Systemic Nonarticular Manifestations of Rheumatoid Arthritis: Focus on Inflammatory Mechanisms

RHEUMATOID ARTHRITIS

Systemic Nonarticular Manifestations of Rheumatoid Arthritis: Focus on Inflammatory Mechanisms Larry W. Moreland, MD,* and Jeffrey R. Curtis, MD, MPH†

Objective: Extra-articular (“nonarticular”) manifestations of rheumatoid arthritis (RA) are common and greatly affect physical and emotional health, as well as prognosis, including survival. Several plausible mechanisms have been advanced for many nonarticular manifestations but there is increasing evidence that pro-inflammatory cytokines (eg, tumor necrosis factor-alpha [TNF-␣], interleukin [IL]-1, and IL-6) are also involved. The purpose of this review is to provide a concise appraisal of recent studies investigating the involvement of inflammatory cytokines in the pathogenesis of nonarticular RA manifestations. Methods: A Medline search for articles published between January 1995 and October 2007 was conducted using the following keywords: rheumatoid arthritis, anemia, cardiovascular, atherosclerosis, bone loss, osteopenia, osteoporosis, pulmonary, thrombocytopenia, lymphadenopathy, keratoconjunctivitis sicca, uveitis, scleritis, keratitis. The review focused on articles describing a potential role of inflammatory mediators in these conditions. Results: Studies of many nonarticular manifestations strongly implicate pro-inflammatory cytokines and specific mechanisms by which these mediators are likely to act have even been elucidated. The inflammatory cytokines implicated are numerous but particularly include members of the TNF family and the interleukins, particularly IL-1 and IL-6. In bone loss, activated T-cells have been shown to express pro-inflammatory cytokines (eg, TNF, IL-1, IL-7, and IL-17) that differentially upregulate and downregulate mechanisms that mediate the balance between bone resorption and formation. Cytokine-mediated inflammation has also been implicated, for example, in the early stages of atherogenesis and this may explain the observed increase in cardiovascular disease among patients with RA. However, for some nonarticular manifestations, the association with pro-inflammatory cytokines has been less firmly established and potential mechanisms are more speculative. Conclusions: Overall, further research in this area will add to our understanding of the mechanisms of extra-articular manifestations in RA patients. These insights should allow clinicians to select therapies to better match the spectrum of joint disease and nonarticular manifestations in individual patients. This may be particularly relevant for newer biologic agents with specific inhibitory effects on cytokines such as TNF-␣ and IL-6. © 2008 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 39:132-143 Keywords: rheumatoid arthritis, extra-articular, nonarticular, systemic, manifestations, complications, cytokines, pro-inflammatory, RA, TNF-␣, IL-6

*Margaret Jane Miller Endowed Professor for Arthritis Research, University of Pittsburgh, Pittsburgh, PA. †Assistant Professor of Medicine, University of Alabama at Birmingham, Birmingham, AL. Address reprint requests to: Larry Moreland, MD, University of Pittsburgh, S711 Biomedical Science Tower, 3500 Terrace Street, Pittsburgh, PA 15261. E-mail: [email protected].

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0049-0172/09/$-see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.semarthrit.2008.08.003

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xtra-articular (or “nonarticular”) manifestations of rheumatoid arthritis (RA) are common in Western countries (1,2). A retrospective review of medical records of 609 cases of RA at the Mayo Clinic (19551994) found at least 1 extra-articular disease manifestation (eg, pericarditis, pleuritis, cutaneous vasculitis, Felty’s syndrome, neuropathy, ophthalmological manifestations, glomerulonephritis, and other types of vasculitis) in 247 patients (41%) over a mean of 11.8 years (range, 0.1 to 42.8 years) (3). This study also found that the incidence of severe extra-articular manifestations had not changed significantly over the decades. However, the prevalence of extra-articular disease in this study may not reflect current prevalence rates, since clinical practice has changed over the last decade and the study period predated the use of more aggressive disease-modifying antirheumatic drug (DMARD) therapy. The introduction of such treatments as well as the results of experimental research has led to a greater appreciation of the important role that inflammatory mediators play in RA and in the extra-articular manifestations of this disease. While previously it was thought that extra-articular manifestations occur late in the disease process (4), the recognition that there is a common mechanism between RA itself and extra-articular manifestations has led to a growing acceptance that extra-articular manifestations are no longer seen only in the most severe cases of RA. Table 1 summarizes published prevalence rates for different extra-articular manifestations of RA observed by individual studies (2,3,5-14). These suggest that constitutional symptoms such as fatigue and cardiac and hemaAbbreviations BFU-E BMD CRP CTLA4 CV CVD DMARD ESR FDA G-CSF HDL HR IL ILD MI NFAT NSAID RA RANKL TNF TNFRSF1A

Erythroid burst-forming units Bone mineral density C-reactive protein Cytotoxic T-lymphocyte antigen 4 Cardiovascular Cardiovascular disease Disease-modifying antirheumatic drug Erythrocyte sedimentation rate Food and Drug Administration Granulocyte colony stimulating factor High-density lipoprotein Hazard ratio Interleukin Interstitial lung disease Myocardial infarction Nuclear factor of activated T-cells Nonsteroidal anti-inflammatory drug Rheumatoid arthritis Receptor activator for nuclear factor-êB ligand Tumor necrosis factor Tumor necrosis factor receptor superfamily, member 1A

133 Table 1 Selected Extraarticular Manifestations Reported in Patients with RA and Prevalence (2,3,5,10,26,27,32, 74,80-83)

Manifestations Hematologic

Constitutional symptoms Bone Cardiac

Ocular

Pulmonary

Examples

Published Prevalence Estimates

Hypochromic-microcytic 33 to 60%a anemia with low serum ferritin and low or normal iron-binding capacity Felty syndrome Fatigue 80 to 93% Osteoporosis Osteopenia Pericarditis Heart failure/ cardiomyopathy/left ventricular failure Myocardial infarction Stroke Uveitis Scleritis Peripheral ulcerative keratitis Pleurisy Parenchymal nodules Interstitial involvement Airway disease Pulmonary vasculitis (rare)

22%b 18%c, 30%d

Rare

⬍5%e

Notes: a, mild anemia; b, prevalence of osteoporosis (T-score ⱕ ⫺2.5) at either the femoral neck or the lumbar spine or at both sites in patients with mean disease duration of 15.4 years; c, angina; d, cardiac chest pain in patients with mean disease duration of 12.5 years; e, prevalence of pleural clinical disease (40 to 75% demonstrate pleural involvement postmortem).

tological diseases appear to be among the most common systemic associations with RA. Nonarticular RA manifestations have a wide range of effects on physical, cognitive, and emotional well-being as well as the prognosis and survival for RA patients (1,15). In 1 retrospective medical record review of 424 patients with RA, extra-articular manifestations of RA were associated with a markedly decreased survival compared with the general population and RA patients without extraarticular manifestations (P ⬍ 0.001), prompting the conclusion that extra-articular disease is a major predictor of mortality in patients with RA (1). Reduced survival has also been positively correlated with the severity of extraarticular manifestations. In recent years, the role of inflammatory mediators in the development of nonarticular complications of RA has been increasingly recognized. Indeed, these systemic manifestations appear to be driven by the same pro-inflammatory cytokines (eg, tumor necrosis factor [TNF], interleukin [IL]-1, and IL-6) responsible for joint damage

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(9,16,17). This understanding is critical to the application of newer therapeutic agents that inhibit the inflammatory pathways associated with RA and the development of agents under investigation. Currently, 3 TNF inhibitors are approved by the U.S. Food and Drug Administration (FDA) for the treatment of RA: etanercept (Enbrel®), infliximab (Remicade®), and adalimumab (Humira®). Anakinra (Kineret®), an IL-1 inhibitor, is also approved by the FDA for the treatment of RA. Tocilizumab (ActemraTM), an IL-6 receptor inhibitor, is under investigation for the treatment of RA; the agent inhibits the IL-6 receptor complex and thus blocks IL-6initiated signaling, which may mediate some manifestations of extra-articular disease. In addition, rituximab (Rituxan®), which depletes B-cells, and abatacept (Orencia®), a cytotoxic T-lymphocyte antigen 4 (CTLA4) antibody that inhibits T-cell activation by binding to CD80 and CD86, can also decrease inflammation and cytokine activity (18). The major objective of the present review is to survey the recent literature with regard to systemic nonarticular manifestations of RA with a focus on inflammatory pathological mechanisms. A secondary aim of this review is to place the above-mentioned biological therapies in perspective with regard to their potential to treat the nonarticular manifestations of RA. METHODS To outline the role of inflammatory mediators in the development of common extra-articular manifestations of RA, the present study searched Medline for recent articles (published between January 1995 and October 2007) related to this topic. These keywords were rheumatoid arthritis, anemia, cardiovascular, atherosclerosis, bone loss, osteopenia, osteoporosis, pulmonary, thrombocytopenia, lymphadenopathy, keratoconjunctivitis sicca, uveitis, scleritis, and keratitis. Articles were selected if they had been published as full journal articles in English (abstracts, poster presentations, conference proceedings, or similar reports were excluded). Articles could be either original research papers or review articles but needed to relate to either disease mechanisms of nonarticular manifestations in RA or treatment studies that shed light on these potential mechanisms. RESULTS The literature search as described in Methods highlighted a number of published studies. These are presented in this section according to the individual extra-articular manifestations presented in the literature. Anemia Anemia in RA patients is well described and several “classical” pathological mechanisms may explain this complication. First, iron-deficiency anemia can occur secondary

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to occult or chronic bleeding caused by therapies used for RA, particularly nonsteroidal anti-inflammatory drugs (NSAIDs). The risk for gastrointestinal bleeding associated with NSAIDs is worsened with concomitant glucocorticoids. An anemia of chronic disease is also common among RA patients. Several studies identified by this review point to possible inflammatory-mediated mechanisms that may mediate the anemia of chronic disease. First, a large-scale prospective database review showed that in 2120 patients with RA, anemia was closely associated with elevated levels of acute-phase reactants (particularly erythrocyte sedimentation rate [ESR] and C-reactive protein [CRP]) (14). Several studies have also provided more specific evidence that implicates pro-inflammatory cytokines (eg, TNF-␣, IL-1, and IL-6) in the pathogenesis of anemia of chronic disease among patients with RA (9,16). In 1 study, serum levels of TNF-␣, IL-1, and IL-6 were significantly higher among anemic RA patients, compared with their nonanemic counterparts (16). Genetic polymorphisms in the TNF-␣ gene (major histocompatibility complex on chromosome 6p21.3) may also play a role, as shown in a study of longitudinal hemoglobin data collected from 262 patients with established or early RA (19). In this study, the tumor necrosis factor receptor I (TNFRSF1A) GG genotype was significantly associated with iron deficiency anemia in established RA (OR, 4.3; P ⫽ 0.01), while there was a weak association of the G allele with anemia of chronic disease (OR, 2.2; P ⫽ 0.04). This suggests that polymorphisms within the TNFRSF1A gene are indeed associated with iron deficiency anemia and, possibly to a lesser extent, anemia of chronic disease in patients with RA (19). Another study has examined a TNF-␣ gene promoter polymorphism in RA patients (20). In patients with RA, circulating levels of TNF-␣ and soluble TNF receptor type I were significantly increased in RA patients with anemia compared with those without anemia (20). In addition, circulating TNF-␣ and soluble tumor necrosis factor receptor type I levels correlated negatively with hemoglobin concentrations, further confirming a role of TNF in the pathology of anemia of chronic disease in RA. Another study found that TNF-␣ production affects erythropoiesis in patients with active RA, and this inhibition may be ameliorated with treatment (21). This study found that erythroid burst-forming units (BFU-Es) were significantly lower in RA patients (and particularly in those with anemia of chronic disease) compared with controls. Increased TNF-␣ levels were also inversely correlated with BFU-Es and hemoglobin levels and positively with the percentage of cells apoptotic to surface cell glycoproteins (such as CD34⫹/CD71⫹) normally found on hematopoietic cells. Furthermore, administration of anti-TNF-␣ antibody (cA2) increased BFU-E numbers and apparently normalized hematopoiesis, thus further substantiating the inhibitory role of TNF-␣ (21). In summary, TNF-␣-mediated apoptotic depletion of bone mar-

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row erythroid cells may contribute to anemia of chronic disease in RA. Hepcidin Hepcidin is a liver-derived acute phase reactant that closely regulates iron homeostasis by controlling the release of iron from cells. Hepcidin production is increased by inflammation via pro-inflammatory cytokines and has an inverse relationship with physiologic hemoglobin levels. Stimulated hepcidin production may be a direct contributor to anemia of chronic disease in RA by interrupting the delivery of iron to erythroid precursor cells (22). Furthermore, IL-6 acts directly on hepatocytes to stimulate hepcidin production during inflammation (23), a process that results in hypoferremia of inflammation (Fig. 1) (24). Clinical Aspects Studies have shown that, in RA patients, anemia of chronic disease can be safely and effectively treated using recombinant human erythropoietin and intravenous iron (25,26). On the other hand, it has been argued that specifically targeting mild-to-moderate anemia of chronic disease may have little clinical relevance. Support for this argument comes from different sources, including results of a study that found that improvement in anemia followed effective RA treatment (combinations of either infliximab ⫹ methotrexate or methotrexate ⫹ placebo) (27). This specifically demonstrates the difficulties which can be involved in determining causality for nonarticular manifestations of RA. Indeed, the demonstrated role of pro-inflammatory cytokines in anemia suggests that biologic agents that target these cytokines may have beneficial effects on hemoglobin levels in RA patients. To date,

Fig. 1 The role of inflammation in the regulation of hepcidin production. In inflammatory states, IL-6 is released from macrophages, and acts on hepatocytes to increase hepcidin production. High circulating levels of hepcidin inhibit the release of iron from macrophages and the intestinal absorption of iron, resulting in hypoferremia. Nat Clin Pract Gastroenterol Hepatol 2004;1:39-45; doi:10.1038/ncpgasthep0019). (Color version of figure is available online.)

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this has been confirmed in at least 1 treatment study involving anti-TNF-␣ antibody therapy (21). This particular study also provided some circumstantial evidence for TNF-␣-mediated apoptotic depletion of bone marrow erythroid cells to account for the anemia of chronic disease in RA, and that anti-TNF-␣ antibody therapy may ameliorate this anemia by down-regulating the apoptotic mechanisms involved in erythropoiesis (21). Thrombocytopenia Few studies concern thrombocytopenia in patients with RA. Traditionally observed as an adverse reaction to DMARDs, particularly methotrexate (28,29), thrombocytopenia has also been associated with TNF-␣ blocking agents, possibly representing an idiosyncratic reaction to individual agents rather than a class effect (30,31). As TNF-␣ regulates pro-inflammatory cytokines such as IL-1, IL-6, and IL-8, as well as macrophage colony stimulating factor, it is also possible that TNF-␣-blocking agents may block stem-cell differentiation with resultant bone marrow failure. Overall, further studies are clearly needed to determine causes of thrombocytopenia related to pro-inflammatory cytokines and similar mechanisms. Fatigue In patients with RA, fatigue is a commonly reported symptom that is often severe and greatly impacts quality of life (32). A wide variety of assessment scales are used to measure fatigue in RA, although most do not have good evidence for validation (33). The heterogeneity among assessment tools makes it difficult to compare fatigue rates between different studies. Clinical and Psychosocial Factors Fatigue in patients with RA may be secondary to or associated with other symptoms, such as pain, anxiety, depression, anemia, inability to exercise, or comorbidities (eg, fibromyalgia). Several of these empirical correlations were confirmed in a study of 229 patients with a duration of RA of at least 5 years (11). In particular, it was found that fatigue is largely explained by pain, but psychosocial factors were also important, especially individual coping abilities and tendency to seek help and social support. On the other hand, laboratory data available for 75 patients did suggest a correlation between fatigue and hemoglobin level (11). A more recent study suggested that fatigue in RA is linked mainly to pain and depression and is secondarily associated with disease activity (10). Evidence for this association was suggested by the fact that treatment with DMARDs or TNF inhibitors reduced fatigue in patients whose RA was associated with pain and depression, independent of somewhat a direct effect on disease activity (10). The argument that fatigue among patients with RA is predominantly mediated centrally is further confirmed by a longitudinal study that examined relationships between psychosocial characteristics and fatigue in 122

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RA patients and 122 matched controls (34). This study found that, although common in healthy controls, fatigue was closely associated with psychosocial factors such as increased anxiety, more disability, less social support, and more social stress in the RA group. Social stress was identified as a relatively unexplored but potentially modifiable variable independently related to fatigue in RA (34). Inflammatory Factors Despite these data indicating that fatigue is centrally mediated and related to psychosocial associations with RA, several studies suggested a potential role of pro-inflammatory cytokines in the etiology of fatigue. The first line of evidence has emerged from several treatment studies involving biologic agents, including etanercept, tocilizumab, and adalimumab (35-37). In 1 of these multicenter, randomized, double-blind clinical trials, patients with recent-onset RA who received etanercept had a significantly faster improvement in fatigue than those receiving methotrexate in the first 2 months and the improvement in fatigue was sustained for up to 46 months (36). Reduction in fatigue was strongly correlated with reduced pain and Health Assessment Questionnaire disability scores. Other evidence has emerged from a study that examined whether chronic interpersonal stress (closely linked with fatigue) is associated with cellular markers of inflammation in RA patients (18). The study found that higher chronic interpersonal stress was associated with greater stimulated IL-6 production (P ⬍ 0.05) as well as greater resistance to hydrocortisone inhibition of IL-6 (P ⬍ 0.05). This study is also significant in that it controlled for pain as a confounding variable (covariate) and found that stimulation of IL-6 contributing to fatigue occurred over and above any contribution by pain (18). Therefore, it appears that there is heightened pro-inflammatory cytokine activity in RA patients at risk for fatigue. However, fatigue symptoms were not found to be related to plasma levels of CRP (18). To further understand whether fatigue is a modifiable risk factor that is specific to a particular class of drugs, a study of 21,016 RA patients (13) concluded that, although anti-TNF therapy may lower fatigue levels, this effect could not be assumed to be greater for anti-TNF therapy than for other RA treatments. Hence, these results appear to argue against a specific role of TNF in the development of fatigue in RA patients. Overall, the literature suggests that inflammatory mediators may at least partially mediate fatigue among RA patients. The effects of pain and biopsychosocial factors are also important in determining how impaired patients are by this symptom and may suggest complementary therapies to those specific for controlling disease activity. As such, there is a definite need for further research in this area. In the meantime, it is clear that fatigue is a symptom that significantly impacts the quality of life of affected individuals and that clinicians should be vigilant in

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screening for and measuring this nonarticular disease manifestation (32,33). Generalized Bone Loss Especially when used long term, corticosteroid treatment for RA comprises a well-established explanation for generalized bone loss as a nonarticular manifestation of RA (38). Another established mechanism is reduced mobility and functional capacity in RA, which influences the ability to perform weight-bearing activity, an important determinant of bone mass. Outside of these causes for generalized bone loss in RA patients, there is evidence from more recent literature that inflammatory mediators operant in several mechanistic pathways are involved in the development of bone loss. Inflammatory Factors The receptor activator for nuclear factor ␬ B ligand (RANKL, otherwise known as osteoprotegerin ligand) is a member of the TNF (ligand) superfamily. Functionally, RANKL is a surface-bound molecule that activates osteoclasts leading to bone resorption. Not surprisingly, RANKL overproduction is implicated in a variety of erosive or destructive bone diseases, including RA. Indeed, increased RANKL production has been observed in the synovial tissue of patients with RA (39). The present review identified different studies suggesting that T-cells may influence bone metabolism through a RANKL-mediated pathway. Activated T-cells express pro-inflammatory cytokines (eg, TNF, IL-1, IL-7, and IL-17) that have been shown to differentially upregulate RANKL and downregulate osteoprotegerin (which inhibits differentiation of osteoclast precursors), thereby altering the RANKL/osteoprotegerin ratio to favor bone resorption. A recent study, for example, found that IL-17 produced by helper T-cells stimulated osteoclastogenesis via a RANKL-mediated pathway (Fig. 2) (40). Other studies point to effects of inflammatory cytokines on bone independent of RANKL pathways. For example, in 1 study, IL-6 and IL-11 were added to cultures of human peripheral blood mononuclear cells in the presence of macrophage colony stimulating factor, which induced the formation of multinucleated cells positive for molecules expressed by osteoclasts (41). Hence, IL-6 and IL-11 appear capable of inducing osteoclast formation by a RANKL-independent mechanism (41). Other studies have suggested that increased IL-1 levels, which occur more frequently in RA patients with active disease may, together with increased IL-1 receptor agonist activity, increase bone resorption by stimulating the release of matrix metalloproteinases and other degradative products as well as by promoting osteoclast differentiation and activation (42,43). In support of a potential role of members of the TNF superfamily in the development of generalized bone loss are studies using anti-TNF antibodies. In 1 study of mice

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ing against generalized bone loss with BMD remaining stable while levels of serum type I procollagen N-terminal propeptide decreased and returned to pretreatment levels only after 1 year (48). Further studies, including those assessing the effects of new treatments, are warranted in this area. Felty’s Syndrome Fig. 2 Inflammatory pathways potentially involved in increased bone destruction observed in RA patients and the sites at which these may be blocked by DMARD antirheumatic therapy (45). Key: Buc, bucillamine; IL-1, interleukin-1; MTX, methotrexate; NFATc1, nuclear factor of activated Tcells; RANK, receptor activator for nuclear factor ␬B; RANKL, receptor activator for nuclear factor ␬B ligand; SFZ, sulfasalazine (salazosulphapyridine); TNF-␣, tumor necrosis factor (alpha). Reproduced with permission from Suematsu A, Tajiri Y, Nakashima T, Taka J, Ochi S, Oda H, et al. Scientific basis for the efficacy of combined use of antirheumatic drugs against bone destruction in rheumatoid arthritis. Mod Rheumatol 2007;17:17-23.

with collagen-induced arthritis, the bone mineral density (BMD) change from baseline to sacrifice was significantly increased by anti-TNF-␣ antibodies (versus saline) (44). Anti-TNF-␣ antibodies also increased trabecular bone thickness (P ⬍ 0.02 versus saline) to a value close to that seen in control mice. Another recent study found that a combination of antirheumatic drugs (methotrexate, bucillamine, and sulfasalazine) with effects on T-cells and proinflammatory cytokines could interfere with a RANKLmediated pathway leading to an inhibitory effect on osteoclastogenesis by acting on osteoclast precursor and osteoclastogenesis-supporting cells (45). The specific pathways involved the downregulation of nuclear factor of activated T-cells (NFAT) c1 induction, which is the master transcription factor for osteoclastogenesis, as well as inhibitory effects on T-cells and RANKL itself (45). One caveat involves the finding that ablation of NFATc1 in mature osteoclasts does not prevent RANKL-mediated bone resorption activity, suggesting NFATc1 is involved in cell fusion events and not bone resorption per se (46). Hence, inhibiting TNF and other pro-inflammatory cytokines in RA patients may provide clinical benefits for local articular and generalized systemic bone loss. The positive results observed even with agents that have less targeted effects on cytokine-mediated pathways opens up strong possibilities for agents that have more specific actions on TNF and cytokines such as IL-1, IL-6, IL-11, and IL-17. However, several studies have failed to show significant benefit in terms of bone loss for agents that inhibit pro-inflammatory cytokines. For example, in 1 study (the BeSt trial), there was no observed difference in BMD after 1 year between infliximab- and corticosteroidtreated RA patients (47). Another study found only modest benefits for long-term infliximab treatment in guard-

Felty’s syndrome is the constellation of RA, neutropenia, and splenomegaly. Literature related to Felty’s syndrome mainly concerns the considerable clinical experience that surrounds the use of the recombinant human hemopoietic growth factors granulocyte (G-CSF) and granulocytemacrophage colony-stimulating factors (49). An immune-mediated neutropenia associated with a terminal defect in neutrophil maturation is likely to underlie this key clinical characteristic of Felty’s syndrome and a high proportion of patients with this nonarticular manifestation have peripheral blood expansions of CD3⫹ and CD8⫹ large granular lymphocytes (50). At least 1 study has analyzed whether the clinical manifestations of Felty’s syndrome, especially neutropenia, might be explained by abnormalities in cytokine production by examining the production of 5 cytokines (IL-1␤, TNF-␣, IL-8, G-CSF, and granulocyte-macrophage colony stimulating factor) involved in the maturation and activation of polymorphonuclear cells (51). This study found that anti-CD3stimulated IL-8 production was significantly increased in both RA and Felty’s syndrome, compared with normal controls. However, it was concluded that the neutropenia of Felty’s syndrome cannot be definitely explained by changes in peripheral blood cytokine production, despite the suggestion of a possible role for G-CSF and IL-8 in the development of certain Felty’s syndrome complications. Treatment studies using agents that target cytokine production reflect, to some extent, this apparent lack of a clear role for cytokines in the pathogenesis of Felty’s syndrome. For example, in 2 patients with refractory RA associated with severe Felty’s syndrome, rituximab therapy was ineffective perhaps owing to the inability of rituximab to bind to plasma cells, which are CD20 negative (52). Etanercept has been shown to severely worsen neutropenia in a patient with longstanding seropositive RA and Felty’s syndrome, despite improving articular inflammation (53). Cardiovascular Disease Cardiovascular disease (CVD) is a major contributor to increased mortality among patients with RA, with studies showing that RA is associated with a higher prevalence of cardiovascular (CV) endpoints such as angina, stroke, and CVD-related mortality (54-56). Increased CV risk among patients with RA is not fully explained by traditional CV risk factors alone. This is clearly demonstrated by a comparison of CV event rates over 1 year in patients with RA and the general population; after adjustments for

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age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index (ie, traditional risk factors), RA was associated with an approximately 4-fold increased risk of CV events (incidence rate ratio, 3.96; 95% CI, 1.86-8.43) (54). Avenues of Enquiry into Mechanisms of Disease The present review identified several mechanisms that may underlie the increased risk of CVD in patients with RA. Research has been performed in 2 broad areas. The first has highlighted the possible effects of cytokines and other pro-inflammatory mediators on the acceleration of atherosclerosis and endothelial dysfunction. Studies in this area tend to look at this issue from a mechanistic or pathophysiological perspective. The second area concerns studies suggesting an influence of RA and its treatment on adversely affecting traditional CV risk factors. Effects of Pro-Inflammatory Cytokines on Atherosclerosis and Endothelial Function Analysis of the third National Health and Nutrition Examination Survey III population concluded that RA and non-RA participants had similar prevalence of traditional CVD risk factors and previous CVD (57). However, RA patients had lower plasma levels of antioxidants and higher levels of CRP. This suggests that inflammation may be at least partially responsible for the increased incidence of CVD in individuals with RA. Other evidence supports the notion that atherosclerosis is an inflammatory disorder sharing common pathological pathways with the pannus formation and synovial inflammation. One study supportive of this hypothesis is a recent investigation by Roman and coworkers that examined clinical and biological markers for atherosclerotic disease in RA patients (58). In this study, 98 RA outpatients and 98 matched controls were assessed for CVD risk factors and by carotid ultrasonography. RA patients were also assessed for disease severity, treatment, and inflammatory markers. Results showed that, despite a more favorable risk factor profile, patients with RA had a 3-fold increase in the prevalence of carotid atherosclerotic plaque (44% versus 15% in controls; P ⬍ 0.001). Although levels of inflammatory mediators did not differ significantly between RA patients and controls, the use of TNF-␣ inhibitors (viewed as a proxy for disease severity and inflammation) was significantly correlated with plaque levels. The authors concluded that chronic inflammation and, possibly, disease severity are atherogenic in this population. Results of more mechanistic studies have suggested a more direct link between inflammatory cytokines such as IL-6, TNF, and IL-1 with atherogenesis (17,59,60). In particular, in fatty streaks and the “cap”/“shoulder” regions of atheromatous plaques, macrophage foam cells and smooth muscle cells express IL-6. This indirectly suggests a role for this cytokine (17) and several lines of

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evidence suggest a central role for IL-6 in the development of CVD. First, IL-6 has a key role in the systemic inflammatory response, as it is the only cytokine capable of stimulating synthesis of all the acute-phase proteins involved in the inflammatory response. Second, IL-6 also influences leukocyte recruitment, the coagulation cascade, the endothelium, and other components of the vasculature. It has also been shown to predict higher levels of critical endothelial biomarkers (vascular cell adhesion molecule-1, intracellular adhesion molecule-1, and endothelial leukocyte adhesion molecule-1), independently of traditional CV factors (59). Epidemiologic support for the role of IL-6 in contributing to CV risk is found in a large-scale study which found that elevated levels of IL-6 in 14,916 apparently healthy men were associated with an increased risk of future myocardial infarction (MI); men with the highest quartile of baseline IL-6 had a 2.3 times higher relative risk of MI than those in the lowest quartile (61). This relationship persisted after control for other factors such as CRP (61). Overall, this suggests a role for cytokinemediated inflammation in the early stages of atherogenesis (61). In another study conducted among 3489 patients with unstable coronary artery disease treated with either an early invasive (n ⫽ 1222) or a noninvasive (n ⫽ 1235) strategy (3269 of whom had plasma samples analyzed for IL-6 levels), plasma levels of IL-6 ⱖ5 ng/L (compared with levels ⬍5 ng/L, the lower detection limit of the system used to measure IL-6 levels) were associated with greatly increased mortality in patients (RR, 3.47; 95% CI, 1.94-6.21), after adjustment for most established CV risk factors (60). It was concluded that circulating IL-6 was a strong independent marker for identifying patients with unstable coronary artery disease who were at an increased risk of death over 6 to 12 months (60). Associations Between RA and Traditional Cardiovascular Risk Factors Despite the results of the National Health and Nutrition Examination Survey III analysis suggesting that the incidence of traditional risk factors is similar between patients with and without RA, it is possible that the systemic inflammation associated with RA may influence the expression of these well-established risk factors. Lipid abnormalities may be a particularly important CV risk factor among RA patients (62), particularly low levels of highdensity lipoprotein (HDL) cholesterol (63). Although most RA treatments affect lipid levels, the clinical relevance of these changes is not clear. This review identified a number of relevant studies in patients with RA. First, data from a 56-week trial of patients with early RA comparing combination therapy (glucocorticoids, methotrexate, and sulfasalazine) versus sulfasalazine alone found total cholesterol increased by a mean of 0.6 mmol/L and HDL cholesterol increased by

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more than 50% in both groups after treatment (64). This produced an improvement of the total cholesterol/HDL ratio, which was particularly rapid in the group receiving combination treatment. Similarly, other studies have demonstrated that TNF inhibitors elevate total cholesterol and HDL levels (65-68). In another study of 359 patients with active RA in whom the response to methotrexate was inadequate in which some patients were treated with the IL-6 receptor inhibitor tocilizumab, some of the tocilizumab-treated patients experienced moderate and reversible increases in the nonfasting total cholesterol and triglyceride levels and reductions in HDL (35). Taken together, these data suggest that anti-inflammatory therapy with either TNF or IL-6 inhibitors may adversely affect lipid profiles; however, since these therapies also typically reduce inflammatory markers, the clinical relevance of the net effect on CV risk is unclear. These changes may be related to the anti-inflammatory effect of these agents, since at least 1 study showed that the lipid changes were correlated with a reduction in RA disease activity (57), but other factors such as favorable changes in insulin sensitivity may also play a role (57). Treatment Perspectives From a practical treatment perspective at both an individual and a population level, the role of inflammation in CVD among RA patients is of considerable importance given that CV is the leading cause of excess mortality for these individuals. Treatment with DMARDs (including sulfasalazine, hydroxychloroquine, and methotrexate) have also been linked with significant CVD risk reduction, even after additional correction for the presence of rheumatoid factor and erosions (69). The findings suggesting a role for inflammatory mediators as a risk factor for CVD are further strengthened in light of treatment studies evaluating the effect of suppressing inflammation on direct markers of vascular function such as endothelium-dependent vasodilation. The present review identified a study that assessed endothelial-dependent vascular function (vasodilatation) of the brachial artery in 11 RA patients with high disease activity treated with infliximab 3 mg/kg at weeks 0, 2, and 6. Compared with baseline, endothelial function substantially improved following 12 weeks’ TNF inhibition using infliximab (from 3.2 ⫾ 0.4% to 4.1 ⫾ 0.5%, P ⫽ 0.018) (70). These improvements with infliximab occurred concurrently with improvements in inflammatory markers and clinical parameters and suggest that, in patients with RA, endothelial dysfunction is part of the disease process and is mediated at least in part by TNF-␣. To put the potential clinical benefit of anticytokine therapy into clinical context, another study found that treatment with etanercept or infliximab significantly reduced the age–sex-adjusted incidence rate of first CVD events compared with RA patients not treated (14.0/1000 person-years at risk versus 35.4/1000 person-years) (71).

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Further evidence supporting the role that inflammation plays in CVD and, in particular, MI comes from data of the British Society for Rheumatology Biologics Register, a national prospective observational study, which compared MI rates in 8670 patients with RA treated with anti-TNF-␣ and 2170 patients with active RA treated with traditional DMARDs (72). In the intent-to-treat analysis, RA patients treated with anti-TNF-␣ did not have a lower incidence of MI compared with RA patients treated with traditional DMARDs; however, a subgroup analysis of those anti-TNF-␣-treated patients who responded to the treatment within 6 months versus those who did not found high differential MI rates between these groups (3.5 events per 1000 person-years in responders and 9.4 events per 1000 person-years in nonresponders). This equated to an adjusted incidence rate ratio (95% CI) for responders compared with nonresponders equal to 0.36 (0.19-0.69) (72). Overall, therefore, there is strong support for the hypothesis that inflammation contributes to the development of CV events, and that suppressing inflammatory mediators such as TNF-␣ may reduce the risk of CVD among RA patients. Similar to cardiac disease (56), the incidence of noncardiac vascular disease (except cerebrovascular disease alone) in patients with RA has also been positively associated with the presence of severe nonarticular RA manifestations (73). This suggests that the excess risk of noncardiac vascular disease in RA is likely to be related, in part, to the systemic inflammation associated with RA. For both traditional and newer biologic therapies, CVD risk reductions have been linked to suppression of inflammation. This is also in keeping with the observation that strategies to prevent CVD and mortality focused solely on controlling traditional CV risk factors may be somewhat less beneficial in RA subjects than in the general population (74). Further research is needed to determine optimal approaches to reducing CV morbidity and mortality in persons with RA, including the development of refined CV risk stratification algorithms that take into account the important role of nontraditional CV risk factors in this population (74). Future studies should also help better ascertain the utility of biological therapies on the incidence and clinical course of this particularly important nonarticular manifestation of RA. Ocular Effects Inflammatory eye diseases associated with RA include keratoconjunctivitis sicca, uveitis, scleritis, and keratitis. The present review identified only a small number of articles dealing with mechanistic aspects of ocular nonarticular manifestations of RA. In terms of studies that investigated a potential role of pro-inflammatory cytokines in the development of ocular complications, 1 source of evidence is derived from a study in which corneal samples were collected from 7 RA patients with corneal ulcer-

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ations/perforations (75). Paraffin sections of these samples were examined using specific gene probes for TNF-␣ and IL-6 and this detected TNF-␣ and IL-6 expression in 71 and 100% of analyzed tissue samples, respectively. Although there was no control group for comparison, the authors of this study concluded that, among RA patients, upregulation of the pro-inflammatory cytokines TNF-␣ and IL-6 may induce the production of metalloproteinases, resulting in collagenolytic corneal damage. In support of this finding, a case report of an RA patient who developed necrotizing scleritis refractory to local measures, systemic corticosteroids, and cyclophosphamide found that this patient responded rapidly to infliximab (76). This report suggests that biologic agents affecting pro-inflammatory cytokines may be useful in ocular nonarticular manifestations of RA, although the evidence is largely limited to case reports. Arguing against a clear role for inflammatory mediators in other ocular manifestations of RA are the results of a recent prospective case-control study in 72 RA patients in whom the severity of dry eye was assessed against that of RA activity (evaluated by assessing duration of morning stiffness, ESR, grip strength, and joint score, the Lansbury index) (77). This study found that, although dry eye (symptomatic of keratoconjunctivitis sicca) was common among enrolled RA patients, there was no apparent correlation between disease activity and the severity of ocular symptoms. This indicates, albeit indirectly, that the correlation between sicca symptoms and inflammation is not as strong as for other ocular manifestations of RA. Hence, there is a definite need for further studies in this area. Pulmonary Complications As with ocular manifestations, pulmonary RA manifestations involve a spectrum of disorders. These can include pleurisy, parenchymal nodules, interstitial involvement, airway disease, and pulmonary vasculitis, although the latter is rare (5). Pleural involvement is the most common pulmonary manifestation and often occurs with pulmonary nodules or interstitial disease. Pulmonary involvement in association with RA may occur as a result of disease factors or secondary to treatment for RA, such as D-penicillamine or gold-induced obliterative bronchiolitis or, more rarely, methotrexate-induced pneumonitis. Treatmentrelated causes will not be covered in detail here. Role of Inflammation in Pulmonary RA Manifestations Review of the literature uncovered a small number of studies that point to a role of inflammation in the development of pulmonary manifestations of RA. In 1 study of 52 patients with RA assessed using high-resolution computed tomography and pulmonary function tests, it was noted that rheumatoid factor titers and ESR were significantly higher in the presence of lung abnormalities detected by computed tomography scans (78). These results

Systemic nonarticular manifestations of RA

concur with those of other studies, albeit not specific to RA, which have shown that the cytokines involved in pulmonary inflammatory and immune disease can be proinflammatory (eg, TNF-␣ and IL-1), anti-inflammatory, or growth-stimulatory. Another study has demonstrated, via staining of paraffin-embedded lung biopsy specimens from interstitial pneumonia patients with RA (n ⫽ 15) and without RA (n ⫽ 16), that patients with RA have increased CD4⫹ cell counts (79). B-lymphocytes, which have emerged as important elements in the events leading to joint destruction in RA, may also be significantly involved in RAassociated interstitial pneumonia (80). This was confirmed in a study that found marked follicular B-cell hyperplasia among patients with RA-associated interstitial pneumonia, which was also associated with higher B-cell cellularity (as compared with idiopathic interstitial pneumonia) (80). Studies related to RA treatments and pulmonary complications have yielded interesting results. One review of hospital and death records found no clear pattern of causal association of RA treatment and interstitial lung disease and no clear evidence to support a causal relationship between infliximab, azathioprine, and hospitalization for this pulmonary manifestation (81). However, among past therapies received by these patients, prednisone (hazard ratio [HR], 3.0; 95% CI, 1.0-8.9), infliximab (HR, 2.1; 95% CI, 1.1-3.8), etanercept (HR, 1.7; 95% CI, 1.0-3.0), and cyclophosphamide (HR, 3.7; 95% CI, 0.9-15.5) were all positively associated with hospitalization for interstitial lung disease (ILD). In another study, 9847 consecutive patients from the BSR Biologics Register with RA who were treated with etanercept (n ⫽ 3969), infliximab (n ⫽ 3231), or adalimumab (n ⫽ 2647) were compared with a similarly recruited cohort of 2906 subjects with active RA requiring DMARD therapy (82). This review found that patients with baseline RAassociated ILD, those in the anti-TNF cohort were more likely to die than those with baseline RA-associated ILD in the DMARD cohort (HR, 2.11; 95% CI, 0.59, 7.59). Overall, anti-TNF-␣ was associated with a worse all-cause and RA-associated interstitial lung disease specific mortality in patients with this condition at baseline. These results suggest that inhibition of TNF-␣ may not be of benefit to patients with fibrosing lung conditions associated with RA. However, confounding by indication may explain these associations between TNFalpha use and interstitial lung disease. Since there is some evidence that inflammation and inflammatory cytokines are central to the pathology of pulmonary nonarticular RA manifestations. However, further investigation (including large-scale randomized studies) is required to better delineate the role for inflammatory cytokines in the etiology of specific pulmonary nonarticular disease and, in particular, treatment with emerging biological therapies.

L.W. Moreland and J.R. Curtis

DISCUSSION Future research in this area is based on finding answers to a number of key questions. A central question, which has not been addressed extensively to date, concerns how patients with systemic RA manifestations differ from RA patients without those manifestations. Answering this question may provide insight into whether there are differing levels of expression of particular pro-inflammatory cytokines between individuals with RA. The basis for such heterogeneity, including genetics and environmental and iatrogenic (eg, treatment) factors, provides a secondary avenue of research. Another question relates to whether the incidence of extra-articular manifestations has decreased in the more contemporary treatment era or if there are recognizable patterns in terms of geographic, gender-based, or other forms of predilection to particular manifestations. Again, answers to these questions may help uncover any associations of nonarticular manifestations with patient-centered or external factors. Furthermore, studies of both disease mechanisms and epidemiological patterns should be able to inform researchers and clinicians how to predict which patients will develop systemic manifestations over the course of the disease. Last and importantly, there are several questions concerning treatment of nonarticular disease that require more complete answers. These include the extent to which currently available RA therapies prevent or promote nonarticular disease. As this review has revealed, several smaller studies have made attempts to answer this question, although the answer is far from complete even for those extra-articular manifestations that have been most rigorously investigated. The other question of practical concern to clinicians should be how nonarticular manifestations can be most effectively treated, including the use of newer biologic therapies. To date, clinical trials of biologic agents that inhibit pro-inflammatory cytokines have not principally focused on extra-articular manifestations of RA. Studies to address the effect of these agents on extra-articular disease need to be large and are potentially complex to conduct. An added complication is that many extra-articular symptoms may be reported as adverse events or may occur for the first time during therapy and may not necessarily be related to treatment. Therefore, randomized controlled trials may have to be supplemented with observational data. Challenges to interpreting results from observational studies is that treatments are not assigned randomly, and patients with more severe RA are typically selected to receive more aggressive treatment regimens, creating spurious associations between extra-articular manifestations and the drugs used. Nevertheless, information from both types of data sources is needed to further inform us regarding whether cytokine inhibition with agents currently available or in development can reduce the burden of extra-articular disease. If convincingly

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