Medical Care
Globally
The diagnosis of CREST syndrome carries with it both physical and psychological consequences, so a holistic approach to patient care should be taken. An evaluation of organ involvement, patient education regarding the clinical course, patient and family support, and treatment based on disease severity and organ involvement are necessary. [62, 63]
A pilot study of multidisciplinary patient education for persons with systemic sclerosis showed that patients may benefit from meeting others with the disease, may learn more about the disease, and may actually experience some pain relief. [64]
Depression affects approximately 45% of patients with systemic sclerosis and 64% also develop anxiety; thus, early assessment and treatment of these psychological issues is recommended. [65, 66]
European investigators have been conducting phase I and II studies on the use of hematopoietic stem cell transplantation for severe systemic sclerosis, and randomized trials are proceeding. Only further research and time will tell if this is a useful therapy for severe scleroderma in the future. [67]
Tamoxifen has been studied for use in patients with scleroderma and CREST syndrome, but it was not shown to be efficacious. [68]
Calcinosis
No large, prospective, placebo-controlled trials have been performed to study the treatment of calcinosis. The literature predominantly consists of reports and series. Therefore, keep in mind that calcinosis has resolved spontaneously in as many as 55% of patients in some series, as noted by Fink and Cook in 1986. [69] Simple surgical management, including curettage, is often sufficient in limited disease. [70]
Treatment with oral corticosteroids is not usually considered effective, but, according to Hazen et al, [71] intralesional corticosteroid therapy has been associated with improvement of calcinosis.
Several case reports have demonstrated the efficacy of probenecid.
Early case reports suggested that diltiazem was associated with regression of calcific deposits and improvement of symptoms. A 1998 case series of 12 patients by Vayssairat et al [72] did not confirm these findings.
A 1987 small randomized placebo-controlled trial by Berger et al [73] using low-dose warfarin reduced urinary levels of Gla protein and reduced extraskeletal uptake on bone scans in 2 of 3 patients after 18 months of follow-up care. No changes in plain radiographs or clinical assessment were noted in these patients. Cukierman et al [74] used low-dose dose warfarin on 3 patients with systemic sclerosis, and 2 of the patients, who had newly diagnosed, diffuse, and relatively small calcinotic lesions, responded to warfarin treatment, with complete resolution of the calcinosis. As reported in 1998, Lassoued et al [75] used warfarin in patients with extensive calcinosis and saw no benefit. Low-dose warfarin may be helpful in selected patients with early or mild disease.
Several case reports have shown that aluminum hydroxide may be useful for calcinosis. [76]
Bisphosphonate treatment has had only limited success. Etidronate appeared to help calcinosis in one patient with scleroderma; however, another study reported failure. Alendronate was used successfully in one patient with calcinosis associated with juvenile dermatomyositis. The other bisphosphonates, pamidronate, risedronate, zoledronate, and ibandronate, have not been studied for calcinosis. [76, 77, 78, 79]
In one case series, 8 of 9 patients with limited systemic sclerosis had a good response to low-dose minocycline. [80]
Suppression of intermittent local inflammatory reactions can be achieved by low-dose colchicine. [81]
Kalajian et al found intravenous immunoglobulin therapy to be unreliable. [82]
In summary, no consistently reliable pharmacological treatment seems to be available to prevent or eliminate calcinosis. One or a combination of the above treatments may be tried on a case-by-case basis; however, larger randomized trials are needed to prove efficacy.
Raynaud phenomenon
Advise all patients with Raynaud phenomenon to use good hand and body warming techniques. Goodfield et al [83] have shown that according to laser Doppler flowmetry, secondary Raynaud phenomenon patients respond appropriately to simple warming techniques compared with controls. Reinforce the wearing of gloves, a hat, and a coat outdoors and, if necessary, indoors. The importance of keeping the core body and hand temperature elevated cannot be overemphasized.
Behavior therapy, including temperature biofeedback and autogenic training, has been evaluated in the treatment of scleroderma-associated Raynaud phenomenon. In 1989, Freedman [84] demonstrated an improvement of finger blood flow and elevation of finger temperature with biofeedback training. A large, randomized, controlled trial, however, showed no clinical benefit with temperature biofeedback; however, this has been criticized because the patients may not have been adequately trained in the technique. [85] These researchers [85] claim that thermal biofeedback is efficacious if proper hand warming technique is used.
Calcium channel blockers are the mainstay of medical therapy for Raynaud phenomenon. Short-acting calcium channel blockers have been effective, yet they are frequently associated with adverse effects (eg, headache, flushing, dizziness, edema). In a recent study by the Raynaud's Treatment Study Investigators, sustained-release nifedipine reduced attack frequency by approximately 60% and was well tolerated. Some literature has suggested that calcium channel blockers are less effective in scleroderma-associated Raynaud phenomenon than in primary Raynaud disease, but Meyrick Thomas et al [86] demonstrated the effectiveness of nifedipine in this group in a longer-duration trial. A 2005 meta-analysis of calcium channel blocker therapy for Raynaud phenomenon by Thompson et al [87] showed a small benefit in reducing the severity and frequency of ischemic attacks (an average of 2.8-5 fewer attacks/wk and a 33% reduction in severity).
Topical nitroglycerin and topical glyceryl trinitrate have been used in patients with Raynaud phenomenon. Several studies have shown that they both increase blood flow at the application site and they may help with symptomatic management of vasospasms. [88, 89, 90]
Prostaglandin E1, prostacyclin I2, and iloprost (a prostacyclin-I2 analogue) have been evaluated for treatment of Raynaud phenomenon. Prostaglandins may be beneficial because of their vasodilatory and antiplatelet effects. None of these treatments is approved by the US Food and Drug Administration for the treatment of Raynaud phenomenon. Use of these agents should be reserved for patients whose Raynaud phenomenon has resulted in severe ischemia or nonhealing ulcers.
Intravenous infusions of prostacyclin I2 (epoprostenol) in patients with severe Raynaud phenomenon demonstrated substantial clinical improvement. The frequency and duration of attacks were reduced, and significant healing of digital ulcers occurred. Intravenous prostaglandin E1 (alprostadil) has been beneficial in some small studies, particularly in patients with sepsis or necrosis. Intravenous epoprostenol has also been used. [91]
Oral iloprost therapy showed a trend toward improvement of the severity and duration of attacks in patients with scleroderma. Intravenous iloprost reduced the severity, frequency, and duration of Raynaud attacks; helped with ulcer healing [92] ; and showed an increase in quality of life. [93]
Antiplatelet therapy has had mixed results. Ticlopidine showed benefit in one case and was ineffective in another study. [94] Clopidogrel has not been studied in Raynaud phenomenon. Cilostazol has shown some benefit in open-label trials, and a recent double-blinded randomized trial showed that it significantly increased the mean brachial artery diameter; however, the patient's subjective symptoms did not appear to improve. [95, 96] Recombinant tissue plasminogen activator produces only transient improvement in blood flow in patients with digital ischemia and is not recommended for Raynaud phenomenon. [97]
A 2000 pilot study by Denton et al [98] suggests that low molecular heparin may be beneficial for severe Raynaud phenomenon; however, further evaluation is necessary.
Some evidence has shown that plasma exchange may help with the symptoms of Raynaud phenomenon; however, it is unlikely to affect the disease course. [99, 100, 101]
Losartan, an angiotensin II inhibitor, has been shown in 2 trials to reduce the frequency and severity of vasospastic episodes. [102, 103] A review of the literature [104] concluded that ACE inhibitors and angiotensin II receptor blockers may provide minor relief for Raynaud phenomenon; however, the benefit is not proven to be any better than the current treatment of choice, which is calcium channel blockers.
Case reports [105, 106] have suggested that the phosphodiesterase V inhibitors, sildenafil and tadalafil, may also be effective. An open-label pilot trial of vardenafil [107] also showed promise.
Alpha-adrenergic antagonists have received some interest recently as a new treatment for Raynaud phenomenon. An experimental selective alpha(2C)-adrenergic receptor blocker was well tolerated and improved digital skin perfusion during recovery from cooling in patients with Raynaud phenomenon associated with scleroderma. [108] One case report describes a patient who paradoxically experienced worsening of Raynaud phenomenon while using the alpha-2 adrenergic antagonist yohimbine. [109] Further research is needed before the efficacy and safety of this class of drugs can be established for use in this disease.
Bosentan, an orally active competitive endothelin-1 antagonist that blocks the endothelin receptors, is being used for systemic sclerosis-associated pulmonary arterial hypertension, and this agent may also help alleviate vasospasm and prevent digital ulceration; however, clinical trials need to be performed first. [110]
A pilot study with fluoxetine and a case report on paroxetine suggest that the selective serotonin reuptake inhibitors might be effective as novel treatments for Raynaud phenomenon. [111, 112]
The following therapeutic ladder is suggested for the treatment of patients with Raynaud phenomenon:
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Reduce and remove risk factors and triggers. Stop smoking, avoid beta-blockers, and avoid any remediable underlying cause (eg, use of vibratory equipment). [113]
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Teach hand and body warming activities.
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Administer long-acting formulations of calcium channel blockers.
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Add topical nitroglycerin paste to this regimen if required.
Esophageal dysmotility
The treatment of esophageal dysmotility and gastroesophageal reflux in scleroderma patients is the same as in patients without scleroderma. Systemic immunosuppressants are not helpful.
Emphasize behavior changes (eg, weight loss; elevating head of bed; reduction of caffeine, tobacco, alcohol, chocolate intake and avoidance prior to recumbency; eating small meals; waiting 3-4 h after eating before lying down).
Administration of H2 blockers (eg, ranitidine, famotidine, nizatidine) may help symptoms, but use of a proton-pump inhibitor should be instituted if erosive esophagitis is present. Motility-promoting agents may help with symptoms. Cisapride has been shown to increase lower esophageal pressure and the amplitude of esophageal contractions in healthy patients and to stimulate esophageal motility with resultant symptomatic improvement in one patient with progressive systemic sclerosis. [114]
Esophageal dilatation can help when significant dysphagia or regurgitation occur in the presence of an esophageal stricture.
Sclerodactyly
Various treatment regimens including corticosteroids, nonsteroidal anti-inflammatory drugs, D-penicillamine, IFN-gamma, cyclosporine, and cytostatic drugs have been used with limited success in scleroderma.
An open-label study of calcitriol had promising results; however, a recent double-blinded, placebo-controlled trial was too small to draw any conclusions. [115] After retrospective data showed the benefits of D-penicillamine for scleroderma skin changes, Clements et al [116] performed the first randomized controlled trial of D-penicillamine in scleroderma. This trial compared high-dose D-penicillamine (750-1000 mg/d) to low-dose D-penicillamine (125 mg qod) in patients with early diffuse cutaneous scleroderma. The mean skin thickness score improved over 2 years of treatment in both groups, and no advantage was seen to using the higher dose of D-penicillamine. [116] This study had no placebo group and the authors concluded later that they were not able to tell whether either dose was effective or ineffective. D-penicillamine cannot, therefore, be recommended until placebo-controlled trials are conducted to show effectiveness.
The natural course of diffuse dermal sclerosis involves skin softening after 4-5 years; therefore, placebo-controlled trials are essential for determining an effective therapy. Skin involvement in limited scleroderma typically is not severe; therefore, attempts are not usually made to treat skin involvement.
Telangiectasia
Pulsed-dye laser treatment has been shown to be effective for the treatment of facial telangiectasia, but this has not been specifically studied in CREST patients. [117] Many treatment modalities have been used with success to treat symptomatic GI telangiectasia (eg, medical treatment with estrogen-progesterone or desmopressin, laser ablation, sclerotherapy).
Surgical Care
Calcinosis
Surgical excision of localized painful large deposits can relieve symptoms; recurrence is rare. Saddic et al report a case of painful fingertip calcinosis treated with surgical debridement. [118] If calcinosis is diffuse, recurrence is more common. Overzealous debridement to remove all calcinosis is apt to compromise digital viability and should be avoided. [119] Successful palliation and significant remission of calcinosis using a carbon dioxide laser has been shown in 2 case reports with a total of 7 patients. [120, 121] Surgical procedures may require extensive planning in patients with limited skin mobility. [122]
Raynaud phenomenon
Cervical sympathectomy is less beneficial for scleroderma patients than for patients with Raynaud phenomenon secondary to peripheral vascular disease. Newer surgical approaches include digital sympathectomy, with or without revision of surgically correctable vascular disease. In the event of nonhealing digital ulcers, amputation, unfortunately, sometimes is unavoidable.
Esophageal dysmotility
Surgical therapy may help gastroesophageal reflux in general. Common techniques use complete or partial surgical wraps around the gastroesophageal junction to increase LES pressure and reduce reflux. The degree of tightness of the wrap inversely correlates with the reduction of reflux; however, the scleroderma cohort of patients may not tolerate a tight wrap. They are more likely to experience abdominal discomfort and dysphagia as a result. Therefore, avoid surgery for reflux in scleroderma patients except in the most severe refractory cases.
Sclerodactyly
If sclerodactyly is causing extensive contractures, a carefully planned and precisely performed operative treatment has been shown to have good success with a high level of patient satisfaction. [119]
Telangiectasia
Bowel resection for uncontrollable GI bleeding from telangiectasia is rarely necessary.
Consultations
Rheumatologists often primarily follow CREST syndrome patients. Referral to a rheumatologist is advised.
Dermatologists are often involved early and aid in the diagnosis of CREST syndrome.
Gastroenterologists may be asked to perform endoscopy for evaluation of esophageal disease. A gastroenterologist also should be consulted for an evaluation of GI bleeding resulting from telangiectasia and for the treatment of the condition.
Psychiatrists may be consulted to evaluate and treat depression and anxiety.
Occupational or physical therapy may be helpful if a patient has digit and hand strength deficits due to sclerodactyly.
Diet
No special recommendations are needed.
Activity
No special recommendations are needed.
Prevention
Raynaud phenomenon
Reinforce the wearing of gloves, a hat, and a coat outdoors and, if necessary, indoors; emphasize the importance of the keeping core body and hand temperature elevated.
Counsel patients to stop smoking.
Esophageal dysmotility
Emphasize behavior changes (eg, weight loss; elevating head of bed; reduction of caffeine, tobacco, alcohol, and chocolate intake and avoidance prior to recumbency; eating small meals; waiting 3-4 h after eating before lying down).
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Calcinosis on dorsal forearm.
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Close-up view of calcinosis.
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Raynaud phenomenon showing pallor of most of the finger tips with a violaceous discoloration (hyperemia) of the thumb tip.
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Sclerodactyly (also with Raynaud phenomenon).
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Sclerodactyly.
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Telangiectasia of the face.
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Telangiectasia of the lip.
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Telangiectasia of the finger.
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Close-up view of telangiectasia.
