management of raynaud’s phenomenon in the patient with connective tissue disease

Current Treatment Options in Cardiovascular Medicine (2010) 12:185–204DOI 10.1007/s11936-010-0065-x

Vascular Disease

Management of Raynaud’sPhenomenon in the PatientWith Connective TissueDisease

Soumya Chatterjee, MD, MS, FRCP

AddressDepartment of Rheumatic and Immunologic Diseases,Orthopedic and Rheumatology Institute,Cleveland Clinic, 9500 Euclid Avenue, Desk A50,Cleveland, OH 44195, USAEmail: [email protected]

Published online: 6 March 2010* Springer Science+Business Media, LLC 2010

Opinion statement

Raynaud’s phenomenon is characterized by intense vasospasm of digital arteries oncold exposure or with emotional stress, leading to well-defined color changes of digitalskin. It may be primary (Raynaud’s disease) or secondary to an underlying condition,including autoimmune rheumatic diseases. Although Raynaud’s disease is predomi-nantly a vasospastic condition, Raynaud’s phenomenon in connective tissue diseasesoften is a result of an underlying vaso-occlusive process. As a result, the manifesta-tions are more severe and persistent and often warrant pharmacologic therapy.Dihydropyridine calcium channel blockers are by far the most commonly studiedand prescribed class of agents for the treatment of Raynaud’s phenomenon. There is someevidence for the efficacy of other classes of drugs, such as topical nitrates, α-antagonists,angiotensin receptor blockers, selective serotonin reuptake inhibitors, and pentoxifylline.However, the data on the efficacy of these agents are not as convincing, and they are notproven to be more effective than calcium channel blockers. Hence, their place in the ther-apy of Raynaud’s phenomenon is limited to patients who fail to respond adequately to orare unable to tolerate calcium channel blockers. More expensive second-line agents, suchas phosphodiesterase-5 inhibitors, endothelin receptor antagonists, and intravenous pros-tanoids, are reserved for refractory cases of secondary Raynaud’s phenomenon with severedigital ischemia leading to ulceration or gangrene. These drugs may be used in isolation oras adjunct therapy to the first-line agents. Chemical and/or surgical sympathectomy maybe considered if sympathetically driven digital ischemia is severe and resistant to pharma-cologic intervention. These procedures may temporarily reverse the digital ischemia andhelp tide over the crisis, whereas the improvement thus achieved can be maintained bycontinuing medical therapy. In cases of ischemic digital ulceration, it is important toachieve adequate analgesia and to identify and treat superadded infection.

IntroductionIn 1862, Auguste-Maurice Raynaud [1], in his thesisLocal Asphyxia and Symmetrical Gangrene of the Extremi-ties, described for the first time color changes of thehands and feet provoked by exposure to cold temper-atures and by emotional stress. Hence Raynaud’s phe-nomenon was named in memory of this Frenchphysician. It is characterized by extreme vasospasmof digital arteries, leading to well-defined cutaneouscolor changes of the digits. The three classical phasesare pallor (vasospasm), dusky cyanosis (deoxygen-ation of static venous blood), and rubor (hyperemiafollowing restoration of blood flow). The attacks areaccompanied by paresthesia and ischemic pain.Whereas primary or idiopathic Raynaud’s phenome-non (also known as Raynaud’s disease) is seen in 5–10% of the general population, Raynaud’s phenome-non is also encountered in about 90% to 95% ofpatients with scleroderma (Fig. 1), about a third ofpatients with systemic lupus erythematosus, andsometimes in patients with other autoimmune rheu-matologic diseases (secondary Raynaud’s phenome-non). Secondary Raynaud’s phenomenon also maydevelop in hematologic conditions such as paraprotei-nemias, cold agglutinin disease, cryoglobulinemia,cryofibrinogenemia, and polycythemia vera.

Raynaud’s disease usually affects women betweenthe ages of 15 years and 30 years, is usually mild,involves fingers and toes symmetrically, and some-times runs in families. The warning signs indicatingthat the Raynaud’s phenomenon may be secondaryto an underlying condition are older age of onset,male gender, asymmetric involvement, and more pro-

longed or severe attacks, often leading to ischemic dig-ital ulceration or infarction. Presence of other clinicalmanifestations of an underlying connective tissue dis-ease (puffy hands and fingers, sclerodactyly, telangiecta-sias, calcinosis, acid reflux disease, dysphagia, shortnessof breath, arthralgias, and microvascular changes onnailfold capillaroscopy), along with a positive antinu-clear antibody test, also should alert the clinician toconsider an underlying autoimmune rheumatologicprocess.

Raynaud’s disease results from an increase in α2-adrenergic responses in the digital vessels and is pre-dominantly a vasospastic condition [2]. In contrast,Raynaud’s phenomenon in connective tissue diseasesoften is a result of an underlying vaso-occlusive pro-cess resulting from either an obliterative vasculopathy(characterized by endothelial dysfunction, intimalproliferation, medial hyperplasia, and adventitialfibrosis) or, less commonly, from vasculitis or vascularthrombosis. The process often begins as a functionalproblem of vasoconstriction resulting from an imbal-ance between the upregulated endothelium-derivedvasoconstrictors (endothelin-1 and thromboxane A2)and the downregulated endothelium-derived vasodila-tors (nitric oxide and prostacyclin). Over time, themitogenic and remodeling effects of the endotheli-um-derived vasoconstrictors, together with profibroticcytokines such as transforming growth factor-β (TGF-β), lead to structural changes in the digital arteries,resulting in an obliterative arteriopathy and eventualdigital vascular rarefaction. This leads to tissue hypox-ia, which is a potent stimulus for further production of

Figure 1. Raynaud’s phenomenon (cyanotic phase) in a pa-tient with limited scleroderma.

186 Vascular Disease

TGF-β and fibroblast activation, enhancing the fibroticprocess [2–4]. Depletion of bone marrow-derived en-dothelial vascular progenitor cells in sclerodermamay impair the ability to repair vascular damage [5].There is increased platelet adhesion and increased ac-tivity of reactive oxygen species following ischemia–reperfusion injury [4]. Thus, the vaso-occlusive processinvolving the digital arteries often leads to severe andpersistent ischemia, requiring pharmacologic therapy.However, because the response to vasodilators is notas robust as it is in Raynaud’s disease, the goals of ther-apy also should be to attempt to reverse vascularremodeling and to address vascular thrombosis.

Dihydropyridine calcium channel blockers are byfar the most commonly studied and effective class ofagents for the pharmacologic therapy of secondaryRaynaud’s phenomenon. Other agents, such as topical

nitrates, α-antagonists, angiotensin receptor blockers,selective serotonin reuptake inhibitors (SSRI), andpentoxifylline, sometimes are used. Data on the effica-cy of these agents are even less convincing, and theyare not proven to be superior to calcium channelblockers. Their use is limited mostly to calcium channelblocker-intolerant patients. Second-line agents, such asphosphodiesterase-5 (PDE5) inhibitors, endothelin re-ceptor antagonists, and prostaglandins, are reservedfor more refractory cases of severe digital ischemia.These agents may be used in isolation or as adjuncttherapy to the first-line agents. Chemical and surgicalsympathectomies are considered for cases resistant topharmacologic intervention and may give short-termrelief of symptoms. In cases of ischemic digital ulcera-tion, it is important to achieve adequate analgesiaand to identify and treat superadded infection.

Nonpharmacologic therapy

& Certain general measures may be adopted to help prevent and ter-minate Raynaud’s attacks. These simple measures can reduce thefrequency, severity, and duration of attacks and include avoidingcold temperatures and temperature fluctuations; alleviating stress;adopting measures to keep the body warm, including adequateclothing (eg, using multiple layers, wearing thermal underwear and awarm hat); and keeping the fingers warm (eg, by using mittens orelectric hand warmers instead of gloves). Placing the hands underwarm water or rotating the arms in a windmill pattern may helpabort Raynaud’s attacks. Both active and passive smoking should beavoided to help minimize the vasoconstrictive effects of tobacco [6].Sympathomimetic drugs (eg, decongestants, stimulants, and ano-rexiants) and vibrating tools also should be avoided.

Pharmacologic treatment

& Various pharmacologic agents have been tried for the treatment ofRaynaud’s phenomenon associated with connective tissue diseases.However, most studies were open label, involved small numbers ofpatients, and had inadequate information on controls. Also, therewas a large placebo effect (10–40%). In most studies, the primaryoutcome measures were subjective, affected by individual variabilityin perception and grading of symptoms. They were based onpatients’ self-report of symptoms and hence were subject to recall

Management of Raynaud’s Phenomenon in the Patient with Connective Tissue Disease Chatterjee 187

bias. Therefore, these outcome measures were not entirely reliable orsensitive to change. Moreover, the clinical effects of the agents testedwere found to be small and often not reproducible in multiple trials.There was significant heterogeneity among patients and populationsbased on the nature of the underlying autoimmune rheumatologicdisease, duration of disease, current medications, comorbidities,ethnic differences, seasonal and geographic differences, and otherfactors, along with significant unexplained individual variability inresponse to therapy. Hence, minor effects of the agents studied oftenwere difficult to interpret because of the presence of too many con-founding variables. Larger, double-blind, placebo-controlled studiesare required to establish the role of these agents in the treatment ofsecondary Raynaud’s phenomenon.

& In this review, only the drugs with some demonstrated efficacy in themanagement of Raynaud’s phenomenon are discussed. The maindrug–drug interactions of the agents discussed are highlighted inTable 1.

Direct vasodilators (drugs that directly induce vascular smooth muscle relaxation)

Calcium channel blockers& Calcium channel blockers are the most commonly used and the most

studied agents for the treatment of both primary and secondaryRaynaud’s phenomenon. They work by blocking voltage-gated cal-cium channels in blood vessels, thus decreasing intracellular calcium,leading to a reduction in vascular smooth muscle contraction. Asystematic review of clinical trials in scleroderma patients revealed 29studies, eight of which were randomized controlled trials eligible forinclusion [7]. These drugs were fairly effective in reducing both thefrequency and the severity of the Raynaud’s attacks. However, insecondary Raynaud’s phenomenon, the effect was moderate at best,and there was a sizeable placebo effect. Among the calcium channelblockers, only nifedipine [8, 9], amlodipine [10], and diltiazem [11]have been found to be efficacious in Raynaud’s phenomenon asso-ciated with connective tissue diseases. In one study, in addition tosubjective improvement, nifedipine caused a decrease in digital skintemperature recovery time following hand immersion in ice water for20 s [12]. Nifedipine was also found to inhibit platelet aggregation,which may be beneficial in digital ischemia associated with sclero-derma [13].

& Short-acting preparations of calcium channel blockers may lead to anacute drop in systemic blood pressure and consequently reducedigital perfusion pressure and blood flow, theoretically worseningdigital ischemia [14]. Moreover, there is a suggestion that theseagents have the potential to increase cardiovascular risk throughsympathetic activation [15]. Hence, extended-release formulations ofcalcium channel blockers are now preferred for the treatment of


Raynaud’s phenomenon. In a randomized, double-blind, placebo-controlled trial, long-acting nifedipine caused a 66% reduction ofattacks in Raynaud’s disease, whereas adverse effects were seen inonly 15% of participants [16], a rate lower than that seen with im-mediate-release nifedipine [17].

& A calcium channel blocker sometimes is combined with anothervasodilator when a single agent alone is ineffective, such as inscleroderma patients with refractory digital ischemia.

Table 1. Main drug interactions of the medications commonly used to treat digital ischemia in connectivetissue diseases

Drug Main drug–drug interactionsNifedipine Coadministration with a β-blocker may precipitate congestive heart failure. Hypotension

may result, especially in patients already taking another antihypertensive drug. Itraco-nazole inhibits CYP3A4 metabolism and may interfere with the clearance of nifedipine,amlodipine, and diltiazem. Nifedipine decreases the renal elimination of digoxin. It alsointerferes with the hepatic breakdown of tacrolimus. Nifedipine reduces the blood levelsof quinidine. Conversely, blood levels of nifedipine are increased by quinidine. Cimeti-dine interferes with hepatic breakdown of nifedipine. Nifedipine should not be takenwith grapefruit juice because grapefruit juice (one glass, approximately 200 mL) inhibitsthe breakdown of nifedipine by the liver.

Amlodipine Coadministration with itraconazole may impair clearance of amlodipine and potentiate therisk of ventricular dysfunction, congestive heart failure, and peripheral and pulmonaryedema, particularly in patients with preexisting risk factors. Tizanidine may potentiatethe hypotensive effect of amlodipine secondary to its α2-adrenergic activity.

Diltiazem Additive reductions in heart rate, cardiac conduction, and cardiac contractility may occurwhen diltiazem is used concomitantly with β-blockers. Diltiazem is a potent inhibitor ofCYP3A4, and coadministration with drugs metabolized by this enzyme potentiates theirtoxicity. Hence, diltiazem is contraindicated with propafenone and may cause toxicityfrom statins, warfarin, amiodarone, carbamazepine, benzodiazepines, azole antifungals,bosentan, and cyclosporine.

Nitroglycerin Concomitant administration of other vasodilators, especially phosphodiesterase-5 inhibi-tors (sildenafil), may cause profound hypotension.

Fluoxetine It is a potent inhibitor of CYP2D6 (the main enzyme responsible for its metabolism). It iscontraindicated in individuals taking monoamine oxidase inhibitors, pimozide, or thio-ridazine. Concomitant ibuprofen use may cause significant intestinal bleeding. Simul-taneous use of fluoxetine with triptans, tramadol, or other serotonergic agents mayresult in a rare but potentially life-threatening adverse drug reaction called serotoninsyndrome.

Sildenafil Concomitant administration of other vasodilators, especially nitrates, may cause profoundhypotension. Also, HIV protease inhibitors inhibit the metabolism of sildenafil.

Pentoxifylline Coadministration of pentoxifylline and sodium thiopental may precipitate acute pulmonaryedema.

Bosentan It is an inducer of CYP2C9 and CYP3A4. It is not recommended for use with cyclosporineand glyburide. It decreases the effectiveness of warfarin and birth control pills. Itinteracts with azole antifungals, statins, HIV protease inhibitors, and tacrolimus.

Prazosin Concomitant administration of other vasodilators may cause profound hypotension.Prostaglandins and analogues Concomitant administration of other vasodilators may cause profound hypotension.


Nifedipine

Standard dosage 10–20 mg three to four times per day.

Contraindications Known hypersensitivity to nifedipine.

Main side effects Dizziness, headache, facial flushing, hypotension, peripheral edema, tachy-cardia, constipation, gingival hyperplasia.

Special points Considerable variability in response is observed in scleroderma patients.

Cost/cost-effectiveness $75.60 to $201.60 per month (based on dosage).

Nifedipine sustained release (long acting)

Standard dosage 30–180 mg/d

Contraindications Same as for short-acting nifedipine.

Main drug interactions Same as for short-acting nifedipine.

Main side effects Same as for short-acting nifedipine.

Cost/cost-effectiveness $39.73 to $153.60 per month.

Amlodipine

Standard dosage 5–20 mg/d



Cost/cost-effectiveness $51.90 to $142.39 per month.

Diltiazem

Standard dosage 120 mg three times a day.

Contraindications Hypersensitivity, sick sinus syndrome, second- or third-degree atrioventric-ular block (except in patients with a pacemaker), severe hypotension, acutemyocardial infarction, pulmonary edema.

Main side effects Peripheral edema, headache, dizziness, bradycardia, atrioventricular block,extrasystoles, facial flushing, hypotension, palpitation, vomiting, diarrhea,weakness, and myalgia.

Cost/cost-effectiveness $110.70 per month.

Other dihydropyridine calcium channel blockers (isradipine and felodipine)

Standard dosage Isradipine: 1.25–2.5 mg twice daily.Felodipine: 5–20 mg once daily.



Special points Published trials of these dihydropyridine calcium channel blockers have onlybeen in Raynaud’s disease. However, based on their efficacy, these agentshave sometimes been successfully used even in connective tissue disease-associated Raynaud’s phenomenon. In equivalent doses, there may not beany difference in efficacy among the effective calcium channel blockers, al-though individual responses may vary.


Cost/cost-effectiveness Isradipine: $82.36 per month.Felodipine: $45.33 to $162.91 per month.

Other direct vasodilators& Apart from calcium channel blockers, many other classes of drugs

have been studied for the treatment of Raynaud’s phenomenon. In2008, a systematic review (Cochrane database) to assess the effectsof various vasodilators on Raynaud’s disease (or primary Raynaud’sphenomenon) revealed 80 different studies using 30 differentdrugs. Of these studies, only eight (290 participants) qualified forevaluation of efficacy [18•]. No convincing evidence for effectivepharmacologic treatment of Raynaud’s disease (apart from calciumchannel blocker therapy) was found, but most studies were smalland of mediocre quality. Problems with study design also werenoted in a review of pharmacotherapy of Raynaud’s phenomenonassociated with scleroderma or other connective tissue diseases[19••].

Topical nitrates& Because of the vasodilating properties of nitrates, these agents have

long been used for treating Raynaud’s phenomenon. Several for-mulations of nitroglycerin, including ointment [20], sublingualtablets [21], tape [22], and transdermal patches [23], have beenshown to improve finger temperature or perfusion in patients withRaynaud’s phenomenon. However, there was a high frequency ofside effects, especially headaches and dizziness [20, 23]. Topicalnitrates are not the preferred form of therapy for Raynaud’s phe-nomenon, as the calcium channel blockers are effective and often arebetter tolerated. Their use is reserved for patients who cannot tolerateor fail to respond adequately to calcium channel blockers. Thetransdermal nitroglycerin patch seems less cumbersome than nitro-glycerin ointment and is the favored formulation.

& Recently, MQX-503 (a new formulation of topical nitroglycerin gel)has attracted attention as a possible therapeutic agent [24•]. Thisagent is discussed under “Emerging Therapies.”

Nitroglycerin transdermal patch

Standard dosage A 0.2-mg/h patch is applied to the dorsum of the hand for 12–14 h a day.

Contraindications Concomitant use of a PDE5 inhibitor, hypersensitivity, significanthypotension.

Main side effects Headache, flushing, dizziness, hypotension, lack of libido, dysuria, anddiarrhea.

Special points Patches should not be applied for more than 12–14 h a day to ensure a drug-free period to prevent tolerance to nitroglycerin.



Indirect vasodilators (drugs that work by inhibiting vasoconstrictor influences)

Selective serotonin reuptake inhibitors& One of the mechanisms by which an SSRI may help alleviate va-

sospasm is by reducing the circulating level of serotonin, a selectivevasoconstrictor. An uncontrolled study with an SSRI (fluoxetine,20 mg/d) suggests that it may be useful in Raynaud’s phenomenon[25]. Also, an open-label randomized 2-week study comparedfluoxetine with nifedipine in Raynaud’s phenomenon [26]. Bothtreatments were effective in alleviating Raynaud’s symptoms, butthe benefits were statistically significant only in the fluoxetinegroup.

Fluoxetine

Standard dosage 20 mg/d.

Contraindications Significant liver disease, mania.

Main side effects Nausea, anorexia, anxiety, insomnia, nervousness, mania, erectile dysfunc-tion, anorgasmia (in females), increased risk of suicide in persons youngerthan 25 years.

Special points Simultaneous use of fluoxetine with triptans, tramadol, or other serotonergicagents may result in a rare but potentially life-threatening adverse drug re-action called serotonin syndrome.


Angiotensin II antagonists& Angiotensin-converting enzyme (ACE) inhibitors: It is hypothesized that

ACE inhibitors may induce cutaneous vasodilation by increasingendogenous tissue bradykinin levels rather than by reducing en-dogenous angiotensin II levels [27]. However, ACE inhibitors werefound to be ineffective in alleviating digital ischemia in scleroderma.An uncontrolled study of captopril in Raynaud’s disease and inRaynaud’s phenomenon associated with scleroderma showed im-provement in patients in the former group but not in the latter,suggesting that the effect of ACE inhibitors on alleviation of thesymptoms of Raynaud’s phenomenon likely is mild (if it exists at all)[28]. Also, in another placebo-controlled study of patients withclinical or serologic evidence of scleroderma, quinapril was ineffec-tive in controlling Raynaud’s phenomenon and ischemic digitalulcers [29].

& Angiotensin receptor blockers: Interestingly, contrary to what wasexpected from previous studies on ACE inhibitors, a randomized,parallel-group, controlled trial found that the angiotensin receptorblocker losartan (which has no effect on tissue bradykinin levels)reduced the severity and frequency of Raynaud’s attacks more effec-tively than nifedipine in Raynaud’s disease and, to a lesser extent, inscleroderma patients [30].


Losartan

Standard dosage 50 mg/d.

Contraindications Hypersensitivity.

Main side effects Hypotension, hyperkalemia.


Phosphodiesterase-5 inhibitors& PDE5 inhibitors inhibit degradation of cyclic guanosine mono-

phosphate, causing intracellular calcium depletion, leading to vas-cular smooth muscle relaxation. Sildenafil [31, 32], tadalafil [33•],and vardenafil [34] all have been used to treat severe digital ische-mia, with varied results. In a randomized placebo-controlled study of20 patients with secondary Raynaud’s phenomenon, sildenafilcaused significant subjective improvement as well as improvement inmean capillary flow velocity [32]. However, bias was introducedbecause the subjects were able to differentiate active drug from pla-cebo by the appearance of the pills.

& In patients with Raynaud’s phenomenon, single-dose tadalafil didnot increase digital blood flow or attenuate cold-induced vasocon-striction [33•]. Moreover, in a randomized, double-blind, placebo-controlled study of women with scleroderma-associated Raynaud’sphenomenon, there were no statistically significant differences insubjective measures of efficacy between the treatment groups [35•].

& In an open-label study, vardenafil was used in patients with sec-ondary Raynaud’s phenomenon. There was improvement both inclinical symptoms and in blood flow in 70% of patients [34].However, the inherent problems of uncontrolled studies must bekept in mind.

& Hence, the data about PDE5 inhibitors are conflicting. Larger, ran-domized, controlled trials are necessary to assess their role in sec-ondary Raynaud’s phenomenon.

Sildenafil

Standard dosage 50 mg twice daily.

Contraindications Concomitant administration of other vasodilators, especially nitrates, severeliver or renal disease, recent stroke, or heart attack.

Main side effects Hypotension, headache, arrhythmias, flushing, dizziness, myocardial in-farction, stroke, blurred vision (rarely blindness), altered color vision, backpain, and priapism (rare).

Special points PDE5 inhibitors are not approved by the US Food and Drug Administrationfor the treatment of digital ischemia; therefore the lack of reimbursement forthese expensive drugs limits their use for this indication.

Cost/cost-effectiveness Sildenafil, 50 mg twice daily: $826.09 per month.Tadalafil, 10–20 mg once daily: $473.50 per month (same price).Vardenafil, 10 mg twice daily: $849.02 per month.


Phosphodiesterase-4 inhibitor (pentoxifylline)& The phosphodiesterase-4 inhibitor pentoxifylline increases intracel-

lular cyclic adenosine monophosphate (cAMP) and stimulatescAMP-dependent protein kinase activity. Pentoxifylline increases redcell deformability [36], reduces platelet aggregation [37], and mayinfluence vascular tone. However, it is believed that improvement inblood flow likely occurs through changes in blood viscosity ratherthan through any direct vascular effect. In one study, pentoxifyllinewas found to be beneficial in treating Raynaud’s disease [38]. Also,intravenous pentoxifylline was used successfully in two patients withscleroderma and digital gangrene [39]. More information about itsefficacy would be beneficial.

Pentoxifylline

Standard dosage 400 mg three times daily.

Contraindications Concurrent use of sodium thiopental, hypersensitivity.

Main side effects Flushing, headaches.


Endothelin receptor antagonists& Endothelin-1 is a potent vasoconstrictor. A randomized trial using

bosentan (RAPIDS 1), an inhibitor of endothelin 1, in sclerodermapatients showed a 48% reduction in the mean number of new digitalulcers during the treatment period [40]. In another prospective,noncontrolled study, 15 patients with scleroderma who startedtreatment with bosentan for ischemic digital ulcers or a history ofdigital ulcers showed a significant reduction in the number of newdigital ulcers [41•]. Interestingly, in RAPIDS 1, there was no reduc-tion in the frequency or intensity of Raynaud’s attacks. However, in asmall observational study, the severity of Raynaud’s attacks signifi-cantly decreased in three patients with scleroderma [42].

& There are conflicting reports in the literature about the role ofbosentan in improving endothelial function. In one controlled studyin scleroderma patients, bosentan induced significant improvementin vascular endothelial function without affecting hemodynamicparameters [43•]. On the other hand, in a single-center, open-labelstudy, patients with limited scleroderma treated with bosentan didnot have significantly improved vasodilator responses, capillarypermeability, or capillary density during treatment, indicating noevidence of improvement of microvascular structure and function inthese patients [44•].

& At this time, there is no consensus about the role of bosentan inimproving digital ischemia. Further studies are needed. Nonetheless,bosentan has received regulatory approval in the United Kingdomand Ireland (but not in the United States) for the reduction of the


number of new ischemic digital ulcers and ongoing digital ulcerdisease in scleroderma patients.

Bosentan

Standard dosage 62.5 mg twice daily for 1 month, then 125 mg twice daily.

Contraindications Abnormal liver function tests pregnancy severe anemia.

Main side effects Teratogenicity, hepatotoxicity, edema, anemia.

Special points Because bosentan has not received regulatory approval in the United Statesfor prevention of ischemic digital ulcers, this expensive medication often isnot reimbursed by insurance companies.

Cost/cost-effectiveness The wholesale acquisition cost for a month’s supply is $4872 for a 60-tabletbottle (regardless of strength).

Sympatholytic agents& Activation of the sympathetic nervous system is believed to play an

important role in maintaining vascular tone. Hence, a rational ap-proach to treating digital ischemia is adrenoreceptor blockade. Var-ious sympatholytic drugs have been tried in Raynaud’s phenomenon,including intra-arterial reserpine, methyldopa, prazosin, and phen-tolamine. Unfortunately, in the absence of randomized trials, nofirm recommendations can be made.

& In controlled clinical trials, prazosin has been shown to be effectivein treating Raynaud’s phenomenon secondary to autoimmune dis-eases [45, 46]. In a double-blind crossover study, most of the benefitwas seen in patients with Raynaud’s disease, systemic lupus erythe-matosus, or mixed connective tissue disease, but not in those withscleroderma [45].

& None of the available sympatholytic agents specifically inhibits theα2c-adrenergic receptor, now considered to be the major mediatorthrough which cold-induced digital vasoconstriction is triggered. Alaboratory-based study using a specific α2c-adrenergic receptor an-tagonist shows some promise (see “Emerging Therapies”) [47].

Prazosin

Standard dosage 1 mg three times daily.

Contraindications Hypersensitivity.

Main side effects Orthostatic hypotension, syncope, nasal congestion, priapism (rare).

Special points Patients should be warned about the “first-dose effect” (orthostatic hypo-tension after initiating prazosin).


Prostaglandins& Certain prostaglandins are potent vasodilators, inhibitors of platelet

aggregation, and modulators of vascular remodeling. They have been


used effectively in the emergency management of critical digitalischemia.

Parenteral and oral prostaglandins and analogues& Prostaglandin E1 (PGE1, or alprostadil) [48, 49], prostacyclin (PGI2,

or epoprostenol) [50, 51], and iloprost (a PGI2 analogue) [52] allhave been effective in treating refractory digital ischemia.

& PGE1 (alprostadil) infusion has been used successfully for refractorydigital ulcers [48]. However, a randomized blinded study usingalprostadil showed no significant clinical benefit in either Raynaud’sdisease or scleroderma [49]. Yet, in an open-label trial, PGE1 α-cy-clodextrin infusion through a peripheral vein reduced the frequencyof Raynaud’s attacks in scleroderma patients [53].

& Intravenous infusion of PGI2 (prostacyclin or epoprostenol) hasbeen beneficial in treating Raynaud’s phenomenon in sclerodermapatients [50, 51]. There was subjective improvement (either completeabolition or reduction in frequency, severity, and duration of Ray-naud’s attacks), which was supported by objective measures of im-provement (increased mean skin temperature measured bythermography) [50].

& Intravenous iloprost provided temporary improvement in the sub-jective measures of Raynaud’s attacks in scleroderma patients [52].This preparation is available in Europe but not in the United States.

& Improvement in digital ischemia and ulceration has been observedin patients with scleroderma who received subcutaneous infusions ofthe PGI2 analogue treprostinil [54]. Treprostinil also may be givenintravenously, which may overcome the drawback of injection sitepain when given subcutaneously.

& Limaprost (an oral PGE1 analogue) improved peak digital bloodvelocity in patients with lupus and mixed connective disease but notin those with scleroderma [55]. In a randomized study, cicaprost (asynthetic prostacyclin analogue) reduced the severity (but not thetotal duration or frequency) of Raynaud’s attacks in sclerodermapatients [56]. Neither of these two agents is commercially availablein the United States.

& Currently, oral treprostinil diethanolamine is undergoing evaluationin a randomized, double-blind, placebo-controlled study of ischemicdigital ulcers in scleroderma. The role of oral prostaglandins in themanagement of digital ischemia associated with connective tissuediseases will need to be defined by the results of large well-designedcontrolled clinical trials.

Alprostadil, epoprostenol, and iloprost

Standard dosage Alprostadil: 6–10 ng/kg/min (through a central intravenous line).Epoprostenol: 2 ng/kg/min initially increased over 1 day to 2 days as toler-ated to 4–8 ng/kg/min (through a peripheral line).


Iloprost: 0.5- to 2.0-ng/kg/min infusion (through a peripheral line). (Avail-able only in Europe.)

Contraindications Hypersensitivity, significant hypotension.

Main side effects Hypotension, tachycardia, flushing, headache, jaw pain, nausea, vomiting,diarrhea, neuropathy.

Cost/cost-effectiveness Alprostadil: $66 per 500-µg vial.Epoprostenol: $21.36 per 0.5-mg vial; $51.59 per 1.5-mg vial ($31.00 fortwo vials of 50-mL diluent).Iloprost: approximately $650 for a 5-day course (available only in Europe).The cost of hospitalization also must be considered. In-patient admission isrequired and a telemetry bed is recommended to monitor the patient’s car-diac parameters closely because of the possibility of profound hypotension.

Anticoagulation and antithrombotic therapy& Anticoagulation and antithrombotic therapy have been considered in

patients with intractable digital ischemia leading to ulceration orimpending gangrene, especially if there is evidence of arterialthrombosis or embolism. Aspirin, clopidogrel, anticoagulation, andthrombolytic therapy all have been tried.

& The role of antiplatelet therapy with low-dose aspirin (81 mg/d) hasnever been formally evaluated, but it is recommended in all patientswith chronic digital ischemia. Anticoagulation or thrombolytictherapy, on the other hand, may be used for acute and critical digitalischemia; however, it is recommended that these therapies be re-served for arterial thrombotic or embolic disease [57].

& Long-term use of low molecular weight heparin was associated withreduction in the severity of Raynaud’s phenomenon in a small pla-cebo-controlled study [58]; the benefit of long-term anticoagulationmost likely is achieved in patients with antiphospholipid antibodieswith severe or recurrent digital ischemia. However, a short course ofheparin also may be used to manage an ischemically threatened digit.

& Thrombolytic therapy with tissue plasminogen activator may benefitpatients with scleroderma-associated Raynaud’s phenomenon [59].However, the level of evidence is low, as placebo-controlled studieshave not yet been conducted.

SurgerySympathectomy

& Sympathectomy may be considered for patients suffering from re-peated bouts of severe/prolonged Raynaud’s phenomenon or forthose with critical digital ischemia.

Chemical sympathectomy& Chemical sympathectomy is performed by infiltration of lidocaine or

bupivacaine (without epinephrine) in the affected digit (ring block),


regionally, or through a catheter with its tip placed close to the cer-vical or lumbar sympathetic ganglia. Pain relief also is achieved. Thisprocedure may be repeated if necessary and can identify the subjectswho have significant vasospastic disease and likely would benefitfrom a subsequent surgical sympathectomy.

& Intradigital injection of botulinum toxin A also has been used suc-cessfully for chemical sympathectomy. In a case series, nine of 11patients with intractable digital ischemia achieved significant painrelief and digital ulcer healing [60•]. However, before this therapycan find a place in the treatment algorithm for intractable digitalischemia, controlled studies need to show its efficacy.

Surgical sympathectomy& Cervical (or lumbar) sympathectomy may be performed in an

acute clinical setting, such as acute vasospasm resulting in drug-refractory severe digital ischemia. Because the benefits usually arenot long lasting, the goal is to continue medical therapy alongwith this procedure in the hope of maintaining the improvementover time.

Cervical sympathectomy& Cervical sympathectomy may be beneficial in Raynaud’s disease, but

not in secondary Raynaud’s phenomenon [61]. The procedure maybe associated with some uncomfortable side effects, such as hypo-hidrosis, Horner’s syndrome, and neuralgia. Also, the benefits usu-ally do not persist over time. In a survey evaluating patients whounderwent sympathectomy, the benefit was persistent in only 19%,whereas 66% lost any benefit after 1 year [62]. Microscopic endo-scopic thoracic sympathectomy (micro-ETS) may be safer, but re-currence is still common [63].

Localized microsurgical digital sympathectomy& Localized microsurgical digital sympathectomy has been claimed

to be a successful yet safer alternative to conventional surgicalsympathectomy, with relatively few complications [64, 65].However, a systematic review of the outcomes of digital sympa-thectomy revealed that the perioperative complication rate amongscleroderma patients was 37% [66]. In this analysis, digital am-putation was necessary in 14% and ulcers recurred in 18% of allpatients. Postoperative complications included hypoesthesia,delayed wound healing, persistent hand edema, fingernail de-tachment, fingertip loss, recurrent infection, and reflex sympa-thetic dystrophy [66]. Despite this report, when surgicalsympathectomy is considered necessary, localized digital sympa-thectomy is now the procedure of choice, over proximal cervical ormicro-ETS procedures.


Vascular reconstruction& Digital ischemia may be exacerbated by proximal occlusion of a

major artery. In scleroderma patients with refractory digital ulcers organgrene, coexistent proximal arterial occlusion often involves theulnar and proper digital arteries [67]. Microsurgical revascularizationprocedures (vascular reconstruction or grafts) involving the ulnarand digital arteries sometimes may be necessary in such cases to re-store digital perfusion.

Other treatmentsCalcitonin gene-related peptide

& In one placebo-controlled study, intravenous calcitonin gene-relatedpeptide (the most potent peptide vasodilator) produced significantimprovement in objective parameters of blood flow in patients withsevere Raynaud’s phenomenon; all digital ulcers also healed in fourof five patients [68]. However, all treated patients developed facialand peripheral flushing.

N-acetylcysteine& Antioxidants are believed to reduce tissue damage resulting from

ischemia-reperfusion injury by scavenging free radicals (eg, super-oxide). Intravenous N-acetylcysteine was found to clinically benefitRaynaud’s phenomenon associated with scleroderma [69].

Statins& Statins may be beneficial for treating the vascular dysfunction in

scleroderma. In an open-label, prospective study, 13 sclerodermapatients received 10 mg of atorvastatin daily for 12 weeks [70].Subjective measures of Raynaud’s phenomenon significantlyimproved. These results are promising and should lead to larger,well-designed, randomized, controlled trials to explore the effectsof statins on scleroderma vasculopathy.

Management of severe ischemia threatening the viabilityof a digit

& Patients with Raynaud’s phenomenon secondary to an underlyingautoimmune rheumatologic disease often have prolonged attacks ofsevere ischemia, leading to digital ulceration (Fig. 2) and gangrene.Severe digital ischemia may develop despite all precautions and is amajor source of morbidity in these patients. Early intervention is thekey. Patients with an ischemically threatened digit need hospitali-zation, preferably in a private room in which the temperature can bekept warm. It is prudent to perform a thorough evaluation to elim-


inate a secondary reversible cause that might have precipitated oraggravated the crisis, including a careful evaluation for correctablemacrovascular disease, superadded infection (skin and deeper struc-tures), severe anemia, systemic hypoxia, or a hypercoagulable state.

& Severe digital ischemic pain will cause sympathetic overactivity,leading to worsening vasospasm and aggravation of the underlyingcondition. Hence, adequate analgesia should be achieved with ap-propriate means and often requires the use of oral or parenteralnarcotic analgesics.

& The patient likely is already on vasodilator therapy with either ex-tended-release nifedipine or amlodipine, as well as antiplatelet ther-apy with aspirin. If not, these are recommended as initial therapies.

& If these measures are ineffective, then a second vasodilator must beadded to the maximized dose of the calcium channel blocker. Thechoice is between a transdermal nitroglycerin patch, a sympatholyticagent (prazosin), and a PDE5 inhibitor (sildenafil).

& Anticoagulation for 24–72 h with a heparin preparation is suggestedif critical digital ischemia progresses despite the aforementionedmeasures. This therapy also is indicated if new onset of arterial oc-clusion is suspected, resulting from acute thrombosis or embolism[58]. However, the benefits of anticoagulation should be weighedcarefully against the risks of gastrointestinal bleeding in sclerodermapatients with possible ulcerative esophagitis or gastric antral vascularectasias.

& Temporary chemical sympathectomy also is suggested when vaso-dilator therapy does not adequately restore digital blood flow. Thiscan be achieved with infiltration of lidocaine or bupivacaine (with-out epinephrine) as a digital or regional block. This procedure maybe repeated when its effect wanes.

& If these measures still do not reverse the ischemia, an intravenousinfusion of a prostaglandin or prostaglandin analogue for 3–5 daysmay be considered. The dose can be uptitrated every few hours to the

Figure 2. Ischemic ulcers at the tips of the left middle (ac-tive ulcer) and ring (healing ulcer) fingers of a patient withdiffuse scleroderma. There is digital pitting at the tip of theindex finger, signifying chronic ischemia.


level tolerated, and the duration of therapy is determined by theclinical outcome. The choice of agents includes alprostadil, epo-prostenol, or iloprost (in Europe only) [52].

& Effective reversal of critical ischemia with a temporary chemicalsympathectomy suggests that the arterial disease is not predomi-nantly vaso-occlusive but still has a significant vasospastic compo-nent. In this situation, if symptoms recur as the effect of the chemicalsympathectomy wanes—even with ongoing use of intravenousprostanoids—then surgical digital sympathectomy should beconsidered.

& If the digital ischemia is advanced and irreversible, then the portionof the digit will become necrotic and will be lost, regardless of allmedical measures. In this situation, autoamputation may be prefer-able to salvage maximum tissue, if the necrotic area is demarcatedclearly and pain and infection are controlled adequately. To mini-mize the ischemic penumbra, intravenous prostanoids should con-tinue. If all measures fail, then surgical amputation of the affectedpart of the digit may be the only option in patients with advancedand irreversible ischemia in which digital gangrene is inevitable.

Emerging therapiesMQX-503

& MQX-503 is a new formulation of topical nitroglycerin gel that absorbsquickly and induces local vasodilatation, with a side effect profilecomparable with that of placebo. Animal and human studies havedemonstrated that this preparation (10% nitroglycerin in propyleneglycol) has a rapid onset of action. Based on preliminary studies indi-cating it ismore effective thanplacebo [24•], studies are nowongoing toevaluate its efficacy in treating Raynaud’s phenomenon.

OPC-28326& The recognition that the α2C-adrenoceptor is cold sensitive suggests

that selective blockade of this receptor might provide a new approachto therapy. A laboratory-based placebo-controlled study using aspecific α2C-adrenoceptor antagonist, OPC-28326, demonstratedimprovement in skin temperature recovery time following coldchallenge, suggesting it may be helpful in treating Raynaud’s phe-nomenon associated with scleroderma [47].

Acknowledgment

The author is grateful to Ms. Marcia Wyman, PharmD, drug information pharmacist atthe Cleveland Clinic, for providing the prices of the individual drugs.


DisclosureDr. Chatterjee is a member of the Scientific Advisory Board for and has also received grant support fromGilead Sciences, Inc. He is an investigator for clinical trials run by United Therapeutics Corporation, Med-Immune, and MediQuest Therapeutics.

References and Recommended ReadingPapers of particular interest, published recently, have beenhighlighted as:• Of importance•• Of major importance

1. Raynaud M: Local Asphyxia and Symmetrical Gan-grene of the Extremities. Paris: L. Leclerc; 1862.

2. Boin F, Wigley FM: Understanding, assessing andtreating Raynaud’s phenomenon. Curr OpinRheumatol 2005, 17(6):752–760.

3. Herrick AL: Pathogenesis of Raynaud’s phenome-non. Rheumatology (Oxford) 2005, 44(5):587–596.

4. Sunderkotter C, Riemekasten G: Pathophysiologyand clinical consequences of Raynaud’s phenome-non related to systemic sclerosis. Rheumatology(Oxford) 2006, 45(Suppl 3):iii33–iii35.

5. Kuwana M, Okazaki Y, Yasuoka H, et al.: Defectivevasculogenesis in systemic sclerosis. Lancet 2004,364(9434):603–610.

6. Harrison BJ, Silman AJ, Hider SL, Herrick AL: Ciga-rette smoking as a significant risk factor for digitalvascular disease in patients with systemic sclerosis.Arthritis Rheum 2002, 46(12):3312–3316.

7. Thompson AE, Shea B, Welch V, et al.: Calcium-channel blockers for Raynaud’s phenomenonin systemic sclerosis. Arthritis Rheum 2001,44(8):1841–1847.

8. Rodeheffer RJ, Rommer JA, Wigley F, Smith CR:Controlled double-blind trial of nifedipine in thetreatment of Raynaud’s phenomenon. N Engl J Med1983, 308(15):880–883.

9. Kallenberg CG, Wouda AA, Kuitert JJ, et al.:Nifedipine in Raynaud’s phenomenon: relation-ship between immediate, short term and long-term effects. J Rheumatol 1987, 14(2):284–290.

10. La Civita L, Pitaro N, Rossi M, et al.: Amlodipine inthe treatment of Raynaud’s phenomenon. Br JRheumatol 1993, 32(6):524–525.

11. Kahan A, Amor B, Menkes CJ: A randomiseddouble-blind trial of diltiazem in the treatmentof Raynaud’s phenomenon. Ann Rheum Dis 1985,44(1):30–33.

12. White CJ, Phillips WA, Abrahams LA, et al.:Objectivebenefit of nifedipine in the treatment of Raynaud’sphenomenon. Double-blind controlled study. Am JMed 1986, 80(4):623–625.

13. Takahara K, Kuroiwa A, Matsushima T, et al.: Effectsof nifedipine on platelet function. Am Heart J 1985,109(1):4–8.

14. Wise RA, Malamet R, Wigley FM: Acute effects ofnifedipine on digital blood flow in human subjectswith Raynaud’s phenomenon: a double blindplacebo controlled trial. J Rheumatol 1987,14(2):278–283.

15. Messerli FH, Grossman E: The calcium antagonistcontroversy: a posthumous commentary. Am JCardiol 1998, 82(9B):35R–39R.

16. Comparison of sustained-release nifedipine andtemperature biofeedback for treatment of primaryRaynaud phenomenon. Results from a randomizedclinical trial with 1-year follow-up. Arch Intern Med2000, 160(8):1101–1108.

17. Ettinger WH, Wise RA, Schaffhauser D, Wigley FM:Controlled double-blind trial of dazoxiben andnifedipine in the treatment of Raynaud’s phenom-enon. Am J Med 1984, 77(3):451–456.

18.• Vinjar B, Stewart M: Oral vasodilators for primaryRaynaud’s phenomenon. Cochrane Database Syst Rev2008, CD006687.

This comprehensive systematic review by the CochranePeripheral Vascular Diseases Group of randomizedcontrolled trials evaluates the effects of various oralvasodilator agents on subjective symptoms in primaryRaynaud’s phenomenon.19.•• Henness S, Wigley FM: Current drug therapy for

scleroderma and secondary Raynaud’s phenome-non: evidence-based review. Curr Opin Rheumatol2007, 19(6):611-618.

This is a nice review examining the efficacy of various phar-macologic therapies in treating scleroderma and Raynaud’sphenomenon secondary to scleroderma or other connectivetissue diseases. Only fully published, randomized, controlledtrials that had a duration of at least 1 month were included.20. Anderson ME, Moore TL, Hollis S, et al.: Digital

vascular response to topical glyceryl trinitrate, asmeasured by laser Doppler imaging, in primaryRaynaud’s phenomenon and systemic sclerosis.Rheumatology (Oxford) 2002, 41(3):324–328.


21. Peterson LL, Vorhies C: Raynaud’s syndrome.Treatment with sublingual administration ofnitroglycerin, swinging arm maneuver, andbiofeedback training. Arch Dermatol 1983,119(5):396–399.

22. Kan C, Akimoto S, Abe M, et al.: Preliminarythermographic evaluation of new nitroglycerinetape on the peripheral circulatory disturbancein systemic sclerosis. Ann Rheum Dis 2002,61(2):177–179.

23. Teh LS, Manning J, Moore T, et al.: Sustained-releasetransdermal glyceryl trinitrate patches as a treat-ment for primary and secondary Raynaud’s phe-nomenon. Br J Rheumatol 1995, 34(7):636–641.

24.• Chung L, Shapiro L, Fiorentino D, et al.: MQX-503, anovel formulation of nitroglycerin, improves theseverity of Raynaud’s phenomenon: a randomized,controlled trial. Arthritis Rheum 2009, 60(3):870–877.

This randomized placebo-controlled study demonstratedthat this novel formulation of topical nitroglycerin is welltolerated and more effective than placebo for treatingprimary or secondary Raynaud’s phenomenon.25. Jaffe IA: Serotonin reuptake inhibitors in Raynaud’s

phenomenon. Lancet 1995, 345(8961):1378.26. Coleiro B, Marshall SE, Denton CP, et al.: Treatment

of Raynaud’s phenomenon with the selective sero-tonin reuptake inhibitor fluoxetine. Rheumatology(Oxford) 2001, 40(9):1038–1043.

27. Warren JB, Loi RK: Captopril increases skin microvas-cular blood flow secondary to bradykinin, nitric oxide,and prostaglandins. FASEB J 1995, 9(5):411–418.

28. Tosi S, Marchesoni A, Messina K, et al.: Treatment ofRaynaud’s phenomenon with captopril. Drugs ExpClin Res 1987, 13(1):37–42.

29. Gliddon AE, Dore CJ, Black CM, et al.: Prevention ofvascular damage in scleroderma and autoimmuneRaynaud’s phenomenon: a multicenter, random-ized, double-blind, placebo-controlled trial of theangiotensin-converting enzyme inhibitor quinapril.Arthritis Rheum 2007, 56(11):3837–3846.

30. Dziadzio M, Denton CP, Smith R, et al.: Losartantherapy for Raynaud’s phenomenon and scleroder-ma: clinical and biochemical findings in a fifteen-week, randomized, parallel-group, controlled trial.Arthritis Rheum 1999, 42(12):2646–2655.

31. Gore J, Silver R: Oral sildenafil for the treatment ofRaynaud’s phenomenon and digital ulcers second-ary to systemic sclerosis. Ann Rheum Dis 2005,64(9):1387.

32. Fries R, Shariat K, von Wilmowsky H, Bohm M:Sildenafil in the treatment of Raynaud’s phe-nomenon resistant to vasodilatory therapy.Circulation 2005, 112(19):2980–2985.

33.• Friedman EA, Harris PA, Wood AJ, et al.: The effectsof tadalafil on cold-induced vasoconstriction inpatients with Raynaud’s phenomenon. Clin Phar-macol Ther 2007, 81(4):503–509.

This well-done mechanistic study in subjects with Raynaud’sphenomenon proved that clinical benefit with PDE5 inhibi-tors, if any, probably involves mechanisms other than acuteinhibition of cold-induced vasoconstriction.34. Caglayan E, Huntgeburth M, Karasch T, et al.:

Phosphodiesterase type 5 inhibition is a noveltherapeutic option in Raynaud disease. ArchIntern Med 2006, 166(2):231–233.

35.• Schiopu E, Hsu VM, Impens AJ, et al.: Randomizedplacebo-controlled crossover trial of tadalafil inRaynaud’s phenomenon secondary to systemicsclerosis. J Rheumatol 2009, 36(10):2264–2268.

This recently published, well-designed, double-blind studydemonstrated the lack of efficacy of oral tadalafil in improvingsubjective measures of Raynaud’s phenomenon in womenwith systemic sclerosis.36. Muller R: Pentoxifylline—a biomedical profile. J

Med 1979, 10(5):307–329.37. Nenci GG, Gresele P, Agnelli G, Ballatori E: Effect

of pentoxifylline on platelet aggregation.Pharmatherapeutica 1981, 2(8):532–538.

38. Neirotti M, Longo F, Molaschi M, et al.: Functionalvascular disorders: treatment with pentoxifylline.Angiology 1987, 38(8):575–580.

39. Goodfield MJ, Rowell NR: Treatment of peripheralgangrene due to systemic sclerosis with intrave-nous pentoxifylline. Clin Exp Dermatol 1989,14(2):161–162.

40. Korn JH, Mayes M, Matucci CM, et al.: Digital ulcersin systemic sclerosis: prevention by treatment withbosentan, an oral endothelin receptor antagonist.Arthritis Rheum 2004, 50(12):3985–3993.

41.• Garcia de la Pena-Lefebvre P, Rodriguez RS, ValeroEM, et al.: Long-term experience of bosentan fortreating ulcers and healed ulcers in systemic scle-rosis patients. Rheumatology (Oxford) 2008,47(4):464–466.

This recently published prospective, observational, noncon-trolled study reinforced the findings of RAPIDS 1 [40] thatbosentan is a safe and effective agent for long-term use inpreventing ischemic digital ulcers in scleroderma.42. Selenko-Gebauer N, Duschek N, Minimair G, et al.:

Successful treatment of patients with severe second-ary Raynaud’s phenomenon with the endothelinreceptor antagonist bosentan. Rheumatology (Oxford)2006, 45(Suppl 3):iii45–iii48.

43.• Sfikakis PP, Papamichael C, Stamatelopoulos KS, etal.: Improvement of vascular endothelial functionusing the oral endothelin receptor antagonistbosentan in patients with systemic sclerosis.Arthritis Rheum 2007, 56(6):1985–1993.

This recently published prospective study demonstrated thatbosentan improves endothelial function, indicating a direct,reversible effect of endothelin in scleroderma vasculopathy.44.• Hettema ME, Zhang D, Stienstra Y, et al.: No effects

of bosentan on microvasculature in patients withlimited cutaneous systemic sclerosis. Clin Rheumatol2009, 28(7):825–833.


This interesting short-term mechanistic pilot study demon-strated no significant changes in vasodilator responses, capil-lary permeability, or capillary density following bosentantreatment, suggesting that bosentan is ineffective in improvingmicrovascular structure and function in limited scleroderma.45. Russell IJ, Lessard JA: Prazosin treatment of

Raynaud’s phenomenon: a double blind singlecrossover study. J Rheumatol 1985, 12(1):94–98.

46. Wollersheim H, Thien T, Fennis J, et al.: Double-blind, placebo-controlled study of prazosin inRaynaud’s phenomenon. Clin Pharmacol Ther 1986,40(2):219–225.

47. Wise RA, Wigley FM, White B, et al.: Efficacy andtolerability of a selective alpha(2C)-adrenergicreceptor blocker in recovery from cold-inducedvasospasm in scleroderma patients: a single-center,double-blind, placebo-controlled, randomized cross-over study. Arthritis Rheum 2004, 50(12):3994–4001.

48. Clifford PC, Martin MF, Sheddon EJ, et al.: Treat-ment of vasospastic disease with prostaglandin E1.Br Med J 1980, 281(6247):1031–1034.

49. Mohrland JS, Porter JM, Smith EA, et al.: A multi-clinic, placebo-controlled, double-blind study ofprostaglandin E1 in Raynaud’s syndrome. AnnRheum Dis 1985, 44(11):754–760.

50. Dowd PM, Martin MF, Cooke ED, et al.: Treatment ofRaynaud’s phenomenon by intravenous infusion ofprostacyclin (PGI2).Br JDermatol 1982, 106(1):81–89.

51. Belch JJ, Newman P, Drury JK, et al.: Intermittentepoprostenol (prostacyclin) infusion in patientswith Raynaud’s syndrome. A double-blind con-trolled trial. Lancet 1983, 1(8320):313–315.

52. Wigley FM, Wise RA, Seibold JR, et al.: Intravenousiloprost infusion in patients with Raynaud phe-nomenon secondary to systemic sclerosis. Amulticenter, placebo-controlled, double-blindstudy. Ann Intern Med 1994, 120(3):199–206.

53. Gardinali M, Pozzi MR, Bernareggi M, et al.: Treatmentof Raynaud’s phenomenon with intravenous prosta-glandin E1alpha-cyclodextrin improves endothelialcell injury in systemic sclerosis. J Rheumatol 2001,28(4):786–794.

54. Chung L, Fiorentino D: A pilot trial of treprostinilfor the treatment and prevention of digital ulcers inpatients with systemic sclerosis. J Am Acad Dermatol2006, 54(5):880–882.

55. Tsukamoto H, Nagasawa K: Successful treatment ofRaynaud’s phenomenon with limaprost, an oral pros-taglandin E1 analogue. Br J Rheumatol 1991, 30(4):317.

56. Lau CS, Belch JJ, Madhok R, et al.: A randomised,double-blind study of cicaprost, an oral prostacyclinanalogue, in the treatment of Raynaud’s phenome-non secondary to systemic sclerosis. Clin ExpRheumatol 1993, 11(1):35–40.

57. Clagett GP, Sobel M, Jackson MR, et al.: Antithrom-botic therapy in peripheral arterial occlusive disease:the Seventh ACCP Conference on Antithrombotic

and Thrombolytic Therapy. Chest 2004,126(3 Suppl):609S–626S.

58. Denton CP, Howell K, Stratton RJ, Black CM:Long-term low molecular weight heparin therapyfor severe Raynaud’s phenomenon: a pilot study.Clin Exp Rheumatol 2000, 18(4):499–502.

59. Hart DA, Fritzler MJ: Regulation of plasminogenactivators and their inhibitors in rheumatic dis-eases: new understanding and the potential for newdirections. J Rheumatol 1989, 16(9):1184–1191.

60.• Van Beek AL, Lim PK, Gear AJ, Pritzker MR: Man-agement of vasospastic disorders with botulinumtoxin A. Plast Reconstr Surg 2007, 119(1):217–226.

This is a very well-written, recently published case series ofpatients with critical digital ischemia, all of whom failedaggressive medical therapy. Most of the patients had sclero-derma or mixed connective tissue disease. Treatment withperivascular injections of botulinum toxin A led to significantandpersistent pain reduction, spontaneousulcer healing, and adecrease in severity and frequency of Raynaud’s episodes.61. Montorsi W, Ghiringhelli C, Annoni F: Indications

and results of the surgical treatment in Raynaud’sphenomenon. J Cardiovasc Surg (Torino) 1980,21(2):203–210.

62. de Trafford JC, Lafferty K, Potter CE, et al.: An epi-demiological survey of Raynaud’s phenomenon.Eur J Vasc Surg 1988, 2(3):167–170.

63. Matsumoto Y, Ueyama T, Endo M, et al.: Endoscopicthoracic sympathicotomy for Raynaud’s phenome-non. J Vasc Surg 2002, 36(1):57–61.

64. Yee AM, Hotchkiss RN, Paget SA: Adventitialstripping: a digit saving procedure in refractoryRaynaud’s phenomenon. J Rheumatol 1998,25(2):269–276.

65. Tomaino MM, Goitz RJ, Medsger TA: Surgery forischemic pain and Raynaud’s phenomenon inscleroderma: a description of treatment protocol andevaluation of results.Microsurgery 2001, 21(3):75–79.

66. Kotsis SV, Chung KC: A systematic review of theoutcomes of digital sympathectomy for treatmentof chronic digital ischemia. J Rheumatol 2003,30(8):1788–1792.

67. Taylor MH, McFadden JA, Bolster MB, Silver RM:Ulnar artery involvement in systemic sclerosis(scleroderma). J Rheumatol 2002, 29(1):102–106.

68. Bunker CB, Reavley C, O’Shaughnessy DJ, Dowd PM:Calcitonin gene-related peptide in treatment ofsevere peripheral vascular insufficiency in Raynaud’sphenomenon. Lancet 1993, 342(8863):80–83.

69. Sambo P, Amico D, Giacomelli R, et al.: IntravenousN-acetylcysteine for treatment of Raynaud’s phe-nomenon secondary to systemic sclerosis: a pilotstudy. J Rheumatol 2001, 28(10):2257–2262.

70. Kuwana M, Kaburaki J, Okazaki Y, et al.: Increase incirculating endothelial precursors by atorvastatinin patients with systemic sclerosis. Arthritis Rheum2006, 54(6):1946–1951.


management of raynaud’s phenomenon in the patient with connective tissue disease

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