Any of a group of diseases involving connective tissue as the pathological target. Connective tissue comprises one of the primary tissues of the body and is distinguished by an abundance of fibrillar and nonfibrillar extracellular components, which help to connect various structures of the body together. Connective tissue diseases (formerly termed collagen vascular diseases because collagen is one of the main protein components of connective tissue) are clinically and pathologically discrete, but have overlapping features. Specific types of connective tissue diseases include lupus erythematosus (Fig. 1), systemic vasculitis, scleroderma (and systemic sclerosis), polymyositis, and Sjögren's syndrome. Each of the diseases can involve multiple organ systems and is often coupled with various immunologic abnormalities. Often, the signs and symptoms of a variety of connective tissue diseases occur simultaneously. Under these circumstances, the condition is called mixed connective tissue disease. See also: Collagen; Connective tissue; Immunology; Tissue
The set of diseases known as lupus erythematosus includes limited, primarily cutaneous disorders [discoid lupus (Fig. 1) and subacute cutaneous lupus] and a diffuse systemic illness (systemic lupus erythematosus), all of which are of unknown cause or causes. Also, a lupuslike reaction known as drug-induced lupus can be caused by certain therapeutic agents.
Systemic lupus erythematosus
Systemic lupus erythematosus is an inflammatory, multisystem disorder in which tissue injury is mediated by immune complexes. In this autoimmune disorder, lymphocytes known as T cells lose some of their control over the antibody production by lymphocytes known as B cells. Thus, in most individuals with systemic lupus, antibodies are found in the blood serum that are not normally present. See also: Antibody; Autoimmunity; Immune complex disease; Inflammation
The immunologic events of systemic lupus are influenced by multiple factors. In some families, a genetic predisposition seems to be present. In addition, the disease sometimes flares up after excessive exposure to ultraviolet light, emphasizing the importance of environmental factors. Finally, hormonal factors also seem to play a contributing role. For example, eight to nine times as many young women compared with men have systemic lupus; and in some animal models of lupus, femaleness is associated with more severe disease. See also: Cellular immunology; Hormone; Ultraviolet radiation (biology)
Although systemic lupus can be an acute and fulminating illness, it is far more often a chronic disorder with long periods (years, sometimes even decades) of remission and good health and with infrequent flare-ups. With the recognition of the immune markers (that is, autoantibodies) in serum, milder forms of the disorder can be identified.
The manifestations and course of systemic lupus vary greatly from one individual to another and even in one person over time. Fever and other constitutional symptoms (for example, fatiguability, lack of appetite, and weight loss) are prominent. Skin rashes are common, and the so-called butterfly rash over the nose and cheeks is most characteristic (Fig. 2). Joint pain and inflammation (arthritis) are among the common features and often are the first manifestations of the disease. Many other parts of the body, including the lungs, heart, skeletal muscles, kidneys, and nervous system, can be involved. Small blood vessels at any site may be inflamed. Hematologic abnormalities also can occur when antibodies reactive with cell membrane antigens are present. Anemia and low levels of white blood cells and platelets are common. Certain autoantibodies affect blood clotting and can be associated with clots in blood vessels anywhere in the body. See also: Arthritis; Hematologic disorders
The diagnosis of systemic lupus is based on a combination of clinical and laboratory findings; no single clinical feature or laboratory test makes the diagnosis. Even the characteristic immune markers in serum (that is, the autoreactive antibodies) are not specific. For example, the routine screening test for antinuclear antibodies (ANAs), which is positive in 95% of patients with systemic lupus erythematosus, can also be positive in those with other connective tissue disorders and certain other diseases, as well as some healthy family members of patients with systemic lupus. Discoid lupus and subacute cutaneous lupus are variants, primarily with skin involvement. Photosensitivity is prominent. Systemic features are infrequent and milder than in systemic lupus erythematosus, and the kidney and nervous systems are usually spared. ANA positivity is often present.
Drug-induced lupus subsides when the offending agent is discontinued. Many drugs that are chemically unrelated to each other can produce the disorder. Genetic factors play a role in susceptibility to induction of lupus by at least some drugs.
Except for drug-related lupus, the cause of systemic lupus and its variants is not known; thus, a rational basis for specific curative therapy does not exist. However, the clinical manifestations of systemic lupus can generally be managed effectively for long years or even decades. Prognosis is steadily improving. Drugs that are used to control the disease by suppressing inflammation and altering the immune system include nonsteroidal anti-inflammatory drugs, an antimalarial agent (hydroxychloroquine), corticosteroids, and immunosuppressive agents. Sound general medical management and vigorous treatment of associated illnesses (especially infections) are essential. See also: Steroid
Systemic vasculitis comprises a series of different clinical illnesses that are characterized by intense inflammation in the walls of blood vessels, especially arteries (that is, arteritis). Notable diseases include polyarteritis, granulomatous arteritis (including temporal arteritis; Fig. 3), and hypersensitivity. These illnesses differ clinically, pathologically, and with respect to therapeutic responsiveness and outcome. Even the age and sex of the typically affected person vary from one to another. In addition, vasculitis can also be a secondary process occurring along with other connective tissue diseases (for example, systemic lupus, polymyositis, and Sjögren's syndrome) and with rheumatoid arthritis, infections, and malignant neoplasms. The existence of this wide array of underlying disorders suggests that various immunologic pathways can lead to vascular injury. See also: Circulation disorders; Rheumatism; Vascular disorders
The clinical pattern of illness varies with the sites of blood vessel involvement and the character of vascular injury. Tissue death in the vessel wall can lead to narrowing, or even blockage, of the vessel or weakening of the wall with formation of an aneurysm. Impaired circulation and altered blood flow result. Symptoms, therefore, can arise not only from the tissue inflammation itself, but also from the lack of adequate blood supply in the organ supplied by that vessel. Vasculitis can be a systemic condition or can be confined to a single organ or to the skin. See also: Aneurysm
Polymyositis involves intense inflammation in skeletal muscle that, if untreated, can lead to destruction of muscle fibers. When typical skin lesions are present, the term dermatomyositis is applied. The pathology of these two entities differs and suggests different mechanisms of inflammation. See also: Muscle
The cause of polymyositis or dermatomyositis is not known in most cases. These conditions can occur alone or in association with other connective tissue disorders (that is, systemic lupus, scleroderma, and Sjögren's syndrome). Dermatomyositis may sometimes accompany malignant tumors. See also: Tumor
Polymyositis may be abrupt or insidious in onset. The dominant manifestation is progressive weakness of the proximal limb-girdle muscle groups. Difficulty rising from a chair, in climbing stairs, lifting modest weights, and keeping the arms elevated are common symptoms. Despite intense inflammation in the skeletal musculature, pain and tenderness of the involved muscles are infrequent. The potential involvement of pharyngeal musculature or the chest muscles is most serious because this may impair swallowing or breathing, respectively.
The inflammatory process is generally responsive to corticosteroid therapy; however, in some cases, the addition of a cytotoxic drug (for example, methotrexate) is required. In the few individuals with tumor-related polymyositis, appropriate treatment of the malignancy is essential. Moreover, when polymyositis occurs together with other connective tissue disorders, such as lupus, the additional features of these illnesses must also be controlled.
If diagnosed early, before loss of muscle fibers and replacement by fibrous scarring is extensive, polymyositis is reversible. Recovery with minimal residual loss of strength is to be expected in almost all patients.
The term scleroderma means "hard skin," designating a disorder in which increased deposition of collagen fibers in the deeper dermis leads to thickened, leathery, bound-down skin. This deposition is variable in extent and degree. When organ involvement is associated with such skin changes, the term systemic sclerosis is used.
Raynaud's phenomenon (a hyperreactivity to cold exposure with blanching and discoloration of the fingers and toes) is the common initial manifestation and may precede sclerodermatous skin changes by decades. Only a small fraction of those with Raynaud's phenomenon eventually develop scleroderma or systemic illness; however, of those who do have scleroderma, at least 80% will have Raynaud's phenomenon. Skin changes may be confined to the distal digits or become generalized.
Systemically, the gastrointestinal tract is commonly involved. Difficulty in swallowing and midchest discomfort result from loss of peristalsis in the esophagus. Diarrhea, inability to absorb nutrients, abdominal pain, and distention can occur with bowel involvement, leading to weight loss and wasting. Scarring of the lungs and decreased pulmonary function occur frequently. The most serious lesions are those of the heart and kidney, and may result from vascular abnormalities. Joint inflammation is mild and uncommon; however, advanced skin changes, especially in the hands, may restrict joint mobility. Polymyositis is occasionally present and is the major indication for corticosteroid therapy in this disorder. See also: Gastrointestinal tract disorders
A variant called the CREST syndrome (calcinosis, Raynaud's phenomenon, esophageal dysmotility, sclerodactyly, and telangiectasia) is notable because of its mildness and slow progression. It is also referred to as limited scleroderma.
Management involves treatment of high blood pressure that can arise because of kidney involvement, use of agents to improve circulation by reducing small-vessel spasm, and reducing gastrointestinal complications with special diets and sometimes antibiotics. In a few cases, skin changes may subside spontaneously.
Sjögren's syndrome (Fig. 4) is characterized primarily by dryness of the membranes due to excretory gland failure, especially dryness of the eyes (xerophthalmia) and mouth (xerostomia) from loss of tears and saliva, respectively. This sicca (dryness) syndrome reflects the infiltration of lacrimal and salivary glands by immunologically competent cells (lymphocytes). See also: Gland
Sjögren's syndrome may be primary or secondary; the latter often occurs in the context of another disorder, such as rheumatoid arthritis or systemic lupus. The typical individual with primary Sjögren's syndrome is a woman later in life. In most cases, the sicca complex dominates, but there can be loss of secretions in the skin, bronchial tree, esophagus, stomach, and vaginal vault. In some people with primary Sjögren's syndrome, systemic features may evolve. Diagnosis is primarily clinical, but ocular dryness can be quantitated. Lip biopsy of the minor salivary glands can confirm the infiltration by immune cells. Noninvasive scanning of the parotids can confirm the loss of functional glandular structure. Autoantibodies in the blood are common and can aid in differentiating Sjögren's syndrome from other causes of dry eyes and dry mouth; however, in no instance is a blood test diagnostic of either Sjögren's syndrome or any companion disorder.
Management involves artificially keeping membranes moist (for example, with artificial tears). Extraglandular inflammatory lesions and associated disorders are treated with anti-inflammatory agents and occasionally cytotoxic agents.