Scleroderma

Scleroderma (from the Greek words "sklerosis" meaning hardness, and "derma" meaning skin), literally means hard skin. Though it is often referred to as if it were a single disease, scleroderma is really a symptom of a group of diseases that involve the abnormal growth of connective tissue, which supports the skin and internal organs. It is sometimes used, therefore, as an umbrella term for these disorders. In some forms of scleroderma, hard, tight skin is the extent of this abnormal process. In other forms, however, the problem goes much deeper, affecting blood vessels and internal organs, such as the heart, lungs, and kidneys.

Other Names

• CREST syndrome
• SSc
• Systemic Scleroderma
• [Systemic Sclerosis
• Dermatosclerosis

Types

The group of diseases we call scleroderma falls into two main classes: localized scleroderma and systemic sclerosis. Both groups include subgroups (See chart) and although there are different ways these groups and subgroups may be broken down or referred to, the following is a common way of classifying these diseases:^[1][2]

Scleroderma classification chart.

1. Localized Scleroderma :localized types of scleroderma are those limited to the skin and related tissues and, in some cases, the muscle below. Internal organs are not affected by localized scleroderma, and localized scleroderma can never progress to the systemic form of the disease. Two subtypes are described; Morphea(from the Greek word that means "form" or "structure"), referring to the local patches of scleroderma, and Linear scleroderma.
2. Systemic Sclerosis (SSc):This is the term for the form of the disease that not only includes the skin, but also involves the tissues beneath, the blood vessels, and the major organs. Systemic sclerosis is typically broken down into limited cutaneous scleroderma (lcSSc) and diffuse cutaneous scleroderma (dcSSc). Sometimes a third subset is added called systemic sclerosis sine scleroderma, in which patients have other manifestations of scleroderma but they do not have any overt skin thickening.^[3][4]

Signs and Symptoms

Localized Scleroderma

Symptoms are limited to the skin and related tissues and,and in some cases, the muscle below. Internal organs are not affected by localized scleroderma, and can never progress to the systemic form of the disease. Often, localized conditions improve or go away on their own over time, but the skin changes and damage that occur when the disease is active can be permanent.

• Morphea: The first signs of the disease are reddish patches of skin that thicken into firm, oval-shaped areas with the center of each patch becoming ivory colored with violet borders. These patches sweat very little and have little hair growth. They appear most often on the chest, stomach, and back and sometimes on the face, arms, and legs. Morphea can be either localized or generalized. Localized morphea limits itself to one or several patches, ranging in size from a 2 to 30 cm. (0.5 to 12 inches) in diameter. This condition sometimes appears on areas treated by radiation therapy. The disease is referred as generalized morphea when the skin patches become very hard and dark and spread over larger areas of the body. Regardless of the type, morphea generally fades out in 3 to 5 years; however, people are often left with darkened skin patches and, in rare cases, muscle weakness.

• Linear scleroderma: As suggested by its name, the disease is characterized by a single line or band of thickened and/or abnormally colored skin. Usually, the line runs down an arm or leg, but in some people it runs down the forehead. People sometimes use the French term en coup de sabre, or "sword stroke," to describe this highly visible line.

Systemic Sclerosis (SSc)

This is the term for the form of the disease that not only includes the skin, but also involves the tissues beneath, the blood vessels, and the major organs. Systemic sclerosis is typically broken down into limited cutaneous scleroderma (lcSSc) and diffuse cutaneous scleroderma (dcSSc). Sometimes a third subset is added called systemic sclerosis sine scleroderma, in which patients have other manifestations of scleroderma but they do not have any overt skin thickening.^[5][6]

• Limited cutaneous scleroderma (lcSSc): Limited cutaneous scleroderma typically comes on gradually and affects the skin only in certain areas: the fingers, hands, face, lower arms, and legs. Most people with limited disease have Raynaud phenomenon for years before skin thickening starts. Telangiectasias and calcinosis often follow (See definitions below).Gastrointestinal involvement occurs commonly and some patients also have severe lung problems, even though the skin thickening remains limited. People with limited disease often have all or some of the symptoms that some doctors call CREST, which stands for the following:

• Calcinosis: the formation of calcium deposits in the connective tissues, which can be detected by x ray. They are typically found on the fingers, hands, face, and trunk and on the skin above elbows and knees. When the deposits break through the skin, painful ulcers can result.
• Raynaud phenomenon: a condition in which the small blood vessels of the hands and/or feet contract (become narrower)in response to cold or anxiety. As the vessels contract, the hands or feet turn white and cold, then blue. As blood flow returns, they become red. Fingertip tissues may suffer damage, leading to ulcers, scars, or gangrene.
• Esophageal dysfunction: impaired function of the esophagus (the tube connecting the throat and the stomach) that occurs when smooth muscles in the esophagus lose normal movement. In the upper and lower esophagus, the result can be swallowing difficulties. In the lower esophagus, the result can be chronic heartburn or inflammation.
• Sclerodactyly: thick and tight skin on the fingers, resulting from deposits of excess collagen within skin layers making it harder to bend or straighten the fingers. The skin may also appear shiny and darkened, with hair loss.
• Telangiectasia: a condition caused by the swelling of tiny blood vessels, in which small red spots appear on the hands and face. While not painful, these red spots can create cosmetic problems.

• Diffuse cutaneous scleroderma(dcSSC): Skin thickening begins in the hands and spreads quickly and over much of the body, affecting the hands, face, upper arms, upper legs, chest, and stomach in a symmetrical fashion (for example, if one arm or one side of the trunk is affected, the other is also affected). People with diffuse disease often are tired, lose appetite and weight, and have joint swelling and/or pain. Skin changes can cause the skin to swell, appear shiny, and feel tight and itchy. The damage of diffuse scleroderma typically occurs over a few years, after the first 3 to 5 years, people with diffuse disease often enter a stable phase lasting for varying lengths of time; progressive skin thickening and organ damage decrease and the skin may begin to soften, which tends to occur in reverse order of the thickening process: the last areas thickened are the first to begin softening. Some patients' skin returns to a somewhat normal state, while other patients are left with thin, fragile skin without hair or sweat glands. Serious new damage to the heart, lungs, or kidneys is unlikely to occur, although patients are left with whatever damage they have in specific organs.People with diffuse scleroderma face the most serious long-term outlook if they develop severe kidney, lung, digestive, or heart problems.^[7]

Virtually all people with systemic sclerosis have some loss of lung function. Some develop severe lung disease, which comes in two forms: pulmonary fibrosis (hardening or scarring of lung tissue because of excess collagen) and pulmonary hypertension (high blood pressure in the artery that carries blood from the heart to the lungs).^[8]

Causes

Like many other rheumatic disorders, scleroderma is believed to be an autoimmune disease, that is, a disease in which the immune system, for unknown reasons, turns against its own body.^[9]In scleroderma, the immune system is thought to stimulate cells called fibroblasts making them produce too much collagen. The collagen then forms thick connective tissue that builds up within the skin and internal organs which can interfere with their functioning. Blood vessels and joints can also be affected.There is some evidence that genes and the environment contribute to the development of scleroderma by affecting the genetic homeostasis (state of equilibrium of the body)of specific genes. ^[10][11]

Diagnosis

A diagnosis of scleroderma is based largely on the medical history and findings from the physical exam. To make a diagnosis, the doctor will ask a lot of questions about what has happened over time and about any symptoms that may be present. Are there any problems with heartburn or swallowing? Do the hands turn white in response to anxiety or cold temperatures?

Finding one or more of the following factors and lab results can help the doctor with the diagnosis:

• Changed skin appearance and texture, including swollen fingers and hands, and tight skin around the hands, face, mouth, or elsewhere.
• Calcium deposits developing under the skin.
• Changes in the tiny blood vessels (capillaries) at the base of the fingernails.
• Thickened skin patches.
• Antitopoisomerase-1 or Anti-Scl-70 antibodies appear in the blood of up to 30% of people with diffuse systemic sclerosis.
• Anticentromere antibodies are found in the blood of as many as 50% of people with limited systemic sclerosis.^[12]

A number of other scleroderma-specific antibodies can occur in people with scleroderma, although less frequently. When present, however, they are helpful in clinical diagnosis and may give additional information as to the risks for specific organ problems.

Because not all people with scleroderma have these antibodies and because not all people with the antibodies have scleroderma, lab test results alone cannot confirm the diagnosis. In some cases, the doctor may order a skin biopsy (the surgical removal of a small sample of skin for microscopic examination) to aid in or help confirm a diagnosis. However, skin biopsies, too, have their limitations: biopsy results cannot distinguish between localized and systemic disease, for example.

Diagnosing scleroderma is easiest when a person has typical symptoms and rapid skin thickening. In other cases, a diagnosis may take months, or even years, as the disease unfolds and reveals itself and as the doctor is able to rule out some other potential causes of the symptoms. In some cases, a diagnosis is never made, because the symptoms that prompted the visit to the doctor go away on their own.

Treatment

Typically, care will be managed by a rheumatologist (a doctor specializing in treatment of musculoskeletal disorders and rheumatic diseases) and then referred to different specialist depending on the organ or system affected.

Currently, there is no treatment that controls or stops the underlying problem,the overproduction of collagen. Thus, treatment and management focus on relieving symptoms and limiting damage. Treatment will depend on the particular problems that exist and will consist of combination of medication, natural and lifestyle changes. ^[13][14]

Here is a listing of the potential problems that can occur in systemic scleroderma and the medical and nonmedical treatments for them. These problems do not occur as a result or complication of localized scleroderma. This listing is not complete because different people experience different problems with scleroderma and not all treatments work equally well for all people.

Raynaud Phenomenon: The following measures may make life more comfortable and help prevent problems:

• Smoke cessation. Smoking narrows the blood vessels even more and makes Raynaud phenomenon worse.
• Dressing warmly, with special attention to hands and feet.
• Relaxation exercises.
• For severe cases calcium channel blockers, such as nifedipine,which can open up small blood vessels may improve circulation.

Stiff, painful joints:

• Stretching exercises under the direction of a physical and/or occupational therapist are extremely important to prevent loss of joint motion. These should be started as soon as the diagnosis of scleroderma is made.
• Regularl excersize. A doctor or physical therapist can develop an exercise plan that will help to increase and maintain range of motion in affected joints. Swimming can help maintain muscle strength, flexibility, and joint mobility.
• nonsteroidal anti-inflammatory drug, as recommended by a doctor, to help relieve joint or muscle pain.
• A physical or occupational therapist can help in learning to perform daily tasks, such as lifting and carrying objects or opening doors, in ways that will put less stress on tender joints.

Skin problems: To ease dry skin:

• Oil-based creams and lotions frequently, and always right after bathing.
• Sunscreen before venturing outdoors, to protect against further damage from the sun's rays.
• Humidifiers to moisten the air in the home in colder winter climates.
• Avoiding very hot baths and showers, as hot water dries the skin.
• Avoiding harsh soaps, household cleaners, and caustic chemicals, if at all possible. Otherwise, making sure to wear rubber gloves when using such products.

Dry mouth and dental problems: There are several ways to avoid tooth and gum problems:

• Brushing and flossing teeth regularly. If hand pain and stiffness make this difficult, an occupational therapist can help with information about specially made toothbrush handles and devices to make flossing easier.
• Regular dental checkups, contacting a dentist immediately if mouth sores, mouth pain, or loose teeth occur.
• Physical therapist can help with facial exercises to help keep the mouth and face more flexible.
• Patient can help keep mouth moist by drinking plenty of water, sucking ice chips, using sugarless gum and hard candy, and avoiding mouthwashes with alcohol. If dry mouth is still a problem, there is saliva substitute, or prescription medications that can stimulate the flow of saliva.

Gastrointestinal (GI) problems:Although GI problems are diverse, here are some things that might help at least some of the problems:

• Small, frequent meals.
• Keeping stomach contents from backing up into the esophagus, standing or sitting for at least an hour (preferably two or three) after eating. When it is time to sleep, keeping the head of the bed raised using blocks.
• Avoiding late-night meals, spicy or fatty foods, alcohol, and caffeine, which can aggravate GI distress.
• Eating moist, soft foods, and chewing them well. If there is any difficulty swallowing, or if the body doesn't absorb nutrients properly, the doctor may prescribe a special diet.
• Asking the doctor about prescription medications for problems such as diarrhea, constipation, and heartburn.

Lung damage: Treatment for the two conditions is different:

• Pulmonary fibrosis may be treated with drugs that suppress the immune system such as cyclophosphamide or azathioprine, along with low doses of corticosteroids.
• Pulmonary hypertension may be treated with drugs that dilate the blood vessels such as prostacyclin, or with newer medications that are prescribed specifically for treating pulmonary hypertension.

Regardless of the particular lung problem or its medical treatment, taking an active role in the treatment process is essentially the same:

• Watching for signs of lung disease, including fatigue, shortness of breath or difficulty breathing, and swollen feet. Report these symptoms to a doctor.
• Flu and pneumonia vaccines as recommended by the doctor.

Heart problems: Common among people with scleroderma, heart problems include scarring and weakening of the heart (cardiomyopathy), inflamed heart muscle (myocarditis), and abnormal heart beat (arrhythmia). All of these problems can be treated. Treatment ranges from drugs to surgery, and varies depending on the nature of the condition.

Kidney problems: Renal crisis occurs in about 10 percent of all patients with scleroderma, primarily those with early diffuse scleroderma. Renal crisis results in severe uncontrolled high blood pressure, which can quickly lead to kidney failure. It's very important to take measures to identify and treat the hypertension as soon as it occurs.

Living With Scleroderma

Having a chronic disease can affect almost every aspect of life, from family relationships to holding a job. For people with scleroderma, there may be other concerns about appearance or even the ability to dress, bathe, or handle the most basic daily tasks. Here are some areas in which scleroderma could intrude.

Appearance and self-esteem: Thick, hardened skin can be difficult to accept, particularly on the face. Systemic scleroderma may result in facial changes that eventually cause the opening to the mouth to become smaller and the upper lip to virtually disappear. Linear scleroderma may leave its mark on the forehead. Although these problems can't always be prevented, their effects may be minimized with proper treatment.

Daily activies: Tight, hard connective tissue in the hands can make it difficult to do what were once simple tasks, such as brushing teeth and hair, pouring a cup of coffee, using a knife and fork, unlocking a door, or buttoning a jacket. If it is difficult using the hands an occupational therapist can recommend new ways of doing things or devices to make tasks easier. Devices as simple as Velcro fasteners and built-up brush handles can help remaining independent easier. Family relationships: It's important to learn as much about the disease in order to share any information with family and friends. Involving them in counseling or a support group may also help them better understand the disease and how they can help.

Sexual relations: For men, the disease's effects on the blood vessels can lead to problems achieving an erection. For women, damage to the moisture-producing glands can cause vaginal dryness that makes intercourse painful. People of either sex may find they have difficulty moving the way they once did. They may be self-conscious about their appearance or afraid that their sexual partner will no longer find them attractive. With communication between partners, good medical care, and perhaps counseling, many of these changes can be overcome or at least worked around.

Pregnancy and childbearing: In the past, women with systemic scleroderma were often advised not to have children. But thanks to better medical treatments and a better understanding of the disease itself, that advice is changing. (Pregnancy, for example, is not likely to be a problem for women with localized scleroderma.) Although blood vessel involvement in the placenta may cause babies of women with systemic scleroderma to be born early, many women with the disease can have safe pregnancies and healthy babies if they follow some precautions. ^[15] One of the most important pieces of advice is to wait a few years after the disease starts before attempting a pregnancy. During the first 3 years, women are at the highest risk of developing severe problems of the heart, lungs, or kidneys that could be harmful to themselves or the unborn baby. If severe organ problems developed within 3 years of the disease's onset, the chances of such problems are less and pregnancy would be safer. But it is important to have both the disease and the pregnancy monitored regularly.

Clinical Trials

Clinical trials recruiting patients: Scleroderma Trials

Research

Leading the way in funding for this research is the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), a part of the Department of Health and Human Services' National Institutes of Health (NIH). Other sources of funding for scleroderma research include pharmaceutical companies and organizations such as the Scleroderma Foundation, the Scleroderma Research Foundation, and the Arthritis Foundation.

Some recent advances in the understanding or treatment of scleroderma include the following:

• A gene associated with scleroderma has been found in Oklahoma Choctaw Native Americans. Scientists believe the gene, which codes for a protein called fibrillin-1, may put people at risk for the disease. Current studies are using new technology to look for other genes associated with the disease's development and severity.
• The drug cyclophosphamide has been found effective in treating lung fibrosis. One recent study suggested that treating lung problems early with this immunosuppressive drug may help prevent further damage and increase chances of survival. Further research is assessing the impact of cyclophosphamide on quality of life in people with lung involvement.
• ACE inhibitors are used increasingly for scleroderma-related kidney problems. For the past two decades, ACE inhibitors have greatly reduced the risk of kidney failure in people with scleroderma. Now there is evidence that use of ACE inhibitors can actually heal the kidneys of people on dialysis for scleroderma-related kidney failure. As many as half the people who continue ACE inhibitors while on dialysis may be able to go off dialysis in 12 to 18 months.
• Several new and exciting drugs are now available to treat pulmonary hypertension. Previously, pulmonary hypertension was associated with a poor outcome, but medications like prostacyclins, endothelin-receptor antagonists, and phosphodiesterase inhibitors have increased the quality of life and life expectancy for people with this dangerous form of lung damage.

Other studies are examining the following:

• The theory that scleroderma is a more aggressive disease associated with more internal organ damage and a worse prognosis in non-Caucasians. Researchers believe that while factors related to both genetics and socioeconomic status may play a role, autoantibodies may be the primary reason that African Americans have such severe disease. A current study is examining that theory. Researchers hope that by better understanding the factors involved in scleroderma, they can design interventions that would improve the course and outcome of the disease.
• The use of ultraviolet-B (UV-B) light to treat the skin manifestations of localized scleroderma. Exposure to UV light has been shown to reduce collagen (which is overproduced in people with scleroderma) in the skin by inducing enzymes that break down collagen and by inhibiting the production of new collagen.
• Changes in the tiny blood vessels of people with scleroderma. By studying these changes, scientists hope to find the cause of cold sensitivity in Raynaud's phenomenon and a way to control the problem.
• Studies have shown that certain chemicals called cytokines, made from cells in the body, enhance the development of increased collagen. New agents that counteract these cytokines may be helpful in preventing skin thickening.
• Skin changes in laboratory mice in which a genetic defect prevents the breakdown of collagen, leading to thick skin and patchy hair loss. Scientists hope that by studying these mice they can answer many questions about skin changes in scleroderma. Scientists are also working to establish mouse models for other problems related to scleroderma. These models will make it easier to understand these problems and develop treatments for them.

Epidemiology

Although scleroderma is more common in women, the disease also occurs in men and children. It affects people of all races and ethnic groups. However, there are some patterns by disease type. For example:

• Localized forms of scleroderma are more common in people of European descent than in African Americans.
• Morphea usually appears between the ages of 20 and 40, and linear scleroderma usually occurs in children or teenagers.
• Systemic scleroderma, whether limited or diffuse, typically occurs in people from 30 to 50 years of age. It affects more women of African American than European descent.

Because scleroderma can be hard to diagnose and it overlaps with or resembles other diseases, scientists can only estimate how many cases there actually are. Estimates for the number of people in the United States with systemic sclerosis range from 40,000 to 165,000. By contrast, a survey that included all scleroderma-related disorders, including Raynaud phenomenon, suggested a number between 250,000 and 992,500.^[16]

Other Resources

• National Institute of Arthritis and Musculoskeletal and Skin Diseases
• American Academy of Dermatology (AAD)
• American College of Rheumatology (ACR)
• Scleroderma Foundation
• Scleroderma Research Foundation
• Arthritis Foundation

References

1. ↑ American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Preliminary criteria for the classification of systemic sclerosis (scleroderma). Subcommittee for scleroderma criteria of the American Rheumatism Association Diagnostic and Therapeutic Criteria Committee. Arthritis Rheum. May 1980;23(5):581-90
2. ↑ Wollheim FA. Classification of systemic sclerosis.Visions and reality.Rheumatology (Oxford). 2005 Oct;44(10):1212-6. Epub 2005 May 3. AbstractFull Text PDF
3. ↑ Slobodin G, Rosner I, Rozenbaum M, et al. Systemic sclerosis sine scleroderma: is it always the same disease? Report of three patients and discussion. Rheumatol Int. 2002 Aug;22(4):170-2. Epub 2002 Jul 2. Abstract
4. ↑ Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum. 2000 Feb;43(2):444-51. Abstract PDF
5. ↑ Slobodin G, Rosner I, Rozenbaum M, et al. Systemic sclerosis sine scleroderma: is it always the same disease? Report of three patients and discussion. Rheumatol Int. 2002 Aug;22(4):170-2. Epub 2002 Jul 2. Abstract
6. ↑ Poormoghim H, Lucas M, Fertig N, Medsger TA Jr. Systemic sclerosis sine scleroderma: demographic, clinical, and serologic features and survival in forty-eight patients. Arthritis Rheum. 2000 Feb;43(2):444-51. Abstract PDF
7. ↑ du Bois RM. Mechanisms of scleroderma-induced lung disease. Proc Am Thorac Soc. 2007 Aug 15;4(5):434-8. Abstract Full Text PDF
8. ↑ du Bois RM. Mechanisms of scleroderma-induced lung disease. Proc Am Thorac Soc. 2007 Aug 15;4(5):434-8. Abstract Full Text PDF
9. ↑ Arnett FC. Is scleroderma an autoantibody mediated disease? Curr Opin Rheumatol. 2006 Nov;18(6):579-81. Abstract
10. ↑ Strickland FM, Richardson BC. Epigenetics in human autoimmunity. Epigenetics in autoimmunity - DNA methylation in systemic lupus erythematosus and beyond. Autoimmunity. 2008 May;41(4):278-86. Abstract
11. ↑ Mayes MD, Trojanowska M. Genetic factors in systemic sclerosis. Arthritis Res Ther. 2007;9 Suppl 2:S5. Abstract Full Text PDF
12. ↑ Harvey GR, McHugh NJ. Serologic abnormalities in systemic sclerosis. Curr Opin Rheumatol. 1999 Nov;11(6):495-502. Abstract
13. ↑ Gaby AR. Natural remedies for scleroderma. Altern Med Rev. 2006 Sep;11(3):188-95. Abstract PDF
14. ↑ Denton CP. Therapeutic targets in systemic sclerosis. Arthritis Res Ther. 2007;9 Suppl 2:S6. Abstract Full Text PDF
15. ↑ Miniati I, Guiducci S, Mecacci F, Mello G, Matucci-Cerinic M. Pregnancy in systemic sclerosis. Rheumatology (Oxford). 2008 Jun;47 Suppl 3:iii16-8. Abstract
16. ↑ Chifflot H, Fautrel B, Sordet C, Chatelus E, Sibilia J. Incidence and prevalence of systemic sclerosis: a systematic literature review. Semin Arthritis Rheum. 2008 Feb;37(4):223-35. Abstract