rheumatology Flashcards
Definition of Osteoarthritis (OA)
a heterogeneous disorder characterized by the destruction (degeneration) of articular cartilage and proliferation (hypertrophy) of the contiguous bone. It represents a common endpoint that results from a variety of biochemical, metabolic, physiologic, and pathologic factors. It is the end stage of all types of arthritis. The clinical features of osteoarthritis include joint pain, decreased joint mobility, hypertrophic bony spurs (osteophytes), infrequent joint inflammation, and lack of systemic involvement.
Symptoms of OA
Pain with use, improved with rest. Stiffness - commonly less than 30 minutes localized to involved joints. Relative preservation of function. Rarely significant symptoms before age 40. Lack of systemic symptoms
Signs of OA
Localized joint tenderness. Bony enlargement. Crepitance (grating sensation or sound with joint movement). Restricted movement. Variable swelling and/or instability
Signs of OA-specific pattern of deformity
Heberden’s and Bouchard’s nodes (bony enlargement in the distal interphalangeal joints and proximal phalangeal joints, respectively. These are often inherited.) Squaring of the 1st carpometacarpal joint. Genu varus (bow-legged). Hallux valgus (bunion on big toe). Cervical and lumbar spine spondylosis (degenerative change)
Clinical Syndromes of OA-Six Types
Primary generalized OA. Inflammatory/erosive OA. Isolated nodule OA. Unifocal large joint OA. Multifocal large joint OA. Unifocal small joint OA
Laboratory in OA
No specific laboratory abnormalities. Synovial fluid analysis: type I fluid, 200-2000 WBCs, 25% polymorphonuclear leukocytes, normal viscosity; negative crystal exam; and normal glucose. Laboratory tests in secondary OA-uric acid, iron, calcium and phosphate, sedimentation rate, C-reactive protein. Investigational: Cartilage degradation products in serum and joint fluid; hyaluronic acid, fragments of aggrecan; type II collagen, and its breakdown products; and cartilage oligomeric protein
Radiographic evaluation
with OA, Loss of cartilage space. Bony sclerosis and eburnation. Cystic changes of subchondral bone. Osteophyte formation. Altered shape of bone. Joint effusion – non-inflammatory
Specific patterns of x-ray changes with OA
“Gull wing” changes in the interphalangeal joints. Medial compartment disease of the knee. Horizontal osteophytes of the spine. Decreased joint space superiorly with relative medial preservation in the hip. Hallux valgus (bunion deformity of the great toe) without other metatarsal disease
Epidemiology/Risk Factors for OA
Most common arthropathy. Incidence varies with diagnostic criteria (e.g., X-ray evidence versus clinical findings). U.S. population aged 25-75 years with symptomatic OA estimated at 12% or about 16 million persons. X-ray prevalence estimates for adults aged 25-75 years are 32% or 42 million persons for OA of the hands. Roentgenographic changes are seen in 4-10% of people aged 15-25 years and in 80% of people over the age of 55. In all studies, the relationship to aging is striking. Advanced age is one of the strongest risk factors. Symptomatic disease is seen in 25% of individuals who have X‑ray evidence of OA of the knees. X-ray evidence correlates better with symptoms of hip OA. At autopsy, pathologic changes in the weight-bearing joints are found in almost 100% of people by the age of 40 years. Overall frequency equal in males and females: < 45 years, males predominate and > 45 years, women have increased incidence. Women have more severe disease and increased frequency of Heberden’s or Bouchard’s nodes. Occupational risks show conflicting data: OA of the hips, knees, shoulders more frequent in miners; OA of the hands more frequent in weavers; and no increase in OA in pneumatic hammer drillers and in Finnish long distance runners. Sports: in general, no increased risk (and exercise may be protective) in recreational participants. Chondrocytes may require some degree of mechanotransduction to maintain function. Trauma/previous injury is associated with OA. Obesity - best correlation with OA of the knees and hands in women. OA can be classified as primary, or idiopathic OA, when no known inciting event or disease can be identified, and secondary OA in which known events or disease induces OA (see predisposing factors below). It should be pointed out that the distribution of joints involved in OA is highly variable; it may involve a single joint, such as the knee or hip, especially after trauma, or occur in a “generalized” form affecting the interphalangeal joints and the first carpometacarpal (CMC) joints. In general, OA primarily affects weight bearing joints and joints that are heavily used. However, it tends to spare the ankle, wrist, shoulder, and elbow, unless significant trauma has occurred, or metabolic or inflammatory disease is present.
Pathology of OA
The joint in OA is grossly characterized by cartilage irregularities and “fissuring”, and hypertrophy of bone adjacent to the joint. At the microscopic level, the articular cartilage surface reveals frayed and disrupted collagen fibers. Chondrocyte cells initially undergo clonal expansion (increased number), and the proteoglycan content of the extracellular matrix (ECM) is decreased. The subchondral bone has increased density, and the periarticular bone is hypertrophic. The synovium has variable findings from normal areas to areas that are inflamed and have cellular infiltrates.
Normal Cartilage of OA
The function of normal cartilage is to allow joint movement with a minimum of friction, and to absorb some of the impact during normal joint loading. The highly hydrophilic nature of cartilage allows it to act like a sponge, with water squeezed out of cartilage during loading, followed by re-expansion during relaxation. Normal cartilage is avascular, and has no nerves.
5 components of cartilage
collagen, proteoglycans, matrix proteins, chondrocytes, and water
Collagen
Makes up 50% of the dry weight of cartilage. 90% of the collagen is Type II, with small amounts of Types IX, X and XI. Collagen forms the rigid framework of the articular cartilage, and “holds in” the hydrophilic matrix.
Proteoglycans
These are highly charged aggregates of glycosaminoglycans that make up the bulk of the extracellular matrix contained within the collagen fibrils. Major components are chondroitin sulfate and keratin sulfate. Because of their charge and tendency to aggregate, they are highly hydrophilic, retaining the major component of cartilage, water, which makes up 70% of the weight of intact cartilage.
Matrix Proteins
A number of other proteins other than the proteoglycans contribute to the extracellular matrix (ECM). Of major importance are the proteolytic enzymes known as the matrix metalloproteinases (MMP): collagenase, gelatinase, and stromelysin. In addition, the matrix contains high levels of tissue inhibitor of metalloproteinase (TIMP), which controls the proteolytic activity of these enzymes.
Chondrocytes
These cells constitute only 5% of the total cartilage volume and synthesize all of the above extracellular components. Chondrocytes are metabolically active. They receive all their nutrition from the synovial fluid or subchondral bone by diffusion through the extra-cellular matrix (ECM).
Cartilage in OA
The cartilage is the main focus of pathology in osteoarthritis. The changes observed in OA cartilage represent the final common pathway of a number of abnormalities that can occur in the collagen, proteoglycans, matrix-proteins including the metalloproteinases, and the chondrocytes. Although we think of OA as a degenerative process with some secondary inflammation, we have come to realize over the last decade that inflammatory mediators play a significant role in OA. Cartilage will normally remodel over time. This requires both destructive factors such as metalloproteinase (particularly collagenase-1, stromelysin-1, and gelatinase) that are able to degrade all components of the extracellular matrix and can rapidly destroy cartilage. It also requires constructive production of collagen (mainly type II collagen) and proteoglycans (aggrecan). Chondrocytes are responsible for both the production of constructive and destructive factors. In the most basic understanding of osteoarthritis, the destructive factors overcome the constructive factors. There are many factors, cytokines, and inflammatory mediators implicated as inciting the local destruction of articular cartilage:
Focal mechanical stress of cartilage
caused by trauma, physical forces, instability of the joint, defects in proprioception, metabolic abnormalities, or crystal disease can injure the chondrocyte causing it to release degradative enzymes that result in collagen fibrillation and matrix breakdown. Type II collagen and its degradative products can be released.
Pro-inflammatories in OA
The chondrocytes and synovium can release pro-inflammatory substances that can promote the progression of cartilage damage. The cytokines and inflammatory mediators implicated in the destruction of cartilage include: IL-1, TNF-alpha, IL-6, IL-17, and IL-18, Nitric oxide (NO), prostaglandins, inhibitory cytokines, adipokines, and complement factors.
Interleukin-1 (IL-1) and OA
promotes extracellular matrix degradation and decreases new matrix formation. It can specifically promote the degradation of type II collagen and aggrecan by stimulating chondrocytes to make matrix metalloproteases (MMP). Secondarily, it stimulates other mediators such as prostaglandins (PGE2), nitric oxide (NO) and interleukin-6. IL-1 has a pivotal role in sustaining inflammation and cartilage degradation.
Tumor necrosis factor α and OA
behaves similar to IL-1. It can stimulate the production of matrix degrading proteinases. It works synergistically with IL-1 to cause cartilage damage.
other pro-inflammatory cytokines and OA
involved in cartilage destruction such as IL-6, IL-17, and IL-18. IL-17 is produced by Th17 T-cells and increases expression of IL-1. IL-18 is produced by macrophages and induces IL-1 and TNF α production.
Nitric oxide (NO) and OA
NO is produced by endothelial cells and chondrocytes. NO exerts catabolic effects on cartilage. Like IL-1, it increases MMP production and inhibits proteoglycan synthesis. As the OA cartilage tries to repair itself, chondrocytes proliferate greatly. NO seems to induce chondrocyte apoptosis (cell death), inhibiting this reparative response.
Prostaglandins and OA
Prostaglandins can have multiple effects on various cells in the joint. Prostaglandin’s negative effects may be the increased production and activation of MMPs (specifically stromelysin).
Inhibitory Cytokines and OA
IL-4, IL-10, IL-13, and IL-1 receptor antagonist (IL-1Ra) decrease the production and activities of the catabolic and proinflammatory cytokines in chondrocytes in vitro and suppress cartilage destruction in vivo. Transforming growth factor-beta (TGF-β) and insulin-like growth factor (IGF-I) are implicated in maintaining cartilage by anabolic mechanisms.
Complement pathway and OA
Evidence supports a role for complement activation in the pathogenesis of OA. Proteomic and transcriptional analyses of synovial fluids and synovial tissues of patients with OA reveal high expression and activation of complement. In a mouse surgical model of OA, the membrane attack complex appears to be critical to the development of OA. It is hypothesized that released or exposed cartilage extracellular matrix components may trigger the complement cascade. The formation of the complement membrane attack complex on chondrocytes could lead to cell death or to the production of degradative enzymes and inflammatory mediators by the chondrocytes resulting in cartilage loss.
Adipokines and OA
Adipokines, cytokines mainly produced by adipose tissue, may be linked to the development of OA. Obesity is associated with systemic low-grade inflammation. The risk of hand OA is increased in individuals with obesity (see Section III above) which is not explained by overloading of the joints.
Water content and cartilage with OA
Initially in the development of OA, the water content increases in the cartilage. The collagen-proteoglycan network weakens and the collagen fibers become weaker with looser “weave.” Then the proteoglycan content begins to decrease such that with advanced OA the content may be 50% or less of normal. This diminution of proteoglycan is accompanied by an increase in degradative enzymes. The chondrocytes initially increase in number, then in later stages of OA die.
Gross morphology of OA
On a gross morphologic level, the cartilage surface becomes disrupted and fragmented with pits and ulcers. Then the bone may develop bare areas. The bone responds by making osteophytes. Bone reparative processes may cause the formation of type I collagen, and fibrocartilage may cap the osteophytes.
Etiology/Predisposing Factors of OA
The etiology of OA remains unknown, but a number of predisposing factors have been identified, some of which may give us clues as to the underlying etiology.
Genetics and OA
It has long been recognized that some forms of OA have a genetic predisposition. Recently, it has been demonstrated that point mutations in the type II collagen gene can result in accelerated familial OA and chondrodysplasia. Although this abnormality accounts for only a tiny percentage of the cases of OA, this work demonstrates that primary abnormalities in collagen can predispose to OA, and that genetic abnormalities of cartilage components may predispose individuals to OA.
Metabolic abnormalities of cartilage in OA
A number of metabolic diseases including hemochromatosis, Wilson’s disease, and ochronosis are associated with accelerated OA. Although the precise mechanism of OA in these diseases is not known, direct chondrocyte toxicity as well as deposition of calcium pyrophosphate crystals in the extra-cellular matrix (ECM) may contribute to the disease process.
Trauma and OA
Trauma in the form of mechanical instability, mechanical incongruity, excessive load (obesity), and denervation (loss of normal pain feedback to protect joints) are the main recognized predisposing factors for OA. A number of experimental models of OA involve disruption of normal joint mechanics (e.g: meniscectomy in the rabbit), which leads to the rapid development of OA. It is postulated that trauma leads to chondrocyte injury, which in turn leads to an imbalance between the anabolic and catabolic products of these cells (mechanotransduction) resulting in ECM degradation and eventual OA.
Inflammatory joint disease and OA
It should be pointed out that cartilage damage initiated by other processes, such as RA, crystals, or infection may also result in development of secondary OA.
Obesity and OA
It required large population studies, such as the Framingham study and the NHANES studies to show that obesity was not only related to knee and hip OA but to hand OA.
Age and OA
75% of persons over age 70 have OA, uncommon under age 40. This may in part be associated with an age-related decrease in chondrocyte number in articular cartilage.
What is important in treating OA?
Biomechanical or biochemical targets. Primary prevention: Reduction of risk factors and 25% to 50% of OA is theoretically preventable by reducing obesity and repetitive activities. Secondary prevention: Interventions that prevent progression and Disease modifying OA drugs (DMOADs). Tertiary treatment: Treatment of consequences of OA
Treatment of OA
A general understanding of an approach to the patient with OA may help in understanding the overall pathophysiology of OA. Discuss the patient’s concerns and what you can and cannot do. Are you treating pain or functional limitation? If one examines factors that might account for the severity of knee pain perception, the degree of true osteoarthritis involvement is disproportionate to the psychosocial variables. To some extent, the complaint of knee pain, with or without incapacity, is a surrogate for difficulty in coping with pain in the knee. Physical modalities are used to help prevent rapid cartilage loss. Weight loss, if obese. Modify activities and occupation. Diminish weight bearing load with canes or crutches. Assistive devices. Physical therapy - gait instruction, strengthening exercises. Exercise may improve general health, modify possible risk-factors in disease progression, increase range of motion and flexibility, increase endurance and strength, reduce fall risk and may even be chondroprotective. Medications: Topical agents, Nonopioid analgesics (e.g., acetaminophen), Anti-inflammatory agents such as nonsteroidal anti-inflammatory drugs, Opioid analgesics, Nutraceuticals and alternative therapies, Intra-articular agents, and Adjunctive therapy such as muscle relaxants. Intra-articular agents include Corticosteroids and Hyaluronic acid is now used to relieve pain in knees of OA patients. Nutraceuticals - most commonly used are glucosamine and chondroitin sulfate. Glucosamine is an aminosaccharide that is a component of glycosaminoglycans, hyaluronan, keratan sulfate and heparin sulfate. Studies mainly from Europe demonstrate pain relief comparable to nonsteroidal anti-inflammatory drugs with few side effects. Surgery - arthroscopic, reparative, reconstructive or total joint replacement.
Summary/Future Directions of OA
Osteoarthritis results from articular cartilage failure due to a complex interaction between genetic, biochemical, biomechanical, metabolic, and inflammatory factors. Earlier diagnosis and treatment may become available through markers in the blood. Virtually every part of cartilage has been investigated to see if its presence in blood correlates with microscopic and macroscopic cartilage loss. These include fragments of aggrecan, keratin sulfate, and chondroitin sulfate; type II collagen, link protein, and osteocalcin; cartilage matrix glycoprotein, and cartilage oligomeric protein (COMP). So far, COMP appears the most promising. Future therapies may include metalloproteinase inhibitors, synthetic proteoglycans, and intra-articular injection of chelators to inhibit MMP. Growth factors to grow cartilage either in vivo, or in vitro with implantation back into the joint, may be utilized. Biologic agents directed against inflammatory proteins and cytokines might be utilized. Experimental plastics are being used to fill in areas of damaged cartilage.
RHEUMATOID ARTHRITIS
Rheumatoid arthritis (RA) is a systemic, inflammatory, autoimmune disorder of unknown etiology that results predominantly in a peripheral, symmetric, inflammatory synovitis often leading to cartilage and bone destruction and joint deformities. Extra-articular manifestations also occur but are usually less extensive and severe than in the other “diffuse connective tissue diseases”.
Joint distribution with RA
Predominantly peripheral synovial joints in a symmetric pattern, particularly the small joints of the hands and feet, although medium and large joints are also involved. DIP often spared. Cervical spine also commonly involved (usually C1-2). Other synovial joints may be involved including the cricoarytenoid, ossicles of inner ear, and temporomandibular joint.
Symptoms of RA
Morning stiffness, soft tissue swelling around joints, and pain. Deformities and loss of function possible.
Signs of RA
Joint warmth and swelling (as a result of synovial tissue proliferation and/or excessive synovial fluid). Tenderness to palpation with limitation of motion. Possible deformities may be present.
Serologic findings of RA
Rheumatoid factor (RF) present in 85%. ESR or C-reactive protein often elevated. Anemia and hypergammaglobulinemia are frequently found. Anti-cyclic citrullinated peptide (CCP) antibodies present in 70%: Anti-CCP antibodies are highly specific (specificity > 90%) for RA. These autoantibodies react with peptides containing citrulline, an arginine residue modified by the enzyme peptidyl arginine deiminase (PAD). Citrullinated proteins can be found in many sites of inflammation; it is unclear why some patients with RA make such high titer antibodies to these proteins. A strong association between cigarette smoking, a known risk factor for RA, and the presence of HLA alleles containing the “shared epitope” (see section V: Etiology, Genetic factors) has been observed in patients with RA who have anti-CCP antibodies.
Synovial fluid analysis with RA
Inflammatory (>2000 WBC/μl) with predominantly neutrophils. Complement and glucose levels usually low.
Radiographic findings with RA
Soft tissue swelling. Juxta-articular osteopenia. Symmetric loss of joint space. Erosions in marginal distribution.
Constitutional symptoms with RA
Common and may predominate over joint symptoms. Fatigue, malaise, anorexia, weight loss, low-grade fever.
Rheumatoid nodules with RA
Present in 20-25%, associated with presence of serum RF. Location: extensor surfaces and tendon sheaths. May be present in a variety of internal organs, particularly lung. It is due to vasculitis
End-organ involvement with RA
Numerous organ systems may be affected in ~20%, including the eyes (scleritis), lungs (pulmonary fibrosis or nodules), pericardium, and peripheral nerves (neuropathy). Pathophysiology: vasculitis or granulomatous infiltration.
Prevalence with RA
1-2 % of the adult population. Female:male ratio ~2.5:1. Any age, but prevalence increases with age (~5 % in >65 y.o.).
Genetic factors with RA
Concordance rate ~30% in monozygotic twins and 3% in dizygotic. HLA-DR4 present in 50% or more (see below).
Pathology with RA
This disease process begins with inflammation in the synovium, with later destruction of the articular cartilage, bone, and peri-articular structures.
Early findings with RA
Mild inflammation with microvascular injury, subsynovial edema, fibrin exudation and minimal synovial lining cell proliferation. Synovial fluid at this stage contains predominantly mononuclear cells.
Later findings with RA
Increase in the synovial lining cells: macrophages (type A cells) derived from blood monocytes, and fibroblasts (type B cells) from local proliferation. Normally acellular sublining region of synovium shows fibroblast proliferation, growth of new blood vessels, and focal aggregates of CD4+ T lymphocytes, B cells and plasma cells. Evidence of microvascular injury continues.
Pannus
an organized mass of granulation tissue consisting of macrophages, T cells, B cells, and fibroblasts, is common in established RA. It arises from inflamed synovium under the influence of numerous cytokines, and covers and invades the articular cartilage and juxta-articular bone, leading to the radiographic findings of loss of joint space and periarticular erosions.
Synovial fluid
contains primarily polymorphonuclear neutrophils at this stage.
Etiology with RA
Unknown. Preclinical autoimmunity may exist for several years before the onset of clinical disease, in the form of RF or anti-CCP antibodies. The disease may remain subclinical for unknown periods of time before joint manifestations appear. The mechanisms of initiation of the disease process may be multiple with a different and common mechanism of perpetuation of inflammation and tissue damage. Whether the mechanisms of initiation are non-specific or immunologically specific is unclear and remains controversial.
Genetic factors with RA.
This is a polygenic disease with possibly different sets of predisposing genes in different population groups. One genetic factor resides within the class II MHC (HLA DR). A short sequence within the third hypervariable portion of the DRB1 gene is probably most important (QKRAA, termed the shared epitope). The disease-associated alleles include HLA-DRB1*0401, *0404, and 0101 in Caucasians, HLA-DRB10405 in Asians and *1402 in Indians. The QKRAA sequence surrounds the antigen-binding groove and may interact both with side chains of the bound antigen and with the T cell receptor. This genetic polymorphism determines both susceptibility to and severity of disease. Anti-CCP antibodies are present in individuals carrying the shared epitope, and citrullination of peptides enhances binding to the shared epitope. Other genes have been noted to be present with an increased frequency in patients with RA: PTPN22 gene (encodes a protein tyrosine phosphatase); STAT4 gene (encodes a transcription factor that transmits signals induced by several key cytokines including IL-12, IL-23, and type 1 interferons); and the TRAF1-C5 gene locus (encodes TNF receptor-associated factor 1 and complement component 5, respectively).
Arthritogenic peptide with RA.
The role of the RA-associated class II molecules may be in their ability to bind and present an arthritogenic peptide. A variety of exogenous infectious agents (EB virus, other viruses, bacterial heat shock proteins) and modified endogenous molecules (collagen) have been suggested as potential antigenic agents in the initiation and/or perpetuation of RA, with presentation probably by dendritic cells, macrophages, and B cells. However, it is unlikely that a single arthritogenic peptide exists either in a single patient or between patients. A variation on this hypothesis would be that the predisposing class II MHC preferentially binds and presents citrullinated peptides, leading to the production of anti-CCP antibodies. A general model for the development of anti-CCP antibodies may be that inflammation (from smoking or other causes) initially generates citrullinated proteins and in the appropriate genetic background (and perhaps under the influence of other inflammatory changes) a patient then develops anti-CCP antibodies; these antibodies in turn may lead to joint disease by direct targeting of citrullinated proteins within the joint (Type II immune reaction) or through formation of immune complexes which then deposit in the joint causing inflammation (Type III immune reaction).
Selection of the T cell repertoire with RA.
The RA-associated class II molecules may be involved in selection of a particular repertoire of T cells within the thymus. These T cells may subsequently be capable of amplifying or perpetuating chronic inflammation upon encountering multiple arthritogenic peptides, either of endogenous or exogenous origin. Alternatively, the QKRAA motif might create a “hole” in the immune repertoire, preventing clearance of an etiologic agent.
Class II peptide as an antigen itself with RA.
There is sequence homology between the shared epitope in the third hypervariable region of the RA-associated class II molecule and sequences present within common viral and bacterial peptides. Antibodies or, more likely, sensitized T cells against the exogenous peptides potentially may cross-react with the class II peptide itself, or with other endogenous antigens, producing an autoimmune response.
Pathogenesis with RA:
Conceptualize as processes within two separate compartments, the fluid-phase and the synovial tissue. The events taking place in the tissue are more important in the disease process.
Synovial fluid compartment with RA:
Neutrophils comprise the major cellular component of the synovial fluid and emigrate from the circulation under the influence of the cytokines, IL-8 and TGF-β, and of adhesion molecules expressed on endothelial cells. Neutrophils in the fluid phase may contribute to tissue damage through the release of prostaglandins, leukotrienes, cytokines, oxygen radicals, and enzymes.
Synovial tissue compartment with RA:
Synovial tissue, in the form of pannus, is directly opposed to the articular cartilage and marginal bone, and is responsible for most of the joint tissue destruction. The majority of infiltrating cells are mononuclear (lymphocytes and macrophages), with intense proliferation of local fibroblasts. Neutrophils are rare in the synovial tissue, in contradistinction to the synovial fluid compartment.