Management of Digital Ischemia


Differential diagnosis

Characterization

Connective tissue diseases

Digital artery fibrosis and hyperplasia leading to vascular occlusion.

Scleroderma

Systemic lupus erythematosus

Mixed connective tissue disease

Vasculitis

Inflammation and fibrinoid necrosis of vascular walls.

Arteriopathies

Insidious widespread arterial disease. Particularly within the retinal, cerebral, coronary, pulmonary, and renal circulations in addition to the limbs and digits.

Occupational diseases

Embolization to digital arteries resulting from constant force or pressure to the ulnar artery.

Paraneoplastic syndrome

Rapid ischemic onset due to impaired anticoagulant and fibrolytic pathways in the presence of cancer.

Steal phenomenon after vascular access shunts

Abnormal blood flow after radial artery shunt placement. Frequently accompanied by numbness and parathesia.

Iatrogenic after radial artery cannulation

Partial or complete vascular occlusion from indwelling catheters.

Septic shock

Decreased peripheral tissue perfusion after severe infection.

Anatomic variants

Abnormal vascular flow due to abnormal arterial anatomy.





Connective Tissue Diseases


Connective tissue diseases are chronic autoimmune diseases that can result in inflammation and vascular pathology. In one study of 50 patients with digital ischemia, connective tissue disease was the predominant underlying disease, associated with 38 % of cases [2]. Forms of connective tissue disease that can present with digital ulcers include systemic sclerosis (SSc), systemic lupus erythematosus (SLE), and mixed connective tissue disease (MCTD) [2]. Digital ulcers and ischemia can occur in up to 50 % of SSc patients over the course of their disease [3]. Although clearly less common than in SSc, the exact incidence and prevalence of digital ischemia are currently unknown in SLE and MCTD patients [4, 5]. SSc is characterized by cutaneous and visceral fibrosis, in addition to vascular disease that involves the arterioles and arteries of the peripheral circulation [1]. Histologically, the digital arteries in patients with SSc are characterized by intimal hyperplastic or fibrotic proliferation, resulting in extensive luminal narrowing (Fig. 21.1) [6, 7]. Digital artery thrombosis can also occur, further compromising the peripheral circulation, leading to both chronic and acute episodes of digital ischemia [8]. The majority of studies on the management of digital ulcers and ischemia summarized below have included patients with SSc.

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Fig. 21.1
Digital artery from a patient who has SSc (amputation specimen) showing marked intimal hyperplasia and almost complete occlusion of the lumen (Reproduced with permission from: Herrick, A. (2008). “Diagnosis and management of scleroderma peripheral vascular disease.” Rheumatic Disease Clinics of North America 34(1): 89–114)


Vasculitis


Vasculitis occurs when there is inflammation and fibrinoid necrosis of blood vessel walls [9, 10]. This leads to vessel destruction and subsequent hemorrhagic and ischemic damage [11]. In addition to affecting the larger blood vessels, inflammation can occur in arterioles, venules, and capillaries. However, digital ischemia typically occurs in association with large or medium vessel vasculitis. Primary vasculitides that can be associated with digital ischemia include giant cell arteritis or Takayasu’s arteritis which affect large vessels; polyarteritis nodosa which affects medium vessels; and anti-neutrophilic cytoplasmic antibody (ANCA)-associated vasculitis, cryoglobulinemic vasculitis, and connective tissue disease-associated vasculitis which can affect small and medium sized blood vessels [12].


Arteriopathies


The most common cause of peripheral vascular disease is obstructive atherosclerosis of the extremities. Atherosclerosis is considered to involve an inflammatory component which may be in part immune-mediated [13]. Traditional risk factors are well known including age, gender, family history, diabetes mellitus, hypertension, hyperlipidemia, cigarette smoking, and obesity with metabolic syndrome [14, 15]. Atherosclerotic plaque can cause stenosis or occlude peripheral vessels causing claudication with physical activity or it can cause cutaneous ulceration. Thrombosis, embolism, and vascular dissection are complications that can cause digital ulcers or peripheral skin ulcerations. In patients with other vascular diseases, underlying larger vessel atherosclerosis is a common complicating factor that must be appreciated and addressed. The prevalence of atherosclerotic cardiovascular disease has been found to be higher in patients with SSc than in the general population [15, 16]. Although the exact mechanisms are unknown, this increased rate may be secondary to the chronic inflammation, altered lipid profiles and function, development of autoantibodies, and vascular dysfunction found in SSc [15].

Fibromuscular dysplasia (FMD) is a systemic arterial disease that is noninflammatory and nonatherosclerotic [17]. FMD has an unknown etiology but has been suggested to be due to hormonal, mechanical or genetic causes [17, 18]. It typically affects the renal and carotid arteries, but can also affect the small arterial beds where it manifests as lesions in the middle or distal arterial segments. Although uncommon, case studies have reported digital ischemia in patients with brachial artery FMD [1921]. FMD predominantly presents in young female adults who are suffering from renal hypertension [18].

Degos disease (also called malignant atrophic papulosis) is a rare condition that can be purely cutaneous (small, white, and firm papules), or that can present as a systemic variant with cutaneous manifestations [22]. The pathogenesis is unknown [2225]. The systemic variant has a high morbidity and can affect the nervous, ophthalmological, gastrointestinal, cardiothoracic, and hepatorenal systems. It has been suggested that the skin lesions of Degos disease are secondary to the slow occlusion of deeper arterioles [25], which can ultimately cause digital ischemia. Histologic findings in one small study noted that all patients with Degos syndrome had varying degrees of lymphocyte-mediated necrotizing vasculitis [24].


Occupational Diseases [See Chap. 9]


Blunt or penetrating injury can lead to vascular trauma and complications of digital ulcerations. Hypothenar hammer syndrome (HHS) is a condition resulting from constant pressure or vibrational force to the ulnar artery. Embolization to digital arteries from the injured ulnar artery can cause unilateral finger ischemia [26]. Occupations that require repetitive movement in which the palm is used as a hammer, such as carpenters, machinists, and mechanics, are most susceptible to digital ischemia related to injury of the ulnar artery [2628]. The incidence of HHS in these occupations is estimated to be 14 % [29]. Symptoms associated with HHS range from mild pain or cold sensitivity to digital gangrene. It has been suggested that individuals who develop HHS may have a preexisting abnormality of their ulnar artery, making it more susceptible to digital artery embolization from traumatic injury [26]. Identifying HHS can be difficult, and it is believed to be underdiagnosed [30]. A thorough patient history for occupation, hobbies, and previous hand trauma is important to properly diagnose the disease [31].


Paraneoplastic Syndrome


Malignant disease can be associated with digital ischemia, and has been reported with a variety of cancers including those of the kidney, ovary, colon, and pancreas [3234]. Although digital ischemia as a paraneoplastic syndrome has been reported in a number of case studies, the prevalence is unknown [32, 3537]. Factors that may contribute to cancer-related ischemia include tumor cell infiltration, impaired blood flow due to hyperviscosity, an increase in circulating coagulant factors, and impaired anticoagulant and fibrinolytic pathways. Tumor antigen–antibody immune complexes can also cause arterial microvascular thrombosis [38]. Generally, onset is sudden and can be rapidly progressive [32]. In some cases, symptoms reduce after therapy for the primary tumor [3941].


Steal Phenomenon After Vascular Access Shunts


If a patient has recently received shunt placement, steal phenomenon should be considered as a possible mechanism for digital ischemia. Placement of upper limb arteriovenous accesses for hemodialysis has been reported to induce hand ischemia in 1.6–8 % of hemodialysis patients [4244]. With vascular steal, extremity ischemia can occur when significant arterial blood flow is shunted directly into the venous outflow of an arteriovenous fistula or graft but a portion of the collateral flow to the distal extremity is taken by the access [43]. Vascular steal can range in intensity. In mild cases, onset is insidious and can be delayed by a few days to a few months. Symptoms include numbness and paresthesia of one or more fingers. Pain, stiffness, and swelling of the fingers may also occur [42]. In severe cases, there is progressive numbness and pain, accompanied by reduced sensation, ischemic ulcers, and dry gangrene of the fingers [42, 44]. Confirmation of the diagnosis is made with digital plethysmography/pulse volume recordings that document digital pressures less than 50 mmHg and augmentation of the pulse wave with fistula compression [42].


Iatrogenic After Radial Artery Cannulation


Although an uncommon complication, ischemic damage from radial artery cannulation may occur [45, 46]. Radial artery cannulation is a procedure that allows precise measurement of blood pressure, blood gases, arterial pulse contour, and cardiac output, and is particularly useful when managing critically ill patients and individuals who will be undergoing major surgery. However, indwelling catheters have been reported to create partial or complete vascular occlusion that results in ischemia and at times gangrene of a digit or hand. Autoimmune diseases, vasospastic conditions such as Raynaud’s phenomenon (RP), severe arteriosclerosis or ischemic disease, and thrombotic tendency have all been identified as risk factors for cannulation complications [46].


Septic Shock


Septic shock occurs when the systemic response to infection leads to hypotension and organ dysfunction [47]. Septic shock is characterized by decreased peripheral tissue perfusion, abnormal cellular metabolism, and misdistribution of blood flow due to vessel constriction, all of which can lead to digital ischemia [48].


Anatomic Variants


Abnormal anatomic structures may influence the occurrence of digital ischemia. Variations in the arterial anatomy of the upper extremities are found in as many as 24 % of patients and are most common in the radial or ulnar artery [49, 50]. Anatomic variation can be observed by arteriogram. Anatomic arterial contribution to abnormal blood flow should be assessed prior to determining the best therapy for digital ulceration [50].


Digital Ulcers



Definition


Digital ulcers (DU) are denuded areas with a defined border, loss of epithelialization, and loss of epidermis and dermis [51]. DU do not include fissures (Fig. 21.2) or paronychia (Fig. 21.3). DU can be related to ischemic causes, from severe recurrent vasospasm related to RP and underlying vascular pathology. Other contributing factors include trauma or underlying calcinosis (Fig. 21.4). They typically present as painful sores on the fingers or toes (Fig. 21.5), but can also occur over the interphalangeal joints of the hands, or other extensor surfaces (Fig. 21.6) [52]. DU can also be partially or completely covered with crust, hyperkeratosis, or fibrin. Chronic ulcers can progress to gangrene, loss of distal tissue, or become infected and lead to osteomyelitis [52].

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Fig. 21.2
(a) Dryness, scaling, and fissuring of the fingers from dehydration related to obliteration of adnexal structures; (b) Fissure of the skin on distal finger


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Fig. 21.3
Chronic paronychia is common due to loss of a functional barrier at the nail fold


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Fig. 21.4
(a) Ulceration over first fingertip related to the presence of calcinosis, (b) X-ray showing subcutaneous calcinosis in fingertip


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Fig. 21.5
Ulceration at fingertips


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Fig. 21.6
Ulceration over the right third distal interphalangeal joint with overlying crust


Pathophysiology


Ischemic DU are a consequence of multiple factors. Although the vasospasm associated with RP is reversible, recurrent and prolonged episodes may contribute to ischemic damage to distal tissues. In addition, vascular injury can result in endothelial dysfunction and abnormal vascular reactivity. For example, increased levels of vasoconstrictors (endothelin-1) and decreased levels of vasodilators (nitric oxide and prostaglandin) are thought to lead to decreased perfusion of the digits in patients with SSc. Finally, the lumen of digital arteries in patients with SSc is compromised due to thrombosis [51] and fibrosis of the intimal layer [53]. Progressive occlusion of arteries from thrombosis can occur in other diseases associated with DU.


Prevention and Treatment of DU


Although treatment with a variety of vasodilators has been shown to be effective in managing RP, DU remain a serious complication for many patients, and a uniform effective therapy is lacking [53]. Below, we will address non-pharmacologic and pharmacologic therapies targeted to treat DU, as well as surgical options. It is important to note that most of the clinical trials investigating agents used to prevent or heal DU have been done in patients with SSc. Therefore, the benefit or not of a given agent in other vascular diseases causing DU is unclear. It is also important to address the underlying cause of the vascular disease with specific therapy if possible. For example, active vasculitis may need corticosteroids or immunosuppressive therapy to control the inflammatory component of the vascular insult.


Non-pharmacologic Therapy


The management of DU includes non pharmacological modalities, including the avoidance of all inciting factors such as cold exposure, emotional distress, smoking, repeated trauma of hands, and some drugs [54], specifically pharmacologic vasoconstrictors such as smoking, cocaine, and sympathomimetics [55]. In patients with scleroderma (SSc), physical therapy is important in improving joint contractures of the digits where abnormal skin stretched over an immobile joint often leads to a trauma-induced DU [1] (Fig. 21.7).

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Fig. 21.7
(a) A traumatic ulcer over the proximal pharyngeal joint in the middle finger, (b) A traumatic ulcer over the proximal pharyngeal joint in the ring finger

Keeping the affected area clean is of utmost importance to promote healing and prevent infection. Also, patients should minimize trauma to their digits as much as possible. Hydrocolloid membranes such as Duoderm can provide protection from repeated trauma and also accelerate DU healing and reduce pain [56]. These dressings decrease oxygen tension and preserve moisture over the damaged area, promoting growth of granulation tissue and the epidermal and dermal layers of the skin [1]. Duoderm is a polyurethane film coated with a strong adhesive that protects skin from bacteria and serves as a barrier against further injury. We use the following approach for the application of Duoderm. First, we recommend cleaning the area over the ulcer with hydrogen peroxide 3 % or an antibacterial soap, drying, and covering with antibacterial ointment, being careful not to get the greasy ointment where the adhesive will be placed. Duoderm should be cut approximately 1/2–1 in. beyond the wound’s margin and applied to the wound after peeling off the adhesive. Tape may be used around the edges of the dressing to aid keeping it in place. The Duoderm dressing should be changed and cleaned every third day, or sooner if the dressing is oozing a lot of fluid.

The removal of damaged tissue can be helpful in improving the healing potential of remaining tissue [57]. Debridement can be performed if the DU appears to be superficial and there is no deep infection or exposed bone [58]. Surgical debridement may be indicated for deeper lesions [see Chap. 22].


Pharmacologic Therapies



Optimization of Raynaud’s Phenomenon (RP) Therapy


We often use pharmacologic agents to treat RP either alone or in combination for the treatment and prevention of DU since RP contributes to the development of ischemic DU, and the majority of validated outcome measures used in DU clinical trials are borrowed from studies of RP [1, 59]. We will focus on treatments that have shown some efficacy specifically for DU. Please refer to Chap. 15 for details on RP management.

Calcium channel blockers (CCBs): CCBs are moderately effective in the treatment of RP, reducing the severity of attacks by 35 % in secondary RP [60] and by 33 % in primary RP [61]. In addition, one study demonstrated a significant reduction in the number of DU compared to baseline after 16 weeks of nifedipine, as compared to intravenous infusions of iloprost, but without change in hand temperature or digital microcirculatory blood flow [62]. Another study compared nifedipine to placebo in the treatment of RP [63] and found no statistically significant difference in the prevention of new DU; however, the trial was underpowered since few new ulcers developed [64]. CCBs may potentially be useful as “background” therapy in patients with DU, and most randomized controlled trials (RCT) for DU permit CCB use at stable doses throughout the studies [52].

Alpha-adrenergic inhibitors: Two RCT showed that prazosin is more effective than placebo in the treatment of RP secondary to SSc [65] and one observational study found that terazosin reduced the number, intensity and duration of vasospastic attacks to the hands in patients with idiopathic and secondary RP [66]. However, although they may reduce RP, alpha-adrenergic blockers have not been directly studied for DU treatment [59].

Angiotensin converting enzyme (ACE)-inhibitors and angiotensin receptor blockers (ARBs): Similarly, ACE-inhibitors and ARBs have limited benefit in the treatment of RP secondary to SSc, but studies evaluating their effects on DU are lacking [1]. One multicenter, randomized, double blind, placebo controlled study included 210 patients with limited scleroderma or with RP and the presence of SSc-specific antinuclear antibodies. This study found that quinapril 80 mg/day, or the maximum tolerated dosage, did not affect the occurrence of new DU or the frequency or severity of RP episodes over a 3-year follow-up period [67].

Nitroglycerin ointment or patches: Nitrates are used in topical, sublingual, or oral formulations, as adjunctive therapy in the treatment of RP and DU in SSc [1], but there is no evidence supporting their role in DU healing [54]. One double blind, placebo-controlled, randomized trial showed that a short-acting topical nitroglycerin gel was more effective than placebo for the treatment of RP but did not prevent new DU [68].

Selective serotonin reuptake inhibitors (SSRI): A small study of 26 patients with primary and 27 patients with secondary RP suggested that SSRI are more effective than nifedipine in reducing the frequency and severity of RP, particularly in female patients and those with primary RP [69]. However, no studies have evaluated the effect of SSRI on the treatment and prevention of DU [59].


Other Vasoactive Drugs


Endothelin-1 receptor antagonists Endothelin receptor antagonists (ETRA) are a class of pulmonary arterial hypertension (PAH)-specific drugs that block the interaction of Endothelin-1 (ET-1) with its receptors (ETA and ETB) interfering with its vasoconstrictive effects [70]. ETA receptors are located on vascular smooth muscle cells and primarily mediate vasoconstriction while ETB receptors are located on endothelial cells mediating vasodilatation by release of nitric oxide and prostanoids, and also on smooth muscle cells mediating vasoconstriction [71]. ET-1 is also noted to promote cell growth and proliferation and thus can also mediate vascular and tissue fibrosis and remodeling.

Bosentan The dual endothelin-1 receptor antagonist bosentan has been shown to prevent the development of new SSc-related DU in two randomized, double-blind controlled clinical trials [53, 72]. In the RAPIDS-1 trial, which included 122 patients with SSc, bosentan 62.5 mg twice daily for 4 weeks and thereafter 125 mg twice daily reduced the occurrence of new ulcers by 48 % after 16 weeks of treatment, particularly in patients with diffuse skin involvement, non-smokers, and patients with a high burden of DU. A slight trend toward slower healing was observed in patients treated with bosentan, but this did not reach statistical significance. RAPIDS-2, which enrolled 188 patients with SSc, confirmed the results of the previous RAPIDS-1 trial: 24 weeks of bosentan therapy was associated with a reduction in the number of new DU compared to placebo, but did not lead to more rapid ulcer healing. The most common side effect among patients treated with bosentan was elevation of liver enzymes, which was reported in 11.4–12.5 % of patients treated in clinical trials [64]; thus its use requires monthly liver function test monitoring. The FDA approved bosentan in the USA in November 2001 for the treatment of WHO functional class III/IV PAH, and in 2009 for the treatment of WHO functional class II PAH, while the EU approved it for PAH in May 2002. In June 2007, the EU extended the indication for bosentan as a therapy to reduce the number of new DU in patients with SSc and ongoing DU disease [70].

Ambrisentan Although evaluated in only a small number of patients, this ETA selective ETRA showed a reduction in the total number of DU in two open-label studies [73, 74]. In the first one, six patients with SSc with DU unresponsive to bosentan were treated with 5 mg daily of ambrisentan for 24 weeks. The recruited patients continued to receive intravenous therapy with prostanoids. Ambrisentan led to a reduction in baseline number of DU per patient with no appearance of new lesions [73]. In the second study, up to 10 mg daily as tolerated of ambrisentan significantly decreased DU burden and mean maximum diameter of lesions after 24 weeks of therapy in 20 patients with SSc. Ambrisentan did not prevent the incidence of new DU and no patients developed elevated transaminases, but 75 % experienced peripheral edema [74]. Ambrisentan does not require monthly liver function test monitoring, is given once daily, and two doses are available (5 and 10 mg). It is approved for the therapy of SSc-associated PAH in the USA, but has not been evaluated in RCT for the prevention and treatment of DU.

Macitentan Macitentan is a dual endothelin-receptor antagonist, developed by modifying the structure of bosentan to increase efficacy and safety. Macitentan was FDA-approved for the treatment of WHO functional class II-IV PAH in October 2013 at a dose of 10 mg once daily. Liver enzyme abnormalities occurred in a similar percentage of patients receiving placebo and macitentan in the PAH trial, but higher percentages of patients in the two macitentan groups had nasopharyngitis, headache, and anemia [75]. There are two ongoing multicenter randomized double-blind placebo controlled parallel group studies aimed to evaluate the effectiveness of macitentan in the prevention of new DU at 16 weeks. Although preliminary data analysis led to the early termination of these trials due to a lack of efficacy over placebo, results of final analyses are pending.

Phosphodiesterase inhibitors By inhibiting the hydrolysis of cyclic guanosine monophosphate (cGMP), agents in this class increase cGMP levels, with consequent vasodilatory, antiproliferative, and pro-apoptotic effects that may reverse pulmonary artery remodeling. Studies have suggested these agents may have a role in the treatment and prevention of DU, but solid evidence is lacking. Common side effects of these medications include headaches, dizziness, dyspepsia, and nasal congestion.

Sildenafil One open uncontrolled study of 16 patients with SSc treated with maximally tolerated doses of sildenafil (mean 114 mg daily for mean 5.2 months), and concomitant vasodilators and platelet inhibitors showed a significant decrease in the total number of DU. However, nine patients developed 12 new DU despite sildenafil therapy [76]. One double-blind placebo-controlled study, which did not measure DU outcomes, included 57 patients with limited cutaneous SSc and showed that 100 mg once daily for 3 days followed by 200 mg once daily for 25 days of modified-release sildenafil reduced RP frequency and was well tolerated [77].

Tadalafil One study concluded that tadalafil as add-on therapy may contribute to DU prevention and healing. 24 patients with SSc or mixed connective tissue disease were treated with 20 mg of tadalafil every other day or placebo for 6 weeks and then crossed over, with concomitant vasodilators (CCBs, ACE-inhibitors, and ARBs) and platelet inhibitors. All 24-fingertip ulcers healed during tadalafil compared to 3 of 13 during placebo treatment. Tadalafil also significantly prevented the appearance of new DU (1 during tadalafil treatment versus 13 during placebo) [78]. However, another randomized, double-blind, placebo-controlled, crossover study of 39 women with RP secondary to SSc receiving 20 mg of tadalafil daily or placebo for a period of 4 weeks showed that tadalafil lacked efficacy as a treatment for RP. There were too few DU in this study population to analyze the role of tadalafil in DU healing or prevention [79].


Prostacyclins


Prostacyclins are potent pulmonary and systemic vasodilators that also inhibit platelet adhesion and aggregation, and smooth muscle cell proliferation in the blood vessels [59, 80]. Common side effects of these medications include hypotension, dizziness, headache, flushing, jaw pain, and gastrointestinal symptoms [81].

Oral Prostanoids Overall, oral forms of prostanoids have not shown benefit in the treatment of DU. In one meta-analysis [64], none of the following studies showed a statistically significant difference in DU healing individually or in pooled analyses, and side effects were more common in subjects who received oral prostanoids compared to the placebo subjects.

Iloprost Although no studies have evaluated the effects of oral iloprost on DU, one study showed that oral iloprost at a dose of 50 mcg twice daily did not significantly improve RP compared to placebo [82]. Higher doses of oral iloprost may be more effective for the treatment of RP and potentially DU, but with increased side effects that may limit tolerability [59].

Beraprost In a study of 107 patients with SSc, the oral prostacyclin analog beraprost sodium at a dose of 60 μg three times daily, showed a trend towards fewer new DU compared to placebo [83]: 48 % of patients had new ulcers in the beraprost group versus 59 % in the placebo group (p = 0.325), but this has not been confirmed in further studies.

Cisaprost Cisaprost, another oral prostacyclin analog showed a trend for minimal improvement in efficacy when given orally at a dose of 2.5 or 5 μg three times daily for the treatment of RP secondary to SSc. This 4-month randomized, double-blind, placebo-controlled study involving 49 patients found that there were not statistically significant differences in the median change from baseline in the total number and duration of attacks, the number of painful attacks and the average severity of attacks between the three groups. However, cisaprost given at 5 μg three times daily produced a greater decrease in severity of RP at week 2 (p = 0.02). There were no significant changes in the number of active DU throughout the study between the three groups, but only five patients had DU at the time of enrollment [84].

Treprostinil A study of 148 subjects with DU showed that the administration of the oral prostacyclin analog treprostinil as a sustained-release osmotic tablet up to 16 mg twice daily for 20 weeks did not result in a statistically significant reduction in net ulcer burden when compared to placebo [85].

Systemic prostanoids Prostanoids delivered systemically, either by intravenous or subcutaneous administration, appear to be more effective for the treatment of DU than oral formulations likely related to better absorption. Intravenous prostanoids, in particular iloprost, are approved in the EU and recommended for the treatment of DU in patients with SSc [86].

Intravenous iloprost Intravenous iloprost (0.5–2 ng/kg per minute for 3–5 consecutive days) significantly improved DU healing, particularly for ischemic digital tip ulcers, in comparison with placebo in two RCT including 35 and 131 SSc patients, respectively [87, 88]. A third small RCT including 17 patients treated over the course of 4 months with monthly 3-h intravenous infusion of 0.5–2.0 ng/kg/min of iloprost or placebo did not find statistically significant differences [89]. In addition, two RCT comparing intravenous iloprost to oral nifedipine for the treatment of RP showed a beneficial effect on DU healing in both groups, but the number of patients with DU was small [62, 90]. The first one included 23 patients with SSc-related RP and the mean number of digital lesions was reduced with iloprost from 3.5 to 0.6 and with nifedipine from 4.3 to 1.4 after 16 weeks. The second study included 46 patients with SSc-related RP, 17 patients had DU at entry into the study. Among these, all the patients treated with nifedipine (3/3) and 12 out of 14 of those treated with iloprost decreased the number of DU after 12 months. In contrast, one meta-analysis showed that intravenous iloprost was beneficial for the prevention of new DU, but did not affect DU healing [64]. Long-term low-dose iloprost (0.5 ng/kg per minute) has been shown to be equally effective and less harmful than high-dose (2 ng/kg per minute) when given for 21 days, with both regimes reducing DU in 70 % of treated patients [91]. There is currently no generally accepted dosage scheme for the administration of iloprost [92]. We recommend the use of 0.5–2 ng/kg per minute for 3–5 consecutive days, then reassessing response for additional infusions.

Intravenous epoprostenol In one study that did not report effects on healing of existing ulcers, intravenous epoprostenol administered continuously for severe SSc-related pulmonary arterial hypertension tended to reduce the number of new DU when compare to conventional therapy [93]. Although not FDA approved for the treatment and prevention of DU, epoprostenol could potentially be used in a similar fashion to intravenous iloprost for the management of DU and digital ischemia.

Subcutaneous Treprostinil Treprostinil is a prostacyclin analog that is currently approved for the treatment of PAH in subcutaneous, intravenous, and oral formulations. In one small study, subcutaneous treprostinil was effective in both the healing and prevention of DU in patients with SSc [94]. However, only 5 of 12 patients were able to tolerate the medication due to severe injection site pain. Intravenous treprostinil has not been evaluated for the treatment of DU.

Anti-platelet Agents: Although a double blind controlled study of aspirin in combination with dipyridamole showed no benefit on RP or DU compared to placebo [95], 81 mg of aspirin daily is often prescribed for patients who do not have a contraindication, keeping in mind that patients with SSc often have gastrointestinal involvement and are at increased risk of side effects [96]. Cilostazol and its metabolites are inhibitors of phosphodiesterase III that increase cyclic adenosine monophosphate (cAMP) levels leading to reversible inhibition of platelet aggregation, vasodilation, and inhibition of vascular smooth muscle cell proliferation [97]. Pentoxifylline reduces blood viscosity and improves peripheral tissue oxygenation presumably through enhanced blood flow increasing leukocyte and erythrocyte deformability and decreasing neutrophil adhesion/activation [98]. A systematic review and network meta-analysis of 26 RCTs evaluated the efficacy and tolerability of cilostazol and pentoxifylline in patients with intermittent claudication due to peripheral arterial disease and found that cilostazol increased maximum and pain-free walking distance with minimal serious adverse events [99]. Although there is biologic rationale to use these agents for the treatment of DU, there is currently no strong evidence supporting their use for this indication. One small study of 11 females with primary RP treated with pentoxifylline 400 mg tid for 2 months showed photoplethysmographic improvement of peripheral blood flow and decrease in duration and frequency of attacks [100].

Statins: Extensive research suggests that the clinical benefits of statins are related to an improvement in vascular function and inhibition of smooth muscle proliferation [101], a reduction in blood thrombogenicity, anti-inflammatory properties, and immunomodulatory actions [102]. One single study involving 84 SSc patients showed that 12 weeks of atorvastatin therapy reduced RP and prevented new DU in comparison to placebo, without statistically significant differences in DU healing [102].

Botulinum toxin: The local administration of botulinum neurotoxin type A is thought to increase blood flow as a result of arteriolar vasodilation through sympathetic blockade [103]. One study of 26 patients found that the use of botulinum toxin type A (BTX-A) injection in patients with recalcitrant ischemia resolved pain in 75 % of patients; improved color in 57 % of patients, and improved transcutaneous oxygen saturation in 56 % of patients. A single treatment with BTX-A resulted in improvement 89 % of the time [104]. A recent review article [105] summarized the findings from four published studies [104, 106108] of patients treated with botulinum neurotoxin A. All patients had overall improvement in pain as well as decrease in frequency and severity of vasospastic attacks and healing of DU. Current problems are the lack of a standardized injection site and dose, in addition to complications that include pain at the site of injection and transient intrinsic hand muscle weakness [104]. Further and longer-term evaluation is necessary to better define the role of botulinum toxin in DU treatment [96].

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Jun 3, 2017 | Posted by in RHEUMATOLOGY | Comments Off on Management of Digital Ischemia

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