Colin Nelson

BOSTON — Thalidomide appears promising for the treatment of nephrogenic fibrosing dermopathy, according to the results of a small, open-label trial.

If larger trials show thalidomide to be more effective than placebo or other therapies, patients who have the intractable condition with few treatment options will need to weigh its benefits against associated risks, which include an increased incidence of fetal abnormalities if taken during pregnancy, Stevens-Johnson syndrome, hypotension, and peripheral neuropathy. Side effects of thalidomide include fatigue and drowsiness.

Jonathan Kay, M.D., and colleagues at Massachusetts General Hospital in Boston treated nine men and women with chronic renal failure and a diagnosis of nephrogenic fibrosing dermopathy (NFD) confirmed by biopsy. All patients in the off-label trial received 50 mg of thalidomide daily. Duration of therapy was from 18 days to more than 13 months.

Overall, “the majority of patients experienced improvement in the hardness and tethering of their skin; some also experienced improvement in their joint contractures,” Dr. Kay said at a meeting on rheumatology sponsored by Harvard Medical School.

NFD typically involves hyper-pigmentation and tethered, thickened skin, as shown on the lower legs of this patient. Courtesy Dr. Jonathan Kay

BOSTON — Thalidomide appears promising for the treatment of nephrogenic fibrosing dermopathy, according to the results of a small, open-label trial.

If larger trials show thalidomide to be more effective than placebo or other therapies, patients who have the intractable condition with few treatment options will need to weigh its benefits against associated risks, which include an increased incidence of fetal abnormalities if taken during pregnancy, Stevens-Johnson syndrome, hypotension, and peripheral neuropathy. Side effects of thalidomide include fatigue and drowsiness.

Jonathan Kay, M.D., and colleagues at Massachusetts General Hospital in Boston treated nine men and women with chronic renal failure and a diagnosis of nephrogenic fibrosing dermopathy (NFD) confirmed by biopsy. All patients in the off-label trial received 50 mg of thalidomide daily. Duration of therapy was from 18 days to more than 13 months.

Overall, “the majority of patients experienced improvement in the hardness and tethering of their skin; some also experienced improvement in their joint contractures,” Dr. Kay said at a meeting on rheumatology sponsored by Harvard Medical School.

NFD typically involves hyper-pigmentation and tethered, thickened skin, as shown on the lower legs of this patient. Courtesy Dr. Jonathan Kay

BOSTON — Thalidomide appears promising for the treatment of nephrogenic fibrosing dermopathy, according to the results of a small, open-label trial.

If larger trials show thalidomide to be more effective than placebo or other therapies, patients who have the intractable condition with few treatment options will need to weigh its benefits against associated risks, which include an increased incidence of fetal abnormalities if taken during pregnancy, Stevens-Johnson syndrome, hypotension, and peripheral neuropathy. Side effects of thalidomide include fatigue and drowsiness.

Jonathan Kay, M.D., and colleagues at Massachusetts General Hospital in Boston treated nine men and women with chronic renal failure and a diagnosis of nephrogenic fibrosing dermopathy (NFD) confirmed by biopsy. All patients in the off-label trial received 50 mg of thalidomide daily. Duration of therapy was from 18 days to more than 13 months.

Overall, “the majority of patients experienced improvement in the hardness and tethering of their skin; some also experienced improvement in their joint contractures,” Dr. Kay said at a meeting on rheumatology sponsored by Harvard Medical School.

NFD typically involves hyper-pigmentation and tethered, thickened skin, as shown on the lower legs of this patient. Courtesy Dr. Jonathan Kay

BOSTON — There has been little consensus among organizational guidelines in the past 5 years about who should be screened for low bone density.

Recommendations range from very conservative to relatively liberal, said Edward Leib, M.D., director of the Osteoporosis Center at the University of Vermont, during a recent symposium on bone health sponsored by Boston University School of Medicine.

The decision to screen is important, since it can affect a patient's well-being and dictates how the health care system allocates billions of dollars.

For many clinicians, the decision is understandably murky. Evidence that bone scans prevent fractures is conflicting, and there is some evidence that screening may indirectly cause harm.

Screening guidelines issued by various organizations answer some questions and raise others. For instance, in 2002, the U.S. Preventive Services Task Force (USPSTF) published letter grade recommendations on osteoporosis screening after reviewing the literature on its diagnosis and treatment. Its evidence-based screening recommendations are among the most conservative to date, said Dr. Leib.

The Task Force noted that bone density screening is an imprecise science, and its accuracy and usefulness is dependent on variable technical and human factors.

Bone density scans lack meaningful predictive value, the Task Force also noted. They don't predict who will and who will not have a fracture. Moreover, if a test is positive, it is unclear what a clinician should do.

“There is little evidence regarding which patients are likely to benefit from screening and treatment,” the Task Force concluded. “It is not known whether women who have a similar overall risk for fracture, but different bone densities, will benefit similarly from treatment. This is clinically important because the lack of accepted criteria for initiating treatment remains a problem.”

The USPSTF also noted that there are several potential harms of screening, although “the empirical data for them are few.”

The Task Force said potential harms from screening include an increased likelihood that a patient will need to receive hormone replacement therapy; increased patient fears and anxiety; inaccuracies and misinterpretations of bone density tests; increased risk for ulcer disease in patients taking alendronate (incidence 2.2% on alendronate vs. 1.2% on placebo); and unknown long-term harms of alendronate.

After considering all of these factors, the USPSTF recommended screening women aged 65 years and older, and women aged 60 years and older who have risk factors for osteoporosis.

The Task Force found insufficient evidence to recommend for or against routine screening in women aged 60 years and younger, or in women aged 60–64 years who are not at increased risk for osteoporotic fractures.

Bone densitometry screening guidelines generally agree that women aged 65 years and older should undergo bone density scans. But what do the guidelines say about younger women, men, and children? Researchers have yet to validate the reliability of screening guidelines in these groups (N. Engl. J. Med. 2005;353:164–71).

The current guidelines suggest that clinicians should take into account a number of risk factors before ordering bone densitometry for them. In women younger than 65, clinicians should consider fragility or low-trauma fracture, family history, and weight, among other things.

Dr. Leib said that his advice on osteoporosis screening is based on evidence and opinion. He recommends bone densitometry for the following individuals: women aged 65 years and older and men aged 70 years or older; postmenopausal women with risk factors for fracture; men aged 50 years or older with risk factors; routine screening of early postmenopausal women; and premenopasual women, children, or younger men with significant risk factors.

Dr. Leib is a consultant to Procter & Gamble and Merck Pharmaceuticals. He receives research support from Eli Lilly and NPS Allelix.

BOSTON — There has been little consensus among organizational guidelines in the past 5 years about who should be screened for low bone density.

Recommendations range from very conservative to relatively liberal, said Edward Leib, M.D., director of the Osteoporosis Center at the University of Vermont, during a recent symposium on bone health sponsored by Boston University School of Medicine.

The decision to screen is important, since it can affect a patient's well-being and dictates how the health care system allocates billions of dollars.

For many clinicians, the decision is understandably murky. Evidence that bone scans prevent fractures is conflicting, and there is some evidence that screening may indirectly cause harm.

Screening guidelines issued by various organizations answer some questions and raise others. For instance, in 2002, the U.S. Preventive Services Task Force (USPSTF) published letter grade recommendations on osteoporosis screening after reviewing the literature on its diagnosis and treatment. Its evidence-based screening recommendations are among the most conservative to date, said Dr. Leib.

The Task Force noted that bone density screening is an imprecise science, and its accuracy and usefulness is dependent on variable technical and human factors.

Bone density scans lack meaningful predictive value, the Task Force also noted. They don't predict who will and who will not have a fracture. Moreover, if a test is positive, it is unclear what a clinician should do.

“There is little evidence regarding which patients are likely to benefit from screening and treatment,” the Task Force concluded. “It is not known whether women who have a similar overall risk for fracture, but different bone densities, will benefit similarly from treatment. This is clinically important because the lack of accepted criteria for initiating treatment remains a problem.”

The USPSTF also noted that there are several potential harms of screening, although “the empirical data for them are few.”

The Task Force said potential harms from screening include an increased likelihood that a patient will need to receive hormone replacement therapy; increased patient fears and anxiety; inaccuracies and misinterpretations of bone density tests; increased risk for ulcer disease in patients taking alendronate (incidence 2.2% on alendronate vs. 1.2% on placebo); and unknown long-term harms of alendronate.

After considering all of these factors, the USPSTF recommended screening women aged 65 years and older, and women aged 60 years and older who have risk factors for osteoporosis.

The Task Force found insufficient evidence to recommend for or against routine screening in women aged 60 years and younger, or in women aged 60–64 years who are not at increased risk for osteoporotic fractures.

Bone densitometry screening guidelines generally agree that women aged 65 years and older should undergo bone density scans. But what do the guidelines say about younger women, men, and children? Researchers have yet to validate the reliability of screening guidelines in these groups (N. Engl. J. Med. 2005;353:164–71).

The current guidelines suggest that clinicians should take into account a number of risk factors before ordering bone densitometry for them. In women younger than 65, clinicians should consider fragility or low-trauma fracture, family history, and weight, among other things.

Dr. Leib said that his advice on osteoporosis screening is based on evidence and opinion. He recommends bone densitometry for the following individuals: women aged 65 years and older and men aged 70 years or older; postmenopausal women with risk factors for fracture; men aged 50 years or older with risk factors; routine screening of early postmenopausal women; and premenopasual women, children, or younger men with significant risk factors.

Dr. Leib is a consultant to Procter & Gamble and Merck Pharmaceuticals. He receives research support from Eli Lilly and NPS Allelix.

BOSTON — There has been little consensus among organizational guidelines in the past 5 years about who should be screened for low bone density.

Recommendations range from very conservative to relatively liberal, said Edward Leib, M.D., director of the Osteoporosis Center at the University of Vermont, during a recent symposium on bone health sponsored by Boston University School of Medicine.

The decision to screen is important, since it can affect a patient's well-being and dictates how the health care system allocates billions of dollars.

For many clinicians, the decision is understandably murky. Evidence that bone scans prevent fractures is conflicting, and there is some evidence that screening may indirectly cause harm.

Screening guidelines issued by various organizations answer some questions and raise others. For instance, in 2002, the U.S. Preventive Services Task Force (USPSTF) published letter grade recommendations on osteoporosis screening after reviewing the literature on its diagnosis and treatment. Its evidence-based screening recommendations are among the most conservative to date, said Dr. Leib.

The Task Force noted that bone density screening is an imprecise science, and its accuracy and usefulness is dependent on variable technical and human factors.

Bone density scans lack meaningful predictive value, the Task Force also noted. They don't predict who will and who will not have a fracture. Moreover, if a test is positive, it is unclear what a clinician should do.

“There is little evidence regarding which patients are likely to benefit from screening and treatment,” the Task Force concluded. “It is not known whether women who have a similar overall risk for fracture, but different bone densities, will benefit similarly from treatment. This is clinically important because the lack of accepted criteria for initiating treatment remains a problem.”

The USPSTF also noted that there are several potential harms of screening, although “the empirical data for them are few.”

The Task Force said potential harms from screening include an increased likelihood that a patient will need to receive hormone replacement therapy; increased patient fears and anxiety; inaccuracies and misinterpretations of bone density tests; increased risk for ulcer disease in patients taking alendronate (incidence 2.2% on alendronate vs. 1.2% on placebo); and unknown long-term harms of alendronate.

After considering all of these factors, the USPSTF recommended screening women aged 65 years and older, and women aged 60 years and older who have risk factors for osteoporosis.

The Task Force found insufficient evidence to recommend for or against routine screening in women aged 60 years and younger, or in women aged 60–64 years who are not at increased risk for osteoporotic fractures.

Bone densitometry screening guidelines generally agree that women aged 65 years and older should undergo bone density scans. But what do the guidelines say about younger women, men, and children? Researchers have yet to validate the reliability of screening guidelines in these groups (N. Engl. J. Med. 2005;353:164–71).

The current guidelines suggest that clinicians should take into account a number of risk factors before ordering bone densitometry for them. In women younger than 65, clinicians should consider fragility or low-trauma fracture, family history, and weight, among other things.

Dr. Leib said that his advice on osteoporosis screening is based on evidence and opinion. He recommends bone densitometry for the following individuals: women aged 65 years and older and men aged 70 years or older; postmenopausal women with risk factors for fracture; men aged 50 years or older with risk factors; routine screening of early postmenopausal women; and premenopasual women, children, or younger men with significant risk factors.

Dr. Leib is a consultant to Procter & Gamble and Merck Pharmaceuticals. He receives research support from Eli Lilly and NPS Allelix.

BOSTON — Raynaud's phenomenon secondary to scleroderma can quickly progress to catastrophic ischemic events resulting in the loss of fingers, toes, and even limbs; at the same time, the efficacy of therapies varies widely.

Determining the root causes of a Raynaud's crisis can be difficult during an emergency. Local vasospasm and/or more complicated and widespread vascular disease can trigger the event. Initial therapies should target vasospasm; if the patient does not respond, treatment should shift to addressing small vessel disease and occlusions, according to Fredrick Wigley, M.D.

Dr. Wigley, of Johns Hopkins University in Baltimore, reviewed the therapies for treating a Raynaud's crisis at a recent meeting on rheumatology sponsored by Harvard Medical School.

In patients with primary Raynaud's disease that is not complicated by scleroderma, the loss of blood flow to the extremities and the subsequent pain or discomfort is typically caused by vasoconstriction, not vasculopathy.

Warmer temperatures or stress reduction may relieve the symptoms in these patients, he said. If lifestyle changes are not sufficient, he recommends trying a calcium channel blocker (for example, amlodipine).

In patients with scleroderma, the clinical picture is considerably more complex. “We see major vascular disease,” said Dr. Wigley. There's occlusion, structural disease, and thrombotic events. Treatment should address vascular disease as well as the vasospasm, he said.

Not all scleroderma patients are equally susceptible to catastrophic Raynaud's episodes, said Dr. Wigley. In his experience, those most prone to a crisis are scleroderma patients who have coexisting macrovascular disease, typically accompanied by recurrent digital ulcers and amputation.

These patients tend to have limited skin disease, are anticentromere positive, and demonstrate granzyme B cleavable autoantigens.

The macrovascular disease is often observed as palmar arch and ulnar artery disease. Symptoms during a crisis are markedly more severe than during a typical episode of primary Raynaud's. “Persistent widespread ischemic pain heralds tissue infarction and gangrene,” he said.

“If a patient comes to your office and says, 'I'm having a Raynaud's attack and my finger will not get warm. And not only that, the palm of my hand is hurting,' and the patient is holding the hand in a downward position, that patient is having a heart attack of the hand,” said Dr. Wigley, adding that it needs to be treated as a medical emergency.

Angiograms of scleroderma patients' hands reveal that not just tiny vessels but also medium-sized arteries “just disappear. … Only collateral flow is keeping the finger alive.”

Dr. Wigley offered the following observations about various treatment options:

▸ Prostaglandin infusions. For those patients already taking a calcium channel blocker, Dr. Wigley administers repeated infusions of a prostaglandin (epoprostenol in the United States and Canada; iloprost in Europe).

“It's effective and quite dramatic,” he observed. And for short periods of continuous infusion, the drugs are relatively inexpensive.

In randomized trials, Dr. Wigley and his colleagues have shown prostaglandin infusions to be beneficial (Ann. Intern. Med. 1994;120:199–206). However, oral therapy is ineffective (Arthritis Rheum. 1998; 41:670–7).

In one recent case series, five women who had suffered seven catastrophic Raynaud's crises received epoprostenol infusions over 5 days at a dose of 8 ng/kg per minute. The crises were completely resolved in two of the five patients, and improved in the remaining three, according to a paper presented at the 2004 annual meeting of the American College of Rheumatology (Arthritis Rheum. 2004; 50[suppl. 9]:S638).

Dr. Wigley recommends starting epoprostenol at a dose of 2 ng/kg per minute. “It's a very low dose and is well tolerated,” he said. He warns against infusing patients who have pulmonary artery hypertension, as these patients require very close attention.

▸ Chemical sympathectomy. In a crisis, Dr. Wigley said he performs a rapid chemical sympathectomy at the bedside or in the office, using lidocaine for a digital block. “It's short acting, but it decreases pain immediately. You can get a dramatic flush to skin and reverse the event if it's vasospastic.”

If the crisis is thrombotic, however, sympathectomy will be ineffective, he said.

▸ Antiplatelet therapy. “Aspirin works,” said Dr. Wigley.

Calcium channel blockers and prostaglandins are also potent vasodilators. “When you give these agents, you affect platelet function.”

Less is known about other agents, such as ticlopidine, clopidogrel, cilostazol, and pentoxifylline, he said.

▸ Anticoagulation. In patients who do not respond rapidly to prostaglandin infusion, sympathectomy, and/or antiplatelet therapy, the crisis is almost surely caused by thrombosis, said Dr. Wigley. In his experience, anticoagulation can help in the acute phase, and he advises treatment for 24 hours, although he acknowledged that there are no controlled trials to support this practice.

Anticoagulation is unproven as chronic therapy for Raynaud's phenomenon unless patients have a secondary hypercoagulation disorder, such as antiphospholipid antibody syndrome.

▸ Thrombolytic therapy. There is little evidence to support the use of thrombolytic therapy in patients with scleroderma who have catastrophic Raynaud's events, and he does not recommend it.

▸ Surgical sympathectomy. Surgical sympathectomy denervates the finger. '“We use a digital sympathectomy when medical therapy is not working,” he said. However, there is conflicting evidence on the efficacy of this procedure.

In a retrospective review of 129 fingers in 38 patients with scleroderma and chronic digital ischemia, 86% reported improved symptoms with periarterial sympathectomy after a follow-up period of up to 41 months.

The study was presented at the 2003 annual meeting of the American College of Rheumatology (Arthritis Rheum. 2003; 48[suppl. 9]:S560).

However, a separate systematic review of 251 digits came to less optimistic conclusions. It found that 14% of all patients required amputation and 18% of patients had ulcer recurrence, after up to nearly 5 years of follow-up.

“Some type of postoperative complication was reported in 37% of patients with systemic sclerosis,” according to the study's authors, who noted that the literature is marred by a number of shortcomings (J. Rheumatol. 2003;30:1788–92).

“Sympathectomy can reverse an ischemic crisis, but may not cure the problem,” said Dr. Wigley. It sometimes leads to finger contractures and fibrosis, “so I don't use it lightly,” he added.

“Usually it gets the patient out of a crisis. A year later the Raynaud's is back, but it tends not to be as severe.”

▸ Vascular surgery. A retrospective case series reported on the outcomes of revascularization of occluded ulnar arteries in eight patients with scleroderma and severe Raynaud's phenomenon with digital ulcers.

The patients had a positive Allen's tests, had angiograms showing occlusive disease, and had failed to improve with nonoperative treatment.

All eight patients “experienced dramatic improvement in Raynaud's phenomenon and refractory digital ulcers,” according to the authors (J. Rheumatol. 2002;29:102–6).

In isolated cases, “you need to consider it,” said Dr. Wigley. However, he advises caution. “You have to be dealing with an experienced vascular surgeon and be very conservative about attacking these blood vessels. … Patients have lost not just their finger but parts of their hands.”

Dr. Wigley said it's rare to find a lesion that is an appropriate target for microsurgical repair. “Most of the time you have the combination of a large vessel, such as an ulnar occlusion, and a microvascular disease, so there's nothing you can connect to, to make a repair.”

Preventing Recurrences

For prevention of recurrent crises, “there's no drug more effective than warm temperatures,” said Dr. Wigley

When cold is unavoidable, Dr. Wigley recommends using continued vasodilator therapy, aspirin, and antioxidants. Statins “will play a bigger role as we learn more about these agents.”

Other options for preventing recurrences include:

▸ Iloprost infusions. Recent trials from Europe suggest that prophylactic infusions of iloprost may reduce the frequency and severity of Raynaud's events among scleroderma patients (Med. Clin. [Barc.] 2004;122:501–4; Clin. Rheumatol. 2002;21:244–50).

▸ Bosentan. Findings from a recent trial demonstrated a reduction in digital ulcers among scleroderma patients after treatment with the endothelin receptor antagonist bosentan (Arthritis Rheum. 2004; 50:3985–93).

BOSTON — Raynaud's phenomenon secondary to scleroderma can quickly progress to catastrophic ischemic events resulting in the loss of fingers, toes, and even limbs; at the same time, the efficacy of therapies varies widely.

Determining the root causes of a Raynaud's crisis can be difficult during an emergency. Local vasospasm and/or more complicated and widespread vascular disease can trigger the event. Initial therapies should target vasospasm; if the patient does not respond, treatment should shift to addressing small vessel disease and occlusions, according to Fredrick Wigley, M.D.

Dr. Wigley, of Johns Hopkins University in Baltimore, reviewed the therapies for treating a Raynaud's crisis at a recent meeting on rheumatology sponsored by Harvard Medical School.

In patients with primary Raynaud's disease that is not complicated by scleroderma, the loss of blood flow to the extremities and the subsequent pain or discomfort is typically caused by vasoconstriction, not vasculopathy.

Warmer temperatures or stress reduction may relieve the symptoms in these patients, he said. If lifestyle changes are not sufficient, he recommends trying a calcium channel blocker (for example, amlodipine).

In patients with scleroderma, the clinical picture is considerably more complex. “We see major vascular disease,” said Dr. Wigley. There's occlusion, structural disease, and thrombotic events. Treatment should address vascular disease as well as the vasospasm, he said.

Not all scleroderma patients are equally susceptible to catastrophic Raynaud's episodes, said Dr. Wigley. In his experience, those most prone to a crisis are scleroderma patients who have coexisting macrovascular disease, typically accompanied by recurrent digital ulcers and amputation.

These patients tend to have limited skin disease, are anticentromere positive, and demonstrate granzyme B cleavable autoantigens.

The macrovascular disease is often observed as palmar arch and ulnar artery disease. Symptoms during a crisis are markedly more severe than during a typical episode of primary Raynaud's. “Persistent widespread ischemic pain heralds tissue infarction and gangrene,” he said.

“If a patient comes to your office and says, 'I'm having a Raynaud's attack and my finger will not get warm. And not only that, the palm of my hand is hurting,' and the patient is holding the hand in a downward position, that patient is having a heart attack of the hand,” said Dr. Wigley, adding that it needs to be treated as a medical emergency.

Angiograms of scleroderma patients' hands reveal that not just tiny vessels but also medium-sized arteries “just disappear. … Only collateral flow is keeping the finger alive.”

Dr. Wigley offered the following observations about various treatment options:

▸ Prostaglandin infusions. For those patients already taking a calcium channel blocker, Dr. Wigley administers repeated infusions of a prostaglandin (epoprostenol in the United States and Canada; iloprost in Europe).

“It's effective and quite dramatic,” he observed. And for short periods of continuous infusion, the drugs are relatively inexpensive.

In randomized trials, Dr. Wigley and his colleagues have shown prostaglandin infusions to be beneficial (Ann. Intern. Med. 1994;120:199–206). However, oral therapy is ineffective (Arthritis Rheum. 1998; 41:670–7).

In one recent case series, five women who had suffered seven catastrophic Raynaud's crises received epoprostenol infusions over 5 days at a dose of 8 ng/kg per minute. The crises were completely resolved in two of the five patients, and improved in the remaining three, according to a paper presented at the 2004 annual meeting of the American College of Rheumatology (Arthritis Rheum. 2004; 50[suppl. 9]:S638).

Dr. Wigley recommends starting epoprostenol at a dose of 2 ng/kg per minute. “It's a very low dose and is well tolerated,” he said. He warns against infusing patients who have pulmonary artery hypertension, as these patients require very close attention.

▸ Chemical sympathectomy. In a crisis, Dr. Wigley said he performs a rapid chemical sympathectomy at the bedside or in the office, using lidocaine for a digital block. “It's short acting, but it decreases pain immediately. You can get a dramatic flush to skin and reverse the event if it's vasospastic.”

If the crisis is thrombotic, however, sympathectomy will be ineffective, he said.

▸ Antiplatelet therapy. “Aspirin works,” said Dr. Wigley.

Calcium channel blockers and prostaglandins are also potent vasodilators. “When you give these agents, you affect platelet function.”

Less is known about other agents, such as ticlopidine, clopidogrel, cilostazol, and pentoxifylline, he said.

▸ Anticoagulation. In patients who do not respond rapidly to prostaglandin infusion, sympathectomy, and/or antiplatelet therapy, the crisis is almost surely caused by thrombosis, said Dr. Wigley. In his experience, anticoagulation can help in the acute phase, and he advises treatment for 24 hours, although he acknowledged that there are no controlled trials to support this practice.

Anticoagulation is unproven as chronic therapy for Raynaud's phenomenon unless patients have a secondary hypercoagulation disorder, such as antiphospholipid antibody syndrome.

▸ Thrombolytic therapy. There is little evidence to support the use of thrombolytic therapy in patients with scleroderma who have catastrophic Raynaud's events, and he does not recommend it.

▸ Surgical sympathectomy. Surgical sympathectomy denervates the finger. '“We use a digital sympathectomy when medical therapy is not working,” he said. However, there is conflicting evidence on the efficacy of this procedure.

In a retrospective review of 129 fingers in 38 patients with scleroderma and chronic digital ischemia, 86% reported improved symptoms with periarterial sympathectomy after a follow-up period of up to 41 months.

The study was presented at the 2003 annual meeting of the American College of Rheumatology (Arthritis Rheum. 2003; 48[suppl. 9]:S560).

However, a separate systematic review of 251 digits came to less optimistic conclusions. It found that 14% of all patients required amputation and 18% of patients had ulcer recurrence, after up to nearly 5 years of follow-up.

“Some type of postoperative complication was reported in 37% of patients with systemic sclerosis,” according to the study's authors, who noted that the literature is marred by a number of shortcomings (J. Rheumatol. 2003;30:1788–92).

“Sympathectomy can reverse an ischemic crisis, but may not cure the problem,” said Dr. Wigley. It sometimes leads to finger contractures and fibrosis, “so I don't use it lightly,” he added.

“Usually it gets the patient out of a crisis. A year later the Raynaud's is back, but it tends not to be as severe.”

▸ Vascular surgery. A retrospective case series reported on the outcomes of revascularization of occluded ulnar arteries in eight patients with scleroderma and severe Raynaud's phenomenon with digital ulcers.

The patients had a positive Allen's tests, had angiograms showing occlusive disease, and had failed to improve with nonoperative treatment.

All eight patients “experienced dramatic improvement in Raynaud's phenomenon and refractory digital ulcers,” according to the authors (J. Rheumatol. 2002;29:102–6).

In isolated cases, “you need to consider it,” said Dr. Wigley. However, he advises caution. “You have to be dealing with an experienced vascular surgeon and be very conservative about attacking these blood vessels. … Patients have lost not just their finger but parts of their hands.”

Dr. Wigley said it's rare to find a lesion that is an appropriate target for microsurgical repair. “Most of the time you have the combination of a large vessel, such as an ulnar occlusion, and a microvascular disease, so there's nothing you can connect to, to make a repair.”

Preventing Recurrences

For prevention of recurrent crises, “there's no drug more effective than warm temperatures,” said Dr. Wigley

When cold is unavoidable, Dr. Wigley recommends using continued vasodilator therapy, aspirin, and antioxidants. Statins “will play a bigger role as we learn more about these agents.”

Other options for preventing recurrences include:

▸ Iloprost infusions. Recent trials from Europe suggest that prophylactic infusions of iloprost may reduce the frequency and severity of Raynaud's events among scleroderma patients (Med. Clin. [Barc.] 2004;122:501–4; Clin. Rheumatol. 2002;21:244–50).

▸ Bosentan. Findings from a recent trial demonstrated a reduction in digital ulcers among scleroderma patients after treatment with the endothelin receptor antagonist bosentan (Arthritis Rheum. 2004; 50:3985–93).

BOSTON — Raynaud's phenomenon secondary to scleroderma can quickly progress to catastrophic ischemic events resulting in the loss of fingers, toes, and even limbs; at the same time, the efficacy of therapies varies widely.

Determining the root causes of a Raynaud's crisis can be difficult during an emergency. Local vasospasm and/or more complicated and widespread vascular disease can trigger the event. Initial therapies should target vasospasm; if the patient does not respond, treatment should shift to addressing small vessel disease and occlusions, according to Fredrick Wigley, M.D.

Dr. Wigley, of Johns Hopkins University in Baltimore, reviewed the therapies for treating a Raynaud's crisis at a recent meeting on rheumatology sponsored by Harvard Medical School.

In patients with primary Raynaud's disease that is not complicated by scleroderma, the loss of blood flow to the extremities and the subsequent pain or discomfort is typically caused by vasoconstriction, not vasculopathy.

Warmer temperatures or stress reduction may relieve the symptoms in these patients, he said. If lifestyle changes are not sufficient, he recommends trying a calcium channel blocker (for example, amlodipine).

In patients with scleroderma, the clinical picture is considerably more complex. “We see major vascular disease,” said Dr. Wigley. There's occlusion, structural disease, and thrombotic events. Treatment should address vascular disease as well as the vasospasm, he said.

Not all scleroderma patients are equally susceptible to catastrophic Raynaud's episodes, said Dr. Wigley. In his experience, those most prone to a crisis are scleroderma patients who have coexisting macrovascular disease, typically accompanied by recurrent digital ulcers and amputation.

These patients tend to have limited skin disease, are anticentromere positive, and demonstrate granzyme B cleavable autoantigens.

The macrovascular disease is often observed as palmar arch and ulnar artery disease. Symptoms during a crisis are markedly more severe than during a typical episode of primary Raynaud's. “Persistent widespread ischemic pain heralds tissue infarction and gangrene,” he said.

“If a patient comes to your office and says, 'I'm having a Raynaud's attack and my finger will not get warm. And not only that, the palm of my hand is hurting,' and the patient is holding the hand in a downward position, that patient is having a heart attack of the hand,” said Dr. Wigley, adding that it needs to be treated as a medical emergency.

Angiograms of scleroderma patients' hands reveal that not just tiny vessels but also medium-sized arteries “just disappear. … Only collateral flow is keeping the finger alive.”

Dr. Wigley offered the following observations about various treatment options:

▸ Prostaglandin infusions. For those patients already taking a calcium channel blocker, Dr. Wigley administers repeated infusions of a prostaglandin (epoprostenol in the United States and Canada; iloprost in Europe).

“It's effective and quite dramatic,” he observed. And for short periods of continuous infusion, the drugs are relatively inexpensive.

In randomized trials, Dr. Wigley and his colleagues have shown prostaglandin infusions to be beneficial (Ann. Intern. Med. 1994;120:199–206). However, oral therapy is ineffective (Arthritis Rheum. 1998; 41:670–7).

In one recent case series, five women who had suffered seven catastrophic Raynaud's crises received epoprostenol infusions over 5 days at a dose of 8 ng/kg per minute. The crises were completely resolved in two of the five patients, and improved in the remaining three, according to a paper presented at the 2004 annual meeting of the American College of Rheumatology (Arthritis Rheum. 2004; 50[suppl. 9]:S638).

Dr. Wigley recommends starting epoprostenol at a dose of 2 ng/kg per minute. “It's a very low dose and is well tolerated,” he said. He warns against infusing patients who have pulmonary artery hypertension, as these patients require very close attention.

▸ Chemical sympathectomy. In a crisis, Dr. Wigley said he performs a rapid chemical sympathectomy at the bedside or in the office, using lidocaine for a digital block. “It's short acting, but it decreases pain immediately. You can get a dramatic flush to skin and reverse the event if it's vasospastic.”

If the crisis is thrombotic, however, sympathectomy will be ineffective, he said.

▸ Antiplatelet therapy. “Aspirin works,” said Dr. Wigley.

Calcium channel blockers and prostaglandins are also potent vasodilators. “When you give these agents, you affect platelet function.”

Less is known about other agents, such as ticlopidine, clopidogrel, cilostazol, and pentoxifylline, he said.

▸ Anticoagulation. In patients who do not respond rapidly to prostaglandin infusion, sympathectomy, and/or antiplatelet therapy, the crisis is almost surely caused by thrombosis, said Dr. Wigley. In his experience, anticoagulation can help in the acute phase, and he advises treatment for 24 hours, although he acknowledged that there are no controlled trials to support this practice.

Anticoagulation is unproven as chronic therapy for Raynaud's phenomenon unless patients have a secondary hypercoagulation disorder, such as antiphospholipid antibody syndrome.

▸ Thrombolytic therapy. There is little evidence to support the use of thrombolytic therapy in patients with scleroderma who have catastrophic Raynaud's events, and he does not recommend it.

▸ Surgical sympathectomy. Surgical sympathectomy denervates the finger. '“We use a digital sympathectomy when medical therapy is not working,” he said. However, there is conflicting evidence on the efficacy of this procedure.

In a retrospective review of 129 fingers in 38 patients with scleroderma and chronic digital ischemia, 86% reported improved symptoms with periarterial sympathectomy after a follow-up period of up to 41 months.

The study was presented at the 2003 annual meeting of the American College of Rheumatology (Arthritis Rheum. 2003; 48[suppl. 9]:S560).

However, a separate systematic review of 251 digits came to less optimistic conclusions. It found that 14% of all patients required amputation and 18% of patients had ulcer recurrence, after up to nearly 5 years of follow-up.

“Some type of postoperative complication was reported in 37% of patients with systemic sclerosis,” according to the study's authors, who noted that the literature is marred by a number of shortcomings (J. Rheumatol. 2003;30:1788–92).

“Sympathectomy can reverse an ischemic crisis, but may not cure the problem,” said Dr. Wigley. It sometimes leads to finger contractures and fibrosis, “so I don't use it lightly,” he added.

“Usually it gets the patient out of a crisis. A year later the Raynaud's is back, but it tends not to be as severe.”

▸ Vascular surgery. A retrospective case series reported on the outcomes of revascularization of occluded ulnar arteries in eight patients with scleroderma and severe Raynaud's phenomenon with digital ulcers.

The patients had a positive Allen's tests, had angiograms showing occlusive disease, and had failed to improve with nonoperative treatment.

All eight patients “experienced dramatic improvement in Raynaud's phenomenon and refractory digital ulcers,” according to the authors (J. Rheumatol. 2002;29:102–6).

In isolated cases, “you need to consider it,” said Dr. Wigley. However, he advises caution. “You have to be dealing with an experienced vascular surgeon and be very conservative about attacking these blood vessels. … Patients have lost not just their finger but parts of their hands.”

Dr. Wigley said it's rare to find a lesion that is an appropriate target for microsurgical repair. “Most of the time you have the combination of a large vessel, such as an ulnar occlusion, and a microvascular disease, so there's nothing you can connect to, to make a repair.”

Preventing Recurrences

For prevention of recurrent crises, “there's no drug more effective than warm temperatures,” said Dr. Wigley

When cold is unavoidable, Dr. Wigley recommends using continued vasodilator therapy, aspirin, and antioxidants. Statins “will play a bigger role as we learn more about these agents.”

Other options for preventing recurrences include:

▸ Iloprost infusions. Recent trials from Europe suggest that prophylactic infusions of iloprost may reduce the frequency and severity of Raynaud's events among scleroderma patients (Med. Clin. [Barc.] 2004;122:501–4; Clin. Rheumatol. 2002;21:244–50).

▸ Bosentan. Findings from a recent trial demonstrated a reduction in digital ulcers among scleroderma patients after treatment with the endothelin receptor antagonist bosentan (Arthritis Rheum. 2004; 50:3985–93).

BOSTON — Maternal cells that pass through the placenta to the fetus during pregnancy may trigger the chronic inflammatory response that marks systemic lupus erythematosus in children, according to the findings of a preliminary investigation presented as a poster at the annual meeting of the Federation of Clinical Immunology Societies.

Healthy children appear to have an intrinsic immunologic tolerance to these circulating maternal cells, but for reasons that remain unknown, children with systemic lupus erythematosus (SLE) may lack this tolerance, causing their immunologic systems to perceive their maternal cells as foreign and turn against them.

Mother and fetus exchange cells during pregnancy. Each may retain the cells of the other for decades—a situation known as either maternal microchimerism (maternal cells in the child) or fetal microchimerism (fetal cells in the mother). The arrangement is usually, but not always, benign.

Researchers have labored long over the contribution of fetal cells to maternal autoimmune disease. More recently, they've also begun to investigate the ways maternal cells may initiate or perpetuate autoimmune disease in the child.

“Preliminary results suggest the hypothesis that immunological tolerance to maternal microchimerism is intrinsic to normal biology but may be lost in chronic inflammatory disease, leading to tissue-specific inflammation,” Anne M. Stevens, M.D., and her colleagues wrote in a poster presentation.

In a study comparing heart sections from neonates who died of neonatal lupus syndrome-associated congenital heart block with sections from babies who died of other causes, Dr. Stevens and colleagues found that babies with neonatal lupus syndrome had maternal T cells in 15 of 15 sections of heart tissue. By contrast, maternal cells were present in only two of eight sections taken from the controls (Lancet 2003;362:1617–23).

Surprisingly, maternal cells had not only migrated to the heart but had differentiated into myocardial cells, as well. Maternal cells had also taken up residence as tissue-specific phenotypes in the liver, pancreas, and other organs.

What isn't clear at this point is whether the presence of maternal myocardial cells triggered an immunologic response that led to the fatal heart block—an assault akin to graft-versus-host disease—or if the neonate recruited the maternal cells to help repair an attack on the heart from some other source.

In a different investigation, Dr. Stevens and her colleagues enrolled 14 children with SLE and 24 healthy controls matched for age and sex. They measured the level of maternal DNA present in a blood sample from each child. To do this, they developed an assay that can detect human leukocyte antigen (HLA) alleles that are present in the mother but not inherent to the child.

To see whether lupus patients mount an immune response to maternal cells when exposed to maternal antigens, they stimulated T cells from all subjects with CD14+ macrophages donated by both the child's mother and an unrelated donor.

The results surprised the investigators once again.

Maternal DNA was apparent in comparable numbers of both SLE patients and controls. And healthy children responded to stimulation from an unrelated donor in a well-recognized pattern, “the way they would to any foreign HLA molecules,” said Dr. Stevens. Some 14% of CD4+ leukocytes produced interferon-γ and 25% produced interleukin-4 (IL-4).

By contrast, only 2% produced interferon-γ and IL-4 in response to maternal cells, suggesting that “the control patient has tolerance to her mother,” said Dr. Stevens.

Children with SLE also displayed a normal immunological response to cells from an unrelated donor. But their response to maternal cells was notably different from that of healthy controls: Some 20% of CD4+ leukocytes produced interferon-γ and 31% produced IL-4.

“The lupus patient has a normal response to an unrelated donor. And [the patient has] twice that response to her mother. So she's hyperactivated,” said Dr. Stevens, a researcher at the Children's Hospital and Regional Medical Center, Seattle.

“Somehow the control patients had developed an immune tolerance to maternal antigens. Only 2% of their cells are actually responding to the mother's, which would explain why they can tolerate maternal microchimerism for decades.”

These results are still preliminary, Dr. Stevens commented. “This has to be substantiated in many, many more people.”

However, if additional evidence shores up her hypothesis, and maternal cells are shown to trigger an autoimmune response in SLE patients, clinicians might be able to halt the disease.

“Conceivably, we could target these maternal antigens or block the maternal HLA molecules and specifically stop this immune response. There are such a tiny number of cells involved that you would not be wiping out huge amounts of tissue. You'd be getting rid of the stimulus, and the rest of the body would be fine,” Dr. Stevens said.

BOSTON — Maternal cells that pass through the placenta to the fetus during pregnancy may trigger the chronic inflammatory response that marks systemic lupus erythematosus in children, according to the findings of a preliminary investigation presented as a poster at the annual meeting of the Federation of Clinical Immunology Societies.

Healthy children appear to have an intrinsic immunologic tolerance to these circulating maternal cells, but for reasons that remain unknown, children with systemic lupus erythematosus (SLE) may lack this tolerance, causing their immunologic systems to perceive their maternal cells as foreign and turn against them.

Mother and fetus exchange cells during pregnancy. Each may retain the cells of the other for decades—a situation known as either maternal microchimerism (maternal cells in the child) or fetal microchimerism (fetal cells in the mother). The arrangement is usually, but not always, benign.

Researchers have labored long over the contribution of fetal cells to maternal autoimmune disease. More recently, they've also begun to investigate the ways maternal cells may initiate or perpetuate autoimmune disease in the child.

“Preliminary results suggest the hypothesis that immunological tolerance to maternal microchimerism is intrinsic to normal biology but may be lost in chronic inflammatory disease, leading to tissue-specific inflammation,” Anne M. Stevens, M.D., and her colleagues wrote in a poster presentation.

In a study comparing heart sections from neonates who died of neonatal lupus syndrome-associated congenital heart block with sections from babies who died of other causes, Dr. Stevens and colleagues found that babies with neonatal lupus syndrome had maternal T cells in 15 of 15 sections of heart tissue. By contrast, maternal cells were present in only two of eight sections taken from the controls (Lancet 2003;362:1617–23).

Surprisingly, maternal cells had not only migrated to the heart but had differentiated into myocardial cells, as well. Maternal cells had also taken up residence as tissue-specific phenotypes in the liver, pancreas, and other organs.

What isn't clear at this point is whether the presence of maternal myocardial cells triggered an immunologic response that led to the fatal heart block—an assault akin to graft-versus-host disease—or if the neonate recruited the maternal cells to help repair an attack on the heart from some other source.

In a different investigation, Dr. Stevens and her colleagues enrolled 14 children with SLE and 24 healthy controls matched for age and sex. They measured the level of maternal DNA present in a blood sample from each child. To do this, they developed an assay that can detect human leukocyte antigen (HLA) alleles that are present in the mother but not inherent to the child.

To see whether lupus patients mount an immune response to maternal cells when exposed to maternal antigens, they stimulated T cells from all subjects with CD14+ macrophages donated by both the child's mother and an unrelated donor.

The results surprised the investigators once again.

Maternal DNA was apparent in comparable numbers of both SLE patients and controls. And healthy children responded to stimulation from an unrelated donor in a well-recognized pattern, “the way they would to any foreign HLA molecules,” said Dr. Stevens. Some 14% of CD4+ leukocytes produced interferon-γ and 25% produced interleukin-4 (IL-4).

By contrast, only 2% produced interferon-γ and IL-4 in response to maternal cells, suggesting that “the control patient has tolerance to her mother,” said Dr. Stevens.

Children with SLE also displayed a normal immunological response to cells from an unrelated donor. But their response to maternal cells was notably different from that of healthy controls: Some 20% of CD4+ leukocytes produced interferon-γ and 31% produced IL-4.

“The lupus patient has a normal response to an unrelated donor. And [the patient has] twice that response to her mother. So she's hyperactivated,” said Dr. Stevens, a researcher at the Children's Hospital and Regional Medical Center, Seattle.

“Somehow the control patients had developed an immune tolerance to maternal antigens. Only 2% of their cells are actually responding to the mother's, which would explain why they can tolerate maternal microchimerism for decades.”

These results are still preliminary, Dr. Stevens commented. “This has to be substantiated in many, many more people.”

However, if additional evidence shores up her hypothesis, and maternal cells are shown to trigger an autoimmune response in SLE patients, clinicians might be able to halt the disease.

“Conceivably, we could target these maternal antigens or block the maternal HLA molecules and specifically stop this immune response. There are such a tiny number of cells involved that you would not be wiping out huge amounts of tissue. You'd be getting rid of the stimulus, and the rest of the body would be fine,” Dr. Stevens said.

BOSTON — Maternal cells that pass through the placenta to the fetus during pregnancy may trigger the chronic inflammatory response that marks systemic lupus erythematosus in children, according to the findings of a preliminary investigation presented as a poster at the annual meeting of the Federation of Clinical Immunology Societies.

Healthy children appear to have an intrinsic immunologic tolerance to these circulating maternal cells, but for reasons that remain unknown, children with systemic lupus erythematosus (SLE) may lack this tolerance, causing their immunologic systems to perceive their maternal cells as foreign and turn against them.

Mother and fetus exchange cells during pregnancy. Each may retain the cells of the other for decades—a situation known as either maternal microchimerism (maternal cells in the child) or fetal microchimerism (fetal cells in the mother). The arrangement is usually, but not always, benign.

Researchers have labored long over the contribution of fetal cells to maternal autoimmune disease. More recently, they've also begun to investigate the ways maternal cells may initiate or perpetuate autoimmune disease in the child.

“Preliminary results suggest the hypothesis that immunological tolerance to maternal microchimerism is intrinsic to normal biology but may be lost in chronic inflammatory disease, leading to tissue-specific inflammation,” Anne M. Stevens, M.D., and her colleagues wrote in a poster presentation.

In a study comparing heart sections from neonates who died of neonatal lupus syndrome-associated congenital heart block with sections from babies who died of other causes, Dr. Stevens and colleagues found that babies with neonatal lupus syndrome had maternal T cells in 15 of 15 sections of heart tissue. By contrast, maternal cells were present in only two of eight sections taken from the controls (Lancet 2003;362:1617–23).

Surprisingly, maternal cells had not only migrated to the heart but had differentiated into myocardial cells, as well. Maternal cells had also taken up residence as tissue-specific phenotypes in the liver, pancreas, and other organs.

What isn't clear at this point is whether the presence of maternal myocardial cells triggered an immunologic response that led to the fatal heart block—an assault akin to graft-versus-host disease—or if the neonate recruited the maternal cells to help repair an attack on the heart from some other source.

In a different investigation, Dr. Stevens and her colleagues enrolled 14 children with SLE and 24 healthy controls matched for age and sex. They measured the level of maternal DNA present in a blood sample from each child. To do this, they developed an assay that can detect human leukocyte antigen (HLA) alleles that are present in the mother but not inherent to the child.

To see whether lupus patients mount an immune response to maternal cells when exposed to maternal antigens, they stimulated T cells from all subjects with CD14+ macrophages donated by both the child's mother and an unrelated donor.

The results surprised the investigators once again.

Maternal DNA was apparent in comparable numbers of both SLE patients and controls. And healthy children responded to stimulation from an unrelated donor in a well-recognized pattern, “the way they would to any foreign HLA molecules,” said Dr. Stevens. Some 14% of CD4+ leukocytes produced interferon-γ and 25% produced interleukin-4 (IL-4).

By contrast, only 2% produced interferon-γ and IL-4 in response to maternal cells, suggesting that “the control patient has tolerance to her mother,” said Dr. Stevens.

Children with SLE also displayed a normal immunological response to cells from an unrelated donor. But their response to maternal cells was notably different from that of healthy controls: Some 20% of CD4+ leukocytes produced interferon-γ and 31% produced IL-4.

“The lupus patient has a normal response to an unrelated donor. And [the patient has] twice that response to her mother. So she's hyperactivated,” said Dr. Stevens, a researcher at the Children's Hospital and Regional Medical Center, Seattle.

“Somehow the control patients had developed an immune tolerance to maternal antigens. Only 2% of their cells are actually responding to the mother's, which would explain why they can tolerate maternal microchimerism for decades.”

These results are still preliminary, Dr. Stevens commented. “This has to be substantiated in many, many more people.”

However, if additional evidence shores up her hypothesis, and maternal cells are shown to trigger an autoimmune response in SLE patients, clinicians might be able to halt the disease.

“Conceivably, we could target these maternal antigens or block the maternal HLA molecules and specifically stop this immune response. There are such a tiny number of cells involved that you would not be wiping out huge amounts of tissue. You'd be getting rid of the stimulus, and the rest of the body would be fine,” Dr. Stevens said.

DEDHAM, MASS. — Has the backlash against hormone therapy gone too far? Should doctors take yet another look at the evidence and find selective uses for HT that maximize its benefits and minimize its risks?

The answer to both questions is yes, according to Isaac Schiff, M.D., professor of gynecology at Harvard Medical School and chief of the ob.gyn. service at Massachusetts General Hospital. At a symposium on bone health sponsored by Boston University School of Medicine, Dr. Schiff recommended discussing HT with select patients as a double-duty medication for bone health and menopausal symptoms.

“Just as the pendulum went too far in the early 1990s—when all the retrospective studies suggested estrogens prevented heart disease, osteoporosis, Alzheimer's disease—after the Women's Health Initiative [WHI], the pendulum swung way too far to the other side, suggesting that estrogens are too risky,” Dr. Schiff said.

News reports about the WHI trial tended to focus on the risks of HT and to overlook benefits. Estrogen therapy is “certainly one of the most potent agents we have available” for preventing hip, vertebral, and wrist fractures, he said.

When the National Institutes of Health announced the landmark findings of the WHI trial, HT prescriptions declined precipitously. “Overall health risks [of HT] exceeded benefits,” investigators concluded after they stopped the trial early (JAMA 2002;288:321–33).

According to the WHI findings, therapy with estrogen plus progestin was associated with a major increase in the relative risk of several serious health problems. For example, it was tied to a 29% increased risk of coronary heart disease (CHD), a 41% increased risk of stroke, a twofold increased risk of pulmonary embolism (PE), and a 26% increased risk of breast cancer.

Many observers found the absolute risks less alarming, however. According to the WHI data, if 10,000 women took estrogen plus progestin for 1 year, there would be an excess risk of seven more CHD events, eight more strokes, eight more PEs, and eight more invasive breast cancers. There would be no extra deaths. Among women with no uterus taking estrogen only, there would be 12 more strokes (JAMA 2004;291:1701–12).

HT would also confer some benefits among those 10,000 women. There would be six fewer colorectal cancers and five fewer hip fractures. Among women with no uterus taking estrogen, there would be six fewer hip fractures. The WHI did not state whether HT would relieve menopausal symptoms.

Dr. Schiff termed the findings on fracture prevention “quite impressive.” Citing the reductions in relative risk, he noted that women taking progestin plus estrogen had a 29% reduction in lower forearm fractures and a 33% reduction in hip fractures. In the estrogen-only arm of the study, there was a 39% decrease in hip fractures and a 38% decrease in vertebral fractures.

Studies of other drugs designed to prevent and treat osteoporosis have had difficulty showing a reduction in hip fractures. The effect of medium-dose HT on fractures “is equivalent to bisphosphonates,” he said.

Hidden amid the WHI data is information on the impact of low-dose estrogens that might help clinicians balance benefits and risks of HT therapy, Dr. Schiff suggested.

At low doses, estrogens increased bone mineral density by 2.4% and 3.9% at the femoral neck and spine, respectively.

Dr. Schiff did not provide evidence from WHI to show that low-dose estrogens were associated with fewer fractures, however. As the NIH noted in a 2000 consensus statement on osteoporosis, improvements in bone density do not always translate to a decrease in fractures. “The risks for osteoporosis, as reflected by low bone density, and the risks for fracture overlap, but are not identical” (NIH Consens. Statement 2000;17[1]:1–36).

Still, Dr. Schiff said that there is enough evidence to support prescribing low-dose estrogen for the prevention of devastating hip fractures.

Citing data on low-dose oral contraceptives in relatively young, healthy women, Dr. Schiff said that, in theory, lower doses of estrogen should yield fewer health risks in the middle-aged and elderly. And “even very-low-dose estrogen is quite effective at maintaining bone density.”

That said, patients must be thoroughly informed about their individual risk profile regarding HT so they can make informed decisions. “A woman of age 50 is not worried about a hip fracture at age 80,” he said. “She is worried about the potential for breast cancer at age 55.”

And the data on estrogens and breast cancer are mixed. Some studies show an increased risk, some do not. “I tell my patients I personally have major concerns about the long-term risk” of breast cancer associated with estrogen therapy, he said.

In general, Dr. Schiff said that he prescribes estrogens for the minority of women with very severe hot flashes. For vaginal dryness topical estrogen therapy can help. Very-low-dose estrogen will also help with urogenital symptoms.

DEDHAM, MASS. — Has the backlash against hormone therapy gone too far? Should doctors take yet another look at the evidence and find selective uses for HT that maximize its benefits and minimize its risks?

The answer to both questions is yes, according to Isaac Schiff, M.D., professor of gynecology at Harvard Medical School and chief of the ob.gyn. service at Massachusetts General Hospital. At a symposium on bone health sponsored by Boston University School of Medicine, Dr. Schiff recommended discussing HT with select patients as a double-duty medication for bone health and menopausal symptoms.

“Just as the pendulum went too far in the early 1990s—when all the retrospective studies suggested estrogens prevented heart disease, osteoporosis, Alzheimer's disease—after the Women's Health Initiative [WHI], the pendulum swung way too far to the other side, suggesting that estrogens are too risky,” Dr. Schiff said.

News reports about the WHI trial tended to focus on the risks of HT and to overlook benefits. Estrogen therapy is “certainly one of the most potent agents we have available” for preventing hip, vertebral, and wrist fractures, he said.

When the National Institutes of Health announced the landmark findings of the WHI trial, HT prescriptions declined precipitously. “Overall health risks [of HT] exceeded benefits,” investigators concluded after they stopped the trial early (JAMA 2002;288:321–33).

According to the WHI findings, therapy with estrogen plus progestin was associated with a major increase in the relative risk of several serious health problems. For example, it was tied to a 29% increased risk of coronary heart disease (CHD), a 41% increased risk of stroke, a twofold increased risk of pulmonary embolism (PE), and a 26% increased risk of breast cancer.

Many observers found the absolute risks less alarming, however. According to the WHI data, if 10,000 women took estrogen plus progestin for 1 year, there would be an excess risk of seven more CHD events, eight more strokes, eight more PEs, and eight more invasive breast cancers. There would be no extra deaths. Among women with no uterus taking estrogen only, there would be 12 more strokes (JAMA 2004;291:1701–12).

HT would also confer some benefits among those 10,000 women. There would be six fewer colorectal cancers and five fewer hip fractures. Among women with no uterus taking estrogen, there would be six fewer hip fractures. The WHI did not state whether HT would relieve menopausal symptoms.

Dr. Schiff termed the findings on fracture prevention “quite impressive.” Citing the reductions in relative risk, he noted that women taking progestin plus estrogen had a 29% reduction in lower forearm fractures and a 33% reduction in hip fractures. In the estrogen-only arm of the study, there was a 39% decrease in hip fractures and a 38% decrease in vertebral fractures.

Studies of other drugs designed to prevent and treat osteoporosis have had difficulty showing a reduction in hip fractures. The effect of medium-dose HT on fractures “is equivalent to bisphosphonates,” he said.

Hidden amid the WHI data is information on the impact of low-dose estrogens that might help clinicians balance benefits and risks of HT therapy, Dr. Schiff suggested.

At low doses, estrogens increased bone mineral density by 2.4% and 3.9% at the femoral neck and spine, respectively.

Dr. Schiff did not provide evidence from WHI to show that low-dose estrogens were associated with fewer fractures, however. As the NIH noted in a 2000 consensus statement on osteoporosis, improvements in bone density do not always translate to a decrease in fractures. “The risks for osteoporosis, as reflected by low bone density, and the risks for fracture overlap, but are not identical” (NIH Consens. Statement 2000;17[1]:1–36).

Still, Dr. Schiff said that there is enough evidence to support prescribing low-dose estrogen for the prevention of devastating hip fractures.

Citing data on low-dose oral contraceptives in relatively young, healthy women, Dr. Schiff said that, in theory, lower doses of estrogen should yield fewer health risks in the middle-aged and elderly. And “even very-low-dose estrogen is quite effective at maintaining bone density.”

That said, patients must be thoroughly informed about their individual risk profile regarding HT so they can make informed decisions. “A woman of age 50 is not worried about a hip fracture at age 80,” he said. “She is worried about the potential for breast cancer at age 55.”

And the data on estrogens and breast cancer are mixed. Some studies show an increased risk, some do not. “I tell my patients I personally have major concerns about the long-term risk” of breast cancer associated with estrogen therapy, he said.

In general, Dr. Schiff said that he prescribes estrogens for the minority of women with very severe hot flashes. For vaginal dryness topical estrogen therapy can help. Very-low-dose estrogen will also help with urogenital symptoms.

DEDHAM, MASS. — Has the backlash against hormone therapy gone too far? Should doctors take yet another look at the evidence and find selective uses for HT that maximize its benefits and minimize its risks?

The answer to both questions is yes, according to Isaac Schiff, M.D., professor of gynecology at Harvard Medical School and chief of the ob.gyn. service at Massachusetts General Hospital. At a symposium on bone health sponsored by Boston University School of Medicine, Dr. Schiff recommended discussing HT with select patients as a double-duty medication for bone health and menopausal symptoms.

“Just as the pendulum went too far in the early 1990s—when all the retrospective studies suggested estrogens prevented heart disease, osteoporosis, Alzheimer's disease—after the Women's Health Initiative [WHI], the pendulum swung way too far to the other side, suggesting that estrogens are too risky,” Dr. Schiff said.

News reports about the WHI trial tended to focus on the risks of HT and to overlook benefits. Estrogen therapy is “certainly one of the most potent agents we have available” for preventing hip, vertebral, and wrist fractures, he said.

When the National Institutes of Health announced the landmark findings of the WHI trial, HT prescriptions declined precipitously. “Overall health risks [of HT] exceeded benefits,” investigators concluded after they stopped the trial early (JAMA 2002;288:321–33).

According to the WHI findings, therapy with estrogen plus progestin was associated with a major increase in the relative risk of several serious health problems. For example, it was tied to a 29% increased risk of coronary heart disease (CHD), a 41% increased risk of stroke, a twofold increased risk of pulmonary embolism (PE), and a 26% increased risk of breast cancer.

Many observers found the absolute risks less alarming, however. According to the WHI data, if 10,000 women took estrogen plus progestin for 1 year, there would be an excess risk of seven more CHD events, eight more strokes, eight more PEs, and eight more invasive breast cancers. There would be no extra deaths. Among women with no uterus taking estrogen only, there would be 12 more strokes (JAMA 2004;291:1701–12).

HT would also confer some benefits among those 10,000 women. There would be six fewer colorectal cancers and five fewer hip fractures. Among women with no uterus taking estrogen, there would be six fewer hip fractures. The WHI did not state whether HT would relieve menopausal symptoms.

Dr. Schiff termed the findings on fracture prevention “quite impressive.” Citing the reductions in relative risk, he noted that women taking progestin plus estrogen had a 29% reduction in lower forearm fractures and a 33% reduction in hip fractures. In the estrogen-only arm of the study, there was a 39% decrease in hip fractures and a 38% decrease in vertebral fractures.

Studies of other drugs designed to prevent and treat osteoporosis have had difficulty showing a reduction in hip fractures. The effect of medium-dose HT on fractures “is equivalent to bisphosphonates,” he said.

Hidden amid the WHI data is information on the impact of low-dose estrogens that might help clinicians balance benefits and risks of HT therapy, Dr. Schiff suggested.

At low doses, estrogens increased bone mineral density by 2.4% and 3.9% at the femoral neck and spine, respectively.

Dr. Schiff did not provide evidence from WHI to show that low-dose estrogens were associated with fewer fractures, however. As the NIH noted in a 2000 consensus statement on osteoporosis, improvements in bone density do not always translate to a decrease in fractures. “The risks for osteoporosis, as reflected by low bone density, and the risks for fracture overlap, but are not identical” (NIH Consens. Statement 2000;17[1]:1–36).

Still, Dr. Schiff said that there is enough evidence to support prescribing low-dose estrogen for the prevention of devastating hip fractures.

Citing data on low-dose oral contraceptives in relatively young, healthy women, Dr. Schiff said that, in theory, lower doses of estrogen should yield fewer health risks in the middle-aged and elderly. And “even very-low-dose estrogen is quite effective at maintaining bone density.”

That said, patients must be thoroughly informed about their individual risk profile regarding HT so they can make informed decisions. “A woman of age 50 is not worried about a hip fracture at age 80,” he said. “She is worried about the potential for breast cancer at age 55.”

And the data on estrogens and breast cancer are mixed. Some studies show an increased risk, some do not. “I tell my patients I personally have major concerns about the long-term risk” of breast cancer associated with estrogen therapy, he said.

In general, Dr. Schiff said that he prescribes estrogens for the minority of women with very severe hot flashes. For vaginal dryness topical estrogen therapy can help. Very-low-dose estrogen will also help with urogenital symptoms.

The admitting diagnosis was septic arthritis. Bilateral arthrocenteses appeared inflammatory. Naproxen and low-dose prednisone were added.

Cultures and liver function were normal, as were WBC and platelet counts. However, WBC bands increased to 56% from 15%, and hemoglobin dropped from 3g to 8.6 g/dL in the first 3 days of admission. Serologies for rheumatic diseases, HIV, and other viruses were negative.

Acute renal failure and liver function abnormalities developed concurrently. Naproxen was discontinued.

After admission to the ICU, “in the course of 10 days, everything worsened,” noted Paulo B. Pinho, M.D., a Staten Island, N.Y., pediatrician and internist. Dr. Pinho reported the case in a poster session at the annual meeting of the Federation of Clinical Immunological Societies in Boston.

The patient's first few days in the ICU were marked by hypotension (BP 90s/30s), tachycardia (110–115 bpm), persistent fevers (>101° F), pancytopenia with bands of 88%, and coagulopathy. Her erythrocyte sedimentation rate (ESR) was low (5 mm/hr), but C-reactive protein (CRP) was elevated (24 mg/dL). Transaminases had climbed to an aspartate transferase level of 2653U/L and alanine transferase of 504 U/L. Ferritin increased to >2,000 ng/mL (fractionated 152,197).

Given right upper quadrant pain and hepatosplenomegaly, an abdominal ultrasound was performed to look for intra-abdominal causes of presumed septic shock. It revealed only sludging.

Admitting diagnosis to the ICU was septic shock. Other diagnoses considered included adrenal insufficiency (potentially induced by corticosteroid withdrawal), thrombotic thrombocytopenia purpura (TTP, worsening renal function and altered mental state), and macrophage activation syndrome (MAS).

All cultures were negative; sepsis was rejected. The absence of microangiopathic hemolytic anemia ruled out TTP. Cortisol levels were consistent with the level of systemic inflammation, so adrenal insufficiency was also abandoned.

A bone marrow biopsy showed variable cellularity (40%–60%) with prominent hemophagocytosis. This finding, along with the markedly elevated ferritin, low ESR, yet elevated CRP suggested that the patient's previously uncharacterized febrile illnesses may have been a subtle presentation of systemic onset juvenile idiopathic arthritis (S-JIA).

The physician team entertained a diagnosis of JIA flare at this point, but the decreased counts of platelets and other cell lines, massive coagulopathy, and markedly elevated ferritin suggested macrophage activation syndrome (MAS), according to Dr. Pinho.

MAS is a relatively rare but potentially fatal complication of S-JIA and other chronic rheumatologic diseases. Its incidence is uncertain; the literature documents only hundreds of cases in patients with S-JIA, said Dr. Pinho. Reported mortality rates range from 8% to 22%.

The cause of MAS is also unclear, but it may be precipitated by infection or medication changes. “The clinical signs and symptoms can be easily explained by the surge of numerous cytokines and chemokines produced by activated macrophages and T cells,” said Dr. Pinho.

MAS presents as a confusing constellation of signs and symptoms. It is often characterized by well-differentiated hallmark macrophages showing hemophagocytosis in the bone marrow. But there are no firm diagnostic criteria.

Angelo Ravelli, M.D., and colleagues recently proposed preliminary diagnostic criteria for differentiating MAS from a disease flare in patients with S-JIA.

The researchers performed a systematic evaluation of the sensitivity and specificity of findings in 74 patients with MAS and 37 patients with S-JIA who had disease flares (J. Pediatr. 2005;146:598–604).

Their criteria focus on laboratory findings, since clinical symptoms of MAS often arrive late. They suggest the presence of any two of the following four criteria is diagnostic: decreased platelet count (≤262 × 109/L); elevated levels of aspartate transferase (>59 U/L); decreased WBC count (≤4.0 × 109/L); or hypofibrinogenemia (≤2.5 g/L).

Hyperferritinemia may also be highly diagnostic. Bone marrow biopsy for macrophage hemophagocytosis should be reserved for confirmation of only doubtful cases because hemophagocytosis is not always present in MAS, they wrote.

Other clinical criteria include CNS dysfunction, hemorrhages, and hepatomegaly.

The patient was bolused with intravenous methylprednisolone and started on cyclosporin A. Intense blood product, ventilatory, and fluid support were essential. Not until day 14 did she begin to improve. By day 18 she was extubated and on day 31 discharged from the hospital with a prednisone taper and cyclosporin.

The extraordinary and swift transformation of a healthy-appearing, young female with a sore knee and sore throat to a desperately ill patient with multiple organ failure points out the need for early recognition and prompt action, two essential components to good outcomes in this disease, according to Dr. Pinho.

His colleagues included Miguel Rodriguez, M.D.; Davida Menasha, M.D.; Manal Youssef-Bessler, M.D.; Bhavna Suri, M.D.; Allen Blaivas, M.D.; Ralph K. Messo Jr., D.O.; Rajendra Kapila, M.D.; and Leonard Bielory, M.D., of New Jersey Medical School and Staten Island University Hospital, New York.

A bone marrow biopsy done at ICU admission showed variable cellularity with prominent hemophagocytosis. Courtesy Dr. Paulo B. Pinho

The admitting diagnosis was septic arthritis. Bilateral arthrocenteses appeared inflammatory. Naproxen and low-dose prednisone were added.

Cultures and liver function were normal, as were WBC and platelet counts. However, WBC bands increased to 56% from 15%, and hemoglobin dropped from 3g to 8.6 g/dL in the first 3 days of admission. Serologies for rheumatic diseases, HIV, and other viruses were negative.

Acute renal failure and liver function abnormalities developed concurrently. Naproxen was discontinued.

After admission to the ICU, “in the course of 10 days, everything worsened,” noted Paulo B. Pinho, M.D., a Staten Island, N.Y., pediatrician and internist. Dr. Pinho reported the case in a poster session at the annual meeting of the Federation of Clinical Immunological Societies in Boston.

The patient's first few days in the ICU were marked by hypotension (BP 90s/30s), tachycardia (110–115 bpm), persistent fevers (>101° F), pancytopenia with bands of 88%, and coagulopathy. Her erythrocyte sedimentation rate (ESR) was low (5 mm/hr), but C-reactive protein (CRP) was elevated (24 mg/dL). Transaminases had climbed to an aspartate transferase level of 2653U/L and alanine transferase of 504 U/L. Ferritin increased to >2,000 ng/mL (fractionated 152,197).

Given right upper quadrant pain and hepatosplenomegaly, an abdominal ultrasound was performed to look for intra-abdominal causes of presumed septic shock. It revealed only sludging.

Admitting diagnosis to the ICU was septic shock. Other diagnoses considered included adrenal insufficiency (potentially induced by corticosteroid withdrawal), thrombotic thrombocytopenia purpura (TTP, worsening renal function and altered mental state), and macrophage activation syndrome (MAS).

All cultures were negative; sepsis was rejected. The absence of microangiopathic hemolytic anemia ruled out TTP. Cortisol levels were consistent with the level of systemic inflammation, so adrenal insufficiency was also abandoned.

A bone marrow biopsy showed variable cellularity (40%–60%) with prominent hemophagocytosis. This finding, along with the markedly elevated ferritin, low ESR, yet elevated CRP suggested that the patient's previously uncharacterized febrile illnesses may have been a subtle presentation of systemic onset juvenile idiopathic arthritis (S-JIA).

The physician team entertained a diagnosis of JIA flare at this point, but the decreased counts of platelets and other cell lines, massive coagulopathy, and markedly elevated ferritin suggested macrophage activation syndrome (MAS), according to Dr. Pinho.

MAS is a relatively rare but potentially fatal complication of S-JIA and other chronic rheumatologic diseases. Its incidence is uncertain; the literature documents only hundreds of cases in patients with S-JIA, said Dr. Pinho. Reported mortality rates range from 8% to 22%.

The cause of MAS is also unclear, but it may be precipitated by infection or medication changes. “The clinical signs and symptoms can be easily explained by the surge of numerous cytokines and chemokines produced by activated macrophages and T cells,” said Dr. Pinho.

MAS presents as a confusing constellation of signs and symptoms. It is often characterized by well-differentiated hallmark macrophages showing hemophagocytosis in the bone marrow. But there are no firm diagnostic criteria.

Angelo Ravelli, M.D., and colleagues recently proposed preliminary diagnostic criteria for differentiating MAS from a disease flare in patients with S-JIA.

The researchers performed a systematic evaluation of the sensitivity and specificity of findings in 74 patients with MAS and 37 patients with S-JIA who had disease flares (J. Pediatr. 2005;146:598–604).

Their criteria focus on laboratory findings, since clinical symptoms of MAS often arrive late. They suggest the presence of any two of the following four criteria is diagnostic: decreased platelet count (≤262 × 109/L); elevated levels of aspartate transferase (>59 U/L); decreased WBC count (≤4.0 × 109/L); or hypofibrinogenemia (≤2.5 g/L).

Hyperferritinemia may also be highly diagnostic. Bone marrow biopsy for macrophage hemophagocytosis should be reserved for confirmation of only doubtful cases because hemophagocytosis is not always present in MAS, they wrote.

Other clinical criteria include CNS dysfunction, hemorrhages, and hepatomegaly.

The patient was bolused with intravenous methylprednisolone and started on cyclosporin A. Intense blood product, ventilatory, and fluid support were essential. Not until day 14 did she begin to improve. By day 18 she was extubated and on day 31 discharged from the hospital with a prednisone taper and cyclosporin.

The extraordinary and swift transformation of a healthy-appearing, young female with a sore knee and sore throat to a desperately ill patient with multiple organ failure points out the need for early recognition and prompt action, two essential components to good outcomes in this disease, according to Dr. Pinho.

His colleagues included Miguel Rodriguez, M.D.; Davida Menasha, M.D.; Manal Youssef-Bessler, M.D.; Bhavna Suri, M.D.; Allen Blaivas, M.D.; Ralph K. Messo Jr., D.O.; Rajendra Kapila, M.D.; and Leonard Bielory, M.D., of New Jersey Medical School and Staten Island University Hospital, New York.

A bone marrow biopsy done at ICU admission showed variable cellularity with prominent hemophagocytosis. Courtesy Dr. Paulo B. Pinho

The admitting diagnosis was septic arthritis. Bilateral arthrocenteses appeared inflammatory. Naproxen and low-dose prednisone were added.

Cultures and liver function were normal, as were WBC and platelet counts. However, WBC bands increased to 56% from 15%, and hemoglobin dropped from 3g to 8.6 g/dL in the first 3 days of admission. Serologies for rheumatic diseases, HIV, and other viruses were negative.

Acute renal failure and liver function abnormalities developed concurrently. Naproxen was discontinued.

After admission to the ICU, “in the course of 10 days, everything worsened,” noted Paulo B. Pinho, M.D., a Staten Island, N.Y., pediatrician and internist. Dr. Pinho reported the case in a poster session at the annual meeting of the Federation of Clinical Immunological Societies in Boston.

The patient's first few days in the ICU were marked by hypotension (BP 90s/30s), tachycardia (110–115 bpm), persistent fevers (>101° F), pancytopenia with bands of 88%, and coagulopathy. Her erythrocyte sedimentation rate (ESR) was low (5 mm/hr), but C-reactive protein (CRP) was elevated (24 mg/dL). Transaminases had climbed to an aspartate transferase level of 2653U/L and alanine transferase of 504 U/L. Ferritin increased to >2,000 ng/mL (fractionated 152,197).

Given right upper quadrant pain and hepatosplenomegaly, an abdominal ultrasound was performed to look for intra-abdominal causes of presumed septic shock. It revealed only sludging.

Admitting diagnosis to the ICU was septic shock. Other diagnoses considered included adrenal insufficiency (potentially induced by corticosteroid withdrawal), thrombotic thrombocytopenia purpura (TTP, worsening renal function and altered mental state), and macrophage activation syndrome (MAS).

All cultures were negative; sepsis was rejected. The absence of microangiopathic hemolytic anemia ruled out TTP. Cortisol levels were consistent with the level of systemic inflammation, so adrenal insufficiency was also abandoned.

A bone marrow biopsy showed variable cellularity (40%–60%) with prominent hemophagocytosis. This finding, along with the markedly elevated ferritin, low ESR, yet elevated CRP suggested that the patient's previously uncharacterized febrile illnesses may have been a subtle presentation of systemic onset juvenile idiopathic arthritis (S-JIA).

The physician team entertained a diagnosis of JIA flare at this point, but the decreased counts of platelets and other cell lines, massive coagulopathy, and markedly elevated ferritin suggested macrophage activation syndrome (MAS), according to Dr. Pinho.

MAS is a relatively rare but potentially fatal complication of S-JIA and other chronic rheumatologic diseases. Its incidence is uncertain; the literature documents only hundreds of cases in patients with S-JIA, said Dr. Pinho. Reported mortality rates range from 8% to 22%.

The cause of MAS is also unclear, but it may be precipitated by infection or medication changes. “The clinical signs and symptoms can be easily explained by the surge of numerous cytokines and chemokines produced by activated macrophages and T cells,” said Dr. Pinho.

MAS presents as a confusing constellation of signs and symptoms. It is often characterized by well-differentiated hallmark macrophages showing hemophagocytosis in the bone marrow. But there are no firm diagnostic criteria.

Angelo Ravelli, M.D., and colleagues recently proposed preliminary diagnostic criteria for differentiating MAS from a disease flare in patients with S-JIA.

The researchers performed a systematic evaluation of the sensitivity and specificity of findings in 74 patients with MAS and 37 patients with S-JIA who had disease flares (J. Pediatr. 2005;146:598–604).

Their criteria focus on laboratory findings, since clinical symptoms of MAS often arrive late. They suggest the presence of any two of the following four criteria is diagnostic: decreased platelet count (≤262 × 109/L); elevated levels of aspartate transferase (>59 U/L); decreased WBC count (≤4.0 × 109/L); or hypofibrinogenemia (≤2.5 g/L).

Hyperferritinemia may also be highly diagnostic. Bone marrow biopsy for macrophage hemophagocytosis should be reserved for confirmation of only doubtful cases because hemophagocytosis is not always present in MAS, they wrote.

Other clinical criteria include CNS dysfunction, hemorrhages, and hepatomegaly.

The patient was bolused with intravenous methylprednisolone and started on cyclosporin A. Intense blood product, ventilatory, and fluid support were essential. Not until day 14 did she begin to improve. By day 18 she was extubated and on day 31 discharged from the hospital with a prednisone taper and cyclosporin.

The extraordinary and swift transformation of a healthy-appearing, young female with a sore knee and sore throat to a desperately ill patient with multiple organ failure points out the need for early recognition and prompt action, two essential components to good outcomes in this disease, according to Dr. Pinho.

His colleagues included Miguel Rodriguez, M.D.; Davida Menasha, M.D.; Manal Youssef-Bessler, M.D.; Bhavna Suri, M.D.; Allen Blaivas, M.D.; Ralph K. Messo Jr., D.O.; Rajendra Kapila, M.D.; and Leonard Bielory, M.D., of New Jersey Medical School and Staten Island University Hospital, New York.

A bone marrow biopsy done at ICU admission showed variable cellularity with prominent hemophagocytosis. Courtesy Dr. Paulo B. Pinho

BOSTON — Children with systemic lupus erythematosus appear to have favorable outcomes, at least in the short term, according to findings of an Israel-based study.

Yosef Uziel, M.D., of Meir Hospital in Kfar-Saba, Israel, and colleagues, retrospectively analyzed the records of all pediatric patients with SLE in an Israeli national registry of children with rheumatic diseases.

They presented their findings on 102 children who were followed for the first 5 years of their disease in a poster session at the annual meeting of the Federation of Clinical Immunological Societies in Boston.

On average, the patients were 13 years old at the time of diagnosis; 81% were female. Initially, 41% had renal involvement; 7% central nervous system problems; 94% hematologic abnormalities; 49% malar rashes; 21% oral or nasal ulcerations; 45% musculoskeletal disorders; and 16% serositis. Their initial mean SLE disease activity index (SLEDAI) score was 17.2.

At the time of their diagnosis, 80% of the children received prescriptions for corticosteroids. Nineteen percent received immunosuppressive drugs.

Five-year data were available on 44 of the children. Of these, 73% were on corticosteroids, and 38% were on immunosuppressive drugs.

The mean SLEDAI score dropped precipitously to 8.2 a year after diagnosis, and disease scores remained relatively stable, falling to a mean of 6.7 at 5 years.

Use of immunosuppressives consistently increased between the 1- and 5-year marks.

According to Dr. Uziel, some children took immunosuppressives as steroid-sparing agents, others for severe organ involvement, including lung, kidney, and central nervous system problems. Five patients developed chronic renal failure. One died.

BOSTON — Children with systemic lupus erythematosus appear to have favorable outcomes, at least in the short term, according to findings of an Israel-based study.

Yosef Uziel, M.D., of Meir Hospital in Kfar-Saba, Israel, and colleagues, retrospectively analyzed the records of all pediatric patients with SLE in an Israeli national registry of children with rheumatic diseases.

They presented their findings on 102 children who were followed for the first 5 years of their disease in a poster session at the annual meeting of the Federation of Clinical Immunological Societies in Boston.

On average, the patients were 13 years old at the time of diagnosis; 81% were female. Initially, 41% had renal involvement; 7% central nervous system problems; 94% hematologic abnormalities; 49% malar rashes; 21% oral or nasal ulcerations; 45% musculoskeletal disorders; and 16% serositis. Their initial mean SLE disease activity index (SLEDAI) score was 17.2.

At the time of their diagnosis, 80% of the children received prescriptions for corticosteroids. Nineteen percent received immunosuppressive drugs.

Five-year data were available on 44 of the children. Of these, 73% were on corticosteroids, and 38% were on immunosuppressive drugs.

The mean SLEDAI score dropped precipitously to 8.2 a year after diagnosis, and disease scores remained relatively stable, falling to a mean of 6.7 at 5 years.

Use of immunosuppressives consistently increased between the 1- and 5-year marks.

According to Dr. Uziel, some children took immunosuppressives as steroid-sparing agents, others for severe organ involvement, including lung, kidney, and central nervous system problems. Five patients developed chronic renal failure. One died.

BOSTON — Children with systemic lupus erythematosus appear to have favorable outcomes, at least in the short term, according to findings of an Israel-based study.

Yosef Uziel, M.D., of Meir Hospital in Kfar-Saba, Israel, and colleagues, retrospectively analyzed the records of all pediatric patients with SLE in an Israeli national registry of children with rheumatic diseases.

They presented their findings on 102 children who were followed for the first 5 years of their disease in a poster session at the annual meeting of the Federation of Clinical Immunological Societies in Boston.

On average, the patients were 13 years old at the time of diagnosis; 81% were female. Initially, 41% had renal involvement; 7% central nervous system problems; 94% hematologic abnormalities; 49% malar rashes; 21% oral or nasal ulcerations; 45% musculoskeletal disorders; and 16% serositis. Their initial mean SLE disease activity index (SLEDAI) score was 17.2.

At the time of their diagnosis, 80% of the children received prescriptions for corticosteroids. Nineteen percent received immunosuppressive drugs.

Five-year data were available on 44 of the children. Of these, 73% were on corticosteroids, and 38% were on immunosuppressive drugs.

The mean SLEDAI score dropped precipitously to 8.2 a year after diagnosis, and disease scores remained relatively stable, falling to a mean of 6.7 at 5 years.

Use of immunosuppressives consistently increased between the 1- and 5-year marks.

According to Dr. Uziel, some children took immunosuppressives as steroid-sparing agents, others for severe organ involvement, including lung, kidney, and central nervous system problems. Five patients developed chronic renal failure. One died.

BOSTON — Current assessment tools aimed at capturing quality of life information on children with systemic lupus erythematosus (SLE) may be considerably off the mark, according to preliminary findings from a cross-sectional study of school absenteeism.

Having lupus may be a pretext to take the day off. Or the instruments that gauge an individual's disease activity may be too crude to quantify the nuances of physical and emotional health that go into the decision to keep a child home from school, said L. Nandini Moorthy, M.D., chief of the division of pediatric rheumatology at Robert Wood Johnson Medical School in New Brunswick, N.J.

Dr. Moorthy and associates studied 24 SLE patients (average age 15/grade 9) using child and parent versions of four standard scales of disease and quality of life, as well a new scale called SMILEY, which researchers are currently testing in pediatric SLE. Dr. Moorthy reported the findings in a poster during the annual meeting of the Federation of Clinical Immunology Societies (FOCIS).

They found that over the previous 30 days, 10 of 24 children missed an average of 3 days of school. On an average of 3 of the previous 30 days, children were “too ill to play” and also “needed someone.”

Missed school days moderately correlated with parents' perception of their children's quality of life (Pediatric Quality of Life Inventory), but did not correlate with any of the child-reported scores. There was little correlation between school absence and lupus disease activity and damage.

“This is a preliminary study,” Dr. Moorthy noted. The cohort is small, while the range and duration of disease activity was broad. The next step is to expand the cohort.

“We need to tease out what missing school really means to [these children], what it means to get good grades versus bad grades.”

And then, she said, the study will “get at the root of” school absence in children living with a debilitating disease.

BOSTON — Current assessment tools aimed at capturing quality of life information on children with systemic lupus erythematosus (SLE) may be considerably off the mark, according to preliminary findings from a cross-sectional study of school absenteeism.

Having lupus may be a pretext to take the day off. Or the instruments that gauge an individual's disease activity may be too crude to quantify the nuances of physical and emotional health that go into the decision to keep a child home from school, said L. Nandini Moorthy, M.D., chief of the division of pediatric rheumatology at Robert Wood Johnson Medical School in New Brunswick, N.J.

Dr. Moorthy and associates studied 24 SLE patients (average age 15/grade 9) using child and parent versions of four standard scales of disease and quality of life, as well a new scale called SMILEY, which researchers are currently testing in pediatric SLE. Dr. Moorthy reported the findings in a poster during the annual meeting of the Federation of Clinical Immunology Societies (FOCIS).

They found that over the previous 30 days, 10 of 24 children missed an average of 3 days of school. On an average of 3 of the previous 30 days, children were “too ill to play” and also “needed someone.”

Missed school days moderately correlated with parents' perception of their children's quality of life (Pediatric Quality of Life Inventory), but did not correlate with any of the child-reported scores. There was little correlation between school absence and lupus disease activity and damage.

“This is a preliminary study,” Dr. Moorthy noted. The cohort is small, while the range and duration of disease activity was broad. The next step is to expand the cohort.

“We need to tease out what missing school really means to [these children], what it means to get good grades versus bad grades.”

And then, she said, the study will “get at the root of” school absence in children living with a debilitating disease.

BOSTON — Current assessment tools aimed at capturing quality of life information on children with systemic lupus erythematosus (SLE) may be considerably off the mark, according to preliminary findings from a cross-sectional study of school absenteeism.

Having lupus may be a pretext to take the day off. Or the instruments that gauge an individual's disease activity may be too crude to quantify the nuances of physical and emotional health that go into the decision to keep a child home from school, said L. Nandini Moorthy, M.D., chief of the division of pediatric rheumatology at Robert Wood Johnson Medical School in New Brunswick, N.J.

Dr. Moorthy and associates studied 24 SLE patients (average age 15/grade 9) using child and parent versions of four standard scales of disease and quality of life, as well a new scale called SMILEY, which researchers are currently testing in pediatric SLE. Dr. Moorthy reported the findings in a poster during the annual meeting of the Federation of Clinical Immunology Societies (FOCIS).

They found that over the previous 30 days, 10 of 24 children missed an average of 3 days of school. On an average of 3 of the previous 30 days, children were “too ill to play” and also “needed someone.”

Missed school days moderately correlated with parents' perception of their children's quality of life (Pediatric Quality of Life Inventory), but did not correlate with any of the child-reported scores. There was little correlation between school absence and lupus disease activity and damage.

“This is a preliminary study,” Dr. Moorthy noted. The cohort is small, while the range and duration of disease activity was broad. The next step is to expand the cohort.

“We need to tease out what missing school really means to [these children], what it means to get good grades versus bad grades.”

And then, she said, the study will “get at the root of” school absence in children living with a debilitating disease.