ﺑﺎﺯﮔﺸﺖ ﺑﻪ ﺻﻔﺤﻪ ﻗﺒﻠﯽ
خرید پکیج
تعداد آیتم قابل مشاهده باقیمانده : 3 مورد
نسخه الکترونیک
medimedia.ir

Treatment of Raynaud phenomenon: Refractory or progressive ischemia

Treatment of Raynaud phenomenon: Refractory or progressive ischemia
Literature review current through: Jan 2024.
This topic last updated: May 19, 2023.

INTRODUCTION — Raynaud phenomenon (RP) is an exaggerated vascular response (ie, vasospasm) to cold temperature or to emotional stress, which is manifested clinically by discomfort and sharply demarcated color changes of the skin of the digits (fingers, toes).

The treatment of severe or resistant RP including measures to limit or reverse acute ischemia and manage progressive ischemia that may be associated with tissue injury and ulceration is reviewed here.

The initial therapy of RP, including general measures, the use of calcium channel blockers (CCBs), and lifestyle modifications, as well as the pathogenesis, clinical manifestations, and diagnosis of RP, are presented separately. (See "Treatment of Raynaud phenomenon: Initial management" and "Pathogenesis and pathophysiology of Raynaud phenomenon" and "Clinical manifestations and diagnosis of Raynaud phenomenon".)

PRETREATMENT ASSESSMENT

General measures for all patients with RP – In patients with Raynaud phenomenon (RP), the goals of therapy are to improve quality of life and to prevent ischemic tissue injury. All patients should be educated about the potential causes of a Raynaud attack as well as the nonpharmacologic measures (eg, cold avoidance, heated garments) to help prevent and terminate the episode. Initial therapy, patient education, and self-management issues are discussed in detail separately. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Goals of therapy' and "Treatment of Raynaud phenomenon: Initial management", section on 'Patient education and self-management'.)

Distinguishing acute ischemia due to RP from other causes – Acute ischemia refers to a rapid onset of reduced flow that compromises the integrity of the tissue. Ischemic attacks can be transient or prolonged, with complete recovery between attacks or with varying levels of tissue injury due to prolonged or progressive reduction in flow (ie, chronic ischemia). Acute ischemia can also be superimposed on chronic ischemia, particularly if underlying structural disease of the blood vessels is present in association with vasospasm.

RP is a symptom of a disturbance of the normal physiologic regulation of cutaneous and digital circulation. RP can be associated with a variety of underlying diseases (table 1). The effectiveness of treatment depends upon the severity as well as the appropriate management of any associated underlying disorder. For example, RP is a prominent clinical feature of systemic sclerosis (scleroderma, SSc), in which an immune-mediated disturbance of small vessels and thermoregulatory pathways lead to the vasospasm of typical RP, as well as to a peripheral vasculopathy with endothelial injury and intimal proliferation causing luminal narrowing and occlusion of small arteries, arterioles, and capillaries. The underlying occlusive vascular component of SSc is associated with critical ischemia with digital ulcers.

Vasospasm that mimics RP can also occur in association with other occlusive diseases (eg, vasculitis, embolism, atherosclerosis). These pathologic processes are commonly lumped under the term secondary RP, but in fact, tissue ischemia may not be cold dependent and present asymmetrically and technically does not constitute RP. These same processes can cause persistent digital ischemia due to a severe compromise in blood flow. The key is to recognize that occlusive disease can compromise local blood flow and mimic typical RP. Treatment of the underlying disease can help improve the vasoconstriction and associated RP-like symptoms.

SEVERE ACUTE ISCHEMIA — Acute ischemia refers to a rapid onset of reduced flow that compromises the integrity of the tissue (algorithm 1). Severe acute ischemia associated with Raynaud phenomenon (RP) requires additional measures to prevent tissue loss. Urgent care including evaluation and management in the inpatient setting may be necessary. Acute ischemia can also be superimposed on chronic ischemia, particularly if underlying structural disease of the blood vessels is present in association with abnormal vascular reactivity and prolonged vasospasm. The initial management of RP including a detailed discussion of first-line RP therapies is discussed separately. (See "Treatment of Raynaud phenomenon: Initial management".)

Initial measures — Aggressive treatment is important in patients who develop severe acute ischemia that threatens all or a portion of a digit (algorithm 1). For patients experiencing an acute severe ischemic event, we immediately institute the following:

Patients with prolonged signs of compromised blood flow (pallor or cyanosis with tissue injury or severe pain) typical of an ischemic digit(s) should be hospitalized, kept warm and quiet, and fully evaluated for a secondary reversible process that is causing or aggravating the ischemia. This includes a careful evaluation for arterial occlusive disease, hypercoagulable states, certain neurologic conditions, and environmental or toxic exposures (table 1).

During a severe acute ischemic event that is threatening digit loss, we initiate anticoagulation to minimize propagation of any possible thrombus [1]. In the absence of superimposed thrombotic process, there are little data to support ongoing anticoagulation or thrombolytic therapy in patients with RP and associated acute or chronic ischemia. We discontinue anticoagulation once a thrombotic cause of acute ischemia is excluded (usually only one to two days are needed). (See "Overview of upper extremity ischemia".)

Pain due to severe ischemia may be intense, and adequate pain control may require the use of opioid analgesics. (See "Pain control in the critically ill adult patient" and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Opioids'.)

In a patient with severe acute digital ischemia related to RP who has not received first-line therapy for RP, we typically start a calcium channel blocker (CCB) as a vasodilator in the acute inpatient setting [2,3]. While some use an immediate-release CCB, given the rapid onset of action, it is reasonable to use an extended-release preparation. We prefer using an extended-release CCB (nifedipine 30 mg or amlodipine 5 mg) because of the reduced risk of increased sympathetic tone compared with the immediate-release CCB [4]. CCBs are generally considered first line in the initial management of RP, and the evidence supporting their use is discussed in detail separately. (See "Treatment of Raynaud phenomenon: Initial management", section on 'Calcium channel blocker'.)

Pharmacologic interventions and procedures

Intravenous prostaglandins — For patients with acute or prolonged digital ischemia who have not responded to optimal therapy with oral or topical vasodilators, we suggest treatment with intravenous (IV) infusions of a prostaglandin (PG), preferably a prostacyclin (PGI2, epoprostenol) or a synthetic analog such as iloprost or treprostinil, depending upon availability (which varies between countries). In an acute ischemic event, a rapid reversal of symptoms usually occurs, and several weeks of improvement may be expected. IV PG therapy is often administered in an inpatient setting, but hospitalization may not be required in patients with an established diagnosis who are not otherwise acutely ill and if an outpatient infusion center with established monitoring is available. The latter approach is often used for administering iloprost outside of the United States. Therapy is generally delivered at intermittent intervals (usually every 10 to 12 weeks) and the continuation of therapy is determined by the clinical response.

There is also rationale to treat patients with a prostacyclin who have severe symptoms that are adversely affecting their quality of life (particularly during winter months in cold climates), those with a history of recurrent digital ulcers to prevent reoccurrence, or those with acute ischemia or prolonged ischemia with vasospasm that is threatening ulceration or digital loss.

A careful review of ongoing vasodilator therapy should be undertaken prior to using IV PG to assure that the use of these first-line agents has been optimized, given the substantial inconvenience and potential cost of IV PG therapies (see "Treatment of Raynaud phenomenon: Initial management"). CCBs and other agents, such as topical nitrates or phosphodiesterase (PDE) inhibitors, are briefly held while patients are receiving a treatment course of IV PG. Side effects of IV PG therapy include headache, flushing, nausea, jaw pain, and hypotension, which are usually reversible with a reduction in dose. The dose of IV PG should be adjusted to the level that is tolerated.

The choice of parenteral PGs and analogs for patients with severe RP is largely based on drug availability (eg, IV epoprostenol, but not iloprost, is available in the United States) as well as clinician preference and experience. We present several studies that have examined the efficacy of iloprost, epoprostenol, treprostinil, and alprostadil for severe refractory RP and in patients with and without ischemic digital ulcers:

Iloprost – Iloprost (a PGI2 analog) is typically administered for a course of three to five consecutive days, at a (continuous) dose of 0.5 to 2 ng/kg per minute (titrated to the maximum dose tolerated by the patient). The infusion can be done over eight hours if done in the outpatient setting or continuous if in the inpatient setting. The largest meta-analysis of randomized trials to assess the efficacy of iloprost for the treatment of RP included 332 patients with RP secondary to systemic sclerosis (SSc, scleroderma) [5]. Five of the seven randomized trials that were included in the analysis compared IV iloprost with placebo, while the other two trials included oral iloprost and oral cisaprost. Dosing regimens, outcome measures, and follow-up periods in the trials varied. Only IV iloprost appeared to decrease the frequency and severity of RP and in some cases, increased digital ulcer healing. One of the higher-quality trials with 126 patients that was included in the meta-analysis found that a five-day infusion of iloprost compared with placebo was associated with a mean reduction in the number of weekly RP attacks (40 versus 22 percent, respectively) and an improvement in the global Raynaud severity score (35 versus 20 percent) during the nine-week follow-up period [6]. Also, at week 3, 14.6 percent more patients receiving iloprost had 50 percent or more lesions heal compared with those who received placebo (95% CI 0.9-30 percent). A small randomized trial with 23 patients with secondary RP associated with SSc found short-term infusions of IV iloprost (for eight hours/day on three consecutive days, with a repeat infusion for one day on week 8) was comparably effective to oral nifedipine (up to 60 mg/day as tolerated for 16 weeks) [7].

Longer-term follow-up data come from an observational study of 30 patients with RP secondary to SSc who received iloprost infusions every three weeks for a median of three years following an initial cycle of infusions over five days [8]. Healing of digital ulcers and a subjective decrease in RP were reported in this study. Larger observational studies support the long-term therapy in SSc patients with severe RP [9,10].

Epoprostenol – Epoprostenol (PGI2) is typically administered through a peripheral line, started at a dose of 2 ng/kg per minute, and increased over a period of one to two days, as tolerated, to 4 to 8 ng/kg per minute for a duration of five hours [11,12]. Epoprostenol has been most widely used for the treatment of idiopathic pulmonary hypertension as well as pulmonary hypertension associated with SSc (see "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Prostacyclin pathway agonists' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy"). A randomized trial including 14 patients with RP found that treatment with IV weekly epoprostenol was associated with a reduction in the frequency and duration of attacks compared with placebo, with a loss in clinical response observed between 8 and 10 weeks after the last infusion [12]. Another randomized trial of epoprostenol for pulmonary hypertension associated with SSc and related disorders showed a favorable but statistically nonsignificant difference in the severity of RP and fewer new digital ulcers in the epoprostenol-treated patients [13].

Treprostinil – Treprostinil (a PGI2 analog) may be given intravenously, by subcutaneous injection, or inhaled [14]. Treprostinil is available for treatment of pulmonary hypertension, but its use in patients with severe symptoms of RP or acute or chronic digital ischemia by either the subcutaneous or IV route has not been investigated to provide specific treatment guidelines. Its use in the setting of RP is largely based on limited indirect evidence that it may have beneficial effects on digital ulcers or necrosis in patients with SSc [14,15].

Alprostadil – Alprostadil (PGE1) may be administered at a dose of 60 mcg intravenously once daily (20 mcg/hour) for a course of five or six consecutive days [16-18]. This regimen may be repeated at 6-week intervals, or a maintenance dose of 60 mcg intravenously once every 30 days may be used [16,19]. Several small observational studies and one small randomized trial suggested benefit of alprostadil for symptoms related to RP as well as improvement in ulcer healing [16-18,20,21]; however, these findings were not substantiated in another small randomized trial [22].

The use of oral prostacyclin analogs has been studied in primary and secondary RP, but there is insufficient evidence to support their use in clinical practice. (See 'Oral prostaglandins and analogs' below.)

Local or regional block — For patients with acute severe ischemia, when oral and/or topical vasodilatory therapy does not quickly result in improvement in digital blood flow and/or when IV PG are not readily available, we suggest digital block or regional block for transient relief of acute digital ischemia, which can provide rapid relief of pain. As needed, we use a digital block for rapid control of pain while arrangements for IV or other therapy are underway.

A digital or regional (eg, wrist) block is usually performed with local infiltration of lidocaine or bupivacaine (without epinephrine) [23,24]. These regional nerve blocks for RP have not been systematically evaluated in clinical trials, and their use in this setting is largely based on clinical experience and extrapolation from other clinical settings. This intervention may be thought of as a temporizing measure as there are also no formal studies to define the impact on complications such as recurrent digital ulcers. Side effects include decreased sensation and orthostatic changes but not paralysis. (See "Overview of peripheral nerve blocks" and "Upper extremity nerve blocks: Techniques" and "Lower extremity nerve blocks: Techniques" and "Digital nerve block".)

More proximal nerve blocks, such as cervical or lumbar injections, are rarely used unless other approaches have failed. Sometimes it is temporarily effective in reversing acute vasospasm [25,26]. (See 'Limited role of proximal sympathectomy' below.)

Treatments lacking efficacy or of uncertain benefit

Botulinum toxin A — Intradigital and palmar botulinum toxin A has also been used for local injection therapy. The role of injections of botulinum toxin in the treatment of RP is not well defined. We reserve its use for patients with severe RP who are not responding to or tolerating vasodilator therapy due to hypotension and have poor quality of life due to RP. Botulinum toxin injection may also be used in conjunction with vasoactive drugs or as a trial prior to surgical intervention. (See 'Digital sympathectomy' below.)

Botulinum toxin reduces release of vasoactive mediators, but its onset of action is not immediate. The use of botulinum toxin is generally limited by cost, access to surgical hand specialists with specialized training in these injections, and the need for repetitive treatments.

Evidence from mostly small observational studies of patients with primary and secondary RP have been favorable, suggesting that intradigital and palmar injection of botulinum toxin A appears to inhibit vasoconstriction, relieve clinical symptoms, improve skin blood flow, and be associated with the healing of digital ulcers [27-39]. However, the only two randomized placebo-controlled trials performed in scleroderma patients with RP have failed to demonstrate significant clinical benefit [40,41].

Oral prostaglandins and analogs — Preparations of oral prostacyclin and analogs are available for study in Japan, Europe, and the United States, but further study, including randomized trials, will be required to establish the role of an oral prostacyclin in the management of severe RP. Mixed results for several different oral agents have been obtained in studies evaluating their efficacy in RP including misoprostol [42], limaprost [43], cisaprost [44], beraprost [45,46], iloprost [47-49], and treprostinil [50,51].

Although in a prior trial treprostinil did not meet its primary outcome of benefit [50], digital blood flow was improved in a later study that included patients with SSc with RP and digital ulcers [52]. In a subsequent study, total burden of digital ulcers increased after discontinuation of treprostinil [51].

REFRACTORY OR PROGRESSIVE ISCHEMIA — Ischemic attacks that are refractory to initial conservative measures or the treatments discussed above can result in varying levels of tissue injury due to prolonged or progressive reduction in flow (ie, chronic ischemia). (See 'Severe acute ischemia' above.)

Options for management of Raynaud phenomenon (RP) patients with refractory or progressive ischemia include combination vasoactive medications, efforts to reverse the underlying vascular disease process, and strategies to protect involved vessels from further injury or occlusion (algorithm 1). For example, in patients with systemic sclerosis (SSc, scleroderma) and recalcitrant or recurrent digital ulcers, an endothelin inhibitor (bosentan) in combination with vasodilator therapy may prevent new ischemic events. Sympathectomy is an option when refractory disease persists. When sympathectomy is chosen, peripheral sympathectomy at the level of the hand (eg, palmar or digital sympathectomy) is preferred to more central procedures (eg, cervical or lumbar).

Digital sympathectomy — Digital sympathectomy should be limited to patients who are not responding adequately to medical therapies and who continue to have refractory or progressive ischemia threatening the involved digit(s), in the absence of any reversible cause such as vasculitis that can be treated otherwise. It is a microsurgical technique that isolates the terminal branches of the sympathetic nerves that travel with the peripheral nerves, dividing these branches and stripping the adventitia of the digital arteries [53-55]. It is important that the procedure is done before irreversible deep tissue damage occurs. [56]. It is a highly specialized procedure, performed only in specialist centers.

Although some cases have reported successful results and few complications following digital sympathectomy or periarterial sympathectomy [57-64], their exact role for refractory RP has not been defined by controlled investigations. One review noted that differences in surgical technique, causes of digital ischemia, and outcome measures made comparisons of reported series difficult [65]. Amputation and recurrent ulceration following digital sympathectomy were frequent (14 and 18 percent, respectively). Among patients with RP and SSc with digital ischemia, the perioperative complication rate was 37 percent [65].

Limited role of proximal sympathectomy — We do not routinely use more proximal sympathectomy (eg, cervicothoracic, thoracic, lumbar) in patients with RP. Selected patients with refractory or progressive ischemia may elect to proceed with this procedure.

Sympathectomy works by disrupting the efferent autonomic pain pathways and attenuating vasoconstriction caused by sympathetic nerves. The resulting vasodilation increases distal perfusion. The sympathetic ganglia can be divided or ablated using an energy (eg, radiofrequency [66]) device. Surgical sympathectomy can be approached using open or minimally invasive techniques. In the upper extremity, resection of the upper thoracic sympathetic chain can be performed via a supraclavicular or axillary incision or by using a thoracoscopic approach. For the lower extremity, the lumbar sympathetic chain can be accessed via an anterior abdominal or retroperitoneal incision or a laparoscopic or retroperitoneoscopic approach.

Several reports have suggested that sympathectomy is helpful in primary RP but not in secondary forms [67-72]. However, patients with primary RP rarely need such an aggressive surgical approach to therapy. Patients with refractory secondary RP may have some immediate improvements in blood flow following sympathectomy, but the degree and duration of improvement are quite variable [73,74]. One survey evaluated 140 patients with RP who had undergone sympathectomy [73]. Only 19 percent claimed lasting benefit, and 66 percent claimed no benefit after one year. However, another series of 25 patients with primary RP and 14 patients with secondary RP demonstrated long-lasting benefits with sympathectomy [75]. In a later systematic review of thoracic sympathectomy (open or thoracoscopic) that included a total of 580 patients, an initial positive response was reported in 92 percent of primary RP and 89 percent of secondary RP patients. A long-term benefit was seen in 58 percent of primary RP and 89 percent of secondary RP patients. Ulcer improvement or healing occurred in 95 percent of patients [71].

Minimally invasive approaches have replaced open surgical approaches because of fewer complications compared with open surgery [71]. As an example, in one study of 28 patients treated using a minimally invasive approach, no major complications occurred, and there were no perioperative deaths [76]. However, a minimally invasive technique does not appear to have any advantage over the open techniques in terms of recurrent symptoms [76,77].

Antithrombotic therapy

Antiplatelet agents in selected patients — We limit the use of low-dose aspirin (75 or 81 mg/day) to patients with secondary RP who have a history of ischemic ulcers or other thrombotic events, and who have no additional risks associated with aspirin use. The benefit of antiplatelet therapy with aspirin is overall uncertain because of the lack of evidence overall for its use in patients with RP. There has been only one small trial with treatment using aspirin plus dipyridamole, aspirin alone, or dipyridamole alone in patients with RP, but most had primary RP [78]. Antiplatelet agents appeared to have no effect on symptoms of RP. Aspirin should be avoided in selected patients such as those with SSc who are at a higher risk of gastrointestinal bleeding from underlying gastric antral vascular ectasia. (See "NSAIDs (including aspirin): Pathogenesis and risk factors for gastroduodenal toxicity" and "Gastrointestinal manifestations of systemic sclerosis (scleroderma)", section on 'Gastric antral vascular ectasia'.)

Some clinicians have used dipyridamole because of its antiplatelet, vasodilating, and antioxidant properties, which may improve vascular tone. However, there is no evidence to support the use of dipyridamole alone or with another antiplatelet agent (eg, aspirin or clopidogrel) for RP with digital ischemia. Otherwise, the use of low-dose aspirin may be appropriate if indicated for other reasons, such as for cardiovascular risk reduction. (See "Prevention of cardiovascular disease events in those with established disease (secondary prevention) or at very high risk".)

No role for long-term anticoagulation — There is no strong evidence to support long-term anticoagulation in patients with chronic ischemia due to RP. The only study to evaluate anticoagulation in the setting of RP was a small placebo-controlled study in which low-molecular weight heparin (LMWH) was associated with a reduction in the severity of RP attacks after 4 and 20 weeks [79]. However, this study only included 30 patients and has never been repeated.

Local care of ischemic digits — Surgical debridement of areas of necrosis and occasionally amputation may be needed for irreversible ischemia. Digital ulcers occur in up to half of patients with SSc. Among 1459 patients with SSc and digital ulcers, ulcers were recurrent in 46.2 percent and chronic in 11.2 percent [80]. Amputation occurred in 7.6 and 15.9 percent of these patients, respectively. Most amputations are minor, involving the distal digit. When proper care is given to digital ulcers, healing typically occurs within 6 to 12 weeks. Treatment of digital ulceration or gangrene is reviewed separately. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds", section on 'Ischemic ulcers and gangrene'.)

ADDITIONAL MEDICATIONS FOR RECURRENT ULCERS IN SYSTEMIC SCLEROSIS — The management of severe Raynaud phenomenon (RP) in patients with systemic sclerosis (SSc, scleroderma) is generally the same as for those with secondary RP due to other causes. However, a few medications may confer additional benefit specifically for patients with SSc who have recurrent digital ulcers.

Phosphodiesterase type 5 inhibitors — In patients with SSc and recalcitrant or recurrent ulcers, we suggest the addition of phosphodiesterase (PDE) type 5 inhibitors rather than calcium channel blockers (CCBs) alone. There are limited data suggesting that PDE type 5 inhibitors reduce the number of ulcer formations in patients with SSc [81-84]. In a trial including 41 patients with RP secondary to SSc, patients were randomly assigned to receive oral sildenafil 100 mg/day (21 patients, mean age 47.2 years) or placebo (20 patients, mean age 41.6 years) [82]. After 8 weeks of treatment, sildenafil improved digital blood flow and RP symptoms. A meta-analysis found that PDE type 5 inhibitors were beneficial in ulcer healing compared with placebo in SSc (relative risk 3.28 [95% CI 1.32-8.13]) [83].

Bosentan — For patients with recurrent digital ulcers associated with SSc despite use of other therapies, including CCBs plus PDE inhibitors, we suggest the use of bosentan, an orally administered inhibitor of the vasoconstrictor endothelin-1, as an alternative to repeated intravenous (IV) prostacyclin. This is based upon randomized trials involving patients with SSc that demonstrated a reduced frequency of new digital ulcers in such patients [85,86]. Bosentan has not been shown to increase the rate of healing of ulcers or reduce the intensity of RP, so we generally limit its use to selected patients with SSc with recurrent ulcers. Bosentan has been used primarily for the treatment of pulmonary hypertension. (See "Pulmonary arterial hypertension in systemic sclerosis (scleroderma): Treatment and prognosis", section on 'Endothelin-1 receptor antagonists' and "Treatment of pulmonary arterial hypertension (group 1) in adults: Pulmonary hypertension-specific therapy".)

Treatment with bosentan is initiated at a dose of 62.5 mg twice daily for four weeks. The dose should be increased to 125 mg twice daily in patients who do not benefit from the initial dose. Liver function tests should be obtained monthly in patients receiving the medication to monitor for hepatic toxicity. Commonly reported side effects are headache, flushing, edema (18 percent), hypotension, liver enzyme elevation (12 percent), and fatigue. Less common but more serious reactions include liver failure, bone marrow suppression, and angioedema. In the clinical trials, approximately 15 percent of patients discontinued therapy due to side effects.

Data from clinical trials suggest that bosentan may help reduce the number of new digital ulcers in patients with SSc, but it has not been shown to improve the healing of existing ulcers. A randomized trial of 122 patients with SSc reported a 50 percent reduction in new ulcers among those who had ulceration at baseline; however, there was no reduction in frequency or intensity of attacks of RP and no improvement in ulcer healing in patients with digital ulcers at baseline. A subsequent trial in 188 patients with SSc with digital ulcers at trial entry found a statistically significant 30 percent reduction in new digital ulcers compared with placebo (1.9 versus 2.7) but also observed no differences in the healing rate of the cardinal ulcer [86,87]. Peripheral edema and elevated aminotransferases were associated with bosentan use.

There may be additional benefit from combination therapy of IV iloprost with bosentan for the prevention of recurrent digital ulcers in SSc patients. In a prospective observational study with 30 SSc patients receiving IV iloprost for severe secondary RP, half of the patients were also given bosentan following the development of digital ulcers or pulmonary arterial hypertension [88]. After four years of follow-up, the iloprost plus bosentan group showed a significant improvement in digital microvasculature structure and function based on absolute nailfold capillary number and fingertip blood perfusion, respectively, which also corresponded with a significant reduction in the incidence of new digital ulcers. This limited study needs confirmation but suggests that combination therapy may be helpful in complex SSc patients with recurrent digital ulcers. Overall, bosentan therapy may indirectly influence functionality and quality of life in patients with SSc by reducing the burden of RP and digital ulcer-related symptoms [89].

In contrast to bosentan, another nonselective endothelin-1 antagonist, macitentan, which is also used to treat pulmonary hypertension, failed to reduce the frequency of new ischemic digital ulcers over 16 weeks, compared with placebo, in two randomized trials involving a total of 554 patients with SSc and active digital ulcers at baseline [90]. Selective endothelin-1 antagonists that are less toxic to the liver may have the potential of being helpful, but evidence regarding their use in this population is not available.

Statins — For patients with SSc with recurrent digital ulcers, a trial of statin therapy is reasonable, in addition to the therapies described above. A small trial that included 84 patents with SSc found that patients in the statin group developed fewer ulcers per patient compared with patients in the placebo group (mean of 1.6 versus 2.6 ulcers, respectively) [91]. There were also improvements in other patient-reported outcomes including pain and Raynaud attack severity. Another small open-label trial also reported long-term favorable effects [92]. The rationale for the use of these agents includes their pleiotropic effects, which may help protect the vasculature or prevent vascular events [93].

MONITORING RESPONSE TO THERAPY

Routine follow-up — Patients should be evaluated periodically for the need for a particular intervention, ideally every three months if the patient is unstable or up to six months if the scenario is less complex. It is important to take into account the risk of the intervention, the clinical evidence for its effectiveness, and the need for continued therapy at the time of the evaluation. In addition, careful evaluation for the underlying disease causing vasospasm or Raynaud phenomenon (RP) is important to define any reversible disease process.

Duration of therapy — There are no clinical trials to clearly define long-term outcomes of the intravenous (IV) prostaglandins (PGs) or injection therapies. Most reported clinical trials are short term, with most studies reporting data based on three months of follow-up. However, there is evidence in patients with systemic sclerosis (SSc, scleroderma) that chronic therapy is well tolerated and reduces risk of digital ulcers [9,10]. Thus, as mentioned above, each patient should be evaluated periodically for the need for continued therapy, balancing the risks of therapy and level of severity of RP. (See 'Routine follow-up' above.)

Careful long-term studies of the outcome following surgical intervention or injection therapy are not adequate to provide guidance. Our experience is that the RP recurs following surgical digital sympathectomy, but is usually not as severe as prior to surgery.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Raynaud phenomenon".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Raynaud phenomenon (The Basics)")

Beyond the Basics topics (see "Patient education: Raynaud phenomenon (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

In patients with Raynaud phenomenon (RP), the goals of therapy are to improve quality of life and to prevent ischemic tissue injury. All patients should be educated about the potential causes of a Raynaud attack as well as the nonpharmacologic measures to help prevent and terminate the episode. (See 'Pretreatment assessment' above.)

Severe RP or vasospasm that is refractory to first-line RP treatments requires additional measures to prevent tissue loss (algorithm 1). Acute ischemia in patients with RP refers to a rapid onset of reduced flow that compromises the integrity of the tissue. Acute ischemia can also be superimposed on chronic ischemia, particularly if underlying structural disease of the blood vessels is present in association with abnormal vascular reactivity and prolonged vasospasm. (See 'Severe acute ischemia' above.)

For patients with RP who are experiencing an acute severe ischemic event, we immediately institute the following (see 'Initial measures' above):

Patients with prolonged signs of compromised blood flow (pallor or cyanosis with tissue injury or severe pain) typical of an ischemic digit(s) should be hospitalized, kept warm and quiet, and fully evaluated for a secondary reversible process that is causing or aggravating the ischemia. This includes a careful evaluation for arterial occlusive disease, hypercoagulable states, certain neurologic conditions, and environmental or toxic exposures (table 1).

During a severe ischemic event that is threatening digit loss, we initiate anticoagulation to minimize propagation of any possible thrombus. In the absence of superimposed thrombotic process, there are little data to support ongoing anticoagulation or thrombolytic therapy in patients with RP and associated acute or chronic ischemia. We discontinue anticoagulation once a thrombotic cause of acute ischemia is excluded (usually only one to two days are needed). (See "Overview of upper extremity ischemia".)

Pain due to severe ischemia may be intense, and adequate pain control may require the use of opioid analgesics. (See "Pain control in the critically ill adult patient" and "Pharmacologic management of chronic non-cancer pain in adults", section on 'Opioids'.)

In a patient with severe acute digital ischemia related to RP who has not received first-line therapy, we typically start an extended-release calcium channel blocker (CCB) in the acute inpatient setting. (See 'Initial measures' above.)

For patients with acute or prolonged digital ischemia related to RP who have not responded to optimal first-line therapy with oral or topical vasodilators, we suggest treatment with intravenous (IV) infusions of a prostaglandin (PG) (Grade 2C). We prefer to use a prostacyclin (PGI2, epoprostenol) or a synthetic analog such as iloprost or treprostinil, depending upon availability (which varies between countries). A digital or regional block is an option if IV PG therapy is not readily available or is ineffective. (See 'Intravenous prostaglandins' above and 'Local or regional block' above.)

The role of botulinum A toxin injections for the treatment of RP is not well defined. We have reserved its use for patients with severe RP who are not responding to or tolerating vasodilator therapy due to hypotension and have poor quality of life due to RP. This may also be used in conjunction with vasoactive drugs or as a trial prior to surgical intervention. The use of botulinum toxin is generally limited by cost, access to surgical hand specialists with specialized training in these injections, and the need for repetitive treatments. (See 'Botulinum toxin A' above.)

In the absence of any reversible cause (eg, vasculitis) that can be treated, digital sympathectomy is an option for patients who are not responding adequately to medical therapies and who continue to have refractory or progressive ischemia, although data supporting its efficacy are limited. In addition, digital sympathectomy is a highly specialized procedure, performed only in specialist centers. (See 'Refractory or progressive ischemia' above and 'Digital sympathectomy' above.)

We do not routinely use more proximal sympathectomy (eg, cervicothoracic, thoracic, lumbar) in patients with RP who are not responding adequately to other medical therapies. Selected patients with refractory or progressive ischemia may elect to proceed with this procedure. (See 'Limited role of proximal sympathectomy' above.)

We limit the use of low-dose aspirin (75 or 81 mg/day) to patients with secondary RP who have a history of ischemic ulcers or other thrombotic events, and who have no additional risks associated with aspirin use. The benefit of antiplatelet therapy with aspirin is uncertain because of the lack of evidence for its use in patients with RP. In addition, there is no strong evidence to support long-term anticoagulation in patients with chronic ischemia due to RP. (See 'Antiplatelet agents in selected patients' above and 'No role for long-term anticoagulation' above.)

The management of severe RP in patients with systemic sclerosis (SSc, scleroderma) is generally the same as for those with secondary RP due to other causes. However, a few medications may confer additional benefit specifically for patients with SSc who have recurrent digital ulcers:

For patients with SSc and recalcitrant or recurrent ulcers, we suggest the addition of phosphodiesterase (PDE) type 5 inhibitors rather than CCBs alone (Grade 2C). (See 'Phosphodiesterase type 5 inhibitors' above.)

For patients with recurrent digital ulcers associated with SSc despite use of other therapies, including CCBs plus PDE type 5 inhibitors, we suggest the use of bosentan, an orally administered inhibitor of the vasoconstrictor endothelin-1, as an alternative to repeated IV prostacyclin (Grade 2C). (See 'Bosentan' above.)

For patients with SSc with recurrent digital ulcers, a trial of statin therapy is reasonable, in addition to the therapies listed above. (See 'Statins' above.)

Patients should be evaluated periodically for the need for a particular intervention, ideally every three months if the patient is unstable or up to six months if the scenario is less complex. It is important to take into account the risk of the intervention, the clinical evidence for its effectiveness, and the need for continued therapy at the time of the evaluation, balancing the risks of therapy and the level of severity of the RP. Careful evaluation for the underlying disease causing vasospasm or RP is also important to define any reversible disease process. (See 'Routine follow-up' above and 'Duration of therapy' above.)

  1. Alonso-Coello P, Bellmunt S, McGorrian C, et al. Antithrombotic therapy in peripheral artery disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141:e669S.
  2. Shapiro SC, Wigley FM. Treating Raynaud phenomenon: Beyond staying warm. Cleve Clin J Med 2017; 84:797.
  3. Herrick AL, Wigley FM. Raynaud's phenomenon. Best Pract Res Clin Rheumatol 2020; 34:101474.
  4. Parker JD, D' Iorio M, Floras JS, Toal CB. Comparison of short-acting versus extended-release nifedipine: Effects on hemodynamics and sympathetic activity in patients with stable coronary artery disease. Sci Rep 2020; 10:565.
  5. Pope J, Fenlon D, Thompson A, et al. Iloprost and cisaprost for Raynaud's phenomenon in progressive systemic sclerosis. Cochrane Database Syst Rev 2000; :CD000953.
  6. Wigley FM, Wise RA, Seibold JR, et al. Intravenous iloprost infusion in patients with Raynaud phenomenon secondary to systemic sclerosis. A multicenter, placebo-controlled, double-blind study. Ann Intern Med 1994; 120:199.
  7. Rademaker M, Cooke ED, Almond NE, et al. Comparison of intravenous infusions of iloprost and oral nifedipine in treatment of Raynaud's phenomenon in patients with systemic sclerosis: a double blind randomised study. BMJ 1989; 298:561.
  8. Bettoni L, Geri A, Airò P, et al. Systemic sclerosis therapy with iloprost: a prospective observational study of 30 patients treated for a median of 3 years. Clin Rheumatol 2002; 21:244.
  9. Foti R, Visalli E, Amato G, et al. Long-term clinical stabilization of scleroderma patients treated with a chronic and intensive IV iloprost regimen. Rheumatol Int 2017; 37:245.
  10. Colaci M, Lumetti F, Giuggioli D, et al. Long-term treatment of scleroderma-related digital ulcers with iloprost: a cohort study. Clin Exp Rheumatol 2017; 35 Suppl 106:179.
  11. Dowd PM, Martin MF, Cooke ED, et al. Treatment of Raynaud's phenomenon by intravenous infusion of prostacyclin (PGI2). Br J Dermatol 1982; 106:81.
  12. Belch JJ, Newman P, Drury JK, et al. Intermittent epoprostenol (prostacyclin) infusion in patients with Raynaud's syndrome. A double-blind controlled trial. Lancet 1983; 1:313.
  13. Badesch DB, Tapson VF, McGoon MD, et al. Continuous intravenous epoprostenol for pulmonary hypertension due to the scleroderma spectrum of disease. A randomized, controlled trial. Ann Intern Med 2000; 132:425.
  14. Chung L, Fiorentino D. A pilot trial of treprostinil for the treatment and prevention of digital ulcers in patients with systemic sclerosis. J Am Acad Dermatol 2006; 54:880.
  15. Engel G, Rockson SG. Treprostinil for the treatment of severe digital necrosis in systemic sclerosis. Vasc Med 2005; 10:29.
  16. Gardinali M, Pozzi MR, Bernareggi M, et al. Treatment of Raynaud's phenomenon with intravenous prostaglandin E1alpha-cyclodextrin improves endothelial cell injury in systemic sclerosis. J Rheumatol 2001; 28:786.
  17. Marasini B, Massarotti M, Bottasso B, et al. Comparison between iloprost and alprostadil in the treatment of Raynaud's phenomenon. Scand J Rheumatol 2004; 33:253.
  18. Bartolone S, Trifiletti A, De Nuzzo G, et al. Efficacy evaluation of prostaglandin E1 against placebo in patients with progressive systemic sclerosis and significant Raynaud's phenomenon. Minerva Cardioangiol 1999; 47:137.
  19. Lloyd SN, Kirk D, Deane RF, Kyle KF. Effect of percutaneous nephrolithotomy on thermoregulation. Br J Urol 1992; 69:132.
  20. Clifford PC, Martin MF, Sheddon EJ, et al. Treatment of vasospastic disease with prostaglandin E1. Br Med J 1980; 281:1031.
  21. Langevitz P, Buskila D, Lee P, Urowitz MB. Treatment of refractory ischemic skin ulcers in patients with Raynaud's phenomenon with PGE1 infusions. J Rheumatol 1989; 16:1433.
  22. Mohrland JS, Porter JM, Smith EA, et al. A multiclinic, placebo-controlled, double-blind study of prostaglandin E1 in Raynaud's syndrome. Ann Rheum Dis 1985; 44:754.
  23. Wigley FM. Clinical practice. Raynaud's Phenomenon. N Engl J Med 2002; 347:1001.
  24. Engelhart M. The effect of sympathetic blockade and cooling in Raynaud's phenomenon. Clin Physiol 1990; 10:131.
  25. Setacci C, de Donato G, Teraa M, et al. Chapter IV: Treatment of critical limb ischaemia. Eur J Vasc Endovasc Surg 2011; 42 Suppl 2:S43.
  26. Greengrass RA, Feinglass NG, Murray PM, Trigg SD. Continuous regional anesthesia before surgical peripheral sympathectomy in a patient with severe digital necrosis associated with Raynaud's phenomenon and scleroderma. Reg Anesth Pain Med 2003; 28:354.
  27. Iorio ML, Masden DL, Higgins JP. Botulinum toxin A treatment of Raynaud's phenomenon: a review. Semin Arthritis Rheum 2012; 41:599.
  28. Sycha T, Graninger M, Auff E, Schnider P. Botulinum toxin in the treatment of Raynaud's phenomenon: a pilot study. Eur J Clin Invest 2004; 34:312.
  29. Van Beek AL, Lim PK, Gear AJ, Pritzker MR. Management of vasospastic disorders with botulinum toxin A. Plast Reconstr Surg 2007; 119:217.
  30. Neumeister MW, Chambers CB, Herron MS, et al. Botox therapy for ischemic digits. Plast Reconstr Surg 2009; 124:191.
  31. Neumeister MW. Botulinum toxin type A in the treatment of Raynaud's phenomenon. J Hand Surg Am 2010; 35:2085.
  32. Fregene A, Ditmars D, Siddiqui A. Botulinum toxin type A: a treatment option for digital ischemia in patients with Raynaud's phenomenon. J Hand Surg Am 2009; 34:446.
  33. Jenkins SN, Neyman KM, Veledar E, Chen SC. A pilot study evaluating the efficacy of botulinum toxin A in the treatment of Raynaud phenomenon. J Am Acad Dermatol 2013; 69:834.
  34. Żebryk P, Puszczewicz MJ. Botulinum toxin A in the treatment of Raynaud's phenomenon: a systematic review. Arch Med Sci 2016; 12:864.
  35. Habib SM, Brenninkmeijer EEA, Vermeer MH, et al. Botulinum toxin type A in the treatment of Raynaud's phenomenon. Dermatol Ther 2020; 33:e14182.
  36. Nagarajan M, McArthur P. Targeted high concentration botulinum toxin A injections in patients with Raynaud's phenomenon: a retrospective single-centre experience. Rheumatol Int 2021; 41:943.
  37. Gallegos JE, Inglesby DC, Young ZT, Herrera FA. Botulinum Toxin for the Treatment of Intractable Raynaud Phenomenon. J Hand Surg Am 2021; 46:54.
  38. Asad U, Austin B, Tarbox M, Paulger B. Botulinum Toxin in the Long-Term Treatment of Refractory Raynaud’s Phenomenon. J Drugs Dermatol 2019; 18:943.
  39. Goldberg SH, Akoon A, Kirchner HL, Deegan J. The Effects of Botulinum Toxin A on Pain in Ischemic Vasospasm. J Hand Surg Am 2021; 46:513.e1.
  40. Bello RJ, Cooney CM, Melamed E, et al. The Therapeutic Efficacy of Botulinum Toxin in Treating Scleroderma-Associated Raynaud's Phenomenon: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial. Arthritis Rheumatol 2017; 69:1661.
  41. Senet P, Maillard H, Diot E, et al. Efficacy and Safety of Botulinum Toxin in Adults with Raynaud's Phenomenon Secondary to Systemic Sclerosis: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Study. Arthritis Rheumatol 2023; 75:459.
  42. Wise RA, Wigley F. Acute effects of misoprostol on digital circulation in patients with Raynaud's phenomenon. J Rheumatol 1994; 21:80.
  43. Tsukamoto H, Nagasawa K. Successful treatment of Raynaud's phenomenon with limaprost, an oral prostaglandin E1 analogue. Br J Rheumatol 1991; 30:317.
  44. Lau CS, Belch JJ, Madhok R, et al. A randomised, double-blind study of cicaprost, an oral prostacyclin analogue, in the treatment of Raynaud's phenomenon secondary to systemic sclerosis. Clin Exp Rheumatol 1993; 11:35.
  45. Vayssairat M. Controlled multicenter double blind trial of an oral analog of prostacyclin in the treatment of primary Raynaud's phenomenon. French Microcirculation Society Multicentre Group for the Study of Vascular Acrosyndromes. J Rheumatol 1996; 23:1917.
  46. Vayssairat M. Preventive effect of an oral prostacyclin analog, beraprost sodium, on digital necrosis in systemic sclerosis. French Microcirculation Society Multicenter Group for the Study of Vascular Acrosyndromes. J Rheumatol 1999; 26:2173.
  47. Belch JJ, Capell HA, Cooke ED, et al. Oral iloprost as a treatment for Raynaud's syndrome: a double blind multicentre placebo controlled study. Ann Rheum Dis 1995; 54:197.
  48. Wigley FM, Korn JH, Csuka ME, et al. Oral iloprost treatment in patients with Raynaud's phenomenon secondary to systemic sclerosis: a multicenter, placebo-controlled, double-blind study. Arthritis Rheum 1998; 41:670.
  49. Pakozdi A, Howell K, Wilson H, et al. Inhaled iloprost for the treatment of Raynaud's phenomenon. Clin Exp Rheumatol 2008; 26:709.
  50. Seibold JR, Wigley FM, Schiopu E, et al. Digital ischemic ulcers in scleroderma treated with oral treprostinil diethanolamine: A randomized, double-blind, placebo-controlled, multicenter study. Arthritis Rheum 2011; 63:S968.
  51. Shah AA, Schiopu E, Chatterjee S, et al. The Recurrence of Digital Ulcers in Patients with Systemic Sclerosis after Discontinuation of Oral Treprostinil. J Rheumatol 2016; 43:1665.
  52. Shah AA, Schiopu E, Hummers LK, et al. Open label study of escalating doses of oral treprostinil diethanolamine in patients with systemic sclerosis and digital ischemia: pharmacokinetics and correlation with digital perfusion. Arthritis Res Ther 2013; 15:R54.
  53. Koman LA, Smith BP, Pollock FE Jr, et al. The microcirculatory effects of peripheral sympathectomy. J Hand Surg Am 1995; 20:709.
  54. Letamendia A, López-Román J, Bustamante-Munguira J, Herreros J. Digital periarterial sympathectomy in the management of post-traumatic Raynaud syndrome. J Vasc Surg 2016; 63:459.
  55. Flatt AE. Digital artery sympathectomy. J Hand Surg Am 1980; 5:550.
  56. Chiou G, Crowe C, Suarez P, et al. Digital Sympathectomy in Patients With Scleroderma: An Overview of the Practice and Referral Patterns and Perceptions of Rheumatologists. Ann Plast Surg 2015; 75:637.
  57. Egloff DV, Mifsud RP, Verdan C. Superselective digital sympathectomy in Raynaud's phenomenon. Hand 1983; 15:110.
  58. Wilgis EF. Evaluation and treatment of chronic digital ischemia. Ann Surg 1981; 193:693.
  59. Drake DB, Kesler RW, Morgan RF. Digital sympathectomy for refractory Raynaud's phenomenon in an adolescent. J Rheumatol 1992; 19:1286.
  60. Yee AM, Hotchkiss RN, Paget SA. Adventitial stripping: a digit saving procedure in refractory Raynaud's phenomenon. J Rheumatol 1998; 25:269.
  61. Tomaino MM, Goitz RJ, Medsger TA. Surgery for ischemic pain and Raynaud's' phenomenon in scleroderma: a description of treatment protocol and evaluation of results. Microsurgery 2001; 21:75.
  62. Momeni A, Sorice SC, Valenzuela A, et al. Surgical treatment of systemic sclerosis--is it justified to offer peripheral sympathectomy earlier in the disease process? Microsurgery 2015; 35:441.
  63. Wasserman A, Brahn E. Systemic sclerosis: bilateral improvement of Raynaud's phenomenon with unilateral digital sympathectomy. Semin Arthritis Rheum 2010; 40:137.
  64. Elshabrawy AA, Elkassaby M, Abdelgawad MS, et al. Outcomes of periarterial sympathectomy in patients with digital ischemia. Vascular 2022; 30:859.
  65. Kotsis SV, Chung KC. A systematic review of the outcomes of digital sympathectomy for treatment of chronic digital ischemia. J Rheumatol 2003; 30:1788.
  66. Gabrhelik T, Michalek P, Adamus M, Berta E. Percutaneous upper thoracic radiofrequency sympathectomy in Raynaud phenomenon: a comparison of T2/T3 procedure versus T2 lesion with phenol application. Reg Anesth Pain Med 2009; 34:425.
  67. Gifford RW Jr, Hines EA Jr, Craig WM. Sympathectomy for Raynaud's phenomenon; follow-up study of 70 women with Raynaud's disease and 54 women with secondary Raynaud's phenomenon. Circulation 1958; 17:5.
  68. Johnston EN, Summerly R, Birnstingl M. Prognosis in Raynaud's phenomenon after sympathectomy. Br Med J 1965; 1:962.
  69. De Takats G, Fowler EF. Raynaud's phenomenon. JAMA 1962; 179:1.
  70. Montorsi W, Ghiringhelli C, Annoni F. Indications and results of the surgical treatment in Raynaud's phenomenon. J Cardiovasc Surg (Torino) 1980; 21:203.
  71. Coveliers HM, Hoexum F, Nederhoed JH, et al. Thoracic sympathectomy for digital ischemia: a summary of evidence. J Vasc Surg 2011; 54:273.
  72. Hoexum F, Coveliers HM, Lu JJ, et al. Thoracic sympathectomy for upper extremity ischemia. Minerva Cardioangiol 2016; 64:676.
  73. de Trafford JC, Lafferty K, Potter CE, et al. An epidemiological survey of Raynaud's phenomenon. Eur J Vasc Surg 1988; 2:167.
  74. Karapolat S, Turkyilmaz A, Tekinbas C. Effects of Endoscopic Thoracic Sympathectomy on Raynaud's Disease. J Laparoendosc Adv Surg Tech A 2018; 28:726.
  75. van de Wal HJ, Skotnicki SH, Wijn PF, Lacquet LK. Thoracic sympathectomy as a therapy for upper extremity ischemia. A long-term follow-up study. Thorac Cardiovasc Surg 1985; 33:181.
  76. Matsumoto Y, Ueyama T, Endo M, et al. Endoscopic thoracic sympathicotomy for Raynaud's phenomenon. J Vasc Surg 2002; 36:57.
  77. Thune TH, Ladegaard L, Licht PB. Thoracoscopic sympathectomy for Raynaud's phenomenon--a long term follow-up study. Eur J Vasc Endovasc Surg 2006; 32:198.
  78. van der Meer J, Wouda AA, Kallenberg CG, Wesseling H. A double-blind controlled trial of low dose acetylsalicylic acid and dipyridamole in the treatment of Raynaud's phenomenon. Vasa Suppl 1987; 18:71.
  79. Denton CP, Howell K, Stratton RJ, Black CM. Long-term low molecular weight heparin therapy for severe Raynaud's phenomenon: a pilot study. Clin Exp Rheumatol 2000; 18:499.
  80. Matucci-Cerinic M, Krieg T, Guillevin L, et al. Elucidating the burden of recurrent and chronic digital ulcers in systemic sclerosis: long-term results from the DUO Registry. Ann Rheum Dis 2016; 75:1770.
  81. Brueckner CS, Becker MO, Kroencke T, et al. Effect of sildenafil on digital ulcers in systemic sclerosis: analysis from a single centre pilot study. Ann Rheum Dis 2010; 69:1475.
  82. Andrigueti FV, Ebbing PCC, Arismendi MI, Kayser C. Evaluation of the effect of sildenafil on the microvascular blood flow in patients with systemic sclerosis: a randomised, double-blind, placebo-controlled study. Clin Exp Rheumatol 2017; 35 Suppl 106:151.
  83. Tingey T, Shu J, Smuczek J, Pope J. Meta-analysis of healing and prevention of digital ulcers in systemic sclerosis. Arthritis Care Res (Hoboken) 2013; 65:1460.
  84. Hachulla E, Hatron PY, Carpentier P, et al. Efficacy of sildenafil on ischaemic digital ulcer healing in systemic sclerosis: the placebo-controlled SEDUCE study. Ann Rheum Dis 2016; 75:1009.
  85. Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346:896.
  86. Korn JH, Mayes M, Matucci Cerinic M, et al. Digital ulcers in systemic sclerosis: prevention by treatment with bosentan, an oral endothelin receptor antagonist. Arthritis Rheum 2004; 50:3985.
  87. Matucci-Cerinic M, Denton CP, Furst DE, et al. Bosentan treatment of digital ulcers related to systemic sclerosis: results from the RAPIDS-2 randomised, double-blind, placebo-controlled trial. Ann Rheum Dis 2011; 70:32.
  88. Trombetta AC, Pizzorni C, Ruaro B, et al. Effects of Longterm Treatment with Bosentan and Iloprost on Nailfold Absolute Capillary Number, Fingertip Blood Perfusion, and Clinical Status in Systemic Sclerosis. J Rheumatol 2016; 43:2033.
  89. Rezus E, Burlui AM, Gafton B, et al. A patient-centered approach to the burden of symptoms in patients with scleroderma treated with Bosentan: A prospective single-center observational study. Exp Ther Med 2020; 19:1739.
  90. Khanna D, Denton CP, Merkel PA, et al. Effect of Macitentan on the Development of New Ischemic Digital Ulcers in Patients With Systemic Sclerosis: DUAL-1 and DUAL-2 Randomized Clinical Trials. JAMA 2016; 315:1975.
  91. Abou-Raya A, Abou-Raya S, Helmii M. Statins: potentially useful in therapy of systemic sclerosis-related Raynaud's phenomenon and digital ulcers. J Rheumatol 2008; 35:1801.
  92. Kuwana M, Okazaki Y, Kaburaki J. Long-term beneficial effects of statins on vascular manifestations in patients with systemic sclerosis. Mod Rheumatol 2009; 19:530.
  93. Kuwana M. Potential benefit of statins for vascular disease in systemic sclerosis. Curr Opin Rheumatol 2006; 18:594.
Topic 7552 Version 33.0

References

آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟