Rheumatoid Arthritis

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Rheumatoid Arthritis Anti-CCP Antibody

• Ryan Griffiths, MD
• AM Report
• Aug. 28th, 2007

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Comparison
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Epidemiology

• Most common autoimmune disease
• Affects 1 of the worlds population
• In pts lt60 3-51 female predominance

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Pathogenesis

• Autoimmune inflammatory destruction of the
  synovium
• AKA pannus
• A proliferative mass of inflammatory vascularized
  tissue
• Can erode into bone and cartilage
• Aided by local generation of metalloproteinases

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RA Classification criteria 1987 American
College of Rheumatology

• Morning stiffness in and around the joints
  lasting at least 1 hour
• At least 3 joint areas simultaneously have had
  soft tissue swelling or fluid (PIP, MCP, wrist,
  elbow, knee, ankle, and MTP)
• At least 1 area swollen (as defined above) in a
  wrist, MCP, or PIP joint
• Symmetical involvement of the same joint areas
  (as defined in 2)
• Subcutaneous nodules over bony prominences,
  extensor surfaces, or in juxta-articular regions
• Postive serum Rheumatoid Factor
• Radiographic changes typical of rheumatoid
  arthritis on hand and wrist radiographs (must
  include erosions or unequivocal bony
  decalcification)
• Need 4 of 7 for Diagnosis

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Laboratory tests

• ESR CRP
• RF (usually IgM)
• ANA
• Anti-CCP (cyclic citrullinated peptide)

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Rheumatoid Factor (RF)

• RFs are human auto-Abs that react with the Fc
  portion of normal polyclonal IgG.
• Most routine clinical assays for RF detect only
  IgM RFs, although RFs can be any class of
  immunoglobulin
• Named thus because their first description was in
  patients with rheumatoid arthritis

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Rheumatoid Factor (RF)

• RF test is approximately 65-75 sensitive for
  the diagnosis
• The presence of RF, even in high titers or large
  amounts, is not specific for RA

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Conditions Assoc. with () Tests for Rheumatoid
Factor

• Rheumatologic Diseases
• Rheumatoid arthritis (70)
• Sjögrens syndrome (90)
• Lupus (20)
• Cryoglobulinemia syndrome (90)
• Lung Diseases
• Interstitial fibrosis
• Silicosis
• Infections
• Hepatitis C virus
• Acute viral infections
• Endocarditis
• Tuberculosis
• Miscellaneous
• Sarcoidosis
• Malignancies

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Anti-CCP

• There are other RA-associated auto-Abs known to
  be specific for rheumatoid arthritis
• Perinuclear factor
• Antikeratin antibodies
• They are not widely used due to technical
  difficulties with their detection

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Anti-CCP

• The epitopes of the antigens (target of Abs) are
  arginyl residues
• These are converted citrullinated by an enzyme
  to citrulline (an amino acid)
• These citrullinated epitopes are recognized by
  other RA-assoc. Abs

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Anti-CCP

• Citrullinated peptides have been synthesized as
  Ags for diagnostic immunoassays
• ELISA
• Wells coated w/ cyclic citrullinated peptides
• Exposed to RA pts serum
• Colorimetric response in Ag-Ab binding

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Meta-analysis

• Diagnostic Accuracy of Anti-CCP Antibody and RF
  for Rheumatoid Arthritis
• Ann Intern Med. 2007146797-808.
• 37 studies of anti-CCP antibody and 50 studies of
  RF
• pooled sensitivity, specificity, and () and (-)
  LRs

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Meta-analysis

• Six studies assessed associations with anti-CCP
  antibody positivity
• All reported that anti-CCP antibody positivity
  was a statistically significant risk factor for
  radiographic progression.
• Of the 4 studies that examined anti-CCP antibody
  and RF
• 3 reported that the risk for radiographic
  progression was greater for patients with
  anti-CCP than for those with IgM RF positivity.

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Anti-CCP

• Anti-CCP antibodies are locally produced in
  inflamed joints
• Anti-CCP antibody is present before symptoms
  develop, therefore,
• Frequently () early in the course of RA when the
  diagnosis may be uncertain.
• Unlike RF, anti-CCP is not associated with Hep C
  infection

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Prognosis

• Presence of CCP antibodies is associated with
  development of erosive arthritis.
• The presence of anti-CCP in high titer has
  important prognostic implications
• Anti-CCP helps in predicting which RA patients
  will have persistent disease, and erosive disease

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Treatment

• Defining markers of a bad prognosis early on in
  RA facilitates therapeutic decision-making.
• New emphasis on more aggressive therapy early on
  in disease course ? Decreases joint morbidity
• Additional markers of a worse prognosis
• elevated markers of inflammation (ESR and CRP)
• rheumatoid nodules
• extra-articular features
• larger numbers of active joints
• early functional impairment
• early appearance of erosions.

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DMARDs

• 1st line MTX, leflunomide, hydroxychloroquine,
  or sulfasalazine
• 2nd line anti-TNF Abs
• Etanercept
• Infliximab
• Adalimumab
• 2nd line also Cyclsporine and combos

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DMARDs

• BeSt (2005) trial actually showed that
  combination (ie. MTX Infliximab) therapy was
  superior to the previous thinking of sequential
  therapy.
• Many of the patients in the initial combo arm
  were able to have their therapy tapered, or even
  discontinued, while maintaining low levels of
  disease activity
• Suggests that early aggressive therapy may be
  able to change the course of RA.

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