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Raynaud disease and phenomenon
Evidence Levels: A Double-blind study B Clinical trial ≥ 20 subjects C Clinical trial < 20 subjects D Series ≥ 5 subjects E Anecdotal case reports
Raynaud phenomenon (RP) is characterized by intermittent peripheral vasoconstriction leading to pallor, cyanosis, and reactive vasodilatation of the arterioles of the fingers and toes. It is caused by vasospasm in response to cold, emotion, hormones, and certain vasospastic drugs. Primary Raynaud disease is a milder, idiopathic form, whereas secondary RP coexists with autoimmune connective tissue disorders, such as systemic lupus erythematosus and systemic sclerosis (SSc), among others, or other conditions that reduce blood flow, such as localized structural abnormalities. The pathogenesis and pathophysiology vary between the primary (idiopathic) and the secondary forms but are still not fully understood.
Primary Raynaud disease is often mild and may not require treatment; the vasospasm is entirely reversible. However, secondary Raynaud disease often involves fixed blood vessel damage in addition to vasospasm; therefore, the ischemia can be more severe. Complications include digital ulcers and gangrene, which can lead to osteomyelitis and even amputation.
Management Strategy
Treatment is often non-pharmacologic, including avoiding cold (especially sudden drops in temperature) and smoking cessation. Counseling should emphasize keeping the core temperature warm (additional layers, hats, etc.) in addition to wearing thick socks and gloves/mittens, in order to prevent vasoconstriction in the periphery. The use of warming devices such as hand or toe warmers can be beneficial. Avoidance of triggers should be stressed (e.g., caffeine, smoking, use of vibratory equipment). Drugs that may exacerbate the condition include β-blockers, amphetamine/dextroamphetamine, bleomycin, cisplatin, ergot preparations, interferon, methysergide, oral contraceptives, reboxetine, tegaserod, and vinblastine.
Pharmacologic therapy is warranted when: 1) the patient’s symptoms impact their quality of life to a substantial degree; and 2) the patient is developing changes, including digital ulcers, loss of digital pulp, etc.
Calcium channel antagonists, such as nifedipine , are considered first-line treatment. The side effect profile includes hypotension, vasodilatation, peripheral edema, and headaches. A common dosing strategy is to initiate nifedipine at 30 mg extended release QHS and increase the dose as needed. Other treatments that have been studied in randomized controlled trials include phosphodiesterase-5 inhibitors (PDE-5) (e.g., sildenafil, 25–50 mg up to four times a day) and nitrates (topical or oral), angiotensin II inhibitors, and selective serotonin reuptake inhibitors (fluoxetine 20–60 mg daily). PDE-5 inhibitors are effective in patients who respond poorly to calcium channel antagonists as an alternative or adjunct. They are used frequently in patients with severe SSc- or other CTD-related RP. For refractory Raynaud disease or its complications, botulinum toxin or prostacyclin agonists may be used. Endothelin receptor blockade with bosentan (62.5 mg twice a day) has been demonstrated to reduce the number of new digital ulcers in patients with systemic sclerosis. However, it does not affect the healing period and has no effect on the number and severity of attacks of RP in those without ulcers.
Specific Investigations
Careful history taking and clinical examination followed by investigation to detect potential underlying disease are essential.
A study comparing videocapillaroscopy and dermoscopy in the assessment of nailfold capillaries in patients with systemic sclerosis spectrum disorders
Hughes M, Moore T, O’Leary N, et al. Rheumatology (Oxford) 2015; 54(8): 1435–42.
In this study, rheumatologists graded nailfold capillary images from dermoscopy and nailfold videocapillaroscopy (NVC) in 32 subjects. Dermoscopy is a comparable technique to NVC in grading nailfold capillary images; however, NVC graded images approximately half a point more severely than dermoscopy due to its higher magnification properties.
Calcium channel blockers for primary Raynaud’s phenomenon
Ennis H, Hughes M, Anderson ME, et al. Cochrane Database Syst Rev 2016; 25: CD002069.
This represents a meta-analysis of seven randomized trials with 296 patients evaluating the effects of nifedipine and nicardipine in the treatment of primary RP only. A decrease in the frequency of attacks was reported for patients on a calcium channel blocker. Doses of nifedipine used included 10–20 mg three times daily and 30–60 mg sustained-release daily. Nicardipine doses ranged between 20 mg and 30 mg thrice daily and 50 mg long-acting preparation twice daily.
Head-to-head comparison of udenafil vs. amlodipine in the treatment of secondary Raynaud’s phenomenon: a double- blind, randomized, cross-over study
Lee EY, Park JK, Lee W, et al. Rheumatology 2014; 53: 658–64.
Twenty-nine patients with secondary RP associated with connective tissue diseases received udenafil 100 mg daily (a phosphodiesterase-5 inhibitor) or amlodipine 10 mg daily for 4 weeks. Both decreased the rate of RP attacks with comparable efficacy.
Phosphodiesterase-5 inhibitors for the treatment of secondary Raynaud’s phenomenon: systematic review and meta-analysis of randomised trials
Herrick AL, van den Hoogen F, Gabrielli A. Ann Rheum Dis 2013; 72: 1696.
Six randomized controlled trials were included: one with sildenafil (50 mg twice daily), one with modified-release sildenafil (200 mg once daily), three with tadalafil (20 mg on alternate days when used as add-on therapy), and 20 mg once daily. One study looked at vardenafil 10 mg twice daily. A meta-analysis showed PDE-5 inhibitors significantly decreased frequency and duration of RP attacks compared with placebo in secondary RP.
Nifedipine cream versus sildenafil cream for patients with secondary Raynaud phenomenon: a randomized, double-blind, controlled pilot study
Wortsman X, Del Barrio-Díaz P, Meza-Romero R, et al. J Am Acad Dermatol 2018; 78(1): 189–90.
In this double-blind study, 10 patients with secondary RP were randomly assigned to receive treatment with 5 g of 10% nifedipine on one hand and 5 g of 5% sildenafil cream on the other hand. Topical sildenafil significantly increased blood flow by 9.2 mm/sec ( p <0.0083), whereas no significant change in blood flow was observed with topical nifedipine.
Combination therapy with bosentan and sildenafil improves Raynaud’s phenomenon and fosters the recovery of microvascular involvement in systemic sclerosis
Bellando-Randone S, Lepri G, Bruni C, et al. Clin Rheumatol 2016; 35(1): 127–32.
In this retrospective study, 123 patients were evaluated based on their treatments: bosentan, sildenafil, bosentan + sildenafil. Patients treated with both bosentan and sildenafil demonstrated a significantly greater improvement in Raynaud Condition Score and reversal of NVC.
Optimisation of botulinum toxin type A treatment for the management of Raynaud’s phenomenon using a dorsal approach: a prospective case series
Dhaliwal K, Griffin MF, Salinas S, et al. Clin Rheumatol 2019; 38(12): 3669–76.
In this prospective case series, 40 patients were injected with 100 units of botulinum toxin type A (BTX-A) in both hands through a dorsal approach; 80% of the patients reported improvement in swelling, color changes, and reduction in pain at 6 weeks. Additionally, 80% of the patients with improved symptoms also reported reduction in the frequency and severity of RP attacks as well as improved cold sensitivity. Significant improvements in the Disabilities of the Arm, Shoulder, and Hand (DASH) score ( p = 0.001), Kapandji (thumb opposition test) score ( p = 0.001), and hand strength ( p <0.05) were also observed. At 12 weeks, improvement in symptoms and hand strength as well as reduction in the DASH and Kapandji scores were still observed but to a lesser degree than 6 weeks.
A 28-day prospective, randomized, double-blind, placebo controlled clinical trial of botulinum toxin type A for Raynaud’s phenomenon
Webb KN, Berry NN, Bueno RA, et al. Plast Reconstr Surg 2014; 133: 13.
A group of 35 patients were treated with either placebo or botulinum toxin type A (BTX-A) 100 U into the palm around involved digital neuromuscular bundles. Of placebo patients, 10% reported pain relief compared with 62% of BTX-A–treated patients ( p = 0.0288). Average pain relief duration was 127 days, and 60% of patients with digital ulcers healed after BTX-A injection.
Double-blind, placebo-controlled study of prazosin in Raynaud’s phenomenon
Wollersheim H, Thien T, Fennis J, et al. Clin Pharmacol Ther 1986; 40: 219–25.
In this study, prazosin 1 mg three times daily was compared with placebo and showed a moderate subjective improvement with a reduction in daily number and duration of attacks.
Treatment of Raynaud’s phenomenon with the selective serotonin reuptake inhibitor fluoxetine
Coleiro B, Marshall SE, Denton CP, et al. Rheumatology 2001; 40: 1038–43.
This crossover study compared fluoxetine, a selective serotonin reuptake inhibitor (20 mg/day), with nifedipine (40 mg/day) as treatment for primary or secondary RP. While attack frequency and severity reduction occurred with both nifedipine and fluoxetine, the effect was only statistically significant with fluoxetine. Females and patients with primary RP reported the greatest response to fluoxetine. Response to thermographic cold challenge was only observed for patients receiving fluoxetine and not with nifedipine. The results confirmed the tolerability of fluoxetine and suggested that it would be effective as a treatment for RP.
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