Rheumatoid Arthritis

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Rheumatoid Arthritis

• About 0.5-1 of adult population
• Characterized by pain, swelling, and destruction
  of joints, with resultant disability
• Untreated, 20 to 30 persons with Rheumatoid
  Arthritis become permanently work-disabled within
  2 to 3 years of diagnosis
• Economic burden direct costs of medial care,
  surgery and hospitalization indirect costs of
  lost productivity and disability
• Significant numbers of RA refractory to both
  conventional therapy and newer biological agents
  such as TNF-a inhibitors

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Rheumatoid arthritis

• Major consequences in RA related to disease
  itself and its associated comorbidities
• Outcomes improved over past few decades with
  advent of new treatments and therapeutic approach
• Still having substantial functional disability
  and loss of ability to work
• Intensive but safe treatments having potential to
  improve long-term outcomes

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Rheumatoid arthritis

• Joint damage, ultimately disability, beginning
  early in the course of RA
• The longer active disease, the less likely
  respond to therapy
• Evidence currently available disease modifying
  antirheumatic drugs (DMARDs) and anticytokine
  agents can control synovitis and may slow, or
  even stop, radiographic progression supporting an
  early aggressive approach to treatment

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Therapies for Rheumatoid Arthritis

• Symptomatic medications, such as corticosteroids,
  NSAIDs, aspirin and analgesics
• Reducing joint pain, stiffness and swelling
• Disease-modifying antirheumatic drugs, such as
  low doses of methotrexate, leflunomide,
  D-Penicillamine, sulfasalazine, gold therapy,
  azathioprine, hydroxychloroquine, cyclosporine
• Could interfere with the disease process
• Biologic agents
• Especially inhibitors of TNF-a, for hitherto
  unseen therapeutic benefit, but frequency and
  degree of responses restricted
• New agents rituximab (anti-CD20), abatacept
  (CTLA-4Ig), tocilizumab (anti-IL6R) etc

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Rheumatoid arthritis

• A consistent trend of declining rates of
  progression of radiographic damage in three
  separate cohorts treated early in the course
  suggestive that early treatment is beneficial
• Coupled with the inability to accurately identify
  individuals with a poor prognosis supporting
  every patient with established active disease
  treated with DMARDs at the earliest stage of
  disease, ideally within three months of onset.

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Early, moderately active rheumatoid arthritis

• Early RA having symptoms/findings of synovitis
  persisting for three months or less, and meeting
  ACR criteria
• Moderately active disease having some combination
  of the clinical features
• This constellation of findings at greater risk of
  developing joint damage and disability
• Presence of moderately active, previously
  untreated (or only NSAID) be treated with DMARD
  in addition to an NSAID

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Early, moderately active rheumatoid arthritis

• Moderately active disease having some combination
  of the following clinical features
• Between 6 and 20 inflamed joints
• Absence of extraarticular disease (most commonly)
  
• Elevated ESR or serum CPR concentration
• Positive RF or presence in serum of anti-CCP
• Evidence of inflammation on plain film
  radiography, findings of osteopenia and
  periarticular swelling no erosions
• A more sensitive modality, such as
  ultrasonography or MRI, may detect erosions of
  bone or cartilage destruction.

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Early, moderately active rheumatoid arthritis

• Initial pharmacologic interventions including
• Full anti-inflammatory doses of NSAIDs
• Single agents or combinations of DMARDs, choice
  of DMARD dependent on
• Relative disease activity, such as the number of
  inflamed joints, the severity of inflammation,
  the number of poor prognostic signs, and the
  degree of functional impairment.
• Some with clinical and laboratory features
  suggesting a poor prognosis being candidates for
  anti-tumor necrosis factor (anti-TNF) alpha
  therapies.

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Rheumatoid arthritis- Remission

• Remission, the best outcome for early therapy
• Best achieved by reducing or eliminating
  inflammation
• Thereby stopping radiographic progression at
  early stage when disease most destructive and
  before joint damage
• Disease activity score (DAS28), the most commonly
  used validated method for measurement of
  remission
• Remission becoming the aim of management of early
  RA

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Rheumatoid arthritis- Remission

• Remission in disease activity and radiographic
  outcomes as primary endpoint in clinical trials
  grown as treatment options improved and
  combined-treatment regimens emerged
• Recent data indicating conventional DMARDs not
  halting radiographic progression, even when
  clinical remission
• Could be attributed to incomplete suppression of
  synovitis
• Combination therapy with methotrexate and
  anti-TNF to be best in this respect, nearly
  halting structural progression and producing and
  clinically relevant responses

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• 1. ????????????????????????????????
  2.
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  ????????DMARD ?????????DAS28 ??,??DMARD
  ?????????????????????????????????X ?????????
  4.
  ?????,????????????DAS28 ??,?????????????????
  5. ?????????(1)(2)(3)??
  ?,???????(4)???,???????(5)???,??????

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• (1) ?????????1987?????????????????
  (2) ????????????
  ? 28 ?????????? (Disease
  Activity Score, DAS 28)????5.1?
  ? ?????????,???????????
  ?,????????????????X ?????????
  ?128 ???????? (????)
  ??,?????????????? DAS28 0.56 vTJC 0.28
  vSJC 0.7 lnESR 0.014 GH
  ?2TJC ?????,SJC
  ?????,ESR ??????? (???mm/h),GH ?100 mm
  ????????????????? (general health status)

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??????????????????????

• (3) ???????????? (Disease-Modifying
  Anti-Rheumatic Drugs, DMARD) ??????????????DMARDs
  (methotrexate ?????,????????????????hydroxychloro
  quine?sulfasalazine?d-penicillamine?azathioprine?l
  eflunomide?cyclosporine ??????) ?????,????????
  ? ???????
  i. DMARD
  ??????,????6 ????,???????????? (????) ????????
  (standard target dose)?
  ii. ????DMARDs
  ????????,???????????,DMARDs ????? (????) ??????
  (therapeutic doses) ??2 ?????
  ? ?????
  DAS28 ???????????(?)1.2,?D
  AS28 ?????3.2 ??

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• (4) ????????
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  iii. ??12
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  ???????,??????????,???? v. ?????????????
  vi. ????????
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  (??????????????10 ????????)
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• (5) ????????
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  ii. ??????????
  iii. ?? (??????)
  iv. ????????? (??????)

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??(????????96?3?)

• ????
• ???54 ???,??????????,??????Etanercept
  (Enbrel)?????????????,DAS ????1.2?,?????????,ESR
  ??,????ESR ??????????????????,????????????????,???
  ???,??DMARDs??,???????????Enbrel?????????????ESR
  ????Enbrel????????,????????
• ????
• ???????

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??(????????96?3?)

• ????
• ?????Etanercept (Enbrel),?DAS28???3.2,???????????
  ????????????ESR ?DAS28 ????????,???ESR
  ?????,????ESR ??????????, ????????Etanercept(Enbre
  l) ????????Etanercept(Enbrel)????????????,??????
  ?,?????

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???????(????????96?3?)

• ????etanercept(?Enbrel)?????,???????????,????????
  
• 1. ESR ?DAS 28 ????????,???ESR ?????????????,????E
  SR ??,???????,?????Etanercept(?Enbrel)?????,??C
  ????(CRP)??????????????,??????Etanercept(?Enbrel)
  ??????CRP ?????
• 2. ???????????(subluxation),????????????????,?????
  ??????,??????????????,????????,?????DAS
  28?????????,???X ??????

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???????(????????96?3?)

• ????etanercept(?Enbrel)?????,???????????,????????
  
• 3.??etanercept(?Enbrel)???,?DAS
  28????????????????,?????????,DAS 28
  ???????????0??????etanercept ???,?????????????????
  ????????etanercept,?DAS 28 ??????????(???????)????
  ????DAS28 ??????gt1.2(????????????),?DAS 28
  ?????3.2,????????
• 4. ????DAS 28 ???,??????????????????????12
  ???????(???)??,???DAS 28 ??????

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???????(????????96?3?)

• ?????????????????
• 1. ?????????,??????????(ACR) ????????,
  ?????DMARDs ??????,????DMARDs????????,??????????(?
  ?etanercept)?????????????????????????????,???????
  ????????
• 2. ?????????????Etanercept(?Enbrel)???????????,??
  ???????????,??????????????????????

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???????(????????96?3?)

• ?????????????????
• 3. ????????Etanercept(?Enbrel)???,???????????????
  ???????????
• 4. ??????Etanercept(?Enbrel)?????,??????????,??X
  ????????????,???????????????????????????????,???
  ??????????????

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?????B??????????????

• Rituximab ???(?Mabthera)????????????????(97/11/1?
  99/2/1)
• 1. ????
• (1) ?????????????? (?etanercept ?adalimumab ?)
  ??,?????,?????????????????????
• I. Etanercept ?adalimumab ?????????DAS28
  ???????????(?)1.2,?DAS28 ?????3.2 ??
• II.???????????etanercept ? adalimumab ???????
• (2) ??methotrexate ??(??methotrexate
  ??,?methotrexate???????????????????????)?

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?????B??????????????

• Rituximab ???(?Mabthera)????????????????(97/11/1?
  99/2/1)
• 1. ????
• (3) ?????????
• I. ???????24 ????,?
• II.?????????? DAS28 ??? ? 3.2,??????rituximab
  ????21 ???,DAS28 ????? ? 0.6?
• (4) ?????????500 ??1,000 ??,????????????,??????
• 2. ?????????????????????????

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?????B??????????????

• 3. ???????????
• (1) ?????????????????????????,????????????DAS28
  ??????????????????HBsAg?Anti-HCV
  ??(?HBsAg?????,???HBV DNA)?
• (2) ???????????????,???????
• I. ??rituximab ??????21 ???DAS28 ???,???????
  1.2,?DAS28 ??? lt 3.2 ?,?????????
• II.?????????????21 ???????1 ??????,???????????2
  ????????,????????????????????????????
• (3)??????????????????

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?????B??????????????

• 4. ????????rituximab ???????
• - ?rituximab ??
• - ????????
• - ?????(New York Heart Association class IV)
• - ???????
• - ????
• - ????????

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?????????????????????

• 1.?????????????????????????
• 2.????????????
• 3.?????????
• (1)??18???
• (2)HLA B27 ??
• (3)X?(plain X Ray)????????????????,??????????????
  ??X??????

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?????????????????????

• 3.?????????
• (4)?????????,????????????
• i.?????????????3????,????????????,????????
• ii.????????,?????????
• iii.????????,?????????
• (5)???????????????2? (NSAIDs)???????,?????????????
  ?????????????????NSAID?????,???????????????,???NS
  AID????????,?????????,??????????????NSAID??????

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?????????????????????

• 3.?????????
• (6)???????????????NSAIDs?sulfasalazine???????,sulf
  asalazine??2 g/day?????4?????,????????????,???????
  ???
• (7)????(1) ???????????????????????????????????(2)?
  ?????????????
• (8)????????????(???????BASDAI 6?ESR gt 28 mm/1
  hr ? CRP gt1 mg/dl,?????????????4????????)
• (9)???????????????????????????????

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?????????????????????

• 4.?????????
• (1)??12????BASDAI??????,??50????????2
  ???,???????
• (2)?????,??12??????
• 5.???????????????,???????????(???????????)
• (1)??????????
• (2)?????????

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?????????????????????

• 5.???????????????,???????????(???????????)
• (3)??????????,??
• i.?????????
• ii.????????(?????TB???,???????????????????,??????,
  ?????????,?????????????????,?????????/???)
• iii.??12????????????
• iv.????????,??????????,????
• v.?????????????
• vi.????????
• (4)????????????(??????????????10????????)

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?????????????????????

• 5.???????????????,???????????(???????????)
• (5)??????(multiplesclerosis)
• 6.????????,?????????????
• (1)?????????????????
• (2)????,??????????????,??
• i.????
• ii.??????????
• iii.??(??????)
• iv.?????????(???????????????)

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Targeted strategies for manipulating the
mechanisms

• Development of biologic therapies target specific
  parts of immune dramatically changed the
  treatment
• By leaving most of immune system intact, these
  finely targeted therapies providing hope for
  safer, yet more effective, treatment
• Biologic response modifiers (BRMs), first
  available TNF-? antagonists
• A central mediator in a number of inflammatory
  arthropathies, including RA and PsA
• An attractive target for biologic therapies in
  1990s

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Rheumatoid arthritis- Remission

• Disease-modifying antirheumatic drugs (DMARDs),
  alone or in combination, been the mainstay of
  treatment for RA
• Clinical remission not commonly reported before
  the era of biological therapy
• New treatment strategies advocating the use of
  earlier, more intensive therapy to prevent joint
  damage and functional disability
• Remission, emerged as a realistic goal,
  especially in patients with early RA

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Thanks for your attention