Elsevier

The Lancet

Volume 388, Issue 10055, 22–28 October 2016, Pages 2023-2038
The Lancet

Seminar
Rheumatoid arthritis

https://doi.org/10.1016/S0140-6736(16)30173-8Get rights and content

Summary

Rheumatoid arthritis is a chronic inflammatory joint disease, which can cause cartilage and bone damage as well as disability. Early diagnosis is key to optimal therapeutic success, particularly in patients with well-characterised risk factors for poor outcomes such as high disease activity, presence of autoantibodies, and early joint damage. Treatment algorithms involve measuring disease activity with composite indices, applying a treatment-to-target strategy, and use of conventional, biological, and newz non-biological disease-modifying antirheumatic drugs. After the treatment target of stringent remission (or at least low disease activity) is maintained, dose reduction should be attempted. Although the prospects for most patients are now favourable, many still do not respond to current therapies. Accordingly, new therapies are urgently required. In this Seminar, we describe current insights into genetics and aetiology, pathophysiology, epidemiology, assessment, therapeutic agents, and treatment strategies together with unmet needs of patients with rheumatoid 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

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.

This online publication has been corrected. The corrected version first

References (168)

  • JS Smolen et al.

    Rheumatoid arthritis therapy reappraisal: strategies, opportunities and challenges

    Nat Rev Rheum

    (2015)
  • JL Nam et al.

    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

    (2014)
  • C Gaujoux-Viala et al.

    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

    (2014)
  • S Ramiro et al.

    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

    (2014)
  • MA Stoffer et al.

    Evidence for treating rheumatoid arthritis to target: results of a systematic literature search update

    Ann Rheum Dis

    (2016)
  • M Cross et al.

    The global burden of rheumatoid arthritis: estimates from the global burden of disease 2010 study

    Ann Rheum Dis

    (2014)
  • GD Kitas et al.

    Cardiovascular disease in rheumatoid arthritis: state of the art and future perspectives

    Ann Rheum Dis

    (2011)
  • T Sokka et al.

    Work disability remains a major problem in rheumatoid arthritis in the 2000s: data from 32 countries in the QUEST-RA study

    Arthritis Res Ther

    (2010)
  • AJ Silman et al.

    Epidemiology and genetics of rheumatoid arthritis

    Arthritis Res

    (2002)
  • AJ Silman et al.

    Twin concordance rates for rheumatoid arthritis: results from a nationwide study

    Br J Rheumatol

    (1993)
  • X Jiang et al.

    To what extent is the familial risk of rheumatoid arthritis explained by established rheumatoid arthritis risk factors?

    Arthritis Rheumatol

    (2015)
  • T Frisell et al.

    Familial aggregation of arthritis-related diseases in seropositive and seronegative rheumatoid arthritis: a register-based case-control study in Sweden

    Ann Rheum Dis

    (2016)
  • Y Okada et al.

    Genetics of rheumatoid arthritis contributes to biology and drug discovery

    Nature

    (2014)
  • PK Gregersen et al.

    The shared epitope hypothesis: an approach to understanding the molecular genetics of susceptibility to rheumatoid arthritis

    Arthritis Rheum

    (1987)
  • S Viatte et al.

    Association of HLA-DRB1 haplotypes with rheumatoid arthritis severity, mortality, and treatment response

    JAMA

    (2015)
  • TL Lenz et al.

    Widespread non-additive and interaction effects within HLA loci modulate the risk of autoimmune diseases

    Nat Genet

    (2015)
  • L Barra et al.

    Lack of seroconversion of rheumatoid factor and anti-cyclic citrullinated peptide in patients with early inflammatory arthritis: a systematic literature review

    Rheumatology (Oxford)

    (2011)
  • V Nell-Duxneuner et al.

    Autoantibody profiling in patients with very early rheumatoid arthritis: a follow-up study

    Ann Rheum Dis

    (2010)
  • K Klein et al.

    Epigenetics in rheumatoid arthritis

    Curr Opin Rheumatol

    (2015)
  • Y Liu et al.

    Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis

    Nat Biotechnol

    (2013)
  • D Baxter et al.

    Novel regulatory mechanisms in inflammatory arthritis: a role for microRNA

    Immunol Cell Biol

    (2012)
  • S Bluml et al.

    Essential role of microRNA-155 in the pathogenesis of autoimmune arthritis in mice

    Arthritis Rheum

    (2011)
  • AJ Silman et al.

    Cigarette smoking increases the risk of rheumatoid arthritis. Results from a nationwide study of disease-discordant twins

    Arthritis Rheum

    (1996)
  • K Millar et al.

    Personality, socio-economic status and inflammation: cross-sectional, population-based study

    PLoS One

    (2013)
  • LF Callahan et al.

    Education, self-care, and outcomes of rheumatic diseases: further challenges to the “biomedical model” paradigm

    Arthritis Care Res

    (1997)
  • JU Scher et al.

    Review: microbiome in inflammatory arthritis and human rheumatic diseases

    Arthritis Rheumatol

    (2016)
  • N Wegner et al.

    Peptidylarginine deiminase from Porphyromonas gingivalis citrullinates human fibrinogen and α-enolase: implications for autoimmunity in rheumatoid arthritis

    Arthritis Rheum

    (2010)
  • A Ebringer et al.

    HLA molecules, bacteria and autoimmunity

    J Med Microbiol

    (2000)
  • IB McInnes et al.

    The pathogenesis of rheumatoid arthritis

    N Engl J Med

    (2011)
  • K Honda et al.

    The microbiome in infectious disease and inflammation

    Annu Rev Immunol

    (2012)
  • JU Scher et al.

    Decreased bacterial diversity characterizes the altered gut microbiota in patients with psoriatic arthritis, resembling dysbiosis in inflammatory bowel disease

    Arthritis Rheumatol

    (2015)
  • D Aletaha et al.

    Rheumatoid factor, not antibodies against citrullinated proteins, is associated with baseline disease activity in rheumatoid arthritis clinical trials

    Arthritis Res Ther

    (2015)
  • A Gonzalez et al.

    Mortality trends in rheumatoid arthritis: the role of rheumatoid factor

    J Rheumatol

    (2008)
  • FA van Gaalen et al.

    Association between HLA class II genes and autoantibodies to cyclic citrullinated peptides (CCPs) influences the severity of rheumatoid arthritis

    Arthritis Rheum

    (2004)
  • X Zhao et al.

    Circulating immune complexes contain citrullinated fibrinogen in rheumatoid arthritis

    Arthritis Res Ther

    (2008)
  • UK Sabharwal et al.

    Activation of the classical pathway of complement by rheumatoid factors. Assessment by radioimmunoassay for C4

    Arthritis Rheum

    (1982)
  • F Anquetil et al.

    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

    (2015)
  • GA Schellekens et al.

    Citrulline is an essential constituent of antigenic determinants recognized by rheumatoid arthritis-specific autoantibodies

    J Clin Invest

    (1998)
  • E Girbal-Neuhauser et al.

    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

    (1999)
  • G Reynisdottir et al.

    Signs of immune activation and local inflammation are present in the bronchial tissue of patients with untreated early rheumatoid arthritis

    Ann Rheum Dis

    (2015)
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