**8. Treatment**

*Vascular Biology - Selection of Mechanisms and Clinical Applications*

polymerase III, anti-topoisomerase I, and anti-U3RNP [36].

Renal involvement in scleroderma is quite common. Even though it appears often as mild renal dysfunction, it can also cause a severe clinical table called scleroderma renal crisis (SRC). The pathogenesis of SRC is not fully known, but studies suggest vasculopathy as a source. Corticosteroids and vasospasm-causing drugs (tacrolimus, cyclosporine, and cocaine) may play a role in the etiology [36]. The risk of SRC development increases in the presence of the autoantibodies anti-RNA

Some patients show a chronic clinical table with gradual decrease in eGFR, increase in serum creatinine concentration, proteinuria, hematuria, and moderate

Decreased glomerular filtration rate, increased serum creatinine, hemolytic anemia, proteinuria, and decreased platelet count are laboratory findings indicating

Antinuclear antibodies (ANA) are 90–95% positive in SSc patients and are the most commonly detected autoantibody. Scleroderma-like diseases should also be considered in the case of ANA negativity. Anti-topoisomerase I (anti-scl 70) antibodies are connected to pulmonary complications, digitals ulcers, and progressive hand involvement. Anti-centromere antibodies are common in limited SSc and positively increase the risk of pulmonary fibrosis and pulmonary hypertension. Anti-RNA polymerase III antibody is associated with renal crisis. Also anti-U3RNP and anti-Th/ To antibodies can be detected positively, and the anti-U3RNP antibody increases the risk of pulmonary artery hypertension and cardiovascular complications [37].

The diagnosis of systemic sclerosis is placed clinically; therefore biopsy is not recommended routinely [38]. It can be used to rule out other diseases for differential diagnosis. Histologically, excessive collagen accumulation, atrophy of pilosebaceous and eccrine glands, subcutaneous fat loss, and lymphocytic infiltrate are observed. Increased collagen can compress adnexal structures, especially eccrine

There are many diseases that may trigger dermal sclerosis. The form and character of skin involvement, history of underlying diseases, and chemical exposures are helpful factors in approaching the diagnosis of a patient with skin thickening. Some laboratory studies may be beneficial in verifying imaging and skin biopsy diagnosis [8]. Eosinophilic fasciitis, scleroderma, scleromyxedema, and nephrogenic systemic fibrosis are important in the differential diagnosis of SSc. SSc can be differentiated from other scleroses by the presence of Raynaud's phenomenon, typical distal extremity involvement, nail fold capillary findings, presence of autoantibodies, and internal organ involvement. While the groove mark, which is a recess caused by the withdrawal of subcutaneous tissues along the path of the superficial vessels, favors the eosinophilic fasciitis [39], the detection of monoclonal gammopathy directs

**4.6 Renal involvement**

arterial hypertension [31].

renal involvement [31].

**5. Autoantibodies**

**6. Histopathology**

**7. Differential diagnosis**

glands [38].

**126**

The pathogenesis of SSc is still unclear. In recent years, advances have been made in the treatment of the disease, resulting in a prominent improvement in survival rates. The efficient treatment of complications increases the chances of success. Disease duration, complications, and disease activity should be taken into consideration when making therapeutic decisions. The treatment is based on modifying agents and organ-specific drugs [41].

Peripheral vascular involvement frequently occurs as Raynaud's phenomenon. In addition, digital ischemia due to digital vasculopathy, digital ulcers, and associated amputations may be the causes for morbidity in SSc.

Patients with Raynaud's phenomenon should protect themselves from the cold. They also should not smoke and should avoid vasoconstrictor agents. Calcium channel inhibitors (nifedipine, diltiazem, amlodipine) should be the first choice as treatment [41]. Iloprost and other intravenous prostanoids can be used in cases that do not respond to the above. Also, phosphodiesterase type 5 (PDE5) inhibitors may be effective in resistant cases. Selective serotonin reuptake inhibitors, pentoxifylline, prazosin, and endothelin receptor antagonists (ERA) are agents that are less effective and used in selected cases [42].

Early treatment of patients with digital ischemia SSc reduces the risk of morbidity. Intermittent infusion of prostacyclin or analogs was found to be effective in the treatment of RF and ischemic digital ulcer [41]. Sildenafil and bosentan are recommended for the treatment of digital ulcers that developed due to unsuccessful treated systemic sclerosis with calcium channel blockers and prostanoid therapies [41]. There are also uncontrolled studies suggesting that atorvastatin, vitamin E, and intravenous N-acetylcysteine may be beneficial. Mesenchymal stem cell therapy is one of the developing methods in the treatment of DU [43].

The first choice for the treatment of pulmonary artery hypertension is phosphodiesterase type 5 inhibitors (e.g., sildenafil or tadalafil) or endothelin receptor antagonists such as bosentan and macitentan. If those are not effective, prostanoids may be added to the treatment [44]. Prostanoids are the first choice in severe cases. If there is no response, combination treatments can be applied. Recently, the guanylate cyclase agonist riociguat has been involved in treatment [41].

The treatment of interstitial lung disease patients is based on immunosuppressive drugs. The first preferred agent is oral mycophenolate mofetil (MMF). One of the applied treatment regimens for nonresponsive patients is the administration of cyclophosphamide (CYC) orally at doses of 1–2 mg/kg/day or iv 600 mg/m2 / month. After the disease activity has been taken under control, it is recommended to continue treatment with azathioprine at a dose of 2.5 mg/kg/day [41]. In selected patients, rituximab (RTX, anti-CD20 monoclonal antibody) can be used as an alternative treatment [41, 45].

Immunosuppressants such as methotrexate (MTX), cyclophosphamide, and mycophenolate mofetil are commonly used in fibrosis of the skin [31]. If the treatment is unsuccessful or if these drugs cannot be used for whatever reason, low-dose systemic corticosteroids or rituximab may be preferred [31]. The effect of d-penicillamine, which has been used for many years, is controversial [46].

In systemic sclerosis, exertional dyspnea, tachycardia, and chest pain may occur due to myocardial involvement. Selective beta-blockers are effective in this kind


*ERA, endothelin receptor antagonists; HSCT, hematopoietic stem cell transplantation; PAH, pulmonary arterial hypertension; PDE-5, phosphodiesterase type 5; PPI, proton pump inhibitor; SRC, scleroderma renal crisis; SSc, systemic sclerosis; RP, Raynaud's phenomenon.*

*\* Treats and reduces the formation of new ulcers.*

*\*\*Blood pressure and renal function should be carefully monitored in SSc patients treated with glucocorticoids.*

#### **Table 2.**

*The updated EULAR recommendations for treatment of systemic sclerosis.*

of symptoms [33]. If cardiac tamponade develops due to pericarditis in cardiac involvement, treatment becomes more difficult. The patient may not respond to systemic corticosteroid therapy, and drainage treatment may become necessary [47]. Some SSc patients may develop microvascular ischemia due to vasospasm of small coronary arteries and arterioles, also called cardiac Raynaud's phenomenon. Nifedipine treatment is quite effective in such patients [48].

SSc patients with GI involvement of dysphagia, pyrosis, esophageal reflux, esophagitis, distention, abdominal pain, and diarrhea can be treated with proton pump inhibitors (PPI), prokinetic drugs, and intermittent antibiotics (gg). Patients that developed gastric antral vascular ectasia may have severe upper GI bleeding. Here, supportive treatment and endoscopic treatment methods can be used. Surgical antrectomy becomes necessary as the last resort in resistant cases [49].

The first choice for patients with scleroderma renal crisis is a high dose of angiotensin receptor antagonists (ACE-I). It was determined that this treatment significantly decreased mortality [31]. In cases with insufficient response, angiotensin receptor blockers (ARB) and calcium channel blockers may be combined with ACE-I treatment of nitrates [31]. Beta-blockers are not recommended due to

**129**

**Author details**

Murat Borlu\* and Eda Öksüm Solak

provided the original work is properly cited.

University, Kayseri, Turkey

Dermatology and Venereology Department, Faculty of Medicine, Erciyes

© 2020 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/ by/3.0), which permits unrestricted use, distribution, and reproduction in any medium,

\*Address all correspondence to: murat\_borlu@hotmail.com

*Systemic Sclerosis*

**9. Result**

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

successful and specific treatment methods.

significantly increase the risk [50].

are summarized in **Table 2**.

their vasoconstriction enhancing effects. Hypotension should be avoided, and close monitoring should be performed for patients using systemic steroids since they

The updated EULAR recommendations for the treatment of systemic sclerosis

As a result, we should not forget that systemic sclerosis is a chronic disease that can cause serious morbidity and mortality and that placing a diagnosis can be difficult from time to time. The disease does not have a specific treatment. The patient should be evaluated according to involved systems and clinical table. In addition, early diagnosis and early initiation of treatment increase the chances of efficacy. A better understanding of the pathogenesis may lead to the development of more

their vasoconstriction enhancing effects. Hypotension should be avoided, and close monitoring should be performed for patients using systemic steroids since they significantly increase the risk [50].

The updated EULAR recommendations for the treatment of systemic sclerosis are summarized in **Table 2**.
