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 and radiological remission of disease and to reduce functional limitations and permanent joint damage.

Rheumatoid%20arthritis Treatment

Principles of Therapy

Goals of Early Treatment

  • To achieve sustained clinical and radiological remission of disease
    • Low disease activity within 6 months is a treatment goal alternative in long-standing disease
  • To reduce functional limitations and permanent joint damage

Principles of Treatment

  • Management should be based on patient’s disease activity, safety, patient factors (eg comorbidities) and structural damage progression 
  • It is recommended that early treatment with disease-modifying anti-rheumatic drugs (DMARDs) should be initiated as soon as a rheumatoid arthritis diagnosis is confirmed to control the signs and symptoms of rheumatoid arthritis and to limit radiographic damage
    • Baseline studies should be obtained prior to initiation of treatment
    • Screen for hepatitis B, HIV and tuberculosis infection before initiating treatment with biological, targeted synthetic or biosimilar DMARDs 
    • ACR and EULAR recommends killed (pneumococcal, influenza, hepatitis B), recombinant (HPV) and live attenuated [herpes zoster (except for TNF inhibitors and non-TNF biologics)] vaccines before initiation of DMARD therapy
      • Killed and recombinant vaccines may be given during treatment with biological DMARDs (bDMARDs) or targeted synthetic DMARDs (tsDMARDs)
      • Live-attenuated herpes zoster vaccine should be administered 4 weeks before treatment initiation and never during treatment with bDMARDs or tsDMARDs
  • A treat-to-target strategy is recommended
  • Disease activity should be monitored frequently, ie every 1-3 months 
  • Treatment goal is almost reached within 3 months and may be attained by the end of 6 months
    • During the 3- to 6-month period, meticulous follow-up should be done and existing treatment should be intensified or changed for another
  • In DMARD-naive patients, conventional synthetic DMARD (csDMARD) monotherapy should be considered
  • Methotrexate should be part of the 1st treatment strategy in patients with early and established rheumatoid arthritis
    • Leflunomide or Sulfasalazine should be used when patient has contraindications to Methotrexate therapy
  • As initial short-term treatment, use of low-dose corticosteroids or nonsteroidal anti-inflammatory drugs (NSAIDs) as either monotherapy or combination therapy with DMARDs has been shown to provide benefits for symptomatic control
  • If the treatment goal has not been achieved with the 1st DMARD strategy, in the absence of poor prognostic factors, switching to or adding another csDMARD should be considered
    • If poor prognostic factors are present, addition of a bDMARD or Jak-inhibitor should be considered
  • For patients who are unable to tolerate csDMARD comedication therapy, interleukin-6 receptor antagonists and tsDMARDs may have some advantages over other bDMARDs
  • In the presence of treatment failure with a bDMARD or tsDMARD, consider switching to another bDMARD or tsDMARD 
  • May consider treatment with another TNF-inhibitor or other DMARDs if patient is unresponsive to previous treatment with a TNF-inhibitor

Pharmacotherapy

Conventional Synthetic DMARDs (csDMARDs)

  • Have the potential to reduce or prevent radiographic progression, improve joint function, maintain joint integrity, and improve the signs and symptoms of rheumatoid arthritis 
  • Choice of initial DMARD should be based on patient’s preferences and existing comorbidities
  • Methotrexate, Leflunomide or Sulfasalazine should be started as early as possible at the time of diagnosis
  • May take up to 8 weeks for effects to be seen thus bridging therapy with corticosteroids is needed

Methotrexate

  • Should be considered 1st among the csDMARDs for the initial treatment strategy unless contraindicated
  • Preferred agent for most combinations and DMARD of choice due its more favorable efficacy and toxicity profiles
  • Can increase the efficacy of biological DMARDs (bDMARDs) if used in combination therapy
  • Considered as one of the most active compounds in terms of frequency of remissions and time to onset of action

Leflunomide, Sulfasalazine

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

Other csDMARDs

  • Eg Gold salts (parenteral), Hydroxychloroquine 
  • Gold salts may be considered as part of the early treatment strategy in patients with contraindication to or intolerance of Methotrexate
    • Patients show improvements from disappearance of rheumatoid nodules, reduction of joint swelling and a fall of CRP levels
  • Hydroxychloroquine is a treatment option used as part of the early treatment strategy for patients with mild 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
    • Shows efficacy as monotherapy or in combination therapy

Targeted Synthetic DMARDs (tsDMARDs)

  • Eg Baricitinib, Tofacitinib, Upadacitinib
  • Janus kinase (Jak) inhibitors are recommended to be added to csDMARDs for patients with treatment failure after csDMARDs monotherapy
  • Other new Jak inhibitors include Peficitinib which has been approved in Japan and Filgotinib which is currently undergoing regulatory evaluation

Baricitinib

  • A Jak-1 and Jak-2 inhibitor that showed better efficacy when compared to placebo and other DMARDs used in several studies
    • In a trial of patients with active rheumatoid arthritis who were receiving background Methotrexate therapy, treatment with Baricitinib demonstrated significant clinical improvements when compared with placebo and Adalimumab in rheumatoid arthritis patients with inadequate response to Methotrexate
    • Further studies are needed to prove its superiority over bDMARDs

Tofacitinib

  • A Jak-1 and Jak-3 activity inhibitor that may also affect all the Jak isoforms showed therapeutic benefits in severalclinical trials
    • In the ORAL Standard trial, significant reductions of signs and symptoms were seen in patients with active rheumatoid arthritis with history of Methotrexate therapy given Tofacitinib compared to those given placebo or Adalimumab
    • In the ORAL Solo and Step trials and in the ORAL Scan and Sync trials, significantly higher ACR20 response rates were seen in patients given Tofacitinib plus Methotrexate after 3 and 6 months, respectively, compared to placebo plus Methotrexate
    • Results of the ORAL Start trial showed significant and clinically meaningful improvements in multiple patient-related outcomes over 24 months with Tofacitinib therapy compared to Methotrexate therapy
    • ACR50 was demonstrated in the ORAL Strategy trial where Tofacitinib plus Methotrexate was given for 6 months, compared to Adalimumab plus Methotrexate and Tofacitinib monotherapy
    • Further studies are needed to prove its superiority over bDMARDs

Upadacitinib

  • A Jak-1 inhibitor that underwent phase III trial testing as monotherapy and combination therapy in various rheumatoid arthritis populations 
    • Results of the Long-Term Extension (LTE) of SELECT-MONOTHERAPY study showed that Upadacitinib monotherapy, when compared to patients who received continued Methotrexate, resulted in continued improvements in the signs and symptoms of rheumatoid arthritis through 84 weeks   
    • Results of the LTE of SELECT-COMPARE study showed higher levels of clinical response, including remission, in patients who received Upadacitinib plus Methotrexate than with Adalimumab plus Methotrexate through 72 weeks   
    • Both SELECT-EARLY and SELECT-COMPARE studies demonstrated radiographic inhibition of structural joint damage in patients receiving Upadacitinib monotherapy or in combination with Methotrexate at approximately 96 weeks
    • Further studies are needed to prove its superiority over bDMARDs
  • Indicated for moderate to severe active rheumatoid arthritis in adults with inadequate response or intolerance to ≥1 DMARDs (with or without Methotrexate or other csDMARDs)

Biological DMARDs (bDMARDs)

  • Generally target cytokines or their receptors or are directed against other cell surface molecules

TNF Inhibitors

  • Eg Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab
  • Binds to TNF-α and blocks interaction with cell-surface TNF-α receptors to neutralize its biological function (ie changes in adhesion molecule levels that causes leukocyte migration)
  • Used in combination with csDMARDs in patients with poor prognostic factors and treatment failure after initial csDMARDs treatment strategy
  • May switch to another TNF inhibitor or to a non-TNF biological in case of treatment failure with current regimen
  • All have been shown to have similar efficacy for clinical remission
  • Reassess treatment effects every after 3 months
  • Have been shown to increase the risk of serious infection and risk of malignancy
  • Contraindicated in patients with severe congestive heart failure

Non-TNF Biologicals

  • Eg (Costimulation inhibitor) Abatacept; (anti-B cell agent) Rituximab; (interleukin-6 receptor antagonists) Sarilumab, Tocilizumab
  • Used in combination with csDMARDs in patients with poor prognostic factors and treatment failure after initial csDMARDs treatment strategy
  • May switch to another non-TNF or to a TNF inhibitor in case of treatment failure with current regimen
  • Reassess treatment effects of Rituximab after 6 months instead of 3 months due to longer peak time in non-TNF biologics
    • Treatment period of Rituximab should not be more frequent than every 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 recently approved for patients with moderate to severe rheumatoid arthritis with treatment failure after treatment with ≥1 DMARDs
  • Other non-TNF biologicals currently being investigated for rheumatoid arthritis include Clazakizumab and Sirukumab which, based on several studies, showed that the efficacy and safety are comparable to Tocilizumab
    • Studies showed that the efficacy of Sirukumab for moderate to severe rheumatoid arthritis is promising but approval for use is yet to be given due to reports of increased mortality

Biosimilar DMARDs

  • Biosimilars of Adalimumab, Etanercept, Infliximab & Rituximab are available
  • Agents that are highly similar to their reference biologics with comparable safety and efficacy 
  • Considered as effective substitutes for bDMARDs and tsDMARDs

Combination Therapy

  • A combination DMARD strategy, rather than sequential monotherapy, should be considered in patients with an inadequate response to initial DMARD therapy
  • Most combinations use Methotrexate as a background drug 
  • Combination of csDMARDs (including Methotrexate and another DMARD with short-term corticosteroids) can be considered as 1st-line treatment
  • Recommended combinations include double and triple therapy (Methotrexate, Hydroxychloroquine and Sulfasalazine)
    • Examples for double DMARD therapy include Methotrexate and Hydroxychloroquine, Methotrexate and Leflunomide, Methotrexate and Sulfasalazine, and Sulfasalazine and Hydroxychloroquine
  • Combinations of csDMARDs and bDMARDs have been used to treat moderate-severe rheumatoid arthritis
  • Combination therapy of Methotrexate and bDMARDs may be considered in DMARD-naive patients with poor prognostic factors
  • For patients in whom DMARD combination therapy is not appropriate, start DMARD monotherapy

Adjunctive Therapy

Analgesics

  • Eg Paracetamol, Aspirin 
  • Used as an adjunct to DMARD and NSAID therapy to provide pain relief

Corticosteroids

  • Eg Oral: Methylprednisolone, Prednisone, Prednisolone; Intra-articular: Betamethasone, Dexamethasone, Methylprednisolone, Prednisolone, Triamcinolone 
  • Low-dose oral corticosteroids (<7.5 mg/day Prednisone equivalent) should be considered in combination with DMARD therapy
    • It has been shown to rapidly improve symptoms of rheumatoid arthritis and reduce radiological damage  
  • May be considered in patients with moderate to high disease activity
  • Timely dose reductions and cessation are important because of the adverse effects associated with long-term use of corticosteroids
    • Short-term use (<3 months) should be considered during initiation of or when switching to another csDMARDs but tapered as rapidly as clinically possible
    • Long-term use may be continued in patients with established disease if all treatment options including bDMARDs and tsDMARDs have been offered provided that the long-term complications have been fully disclosed 
    • In cases of persistent remission involving combination therapy with DMARDs, corticosteroids should be tapered 1st
  •  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 (1000-1200 mg) and vitamin D (600-800 IU) should be given to limit bone demineralization
  • Fracture risk assessment should be done in patients with and without established osteoporosis but with moderate to high fracture risk

Nonsteroidal Anti-inflammatory Drugs (NSAIDs)

  • Eg (Acetic acid derivatives) Aceclofenac, Acemetacin, Diclofenac, Etodolac, Indomethacin, Proglumetacin, Sulindac; (Butylpyrazolidine) Phenylbutazone; (Coxibs) Celecoxib, Etoricoxib; (Oxicam derivatives) Meloxicam, Piroxicam, Tenoxicam; (Propionic acid derivatives) Dexketoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Loxoprofen, Naproxen; (Other NSAID) Nabumetone 
  • Interferes with prostaglandin synthesis through inhibition of the enzyme cyclo-oxygenase
  • Reduces pain, swelling and stiffness caused by rheumatoid arthritis and improves joint function
  • 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 and joint stability, increase aerobic capacity and physical performance
  • Can improve the overall pain control and 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 and previous activity level

Physical Therapy

  • Aimed to provide pain relief, reduction of inflammation and preservation of joint integrity and function
  • Involves passive and active exercises to improve and maintain the range of motion of joints, heat or cold application and 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 and improve their level of independence
  • Focus of therapy is on upper extremity activities
  • May involve education on joint protection and self care, and instruction on the use of assistive devices

Nutrition Therapy and 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 and vegetables, less meat, and plant oils

Splints

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