CREST Syndrome – Clinical Features, Diagnosis, Self-Care Tips and Treatment

CREST syndrome is a limited or a less severe form of systemic sclerosis (lcSSc).

Systemic sclerosis is a multisystem connective tissue disorder and an autoimmune disease.

The acronym “CREST” refers to the five main clinical features:

• Calcinosis
• Raynaud’s phenomenon
• Esophageal dysmotility
• Sclerodactyly
• Telangiectasia

Scleroderma is a rare connective tissue disorder. It can be divided into two forms:

• Localized Scleroderma (Morphea, Linear Scleroderma and Scleroderma en coup de sabre)
• Systemic sclerosis. It is further classified into two types
  • Limited cutaneous Systemic Sclerosis (CREST syndrome)
  • Diffuse cutaneous Systemic Sclerosis

Systemic sclerosis is a rare disease with an incidence of 19.3 new cases per million adults per year and a prevalence of 242 cases per million adults in the United States. It is estimated that CREST syndrome accounts for about one-fourth of all cases of systemic sclerosis. However, epidemiologic studies studying the true incidence and prevalence of CREST syndrome are lacking.

It is more common in blacks than in whites.

Females are affected more commonly than males with a female to male ratio of about 5:1. Also the females tend to develop the disease at an earlier age than males.

The usual age of onset of the disease is 30-65 years. Black women usually present at an earlier age.

Clinical Features

Calcinosis – thickening and tightening of the skin with painful nodules of calcium in the skin. It can involve the fingers or other parts of the body.

Raynaud’s phenomenon – White, blue, cold, or numb skin on the hands and feet in response to cold or emotional stress. It occurs due to the spasm of the blood vessels which causes blockage of the flow of blood. Once the blood circulation improves, the skin becomes reddened and painful.

It is usually the first manifestation of CREST syndrome.

Esophageal dysfunction – Poor functioning of the muscles of the esophagus (the tube that connects the mouth to the stomach) results in difficulty in swallowing food, chest pain, or cough. It may also cause acids from the stomach to enter back into the esophagus, resulting in heartburn or inflammation and scarring of the esophagus.

Sclerodactyly – Thickening and tightening of the skin of fingers or toes which makes bending of the fingers difficult. Initially, the skin appears edematous and inflamed while in later stages, the skin becomes tightened. Many patients may develop ulcers on the distal fingers.

Telangiectasias — Swelling of small blood vessels near the skin’s surface results in small red spots or lines on the skin. They are painless and occur mainly on the hands and face.

Cause of CREST Syndrome

The exact cause of CREST syndrome is not known. It is thought to be an autoimmune disorder.

In autoimmune diseases, the immune system of the body mistakenly identifies certain parts of one’s own body as foreign invaders. In response, it releases special antibodies, called autoantibodies that attack a person’s own cells and tissues. These autoantibodies can attack and damage the connective tissue and a variety of other organs.

In CREST syndrome, the immune system stimulates the body to produce an excess of collagen, which is the main component of connective tissue. This excess collagen gets deposited in the skin and internal organs and impairs their normal functioning.

Risk Factors

• Age: It is more common between the ages of 30 and 65 years.
• Sex: Similar to all autoimmune diseases, CREST syndrome is more common in females.
• Race: It is more common and severe in blacks and Native Americans than in whites.
• Genetic factors: Presence of any autoimmune disease in the family increases the risk of developing CREST syndrome.
• Environmental factors: Exposure to toxins like polyvinyl chloride, benzene, silica, etc can trigger CREST syndrome in people who have a genetic predisposition for the disease.

Complications

In contrast with diffuse scleroderma, CREST syndrome is associated with better survival rates and a lower incidence of complications.

Mortality in patients with limited skin involvement is a result of pulmonary, cardiac, and gastrointestinal causes.

Gastrointestinal complications

Fibrosis of the distal esophagus may lead to dysphagia (difficulty in swallowing), chronic heartburn, esophageal strictures and even bleeding. Involvement of the stomach can lead to delayed gastric emptying resulting in early satiety.

Intestinal involvement can cause bloating, constipation, diarrhea, nausea, vomiting, and anorexia leading to malnutrition and weight loss.

Lung complications

It is the leading cause of deaths in patients of CREST syndrome as it may cause progressive respiratory failure.

The deposition of excess collagen in between the air sacs of the lungs makes the lung tissue stiffer resulting in reduced functioning of the lungs.

It may also cause pulmonary artery hypertension (increased blood pressure in the arteries between the heart and lungs) which may ultimately lead to cor pulmonale (heart failure).

Heart Complications

Fibrosis and scarring of heart tissue can result in arrhythmias (abnormal heart rhythms) or dilated cardiomyopathy (enlargement and weakening of the heart). There can also occur myocarditis (inflamed heart muscle), pericardial effusion (fluid in pericardial sac), etc.

Kidney complications

Kidney damage is more common in diffuse form of scleroderma. However, it can occur in limited scleroderma as well. The involvement of the blood vessels causes reduced blood flow to the kidneys resulting in renal crises and kidney failure.  The patient may present with high blood pressure.

Ulcers on fingers and toes

Raynaud’s phenomena, if severe, can cause obstruction of blood flow to the fingers and toes. This can cause ulcers that don’t heal easily. Disruption of the blood flow may even lead to gangrene of fingers or toes, which may necessitate amputation.

Endocrinal complications

Fibrosis of the thyroid gland may cause hypothyroidism. Also, autoimmune thyroid diseases like Hashimoto’s thyroiditis and Grave’s disease are more common in CREST syndrome patients.

Other complications

CREST syndrome patients are at an increased risk for other autoimmune diseases such as primary biliary cirrhosis and secondary Sjogren’s syndrome.

These patients can also have overlapping symptoms similar to rheumatoid arthritis and polymyositis.

They are also at an increased risk of psychological disorders such as depression.

Diagnosis and Investigations

Like all autoimmune diseases, CREST syndrome is difficult to diagnose since the clinical features vary widely and there is a significant overlap of signs and symptoms with other diseases.

The diagnosis is made mainly on the basis of signs and symptoms and therefore a thorough clinical examination is a must.

Clinical evaluation

• Changes in the color, appearance, and texture of the skin are noted.
• The thickness of the skin is evaluated periodically as its progression is associated with poor prognosis. The modified Rodnan skin score is used according to which scores are given from 0 to 3 (score 0 is given for uninvolved areas while score 3 is assigned to skin thickening).
• Nail fold capillary exam should be performed in all patients with Raynaud’s phenomena, if there is a suspicion of scleroderma.
• A thorough physical examination should be performed regularly to detect underlying organ involvement.
• Blood pressure monitoring should be carried out regularly.

Autoantibody tests

They are used for both diagnosis and prognostic purposes.

Antinuclear Antibodies (ANA) are positive in more than 90% of the patients.

Read more about Antinuclear antibodies Test (ANA Test)

Anti centromere antibodies are found in about 80-90% of patients with CREST syndrome. They can also be seen in Sjogren’s syndrome and systemic lupus erythematosus.

Anti-Scl-70 (anti-topoisomerase I) antibody is usually associated with diffuse scleroderma and is rarely present in CREST syndrome. It is associated with a worse prognosis.

Other autoantibodies like anti-Th/To, anti-PM/Scl, anti-U1-RNP, anti-U3-RNP may also be present in patients of CREST syndrome.

Complete blood counts

To look for anemia which could be due to multiple factors

Nonspecific indicators of inflammation

• Mild leukocytosis
• Elevated erythrocyte sedimentation rate (ESR)
• Elevated C-reactive protein

Although of limited significance, these tests may be significantly elevated in the case of active disease.

Serum calcium and phosphorus levels

Calcinosis seen in CREST syndrome is not associated with calcium or phosphorus abnormalities. Abnormal levels are seen in case of metabolic disturbances and used to differentiate these disorders from CREST syndrome.

Renal function tests

To detect renal dysfunction and renal crisis

Thyroid function tests

To detect thyroid involvement. Thyroid disease is also a cause of edematous or thickened skin.

X-ray of extremities

To detect calcinosis

Doppler ultrasonography or angiography

To detect blood vessel occlusion in the case of Raynaud’s phenomenon.

Electromyogram/nerve conduction velocity test

In the case of suspected muscle involvement.

Pulmonary function tests

Including spirometry to detect lung disorders.

Electrocardiography and Holter monitoring

To detect heart diseases and arrhythmias.

Upper GI endoscopy, esophageal manometry, barium swallow studies

To detect esophageal and intestinal disorders

CT scan

To detect interstitial lung disease

Skin biopsy

A tiny sample of the affected skin is removed and examined by a pathologist under a microscope to look for specific features seen in scleroderma.

Self –Care Tips

Keep warm

To prevent symptoms of Raynaud’s, keep your hands and feet covered with gloves and socks in cool weather.

Similarly, in winters, wear proper woolen clothes and cover your head with a head or scarf to maintain the body’s core temperature.

Quit smoking

Since nicotine constricts the blood vessels, symptoms of Raynaud’s phenomena tend to worsen with smoking. Avoiding smoking completely is essential to prevent Raynaud’s symptoms.

Exercise regularly

Regular exercise helps you to maintain an ideal body weight along with keeping the body flexible and strong. An occupational therapist or physiotherapist may be consulted regarding the appropriate exercises to be performed in case of deformities or contractures.

Healthy eating habits

In case of difficulty in swallowing, eat soft and moist foods, and chew the food slowly and properly. Eat balanced and nutritious meals frequently.

To prevent acid reflux

• Eat small and frequent meals.
• Avoid spicy or fatty foods.
• Avoid excess of tea, coffee, or alcohol.
• Stay upright for two or three hours after a meal.
• Don’t eat immediately before bedtime.
• Don’t exercise immediately before or after eating.
• Elevate the head-end of your bed.

Take care of your skin

The deposition of excess collagen can destroy the sweat and oil glands of the skin, making the skin stiff and dry. To help soften the skin:

• Use skin creams or emollients to moisturize your skin and prevent dryness.
• Avoid frequent baths.
• Use lukewarm water for bathing in cold weather. Do not use hot water as it irritates the skin.
• Oatmeal can be added to water for bathing.
• Use a mild soap for bathing. The soap used should not rob the skin of its natural moisture or irritate your skin.
• Cleansing agents or soaps used should have a low pH so as to maintain the acidic pH of the skin. This helps to preserve the skin barrier function and reduces skin irritation.
• Wear rubber gloves when doing the dishes or cleaning.
• Use sunscreens when out in the sun to prevent sunburns and skin damage.
• Avoid fabrics that irritate the skin, such as synthetics. Use cotton clothing and bedsheets. Even in winters, do not let the woolen clothes come in direct contact with the skin. Always wear a layer of cotton clothing underneath the woolens.
• Avoid excess use of heaters or air conditioners as they make the skin dry. A humidifier can be used to increase the moisture.

Practice good oral hygiene

• Have regular dental checkups.
• If you have dry mouth, drink more water frequently, or suck ice cubes or sugar-free lozenges.
• Use special mouthwashes or rinses for proper oral hygiene.

Treatment

There is no definite cure for CREST syndrome. The treatment aims at alleviating signs and symptoms and preventing complications.

Early diagnosis of disease and the detection of complications lead to better outcomes. The patient should be educated about the natural course of the disease and informed about the importance of a balanced nutritious diet, regular exercise, and a healthy lifestyle. Emotional support must be provided to every patient.

Medicinal treatment

Pain relief medication

Non-steroidal anti-inflammatory drugs (NSAIDs) may be given for pain relief. Corticosteroids are usually avoided as they can precipitate scleroderma renal crisis.

Antibiotics

Oral or intravenous antibiotics may be required in case of infected skin ulcers.

Antacids

They are used to provide relief from heartburn, acid reflux, etc.

Medicines to treat dry mouth

Medicines to stimulate the flow of saliva may be prescribed in severe cases. These include secretagogues such as pilocarpine or cevimeline.

Immunosuppressive drugs

These medicines suppress the immune system and prevent the deposition of excessive amounts of collagen. Commonly used immunosuppressive drugs include mycophenolate mofetil, cyclophosphamide, methotrexate, azathioprine, and hydroxychloroquine.

Penicillamine

This medicine slows down the progression of skin thickening and also delays damage to internal organs.

Calcinosis

Painful localized large deposits of calcinosis can be surgically removed. This helps to alleviate symptoms and recurrence is rare.

Raynaud’s phenomenon

The aim is to prevent ulcers and gangrene of the digits.  The patients should be instructed to keep the extremities warm and also avoid smoking, stress, and beta-blockers.

Vasodilator therapy such as nifedipine, amlodipine, pentoxifylline, etc is quite effective for treating Raynaud’s phenomenon.

Vasodilator pumps may be used in patients who are unable to tolerate vasodilator therapy.

Proximal/distal sympathectomy can be tried in patients not responding to treatment.

Proper wound care is of utmost importance in the management of digital ulcers.

In the case of nonhealing ulcers and gangrene of the fingers and toes, amputation of the affected digit may have to be carried out.

Esophageal dysfunction

Antacids and proton pump inhibitors are used to treat acid reflux and heartburn.

Patients with gastroparesis (reduced gastric motility) may be treated with motility agents such as metoclopramide.

Laser coagulation can be considered in patients with bleeding occurring due to gastric antral vascular ectasia.

In severe and refractory cases, surgical treatment may be used to treat gastroesophageal reflux. Complete or partial surgical wraps around the gastroesophageal junction help to increase lower esophageal pressure and reduce reflux.

Sclerodactyly

In the case of extensive contractures due to sclerodactyly, surgical treatment can prove to be beneficial.

Telangiectasias

These usually do not require any treatment. If the cosmetic aspect is of concern, laser therapy can be used.

Treatment of complications

The presence of complications would require specific treatment.

• Treatment of arrhythmias includes antiarrhythmic agents and in severe cases, pacemaker placement.
• Pulmonary arterial hypertension: Supplemental oxygen, diuretics, and anticoagulation are used for treatment.  Vasodilators therapy is recommended and can include phosphodiesterase – 5 inhibitors (tadalafil, sildenafil), endothelin receptor antagonists, and/or prostacyclin analogs.
• Angiotensin-converting enzyme (ACE) inhibitors are the only effective treatment for scleroderma renal crisis. Captopril, a shorter-acting ACE-inhibitor, is the preferred drug. Treatment should be initiated at the earliest signs of renal crisis. However, prophylactic use of ACE-inhibitors will not prevent scleroderma renal crisis and is not recommended.
• Physiotherapy for treating deformities
• Treatment for depression and anxiety associated with the disorder.

References

• Düzgün N. Cutaneous calcinosis in a patient with limited scleroderma: CREST Syndrome. Eur J Rheumatol. 2017 Dec. 4 (4):305-306.
• Mayes MD, Lacey JV Jr, Beebe-Dimmer J, Gillespie BW, Cooper B, Laing TJ, et al. Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population. Arthritis Rheum. 2003 Aug. 48(8):2246-55.
• Meyer O. [Crest Syndrome]. Ann med Interne (Paris). 2002. 153(3):183-188.
• LeRoy EC. Systemic sclerosis. A vascular perspective. Rheum Dis Clin North Am. 1996 Nov. 22(4):675-94.