ReviewExtra-articular manifestations of rheumatoid arthritis: An update
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
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There is currently no consensus in the classification of extra-articular manifestations (EAM) of RA.
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Patients with EAM have a higher incidence of co-morbidities and a worse prognosis.
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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.
References (130)
- et al.
Rheumatoid arthritis
Lancet
(2010) - et al.
Extra-articular manifestations and complications of rheumatoid arthritis
Best Pract Res Clin Rheumatol
(2007) - et al.
Systemic nonarticular manifestations of rheumatoid arthritis: focus on inflammatory mechanisms
Semin Arthritis Rheum
(2009) - et al.
Vasculitis associated with rheumatoid arthritis
Rheum Dis Clin North Am
(1990) - et al.
Familial disease, the HLA-DRB1 shared epitope and anti-CCP antibodies influence time at appearance of substantial joint damage in rheumatoid arthritis
J Autoimmun
(2009) - et al.
Genetics of rheumatoid arthritis: underlying evidence of ethnic differences
J Autoimmun
(2009) - et al.
The environment, geo-epidemiology, and autoimmune disease: rheumatoid arthritis
J Autoimmun
(2010) - et al.
Epigenetics and rheumatoid arthritis: the role of SENP1 in the regulation of MMP-1 expression
J Autoimmun
(2010) - et al.
Epigenetics and autoimmunity
J Autoimmun
(2010) - et al.
Systemic rheumatoid vasculitis: a review
Semin Arthritis Rheum
(2006)
Rheumatoid arthritis: a review of the cutaneous manifestations
J Am Acad Dermatol
Treatment of Raynaud's phenomenon
Autoimmun Rev
Pulmonary manifestations of rheumatoid arthritis
Clin Chest Med
Pulmonary manifestation of rheumatoid arthritis
Rev Mal Respir
Effects of tumor necrosis factor-alpha inhibitors on lung lesions with rheumatoid arthritis
Chest
Cardiovascular risk in rheumatoid arthritis
Autoimmun Rev
Cardiac involvement in systemic rheumatic diseases: an update
Autoimmun Rev
The heart in rheumatoid arthritis
Autoimmun Rev
CD28(−) T cells: their role in the age-associated decline of immune function
Trends Immunol
Cardiac involvement in rheumatoid disease
Clin Med
An update on the classification and treatment of vasculitic neuropathy
Lancet Neurol
Bone marrow edema in the cervical spine of symptomatic rheumatoid arthritis patients
Semin Arthritis Rheum
Cerebral vasculitis in a patient with rheumatoid arthritis
Joint Bone Spine
Isolated cerebral vasculitis associated with rheumatoid arthritis
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
Interstitial lung disease has a poor prognosis in rheumatoid arthritis: results from an inception cohort
Rheumatology (Oxford)
No improvement in survival of patients with amyloidosis associated with inflammatory rheumatic diseases — data from the Finnish national registry for kidney diseases
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
Rheumatoid arthritis in Spain: occurrence of extra-articular manifestations and estimates of disease severity
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
Ann Rheum Dis
Factors associated with the development of vasculitis in rheumatoid arthritis: results of a case–control study
Ann Rheum Dis
Homozygosity for the HLA-DRB1 allele selects for extraarticular manifestations in rheumatoid arthritis
J Clin Invest
Genetics of rheumatoid arthritis: is there a pattern predicting extraarticular manifestations?
Arthritis Rheum
Predictors of extra-articular manifestations in rheumatoid arthritis
Scand J Rheumatol
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