Rhem 1/2 Rheumatoid Arthritis and Spondyloarthropathies Dr. Shuntary Shinada, May 7, 2012 A.

Introduction to Rheumatology
1. Recognize that there is a great variety of rheumatic diseases. 2. Recognize that rheumatic diseases affect all age groups. 3. Appreciate the financial impact of rheumatic diseases on society. MSK - $215 billion, Arthritis 82.5 billion 4. Appreciate the impact on the patient and family: emotional, financial, quality and quantity of life, disability.

B. Rheumatoid arthritis 1. Be familiar with the definition and clinical picture of Adult and Juvenile Idiopathic Arthritis.
RA: chronic, inflammatory diseases, which the major target o synovial joints Joint involvement in symmetrical Joint inflammation cause swelling and pain. Morning stiffness and fatigue are prominent sx. JIA: form of arthritis with onset under 18yo. IT differs from adult RA in modes of onset and can cause growth

abnormalities. Nodules are less frequent and Rheumatoid factor is only positive in 8-15% of cases. 2. Identify the role of genetics in rheumatoid arthritis.
Gender difference: Female-male: 3-1 Family studies show high prevalence in persons with 1 relatives. Associations vary by races and ethnicity: HLA-DR4 Ag in 50-70% of white American and N. European, 36-56% of Afro-Americans with RA HLA-DRB1 is the responsible gene with many alleles associated in difference races.

3. Appreciate pathogenesis mechanisms of rheumatoid arthritis.

In RA the synovium contains activated T-cells, B-lymphocytes, plasma cells, and monocytes/M, which produce cytokines (IL-1, TNF, Igs, etc.), which propagates the inflammation. Synovial Ms and fibroblasts produce matrix metalloproteinases. Synovial fluid increases in volume and # of inflammatory cells.

4. Identify the mechanisms of tissue damage.

Joint structures are damaged by substances produced by the inflamed hypertrophic synovium, pannus and leukocytes. Collagen degraded by synovial & neutrophil collagenases, and proteoglycans degraded by neutral protease and elastase. Granulomas (rheumatoid nodules) are seen in pressure points and produce IFN- and IL-4. As the disease progresses, granulation tissue forms as the edges of the synovial lining, known as pannus, with extensive angiogenesis (formation of new vessels) and production of enzymes that cause tissue damages. Osteoclast differentiating factor, IL1, and TNF cause M differentiation into osteoclasts which leads to bone erosion. Also, immune complexes are deposited in articular cartilage, where there is no mechanism for paid clearance.

5. Recognize the multisystemic nature of the disease.

Anemia present in ~80% patients, chronic disease anemia Muscle atrophy, rheumatoid myopathy, rheumatoid nodules (granulomas) in pressure areas Vasculitis in 10% of patients leg ulcers, digital gangrene, neuropathy Pleuropulmonary manifestations, Carditis in 10% of pts, Premature CV disease Neuro- peripheral nerve compression Cancer increase risk of lymphoma Ocular inflammations episcleritis, sceromalacia, keraomalacia,

6. Identify therapeutic modalities for RA and comprehend their mechanisms of action.

Laboratory: Rheumatoid Factor (RF), Anti-CCP NSAIDs, COS inhibitors: short term relief of inflammation and pain Disease Modifying Anti-Rheumatic Drugs (DMARDs) or Remittive Drugs may require 1-6 months for effectiveness, but may induce remission of disease activity with cessation of inflammation and pain, and normal sed rate. Combos used early to control Biologic drugs attack mediators of inflammation and tissue damage etanercept, adalimumab, golimumab, certolizumab, infliximab, rituximab, tocilzumab, abatecept Corticosteroids are used for control of rheumatoid synovitis in two forms: intraarticular injections of long-acting esters for relief of local synovitis, and on occasionally orally in the smallest possible dose Physical medicine and Rehab: rest, exercise, splinting of joints, head and cold applications Reconstructive ortho surgery for severely damaged joints

C. Seronegative Spondyloarthropathies 1. Define and recognize the clinical picture of the Spondyloarthropathies:
HLA-B27 associated arthritides, which differ from RA are:
1. High incidence of spinal joint (axial skeleton) involvement

2. 3. 4. 5.

Usually, asymmetrical lower extremity joint involvement Mend involved much more frequently than women High frequency of HLA-B27, esp with spinal arthritis RF usually absent

Ankylosing Spondylitis: chronic, inflammatory, systemic disease with major target of sacroiliac joints, and cartilaginous and synovial joints of the spine; Symmetrical joint involvement; occurs mainly in young men. Characteristic outcome is ankylosis (fusion) of joints and ossification of paraspinal ligaments Clinical features: spinal features, peripheral arthritis, enthesopathy, extra-articular features Reactive Arthritis: chronic, recurring, inflammatory disease, consisting of urethritis or infectious diarrhea, conjunctivitis, arthritis, and mucocutaneous lesions. Exposure to certain infectious agents in a person positive for HLAB27 is considered to be part of the development of disease. Clinical features: arthritis, mainly lower extremities (asymmetrical), self-limited (2-6mo), recurs in 50% of pts, sausage toes/digits or dactylitis, uncommon permanent joint damage, X-rays may show periostitis near and involved joint. Enteropathy-associated (Crohns Disease, Ulcerative Colitis) arthritis: Psoriatic arthritis: chronic skin disease of unknown etiology with accompanying arthritis in 6% of pts. Involve peripheral joints, or sacroiliac (30%) and spinal joints (12%). Psoriatic spondylitis is assoc in 30-50% of pts. Clinical features: DIP joints commonly involved, nail pitting, sausage fingers/toes, skin lesions and arthritis exacerbate and remit together, remissions more frequent, radiology pencil-in-cup, whittling, periostitis, non-marginal spinal syndesmophytes

2. Identify the genetic susceptibility to ankylosing spondylitis.

M:F 9:1. Familial aggregation studies estimate that genetic risk factors contribute to 80-90% of susceptibility to AS. Stronger concordant rates between dizygotic vs monozygotic twins.

3. Recognize the multisystemic nature of these diseases. 4. Identify therapeutic modalities and their mechanisms of action.
Patient and family education Pharm: NSAIDS, methotrexate and sulfasalazine, Anti-TNF PT is crucial: postural exercises, breathing exercises, swimming Reconstructive surgery of hips, spine may be needed Reactive Arthritis add antibiotics for infection, topical corticosteroid for eye or skin involvement Psoriatic Arthritis skin manifestations need attention, corticosteroid, tar creams, UV light Reactive arthritis: nongonocooccal urethitrists, conjuctiviis and arthrirs after a diarrheal illness -moststly a lower extremity oligoarthritis tiggeried by infusion. General characteristics: occurs secondary to chlamydial urethiros or GI infections, often occurs in young adulthood, HLA B27 seen I most patieitns, gerenal predispotiion Clinical features: - acute onset characterized by asymmetric arthhriiti in akles an knee - 3 typical features: diffuse swelling of finger or toe (sausage digit), tenderness of achillles, low back pian associated with sacroiliitis - conjunctivitits - mucocutaneous lesions : balanitis circinata (small shwllo painless ulcers of glans penis) and keratoderma blennorrhagicum (hyperkeratotic scaling skin lesions similar to posriaias on palms and soles Lab features: - elecated ESR and leukoctosis, HLA b27 linked - synovial lfuid aspiration indicates 5---75000 cells with PMNs predominance - radiography: erosion at iscial tuberosity, gereater trochanter

Rheum 3 Pathogenesis of Systemic Lupus Erythematosus Dr. David Horwitz, May 9, 2012 1. Define Lupus
Systemic disorder of generalized autoimmunity with a wide variety of clinical symptoms, characterized by the production of antibodies to the cell nucleus, which predominantly affects young women. SLE is a T and B cell disorder of immune regulation caused by a loss of tolerance to self-antigens with the consequence of altered homeostasis often triggered by infections, and followed by decreased clearance of apoptotic cells and impaired regulators. 2

2. Describe the Pathogenesis of SLE

1. Multiple etiologies: genetic, gender, environment 2. T cells lose self-tolerance altered immune homeostasis
a. Clonal deletion: auto-aggressive T-cells escape destruction in thymus b. Clonal anergy: signal 1 stimulates immunity w/o signal 2 c. Apoptosis: auto reactive T/B cell apoptosis and clearance of dead cells (leads to ANA) d. T-regs: impaired function and decreased # inability to block T-cell prolif, inability to control immunogenic APCs (Bcells + DCs), loss of tolerogenic APCs, decreased production of anti-inflammatory cytokines like IL-10 and TGF

3. B cell abnormalities:
a. spontaneous activation b. Become APCs for nuclear auto-antigens producing numerous autoantibodies IFN stimulates APCs to activate autoreactive T cells c. Hyper-responsive d. Failure of Abs binding FcR to inhibit Ig production and further production of auto Abs

3. Explain susceptibility and environmental triggers

Genetics: 25% identical twin concordance, complement deficiency (C1q, C2, C4), immune R dysfunction (HLA-D2, low TNF, FcR 2/3a/b, IL10, TLR, IRF-5, PTPN22, MBL) Environmental Triggers: Infections agents (co-stim for activating autoreactive T-cells), Sunlight (cellular injury from UV radiation alters self-Abs), Drugs (procainamide, hydralazine inhibits DNA-methylation)

Rheum 4 Systemic Lupus Erythematosus Dr. Francisco Quasimorio, May 9, 2012 1. Present a clinical overview of systemic lupus erythematosus (SLE), a prototype of human autoimmune dz
The clinical course of this disease is a chronic irregular course with periods of active disease in between periods of inactivity, but patients may go into disease remission. Patients who die early often die of opportunistic infection, while patients that die later die of accelerated atherosclerosis or other complications. Derm: Malar Skin Rash: butterfly distribution (nasolabial fold spared), photosensitivity, alopecia, cutaneous vasculitis (around nail beds), mucosal ulcers, chronic discoid LE, Inflammatory dermatitis MSK: polyarthritis, myalgia, synovitis, myositis Visceral: serositis, pneumonitis, FUO Renal: proteinuria, nephritic syndrome, hpt, edema, glomerulonephritis, major cause of M&M Neuropsych: strokes, seizures, psychosis Hematologic/Vascular: anemia, leucopenia, tcp, purpura, vasculitis, thrombosis (gangrene), accel. Atherosclerosis Resp: Pleurisy w or w/o effusion, interstitial lung fibrosis, acute lupus pneumonitis, alveolar hemorrhage, functional abnormalities, pulmonary HTN, diaphragmatic dysfunction, airways obstructed Cardiac: pericarditis +/- effusion, pericardial tamponade, constrictive pericarditis, myocarditis, Libman Sacks endocarditis, Pathology: Inflammatory changes, blood vessel abnormality, immune complex deposits Dx: multisystem involvement, immunologic abnormality, and exclusion of other medical conditions. AND 4+ of:
1.Malar rash 2.Discoid rash 3.Photosensitivity 4.Oral Ulcers 5.Arthritis, non-erosive 6.Serositis 7.Renal disorder 8.Hematologic disorder 9.Neurological disorder 10.Immunologic disorder 11.Positive ANA

2. To discuss the role of antinuclear antibodies and other types of autoantibodies in the pathogenesis of tissue injury in SLE
ANA are autoantibodies to nuclear Ags, and there are several types with varying antigenic specificity (IgG, M, A isotypes). ANA are seen in SLE and other diseases. There are 2 specific types characteristic of SLE: Anti-dsDNA, and Anti-Smith (spliceosome). ANA alone does not cause lupus does not affect fetuses that are ANA + (mother has SLE), nor does it affect human volunteers injected with ANA containing plasma or have any cytotoxicity in culture. ANA may be secondary as a DNA Ag may bind to the renal glomeruli and the circulating ANA reacts to the planted DNA to form immune complexes in situ. These immune complexes activate the complement system causing inflammation and further damage. The source of DNA Ags may be from defects in apoptosis. DNA Ags are taken up by dendritic cells and presented to T/B cells and ANA are formed.

Rheum 5 Systemic Sclerosis Dr. Elizabeth Ortiz, May 9, 2012 1. Present the clinical features of systemic sclerosis (SSc). Discuss the various categories of SSc.
1. Limited SSc: CREST a. Calcinosis: joint deposition, not really treatable b. Raynauds Phenomenon: over exaggeration of normal vascular response to hot/cold (2-4th digits, white, blue or red in
fingers), + tingling, numbing from lack of blood flow to digits

c. Esophageal dysfunction: collagen deposition of smooth muscle of lower 2/3 of esophagus d. Sclerodactyly: fibrosis and thickening of skin around digits and joints, joints themselves spared, contractures and
ulcerations, hypopigmentation of skin, can get ischemia and autoamputation

e. Telangiectasia: dilated blood vessels in face, palate (non-specific) blanch when touched 2. Diffuse: skin is thick, waxy and tight; stages of skin involvement edema, induration then atrophy a. CREST b. MSK: arthritis (symmetric, polyarticular, small/large joints), tendon rubs (squeaky, leathery rubs w/ movement, worse
prognosis), muscle atrophy, myositis c. GI: Esophagus (dilation, impairs mobility, lower esophageal sphincter dysfunction, GERD with mucosal ulcerations), Stomach (delayed gastric emptying, gastric antral vascular exctasia watermelon stomach), Small Intestine (atony with obstruction, stasis with malabs, pneumotosis cystoids), Large Intestine (Pseudo -diverticula, infarction); overall, atrophy of smooth m and replacement with collagen, atrophy and fibrosis of submucosa/mucosa, degenerative and inflammatory changes in BVs d. Pulmonary: pulmonary fibrosis, hyperplasia and sclerosis of pulmonary a and branches (pulm HTN), superimposed infection, micro-aspirations +/- aspiration pneumonia, lung cancer e. CV: myocardial fibrosis, conduction deficits, pericarditis, pulmonary HTN heart failure f. Renal: malignant HTN + renal insufficiency = scleroderma renal crisis

3. Localized Scleroderma: only affects the skin, no internal organ problems a. Morphoea: plaque-like, most common, lesions usually oval, on 1 area of the body, >1cm, not painful b. Linear Scleroderma: most common in children, longitudinal band-like lesions, usually on limbs, can lead to joint
contractures and muscle atrophy

2. Discuss the pathogenesis, theories and the possible role of lymphocytes, cytokines and other factors Incompletely understood, but key elements include immune activation, vascular damage, excessive synthesis of extracellular matrix (deposition of increased amts of structurally normal collagen) Theory: immunologic activity + vascular changes = # activated fibrogenic fibroblasts Immune abnormalities: 95% of pts have auto-Abs, pathogenic capabilities still unclear Theory: Initiating event vascular bed change (immune cells, fibroblasts, endothelial cells) GF and cytokine production fibroblast activation fibrosis Rheum 6 Inflammatory Myopathies Dr. Thomas Beardmore, May 11, 2012 1. Evaluate a patient with complaints of muscular weakness and pain.
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Inflammatory Myopathy: Proximal Muscle Weakness, Elevated muscle enzymes (CK, Aldolase, ALT, AST, LDH), Myopathic EMG changes, Muscle biopsy with inflammation, Skin rash for DM, Routine blood tests normal

2. Differentiate the clinical features of Dermatomyositis and polymyositis.

Polymyositis Insidious onset over several months, usually with systemic sx Weakness of shoulder and pelvic girdle, neck muscles, 50% with pain and tenderness, occ. involvement of pharyngeal m Pulmonary: interstitial fibrosis Cardiac: rare, usually subclinical Muscle fibers in various stages of necrosis and regeneration Predominantly endomesial, particularly CD8+ Muscle fibers displaced w/ fibrous CT and fat over time EMG: Triad
1. insertional activity, fibrillations, sharp + waves 2. spontaneous, bizarre high-freq discharges 3. Polyphasic short duration, low amplitude motor unit potentials

Dermatomyositis PM findings + Grottons papules, heliotropic discoloration of eyelids with/without periorbital edema, Shawl sign, V sign, cuticle changes Fiber invasion rare, perivascular B lymphocytes and CD4 + cells EMononuc. infiltrates, Prifasscicular infiltrates, fiber atrophy

3. Recognize the histologic features of muscle in inflammatory myopathies.

Inflammatory invasion of muscle tissue, ESP in perimysium, In DM see mononuclear cell infiltrates, fiber atrophy

4. Recognize the serologic muscle enzyme changes seen in myopathies.

CPK: up to 10-12x normal Aldolase, AST, ALT, LDH Myoglobinuria usually absent Acute phase reactants frequently normal Routine blood tests are normal

5. Know how proximal and distal muscular weakness is manifest and that proximal weakness predominates in dermatomyositis and polymyositis.

Rheum 7 Osteoarthritis Dr. Daniel Arkfeld, May 7, 2012 1. Define osteoarthritis and distinguish its primary and secondary forms. Recognize the pattern of joint involvement.
Primary OA: no identifiable cause, involves: small joints in hand, C/L spine, hips and knees, 1st MTPs Secondary OA: had identifiable cause and involve any joint

2. Identify factors predisposing to osteoarthritis.

Trauma from overuse (athletes), Hypermobility Syndrome, Repeated hemorrhage (hemophilia, Marfans, bleeding do) Structural abnormalities: meniscectomy, congenital abn, avascular necrosis (AVN), and infection Charcot Jnts (Neuropathic Origin): Tabes dorsalis (knee), Diabetes (foot/ankle), syringomyelia (shoulder), and peripheral nerve injury Metabolic d/os: Acromegaly, alkaptonuria, gout, hemochromatosis, chondrocalcinosis, Ocronosis (dark urine, dark pigment in eye, buildup of homogenitis acid in joints/tissues) Consider 2 OA if arthritis is present in unusual locations or below age of 50 RFs: Aging, obesity, quadriceps muscle weakness, joint overuse/injury, genetic susceptibility, dev abn

3. Differentiate between the clinical presentations of osteoarthritis and inflammatory arthritis. Osteoarthritis has osteophytes in joint while RA has smooth but compressed joint spaces 4. Identify the objectives of current treatment programs for osteoarthritis and the therapeutic modalities currently available to achieve these objectives. Non-pharm: patient education, weight loss, exercise (tai chi, yoga, pilates, water exercise), PT
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Pharm: control of pain Rheum 8 Crystal-Induced Arthropathies Dr. Glenn, Ehresmann, May 11, 2012 1. Identify characteristic crystals associated with arthritis.
Crystal Monosodium Urate Calcium Pyrophosphate (CPP) Hydroxyapatite Calcium Oxalate Crystalline Lipids Crystalized Proteins Crystine Crystals Clinical DO Gout Pseudogout Calcified periarthritis Primary/Secondary Oxalate Gout Cholesterol Emboli Syndrome Cryoglobulinemia Cystinosis

2. Understand the pathogenesis of hyperuricemia and gout based on the purine biosynthetic pathway and renal handling of urate.
In gout, there is altered metabolism of uric acid which results in tissue deposition of monosodium urate from supersaturated ECFs. Clinical features: arthritis, tophi, kidney stones, and nephropathy. Stimulate release of inflammatory mediators arachidonic acid metabolites, IL 1, 6, 8, and TNF Systemic Sx (fever, chills). Major problem lies in purine metabolism: De novo synthesis: substrates, aminotransferase, IMP Purine Degradation: Common pathway via xanthine oxidase (XO) to uric acid excretory product Renal handling: normally there is large renal excretion/smaller gut excretion, solubility is important. In gout, there is overproduction via the de novo pathway (large excretion) or under-excretion with normal purine metabolism can be exacerbated by diuretics and low dose ASA.

3. Understand the pathogenesis and treatment of Ca2+ pyrophosphate deposition dz (CPPD) or Pseudogout.
Pathogenesis: normal plasma and urinary excretion of inorganic phosphate, but synovial fluid pyrophosphate elevated. Chondrocytes liberate PP; crystals form in joint fluid and cytokine production increased Can be present in cartilage, unlike gout. First attack tends to be in the knee (patella-femoral joint), self-limited but responds to treatment. Asymptomatic between attacks, low-grade fever common with acute attack. CPPD deposition is associated with aging and degenerative arthritides and suspected to be associated with various endocrinopathy, most notably hyperparathyroidism and hemochromatosis. Ca containing crystals appear to activate PMNs in the same manner as MSU crystals. Treatment: does not remove crystals, aspiration of affected joints and corticosteroids helpful, but cannot treat the long-term course of disease.

SPP #3 Crystal Induced Arthropathy 1. Recognize that naturally occurring crystals can cause arthritis. 2. Recognize the relationship between hyperuricemia and gout. All patients with gout are hyperuricemia but not all hyperuricemics have gout. - Understand the relationship between the purine biosynthetic pathway, overproduction of uric acid & gout. Gout patients way have high uric acid production, which leads to deposits. This overproduction stems from the de novo purine synthesis pathway, where there is an over production of IMP, the precursor of uric acid or an over expression of xanthine oxidase, the enzyme that converts IMP to uric acid. - Understand the relationship of increased/decreased excretion of uric acid with the development of gout. If a patient has normal production of uric acid, but decreased secretion, there can be a build up of uric acid which can lead to gout. This is much more common (90% of patients), and thus can be a target of drugs (uricosuric agents) 3. Recognize the difference between treatment of acute inflammation in gout and treatment of the hyperuricemic state.
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Crystals are taken up by leukocytes, which then secrete inflammatory factors, and cause many of the symptoms of acute attack and thus are a good target for therapeutic intervention. For over-producers, it makes sense to treat the production problem through inhibition of the purine synthesis pathway. 4. Identify crystals through their characteristic findings on microscopy. Gout: Parallel yellow, perpendicular blue CPPD: Parallel blue, Perpendicular yellow