Rheumatoid%20arthritis Treatment

Treatment

Principles of Therapy

Goals of Early Treatment

To achieve sustained clinical and radiological remission of disease
- May initially consider aiming for low disease activity and then subsequently consider targeting a goal of remission after an individualized and systematic reassessment of the patient
- 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 a shared decision-making approach including patient’s preference, disease activity, safety, patient factors (eg comorbidities), structural damage progression and drug cost and availability
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 (eg CBC, ESR, CRP, liver and kidney function test, chest X-ray) should be obtained prior to initiation of DMARD treatment
- Screen for hepatitis B and C prior to initiating csDMARD therapy and for hepatitis B, HIV and tuberculosis infection (eg tuberculin skin test and interferon-gamma release assays) 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, particularly for patients who have not been treated previously with bDMARDS or tsDMARDS
Disease activity should be monitored frequently, ie every 1-3 months
Treatment goal is at least 50% improvement within 3 months and achieved 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 if without improvement or treatment goal was not reached
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 csDMARD 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 a JAK inhibitor should be considered
For patients who are unable to tolerate csDMARD comedication therapy, IL-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 of a different class or tsDMARD
May consider treatment with another TNF inhibitor/IL-6 receptor antagonist or other DMARDs if patient is unresponsive to previous treatment with a TNF inhibitor or an IL-6 receptor antagonist

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
It is recommended to initiate a csDMARD without long-term (≥3 months) glucocorticoid therapy than with long-term glucocorticoid therapy in DMARD-naive patients with moderate to high disease activity

Methotrexate

Should be considered 1st among the csDMARDs for the initial treatment strategy unless contraindicated
In initiating treatment in DMARD-naive patients with moderate to high disease activity, Methotrexate monotherapy is recommended over the following:
- Sulfasalazine or Hydroxychloroquine (initial treatment options for patients with low disease activity)
- Monotherapy with bDMARD or tsDMARD
- Combination therapy with Methotrexate and a non-TNF inhibitor bDMARD or tsDMARD
Preferred agent for most combinations and DMARD of choice due its more favorable efficacy and toxicity profiles
Can increase the efficacy of biological DMARDs 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 early 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 Azathioprine, Chloroquine, Ciclosporin, Gold salts (parenteral), Hydroxychloroquine
Azathioprine may be used to treat active rheumatoid arthritis; Aspirin, NSAIDs and/or low-dose corticosteroids may be continued during Azathioprine treatment
Ciclosporin may be given for the treatment of severe rheumatoid arthritis in patients unresponsive to conventional therapy, alone or in combination with Methotrexate when the disease has not responded adequately to Methotrexate
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 intolerable
- In cases of mild or palindromic cases without poor prognostic factors, Hydroxychloroquine is an alternative to oral Methotrexate, Leflunomide or Sulfasalazine
- Shows efficacy as monotherapy or in combination therapy

Biological DMARDs (bDMARDs)

Generally target cytokines or their receptors or are directed against other cell surface molecules
Should be added to csDMARDs as combination therapy

Tumor Necrosis Factor (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 Abatacept (costimulation inhibitor); Rituximab (anti-B cell agent); Sarilumab, Tocilizumab (IL-6 receptor antagonists)
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 of 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
Abatacept and Rituximab are not preferred in rheumatoid arthritis-seronegative patients but are beneficial in ACPA-positive patients
Sarilumab is 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 and 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, especially in biologic-naive patients
Do not use a biosimilar if there has been an inadequate response to the bio-originator (or another biosimilar of the same molecule) or vice versa

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
When prescribing a JAK inhibitor, consider risk factors for cardiovascular events and malignancies

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 several clinical 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
- Upadacitinib was superior to Adalimumab in the SELECT-COMPARE trial based on the achievement of a DAS28-CRP score of ≤3.2, ACR50 response rate, change in pain severity score, and change in the Health Assessment Questionnaire-Disability Index (HAQ-DI) at week 12
- In the SELECT-CHOICE clinical trial, Upadacitinib was shown to be superior to Abatacept in the change from baseline in DAS28-CRP and achievement of clinical remission at week 12 in patients with rheumatoid arthritis and inadequate response to bDMARDs but was associated with more serious adverse events
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)

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 or Leflunomide, 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 to 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 csDMARD 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
- Discontinue short-term corticosteroid bridging during csDMARD therapy within 3-6 months; avoid bridging therapy when a bDMARD or tsDMARD is started due to increased risk of infection
After discontinuation of corticosteroids, may consider reducing DMARD dose in patients in sustained remission
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 Aceclofenac, Acemetacin, Diclofenac, Etodolac, Indomethacin, Proglumetacin, Sulindac (acetic acid derivatives); Phenylbutazone (butylpyrazolidine); Celecoxib, Etoricoxib (coxibs); Meloxicam, Piroxicam, Tenoxicam (oxicam derivatives); Dexketoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Loxoprofen, Naproxen (propionic acid derivatives); Nabumetone (other NSAID)
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
- Reduce dose or stop treatment when there is symptom relief with DMARD therapy

Non-Pharmacological Therapy

Exercise

Has been shown to increase muscle strength, improve muscle function and joint stability, increase aerobic capacity and physical performance
Consistent exercise is recommended and may include aerobic, aquatic, flexibility, resistance or mind-body exercise
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 (eg hand therapy exercises), 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 techniques and self care, and instruction on the use of assistive devices
May also consider vocational rehabilitation, ie evaluations and/or modifications in the work site

Nutrition Therapy and Weight Management

Advise patient to regularly exercise and eat a well-balanced diet
Encourage obese patients to lose weight and maintain a healthy body 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