Rheumatoid%20arthritis Treatment

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% clinical improvement in a validated disease activity measure within 3 months and achievement of remission or low disease activity within 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 first 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 combination therapy with DMARDs has been shown to provide benefits for symptomatic control
• If the treatment goal has not been achieved with the first 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
• Consider reducing DMARD dose in patients in sustained remission after corticosteroid discontinuation  
• Prophylactic antiviral therapy for hepatitis B infection is recommended over frequent monitoring alone for patients with chronic (HBsAg positive) and occult (HBsAg negative, anti-HBc positive and HBV DNA positive) HBV infection who will be starting bDMARD or tsDMARD therapy

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 csDMARD with long-term glucocorticoid therapy in DMARD-naive patients with moderate to high disease activity

Methotrexate

• Should be considered first 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
  • Efficacy is similar to Leflunomide

Other csDMARDs

• Eg Azathioprine, Ciclosporin, 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 
• 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 recommended 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

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
  • Results from the RA-BUILD trial, which is a phase III study of Baricitinib, showed clinical improvement and inhibition of progression of radiographic joint damage in patients with moderately-severely active RA who were refractory to or intolerant of csDMARDs   
  • Results from the RA-BEYOND study showed up to 7 years of maintenance in efficacy of Baricitinib in the treatment and maintenance of physical function of patients with moderate-severe RA who are refractory to or intolerant of csDMARDs
  • 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 first-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) may 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 first
  • 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 and/or 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, Rofecoxib, Valdecoxib (cyclooxygenase-2 [COX-2]-selective 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 cyclooxygenase
• 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

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
  • Aerobic exercises improve cardiorespiratory fitness and muscular endurance and include aerobics, biking or cycling, hiking, rowing, running, swimming, use of elliptical machine and walking 
  • Aquatic exercises are exercises done in water (eg swimming, water aerobics, water jogging or walking)   
  • Resistance exercises increase muscular strength (eg free weights, resistance bands, Pilates, weight machines)     
  • Mind-body exercise combines movement, mental focus and controlled breathing (eg qigong, tai chi, yoga)
• 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

Rehabilitation

Comprehensive Occupational Therapy

• Helps patients maximize physical function and improve their level of independence
• Focus of therapy is on upper extremity activities
• May involve activity pacing, education on joint protection techniques and self care, evaluation of daily living activities and training, pain and stress management training, exercises to improve and maintain the range of motion of joints (eg hand therapy exercises), environmental adaptations, provision of assistive and adaptive devices and splinting, orthoses or compression    
  • Activity pacing involves approaches to balance activity and rest to perform activities including activity pacing, energy conservation, activity modification and fatigue management techniques   
  • Joint protection techniques provided to patients help maintain joint function by altering work methods and movement patterns of affected joints to reduce pain, inflammation and joint stress 
  • Adaptive equipment are devices used for daily living assistance (eg built-up and/or long-handled equipment, button hook, cellphone holders, pill cutters, reachers, sock aide) 
  • Hand exercises help improve mobility and hand strength  
  • Environmental modifications for safety improvement (eg adaptations for toileting [raised toilet seat, commode, toilet safety rail], showering [handheld shower, tub seat, walk-in bath], grab bars, ramps, stair lifts, home modification)  
  • Assistive devices are used for mobility assistance (eg canes, crutches, scooters, tricycles, walkers, wheelchairs)    
  • Bracing and orthoses (eg compression gloves, foot or knee orthoses, finger and wrist splints, taping) to correct and support musculoskeletal function, improve joint alignment or for joint protection 
• May also consider vocational rehabilitation, evaluations and/or modifications in the work site, work simplification and fatigue management, work and leisure counseling or rehabilitation, work site assessment, sexual advice, relaxation, pain and stress management training    
  • Vocational rehabilitation involves training programs for overcoming barriers to successful employment   
  • Work site evaluation and modifications involve evaluation of and adjustment of work site conditions and duties for patient safety and well-being 

Comprehensive Physical Therapy

• Aimed to provide pain relief, reduction of inflammation and preservation of joint integrity and function
• Involves passive and active exercises, energy conservation, electrotherapy, functional training and physical activity, heat or cold application, instruction on the use of assistive devices, manual therapy, mobility and gait training, orthoses application, pain management (eg thermal therapy), self-management education and workplace accommodations 
• Podiatry referral should be offered to all patients
  • Rheumatoid arthritis patients with foot problems (eg pain or foot alignment abnormalities) are advised to use functional insoles or therapeutic footwear

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 whole grains, nuts, seeds, fruits, fish and vegetables, less meat, and plant oils

Other Integrative Interventions

• May include acupuncture, chiropractic, electrotherapy, massage therapy, thermal modalities, tobacco cessation and vagal nerve stimulation    
  • Acupuncture involves stimulation of specific body points through thin needle insertion   
  • Chiropractic involves diagnosis and manipulation of malaligned joints especially the spine   
  • Electrotherapy involves use of heat and cold for medical therapy (eg cryotherapy, heat, infrared sauna, laser therapy, paraffin therapy, therapeutic ultrasound)   
  • Massage therapy involves using the hands to rub and knead muscles and joints (eg deep tissue, Swedish, trigger point)   
  • Tobacco cessation involves counseling, participation in tobacco cessation programs, use of nicotine replacement therapies or use of medications without nicotine  
  • Vagal nerve stimulation is the implantation of a device to stimulate the vagus nerve with electrical impulses       

Cognitive Behavioral Therapy 

• Psychological therapy for identification and changing of thought and behavior patterns   

Mind-Body Approaches   

• Techniques to engage both mind and body functions (eg biofeedback, breathing exercises, goal setting, guided imagery, meditation, mindfulness, progressive muscle relaxation)   

Self-Management Program   

• Standardized program for self-management guidance (eg Arthritis Self-Management Program, Better Choices Better Health, Chronic Disease Self-Management Program, On-Demand Program to EmpoweR Active Self-Management [OPERAS], Rheumatoid Arthritis Self-Management Intervention)