Systemic Sclerosis (CREST syndrome)

Article Author:
Rotimi Adigun
Article Editor:
Anis Hariz
Updated:
1/11/2019 1:07:11 PM
PubMed Link:
Systemic Sclerosis (CREST syndrome)

Introduction

Systemic sclerosis, otherwise known as Scleroderma, is a rare connective tissue disorder. Although the etiology is not fully elucidated, systemic sclerosis is considered to be an autoimmune disease. The condition is characterized by a variable degree of systemic manifestations, including fibrosis (affecting multiple organs system); and telangiectasias and abnormalities of the digestive system. The condition is usually classified based on clinical and serological criteria into two major types: A diffuse, generalized and more debilitating type known as systemic sclerosis or scleroderma (dcSSc); and a more localized variant (lcSSc), characterized by Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, Syndactyl, and Telangiectasias (CREST syndrome). LcSSc is also known as morphea.

Diffuse Systemic Sclerosis is distinguished from the localized variant (CREST) mainly based on the extent of cutaneous symptoms which are more extensive and prevalent in diffuse sclerosis.

The organs most frequently affected by scleroderma are skin, gastrointestinal tract, lungs, kidneys, skeletal muscle, and pericardium.[1][2][3]

Etiology

Systemic sclerosis is an inherited condition, and a positive family history is one of the major identifiable risk factors for this condition. Autoimmunity is considered the major mechanism responsible for this disorder. Although several environmental triggers are suspected, there is no identified definitive etiological agent. Some of the factors that have been implicated include Cytomegalovirus (CMV) infection(CMV antibody has been demonstrated in a significant proportion of patients with systemic sclerosis) and industrial exposures to vinyl chloride, solvent, and silica. [4][5]

Epidemiology

Due to its rarity, epidemiological data for systemic sclerosis are sparse. There also exist significant variation in data when grouped by gender, time and geography. Global prevalence is approximately 0.3 to 24 per 100,000 population. Studies indicate higher prevalence for North America, Australia, and Western Europe compared to prevalence data for Japan and Asia. Estimated incidence for the United States is 67 males and 267 females per 100,000 population annually. There has been a significant increase in reported incidence starting from the 1950s. There is an overall female predominance. This is more pronounced for CREST syndrome, with a female to male ratio of 10:1. The diffuse variant is more evenly distributed among the sexes.

All racial groups are affected. It seems there is a higher incidence in European ancestry compared to Japanese or Asian ancestry. African American and Native American ancestry seem to be associated with increased disease severity. Systemic sclerosis is rare in children.[6]

Pathophysiology

Systemic sclerosis occurs as a result of excessive activation of the process repair known as fibrosis in affected individuals. Fibrosis is a process of wound healing that accompanies chronic inflammation which is characterized by proliferation of collagen-producing cells known as fibroblasts.

Murine experiments have shown that systemic sclerosis arises as a result of an interplay which involves autoimmunity, obliterative vascular lesions, and chronic inflammation. The interplay leads to excessive production of fibrosis-inducing cytokines, such as Transforming growth factor Beta (TGF-ß); platelet-derived growth factor (PDGF), and interleukin-4(IL-4).

Infectious agents such as Cytomegalovirus have been found to contribute to the development of systemic sclerosis by triggering fibroblast activation through activation of fibroblastic cytokines. 

Vasculopathy in systemic sclerosis includes a destructive vasculitis characterized by loss of small vessels and a progressive obliterative vasculopathy due to excessive fibrosis and diminished new vessel formation. These two mechanisms cause endothelial dysfunction, target organ ischemia and the other vascular complications seen in this disorder.

Other mediators of disease in systemic sclerosis are human leukocyte antigens(HLA). The following HLAs have been implicated in the causation of this disorder: HLA-B8, HLA-DR5, HLA-DR3, HLA-DQB2, and HLA- DR-52.[7]

History and Physical

History and Physical findings differ significantly between Systemic Sclerosis and the limited scleroderma. The clinical presentation also varies significantly among affected individuals.

Diffuse Systemic Sclerosis

Skin: Raynaud's phenomenon characterized by color changes in the hands-on exposure to cold is a frequent cutaneous finding. Other findings in the skin include pruritus, tightening of the skin, ulceration of the skin, claw fingers (sclerodactyly), skin atrophy, dilated blood vessels(telangiectasia), Alternating hypopigmentation with hyperpigmentation in the limbs(salt and pepper appearance).

Gastro-Intestinal System: Swallowing difficulty, bloating, flatulence, altered bowel movement, and weight loss.

Lungs: A non-productive cough, chest tightness, and chest pain

Musculoskeletal System: weakness, Joint pain, and myopathy.

Pulmonary fibrosis, cardiac lesion, and renal disease is relatively early onset in diffuse systemic sclerosis compared to the limited form.

Limited Scleroderma (CREST) syndrome

The clinical features and disease progression are more insidious. Limited scleroderma (formerly known as CREST) syndrome is characterized by Calcinosis, Raynaud's phenomenon, Esophageal dysmotility, sclerodactyly, and telangiectasia.

Multiple organ systems including the lungs and skin are affected. However, the progression of fibrosis is slower in the CREST syndrome compared to the diffuse form of the disease.

Pulmonary hypertension and pulmonary fibrosis are leading causes of death in scleroderma.

Evaluation

The mainstay of diagnosis in systemic sclerosis remains the clinical presentation. Several investigations could provide additional information for classification and prognostication. The Rodnian skin score is used for classification, prognostication, and staging of clinical severity. Primary care professionals have a critical role in early detection and management of this disease and should exhibit a high index of suspicion in patients with a family history or symptoms of early disease. Raynaud's phenomenon is the most frequent early clinical presentation.  [8][9][10] Patients with clinical signs or symptoms of systemic sclerosis are evaluated with the following:

Antibody Tests

Like most autoimmune disorders, several antibodies are useful in the evaluation of this disease. Two antibody tests are especially important for diagnosis and classification. They are, Anti-Scl- 70 (Topoisomerase I)  and anti-centromere antibody. Positive test for anti scl70 is seen in about 30% of diffuse sclerosis. This test is negative in most cases of the limited scleroderma syndrome. On the other hand, the anti-centromere antibody is seen about 60 % of limited scleroderma.

Other positive auto-antibodies includes Anti-nuclear antibodies(ANA), RNA polymerase III, U1-RNP.

Blood Tests

Complete Blood Count -for anemia

Blood Glucose, comorbid autoimmune metabolic disorders.

Inflammatory Markers-C-reactive protein, ESR, serum protein electrophoresis,

Imaging Studies

X-Rays- (lungs, joints, digits)

Evaluation of Specific Target Organ

Fibrosis - biopsy

Lung fibrosis and restrictive lung disease (pulmonary X-yay), Spirometry studies, Lung biopsy.

Liver - Serum albumin

Kidney (Blood urea, creatinine, and electrolytes)

Heart - Echocardiography

Treatment / Management

There is no definitive treatment or universally accepted disease-modifying agent. However, management of the affected system or systems has proven effective. Early diagnosis is also a key strategy to achieving improved outcomes.[11][3][12]

Clinical evaluation and identification of affected organ and disease progression are critical to treatment efficacy. Furthermore, it is important that treatment goals be holistic and tailored towards optimizing the quality of life for the affected patients. Hence, in addition to symptomatic management of affected organ systems, care should be taken to resolve emotional, psychological, functional and nutritional problems that may arise. Co-morbid diagnoses such as other auto-immune disorders should also be sought for and treated if present.

The firsts goal of treatment is to limit or prevent disease progression. This is most feasible when the disease is detected early and with minimal internal organ fibrosis. With widespread internal organ, fibrosis, treatment goals become more limited. Management of systemic sclerosis is tailored towards the clinical characteristic (phenotype) in the patient. As stated earlier, the two major categories are the limited type and the more diffuse type. Symptomatic management is the mainstay of treatment in both categories. Treatment options focusing on preventing complications or achieving complete remission are currently under evaluation. In addition to the clinical phenotype, the clinical stage of disease should be evaluated in customizing treatment for different individuals. Rodnian skin score test is widely utilized for this evaluation.

Specific Therapies in Scleroderma

Raynaud's Phenomenon

Counseling regarding cold avoidance is an effective preventative measure for scleroderma.

Vasodilator therapy has been proven to provide relief from Raynaud's. Non-dihydropyridine calcium channel blockers such as nifedipine are the first line medication of managing this common clinical presentation in scleroderma. Other vasodilators include Prostacyclin, Nitroglycerin, Phosphodiesterase inhibitors.

Other therapies for Raynaud's includes endothelin receptor antagonist such as Bosentan (used for refractory cases).

Treatment goal in Raynaud's includes reducing recurrent rate and prevention of digital ischemia.

Skin Disease/Musculoskeletal

Serial monitoring and observation are carried out to see the progression and determine a need for drug management. Immunosuppressive agents are the principal medication for treating skin and musculoskeletal lesions in scleroderma.

Commonly used agents are methotrexate, cyclophosphamide, and mycophenolate.

Lungs

Lung disease is the leading cause of death in scleroderma. The two major culprits are fibrosis with restrictive type lung disease and pulmonary arterial hypertension (PAH).

Immunosuppressants, mycophenolate, cyclophosphamide and azathioprine are the drugs of choice for preventing Interstitial lung fibrosis.

Pulmonary hypertension is managed with vasodilator therapy such as intravenous prostacyclin analog (epoprostenol, treprostinil or iloprost), endothelin receptor antagonists (Bosentan, Ambrisentan) and phosphodiesterase - 5 inhibitors (tadalafil, sildenafil).

Lung transplant is a last resort for patients with intractable pulmonary disease.

Gastrointestinal System

Esophageal disorders are the leading cause of morbidity in scleroderma. Patients present with symptoms such as heart burns and dysphagia. Barret esophagus may complicate esophagitis in patients with chronic reflux as a result of esophageal dysmotility.

A combination of dietary modifications with high fiber diet and use of antacid therapy is recommended to manage esophageal diseases.

Kidneys

Scleroderma renal crisis. This is managed with angiotensin-converting enzyme inhibitors(ACE-I). Positive anti-RNA Polymerase III antibodies are associated with a higher incidence of this complication. Patients would present with accelerated hypertension, oliguria and elevated levels creatinine. 

Differential Diagnosis

  • Eosinophilia-myalgia syndrome
  • Reflex sympathetic dystrophy
  • Morphea
  • Radiation exposure
  • Porphyria cutanea tarda

Complications

  • Myositis
  • Digital infarctions
  • Renal failure
  • Pulmonary hypertension
  • Chronic wound infections

Pearls and Other Issues

Disease modification is a target that has been elusive for scleroderma.This is an area of active research. Development of effective anti-fibrotic agents to specifically prevent deposition of collagen and prevent scar tissue formation is another active research objective in scleroderma management.

Therapeutic plasma exchange (TPE) has shown both long and short-term benefits in the management of systemic sclerosis.

Enhancing Healthcare Team Outcomes

Scleroderma has enormous morbidity on patients, leading to severe disability. The disease has no cure and only symptomatic treatment is available. The condition can affect many organs in the body and hence a multidisciplinary approach is recommended. At the same time, nurses and pharmacists also play a vital role in patient education. To lower the risk of Raynaud phenomenon, patients must be educated on protecting their body from the cold by wearing warm clothes and maintaining their core body temperature on the warmer side. Patients should be encouraged to discontinue smoking and also avoid exposure to second-hand smoke. Further, the patient should be told to avoid all skin trauma and see a healthcare provider the moment skin breakdown occurs. The pharmacist should ensure that the patient is on no medications that cause vasoconstriction and should educate the patient on the importance of compliance with the blood pressure medications. All patients with scleroderma need to be followed up every 3-6 months. [13][14](Level V)

Outcomes

The outcomes in patients with scleroderma depend on the extent of skin and other organ involvement. Over the years, for those who only have skin disease have a 5-year survival that approaches close to 90%. Factors that portend a poor prognosis include 1) African American race 2) young age at diagnosis 3) anemia 4) involvement of the kidneys, lungs or the heart 5) rapid progression of skin lesions and 6) elevated ESR.

Of all the collagen vascular disorders, systemic sclerosis has the highest case-specific mortality. The cause of death in most cases is renal crises, end-stage lung disease, and pulmonary hypertension. While survival has slightly improved over the past decade, patients with systemic sclerosis still only have a very low 5-year survival. With the availability of angiotensin converting enzyme inhibitors, the mortality of renal crises has also slightly dropped. In contrast, there has been no improvement in deaths from pulmonary hypertension. [11][15][16](Level V)


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