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Rheumatoid arthritis

Definition
  • Chronic inflammatory condition primarily affecting the small joints of the hands and feet
Risk Factors
  • Genetic
  • Smoking?
Differential diagnosis
Epidemiology
  • Prevalence 1% to 2%
  • Incidence 0.25 - 0.4 per 1000 person years
  • Patients are usually in their 50s when diagnosed 
  • In younger patients, females have a 2:1 predominance but as age increases this becomes closer to 1:1.
Aetiology
  • Aetiology is unclear
  • The presence of major histocompatibility complex class II allele HLA (human leukocyte antigen) DRw4 is more common in patients with RA
    • The product of RA-related HLA alleles shares an amino acid sequence that has been named the shared epitope and seems to be involved in the pathogenesis of RA
  • Certain genetic variants of PTPN22 and other genes were identified as a risk factor for RA. [10]
  • An infection as a triggering factor for RA in genetically susceptible individuals has been proposed but no specific infectious agent has been identified so far
Clinical features
  • active symmetric arthritis lasting >6 weeks
  • age 50-55 years
  • female
  • joint pain and swelling
  • rheumatoid nodules over the extensor surfaces of tendons
    • Only seen in very active disease
  • symptoms worse in the morning
Pathophysiology
  • Inflamed synovium is central to the pathogenesis
    • Increased angiogenesis
    • Cellular hyperplasia
    • Influx of inflammatory cells
    • Changes in the expression of cell surface adhesion molecules
    • Many cytokines
    • Development of pannus 
  • Synovial lining becomes hyperplastic, with infiltration of the sublining with mononuclear cells including T-cells, B cells, macrophages and plasma cells
  • This formation of locally invasive synovial tissue is characteristic and it is involved in causing the erosions seen in RA
  • Cytokines affect all phases of the inflammatory process
    • Tumour necrosis factor (TNF) and interleukin (IL-1) seem to be the most abundant in the joint
    • Both are stimulators of proliferation, metalloproteinase expression, adhesion molecule expression, and further secretion of other cytokines
  • High levels of metalloproteinase activity are thought to contribute to joint destruction
  • Angiogenesis is active and leads to new blood vessels proliferating to provide for the hypertrophic synovium
  • This very inflammatory setting, when not treated, leads to the eventual destruction of the involved joint.
Investigations
  • Rheumatoid factor (RF)
    • One of the autoantibodies frequently seen in patients with RA
    • Can be seen with other conditions like hepatitis C, chronic infections and other rheumatological conditions
    • Approximately 30% of RA patients are RF negative
    • Values that are very high (i.e., >100 international units) are more specific for RA
      • However, values over 1000 international units are not common
      • Should prompt consideration of other conditions like hepatitis C and cryoglobulinaemia as the cause
  • Anti-cyclic citrullinated peptide (anti-CCP) antibody
    • Positive in 70%-80% of RA patients
    • Helpful in RF-negative patients since it may be positive in these patients
    • If the RF is positive, anti-CCP does not seem to add any valuable information, although it is helpful in early and very early disease.
  • X-rays
    • Erosions start at the margins of the joint and parts of the bone not covered by cartilage
    • Affect the subchondral bone first and later progress to cause joint space narrowing
    • Radiographs are done at baseline and then annually to monitor progress of disease#
    • Even though they are the most pathognomonic signs of RA, erosions are seldom useful for treatment decisions since they are seen in late disease
    • Erosions signify a worse prognosis.
  • Disease activity score(s)
    • On diagnosis it is useful to determine the level of disease activity 
    • Composite disease measures are derived from the ACR (American College of Rheumatology) core data set
    • Includes:
      • tender joint count
      • swollen joint count
      • functional status measured by a health assessment questionnaire (HAQ)
      • multidimensional HAQ (MDHAQ) or its derivatives
      • pain
      • patients and physician global assessment of disease activity
      • either an ESR or CRP as a marker of inflammation.
    • Any three or more of these combined into a composite index can be used for disease activity monitoring
    • Each disease activity measure has its own thresholds of disease activity
    • For consistency the same disease activity measure is used throughout the patient's management
Management

a) conservative
  • The current approach to treatment can be summarised as early and aggressive
b) medical
  • Patients with mild to moderate disease are usually started on a single DMARD
    • Methotrexate is the most common DMARD used first line
    • Other commonly used first-line DMARDs include leflunomide, sulphasalazine, and hydroxychloroquine
    • Hydroxychloroquine is thought to be a less effective DMARD compared to the others
  • If the patient has severe disease with poor prognostic factors a more aggressive approach to initial therapy may be needed
    • Methotrexate plus biological agents, such as a tumour necrosis factor (TNF)-alpha inhibitor or abatacept
    • Occasionally, a biological agents may be started as monotherapy.
  • If a patient has not reached a level of low disease activity after 3 months of a DMARD being started, another DMARD should be added to the treatment regimen
    • A small minority of patients may respond to triple therapy (methotrexate with sulphasalazine and hydroxychloroquine) 
  • If a combination of the more conventional DMARDs fails to control the disease adequately, combination therapy with a biological agent can be tried
  • TNF-alpha inhibitors used for the treatment of RA include etanercept, infliximab and adalimumab.
    • Etanercept is a soluble receptor that binds TNF-alpha
    • Infliximab and adalimumab are monoclonal antibodies to TNF-alpha
      • Adalimumab is the fully humanised version of the two
    • Abatacept is a T-cell modulator considered to be at the same level as a TNF-alpha inhibitor.
  • If a patient still does not improve, a combination of a DMARD with the B-cell inhibitor rituximab or the interleukin 6 inhibitor (IL-6) tocilizumab is used
  • The role of corticosteroids in the treatment of RA is controversial
    • They can be used as an adjunct to the first-line DMARDs in the case of disease flare
    • In addition to working faster than methotrexate and most other DMARDs, corticosteroids also have some disease-modifying effect
    • If corticosteroids are given daily, calcium and vitamin D supplementation and yearly to biannual bone density assessment are recommended
c) surgical

Prognosis
  •  factors suggesting poor prognosis (functional limitation, extra-articular disease, positive rheumatoid factor, positive anti-CCP, bony erosions on radiograph)
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