Management of rheumatoid arthritis: consensus recommendations from the Hong Kong Society of Rheumatology
Given the recent availability of novel biologic agents for the treatment of rheumatoid arthritis (RA), the Hong Kong Society of Rheumatology has developed consensus recommendations on the management of RA, which aim at providing guidance to local physicians on appropriate, literature-based management of this condition, specifically on the indications and monitoring of the biologic disease-modifying anti-rheumatic drugs (DMARDs). The recommendations were developed using the European League Against Rheumatism (EULAR) recommendations for the management of early arthritis as a guide, along with local expert opinion. As significant joint damage occurs early in the course of RA, initiating therapy early is key to minimizing further damage and disability. Patients with serious disease or poor prognosis should receive early, aggressive therapy. Because of its good efficacy and safety profile, methotrexate is considered the standard first-line DMARD for most treatment-naïve RA patients. Patients with a suboptimal response to methotrexate monotherapy should receive step-up (combination) therapy with either the synthetic or biologic DMARDs. In recent years, combinations of methotrexate with tocilizumab, abatacept, or rituximab have emerged as effective therapies in patients who are unresponsive to traditional DMARDs or the anti-tumor necrosis factor (TNF)-α agents. As biologic agents can increase the risk of infections such as tuberculosis and reactivation of viral hepatitis, screening for the presence of latent tuberculosis and chronic viral hepatitis carrier state is recommended before initiating therapy.
KeywordsHong Kong Management Recommendations Rheumatoid arthritis
Rheumatoid arthritis (RA) is a chronic, autoimmune, systemic, inflammatory disease mainly affecting the joints characterized by pain, swelling, and stiffness, resulting in progressive joint destruction, deformity, and loss of function. In addition to articular symptoms, other organ systems may also be involved. RA affects approximately 0.5% to 1% of the adult population in the developed world . It is less prevalent in mainland China and in Hong Kong, with a reported prevalence of 0.37% and 0.35%, respectively [2, 3].
Although the etiology of RA remains largely unknown, both genetic and nongenetic causes have been implicated. Inflammation is initially localized in the synovial lining where there is synovial cell proliferation (pannus formation) and infiltration by inflammatory cells. The pannus invades and destroys cartilage and bone, leading to irreversible joint destruction and deformity . Erosions of the feet joints on extremity magnetic resonance imaging (MRI) are found in up to 91% of patients early in the course of the disease . Therefore, early diagnosis and treatment are crucial for preventing further joint damage. Currently, the classification of RA is based on the 1987 American College of Rheumatology (ACR) clinical classification criteria using history, physical examination, and laboratory and radiographic findings ; this set of criteria has been criticized for lack of sensitivity in early disease. A new set of joint ACR-European League Against Rheumatism (EULAR) criteria for RA classification has recently been published .
The goals of treatment of RA are to alleviate symptoms, slow or stop disease progression, and reduce disability. The current RA treatment armamentarium comprises both synthetic and biologic disease-modifying anti-rheumatic drugs (DMARDs).
In 2005, the Hong Kong Society of Rheumatology (HKSR) published consensus recommendations on the use of anti-tumor necrosis factor (TNF)-α agents in the treatment of RA, ankylosing spondylitis, and psoriatic arthritis . However, consensus recommendations on overall RA management had yet to be developed. Given the availability of newer biologic agents for RA treatment, the HKSR initiated the development of these consensus recommendations, which are aimed at providing guidance to Hong Kong physicians on appropriate, literature-based management of this condition, specifically on the indications and monitoring of the novel biologic DMARDs.
Strength of clinical evidence
At least one RCT or meta-analyses of RCTs, or reviews if these contain category A references
At least one controlled trial without randomization or at least one other type of experimental study, or extrapolated recommendations from RCTs or meta-analyses
Non-experimental descriptive studies, such as comparative studies, correlational studies, and case-control studies, which are extrapolated from RCTs, non-randomized controlled studies, or other experimental studies
Expert committee reports or opinions or clinical experience of respected authorities. Also includes all abstracts
Panel recommendations on RA management
- Recommendation 1: General principles
Early RA treatment improves the rate of clinical response and ultimate outcome. Early, aggressive therapy is required for patients with serious disease and/or poor prognostic factors. Treatment must be individualized, based on physicians' and patients' preference, and medical contraindications, among others.
- Recommendation 2: Patient assessment
Anti-cyclic citrullinated peptide (anti-CCP) antibody testing, ultrasound, and MRI may be utilized in the early diagnosis of RA. These tests are not recommended as routine tests but should be used for specific indications only.
- (b)Disease Activity Score using 28 joint counts (DAS28) should be utilized in the assessment of RA disease activity. Clinicians should try to compute the DAS28 at regular intervals, preferably during each clinic visit.
High disease activity (HDA): DAS28 > 5.1
Moderate disease activity (MDA): DAS28 = 3.2–5.1
Low disease activity (LDA): DAS28 = 2.6–3.2
Remission: DAS28 < 2.6
Factors indicating an unfavorable prognosis of RA include chronic smoking, high titres of anti-CCP or RF, radiologic erosion at onset, positive family history, HDA, severe functional limitation, and extra-articular manifestations (e.g., rheumatoid nodules).
Clinicians should regularly assess the extent of their patients' disability and functional capacity. Possible assessment tools include the Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study short-form health survey (SF-36).
- Recommendation 3: Treatment
The goal of treatment is disease remission (i.e., DAS28 < 2.6), regardless of whether the patient has early or established RA. It should be emphasized that treatment of early RA results in better response rates and a higher probability of drug-free remission.
Treatment with synthetic DMARDs should be initiated as soon as possible after a diagnosis of RA is made. DMARD-naïve patients should be started on methotrexate monotherapy. Methotrexate should be given for a duration of no less than 3 months at the maximally tolerated dose. Patients without poor prognostic factors (i.e., with no erosions, are RF-negative, with low CRP levels, or with low disease activity) or those who cannot tolerate methotrexate may receive other DMARDs, such as leflunomide, sulfasalazine, hydroxychloroquine, or injectable gold. Corticosteroids, given orally, intramuscularly, or intra-articularly, may be used as bridging therapy as appropriate. A combination of DMARDs, or methotrexate combined with an anti-TNF-α agent, may be considered in patients with very serious disease and poor prognostic factors. However, the cost-effectiveness of the latter approach has yet to be determined.
Suboptimal treatment response is defined as failure to achieve remission (i.e., DAS28 < 2.6) after 3 months of methotrexate at a dose of at least 15 mg/week. Such patients (i.e., DAS28 ≥ 2.6 despite methotrexate) should receive step-up therapy, i.e., combination therapy of methotrexate plus another agent: methotrexate plus leflunomide, methotrexate plus sulfasalazine plus hydroxychloroquine, or methotrexate plus a biologic agent.
Patients who require methotrexate plus a biologic agent may be administered any one of the following combinations: methotrexate plus an anti-TNF-α agent, methotrexate plus tocilizumab, methotrexate plus abatacept, or methotrexate plus rituximab. The choice of biologic will depend on various factors, including patient's and physician's preferences, availability of funding, and medical history.
The value of the combination of methotrexate and anti-TNF-α agents in improving radiographic, clinical, and functional outcomes is well established (category A) [12, 13, 36, 41, 42, 43]. In recent years, several novel biologic drugs with different mechanisms of action have emerged as potential additions to rheumatologic pharmacotherapy. These include the interleukin (IL)-6 inhibitor tocilizumab, the selective T-cell co-stimulation modulator abatacept, and the chimeric, anti-CD20 monoclonal antibody rituximab. Several recent randomized, double-blind, placebo-controlled trials have demonstrated superior therapeutic efficacy when each of these agents was co-administered with methotrexate in RA patients [44, 45, 46, 47, 48, 49, 50, 51].
Anti-TNFα failure patients (failure of DAS28 to improve by 1.2 or <5.1 over 16 weeks) may be administered any one of the following: another anti-TNF-α agent, tocilizumab, abatacept, or rituximab. There is less evidence to support the efficacy of rituximab in seronegative RA patients.
Recommendation 4: Safety considerations
Prior to using a biologic agent, the clinician should screen the patient for both active and latent tuberculosis infection. Patients with active tuberculosis should be adequately treated with the standard regimen before reconsideration of biologic treatment. Patients who screen positive for latent tuberculosis infection (i.e., with a positive purified protein derivative (PPD) test, defined as an induration of ≥10 mm in diameter) should be given isoniazid treatment for 9 months. If the indication for biologic use is not urgent, isoniazid should be given for 4 weeks, to assess tolerability, before administration of the biologic agent. For patients who test PPD-negative, there is insufficient evidence to recommend annual retesting unless there is recent exposure to tuberculosis or the risk of transmission is high.
In addition, the hepatitis B and C status of patients should be screened. Chronic carriage of hepatitis B and C virus (HBV and HCV, respectively) is a relative contraindication for the use of anti-TNF-α agents. Active hepatitis has to be excluded and baseline HBV DNA or HCV RNA levels should be checked for chronic carriers of HBV and HCV. Appropriate antiviral therapy, as determined by the co-managing hepatologist, is indicated. Patients should be warned of the risk of fulminant hepatitis reactivation. Rituximab is contraindicated in chronic hepatitis B or C carriers. There is little information regarding the safety of tocilizumab and abatacept in chronic viral hepatitis carriers.
History of solid tumor is not a contraindication for use of anti-TNF-α agents if there is no recurrence in the past 5 years. Anti-TNF-α agents should be avoided in patients with a history of lymphoproliferative disorders.
Use of anti-TNF-α agents is contraindicated in patients with severe heart failure, demyelinating disorders, or lupus-like features.
Live attenuated vaccines are not recommended for patients being treated with biologic agents. Killed vaccines (e.g., influenza vaccine, pneumococcal vaccine), if required, should be given prior to administration of biologic agent.
- (f)Patients on biologic agents should be closely monitored for side effects.
Patients should be very closely monitored for infective complications, including opportunistic infections.
Patients should be monitored for symptoms of tuberculosis infection, both within and outside the respiratory system. Chest X-ray should be performed every 3 months during the first year of therapy and annually thereafter, or when the patient develops symptoms.
Complete blood count, renal/liver function tests, lymphocyte count (for rituximab), and neutrophil count (for tocilizumab) should be regularly checked.
Fasting lipid levels should be regularly surveyed (particularly for tocilizumab) and statins should be given whenever appropriate.
Look out for new neurological symptoms in patients administered rituximab.
Look out for gastrointestinal symptoms in patients administered tocilizumab, especially those with a history of diverticulitis or intestinal ulceration.
Adverse events, especially serious adverse events, should be reported to the HKSR Biologics Registry.
- Recommendation 5: Cardiovascular risk factors and bone mineral density
Patients with RA should be screened for risk factors for cardiovascular (CV) disease and for osteoporosis. Once detected, these conditions should be managed as appropriate.
RA patients are more prone to CV disease: the standardized incidence ratio of myocardial infarction and stroke is 1.5 to 1.7 times that of the incidence in the general population (category A) [71, 72, 73, 74]. This is attributable to an increased prevalence of traditional CV risk factors and persistent elevation of inflammatory cytokines in this population. Early identification, adequate management, and ongoing monitoring of risk factors are necessary to reduce this excess CV risk. The latest EULAR recommendations for CV risk management in patients with RA and other forms of inflammatory arthritis states that the first principle of management is to assess and control all components of total CV risk, which includes providing appropriate, evidenced-based advice with regard to smoking, physical activity, diet, weight, and blood pressure, as well as aggressive suppression of the inflammatory process to further lower risk (category D) . Similarly, RA patients are more likely to develop osteoporosis and fragility fractures (category A) . Appropriate screening, monitoring and therapy for osteoporosis is deemed mandatory.
Panel recommendations on RA management—summary
Recommendation 1: General principles
Early RA treatment improves the outcome. Early, aggressive therapy is indicated for patients with serious disease and/or poor prognostic factors
Recommendation 2: Patient assessment
(a) Anti-CCP antibody testing, ultrasound and MRI may be utilized to aid early diagnosis of RA but they are not recommended for routine use
(b) DAS 28 should be utilized in the assessment of RA disease activity. Clinicians should try to compute the DAS28 at regular intervals
(c) Factors indicating an unfavorable prognosis of RA include chronic smoking, high titres of anti-CCP or RF, radiologic erosion at onset, positive family history, HDA, severe functional limitation, and extra-articular manifestations (e.g., rheumatoid nodules)
(d) Clinicians should regularly assess the extent of their patients' disability and functional capacity
Recommendation 3: Treatment
(a) The goal of treatment is disease remission (i.e., DAS28 < 2.6)
(b) Treatment with synthetic DMARDs should be initiated as soon as possible after a diagnosis of RA is made. DMARD-naïve patients should be started on MTX monotherapy. A combination of DMARDs, or MTX combined with an anti-TNF-α agent, may be considered in patients with very serious disease and poor prognostic factors
(c) Suboptimal treatment response is defined as failure to achieve remission after 3 months of MTX at its maximally tolerated dose. Such patients should receive step-up therapy, i.e., combination therapy of MTX plus another agent (e.g., LEF, SSz/HCQ, biologic agent)
(d) Patients who require MTX plus a biologic agent may be administered any one of the following combinations: MTX plus an anti-TNF-α agent, tocilizumab, abatacept, or rituximab
(e) Anti-TNF therapy failure patients may be administered another anti-TNF-α agent, tocilizumab, abatacept or rituximab
Recommendation 4: Safety considerations
(a) Prior to using a biologic agent, patients should be screened for tuberculosis infection. Patients with active tuberculosis should be adequately treated before reconsideration of biologic treatment. Patients who screen positive for latent tuberculosis infection receive isoniazid treatment for 9 months
(b) The hepatitis B and C status of patients should be screened. Active hepatitis has to be excluded and baseline HBV DNA or HCV RNA levels should be checked for chronic carriers. Appropriate antiviral therapy is indicated. Patients should be warned of the risk of fulminant hepatitis reactivation. Rituximab is contraindicated in chronic hepatitis B or C carriers
(c) Patients should be regularly monitored for side effects. Investigations such as chest radiograph, complete blood counts, lymphocyte count, liver and renal function tests, and lipid level should be assessed at regular intervals
Recommendation 5: Cardiovascular risk factors and bone mineral density
Patients with RA should be screened for risk factors for CV disease and for osteoporosis. Once detected, these conditions should be managed as appropriate
These recommendations will be reviewed periodically, in light of new published evidence and adverse event reports. As these recommendations evolve and gradually become more explicit, they will provide even more specific guidance to rheumatologists and other physicians who treat patients with RA, ultimately leading to improved clinical outcomes.
The Hong Kong Society of Rheumatology would like to thank the following full members who were involved in the review of these consensus recommendations: Eric Yuk Tat Chan, Ka Ho Chan, Ka Man Chan, Ka Yan Helen Chan, Pui Shan Julia Chan, Yee Ki Chan, Shuk Yi Lucia Chau, Tak Cheong Cheung, Ho Yin Chung, Carmen Ho, Ling Yin Ho, Emily Kun, Lai Wa Kwok, Man Leung Kwok, Weng Ng Lao, Chak Sing Lau, Yu Lung Lau, Anthony Kai Yiu Lee, Ka Lai Lee, Kwok Fai, Tony Lee, Kwok Kei Lee, Man Yee Jolly Lee, Shui Shan Lee, Tsz Leung Lee, Tsz Yan, Samson Lee, Man Chi Leung, Moon Ho, Alexander Leung, Ying Ying Leung, Hor Ming Liu, Ming Chi Luk, Kai Yiu Ma, Lai Wo Mak, Mo Yin Mok, Kam Hung Daniel Ng, Woon Leung Ng, Chi Keung Sung, Ronald F. Tan, Shuk Kuen Sandy Tang, Chi Hung To, Hing Sum Tsui, John Chun Ming Wan, Man Choi Wan, Kong Chiu Wong, Shiu Man Jude Wong, Woon Sing Raymond Wong, Wai Shan Sandy Woo, Cheuk Wan Yim, Shirley King Yee Ying, Man Lung Yip, Ka Lung Carrel Yu, and Ka Yan Catherine Yuen.
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- 8.Mok CC, for the working group on the use of TNF inhibitors for the treatment of rheumatic diseases in Hong Kong (2005) Consensus statements on the indications and monitoring of anti-tumor necrosis factor (TNF) therapy for rheumatic diseases in Hong Kong. Hong Kong Bull Rheum Dis 5:19–25Google Scholar
- 12.Breedveld FC, Weisman MH, Kavanaugh AF et al (2006) The PREMIER Study. A multicenter, randomized, double-blind clinical trial of combination therapy with adalimumab plus methotrexate versus methotrexate alone or adalimumab alone in patients with early, aggressive rheumatoid arthritis who had not had previous methotrexate therapy. Arthritis Rheum 54:26–37PubMedCrossRefGoogle Scholar
- 19.University Medical Centre Nijmegen. DAS-SCORE.NL. Home of the DAS. Available at: http://www.das-score.nl/www.das-score.nl/. Accessed 1 June 2010.
- 37.Finckh A, Bansback N, Marra CA et al (2009) Treatment of very early rheumatoid arthritis with symptomatic therapy, disease-modifying antirheumatic drugs, or biologic agents: a cost-effectiveness analysis. Ann Intern Med 151:668–669Google Scholar
- 39.US Food and Drug Administration (FDA) Web site. FDA Drug Safety Communication: New boxed warning for severe liver injury with arthritis drug Arava (leflunomide). Available at: http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm218679.htm. Accessed 31 July 2010.
- 42.Keystone EC, Kavanaugh AF, Sharp JT et al (2004) Radiographic, clinical, and functional outcomes of treatment with adalimumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 52-week trial. Arthritis Rheum 50:1400–1411PubMedCrossRefGoogle Scholar
- 44.Emery P, Keystone E, Tony HP et al (2008) IL-6 receptor inhibition with tocilizumab improves treatment outcomes in patients with rheumatoid arthritis refractory to anti-tumour necrosis factor biologics: results from a 24-week multicentre randomised placebo-controlled trial. Ann Rheum Dis 67:1516–1523PubMedCrossRefGoogle Scholar
- 45.Maini RN, Taylor PC, Szechinski J et al (2006) Double-blind randomized controlled clinical trial of the interleukin-6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate. Arthritis Rheum 54:2817–2829PubMedCrossRefGoogle Scholar
- 48.Kremer J, Fleischmann R, Halland A, et al. (2008) Tocilizumab inhibits structural joint damage in rheumatoid arthritis patients with an inadequate response to methotrexate: the LITHE study [abstract]. Ann Rheum Dis;58:abstr L14.Google Scholar
- 51.Cohen SB, Emery P, Greenwald MW et al (2006) Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy: results of a multicenter, randomized, double-blind, placebo-controlled, phase III trial evaluating primary efficacy and safety at 24 weeks. Arthritis Rheum 54:2793–2806PubMedCrossRefGoogle Scholar
- 53.Isaacs JD, Olech E, Tak PP et al (2009) Autoantibody-positive rheumatoid arthritis (RA) patients (pts) have enhanced clinical response to rituximab (RTX) when compared with seronegative patients. Ann Rheum Dis 68(Suppl 3):442Google Scholar
- 55.American Thoracic Society, Centers for Disease Control and Prevention (2000) This official statement of the American Thoracic Society was adopted by the ATS Board of Directors, July 1999. This is a Joint Statement of the American Thoracic Society (ATS) and the Centers for Disease Control and Prevention (CDC). This statement was endorsed by the Council of the Infectious Diseases Society of America (IDSA), September 1999, and the sections of this statement. Am J Respir Crit Care Med 161:S221–S247Google Scholar
- 58.Matsue K, Kimura SI, Takanashi Y, et al. (2010) Reactivation of hepatitis B virus after rituximab-containing treatment in patients with CD20-positive B-cell lymphoma. Cancer. [Epub ahead of print]Google Scholar
- 59.Ji D, Cao J, Hong X, et al. (2010) Low incidence of hepatitis B virus reactivation during chemotherapy among diffuse large B-cell lymphoma patients who are HBsAg-negative/HBcAb-positive: a multicenter retrospective study. Eur J Haematol. [Epub ahead of print]Google Scholar
- 64.Chung ES, Packer M, Lo KH, Fasanmade AA (2003) Anti-TNF Therapy Against Congestive Heart Failure Investigators. Randomized, double-blind, placebo-controlled, pilot trial of infliximab, a chimeric monoclonal antibody to tumor necrosis factor-alpha, in patients with moderate-to-severe heart failure: results of the anti-TNF Therapy Against Congestive Heart Failure (ATTACH) trial. Circulation 107:3133–3140PubMedCrossRefGoogle Scholar
- 66.Galloway JB, Hyrich KL, Mercer LK, et al. (2010) Anti-TNF therapy is associated with an increased risk of serious infections in patients with rheumatoid arthritis especially in the first 6 months of treatment: updated results from the British Society for Rheumatology Biologics Register with special emphasis on risks in the elderly. Rheumatology (Oxford). [Epub ahead of print]Google Scholar
- 76.Deane K (2006) Increased prevalence translates into increased fractures—Osteoporosis in RA: a common comorbidity. J Musculoskel Med 23:838–844Google Scholar