Mono and Poly Arthropathies PDF

Mono and Polyarthropathies Brian Martin, Ph.D. Thomas Rosenzweig, M.D. Near Weber Canyon, UT 1  Session Objectives Understand that osteoarthritis (degenerative joint dise...

Mono and Polyarthropathies Brian Martin, Ph.D. Thomas Rosenzweig, M.D. Near Weber Canyon, UT 1  Session Objectives Understand that osteoarthritis (degenerative joint disease) is a degenerative process of articular cartilage in which matrix breakdown exceeds synthesis. Describe how rheumatoid arthritis is caused by a cellular and humoral immune response against self-antigens, particularly citrullinated proteins. Recognize that the seronegative spondyloarthropathies are a heterogeneous group of likely autoimmune arthritides that preferentially involve the sacroiliac and vertebral joints and are associated with HLA-B27. Understand that gout and pseudogout result from inflammatory responses triggered by precipitation of urate or calcium pyrophosphate, respectively. BKM 2  Reference Robbins Basic Pathology, Eleventh Edition. Chapter 5, Chapter 19, (Joints, Arthritis discussion) BKM 3  Introduction Joints allow movement while providing mechanical stability. They are classified as solid (nonsynovial) and cavitated (synovial) joints. Solid joints (synarthroses) provide structural integrity and allow only minimal movement. Synovial joints have a joint space, allowing for a wide range of motion. Synovial membranes enclose synovial joints. BKM 4  Introduction Synovial membranes are lined by type A synoviocytes, specialized macrophages with phagocytic activity, and type B synoviocytes, similar to fibroblasts, that synthesize hyaluronic acid and various proteins.* Synovial fluid is a plasma filtrate containing hyaluronic acid that acts as a viscous lubricant, and provides nutrition for the articular cartilage. BKM 5  Introduction Hyaline cartilage serves as an elastic shock absorber and wear-resistant surface. It is composed of water, type II collagen, proteoglycans, and chondrocytes. The collagen resists tensile stresses, and transmits vertical loads. The water and proteoglycans resist compression and limit friction. The chondrocytes synthesize the ECM, and enzymatically digest it.* BKM 6  Osteoarthritis BKM 7  Osteoarthritis Osteoarthritis (OA), also called degenerative joint disease, is characterized by degeneration of cartilage that results in structural and functional failure of synovial joints. BKM 8  Osteoarthritis Osteoarthritis is the most common disease of joints. It usually appears insidiously, without apparent initiating cause, as an aging phenomenon (primary osteoarthritis).* The prevalence of osteoarthritis increases exponentially beyond the age of 50. About 40% of people older than 70 are affected. In about 5% of cases, OA appears in younger individuals with some predisposing condition, such as joint deformity, a previous joint injury, or an underlying systemic disease that places joints at risk (secondary osteoarthritis). BKM 9  Osteoarthritis Pathogenesis The lesions of OA stem from degeneration of the articular cartilage and its disordered repair. Repeated biomechanical stress and genetic factors may predispose to chondrocyte injury, which leads to alteration of the extracellular matrix… BKM 10  Osteoarthritis Pathogenesis Chondrocytes proliferate, synthesize and secrete proteoglycans, but degradation exceeds synthesis, and the composition of proteoglycans changes as the disease progresses. Matrix metalloproteinases (MMPs) secreted by chondrocytes degrade the type II collagen network.* BKM 11  Osteoarthritis Pathogenesis Chondrocyte loss and a severely degraded extra- cellular matrix mark the late stage of the disease. BKM 12  Osteoarthritis Morphology In the early stages of OA, the normally horizontally arranged collagen type II fibers are cleaved, yielding fissures and clefts at the articular surface. BKM 13  Osteoarthritis Morphology Eventually, full-thickness portions of the cartilage are sloughed. The dislodged pieces of cartilage and subchondral bone tumble into the joint, forming loose bodies (joint mice). The exposed subchondral bone plate becomes the new articular surface, and friction with the opposing surface rubs the exposed bone, giving it the appearance of polished ivory (bone eburnation). BKM 14  Osteoarthritis Morphology Small fractures through the articulating bone are common, and the fracture gaps allow synovial fluid to be forced into the subchondral regions in a one-way, ball valve-like mechanism forming fibrous-walled cysts. BKM 15  Osteoarthritis Morphology Outgrowths (osteophytes) develop at the margins of the articular surface and are capped by cartilage that gradually ossifies. BKM 16  Osteoarthritis Clinical Course The joints commonly involved include the hips, knees, lower lumbar and cervical vertebrae, proximal and distal interphalangeal joints of the fingers, first carpometacarpal joints, and first tarsometatarsal joints. BKM 17  Osteoarthritis Clinical Course Heberden nodes, prominent osteophytes at the distal interphalangeal joints, are common in women. BKM 18  Osteoarthritis Clinical Course Primary osteoarthritis usually presents in patients that are in their 50s. If a young person has significant manifestations of osteoarthritis, a search for some underlying cause should be made. Characteristic symptoms include joint pain that worsens with use, morning stiffness, crepitus, and limitation of range of movement. Impingement on spinal foramina by osteophytes results in cervical and lumbar nerve root compression and radicular pain, muscle spasms, muscle atrophy, and neurologic deficits. Therapy includes management of pain, NSAIDs to reduce inflammation, intra-articular corticosteroids, activity modification, and, for severe cases, arthroplasty. BKM 19  Rheumatoid Arthritis BKM 20  Rheumatoid Arthritis Rheumatoid arthritis (RA) is a chronic inflammatory disorder of autoimmune origin that principally attacks the joints, producing a non-suppurative, proliferative and inflammatory synovitis. It often progresses to the destruction of the articular cartilage and, in some cases ankylosis (adhesion) of the joints. Extra-articular lesions may occur in the skin, heart, blood vessels, and lungs. The prevalence in the United States is about 1%, and it is three times more common in women than in men. The peak incidence is in the third through fifth decades of life. BKM 21  Rheumatoid Arthritis Pathogenesis As in other autoimmune diseases, genetic predisposition and environmental factors contribute to rheumatoid arthritis… BKM 22  Rheumatoid Arthritis Pathogenesis It is estimated that 50% of the risk of developing RA is related to inherited genetic susceptibility. It is associated with HLA class II locus. Other genetic associations have been reported. BKM 23  Rheumatoid Arthritis Pathogenesis Various environmental factors whose antigens promote autoimmunity have been proposed. Infection (including periodontitis) and smoking may promote citrullination of self-proteins, creating new epitopes that trigger autoimmune reactions. BKM 24  Rheumatoid Arthritis Pathogenesis CD4 + T helper cells may initiate the autoimmune response in RA by reacting with an arthritogen. The T cells produce cytokines that stimulate other inflammatory cells to effect tissue injury: IFN-γ from TH1 cells activates macrophages, and synovial cells. IL-17 from TH17 cells recruits neutrophils and monocytes. RANKL expressed on activated T cells stimulates osteoclasts and bone resorption. TNF and IL-1 from macrophages stimulate synovial cells to secrete proteases that destroy hyaline cartilage.* BKM 25 BKM 26  Rheumatoid Arthritis Pathogenesis The synovium of RA contains plasma cells that produce antibodies, some of which may be against self-antigens. Many of the serum autoantibodies are specific for citrullinated peptides in which arginine residues are post-translationally converted to citrulline. Complexes of antibodies with citrullinated proteins deposit in the joints. BKM 27  Rheumatoid Arthritis Pathogenesis About 80% of patients have serum autoantibodies that bind to the Fc portions of their own IgG. These autoantibodies are called rheumatoid factor (RF) and may also deposit in joints as ICs. Rheumatoid factor is not entirely sensitive or specific for rheumatoid arthritis. BKM 28  Rheumatoid Arthritis Pathogenesis The inflammation localizes to the joint, recruiting macrophages and triggering activation and/or proliferation of synovial cells, chondrocytes, and fibroblasts. The production of proteolytic enzymes and cytokines contributes to the destruction of cartilage and bone. BKM 29  Rheumatoid Arthritis Morphology RA is typically a symmetric arthritis principally affecting the small joints of the hands and feet. BKM 30  Rheumatoid Arthritis Morphology The characteristic histologic features include (1) synovial cell hyperplasia and proliferation (2) dense inflammatory infiltrates of CD4+ helper T cells, B cells, plasma cells, and macrophages (3) increased vascularity (4) neutrophils and aggregates of organizing fibrin on the synovial and joint surfaces; (5) osteoclastic activity in underlying bone. These changes produce a pannus: a mass of edematous synovium, inflammatory cells, granulation BKM tissue, and fibroblasts that grows over the articular cartilage and causes its erosion. 31  Rheumatoid Arthritis Morphology In advanced untreated cases, the pannus can bridge the bones to form a fibrous ankylosis, which may later ossify as a bony ankylosis. BKM 32  Rheumatoid Arthritis Morphology Rheumatoid nodules are an infrequent manifestation of RA and typically occur in subcutaneous tissue including the forearm, elbows, occiput, and lumbosacral area.* They resemble necrotizing granulomas. BKM 33  Rheumatoid Arthritis Clinical Course Rheumatoid arthritis can be distinguished from other forms of polyarticular inflammatory arthritis by the presence of anticitrullinated protein antibodies, and by characteristic radiographic findings. In about half of patients, rheumatoid arthritis begins slowly and insidiously with malaise, fatigue, and generalized musculoskeletal pain. After several weeks to months, the joints become involved. 34  Rheumatoid Arthritis Clinical Course The pattern of joint involvement is generally symmetrical, and the hands and feet, wrists, ankles, elbows, and knees are most commonly affected. The metacarpophalangeal and proximal interphalangeal joints are frequently involved. Inflammation in the tendons, ligaments, and occasionally the adjacent skeletal muscle frequently accompanies the arthritis, and produces the characteristic ulnar deviation of the fingers, and flexion-hyperextension of the fingers (swan-neck deformity, boutonnière deformity). 35  Rheumatoid Arthritis Clinical Course Radiographic findings are joint effusions and juxtaarticular osteopenia with erosions, narrowing of the joint space and loss of articular cartilage. 36 37  Rheumatoid Arthritis Clinical Course Involved joints are swollen, warm, painful, and particularly stiff when rising in the morning or following inactivity. The typical patient has progressive joint enlargement and decreased range of motion pursuing a chronic waxing and waning course.* The treatment for rheumatoid arthritis consists of corticosteroids, other immunosuppressants such as methotrexate, and TNF antagonists.** 38  Juvenile Idiopathic Arthritis Juvenile idiopathic arthritis (JIA) is a heterogeneous group of disorders of unknown cause that present with arthritis before age 16 and persist for at least 6 weeks. In contrast to RA, in JIA: (1) oligoarthritis is more common, (2) systemic disease is more frequent, (3) large joints are affected more often than small joints, (4) rheumatoid nodules and rheumatoid factor are usually absent, and (5) anti-nuclear antibody seropositivity is common. The pathogenesis is unknown but similar to adult rheumatoid arthritis. Risk factors include HLA and PTPN22 variants. Also, like adult rheumatoid arthritis, damage in juvenile idiopathic arthritis appears to be caused by T H 1 and T H 17 cells and cytokines produced by these and other inflammatory cells. Treatment is similar to adult RA with some success in using an IL- 6 receptor antibody in the systemic form. Long-term prognosis of JIA is very variable.* 39  Seronegative Spondyloarthropathies 40  Seronegative Spondyloarthropathies The spondyloarthropathies are a heterogeneous group of disorders that share the following features: Absence of rheumatoid factor Pathologic changes in the ligamentous attachments rather than synovium Involvement of sacroiliac joints, and/or other joints Association with HLA-B27 Bony proliferation leading to ankylosis (fusion of joints) 41  Seronegative Spondyloarthropathies Pathogenesis The manifestations are immune mediated and are triggered by a T cell response presumably directed against an undefined antigen, possibly infectious, that may cross - react with antigens expressed on cells of the musculoskeletal system. 42  Seronegative Spondyloarthropathies Ankylosing spondylitis, the prototypical spondyloarthritis, causes destruction of articular cartilage and bony ankylosis, especially of the sacroiliac and vertebral apophyseal joints. The disease becomes symptomatic in the second and third decades of life as lower back pain and spinal immobility. Involvement of peripheral joints, such as the hips, knees, and shoulders, occurs in at least one-third of affected individuals. Approximately 90% of patients are HLA-B27 positive, but how the HLA-B27 allele contributes to the disease is not known. An anti-IL-17 antibody has shown some worth in treating ankylosing spondylitis. 43  Ankylosing Spondylitis Bamboo spine in ankylosing spondylitis.* 44  Seronegative Spondyloarthropathies Reactive arthritis is defined as mono- or oligoarticular arthritis arising days to weeks after an enteric (e.g., Shigella, Salmonella, Yersinia, Campylobacter, and Clostridioides difficile) or genitourinary (e.g., Chlamydia) infection. A subset of patients present with a triad of symptoms: arthritis, urethritis or cervicitis, and conjunctivitis. Culture of joint fluid is negative for pathogens. Most affected individuals are young adults, and HLA-B27 positivity is common. The disease is probably caused by an autoimmune reaction initiated by the infection. 45  Reactive Arthritis Within several weeks of the initial infection, patients experience low back pain. The ankles, knees, and feet are affected most often, frequently in an asymmetric pattern. Patients with severe chronic disease have involvement of the spine that is indistinguishable from ankylosing spondylitis. 46  Seronegative Spondyloarthropathies Psoriatic arthritis is a chronic inflammatory arthropathy associated with psoriasis that affects peripheral and axial joints and ligaments and tendons. It develops in over 10% of the psoriatic population. Susceptibility to the disease is genetically determined and related to HLA-B27 and HLA-Cw6. Symptoms manifest between the ages of 30 and 50. 47  Psoriatic Arthritis The sacroiliac joints are involved in 20% of pts, but this is predominantly a peripheral arthritis of the hands and feet. The distal interphalangeal joints of the hands and feet are first affected in an asymmetric distribution in over 50% of patients, producing the characteristic “pencil in cup” deformity. It is usually not as severe as rheumatoid arthritis, remissions are more frequent, and joint destruction is less frequent. 48 Gout 49  Gout Gout is marked by transient attacks of acute arthritis initiated by monosodium urate (MSU) crystals deposited in and around joints. There are primary or secondary forms. In the primary form (90% of cases), gout is the major manifestation of the disease, and the cause is usually unknown. 50  Gout Pathogenesis Hyperuricemia (plasma urate level over 6.8 mg/dL) is necessary, but not sufficient, for the development of gout. Uric acid metabolism can be summarized as follows: Synthesis Uric acid is the end product of purine catabolism. * Excretion Uric acid is filtered by the glomerulus and resorbed by the proximal tubule of the kidney. A small fraction of the resorbed uric acid is secreted by the distal nephron and excreted in the urine. 51  Gout Pathogenesis In primary gout, elevated uric acid most commonly results from reduced excretion, the basis of which is unknown in most patients.* Secondary gout can be caused by increased production, e.g., rapid cell lysis during chemotherapy for leukemia, so-called tumor lysis syndrome, or decreased excretion, e.g., chronic renal disease.** 52  Gout Pathogenesis The inflammation in gout is triggered by precipitation of urate crystals in the joints, stimulating the production of cytokines that recruit leukocytes. The result is an acute arthritis, which typically remits spontaneously in days to weeks. 53  Gout Pathogenesis Repeated attacks of acute arthritis lead to the formation of tophi, aggregates of urate crystals and inflammatory tissue in the inflamed synovial membranes and periarticular tissue. Severe damage to the cartilage develops, and the function of the joints is compromised. 54  Gout Pathogenesis About 10% of pts with hyperuricemia develop gout. Thus, other factors contribute to symptomatic gout: Age of the individual and duration of the hyperuricemia.* Genetic predisposition Alcohol consumption Obesity Drugs (e.g., thiazides) that reduce excretion of urate. 55  Gout Morphology The morphologic changes in gout are: 1. Acute arthritis 2. Chronic tophaceous arthritis 3. Tophi in various sites 4. Gouty nephropathy.* 56  Gout Morphology Acute arthritis is characterized by a dense inflammatory infiltrate in the synovium and synovial fluid. Urate crystals are frequently found in the cytoplasm of the neutrophils and in small clusters in the synovium. They are long, slender, and needle-shaped, and are negatively birefringent.* The synovium is edematous, congested, and contains scattered lymphocytes, plasma cells, and macrophages. 57  Gout Morphology Chronic tophaceous arthritis evolves from the repetitive precipitation of urate crystals during acute attacks. The crystals encrust the articular surface and form visible chalky deposits in the synovium. The synovium becomes hyperplastic, fibrotic, and thickened by inflammatory cells and forms a pannus that destroys the underlying cartilage. 58  Gout Morphology Tophi in the articular cartilage, ligaments, tendons, and bursae are pathognomonic of gout.* They are formed by large aggregations of urate crystals surrounded by a foreign body giant cell reaction. 59  Gout Clinical Course Gout is associated with male sex, obesity, metabolic syndrome, excess alchohol intake, renal failure, and age over 30 years. Four clinical stages are recognized: Asymptomatic hyperuricemia appears around puberty in men and after menopause in women. Acute arthritis presents after several years as sudden onset excruciating joint pain, localized hyperemia, and warmth.* Most first attacks are monoarticular 50% occur in the first metatarsophalangeal joint. Asymptomatic intercritical period: Resolution of acute arthritis leads to a symptom - free interval.** Chronic tophaceous gout develops on average about 12 yrs after the initial acute attack. 60  Gout Clinical Course Treatment of gout aims at lifestyle modification, and medication to reduce symptoms (e.g., NSAIDs) and lower urate levels (e.g., xanthine oxidase inhibitor). 61  Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout) 62  Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout) Calcium pyrophosphate crystal deposition disease (CPPD), AKA pseudogout, usually occurs in individuals over 50 yrs of age and becomes more common with increasing age. The genders and races are equally affected. It is divided into sporadic (idiopathic), hereditary, and secondary types. The autosomal dominant variant is caused by germline mutations in the pyrophosphate transport channel resulting in crystal deposition and arthritis relatively early in life. Various disorders, including previous joint damage, hyperparathyroidism, hemochromatosis, and diabetes mellitus, predispose to the secondary form. 63  Calcium Pyrophosphate Crystal Deposition Disease (Pseudogout) Studies suggest that articular cartilage proteoglycans, which normally inhibit mineralization, are degraded, allowing crystallization around chondrocytes.* 64  Pseudogout Morphology The crystals first develop in the articular cartilage, menisci, and intervertebral discs, and as the deposits enlarge they may rupture and seed the joint. The crystals form chalky, white friable deposits, seen histologically in H&E-sections as oval blue-purple aggregates. Individual crystals are rhomboid, 0.5 to 5 µm in greatest dimension, and are positively birefringent. Inflammation is usually milder than in gout. 65  Pseudogout Clinical Course Pseudogout is frequently asymptomatic. It may also produce acute, subacute, or chronic arthritis. The joint involvement may last from several days to weeks, and may be monoarticular or polyarticular; the knees, followed by the wrists, elbows, shoulders, and ankles, are most commonly affected. Eventually, approximately 50% of affected individuals experience significant joint damage. Therapy is supportive. There is no known treatment that prevents or slows crystal formation. 66 67 Questions?