**5. Primary Raynaud's phenomenon**

In a recent systematic literature review, the prevalence of primary RP is reported to vary from 1.6 to 7.2% (calculated pooled prevalence—4.85%) [29]. As mentioned above, the primary RP is characterized with early age of onset, mainly at puberty. This classic type of presentation predominates in female patients with family history. Despite the fact that the age of onset is considered to be a discriminating factor between primary and secondary RP, it should be interpreted individually as primary RP with late onset (above the age of 40) is also possible [30].

#### **5.1. Diagnosis of primary Raynaud's phenomenon**

Wide application in clinical practice have the diagnostic criteria of Le Roy and Medsger (1992) that encompass the following findings:


**4. Pathogenesis of Raynaud's phenomenon**

ties that lead to tissue damage.

30 Newest Updates in Rheumatology

son with SSc [10, 27].

**5. Primary Raynaud's phenomenon**

found [28].

The vasospasm in primary RP is reversible, while the secondary Raynaud's phenomenon in systemic sclerosis is associated with endothelial injury and subsequent structural abnormali-

*Adrenergic alpha-2 receptors* that are more important than alpha-1 receptors in the control of vasoconstriction of digital arteries are suggested to be abnormal in RP. The receptor subtype alpha-2c is found to predominate in the vascular smooth muscle cells of distal cutaneous vessels [16, 17]. Alpha-2c adrenergic receptors are not active at room temperature. In response to cold exposure, they are activated as a result from translocation from the Golgi complex to the plasmatic membrane [18, 19]. Estrogens also activate alpha-2c adrenoreceptors that could explain the predominance of primary RP in females and the increased severity of symptoms between menarche and menopause [20]. An association between enhanced contractile response to alpha-2c agonists and increased protein tyrosine kinase activity and tyrosine phosphorylation has been found. Greater intracellular tyrosine phosphorylation in response to cooling (31°C) has been found in arterioles in both primary and secondary RP patients vs.

controls using immunofluorescence and an antiphosphotyrosine antibody [21, 22].

The endothelium controls blood vessel tone via production of vasodilators (nitric oxide (NO), prostacyclin) and vasoconstrictors (endothelin-1, angiotensin). Endothelial damage in secondary RP in SSc leads to disbalance between vasodilators and vasoconstrictors [10, 23]. In SSc-related RP, increased level of asymmetric dimethylarginine (an endogenous NO synthesis inhibitor produced by endothelial cells) was observed. Elevated plasma level of endothelin-1 was found in SSc as compared with primary RP [24]. Increased expression of endothelin-1 in the skin of SSc patients was also detected [25]. Besides its properties of vasoconstrictor, it has been confirmed that endothelin-1 promotes fibrosis in scleroderma patients [26]. In SSc, endothelial injury represents a key pathogenic step that mediates the processes of inflammation, thrombus formation, and fibrosis [23]. The role of endothelin-1 in pathogenesis of primary RP has also been implicated in some studies, but the evidence is weaker in compari-

Calcitonin gene-related peptide (CGRP) is a neuropeptide and a potent vasodilator produced by peripheral sensory nerves. In RP (primary and secondary RP in SSc), especially the secondary forms in SSc, a reduction in the number of CGRP immunoreactive neurons in the skin was

In a recent systematic literature review, the prevalence of primary RP is reported to vary from 1.6 to 7.2% (calculated pooled prevalence—4.85%) [29]. As mentioned above, the primary RP is characterized with early age of onset, mainly at puberty. This classic type of presentation predominates in female patients with family history. Despite the fact that the age of onset is considered to be a discriminating factor between primary and secondary RP, it should be interpreted individually as primary RP with late onset (above the age of 40) is also possible [30].


Maverakis et al. published an international consensus for diagnosis of primary RP, which includes the following criteria: (1) normal capillaroscopy; (2) negative physical examination for findings suggestive of secondary causes such as ulcerations, tissue necrosis or gangrene, sclerodactyly, calcinosis, or skin fibrosis; (3) no history of existing CTD; and (4) negative or low titer ANA as low titer is considered (1:40) by indirect immunofluorescence. In the newly accepted criteria of Maverakis et al., the presence of normal erythrocyte sedimentation rate is not included, and negative test for ANA is not required [3] (**Table 2**). Normal capillaroscopic pattern exists in both sets of criteria.

In primary RP, capillary morphology and capillary density are normal. Slightly enlarged capillary diameters could be found [32–34].
