rheumatology notes and learning objectives

7/28/2019 Rheumatology Notes and Learning objectives

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Rhem 1/2Rheumatoid Arthritis and Spondyloarthropathies

Dr. Shuntary Shinada, May 7, 2012

A. Introduction to Rheumatology1. 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, Arthritis82.5 billion

4. Appreciate the impact on the patient and family: emotional, financial, quality and quantity of life, disability .

B. Rheumatoid arthritis1. 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 growthabnormalities. 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: 3-1Family studies show high prevalence in persons with 1relatives. Associations vary by races and ethnicity:HLA-DR4 Ag in 50-70% of white American and N. European, 36-56% of Afro-Americans with RAHLA-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 producecytokines (IL-1, TNF, Igs, etc.), which propagates the inflammation. Synovial Ms and fibroblasts produce matrixmetalloproteinases. 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 diseaseprogresses, 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 depositedin 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 patientsleg ulcers, digital gangrene, neuropathy

Pleuropulmonary manifestations, Carditis in 10% of pts, Premature CV diseaseNeuro- peripheral nerve compression

Cancerincrease risk of lymphoma

Ocular inflammationsepiscleritis, sceromalacia, keraomalacia,6. Identify therapeutic modalities for RA and comprehend their mechanisms of action.

Laboratory: Rheumatoid Factor (RF), Anti-CCPNSAIDs, 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 controlBiologic drugs attack mediators of inflammation and tissue damageetanercept, adalimumab, golimumab,

certolizumab, infliximab, rituximab, tocilzumab, abatecept

Corticosteroids are used for control of rheumatoid synovitis in two forms: intraarticular injections of long-actingesters 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 applicationsReconstructive ortho surgery for severely damaged joints

C. Seronegative Spondyloarthropathies1. 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


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2. Usually, asymmetrical lower extremity joint involvement3. Mend involved much more frequently than women4. High frequency of HLA-B27, esp with spinal arthritis5. 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. Characteristicoutcome 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 HLA-B27 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 jointdamage, 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. Clinicalfeatures: DIP joints commonly involved, nail pitting, sausage fingers/toes, skin lesions and arthritis exacerbate and remit

together, remissions more frequent, radiologypencil-in-cup, whittling, periostitis, non-marginal spinal syndesmophytes

2. Identify the genetic susceptibility to ankylosing spondylitis.M:F9:1. 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 educationPharm: NSAIDS, methotrexate and sulfasalazine, Anti-TNFPT is crucial: postural exercises, breathing exercises, swimmingReconstructive surgery of hips, spine may be neededReactive Arthritisadd antibiotics for infection, topical corticosteroid for eye or skin involvement

Psoriatic Arthritisskin 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, HLAB27 seen I most patieitns, gerenal predispotiionClinical 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 solesLab 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 3Pathogenesis of Systemic Lupus Erythematosus

Dr. David Horwitz, May 9, 2012

1. Define LupusSystemic 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 oftentriggered by infections, and followed by decreased clearance of apoptotic cells and impaired regulators.


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2. Describe the Pathogenesis of SLE1. Multiple etiologies: genetic, gender, environment2. 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 2c. 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 (B-

cells + DCs), loss of tolerogenic APCs, decreased production of anti-inflammatory cytokines like IL-10 and TGF

3. B cell abnormalities:a. spontaneous activationb. Become APCs for nuclear auto-antigens producing numerous autoantibodiesIFN stimulates APCs to activate auto-

reactive 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 triggersGenetics: 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 fromUV radiation alters self-Abs), Drugs (procainamide, hydralazine inhibits DNA-methylation)

Rheum 4Systemic Lupus Erythematosus

Dr. Francisco Quasimorio, May 9, 2012

1. Present a clinical overview of systemic lupus erythematosus (SLE), a prototype of human autoimmune dzThe 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, whilepatients that die later die of accelerated atherosclerosis or other complications.

Derm: Malar Skin Rash: butterfly distribution (nasolabial fold spared), photosensitivity, alopecia, cutaneousvasculitis (around nail beds), mucosal ulcers, chronic discoid LE, Inflammatory dermatitis

MSK: polyarthritis, myalgia, synovitis, myositisVisceral: serositis, pneumonitis, FUORenal: proteinuria, nephritic syndrome, hpt, edema, glomerulonephritis, major cause of M&MNeuropsych: strokes, seizures, psychosisHematologic/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, functionalabnormalities, pulmonary HTN, diaphragmatic dysfunction, airways obstructed

Cardiac: pericarditis +/- effusion, pericardial tamponade, constrictive pericarditis, myocarditis, Libman Sacksendocarditis,

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-erosive6.Serositis

7.Renal disorder8.Hematologic disorder

9.Neurological disorder

10.Immunologic disorder11.Positive ANA


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2. To discuss the role of antinuclear antibodies and other types of autoantibodies in the pathogenesis of tissueinjury 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, andAnti-Smith (spliceosome).

ANA alone does not cause lupusdoes not affect fetuses that are ANA + (mother has SLE), nor does it affect humanvolunteers injected with ANA containing plasma or have any cytotoxicity in culture. ANA may be secondary as a DNA Agmay 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 5Systemic 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 treatableb. Raynauds Phenomenon: over exaggeration of normal vascular response to hot/cold (2-4 th 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 esophagusd. 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 touched2. Diffuse: skin is thick, waxy and tight; stages of skin involvementedema, induration then atrophy

a. CRESTb. MSK: arthritis (symmetric, polyarticular, small/large joints), tendon rubs (squeaky, leathery rubs w/ movement, worse

prognosis), muscle atrophy, myositisc. 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, atrophyof 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), superimposedinfection, micro-aspirations +/- aspiration pneumonia, lung cancere. CV: myocardial fibrosis, conduction deficits, pericarditis, pulmonary HTNheart failuref. 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 painfulb. 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 synthesisof 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 unclearTheory: Initiating eventvascular bed change (immune cells, fibroblasts, endothelial cells)GF and cytokineproduction fibroblast activation fibrosis

Rheum 6Inflammatory 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 Dermatomyositis

Insidious onset over several months, usually with systemic sxWeakness of shoulder and pelvic girdle, neck muscles, 50% with

pain and tenderness, occ. involvement of pharyngeal m

Pulmonary: interstitial fibrosis

Cardiac: rare, usually subclinical

PM findings + Grottons papules, heliotropic discoloration ofeyelids with/without periorbital edema, Shawl sign, V sign,

cuticle changes

Muscle fibers in various stages of necrosis and regenerationPredominantly endomesial, particularly CD8+Muscle fibers displaced w/ fibrous CT and fat over time

EMG: Triad1.insertional activity, fibrillations, sharp + waves2.spontaneous, bizarre high-freq discharges3.Polyphasic short duration, low amplitude motor unit potentials

Fiber invasion rare, perivascular B lymphocytes and CD4+ cellsEMononuc. 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 normalAldolase, AST, ALT, LDHMyoglobinuria usually absentAcute phase reactants frequently normalRoutine blood tests are normal

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

dermatomyositis and polymyositis.

Rheum 7Osteoarthritis

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, 1stMTPsSecondary 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 infectionCharcot Jnts (Neuropathic Origin): Tabes dorsalis (knee), Diabetes (foot/ankle), syringomyelia (shoulder), and

peripheral nerve injuryMetabolic 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 50RFs: 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 8Crystal-Induced Arthropathies

Dr. Glenn, Ehresmann, May 11, 2012

1. Identify characteristic crystals associated with arthritis.Crystal Clini cal DO

Monosodium Urate Gout

Calcium Pyrophosphate (CPP) PseudogoutHydroxyapatite Calcified periarthritis

Calcium Oxalate Primary/Secondary Oxalate Gout

Crystalline Lipids Cholesterol Emboli Syndrome

Crystalized Proteins Cryoglobulinemia

Crystine Crystals 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 ofinflammatory mediatorsarachidonic acid metabolites, IL 1, 6, 8, and TNFSystemic Sx (fever, chills).

Major problem lies in purine metabolism:

De novo synthesis: substrates, aminotransferase, IMPPurine 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 isoverproduction via the de novo pathway (large excretion) or under-excretion with normal purine metabolismcan beexacerbated 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 butresponds to treatment. Asymptomatic between attacks, low-grade fever common with acute attack. CPPD deposition isassociated 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 manneras MSU crystals.

Treatment: does not remove crystals, aspiration of affected joints and corticosteroids helpful, but cannot treat thelong-term course of disease.

SPP #3Crystal 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 oran 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 acidwhich 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 thehyperuricemic state.


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Crystals are taken up by leukocytes, which then secrete inflammatory factors, and cause many of thesymptoms of acute attack and thus are a good target for therapeutic intervention. For over-producers, it makessense 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

rheumatology notes and learning objectives

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