Extra-articular manifestations of rheumatoid arthritis: An update

Autoimmunity Reviews 11 (2011) 123–131

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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

a r t i c l e

i n f o

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

a b s t r a c t 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. © 2011 Elsevier B.V. All rights reserved.

Contents 1. 2. 3. 4. 5. 6.

Introduction . . . . . . . . . . . . . . . . . Methods . . . . . . . . . . . . . . . . . . . Nosographic setting of EAM . . . . . . . . . . Incidence . . . . . . . . . . . . . . . . . . . Predisposing factors . . . . . . . . . . . . . . Rheumatoid vasculitides and EAM . . . . . . . 6.1. Cutaneous EAM . . . . . . . . . . . . . 6.1.1. Rheumatoid nodules . . . . . . 6.1.2. Raynaud's phenomenon . . . . 6.1.3. Accelerated rheumatoid nodulosis 6.2. Visceral EAM . . . . . . . . . . . . . . 6.2.1. Pulmonary system . . . . . . . 6.2.2. Heart . . . . . . . . . . . . . 6.2.3. Nervous system . . . . . . . . 6.2.4. Eyes . . . . . . . . . . . . . . 6.2.5. Hematologic system . . . . . . 6.2.6. Kidneys . . . . . . . . . . . . 7. Therapeutic perspectives . . . . . . . . . . . . 8. Conclusions . . . . . . . . . . . . . . . . . . Take-home messages . . . . . . . . . . . . . . . . Acknowledgements . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . .

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⁎ 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: [email protected] (F. Perosa). 1568-9972/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.autrev.2011.09.001

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M. Prete et al. / Autoimmunity Reviews 11 (2011) 123–131

1. 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. 2. 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. 3. 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, anemia (mainly responsible for asthenia) and thrombocytosis; since the expression of these symptoms can also be related to concomitant infections (classic co-morbidities) or to therapies, they may represent confounding factors in the evaluation of the effective incidence of those EAM which are strictly related to RA. Similar to the Malmö criteria, osteoporosis, septic arthritis and cardiovascular disease, which have been considered EAM by some authors [6], were included under co-morbidities as they appear to be related to duration of disease and to drug therapies [1]. Finally, at variance from two previous investigations [2,7], we classified interstitial lung disease and amyloidosis as severe EAM; this decision was based on new information from three subsequent studies on interstitial lung disease [8–11] and from a report indicating that amyloidosis markedly worsens prognosis in these patients [12]. Besides applying a classification according to severity, we have also distinguished EAM into cutaneous and visceral forms. Nonetheless, many EAM are traceable to: 1) small vessel vasculitides triggered in part by circulating IgM rheumatoid factor (RF)-containing immune complexes and, more rarely, 2) ischemic damage as the consequence of small–medium-sized vessel occlusion [13,14].

4. 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 have been reported in northern European countries than in southern countries [23,24], suggesting that environmental and genetic factors play a role in the pathogenesis of these complications. Moreover, incidence is higher in hospitalbased than community studies [7,18], as would be expected from the inclusion of patients with more severe, complicated disease in the first situation [7,16]. Nevertheless, no decline in the occurrence of EAM has been observed over the decades in community-based studies [24], though studies based on hospital cohorts have shown a decreased incidence of severe EAM (i.e. vasculitides) [25], probably related to a more aggressive management of RA.

Table 1 Extra-articular manifestations (EAM) in rheumatoid arthritis (RA), according to the Malmö criteria [2] with some modifications, and comparison to common co-morbidities. Affected tissue or organ

Skin Pulmonary system Heart

Nervous system Eyes

EAM Severe

Nodules Raynaud's phenomenon Bronchiolitis obliterans Organizing pneumonia Valvular heart disease Myocarditis Arrhythmias None identified

Petechiae, purpura, ulcers, gangrene

Cancer

Pleuritis Interstitial lung disease Pericarditis Coronary vasculitis and aortitis Mono/polyneuritis multiplex Central nervous system vasculitis Episcleritis or scleritis Retinal vasculitides Felty's syndrome

Lung carcinoma

Hematological system

Secondary Sjögren syndrome Sicca syndrome None identified

Kidneys

None identified

Bone

None identified

a

Co-morbidities

Not severe

Caused by anterior atlanto-axial and subaxial subluxation.

Glomerulonephritis Interstitial nephritis Amyloid deposition None identified

Hypertension Heart failure Ischemic heart disease Depressive syndrome Cervical myelopathya None identified Non-Hodgkin lymphoma Lymphadenopathy Splenomegaly None identified

Osteoporosis

M. Prete et al. / Autoimmunity Reviews 11 (2011) 123–131

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Table 2 Studies reporting EAM in large cohorts of RA patients. Type of study

Patients, EAM incidence Period of Median follow-up n patient Subgroups, Individual types, % inclusion (years) %

Retrospective (Swedish cohort)

1990– 1994

4

489

Retrospective (Italian cohort)

1991

NR

587

Prospective (English cohort)

Before 1994

5

732

Prospective (Swedish cohort)

1985– 1989

10

183

Retrospective 1955– (Rochester, USA cohort) 1985

14.8

424

Retrospective (Spanish cohort)

10

788

Retrospective 1955– (Rochester, USA cohort) 1994

11.8

609

Retrospective (Turkish cohort)

1988– 2003

NR

526

Retrospective (Swedish cohort)

1985– 1989

15.4

183

Retrospective (Swedish cohort)

1996– 2000

7.6

2900

Retrospective (Turkish cohort)

2004– 2007

4

140

8.4

463

1989– 1999

Retrospective (Olmsted 1995– country cohort) 2007

Serositis, a(3.5); cutaneous vasculitides, (3.0); neuropathy, (0.6); glomerulonephritis, (0.6); Felty's syndrome, (0.2) Sicca syndrome, (17.5); nodules, (16.7); Raynaud's All, 40.9; phenomena, (6.3%); serositis, (4.4); interstitial lung Severe, disease, (4.2); cutaneous vasculitides, (3.7); 15.0 neuropathy, (1.7); Felty's syndrome, (0.7); amyloidosis, (0.7) All, 36.8; Nodules, (28.5); Sjögren syndrome, (7.3), interstitial Severe, 8.4 lung disease, (2.2); neuropathy, (2.2), vasculitides, (3.5); Felty's syndrome, (0.5) All, 39.9; Nodules, (38.2); interstitial lung disease, (2.2); Severe, 9.8 pleuritis, (1.6); cutaneous vasculitides, (2.2); neuropathy, (1.6); amyloidosis, (1.6); glomerulonephritis, (1.1) Severe,15.5 Serositis, (4.9); cutaneous vasculitides, (3.3); vasculitides, (4.7), neuropathy, (1.9); Felty's syndrome, (0.7) Nodules, (24.5); Sjögren syndrome, (17.1); interstitial All, 36.2; lung disease, (3.7); serositis, (2.4); scleritis and Severe, episcleritis, (2.5); vasculitides, (1.3); amyloidosis, 10.6 (0.6); Felty's syndrome, (0.3) Nodules, (28.2); Sjögren syndrome and sicca All, 40.6; syndrome, (19.6); serositis, 6.9; interstitial lung Severe, disease, (5.6); cutaneous vasculitis, (3.1); neuropathy, 21.5 (1.8); scleritis and episcleritis, (1.5); Felty's syndrome (1.5); amyloidosis, (0.4) All, 38.4; Nodules, (18.1); sicca syndrome, (11.4); interstitial Severe, 7.4 lung disease, (4.8); Raynaud's phenomena, (3.0); vasculitides, (1.3), Felty's syndrome, (0.3) Severe, Serositis, (4.9); interstitial lung disease, (2.8); 17.5 neuropathy, (2.8); vasculitides, (2.2); scleritis and episcleritis, (2.1); glomerulonephritis, (1.7); Felty's syndrome, (1.1) Severe, 1.5 Serositis, (1.4); interstitial lung disease, (0.6), neuropathy, (0.2); cutaneous vasculitides, (0.13); scleritis and episcleritis, (0.1); Felty's syndrome, (0.03) Interstitial lung disease, (7.1); serositis, (5.7); All, 17.8; amyloidosis, (4.3); vasculitides, (1.4); nodules, (2.1); Severe, Sjogren syndrome, (1.4); Felty's syndrome, (0.7) 14.2 All, 39.7; Nodules, (23.7); sicca syndrome, (15.9); Sjögren Severe, 9.1 syndrome, (8.2); interstitial lung disease, (4.1); serositis, (3.1); neuropathy, (1.3); episcleritis, (0.6); vasculitides, (0.4), Felty's syndrome, (0.4); amyloidosis (0) Severe, 7.5

Predictor factors of EAM

Mortality

NR

Increased [2]

ANA positivity, RF positivity, male gender

NR

[15]

NR

NR

[16]

NR

NR

[17]

NR

Increased [18]

NR

NR

[19]

Smoking and early disability, ANA positivity, RF positivity

NR

[20]

RF positivity,

NR

[21]

Lower C4, RF positivity

NR

[7]

High CRP, high DAS-28, smoking, RF positivity (during first 2 years of follow-up) RF

NR

[8]

RF positivity and joint erosions

Ref.

Increased [5]

Increased [22]

NR: not reported; ANA: antinuclear antibodies; Anti-CCP: antibodies to cyclic citrullinated peptide; CRP: C-reactive protein; DAS-28: disease activity score; RF: rheumatoid factor. a They include pleuritis and pericarditis.

To get a clear idea of the incidence of EAM, overall and for the individual forms, we selected papers reporting epidemiological data from large RA cohorts (N100 patients). Table 2 summarizes results from 12 studies, and includes not only incidence rates but also information on predisposing factors and impact of EAM on mortality. The studies reported on 8024 RA patients, of whom 2249 had EAM for an overall incidence of 28%; this group included 1586 patients with non-severe EAM and 663 (8.3%) with severe EAM. Among these studies, only four [2,7,8,18] considered severe EAM and only four [2,5,18,22] evaluated their influence on mortality. Severe EAM were associated with increased mortality in two studies [2,18] and, in a subsequent analysis of 609 patients from the Rochester cohort, it was found that the presence of multiple EAM was associated with an increased overall mortality in RA [3]; however, a subsequent population-based inception-cohort study did not confirm these latter findings [22]. These patients died mainly from ischemic complications, so that severe EAM were considered a major determinant of cardiovascular morbidity in RA [26]. Many studies have reported that smoking [8,20], early disability [20], antinuclear antibodies

(ANA) and RF positivity [7,15,20–22] are the principal predictor factors of severe EAM. Gender has not been found to have any effect on overall EAM incidence or mortality, with the exception of one study of an Italian cohort [15] which reported that the risk of developing any EAM was higher in men than in women (odds ratio, 1.68). Data from these 12 studies were extracted to determine incidence rates for individual EAM (Table 3). From this analysis, it emerged that non-severe EAM were prevalent overall. The incidence of severe EAM was 8.3% and, among them, vasculitides, interstitial lung disease and serositis were the most common. Caution must be exercised in the interpretation of these results, since: 1) retrospective and prospective studies have been combined; and 2) EAM were not homogenously recorded in the 12 studies analyzed; for instance, Raynaud's phenomenon and scleritis/episcleritis were not recorded in many of these studies. 5. Predisposing factors Gender is a known predisposing factor only for rheumatoid nodules which were the most representative manifestation with a male

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Table 3 Incidence of extra-articular manifestations (EAM) in 8024 patients identified from all the studies cited in Table 2 between 1999 and 2011. EAM Subgroup

Type

Not severe EAM

All Nodules Sicca syndrome Sjögren syndrome Raynaud's phenomenon All Interstitial lung disease Serositis (pleuritis and pericarditis) Vasculitides (cutaneous and systemic) Peripheral neuropathy Scleritis and episcleritis Felty's syndrome Secondary amyloidosis Glomerulonephritis

Severe EAM

Patients, n (%) 1586 950 298 285 53 663 174 169 148 67 35 30 27 13

(19.7) (11.8) (3.7) (3.5) (0.6) (8.3) (2.2) (2.1) (1.8) (0.8) (0.4) (0.3) (0.3) (0.2)

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 [28–30], the tyrosine-phosphatase gene PTPN22 [31,32] and epigenetic changes [33,34]. The presence of nodules, a not severe EAM, was predictive of severe EAM (odds ratio, 3) in one retrospective analysis [35]. Additional predictors of EAM include environmental and behavioral factors, with smoking being the most important [36,37]. The effects of smoking may be related to its modulatory action on the immune system [38], as indicated by a positive correlation of smoking with anti-CCP antibodies [36,39]; or to its endothelial insults that promote inflammatory vascular damage [29]. Indeed, RA patients with EAM have increased mortality from cardiovascular disease than those without EAM [26]. Nevertheless, the ability of smoking-cessation programs to reduce patients' risk of developing severe EAM or dying from ischemic complications has not been assessed in controlled trials [26,29,38,40]. Additional disease markers often identified in RA patients with EAM are ANA, erythrocyte sedimentation rate, C-reactive protein, RF and antibodies to cyclic citrullinated peptides [4,41]. Even so, there are no reliable predictors for the development of EAM in early RA. Recent studies have investigated an association between EAM and a polymorphism in the promoter region of the endothelial nitric oxide synthase gene. This 786C/C polymorphism, found more frequently in RA patients than in healthy individuals (p b 0.0001) [42], increases the risk of EAM as compared to T/T and T/C genotypes (odds ratio, 4.9) [43].

6. Rheumatoid vasculitides and EAM The majority of EAM can be considered an expression of rheumatoid vasculitis. This rare complication, which affects from b1% 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, petecchiae, purpura, peripheral gangrene), while 40% has peripheral nerve lesions (mononeuritis multiplex, sensory symmetric neuropathy) [45]. Rarely, the central nervous system, eyes, heart, lungs, gastrointestinal tract or kidneys are involved. Although there are no specific signs or symptoms to guide a diagnosis, the clinician must first rule out other conditions (e.g. diabetes, atherosclerosis or infection) and, whenever possible, should request histopathological analysis to search for the presence of acute necrotizing arteritis in small vessels of the affected organs.

Management of rheumatoid vasculitides remains largely empirical, based on steroids and cytotoxic drugs. No clinical trial has assessed the efficacy of new biological therapies. Contrasting data have been reported on the role of TNF-α inhibitors [46–48]. Rituximab was reported to be successful in treating rheumatoid vasculitides-associated ulcers, not responsive to cyclophosphamide, in five patients [49,50]. Additional studies are warranted to define the best clinical and therapeutic management of these patients. 6.1. Cutaneous EAM The skin is the most common extra-articular target of RA. Cutaneous EAM include rheumatoid nodules as well as Raynaud's phenomenon and cutaneous vasculitides. Moreover, patients receiving methotrexate treatment may also develop accelerated rheumatoid nodulosis. 6.1.1. Rheumatoid nodules Rheumatoid nodules are defined as subcutaneous nodules with a diameter N5 mm. They occur in about 30% of RA patients and are more frequent in RF-positive subjects (incidence, about 90%) than in those who are RF-negative [51]. RF positivity, smoking habit and homozygosity for HLA-DRB1 are independent factors for an increased risk of nodular manifestations [52]. Rheumatoid nodules generally develop during the course of disease, although some nodules can form before joint involvement and may be associated with an increased risk of other EAM [53]. Their preferred localizations are sites of external pressure or repetitive irritation, such as the extensor surfaces of the forearm, fingers, occipitus, and heel. Other locations include sacral prominences, buttocks, ears and nose. Nodules also appear in internal organs (e.g. lung, pleura, pericardium, synovium, meninges), thus contributing to visceral and articular damage. Rheumatoid nodules can be solitary or multiple; they generally have a subcutaneous development, can adhere to the underlying periosteum and are usually painless, although they may cause functional limitations when localized on fingers or feet. Microscopic analysis of rheumatoid nodules shows three definite, classic histological zones of the granuloma: a central necrotic area that includes cellular debris, collagen, fibrin; an intermediate area with palisading macrophages, displaying an increased expression of HLA-DR antigen; and a surrounding zone of tissue affected by perivascular cellular infiltration enriched with lymphocytes, plasma cells and histiocytes [54]. The pathogenesis of this granulomatous lesion is not completely defined. Some observations support the role of IgM RF-containing immune complexes and complement activation on the endothelial surface after vascular injury [55]. Similar to what has been observed for synovial lesions, high levels of interleukin (IL)-1β and tumor necrosis factor (TNF)-α have been found in rheumatoid nodules, indicating a Th1-mediated inflammatory mechanism [56]. Rheumatoid nodules do not usually require treatment, unless they ulcerate or compress nerves or articular structures. The nodules may regress with standard therapy but sometimes they persist or worsen with treatment [57]. 6.1.2. Raynaud's phenomenon Raynaud's phenomenon, a vasospastic disorder causing triphasic color change of the extremities (usually fingers and toes) in response to cold or emotional stress, affects 5%–17% of RA patients [58]. Its course is generally benign and it rarely causes ulceration or ischemic gangrene in these patients [4]. Its presence, in fact, does not appear to compromise patients' hand function or prognosis [59]. However, the appearance of Raynaud's phenomenon several years after RA onset may predict the beginning of a more severe course and a higher probability of the onset of vasculitides [58,60]. As in other connective

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diseases, medical treatment of Raynaud's phenomenon in the setting of RA remains unsatisfactory [61]. 6.1.3. Accelerated rheumatoid nodulosis RA patients receiving methotrexate treatment are also susceptible to developing another form of cutaneous EAM, namely accelerated rheumatoid nodulosis [62,63]. This clinical manifestation occurs in 8%–11% of methotrexate-treated RA patients and long-term therapy with this drug appears to be a predisposing factor. The condition regresses when methotrexate is reduced or withdrawn and if hydroxychloroquine or sulphasalazine treatment is started [64]. Accelerated rheumatoid nodulosis may develop despite improvement of arthritic symptoms [65]. Nodules are preferentially located in the fingers or in the metacarpophalangeal and proximal interphalangeal joints. The pathogenetic mechanism of methotrexate-induced nodulosis is still obscure, though one investigation identified an adenosine-1 receptor-mediated pathway as responsible for macrophage recruitment and multinucleated giant cell promotion [66]. Blockade of this pathway with colchicine caused regression of the nodulosis in vitro and in vivo [67]. Although no further investigation has confirmed or disputed these findings, clinical experience suggests that colchicine is ineffective. Indeed, no effective treatement is so far available for accelerated rheumatoid nodulosis. It is intriguing that this manifestation has never been observed in cancer patients treated with higher doses of methotrexate, suggesting that the pathogenetic mechanisms of RA are an essential requirement for methotrexate to induce nodulosis. Accelerated rheumatoid nodulosis (and vasculitides) has also been reported, in 2002, in RF-positive patients treated with etanercept (anti-TNF-α) and refractory to a number of disease-modifying drugs, including hydroxychloroquine, methotrexate and azathioprine [68,69]. An additional report indicated the appearance of nodulosis in patients treated with leflunomide [70]. Although a recent meta-analysis of the efficacy and safety of etanercept and other biological agents used in RA treatment excluded the possibility that multiple nodulosis may be triggered by this anti-TNF-α antibody [71], the above-mentioned papers offered hypotheses on the pathogenetic mechanisms underlying this complication [68]: a) involvement of transforming growth factor (TGF)-β and IL-1 in granuloma formation; b) drug-induced recruitment of other inflammatory cells; and c) nodulosis as part of the natural history of aggressive RA. Despite these interesting mechanistic proposals, the pathogenesis of nodulosis remains obscure. 6.2. Visceral EAM Visceral EAM refer to the involvement of heart, lung, kidney, eyes and nervous system during the course of RA. The histological lesion is characterized by a cellular infiltrate made of lymphomonocytes, histiocytes and macrophages, which may organize to form nodular granulomatous lesions, similar to that observed at the dermal level. The initial event leading to these lesions is likely to be a vasculitis. Visceral EAM may markedly compromise the function of the affected organ either directly or by predisposing to an infectious process, thus worsening patients' prognosis. Patients with visceral EAM must be strictly monitored because of the possibility of a sudden onset of complications. 6.2.1. Pulmonary system Lung involvement is common, affecting 5%–10% of RA patients, and is often their major cause of morbidity and mortality [11]. It has a heterogeneous clinical presentation, with interstitial lung disease, small airway disease, rheumatoid nodules, pleural effusion and pulmonary vasculitides. Histopathological studies show lymphoid infiltrates similar to those observed in cutaneous nodules [72]. Visceral pulmonary nodules are usually asymptomatic, but may exacerbate and increase the risk of infections and pneumothorax.

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Solitary, intrapulmonary nodules may pose a diagnostic dilemma, mimicking lung carcinoma. Multiple intrapulmonary nodules may mimic idiopathic pulmonary fibrosis. Pulmonary EAM are rarely symptomatic in the early phases of RA [4,11]. The best approach for an early diagnosis of lung involvement is to use high resolution computed tomography (HRCT). Its diagnostic power has been documented in a study in which HRCT revealed interstitial lung disease in about 50% of RA patients, of whom only 10% had clinically significant symptoms [73]. Treatment is mainly based on systemic steroids and cyclophosphamide. Interstitial lung involvement responds better than idiopathic pulmonary fibrosis to immunosuppressive therapy [74]. However, no clinical trial has been published on the use of rituximab for interstitial lung disease in RA [75]. A beneficial effect of anti-CD20 therapy has been described in several case reports of patients with pulmonary involvement related to primary vasculitis or other connective tissue diseases, such as Churg–Strauss syndrome [76], Wegener's granulomatosis [77] or dermatomyositis [78]. In addition, long-term rituximab treatment of RA patients did not appear to be associated to the onset of this complication [79]. On the other hand, when deciding whether or not to use rituximab in RA patients with pulmonary disease, the physician should be aware that this drug can trigger or worsen pulmonary fibrosis [80]. There are conflicting data about a response to pleural methylprednisolone infusion in patients with pleuritis [81] even if, as Turesson and Matteson commented in their review [36], this treatment may be useful. Case reports have suggested a response to antiTNF-α inhibitors [82,83], hypothesizing a possible role of T cells in the pathogenesis. The role of TNF-α inhibitors in treating pulmonary lesions of RA has not been investigated, and prospective clinical trials are warranted.

6.2.2. Heart Cardiac involvement may affect the course of RA [84]. All cardiac structures can be involved and pericarditis, myocarditis, valvular disease, arrhythmias, and ischemic heart disease may occur [85]. All of them are associated with an unfavorable prognosis. Their early detection in an asymptomatic stage is essential. The commonest complication is pericarditis, while symptomatic myocarditis, endocarditis, coronary arteritis and aortitis rarely occur. The latter two conditions, which are most often associated with rheumatoid vasculitis, are almost exclusively demonstrated by autopsy. Moreover, since these patients typically have accelerated atherosclerosis, it is difficult to determine the extent to which their blood vessel lesions are actually caused by vasculitis or atherosclerosis [45,86]. Symptomatic pericarditis is found in about 1%–4% of patients, even if histopathological abnormalities are demonstrated in 30%–50% of cases by echocardiography or autopsy [87]. Symptomatic pericarditis frequently occurs in seropositive male patients with RA, generally after the onset of arthritis. Symptomatic pericarditis can rarely be the first clinical sign of RA [88]. Recent studies have investigated the pathogenetic mechanisms that subtend the early cardiovascular involvement in RA. These studies have revealed that numerous factors are involved in altered arterial endothelium function, including genetic background, smoking habit, presence of autoantibodies to cyclic citrullinated peptides and expansion of circulating CD4+ CD28− T cells [89–91]. The majority of cardiac complications in RA are silent and do not require treatment. In symptomatic pericardial disease, with dull chest pain or pericardial fluid without hemodynamic compromise, non-steroidal anti-inflammatory drugs or steroids may bring upon a rapid resolution [92]. When pericardial effusion recurs, immunosuppressive treatment with cyclophosphamide or other drugs may be necessary. Constrictive pericarditis and rapidly progressive, effusive

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pericarditis require emergency intervention and can worsen the outcome of patients [36]. 6.2.3. Nervous system Neurological complications of RA are rare (affecting 1% of patients) but may involve both the peripheral and central nervous systems [93]. The underlying mechanism is a vasculitis with immune complex deposition that affects the vasa vasorum of the nerves with ischemic damage and demyelinization. As mentioned before, mononeuritis multiplex (i.e. acute peripheral sensorimotor neuropathy) is one of the most common vasculitic manifestations in a wide spectrum of systemic RA vasculitides [94]. The disorder typically occurs as a late manifestation of a severe RF-seropositive disease. Nervous system involvement, such as carpal tunnel syndrome or cervical myelopathy due to atlanto-axial subluxation, occurs frequently in patients with long-standing disease and has been considered a consequence of local synovitis or of a bone deformity [95,96]. This complication often requires surgical intervention [97]. In a recent report [98], 108 patients with RA were evaluated clinically and electrophysiologically for evidence of peripheral neuropathy: neuro-electrophysiologic alterations were detected in 62 patients (57%) and were attributed to mononeuritis multiplex (in 85% of cases), chronic inflammatory demyelinating polyneuropathy (14%) and carpal tunnel syndrome (10%) [98]. Central nervous system vasculitis is extremely rare in RA. Case reports have indicated that headaches, meningoencephalopathy, seizures, neuropsychiatric symptoms and relapsing focal neurological deficits are the main clinical manifestations. The diagnosis is supported by magnetic resonance (MR) imaging, alone or with MR angiography, which shows segmental vascular stenosis with a typical appearance of vasculitis [99,100]. Cerebral vasculitis is usually treated with methylprednisolone and cyclophosphamide pulse therapy, which leads to a rapid resolution of the clinical pattern [99,100]. Occasionally, anti-TNF therapy has been used successfully in patients resistant to conventional treatment [99,100]. 6.2.4. Eyes Ophthalmic rheumatologic presentations include secondary Sjögren's syndrome, episcleritis, scleritis, keratitis and retinopathy. According to one study on 691 RA patients, ocular involvement occurs in 27% of them [101]. Among them, secondary Sjögren's syndrome and scleritis are the most frequent ophthalmic EAM [101]. There are three types of anterior scleritis: diffuse, nodular and necrotizing. The latter is also referred to as scleromalacia perforans. Scleromalacia perforans, the most severe type of scleritis, is a rare EAM reported in only b1% of patients [102]. It is a degenerative thinning of the sclera that occurs in female patients with high RF titer. It has been attributed to a vasculitic process with deposition of immune complexes. A high level of RF could predispose to this complication [102]. This condition is often painless and, when it goes untreated, can evolve to scleral perforation. This evolution can be prevented by anti-inflammatory drugs or disease-modifying antirheumatic drugs (DMARDs). Recently, biological treatment with anti-TNF-α [103,104] or anti-CD20 (rituximab) [105] has dramatically improved ocular complications, but clinical trials have not yet been reported. 6.2.5. Hematologic system Felty's syndrome is defined as a combination of chronic polyarthritis, neutropenia and splenomegaly. It appears in less than 1% of patients and is often associated with aggressive disease [106]. It usually develops after a long course of RA and frequently occurs in patients with severe joint involvement. Almost 75% of patients with Felty's syndrome will present cutaneous nodules [106]. Rarely, Felty's syndrome can be an initial presentation of RA in absence of clinical evidence of arthritis [107]. RF positivity is detected in a high percentage of patients, in association with antibodies to cyclic citrullinated

peptides and low complement levels [41,106,108]. Neutropenia is the main clinical condition in these patients and the main cause of the high rate of bacterial infections, leading to high mortality. Neutropenia responds to granulocyte colony-stimulating factor when administered with standard DMARDs [109]; the best results were obtained with low doses of methotrexate [110]. Rarely, splenectomy is considered an early therapeutic option, because of a higher incidence of post-splenectomy infections [106]. Some investigators reported a response of Felty's syndrome to rituximab [111], while others found this treatment questionable [112]. 6.2.6. Kidneys Renal involvement is a rare EAM of RA. In some patients, renal injury is induced by drugs (e.g. non-steroidal anti-inflammatory agents and DMARDs). Glomerulonephritis (mainly mesangial) occurs in about 60% of cases of renal involvement, secondary amyloidosis is diagnosed in 25%, and interstitial nephritis is rarely observed [113]. Secondary amyloidosis, detected in patients with severe proteinuria and nephrotic syndrome, markedly influences these patients' outcomes [114]. Usually, the diagnosis of secondary amyloidosis is made in patients with already established organ damage. One study of factors able to reveal subclinical amyloidosis found that abdominal fat aspiration biopsy gives a higher prevalence of positivity than biopsy of minor salivary glands (21.5% vs 3.7%) [115]. The main risk factors favoring amyloid deposition are longstanding disease (7–10 years) and poor response to therapy [115]. Amyloid deposition is not unique to RA, and can be observed in other chronic inflammatory diseases (e.g. autoinflammatory diseases, Crohn's disease, tuberculosis) [116]. Secondary amyloidosis involves deposition of amyloid A (AA) fibrils, which derive from degradation of serum amyloid A (SAA). SAA is an acute phase serum protein produced by the liver during inflammation. It is expressed at high levels in sera of patients with uncontrolled RA, although AA deposition in liver, kidney and rheumatoid synovium occurs only in some of these patients [117], indicating that other yet unknown factors influence fibril accumulation [118]. Among the known factors favoring AA deposition, some genotypes at SAA1 loci [119] and some SAA isoforms [120] should be highlighted [120]. A Japanese study reported a narrow association between the SAA1.3 allele and the early appearance of severe AA amyloidosis in RA patients [121]. Moreover, macrophages adjacent to amyloid deposits are believed to play an important role favoring amyloid deposition. Macrophages release proteases (e.g. cathepsin k), which may initiate the process of SAA degradation with AA amyloid formation [122]. Pro-inflammatory cytokines, such as IL-1, IL-6 and TNF-α, appear to be involved in the maintenance of the process [123]. Currently, the standard treatment for AA amyloidosis is based on colchicine, chlorambucil [124] or cyclophosphamide associated with corticosteroids [125]. Anti-cytokine therapy gave encouraging results, by reducing inflammation and ameliorating renal function [126–128]. 7. 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 nonrandomized 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 are retrospective analyses that included patients with a disease onset in the pre-biological era (Table 2); second, patients with EAM have been excluded from controlled clinical trials in which traditional DMARDs were randomized against biological agents [4,129]. Although evidence from randomized controlled trials

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Table 4 Currently used therapies for EAM in RA patients. Affected tissue or organ

EAM

Therapy

References

Skin

Subcutaneous nodules; Accelerated rheumatoid nodulosis; Cutaneous vasculitides Raynaud's phenomenon

Steroids alone or with methotrexate or azathioprine; Anti-TNF-α; Anti-CD20

[44,45,48,49,51,55]

Symptomatic treatment; calcium antagonists (dihydropyridine); vasoactive drugs (analogue of prostacyclin PGI2) Steroids and cyclophosphamide; rituximab

[59–61]

Pericardiocentesis; steroids

[36,85,87,88]

Steroids and cyclophosphamide; anti-CD20; anti-TNF-α

[4,93,97–99]

Local steroids; cyclosporine; anti-TNF-α; anti-CD20 Methotrexate; anti-CD20; splenectomy Steroids and cyclophosphamide; chlorambucil; colchicine; anti-TNFα; anti-IL-6; hemodialysis

[101–105] [106,107,111] [124–127]

Pulmonary system

Heart Nervous system

Eyes Hematological system Kidneys

Pulmonary nodules; Interstitial lung disease; Pulmonary fibrosis; Pleuritis Pericarditis Myocarditis or endocarditis Mononeuritis multiplex; Sensory peripheral neuropathy; Central nervous system vasculitis Scleritis or episcleritis; Retinal vasculitis Felty's syndrome Glomerulonephritis; Interstitial nephritis; Secondary amyloidosis

is lacking, an early and more aggressive management of RA should ameliorate the effects of EAM on outcomes, as many manifestations are related to disease activity and severity [1,130]. Further knowledge of the pathogenesis of EAM may lead to a more rational use of drug therapies, including the inhibitors of IL-1 [6]. 8. 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 at as soon as possible with an appropriate grouping of all clinical manifestations. A homogeneous classification of EAM may represent the starting point to analyze data from comparative effectiveness registries and for planning controlled clinical trials to definitively assess the effectiveness of biological reagents. Of particular interest are inhibitors of IL-1, which have only a moderate effect on EAM-free RA but might be effective on those EAM with an autoinflammatory pathogenesis. Take-home messages • There is currently no consensus in the classification of extraarticular 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.

[36,72]

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Blood testing for TSH receptor antibody is useful for the differential diagnosis of hyperthyroidism While it is established that tyrotropin (TSH) receptor antibodies (TRAbs) have a pathogenetic role in Graves’ disease, the diagnostic utility of testing for TRAbs is still a matter of debate. Current assays for the detection of serum TRAbs are more accurate and feasible than the previous generation ones. However, a limit still exists to their widespread application in clinical practice, that is the cost-effectiveness balance. In this review article, Matthews et al. (Eur J Int Med 2011;22:213-6) described the clinical evidence of the utility of TRAb testing for the diagnosis and clinical management of hyperthyroidism. In particular, several ambiguous forms of hyperthyroidism can benefit of the TRAb measurement in serum, such as unilateral exophthalmos, painless thyroiditis, euthyroid Graves’ ophthalmopathy, subclinical hyperthyroidism, amiodarone-induced tyrotoxicosis, and, in addition, women with Graves’ disease during the third trimester of pregnancy to predict the risk of neonatal thyroid dysfunction. In these conditions, current tests for TRAb are more sensitive and specific that the routinely used tests for thyroid peroxidase antibodies, and cheaper than the radiographic scans. Moreover, TRAb testing may help to predict the clinical course of Graves’ disease and a recurrence during medical therapy. Anna Ghirardello