rheumatoid%20arthritis
RHEUMATOID ARTHRITIS

Rheumatoid arthritis is a systemic autoimmune rheumatic disorder of unknown etiology.
It is the most common form of inflammatory arthritis.
Patient usually complains of joint pain and/or swelling with morning stiffness that lasts for more than an hour.

Goals of treatment are clinical & radiological remission of disease and to reduce functional limitations & permanent joint damage.

Principles of Therapy

Goals of Early Treatment

  • To achieve clinical & radiological remission of disease
    • Low disease activity is a treatment goal alternative in long standing disease
  • To reduce functional limitations & permanent joint damage

Principles of Treatment

  • It is recommended that early treatment with disease-modifying antirheumatic drugs (DMARDs) is initiated to control the signs & symptoms of rheumatoid arthritis & to limit radiographic damage
  • A treat-to-target strategy is recommended
  • Treatment should also be adjusted at least every 3 months with strict monitoring
  • Treatment target is almost reached within 3 months & may be attained by the end of 6 months
    • During 3-6 month period, meticulous follow-up should be done & existing treatment should be intensified or changed for another
  • If the treatment target has not been achieved with the 1st DMARD strategy, in the absence of poor prognostic factors, switching to another non-biological DMARD should be considered
    • If poor prognostic factors are present, addition of a biological DMARD may be considered
  • DMARD treatment should be started upon diagnosis of rheumatoid arthritis
    • Baseline studies should be obtained prior to initiation of treatment
  • Methotrexate should be part of the 1st treatment strategy in patients with early & established rheumatoid arthritis
  • In DMARD-naive patients, non-biological DMARD monotherapy & combination therapy should be considered
  • As initial short-term treatment, addition of corticosteroids to either monotherapy or combination therapy with DMARDs has been shown to provide benefits
  • Adjunctive therapies eg corticosteroids, NSAIDs are given initially for control of symptoms

Severity of Disease

  • May be used as the basis for the treatment approach
  • Rheumatoid arthritis can be characterized as mild, moderate or severe which is best applied to untreated patients

Mild Disease

  • Patients meet the criteria for rheumatoid arthritis, have <6 inflamed joints, with absence of extra-articular involvement & evidence of bone erosions or cartilage loss on X-ray

Moderate Disease

  • Patients have 6-10 inflamed joints
  • Presence of some of the following: elevated erythrocyte sedimantation rate (ESR) &/or C-reactive protein (CRP), positive rheumatoid factor (RF) &/or anti-citrullinated protein antibody (ACPA), appearance of inflammation as well as minimal joint space narrowing & small peripheral erosions on X-ray, absence of extra-articular disease

Severe Disease

  • Patients have >20 inflamed joints, elevated erythrocyte sedimantation rate &/or C-reactive protein
  • Presence of ≥1 of the following clinical features: anemia of chronic disease &/or hypoalbuminemia, positive rheumatoid factor &/or anti-citrullinated protein antibody, appearance of bone erosions & cartilage loss on X-ray, presence of extra-articular disease

Tapering of DMARDs

  • In persistent remission of at least 12 months, biological DMARDs should be slowly tapered by expanding the interval between doses or dose reduction, while continuing non-biological DMARDs
  • Ceasing treatment with non-biological DMARDs is associated with increased flare frequency, hence tapering should be done cautiously & should be evaluated rigorously

Pharmacotherapy

Non-biological DMARDs

  • Have the potential to reduce or prevent radiographic progression, improve joint function, maintain joint integrity, & improve the signs & symptoms of rheumatoid arthritis (RA)
  • Choice of initial DMARD should be based on patient’s preferences & existing comorbidities
  • There is no strong evidence that there is a difference in efficacy or safety among Methotrexate, Leflunomide or Sulfasalazine
  • Methotrexate & Leflunomide are preferred to Sulfasalazine in patients with high disease activity

Gold Salts (Parenteral)

  • Recommended as part of the initial treatment strategy in patients with contraindication to or intolerance of Methotrexate
  • Patients shows improvements from disappearance of rheumatoid nodules, reduction of joint swelling & a fall with C-reactive protein (CRP) levels

Hydroxychloroquine & Chloroquine

  • Is the same as the other DMARDs on its slow onset action, however, fails to show evidence for radiological protection, thus, is not considered a true DMARD
  • Show efficacy as monotherapy or in combination therapy
  • Hydroxychloroquine is a treatment option for patients with early or established rheumatoid arthritis if Methotrexate is unavailable or with intolerance

Leflunomide

  • Recommended as part of the initial treatment strategy in patients with contraindication to or intolerance of Methotrexate
  • It is recommended for all degrees of disease activity, irrespective of poor prognostic features

Methotrexate

  • Preferred DMARD for both early & established rheumatoid arthritis 
  • Preferred agent for most combinations & DMARD of choice due its more favourable efficacy and toxicity profiles
  • Can increase the efficacy of biologic DMARDs when used in combination
  • Considered as one of the most active compounds in terms of frequency of remissions & time to onset of action

Sulfasalazine

  • Recommended as part of the initial treatment strategy in patients with contraindication to or intolerance to Methotrexate
  • One of the most active compounds in terms of frequency of remissions & time to onset of action
  • Provides a good risk-benefit ratio

Biological DMARDs

  • Biologic DMARDs generally target cytokines or their receptors or are directed against other cell surface molecules
  • Monotherapy recommended for early RA patients including all levels of disease activity (low to high)
  • The American College of Rheumatology (ACR) recommends killed (pneumococcal, influenza, hepatitis), recombinant (HPV) and live attenuated (herpes zoster [except for TNF inhibitors and non-TNF biologics]) vaccines before and during initiation of DMARD therapy

TNF Inhibitors/Anti-TNF Biologicals

  • Eg Adalimumab, Certolizumab pegol, Etanercept, Infliximab, Golimumab
    • Adalimumab is a human-sequence antibody that specifically binds to TNF-α & blocks interaction with cell-surface TNF-α receptors to neutralize its biological function (ie changes in adhesion molecule levels that causes leukocyte migration)
    • Certolizumab pegol is a TNF-α specific Fab fragment of humanized monoclonal antibody which highly binds with soluble & membrane-bound TNF-α that causes inhibition of its activity
    • Etanercept is a recombinant human TNF-α receptor fusion protein that interferes with inflammatory cascade by binding to TNF-α & then blocking its interaction with cell-surface receptors
    • Infliximab is a chimeric monoclonal antibody that neutralizes TNF-α function by binding to it
    • Golimumab is a human monoclonal antibody specific for TNF-α & prevents its interaction by forming high affinity complexes
  • Recommended for the following:
    • Early rheumatoid arthritis patients with high disease activity (with or without Methotrexate)
    • Established RA patients with low disease activity where DMARD monotherapy with added Methotrexate, Hydroxychloroquine & Leflunomide have failed
    • Established RA patients where 1st TNF inhibitor regimen has failed (ACR recommends switching to another TNF inhibitor or replacing the TNF inhibitor with Abatacept, Rituximab or Tocilizumab)
    • Adalimumab, Etanercept & Certolizumab may be given as monotherapy in patients with intolerance of Methotrexate or if treatment with Methotrexate is considered to be inadequate
    • Certolizumab in combination with Methotrexate is indicated for the treatment of moderate-severe rheumatoid arthritis in patients whose response to non-biological DMARDs including Methotrexate, has been inadequate
  • All have been shown to have similar efficacy for clinical remission
  • Not recommended in patients with severe, active & progressive rheumatoid arthritis not previously treated with Methotrexate or other DMARDs
  • Reassess treatment effects every after 3 months
  • Have been shown to increase the risk of serious infection, & risk of malignancy
  • Contraindicated in patients with severe congestive heart failure

Non-TNF Biologicals

  • Eg Abatacept, Rituximab, Tocilizumab, Tofacitinib
  • Reassess treatment effects after 6 months instead of 3 months due to longer peak time in non-TNF biologics
  • Abatacept or Rituximab is recommended for established RA patients with low disease activity or moderate-high disease activity intolerant or unresponsive to Methotrexate monotherapy or combination DMARD therapy
  • Abatacept is recommended for patients with contraindication to Rituximab, or when Rituximab is withdrawn due to adverse effect
  • Treatment period of Rituximab should not be more frequent than every 6 months
  • Abatacept-Methotrexate combination is recommended when double DMARD regimen results in treatment failure or toxicity
  • Switching to Tocilizumab is recommended when Rituximab or Abatacept regimen results in treatment failure after 6 months
  • Resuming or starting Rituximab is recommended in rheumatoid arthritis patients with a previously treated melanoma skin cancer, lymphoproliferative malignancy, solid malignancy or nonmelanoma skin cancer within the last 5 years

Combination Therapy

  • A combination DMARD strategy, rather than sequential monotherapy, should be considered in patients with an inadequate response to initial DMARD therapy
  • For early RA, combination of DMARDs (including Methotrexate & another DMARD with short-term corticosteroids) can be considered as 1st-line treatment
  • Recommended combinations include double & triple therapy (Methotrexate, Hydroxychloroquine & Sulfasalazine)
  • Examples for double DMARD therapy include Methotrexate & Hydroxychloroquine, Methotrexate & Leflunomide, Methotrexate & Sulfasalazine, & Sulfasalazine & Hydroxychloroquine
  • For patients where DMARD combination therapy is not appropriate, start DMARD monotherapy
  • Combinations of non-biological & biological DMARDs have been used to treat moderate-severe rheumatoid arthritis
  • Most combinations use Methotrexate as a background drug
  • Recommended for all early rheumatoid arthritis patients with poor prognosis including all levels of disease activity (low to high), & established rheumatoid arthritis patients with low disease activity & poor prognosis or moderate-high disease activity
  • Combination therapy of Methotrexate & biologic DMARDs may be considered in DMARDs-naive patients with poor prognostic factors

Adjunctive Therapy

Analgesics

  • Used as an adjunct to DMARD & NSAID therapy to provide pain relief

Corticosteroids

  • Low-dose oral corticosteroids can be used in combination with DMARD therapy for short term relief of signs and symptoms, and in the medium to long term to minimize radiological damage
  • It has been shown to improve symptoms of rheumatoid arthritis & reduce radiological damage 
  • May be considered in patients with moderate to high disease activity in early rheumatoid arthritis
  • Timely dose reductions & cessation are important because of the adverse effects associated with long-term use of corticosteroids
    • In cases of persistent remission involving combination therapy with DMARDs, corticosteroids should be tapered first
  • Intra-articular corticosteroids are used to provide rapid, symptomatic relief in the target joints
    • May be administered to any joint not >3-4x/year
  • Oral supplementation with daily calcium (Ca) (1500 mg) & vitamin D (400-800 IU) should be given to limit bone demineralization

NSAIDs

  • Interferes with prostaglandin synthesis through inhibition of the enzyme cyclo-oxygenase
  • Reduces pain, swelling & stiffness caused by rheumatoid arthritis
  • Gastroprotection should be introduced for patients with rheumatoid arthritis at risk of NSAID-associated gastroduodenal ulcers
  • Lowest NSAID dose compatible with symptom relief should be prescribed

Non-Pharmacological Therapy

Exercise

  • Has been shown to increase muscle strength, improve muscle function & joint stability, increase aerobic capacity & physical performance
  • Can improve the overall pain control & quality of life without increase in disease activity
  • Range of motion exercises help restore or preserve joint motion
  • Exercise programs should be tailored based on patient’s disease severity, body build & previous activity level

Physical Therapy

  • Aimed to provide pain relief, reduction of inflammation & preservation of joint integrity & function
  • Involves passive & active exercises to improve & maintain the range of motion of joints, heat or cold application & relaxation techniques
  • Podiatry referral should be offered to all patients

Occupational Therapy

  • Helps patients maximize physical function & improve their level of independence
  • Focus of therapy is on upper extremity activities
  • May involve education on joint protection & self care, & instruction on the use of assistive devices

Nutrition Therapy & Weight Management

  • Encourage obese patients to lose weight
  • Food rich in fish oil or eicosapentaenoic acid or docosahexaenoic acid may provide decrease in symptoms

Splints

  •  Resting & working splints have been shown to provide pain relief, increase joint stability & improve function

 Vaccinations

  •  Influenza & pneumococcal vaccines should be administered to all rheumatoid arthritis patients who are going to be or are already treated with immunosuppressive medications
  •  Should give Hepatitis B vaccine prior to treatment with Methotrexate, Leflunomide & all biologic DMARDs
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