rheumatology Flashcards

Question

Inhibitory Cytokines and OA

Answer 1

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.

Answer 2

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.

Answer 3

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.

Answer 4

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.

Answer 5

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.

Answer 6

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.

Answer 7

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.

Answer 8

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.

Answer 9

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.

Answer 10

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.

Answer 11

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.

Answer 12

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.

Answer 13

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

Answer 14

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.

Answer 15

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.

Answer 16

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".

Answer 17

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.

Answer 18

Morning stiffness, soft tissue swelling around joints, and pain. Deformities and loss of function possible.

Answer 19

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.

Answer 20

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.

Answer 21

Inflammatory (>2000 WBC/μl) with predominantly neutrophils. Complement and glucose levels usually low.

Answer 22

Soft tissue swelling. Juxta-articular osteopenia. Symmetric loss of joint space. Erosions in marginal distribution.

Answer 23

Common and may predominate over joint symptoms. Fatigue, malaise, anorexia, weight loss, low-grade fever.

Answer 24

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

Answer 25

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.

Answer 26

1-2 % of the adult population. Female:male ratio ~2.5:1. Any age, but prevalence increases with age (~5 % in >65 y.o.).

Answer 27

Concordance rate ~30% in monozygotic twins and 3% in dizygotic. HLA-DR4 present in 50% or more (see below).

Answer 28

This disease process begins with inflammation in the synovium, with later destruction of the articular cartilage, bone, and peri-articular structures.

Answer 29

Mild inflammation with microvascular injury, subsynovial edema, fibrin exudation and minimal synovial lining cell proliferation. Synovial fluid at this stage contains predominantly mononuclear cells.

Answer 30

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.

Answer 31

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.

Answer 32

contains primarily polymorphonuclear neutrophils at this stage.

Answer 33

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.

Answer 34

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-DRB1*0405 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).

Answer 35

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).

Answer 36

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.

Answer 37

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.

Answer 38

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.

Answer 39

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.

Answer 40

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.

Answer 41

May play a central role in RA through their capacity to synthesize and secrete several pro-inflammatory cytokines (IL-1, TNFα, and IL-6) and proteolytic enzymes. The major influence driving macrophages is unclear, but involves direct contact with lymphocytes at some time in the disease process. However, in the chronic phase, macrophages and fibroblasts may experience autocrine and paracrine mechanisms of stimulation with tissue destruction becoming autonomous or self-perpetuating with time. Mast cells in the synovium also may play a role in the release of enzymes and cytokines. Synovial macrophages also may give rise to osteoclasts that lead to destruction of marginal bone.

Answer 42

such as IL-1, TNFα, IL-6, and IL-17 are produced in significant amounts in this tissue. Their systemic effects (mostly IL-6) include anorexia, fever, and stimulation of hepatic synthesis of acute-phase proteins (CRP, serum amyloid A, etc.). Local pro-inflammatory effects in the joints (mostly IL-1 and TNF) include chemotaxis of inflammatory cells, release of PGE2, and induction of collagenase and neutral proteinase production by synovial fibroblasts and chondrocytes in the superficial layer of the articular cartilage. This latter mechanism is most important in the process of cartilage and bone destruction. TNFα, IL-1, and IL-17 can also induce osteocyte lineage cells to express a factor called Receptor Activator of Nuclear Factor kB Ligand (RANKL) that interacts with the RANK receptor on osteoclast precursors resulting in activation and osteoclastic resorption of bone. In normal bone, osteoprotegerin (OPG) competitively binds RANKL and modulates its activity. Bony resorption in RA is due to an elevated RANKL/OPG ratio; anti-TNF therapies decrease this ratio and bone resorption. A monoclonal antibody against RANKL (denosumab) is a treatment option for osteoporosis.

Answer 43

such as IL-1Ra (IL-1 receptor antagonist), and soluble receptors for IL-1 and TNFα, are also produced in the rheumatoid synovium. The net inflammatory response depends on the local balance between pro- and anti-inflammatory molecules.

Answer 44

The majority are CD4+ memory T cells. A variable number of B cells and plasma cells are also present. Despite the fact that T cells are often a predominant cell in the RA synovium, they do not appear to be activated and the T cell cytokines IL-2 and IFNγ are sparse. Th17 T cells, as above, play a significant role through the secretion of IL-17. There appears to be a deficiency of Th2 and regulatory T cells (Tregs). Synovial tissue T and B cells are involved in the disease process, probably varying in their importance between patients or in a single patient over time, with two main hypotheses suggested for their role. T cells may recognize citrullinated peptides; or proteoglycan or collagen molecules altered by enzymatic digestion with presentation of neoepitopes. This process may explain, in part, the chronicity of the disease. B cells make RF and anti-CCP antibodies that may lead to the production of immune complexes, further enhancing local inflammation. However, the beneficial effects of anti-B cell antibody therapy (rituximab) in the treatment of RA suggest additional roles for B cells, possibly as antigen-presenting cells or in sustaining local T cell function.

Answer 45

are immunoglobulins that recognize epitopes present within the Fc portion of IgG. RF are produced locally within the synovial tissue in many patients with RA and are associated with more severe disease. Most RF are IgM but some may be IgG and IgA. Immune complexes formed by the interaction of RF with IgG are present within both the synovial tissue and synovial fluid. These immune complexes may lead to complement activation via the classical pathway, producing inflammatory consequences. RF are also present in low levels in normal individuals and are found in other diseases characterized by chronic infection or inflammation; thus they are not specific for RA. RF are present on the surface of B cells which may bind immune complexes and function as antigen-presenting cells.

Answer 46

The therapeutic approach to rheumatoid arthritis has four main elements: Anti-inflammatory/analgesic drugs, Disease-modifying anti-rheumatic drugs (DMARDs), Physical therapy, and Surgery.

Answer 47

are used to relieve patient symptoms, but these do not prevent tissue destruction. These medications include aspirin, other NSAIDs, acetaminophen, and prednisone (oral or by intraarticular injection). The mechanisms of action include inhibition of production of inflammatory mediators.

Answer 48

are instituted early after diagnosis in an effort to prevent tissue destruction. These medications include hydroxychloroquine, sulfasalazine, leflunomide, or methotrexate. These drugs have many mechanisms of action but they primarily inhibit various macrophage and lymphocyte functions. Newer therapeutic agents include biologic agents that inhibit the effects of cytokines, particularly IL-1 (anakinra), TNFα (etanercept, infliximab, adalimumab, certolizumab, and golimumab) and IL-6 (tocilizumab); inhibit a T cell costimulator molecule and modulate T cell activation (abatacept); or deplete B cells (rituximab). Other agents that inhibit cytokines; deplete particular cells; or inhibit intracellular tyrosine kinases (oral agents termed “small molecules”) are under investigation. Tofacitinib, a novel oral Janus tyrosine-specific kinase (JAK) inhibitor, was recently FDA-approved for the treatment of RA.

Answer 49

with exercise and physical modalities.

Answer 50

for selected patients, including total joint replacements.

Answer 51

Rheumatoid arthritis is a common disease with characteristic articular and extra-articular clinical manifestations, and helpful X-ray and laboratory findings. This is a polygenic disease with different sets of genes being involved in different population groups. Specific HLA-DR molecules appear to predispose both to acquiring the disease and to developing greater degrees of severity of joint tissue destruction. The pathology is an inflammatory synovitis with fibroblasts, macrophages, mast cells, T cells, B cells, plasma cells and dendritic cells in the synovium all involved, as well as chondrocytes in the articular cartilage. The pathophysiology involves predisposing autoimmunity with possibly multiple mechanisms of initiation of clinical disease and with a common mechanism of perpetuation of the chronic inflammation leading to tissue destruction. CD4+ T cells in the synovium may be important in initiation and maintenance of the disease process through recognition of arthritogenic peptides. B cells also are important both through production of autoantibodies and sustaining T cell function. The destruction of articular cartilage and marginal bone is carried out by neutral proteinases released by proliferating fibroblasts in the synovium, called pannus, and by chondrocytes in the articular cartilage under the influence of IL-1 and TNFα primarily derived from synovial macrophages. IL-1, TNFα, and IL-17 also play a role in osteoclast formation. Neutrophils in the synovial fluid also may contribute to tissue destruction. Synovial macrophages stimulated by T cells, or both macrophages and fibroblasts in chronic rheumatoid synovitis may function in an autonomous and self-perpetuating fashion.

Answer 52

a heterogeneous group of diseases in which tissue deposition of monosodium urate (MSU) crystals occurs due to hyperuricemia (MSU supersaturation of extracellular fluids), resulting in one or more of the following manifestations: Gouty arthritis: recurrent attacks of severe acute or chronic articular and periarticular inflammation. Tophi: aggregated deposits of MSU occurring in joints, bones, and soft tissue. Gouty nephropathy: renal interstitial, glomerular, and/or tubular deposition of MSU crystals. Uric acid nephrolithiasis (kidney stones). Gout usually refers to acute or chronic arthritis secondary to MSU crystals. Hyperuricemia without symptoms is referred to as “asymptomatic hyperuricemia,” not gout.

Answer 53

Asymptomatic hyperuricemia, Acute Gouty Arthritis, Intercritical gout, Chronic Tophaceous Gout

Answer 54

Elevated serum uric acid level without gouty arthritis, tophi, or uric acid nephrolithiasis. A serum urate level is elevated when it exceeds the limit of solubility of MSU in serum. At 37° C, the saturation value of MSU in serum is 7.0 mg/dl; a value above this represents supersaturation of MSU.

Answer 55

Abrupt onset of an exquisitely painful, warm, red, swollen joint often during the night or early morning. The metatarsophalangeal (MTP) joint of the great toe is involved most often (termed podagra) followed by the insteps, ankles, heels, knees, wrists, fingers, and elbows. Early attacks often spontaneously resolve over 3-10 days. Gouty arthritis has a predilection for cooler, acral sites where the solubility of MSU crystals may be diminished due to the cooler temperature.

Answer 56

The asymptomatic intervals between acute attacks of gout.

Answer 57

Development of subcutaneous, synovial, or subchondral bone deposits of MSU crystals. Tophi commonly occur on the digits of the hands and feet, olecranon bursa, extensor surface of the forearm, Achilles tendon, and less commonly, the antihelix of the ear.

Answer 58

Gout is predominantly a disease of adult men typically occurring after the age of 30 with a peak incidence in the fifth decade. In females, gout occurs after menopause. The prevalence of gout is > 2% in men older than 30 years of age and in women older than 50 years of age. In men and women older than 80 years of age, the prevalence increases to 9% and 6%, respectively. Gout is the most common cause of inflammatory arthritis in men over age 40. The most common medical conditions associated with gout are alcohol abuse, obesity, insulin resistance syndrome, and hypertension.

Answer 59

Fresh synovial fluid must be examined for the presence of MSU crystals. The intracellular crystals in PMNs are needle-shaped and negatively birefringent (yellow when parallel to the axis of the red compensator) on polarizing microscopy. The synovial fluid is inflammatory (typically 20,000-100,000 leukocytes/mm3 ) with a predominance of neutrophils. Hematological evaluation may show an elevated ESR, mild neutrophil leukocytosis, and possibly reactive thrombocytosis.

Answer 60

Hyperuricemia can result from increased production or decreased renal excretion of urate. In the steady state: Urate Produced + Urate Absorbed by the GI tract = Urate Excreted + Urate Loss by the GI tract. A 24h urinary excretion of uric acid >750 mg on a regular diet suggests an overproduction of uric acid where a value <750 mg/24h would imply underexcretion of uric acid. The majority of patients (90%) with primary gout are underexcretors of uric acid. Urinary uric acid excretion occurs through a four compartment model: 1) glomerular filtration (almost 100% of the filtered uric acid load) followed in the proximal tubule by 2) pre-secretory reabsorption, 3) secretion back into the tubule, and 4) post-secretory reabsorption. Net tubular reabsorption is about 90% of the filtered uric acid; thus only 10% of the filtered uric acid is excreted in the urine. A urate/organic anion exchanger (URAT1) in the proximal tubule plays a role in the pre-secretory and post-secretory reabsorption of uric acid. The reabsorption of uric acid in the proximal tubule is favored in exchange for the tubular secretion and excretion of unwanted organic acids such as lactate, acetoacetate, hydroxybutyrate and succinate. Certain drugs/metabolites decrease the renal excretion of uric acid (resulting in hyperuricemia) by activating URAT1: nicotinate, pyrazinoate, diuretics, and low-dose aspirin. In contrast, other medications are inhibitors of URAT1 resulting in increased urinary excretion of uric acid (uricosurics): probenecid, sulfinpyrazone, a metabolite of losartan, and high-dose aspirin. Specific URAT1 inhibitors are in development. Although the function of URAT1 explains several aspects of renal tubular handling of uric acid and the effects of several drugs/metabolites on uric acid transport in the kidney, it does not explain renal uric acid transport in individuals with primary gout who are underexcretors of uric acid (mechanism is still unknown). Other renal apical surface urate transporters include OAT4, OAT10, and GLUT9a. ABCG2 and MRP4 are two major proteins on the apical surface that extrude urate from the epithelial cell into the tubular urine. Of interest, polymorphisms of ABCG2 are associated with decreased renal secretion of uric acid resulting in hyperuricemia and gout.

Answer 61

Uric acid is a product of purine metabolism. Humans lack the enzyme uricase, which in other species can oxidize uric acid (sparingly soluble) to allantoin (highly soluble). The human uricase gene is crippled by 2 mutations that induce premature stop codons. In humans, uric acid may serve as a primary antioxidant. In rare cases, overproduction of uric acid can be due to superactivity of PRPP (phosphoribosyl-pyrophosphate) synthetase or deficiencies of HGPRT (hypoxanthine-guanine phosphoribosyltransferase) (see figure below). Complete deficiency of HGPRT results in the Lesch-Nyhan syndrome (mental retardation, spasticity, choreoathetosis, and self-mutilation).

Answer 62

Supersaturation of serum or synovial fluid with MSU. Factors which affect urate solubility: Temperature: urate saturation is 7.0 mg/dl at 37° C; 4.5 mg/dl at 30° C. Acute gouty arthritis affects primarily peripheral joints with lower temperatures. Dehydration or volume fluxes: overnight intra-articular dehydration may concentrate uric acid and crystallization promotors leading to the onset of acute gouty arthritis in the awakening morning hours. Trauma: release of articular MSU crystals, which trigger an attack. Intact proteoglycans bind and solubilize MSU. Proteoglycan abnormalities (as seen in osteoarthritis) may alter local urate levels and precipitate an attack. pH: MSU crystals are less soluble at a lower pH.

Answer 63

Uric acid crystals initially interact with synovial lining cells leading to the activation of monocytes and mast cells. Initial recognition of naked MSU crystals by Toll-like receptors (TLR2/TLR4) is critical to the inflammatory response. MSU crystals also engage the caspase-1 activating NLRP3 inflammasome resulting in IL-1β production. In addition, these activated monocytes produce TNF-α, IL-6, and IL-8. The inflammatory response to MSU crystals depends on PMNs. PMN influx is promoted by IL-8 and neutrophil chemoattractant protein-1 along with endothelial activation by cytokines such as IL-1 and TNF. MSU crystals may activate complement, promote leukotriene and prostaglandin production, induce additional cytokine release (IL-6 and IL-8), and cause superoxide radical generation. IgG binds to the crystal surface through charge interactions and hydrogen bonding facilitating phagocytosis of MSU crystals by PMNs whereas later, apolipoprotein-B coating of crystals inhibits phagocytosis and a cellular response. Phagocytosis of crystals by PMNs results in PMN lysis with release of proteolytic enzymes.

Answer 64

Different proteins coating the crystals (IgG or Apo-B) may modulate the cellular response. Phagocytosis and degradation of crystals by PMNs decreases the crystal concentration; eventual neutrophil apoptosis. The heat associated with the inflammatory response may result in increased urate solubility. Enhanced ACTH secretion may suppress the inflammatory response. Proinflammatory cytokines (IL-1 and TNF) are balanced by the production of cytokine inhibitors and regulatory cytokines such as transforming growth factor-β (TGF-β).

Answer 65

Lifestyle and nutritional modifications including weight loss, reduction of dietary intake of foods high in purines such as meats and shellfish, and limitation of fructose and alcohol consumption can improve hyperuricemia. However, it is difficult to treat hyperuricemia by diet alone as the purine content of the diet only contributes about 1.0 mg/dl to the serum uric acid concentration. Consumption of meat, seafood, fructose, and alcohol should be done in moderation. Recent studies show that low-fat dairy products, coffee, vitamin C, and moderate wine intake might be protective of hyperuricemia and gout. The acute gouty attack can be effectively treated with anti-inflammatory medications such as nonsteroidal anti-inflammatories (NSAIDs), colchicine (binds to intracellular tubulin, preventing its polymerization into functional microtubules resulting in diminished migration, metabolic, and phagocytic activity of PMNs; colchicine may also block the activation of the NLRP3 inflammasome in monocytes by MSU crystals), or corticosteroids (systemic or intra-articular administration). For chronic treatment of symptomatic hyperuricemia, the following anti-hyperuricemic medications are effective in reducing serum uric acid levels below supersaturation levels: a uricosuric such as probenecid is used to enhance renal excretion of uric acid if the patient is an under-excretor; a xanthine oxidase inhibitor such as allopurinol or febuxostat is used to decrease uric acid production if the patient is an over-producer of uric acid. Patients at increased risk for severe allopurinol hypersensitivity reaction (e.g, Koreans with stage 3 or worse chronic kidney disease, and patients of Han Chinese or Thai descent) should undergo HLA-B*5801 screening prior to starting allopurinol. Intravenous PEGylated-uricase (pegloticase) can be considered in patients with a severe gout burden who are intolerant of oral urate-lowering therapy or who have refractory disease despite urate-lowering therapy.

Answer 66

CPDD is a type of arthritis associated with the release of calcium pyrophosphate dihydrate (CPPD) crystals into the joint space and chondrocalcinosis (calcified joint cartilage). Pseudogout is the term used to describe an acute episodic arthritis due to CPPD crystals.

Answer 67

Pseudogout attacks are characterized by a sudden onset of severe pain, swelling, warmth, and redness of usually a large joint, most often the knee, and less frequently the wrist and ankle. Unlike gout, the first MTP is rarely involved.

Answer 68

CPDD is predominantly a disease of elderly individuals although associations with metabolic diseases such as hyperparathyroidism and hemochromatosis, and rare familial forms exist. CPDD is strongly associated with aging and concurrent osteoarthritis. The prevalence of chondrocalcinosis according to age is 65 to 74 – 15%, 75 to 84 – 36%, and > 84 – almost 50%. In younger individuals, joint trauma or prior joint surgery are risk factors for the development of CPPD crystal deposition.

Answer 69

Fresh synovial fluid must be examined for the presence of CPPD crystals. CPPD crystals are rhomboid-shaped and positively birefringent (blue when parallel to the axis of the red compensator) on polarizing microscopy. The synovial fluid is inflammatory (typically 2,000-80,000 leukocytes/mm3) with a predominance of neutrophils. Peripheral blood WBC and ESR may be increased during acute attacks. Serum calcium, phosphorus, and iron studies are helpful in searching for associated metabolic causes of CPDD.

Answer 70

Source of PPi is from the metabolism of nucleoside triphosphates (NTP), particularly from articular chondrocytes. Synovial fluid PPi levels are elevated in CPDD and in osteoarthritis. This is most likely a result of a chondrocyte surface enzyme, NTP pyrophosphohydrolase, that hydrolyzes the phosphodiesterase 1 bond generating NMP and PPi. In addition, mutations of the ank gene (ANKH) that produces a transmembrane PPi transporter protein in chondrocytes could promote CPPD crystal formation and deposition by allowing excess intracellular PPi egress from chondrocytes. Alternatively, chondrocyte ANKH function could be increased by overexpression of normal ANKH. Increased extracellular PPi levels then precipitate with calcium forming CPPD crystals in mid-zonal cartilage layers around the chondrocytes.

Answer 71

Unlike MSU crystals, CPPD crystals do not form in synovial fluid by spontaneous precipitation of supersaturated solutions. CPPD crystals are released into synovial fluids by a “shedding phenomenon” or “enzymatic strip mining” of pre-formed crystals in the cartilage matrix. The inflammatory response: similar to the inflammatory response to MSU crystals (see Gout, Pathophysiology).

Answer 72

Anti-inflammatory drugs are used to treat acute pseudogout (see Gout, Treatment). Unlike gout, there is no way to remove CPPD crystals from the joints or to retard further progression of the disease.

Answer 73

The axial arthropathies are a group of diseases characterized by axial arthritis (spine, sacroiliac joints), peripheral arthritis, enthesitis (inflammation of the ligamentous-osseous junctions), mucocutaneous lesions (skin rash, conjunctivitis), and genetic association with the HLA class I marker HLA-B27. Ankylosing spondylitis (AS), reactive arthritis, psoriatic arthritis, the arthropathies associated with regional enteritis (Crohn's disease) and ulcerative colitis, and the undifferentiated spondyloarthropathies belong to this group of diseases. The exact pathogenesis of the disease entities is uncertain. However, there is a strong association with the HLA-B27 antigen suggesting the possibility of an unknown infectious organism triggering an abnormal immune response in a genetically susceptible individual resulting in clinical disease.

Answer 74

Affects males > females (7:3 ratio). Onset occurs between 16 and 40 years old, rarely younger or older. Caucasians affected more than other racial groups.

Answer 75

All patients have inflammatory back pain characterized by: Insidious onset of pain lasting > 3 months, Prolonged morning stiffness (> 30-60 minutes), Improvement of pain with exercise, No neurologic sequelae. Physical examination of back shows: SI joint tenderness, Global loss of spine range of motion, Late in disease course may find back deformities and reduced chest expansion. Approximately 25% of AS patients have peripheral arthritis usually of hips and shoulders (i.e. joints close to spine). Unlike rheumatoid arthritis, ankylosing spondytis frequently affects synchondroses, which are areas of cartilaginous union with bone. This includes manubriosternal joint, costovertebral joints, and pubic ramis.

Answer 76

Acute anterior uveitis (an inflammation of the middle layer of the eye, which includes the iris (colored part of the eye) and adjacent tissue, known as the ciliary body)- 25%. Osteoporosis-19-62%. Microscopic colitis- 22-69%, Crohn’s-like lesions 7%. Pulmonary apical fibrosis - 2%. Cardiovascular disease with aortitis, aortic insufficiency, and varying degrees of heart block - up to 10% of patients with long-standing disease. Cauda equina syndrome (damage to the cauda equina causes acute loss of function of the lumbar plexus, (nerve roots) of the spinal canal below the termination (conus medullaris) of the spinal cord) – rare.

Answer 77

Elevated sedimentation rate (ESR); negative rheumatoid factor (RF), negative ANA (serologically negative). Radiographs show sacroiliitis characterized by bone erosion and sclerosis (+/- bony fusion) in 100% of patients with AS by age 45. Over 66% of AS patients develop radiographic spondylitis with thin, marginal syndesmophytes. Only 10% develop complete spinal fusion (bamboo spine). Peripheral joint radiographs can show inflammatory hip disease, which can lead to bony fusion (20-25%).

Answer 78

Affects males > females (5-10:1 ratio). Onset occurs from childhood to age 40-50. Caucasians affected more than other racial groups.

Answer 79

History of infectious diarrhea or urethritis precedes onset of arthritis by 2-4 weeks. Diarrhea due to shigella, salmonella, yersinia, or campylobacter. Urethritis due to chlamydia. Abrupt onset of inflammatory peripheral arthritis, typically lower extremities. May also have inflammatory back pain symptoms and/or extraarticular manifestations.

Answer 80

Peripheral arthritis is asymmetric, oligoarticular, predominately lower extremity arthritis - knees and ankles most common. Dactylitis (20-50%) - diffusely swollen toes (sausage digit) due mainly to tendon inflammation. Axial (back) arthritis- up to 25% will develop persistent inflammatory back disease similar to AS. Enthesopathy - Achilles tendinitis and/or plantar fasciitis (20%). Extraarticular manifestations including inflammatory eye disease - conjunctivitis (50%); acute anterior uveitis (20%); mucocutaneous lesions (20%) - painless oral ulcers, balanitis, keratoderma blennorrhagicum; and aortitis and cardiac conduction defects – rare. The combination of arthritis, urethritis, inflammatory eye disease, and mucocutaneous lesions was formerly termed Reiter’s syndrome.

Answer 81

Elevated ESR; negative RF and ANA (seronegative). Peripheral joint radiographs show erosive changes of feet > ankles/knees. Hips usually spared. Radiographs of SI joint and spine are abnormal in 25%. Changes similar to AS although sacroiliitis tends to be asymmetric and syndesmophytes tend to be larger and non-marginal (jug handles). Radiographs can show erosions and calcification at enthesis insertion sites - heel, etc.

Answer 82

Inflammatory peripheral arthritis occurs in 10-20% of patients with inflammatory bowel disease. Frequently arthritis follows activity of bowel disease. Axial arthritis involving sacroiliac joints and spine occurs in 5% of patients and resembles AS. Does not follow activity of bowel disease.

Answer 83

Up to 10% of patients with psoriasis develop peripheral and/or axial arthritis. Skin disease severity does not correlate with arthritis severity. Inflammatory peripheral arthritis predominantly involves upper extremities especially DIP, PIP, and MCP joints usually in an asymmetric pattern. Dactylitis of fingers can occur. Axial arthritis of spine resembles that seen in reactive arthritis. Occurs in 5-10% of psoriatic arthritis patients.

Answer 84

The relationship between the major histocompatibility antigen HLA-B27 and ankylosing spondylitis is the strongest of all associations between class I HLA and disease. Over 90% of Caucasian AS patients are HLA-B27 positive. The estimated frequency of AS in the general population is 0.1% to 0.2%. The chance of developing AS is about 1-2% if you are HLA-B27 positive and increases to 10-20% if a first-degree relative has ankylosing spondylitis. Identical twins have a concordance rate of up to 60%. Hence, these diseases tend to run in families. There is also an association of reactive arthritis, psoriatic and colitic spondylitis with HLA-B27. Since not all persons who possess HLA-B27 develop a spondyloarthropathy, it is proposed that a genetically susceptible individual develops the disease when exposed to an environmental trigger. Bacteria such as salmonella, shigella, yersinia, campylobacter, and chlamydia induce reactive arthritis in 20% of B27 positive individuals. The trigger for ankylosing spondylitis is unknown although normal bowel bacteria has been proposed.

Answer 85

The primary and unique pathologic site is the enthesis. This enthesitis is inflammation of ligamentous, tendinous, and fibrous structures as they insert into bone (Achilles tendon, annulus fibrosis, plantar fascia, joint capsules). The synovium lining the joint can also be inflamed. The inflammatory infiltrate consists mainly of macrophages, T cells (CD4+ and CD8+), and cytokines (TNF-α, IL-17, and TGF-β). Unlike rheumatoid arthritis, synovial pannus is not seen. TGF-β, bone morphogenic proteins (BMP), and the WNT family of proteins may contribute to the development of calcification at sites of entheses and occasionally in joints such as the SI joints or hips. Inhibitors of TNF, which can suppress the inflammatory response and symptoms of AS, unfortunately do not stop the progression of calcification and syndesmophyte formation.

Answer 86

Animal studies have recently shed light on the influence of HLA-B27 on the pathogenesis of the axial arthropathies. Human B27 and β-2 microglobulin genes have been introduced into rats. These transgenic rats spontaneously developed inflammatory disease involving the GI tract, peripheral and vertebral joints, male genital tract, skin, nails and heart. This pattern of disease bears a striking resemblance to human B27-related axial arthropathies giving credence to the hypothesis that HLA-B27 is directly involved in the disease process. The exact immunologic mechanism has not been clearly elucidated. However, the disease manifestations don’t develop in these B27 transgenic rats if they are raised in sterile environments suggesting an environmental trigger is also important.

Answer 87

Caucasians with the HLA-B27 gene have a relative risk of developing AS which is 50-100x more than someone who is HLA-B27 negative. Based on genome-wide association studies, genetics accounts for 90% of the risk for developing AS. Only 40% of this genetic risk is due to HLA-B27. It is estimated that several other genes may contribute to the genetic risk. This helps to explain why only 1-2% of HLA-B27 positive individuals actually get AS during their lifetime. The other genes associated with an increased risk of AS are: endoplasmic reticulum aminopeptidase 1 (ERAP1), interleukin-23 receptor (IL23R), IL-1 receptor type II (IL-1R2), anthrax toxin receptor 2 (ANTXR2), two loci not encoding gene sequences (gene deserts), RUNX3, IL12B, and TNF pathway-associated genes.

Answer 88

The trigger is unknown but felt to be common to all patients. A reasonable candidate is normal bowel bacteria. Most patients with AS have asymptomatic microscopic colitis that could allow bowel bacterial antigens to breach the mucosal immune system.

Answer 89

Bacterial antigens from the gut could drain through the veno-lymphatic plexus (Batson’s plexus) into the area of the sacroiliac joints and spine. These antigens could disseminate or be transported by monocytes to joints which lack a vascular basement membrane or to entheses. Bacterial antigens that reach joints/entheses are taken up by antigen presenting cells through Toll-like receptors. Antigen presenting cells with these bacterial fragments can stimulate the adaptive immune system leading to inflammation.

Answer 90

The arthritogenic response might involve specific microbial peptides that bind to HLA-B27 and then are presented in a unique manner to CD8+ (cytotoxic) T cells resulting in disease.

Answer 91

The induction of autoreactivity to self-antigens might develop as a result of “molecular mimicry” between sequences or epitopes on the infecting organism or antigen and a portion of the HLA-B27 molecule or other self-peptides.

Answer 92

HLA-B27 heavy chains can form stable homodimers with no associated β-2 microglobulin on the cell surface. These homodimers can trigger direct activation of natural killer (NK) cells though recognition via killer cell immunoglobulin-like receptors (KIR).

Answer 93

HLA-B27 has a propensity to misfold in the endoplasmic reticulum causing an unfolded protein stress response. This results in the release of inflammatory cytokines such as IL-23 which can activate proinflammatory Th 17 cells. Notably, endoplasmic reticulum aminopeptidase 1 (ERAP-1) is involved in the trimming of peptides for loading MHC molecules (ie HLA-B27) into the endoplasmic reticulum. Abnormal loading may contribute to misfolding of HLA-B27 resulting in an unfolded protein stress response and IL-23 production. ERAP-1 and IL-23 polymorphisms both contribute to the genetic risk of developing AS.

Answer 94

The final common pathway proposed is that the inflammation leads to cartilage injury with release of cartilage components such as aggrecan. T cells have been demonstrated in the joints and entheses of AS patients to react to aggrecan. Thus, aggrecan may cause an autoimmune response resulting in more inflammation. Release of cytokines such as TNF-α and IL-17 can cause inflammation and erosions while TGF-β, bone morphogenic proteins (BMP), and the WNT family of proteins can lead to calcifications of joints and entheses.

Answer 95

Chlamydia causing urethral infections. Salmonella, yersinia, shigella and campylobacter causing intestinal infections. Only certain bacterial subtypes can induce reactive arthritis.

Answer 96

Each of the above bacterial environmental triggers are transported to the joints inside monocytes. Chlamydia reach the joint and remain alive but in a latent form. Yersinia, salmonella, and shigella reach the joint but are dead or in the form of fragments of bacterial lipopolysaccharides.

Answer 97

HLA-B27 is neither necessary nor sufficient to cause a reactive arthritis. Clearly, the majority of HLA-B27 positive individuals never develop disease whereas HLA-B27 negative individuals can develop disease. Other genes must contribute to the risk.

Answer 98

Molecular mimicry – Shigella antigens and Chlamydia antigens resemble HLA-B27. Arthritogenic peptide hypothesis. HLA-B27 free heavy chain theory. HLA-B27 unfolded protein hypothesis

Answer 99

Both CD4 and CD8 T cells participate in the immune response resulting in synovitis and other clinical manifestations. The cytokine profile of the T cells and macrophages/monocytes involved in the synovitis show a low Th-1 cytokine (IFNγ) response and elevated Th-2 cytokine (IL-4, IL-10) response. This may contribute to bacterial persistence. This abnormal cytokine pattern may be partly genetically determined. The bacterial antigenic epitope which T cells are responding to in reactive arthritis is unknown although bacterial heat shock protein 60 (hsp 60) is a leading candidate.

Answer 100

The pathogenesis of the other spondyloarthropathies is less well understood but is felt to be similar to AS and reactive arthritis. The bacterial triggers, however, are unknown.

Answer 101

Tests should be ordered only to enhance the diagnosis of a particular disease in clinical practice. Since the prevalence of HLA-B27 in the Caucasian population is 6-9% and the number of patients with HLA-B27 developing a spondyloarthropathy is small, the positive predictive value of an HLA-B27 test is exceedingly low. (Close attention to the clinical manifestations of the disease entities is paramount!). Occasionally a young male with chronic back pain but with normal X‑rays or a female with possible reactive arthritis may present a difficult diagnostic challenge. In this setting an HLA-B27 test could help in clarifying whether a spondyloarthropathy is more probable but would not definitively rule it in or out.

Answer 102

In AS, specific back exercises and good posture should be emphasized; sleep with either no pillow or a small pillow. Smoking should be avoided in AS patients as they can lose chest wall function secondary to the disease process. Nonsteroidal anti-inflammatory agents are usually the first drugs used for spondyloarthropathies. The indole derivatives such as indomethacin or tolmetin are usually used first. Steroid injections into the peripheral joints may be of benefit. Sulfasalazine has been useful in some cases of peripheral arthritis. Spondyloarthropathy patients (AS, reactive arthritis, psoriatic) who have refractory peripheral arthritis may benefit from methotrexate. Tetracycline early in the course of chlamydial-induced reactive arthritis may ameliorate the course of the arthritis. In cases of established arthritis, a three-month course of tetracycline or erythromycin may be beneficial, although usually it is not. It is unclear if a three-month course of antibiotics (quinolone) in reactive arthritis secondary to enteric pathogens (Shigella, Salmonella, etc.) is beneficial, although usually it is not. For patients with sacroiliitis, spondylitis, peripheral arthritis, and/or enthesitis who failed standard therapy, anti-TNF biologic agents have been very effective therapies. Unfortunately, these agents do not stop the progression of bony erosions or the formation of syndesmophytes.

Answer 103

Sacroiliitis and spondylitis. Enthesitis which is the hallmark of the disease. Peripheral arthritis tends to involve large joints in an asymmetric distribution. Mucocutaneous lesions and ophthalmologic disease are characteristic and common. Genitourinary and gastrointestinal involvement is common. Oftentimes infections of these mucosal surfaces trigger the reactive arthritis. Association with HLA-B27 causes disease to run within families. Negative rheumatoid factor and antinuclear antibodies.

Answer 104

The HLA-B27 transgenic rat has provided valuable insight into the pathophysiology of the axial arthropathies. An environmental trigger is probably necessary for the diseases to develop. HLA-B27 is important in the pathogenesis. T cells are critical to the pathogenesis. Cytokine response may be abnormal allowing for persistence of bacterial products in the joint (Th-2 profile).

Answer 105

Sulfasalazine is used to decrease bowel inflammation in AS and inflammatory bowel disease which leads to improvement in peripheral arthritis. Tetracycline is used in reactive arthritis due to Chlamydia to eradicate persisting latent organisms causing ongoing inflammation. Anti-TNF biologic agents are used for severe and resistant cases because excess amounts of TNF-α has been demonstrated in the joints and entheses, and drive the inflammation. Anti-IL-17 therapies may hold promise.

Answer 106

Autoimmunity is defined as the generation of an immune response directed against self. An autoimmune response results in the body's attempt to remove or destroy self-antigens which it recognizes erroneously as foreign. The result is an immune response directed against self-causing destruction of normal tissues. Clinically, autoimmunity can be divided into two categories, organ specific and systemic autoimmunity.

Answer 107

is defined as an immune response directed against a single autoantigen or a restricted group of autoantigens within a given organ. The result is autoimmune destruction of only those organs expressing the relevant autoantigens. Examples of organ-specific autoimmunity include myasthenia gravis (antibodies to acetylcholine receptors), Goodpasture's syndrome (antibodies to basement membrane type IV collagen of the kidney and lung), autoimmune thyroiditis, and type I diabetes mellitus.

Answer 108

is defined as an immune response against multiple autoantigens rather than to autoantigens of a given organ. The resulting disease affects multiple organs both on the basis of circulating immune complexes and direct immune attack against organs. The prototype systemic autoimmune disease is systemic lupus erythematosus (SLE). Many of the rheumatic diseases have features of systemic autoimmunity, including Sjögren's syndrome and mixed connective tissue disease. Other rheumatic diseases are felt to be autoimmune in origin and have features of systemic autoimmune disease although they may focus on specific organs. Examples of this include polymyositis (muscle) and rheumatoid arthritis (synovium of the joints).

Answer 109

SLE is a chronic, systemic autoimmune disease which affects multiple organ systems including the skin, joints, serosal surfaces (pleura and pericardium), kidneys, central nervous system, lungs, and hematologic system. For most of the disease manifestations of SLE, antibody-mediated effector mechanisms appear to be operative. Organ damage can result from either type II mediated immunologic damage (direct antibody binding to specific cells or tissues), or type III mediated immunologic damage (formation of immune complexes).

Answer 110

SLE is a chronic, systemic autoimmune disease which affects multiple organ systems including the skin, joints, serosal surfaces (pleura and pericardium), kidneys, central nervous system, lungs and hematologic system. There is no specific marker which is diagnostic for the disease, and in reality SLE is a syndrome composed of multiple manifestations. Criteria for disease classification include 1. Malar rash, 2. Discoid rash, 3. Photosensitivity, 4. Oral ulcers, 5. Arthritis, 6. Serositis, 7. Renal involvement, 8. Central nervous system involvement (seizures or psychosis), 9. Hematologic disorders (hemolytic anemia, leukopenia, lymphopenia, thrombocytopenia), 10. Immunologic disorders (antibodies to native DNA, Smith antigen, anticardiolipin IgG or IgM, lupus anticoagulant, or a false-positive serologic test for syphilis), and 11. Antinuclear antibody (ANA). Positivity for at least 4 of the 11 criteria allows classification of a patient having SLE. The clinical manifestations of SLE may vary over time within a given patient and may vary dramatically from patient to patient. Thus, one patient may have predominantly renal disease whereas another may have predominantly hematologic and/or CNS disease. Specific clinical features are described in detail in the pathology section.

Answer 111

SLE is a disease primarily of the young women with a female to male ratio of 9:1, with onset after puberty reaching a peak during the childbearing years. The prevalence varies in different populations and varies from 0.5 to 5 per thousand and is more common in certain ethnic groups, particularly African Americans, Asians, and Hispanic Americans.

Answer 112

Although the etiology of SLE is unclear, there is overwhelming evidence for a genetic predisposition. Increased incidence of SLE among relatives of patients. (relative risk 2-3). Twin studies showing a concordance rate of about 35% in monozygotic twins compared to ≈ 2% in dizygotic twins. Association of SLE with HLA-DR3; and C4A null alleles (strongest association). Other genes associated with innate immunity and interferon alpha pathways may predispose to developing SLE. Interferon (IFN)-α and IFN-β upregulate the expression of a variety of genes in lymphocytes. This “IFN signature” of gene expression is more prevalent in patients with active SLE. In the murine models of SLE, multiple gene loci appear to be involved in a complex fashion. In the NZB/NZW mouse model of lupus, one involved locus is linked to the MHC and another to an IFN-inducible gene. Other involved loci are being studied.

Answer 113

The expression of disease manifestations can be greatly affected by environmental factors. Sex hormones: There is a markedly increased incidence of SLE in women of childbearing age. The female to male ratio is approximately 9 to 1. This strongly suggests that sex hormones affect the expression of disease. The disease-accelerating effect of estrogens and the protective effect of androgens have been elegantly demonstrated in the NZB/NZW murine lupus model. Sun exposure: SLE skin disease can be exacerbated by exposure to U.V. light (photosensitivity). Ultraviolet light may stimulate keratinocytes to express more snRNAs on their cell surface and secrete more inflammatory cytokines resulting in B cell activation with antibody production. Patients can sometimes have marked systemic or generalized flares of disease after excessive sun exposure.

Answer 114

For most of the disease manifestations of SLE, antibody-mediated effector mechanisms appear to be important. Organ damage can result from either type II mediated immunologic damage (direct antibody binding to specific cells or tissues), or type III mediated immunologic damage (formation of immune complexes). The pathology of disease reflects the following mechanisms: type II hypersensitivity, type III hypersensitivity, and anti-nuclear antibodies

Answer 115

includes hemolytic anemia, anti-phospholipid antibodies, and CNS manifestations

Answer 116

(Coombs' positive). Although most patients with SLE have a low red blood cell count (anemia of chronic inflammation), a minority (≈ 10%) manifest clinically significant red blood cell destruction (hemolysis). These patients exhibit a positive direct Coombs' test, and most can be demonstrated to have both antibody (IgG) and complement on the red cell surface. The mechanism of red cell destruction is identical to that in other forms of autoimmune hemolytic anemia; the IgG and complement bound to the RBC results in sequestration and destruction of these cells in the reticuloendothelial system of the liver and spleen (via Fc and complement receptors).

Answer 117

(the lupus anticoagulant): Some patients with SLE produce antibodies to phospholipids, which can block prothrombin activation in the clotting cascade. This results in an elevated partial thromboplastin test (PTT), suggesting a clotting factor abnormality. However, this "anticoagulant" is associated with increased clotting. The exact mechanism by which antiphospholipid antibodies (aPL) cause clotting is still unknown. In animal models of experimentally-induced antiphospholipid syndrome, aPL appear to play a pathogenic role. Another serum cofactor (β2 –glycoprotein I), a powerful natural anticoagulant, is necessary to enhance the binding of aPL to phospholipids. In patients with autoimmune disorders, aPL are directed against a complex antigen of which β2 –glycoprotein I is an essential component. It is possible that β2 –glycoprotein I binds to platelets forming the epitope for aPL binding with resultant platelet aggregation and thrombotic events. In addition, several processes such as infection, trauma (including surgical procedures), pregnancy, withdrawal of anticoagulation, and drug administration (oral contraceptives, estrogens, and sulfur containing compounds) are additional risk factors or triggers for thrombosis in patients with aPL. Any process that causes endothelial cell activation (infection, trauma) could result in the binding of aPL to β2 –glycoprotein I. Antiphospholipid antibodies could neutralize the anticoagulant effects of β2 –glycoprotein I resulting in thrombosis. In mouse pregnancy experiments, complement activation, mediated by aPL binding to endothelial cell surfaces, may cause damage to endothelial cells resulting in thrombosis and fetal wastage. Thus, the beneficial effect of heparin in treating and preventing thrombosis in the aPL syndrome my in part act through its inhibition of complement activation.

Answer 118

Neuropsychiatric manifestations (depression, cognitive dysfunction, psychosis, organic brain syndromes, and seizures) occur in up to 66% of patients with SLE. Autoantibodies that bind to neurons (anti-neuronal antibodies) may account for some of these CNS manifestations. Other forms of CNS involvement such as stroke and movement disorders (chorea) are due to vascular ischemia from vasculitis, thrombosis due to aPL, or embolic disease.

Answer 119

Lupus nephritis. The most important determinant of prognosis in SLE is the presence and degree of kidney involvement (especially glomerular involvement). Nearly all patients with SLE will have abnormalities on renal biopsy, and over 50% will have clinical evidence of renal disease. However, the extent of renal damage and the clinical course vary considerably. In almost all SLE patients, histologic evaluation reveals immune complex and complement deposition in the glomerulus, as demonstrated by electron microscopy and immunofluorescence microscopy. This is the result of deposition of circulating immune complexes or binding of antibodies directly to glomerular antigens.

Answer 120

may be involved in the SLE pathogenesis. Once complexes are formed or deposited in the glomerulus, complement activation is important for pathologic damage to occur. Thus, complement-fixing anti-DNA antibodies are important causes of damage in lupus glomerulonephritis.

Answer 121

Antinuclear antibodies are the hallmark of abnormal antibody production in SLE. Over 95% of patients with SLE have evidence of excessive ANA production, as evidenced by elevated serum levels. Antibodies are directed to multiple nuclear antigens, including DNA, RNA, histone, and others. This antibody response is a classic example of systemic (as opposed to organ specific) autoimmunity. ANAs are not specific for SLE as they can occur in other autoimmune disorders.

Answer 122

ANA are detected in most laboratories by an indirect immunofluorescence assay. The substrate (human epithelial cell tumor line) is "fixed" onto a slide and thus is permeable to antibodies. Diluted serum from a patient is then placed onto the tissue. After washing, any antibodies that have bound to nuclei are detected by adding a fluorescein-conjugated anti-human Ig antisera.

Answer 123

The above test will detect most antibodies to nuclear antigens. Laboratory tests have also been developed to measure ANA with particular specificities. Some of these antibodies are now routinely measured by radioimmunoassay (RIA), enzyme-linked immunoassay (ELISA), and immunoprecipitation.

Answer 124

Antibodies to double-stranded or native DNA (anti-dsDNA) are highly specific for SLE. As discussed above, they appear to be especially important in renal disease. Antibodies against single stranded or denatured DNA have much less specificity for SLE.

Answer 125

These antibodies are frequently present in both SLE and in drug-induced lupus.

Answer 126

Some of these antibodies have been associated with specific disease manifestations. For example, antibodies to SS-A antigen have been associated with neonatal lupus as well as photosensitivity. The importance of ANA in tissue damage other than those that form immune complexes (i.e. anti-dsDNA) is presently unclear.

Answer 127

The fundamental defect in autoimmunity is the misdirected recognition of self as foreign, resulting in an autoimmune response. The etiology of autoimmune disease is not known, and probably autoimmunity can arise by several pathways. Environmental exposures in a genetically susceptible individual result in activation of both the innate and adaptive immune responses with resultant loss of tolerance to self-antigens. The misdirected recognition of self as foreign results in an autoimmune response. Normal individuals possess autoreactive B cells which continuously produce low levels of autoantibodies. These autoantibodies are usually IgM and bind with low avidity to their self-antigens with resultant clearance though receptor binding by phagocytes. T cell help is required to stimulate these cells and induce somatic mutation to allow them to produce high avidity pathogenic IgG antibodies. Central (deletion) and peripheral mechanisms (anergy; suppression by regulatory molecules or cells; or receptor editing) that remove or suppress self-reactive immature B cells are defective in SLE. Autoantibodies can be present for years before the clinical onset of disease. In SLE, the clearance of immune complexes, apoptotic cells, and cell debris also appears to be defective resulting in the persistence of antigen and immune complexes. Additional theories have been put forth to explain autoimmunity including polyclonal B cell activation, molecular mimicry, illicit help, sequestered antigens, and immunodeficiency

Answer 128

The innate immune system can be activated by nucleic acids. Plasmacytoid dendritic cells are activated by the binding of DNA-containing immune complexes or RNA/protein-containing immune complexes by TLR-9 and TLR-7, respectively. This results in the activation of transcription factor NFκβ and the production of type I interferons (IFN) by dendritic cells. Type I interferons have multiple proinflammatory functions. Of interest, hydroxychloroquine, an antimalarial drug used to treat SLE, may block TLR 7 and 9 signaling. Neutrophils also appear to be activated in SLE through the FcR-mediated uptake of circulating autoantibody/nucleic acid immune complexes. Activated neutrophils die in a unique process called NETosis where they extrude large amounts of DNA in the form of web-like structures called neutrophil extracellular traps (NETs). NETs are associated with antimicrobial peptides and permit bacterial trapping and killing. NET-DNA would then be available for dendritic cell activation and IFN production.

Answer 129

The adaptive immune system is also activated in SLE. As cells break down, certain antigens (nuclear and self-peptides) are processed into peptides by antigen-presenting cells (APCs). A peptide-MHC complex forms and results in the activation and clonal expansion of CD4+ autoreactive T cells. These cells through cytokine release cause autoreactive B cells to become activated and differentiate into plasma cells that make antibodies to select nuclear and self-antigens. Survival of autoreactive B cells is also supported through the increased production of B cell activating factor (BAFF, also known as B lymphocyte stimulator or BLyS) in SLE by primarily neutrophils and monocyte/macrophages. Belimumab, a human monoclonal antibody against BAFF/BLyS, is approved for the treatment of SLE. The combined T and B cell abnormalities in SLE result in the production of pathogenic autoantibodies.

Answer 130

Since we all possess autoreactive B cells, agents such as LPS (endotoxin) or unknown factors may polyclonally stimulate B cells resulting in increased production of all antibodies.

Answer 131

An exogenous antigen with molecular similarities to autoantigens may be introduced to the immune system, resulting in an appropriate immune response which then cross-reacts with self-antigens. The classical example of this is rheumatic heart disease, but this model may also apply to rheumatoid arthritis and other autoimmune diseases.

Answer 132

A foreign antigen may be combined with an autoantigen such that the foreign antigen may be processed and presented to the T cell, thereby allowing the T cell to provide help. Because of the autoantigen component, the combined antigen may also be capable of binding directly to B cells and receiving the "illicit" T cell help provided by the foreign antigen.

Answer 133

This hypothesis states that certain autoantigens are kept in sequestered compartments such as in the eye, and are never seen by the immune system. If tissue damage occurs, these antigens may be released, thereby eliciting an immune response. Although this mechanism may apply in autoimmune eye disease, such as some forms of uveitis, most autoantigens appear to be ubiquitous and this mechanism probably does not apply to most forms of autoimmunity.

Answer 134

Individuals with complement deficiencies of C1q, C4 and C2 have a very high incidence of an SLE-like disease. Fc receptor deficiencies are also associated with SLE. Some individuals believe that SLE is a manifestation of immunodeficiency leading to ineffective clearance of immune complexes and that loss of tolerance is also related.

Answer 135

The best study systems to investigate the cellular immune mechanisms involved in ANA production have been murine models of lupus. SLE patients are nearly always studied after they present with clinical disease. Thus, immunologic abnormalities that are "causal" are difficult to separate from those that are secondary to the disease. Some inbred strains of mice, including the New Zealand Black x New Zealand White hybrid (NZB/NZW F1), MRL-lpr/lpr, and BXSB strains, spontaneously develop a syndrome characterized by high levels of ANA and a fatal lupus-like glomerulonephritis. Lupus-like disease and ANA production can also be induced in certain strains by creating graft-versus-host disease. Although multiple autoantibodies (including ANA) are produced in SLE and murine models of SLE, antibodies are not produced to all autoantigens. Therefore, autoantibody production does not appear to be simply due to polyclonal activation of autoreactive B cells. There is also evidence that T cell help is necessary for the production of pathogenic antibodies and clinical disease. In the MRL-lpr/lpr mouse, a defect in the induction of lymphocyte apoptosis by Fas results in the development of SLE-like disease. Altered apoptosis in human SLE has been demonstrated.

Answer 136

Treatment of SLE is directed at decreasing exposure to disease triggers (sun blocks), decreasing the inflammatory response [NSAIDs, and corticosteroids (both topical and systemic)], and decreasing the cellular/humoral immune responses (anti-malarials; immunosuppressive drugs including azathioprine, mycophelolate, and cyclophosphamide; and rituximab). Another anti-B cell therapy, belimumab (monoclonal antibody that inhibits BAFF/BLyS), is approved for the treatment of SLE. Other treatment modalities such as intravenous immunoglobulin (IVIG) have been shown to work in certain autoimmune disease states but there is no clear mechanism for their efficacy.

Answer 137

SLE is a multigenic disease with a major MHC contribution. The pathophysiology of SLE involves both Type II and III antibody-mediated mechanisms. Both the innate and adaptive immune systems are involved in the misdirected recognition of self as foreign in SLE. SLE flares can be triggered by environmental exposures such as the sun. The kidney is a major target organ in SLE, and the extent of damage is directly correlated with overall patient outcomes. The presence of high-titer ANA in SLE patients is a manifestation of loss of tolerance to self-antigen as well as a useful diagnostic marker.

rheumatology Flashcards

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