[의학] Disease review of Systemic Sclerosis 의학

1. Definition
 - Systemic sclerosis (SSc) 
 : a connective tissue disorder of unknown etiology, heterogeneous clinical manifestations, and chronic and often progressive course, Patients can be classified into two principal subsets - Limited cutaneous SSc & Diffuse cutaneous SSc

2. Epidemiology
 - Acquired sporadic disease with a worldwide distribution and affecting all races
 - In the United States, the incidence is estimated at 9–19 cases per million per year
 - There are an estimated 100,000 cases in the United States
 - Other connective tissue diseases, SSc shows a female predominance that is most pronounced in the childbearing years and declines after menopause
 - Most common age of onset is in the range of 30–50 years

3. Genetic Considerations
 - Non-Mendelian pattern of inheritance
 - Monozygotic twins have a relatively low concordance rate for SSc (4.7%), although concordance for antinuclear antibodies is significantly greater.
 - The risk of other autoimmune diseases, including systemic lupus erythematosus (SLE) and rheumatoid arthritis is also increased

4. Pathogenesis
 - Pathogenesis of SSc must incorporate the three cardinal features of the disease
 (1) vasculopathy
 (2) cellular and humoral auto immunity
 (3) progressive visceral and vascular fibrosis in multiple organs


6. GENERAL MANIFESTATIONS
 - Fatigue, arthralgias, and myalgias are common symptoms in patients with SSc
 - Less commonly noted symptoms were breathlessness, upset stomach, sore eyes, depression, nausea, and weight loss

7. SKIN INVOLVEMENT
- Skin involvement is a nearly universal feature of SSc
  Fingers, hands, and face are generally the earliest areas of the body involved
- The assessment of skin 
  Skin thickness, pliability (hardness), and fixation to underlying structures (tethering)
  The modified Rodnan skin score : 0 (normal) to 3 (most severe) in 17 distinct areas of the body
- Radiographs of the hands 
  Soft tissue calcifications (calcinosis cutis) 
  Resorption of the distal phalangeal tufts (acro-osteolysis)

8. Limited cutaneous SSc 
  - skin sclerosis is restricted to the hands, the distal forearm, and, to a lesser extent, the face and neck
  - prominent vascular manifestations, including severe Raynaud phenomenon and cutaneous telangiectasia. 
  - the CREST syndrome 
  (Calcinosis cutis, Raynaud phenomenon, Esophageal dysmotility, Sclerodactyly, and Telangiectasia)

9. Diffuse cutaneous SSc
 - Sclerotic skin on the chest, abdomen, or upper arms and shoulders
 - Patients with dcSSc are more likely to have, or to develop, significant internal organ damage due to ischemic injury or fibrosis than those with limited cutaneous SSc

10. Vascular disease
 - The most characteristic clinical manifestation of vascular dysfunction of SSc is Raynaud phenomenon
due to arterial vasoconstriction in the digits. The color changes of pallor ("white"), acrocyanosis ("blue"), and reperfusion hyperemia ("red") are characteristic
Vascular injury and consequent chronic tissue damage underlie other serious complications of SSc, 
pulmonary artery hypertension, scleroderma renal crisis, and gastric antral vascular ectasia, and also contribute to the pathogenesis of cardiac and gastrointestinal complications

11.Extracutaneous organ involvement
 - Extracutaneous organ involvement is virtually universal in SSc
   Along with musculoskeletal involvement, the lungs, kidneys, gastrointestinal tract, and heart are commonly affected
12. Cancer Risk
 - The most significant association appears to be with lung cancer
    In a study of 632 Australian patients with SSc, 19 developed lung cancer 
 - The cause of an increased cancer risk in SSc is not well understood
 - The association with lung and skin cancers suggests that sites of disease activity may be prone to malignant transformation

13. Treatment
  - No therapy has been shown to significantly alter the natural history of SSc
    multiple interventions are highly effective in alleviating the symptoms and in slowing the progression of the cumulative organ damage

14. Anti-Fibrotic Therapy
 - Widespread tissue fibrosis causes progressive organ damage in dcSSc 
    drugs that interfere with the fibrotic process represent a rational approach to therapy
 - D-Penicillamine has been extensively used as an antifibrotic agent
    Retrospective studies in SSc indicated that D-penicillamine stabilized and improved skin induration, prevented new internal organ involvement, and improved survival
    However, RCT in early active SSc, no difference in the extent of skin involvement between standard-dose (750 mg/d) or very low-dose(125 mg every other day) D-penicillamine

15. Vascular Therapy
- The goal of vascular therapy is to control Raynaud's phenomenon
   Calcium channel blockers(nifedipine or diltiazem) : commonly used but show only moderate benefit
   ARB(losartan) : effective and generally well tolerated
   Low-dose aspirin and dipyridamole 
   Endothelin-1 receptor antagonist(bosentan)
   Digital sympathectomy and local injections of botulinum type A (botox)

16. Treatment of Gastrointestinal Complications
- Gastroesophageal reflux is very common
  > All patients with SSc should be treated for this complication
  > Significant reflux may occur in the absence of symptoms
  > Proton pump inhibitors may need to be given in relatively high doses
- Recurrent gastrointestinal bleeding from vascular ectasia in the gastric antrum 
  > Amenable to treatment with laser photocoagulation
- Bacterial overgrowth due to small-bowel dysmotility causes abdominal bloating and diarrhea and may lead to malabsorption and severe malnutrition

17. Treatment of Pulmonary Arterial Hypertension (PAH)
- When PAH is symptomatic, treatment should be started with an oral endothelin-1 receptor antagonist or a phosphodiesterase inhibitor such as sildenafil
  > also require diuretics, oral anticoagulation, and digoxin when appropriate
  > Prostacyclin analogues such as epoprostenol or treprostinil can be administered intravenously or by continuous subcutaneous infusion, or frequent inhalations via nebulizer. 
- Lung transplantation remains an option for patients with SSc-associated PAH who fail medical therapy

18. Treatment of Renal Crisis
- Potentially nephrotoxic drugs should be avoided, and glucocorticoids used only when absolutely necessary, and at low doses
- When renal crisis occurs, treatment should be started promptly with short-acting ACE inhibitors, with the goal of achieving rapid normalization of the blood pressure
- Kidney transplantation is appropriate for patients who are unable to discontinue dialysis after 2 years

19. Skin Care
- The inflammatory symptoms of early skin involvement can be effectively controlled with systemic antihistamines and cautious and short-term use of low-dose glucocorticoids (<5 mg/d of prednisone)
- Cyclophosphamide and methotrexate have also been shown to have modest effects on skin induration.

20. PROGNOSIS
- Mortality
  The overall mortality rate of patients with dcSSc is approximately five- to eightfold higher than that of the general population d/t pulmonary fibrosis and/or pulmonary hypertension
  For patients with limited skin involvement, the increase in the standardized mortality ratio is about twofold.
- Risk factors for increased mortality
   cardiac and/or gastrointestinal involvement and hypertension
  > Extent of skin involvement
   more severe skin sclerosis, as assessed by skin score, is associated with increased mortality
  > Pulmonary hypertension
   The severity of pulmonary hypertension is correlated with the risk of premature death
    An elevated mean right atrial pressure and/or decreased cardiac index were other poor prognostic findings

<Reference>
Chap. 323. Systemic Sclerosis and Related Disorders, Harrison’s Priciples of Internal Medicine, 18th ed. 
Overview of the clinical manifestations of systemic sclerosis (scleroderma) in adults, , UpToDate
Overview of the treatment and prognosis of systemic sclerosis (scleroderma) in adults, UpToDate

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