the subject of digital ischemia in systemic sclerosis is complex and poses various challenges in terms of diagnosis , classification , risk factors , therapy , and morbidity . raynaud 's phenomenon ( rp ) , characterized by exaggerated but reversible vasospasm in response to cold or stress , is the presenting symptom in over 90% of the patients with ssc . rp is the most common manifestation of the ssc - related endothelial dysfunction and digital ulcers ( dus ) are a clinical manifestation of ssc - related vasculopathy . digital ulcers in ssc are defined as necrotic lesions occurring at the distal aspects of fingers or toes . the underlying phenomenon is compromise of the arterial lumen which occurs as a combination of 2 major contributing factors :    vascular wall structural ( intimal proliferation ) and functional ( overproduction of vasoconstrictors ) abnormalities ,   a variable degree of intraluminal thrombosis . dus are painful , heal slowly , and lead to a great deal of disability . due to the inadequate blood supply and break in the skin , the ischemic lesions are prone to infection , loss of digital tissue , and progression to gangrene that requires amputation .    currently , there is no official algorithm for diagnosis and therapy of digital ischemia in ssc . a conventional therapeutic approach to digital lesions should include vasoactive medications , antiplatelet agents , antibiotics as needed , and analgesia . there is a visible need for strategies to facilitate healing of the dus and to prevent occurrence of new ones . the correct diagnosis of dus is instrumental both in clinical practice and in clinical trials focused on digital ischemia . almost all ssc patients experience involvement of their hands : ischemic lesions , local infection , calcinosis , and traumatic ulcers occurring in areas affected by flexion contractions . although the ssc - related vasculopathy affects the healing time of all the acral lesions , it is crucial to clinically define the true ischemic lesion . a recent study tested the intra- and interobserver variability in defining dus among clinicians with an interest in scleroderma . 50 individuals ( mostly rheumatologists ) were shown pictures of various hand lesions and were asked to qualify the lesions (  ulcer  versus  no ulcer  ) and if  ulcer  , to quantify it as  active  or  inactive  . although the intrarater reliability was high ( average kappa value of 0.81 ) , the interrater reliability was poor ( kappa coefficient of 0.46 ) , so individual examiners were consistent with their assessment , while different examiners disagreed . this lack of agreement among rheumatologists who evaluate digital lesions on a regular basis may have an impact on interpretation of the results of clinical studies and more so on initiating and maintaining treatment of dus in clinical practice . one of the more precise definitions of ssc - dus was described in the rapids-1 clinical trial . the definition was based on expert consensus and is currently used in the majority of trials focused on dus . digital ulcers are defined as a denuded area with well demarcated borders , involving loss of dermis and epidermis . they are located on the volar surface of the fingers , distal to the proximal interphalangeal joints ( figure 1 ) . the dus do not occur in the interphalangeal creases and should not be confused with paronychia , areas with underlining calcinosis , or traumatic lesions located on the dorsum of the hands ( pips or mcps ) ( figure 2 ) . a recent article focused on definitions and subclasses of ssc - dus ( 1614 digital lesions were prospectively observed over 4 years ) . the digital lesions were classified as digital pitting scars ( dpss ) , dus , calcinosis , and gangrene . clinical characteristics , depth ( superficial , intermediate , and deep ) and time to healing of the lesions were recorded . the digital lesions were located more frequently on the second and third digit and mostly on the fingertip area . presence of calcinosis , wet or dry necrosis , and infection significantly delayed the time to healing . in this study , the definition used for the  pure  dus matched the one from the rapids studies and the dus had a distinct natural history . the authors concluded that a precise classification of the subtype of digital lesion is important when different therapies are entertained : dus due to calcinosis may not be as responsive to vasodilators as a purely ischemic dus would be . it is believed that smooth muscle cells migrate into the intimal layer of the microvasculature and differentiate into myofibroblasts that secrete collagen and an other extracellular matrix . this process leads to a fixed narrowing of the intravascular lumen which hinders the blood flow and causes chronic tissue ischemia . histological studies showed that 18 ( 79% ) of the 23 evaluable biopsies of digital arteries of patients with ssc had greater than 75% luminal narrowing .    aside from the structural change , the endothelial cells are perturbed , possibly through ischemia - reperfusion injury or an autoimmune insult   leading to an increased production of vasoconstrictors such as endothelin and an underproduction of vasodilators such as prostacyclin and nitric oxide . one other possible consequence of the endothelial damage is platelet activation with release of thromboxane   which leads to intraluminal thrombosis . various studies have revealed that 15%25% of ssc patients have active dus   and 35%50% had a history of dus . dus are painful , disabling , and associated with a variable rate of progression to gangrene or infection leading to amputation . a particularly emergent situation is the ischemically threatened digit ( figure 3 ) due to the high rate of need for surgical intervention . although a prospective registry of patients with ssc - dus is lacking , the available data from retrospective analysis [ 11 , 12 ] outline the following risk factors for developing dus :   presence of pulmonary hypertension and/or lower dlco ,   diffuse subset of the disease ,   presence of antitopoisomerase i antibodies ( anti - topo i ) ,  
				 patients with dus developed internal organ involvement 2 - 3 years earlier compared to patients without ulcers . the use of nailfold videocapillaroscopy ( nvc ) may be a novel tool useful to predict development of ssc - dus : the specificity and sensitivity were as high as 85.9% and 94.3% , respectively . episodes of dus tend to reoccur , with 66% of patients having more than one episode and 50% having more than 2 episodes over a period of 7.26 years   despite the use of vasodilators . in the same cohort , the ulcers occurred   more frequently in the second and third digits ( ii : 32.5% , iii : 32.5% ) and were equally distributed among both hands . thirty patients ( 67% ) had critical finger ischemia at least once , and 43% of patients received at least one course of intravenous iloprost ; 7% of patients underwent surgical amputation . the disability measured by the scleroderma haq ( shaq ) was significantly greater in patients with persistent dus . patients also had more hospitalizations and more hospitalizations for antibiotics than patients without dus ( 16 versus 9% ) . the incidence of gangrenous lesions was 11% and increased with the length of time since the first dus , especially after 4 years . data from the randomized placebo - controlled study on prevention of dus in ssc ( rapids-2 ) trial conducted in 188 patients with active dus reported the incidence of amputation to be 11% ( 1 - 2%/patient - year of followup ) .   a retrospective analysis of all the hospitalized cases due to ischemically threatened digits ( itds ) over a period of 10 years in a tertiary care center identified 79 patients , of which 22.8% had ssc . in that particular cohort , the rate of amputation was 48.1% , and male sex , a history of previous it d , or it d developed in the hospital were associated with a higher rate of amputation . the pathogenesis of ssc - dus is complex , and it involves multiple pathways which need to be addressed concomitantly . response to the instituted medical therapy needs to be continuously assessed to detect the need for additional drug therapies or to consider surgical options .   the available clinical trials for treatment of active ssc - dus , although largely negative , have contributed to our knowledge about outcome measures in this disease . the crude measurement of the depth and length of dus is not feasible due to the location of the ulcerations and the associated pain . the only direct parameter remains the absolute healing of the dus , which includes an anatomical ( re - epithelialization of the area ) and a physiological ( pain cessation ) component . other indirect parameters , like instruments focusing on quality of life ( haq ) and function of the hand ( ukfs and the michigan hand questionnaire ) require further validation studies . the dus therapeutic approach includes : supportive measures , pharmacological interventions , and surgical options . patients who develop ssc - dus must be educated to keep their whole body warm ( not just the hands ) and to avoid direct trauma to the tips of the digits . pain related to ssc - dus is exquisite and lasts as long as the dus is active , which could be months . the intensity of the dus - related pain is significant and could lead to anxiety which potentially worsens the raynaud 's symptoms which in turn could contribute to a lengthier healing process . although the nonsteroidal anti - inflammatory drugs are very efficient , they should be avoided in favor of acetaminophen or opiates due to their vascular side effects . since the cause of the pain is tissue ischemia , the real solution is improving the oxygen delivery to the affected area .    infections are common in ssc - dus and heal slowly because of the poor circulation . clinical clues to dus infection are an increase in the amount of pain ( and a change of character to throbbing ) and presence of purulent discharge . simple gram positive coverage is usually very efficient but broad coverage antibiotics might be used if the ulcers are more extensive . if osteomyelitis is suspected , patients should be managed by a multidisciplinary team that includes infectious disease and orthopedic specialists . the purpose of the dus treatment is to reduce their overall burden and impact on quality of life . aside from controlling the pain and preventing infections , clinicians need to restore the hand function , improve the digital circulation , and promote healing of the existing dus while preventing formation of new ulcers . despite the substantial impact that ssc - dus have on function and quality of life , the treatment algorithm should mirror the pathogenesis of ssc - dus and should include antiplatelet agents and vasoactive agents . it has become common practice that patients with a history of dus or an active dus should take at least a low dose of aspirin ( 81  mg ) daily . clopidrogrel is being used with or without aspirin for active dus but there are no published data on safety and overall efficacy . vasoactive therapy includes the background therapy for raynaud 's phenomenon ( rp ) and agents from a few available classes that were shown to improve ssc - dus or are undergoing experimental trials . calcium channel blockers ( ccbs ) are widely used for the treatment of primary and secondary rp , reducing the severity of attacks by 35% . the effect of ccb on ssc - dus was reported in a small 16-week randomized controlled trial that compared oral nifedipine with intravenous iloprost : the mean number of ulcers decreased ( from 4.3 to 1.4 ) but there were no physiological changes in the microvasculatory blood flow or the temperature of the hands . phosphodiesterase-5 inhibitors ( pde5 inhibitors ) induce vasodilatation by increasing the levels of available endogenous nitric oxide ( no ) . the positive effect of sildenafil on rp was shown in a randomized controlled crossover study   and case reports and series indicate the benefit of sildenafil in ssc - dus [ 22 , 23 ] . an open label pilot study using a maximum dose of sildenafil in 19 patients with ssc - dus showed a total reduction of ulcers from 49 to 17 ( p < .001 ) after 6 months . shenoy et al . presented ssc - dus healing results in a crossover trial of tadalafil . this is contradicted by another randomized crossover trial of tadalafil in ssc - rp which showed no benefit of the drug over placebo . the role of pde5 inhibitors in ssc - dus needs to be further evaluated in prospective , randomized trials . the endothelial injury that is the hallmark of ischemic digital ulcers corresponds with an increase in levels of endothelin 1 ( et-1 ) [ 27 , 28 ] . et-1 is a potent vasoconstrictor that mediates its actions through two different receptors : endothelin type a ( et - a ) receptors are found on vascular smooth muscle cells while endothelin type b ( et - b ) receptors are found on both endothelial cells and vascular smooth muscle cells . bosentan is a receptor antagonist with activity against both types of receptors , et - a and et - b . anecdotal reports and case series have suggested that bosentan may be helpful in reducing ulcer size or improving healing [ 2931 ] . other studies have demonstrated an improvement in flow - mediated dilatation of microvasculature with bosentan therapy in patients with systemic sclerosis . the rapids-1 trial analyzed the effect of bosentan on the prevention and treatment of existing digital ulcers . this randomized , placebo - controlled study of 122 patients with systemic sclerosis and preexisting digital ulcers evaluated a primary outcome of bosentan on number of new digital ulcers during a 16-week study period .   patients were treated with bosentan 62.5  mg twice daily for four weeks then 125  mg twice daily for 12 weeks . while no significant difference was seen in healing of existing ulcers , there were significant differences in hand function and number of new ulcers in the treatment group ( 1.4 versus 2.7 ) . in the open - label extension of the study 88 patients continued bosentan for 12 additional weeks ( 57 of these patients were previously treated with bosentan for 16 weeks and so received a total of 28 weeks of treatment ) . at the end of the extension period , 65% of patients did not develop any new digital ulcers while 8% ( 7 patients ) developed more than two new ulcers . the mean number of new dus after 12 weeks of open - label therapy was 0.7 ( all subjects ) , 0.5 ( subjects previously on placebo ) , and 0.8 ( previously on bosentan ) . rapids-2 was designed to confirm the positive effects of bosentan at reducing new dus in 188 patients with at least an active ssc - dus over a variable treatment course . patients received 62.5  mg bosentan twice daily for 4 weeks then 125  mg twice daily for 20 to 32 weeks . none of the measures of digital ulcer healing differed between the two groups ( time to healing of a selected cardinal ulcer , time to healing of all digital ulcers , and percent of patients with complete healing ) . however , the total number of new ulcers during a 24-week followup period was 1.9 on bosentan and 2.7 on placebo ( p = .035 ) . unlike what is known of rp , there was no clear influence of season on ssc - dus , indicating that dus may be more related to the severity of vasculopathy . overall , oral bosentan at a dose of 125  mg twice daily had no effect on ulcer healing in patients with digital ulcers and ssc . although bosentan seemed to have lessened the ulcer burden in patients with more than four concomitant ulcers , it had no effect on rp . this case report of a 73-year - old patient with systemic sclerosis reveals that she was treated with both sildenafil and bosentan which resulted in complete healing of the digital ulcers . sitaxentan is a selective endothelin type a receptor antagonist that has been reported to help heal ssc - dus in case reports , but no randomized clinical trials are ongoing . prostacyclins are potent vasodilators that also inhibit platelet aggregation and smooth muscle proliferation in the blood vessels walls . various forms of prostacyclins are approved for use in idiopathic and connective tissue - related pulmonary arterial hypertension ( pah ) . epoprostenol is an intravenous prostanoid . in the pivotal randomized controlled trial of epoprostenol in patients with ssc - related pah , the patients on epoprostenol had 50% fewer new dus than those treated with conventional therapy , although no effect on healing of the existing dus was reported . iloprost is the most studied prostacyclin analog and is available in intravenous ( iv ) , oral , and inhaled formulations . outside the usa , cyclic use of intravenous iloprost is the standard of care for treatment of ischemically threatened digits and severe ssc - dus . the most important clinical trial supporting the use of iloprost was a 9-week , double - blind placebo - controlled multicenter trial in patients with ssc - rp . in this trial , the intervention consisted of iv iloprost 6-hours infusion ( dose of 0.52  ng / kg per minute ) for 5 days . a significant proportion of the patients receiving the active drug had at least 50% reduction in the number of dus . interestingly , although the dus healing was noted at earlier time points , the effect persisted at 9 weeks , suggesting a potential  reset  effect that iloprost might have on the endothelium . in this particular trial , a randomized controlled trial of oral iloprost at a fixed dose for patients with ssc - rp had negative results , most likely because there was no titration to the maximum tolerated dose . higher doses of iloprost may be more effective in ssc - rp at the expense of increased side effects . oral beraprost , another available prostacyclin analog , was evaluated in a randomized controlled trial for ssc - rp   and it showed a trend towards fewer new dus in the treatment group but no effect of the rp . a pilot study of subcutaneous treprostinil in patients with ssc - dus over a 12-week treatment period showed both healing and prevention of the dus but only a few subjects were able to tolerate the injection site pain . treprostinil diethanolamine ( tde - sr ) is an innovative salt form of treprostinil for oral delivery as a sustained release osmotic tablet for twice daily dosing . the pharmacokinetic profile of tde - sr in patients with ssc - dus is comparable to that of healthy controls   despite a variable degree of absorption related to ssc . an ongoing phase ii randomized , double blinded , multicenter clinical trial of oral treprostinil in ssc - dus is currently recruiting . it is well recognized that statins ( 3-hydroxy-3-methylglutaryl - coenzyme a reductase inhibitors ) have beneficial effects on ischemic vascular events and consequences of vascular injury . an open - label study of 14 ssc patients showed that 12 weeks of atorvastatin improved the raynaud 's severity and prevented new ssc - dus . a large randomized , double - blinded , placebo controlled study of 84 patients with ssc and history of dus showed a significant difference in the number of new dus in the treatment group compared to placebo over 4 months ( 1.6 versus 2.5 ) . significant improvement in the scleroderma health assessment questionnaire disability index ( shaq - di ) score and endothelial markers from the baseline was noted . the role of acei in the management of scleroderma renal crisis has changed the primary cause of mortality in ssc from renal to pulmonary complications . ace inhibition counteracts the renin - driven hypertension but it also improves endothelial function and promotes vascular remodeling in chronic hypertension .    a study of the long - acting acei , quinapril , used the rate of occurrence of new dus in patients with ssc as primary outcome . this was a multicenter , randomized , double - blind , placebo - controlled study of quinapril at 20  mg daily for at least 2 years but not more than 3 years . of the 213 patients enrolled , 109 patients were followed for the full 3 years . at the end of the study there was no difference between the treatment and the placebo group in the number of new dus , the total number of dus , and measurements of rp ( frequency and severity ) . as the authors commented , the lack of therapeutic effect was not attributable to insufficient statistical power .   in a randomized 12-week trial comparing nifedipine to losartan , an arb , in patients with primary and secondary rp ( total number of patients of 52 ) , this study focused mainly on rps and there was no mention of ssc - dus . n - acetylcysteine ( nac ) is the precursor of a major antioxidant , glutathione , and may have beneficial effects in ssc - dus due to its vasodilating properties and impact on platelet aggregation . a pilot study of intravenous nac in 20 patients with ssc - dus showed that more than half of the dus present at baseline completely healed after the 5-day infusion . the median treatment was 3 years , and the mean of ulcers / patient / year decreased significantly from 4.5 to 0.81 with minimal reported side effects . although promising , in order to better establish its use in ssc - dus , this agent should be evaluated in a prospective , placebo controlled , randomized fashion . vitamin e has been used for chronic cutaneous lesion and ulceration treatment based on its antioxidant and anti - inflammatory effects . an open - label study of 27 patients with ssc - dus randomly assigned 15 subjects to vitamin e gel . patients treated with vitamin e experienced significantly reduced healing time ( 13.2 versus 20.0 weeks , p < .0001 ) when compared to controls and improved pain resolution ( p = .0022 ) . surgical options are reserved for treatment of severe or recurrent dus that are recalcitrant to medical therapy . available procedures are microsurgical revascularization of the hand and digital sympathectomy . since the size of the blood vessels involved in the pathogenesis of ssc - dus is usually small , revascularization is not readily applicable . sympathectomies are aiming to block the sympathetic nerve - mediated vasospasm which is thought to have an important role in digital ischemia . local digital sympathectomy has the advantage of interrupting the sympathetic fiber more distally . during digital sympathectomy , the adventitia is excised , removing sympathetic fibers contained in the adventitia and most likely , the media . this procedure has been shown to help healing of ssc - dus , improvement in pain , and prevention of new dus for a mean of 31 months after the surgery . the results of digital sympathectomies in patients with connective tissue disorders may not be as favorable as in patients with other diagnoses . although the microvascular involvement in ssc is well known , there are reports of macrovascular involvement as well . a small study   of 8 patients with dus or gangrene related to ssc found macrovascular involvement of the ulnar artery ( 3 patients ) and radial artery ( 1 patient ) by arteriography . a larger retrospective study identified 12 ( 63.2% ) of 19 patients with ssc who underwent brachial arteriography to have ulnar artery involvement ( occlusion and/or stenosis ) . potential for revascularization in selected ssc patients with arteriographic evidence of ulnar involvement was shown in a retrospective chart review : 15 patients with ssc - dus and ulnar artery occlusive disease confirmed by angiography were reviewed . eight patients who underwent ulnar revascularization combined with digital sympathectomy had improvement in the healing of the ulcers . the current evidence is limited but there is a role for brachial arteriography in selected patients with ssc - dus to diagnose macrovascular involvement . more interventional trials are needed to assess the efficacy of ulnar revascularization in ssc - dus prevention and treatment . a precise definition of the ssc - du would be useful for the research community and also in clinical practice . the effect on function and quality of life of the ssc - du is significant , so therapies focused on rapid healing and prevention of new ulcers are needed . although patients note reduced pain and improved function when exposed to parenteral agents like iloprost , the more subtle agents that seem to be better at prevention ( e.g. , bosentan ) offer very little benefit on pain and quality of life . important clinical trials of oral or topical drugs with overall burden of the ssc - dus as main outcome measure are ongoing .
systemic sclerosis ( scleroderma , ssc ) is a disease of unknown etiology characterized by widespread vasculopathy and extracellular matrix deposition leading to fibrosis and autoimmune processes . digital ischemia ( digital ulcers ( dus ) ) 
 is the hallmark of ssc - related vasculopathy and is characterized by endothelial dysfunction leading to intimal proliferation and thrombosis . 
 it happens frequently ( 30% of the patients each year ) and it is associated with significant morbidity . 
 this paper summarizes the current information regarding pathogenesis , definitions , management , and exploratory therapies in dus associated with ssc .