Rheumatoid Arthritis Điều trị

Evaluation

Several indices, which are developed to assess disease activity, are useful in monitoring the response to therapy and in defining remission. The preferred rheumatoid arthritis disease activity measurements by the American College of Rheumatology for regular clinical use include the Disease Activity Score in 28 Joints (DAS28) with erythrocyte sedimentation rate and C-reactive protein level, Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index, Patient Activity Scale (PAS)-II, and Routine Assessment of Patient Index Data 3 (RAPID 3). The scores are categorized into low, moderate, and high disease activity.

Disease Activity Score 28 (DAS28) 

This index assesses the patient’s rheumatoid arthritis disease by measuring the number of swollen joints in the hands (interphalangeal thumb joints, metacarpophalangeal joints, and/or proximal interphalangeal joints), wrists, shoulders, knees, elbows, and feet (2nd to 5th metatarsophalangeal joints), serum erythrocyte sedimentation rate and C-reactive protein, and the Visual Analogue Score to assess the patient’s global assessment of disease activity on the day of examination. 

The results are combined and assessed based on the total score and are evaluated as:

• <2.6: Disease remission
• 2.6-<3.2: Low disease activity
• 3.2-≤5.1: Moderate disease activity
• >5.1: High disease activity

Clinical Remission 

The goal of treatment is clinical remission (reached after 6 months of therapy) or if unlikely, at least a low disease activity. If the improvement is inadequate (<50% reduction in disease activity) after 3 months of therapy, modification of therapy may be done.

ACR/EULAR proposed two definitions of clinical remission in rheumatoid arthritis and were suggested to be used in clinical trials as an outcome measure and these are one Boolean-based definition and one based on a composite index of rheumatoid arthritis activity.

The Boolean-based definition may be done at any time point and the patient should have all of the following including a tender joint count ≤1 (feet and ankles should be included in the evaluation of the joints), swollen joint count ≤1 (feet and ankles should be included in the evaluation of the joints), C-reactive protein of ≤1 mg/dL, and a patient global assessment of ≤1 (on a scale of 0-10) which is based on the patient’s current feeling about their disease. The other definition is the index-based definition which may also be done at any time point. In this definition, the patient should have an SDAI score of ≤3.3.

Sustained remission is ≥6 months according to the ACR/EULAR Boolean- or index-based definition. Persistent remission is defined as remission of ≥6 months in some studies. According to ACR/EULAR persistent remission is associated with the lowest flare risk and dose tapering. 

Principles of therapy

The first goal of early treatment is to achieve sustained clinical and radiological remission of the disease. One 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.  A low disease activity within 6 months is a treatment goal alternative in a long-standing disease. The second goal of early treatment is to reduce functional limitations and permanent joint damage.

Management should be based on a shared decision-making approach including the patient’s preference, disease activity, safety, patient factors (eg comorbidities), and structural damage progression. It is recommended that early treatment with disease-modifying antirheumatic drugs (DMARDs) should be initiated as soon as a diagnosis of rheumatoid arthritis is confirmed to control its signs and symptoms and to limit radiographic damage. 

Baseline studies should be obtained prior to the initiation of treatment. Screening for hepatitis B, human immunodeficiency virus (HIV), and tuberculosis (TB) infection should be done before initiating treatment with biological, targeted synthetic, or biosimilar DMARDs. 

ACR and EULAR recommend killed (pneumococcal, influenza, hepatitis B), recombinant (human papillomavirus [HPV]), and live attenuated (herpes zoster except for tumor necrosis factor [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 DMARD (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). The 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 there are no improvement or treatment goal was not reached. 

In DMARD-naive patients, conventional synthetic DMARDs (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 the patient has contraindications to Methotrexate therapy. 

As an initial short-term treatment, the use of low-dose corticosteroids or 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 DMARD strategy, in the absence of poor prognostic factors, switching to or adding another csDMARD should be considered. If poor prognostic factors are present, the addition of a bDMARD or a 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 of a different class. If the patient is unresponsive to the previous treatment with a TNF inhibitor, treatment with another TNF inhibitor or other DMARDs may be considered. 

In patients in sustained remission after corticosteroid discontinuation, may consider reducing DMARD dose. 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.

Pharmacological therapy

Conventional Synthetic DMARDs (csDMARDs)

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. The choice of initial DMARD should be based on the patient’s preferences and existing comorbidities. Methotrexate, Leflunomide, or Sulfasalazine should be started as early as possible at the time of diagnosis. It 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 

Methotrexate should be considered first among the csDMARDs for the initial treatment strategy unless there are contraindications to its use.  It is the preferred agent for most combinations and is the DMARD of choice due to its more favorable efficacy and toxicity profile. It is also considered one of the most active compounds in terms of frequency of remissions and time to onset of action. It can increase the efficacy of bDMARDs if used in combination therapy.

In initiating treatment in DMARD-naive patients with moderate to high disease activity, Methotrexate monotherapy is recommended over 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.  

Leflunomide, Sulfasalazine 

Leflunomide and Sulfasalazine are both recommended as part of the initial treatment strategy in patients who have contraindications 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. Based on clinical trials, Sulfasalazine efficacy is similar to Leflunomide but with more side effects and lower compliance.

Other csDMARDs
Drugs: 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 with intolerance. In cases of mild or palindromic cases, Hydroxychloroquine is an alternative to oral Methotrexate, Leflunomide, or Sulfasalazine. It shows efficacy as monotherapy or in combination therapy.

Targeted Synthetic DMARDs (tsDMARDs)
Drugs: Baricitinib, Tofacitinib, Upadacitinib

Janus kinase (JAK) inhibitors are recommended to be added to csDMARDs for patients who had 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 which showed better efficacy when compared to a placebo and other DMARDs used in several studies. Further studies are needed to prove its superiority over bDMARDs.

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. The 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 rheumatoid arthritis who are refractory to or intolerant of csDMARDs.

Tofacitinib

A JAK-1 and JAK-3 activity inhibitor that may also affect all the JAK isoforms which showed therapeutic benefits in several clinical trials. Further studies are needed to prove its superiority over bDMARDs.

In the ORAL Standard trial, significant reductions of signs and symptoms were seen in patients with active rheumatoid arthritis with a history of Methotrexate therapy given Tofacitinib compared to those given a placebo or Adalimumab. 

In the ORAL Solo and Step trials and in the ORAL Scan and Sync trials, it exhibited significantly higher ACR20 response rates 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. 

Upadacitinib

A JAK-1 inhibitor that underwent phase III trial testing as monotherapy and combination therapy in various rheumatoid arthritis populations. It is 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). 

Results of the Long-Term Extension (LTE) of the 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.

Biological DMARDs (bDMARDs)

bDMARDs generally target cytokines or their receptors or are directed against other cell surface molecules. 

Tumor Necrosis Factor (TNF) Inhibitors 
Drugs: Adalimumab, Certolizumab pegol, Etanercept, Golimumab, Infliximab

These drugs bind to TNF-α and block its interaction with the cell-surface TNF-α receptors to neutralize its biological function (ie changes in adhesion molecule levels that causes leukocyte migration). It is used in combination with csDMARDs in patients with poor prognostic factors and who had treatment failure after the initial csDMARDs treatment strategy. One may switch to another TNF inhibitor or to a non-TNF biological in case of treatment failure with the current regimen. All have been shown to have similar efficacy for clinical remission. 

It is important to reassess treatment effects every after 3 months. These drugs have been shown to increase the risk of serious infection and risk of malignancy and are generally contraindicated in patients with severe congestive heart failure. 

Non-TNF Biologicals 
Drugs: Abatacept (costimulation inhibitor); Rituximab (anti-B cell agent); Sarilumab, Tocilizumab (interleukin-6 receptor antagonists) 

These drugs are used in combination with csDMARDs in patients with poor prognostic factors and treatment failure after initial csDMARDs treatment strategy. One may switch to another non-TNF or to a TNF inhibitor in case of treatment failure with the current regimen. 

It is important to reassess the treatment effects of Rituximab after 6 months instead of 3 months due to the longer peak time of non-TNF biologics. The 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 RA-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. These agents are highly similar to their reference biologics with comparable safety, and efficacy. They are 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. A 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 of 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 for whom DMARD combination therapy is not appropriate, one may start DMARD monotherapy.

Adjunctive Therapy

Analgesics
Drugs: Paracetamol, Aspirin  

Analgesics are used adjuncts to DMARD and NSAID therapy to provide pain relief.  

Corticosteroids
Drugs: 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 as it has been shown to rapidly improve symptoms of rheumatoid arthritis and reduce radiological damage. Corticosteroids may also be considered in patients with moderate-high disease activity. Intra-articular corticosteroids are used to provide rapid, symptomatic relief in the target joints and may be administered to any joint not >3-4x/year. 

Timely dose reductions and cessation are important because of the adverse effects associated with the 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 an 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.

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) 
Drugs: Aceclofenac, Acemetacin, Diclofenac, Etodolac, Indomethacin, Proglumetacin, Sulindac (acetic acid derivatives); Phenylbutazone (butylpyrazolidine); Celecoxib, Etoricoxib (cyclooxygenase-2 [COX-2]-selective coxibs); Meloxicam, Piroxicam, Tenoxicam (oxicam derivatives); Dexketoprofen, Flurbiprofen, Ibuprofen, Ketoprofen, Loxoprofen, Naproxen (propionic acid derivatives); Nabumetone (other NSAID)

NSAIDs interfere with prostaglandin synthesis through inhibition of the enzyme cyclo-oxygenase (COX), thereby reducing pain, swelling, and stiffness caused by rheumatoid arthritis while also improving joint function. Gastroprotection should be introduced for patients with rheumatoid arthritis at risk of NSAID-associated gastroduodenal ulcers. The lowest NSAID dose compatible with symptom relief should be prescribed to be taken for the shortest possible time. 

Lifesstyle Modification

Exercise

Exercise has been shown to increase muscle strength, improve muscle function and joint stability, and increase aerobic capacity and physical performance. It can also improve overall pain control and quality of life without increasing disease activity. 

Consistent exercise is recommended and may include aerobic, aquatic, resistance, or mind-body exercise. Aerobic exercises can improve cardiorespiratory fitness and muscular endurance that 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 can increase muscular strength (eg free weights, resistance bands, Pilates, weight machines). The mind-body exercise combines movement, mental focus and controlled breathing (eg qigong, tai chi, yoga)

Nutrition Therapy and Weight Management

Aside from exercise, it is also important to advise patients to eat a well-balanced diet. Encourage obese patients to lose weight and maintain healthy body weight. Foods rich in fish oil or eicosapentaenoic acid or docosahexaenoic acid may provide a reduction 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.

Range of motion exercises may help restore or preserve joint motion. Exercise programs should be tailored based on the patient’s disease severity, body build, and previous activity level. 

Patient Education

Other Non-pharmacological Modalities

Comprehensive Physical Therapy

Physical therapy aims to provide pain relief, reduction of inflammation, and preservation of joint integrity and function. It 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. 

Rheumatoid arthritis - Management

Surgery

Surgical referral should be done before damage or deformity becomes irreversible in cases such as actual or imminent tendon rupture, nerve compression (eg carpal tunnel syndrome), and stress fractures. It is beneficial for progressive deformity prevention or correction of deformity, joint function improvement and/or prevention of further deterioration, and pain relief. With this, surgical intervention is generally indicated in patients who suffer from an unacceptable level of pain with activity or at rest in patients with severe rheumatoid arthritis after failure of all nonsurgical approaches to rheumatoid arthritis management (eg DMARDs, NSAIDs, rehabilitation therapies). Surgery is also indicated if the patient has persistent localized synovitis, worsening joint function (ie instability or severe loss of range of joint motion) and damage, and progressive deformity. 

Arthrodesis

Arthrodesis has the advantage of providing stability and relief from pain. It is mainly indicated for young active patients with severe unilateral joint involvement. However, it is contraindicated in patients with involvement of the contralateral hip. 

Arthroplasty

Total knee arthroplasty is the surgical treatment of choice in most patients with rheumatoid arthritis affecting the knees. It relieves pain and may increase the range of motion in patients with advanced rheumatoid arthritis who did not benefit from synovectomy. 

However, there is a risk of complications like deep wound infection, poor tissue healing, severe flexion contracture, joint laxity, and osteopenia, which may involve multiple joints limiting rehabilitation. These complications may be minimized by utilizing antibiotic-containing bone cement and optimizing preoperative nutrition.  

Synovectomy

Synovectomy is indicated in patients refractory to pharmacologic management after 6 months. It is indicated if the disease is only limited to the synovial membrane but may involve little cartilage or bone or if there is any narrowing of the joint seen on a radiograph. A high failure rate was observed in advanced stages of rheumatic arthritis if a late synovectomy is done. Arthroscopic knee synovectomy controls synovitis, improves pain, and preserves the existing range of motion. 

The advantages of arthroscopic synovectomy are minimal incision, more complete synovial resection, decreased incidence of infection, hemarthrosis, increased or maintained range of motion, intact quadriceps muscle, lesser postoperative physical therapy, and is cost-effective with a high patient acceptance. 

Other Surgical Procedures

Other surgical procedures that may be offered to patients with rheumatoid arthritis include carpal tunnel release, cervical C1-C2 fusion, finger small joints fusion or arthroplasty, tendon reconstruction, tendon transfers, total joint arthroplasty, and tenosynovectomy.