The Treadment Of Osteoarthritis

A wide variety of treatments are available for patients with osteoarthritis. Although guidelines for the management of osteoarthritis have been published, rational therapy for individual patients remains difficult because of our relative lack of understanding of the disease process and its outcome.

It is important to let patients know that a diagnosis of osteoarthritis does not necessarily imply progressive disability and declining mobility. In the treatment of osteoarthritis, the goals of therapy include:

• symptom relief
• maintaining and improving optimal and handicap
• minimizing the risk of progression
• facilitating joint healing
• improving the quality of life, and
• helping avoid drug toxicity

The treatment of osteoarthritis should be based on the severity of joint involvement and a full assessment of the patient to determine if local anatomic abnormalities, joint complications, or psychosocial factors contribute to pain and disability. A pyramidal approach may be  used to match the severity of the disease to appropriate nonpharmacologic, pharmacologic, and surgical therapies.

Pathophysiology Of Osteoarthritis

Our understanding of the pathogenesis of osteoarthritis has evolved considerably over the past decade. We now know that osteoarthritis is a dynamic disease process characterized by a disruption in the normal balance between degradation and repair in articular cartilage and subchondral bone. This leads to an abrasion of the articular cartilage on weight-bearing surfaces and the formation of new bone at the edges of the joint. Ultimately, the result is a deterioration of joint funtion.

Many investigators believe that osteoarthritis is initiated by mechanical stress to the joint that alters chondrocyte metabolism. This results in an increased production of degradative enzymes. Cytokines, such as IL-1 and TNF-a, and a variety of growth factors. An imbalance is created between the production of degradative enzymes and the TIMPs that inhibit them. This eventually leads to degradation of the extracellular matrix.

In addition to this degradative process, an ongoing repair process likes place in osteoarthritis characterized by increased synthesis of collagen and proteoglycan. The collagen produced is abnormal, however, and an immature form of aggrecan is synthesized.

It is interesting to note that the structure of aggrecan molecules in the extracellular matrix changes with aging. These chantes include a decrease in the length of chondroitin sulfate chains and an increase in the number and length of keratan sulfate chains. These changes many reflect alterations inthe synthesis of collagen and aggrecan or the cumulative effects of degradative enzymes on the matrix structure.

Similar changes in the composition of aggrecan have been noted in patients with osteoarthritis. Although new proteoglycan continues to be synthesized, even in advanced osteoarthritis, the form of aggrecan produced in an immature, fetal form. This suggests that the chondrocytes revert back to an immature pattern of synthesis.

Summary Points

• Osteoarthritis is characterized by degenerative changes in articular cartilage and by an ongoing repair process.
• Chondrocytes are articular cartilage cells which produce and maintain the extracellular matrix. They occupy only about 1% to 2% of the articular cartilage volume.
• The three primary constituents of the extracellular matrix are water, proteoglycans and collagen.
• Chondrocytes synthesize metalloproteinases and other proteases that can degrade the matrix proteins. These are held in check by inhibitors, such as TIMP and PAI-1.
• Interleukin-1 (IL-1) plays an important role in the stimulation of cartilage degradation. Tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6) appear to act synergistically with IL-1 to promote matrix breakdown.
• Insulin-like growth factor-1 (IGF-1) and transforming growth factor-b (TGF-b) are synthesized by chondrocytes and stimulate chondrocytes to synthesize proteoglycans. They play an important role in the matrix repair process.

The Breakdown and Repair of Articular Cartilage

The structure of the extracellular matrix plays a critical role in the function of articular cartilage. In normal joints, this matrix is constantly being degraded and repaired by chondrocytes. Since matrix synthesis and matrix degradation occur at equal rates, the two processes are normally kept in balance. Both the repair and breakdown processes are controlled by extracellular growth factors and cytokines. A disturbance or alteration in these chemical messengers can initiate disease.

In normal articular cartilage, the turnover rate of extracellular matrix components is slow and the capacity for repair is limited. Collagen turnover is particularly slow. Proteoglycans are more susceptible to enzymatic breakdown and are continually being resynthesized, however.

Insulin-like growth factor-I (TGF-I) and transforming growth factor-b (TGF-b) are synthesized by chondrocytes and stored in the extracellular matrix. When activated, they stimulate chondrocytes to synthesize proteoglycans. IGI-I and TGF-b regulate matrix metabolism in normal cartilage and may play a role in matrix repair in patients with osteoarthritis.

The chondrocytes also synthesize a number of enzymes that can degrade the matrix structure. These are released into the extracellular matrix in an inactive form. Among the enzymes that have been identified as playing a major role in the degradation of collagen and aggrecan molecules are metalloproteinases, such as collagenase, stromelysin, and gelatinase; and serine proteases, such as tissue plasminogen activator.

The activation of these degradative enzymes is held in check by inhibitors, such as tissue inhibitor of metalloproteinase (TIMP) and plasminogen activator inhibitor (PA1-I). TIMP  and PA1-I are synthesized by chondrocytes and limit the degradative activity of active metalloproteinases and plasrainogen activator. If TIMP and PA1-I are destroyed or present insufficient quantities, metalloproteinases and plasmin are free to act on matrix components. Normally, there is a balance between these inhibitors and the degradative enzymes they inhibit.

Thee cytokine interleukin-1 (IL-1) plays an importane role in the stimulation of cartilage degradation. Il-1, which is produced by chondrocytes and other cells in the joint, stimulates the synthesis of degradative enzymes and inhibits the production of proteoglycan. IL-1 may also inhibit the synthesis of TIMP.

Other cytokines that appear to act synergistically with IL-1 to promote matrix breakdown are tumor necrosis factor-alpha (TNF-a) and interleukin-6 (IL-6). All of these cytokines are routinely found in inflamed joints.

DEFINING OSTEOARTHRITIS

Ostcoarthritis is no a single disease, but an extremely common group of disorders that affect synovial joints and are linked to advancing age. A satisfactory clinical definition of osteorathritis has not been determined due to the heterogeneity of the condition and the fact that it can result from a number of different joint insults. Although definitions of osteorthritis vary, most acknoledge that osteoarthritis is characterized by degenerative changes in articular cartilage. Thus, osteoarthritis has been difined as an inherently noninflammatory disorder of movable joints characterized by deterioration of articular cartilage and by the formation of new bone at the joint surfaces and margins.

Osteoarthritis has also been defined as a combination of interactive degradative and repair process in cartilage, bone, and synovium with secondary components of inflammation. Although originally thought of as a noninflammatory, hypertrophic form of arthritis, osteoarthritis is now known to involve a disruption in the normal balance between cartilage synthesis and degradation, often involving some degree of inflammation.

A third definition, offered by the American College of Rheumatology (ACR), defines osteoarthritis as a heterogeneous group of conditions that lead to joint symptoms and signs which are associated with defective integrity of articular cartilage, in addition to related changes in the underlying bone at the joint margin.

Joint Physiology

Osteoarthritis is primarily a disorder of articular cartilage and subchondral bone, However, all tissues of the synovial joint are involved in the disease process.

Articular Cartilage

Articular  cartilage distributes loads over bone surfaces and provides a low friction surface over which bones can move. The articular cartilage contains no blood vessels, nerves, or lymphatic vessels, and is largely composed of extracellular matrix tissue. Only 1% to 2% of the cartilage volume is occupied by cells, while 98% to 99% of the tissue volume is composed of matrix tissue.

Chondrocytes

 The cells of articular cartilage are called chondrocytes. Although these cells are metabolically very active, they normally do not divide after adolescence. Since articular cartilage contains no blood vessels, chondrocytes must receive their nutricnts by diffusion from the underlying subchondral bone, or from the synovial fluid that bathes the cartilage surface. These cells are responsible for the production and maintenance of the extracellular matrix.

Extracellular Matrix

The critical biomechanical properties of articular cartilage depend on the integrity of its extracellular matrix. The three primary constituents of the extracellular matrix are proteoglycans, type II collagen and water.

Proteoglycans

Proteoglycans make up most of the volume of the extracellular matrix and are responsible for the stiffness of the tissue. As many as 200 large proteoglycan molecules (called aggrecan) assemble around a hyaluronic acid chain to form conglomerates, or aggregates. The molecular structure of these aggregates creates an overall negative charge, which attracts molecules of water. Together, the water and proteoglycan aggregates are restrained by a network of crosslinked collagen fibers.

Aggrecan consists of a protein core in which proteoglyean molecules, such as chondroitin sulfate, are attached. About 100 chondrohin sulfate chains and about 30 keratan sulfate chains are attached to a single core protein. The protein and its attached chains are referred to as an aggreean monomer. About 100 agrecan monomers are linked to a string of byaluronic acid to form a proteoglycan aggregate. Other proteoglycans and proteins have been identified in articular cartilage. Compounds such as fibromodulin, fibronectin, and anchorin II may play important roles in maintaining the integrity and function of the extracellular matrix tissue.

Collagen

 This type of collagen is found in only a few other body tissues. Smaller quantities of types IX, X, XI and VI collagen may also be found. In the extracellular matrix, type II collagen, forms a tight network that restricts the hydration and expansion of the proteoglycan aggrecans. This collagen network provides articular cartilage with tensile strength between and resistance to shearing forces, Type IX collagen forms cross links between the collagen fibers, increasing the strength of the collagen "net". It also forms links between the collagen fibers and aggrecan molecules. Type X and type VI collagen are associated with metabolically active chondrocytes. Their levels may be increased in patients with osteoarthritis.

Water

When weight is applied to a joint and the cartilage is compressed, water molecules are forced out of the extracellular matrix. When the pressure is removed, water moves back into the matrix until the swelling pressure of the proteoglycans is balanced by the resistance of the collagen network. This gives articular cartilage the property of reversible deformation.

The Categorization Of Pain

Acute Pain

Pain may be categorized as either acute or chronic. Acute pain originates from a known stimulus that causes tissue injury. Dental pain following oral surgery is the most thoroughly studied type of acute pain and is frequently used in clinical trials as the model of acute pain. This type of pain is medicated by the inflammatory substances discussed earlier. Other common types of acute pain include menstrual pain associated with dysmenorrhea, and pain following injury.

Acute pain can be further classified as somatic, visceral or referred. Somatic pain is superficial. Coming from the surface of the body (e.g., a paper cut). Visceral pain involves one or more internal organs and is usually poorly localized and often radiates (e.g., intestinal gas pain). Referred pain is pain that exists in an area that is distant from the site of the disorder.

Chronic Pain

Chronic pain is usually defined as pain that lasts for longer than six months, and which remains after the healing of tissue injury. Chronic pain can be further broken down into malignant and nonmalignant pain. Examples of nonmalignant chronic pain include back pain, neck pain, migraine headache, and arthritis pain. Chronic pain of malignant origin is primarily pain caused by cancer, which is managed with different treatment strategies than those used to treat nonmalignant pain.

The following table compares the characteristics of acute and chronic pain.

         Characteristics of Acute and Chronic Pain

Characteristic	Acute Pain	Chronic Pain
Types	Somatic, Visceral referred	Persistent (e.g., low back pain) Or intermittent (e.g., migraine)
Source	Acute or potential tissue damage	Usually unknown
Onset/Duration	Sudden, up to 6 months	Sudden or insidious, >6 months to years
Physiologic	Elevated heart rate, Respiratory rate, blood Glucose, Decreased GI motility and receptions, an and blood flow to visceral organs, Occasional nausea	Similar to acute pain but adaptation occurs and heart rate, respiratory rate and blood pressure are normalized
Psychologic Responsea	Fear, anxiety and uneasiness	Depression, behavior modification, insomnia  and denial
Prognosis	Complete relief probable	Complete relief unlikely

MECHANISMS OF PAIN

The sensation of pain ranges from mild discomfort to excruciating agony and is experienced when sensory nerve fibers are stimulated by mechanical thermal, or chemical stimuli. These stimuli may be associated with tissue injury or inflammation. The pain threshold, which is the degree of stimulus required to cause the perception of pain, is variable among individuals.

Pain is a complex phenomenon composed of the physiological mechanisms associated with sensory stimuli and transmission and the individual's interpretation of those stimuli and transmission and the individual's interpretation of those signals molded by emotions, memory and expectations.

There are three physiologic components that affect pain perception afferent pathways the central nervous system (CNC), and efferent pathways. The sensation of pain begins with stimulation of peripheral free nerve endings (nociceptors) located in the skin, blood vessels, subcutaneous tissues, viscera joints and other structures throughout the body.

Among the substances that can stimulate nociceptors are prostaglandins, leukotrientes, and bradykinin. Prostaglandins, particularly prostaglandin, sensitize nerve endings so that they are more responsive to the actions of other stimuli, such as bradykinin.

Activation of nociceptors results in the transmission of an impulse along the afferent nerve fibers to the spinal column, and then onto the brain. There are two subtypes of afferent nerves: C fibers and A fibers. C fibers are unmyelinated nerves that transmit impulses slowly. They detect burning, aching and diffuse pain. Conversely, A fibers are covered with a myelin sheath, which allows for fast transmission of impulses, and are responsible for our ability to feel sharp localized sensations of pain.

The second area of pain perception is the CNS, consisting of the spinal column and the brain. The CNS is responsible for our ability to interpret the pain signal. For example our ability to differentiate between an aching or a sharp pain and our ability to localize the pain source. The efferent pathways travel from the brain towards the peripheral nerve endings and provide our ability to modify pain sensation.

Prostaglandins, leukotrienes, bradykinin, substance P and other substances released by mast cells, such as histamine and serotonin, appear to act synergistically to enhance the transmission of pain signals and augment the inflammatory response. The number of cells and chemical mediators involved in the production and maintenance of pain illustrate the complexity of this biological response.

We will explore the role of prostaglandins as mediators of pain and inflammation in greater details in subsequent section of this program.

The Body Immune System

There are many different types of pathogenic microorganisms in our environment. When these organisms gain entry into our bodies, they can cause disease. The body's immune system works to eliminate these pathogens and minimize any damage they may cause.

Intact skin provides an effective barrier to penetration and represents one of the body's most important first lines of defense. When this defense fails a sophisticated immune system is called into action.

In order to launch an immune response the pathogen or foreign material must first be recognized as "nonself". Only then can an immune reaction be mounted. Human leukocyte antigens (HLA antigens) are proteins found on the surface of nearly all body cells. These proteins help the body recognize a cell or tissue as "self" rather than as foreign. Each person (with the exception of identical twins) has different HLA antigens.

There are two basic types of immune responses. These are known as the innate response and the specific or adaptive response. The primary difference between these two types of responses is that immune mechanisms are active against a wide range of pathogens while the adaptive mechanisms are active against one specific invader.

Innate immunity is provided by phagocytic cells that ingest foreign matter and digest it. Neutrophils or polymorphonucleocytes (PMNs) are the most frequently encountered short-lived phagocytic cells in the blood. They engulf foreign matter destroy it and then die.

Mononuclear phagocytes live longer. These cells arise in the bone marrow and become monocytes when they enter the bloodstream. Eventually these cells migrate out into tissues where they develop into macrophages. As already noted, Type A synoviocytes resemble tissue macrophages in both form and function. They ingest foreign particles and destroy them. They are also very effective at "presenting" foreign matter to other immune system cells.

Adaptive or specific immunity is provided by a different type of white blood cell known as a lymphocyte. These cells have receptors on their surface that are capable of binding to specific foreign protens (i.e. antigens) found on the surface of foreign cells. B-lymphocytes are genetically programmed to recognize one and only one antigen. When a B-lymphocyte encounters its specific antigen it rapidly differentiates into a plasma cell which manufactures antibodies.

Another cell type that participates in the specific immune response is the T-lymphocytes and T-lymphocyte. There are several different types of T-lymphocytes and each performs a different function. T-helper (TH) cells interact with B-lymphocytes to help them divide and differentiate into plasma cells. They also interact with mononuclear phagocytes to help them destroy intracellular pathogens. T-cytotoxic (TC) cells pay an important role in killing host cells that are infected with viruses.

Many of the effects of T-lymphocytes are accomplished through the release of chemical messengers called cytokines. These include interferons, interleukins colony stimulating factors and other cytokines such as tumor necrosis factor.

Another important immune system component is complement. The complement system is a group of about 20 serum proteins that help control inflammation. Complement proteins interact with each other and with other elements of the immune system to facilitate phagocytosis and attract phagocytic cells to sites of infection. They also increase blood flow in inflamed areas and increase the permeability of capillaries to large plasma proteins. Complement can "punch a hole" in the cell membrane of a foreign invader, and can also interact with other immune system cells to enhance the release of inflammatory substances.

The different components of the immune system work together to generate a well-orchestrated attack on foreign invaders. Unfortunately, this system sometimes fails and actually produces disease.

As we have noted, the various immune system components normally react to the presence of foreign proteins (Antigens) These same cells generally ignore the body's own proteins because they are recognized as "self". Occasionally, an error occurs that causes immune system components to react to the body's own proteins. This is the basis for autoimmune disease.

Signs And Symptoms Of Arthritic Disease

Medical Encyclopedia


Among the most common symptoms of arthritis are pain, stiffness, or locking of the joints, swelling, weakness, or difficulty moving, and fatigue, often resulting in emotional swings, such as anxiety or depression. Pain is the most common of these symptoms.

The kind of joint stiffness experienced by patients can help differentiate between different arthritic conditions. In osteoarthritis, patients may experience a gelling phenomenon which is a short-lived stiffness after periods of joint inactivity. This stiffness is relieved by exercising the affected joint inactivity. This stiffness is relieved by exercising the affected joint. In contrast the stiffness of rheumatoid arthritis is prolonged.

The number and type of joints affected can also vary with different forms of arthritis. Osteoarthritis usually involves one, or only a few, joints. It is asymmetric, in that it usually does not affect the same joint on both sides of the body. Rheumatoid arthritis tends to be polyarticular, effecting three  or more joints. In addition joint involvement tends to be symmetrical.


The specific joints affected by the disease also provide an important clue. In osteoarthritis, the distal interphalangeal (DIP) joint and the joint at the base of the thumb are frequently affected, while in rheumatoid arthritis, the proximal interphalangeal (PIP) joints, metacarpophalangeal (MCP) joints, and wrist are frequently affected.

Other signs and symptoms that may be associated with arthritis include swelling, inflammation, and a reduction in the range of motion of a joint. Patients may also experience a sensation of joint instability and /opr a dry. cracking sound or sensation from within the joint.

In advance disease, there is often evidence of destruction of cartilage, bone, and soft tissues of the joint. This can lead to functional impairment, which may be very disabling to the patient.

In addition to the physical symptoms attributable to joint involvement, patients may experience fatigue and mental depression. Thus, a number of psychosocial issues are as important as the treatment of physical symptoms in patients with arthritis.

Summary Point:

• The most common symptoms of rheumatic diseases are pain, stiffness, swelling, weakness, difficulty moving joints, fatigue, and emotional swings.

• Pain is the most frequently reported symptom of arthritis. 
  

Synovial Joint

Arthritis is a general term for a group of disorders that cause inflamed. swollen, and painful joints. Joints are found wherever two or more bones or cartilage and bone meet. There are many different kinds of joints in the body. They can be categorized according to structure or function. Among the structure variations are:

>   Fibrous joints.

>   Cartilaginous joints, and

>    Synovial joints

Joints can also be classified according to their ability to provide movement immovable joints are called synarthroses, slightly movable joints are called amphiarthroses, and freely movable joints are called diarthroses. Diarthroses are the most common joints in the body and they are the primary type of joint found in the extremities. Diarthrodial joints are often referred to as synovial joints because they contain a synovial membrane and synovial fluid. Arthritis occurs primarily in freely movable, synovial joints.

Fibrous joints, such as those that are found between the separate bony plates that make up the skull are fastened tightly together by a thin layer of fibrous connective tissue. In general, these joints allow little, if any movement and are therefore synarthroses.

The bones of cartilaginous joints are connected by cartilage. One example is the joint are connected by cartilage. One example is the joint between the public bones of the pelvic girdle. These joints allow limited movement, and are, therefore, amphiarthrotic.

The synovial, or diarthrotic, joint is of greatest interest in the study of arthritis. These joints are freely movable, and are much more complex than fibrous and cartilaginous joints.

Among the joints most commonly affected by osteoarthritis and rheumatoid arthritis are the joints in the fingers, toes, hips knees, wrists, and ankles. The proximal and distal interphalangeal joints of the fingers are hinge joints, while the metacarpophalangeal joints are modified hinge joints or condyloid joints. Hinge joints permit movements in different planes.

The hip and shoulder joints are ball and socket joints. This type of joint consists of a bone with a globular or slightly egg-shaped head that articulates with the cup-shaped cavity of another bone. This arrangement permits movement in a wide variety of planes, and includes movement around a central point or axis.

The knee joint is the largest and most complex of the synovial joints. It includes the upper leg bone the lower leg bone (the tibia), and the kneecap (patella). Although the knee is sometimes considered a modified hinge joint, the connection between the femur and tibia more closely resembles a condyloid joint, while the atriculation of the femur and patella is a gliding joint. In addition, this joint contains two crescent-shaped, fibro-cartilaginous menisci that project into the space between the femur and tibia. The menisci contribute to the stability of the joint and help distribute the body weight that is applied to it. The knee also contains bursae that act as cushions and facilitate the movement of tendons over bony surfaces.

Musculoskeletal - Rheumatic Disorders

Musculoskeletal disorders are among the most important causes of chronic pain and disability throughout of the world. Osteoarthritis, which is one of the most common of these disorders, is the single greatest cause of human locomotor problems. Although nonsteroidal anti-inflammatory drugs (NSAIDs) have been used for many years of treat these conditions, they are associated with number of potentially serious side effects.

RHEUMATIC DISORDERS IN PERSPEVTIVE

There are more than 100 distinct conditions that can be categorized as rheumatic or musculosketal. Some of these conditions involve multiple body systems while others affect primarily musculoskeletal tissues. Overall, these disorders are more prevalent, and a more frequent cause of disability, than either heart dieased or cancer. No age or racial group is spared, and clinical manifestations are diverse.

Arthritis and musculoskeletal diseases are among the most common reasons for physician office visits, as well as visits to surgeons, family doctors and specialists. These diseases are time-consuming to evaluate and manage. The economic impact of these diseases is associated with indirect physician visits, physical therapy, and drugs.

Osteoarthritis, also known as degenerative joint disease, is the most common form of joint disorder. Osteoarthritis of the knee and hip is the leading cause of chronic disability in developed countries. In some people, evidence for osteoarthritic changes may be present by the second or third decade (usually without associated symptoms) By age 40, almost everyone has evidence of some osteoarthritic changes in weight-bearing joints, although most people remain asymptomatic.

Interestingly, historic evidence for the existence of osteoarthritis has been found in nearly all vertebrate animals, including ancient fish, dinosaurs, birds, bears, whales, and dolphins. This suggests that osteoarthritis has an evolutionary origin. In man, the primary joints affected by osteoarthritis (joints in the knees, hips, spine, fingers and feet) suggest that this condition is a response to the special demands of the upright posture and prehensile grip.

Nonsteriodal anti-inflammatory drugs (NSAIDs) are a primary class of therapy prescribed for the symptomatic relief of the pain and swelling associated with arthritic disorders. They are the single largest group of medication used worldwide, with annual sales in excess of $US 2 billion. 

   Despite of the fact that NASIDs are the most widely used drugs for the treatment of arthritis, side effects may occur with these agents, and some of these reactions constitute a serious drawback to their use.