Extra-articular manifestations of rheumatoid arthritis: An update

doi:10.1016/j.autrev.2011.09.001

Autoimmunity Reviews

Volume 11, Issue 2, December 2011, Pages 123-131

https://doi.org/10.1016/j.autrev.2011.09.001 Get rights and content

Abstract

Rheumatoid arthritis (RA) is an immune-mediated disease involving chronic low-grade inflammation that may progressively lead to joint destruction, deformity, disability and even death. Despite its predominant osteoarticular and periarticular manifestations, RA is a systemic disease often associated with cutaneous and organ-specific extra-articular manifestations (EAM). Despite the fact that EAM have been studied in numerous RA cohorts, there is no uniformity in their definition or classification. This paper reviews current knowledge about EAM in terms of frequency, clinical aspects and current therapeutic approaches. In an initial attempt at a classification, we separated EAM from RA co-morbidities and from general, constitutional manifestations of systemic inflammation. Moreover, we distinguished EAM into cutaneous and visceral forms, both severe and not severe. In aggregated data from 12 large RA cohorts, patients with EAM, especially the severe forms, were found to have greater co-morbidity and mortality than patients without EAM. Understanding the complexity of EAM and their management remains a challenge for clinicians, especially since the effectiveness of drug therapy on EAM has not been systematically evaluated in randomized clinical trials.

Introduction

Rheumatoid arthritis (RA) is an immune-mediated inflammatory disease affecting about 1% of people in western countries [1]. It is characterized by a selective joint predilection (mainly affecting diarthrodial joints) and a varied course, which ranges from spontaneously remitting symmetric synovitis to aggressive ankylosing, severely disabling joint disease [1]. The natural history of the disease in most patients involves chronic low-grade inflammation, with periodic flares, that may progressively lead to joint destruction, deformity, disability and even premature death. Despite its predominant osteoarticular and periarticular manifestations, RA is a systemic disease, often associated with extra-articular manifestations (EAM).

EAM affect various tissues and organ systems, and are distinct from the common co-morbidities occurring in the same bodily compartments (Table 1). EAM themselves are distinguished into severe conditions (indicated in the Malmö criteria) and not the severe ones [2]. Severe EAM are usually associated with greater co-morbidity and premature death [3]. EAM can develop at any time during the course of the disease, even in the early stages. Given their variable and complex presentations, managing EAM is a challenge for clinicians. This paper provides an overview of major manifestations of EAM, and focuses on incidence, clinical features and therapeutic approaches.

Section snippets

Methods

We conducted a literature search in the MEDLINE database through the PubMed interface. Main search terms were: RA, extra-articular manifestations of RA, and systemic rheumatoid vasculitides. Additional terms were: ocular, cardiac, and pulmonary manifestations; secondary amyloidosis; cutaneous, neurological and renal involvement. All relevant articles published up to June 2011 were reviewed.

Nosographic setting of EAM

There is no consensus on how to distinguish EAM from co-morbidities nor on how to classify severe and non-severe forms. This is likely due to the lack of sufficient information on the mechanisms underlying the pathogenesis of the disease. The classification adopted in the present review is shown in Table 1. Varying from previous studies [4], [5] but according to what has been indicated in the Malmö criteria [2], we avoided considering as EAM constitutional symptoms such as weight loss, fever,

Incidence

The reported incidence of EAM varies among studies and geographical settings. Part of this variation is due to the fact that reporting has been inconsistent, as some investigators have considered all possible EAM, whereas others focused only on severe ones. As mentioned, there has also been a lack of clear consensus in selecting EAM as severe or not severe forms. As shown in Table 2, EAM occur in 17.8–40.9% of RA patients and 1.5%–21.5% of them present the most severe forms. Higher frequencies

Predisposing factors

Gender is a known predisposing factor only for rheumatoid nodules which were the most representative manifestation with a male predilection [21]. Rheumatoid vasculitides was also reported to have a higher incidence in men [27]. A genetic factor predisposing to EAM is homozygosity for human leukocyte histocompatibility antigen (HLA) class II DRB1*04 subtypes [28], [29], [30], the tyrosine-phosphatase gene PTPN22 [31], [32] and epigenetic changes [33], [34]. The presence of nodules, a not severe

Rheumatoid vasculitides and EAM

The majority of EAM can be considered an expression of rheumatoid vasculitis. This rare complication, which affects from < 1% to 5% of RA patients, causes various cutaneous and organ-specific manifestations [44]. It affects mainly RF-positive RA patients who have established rheumatic disease, irrespective of the extent of arthritic involvement. Rheumatoid vasculitides can occur in any organ, although about 90% of cases has cutaneous lesions (e.g. focal digital ischemia, deep cutaneous ulcers,

Therapeutic perspectives

The current therapy for EAM is disappointing and limited, except for steroids and cyclophosphamide for systemic vasculitides [44]. The main therapeutic guidelines for EAM, deduced from non-randomized studies, have been discussed in the preceding sections and are summarized in Table 4.

No controlled studies have analyzed the influence of biological therapy on EAM in terms of incidence, severity and response to treatment for the following reasons: first, the majority of the largest studies on EAM

Conclusions

Despite the widespread belief that severe EAM are becoming less common, many of these manifestations are associated with a more active and aggressive course of RA, although they are not always associated with the severity of joint involvement or with longstanding inflammation.

Because of the important prognostic information EAM can provide, it is necessary to overcome the heterogeneity in the classifications and definitions of EAM: a consensus on their diagnostic classification should be arrived

Take-home messages

•
There is currently no consensus in the classification of extra-articular manifestations (EAM) of RA.
•
Patients with EAM have a higher incidence of co-morbidities and a worse prognosis.
•
Current therapy for EAM is disappointing and has not been systematically evaluated in randomized controlled trials.

Acknowledgements

This work was supported by grants from “Fondazione Cassa di Risparmio di Puglia”, “University of Bari” and from AIRC, Milan, Italy .The authors are grateful to Mr. Vito Iacovizzi for his excellent secretarial assistance. Valerie Matarese provided scientific editing.

The authors declare that they have no conflicts of interest.

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ReviewExtra-articular manifestations of rheumatoid arthritis: An update

Abstract

Introduction

Section snippets

Methods

Nosographic setting of EAM

Incidence

Predisposing factors

Rheumatoid vasculitides and EAM

Therapeutic perspectives

Conclusions

Take-home messages

Acknowledgements

Lancet

Best Pract Res Clin Rheumatol

Semin Arthritis Rheum

Rheum Dis Clin North Am

J Autoimmun

J Autoimmun

J Autoimmun

J Autoimmun

J Autoimmun

Semin Arthritis Rheum

J Am Acad Dermatol

Autoimmun Rev

Clin Chest Med

Rev Mal Respir

Chest

Autoimmun Rev

Autoimmun Rev

Autoimmun Rev

Trends Immunol

Clin Med

Lancet Neurol

Semin Arthritis Rheum

Joint Bone Spine

Joint Bone Spine

Extra-articular rheumatoid arthritis: prevalence and mortality

Rheumatology (Oxford)

Multiple extra-articular manifestations are associated with poor survival in patients with rheumatoid arthritis

Ann Rheum Dis

Extra-articular manifestations of rheumatoid arthritis: a hospital-based study

Ann Saudi Med

Incidence and predictors of severe extra-articular disease manifestations in an early rheumatoid arthritis inception cohort

Ann Rheum Dis

High disease activity disability burden and smoking predict severe extra-articular manifestations in early rheumatoid arthritis

Rheumatology (Oxford)

Incidence and mortality of interstitial lung disease in rheumatoid arthritis: a population-based study

Arthritis Rheum

Rheumatoid arthritis-associated interstitial lung disease: diagnostic dilemma

Pulm Med

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Rheumatology (Oxford)

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J Rheumatol

Clinical approach to cutaneous vasculitis

Am J Clin Dermatol

Extra-articular manifestations in 587 Italian patients with rheumatoid arthritis

Rheumatol Int

How does functional disability in early rheumatoid arthritis (RA) affect patients and their lives? Results of 5 years of follow-up in 732 patients from the Early RA Study (ERAS)

Rheumatology (Oxford)

Ten year outcome in a cohort of patients with early rheumatoid arthritis: health status, disease process, and damage

Ann Rheum Dis

Occurrence of extraarticular disease manifestations is associated with excess mortality in a community based cohort of patients with rheumatoid arthritis

J Rheumatol

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Ann Rheum Dis

Extra-articular disease manifestations in rheumatoid arthritis: incidence trends and risk factors over 46 years

Ann Rheum Dis

Extra-articular manifestations of rheumatoid arthritis: results of a university hospital of 526 patients in Turkey

Clin Exp Rheumatol

Incidence of extraarticular rheumatoid arthritis in Olmsted County, Minnesota, in 1995–2007 versus 1985–1994: a population-based study

J Rheumatol

Rheumatoid arthritis in Greek and British patients. A comparative clinical, radiologic, and serologic study

Arthritis Rheum

No decrease over time in the incidence of vasculitis or other extraarticular manifestations in rheumatoid arthritis: results from a community-based study

Arthritis Rheum

Decline in rheumatoid vasculitis prevalence among US veterans: a retrospective cross-sectional study

Arthritis Rheum

Severe extra-articular disease manifestations are associated with an increased risk of first ever cardiovascular events in patients with rheumatoid arthritis

Review
Extra-articular manifestations of rheumatoid arthritis: An update