Scleroderma, Intolerable Finger Pain, and Progressive Digital Gangrene

Robert Fox, MD

Disclosures

April 27, 2005

Question

A 35-year-old patient who is a man presented with a history of more than 10 years of scleroderma, with reflux esophagitis and no renal, respiratory, or cardiac involvement. The patient also presented with intolerable finger pain and digital gangrene of the right big toe and right index finger. The latter is progressing despite pulsed steroid therapy. What is your advice for therapeutic management of this patient's pain, and should amputation be considered?

Sabah Zangana

Response from Robert Fox, MD

The most pressing issues in this patient are the treatment of progressive gangrene in affected digits and the prevention of future digital gangrene. The specific therapies that have been used for the treatment of this patient (other than corticosteroids) have not been listed. Also, the types of diagnostic studies to determine the etiology of ischemia are not described. Therefore, it may be best to start by reviewing the diagnostic and therapeutic approaches to gangrene management in the setting of scleroderma. It is important to recognize that embolic and other disease may also cause gangrene in the scleroderma patient. The patient should have imaging studies (including magnetic resonance angiography [MRA] or contrast angiography) to determine whether the cause is vasculopathy, vasculitis (ie, polyarteritis), or perhaps embolic. Therapies may include medical treatment of ischemia (vasodilators, bosentan, or iloprost) or surgical treatments of ischemia (including vascular bypass or amputation), as well as treatments for vasculitis if indicated on imaging studies.

Gangrene is characterized by cyanotic, anesthetic tissue associated with or progressing to necrosis; it occurs when the arterial blood supply falls below the necessary minimal metabolic requirements. Gangrene can be described as either dry or wet .

Dry gangrene is characterized by its hard, dry texture, usually occurring in the distal aspects of the toes and fingers -- often with a clear demarcation between viable and necrotic tissue. This form of gangrene is more common in patients with atherosclerotic disease and frequently results from embolization to the toe or forefoot.

Once demarcation has occurred, the involved digit may be allowed to autoamputate without further proximal progression of gangrene. However, this is often a process that is both lengthy and disturbing to the patient. On the other hand, many patients with dry gangrene do not have adequate circulation to heal a distal amputation. As a result, most patients should be evaluated with angiography for possible distal bypass in order to improve the chances of healing a distal amputation and obtaining limb salvage.

Wet gangrene is characterized by its moist appearance, gross swelling, and frequent blistering. It is a true emergency, often occurring in diabetics with decreased sensation who sustain an unrecognized trauma to the toe or foot. If sufficient viable tissue is present to maintain a functional foot, emergent debridement of all affected tissue often results in healing. If the wet gangrene involves an extensive portion of the foot, emergent guillotine amputation may be warranted, with revision to below-knee or above-knee amputation 72 hours later.

The vascular evaluation of a patient with limb-threatening ischemia begins with a detailed history and careful physical examination. In addition to scleroderma, patients may have evidence of an underlying medical disease, including heart disease and diabetes. The physical examination should include a careful search for bruits, aneurysms, and malignancy. The extremities should be carefully evaluated for the presence and strength of pulses, tissue changes, and evidence of prior vascular intervention.

Noninvasive testing: The findings are neither specific nor sensitive enough to design operative therapy. As a result, all patients with evidence of peripheral ischemia should undergo objective testing. This includes the subsequent tests.

Ankle-brachial index: The ankle-brachial index (ABI [or ankle-arm index]) is a simple test, which can be performed at the bedside. The ABI is the ratio of the ankle systolic blood pressure divided by the brachial systolic pressure detected with a Doppler probe. The normal value is 1.1-1.2. In general, patients with claudication have an ABI between .4 and .95, whereas those with rest pain or tissue loss have an ABI in the ranges of .2-.5 and 0-.4, respectively.

Segmental Doppler pressures and volume plethysmography: Once the presence of arterial occlusive disease has been verified with ABI measurements at rest or during exercise, the level and severity of peripheral vascular disease are routinely assessed by segmental limb pressures or volume plethysmography. Segmental Doppler measurements involve the placement of cuffs at the levels of the proximal and distal thigh, calf, and ankle. A 20-mm Hg or greater reduction in pressure is considered significant if such a gradient is present either between segments along the same leg or when compared with the same level of the opposite leg.

Plethysmography, or the measurement of volume change in an organ or limb, is usually used in conjunction with segmental limb pressures to assess the level of arterial disease. This technique is performed by injecting a standard volume of air into the pneumatic cuffs placed at various levels along the extremity. Volume changes in the limb segment below the cuff are translated into pulsatile pressure, which is detected by a transducer and then displayed as a pressure pulse contour. This technique is especially helpful in diabetic patients with relatively incompressible proximal vessels.

Duplex imaging: Duplex imaging can, in experienced hands, provide accurate localization and quantification of lesions; it can also help differentiate stenoses from occlusions, an advantage over segmental Doppler pressures or plethysmography. However, a great deal of time and expertise are required to perform a complete screening examination of the lower extremity vessels with duplex imaging; as a result, this modality is not the first choice for screening in many vascular laboratories. Nevertheless, the ability of duplex imaging to answer precise questions about specific arterial segments and to measure flow velocities in bypass grafts makes it a useful tool in following known lesions for evidence of progression and for monitoring vascular reconstructions for the development of stenoses.

MRA: MRA is becoming increasingly popular for the evaluation of lower extremity ischemia, particularly in patients who have a contraindication to standard contrast angiography. Its successful use as a replacement for conventional contrast angiography requires careful evaluation and significant experience with MRA, and cooperation between the radiologist and the vascular surgeon.

Contrast angiography: Contrast angiography remains the gold standard in the evaluation of lower extremity ischemia. It should be performed in patients without a contraindication who are expected to undergo revascularization. Complete studies of the aorta and the iliac, femoral, popliteal, and runoff vessels are usually done on both the affected and contralateral sides because atherosclerotic disease is usually bilateral and occurs at multiple levels.

The management of Raynaud's phenomenon (RP) should be performed in a graduated fashion. Avoidance of cold, stress, nicotine, caffeine, and sympathomimetic decongestant medications (eg, pseudoephedrine) are valuable nonpharmacologic elements to prevent or avoid exacerbating RP. A wide variety of treatment options are available for RP. However, these therapies only provide symptomatic relief; they do not cure the disease. Treatment of RP in patients with systemic sclerosis is generally the same as for others with the disorder.

However, some agents used for treating other features of systemic sclerosis may have a role in treating RP in patients with systemic sclerosis. Some examples follow.

Bosentan: The nonselective endothelin antagonist, bosentan, which has been approved for treatment of pulmonary hypertension in patients with scleroderma, may have a beneficial effect on digital ischemia and may reduce the incidence of digital ulceration. This was illustrated in a multicenter study that randomly assigned 122 patients with systemic sclerosis to receive bosentan (62.5 mg twice daily with dose escalation to 125 mg twice daily as tolerated) or placebo for 16 weeks.[1] The mean number of new digital ulcers that developed was significantly less in those receiving bosentan than placebo (1.4 vs 2.7 per patient); for the subset of patients with at least 1 digital ulcer at the initial visit, the incidence of new ulcers was decreased by 50% with bosentan.

Although this approach may prevent new ulcers, it is uncertain whether the healing of established digital ulcers is facilitated. As has been noted in patients treated for pulmonary hypertension, elevation of serum aminotransferases was more frequent in the bosentan-treated group.

Prostacyclin analogs: The synthetic analog of prostacyclin, iloprost (carbaprostacyclin, given parenterally at 0.5-2 ng/kg/minute), is a potent vasodilator that also inhibits platelet aggregation and adhesion, increases red blood cell deformability, alters neutrophil function (including free-radical production), and may help repair damaged endothelium. It also decreases the production and release of the profibrotic cytokine, connective tissue growth factor from fibroblasts, thereby reducing its concentration in sclerodermatous skin.[2]

The possible efficacy of iloprost was evaluated in a double-blind, controlled trial in which 131 patients with RP secondary to scleroderma were randomly assigned to either placebo or iloprost (given as 5 daily sequential 6-hour infusions at a dose of 0.5-2.0 ng/kg/minute).[3] The following benefits were noted in the patients treated with iloprost after follow-up of at least 6 weeks:

  • A greater reduction in the number of weekly attacks (39% vs 22% with placebo);

  • A greater mean reduction in the global Raynaud severity score (35% vs 20%); and

  • Fifteen percent more patients showed healing of at least 50% of digital cutaneous lesions.

Although side effects were more common during the iloprost infusion, it was concluded that iloprost was effective for the short-term palliation of severe RP in scleroderma. In particular, it may help to avoid amputation of the distal tip of a digit. However, intravenous iloprost is not available in the United States.

Efforts have been made to develop an oral prostaglandin analog that is safe and effective. One such analog, beraprost, was evaluated in a prospective, placebo-controlled, randomized study of 107 patients with systemic sclerosis and digital necrosis.[4] Active therapy was associated with a nonsignificant trend for benefit.

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