**3. Diagnostic criteria and classification**

esophageal motility disorder, sclerodactyly, telangiectasia) was first defined in 1959,

SSc is a heterogeneous disease and this disease spectrum contains different


**123**

*Systemic Sclerosis*

cal pictures.

**4. Clinical findings**

**4.1 Cutaneous involvement**

hands, feet, tongue, ears, and nose [24].

stated in the classification criteria [21].

results in an appearance of "salt and pepper" on the skin.

*DOI: http://dx.doi.org/10.5772/intechopen.91318*

defined, it is recommended not to use it nowadays [19].

it does not fit any classification criteria, and since a subgroup has not been fully

Systemic sclerosis is divided into two subgroups, according to cutaneous involvement: limited systemic sclerosis and diffuse systemic sclerosis. If cutaneous involvement is limited to distal extremities and the face, it is classified as limited systemic sclerosis, and if the involvement is present in the truncus and extremities, it is classified as diffuse systemic sclerosis [22]. Also, systemic sclerosis sine scleroderma, of which 5% of SSc patients are affected, shows typical SSc symptoms but no fibrosis of the skin [23]. Raynaud's phenomenon is seen in more than 90% of SSc patients and is triggered by exposure to cold or emotional stress. It is characterized by white, blue, and red discoloration after triggering and most often affects the

Cutaneous involvement generally consists of three phases. In the first stage, the edematous phase, non-pitting edema, facial mask appearance, and swelling of the fingers can be seen. After that comes the indurative phase, where the skin hardens and gets a shiny and tense appearance. The last stage is the atrophic phase, characterized by claw hand and sclerodactyly. Sharpening of the nose, thinning of the lips, vertical streaks around the mouth (**Figure 1**), and facial mimic loss may be seen. Skin lines or hyperpigmentation of skin areas exposed to trauma and depigmentation areas on the truncus, face, hand back, and leg fronts may develop. In some cases, the presence of depigmented areas, where perifollicular areas are preserved,

In systemic sclerosis disease-specific capillary dilatation, stumps and the presence of avascularity areas can be shown with nail bed capillaroscopy [25]. Sweat and atrophy of the sebaceous gland may lead to dry skin, flaking, and itching. Depending on the calcium accumulation in the skin, hard subcutaneous nodules may appear around the small joints of the hand (calcinosis cutis), which may open to the outside and become ulcers [26]. Ulcers (**Figure 2**) may also develop due to ischemia, trauma, and fibrotic tissue. Telangiectasia is commonly seen in SSc and is

The criteria published by the American Radiology Associates (ARA) in 1980 have been used for classification for a long time. According to this, symmetrical skin sclerosis in the metacarpophalangeal joint or proximal of the metatarsophalangeal joint is a major criterion, while sclerodactylia, digital atrophic cicatrice, and the loss of finger fat tissue in the distal and bilateral fibrosis in the lungs constitute minor criteria. Diagnosis is possible with the presence of the major criteria or two minor criteria [20]. The ARA criteria do not include patients with limited skin involvement or early SSc and do not involve capillaroscopy/autoantibody tests. In 2013, the American College of Rheumatology/European League against Rheumatism (ACR/EULAR) classification criteria were defined. Sensitivity and specificity of these criteria were shown to be higher than the ARA criteria [21]. **Table 1** shows the ACR/EULAR 2013 systemic sclerosis classification criteria. The total score is the sum of the points received from different categories. Patients with a score of nine or higher are classified as definitive systemic sclerosis. However, the use is not recommended in patients with skin thickening that does not involve the fingers, in the presence of scleroderma-like diseases or better clini-

#### **Table 1.**

*ACR/EULAR 2013 systemic sclerosis classification criteria (adapted from source [21]).*

#### *Systemic Sclerosis DOI: http://dx.doi.org/10.5772/intechopen.91318*

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

tissue fibrosis with activation of fibroblasts [9].

**3. Diagnostic criteria and classification**

and internal organs [17].

2. Skin hardening of the fingers

3. Fingertip lesions

polymerase III)

via IL 6 [18].

Basic pathogenicities of the disease are microvascular function disorder (vasculopathy) and immune activation, and the final effect of these events is progressive

Vascular disease is observed earliest in SSc pathogenesis. The disease plays an important role in the occurrence of pulmonary artery hypertension, Raynaud's phenomenon, renal damage, and digital ulcers (DU) [10–13]. Raynaud's phenomenon, a typical clinical characteristic of SSc, is a finding characterized by persistent vasospasm and increased adhesion molecules following ischemia and reperfusion attacks [14]. Increased adhesion molecules trigger platelets and neutrophils that bind to endothelial cells and produce superoxide radicals responsible for endothelial cell damage [15]. In addition, an imbalance between vasoconstrictor agents such as endothelin-1 (ET-1) and vasodilating agents such as nitric oxide was observed in SSc, which plays a role in the change of vascular permeability [16]. Increased ET-1 expression plays a role in vascular fibrosis, inflammation, and increased smooth muscle cell proliferation [12]. An impaired cross talk between endothelial cells and perivascular cells may induce an abnormal expression of endothelial growth factor (VEGF), TGF-β, and platelet-derived growth factor (PDGF) in SSc. This may lead to a disruption of peripheral vascularization, which results in fibrosis of the skin

It has been determined that Th2 cytokines such as IL 4, IL 5, and IL 13 are oversecreted in SSc patients. It increases IL 4 collagen synthesis and TGF-β production. With IL 13, however, fibroblast activity and TGF-β stimulation are carried out [18]. Also, B-cells produce antibodies and carry out direct fibroblast stimulation

SSc is a heterogeneous disease and this disease spectrum contains different forms. Although the CREST syndrome (calcinosis, Raynaud's phenomenon,

**Criteria Score** 1. Skin hardening of the fingers of both hands spreading proximal to the MKF joints 9

• Puffy fingers 2 • Sclerodactyly (only high scores will be counted) 4

• Digital ulcers 2 • Digital pitting (only high scores will be counted) 3 4. Telangiectasia 2 5. Capillary changes such as abnormal fingernails 2 6. Pulmonary arterial hypertension 2 • Interstitial lung disease (maximum 2 points) 2 7. Raynaud's phenomenon 3

3

8. SSc-related autoantibodies (anti-centromere, anti-topoisomerase I, anti-RNA

*ACR/EULAR 2013 systemic sclerosis classification criteria (adapted from source [21]).*

esophageal motility disorder, sclerodactyly, telangiectasia) was first defined in 1959,

**122**

**Table 1.**

it does not fit any classification criteria, and since a subgroup has not been fully defined, it is recommended not to use it nowadays [19].

The criteria published by the American Radiology Associates (ARA) in 1980 have been used for classification for a long time. According to this, symmetrical skin sclerosis in the metacarpophalangeal joint or proximal of the metatarsophalangeal joint is a major criterion, while sclerodactylia, digital atrophic cicatrice, and the loss of finger fat tissue in the distal and bilateral fibrosis in the lungs constitute minor criteria. Diagnosis is possible with the presence of the major criteria or two minor criteria [20]. The ARA criteria do not include patients with limited skin involvement or early SSc and do not involve capillaroscopy/autoantibody tests.

In 2013, the American College of Rheumatology/European League against Rheumatism (ACR/EULAR) classification criteria were defined. Sensitivity and specificity of these criteria were shown to be higher than the ARA criteria [21]. **Table 1** shows the ACR/EULAR 2013 systemic sclerosis classification criteria. The total score is the sum of the points received from different categories. Patients with a score of nine or higher are classified as definitive systemic sclerosis. However, the use is not recommended in patients with skin thickening that does not involve the fingers, in the presence of scleroderma-like diseases or better clinical pictures.
