usually is mild and most commonly seen in patients who also have Raynaud's phenomenon. In one series, mild pulmonary hypertension was detected in 14% of patients, but 5 years later that number had increased to 43%. “There's a lot of mild pulmonary hypertension out there, and with greater survival among lupus patients this is going to become more of a clinical issue that we will have to address,” she said.
Most of these severe pulmonary complications of lupus fortunately are rare, but the rarity itself presents challenges. “The only way we are going to make progress with these rare manifestations is through collaboration between all the lupus cohorts worldwide,” she said. “We need that, and we needed it yesterday.”
LONDON — Long-term follow-up of the 1,500-patient Johns Hopkins lupus cohort is providing some much needed data about the profile and natural history of pulmonary disease in patients with systemic lupus erythematosus, according to Michelle Petri, M.D.
Pleurisy is the most common pulmonary manifestation of lupus, with a prevalence of approximately 40%–60%. The majority of patients who ever experience pleurisy have their first episode within a year of their lupus diagnosis, Dr. Petri said at the Sixth European Lupus Meeting.
The condition, which can be unilateral or bilateral, is more common among African Americans and is often accompanied by fever and lymphadenopathy. Patients also typically have other manifestations of lupus such as Raynaud's phenomenon, arthritis, and cardiac murmurs, said Dr. Petri, professor in the division of rheumatology, Johns Hopkins University, Baltimore.
“Once patients develop pleurisy, our cohort database suggests they are going to have other pulmonary problems, including pneumonitis, pulmonary hypertension, and pneumonia,” she said.
With acute lupus pneumonitis—a rare but dangerous complication—patients present with fever, dyspnea, tachypnea, and hemoptysis. “Your job in the first 24 hours is to treat and rule out infection at the same time,” Dr. Petris said at the meeting, which was sponsored by the British Society for Rheumatology.
Lung biopsy is often required, and findings include a diffuse lymphocytic infiltrate, lymphoid nodules, and bronchiolitis. “There also is deposition of both immunoglobulin and complement, which proves this is an immune-complex-mediated condition,” she said.
In one early series, 50% of patients with lupus pneumonitis died (Medicine [Baltimore] 1975;54:397–409). “That has not been my experience. My patients have done well when treated aggressively with intravenous pulsed methylprednisolone therapy,” she said. If the patient does not stabilize within the first 48 hours and infection has been ruled out, usually with a bronchoscopy, intravenous cyclophosphamide is begun.
Another rare and equally dangerous manifestation is pulmonary hemorrhage, where patients present with fever, dyspnea, cough, and blood-tinged sputum. This condition is usually rapidly progressive, with a dramatic drop in hematocrit and bilateral pulmonary infiltrates. Diagnosis may require bronchoscopy, MRI, or CT, she said.
Treatment is similar to that for acute lupus pneumonitis, but with the addition of plasmapheresis in patients who do not stabilize. Prognosis is not good, with reported survival rates ranging from 50% to 75%.
“Pulmonary embolism is something we all have seen.” In addition to their tendency to develop nephrotic syndrome, their antiphospholipid antibody and homocysteine levels may also contribute to making them hypercoagulable.
“In our cohort data we found that, if lupus anticoagulant was present at the time of diagnosis, the patient had about a 50% chance of having a venous thromboembolism within the next 20 years,” she said.
Prevention is key in these patients, and includes some simple measures like avoiding oral contraceptives in patients with lupus anticoagulant at the time of diagnosis. “But prospective data from our cohort show that patients who are on hydroxychloroquine at more than 50% of their clinic visits had a remarkable reduction in venous thrombosis, with an odds ratio of 0.36,” she said.
Hydroxychloroquine may have a beneficial effect by lowering titers of antiphospholipid antibodies, and/or by reducing thrombus size.
Pulmonary hypertension is increasingly recognized as a complication of lupus. The condition usually is mild and most commonly seen in patients who also have Raynaud's phenomenon. In one series, mild pulmonary hypertension was detected in 14% of patients, but 5 years later that number had increased to 43%. “There's a lot of mild pulmonary hypertension out there, and with greater survival among lupus patients this is going to become more of a clinical issue that we will have to address,” she said.
Most of these severe pulmonary complications of lupus fortunately are rare, but the rarity itself presents challenges. “The only way we are going to make progress with these rare manifestations is through collaboration between all the lupus cohorts worldwide,” she said. “We need that, and we needed it yesterday.”
LONDON — Long-term follow-up of the 1,500-patient Johns Hopkins lupus cohort is providing some much needed data about the profile and natural history of pulmonary disease in patients with systemic lupus erythematosus, according to Michelle Petri, M.D.
Pleurisy is the most common pulmonary manifestation of lupus, with a prevalence of approximately 40%–60%. The majority of patients who ever experience pleurisy have their first episode within a year of their lupus diagnosis, Dr. Petri said at the Sixth European Lupus Meeting.
The condition, which can be unilateral or bilateral, is more common among African Americans and is often accompanied by fever and lymphadenopathy. Patients also typically have other manifestations of lupus such as Raynaud's phenomenon, arthritis, and cardiac murmurs, said Dr. Petri, professor in the division of rheumatology, Johns Hopkins University, Baltimore.
“Once patients develop pleurisy, our cohort database suggests they are going to have other pulmonary problems, including pneumonitis, pulmonary hypertension, and pneumonia,” she said.
With acute lupus pneumonitis—a rare but dangerous complication—patients present with fever, dyspnea, tachypnea, and hemoptysis. “Your job in the first 24 hours is to treat and rule out infection at the same time,” Dr. Petris said at the meeting, which was sponsored by the British Society for Rheumatology.
Lung biopsy is often required, and findings include a diffuse lymphocytic infiltrate, lymphoid nodules, and bronchiolitis. “There also is deposition of both immunoglobulin and complement, which proves this is an immune-complex-mediated condition,” she said.
In one early series, 50% of patients with lupus pneumonitis died (Medicine [Baltimore] 1975;54:397–409). “That has not been my experience. My patients have done well when treated aggressively with intravenous pulsed methylprednisolone therapy,” she said. If the patient does not stabilize within the first 48 hours and infection has been ruled out, usually with a bronchoscopy, intravenous cyclophosphamide is begun.
Another rare and equally dangerous manifestation is pulmonary hemorrhage, where patients present with fever, dyspnea, cough, and blood-tinged sputum. This condition is usually rapidly progressive, with a dramatic drop in hematocrit and bilateral pulmonary infiltrates. Diagnosis may require bronchoscopy, MRI, or CT, she said.
Treatment is similar to that for acute lupus pneumonitis, but with the addition of plasmapheresis in patients who do not stabilize. Prognosis is not good, with reported survival rates ranging from 50% to 75%.
“Pulmonary embolism is something we all have seen.” In addition to their tendency to develop nephrotic syndrome, their antiphospholipid antibody and homocysteine levels may also contribute to making them hypercoagulable.
“In our cohort data we found that, if lupus anticoagulant was present at the time of diagnosis, the patient had about a 50% chance of having a venous thromboembolism within the next 20 years,” she said.
Prevention is key in these patients, and includes some simple measures like avoiding oral contraceptives in patients with lupus anticoagulant at the time of diagnosis. “But prospective data from our cohort show that patients who are on hydroxychloroquine at more than 50% of their clinic visits had a remarkable reduction in venous thrombosis, with an odds ratio of 0.36,” she said.
Hydroxychloroquine may have a beneficial effect by lowering titers of antiphospholipid antibodies, and/or by reducing thrombus size.
Pulmonary hypertension is increasingly recognized as a complication of lupus. The condition usually is mild and most commonly seen in patients who also have Raynaud's phenomenon. In one series, mild pulmonary hypertension was detected in 14% of patients, but 5 years later that number had increased to 43%. “There's a lot of mild pulmonary hypertension out there, and with greater survival among lupus patients this is going to become more of a clinical issue that we will have to address,” she said.
Most of these severe pulmonary complications of lupus fortunately are rare, but the rarity itself presents challenges. “The only way we are going to make progress with these rare manifestations is through collaboration between all the lupus cohorts worldwide,” she said. “We need that, and we needed it yesterday.”
Out of Africa: Retrovirus Linked to Autoimmunity
BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.
Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.
The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 22%, compared with 4% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.
Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.
“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.
“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” he said. Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 16%, compared with 4% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 12%, he said.
Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.
An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases. Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome. “The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.
The upper number is the prevalence of human endogenous retrovirus (HERV)-K113 in each country. The lower number is the prevalence of HERV-K115. Courtesy Dr. David Moyes
BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.
Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.
The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 22%, compared with 4% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.
Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.
“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.
“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” he said. Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 16%, compared with 4% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 12%, he said.
Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.
An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases. Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome. “The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.
The upper number is the prevalence of human endogenous retrovirus (HERV)-K113 in each country. The lower number is the prevalence of HERV-K115. Courtesy Dr. David Moyes
BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.
Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.
The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 22%, compared with 4% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.
Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.
“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.
“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” he said. Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 16%, compared with 4% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 12%, he said.
Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.
An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases. Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome. “The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.
The upper number is the prevalence of human endogenous retrovirus (HERV)-K113 in each country. The lower number is the prevalence of HERV-K115. Courtesy Dr. David Moyes
Out of Africa: Retrovirus Linked to Autoimmunity
BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.
Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.
The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 21.8%, compared with 4.2% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.
Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.
“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.
“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” Dr. Moyes said.
Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 15.6%, compared with 4.2% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 11.6%, he said.
Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.
An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases.
Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome.
“The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.n
Map shows the prevalence of human endogenous retrovirus (HERV)-K113 (upper number) and the prevalence of HERV-K115 (lower number) in each country. Courtesy Dr. David Moyes
BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.
Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.
The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 21.8%, compared with 4.2% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.
Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.
“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.
“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” Dr. Moyes said.
Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 15.6%, compared with 4.2% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 11.6%, he said.
Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.
An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases.
Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome.
“The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.n
Map shows the prevalence of human endogenous retrovirus (HERV)-K113 (upper number) and the prevalence of HERV-K115 (lower number) in each country. Courtesy Dr. David Moyes
BIRMINGHAM, ENGLAND — A newly identified human endogenous retrovirus that is much more prevalent in Africa than in other parts of the world may place its carriers at risk for certain autoimmune diseases, David Moyes, Ph.D., said at the joint meeting of the British Society for Rheumatology and the German Society for Rheumatology.
Patients with autoimmune diseases often have elevated antibody levels to certain structural proteins of human endogenous retroviruses (HERVs), suggesting a possible role for these viruses in autoimmune disease, Dr. Moyes said.
Until recently it was thought that HERVs were ubiquitous and fixed in the population, having been incorporated into the genome before the initial wave of human migration out of Africa some 200,000 years ago. But two of these viruses, HERV-K113 and HERV-K115 are now known to vary widely in prevalence across different populations. “This means that both viruses are likely to have been incorporated into the genome during more recent human evolution and that both could potentially induce an autoimmune response,” he said.
The mean prevalence of HERV-K113 identified by polymerase chain reaction testing in a sample of 174 subjects from Kenya, Malawi, and Côte d'Ivoire was 21.8%, compared with 4.2% in a sample of 96 subjects from the United Kingdom, said Dr. Moyes of the Kennedy Institute of Rheumatology, Imperial College, London.
Similarly, HERV-K115 was present in 34% of subjects from Africa and in only 1% of those in the United Kingdom.
“When you move off the African continent to the Arabian peninsula the prevalence drops off markedly. Neither virus was detected in any of 54 samples from Papua New Guinea,” he said.
“Because of the possibility that one or both of these retroviruses could be involved in autoimmune disease, we went on to analyze their prevalence in two U.K. disease cohorts,” Dr. Moyes said.
Among 96 patients with Sjögren's syndrome, the prevalence of the K113 allele was significantly increased, at 15.6%, compared with 4.2% among 96 normal controls. The allele also was more prevalent among 100 patients with multiple sclerosis, at 11.6%, he said.
Increases in these diseases were not associated with K115, however, which is a defective virus. “Both are full length proviruses, but HERV-K113 is a complete virus that has open reading frames and can fully express all its genes. HERV-K115 has a single deletion that prevents the expression of the Pro/Pol genes,” he said.
An audience member asked if there was any evidence that these viruses were pathogenic, and whether there was an association with the autoantibodies Ro and La that are present in many autoimmune diseases.
Dr. Moyes replied that there does not appear to be an association with Ro and La specifically, but that there is an increase in many other autoantibodies seen in patients with scleroderma, rheumatoid arthritis, and Sjögren's syndrome.
“The exact relevance of those increases is open to question, but there is also a degree of evidence suggesting that proteins from these viruses can induce inflammation,” he said.n
Map shows the prevalence of human endogenous retrovirus (HERV)-K113 (upper number) and the prevalence of HERV-K115 (lower number) in each country. Courtesy Dr. David Moyes
Consider Risk Factors in Osteoporosis Therapy : Increased fracture risk seen in those with T scores below −1.8, previous fracture, and fair or poor health.
NEW YORK — While bone mineral density T scores clearly are predictive of a postmenopausal woman's osteoporotic fracture risk, treatment decisions should take into account other factors, including her overall health and history of previous fractures, Stephen Honig, M.D., said at a rheumatology meeting sponsored by New York University.
“We have to do better than the T score in deciding who needs treatment for osteoporosis, because the long-term use of bisphosphonates has not been determined to be safe,” said Dr. Honig, director of the osteoporosis center at the Hospital for Joint Diseases Spine Center in New York.
Very long-term bisphosphonate therapy may lead to oversuppression of bone turnover, he said. This superhardening can hinder subsequent fracture healing, as was seen in a recent report of nine patients who sustained spontaneous, nonhealing fractures while on alendronate therapy (J. Clin. Endocrinol. Metab. 2005;90:1294–301).
These patients showed histomorphometric evidence of markedly suppressed bone formation, Dr. Honig said.
This new finding has heightened interest in targeting osteoporosis treatment. Research findings have begun to provide guidance on which patients can most benefit from treatment.
Most notable was the National Osteoporosis Risk Assessment (NORA) study, which enrolled 200,160 postmenopausal women aged 50 and older.
In that study, bone mineral density (BMD) measurements were obtained at baseline, and the participants were followed for 1 year.
At follow up, one-third of all fractures and one-fifth of all hip fractures in particular occurred in women aged 50–64. Although the majority of fractures did occur in women 65 and older, the high number in the younger cohort “was a little surprising,” said Dr. Honig.
Another finding that emerged from NORA was that 80% of the women who had fractures during the yearlong study had T scores that were higher than −2.5 and therefore did not meet the World Health Organization definition of osteoporosis.
Most fell between −1 and −2.5, the osteopenic range, he said.
“We want to identify patients at risk in this middle range and not wait until they have obvious fractures,” he commented.
The NORA investigators subsequently followed 57,421 osteopenic women and developed an algorithm for determining risk.
As it turns out, identifying patients with a previous fracture, a T score below −1.8, a self-reported health status of fair or poor, and poor mobility were all factors significantly predictive of fracture risk (Arch. Intern. Med. 2004;164:1113–20).
Another prospective study conducted in France followed 672 healthy postmenopausal women for more than 5 years, and found an annual incidence of osteoporotic fractures of 21 per 1,000 women per year (Bone 2003;32:78–85).
The French investigators identified the key risk factors (listed in order of importance) to be a past fracture, hip BMD, low physical activity, low grip strength, age over 65, maternal fracture history, and past falls.
Other studies have also suggested additional risk factors, including smoking, low body mass index, and increased markers of bone absorption.
Based on the available data and tools at hand, Dr. Honig recommends that clinicians now consider treatment for the following patients:
▸ Women 65 and older, with or without a history of fracture, who have low BMD or other risk factors, such as low BMI and family history.
▸ Women 50 and older with a previous fracture and a T score of −1.8 or less.
▸ Women in poor overall health with mobility problems and low BMD.
▸ Women with low BMD and increased markers of bone resorption.
But questions remain, he said. How long can a bisphosphonate be used? When should teriparatide or a selective estrogen receptor modulator be used? What place does hormone therapy have in treatment strategies?
“There is some new evidence that postmenopausal women with certain levels of endogenous estradiol levels have a lower incidence of fractures. This may translate into using very low-dose [hormone therapy], which conceivably could be safer than what was seen in the Women's Health Initiative,” he said.
Dr. Honig disclosed that he receives support from Eli Lilly & Co. and is on the speakers' bureau of Sanofi-Aventis.
NEW YORK — While bone mineral density T scores clearly are predictive of a postmenopausal woman's osteoporotic fracture risk, treatment decisions should take into account other factors, including her overall health and history of previous fractures, Stephen Honig, M.D., said at a rheumatology meeting sponsored by New York University.
“We have to do better than the T score in deciding who needs treatment for osteoporosis, because the long-term use of bisphosphonates has not been determined to be safe,” said Dr. Honig, director of the osteoporosis center at the Hospital for Joint Diseases Spine Center in New York.
Very long-term bisphosphonate therapy may lead to oversuppression of bone turnover, he said. This superhardening can hinder subsequent fracture healing, as was seen in a recent report of nine patients who sustained spontaneous, nonhealing fractures while on alendronate therapy (J. Clin. Endocrinol. Metab. 2005;90:1294–301).
These patients showed histomorphometric evidence of markedly suppressed bone formation, Dr. Honig said.
This new finding has heightened interest in targeting osteoporosis treatment. Research findings have begun to provide guidance on which patients can most benefit from treatment.
Most notable was the National Osteoporosis Risk Assessment (NORA) study, which enrolled 200,160 postmenopausal women aged 50 and older.
In that study, bone mineral density (BMD) measurements were obtained at baseline, and the participants were followed for 1 year.
At follow up, one-third of all fractures and one-fifth of all hip fractures in particular occurred in women aged 50–64. Although the majority of fractures did occur in women 65 and older, the high number in the younger cohort “was a little surprising,” said Dr. Honig.
Another finding that emerged from NORA was that 80% of the women who had fractures during the yearlong study had T scores that were higher than −2.5 and therefore did not meet the World Health Organization definition of osteoporosis.
Most fell between −1 and −2.5, the osteopenic range, he said.
“We want to identify patients at risk in this middle range and not wait until they have obvious fractures,” he commented.
The NORA investigators subsequently followed 57,421 osteopenic women and developed an algorithm for determining risk.
As it turns out, identifying patients with a previous fracture, a T score below −1.8, a self-reported health status of fair or poor, and poor mobility were all factors significantly predictive of fracture risk (Arch. Intern. Med. 2004;164:1113–20).
Another prospective study conducted in France followed 672 healthy postmenopausal women for more than 5 years, and found an annual incidence of osteoporotic fractures of 21 per 1,000 women per year (Bone 2003;32:78–85).
The French investigators identified the key risk factors (listed in order of importance) to be a past fracture, hip BMD, low physical activity, low grip strength, age over 65, maternal fracture history, and past falls.
Other studies have also suggested additional risk factors, including smoking, low body mass index, and increased markers of bone absorption.
Based on the available data and tools at hand, Dr. Honig recommends that clinicians now consider treatment for the following patients:
▸ Women 65 and older, with or without a history of fracture, who have low BMD or other risk factors, such as low BMI and family history.
▸ Women 50 and older with a previous fracture and a T score of −1.8 or less.
▸ Women in poor overall health with mobility problems and low BMD.
▸ Women with low BMD and increased markers of bone resorption.
But questions remain, he said. How long can a bisphosphonate be used? When should teriparatide or a selective estrogen receptor modulator be used? What place does hormone therapy have in treatment strategies?
“There is some new evidence that postmenopausal women with certain levels of endogenous estradiol levels have a lower incidence of fractures. This may translate into using very low-dose [hormone therapy], which conceivably could be safer than what was seen in the Women's Health Initiative,” he said.
Dr. Honig disclosed that he receives support from Eli Lilly & Co. and is on the speakers' bureau of Sanofi-Aventis.
NEW YORK — While bone mineral density T scores clearly are predictive of a postmenopausal woman's osteoporotic fracture risk, treatment decisions should take into account other factors, including her overall health and history of previous fractures, Stephen Honig, M.D., said at a rheumatology meeting sponsored by New York University.
“We have to do better than the T score in deciding who needs treatment for osteoporosis, because the long-term use of bisphosphonates has not been determined to be safe,” said Dr. Honig, director of the osteoporosis center at the Hospital for Joint Diseases Spine Center in New York.
Very long-term bisphosphonate therapy may lead to oversuppression of bone turnover, he said. This superhardening can hinder subsequent fracture healing, as was seen in a recent report of nine patients who sustained spontaneous, nonhealing fractures while on alendronate therapy (J. Clin. Endocrinol. Metab. 2005;90:1294–301).
These patients showed histomorphometric evidence of markedly suppressed bone formation, Dr. Honig said.
This new finding has heightened interest in targeting osteoporosis treatment. Research findings have begun to provide guidance on which patients can most benefit from treatment.
Most notable was the National Osteoporosis Risk Assessment (NORA) study, which enrolled 200,160 postmenopausal women aged 50 and older.
In that study, bone mineral density (BMD) measurements were obtained at baseline, and the participants were followed for 1 year.
At follow up, one-third of all fractures and one-fifth of all hip fractures in particular occurred in women aged 50–64. Although the majority of fractures did occur in women 65 and older, the high number in the younger cohort “was a little surprising,” said Dr. Honig.
Another finding that emerged from NORA was that 80% of the women who had fractures during the yearlong study had T scores that were higher than −2.5 and therefore did not meet the World Health Organization definition of osteoporosis.
Most fell between −1 and −2.5, the osteopenic range, he said.
“We want to identify patients at risk in this middle range and not wait until they have obvious fractures,” he commented.
The NORA investigators subsequently followed 57,421 osteopenic women and developed an algorithm for determining risk.
As it turns out, identifying patients with a previous fracture, a T score below −1.8, a self-reported health status of fair or poor, and poor mobility were all factors significantly predictive of fracture risk (Arch. Intern. Med. 2004;164:1113–20).
Another prospective study conducted in France followed 672 healthy postmenopausal women for more than 5 years, and found an annual incidence of osteoporotic fractures of 21 per 1,000 women per year (Bone 2003;32:78–85).
The French investigators identified the key risk factors (listed in order of importance) to be a past fracture, hip BMD, low physical activity, low grip strength, age over 65, maternal fracture history, and past falls.
Other studies have also suggested additional risk factors, including smoking, low body mass index, and increased markers of bone absorption.
Based on the available data and tools at hand, Dr. Honig recommends that clinicians now consider treatment for the following patients:
▸ Women 65 and older, with or without a history of fracture, who have low BMD or other risk factors, such as low BMI and family history.
▸ Women 50 and older with a previous fracture and a T score of −1.8 or less.
▸ Women in poor overall health with mobility problems and low BMD.
▸ Women with low BMD and increased markers of bone resorption.
But questions remain, he said. How long can a bisphosphonate be used? When should teriparatide or a selective estrogen receptor modulator be used? What place does hormone therapy have in treatment strategies?
“There is some new evidence that postmenopausal women with certain levels of endogenous estradiol levels have a lower incidence of fractures. This may translate into using very low-dose [hormone therapy], which conceivably could be safer than what was seen in the Women's Health Initiative,” he said.
Dr. Honig disclosed that he receives support from Eli Lilly & Co. and is on the speakers' bureau of Sanofi-Aventis.
On the Horizon: Designer Glucocorticoids Providing Benefits Without Side Effects
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.
HDL May Predict Lupus Atherosclerosis
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.