Connective Tissue Diseases - Case Study Example

CONNECTIVE TISSUE DISORDERS INTRODUCTION Connective tissues are among the most widely distributed and abundant tissues in the body (Volk, . Theyare involved in many functions in cells: providing shape and mechanical support, modulation of migration, nutrient transport, growth and differentiation. The basic components of connective tissue are ground substances, fibrous components and migratory cells (Connective Tissue, 2010). The fibrous component is made up of collagenous, reticular and elastic fibres, which differ markedly in their chemical and physical properties. The most abundant component is collagen, a protein found in many cell types. The major component of skin is elastin fibre which can be stretched and returned to its original shape. Ground substances are carbohydrates and carbohydrate-protein complexes; the more common being chondroitin sulphate and hyaluronic acid. The cells of connective tissues may be the migrating type (macrophages, eisonophils, plasma, mast cells) or stationary like adipocytes and fibrocytes (Connective Tissue, 2010). Tendons and ligaments are dense connective tissues. Loose vascular tissue has the synovial membrane which produces synovial fluid which functions as a lubricant for the joints. Cartilage is a connective tissue that has a large amount of ground tissue responsible for its gel-like consistency and flexibility. Other cartilages are made up of hyaline and elastic fibres. Bone and blood are also connective tissues. Red blood cells comprise blood tissues while calcium phosphate is an important component of bone tissue (Connective Tissue, 2010). Connective tissue disorders result when they are damaged and become dysfunctional. There is a wide and diverse range of these diseases, but they can be grouped into three main categories (Connective Tissue Disease, 2010). The first type of connective tissue disorders are autoimmune disorders which occur when one’s own immune system attacks the connective tissues resulting in inflammation and damage. These diseases can be characterized by an overproduction of nuclear antibodies that can be measured in the blood. The second type of connective tissue disorders are due to inherited genetic defects or gene abnormalities. Usually, these disorders also cause tissue abnormalities in other organs like the heart, lungs, eyes, and bones. Some connective tissue disorders also show general symptoms for the early stage of the disorders, but the symptoms may or not progress to a full stage disease. These disorders fall under the third and general classification of “undifferentiated connective tissue disorder” or UCTD (Berman, 2003). It is important to study connective tissue diseases because of their wide prevalence in the population, and their potential to develop life-threatening complications like heart and lung disorders (Antoniou, Margaritopoulos, Economiduo, and Siafakas, 2009). This paper will focus on the more commonly known autoimmune connective tissue diseases. Background information on the heritable connective tissue diseases will be discussed briefly. THE PATHOPHYSIOLOGY AND DIAGNOSIS OF THE CONNECTIVE TISSUE DISEASES Autoimmune connective tissue diseases There are many types of autoimmune connective tissue disorders, but this paper will focus on lupus, rheumatoid arthritis and scleroderma which have a higher prevalence in the population. Systemic lupus erythematosus Lupus or SLE is a chronic inflammation of the connective tissues which can affect the skin, joints, lungs, kidneys and other organs of the body (Ginzler, 2008; Choi and Abueg, 2009). Symptoms of lupus are arthritis or pain in the joints that could last for weeks; skin rashes (butterfly shaped rash on the cheeks, and other skin areas that are exposed to the sun) (Figure 1); general fatigue, sores, loss of hair and seizures, heartburn, chest and abdominal pain. Pregnant women may also experience miscarriage. Since the symptoms develop gradually, lupus is not detected immediately which can lead to damage of the kidneys, lungs and brain. Figure 1. Butterfly-shaped or malar rash is one of the most common cutaneous symptoms of systemic lupus erythematosus (Photo from Gill, Quisel, Rocca, and Walters, 2003). There are eleven essential criteria for diagnosing SLE (Tan, et al., 1982; Gill, Quisel, Rocca, and Walters, 2003). Of these, four must be met for a diagnosis of SLE. The primary test is the anti-nuclear antibody titre (ANA), although it has low predictive value in patients who do not have the usual clinical symptoms. When the ANA points to a positive result in these patients, other antibody tests must be performed to confirm the diagnosis (Gill, Quisel, Rocca, and Walters, 2003). Rheumatoid arthritis Rheumatoid arthritis is a chronic disease characterized by membrane inflammation around multiple joints resulting in stiffness, swelling, and pain (Ruderman and Tambar, 2008). While more common in small joints in hands and feet, rheumatoid arthritis also affects larger joints, and other organs. A unique characteristic of the disease is the occurrence of prolonged stiffness in the morning, which is not observed in other arthritis types. Symptoms of rheumatoid arthritis are loss of appetite and energy, presence of low-grade fevers, dry mouth and eyes, and presence of rheumatoid nodules, which are hard lumps, underneath the skin of hands and elbows (Figure 2). Figure 2. Hands of a patient with rheumatoid arthritis. Photograph from Cedars-Sinai (2010). The synovium has been the focus of studies aimed at understanding the pathogenesis and pathophysiology of rheumatoid arthritis. The synovium is the thin lining surrounding the cartilage of the joints and is a major source of nutrients of the cartilage. In normal cells, the lining is 1-3 cells thick while it is 5 – 7 cells thicker in rheumatoid arthritis (Bathon, 2010). The synovium is where events leading to inflammation occur. The first theory regarding the pathogenesis of rheumatoid arthritis states that T cells of the immune system interact with unidentified antigens, initiating the inflammatory process. Increased amounts of class II major histocompatibility antigens, CD4+ T cells, and T cell receptor gene usage have been observed in the synovium (Bathon, 2010). Another theory postulates that macrophages and fibroblasts cause the perpetuation of the inflammation, based on results of studies showing that activated T cells phenotypes are relatively absent in chronic rheumatoid arthritis, while there is a proliferation of activated macrophages and fibroblasts. The macrophages produce cytokines IL-1 and tumour necrosis factor TNF that activate the fibroblasts to secrete prostaglandins, proteases and other cytokines (IL-6, IL-8) to promote inflammation, and erode bone and cartilage (Bathon, 2010; Maini, et al., 1999). Rheumatoid arthritis is also difficult to diagnose, especially during the early stages because of symptoms that are similar to other joint disorders (Ruderman and Tambar, 2008). Therefore, a skilled rheumatologist is necessary for the correct diagnosis of the clinical symptoms. Physical examination of the joints is necessary and laboratory tests have to be performed to assess organ damage, if ever. Red blood cell count must be performed, since anaemia is common in patients with rheumatoid arthritis. In addition, tests for rheumatoid factor, antibodies to citrullinated peptides, and erythrocytes sedimentation rates have to be performed (Ruderman and Tambar, 2008). In the late stages of the disease, X-rays can be helpful in diagnosis. A single test will not confirm a diagnosis, thus several tests have to be conducted for confirmation. Scleroderma Scleroderma or sclerosis is a rare autoimmune disease that affects the skin characterized by a tightening and thickening of the cells (Figure 3). The activation of immune cells results in the production of scar tissue in skin, small blood vessels and internal organs (Merkel, 2008). For many forms of the disease, scleroderma is not yet curable. Changes in scleroderma are due to increased and accumulated collagen, extending from the skin to other internal organs. Blood vessels are also damaged which can cause poor blood flow, gangrene and ulcers. All these result in scarring, and could be life-threatening. Studies in recent years show that interdependence exists among the vascular and immune systems, and the connective tissues, which could contribute to the development of scleroderma. Moreover, immune cells produce the cytokine, transforming growth factor β, and platelet-derived growth factor that activate the differentiation of fibroblasts into myofibroblasts, and subsequent skin thickening (Hunzelman and Brinckmann, 2010; Distler and Muller-Ladner, 2006; Krieg, Abraham, and Lafyatis, 2007). Figure 3. Symptoms of scleroderma showing thickening and tightening of skins in hands and fingers (A), and small calcium deposits and ulcerated finger (B). Photos are from Choi and Abueg, (2009). Diagnosis of scleroderma is based on physical and clinical examinations. Aside from thickening of the skin, blood vessels may be dilated in the face, and other parts of the body. Calcium deposits can also be found in skin and other organs. Laboratory tests for auto-antibodies are also used, but results may not be conclusive (Scleroderma, 2006). Inherited connective tissue diseases A considerable number of connective tissue diseases are due to genetic aberrations and are heritable (National Institute of Arthritis and Muskoskeletal and Skin Diseases, 2007). Osteogenesis imperfecta (OI) is characterized by fragility and fractures of the bones caused by mutations in the genes that code for chains of type I collagen (Byers and Cole, 2002). There are four types of OI, with varying degrees of bone fragility. The disease can be diagnosed using medical history, clinical manifestations, collagen analysis of dermal fibroblasts, and gene analysis. Another inherited disease caused by mutations in collagen genes is the Ehlers-Danlos syndrome (EDS). The main characteristics of EDS are skin hyperextensibility and fragility, and joint hypermobility (Steinmann, Royce, and Superti-Furga, 2002). The most severe type of EDS leads to short lifespan due to spontaneous rupture of internal organs. Cutis laxa is due to mutations in the genes encoding for elastin. It is characterized by deeply wrinkled skin, progeria or early aging, hyperketosis and arteriosclerosis (Davidson and Giro, 2002). Depending on the severity, this disorder is usually associated with other disorders such as Wiedemann- Rautenstrauch syndrome, Cantu syndrome and Hallerman-Streiff syndrome. Marfan syndrome is an autosomal dominant disorder characterized by abnormalities in the ocular, cardiovascular and skeletal systems (Pyeritz and Dietz, 2002). Furthermore, Marfan syndrome is associated with cervical incompetence and pre-term birth (Anum, Hill, Pandya, and Strauss, 2009). Diagnosis of the heritable diseases is done by clinical analysis, physical examination, laboratory tests and genetic analysis, which has greatly enhanced diagnostic capacity. REFLECTION ON THE RATIONALE FOR THE SELECTION OF TYPES OF TESTS CARRIED OUT The diagnosis of the connective tissue diseases is difficult because of the similarities in symptoms, especially when the disorder is in the early stage, or when a combination of the different disorders is present. Diagnosis usually involves a thorough physical examination, clinical analysis, which includes a careful evaluation of medical history, and laboratory testing. Therefore, many tests need to be performed to come up with the correct diagnosis. The type of tests carried out for the connective tissue diseases depends on the symptoms that are presented. Clinical tests will correlate the symptoms with known disorders. A medical history will reveal any genetic inclination to inherit a disorder. Blood tests are performed to detect if there are increased metabolites that can indicate organ or tissue damage. In connective tissue diseases, there is no single laboratory test that can identify the specific disease. However, since these are autoimmune diseases, the laboratory testing will check for the increased production of anti-nuclear antibodies (ANA). Nuclear antibodies are present in increased amounts in the nucleus of cells when the immune system is predisposed to cause inflammation within its own body. This is also an area where disease markers can be developed. The advent of genetic testing has made the diagnosis of the inherited mutations easier. INVOLVEMENT OF THE PATHOLOGICAL SERVICE IN MONITORING OR TREATMENT REGIMES Once a diagnosis is achieved, then a treatment regime should be designed based on the symptoms and severity of the disease. It should be noted there is currently no cure for the autoimmune diseases. However, the symptoms can be alleviated through drug therapy and in some cases, alternative interventions like acupuncture. Pain and inflammation reduction is a primary consideration; therefore the drug therapy includes non-steroidal anti-inflammatory drugs (NSAIDs) (e.g. aspirin and ibuprofen). However, when there is severe inflammation, use of steroidal drugs (corticosteroids) and immunosuppressants (cyclosporine, cyclophosphamide) become necessary (Ginzler, 2008). For rheumatic disorders and complications, disease-modifying anti-rheumatic drugs (e.g. methotrexate, hydroxychloroquinone, and sulfazaline) are given in combination with NSAIDs and low dose corticosteroids (Ruderman and Tambar, 2008). In the case of scleroderma, there is no treatment yet for reversing the skin thickening process (Merkel, 2008). Drug agents that can suppress the immune system are also recommended. Antimalarial medications like quinine are useful because they repress the immune system. The identification of the tumour necrosis factor (TNF) and some cytokines that are highly expressed led to the search for drugs that can target these compounds. Currently, studies are identifying ways to reduce cytokine activation and expression of inflammatory genes (Vasoo and Hughes, 2005; Maini, et al., 1999). Since the diseases undergo a cycle of remission and relapse, it is important to be aware of the conditions when these periods occur, so that drug therapy may be stopped or resumed to prevent accumulation of side effects. CONCLUSION Connective tissue diseases can lead to significant mortality if left untreated. It is important to know the symptoms for these disorders, and to undergo testing to confirm diagnosis. There is no clear understanding of what triggers the immune system to attack its own tissues and organs, which makes it difficult to cure the diseases. However, some of the metabolites that are activated by the immune system have been identified. 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