BMS150 Rheumatology 1 Week 4 PDF

Path RA, OA, infectious arthropathies BMS 150 Week 4 Instructor: Dr. Albert Iarz, ND, RMT Objectives Discuss the pathophysiology, epidemiology, clinical features, diagnosis and prognosis of the following diseases: Rheumatoid arthritis Juvenile Rheumatoid arthritis Discuss the pathophysio...

Path RA, OA, infectious arthropathies BMS 150 Week 4 Instructor: Dr. Albert Iarz, ND, RMT Objectives Discuss the pathophysiology, epidemiology, clinical features, diagnosis and prognosis of the following diseases: Rheumatoid arthritis Juvenile Rheumatoid arthritis Discuss the pathophysiology, epidemiology, clinical features, diagnosis and prognosis of the following diseases: Osteoarthritis Infectious arthritides (Lyme disease, TB arthritis, viral arthritis, suppurative arthritis) Rheumatoid Arthritis (RA) - Intro Chronic autoimmune disorder that typically involves inflammation of the synovium of typical joints progressing to articular cartilage destruction. ▪ Pathologic changes mediated by: Inflammatory cytokines Damage to cartilage and bone due to macrophage and neutrophil activity Antibodies against self-antigens ▪ Usually a relapsing-remitting illness Can involve extra-articular manifestations Significant minority of patients exhibit these complications ▪ Prevalence: Common 0.5-1% of the population worldwide 2-3X more common in women RA – Etiology and Pathogenesis Pathogenesis: ▪ FYI - 20 - 50% of the etiology is because of genetic factors ▪ Genes implicated: CTLA-4 HLA DR1: ▪ Associated with increased anti-CCP antibodies and more severe disease PTPN-22: gain-of-function mutation in a tyrosine phosphatase that is hypothesized to result in the abnormal thymic selection of autoreactive T and B cells  RA – Etiology and Pathogenesis Pathogenesis: ▪ Environmental factors: Smoking – increases risk between 1.5 – 3.5X (persists up to 15 years post-cessation) Some infections have been suggested to play a role in the development of RA ▪ Eg. EBV ▪ Difficult to prove RA - Pathophysiology Pathophysiology ▪ CD4+ T-cells released inflammatory mediators that stimulate other inflammatory cells leading to tissue injury Key cytokines involved include: ▪ INF-𝛾 secreted from ____ cells activates macrophages and resident synovial cells ▪ IL-17 from _____cells recruits neutrophils and monocytes RA - Pathophysiology Pathophysiology ▪ CD4+ T-cells released inflammatory mediators that stimulate other inflammatory cells leading to tissue injury Key cytokines involved include: ▪ TNF and IL-1 from macrophages stimulates resident synovial cells to secrete proteases that destroy hyaline cartilage ▪ RANKL expressed on activated T cells (especially Th 17 cells) stimulates bone resorption More coming on RANKL in bone physiology at a (much) later date RA – Pathophysiology cont. Pathophysiology ▪ Joint synovium contains germinal centers with secondary follicles and lots of plasma cells Some of these plasma cells are secreting antibodies that recognize self-antigens ▪ A significant one being anti-CCP (anti-citrullinated peptide) Detected in serum in up to 70% of patients with RA ▪ Another being IgM and IgA auto-antibodies that bind IgG Fc region, collectively referred to as rheumatoid factor Detected in serum in up to 80% of patients with RA Deposited in joints as immune complexes RA – Pathophysiology cont. Pathophysiology: ▪ Citrullinated proteins continued What is citrulline? ▪ Within a protein arginine amino acids can be converted to citrulline Found within many different joint proteins: FYI - Fibrinogen, type II collagen, alpha-enolase, vimentin HLA-DR4 allele is associated with anti-citrulline antibody ▪ Possible that an epitope of a citrullinate protein (FYI – vinculin) mimics an epitope on many microbe and gets presented by the HLA-DR4 molecule. Environmental factors (eg. Smoking) may promote citrullination of self-proteins RA - Pathogenesis In B, a microbial infection sensitizes CD4+ cells that are capable of recognizing self ▪ The microbial antigen resembles the self-antigen ▪ Since an infection triggers PRRs, then the APC expresses costimulatory molecules ! T-cell activation instead of anergy This process is known as molecular mimicry ▪ Thought to be important in the pathophysiology of many autoimmune/ hypersensitivity disorders (rheumatoid arthritis, rheumatic fever for example) Slide 10 RA – big picture What are we missing? ▪ Macrophages are activated by Th17 and Th1 cytokines ▪ They then secrete pro- inflammatory cytokines and pro-repair cytokines that contribute to pannus formation RA – Joint morphology RA joints affected: ▪ Most common joints affected include the small joints of the hands and feet Especially the MCPs and PIP joints ▪ Next most likely (in decreasing frequency): wrist, ankles, elbows, knees Characteristic morphologic features within the joint includes formation of a pannus ▪ Pannus: mass of edematous synovium, inflammatory cells, granulation tissue, and fibroblast growth causing articular cartilage erosion. RA – Joint morphology Pannus formation – the details ▪ Joint synovium becomes edematous & thickened Hyperplasia and proliferation results in transformation from smooth surface to one covered by villous, finger- like projections into the joint Prominent angiogenesis in the synovium ▪ Inflammatory cells infiltrate the pannus CD4+ T helper cells, B cells, plasma cells, dendritic cells, and macrophages ▪ Fibrinopurulent exudate is deposited on synovial and joint surfaces ▪ Osteoclastic activity in subchondral bone causes bony erosion around the joint ! osteopenia Pannus that migrates over the cartilage surface + recruitment of leukocytes into synovial space ! loss of cartilage and joint function RA – Joint destruction Ankylosis: ▪ Over time, after articular cartilage destruction, pannus forms a “bridge” between apposing bones forming a fibrous ankylosis Ankylosis ! a “bridge” across a joint that limits range of motion ▪ A feature of inflammatory arthritis, continuous with the synovial membrane Eventually this can ossify resulting in a bony ankylosis that “fuses” bones across a joint Joint damage encompasses: ▪ Destruction of cartilage ▪ Destruction of bone next to the joint ▪ Damage to joint capsules, tendons, ligaments ▪ Ankylosis ! decreased range of motion Greatest joint damage occurs in first 4-5 years – the younger the age of onset, often the more severe the course of disease RA – Histology (FYI) Notes  Clinical Features in RA Articular findings: Tends to be symmetrical distribution Joints are warm, tender and swollen ! progresses to instability, deformity and loss of function over years Typical small joints: ▪ MCP, PIP, MTP, wrist, ankle ! > 50% affected ▪ C1 – C2 ! 40 – 50% Typical large joints: ▪ Knee, shoulder ! > 50% ▪ Hip - ~ 30% In general, RA is suggested when many small joints and a few large typical joints are affected in a symmetrical fashion Slide 16  Clinical Features in RA Articular findings: Inflammatory joint pain often exhibits “gelling” or morning stiffness ▪ Severe stiffness and pain of the joint after it has been inactive for prolonged periods of time (i.e. during sleep) ▪ After the joint “warms up” with activity, then pain is reduced and ROM improves “Inflammatory” morning stiffness typically lasts greater than one hour ▪ Osteoarthritis can exhibit morning stiffness, but it lasts for less than an hour (usually half an hour or less) Slide 17 RA – characteristic hand findings Inflammation in tendons, ligaments, and even adjacent skeletal muscle results in characteristic wrist signs: ▪ Radial deviation of the wrist ▪ Ulnar deviation of the fingers ▪ Flexion-hyperextension abnormalities of the fingers (swan neck, boutonnière) The hands are involved in almost all RA patients Retrieved from: https://commons.wikimedia.org/ wiki/File:Rheumatoid_arthritis_--_Smart- Slide 18 Servier_(cropped).jpg RA – characteristic hand findings Swan Neck Deformity: Due to the intrinsic hand muscle contracture PIPs are HYPER-EXTEND DIPs are Flex Boutonniere (Buttonhole): Due to ruptures of the central slip of the extensor tendons PIPs are Flexed DIPs are Hyper-extended RA – characteristic hand findings RA – Radiographic hallmarks Radiographic hallmarks: ▪ juxta-articular osteopenia and bone erosions with narrowing of the joint space from loss of articular cartilage  Clinical Features in RA Systemic Findings: Fatigue, weight loss, and low-grade fever are very common ▪ Worsen during a flare Extra-articular manifestations – discussed in the next two slides Patients are often anemic due to long-lasting systemic inflammation ▪ Known as anemia of chronic disease – will be covered in hematology Slide 20 RA – extra-articular manifestations Rheumatoid nodules are most common skin lesion ▪ Arise in regions subject to pressure: Ulnar aspect of forearm, elbows, occiput, and lumbosacral area ▪ Small, firm, non-tender, and round to oval in shape ▪ Microscopically: Central zone of fibrinoid necrosis surrounded by activated macrophages, lymphocytes, and plasma cells  RA – extra-articular manifestations Additional extra-articular manifestations & complication Pericarditis and pulmonary fibrosis Cardiovascular mortality from heart attack and stroke are 2-3x that of normal population Thought to be due to chronic damage of vascular endothelium due to systemic inflammatory mediators Vasculitis can result in a wide range of symptoms, depending on organ involved: Can involve skin, vessels of heart, vessels of lung, digits resulting in a wide range of symptoms RA – Diagnosis Mostly based on signs and symptoms Laboratory contributions include: ▪ Positive rheumatoid factor in 75 – 80% of those with RA, IgM RF usually measured Also found in Sjogren’s, Lupus, and bacterial endocarditis ▪ Positive anti-citrulline antibodies Present in majority of those with RA More specific than RF Higher values indicate worse outcome ▪ Elevated C-reactive protein (CRP) Extremely non-specific test, elevated in many conditions ▪ For all three labs, diagnosis is more certain when levels are highly elevated (> 3X normal) RA – Illness script Clinical Features Complications & Treatments Prognosis (coming soon) Symptoms begin with malaise, fatigue, Chronic waxing and generalized musculoskeletal pain. Joint pain waning begins in weeks to months Life expectancy Joint pain: reduced by 3-7 Symmetrical, polyarticular arthritis years due to Joints are swollen, warm, and painful complication Joint stiffness in morning and with inactivity. Complications: Morning stiffness lasts > 1 hour and does not Pericarditis and subside with activity pulmonary fibrosis Locations: (highest frequency to lowest) Higher risk of MCPs and PIPs*, Bones of ankles and wrist, cardiovascular Elbows and knees, Cervical spine, Hips, lumbar mortality spine (rarely) Vasculitis & Characteristic wrist findings on PE: radial systemic deviation of wrist, ulnar deviation of fingers, amyloidosis flexion-hyperextension abnormalities of the Iatrogenic effects fingers (swan neck, boutonnière) of therapy *Can involve DIPs RA – Iatrogenic complications (Preview) Iatrogenic effects of therapy can include: GI bleeding caused by long-term use of anti- inflammatory drugs Infections associated with chronic steroid use Juvenile idiopathic arthritis - intro Heterogenous group of disorders ▪ Occur prior to age 16 years and persist for at least 6 weeks Idiopathic – no clearly described etiology ▪ Shares some pathogenic features with RA Involvement of Th1 & Th17 cells and inflammatory mediators like IL-1, IL-17 and INF-y ▪ Associated with HLA and PTPN22 gene variants 30,000 – 50,000 children affected in the US Juvenile idiopathic arthritis Differs from adult rheumatoid arthritis in that: ▪ Oligo-arthritis is more common ▪ Systemic disease is more frequent ▪ Large joints are affected more often than small joints ▪ Rheumatoid nodules and rheumatoid factor are usually absent ▪ Antinuclear antibody (ANA) seropositivity is common ▪ Variable prognosis: only 10% tend to progress to severely disabling disease Juvenile idiopathic arthritis - types Systemic arthritis: abrupt onset, is associated with remitting, high spiking fevers (also known as Still’s disease) ▪ Skin rash, hepatosplenomegaly, and serositis ▪ Long-term follow-up shows that recurrent flares or persistent disease may be associated with significant morbidity and serious complications Oligoarthritis: Arthritis affecting four or fewer joints during the first 6 months of disease in the absence of psoriasis and an HLA-B27 genotype defines the oligoarthritis variant. ▪ Asymmetric, develops at an early age (younger than 6 years), and is commonly associated with iridocyclitis and a positive ANA. Juvenile idiopathic arthritis - types Rheumatoid-factor positive polyarthritis: ▪ Similar to adult RA, usually found in teenage girls Enthesitis-related arthropathy ▪ Primarily found in younger males ▪ HLA-B27 positive, tends to affect joints of lower limbs and insertions of tendons More discussion of HLA-B27 and seronegative arthritis in the e-learning next week ▪ Seronegative = no autoantibodies detected Osteoarthritis (OA) - intro Characterized by articular cartilage degeneration resulting in structural and functional synovial joint failure ▪ Can be primary or secondary Primary – insidious onset without apparent initiating cause; considered an aging phenomenon Secondary – occurs in younger populations secondary to joint deformity, prior injury, or underlying systemic disease* that places joints at risk ▪ *eg. Diabetes, hemochromatosis, marked obesity Osteoarthritis (OA) - Epidemiology Most common joint disease Epidemiology: ▪ Very Common: 80-90% of the population have some radiological evidence of osteoarthritis by age 65 50% are significantly affected by osteoarthritis by age 65 ▪ About 5% of cases occur in younger patients Secondary osteoarthritis Osteoarthritis (OA) - Etiology Etiology ▪ Risk factors include: Age, genetics Trauma, repetitive use, obesity, other orthopedic disease Reproductive hormones ▪ seems to be linked to lower estrogen Osteoarthritis (OA) - Etiology Although the name denotes an inflammatory process, there is minimal presence of leukocytes. There is however, evidence of inflammation: ▪ Elevated tissue metalloproteinases & mild synovial inflammation This suggests an inflammatory and degenerative combination OA lesions within the joint stem from: ▪ Degeneration of the articular cartilage ▪ Disordered repair Osteoarthritis (OA) - Pathophysiology Articular cartilage along areas of highest stress tend to be affected Chondrocytes will proliferate to try and maintain the hyaline cartilage by increasing proteoglycan synthesis ▪ Cartilage swells Osteoarthritis (OA) - Pathophysiology Chondrocytes also secrete metalloproteases (MMPs), that degrade type II collagen ▪ Results in fissures and clefts on the articular surface Chondrocytes and synovial cells secrete a variety of cytokines and additional diffusible factors, particularly: ▪ TGF-Beta, TNF, prostaglandins, nitric oxide Fissures and clefts on articular surface Osteoarthritis (OA) - Pathophysiology Late OA is characterized by chondrocyte loss and severe matrix degradation ▪ As chondrocytes die, full thickness portions of cartilage are sloughed off into the joint forming loose bodies Loose bodies can lead to joint Aka joint mice locking and cause further ▪ Loss of cartilage results in cartilage damage. narrowing of joint spaces and exposed subchondral bone FYI – Friction on bone gives it becomes the new articular a polished appearance (aka surface bone eburnation) Osteoarthritis (OA) - Pathophysiology Within the subchondral bone there are a variety of changes: ▪ Bone undergoes rebuttressing and sclerosis ▪ Small fractures develop, creating gaps for synovial fluid to be pushed down into the subchondral regions (within the 1. Eburnated articular surface epiphysis) 2. Subchondral cyst As fluid collects it forms 3. Original articular surface fibrous, walled-off cysts ▪ Increased vascularity within and below the joint Osteoarthritis (OA) - Pathophysiology Within the subchondral bone there are a variety of changes (continued): ▪ Osteophytes formation Mushroom-shaped bony growths that develop at the margins of the articular surface Caused by osseus metaplasia of the synovial membrane Initially capped by Main clinical finding of slowly fibrocartilage and hyaline progressive joint pain is likely due to: cartilage that gradually ossifies elevation of periosteum, synovitis, joint effusion and capsule stretching OA – Radiographic hallmarks While radiographic findings are used to guide diagnosis, level of disease severity detected via X-ray does not correlate with well with pain and disability Findings: Narrowed joint space Subchondral sclerosis with scattered oval radiolucent cyst Peripheral osteophyte lipping (denoted with arrows) Osteoarthritis – Clinical Features Articular findings: Typically less symmetrical than RA with a predilection for larger joints, although certain joints of the hands and wrist can be affected Large joints: ▪ Hip, knee, lumbar spine ▪ Uncommon – shoulder (unless a history of trauma or overuse) Small joints: ▪ PIPs, DIPs of hands plus 1st CMC joint and first MTP ▪ Lower cervical spine (C1 – C2 uncommon) ▪ Less common – MCPs Slide 40 Osteoarthritis – Clinical Features Articular findings: Morning stiffness lasts for less time (less than an hour) and is usually less debilitating Does not tend to flare, though barometric changes due to weather can cause exacerbation of pain Less likely to have warm joints, but can still be swollen and tender Heberden’s Nodes (Osteophyte formations at the DIPS) accompanied by lateral joint deviation Bouchard’s nodes are found at the PIPS No systemic symptoms Slide 41 Osteoarthritis – Clinical Features Slide 41 OA – Illness script Clinical Features Complications & Treatments Prognosis (coming soon) Slowly progressive pain over years to decades Joint slowly Joint Joint pain: deteriorates over prosthesis One or only a few joints involved time with Deep, achy pain that worsens with rest mediations Brief joint stiffness in morning, lasting < 30 providing only minutes symptomatic relief Additional symptoms: Crepitus and limited range of movement Osteophytes can results in cervical and lumbar nerve root compression with radiculopathy Locations: Knees and hips Lower lumbar and cervical vertebrae Fingers – typically DIPs*, PIPs, and 1st carpometacarpal joint Toes – first tarsometatarsal joint Shoulders are less commonly involves *Osteophytes in the DIPs are called Heberden nodes Infectious Arthritis Can occurs from hematogenous seeding or contiguous spread (i.e. soft tissue abscess or osteomyelitis) ▪ Cartilage has limited regenerative capacity, so rapid joint destruction can result in permanent joint deformities Prompt recognition and treatment is essential Types: Suppurative Mycobacterial Lyme Viral Infectious Arthritis - Suppurative Bacterial infection entering joints from distant sites via hematogenous spread Risk factors: Individuals with deficiencies in complement factors C5 - C9 Inability to form membrane attack complex (MAC) Immunodeficiencies, joint trauma, chronic arthritis, & IV drug use Organisms of note: – N. gonorrhea, Chlamydia – Staphylococcus, Streptococcus – H. influenzae, E. coli, Salmonella Infectious Arthritis - Suppurative Clinical Features Sudden development of an acutely painful, swollen joint with limited range of motion Fever & leukocytosis Joint aspiration – purulent fluid and identification of infectious organism Joints involved: Single, large peripheral joint - knee, shoulder, hip, elbow Complications and Prognosis – Up to 50% can have long-term joint pain after the infection resolves, even with quick recognition and treatment – Since it is often associated with sepsis, can also be associated with severe outcomes Staph aureus septic arthritis also carries a very high (some references say 50%) mortality rate Infectious Arthritis - Mycobacterial Chronic progressive monoarticular infections caused by M. tuberculosis Occurs primarily in adults as a complication of adjacent osteomyelitis or disseminated from visceral site of infection (ie. Lungs) Insidious onset of increasing joint pain Joint commonly affected: hips, knees, ankles Infectious Arthritis - Lyme Caused by spirochete, Borrelia burgdorferi If untreated, up to 80% of patients will develop a migratory arthritis lasting weeks to months Onset months after the initial infection, Joint paint - periodic oligo-articular arthritis that comes and goes and lasts for weeks-months Joints affected – knees, shoulders, elbows, ankles Infectious Arthritis - Viral Arthritis can occur with a variety of viral infections Eg. Alphavirus, parovirus B19, rubella, Epstein-Barr, Hepatitis B & C Clinical features Acute to subacute arthritis Joint symptoms can be caused by the virus itself or an autoimmune reaction triggered by the infection More next week! Study guiding Questions Build a diagram for the pathogenesis and pathophysiology of RA Build a diagram for the pathogenesis and pathophysiology of OA Compare the key clinical features and joints involved OA, RA, and suppurative infectious arthritis Compare the joint morphology between OA and RA Using the class notes, build a complete illness scrip for OA, RA, and infectious arthritis, including: Etiology, Pathogenesis & pathophysiology, Clinical Features, Diagnosis, and Prognosis & Complications. Review the pathogenesis & pathophysiology by summarizing into key bullet points