Review Extra-articular manifestations of rheumatoid arthritis: An update Marcella Prete, Vito Racanelli, Liboria Digiglio, Angelo Vacca, Franco Dammacco, Federico Perosa ⁎ Department of Internal Medicine and Clinical Oncology (DIMO), University of Bari Medical School, Bari, Italy abstract article info Article history: Received 22 August 2011 Accepted 3 September 2011 Available online 10 September 2011 Keywords: Rheumatoid arthritis Extra-articular manifestation Co-morbidities Classification Incidence/rate Vasculitides Amyloidosis Felty's syndrome 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 nu- merous 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 man- ifestations 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. Under- standing 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. © 2011 Elsevier B.V. All rights reserved. Contents 1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 2. Methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 3. Nosographic setting of EAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 4. Incidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124 5. Predisposing factors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 125 6. Rheumatoid vasculitides and EAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 6.1. Cutaneous EAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 6.1.1. Rheumatoid nodules . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 6.1.2. Raynaud's phenomenon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 126 6.1.3. Accelerated rheumatoid nodulosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 6.2. Visceral EAM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 6.2.1. Pulmonary system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 6.2.2. Heart . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 127 6.2.3. Nervous system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 6.2.4. Eyes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 6.2.5. Hematologic system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 6.2.6. Kidneys . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 7. Therapeutic perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 128 8. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Take-home messages . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 Autoimmunity Reviews 11 (2011) 123–131 ⁎ Corresponding author at: Department of Internal Medicine and Clinical Oncology (DIMO), Rheumatology Unit, University of Bari Medical School, Piazza G. Cesare 11, I-70124 Bari, Italy. Tel.: +39 080 547 8891; fax: +39 080 547 8820. E-mail address: f.perosa@dimo.uniba.it (F. Perosa). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.09.001 Contents lists available at SciVerse ScienceDirect Autoimmunity Reviews journal homepage: www.elsevier.com/locate/autrev