CHAPTER 97

Autoimmune Disorders of Connective Tissue

In an autoimmune disorder, antibodies or cells produced by the body attack the body’s own tissues (see page 1124). Many autoimmune disorders affect connective tissue in a variety of organs. Connective tissue is the structural tissue that gives strength to joints, tendons, ligaments, and blood vessels.

In autoimmune disorders, inflammation and the immune response may result in connective tissue damage, not only in and around joints but also in other tissues, including vital organs, such as the kidneys and organs in the gastrointestinal tract. The sac that surrounds the heart (pericardium), the membrane that covers the lungs (pleura), and even the brain can be affected. The type and severity of symptoms depend on which organs are affected.

An autoimmune disorder of connective tissue is diagnosed on the basis of its particular symptom pattern, the findings during a physical examination, and the results of laboratory tests. Sometimes the symptoms of one disease overlap with those of another so much that doctors cannot make a distinction. In this case, the disorder may be called undifferentiated connective tissue disease or an overlap disease.

Systemic Lupus Erythematosus

Systemic lupus erythematosus (disseminated lupus erythematosus or lupus) is a chronic inflammatory connective tissue disorder that can involve joints, kidneys, mucous membranes, and blood vessel walls.

Problems in the joints, nervous system, blood, skin, kidneys, gastrointestinal tract, and other tissues and organs can develop.

The blood count and the presence of autoimmune antibodies are tested.

People with active lupus often need corticosteroids or other drugs that suppress the immune system.

About 70 to 90% of people who have lupus are young women in their late teens to 30s, but children (mostly girls) and older men and women can also be affected. Lupus occurs in all parts of the world but may be more common among blacks and Asians.

The cause of lupus is usually not known. Occasionally, the use of certain drugs (such as hydralazine and procainamide, which are used to treat heart conditions, and isoniazid, which is used to treat tuberculosis) can cause lupus. Drug-induced lupus usually disappears after the drug is discontinued.

The number and variety of antibodies that can appear in lupus are greater than those in any other disorder. These antibodies, which are the underlying physiologic problem in lupus, along with other unknown factors, may sometimes determine which symptoms develop. However, the levels of these antibodies may not always be proportional to the person’s symptoms.

Discoid lupus erythematosus is a form of lupus that affects only the skin. In this condition, raised round rashes occur, sometimes with scarring and hair loss in affected areas. In 10% of people, manifestations of systemic lupus—for example, those affecting the joints, kidneys, and brain—may occur but are generally mild.

Symptoms

Symptoms vary greatly from person to person. Symptoms may begin suddenly with fever, resembling a sudden, severe (acute) infection. Or symptoms may develop gradually over months or years with episodes (called flare-ups) of fever, feeling unwell, or any of the symptoms discussed below alternating with periods when symptoms are absent or minimal.

Migraine-type headaches, epilepsy, or severe mental disorders (psychoses) may be the first abnormalities that are noticed. Eventually, however, symptoms may affect any organ system.

Joint Problems: Joint symptoms, ranging from intermittent joint pains (arthralgias) to sudden inflammation of multiple joints (acute polyarthritis), occur in about 90% of people and may exist for years before other symptoms appear. In long-standing disease, marked joint deformity may occur (Jaccoud’s arthropathy) but is rare. However, joint inflammation is generally intermittent and usually does not damage the joints.

Skin and Mucous Membrane Problems: Skin rashes include a butterfly-like redness across the nose and cheeks (malar butterfly rash); raised bumps or patches of thin skin; and red, flat or raised areas on the face and sun-exposed areas of the neck, upper chest, and elbows. Blisters and skin ulcers are rare, although ulcers do commonly occur on mucous membranes, particularly on the roof of the mouth, on the inside of the cheeks, on the gums, and inside the nose. Generalized or patchy loss of hair (alopecia) is common during flare-ups. Mottled red areas on the sides of the palms and up the fingers; redness and swelling around the nails; and flat, reddish purple blotches between the knuckles on the inner surfaces of the fingers also may occur. Purplish spots (petechiae) may occur because of bleeding in the skin as a result of low platelet levels in the blood. Sensitivity to sunlight (photosensitivity) occurs in most people with lupus, particularly fair-skinned people.

Lung Problems: It is common for people with lupus to feel pain when breathing deeply. The pain is due to recurring inflammation of the sac around the lungs (pleurisy), with or without fluid (effusion) inside this sac. Inflammation of the lungs (lupus pneumonitis), resulting in breathlessness, is rare, although minor abnormalities in lung function are common. Life-threatening bleeding into the lungs may rarely occur. Blockage of arteries in the lung caused by the formation of blood clots (thrombosis) can also occur.

Heart Problems: People with lupus may have chest pain due to inflammation of the sac around the heart (pericarditis). More serious but rare effects on the heart are inflammation of the walls of the coronary arteries (coronary artery vasculitis), which can lead to angina (see page 406), and inflammation of the heart muscle with scarring (fibrosing myocarditis), which can lead to heart failure (see page 352). The valves of the heart can rarely be involved and may need to be surgically repaired. People are at increased risk of coronary artery disease.

Lymph Node and Spleen Problems: Widespread enlargement of the lymph nodes is common, particularly among children, young adults, and blacks of all ages. Enlargement of the spleen (splenomegaly) occurs in about 10% of people. People may experience nausea, diarrhea, and vague abdominal discomfort. The occurrence of these symptoms may be the forewarning of a flare-up.

Characteristics of Lupus

At least four of the following symptoms are usually present for a diagnosis to be made:

Red, butterfly-shaped rash on the face, affecting the cheeks

Typical skin rash on other parts of the body

Sensitivity to sunlight (for example, rash or persistent burn)

Mouth sores

Joint inflammation (arthritis)

Fluid around the lungs, heart, or other organs (serositis)

Kidney dysfunction

Low white blood cell count, low red blood cell count, or low platelet count

Nerve or brain dysfunction

Positive results of a blood test for antinuclear antibodies

Positive results of a blood test for antibodies to double-stranded DNA or to phospholipids or for anti-smith antibody

Nervous System Problems: Involvement of the brain (neuropsychiatric lupus) can cause headaches, mild impairment of thinking, personality changes, stroke, epilepsy, severe mental disorders (psychoses), or a condition in which a number of physical changes may occur in the brain, resulting in disorders such as dementia. The nerves in the body or spinal cord may also be damaged.

Kidney Problems: Kidney involvement may be minor and without symptoms or may be relentlessly progressive and fatal. The most common result of this impairment is protein in the urine that leads to swelling (edema) in the legs.

Blood Problems: The numbers of red blood cells, white blood cells, and platelets may decrease. Platelets assist in blood clotting, so if these numbers decrease greatly, bleeding may occur. Also, and for other reasons, the blood may clot too easily, which accounts for many of the problems that can affect other organs (such as strokes and blood clots to the lungs or recurrent miscarriages).

Gastrointestinal Tract Problems: Impairment of blood supply to various parts of the gastrointestinal tract may result in abdominal pain, damage to the liver or pancreas (pancreatitis), or a blockage or tear (perforation) of the gastrointestinal tract.

Pregnancy Problems: Pregnant women have a higher-than-normal risk of miscarriage and stillbirth.

Diagnosis

Doctors suspect lupus mainly on the basis of the person’s symptoms and findings during a careful physical examination, particularly in a young woman. Nonetheless, because of the wide range of symptoms, distinguishing lupus from similar diseases can be difficult.

Laboratory tests can help doctors confirm the diagnosis. A blood test can detect antinuclear antibodies, which are present in almost all people who have lupus. However, these antibodies also occur in other diseases. Therefore, if antinuclear antibodies are detected, a test for antibodies to double-stranded DNA, as well as a test for other autoimmune antibodies (autoantibodies, such as anti-smith antibodies and others), are done. A high level of these DNA antibodies almost definitely means the person has lupus, but not all people who have lupus have these antibodies. Other blood tests, such as measuring the level of complement, are also performed and can help to predict the activity and course of the disease in some people. Women with lupus who have repeated miscarriages or have had problems with blood clots should be tested for antiphospholipid antibodies. This is an important test when planning contraceptive methods or pregnancy. This blood test, which detects antibodies to phospholipids, can help identify people at risk of recurrent blood clots. Women with positive antibodies to phospholipids should not take estrogen-containing oral contraceptives and should choose other methods of contraception. Blood tests can also indicate anemia, a low white blood cell count, or a low platelet count.

Laboratory tests can detect the presence of protein or red blood cells in the urine or an elevation of creatinine in the blood. These findings indicate kidney damage caused by inflammation of the filtering structure in the kidneys (glomeruli), a condition referred to as glomerulonephritis. Sometimes a kidney biopsy (removal of tissue for examination and testing) must be performed to help the doctor plan treatment. People who have lupus should be tested from time to time for kidney damage even if they have no symptoms. Testing includes blood and urine tests.

Prognosis

Lupus tends to be chronic and relapsing, often with symptom-free periods that can last for years. Flare-ups can be triggered by sun exposure, infection, surgery, or pregnancy. Flare-ups occur less often after menopause. Because many people are being diagnosed earlier than in the past and because better treatment is available, the prognosis has improved markedly over the last two decades. However, because the course of lupus is unpredictable, the prognosis varies widely. Usually, if the initial inflammation is controlled, the long-term prognosis is good. Early detection and treatment of kidney damage reduce the incidence of severe kidney disease.

Treatment

Treatment depends on which organs are affected and how active the inflammation of lupus is. The severity of the lupus is not necessarily the same as the activity of the inflammation. For example, organs may be permanently damaged and scarred from lupus that caused inflammation in the past. Such damage may be referred to as “severe,” even if the lupus is not active (that is, it is not causing any inflammation or any further damage at this time). The goal of treatment is to decrease the activity of lupus—that is, to decrease inflammation, which in turn should prevent damage.

If lupus is not very active (sometimes called mild lupus), treatment may not need to be intensive. Nonsteroidal anti-inflammatory drugs (NSAIDs—see page 644) often can relieve joint pain. Hydroxy-chloroquine, chloroquine, or quinacrine, sometimes taken in combination, helps relieve joint and skin symptoms. Sunscreen lotions (with a sun protection factor of at least 30) should be used, especially by people who have skin rashes.

Very active lupus (sometimes called severe lupus) is treated immediately with a corticosteroid such as prednisone (see box on page 568). The dose and duration of treatment depend on which organs are affected. Sometimes an immunosuppressive drug such as azathioprine or cyclophosphamide is given to suppress the body’s autoimmune attack. Mycophenolate mofetil is an alternative immunosuppressive drug. The combination of a corticosteroid and an immunosuppressive drug is most often used for severe kidney disease or nervous system disease and for vasculitis.

Once the initial inflammation is controlled, a doctor determines the dose that most effectively suppresses inflammation over the long term. Usually, the dose of prednisone is gradually decreased when symptoms are controlled and laboratory test results show improvement. Relapses or flare-ups can occur during this process. For most people who have lupus, the dose of prednisone can eventually be decreased or occasionally discontinued.

Surgical procedures and pregnancy may be more complicated for people who have lupus, and they require close medical supervision. Miscarriages and flare-ups during pregnancy are common. Pregnancy should be avoided during a flare-up, and conception should be delayed until the disease seems likely to be inactive.

People who take corticosteroids should be tested periodically and, if necessary, treated for osteoporosis (thinning of the bones), which can occur with chronic corticosteroid use. People should be monitored closely by a doctor for coronary artery disease. Other risk factors for coronary artery disease (for example, high blood pressure and high cholesterol levels) should be controlled as well as possible.

Systemic Sclerosis

Systemic sclerosis (scleroderma) is a rare, chronic disorder characterized by degenerative changes and scarring in the skin, joints, and internal organs and by blood vessel abnormalities.

Swelling of the fingers, intermittent coolness and blue discoloration of the fingers, joints freezing in permanent (usually flexed) positions (contractures), and damage to the gastrointestinal system, lungs, heart, or kidneys may develop.

People often have antibodies in the blood characteristic of an autoimmune disorder.

No treatment changes the course of the disorder.

Symptoms and organ dysfunction are treated.

The cause of systemic sclerosis is not known. The disorder is 4 times more common among women than men and is rare among children. Symptoms of systemic sclerosis may occur as part of mixed connective tissue disease, and some people with mixed connective tissue disease develop severe systemic sclerosis. Systemic sclerosis can occur in limited forms, for example, sometimes affecting just the skin or mainly only certain parts of the skin or as CREST syndrome. However, systemic sclerosis often causes damage that is widespread throughout the body (called diffuse or generalized systemic sclerosis).

Symptoms

The usual initial symptom of systemic sclerosis is swelling, then thickening and tightening of the skin at the ends of the fingers. Raynaud’s syndrome, in which the fingers suddenly and temporarily become very pale and tingle or become numb, painful, or both in response to cold or emotional upset (see page 426), is also common. Fingers may become bluish. Heartburn, difficulty in swallowing, and shortness of breath are occasionally the first symptoms of systemic sclerosis. Aches and pains in several joints often accompany early symptoms. Sometimes inflammation of the muscles (polymyositis), with its accompanying muscle pain and weakness, develops.

Skin Changes: Systemic sclerosis can damage large areas of skin or only the fingers (sclerodactyly). Sometimes systemic sclerosis tends to stay restricted to the skin of the hands. Other times, the disorder progresses. The skin becomes more widely taut, shiny, and darker than usual. The skin on the face tightens, sometimes resulting in an inability to change facial expressions. Sometimes dilated blood vessels (telangiectasia often referred to as spider veins) can appear on the fingers, chest, face, lips, and tongue, and bumps composed of calcium can develop on the fingers, on other bony areas, or at the joints. Sores can develop on the fingertips and knuckles.

Joint Changes: Sometimes, a grating sound can be felt or heard as inflamed tissues move over each other, particularly at and below the knees and at the elbows and wrists. The fingers, wrists, and elbows may become stuck (forming a contracture) in flexed positions because of scarring in the skin.

Gastrointestinal System Changes: Scarring commonly damages the lower end of the esophagus (the tube connecting the mouth and stomach). The damaged esophagus can no longer propel food to the stomach efficiently. Swallowing difficulties and heartburn eventually develop in many people who have systemic sclerosis. Abnormal cell growth in the esophagus (Barrett’s esophagus—see page 189) occurs in about 33% of the people, increasing their risk of esophageal blockage (stricture) due to a fibrous band or their risk of esophageal cancer. Damage to the intestines can interfere with food absorption (malabsorption) and cause weight loss.

Lung and Heart Changes: Systemic sclerosis can cause scar tissue to accumulate in the lungs, resulting in abnormal shortness of breath during exercise. The blood vessels that supply the lungs can be affected (their walls thicken), so they cannot carry as much blood. Therefore blood pressure within the arteries that supply the lungs can increase (a condition called pulmonary hypertension—see page 522). Systemic sclerosis can also cause several life-threatening heart abnormalities, including heart failure and abnormal rhythms.

Kidney Changes: Severe kidney disease can result from systemic sclerosis. The first symptom of kidney damage may be an abrupt, progressive rise in blood pressure. High blood pressure is an ominous sign, although treatment usually controls it.

CREST Syndrome: CREST syndrome, also called limited cutaneous systemic sclerosis (sclerosis) is usually a less severe form of the disorder that is less likely to cause serious internal organ damage. It is named for its symptoms: Calcium deposits in the skin and throughout the body, Raynaud’s syndrome, Esophageal dysfunction, Sclerodactyly (skin damage on the fingers), and Telangiectasia (dilated blood vessels or spider veins). Skin damage is limited to the fingers. People who have CREST syndrome can develop pulmonary hypertension, which can cause heart and lung failure. The drainage system from the liver may become blocked by scar tissue (biliary cirrhosis), resulting in liver damage and jaundice.

Diagnosis

A doctor diagnoses systemic sclerosis by the characteristic changes in the skin and internal organs. The symptoms may overlap with those of several other disorders, but the whole pattern is usually distinctive. Laboratory tests alone cannot identify systemic sclerosis because test results, like the symptoms, vary greatly. However, antinuclear antibodies are present in the blood of more than 90% of people with systemic sclerosis. An antibody to centromeres (part of a chromosome) is often present in people who have CREST syndrome. A different antibody (called anti-topoisomerase) is often present in people with the more diffuse generalized form.

Prognosis

Sometimes systemic sclerosis worsens rapidly and becomes fatal. At other times, it affects only the skin for decades before affecting internal organs, although some damage to internal organs (such as the esophagus) is almost inevitable, even in CREST syndrome. The course is unpredictable. Overall, about 65% of people live for at least 10 years after the diagnosis is made. The prognosis is worst for those who have heart, lung, or, particularly, kidney damage.

Treatment

No drug can stop the progression of systemic sclerosis. However, drugs can relieve some symptoms and reduce organ damage. Nonsteroidal anti-inflammatory drugs (NSAIDs—see page 644) help relieve joint pain. If the person has weakness because of polymyositis, corticosteroids may be needed. Drugs that suppress the immune system, such as cyclophosphamide and azathioprine, may help some people whose lungs are affected. Doctors treat severe pulmonary hypertension with the drugs bosentan or epoprostenol. The person may also be given anticoagulants.

Heartburn can be relieved by eating small meals, taking antacids, and using proton pump inhibitors, which block stomach acid production. Sleeping with the head of the bed elevated often helps. Areas of the esophagus narrowed by scar tissue can be surgically widened (dilated). Tetracycline or other antibiotics can help prevent malabsorption of food caused by excessive growth (overgrowth) of bacteria in the damaged intestine. A calcium channel blocker (such as nifedipine) may relieve the symptoms of Raynaud’s syndrome (see page 426) but may also increase the reflux of stomach acid. Drugs for high blood pressure, particularly angiotensin-converting enzyme (ACE) inhibitors, are useful in treating kidney disease and the rise in blood pressure.

Physical therapy and exercise can help to maintain muscle strength but cannot totally prevent joints from freezing in contractures.

Sjögren’s Syndrome

Sjögren’s syndrome is characterized by excessive dryness of the eyes, mouth, and other mucous membranes.

White blood cells can infiltrate and damage glands that secrete fluids, and sometimes other organs can be damaged.

Tests can be done to measure gland function and assess the presence of abnormal antibodies in the blood.

Usually, measures to keep surfaces such as the eyes and mouth moist are sufficient.

When internal organ damage is severe, corticosteroids or cyclophosphamide can be given by mouth.

Sjögren’s syndrome is thought to be an autoimmune disorder, but its cause is not known. It is more common among women than men. Some people with Sjögren’s syndrome also have other autoimmune disorders, such as rheumatoid arthritis, systemic lupus erythematosus, systemic sclerosis, vasculitis, mixed connective tissue disease, Hashimoto’s thyroiditis, primary biliary cirrhosis, and chronic autoimmune hepatitis.

White blood cells infiltrate the glands that secrete fluids, such as the salivary glands in the mouth and the tear glands in the eyes. The white blood cells injure the glands, resulting in a dry mouth and dry eyes—the hallmark symptoms of this syndrome.

Symptoms

In some people, only the mouth or eyes are dry (a condition called sicca complex or sicca syndrome). Dryness of the eyes may severely damage the cornea, resulting in a scratchy or irritated sensation, and a lack of tears can cause permanent eye damage. Insufficient saliva in the mouth can dull taste and smell, make eating and swallowing painful, and can cause cavities. The salivary glands in the cheeks (parotids) become enlarged and slightly tender in about one third of people. The mouth may also burn, which may sometimes indicate a complicating yeast infection.

In other people, many organs are affected. Sjögren’s syndrome can dry out the mucous membranes lining the digestive tract, windpipe (trachea), vulva, and vagina. Dryness of the vulva and vagina can make sexual intercourse difficult. Dryness of the trachea can cause cough. The protective sac surrounding the heart (pericardium) may be inflamed—a condition called pericarditis. Nerve, lung tissue, and other tissues may be damaged by the inflammation.

Joint inflammation (arthritis) occurs in about one third of people, affecting the same joints that rheumatoid arthritis affects, but the joint inflammation of Sjögren’s syndrome tends to be milder and is usually not destructive. Lymph nodes may enlarge throughout the body. Lymphoma, a cancer of the lymphatic system, is more common among people who have Sjögren’s syndrome than the general population. Skin rashes, kidney damage, Raynaud’s syndrome, and vasculitis that causes damage to the peripheral nerves may occur.

Diagnosis

Although a sensation of dry mouth or dry eyes is fairly common, a sensation of dry mouth and dry eyes accompanied by joint inflammation may indicate that the person has Sjögren’s syndrome. Various tests can help a doctor diagnose this disorder and differentiate it from other disorders that can cause similar symptoms.

The amount of tears produced can be estimated by placing a filter paper strip under each lower eyelid and observing how much of the strip is moistened (Schirmer’s test). A person who has Sjögren’s syndrome may produce less than one third of the normal amount. An ophthalmologist can test for damage to the eye’s surface. More sophisticated tests to evaluate salivary gland secretion may be performed, and a doctor may order scans or the removal of tissue for examination and testing (biopsy) of the salivary glands.

Blood tests can detect abnormal antibodies, including SS-A, an antibody that is present in Sjögren’s syndrome. Antinuclear antibodies (which are found in people with lupus) and rheumatoid factor (which is found in people with rheumatoid arthritis) can also be found in people with Sjögren’s syndrome. The erythrocyte sedimentation rate (ESR), a test that measures the rate at which red blood cells settle to the bottom of a test tube containing blood, is elevated in about 7 of 10 people. About 1 of 3 people has a decreased number of red blood cells (anemia), and 1 in 4 people has a decreased number of certain types of white blood cells (leukopenia).

Prognosis and Treatment

The prognosis is generally good. However, if the lungs, kidneys, or lymph nodes are damaged by the antibodies, pneumonia, kidney failure, or lymphoma may result.

No cure for Sjögren’s syndrome is available, but symptoms can be relieved. Dry eyes can be treated with artificial tear drops during the day and a lubricating ointment at night. A prescription eye drop containing cyclosporine can also be used.

Shields can be fitted on the sides of glasses, helping to protect the eyes from air and wind, reducing evaporation of tears. A simple surgical procedure called punctal occlusion can be performed. In this procedure, an ophthalmologist inserts small plugs into the tear ducts in the corner of the lower eyelid, so the person’s tears stay on the eye longer.

A dry mouth can be moistened by continuously sipping liquids, chewing sugarless gum, or using a saliva substitute mouth rinse. Drugs that reduce the amount of saliva, such as decongestants, antidepressants, and antihistamines, should be avoided because they can worsen the dryness. The drug pilocarpine or cevimeline may help stimulate the production of saliva if the salivary glands are not too severely damaged.

Fastidious dental hygiene and frequent dental visits can minimize tooth decay and loss. Painful, swollen salivary glands can be treated with analgesics and warm compresses. Because joint symptoms are usually mild, treatment with nonsteroidal anti-inflammatory drugs (NSAIDs) and rest is often sufficient. Antimalarial drugs (such as hydroxychloroquine) can relieve joint pain, swollen lymph nodes, and skin problems. Very rarely, the drug methotrexate may be given. When symptoms resulting from damage to internal organs are severe, corticosteroids (such as prednisone) or cyclophosphamide taken by mouth can be useful.

Sjögren’s syndrome that occurs along with other autoimmune diseases, such as lupus, rheumatoid arthritis, and systemic sclerosis, is referred to as secondary Sjögren’s syndrome. People with secondary Sjögren’s syndrome receive additional treatment for the other disease.

Polymyositis and Dermatomyositis

Polymyositis is characterized by inflammation and degeneration of the muscles. Dermatomyositis is polymyositis accompanied by skin inflammation.

Muscle damage may cause muscle pain and difficulty lifting the arms above the shoulders, climbing stairs, or arising from a sitting position.

Doctors check muscle enzymes in the blood and sometimes test electrical activity of muscles, perform magnetic resonance imaging (MRI) on muscles, check levels of muscle enzymes in the blood, examine a piece of muscle tissue (biopsy), or a combination.

Oral corticosteroids are usually helpful.

These disorders result in disabling muscle weakness. The weakness typically occurs in the shoulders and hips but can affect muscles symmetrically throughout the body.

Polymyositis and dermatomyositis usually occur in adults from ages 40 to 60 or in children from ages 5 to 15 years. Women are twice as likely as men to develop either disorder. In adults, these disorders may occur alone or as part of other connective tissue disorders, such as mixed connective tissue disease.

The cause of polymyositis and dermatomyositis is unknown. Viruses or autoimmune reactions may play a role. Cancer may also trigger polymyositis and dermatomyositis. It is possible that an immune reaction against cancer may be directed against a substance in the muscles.

Symptoms

Polymyositis: In polymyositis, the symptoms are similar for people of all ages, but the disorder usually develops more abruptly in children than in adults. Symptoms, which may begin during or just after an infection, include symmetrical muscle weakness (particularly in the upper arms, hips, and thighs), joint pain (but often little muscle pain), difficulty in swallowing, fever, fatigue, and weight loss. Raynaud’s syndrome (in which the fingers suddenly become very pale and tingle or become numb in response to cold or emotional upset—see page 426) occurs more commonly among people who have polymyositis along with other connective tissue disorders.

Muscle weakness may start slowly or suddenly and may worsen for weeks or months. Because muscles close to the center of the body are affected most, tasks such as lifting the arms above the shoulders, climbing stairs, and getting out of a chair can become very difficult. If the neck muscles are affected, even raising the head from a pillow may be impossible. Weakness in the shoulders or hips can confine a person to a wheelchair or bed. Muscle damage in the upper part of the esophagus can cause swallowing difficulties and regurgitation of food. The muscles of the hands, feet, and face, however, are not affected.

Joint aches and inflammation occur in about 30% of people. The pain and swelling tend to be mild.

Polymyositis usually does not affect internal organs other than the throat and esophagus. However, the lungs and heart may be affected, causing shortness of breath and a cough.

Dermatomyositis: In dermatomyositis, all the symptoms of polymyositis occur. In addition, rashes tend to appear at the same time as muscle weakness and other symptoms. A shadowy-red or purplish rash (heliotrope rash) can appear on the face with reddish purple swelling around the eyes. Another rash, which may be scaly, smooth, or raised, may appear almost anywhere on the body but is especially common on the knuckles and sides of the hands. The nail beds may redden. When the rashes fade, brownish pigmentation, scarring, shriveling, or pale depigmented patches may develop on the skin.

Diagnosis

Doctors use the following criteria to make the diagnosis of polymyositis or dermatomyositis:

Muscle weakness at the shoulders or hips

A characteristic rash

Increased blood levels of certain muscle enzymes (especially creatine kinase) in the blood, indicating muscle damage

Abnormalities in muscle electrical activity as measured by electromyography (see page 636), or on appearance on a magnetic resonance imaging (MRI) scan

Characteristic changes in muscle tissue obtained by biopsy and observed under a microscope (the most conclusive evidence)

Laboratory tests are helpful but cannot specifically identify polymyositis or dermatomyositis. Muscle enzymes are measured repeatedly in blood samples to monitor the disorder; the levels usually fall to normal or near normal with effective treatment. Magnetic resonance imaging (MRI) may also show areas of inflammation and help the doctor select a site for biopsy. Special tests performed on muscle tissue samples may be needed to rule out other muscle disorders.

Prognosis

Within 5 years, up to 50% of people (especially children) who have received treatment experience a long remission (even apparent recovery). However, the disorder may still return at any time. About 75% of people survive at least 5 years after the diagnosis is made. This percentage is even higher among children. Adults are at risk of death from severe and progressive muscle weakness, difficulty swallowing, undernutrition, inhaling food that causes pneumonia (aspiration pneumonia), and respiratory failure, which often occurs at the same time as pneumonia. Polymyositis tends to be more severe and resistant to treatment in people whose heart or lungs are affected. In people who have cancer, it is the cancer, rather than the polymyositis, that is the cause of death.

Treatment

Modest restriction of activities when the inflammation is most intense often helps. Generally, a corticosteroid, usually prednisone, given by mouth in high doses slowly improves strength and relieves pain and swelling, controlling the disease. After about 6 to 12 weeks, when the muscle enzyme levels have returned to normal and muscle strength has returned, the dose is gradually decreased. Many adults must continue taking a low dose of prednisone or an alternative drug for many years or even indefinitely to prevent a relapse. After about a year, children may be able to stop taking the drug and stay symptom-free.

In some people, corticosteroids are not very effective or must be taken at very high doses to be effective. In some people, corticosteroids may cause muscle damage and weakness (see box on page 568). In such situations, an immunosuppressive drug (methotrexate, azathioprine, or cyclosporine) is used instead of or in addition to prednisone. When other drugs are ineffective, gamma globulin (a substance that contains large quantities of many antibodies) may be given by vein (intravenously). Other new remedies that may be effective in treating polymyositis and dermatomyositis include rituximab and a class of drugs (such as infliximab and etanercept) that inhibit a chemical called tumor necrosis factor (tumor necrosis factor inhibitors).

When polymyositis is associated with cancer, it usually does not respond well to prednisone. However, the condition usually lessens in severity if the cancer can be successfully treated.

Because people who take corticosteroids are at risk of fractures related to osteoporosis, they should be closely screened and treated for osteoporosis. Preventive measures (such as treatment of high blood pressure, high blood cholesterol levels, and osteoporosis) should be taken.

Mixed Connective Tissue Disease

Mixed connective tissue disease is a term used by some doctors to describe a disorder characterized by features of systemic lupus erythematosus, systemic sclerosis, and polymyositis.

Raynaud’s syndrome, joint pains, various skin abnormalities, weakness, and problems with internal organs can develop.

Characteristic abnormal antibodies are usually detectable in blood.

Treatment is similar to that of systemic lupus erythematosus, often with corticosteroids.

About 80% of people who have this disease are women. Mixed connective tissue disease affects people from ages 5 to 80. Its cause is unknown, but it seems to be an autoimmune disorder.

Symptoms

The typical symptoms are Raynaud’s syndrome (in which the fingers suddenly become very pale and tingle or become numb or blue in response to cold or emotional upset—see page 426), joint inflammation (arthritis), swollen hands, muscle weakness, difficulty in swallowing, heartburn, and shortness of breath. Raynaud’s syndrome may precede other symptoms by many years. Regardless of how mixed connective tissue disease starts, it tends to worsen, and symptoms spread to several parts of the body.

The hands are frequently so swollen that the fingers look like sausages. A purplish butterfly-shaped rash on the cheeks and bridge of the nose, red patches on the knuckles, a violet discoloration of the eyelids, and red spider veins on the face and hands all may appear. Skin changes similar to those in systemic sclerosis also may occur. The hair may thin.

Almost everyone with mixed connective tissue disease has aching joints. About 75% develop the swelling and pain typical of joint inflammation (arthritis). Mixed connective tissue disease damages the muscle fibers, so the muscles may feel weak and sore, especially in the shoulders and hips. Tasks such as lifting the arms above the shoulders, climbing stairs, and getting out of a chair can become very difficult.

Fluid may collect in or around the lungs. In some people, abnormal lung function is the most serious problem, causing shortness of breath during exertion.

Occasionally, the heart is weakened, leading to heart failure (see page 352). Symptoms of heart failure may include fluid retention, shortness of breath, and fatigue. The kidneys and nerves are affected in only 10% of people, and the damage is usually mild compared to the damage caused by lupus. Other symptoms may include fever, swollen lymph nodes, abdominal pain, and persistent hoarseness. Sjögren’s syndrome may develop. Over time, most people develop symptoms that are more typical of lupus or systemic sclerosis.

Diagnosis

Doctors suspect mixed connective tissue disease when some symptoms from lupus, systemic sclerosis, polymyositis, or rheumatoid arthritis overlap.

Blood tests are performed to detect an antibody to ribonucleoprotein, which is present in almost all people who have mixed connective tissue disease. A high level of this antibody without the other antibodies present in lupus is characteristic of mixed connective tissue disease.

Prognosis

Despite treatment, mixed connective tissue disease worsens in about 13% of the people, causing potentially fatal complications in 6 to 12 years. The prognosis is worse for people who have mainly features of systemic sclerosis or polymyositis. Overall, 80% of people survive at least 10 years after the diagnosis is made. Symptom-free periods can last for many years with little or no continuing treatment with a corticosteroid.

Treatment

The treatment is similar to that of lupus. Corticosteroids are usually effective, especially when the disease is diagnosed early. Mild cases can be treated with aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs), hydroxychloroquine or similar drugs, or very low doses of corticosteroids. The more severe the disease, the higher the dose of corticosteroid needed. In severe cases, immunosuppressive drugs (such as azathioprine, methotrexate or cyclophosphamide) may also be needed.

In general, the more advanced the disease and the greater the organ damage, the less effective the treatment. Systemic sclerosis-like damage to the skin and esophagus is least likely to respond to treatment.

Relapsing Polychondritis

Relapsing polychondritis is characterized by episodes of painful, destructive inflammation of the cartilage and other connective tissues in many organs.

The ears or nose may become inflamed and tender.

Other cartilage in the body can be damaged, leading to various symptoms, such as red or painful eyes, hoarseness, cough, difficulty breathing, rashes, and pain in the breastbone.

Blood tests are done and a piece of tissue may be removed for examination and testing (biopsy).

If symptoms or complications are moderate or severe, corticosteroids usually help.

This disorder affects men and women equally, usually in middle age. The cause is unknown, but autoimmune reactions to cartilage are suspected.

Symptoms

Typically, one or both ears become red, swollen, and very painful. At the same time or later, a person can develop joint inflammation (arthritis), which may be mild or severe. Cartilage in any joint may be affected, and the cartilage that connects the ribs to the breastbone may become inflamed. Cartilage in the nose is also a common site of inflammation. The nose may become tender, and cartilage can collapse.

Other affected sites include the eyes, resulting in scleritis (inflammation of the white part of the eye), and the voice box (larynx) and windpipe (trachea), resulting in hoarseness, a nonproductive cough, shortness of breath, and tenderness over the Adam’s apple. Rarely the cornea may develop a hole (perforate), resulting in blindness. Less often, the heart is involved, leading to heart murmurs and occasionally to heart failure. The skin may become inflamed, resulting in a variety of rashes.

Flare-ups of inflammation and pain last a few weeks, subside, then recur over a period of several years. Eventually, the supporting cartilage can be damaged, resulting in floppy ears; a sloping saddle nose; and vision, hearing, and balance problems.

People who have this disorder may die if the cartilage in their airways collapses, blocking the flow of air, or if their heart and blood vessels are severely damaged.

Diagnosis and Treatment

Relapsing polychondritis is diagnosed when a doctor observes at least three of the following symptoms developing over time:

Inflammation of both ears

Painful swelling in several joints

Inflammation of the cartilage in the nose

Inflammation of the eye

Cartilage damage in the respiratory tract

Hearing or balance problems

A biopsy of the affected cartilage may show characteristic abnormalities. Blood tests, such as the erythrocyte sedimentation rate (ESR), can detect evidence of chronic inflammation.

Mild relapsing polychondritis can be treated with nonsteroidal anti-inflammatory drugs (NSAIDs—see page 644) or dapsone. In more severe cases, daily doses of prednisone are given, then tapered off as the symptoms begin to lessen. Sometimes very severe cases are treated with immunosuppressive drugs such as cyclosporine, cyclophosphamide, or azathioprine. These drugs treat the symptoms but have not been shown to alter the ultimate course of the disorder.

Eosinophilic Fasciitis

Eosinophilic fasciitis is a rare disorder in which the skin of the arms and legs becomes painfully inflamed and swollen and gradually hardens.

The connective tissue is probably damaged by an autoimmune reaction.

Some tissue is removed for examination and testing (biopsy).

Corticosteroids are helpful.

The word eosinophilic refers to the initially high blood levels of a type of white blood cell called eosinophils. The word fasciitis refers to inflammation of the fascia, which is the tough fibrous tissue that lies beneath the skin.

The cause of eosinophilic fasciitis is unknown. The disorder occurs mainly in men aged 40 to 50, but it may occur in women and children.

Symptoms

The usual initial symptoms are pain, swelling, and inflammation of the skin, particularly over the inside of the arms and the front of the legs. The skin of the face, chest, and abdomen may occasionally be affected also. In contrast to systemic sclerosis, the skin of the feet and hands is not affected and Raynaud’s syndrome does not occur.

Symptoms may first be noticed after strenuous physical activity. Symptoms usually progress gradually. After weeks, the inflamed skin begins to harden, eventually acquiring a texture similar to an orange peel.

As the skin gradually hardens, the arms and legs become difficult to move. Eventually, the arms and legs may become stuck in unusual positions. Weight loss and fatigue are common. Muscle strength does not usually decrease, but muscle and joint pain may occur. Rarely, if the arms are involved, the person may develop carpal tunnel syndrome (see page 601).

Sometimes, the numbers of red blood cells and platelets in the bloodstream become very low, resulting in fatigue and a tendency to bleed easily.

Diagnosis

A doctor suspects eosinophilic fasciitis because of its typical symptoms. The number of eosinophils is increased in the blood, as is the erythrocyte sedimentation rate (ESR). This increase indicates inflammation.

The diagnosis is confirmed by taking a biopsy of affected skin and the tissues underneath it (the fascia). The biopsy sample must include all skin layers down to the muscle. Magnetic resonance imaging (MRI) can also help make the diagnosis but is not as conclusive as muscle biopsy.

Prognosis and Treatment

The long-term outlook is unknown.

Most people respond rapidly to high doses of corticosteroids. Treatment should be started as early as possible to prevent scarring, tissue loss (atrophy), and contractures. Corticosteroids may not reverse atrophied and scarred tissue. Doses are gradually reduced, but corticosteroids may need to be continued at low levels for 2 to 5 years. For people who cannot use corticosteroids or do not fully respond to corticosteroids, other drugs (for example, hydroxychloroquine or cyclosporine) can be tried.

Monitoring with blood tests is advised because the occasional person develops another blood disorder.