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) should be initiated to control the signs & symptoms of rheumatoid arthritis & to limit radiographic damage
    • Baseline studies should be obtained prior to initiation of treatment
  • 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 or Jak-inhibitor should be considered
  • As initial short-term treatment, use of corticosteroids or NSAIDs as either monotherapy or combination therapy with DMARDs has been shown to provide benefits for symptomatic control 
  • Methotrexate should be part of the 1st treatment strategy in patients with early & established rheumatoid arthritis
    • Leflunomide or Sulfasalazine should be used when patient has contraindications to Methotrexate therapy
  • In DMARD-naive patients, non-biological DMARD monotherapy & combination therapy should be considered
    •  Combination with biological & Jak-inhibitor DMARDs is recommended
  • For patients who are unable to tolerate non-biological DMARD therapy, IL-6 pathway inhibitor & Jak-inhibitor monotherapy are preferred over other biological DMARDs
  • In the presence of treatment failure with a biological DMARD or Jak-inhibitor, consider switching to another biological DMARD or Jak-inhibitor
  • May consider treatment with another TNF-inhibitor or other DMARDs if patient is unresponsive to previous treatment with a TNF-inhibitor
  • For patients in persistent remission, may considering tapering biologic DMARD therapy after tapering glucocorticoid therapy
    • Tapering of conventional synthetic DMARD therapy may also be considered

Pharmacotherapy

Non-biological (Conventional Synthetic) 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 or Sulfasalazine should be started as early as possible & in cases of persistent symptoms starting within 3 months of onset
  • Methotrexate & Leflunomide are preferred to Sulfasalazine in patients with high disease activity

Gold Salts (Parenteral)

  • Recommended as part of the early 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

  • 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
  • In cases of mild or palindromic cases, Hydroxychloroquine is an alternative to oral Methotrexate, Leflunomide or Sulfasalazine

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

  • Recommended as part of the initial treatment strategy 
  • 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, Sarilumab, Tocilizumab
  • 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
  • Sarilumab is an interleukin-6 receptor antagonist recently approved for patients with moderate to severe RA with treatment failure after treatment with one or more DMARDs
  • Other non-TNF biologicals currently being investigated for rheumatoid arthritis include Clazakizumab, & Sirukumab which,based on several studies, showed that the efficacy & safety are comparable to Tocilizumab
    • Studies showed that the efficacy of Sirukumab for moderate to severe RA is promising but approval for use is yet to be given due to reports of increased mortality

Targeted Synthetic DMARDs

  • Eg Baricitinib, Tofacitinib
  • Janus kinase (Jak) inhibitors are recommended for patients with treatment failure after biologic DMARDS
    • May also be considered as initial therapy in DMARD-naive patients
  • Tofacitinib inhibits Jak-1 & Jak-3 activity, but may also affect all the Jak isoforms
    • Studies showed that treatment with Tofacitinib was more beneficial when compared to placebo therapy in patients with active RA with inadequate response to Methotrexate
    • One study showed that Tofacitinib monotherapy resulted in significant reductions of signs & symptoms in patients with active RA
  • Baricitinib is a Jak-1 & Jak-2 inhibitor that showed better efficacy when compared to placebo & other active DMARDs in several studies
    • One study suggested that Baricitinib whether given alone or in combination with Methotrexate showed better efficacy rates than a TNF-inhibitor in patients with active RA with inadequate response to Methotrexate
  • Further long-term studies are needed to make a recommendation whether efficacy & safety is better when given to patients as monotherapy or in combination with conventional DMARDs

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

  • Eg Paracetamol, Aspirin 
  • 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 
  • In cases of recent onset or established disease flares on adults, short-term treatment may be started to rapidly decrease inflammation 
  • 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
    • Short-term use may be considered during initiation of or when switching to non-biological DMARDs
    • Long-term use may be continued in patients with established disease if all treatment options including biological & targeted synthetic DMARDs has been offered provided that the long-term complications has been fully disclosed 
    • 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) (1000-1200 mg) & vitamin D (600-800 IU) should be given to limit bone demineralization
  • Fracture risk assessment should be done in patients with & without established osteoporosis but with moderate to high fracture risk

Nonsteroidal Anti-inflammatory Drugs (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 to be taken for the shortest possible time

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
    • All adults with rheumatoid arthritis are advised to use functional insoles or therapeutic footwear

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
  • Patients may follow principles of Mediterranean diet which is composed of a diet rich in bread, fruits, fish & vegetables, less meat, & plant oils

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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