We searched MEDLINE using the terms “rheumatoid arthritis” in conjunction with “diagnosis”, “classification”, “epidemiology”, and “pathogenesis”. For treatment, we used recent systematic literature searches, and updated the respective searches in October, 2015, including terms on novel therapies and “treatment strategy”. Selection of articles was based on our personal judgment of relevance within the scope of this Seminar.
SeminarRheumatoid arthritis
Introduction
Rheumatoid arthritis is one of the most prevalent chronic inflammatory diseases. It primarily involves the joints, but should be considered a syndrome that includes extra-articular manifestations, such as rheumatoid nodules, pulmonary involvement or vasculitis, and systemic comorbidities. A therapeutic revolution in the treatment of rheumatoid arthritis in the past decade—with the advent of novel therapeutics, introduction of early therapy, development of new classification criteria, and application of new effective treatment strategies—has transformed articular and systemic outcomes.1, 2, 3, 4, 5, 6 In this Seminar, we highlight recent insights into most aspects of rheumatoid arthritis, from diagnosis to treatment strategies, and from aetiology to novel therapies. There is still a considerable unmet need in rheumatoid arthritis; full or stringent remission is not typical, nor is it usually sustained without continuing treatment, and as such it should now be the priority of research efforts.
Section snippets
Epidemiology, genetics, and aetiology
Rheumatoid arthritis is a chronic disease that carries a substantial burden for both the individual and society.7 The individual burden results from musculoskeletal deficits, with attendant decline in physical function, quality of life, and cumulative comorbid risk.8 The socioeconomic burden, aside from major direct medical costs, is a consequence of functional disability, reduced work capacity, and decreased societal participation.9 Efforts to establish the diagnosis early, initiate treatment
Autoimmune response
Rheumatoid arthritis is pathologically heterogeneous. The presence of autoantibodies (seropositivity) is associated with more severe symptoms and joint damage, and increased mortality.35, 36, 37, 38, 39 This is most likely due to formation of immune complexes by ACPAs with citrulline-containing antigens and subsequent binding of RF, which can lead to abundant complement activation.40, 41, 42 The detection of autoimmune responses to citrullinated self-proteins is a major advance.43, 44 ACPAs can
Diagnostic approach and differential diagnosis
No diagnostic criteria exist for rheumatoid arthritis. The typical patient presents with tender and swollen joints of recent onset, morning joint stiffness, and abnormal laboratory tests such as elevated concentrations of C-reactive protein or erythrocyte sedimentation rate. Unfortunately, this presentation is not specific to rheumatoid arthritis. Other causes of arthritis need to be considered, such as reactive arthritis, osteoarthritis, psoriatic arthritis, infectious arthritis (viral or
Extra-articular manifestations and comorbidities
Patients with insufficiently treated rheumatoid arthritis can have various extra-articular manifestations, including vasculitis or interstitial lung disease.69 Moreover, the chronic inflammatory state of rheumatoid arthritis has been associated with secondary amyloidosis, lymphoma,70 and cardiovascular disease8 and increased mortality.71 All these risks appear to be strikingly reduced with modern therapeutic strategies.72, 73 Of note, methotrexate can induce nodulosis, which is
Disease assessment and definition of treatment targets
Assessment of disease activity is crucial in the follow-up of patients with rheumatoid arthritis.76, 77 Composite measures that include joint counts have been recommended for daily practice.77 The ACR improvement criteria78 distinguish a change from baseline of several defined variables by at least 20% (ACR20, minimal response), 50% (ACR50, moderate response), or 70% (ACR70, major response). They were developed to differentiate active therapy from placebo in clinical trials (in particular,
Treatment strategies
Because inflammation is at the apex of clinical events (driving clinical symptoms, joint damage, disability, and comorbidity),33 its reversal is the major therapeutic target; if inflammation subsides rapidly, damage or its progression are prevented, and physical function can be maximally improved without further sequelae. Treatment of rheumatoid arthritis thus requires a strategic approach whereby regular assessment of disease activity drives therapeutic adaptations or changes of drugs in
Therapeutic approaches
Disease-modifying antirheumatic drugs (DMARDs) target inflammation and by definition must reduce structural damage progression. Non-steroidal anti-inflammatory drugs (NSAIDs), while reducing pain and stiffness and improving physical function, do not interfere with joint damage and are thus not disease modifying. Glucocorticoids offer rapid symptomatic and disease-modifying effects,111 but are associated with serious long-term side-effects.
There are two major classes of DMARDs: synthetic and
Open questions, unmet needs, and future therapeutics
Despite advances made over the past two decades, many open issues remain. First, we do not understand how therapies targeting different molecules achieve such similar efficacies, and we do not even know if profound responses are elicited by these agents in the same, totally different, or overlapping patient populations. Second, we cannot predict optimal responses or toxic risk for a given treatment; molecular analyses have failed to answer this question,161, 162, 163 although we firmly believe
Conclusions
The therapeutic insights presented in this Seminar constitute the basis for recommendations for the management of rheumatoid arthritis (figure 4).89 Early diagnosis and initiation of DMARD therapy are pivotal to prevent damage from occurring or becoming clinically significant.164 The lower the disease activity achieved at 6 months, the better the long-term outcome; reaching stringent clinical remission within 3–6 months halts damage progression independent of the type of therapy used.85, 91
Search strategy and selection criteria
This online publication has been corrected. The corrected version first
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