**8. Treatment**

### **8.1. Primary RP**

The mild forms of primary RP are controlled by non-pharmacological measures, e.g., patient education in avoiding exposure to cold, use of warm clothes and gloves, smoking cessation, using protective devices in working with vibration. Caffeine consumption, administration of vasoconstrictors such as beta-blockers, and use of interferons should be avoided when possible [9].

*Dihydropyridine-type CCBs* have been the treatment of choice for patients with both primary and secondary RP for many years. They have proven efficacy for reduction of the severity and frequency of ischemic attacks in primary RP and secondary RP in SSc. Diltiazem (benzothiazepine class CCBs) could also be used in RP. It is administered at a dose of 30–120 mg three times daily orally. Verapamil (diphenylalkylamine class of CCBs) does not possess therapeutic effect in RP patients [75–77]. Nifedipine is the best studied and the most often used drug from dihydropyridine class CCBs. It is used at a dose of 10–40 mg twice daily orally. Other dihydropyridines commonly used in patients with RP are felodipine (2.5–10 mg twice daily orally) and amlodipine (5–10 mg daily orally) [1, 9]. Dihydropyridine class CCBs are vasodilators with direct effect on vascular smooth muscles. They are indicated for the treatment of arterial hypertension and stable angina, and some of them are also officially approved for vasospastic angina [78]. In RP patients, their use is off-label. Side effects of CCBs are common, e.g., flushing, hypotension, dizziness, headache, tachycardia, ankle edema, constipation, etc. Slow-release forms are better tolerated and preferred in clinical practice [1]. Pregnancy is a contraindication for administration of CCBs—a fact that deserves attention considering the high prevalence of primary RP in young women. This patient category requires specific instructions, and those women at childbearing age who plan conception or do not use effective contraception should not receive CCBs. Alternative, better-tolerated therapeutic options are often preferred in primary RP considering the milder clinical course and good prognosis of this condition as well as the side effects of CCBs.

*Pentoxifylline* inhibits phosphodiesterase and elevates cyclic adenosine monophosphate (cAMP) levels in polymorphonuclear leukocytes and other cells [79]. It exerts beneficial effects on microcirculation via improvement of blood fluidity, especially influencing erythrocyte flexibility [80]. Its maximal daily dose is 1200 mg (400 mg three times daily or 600 mg twice daily orally). It is not proven to be effective in severe forms of RP [1].

Therapeutic effect of *Ginkgo biloba* has been studied in patients with primary RP in doubleblind, placebo-controlled trial. Significant reduction in the number of attacks has been observed in the group treated with high dose of *Ginkgo biloba* (360 mg daily) as compared with the placebo group (56 vs. 27%). It is suggested that *Ginkgo biloba* together with its vasodilator properties possesses also antiplatelet and radical scavenging effects [81].

#### **8.2. Secondary RP in systemic sclerosis**

absence of an accompanying cause, acrocyanosis is considered primary (idiopathic, essential) that is suggested to be a benign condition and typically does not require specific treatment. It does not evolve into CTD or other diseases and may spontaneously resolve. secondary acrocyanosis is a manifestation of other major diseases. Both acrocyanosis and RP are influenced by cold exposure and emotional stress, but in acrocyanosis, there is relative persistence of skin color changes, symmetry, and absence of paroxysmal pallor. Of note, RP may occur concomitantly with acrocyanosis. In addition, the persistence of acrocyanosis is also relative, and it may also demonstrate improvement in the summer as well as in horizontal and elevated

*Perniosis (chilblain)* is a localized cutaneous inflammatory reaction in response to acute or repetitive exposure to damp cold above the freezing point. The skin lesions are edematous plaques that may be purple or red and are often painful or pruritic. In severe cases, ulceration, superinfection, and scarring may occur. Fingers and toes are most commonly affected although other areas, e.g., nose, ears, buttocks, or thighs, could also be involved. Primary and secondary forms are recognized. Secondary perniosis could be associated with a variety of underlying

*Erythromelalgia* is characterized with episodic, symmetric, and painful hyperthermia and erythema of hands and feet. Contrary to RP, erythromelalgia is provoked by exposure to heat or physical exercise. Primary and secondary forms are also recognized, primary being a rare hereditary disease that manifests in children and young people, while secondary is met in the context of myeloproliferative disorders, diabetes, and SLE and during drug treatment with

The mild forms of primary RP are controlled by non-pharmacological measures, e.g., patient education in avoiding exposure to cold, use of warm clothes and gloves, smoking cessation, using protective devices in working with vibration. Caffeine consumption, administration of vasoconstrictors such as beta-blockers, and use of interferons should be avoided when possible [9].

*Dihydropyridine-type CCBs* have been the treatment of choice for patients with both primary and secondary RP for many years. They have proven efficacy for reduction of the severity and frequency of ischemic attacks in primary RP and secondary RP in SSc. Diltiazem (benzothiazepine class CCBs) could also be used in RP. It is administered at a dose of 30–120 mg three times daily orally. Verapamil (diphenylalkylamine class of CCBs) does not possess therapeutic effect in RP patients [75–77]. Nifedipine is the best studied and the most often used drug from dihydropyridine class CCBs. It is used at a dose of 10–40 mg twice daily orally. Other dihydropyridines commonly used in patients with RP are felodipine (2.5–10 mg twice daily orally) and amlodipine (5–10 mg daily orally) [1, 9]. Dihydropyridine class CCBs are vasodilators with direct effect on vascular smooth muscles. They are indicated for the treatment of

pathological conditions such as hepatitis, autoimmune disease, and cryopathies [73].

position of the hand vs. dependent position [72].

36 Newest Updates in Rheumatology

calcium channel blockers (CCBs) [74].

**8. Treatment**

**8.1. Primary RP**

EULAR recommends *dihydropyridine-type CCBs* as first-line therapy for RP in SSc [82]. A metaanalysis, including 8 randomized clinical trials (7 with nifedipine and 1 with nicardipine) with 109 SSc patients, indicates that dihydropyridine-type CCBs reduce the frequency and severity of ischemic attacks in SSc-related RP [77]. Apart from their effect to reduce the severity and frequency of vasospastic attacks, it has been demonstrated that CCBs lead to healing of digital ulcers [83]. In SSc with severe RP and/or those who do not respond satisfactorily to CCBs, *phosphodiesterase-5 enzyme inhibitors* are recommended (EULAR recommendation) [82]. NO is the main endothelium-derived vasodilator and an inhibitor of platelet activation and vascular smooth muscle proliferation. Its synthesis is regulated by the family of NO synthases, and its effect is mediated via cyclic guanosine monophosphate (cGMP). The intracellular concentration of cGMP is regulated by phosphodiesterases, which rapidly degrade cGMP in vivo [84]. A meta-analysis, including six randomized clinical trials (two with sildenafil, three with tadalafil, and one with vardenafil), demonstrated that phosphodiesterase-5 inhibitors have a significant effect on frequency and duration of RP attacks. Efficacy on healing of digital ulcers has been also reported. The therapeutic regimens used were as follows: sildenafil 50 mg twice daily or 200 mg once daily, tadalafil 20 mg daily or 20 mg on alternate days, and vardenafil 10 mg twice daily. The dosage regimens depend on half-lives of the different drugs that are 3–5 h for sildenafil and vardenafil (administered twice daily apart from modified-release sildenafil that is administered as a single dose) and about 18 h for tadalafil (administered once daily or on alternate days) [85]. Side effects during treatment with phosphodiesterase-5 inhibitors included different forms of vasomotor reactions, myalgias, allergic reaction, chest pain, dyspepsia, nasal stuffiness, and visual abnormalities. Considering long-term experience and good safety profile, EULAR experts recommend CCBs as first-line therapy for SSc-related RP and phosphodiesterase-5 inhibitors for SSc with severe RP and/or in cases with insufficient effect from the treatment with CCBs [82].

**Author details**

Plovdiv, Bulgaria

**References**

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Sevdalina Nikolova Lambova

Address all correspondence to: sevdalina\_n@abv.bg

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Raynaud's Phenomenon

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*Intravenous iloprost* possesses proven efficacy for reduction of the frequency and severity of SSc-related RP. Considering costs and feasibility, it is recommended after failure of oral therapies (CCBs and phosphodiesterase-5 inhibitors). Intravenous iloprost is also efficacious in the treatment of digital ulcers in SSc that is proved in randomized, placebo-controlled clinical trials [86, 87]. However, the need for hospitalization, the prolonged intravenous infusion (6 hours at the dose of 0.5–2 ng/kg/min), side effects, and high price are limiting factors for the administration of iloprost. Adverse effects include headache, nausea, vomiting, diarrhea, myalgia, arthralgia, chills, fever, arrhythmia, hypotension, chest pain (especially in patients with coronary heart disease), erythema, and pain at the infusion site. Thus, concomitant pathology should be assessed and hemodynamic parameters of the patients closely observed, e.g., blood pressure, heart rate, and pulse at the beginning and at every increase of the infusion rate. The risk for orthostatic hypotension should be also considered. Apart from its properties as a vasodilator, iloprost inhibits platelet aggregation, leukocyte chemotaxis, and adhesion to the endothelium. Iloprost also downregulates the expression of adhesion molecules on endothelial cells and phagocytes and enhances fibrinolytic activity [86–88].

In addition, in the most recent EULAR recommendation, *fluoxetine* (a serotonin-specific reuptake inhibitor and antidepressant) is suggested as an option in SSc-related RP despite the scarce published evidence [82]. In a small study that included 26 patients with primary RP and 27 with SSc-related RP, fluoxetine (20 mg daily) showed superior efficacy vs. nifedipine (40 mg daily). Observed side effects of fluoxetine were apathy, lethargy, and impaired concentration [89]. Despite the relatively low quality of published evidence, EULAR experts suggest fluoxetine as a useful alternative for treatment of SSc-related RP, especially in SSc patients who do not tolerate or fail to respond to vasodilators [82].

In SSc patients, in whom RP has complicated with digital ulcers, EULAR experts recommend *intravenous iloprost* and *phosphodiesterase-5 inhibitors* for treatment of digital ulcers and *bosentan (endothelin receptor antagonist)* for reduction of the number of new digital ulcers [82].
