**7. Differential diagnosis of RP with other vascular acrosyndromes**

*Acrocyanosis* represents painless bluish discoloration in the distal body parts, most commonly in the hands and feet and less frequently in the face that are affected symmetrically. In acrocyanosis, the bluish skin discoloration is a persistent finding that is aggravated by cold exposure and frequently is associated with local hyperhidrosis and edema of the hands and feet. In the 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 position of the hand vs. dependent position [72].

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

Raynaud's Phenomenon

37

http://dx.doi.org/10.5772/intechopen.79362

*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

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

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

of this condition as well as the side effects of CCBs.

**8.2. Secondary RP in systemic sclerosis**

daily orally). It is not proven to be effective in severe forms of RP [1].

properties possesses also antiplatelet and radical scavenging effects [81].

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

*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 calcium channel blockers (CCBs) [74].
