Raynaud phenomenon (RP) and associated digital ischemia can be among the most vexing clinical problems for patients with systemic sclerosis (scleroderma). Understanding the treatment approach to RP and associated ischemia and how to prevent digital ulcers is important for clinicians caring for these patients. This article reviews the management of RP and digital ischemic ulcers. The magnitude of the problem and pathophysiology of RP are first discussed, with an emphasis on recent advances in understanding of the disease process. Options for the practical pharmacologic and nonpharmacologic interventions for RP and digital ischemic ulcers are detailed.
Key points
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The pathophysiology of Raynaud phenomenon (RP) and digital ulcers in scleroderma is complex, involving both vasospasm and structural disease of the vasculature.
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Therapy for RP and digital ulcers should involve both nonpharmacologic and pharmacologic treatments.
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Pharmacologic therapy for RP should include a combination of vasoactive agents that can reverse vasoconstriction and address biological pathways to prevent the progression of the underlying vasculopathy.
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Digital ulcers are a common complication of scleroderma vascular disease that requires both systemic and local tissue therapy.
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Critical digital ischemia is a medical emergency and requires urgent treatment. Multiple modalities are available to reverse an event and prevent digital loss.
Background
Raynaud phenomenon (RP) is one of the most common clinical manifestations of scleroderma, experienced by 90% to 98% of patients, usually as the first symptom in the course of the disease ( Box 1 , Table 1 ). The new 2013 classification criteria of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) now recognizes the importance of RP by including it as a feature to confirm a diagnosis of scleroderma. RP often predates other symptoms and signs by several years, which suggests that the peripheral vasculature is the initial target of the scleroderma disease process. The presence of RP alone is a clinical symptom that is also a predictor of developing scleroderma. This concept is supported by studies finding that patients with a very early diagnosis of scleroderma already have RP. Although a patient presenting with only RP, abnormal nail fold capillaries typical of scleroderma, and the presence of a specific scleroderma-related autoantibody do not meet the new ACR/EULAR criteria, studies do find that almost 80% of such patients develop scleroderma over subsequent years of follow-up. A recent survey of anti-nuclear antibodies (ANA)-negative patients with scleroderma who did not have RP found that they often had a malignancy, suggesting that these patients may have a cancer-associated syndrome.
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Confirm that it is a digital ischemic ulcer and not another digital lesion
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Maximize vasodilatation
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Add other proven medications in addition to vasodilators
- •
Do not neglect local therapy
- •
Evaluate for and treat superinfection
- •
Evaluate for macrovascular disease, which can worsen digital ulcers
| Class of Medication | Mechanism of Action | Specific Drugs | Evidence | Strength of Evidence |
|---|---|---|---|---|
| Calcium channel blockers | Prevents calcium from entering muscle cells and inducing vasospasm | Nifedipine Nicardipine Amlodipine Felodipine Diltiazem | RCT, meta-analysis | Level 1 |
| PDE-5 inhibitors | Inhibits degradation of cGMP promoting vasodilation by NO | Sildenafil Tadalafil Vardenafil | RCT, meta-analysis | Level 1 |
| Prostacyclins | Directly dilate blood vessels, inhibit platelet aggregation | Epoprostenol Iloprost | RCT | Level 2 |
| Topical nitrate | Stimulates cGMP production causing vasodilation | Glyceryl trinitrate | RCT | Level 2 |
| Endothelin receptor antagonists | Blocks vasoconstrictive effects of endothelin-1 | Bosentan Ambrisentan Macitentan | RCT (ulcers only) | Level 2 |
| Statins | Inhibit HMG-CoA reductase reducing LDL cholesterol levels, likely other effects in RP and digital ulcers | Atorvastatin Rosuvastatin Pravastatin | RCT of atorvastatin (RP and ulcers) | Level 2 |
| Angiotensin receptor blockers | Antagonize angiotensin receptors | Losartan Irbesartan Olmesartan | RCT (losartan in RP) | Level 2 |
| Selective serotonin reuptake inhibitors | Prevent serotonin entry into vascular smooth muscle | Fluoxetine Sertraline Paroxetine | RCT for fluoxetine in RP | Level 2 |
| Botulinum toxin | Likely by arterial vasodilation from sympathetic blockade | Botulinum toxin | Case series | Level 3 |
| Immunosuppression | Decreases | Cyclophosphamide Mycophenolate mofetil Azathioprine | No dedicated studies, suggested benefit in 1 study of CYC for other purpose | Level 3 |
| Antiplatelet | Inhibit platelet aggregation | Aspirin Clopidogrel | Negative trials in RP No trials in ulcers | Level 4 |
| Anticoagulation | Inhibit coagulation cascade | Enoxaparin Warfarin | No studies in scleroderma | Level 4 |
| Rho-kinase inhibitors | Prevent vasospasm through Rho-kinase pathway | Fasudil | One small negative trial in RP | Level 4 |
| Guanylate cyclase stimulators | Potentiates vasodilatory effects of nitric oxide | Riociguat | No evidence in RP or ulcers at present | N/A |
To be diagnosed with RP, patients should experience episodic cold-induced or stress-induced sensitivity associated with pallor or cyanosis of the digits. The pallor or cyanosis that accompanies the ischemic phase of an attack may be followed by erythema as a result of reactive hyperemia. Most patients do not experience all phases of color change: pallor, cyanosis, and erythema. The involvement of digital arteries, along with vasoconstriction of cutaneous arterioles, is responsible for the initial color change of pallor witnessed during RP. When veins dilate and there is pooling of deoxygenated blood, the digits take on a cyanotic appearance. Patients with scleroderma are considered to have secondary RP and are more likely to experience digital ulceration and critical digital ischemia than patients with primary RP. Patients with primary RP are less likely to have involvement of the thumb than patients with scleroderma.
In both primary and secondary RP, there is increased reactivity of the blood vessels to cold and increased sympathetic tone. In vitro studies show that increased sympathetic tone is mediated by an increased expression of alpha-2c adrenergic receptors on smooth muscle of cutaneous arteries. Exposure to cold leads to activation of the Rho/Rho-kinase signaling pathway and increased transport of alpha-2c receptors to the cellular membrane. The translocation of these receptors is associated with increased cellular responsiveness to cold-induced adrenergic signals. Ex vivo studies of scleroderma blood vessel have shown that vascular smooth muscle of the arterioles display a selective increase in alpha2-adrenergic reactivity, suggesting that RP in scleroderma is in part caused by upregulation of the adrenergic receptors. In scleroderma, there is also evidence of dysfunction of the endothelium resulting in an imbalance between vasoconstricting and vasodilatory stimuli. Studies have suggested an overproduction of the vasoconstrictor endothelin-1 and an underproduction of the vasodilators nitric oxide and prostacyclin by the endothelial cells is involved RP of the peripheral blood vessels.
In humans, the response of the cutaneous circulation to ambient temperature is critical to maintain a normal core temperature. Thermoregulatory vessels are present in the form of arteriovenous shunts in the microcirculation. These vessels are densely distributed in the globular skin of the digits of the hands and feet, accounting for the capacity to rapidly shunt blood from the surface of the skin to deeper tissues to preserve heat. Linked to the thermoregulatory vessels are arterioles and capillaries that provide tissue oxygenation, metabolism, and nutrition. Normally, nutritional flow is not compromised while the thermoregulatory vessels rapidly respond to cold or warm ambient temperatures. The regulation of these thermoregulatory vessels and nutritional vessels is complex, involving both neuropeptides and sympathetic innervation. In patients with severe RP, cold or sympathetic-induced vasospasm occurs in both the superficial thermoregulatory arteriovenous anastomoses in the skin and in blood vessels responsible for nutritional blood flow, whereas in normal control subjects, only flow through thermoregulatory vessels is affected. The nutritional blood flow is more severely disrupted in scleroderma compared with normal individuals and those with primary RP, contributing to the increased severity of attacks in scleroderma and the events of tissue ischemia. The increased compromise to tissues in scleroderma is a result of not only an exaggerated response of the thermoregulatory vessels but also a fibro-occlusive vasculopathy of the larger digital arteries, with disease extending into cutaneous capillaries that are critical for tissue nutrition.
The disparate outcomes in RP secondary to scleroderma and primary RP are related to structural abnormalities in blood vessels that develop with scleroderma. Evidence of this can be seen at the bedside when examining the rewarming phase after an RP event. In RP associated with scleroderma, the hyperemic phase after an ischemic event is dampened and blood flow normalization is dramatically prolonged ( Fig. 1 ). Abnormalities also occur in the density and structure of arteries, arterioles, and capillaries in scleroderma. RP in scleroderma therefore is associated with loss of the nutritional vasculature to the digits. In addition, the larger digital arteries are compromised with occlusive intimal hyperplasia and fibrosis caused by increased deposition of collagen. A histologic study of digital arteries showed a greater than 75% reduction in the lumen diameter in 79% of vessels studied. These vascular changes are not limited to the skin or digital vessels but can take place throughout the microcirculation of the vascular system; especially in organs such as the heart, lung, kidneys, and gastrointestinal tract.
In addition to exaggerated vasospasm and structural changes occurring in RP secondary to scleroderma, microthrombi form in blood vessels, leading to tissue damage. This process is likely related to both platelet activation and impaired fibrinolysis. Markers of platelet activation have been shown to be at increased levels in scleroderma, including thromboxane A2, β-thromboglobulin, serotonin, platelet-derived microparticles, and platelet-derived growth factor. Serum levels of one product of platelet activation, CXCL4 (previously known as platelet factor 4), have recently been shown to correlate with the presence of various manifestations of scleroderma, including pulmonary fibrosis and pulmonary hypertension. This study also showed increasing levels of CXCL4 in patients with RP and antinuclear antibodies compared with those with RP alone; even higher levels were found in early scleroderma. Increased levels of tissue plasminogen activator and von Willebrand factor are seen in the plasma of patients with scleroderma, and there is also a defect in fibrinolysis in these patients.
The key concept is that scleroderma involves both abnormal vasoreactivity, as is encountered in primary RP, but in addition patients with scleroderma have structural vascular disease and an increased risk of occlusion from abnormally functioning endothelium, platelet activation, and microthrombi. Therefore, managing RP in scleroderma requires more than just vasodilator therapy.
The pathogenesis of scleroderma vascular disease is complex and has been reviewed in several recent articles. This article focuses on the management of the clinical consequences of scleroderma peripheral vascular disease.
Background
Raynaud phenomenon (RP) is one of the most common clinical manifestations of scleroderma, experienced by 90% to 98% of patients, usually as the first symptom in the course of the disease ( Box 1 , Table 1 ). The new 2013 classification criteria of the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) now recognizes the importance of RP by including it as a feature to confirm a diagnosis of scleroderma. RP often predates other symptoms and signs by several years, which suggests that the peripheral vasculature is the initial target of the scleroderma disease process. The presence of RP alone is a clinical symptom that is also a predictor of developing scleroderma. This concept is supported by studies finding that patients with a very early diagnosis of scleroderma already have RP. Although a patient presenting with only RP, abnormal nail fold capillaries typical of scleroderma, and the presence of a specific scleroderma-related autoantibody do not meet the new ACR/EULAR criteria, studies do find that almost 80% of such patients develop scleroderma over subsequent years of follow-up. A recent survey of anti-nuclear antibodies (ANA)-negative patients with scleroderma who did not have RP found that they often had a malignancy, suggesting that these patients may have a cancer-associated syndrome.
- •
Confirm that it is a digital ischemic ulcer and not another digital lesion
- •
Maximize vasodilatation
- •
Add other proven medications in addition to vasodilators
- •
Do not neglect local therapy
- •
Evaluate for and treat superinfection
- •
Evaluate for macrovascular disease, which can worsen digital ulcers
| Class of Medication | Mechanism of Action | Specific Drugs | Evidence | Strength of Evidence |
|---|---|---|---|---|
| Calcium channel blockers | Prevents calcium from entering muscle cells and inducing vasospasm | Nifedipine Nicardipine Amlodipine Felodipine Diltiazem | RCT, meta-analysis | Level 1 |
| PDE-5 inhibitors | Inhibits degradation of cGMP promoting vasodilation by NO | Sildenafil Tadalafil Vardenafil | RCT, meta-analysis | Level 1 |
| Prostacyclins | Directly dilate blood vessels, inhibit platelet aggregation | Epoprostenol Iloprost | RCT | Level 2 |
| Topical nitrate | Stimulates cGMP production causing vasodilation | Glyceryl trinitrate | RCT | Level 2 |
| Endothelin receptor antagonists | Blocks vasoconstrictive effects of endothelin-1 | Bosentan Ambrisentan Macitentan | RCT (ulcers only) | Level 2 |
| Statins | Inhibit HMG-CoA reductase reducing LDL cholesterol levels, likely other effects in RP and digital ulcers | Atorvastatin Rosuvastatin Pravastatin | RCT of atorvastatin (RP and ulcers) | Level 2 |
| Angiotensin receptor blockers | Antagonize angiotensin receptors | Losartan Irbesartan Olmesartan | RCT (losartan in RP) | Level 2 |
| Selective serotonin reuptake inhibitors | Prevent serotonin entry into vascular smooth muscle | Fluoxetine Sertraline Paroxetine | RCT for fluoxetine in RP | Level 2 |
| Botulinum toxin | Likely by arterial vasodilation from sympathetic blockade | Botulinum toxin | Case series | Level 3 |
| Immunosuppression | Decreases | Cyclophosphamide Mycophenolate mofetil Azathioprine | No dedicated studies, suggested benefit in 1 study of CYC for other purpose | Level 3 |
| Antiplatelet | Inhibit platelet aggregation | Aspirin Clopidogrel | Negative trials in RP No trials in ulcers | Level 4 |
| Anticoagulation | Inhibit coagulation cascade | Enoxaparin Warfarin | No studies in scleroderma | Level 4 |
| Rho-kinase inhibitors | Prevent vasospasm through Rho-kinase pathway | Fasudil | One small negative trial in RP | Level 4 |
| Guanylate cyclase stimulators | Potentiates vasodilatory effects of nitric oxide | Riociguat | No evidence in RP or ulcers at present | N/A |
To be diagnosed with RP, patients should experience episodic cold-induced or stress-induced sensitivity associated with pallor or cyanosis of the digits. The pallor or cyanosis that accompanies the ischemic phase of an attack may be followed by erythema as a result of reactive hyperemia. Most patients do not experience all phases of color change: pallor, cyanosis, and erythema. The involvement of digital arteries, along with vasoconstriction of cutaneous arterioles, is responsible for the initial color change of pallor witnessed during RP. When veins dilate and there is pooling of deoxygenated blood, the digits take on a cyanotic appearance. Patients with scleroderma are considered to have secondary RP and are more likely to experience digital ulceration and critical digital ischemia than patients with primary RP. Patients with primary RP are less likely to have involvement of the thumb than patients with scleroderma.
In both primary and secondary RP, there is increased reactivity of the blood vessels to cold and increased sympathetic tone. In vitro studies show that increased sympathetic tone is mediated by an increased expression of alpha-2c adrenergic receptors on smooth muscle of cutaneous arteries. Exposure to cold leads to activation of the Rho/Rho-kinase signaling pathway and increased transport of alpha-2c receptors to the cellular membrane. The translocation of these receptors is associated with increased cellular responsiveness to cold-induced adrenergic signals. Ex vivo studies of scleroderma blood vessel have shown that vascular smooth muscle of the arterioles display a selective increase in alpha2-adrenergic reactivity, suggesting that RP in scleroderma is in part caused by upregulation of the adrenergic receptors. In scleroderma, there is also evidence of dysfunction of the endothelium resulting in an imbalance between vasoconstricting and vasodilatory stimuli. Studies have suggested an overproduction of the vasoconstrictor endothelin-1 and an underproduction of the vasodilators nitric oxide and prostacyclin by the endothelial cells is involved RP of the peripheral blood vessels.
In humans, the response of the cutaneous circulation to ambient temperature is critical to maintain a normal core temperature. Thermoregulatory vessels are present in the form of arteriovenous shunts in the microcirculation. These vessels are densely distributed in the globular skin of the digits of the hands and feet, accounting for the capacity to rapidly shunt blood from the surface of the skin to deeper tissues to preserve heat. Linked to the thermoregulatory vessels are arterioles and capillaries that provide tissue oxygenation, metabolism, and nutrition. Normally, nutritional flow is not compromised while the thermoregulatory vessels rapidly respond to cold or warm ambient temperatures. The regulation of these thermoregulatory vessels and nutritional vessels is complex, involving both neuropeptides and sympathetic innervation. In patients with severe RP, cold or sympathetic-induced vasospasm occurs in both the superficial thermoregulatory arteriovenous anastomoses in the skin and in blood vessels responsible for nutritional blood flow, whereas in normal control subjects, only flow through thermoregulatory vessels is affected. The nutritional blood flow is more severely disrupted in scleroderma compared with normal individuals and those with primary RP, contributing to the increased severity of attacks in scleroderma and the events of tissue ischemia. The increased compromise to tissues in scleroderma is a result of not only an exaggerated response of the thermoregulatory vessels but also a fibro-occlusive vasculopathy of the larger digital arteries, with disease extending into cutaneous capillaries that are critical for tissue nutrition.
The disparate outcomes in RP secondary to scleroderma and primary RP are related to structural abnormalities in blood vessels that develop with scleroderma. Evidence of this can be seen at the bedside when examining the rewarming phase after an RP event. In RP associated with scleroderma, the hyperemic phase after an ischemic event is dampened and blood flow normalization is dramatically prolonged ( Fig. 1 ). Abnormalities also occur in the density and structure of arteries, arterioles, and capillaries in scleroderma. RP in scleroderma therefore is associated with loss of the nutritional vasculature to the digits. In addition, the larger digital arteries are compromised with occlusive intimal hyperplasia and fibrosis caused by increased deposition of collagen. A histologic study of digital arteries showed a greater than 75% reduction in the lumen diameter in 79% of vessels studied. These vascular changes are not limited to the skin or digital vessels but can take place throughout the microcirculation of the vascular system; especially in organs such as the heart, lung, kidneys, and gastrointestinal tract.
