Current Concepts of Rheumatoid Arthritis

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Current Concepts ofRheumatoid Arthritis

• Vladimir Ognenovski, MDJoseph McCune, MD
• University of Michigan

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Rheumatoid Arthritis

• A chronic, systemic autoimmune disease of unknown
  etiology
• Characterized by symmetric, errosive,
  diarthrodial joint synovitis
• May involve multiple organ systemscardiovascular
  , pulmonary, renal, hematologic, and peripheral
  nervous systems, skin and eyes

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Epidemiology

• affects 1 of U.S. adults
• has an incidence of 150,000 new cases annually
• most frequently diagnosed during the 4th-6th
  decade of life
• occurs at a female-to-male ratio of 21 to 31

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Genetic Factors

• Strong association with class II major
  histocompatibility complex human leukocyte
  antigen on chromosome 6
• HLA-DR4 - N European and Americans
• HLA-DR1 - Italian, Israeli Jewish, some Hispanics
• HLA-DR14 - Yakima Indians

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Etiology and Pathogenesis

• Suspected infectious agents
• bacteria (mycoplasma, mycobacteria, enteric
  bacteria)
• viruses (HTLV, retrovirus, herpesvirus,
  Epstein-Barr virus, rubella, parvovirus)
• Defective recognition of autoantigen
• pregnancy induced remission linked to
  maternal-fetal HLA mismatch

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Rheumatoid Factor

• most common autoantibody in RA
• binds to the Fc portion of IgG molecule
• usually an IgM antibody
• less often an IgG or IgA antibody
• detected in 70-80 of RA patients
• high titer predicts adverse outcome
• erosive arthritis, vasculitis

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Rheumatoid Factor

• Methods of detection
• agglutinationIgG coated latex beads or
  erythrocytes
• laser nephelometry
• indirect immunofluorescence
• radioimmuno assay
• enzyme-linked immunosorbent assay

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Disease associated with RF

• rheumatoid disease
• viral disease
• parasitic infections
• chronic bacterial infections
• other hyper-?-globulinemic states

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Disease associated with RF

• 1. Rheumatoid disease
• rheumatoid arthritis
• systemic lupus erythematosus
• scleroderma
• mixed connective tissue disease
• Sjogrens syndrome

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Disease associated with RF

• 2. Viral disease
• AIDS
• mononucleosis
• epatitis
• influenza

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Disease associated with RF

• 3. Parasitic infections
• trapanosomiasis
• malaria
• Kala-azar
• schistosomiasis
• filariasis

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Disease associated with RF

• 4. Chronic bacterial infections
• tuberculosis
• syphilis
• leprosy
• brucellosis
• yaws
• salmonellosis
• subacute bacterial endocarditis

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Disease associated with RF

• 5. other hyper-?-globulinemic states
• hyper-?-globulinemic purpura
• cryoglobulinemia
• chronic liver disease
• sarcoidosis
• other chronic pulmonary diseases

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Rheumatoid Arthritis pathology

• Hallmark - synovitis characterized by hypertrophy
  and hyperplasia of the synovial cells and
  subsynovil stroma
• inflammatory cells infiltrate the synovial lining
• microvascular endothelial injury is the principal
  abnormality

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Rheumatoid Arthritisclinical features and
diagnosis

• synovitis (joint inflammation)
• onset is usually insidious (wks-months) and
  unrelenting
• 15 may be acute (within a few days)
• earlier clinical features
• morning stiffness
• joint tenderness and swelling with restricted
  range of motion

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Rheumatoid Arthritisclinical features and
diagnosis

• Progressive clinical features
• joint deformity and dysfunction from tendon and
  ligament inflammation
• ulnar deviation, z-deformity of the thumb,
  swan-neck and boutonniere deformities of the
  interphalangeal joints
• low grade fever
• subcutaneous nodules of extensor area

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Rheumatoid Arthritisclinical features and
diagnosis

• Joint involvement
• typically symmetrical
• MCP, wrist, PIP, MTP, shoulder, knee, ankle, and
  elbow joints (in order of decreasing frequency of
  involvement)
• cervical spine involvement may lead to
  atlantoaxial subluxation

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Rheumatoid Arthritisimaging studies

• radiographic features
• bony erosion
• cartilage loss
• juxta-articular osteopenia
• soft tissue swelling
• magnetic resonance imaging
• atlantoaxial subluxation

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Rheumatoid Arthritisextra-articular
manifestations

• dermatologicsubcutaneous nodules
• hematologicanemia, thrombocytopenia,
  eosinophilia, leukopenia (Feltys syndrome)
• hepaticelevated transaminases, nodular
  regenerative hyperplasia

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Rheumatoid Arthritisextra-articular
manifestations

• cardiacpericarditis, myocardial nodular
  granulomas
• pulmonaryfibrosis, nodules, pleural effusion
• ocularkeratoconjunctivitis, episcleritis,
  sleritis

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Rheumatoid Arthritislaboratory abnormalities

• Serologic findingsanemia, thrombocytopenia, mild
  leukocytosis, positive RF and elevated ESR,
  C-reactive protein, serum globulin
• Synovial fluid findingsstraw-colored and
  slightly cloudy fluid, leukocytosis 5,000 to
  25,00/mm3, 85 polymorphonuclear cells

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Rheumatoid Arthritisdifferential diagnosis

• osteoarthritis
• spondyloarthritis
• gout and pseudogout
• chronic fatigue syndrome, fibromyalgia
• polymyalgia rheumatica, giant cell arteritis
• systemic lupus erythematosus
• infectious arthritis

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Rheumatoid Arthritistreatment

• Goal prevention of joint disease progression to
  irreversible damage
• remission is rare
• multidisciplinary approach
• patient education treatment plan, compliance,
  understanding of disease
• psychotherapy manage pain and stress
• rehabilitation exercise, joint protection

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Rheumatoid Arthritisdrug therapy

• early aggressive treatment
• control swelling and pain
• reduce the probability of irreversible joint
  damage

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Rheumatoid Arthritis Non-steroidal
anti-inflammatory drugs

• NSAIDS are anti-inflammatory and analgesic
• do not modify the disease course
• GI side effects are common
• take NSAIDS with food or misoprostol
• monitor older patients closely (hypertension,
  congestive heart failure, diabetes, and renal
  insufficiency)
• ? substitute low-dose prednisone in the elderly
  because of risk of GI bleed

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Rheumatoid Arthritis Disease-modifying
antirheumatic drugs

• DMARDs can alter the progression of RA
• should be used before joints are damaged
• may be initiated within the first 3 months of
  diagnosis in patients with ongoing inflammation
  despite treatment with NSAIDS
• a rheumatologist should be consulted when
  steroids or DMARDs are used
• may take 2wks - 6 months for a response

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Rheumatoid Arthritis choice of DMARDs

• cost
• convenience of administration
• convenience of toxicity monitoring
• compliance
• comorbid disease
• toxicity
• severity and prognosis of patient

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• hydroxychloroquine retinal toxicity, diarrhea
• sulfasalazine bone marrow suppression, GI
  intolerance
• HCQ and sulfasalazine are often initially
  selected for milder disease because of the safety
  and convenience of the drugs
• need semiannual eye exam for HCQ

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• methotrexate bone marrow suppression, hepato
  and pulmonary toxicity GI intolerance,
  stomatitis, rash
• MTX is selected for more severe disease
• has the most rapid onset and sustained benefit
• given on a weekly basis
• requires close monitoring

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• gold salts bone marrow suppression, rash,
  stomatitis, proteinuria
• administered intramuscularly on a weekly basis
  for 3-5 months, followed by less frequent dosing
• requires close monitoring of bone marrow and
  renal toxicity

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• azathioprine bone marrow suppression, hepatoto
  xicity, GI symptoms
• AZA is used when disease activity persists on
  other DMARDs
• may be safer than MTX for patients gt 65 years
  with renal insufficiency

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• D-penicillamine bone marrow suppression, rash,
  stomatitis, dysgeusia, proteinuria, autoimmune
  disease
• d-penicillamine is used when disease activity
  persists on other DMARDs
• associated with high incidence of lupus,
  myasthenia gravis, pemphigus, Goodpastures

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• cyclophosphamide bone marrow suppression hemorrha
  gic cystitis, malignancy, infertility
• oral immunosuppressive agent, very toxic
• used for severe vasculitis and other
  extra-articular involvement

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• cyclosporin A renal toxicity, hypertension hepato
  toxicity
• oral immunosuppressive agent
• not yet approved for treatment of RA by the FDA

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Rheumatoid Arthritis choice of DMARDs

• Drug Side Effects
• cyclosporin A renal toxicity, hypertension hepato
  toxicity
• oral immunosuppressive agent
• not yet approved for treatment of RA by the FDA

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Rheumatoid Arthritis glucocorticoids

• the most potent and rapidly acting
  anti-inflammatory agent
• used as a bridge therapy until DMARDs become
  effective local injection is efficacious and
  less toxic than DMARDs
• low dose systemic therapy, may slow the rate of
  joint damage, and is effective in refractory RA

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Rheumatoid Arthritis glucocorticoids

• Side effects
• osteoporosis, cushingoid state, hypertension,
  premature athersclerosis, infection
• Reducing the risk of osteoporosis
• regular exercise, timely estrogen therapy,
  supplemental calcium and vitamin D
• calcitonin or biphosphonates in patients with low
  bone mass and refractory to hormone replacement
  therapy

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Rheumatoid Arthritis new drug therapies

• Tetracycline
• radiation synovectomy with isotopes
• immunotherapy anti-CD4 monoclonal
  antibodiesanti-TNF-? antibodiesanti-IL-2r

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Rheumatoid Arthritis surgical therapy

• to prevent damage to joints or tendons by
  inflammatory synovium
• to correct structural joint damage resulting in
  discomfort and limitation of function
• most useful for upper extremity
• tenosynovectomy for exuberant nodule formation or
  synovitis in extensor tendons
• joint fusion or joint replacement

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Rheumatoid Arthritis prognosis

• Progressive in 2/3 of patients resulting in
  disabling and destructive disease
• 20 may have mild and intermittent course
• 10 may achieve complete remission
• factors predicting poor prognosismale, age gt50,
  poor functional capacity, positive RF, presence
  of nodules, HLA-DR4 haplotype

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Rheumatoid Arthritis prognosis

• 3- to10-years decrease in survival in 50 of
  patients
• cause of premature death
• cardiovascular
• malignancy
• infection or sepsis
• vasculitis, rheumatoid lung
• GI hemorrhage and perforation

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References

• The American Rheumatism Association 1987 revised
  criteria for the classification of rheumatoid
  arthritis. Arthritis Rheum 198831315-324
• Ad Hoc Committee on Clinical Guidelines
  Guidelines for the management of rheumatoid
  arthritis. Arthritis Rheum 199639713-722
• Ad Hoc Committee on Clinical Guidelines
  Guidelines for monitoring drug therapy in
  rheumatoid arthritis. Arthritis Rheum
  199639723-731
• Am College of Rheumatology Task Force on
  Osteoporosis Guidelines Recommendations for the
  prevention and treatment of glucocorticoid-induced
  osteoporosis. Arteritis Rheum 1996391791-1801