Avenues for protecting against vasculopathy in systemic sclerosis

DESTIN, FLA. – Scleroderma is generally thought of as a fibrotic autoimmune disease, but a vascular process is also fundamental to its underlying pathogenesis, according to Dr. Fredrick M. Wigley.

In essence, it is believed that this process involves an immunologic insult to the blood vessels, which leads to intimal proliferation, which in turn leads to narrowing of the lumen. Occlusion occurs, the blood vessels leak, and activated vascular endothelial growth factor leaks out into tissues, causing the fibrosis that is seen clinically in this disease, Dr. Wigley, director of the Johns Hopkins Scleroderma Center at Johns Hopkins University, Baltimore, explained at the annual Congress of Clinical Rheumatology.

A number of strategies exist or are emerging to provide protection against vasculopathy in patients with scleroderma, he said.

Immunosuppressive therapy

Vasculopathy in systemic sclerosis "is an inflammatory process caused by T cells helping granzymes out, so why don’t we try to use immunosuppressive therapy more than we do for the vascular disease?" he said.

In fact, there have been numerous case reports supporting this idea, including several reports of patients who experienced improvement of their nailfold capillary bed after treatment with cyclophosphamide for another indication.

"There also are case reports of bleeding from GAVE [gastric antral vascular ectasia] responding to infusion of cyclophosphamide ... and then there was evidence of capillary regeneration after immunoablation stem cell rescue, reported by several investigators," said Dr. Wigley, who also is professor of medicine and associate director of the division of rheumatology at the university.

In the latter cases, capillary loops were present prior to therapy, and 5 months later, the capillary beds looked normal. This suggests that in patients who receive high-dose cyclophosphamide with stem cell rescue, there is "some fundamental effect on the vasculature and its ability to recover," Dr. Wigley said, adding: "I think this is way too premature for us to put in our back pocket, but I think the use of immunosuppression in active disease is something that we need to study and think carefully about."

In another study, cyclophosphamide was associated with improvement in the number of vascular injury markers after treatment, suggesting the treatment was improving the vascular insult.

"Unfortunately, we don’t have much more information than that, but there are investigators who are taking a giant leap, and saying, ‘Well, if this is a vascular insult, why not use rituximab?’ " he said, noting that preclinical data and anecdotal reports suggest that immunomodulation of B cells may play a role in the management of systemic sclerosis-associated pulmonary arterial hypertension. A randomized, double-blind, phase II trial is now underway to evaluate the effects of rituximab on disease progression in patients with this condition.

Statins

Statins are also important for vascular protection, as there is good rationale that they can improve and protect blood vessel integrity, Dr. Wigley said.

"As you know, [statins] can stimulate some of those progenitor cells that we know are defective. There is evidence that they can improve endothelial function, they have antifibrotic properties and antioxidant properties, and they can modulate the immune system," he explained.

Atorvastatin, for example, has been shown to induce a significant increase in progenitor cells in patients with scleroderma and deficiency of such cells.

"And we know from other diseases that statins will increase release of progenitor cells from bone marrow that could, theoretically, go and help repair [blood vessels]," he said.

In a 2008 study from Egypt, patients treated with 40 mg of atorvastatin had a decrease in the evolution of new digital ulcers, compared with those who received placebo. The patients also experienced clinically important improvements in quality of life and pain measures (J. Rheumatol. 2008;35:1801-8).

"Frankly, in a difficult situation where I have recurrent digital ulcers and I’m giving them vasodilation therapy and antiplatelet therapy, I have a low threshold for trying statins because it makes biological sense that it could be helpful," he said.

Prostaglandins

Prostaglandins are being used in Europe intermittently – not just for vasospasm, but also for the possible "fundamental benefit for blood vessels," Dr. Wigley said.

They can inhibit platelets, down-regulate proliferation of smooth muscle, protect endothelial cells, and they can also stimulate production of stem cells from the marrow, so their intermittent use may make sense, he added.

The only oral prostaglandin – Beraprost – is approved for use in Japan but not in the United States, and has been shown to be helpful for the treatment of pulmonary hypertension, but not for Raynaud’s phenomenon, he noted.

"I think oral prostaglandins are something you are going to hear more about as companies take time to develop these agents," he said.

Endothelin inhibitors

Endothelin inhibitors also may play a role in vascular protection. Endothelin is secreted in scleroderma and is a potent vasoconstrictor. Endothelin inhibition has been shown to have benefit for pulmonary hypertension, but unlike in primary pulmonary hypertension, it does not appear to affect long-term survival in patients with scleroderma. However, endothelin inhibitors have some transient benefit in scleroderma patients with respect to measures of walking and pulmonary vascular resistance.

"It makes sense, because endothelin is a stimulant, not only for the vasoconstrictive pathway (by blocking nitric oxide), but it also stimulates proliferation of smooth muscle," he said.

In a controlled trial, bosentan was associated with fewer digital ulcers when compared with placebo, and also was associated with improvement in subjective hand function (Arthritis Rheum. 2004;50:3985-93). There was no benefit for Raynaud’s attack rate or duration of attack, so based on this trial the treatment was approved in Europe only for scleroderma patients with recurrent digital ulcers.

A study of another endothelin inhibitor – macitentan – was terminated for lack of benefit for digital ulcers, but a subanalysis of the patients showed an evolution of new ulcers in those who had been receiving active treatment, compared with those who had been receiving placebo, so there may be some benefit that the study design did not quite show, he said.

Angiotensin II type 1 receptor blockers

Angiotensin receptor blockers (ARBs) that block angiotensin 1 – and thereby decrease the angiotensin hormone’s signal to increase levels of the fibrosis-promoting transforming growth factor beta – have been shown to have dramatic effect for the vascular disease in Marfan’s syndrome. Marfan’s syndrome involves a fibrotic reaction similar to that seen in scleroderma.

"So it’s possible that using an ARB would be helpful," Dr. Wigley said.

In an uncontrolled trial in the United Kingdom, losartan at 50 mg was comparable or better than was nifedipine at 40 mg for treating Raynaud’s phenomenon, so losartan may be an option for those who don’t respond to or can’t tolerate nifedipine, he said.

Tyrosine kinase and Rho-kinase inhibitors

Tyrosine kinase and Rho-kinase inhibitors have also been evaluated for the treatment of pulmonary hypertension. Tyrosine kinase inhibitors were associated with dramatic reversal of disease, but are limited by cardiac toxicity. Rho-kinase inhibitors "make sense biologically" because of the role of the RhoA/Rho kinase pathway in regulating numerous pathologic processes including vasoconstriction, vascular remodeling, and fibrosis, Dr. Wigley said.

One Rho-kinase inhibitor – fasudil – is approved for use in Japan, and an inhaled formulation is currently being studied for pulmonary hypertension.

Stem cells

Studies in Japan of human mesenchymal stem cells suggest that bone-marrow-derived stem cells injected directly into the skin of patients with digital ulcers leads to improvement in the ulcers over time.

"There was no control group, so it’s not clear that the treatment was the reason for the benefit, but it is an interesting concept. Instead of stimulating the bone marrow to get stem cells, why not just inject them into the skin," he said.

These are just some of the approaches being looked at to provide vascular protection in patients with scleroderma, said Dr. Wigley, who also reviewed approaches for managing vasospasm, hypoxia, and superoxide injury, and vascular occlusion.

"I hope [these approaches] will stimulate your interest in looking at what may happen in the future," he said.

Dr. Wigley disclosed that he lectures, conducts research, and/or serves as a consultant for Actelion, CSL Behring, Hoffman-La Roche, KineMed, MedImmune, Novartis, Sanofi-Aventis, and United Therapeutics.

DESTIN, FLA. – Scleroderma is generally thought of as a fibrotic autoimmune disease, but a vascular process is also fundamental to its underlying pathogenesis, according to Dr. Fredrick M. Wigley.

In essence, it is believed that this process involves an immunologic insult to the blood vessels, which leads to intimal proliferation, which in turn leads to narrowing of the lumen. Occlusion occurs, the blood vessels leak, and activated vascular endothelial growth factor leaks out into tissues, causing the fibrosis that is seen clinically in this disease, Dr. Wigley, director of the Johns Hopkins Scleroderma Center at Johns Hopkins University, Baltimore, explained at the annual Congress of Clinical Rheumatology.

A number of strategies exist or are emerging to provide protection against vasculopathy in patients with scleroderma, he said.

Immunosuppressive therapy

Vasculopathy in systemic sclerosis "is an inflammatory process caused by T cells helping granzymes out, so why don’t we try to use immunosuppressive therapy more than we do for the vascular disease?" he said.

In fact, there have been numerous case reports supporting this idea, including several reports of patients who experienced improvement of their nailfold capillary bed after treatment with cyclophosphamide for another indication.

"There also are case reports of bleeding from GAVE [gastric antral vascular ectasia] responding to infusion of cyclophosphamide ... and then there was evidence of capillary regeneration after immunoablation stem cell rescue, reported by several investigators," said Dr. Wigley, who also is professor of medicine and associate director of the division of rheumatology at the university.

In the latter cases, capillary loops were present prior to therapy, and 5 months later, the capillary beds looked normal. This suggests that in patients who receive high-dose cyclophosphamide with stem cell rescue, there is "some fundamental effect on the vasculature and its ability to recover," Dr. Wigley said, adding: "I think this is way too premature for us to put in our back pocket, but I think the use of immunosuppression in active disease is something that we need to study and think carefully about."

In another study, cyclophosphamide was associated with improvement in the number of vascular injury markers after treatment, suggesting the treatment was improving the vascular insult.

"Unfortunately, we don’t have much more information than that, but there are investigators who are taking a giant leap, and saying, ‘Well, if this is a vascular insult, why not use rituximab?’ " he said, noting that preclinical data and anecdotal reports suggest that immunomodulation of B cells may play a role in the management of systemic sclerosis-associated pulmonary arterial hypertension. A randomized, double-blind, phase II trial is now underway to evaluate the effects of rituximab on disease progression in patients with this condition.

Statins

Statins are also important for vascular protection, as there is good rationale that they can improve and protect blood vessel integrity, Dr. Wigley said.

"As you know, [statins] can stimulate some of those progenitor cells that we know are defective. There is evidence that they can improve endothelial function, they have antifibrotic properties and antioxidant properties, and they can modulate the immune system," he explained.

Atorvastatin, for example, has been shown to induce a significant increase in progenitor cells in patients with scleroderma and deficiency of such cells.

"And we know from other diseases that statins will increase release of progenitor cells from bone marrow that could, theoretically, go and help repair [blood vessels]," he said.

In a 2008 study from Egypt, patients treated with 40 mg of atorvastatin had a decrease in the evolution of new digital ulcers, compared with those who received placebo. The patients also experienced clinically important improvements in quality of life and pain measures (J. Rheumatol. 2008;35:1801-8).

"Frankly, in a difficult situation where I have recurrent digital ulcers and I’m giving them vasodilation therapy and antiplatelet therapy, I have a low threshold for trying statins because it makes biological sense that it could be helpful," he said.

Prostaglandins

Prostaglandins are being used in Europe intermittently – not just for vasospasm, but also for the possible "fundamental benefit for blood vessels," Dr. Wigley said.

They can inhibit platelets, down-regulate proliferation of smooth muscle, protect endothelial cells, and they can also stimulate production of stem cells from the marrow, so their intermittent use may make sense, he added.

The only oral prostaglandin – Beraprost – is approved for use in Japan but not in the United States, and has been shown to be helpful for the treatment of pulmonary hypertension, but not for Raynaud’s phenomenon, he noted.

"I think oral prostaglandins are something you are going to hear more about as companies take time to develop these agents," he said.

Endothelin inhibitors

Endothelin inhibitors also may play a role in vascular protection. Endothelin is secreted in scleroderma and is a potent vasoconstrictor. Endothelin inhibition has been shown to have benefit for pulmonary hypertension, but unlike in primary pulmonary hypertension, it does not appear to affect long-term survival in patients with scleroderma. However, endothelin inhibitors have some transient benefit in scleroderma patients with respect to measures of walking and pulmonary vascular resistance.

"It makes sense, because endothelin is a stimulant, not only for the vasoconstrictive pathway (by blocking nitric oxide), but it also stimulates proliferation of smooth muscle," he said.

In a controlled trial, bosentan was associated with fewer digital ulcers when compared with placebo, and also was associated with improvement in subjective hand function (Arthritis Rheum. 2004;50:3985-93). There was no benefit for Raynaud’s attack rate or duration of attack, so based on this trial the treatment was approved in Europe only for scleroderma patients with recurrent digital ulcers.

A study of another endothelin inhibitor – macitentan – was terminated for lack of benefit for digital ulcers, but a subanalysis of the patients showed an evolution of new ulcers in those who had been receiving active treatment, compared with those who had been receiving placebo, so there may be some benefit that the study design did not quite show, he said.

Angiotensin II type 1 receptor blockers

Angiotensin receptor blockers (ARBs) that block angiotensin 1 – and thereby decrease the angiotensin hormone’s signal to increase levels of the fibrosis-promoting transforming growth factor beta – have been shown to have dramatic effect for the vascular disease in Marfan’s syndrome. Marfan’s syndrome involves a fibrotic reaction similar to that seen in scleroderma.

"So it’s possible that using an ARB would be helpful," Dr. Wigley said.

In an uncontrolled trial in the United Kingdom, losartan at 50 mg was comparable or better than was nifedipine at 40 mg for treating Raynaud’s phenomenon, so losartan may be an option for those who don’t respond to or can’t tolerate nifedipine, he said.

Tyrosine kinase and Rho-kinase inhibitors

Tyrosine kinase and Rho-kinase inhibitors have also been evaluated for the treatment of pulmonary hypertension. Tyrosine kinase inhibitors were associated with dramatic reversal of disease, but are limited by cardiac toxicity. Rho-kinase inhibitors "make sense biologically" because of the role of the RhoA/Rho kinase pathway in regulating numerous pathologic processes including vasoconstriction, vascular remodeling, and fibrosis, Dr. Wigley said.

One Rho-kinase inhibitor – fasudil – is approved for use in Japan, and an inhaled formulation is currently being studied for pulmonary hypertension.

Stem cells

Studies in Japan of human mesenchymal stem cells suggest that bone-marrow-derived stem cells injected directly into the skin of patients with digital ulcers leads to improvement in the ulcers over time.

"There was no control group, so it’s not clear that the treatment was the reason for the benefit, but it is an interesting concept. Instead of stimulating the bone marrow to get stem cells, why not just inject them into the skin," he said.

These are just some of the approaches being looked at to provide vascular protection in patients with scleroderma, said Dr. Wigley, who also reviewed approaches for managing vasospasm, hypoxia, and superoxide injury, and vascular occlusion.

"I hope [these approaches] will stimulate your interest in looking at what may happen in the future," he said.

Dr. Wigley disclosed that he lectures, conducts research, and/or serves as a consultant for Actelion, CSL Behring, Hoffman-La Roche, KineMed, MedImmune, Novartis, Sanofi-Aventis, and United Therapeutics.

DESTIN, FLA. – Scleroderma is generally thought of as a fibrotic autoimmune disease, but a vascular process is also fundamental to its underlying pathogenesis, according to Dr. Fredrick M. Wigley.

In essence, it is believed that this process involves an immunologic insult to the blood vessels, which leads to intimal proliferation, which in turn leads to narrowing of the lumen. Occlusion occurs, the blood vessels leak, and activated vascular endothelial growth factor leaks out into tissues, causing the fibrosis that is seen clinically in this disease, Dr. Wigley, director of the Johns Hopkins Scleroderma Center at Johns Hopkins University, Baltimore, explained at the annual Congress of Clinical Rheumatology.

A number of strategies exist or are emerging to provide protection against vasculopathy in patients with scleroderma, he said.

Immunosuppressive therapy

Vasculopathy in systemic sclerosis "is an inflammatory process caused by T cells helping granzymes out, so why don’t we try to use immunosuppressive therapy more than we do for the vascular disease?" he said.

In fact, there have been numerous case reports supporting this idea, including several reports of patients who experienced improvement of their nailfold capillary bed after treatment with cyclophosphamide for another indication.

"There also are case reports of bleeding from GAVE [gastric antral vascular ectasia] responding to infusion of cyclophosphamide ... and then there was evidence of capillary regeneration after immunoablation stem cell rescue, reported by several investigators," said Dr. Wigley, who also is professor of medicine and associate director of the division of rheumatology at the university.

In the latter cases, capillary loops were present prior to therapy, and 5 months later, the capillary beds looked normal. This suggests that in patients who receive high-dose cyclophosphamide with stem cell rescue, there is "some fundamental effect on the vasculature and its ability to recover," Dr. Wigley said, adding: "I think this is way too premature for us to put in our back pocket, but I think the use of immunosuppression in active disease is something that we need to study and think carefully about."

In another study, cyclophosphamide was associated with improvement in the number of vascular injury markers after treatment, suggesting the treatment was improving the vascular insult.

"Unfortunately, we don’t have much more information than that, but there are investigators who are taking a giant leap, and saying, ‘Well, if this is a vascular insult, why not use rituximab?’ " he said, noting that preclinical data and anecdotal reports suggest that immunomodulation of B cells may play a role in the management of systemic sclerosis-associated pulmonary arterial hypertension. A randomized, double-blind, phase II trial is now underway to evaluate the effects of rituximab on disease progression in patients with this condition.

Statins

Statins are also important for vascular protection, as there is good rationale that they can improve and protect blood vessel integrity, Dr. Wigley said.

"As you know, [statins] can stimulate some of those progenitor cells that we know are defective. There is evidence that they can improve endothelial function, they have antifibrotic properties and antioxidant properties, and they can modulate the immune system," he explained.

Atorvastatin, for example, has been shown to induce a significant increase in progenitor cells in patients with scleroderma and deficiency of such cells.

"And we know from other diseases that statins will increase release of progenitor cells from bone marrow that could, theoretically, go and help repair [blood vessels]," he said.

In a 2008 study from Egypt, patients treated with 40 mg of atorvastatin had a decrease in the evolution of new digital ulcers, compared with those who received placebo. The patients also experienced clinically important improvements in quality of life and pain measures (J. Rheumatol. 2008;35:1801-8).

"Frankly, in a difficult situation where I have recurrent digital ulcers and I’m giving them vasodilation therapy and antiplatelet therapy, I have a low threshold for trying statins because it makes biological sense that it could be helpful," he said.

Prostaglandins

Prostaglandins are being used in Europe intermittently – not just for vasospasm, but also for the possible "fundamental benefit for blood vessels," Dr. Wigley said.

They can inhibit platelets, down-regulate proliferation of smooth muscle, protect endothelial cells, and they can also stimulate production of stem cells from the marrow, so their intermittent use may make sense, he added.

The only oral prostaglandin – Beraprost – is approved for use in Japan but not in the United States, and has been shown to be helpful for the treatment of pulmonary hypertension, but not for Raynaud’s phenomenon, he noted.

"I think oral prostaglandins are something you are going to hear more about as companies take time to develop these agents," he said.

Endothelin inhibitors

Endothelin inhibitors also may play a role in vascular protection. Endothelin is secreted in scleroderma and is a potent vasoconstrictor. Endothelin inhibition has been shown to have benefit for pulmonary hypertension, but unlike in primary pulmonary hypertension, it does not appear to affect long-term survival in patients with scleroderma. However, endothelin inhibitors have some transient benefit in scleroderma patients with respect to measures of walking and pulmonary vascular resistance.

"It makes sense, because endothelin is a stimulant, not only for the vasoconstrictive pathway (by blocking nitric oxide), but it also stimulates proliferation of smooth muscle," he said.

In a controlled trial, bosentan was associated with fewer digital ulcers when compared with placebo, and also was associated with improvement in subjective hand function (Arthritis Rheum. 2004;50:3985-93). There was no benefit for Raynaud’s attack rate or duration of attack, so based on this trial the treatment was approved in Europe only for scleroderma patients with recurrent digital ulcers.

A study of another endothelin inhibitor – macitentan – was terminated for lack of benefit for digital ulcers, but a subanalysis of the patients showed an evolution of new ulcers in those who had been receiving active treatment, compared with those who had been receiving placebo, so there may be some benefit that the study design did not quite show, he said.

Angiotensin II type 1 receptor blockers

Angiotensin receptor blockers (ARBs) that block angiotensin 1 – and thereby decrease the angiotensin hormone’s signal to increase levels of the fibrosis-promoting transforming growth factor beta – have been shown to have dramatic effect for the vascular disease in Marfan’s syndrome. Marfan’s syndrome involves a fibrotic reaction similar to that seen in scleroderma.

"So it’s possible that using an ARB would be helpful," Dr. Wigley said.

In an uncontrolled trial in the United Kingdom, losartan at 50 mg was comparable or better than was nifedipine at 40 mg for treating Raynaud’s phenomenon, so losartan may be an option for those who don’t respond to or can’t tolerate nifedipine, he said.

Tyrosine kinase and Rho-kinase inhibitors

Tyrosine kinase and Rho-kinase inhibitors have also been evaluated for the treatment of pulmonary hypertension. Tyrosine kinase inhibitors were associated with dramatic reversal of disease, but are limited by cardiac toxicity. Rho-kinase inhibitors "make sense biologically" because of the role of the RhoA/Rho kinase pathway in regulating numerous pathologic processes including vasoconstriction, vascular remodeling, and fibrosis, Dr. Wigley said.

One Rho-kinase inhibitor – fasudil – is approved for use in Japan, and an inhaled formulation is currently being studied for pulmonary hypertension.

Stem cells

Studies in Japan of human mesenchymal stem cells suggest that bone-marrow-derived stem cells injected directly into the skin of patients with digital ulcers leads to improvement in the ulcers over time.

"There was no control group, so it’s not clear that the treatment was the reason for the benefit, but it is an interesting concept. Instead of stimulating the bone marrow to get stem cells, why not just inject them into the skin," he said.

These are just some of the approaches being looked at to provide vascular protection in patients with scleroderma, said Dr. Wigley, who also reviewed approaches for managing vasospasm, hypoxia, and superoxide injury, and vascular occlusion.

"I hope [these approaches] will stimulate your interest in looking at what may happen in the future," he said.

Dr. Wigley disclosed that he lectures, conducts research, and/or serves as a consultant for Actelion, CSL Behring, Hoffman-La Roche, KineMed, MedImmune, Novartis, Sanofi-Aventis, and United Therapeutics.