**6. Secondary Raynaud's phenomenon**

Older age of onset, thumb involvement, severe course with trophic alterations of the fingers (digital ulcers, digital necrotic lesions), clinical features suggestive of autoimmune disease, positive autoantibodies, and abnormal capillaroscopic findings are characteristic features of secondary RP in rheumatic diseases [4, 6, 7].

#### **6.1. Raynaud's phenomenon in systemic sclerosis**

RP is one of the most common symptoms in SSc with frequency of about 95% [8]. It is usually the initial clinical feature that appears years before other disease symptoms. SSc-related RP is severe and often complicates with development of digital ulcers. The capillaroscopic pattern in SSc is specific and is characterized with the presence of dilated and giant capillaries, hemorrhages, avascular areas, and neoangiogenic capillaries. It has been described by Maricq et al. and is termed "scleroderma" type capillaroscopic pattern, which is a reference capillaroscopic pattern in rheumatology. Maricq et al. also observed components of this pattern in diseases from the scope of scleroderma-spectrum disorders, e.g., mixed connective tissue disease (MCTD), undifferentiated connective tissue disease (UCTD), and dermatomyositis (DM)—the so-called "scleroderma-like" pattern [35–37].


For establishing the diagnosis of SSc according to the ACR criteria (1980), the presence of the major criterion (skin thickening proximal to metacarpophalangeal joints of the hands) or two minor criteria ((1) sclerodactyly, (2) fingertip pitting scars, (3) bibasilar pulmonary fibrosis) is required [42]. These criteria have been proposed prior to the discovery of SSc-related autoantibodies and the characteristic capillaroscopic findings, which both had been found to improve the early diagnosis of SSc [43, 44]. Thus, Le Roy and Medsger suggested patients with RP and "scleroderma" type capillaroscopic changes or positive SSc-related autoantibodies to be diagnosed as "prescleroderma" *or limited SSc* even if other disease symptoms are absent [45]. The multicenter project VEDOSS (Very Early Diagnosis of Systemic Sclerosis) resulted in the new classification criteria for SSc (European League Against Rheumatism (EULAR)/ACR, 2013), which aim to detect SSc in early stages. In the new EULAR/ACR classification criteria, RP is scored with 3 points (1), the abnormal capillaroscopic pattern with 2 points (2), and presence of SSc-related autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70), anti-RNA polymerase) with 3 points (maximum score for the immunologic criterion is 3) (3). The other criteria (overall 8 criteria) are as follows: telangiectasia (2 points) (4); fingertip lesions (digital tip ulcers - 2 points or fingertip pitting scars - 3 points), only the higher score is counted (5); pulmonary arterial hypertension and/or interstitial lung disease are scored with 2 points (6); skin thickening of the fingers (puffy fingers - score 2; sclerodactyly of the fingers - score 4), only the higher score is counted (7); skin thickening of both hands proximal to the metacarpophalangeal joints is scored with 9 points (8). A score ≥ 9 is necessary for a definite diagnosis

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MCTD combines symptoms of systemic lupus erythematosus (SLE), SSc, polymyositis (PM)/DM, arthritis, and the presence of a specific immunologic marker—anti-U1 RNP (an antibody against extractable nuclear antigen)—the latter being an obligatory classification criterion for the disease [48]. RP is met in 85% of patients with MCTD [8] and is the most common initial symptom [49]. Currently, the classification criteria for MCTD used in clinical practice are suggested by different author groups and not by professional organizations (criteria of Alarcon-Segovia, Kasukawa, Sharp, Kahn). RP is included in all of them because of its high frequency in MCTD [50]. Of note, the "SSc-like" capillaroscopic changes could be observed in a significantly lower proportion of MCTD patients in comparison with SSc. Maricq et al. have observed "SSc-like" pattern in 54% of cases in the examined group of 26 MCTD patients [36]. Bergman et al. detected "SSc-like" pattern in 50% (4/8) of the cases [51] and de Holanda Mafaldo Diógenes et al. in 65–71.5% [52]. Granier et al. observed a similar frequency of

In UCTD patients, there are different symptoms of systemic rheumatic disease, but there is no full set of criteria of a well-defined rheumatic disorder. RP is a frequent symptom that may be observed in about 80% of the patients with UCTD. In evolution, a proportion of these patients (1/4–1/3) develop a distinct rheumatic disease, the most frequent being SSc, SLE, rheumatoid arthritis (RA), and Sjögren syndrome, but the majority of cases remain in a clinically

of SSc [46, 47].

**6.2. Raynaud's phenomenon in mixed connective tissue disease**

"scleroderma-like" capillaroscopic pattern—63.6% [53].

**6.3. Raynaud's phenomenon in undifferentiated connective tissue disease**

**Table 2.** Diagnostic criteria for primary Raynaud's phenomenon (Le Roy and Medsger [31]; Maverakis et al. [3]).

Cutolo et al. [38] described three phases of capillaroscopic changes in SSc:


"Scleroderma" type capillaroscopic pattern is found in the majority of SSc patients (about 90%). Maricq et al. detected "scleroderma" pattern in 82–95% of SSc patients [36, 37]. In an own study, "scleroderma" pattern of the hands was detected in 97.2% (35/36) of SSc patients [34, 39, 40].

In addition, it has been found that a number of patients with a definite diagnosis of SSc (those with sclerodactyly, telangiectasia, subcutaneous calcinosis, esophageal dysmotility, etc.) do not fulfill the ACR (American College of Rheumatology) classification criteria for the disease (1980). An abnormal "scleroderma" type capillaroscopic pattern was found in these cases [41].

**Figure 1.** "Scleroderma type" capillaroscopic pattern in SSc (1) "early" phase, there is a single giant capillary loop and a single hemorrhage; (2) "active" phase, magnification 200×.

For establishing the diagnosis of SSc according to the ACR criteria (1980), the presence of the major criterion (skin thickening proximal to metacarpophalangeal joints of the hands) or two minor criteria ((1) sclerodactyly, (2) fingertip pitting scars, (3) bibasilar pulmonary fibrosis) is required [42]. These criteria have been proposed prior to the discovery of SSc-related autoantibodies and the characteristic capillaroscopic findings, which both had been found to improve the early diagnosis of SSc [43, 44]. Thus, Le Roy and Medsger suggested patients with RP and "scleroderma" type capillaroscopic changes or positive SSc-related autoantibodies to be diagnosed as "prescleroderma" *or limited SSc* even if other disease symptoms are absent [45]. The multicenter project VEDOSS (Very Early Diagnosis of Systemic Sclerosis) resulted in the new classification criteria for SSc (European League Against Rheumatism (EULAR)/ACR, 2013), which aim to detect SSc in early stages. In the new EULAR/ACR classification criteria, RP is scored with 3 points (1), the abnormal capillaroscopic pattern with 2 points (2), and presence of SSc-related autoantibodies (anticentromere, anti-topoisomerase I (anti-Scl-70), anti-RNA polymerase) with 3 points (maximum score for the immunologic criterion is 3) (3). The other criteria (overall 8 criteria) are as follows: telangiectasia (2 points) (4); fingertip lesions (digital tip ulcers - 2 points or fingertip pitting scars - 3 points), only the higher score is counted (5); pulmonary arterial hypertension and/or interstitial lung disease are scored with 2 points (6); skin thickening of the fingers (puffy fingers - score 2; sclerodactyly of the fingers - score 4), only the higher score is counted (7); skin thickening of both hands proximal to the metacarpophalangeal joints is scored with 9 points (8). A score ≥ 9 is necessary for a definite diagnosis of SSc [46, 47].

#### **6.2. Raynaud's phenomenon in mixed connective tissue disease**

MCTD combines symptoms of systemic lupus erythematosus (SLE), SSc, polymyositis (PM)/DM, arthritis, and the presence of a specific immunologic marker—anti-U1 RNP (an antibody against extractable nuclear antigen)—the latter being an obligatory classification criterion for the disease [48]. RP is met in 85% of patients with MCTD [8] and is the most common initial symptom [49]. Currently, the classification criteria for MCTD used in clinical practice are suggested by different author groups and not by professional organizations (criteria of Alarcon-Segovia, Kasukawa, Sharp, Kahn). RP is included in all of them because of its high frequency in MCTD [50]. Of note, the "SSc-like" capillaroscopic changes could be observed in a significantly lower proportion of MCTD patients in comparison with SSc. Maricq et al. have observed "SSc-like" pattern in 54% of cases in the examined group of 26 MCTD patients [36]. Bergman et al. detected "SSc-like" pattern in 50% (4/8) of the cases [51] and de Holanda Mafaldo Diógenes et al. in 65–71.5% [52]. Granier et al. observed a similar frequency of "scleroderma-like" capillaroscopic pattern—63.6% [53].

#### **6.3. Raynaud's phenomenon in undifferentiated connective tissue disease**

**Figure 1.** "Scleroderma type" capillaroscopic pattern in SSc (1) "early" phase, there is a single giant capillary loop and a

Cutolo et al. [38] described three phases of capillaroscopic changes in SSc:

I. An "early" phase—appearance of few dilated and/or giant capillaries and few hemorrhages. In this phase, the distribution is relatively preserved without loss of capillaries. II. An "active" phase—the changes in this phase include a higher number of giant capillaries and hemorrhages, a moderate loss of capillaries, slight derangement, and, in some cases,

**Table 2.** Diagnostic criteria for primary Raynaud's phenomenon (Le Roy and Medsger [31]; Maverakis et al. [3]).

**1.**Normal capillaroscopy

calcinosis, or skin fibrosis) **3.**No history of existing CTD

**2.**Negative physical examination for findings suggestive of secondary causes (e.g., ulcerations, tissue necrosis or gangrene, sclerodactyly,

**4.**Negative or low titer ANA (e.g., 1:40 by indirect immunofluorescence)

III. A "late" phase—it is characterized with extensive avascular areas, severe capillary

"Scleroderma" type capillaroscopic pattern is found in the majority of SSc patients (about 90%). Maricq et al. detected "scleroderma" pattern in 82–95% of SSc patients [36, 37]. In an own study, "scleroderma" pattern of the hands was detected in 97.2% (35/36) of SSc patients [34, 39, 40].

In addition, it has been found that a number of patients with a definite diagnosis of SSc (those with sclerodactyly, telangiectasia, subcutaneous calcinosis, esophageal dysmotility, etc.) do not fulfill the ACR (American College of Rheumatology) classification criteria for the disease (1980). An abnormal "scleroderma" type capillaroscopic pattern was found in these cases [41].

single hemorrhage; (2) "active" phase, magnification 200×.

diffuse pericapillary edema (**Figure 1**).

**Le Roy and Medsger [31] Maverakis et al. [3]**

**1.**Vasospastic attacks precipitated by cold or

**3.**Absence of digital ulcerations or gangrenes **4.**Normal erythrocyte sedimentation rate

emotional stress **2.**Symmetric attacks

32 Newest Updates in Rheumatology

**5.**Negative test for ANA

**6.**Normal capillaroscopic picture

derangement, and bushy and ramified capillaries [38].

In UCTD patients, there are different symptoms of systemic rheumatic disease, but there is no full set of criteria of a well-defined rheumatic disorder. RP is a frequent symptom that may be observed in about 80% of the patients with UCTD. In evolution, a proportion of these patients (1/4–1/3) develop a distinct rheumatic disease, the most frequent being SSc, SLE, rheumatoid arthritis (RA), and Sjögren syndrome, but the majority of cases remain in a clinically and laboratory stable condition in the scope of the term "UCTD." In UCTD, the frequency of "scleroderma-like pattern" is lower as compared with SSc (13.8%, Nagy et al. [41]; 38%, Lambova et al.) [34, 54]. The presence of "scleroderma-like" capillaroscopic pattern in patients with UCTD is considered to be a reliable predictive factor for the development of SSc [41].

et al. observed the following capillaroscopic changes: presence of elongated capillary loops, increased capillary tortuosity, and prominent subpapillary plexus. A "SSc-like" pattern was not detected in RA [55]. Nagy et al. also did not observe "SSc-like" pattern in a group of 14

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Of note, in an own study that included higher number of patients with RA (n = 62) with and without RP, a "SSc-like" pattern was observed in 14.5% (9/62; 2 males and 7 females). In one of the nine cases with such capillaroscopic changes, an overlap syndrome (RA overlap to SLE) with secondary RP and secondary vasculitis of peripheral vessels was evident. While in the rest eight out of nine patients, no overlap with other CTD was present. All RA patients with "SSc-like" capillaroscopic pattern (9/9) exhibited symptoms of secondary RP, and 2/9 a secondary vasculitis of peripheral vessels, respectively. Our results suggest that "SSc-like" capillaroscopic pattern could be observed in RA patients with secondary RP and with vasculitis of peripheral vessels although with low frequency. However, its presence is not mandatory

RP may be a paraneoplastic symptom. When RP is newly appeared with late onset after the age of 60, it may also be an indicator for an underlying malignancy. Ischemia of the fingers has been reported in patients with carcinomas of the breast, the stomach, and the esophagus as well as in patients with oncohematologic disease (multiple myeloma, thrombocythemia, etc.). In a part of the cases, paraneoplastic RP is caused by secretion of vasoactive substances by the tumor cells and the respective immune response of the body, while in others like multiple myeloma and thrombocytopenia, it is associated with increased blood viscosity [64, 65]. We have not observed differences between microvascular changes in paraneoplastic rheumatic

Fibromyalgia is an idiopathic, chronic, musculoskeletal, pain syndrome characterized with diffuse pain and presence of multiple tender points [67]. Primary fibromyalgia is an isolated disorder, while secondary fibromyalgia could be observed in different rheumatic diseases, e.g., RA, SLE, Sjögren syndrome, etc. [68]. RP is met in both primary and secondary fibromyalgia. The frequency of RP in fibromyalgia patients is about 17–30% [69, 70]. In an own study that included 26 patients with primary fibromyalgia, the most frequent capillaroscopic finding was the presence of dilated capillary loops analogous to primary RP. Capillaroscopic

conditions in comparison with the respective idiopathic rheumatic diseases [66].

**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

patients with RA [41].

in the context of overlap syndromes [34, 63].

**6.7. Paraneoplastic Raynaud's phenomenon**

**6.8. Raynaud's phenomenon in fibromyalgia**

signs of microangiopathy were not detected [71].

#### **6.4. Raynaud's phenomenon in systemic lupus erythematosus**

The prevalence of RP in SLE is between 10 and 45% [8]. Although in a proportion of cases with SLE peripheral vessel is affected by vasculitis, RP usually tends to have a benign course without the development of digital ulcers or necrosis [9]. Microvascular capillaroscopic changes in SLE are less specific vs. those in scleroderma-spectrum disorders. However, several capillaroscopic features have been noted in SLE that are termed "SLE" type capillaroscopic pattern [51, 53, 55], which includes the presence of elongated [53, 56] and dilated capillary loops, tortuous and meandering capillaries [55], and prominent subpapillary plexus [53, 56]. "Scleroderma-like" capillaroscopic pattern is a rare finding in SLE with frequency varying between 2 and 15% [36, 41, 51, 56, 57]. An association between "scleroderma-like" capillaroscopic pattern and the presence of RP and anti-U1 RNP antibody has been observed that is suggested to be in the context of a possible subclinical overlap syndrome with SSc [57]. In an own study of 30 SLE patients, RP was found in 73% of cases, and "scleroderma-like" capillaroscopic pattern in 13.3% of the patients (4/30). Such changes were observed in patients with high immunological activity, two of whom were with active vasculitis of peripheral vessels and two with secondary RP. They did not exhibit signs of overlap with SSc or other CTD. Anti-RNP antibody was positive in a single case in a patient with symptoms of secondary RP without peripheral vessel vasculitis, while in the other three cases with "sclerodermalike" pattern, this immunological marker was negative [34, 54]. Thus, it could be concluded that "scleroderma-like" capillaroscopic pattern could be found in SLE patients with high immunological activity, both in cases with active vasculitis of peripheral vessels and only with symptoms of secondary RP but without evidence for overlap with SSc or other CTD.

#### **6.5. Raynaud's phenomenon in dermatomyositis and polymyositis**

RP occurs in about 20% of DM/PM patients [8]. Digital gangrenes of the hands are usually not observed. When such changes are evident, the presence of neoplasm should be suspected. RP is characteristic for the antisynthetase syndrome, which is a subset of myositis characterized with positive anti-Jo-1 antibodies (against histidyl-tRNA synthetase), interstitial lung disease, nonerosive symmetric polyarthritis in small joints, and cracking and fissuring of the skin of the fingers ("mechanic's hands") [58]. In a part of the cases with DM, "scleroderma-like "capillaroscopic findings could be observed [35]. Although the capillaroscopic changes in DM and SSc are usually indistinguishable, it is suggested that bushy and branching capillaries could be found more frequently in DM [59]. The frequency of "SSc-like" pattern detected by Bergman et al. in 11 patients with DM was 63.6% [51].

#### **6.6. Raynaud's phenomenon in rheumatoid arthritis**

The prevalence of RP in RA varies between 3 and 17% (2.7%, Carrol et al., North Australia [60]; 4.6%, Grassi et al., Italy [61]; and 17.2%, Saraux et al., France) [62]. In 31 RA patients, Redisch et al. observed the following capillaroscopic changes: presence of elongated capillary loops, increased capillary tortuosity, and prominent subpapillary plexus. A "SSc-like" pattern was not detected in RA [55]. Nagy et al. also did not observe "SSc-like" pattern in a group of 14 patients with RA [41].

Of note, in an own study that included higher number of patients with RA (n = 62) with and without RP, a "SSc-like" pattern was observed in 14.5% (9/62; 2 males and 7 females). In one of the nine cases with such capillaroscopic changes, an overlap syndrome (RA overlap to SLE) with secondary RP and secondary vasculitis of peripheral vessels was evident. While in the rest eight out of nine patients, no overlap with other CTD was present. All RA patients with "SSc-like" capillaroscopic pattern (9/9) exhibited symptoms of secondary RP, and 2/9 a secondary vasculitis of peripheral vessels, respectively. Our results suggest that "SSc-like" capillaroscopic pattern could be observed in RA patients with secondary RP and with vasculitis of peripheral vessels although with low frequency. However, its presence is not mandatory in the context of overlap syndromes [34, 63].

#### **6.7. Paraneoplastic Raynaud's phenomenon**

and laboratory stable condition in the scope of the term "UCTD." In UCTD, the frequency of "scleroderma-like pattern" is lower as compared with SSc (13.8%, Nagy et al. [41]; 38%, Lambova et al.) [34, 54]. The presence of "scleroderma-like" capillaroscopic pattern in patients with UCTD is considered to be a reliable predictive factor for the development of SSc [41].

The prevalence of RP in SLE is between 10 and 45% [8]. Although in a proportion of cases with SLE peripheral vessel is affected by vasculitis, RP usually tends to have a benign course without the development of digital ulcers or necrosis [9]. Microvascular capillaroscopic changes in SLE are less specific vs. those in scleroderma-spectrum disorders. However, several capillaroscopic features have been noted in SLE that are termed "SLE" type capillaroscopic pattern [51, 53, 55], which includes the presence of elongated [53, 56] and dilated capillary loops, tortuous and meandering capillaries [55], and prominent subpapillary plexus [53, 56]. "Scleroderma-like" capillaroscopic pattern is a rare finding in SLE with frequency varying between 2 and 15% [36, 41, 51, 56, 57]. An association between "scleroderma-like" capillaroscopic pattern and the presence of RP and anti-U1 RNP antibody has been observed that is suggested to be in the context of a possible subclinical overlap syndrome with SSc [57]. In an own study of 30 SLE patients, RP was found in 73% of cases, and "scleroderma-like" capillaroscopic pattern in 13.3% of the patients (4/30). Such changes were observed in patients with high immunological activity, two of whom were with active vasculitis of peripheral vessels and two with secondary RP. They did not exhibit signs of overlap with SSc or other CTD. Anti-RNP antibody was positive in a single case in a patient with symptoms of secondary RP without peripheral vessel vasculitis, while in the other three cases with "sclerodermalike" pattern, this immunological marker was negative [34, 54]. Thus, it could be concluded that "scleroderma-like" capillaroscopic pattern could be found in SLE patients with high immunological activity, both in cases with active vasculitis of peripheral vessels and only with symptoms of secondary RP but without evidence for overlap with SSc or other CTD.

**6.4. Raynaud's phenomenon in systemic lupus erythematosus**

34 Newest Updates in Rheumatology

**6.5. Raynaud's phenomenon in dermatomyositis and polymyositis**

Bergman et al. in 11 patients with DM was 63.6% [51].

**6.6. Raynaud's phenomenon in rheumatoid arthritis**

RP occurs in about 20% of DM/PM patients [8]. Digital gangrenes of the hands are usually not observed. When such changes are evident, the presence of neoplasm should be suspected. RP is characteristic for the antisynthetase syndrome, which is a subset of myositis characterized with positive anti-Jo-1 antibodies (against histidyl-tRNA synthetase), interstitial lung disease, nonerosive symmetric polyarthritis in small joints, and cracking and fissuring of the skin of the fingers ("mechanic's hands") [58]. In a part of the cases with DM, "scleroderma-like "capillaroscopic findings could be observed [35]. Although the capillaroscopic changes in DM and SSc are usually indistinguishable, it is suggested that bushy and branching capillaries could be found more frequently in DM [59]. The frequency of "SSc-like" pattern detected by

The prevalence of RP in RA varies between 3 and 17% (2.7%, Carrol et al., North Australia [60]; 4.6%, Grassi et al., Italy [61]; and 17.2%, Saraux et al., France) [62]. In 31 RA patients, Redisch RP may be a paraneoplastic symptom. When RP is newly appeared with late onset after the age of 60, it may also be an indicator for an underlying malignancy. Ischemia of the fingers has been reported in patients with carcinomas of the breast, the stomach, and the esophagus as well as in patients with oncohematologic disease (multiple myeloma, thrombocythemia, etc.). In a part of the cases, paraneoplastic RP is caused by secretion of vasoactive substances by the tumor cells and the respective immune response of the body, while in others like multiple myeloma and thrombocytopenia, it is associated with increased blood viscosity [64, 65]. We have not observed differences between microvascular changes in paraneoplastic rheumatic conditions in comparison with the respective idiopathic rheumatic diseases [66].
