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
References (168)
- et al.
Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rheumatology criteria: a systematic review
Semin Arthritis Rheum
(2006) - et al.
Psoriasis genetics: breaking the barrier
Trends Genet
(2010) - et al.
Smoking, citrullination and genetic variability in the immunopathogenesis of rheumatoid arthritis
Semin Immunol
(2011) - et al.
New therapies for the treatment of rheumatoid arthritis
Lancet
(2007) - et al.
Carbamylation and antibodies against carbamylated proteins in autoimmunity and other pathologies
Autoimmun Rev
(2014) - et al.
TRANCE/RANKL knockout mice are protected from bone erosion in a serum transfer model of arthritis
Am J Pathol
(2001) - et al.
Metalloproteases and inhibitors in arthritic diseases
Best Pract Res Clin Rheumatol
(2001) Extraarticular manifestations of rheumatoid arthritis
Semin Arthritis Rheum
(1979)- et al.
Methotrexate and mortality in patients with rheumatoid arthritis: a prospective study
Lancet
(2002) - et al.
2010 rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative
Ann Rheum Dis
(2010)
Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges
Nat Rev Rheum
Efficacy of biological disease-modifying antirheumatic drugs: a systematic literature review informing the 2013 update of the EULAR recommendations for the management of rheumatoid arthritis
Ann Rheum Dis
Efficacy of conventional synthetic disease-modifying antirheumatic drugs, glucocorticoids and tofacitinib: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis
Ann Rheum Dis
Safety of synthetic and biological DMARDs: a systematic literature review informing the 2013 update of the EULAR recommendations for management of rheumatoid arthritis
Ann Rheum Dis
Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update
Ann Rheum Dis
The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study
Ann Rheum Dis
Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives
Ann Rheum Dis
Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study
Arthritis Res Ther
Epidemiology and genetics of rheumatoid arthritis
Arthritis Res
Twin concordance rates for rheumatoid arthritis: results from a nationwide study
Br J Rheumatol
To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors?
Arthritis Rheumatol
Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case-control study in Sweden
Ann Rheum Dis
Genetics of rheumatoid arthritis contributes to biology and drug discovery
Nature
The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis
Arthritis Rheum
Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response
JAMA
Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases
Nat Genet
Lack of seroconversion of rheumatoid factor and anti-cyclic citrullinated peptide in patients with early inflammatory arthritis: a systematic literature review
Rheumatology (Oxford)
Autoantibody profiling in patients with very early rheumatoid arthritis: a follow-up study
Ann Rheum Dis
Epigenetics in rheumatoid arthritis
Curr Opin Rheumatol
Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis
Nat Biotechnol
Novel regulatory mechanisms in inflammatory arthritis: a role for microRNA
Immunol Cell Biol
Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice
Arthritis Rheum
Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins
Arthritis Rheum
Personality, socio-economic status and inflammation: cross-sectional, population-based study
PLoS One
Education, self-care, and outcomes of rheumatic diseases: further challenges to the “biomedical model” paradigm
Arthritis Care Res
Review: microbiome in inflammatory arthritis and human rheumatic diseases
Arthritis Rheumatol
Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis
Arthritis Rheum
HLA molecules, bacteria and autoimmunity
J Med Microbiol
The pathogenesis of rheumatoid arthritis
N Engl J Med
The microbiome in infectious disease and inflammation
Annu Rev Immunol
Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease
Arthritis Rheumatol
Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials
Arthritis Res Ther
Mortality trends in rheumatoid arthritis: the role of rheumatoid factor
J Rheumatol
Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis
Arthritis Rheum
Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis
Arthritis Res Ther
Activation of the classical pathway of complement by rheumatoid factors. Assessment by radioimmunoassay for C4
Arthritis Rheum
IgM and IgA rheumatoid factors purified from rheumatoid arthritis sera boost the Fc receptor- and complement-dependent effector functions of the disease-specific anti-citrullinated protein autoantibodies
J Immunol
Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies
J Clin Invest
The epitopes targeted by the rheumatoid arthritis-associated antifilaggrin autoantibodies are posttranslationally generated on various sites of (pro) filaggrin by deimination of arginine residues
J Immunol
Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis
Ann Rheum Dis
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