iterature review assignment,

ARTICLE ONE APA

(American Psychological Assoc.)

References

Goronzy, J. J., & Weyand, C. M. (2005). Rheumatoid arthritis. Immunological Reviews, 204(1), 55-73. doi:10.1111/j.0105-2896.2005.00245.x

tment of Medicine, Kathleen B. and Mason I. Lowance Center for Human Immunology, Emory School of Medicine, Atlanta, GA, USA. Correspondence to: Jo¨rg J. Goronzy, MD, PhD Lowance Center for Human Immunology Emory University School of Medicine Room 1003 Woodruff Memorial Research Building 101 Woodruff Circle Atlanta, GA 30322 USA Tel.: þ1 404 727 7310 Fax: þ1 404 727 7371 E-mail: [email protected] Acknowledgements We thank Dr S. Pryshchep for help in the preparation of the figures, L. Arneson for secretarial support, and T. Yeargin for editorial support. This work was funded in part by grants from the National Institutes of Health (RO1 AR 42527, RO1 AI 44142, RO1 AR 41974, and RO1 AG 15043). Summary: Therapeutic efficacy of depleting B cells or blocking T-cell costimulation in rheumatoid arthritis (RA) has confirmed the critical pathogenic role of adaptive immune responses. Yet, RA preferentially affects elderly individuals, in whom adaptive immunity to exogenous antigens begins to fail. Here, we propose that senescence of the immune system is a risk factor for RA, with chronic inflammation resulting from the accumulation of degenerate T cells that have a low threshold for activation and utilize a spectrum of novel receptors to respond to microenvironmental cues. The process of immunosenescence is accelerated in RA and precedes the onset of disease, the acceleration, in part, being conferred by the HLA-DR4 haplotype. Naive CD4þ T cells in RA are contracted in diversity and restricted in clonal burst. Senescence of effector CD4þ T cells is associated with the loss of CD28 and the de novo expression of KIR2DS2, NKG2D, and CX3CR1, all of which function as costimulatory molecules and reduce the threshold for T-cell activation. The synovial microenvironment promotes chronic persistent immune responses by facilitating ectopic lymphoid neogenesis, such as the formation of aberrant germinal centers. With the propensity to develop complex lymphoid architectures and to provide optimal activation conditions for senescent CD4þ T cells, the synovium becomes a natural target for pathogenic immune responses in prematurely aged individuals. Introduction In the broad spectrum of inflammatory joint diseases, rheumatoid arthritis (RA) has a prominent position. By causing symmetrical and destructive inflammation in the small and large joints, RA leads to pain and joint failure, eventually resulting in disfiguration and disability. RA is a quintessential example of an immune-mediated disease with chronic smoldering immune responses causing tissue damage. The syndrome is unequivocally systemic in nature, but synovitis of the diathrodial joints is the most visible manifestation. The most significant risk factors for RA are female gender, advanced age, and a positive family history. In recent years, the therapeutic management of patients with RA has seen a major evolution (1). A number of biological reagents have been developed that allow for marked suppression of inflammation, at least in a subset of patients. Spearheaded by Immunological Reviews 2005 Vol. 204: 55–73 Printed in Singapore. All rights reserved Copyright Blackwell Munksgaard 2005 Immunological Reviews 0105-2896 55 the efficacy of tumor necrosis factor-a (TNF-a) blocking agents (2, 3), a number of other anti-cytokine therapies are making their way into clinical application. Preliminary data suggest that anti-interleukin-6 (anti-IL-6) therapy has profound anti-inflammatory activity (4), and encouraging results for blockade of IL-15 are emerging (5). Other therapeutic strategies have targeted cellular pathways in the rheumatoid disease process. Remarkably, impressive therapeutic responses are being reported for B-cell-depleting regimens using anti-CD20 antibodies (6). Similarly, blocking CD28-mediated costimulation with cytotoxic T-lymphocyte antigen 4-immunoglobulin fusion protein (CTLA4-Ig) has shown convincing therapeutic benefits, and follow-up studies of patients treated with CTLA4-Ig have suggested therapeutic responses qualifying as remission (7). The clinical efficacy of many novel immunosuppressive therapies in RA has emphasized the complexity of the disease process and has challenged a disease model that proposes a single and straightforward pathomechanism. A multitude of pathways appear to contribute to persistent and tissue-injurious inflammation. While initial success of TNF-a blockade suggested a gatekeeper function of this cytokine in rheumatoid synovitis (3), similar claims can now be made for B cells, T-cell costimulation, and an array of other cytokines. A number of important lessons have been learned from examining the therapeutic effects of immunomodulatory interventions. While diverse in the molecular targets, multiple strategies have been successful. As a rule, treatment responses are partial instead of complete. Continuous immunosuppression is required to maintain clinical benefits, documenting that the key abnormalities have not been removed. Accumulating clinical experience supports heterogeneity in the disease process (8), emphasizes the coexistence of systemic and joint-directed disease components (9), and stresses the need for identifying the ultimate principle causing autoimmunity in RA. Current animal models recapitulate just a single facet of the disease and fail to provide a unifying concept. Considering that all novel immunosuppressants make the patient an immuno-compromised host, susceptible to life-threatening infections and possibly tumors (10), efforts should go towards developing therapies that restore instead of impair immunocompetence. The rationale for current therapeutic strategies has derived from a focus on common pathways in tissue inflammation, many of them not at all unique for RA. It is unlikely that disrupting or suppressing generalized pathways of inflammation can eradicate RA. In the search for characteristics that are typical for RA, two features of this autoimmune disorder come to mind. While systemic in nature, the chronic persistent immune response seeks out the synovial membrane of selected joints. The classical paradigm that joint specificity can be explained as an immune response to joint-specific antigens has lost attraction. Other elements of tissue susceptibility have to be considered that define the preference for the synovial space (11). Also, RA is a disease of the elderly, not of the young. Incidence rates of RA are highest in postmenopausal women and increase steadily with advancing age (12). How can a host in whom the aging process gradually but profoundly compromises immunity be most susceptible to self-aggressive immune responses? The traditional concepts of a defect in central and peripheral tolerance were developed with the young and evolving immune system in mind; new theories are needed to understand loss of tolerance during the second half of life. This review will summarize recent data on the synovial microenvironment as a disease susceptibility factor and the contribution of immunosenescence in the derailing of immune tolerance. Tissue specificity and autoantigen expression In the classical model of autoimmunity, tissue specificity is determined by the tissue-specific recognition of autoantigens that elicit adaptive immune responses. Consequently, studies into the pathogenesis of RA have implicated antigens that are locally expressed in the joint. Prominent candidate antigens have included type II collagen, the cartilage protein gp39, and proteoglycans. These antigens have been shown to induce autoimmunity and arthritis in rodent models. However, their relevance for the pathogenesis of RA is at best uncertain. None of these autoantigen-directed responses have been found to associate uniformly with RA. Autoantibodies that are being produced in RA are generally specific for ubiquitous antigens. One of the best examples is the rheumatoid factor, an autoantibody specific for the Fc portion of IgG. While rheumatoid factor is occasionally found in some other autoimmune diseases, it remains one of the most sensitive laboratory tests for RA. Even higher specificity and equal sensitivity have been reported for antibodies that are directed to citrullinated proteins (13). These antibodies that detect cyclic citrullinated peptides in many different proteins, such as fillagrin, are detected in about 80% of patients with RA at a specificity of 98%. Several lines of evidence suggest that citrullinated antigens have direct involvement in the rheumatoid disease process. Citrullination is mediated by peptidylarginine deiminases. One of the deiminases, PAD4, has been identified as an RA susceptibility gene (14). Moreover, citrullinated peptides Goronzy & Weyand Rheumatoid arthritis 56 Immunological Reviews 204/2005 appear to bind with high affinity to the RA-associated human leukocyte antigen (HLA)-DRB1*04 alleles (15). Citrullinated proteins may be present in the RA synovium. However, this association is controversial, and possible candidate autoantigens, such as citrullinated fibrins, citrullinated vimentin, and citrullinated histones, are certainly not synovium specific (13). Also, anti-cyclic citrullin peptide antibodies precede the clinical development of synovitis by many years (16, 17). Together, these data support the concept that RA-associated autoantibodies are indicators of general immune defects and are not the mediators of classical autoimmune responses to autoantigens uniquely available in the synovium. This argument holds for antibody and T-cell responses to a variety of other autoantigens that have been described in patients with RA, including responses to several heat-shock proteins, such as BiP (18). The rheumatoid synovium: facilitator of aberrant immune responses The tissue preference of the immune response in RA appears not to be conferred by tissue-specific expression of autoantigens. In an alternative model, the rheumatoid synovium provides an exceptional microenvironment for abnormal immune responses that settle in while immune abnormalities occur systemically. Examples for the importance of the tissue microarchitecture in directing and facilitating immune responses are widely known from developmental biology (19, 20). In fact, the formation of secondary lymphoid structures in lymph nodes and the gastrointestinal tract is a prime example of how the structural organization of the tissue site determines whether and how immune responses occur. This concept has been explored less in diseased non-lymphoid tissues, where it is likely to play a major role in explaining the pathogenesis of chronic inflammatory diseases (21). Numerous studies in the last two decades have stressed the point that activation events in the rheumatoid synovium and, in particular, the interactions between T cells and fibroblastlike synoviocytes, are cell–cell contact dependent and therefore assign particular importance to tissue architecture and spatial relationships (22–26). A major reason why this issue has not been more aggressively pursued is that it resists a reductionist scientific approach. Obviously, appropriate models would have to integrate the whole complexity of the threedimensional structure in which cells function. In such a model, it is not one major factor but rather a spectrum of minor factors that act in concert to determine tissue and disease susceptibility. The cellular composition of rheumatoid synovitis is relatively simple and includes resident fibroblast-like and macrophage-like synoviocytes, some ill-defined cells, and endothelial cells. The inflammatory infiltrate consists of T cells, B cells, dendritic cells (DCs), macrophages, plasma cells, mast cells, and a few granulocytes. However, the topography of these cells is complex and organized (27). Tissueinfiltrating inflammatory cells assume defined yet different architectures in distinct individuals, with profound qualitative and quantitative impact on the pathological immune response (Fig. 1). It is highly likely that the organization of synovial infiltrates directly affects therapeutic responses to immunomodulators. The least frequent type of rheumatoid synovitis is characterized by granuloma formation, very similar to the histology of rheumatoid nodules that frequently form in patients with RA at extra-articular sites (28). Granulomatous synovitis only accounts for a few percent of all patients with RA. The most frequent type of rheumatoid synovitis is a diffuse inflammatory infiltrate in which infiltrating T cells, B cells, and macrophages are scattered among tissue-resident cells, and the infiltrate by itself does not accomplish a higher level of organization. In the remaining 40–50% of patients, B cells, T cells, and DCs organize themselves into follicular structures. Such T/B-cell follicles occur in two apparently different forms. In 25% of the patients, the lymphoid follicles show all characteristics of ectopic lymphoid tissue with germinal center (GC) formation, unmistakably separated T- and B-cell zones, vigorous B-cell proliferation, and affinity maturation (29–31). In the other 25% of patients, however, lymphoid follicles lack signs of GC reactions. One of the most Fig. 1. The architecture of rheumatoid synovitis. Immunohistologies representing different forms of lymphoid organization of the synovial inflammatory infiltrate are shown. (A) Follicular synovitis with germinal center formation. (B) T-B cell aggregates without follicular dendritic cells. (C) Diffuse synovitis with T and B cells intermingled with fibroblast-like synoviocytes. Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 57 distinguishing features is the absence of follicular DCs (FDCs). The absence of FDCs sets these aggregates apart from primary lymphoid follicles (32). When specimens from different joints and time points are compared, the four forms of synovitis do not appear to be different stages that occur in a sequential manner. They appear to be variants of the disease that occur in different patients (own unpublished observations). There is currently no known correlate of the synovial lymphoid aggregates without FDCs in normal lymphoid ontogeny, and it is unclear what functional implications are associated with these organizational structures. On the contrary, follicles with GC formation resemble the normal structures that are typical for lymph nodes, with obvious functional implications. It is an attribute of any adaptive immune response that infrequent recognition events have to surpass a threshold to initiate immunity. This need is likely even more relevant for autoimmune responses. Both the T-cell and B-cell repertoires have been selected against high-affinity recognition of autoantigens, and it should be explicitly difficult to reach sufficient signal density to break through the threshold and activate the immune cascade. Primary and secondary lymphoid follicles provide optimized threedimensional structures overcoming the challenges brought on by the low frequency of activation events and their tendency to be dispersed. The spatial arrangement of antigen-presenting cells (APCs) provides the most advantageous conditions for antigen requisition, storage, processing, and presentation. FDCs concentrate antigens adsorbed on the cell surface and present the antigens to B cells, that are being selected for the appropriate specificity. Such B cells, as well as the close network of myeloid DCs in the T-cell zone, optimize the conditions for T-cell activation. Formation of such sophisticated structures at extranodal sites undoubtedly will favor the recognition of antigens irrespective of whether they represent exogenous or endogenous antigens (Fig. 2). The extranodal location of such structures in non-immune tissue therefore represents a major challenge to maintain peripheral tolerance. Thus, the rheumatoid synovium, similar to a few other selected tissue sites [the salivary glands in Sjo¨gren’s disease and the thymus in myasthenia gravis (33, 34)], appears to be uniquely suited to support the induction of primary and secondary follicles. It is not only the organization of the immune infiltrate that allows for the distinction of different types of synovitis; resident cells also develop a different level of organization. This organization is particularly so for endothelial cells involved in the process of angiogenesis (35). Synovial tissues containing aggregates and especially tissues containing GCs are densely vascularized. Increased angiogenesis is not limited to the areas just adjacent to the lymphoid microstructures but occurs throughout the tissue. The patterns of vascularization, however, are slightly different in these two types of tissue. In GC synovitis, small vessels are clustered around the follicles, whereas in the aggregate tissues, angiogenesis is more prominent in the sublining. In contrast, tissues with diffuse infiltrates show little vascularization. Surprisingly, differences in neoangiogenesis in different tissue types do not correlate with well-known pro-angiogenic mediators, such as vascular endothelial growth factor, angioprotein 1, and angioprotein 2, but with the concentration of the matricellular protein thrombospondin 2 (TSP2) that is known to function as an angioinhibitor. The role of TSP2 in regulation of angiogenesis was confirmed in in vivo experiments using a human synovium-severe combined immunodeficiency (SCID) mouse chimera model. In this model, synovial tissue from patients Fig. 2. Architecture as a risk factor for autoimmunity. The schematic diagram illustrates how the three-dimensional arrangement and the complexity of lymphoid organization improves the conditions for successful immune activation and, if occurring at an ectopic tissue site, predisposes for autorecognition and autoimmune responses. DC, dendritic cell; FDC, follicullar dendritic cell; GC, germinal center. Goronzy & Weyand Rheumatoid arthritis 58 Immunological Reviews 204/2005 with RA is engrafted into SCID mice. Features of the synovial inflammation generally persist in the engrafted tissue (36). The chimeric mice can be used to examine the relative importance of different cells such as CD4þ T cells, CD8þ T cells, and B cells in maintaining tissue inflammation and the spatial organization of the infiltrate (32, 37, 38). Treatment with TSP2, using a cell-based gene therapy approach, not only significantly decreased the degree of angiogenesis in the synovial tissue, but also resulted in the depletion of T cells and the collapse of the secondary lymphoid structures in the engrafted tissue (35). The major TSP2-producing cell type in the rheumatoid synovium is the fibroblast-like synoviocyte and possibly endothelial cells themselves. These data indicate that neoangiogenesis drives the spatial organization of lymphoid microstructures and that at least one important mediator in inhibiting this response is TSP2, produced by fibroblast-like synoviocytes. Suppression of endogenous TSP2 production, which is critically involved in preventing new blood vessel formation by resident cells, appears to be an important component in facilitating extranodal lymphoid structures. Similar immune suppressive activities were seen with a cartilage-derived angiogenesis inhibitor, chondromodulin I (39). The critical role of B cells in synovial inflammation How important are lymphoid follicles for the immune response in the synovium? One of the shared denominators of the microstructures is the presence of B cells, regardless of whether they are actively dividing B cells in GCs or non-dividing B cells in lymphoid aggregates. To address the question of whether the T-cell response is dependent on the lymphoid organization, synovial tissues were implanted into SCID mice, B cells were depleted by treatment with anti-CD20, and the T-cell response was then assessed (40). As expected, B-cell depletion led to a collapse of the lymphoid microstructure. More importantly, B-cell depletion diminished the T-cell response in that the production of T-cell-derived cytokines, such as interferon-g (IFN-g), declined markedly in anti-CD20 treated human synovium-mouse chimeras. Thus, the presence of DCs alone as APCs was not sufficient to sustain T-cell responses. The B-cell dependence of T-cell activation was confirmed in adoptive transfer experiments. In these experiments, rheumatoid synovium-derived T-cell clones were adoptively transferred into human rheumatoid synoviumSCID mouse chimeras. The adoptively transferred T cells homed to the implanted human synovium. Following the adoptive transfer, in situ production of IFN-g increased in the human synovial tissue, which confirmed the in situ activation of transferred T cells. This activation was dependent on HLADR matching between the patients from whom the T-cell lines were derived and those from whom the tissues were harvested. In addition to HLA-DR matching, T-cell activation was clearly dependent on the synovial tissue being B-cell rich and having lymphoid microstructures. The adoptive transfer of T cells into mice engrafted with tissue that was classified as B-cell poor did not result in T-cell activation. It is possible that the distinct tissue types differ fundamentally in the antigens that they recognize. The second and more likely interpretation is that the T-cell response is fundamentally dependent on the presence of lymphoid microstructures. B cells are key players in these microstructures, and the T-cell response is therefore B-cell dependent (41). Subsequent clinical studies have confirmed the important role of B cells in maintaining disease activity in RA (6). B-cell depletion with anti-CD20 antibodies profoundly inhibited inflammation in a substantial proportion of patients, and in some of these patients, the treatment response was dramatic. It remains to be determined whether the patients who benefit most from B-cell depletion are those who have highly organized lymphoid microstructures in their tissue. Critical determinants of lymphoid follicle formation in synovial tissue Lymphoid organ formation is a well-defined developmental process in ontogeny (19, 20). The formation of lymphoid follicles in lymph nodes and other secondary lymphoid organs is essential for the priming of adaptive immune responses and guarantees the orderly execution of an immune response (42–44). Therefore, it makes sense that the mechanisms leading to such organ formation are restricted in space and developmental time. Are these developmental pathways reactivated in the rheumatoid synovium, or does the rheumatoid synovium use different means? Members of the TNF family, in particular lymphotoxin (LT)-a and LT-b, have been identified as key players in the development of lymphoid organs (45, 46). LT-a forms a homotrimer to be functionally active; it can also complex with LT-b as a heterotrimer. Both LTs are involved in lymphoid organ development, however, in slightly different traits. The homotrimer and the heterotrimer are required for the formation of peripheral lymph nodes, whereas the generation of mesenteric lymph nodes appears to be dependent on LT-a1b2 (47). One of the functions of LTs relates to the induction of adhesion molecules. Overexpression of LT-a is sufficient to induce the expression of the mucosal addressin cell adhesion molecule and leads to the recruitment of T cells and B cells (48, 49). Among other functions, LT-a1b2 Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 59 regulates sulfotransferase, the expression of which is restricted to high endothelial venules. This sulfotransferase modifies the sulfation of L-selectin ligands. One of the major L-selectin ligands involved in lymphoid organ formation is peripheral node addressin, which is expressed on high endothelial venules in peripheral lymph nodes. Multiple interlinked processes contribute to the correct spatial compartmentalization of cell subsets in lymphoid organ development. Recognized pathways include the expression of adhesion molecules, the patterning of blood vessel formation and, finally, the production of chemoattractant mediators that recruit selected cell populations into the tissue (44, 50–52). Takemura et al. (32) did a multivariant analysis to determine which of the different mediators involved in ontogenic lymphoid organ development also plays a role in the formation of ectopic lymphoid tissue in the synovium or whether different mechanisms apply. This analysis showed striking similarities but also highlighted some differences that are important in ectopic lymphoid neogenesis (Table 1). LT-b and the B-cell chemoattractant CXCL13 emerged as the two most powerful correlates of GC formation in the synovial tissue. All of the other variables tested did not reach statistical significance. In particular, there was no evidence that LT-a plays a role independent of LT-b. In contrast to GC formation, the formation of lymphoid aggregates did not correlate with mediators important in secondary lymphoid organ development, again consistent with the notion that the lymphoid aggregates in the synovium do not represent primary follicles. The major cellular source of LT-b in synovial lesions was a subset of mantle-zone B cells. CXCL13 was produced by several cell populations, including synovial fibroblasts, selected endothelial cells, and FDCs (32, 53). In addition, CXCL12 produced by fibroblast-like synoviocytes may be important in the compartmentalization of CD4þ and CD8þ T cells (54). The single most important variable in predicting GC formation was the presence of FDCs, as determined by the expression of CD21L, a marker selectively expressed by FDCs, in the synovial tissue. All tissues that express CD21L had evidence of GC formation, irrespective of how high the transcription levels of LT-b, CXCR13, and other mediators were. It is currently unclear whether follicular DCs develop from resident cells in the synovial tissue or whether they are recruited from the circulation. Bofill et al. (55) and Lindhout et al. (56) have demonstrated that certain features of follicular DCs can be induced in fibroblast-like synoviocytes, but these reports have not yet been corroborated. Alternatively, FDCs or their precursors need to be imported into the non-lymphoid tissue site. Elucidating the mechanisms of how FDCs emerge in the synovium likely will be central to gaining an understanding of how ectopic lymphoid neogenesis occurs in humans. The role of B-lymphocyte stimulator (BLyS)/a proliferation-inducing ligand (APRIL) in rheumatoid synovitis Two members of the TNF superfamily, BLyS and APRIL, have been implicated in regulating B-cell differentiation, survival, and function (57). Given the importance of B cells in the Table 1. Characteristics of different types of rheumatoid synovitis Ectopic germinal center Aggregate Diffuse Cells CD4 þþ þþ þþ CD8 CD40LþINF-gþ Perforin– þþ Variable Dendritic cell þþþ (in T-cell zone) þþ þþ Follicullar dendritic cell þ – – B cells Ki-67þ mantle zone Ki-67– IgDþ Ki-67– Plasma cells þþ þþ þþ Cytokines Interferon-g (IFN-g) þþþ þþ þ Tumor necrosis factor-a þþþ þþ þ Lymphotoxin-a þþþ þ – Lymphotoxin-b þþþ – – Chemokines CCL2 þþ þþ þþ CCL18 þþ þ þ CCL21 þþ þ þ CXCL13 þþþ – – Matrix/Angiogenesis Thrombospondin 2 (þ) (þ) þþþ Vascular endothelial growth factor þþ þþ þþ Angioprotein 1 þþ þþ þþ Angioprotein 2 þþ þþ þþ Goronzy & Weyand Rheumatoid arthritis 60 Immunological Reviews 204/2005 structural organization of the synovial infiltrate, the role of BLyS and APRIL in synovitis were examined by Seyler et al. (58). For these studies, a soluble receptor construct, transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI)-Ig, was used to block BLyS and APRIL in vivo. As one would expect, the function of GCs in the synovium was dependent upon APRIL/BLyS. When human synovium-SCID mice chimeras implanted with GC-containing tissues were treated, T-cell activation, DC function, and Ig production declined markedly. The function of APRIL/BLyS in aggregate tissues and in tissues with diffuse synovitis was very different. In vivo blocking studies demonstrated that removal of APRIL and BLyS led to enhanced production of IFN-g, suggesting that one or both of these two TNF-like ligands actually provide a negative signal. The inhibitory function may relate to the presence of TACIþ T cells that may have regulatory function in these tissues (59). It remains unclear from these studies whether BLyS or APRIL is the more important factor. Surprisingly, in situ production of APRIL, but not of BLyS, correlated with ectopic lymphoid neogenesis. APRIL production in the tissue was by far the highest in GC synovitis. The concentration of APRIL was significantly lower in tissues with aggregates and very low in synovial tissues that lacked an obvious structural organization of the infiltrate. In contrast, the concentration of BLyS was not distinguishable between different tissue types. Differences between synovial follicles and follicles in secondary lymphoid tissues While the similarities between ectopic synovial and physiologic lymphoid GCs are evident, important differences have been noted. One of these differences relates to the activation of DCs. Page and Miossec (60) have directly compared rheumatoid synovium and lymph node tissues from patients with RA. While the spatial organization of T and B cells and the mean GC size were similar in both tissue sources, the authors noticed a difference in the activation status of DCs. Lymph nodes had a higher frequency of mature myeloid and plasmacytoid DCs that expressed DC-lysosomal membrane glycoprotein, whereas the synovial GCs had more immature CD1a-positive DCs. The authors speculated that a high expression of CCL20 in the synovium leads to the recruitment of immature DCs. In contrast, lymph nodes expressing little CCL20 recruit mature DCs that have been activated in the periphery and therefore carry an antigenic peptide repertoire representative of the site of DC activation. Immature DCs are tolerogenic, a notion that is difficult to reconcile with the findings of T-cell activation and GC formation in the rheumatoid synovium. It is possible, however, that synovial DCs are locally activated in the synovium, implying that these DCs would sensitize to locally expressed antigens instead of facilitating the immune response to imported antigens. A second difference relates to the role of CD8þ T cells in ectopic GCs. GCs in the rheumatoid synovium, but not in tonsillar tissue, contain a population of CD8þ T cells that accumulate at the edge of the mantle zone. These CD8þ T cells produce IFN-g and express the CD40 ligand but lack the enzyme perforin and typical cytolytic activity (31). In fact, these synovial CD8þ T cells accounted for the majority of IFN-g positive cells in synovial infiltrates. Laser dissection experiments demonstrated that CD8þ T cells with identical T-cell receptor structures were present in different synovial GCs from the same patient, further supporting the notion that CD8þ T cells recognize a restricted antigenic repertoire in rheumatoid synovitis (38). The contribution of antigenrecognizing CD8þ T cells is central for sustaining functional GCs. The depletion of CD8þ T cells in the human synoviumSCID mouse chimeras caused disintegration of the GCcontaining lymphoid follicles. FDC networks disappeared, the production of LT-a1b2 markedly decreased, and Ig production ceased. Various studies have shown that GC function in lymph nodes is dependent on the activation of CD4þ T cells and that intervention such as the blocking of costimulation through CD28 or blocking of CD40 ligand activity is detrimental for GC function (61). In the rheumatoid synovium, these functions appear to be primarily mediated through CD8þ T cells. CD8þ T cells in GCs are a minority compared to CD4þ T cells, but they represent the majority of activated T cells, and GC function is absolutely dependent on them. This dependence is of particular interest, as it indicates that major histocompatibility complex (MHC) class Irestricted recognition and not the disease-associated HLADRB1*04 alleles are important in GC formation. CD8þ T cells are strategically positioned to interact with interdigitating DCs, as well as mantle zone B cells that have not encountered antigens presented on follicular DCs. Antigens recognized by synovial CD8þ T cells have not been identified yet. Given that this response is MHC class I restrictive, it may be an endogenous antigen. Previous studies have suggested that Epstein–Barr virus (EBV)-derived peptides, such as the EBV transactivators BZLF1 and BMLF1, are recognized by synovial CD8þ T cells (62). However, the accumulation of EBV-specific CD8þ T cells is not specific for RA (63), and the CD8þ T cells isolated from synovial GCs do not recognize EBV. Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 61 Autoimmunity and age of onset in RA: a paradox? The therapeutic efficacy of B-cell depletion or blockade of T-cell costimulation has provided, for the first time, direct and unequivocal evidence that RA activity is driven by adaptive immune responses. In addition, the risk of developing rheumatoid synovitis appears to be related to the ability to successfully structure the inflammatory infiltrate in three-dimensional space, resulting in the formation of ectopic lymphoid tissue in the synovium. While the synovium may provide optimal conditions for lymphoneogenesis, the process largely follows the same rules that apply for the developing immune system. Thus, all evidence suggests that the generation of adaptive immune responses is flawed in individuals susceptible to RA. Curiously, rheumatoid factor-positive RA is not a disease of childhood or of young adults, when the adaptive immune system is most competent. On the contrary, advancing age is a strong risk factor for developing RA, with the majority of women being diagnosed after menopause. In fact, the incidence rates increase with age and peak in 75- to 85-year-old individuals (12). It is difficult to reconcile these epidemiological observations with the concept that RA is a misguided adaptive immune response (Fig. 3). The aging process affects all aspects of the immune system but particularly the adaptive immune system. Clinical evidence for failing adaptive immune response in the elderly is abundant (64, 65). During the second half of life, chronic infections are reactivated. The risk of the elderly to develop cancer has been attributed to declining immunosurveillance. Evidence for age-related immune degeneration is already apparent in the sixth decade of life, which is the same time when the incidence of RA starts to accelerate. As an example, pneumonia and influenza infections are the tenth leading causes of death in 45- to 64-yearold individuals and the fifth leading cause in individuals aged 65 and over (66). Several mechanisms have been cited as causing this decline in immune function. It is well known that the involution of the thymus begins at birth and accelerates during adolescence. Studies in patients undergoing chemotherapy, therapeutic antibody-mediated T-cell depletion, or autologous bone marrow transplantation have all shown that the ability to generate new naive T cells in the thymus is minute to absent after the age of 40 years (67–69). Besides the demise of thymic activity, declines in DC function and, in particular, the inability to build GCs have been described (61, 70). It is not surprising therefore that primary T-cell responses are particularly affected by age. However, it is exactly these mechanisms that appear to be pivotal in the pathogenesis of RA. How old is the immune system in patients with RA? The functionality of the immune system is tightly linked to its proliferative capacity, placing enormous proliferative stress onto lymphocytes. The ability to generate adaptive immune response highly depends on clonal bursts in response to antigens, i.e. rapid clonal expansion of the responding T-cell function. In adults, the need to replace lost lymphocytes adds additional proliferative demand, as homeostasis of lymphocyte numbers is controlled through mature cell duplication instead of novel cell generation. Normal somatic cells have an intrinsic property that limits their proliferation. As cells age, their ability to proliferate dwindles until they reach replicative senescence. Determinants that control senescence and cause growth arrest include the length and function of telomeres. The structural units of telomeres are repetitive DNA sequences that cap the ends of linear chromosomes. With each cell division and DNA replication, approximately 50 bases at the Fig. 3. Thymic function and rheumatoid arthritis (RA) incidence – an inverse relationship. The incidence of RA (A) is low before menopause and peaks in the seventh to eighth decades of life (12). Thymic function rapidly declines with age and is minimal after the age of 40 years. Shown are the involution of thymic epithelial space (TES) (B) and the frequencies of recent thymic emigrants as estimated by the concentrations of peripheral T cells with T-cell receptor excision circles (TRECs) (C). Goronzy & Weyand Rheumatoid arthritis 62 Immunological Reviews 204/2005 30 end of the telomere do not replicate and are lost. The loss of telomere length can therefore be used to estimate the number of cell cycles that have been completed. T and B cells have the ability to upregulate telomerase, and they are able to prolong their lifespan. However, they are not resistant to telomere erosion (71). Telomeres in CD4þ and CD8þ T cells of healthy individuals progressively erode until age 65, when they level off at a rather short length. Telomeric erosion affects the memory and naive T-cell subsets. Telomere length therefore serves as a good marker to estimate the age and replicative history of an immune system. Healthy individuals lose an average of 2 kb of telomeric repeat between the ages of 20 and 70 years. Telomeric erosion is clearly accelerated in patients with RA, regardless of age (72). Even in those few patients with seropositive RA that develop the disease between the ages of 20 and 30 years, telomeres are shortened by about 1 kb compared to healthy age-matched controls. Thus, by the age of 30, a patient with RA has already used up half of the telomeric reserve. Loss of 1 kb of telomeric repeats corresponds to an additional 20 cell cycles the cells have passed through. This cycling is comparable to another important benchmark of T-cell proliferation, namely the number of T-cell doublings that occur in antigen-specific immune responses. Memory T cells generally have a significantly shorter telomere length than naive T cells. However, in patients with RA, both naive and memory T cells equally show evidence of age-inappropriate telomeric shortening. This finding is not the consequence of an isolated antigenspecific response as part of the disease process but appears to be an indicator of an accelerated aging of the global immune system. The immune system of patients with RA is considerably older than their chronological age and certainly not younger (Table 2). These findings do not provide an easy solution to the apparent paradox that the risk of individuals developing misguided adaptive immune response leading to RA increases with age. Rather, these observations provide support for the counterintuitive hypothesis that aging is a risk factor for developing such an immune response (73). The finding that telomere shortening also affects naive T cells provides clues that the replicative stress in patients with RA occurs early in T-cell ontogeny. One possible explanation is that the influx of newly generated T cells from the thymus is decreased in individuals at risk for RA and that this reduced regenerative capacity increases homeostatic proliferation of the peripheral T-cell compartment. Alternatively, replicative stress may already occur at the level of lymphocyte precursor cells. Studies have shown that both hypotheses are correct and both mechanisms contribute to T-cell abnormalities in patients with RA. As initially proposed by Kong et al. (74) and subsequently further developed by Douek et al. (75), a minimal estimate of thymic activity can be derived from the frequency of naive T cells expressing signal joint T-cell receptor excision circles (TRECs). At least two studies have shown that the frequency of TRECþ T cells were significantly lower in RA patients as compared to age-matched controls. Koetz et al. (72) have interpreted this reduced frequency of TRECþ T cells as evidence of a diminution of thymic production that had already occurred earlier in life. Individuals susceptible for RA would enter adulthood with less thymic activity, while the subsequent age-dependent decline in thymic output would not differ between patients and controls. A similar reduction of TRECþ T cells in patients with RA was described by Ponchel et al. (76), who favored the hypothesis that the reduced thymic output is still reversible in adult patients. These authors also demonstrated that reduced thymic output was associated with phenotypic changes in the compartment of naive T cells, clearly demonstrating downstream events of reduced thymic Table 2. Markers of immunosenescence in healthy individuals and rhematoid arthritis (RA) patients Cell/tissue Marker/function Healthy RA* References Neutrophils Telomeres Loss of 2 kb between ages 20 and 60 years Shortened by 1 kb (80) Thymus TRECs Decline by 3%/year Reduced by approximately 50% (72, 75, 76) Naive CD4 T cells Telomeres Loss of 2kb between ages 20 and 60 years Shortened by approximately 1 kb (71, 72, 80) Phenotype CD45RBþ (76) Clonal burst 104 -fold 103 -fold (72) Diversity Contraction after age 60 Contracted by approximately 90% (94, 100) Memory T cells Telomeres Loss of approximately 1 kb with age Shortened by approximately 0.5 kb (71, 72) Phenotype Loss of CD28 with age Increased frequencies of CD28– CD4þ T cells (99, 104, 130) Expression of KIRs, NGK2D, CX3CR1 (97, 108, 115, 117, 125, 129), Diversity Oligoclonality Increased oligoclonality (92, 94–96, 98, 100, 133) B cells Diversity Oligoclonality (82) *Compared to age-matched healthy controls. KIRs, killer cell immunoglobulin-like receptors; TRECs, T-cell receptor excision circles. Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 63 output. As discussed by Hazenberg and colleagues (77, 78), the data can also be explained by a history of increased turnover in the naive compartment. TRECs are not being replicated during proliferation, and TREC concentrations are therefore as much influenced by peripheral turnover as by the influx of new TRECþ T cells. If increased turnover and sustained thymic output are to explain the findings in patients with RA, the time of increased turnover must have preceded the onset of RA. At the time of disease onset, there is no increase in homeostatic proliferation, as estimated by the frequency of Ki67þ cells in the naive T-cell compartment and as estimated by the slope of TREC loss with age. Irrespective of the primary defect, the data suggested that patients have a history of increased homeostatic proliferation of naive T cells that predated the disease (79). Other measures of thymic activity, such as the imaging of thymic epithelial space, will have to be explored to determine what the underlying defect is. However, irrespective of the mechanism, the interpretation will stay unchanged. Patients with RA have changes in their naive T-cell repertoire that are characteristic of an accelerated aging process. A second confounding factor that determines the telomere lengths in peripheral lymphocytes is the replicative history of the pre-T lymphocyte precursor cells. To examine this question, Schonland et al. (80) determined telomere lengths in granulocytes in patients with RA and compared them to agematched controls. Telomere lengths in granulocytes accurately reflect the telomeric erosion in the hematopoietic stem cell (HSC), because granulocyte differentiation only requires very few cell cycles. These studies showed that the telomeric lengths in granulocytes are clearly reduced in patients with RA when compared to the age-matched controls, suggesting that some of the observed defects occurred at a level of HSC proliferation (81). Such a global hematopoietic defect would also be consistent with the observation that patients with RA exhibit a restricted B-cell repertoire that shows evidence of senescence (82, 83). Implicating HSCs would also be consistent with the concept that the changes predate the clinical onset of RA. The formation of the naive T-cell repertoire is largely concluded during early adolescence. Therefore, any changes in the naive T-cell repertoire that are attributed to HSC abnormalities must have occurred before that time. Genetic determinants of accelerated HSC aging in RA HSC function can clearly be influenced by inflammation, and it is well known that the dysfunction of hematopoiesis in RA is dependent on disease activity. The defective clonogenic potential of bone marrow CD34þ cells has been attributed to extrinsic factors in the bone marrow microenvironment. In particular, high amounts of TNF-a lead to increased HSC apoptosis and a reduction of HSC clonogenic potential (84). However, the telomere shortening observed in HSC of patients with RA appears to predate the onset of disease and must therefore reflect the environmental events that have preceded the disease, the genetic risk factors, or a combination of both. RA is a complex genetic disorder with numerous genes contributing to disease pathogenesis. The strongest genetic component has been mapped to the MHC region. Most pathogenic models rely on the association with the HLA-DRB1*04 polymorphism (8). Additional genetic polymorphisms in the MHC region also appear to play a role in RA (85). Schonland et al. (80) therefore have addressed the question of whether the premature aging of HSC can be mapped to the MHC region and have compared the telomeric lengths of myeloid and lymphoid cells in healthy individuals who express an HLADR4 haplotype with those of HLA-DR4– individuals (80). These studies showed that HLA-DR4 is associated with premature telomeric erosion in granulocytes as well as in T lymphocytes. The findings were very similar to the earlier findings in patients with RA, suggesting that most of the accelerated telomeric shortening in RA can be attributed to having the HLA-DR4 haplotype. Accelerated telomeric erosion in HSCs is acquired during the first two decades of life. Schonland (80) compared cord blood cells from HLA-DR4þ and HLA-DR4– newborns and found no significant differences. Subsequent studies have mapped the time period of accelerated telomeric erosion to the second decade of life (own unpublished observations). At the age of 20 years, HLA-DR4þ individuals had lost more than a 1000 base pairs in telomeric sequences compared to HLA-DR4– individuals. Stem cell populations are known to have a very efficient telomeric repair mechanism. Telomerase activity was tested in HLA-DR4þ and HLA-DR4– lymphocytes and showed high activity in both cohorts. Also, no difference in telomeric erosion was seen in HLA-DR4þ to HLA-DR4– sperm cells, a cell population that is highly dependent on telomeric repair to avoid jeopardizing telomeric intactness in fertilized eggs. However, it remains possible that telomerase activity is selectively reduced in the HSCs of HLA-DR4þ individuals. Alternatively, HLA-DR4 individuals may have an accelerated turnover of HSCs, possibly in response to environmental stimuli during the first two decades of life. Healthy HLA-DR4 individuals also show downstream effects of HSC aging when the peripheral T-cell compartment is studied. These findings are similar to those in patients with Goronzy & Weyand Rheumatoid arthritis 64 Immunological Reviews 204/2005 RA, in that HLA-DR4 individuals have telomeric erosion in their naive as well as in their memory T-cell population. This erosion occurs even in the absence of any significant reduction in the frequencies of TRECþ T cells. Also, normal HLA-DR4 individuals already show signs of senescence in post-thymic cells. The proliferative potential of their naive CD4þ T cells is significantly reduced (80), and memory T cells with a phenotype of cellular senescence, such as the loss of CD28, are expanded (86). A number of lessons can be learned from these data. The reduced thymic activity in patients with RA is not exclusively a consequence of HSC aging; patients with RA might have additional contributing factors originating from the thymic microenvironment, such as reduced production of IL-7 (87). Also, the data document that changes in the T-cell compartment are only partly imposed by thymic activity and T-cell homeostatic proliferations. T-cell repertoire contraction: a mechanism of autoimmunity? How can the process of immunosenescence be accelerated and T-cell responsiveness be impaired, yet the individual is at greater risk for autoimmunity? This co-occurrence may not be paradoxical. Is it possible that aging predisposes for autoimmunity and that age-dependent immune degeneration is associated with an increased risk of disease, even if the general responsiveness to exogenous antigens is compromised? This view is not as heretical as it first appears. Evidence has clearly shown that many autoimmune diseases occur most frequently in older patients and that autoimmunity therefore is not an inborn error or an error that has been acquired early during development. Even more strikingly, a large number of elderly individuals display evidence of autoimmune phenomena even if they are not apparently sick. For instance, the frequency of healthy elderly individuals with autoantibodies is high (88). It has been estimated that the incidence of rheumatoid factor positivity in healthy elderly is as high as 10%. We have proposed a model in which peripheral selection mechanisms shaping the repertoire during homeostatic proliferation favor the selection of autoreactive clones, eventually leading to an autoimmune receptor repertoire (79). It is generally accepted that T-cell survival and turnover for naive cells depend on the recognition of self-MHC antigens (89, 90). Homeostatic T-cell proliferation already contributes to T-cell generation in the early months of life (91). With increasing thymic decline during adulthood, homeostatic proliferation has to take over as the major source of T-cell generation. As autoproliferation is under selective pressure, it may ultimately lead to TCR diversity contraction. Indeed, large clonal expansions of T cells are common with increasing age, even more so in the CD8þ T-cell population than in the CD4þ T-cell population (92, 93). Large clonal populations are generally memory T cells that display a phenotype typical for replicatively stressed cells. Preliminary evidence from our laboratory suggests that the diversity of the naı¨ve repertoire is maintained until the age of 60 approximately. In subsequent years, diversity markedly contracts by about the factor of 100 (94). Repertoire contraction occurs much earlier in RA. The first evidence that T-cell homeostasis is not intact in patients with RA came from the observation that these patients carry large clonally expanded populations of CD4þ and CD8þ T cells in their memory compartment (95–98). These clonal expansions were more frequent than in healthy individuals and disproportionate for the age of the individuals. Also, patients with RA had increased frequencies of T cells with phenotypic markers that are associated with replicative stress. The most prominent of these markers is the loss of CD28 and CD7 and the gain of CD57 (97). Patients with RA, in particular patients with extra-articular manifestations of RA, display increased frequencies of such cells (99). These clonal expansions were initially interpreted as examples of antigen-specific responses that occur as part of the rheumatic disease process. Wagner et al. (100), however, demonstrated that the repertoire changes were global and cannot be interpreted as an epiphenomenon of this disease. These authors also showed that repertoire contraction already involved the naive T-cell compartment. Compared to age-matched controls, patients with RA had about a 10-fold contraction of their naive CD4þ T-cell repertoire. These data would indicate that 40- to 50-year-old patients with RA have already lost approximately 90% of their available T-cell receptors, while the remaining T cells of the naive compartment had to compensatorily expand to 10 times larger clonal sizes. In the past decades, models of immune tolerance have mainly focused on individual cell function. These models have neglected the contribution of system-wide mechanisms and how they impact maintaining tolerance. It is almost certain that features such as competition for space and critical threshold phenomena play a major role (101). It is reasonable therefore to hypothesize that lymphopenia, peripheral repertoire selection, and lack of diversity set the stage for autoimmune deviations. A murine model suggesting that this may be the case is the autoimmunity observed in the lymphopenic mouse that occurs after neonatal thymectomy (102). Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 65 Novel costimulatory pathways associated with T-cell senescence Replicative stress of cells leads to cellular senescence (103). The immune system and, in particular, the T-cell system in patients with RA are not exceptions to this rule (Fig. 4). The best-known feature of senescence is the dwindling of the proliferative capacity. Adaptive immune responses are highly dependent upon clonal bursts providing sufficient cell numbers after exposure to a pathogen. Studies in patients with RA, but also in healthy HLA-DR4 individuals, have shown that clonal burst capacity is diminished (72, 80). The consequences for disease are not clear. One could speculate that immune responses are less brisk and more smoldering. A second well-known feature of senescent cells is their resistance to apoptotic cell death. A third feature, which has been generally less appreciated but may be most important for understanding the pathological consequences of senescence, is that senescent cells undergo changes in gene expression; notably, gain in gene expression is at least as common as its loss. A classical example is the production of inflammatory cytokines in senescent fibroblasts (103). Because senescenceassociated changes in cellular function occur after the reproductive period of the host, they are exempt from evolutionary pressure and selection. Therefore, they may have deleterious effects on the aged host. Consistent with this model, CD4þ and CD8þ T cells undergo multiple phenotypic and functional changes with replicative stress. A few of these changes are associated with a loss in function, such as the loss of CD28 and CD40 ligands (104–107). In parallel, the expression of many genes is gained. Curiously, many of these genes are directly involved with effector functions and are frequently expressed on natural killer (NK) cells (108). Classic examples are the expressions of perforin and granzymes that occur in senescent CD4þ T cells that allow them to acquire cytotoxic activity (109). Such cytotoxic CD4þ T cells are part of the synovial infiltrate in rheumatoid synovitis (110). With entering cellular senescence, CD4þ T cells undergo fundamental changes in function. Effector functions traditionally associated with CD4þ T cells are upregulated; for example, senescent CD4þ T cells produce higher amounts of IFN-g and TNF-a on a per cell basis than most other memory T cells. They have lost the expression of the CD27 molecule and frequently express the CCR5 chemokine receptor. However, in contrast to short-lived effector cells, they are resistant to apoptosis (111, 112) and continue to express the CCR7 molecule, which allows them to home to secondary lymphoid tissue (113). In summary, senescent CD4þ T cells represent a population of effector cells that are able to mediate MHC class II-restricted cytotoxicity and produce high amounts of inflammatory cytokines. The expansion of such a cell population in patients with RA must represent a risk factor for tissue injury. Their propensity to inflict tissue injury is further increased because they have extended their life span and altered their tissue-homing pattern. Of particular importance for the biological function of these cells is the acquisition of a number of regulatory molecules. The shift in regulatory molecules from the classic CD28-CD80/CD86 pathway to alternate immunoreceptors changes the cellular context in which T-cell stimulation is facilitated (114). This context information is not only important for the synovium, but also for the extra-articular manifestations of RA, such as autoimmune vasculitis (115). Remarkably, evidence has been presented that CD4þ T-cell senescence, with the appearance of novel regulatory receptors, plays a critical role in the comorbidities of RA that have not been considered immune-mediated, such as atherosclerotic coronary artery disease (116). Molecules that provide costimulatory function in senescent T cells include members of the killer cell immunoglobulin-like receptor (KIR) family, NKG2D, and the fractalkine receptor (117). Curiously, all of these regulatory molecules are typically present on NK cells, while the expression of these molecules on T cells is highly selective. Expression of NK receptors in vivo is limited to CD28– cells that have an extensive replicative history (118). The profile of KIRs on T cells follows a very similar pattern to that on NK cells. Expression starts during clonal expansion and is cumulative (119). Accordingly, clonally expanded T cells have a diverse Fig. 4. Functional and phenotypic changes of T-cell senescence. With accumulative replicative stress imposed by clonal burst during immune responses as well as the need for T-cell replenishment with aging, memory CD4þ and CD8þ T cells tend to lose the expression of CD28 and CD40L. CD4þCD28null T cells are highly potent effector cells. They acquire expression of a variety of regulatory molecules that are generally expressed on natural killer cells and not on CD4þ T cells, such as killer cell immunoglobulin-like receptors (KIR), NKG2D, and the fractalkine receptor CX3CR1. Ligands for these receptors are abundant in the synovial microenvironment and costimulate suboptimal T-cell receptor-mediated signals. IFN-g, interferon-g; IL, interleukin. Goronzy & Weyand Rheumatoid arthritis 66 Immunological Reviews 204/2005 repertoire of KIRs. In RA, particularly in patients with extraarticular manifestations, oligoclonal T-cell populations preferentially express the stimulatory KIR2DS2 gene, often in absence of inhibitory KIRs or of inhibitory receptors of the C-type lectin family CD94-NKG2A (115). Selective expression of stimulatory KIRs provides costimulatory function and amplifies IFN-g production in response to subthreshold TCR stimulation. In contrast to NK cells, stimulatory KIRs on T cells are not a fully stimulatory unit but need to be combined with additional signals from the T-cell receptor (120). Stimulatory KIRs have a short cytoplasmic domain with no known signaling motifs. The stimulatory activity requires the presence of the adapter molecule DAP12, which is ubiquitously expressed in NK cells. DAP12 is an integral membrane protein, which contains two cytoplasmic immunoreceptor tyrosine-based activation motifs (ITAMs) that are phosphorylated by Src family kinases. The phosphorylated ITAMs recruit signaling molecules with Src homology 2 domains, such as Syk and z-associated protein of 70 kDa (ZAP70). However, DAP12 is not expressed in most T cells. Stimulation of KIR2DS2 therefore takes a different signaling pathway that has only been mapped partially (121). Apparently, this signaling pathway does not involve ZAP70, does not lead to extracellular regulated kinase phosphorylation, and is therefore completely distinct from T-cell receptor-mediated signaling. Stimulation with KIR2DS2 activates c-Jun N-terminal kinases, an important pathway used by numerous costimulatory molecules. The nature of the adapter molecule that transmits KIR2DS2 stimulation in T cells is unclear. Costimulatory activity of KIR2DS2 was blocked by Wortmannin, a phosphoinositide 3-kinase inhibitor, suggesting that the adapter molecule may be DAP10. However, immune precipitation and cotransfection experiments have failed to demonstrate an association between KIR2DS2 and DAP10. Irrespective of the signaling pathway, the costimulatory function of KIR2DS2 provides different context information than the classical CD28 pathway. The ligands of costimulatory KIRs have not been conclusively identified. Inhibitory KIRs recognize HLA-C polymorphisms. Stimulatory KIRs that share an extensive sequence polymorphism with inhibitory KIRs have a much lower affinity for HLA-C molecules, but possibly recognize HLA-C if complexed with certain peptides. In essence, senescent T cells should receive continuous costimulatory signals, because both the expression of HLA-C on target cells and the expression of KIRs on T cells are constitutive and do not depend on cell activation. Infrequently, T cells also acquire the expression of DAP12. It is unclear what mechanisms induce de novo expression of DAP12, but one of the major pathways may be cumulative replicative stress. DAP12 expression in T cells is only observed in T-cell subsets that are oligoclonally expanded and have lost the expression of CD28. In such T cells, the coexpression of stimulatory KIRs and DAP12 endows the T cells with full stimulatory capacity, independent of T-cell receptor triggering (122). As a functional consequence, T cells can be stimulated to be cytotoxic even in the absence of antigenic peptides. It is unclear at present how often this full gene complementation occurs in patients with RA and whether it is associated with more severe disease or disease complications. The expression of stimulatory KIR receptors is influenced, in part, by genetic diversity. KIRs constitute a family of genes with genetic and allelic diversity (123). There are at least eight different KIR haplotypes with a varying number of KIR genes. The most frequent KIR haplotype has only KIR genes with inhibitory function. The stimulatory KIR2DS2 gene is present in 40% of healthy individuals and has been shown to function as a risk factor for rheumatoid vasculitis (115). Association studies also suggested a role for KIRDS1 and KIRDS2 in conferring risk for psoriatic arthritis (124). A similar role as for stimulatory KIR molecules in RA has recently been proposed for NKG2D (125). NKG2D is a stimulatory receptor of the C-type lectin family that is typically expressed on NK cells and, in humans, also on all CD8þ T cells (126). Whereas induction of cell-surface expression of KIRs in vitro has not been possible, culturing in IL-15 promptly upregulates NKG2D on CD4þ T cells. IL-15 has been implicated in the pathogenesis of RA. It is expressed in the synovial membrane and has been shown to mediate monocyte activation in the synovium membrane. The action of IL-15 appears to be upstream of TNF-a (23). Therefore, it does not come as a surprise that NKG2D is expressed on CD4þ T cells from patients with RA. However, the expression in vivo is much more limited than one would expect from the in vitro studies; additional mechanisms controlling NKG2D expression must play a role. Again, NKG2D is exclusively expressed on oligoclonal populations of CD4þ T cells that have lost CD28 expression, suggesting a connection to replicative senescence. The ligands for NKG2D are MHC class I chain-related gene A (MICA) and MICB, glycoproteins that are found on intestinal epithelium and can be stress-induced in some permissive tissues. Interestingly, MICA and MICB are detected on synovial fibroblasts that are able to activate autologous T cells in an NKG2D-dependent manner. Again, NGK2D acts as a costimulatory receptor, which is different from the NKG2D function in NK cells, where it is fully stimulatory (120). Human NKG2D associates with DAP10 that is expressed in both NK cells and T cells. The reason for the different functional Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 67 outcomes remains unclear. Nevertheless, the biological implications are potentially profound. Replicatively stressed T cells express a set of molecules that allows them to receive a diverse set of costimulatory signals in the synovial membrane, which may be sufficient to sustain a chronic autoreactive T-cell response. Further support for this concept comes from recent studies exploring the role of the fractalkine receptor CX3CR1 in RA (127). The vast majority of NK cells and a subpopulation of CD8þ T cells possess CX3CR1, whereas only very few CD4þ T cells are positive for this chemokine receptor. However, patients with RA have increased frequencies of CD4þCX3CR1þ T cells (128, 129). Again, the fractalkine receptor-positive cells are those cells that have undergone extensive replication and have lost the CD28 molecule. The ligand for CX3CR1, fractalkine, is found on the surface of synovial fibroblasts. Fractalkine–fractalkine receptor interactions are known to play a major role in adhesion and chemotaxis. Indeed, the adherence of CD4þCD28– T cells to synovial fibroblasts is, in part, dependent on this interaction. Beyond its role in cell adhesion, the fractalkine receptor also delivers costimulatory signals to T cells and enhances the responsiveness to T-cell receptor-mediated signals. Surprisingly, this costimulatory activity is not limited to the production of cytokines, a function known to be subject to costimulatory modulation. CX3CR1þCD4þ T cells also obtain amplifying signals for the expulsion of cytotoxic granules. These observations suggest the following general model for dysfunctional T-cell responses in RA (Fig. 5). Patients with RA have accumulated a population of T cells that are ideally equipped to function in the synovial microenvironment where they receive survival signals, interact with nonprofessional APCs, release powerful cytokines, and display novel functional activities, such as cytolysis. While healthy T cells rely on stimulatory signals from processed antigens and CD80/CD86, senescent T cells are much more promiscuous and receive activating signals from an extended spectrum of receptor–ligand interactions. The danger associated with this scenario is obvious. While healthy T cells remain below the threshold of activation, senescent T cells integrate a number of signals and are able to respond to TCR stimulation with lowaffinity antigens. The pathways that lead to the accumulation of such T cells are incompletely understood but there is overwhelming evidence that cumulative replicative stress encourages the emergence of such cells. Replicative stress is a normal physiologic challenge but may turn into a disease risk factor when extensive and beyond the compensatory reserve mechanisms of the immune system. To date, there is clinical evidence that the accumulation of senescent CD4þ T cells is a risk factor for several clinical conditions of tissue injury; in particular, progressive erosive RA, extra-articular manifestations, and the vascular comorbidity limiting the life expectancy of patients with RA (130–132). Conclusions RA is a chronic inflammatory disease that displays its tissuedamaging potential most visibly in the joint but debilitates the affected host also through a systemic inflammatory syndrome and acceleration of atherosclerosis. Much attention has been given to understanding the mechanisms of inflammation. Fig. 5. Immunosenescence as a risk factor for autoimmunity. The schematic diagram demonstrates the functional consequences of the cellular senescence program, for both the tissue environment of the synovium and the adaptive immune system. With abnormalities in their functional profile, senescent T cells find best conditions for activation and survival in the inflamed synovium, rendering the host susceptible to breakdown of self-tolerance and chronic autoimmune disease. APC, antigenpresenting cell; KIR, killer cell immunoglobulin-like receptor; RA, rheumatoid arthritis. Goronzy & Weyand Rheumatoid arthritis 68 Immunological Reviews 204/2005 These mechanisms will likely be generic to a multitude of inflammatory diseases but lack disease specificity for RA. The final pathway of inflammation, whenever and wherever it occurs, will be a conglomerate of mediators of which cytokines and chemokines are only minor constituents. To develop strategies to suppress inflammation, it is important to understand which mediators are present and how they can be blocked. Such inhibitors have entered and will be entering clinical practice. Under optimal conditions, it will be possible to suppress inflammation, but this treatment will not cure the disease. If the goal is to find curative interventions, then we cannot escape the need to understand abnormalities that lie upstream from tissue damage and inflammation. What distinguishes RA among the vast spectrum of inflammatory diseases? Despite intense efforts, we have failed to identify an infectious instigator, reinforcing the concept that failure of the immune system is intrinsic to the system and relates to fundamental principles of tolerance. The disease occurs in the joint, attesting to the fact that the synovial membrane provides a fostering environment for failing immune responses. Additionally, RA essentially never attacks young children but typically manifests in elderly women, most frequently during the seventh and eighth decades of life. Thus, RA strikes when immune regulation fails, when degeneration outweighs the regenerative power of the body. Understanding how the aging process of the immune system affects tolerance and chronic inflammation is necessary to explain this epidemiological fact. Strong support for an ‘accelerated aging model of RA’ comes from data connecting T-cell senescence with the propensity of synovial inflammation. With an abundance of costimulatory signals, the synovial microenvironment appears to lend ideal conditions to T cells that have learned to respond to new environmental cues. Instead of depending on antigen and CD28-mediated costimulation, old and end-differentiated T cells bring to their surface a novel panel of receptor molecules and thus respond to triggers that usually are ineffective in lowering the threshold for T-cell activation. This scenario qualifies as a major breakdown in self-tolerance, as antigens lose their gatekeeper function in driving T cells, and microenvironmental cues move to the forefront. Senescent CD4þ T cells can be triggered through KIR2DS2, NKG2D, and the fractalkine receptor CX3CR1. All ligands are expressed on synovial fibroblasts, making them ideal partners to support such senescent CD4þ T cells. One nagging question remains. Why are all these de novo expressed receptors borrowed from NK cells? T-cell senescence is a physiologic event as lymphocytes proliferate vigorously to function, yet their proliferative capacity is restricted, partially through their telomeric reserve. Available data suggest that two pathways contribute to accelerating immunosenescence in RA. HSCs, precursor cells for the lymphoid lineage, are prematurely aged and no longer have unlimited replicative capacity. Indirect evidence suggests that superimposed upon insufficient HSC function are defects in thymic T-cell production, leading to unsatisfactory replenishment with novel T cells. With intense demand for lymphocyte turnover, the system is prone to fail. T-cell clonal burst is impaired in patients with RA and the inherent diversity of the receptor repertoire suffers, leaving the host with a lymphocyte pool contracted in diversity and with diminished ability to generate clonal offspring. It will be interesting to explore whether sluggishness of clonal burst and contracted diversity favor breakdown of tolerance or persistence of infectious organisms and how either one or possibly both play a role in RA. An intriguing aspect of the accelerated aging model of RA lies in the recent finding that the HLA-DR4 haplotype, known to confer risk for RA, speeds up HSC aging. Immune aging is more advanced in healthy individuals that carry the HLA-DR4 haplotype. While the accelerated aging model of RA provides a plausible explanation for the role of T cells in driving chronic inflammation and the vulnerability of postmenopausal women for the disease, it is more difficult to explain the susceptibility of the synovial membrane. Progress has been made to decipher the permissive role of the synovial space in supporting chronic immune responses. Angiogenesis, a key component of maintaining inflammatory lesions, is most enhanced in synovial tissues that lack production of the angio-inhibitor TSP2, suggesting a failure in protective mechanisms that normally prevent the outgrowth of new blood vessels. Equally helpful for chronic synovitis is the propensity of the synovium to promote formation of highly complex lymphoid structures. Inflammatory infiltrates in rheumatoid synovitis are complex and organized, in some patients cumulating in the establishment of functional GCs. The molecular pathways of ectopic GC formation in RA recapitulate developmental pathways utilized in building lymph nodes and other specialized tissues. Re-induction of such developmental pathways outside of lymphoid tissues exemplifies failure of tolerance mechanisms. Indeed, one may postulate a generic abnormality of aging and degeneration. Senescent T lymphocytes utilize regulatory immunoreceptors to sustain misplaced immune responses, and the synovial microenvironment utilizes effective developmental pathways to form stable and robust lymphoid architectures. In both cases, the defect lies in genes expressed at the wrong place at the wrong time, a defect that may be generalizable when it comes to aging. Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 69 References 1. Kremer JM. Rational use of new and existing disease-modifying agents in rheumatoid arthritis. Ann Intern Med 2001;134: 695–706. 2. Feldmann M, Maini RN. Lasker Clinical Medical Research Award. TNF defined as a therapeutic target for rheumatoid arthritis and other autoimmune diseases. Nat Med 2003;9:1245–1250. 3. Feldmann M, Maini RN. Anti-TNF alpha therapy of rheumatoid arthritis: what have we learned? Annu Rev Immunol 2001;19:163–196. 4. Nishimoto N, et al. Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, doubleblind, placebo-controlled trial. Arthritis Rheum 2004;50:1761–1769. 5. McInnes IB, Gracie JA. Interleukin-15: a new cytokine target for the treatment of inflammatory diseases. Curr Opin Pharmacol 2004;4:392–397. 6. Edwards JC, et al. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 2004;350:2572–2581. 7. Kremer JM, et al. Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 2003;349:1907–1915. 8. Weyand CM, Klimiuk PA, Goronzy JJ. Heterogeneity of rheumatoid arthritis: from phenotypes to genotypes. Springer Semin Immunopathol 1998;20:5–22. 9. Weyand CM, Goronzy JJ. T-cell responses in rheumatoid arthritis: systemic abnormalities-local disease. Curr Opin Rheumatol 1999;11:210–217. 10. Fleischmann R, Yocum D. Does safety make a difference in selecting the right TNF antagonist? Arthritis Res Ther 2004;6: S12–S18. 11. Weyand CM, Kang YM, Kurtin PJ, Goronzy JJ. The power of the third dimension: tissue architecture and autoimmunity in rheumatoid arthritis. Curr Opin Rheumatol 2003;15:259–266. 12. DoranMF,PondGR,CrowsonCS,O’FallonWM, Gabriel SE. Trends in incidence and mortality in rheumatoid arthritis in Rochester, Minnesota, over a forty-year period. Arthritis Rheum 2002;46:625–631. 13. Vossenaar ER, Van Venrooij WJ. Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 2004;6:107–111. 14. Suzuki A, et al. Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 2003;34:395–402. 15. Hill JA, Southwood S, Sette A, Jevnikar AM, Bell DA, Cairns E. Cutting edge: the conversion of arginine to citrulline allows for a high-affinity peptide interaction with the rheumatoid arthritis-associated HLADRB1*0401 MHC class II molecule. J Immunol 2003;171:538–541. 16. Berglin E, et al. A combination of autoantibodies to cyclic citrullinated peptide (CCP) and HLA-DRB1 locus antigens is strongly associated with future onset of rheumatoid arthritis. Arthritis Res Ther 2004;6:R303–R308. 17. Nielen MM, et al. Specific autoantibodies precede the symptoms of rheumatoid arthritis: a study of serial measurements in blood donors. Arthritis Rheum 2004;50:380–386. 18. Blass S, et al. The stress protein BiP is overexpressed and is a major B and T cell target in rheumatoid arthritis. Arthritis Rheum 2001;44:761–771. 19. Nishikawa S, Honda K, Vieira P, Yoshida H. Organogenesis of peripheral lymphoid organs. Immunol Rev 2003;195:72–80. 20. Mebius RE. Organogenesis of lymphoid tissues. Nat Rev Immunol 2003;3:292–303. 21. Weyand CM, Kurtin PJ, Goronzy JJ. Ectopic lymphoid organogenesis: a fast track for autoimmunity. Am J Pathol 2001;159: 787–793. 22. Lacraz S, Isler P, Vey E, Welgus HG, Dayer JM. Direct contact between T lymphocytes and monocytes is a major pathway for induction of metalloproteinase expression. J Biol Chem 1994;269:22027–22033. 23. McInnes IB, Leung BP, Sturrock RD, Field M, Liew FY. Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factor-alpha production in rheumatoid arthritis. Nat Med 1997;3: 189–195. 24. Miossec P. Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy. Arthritis Rheum 2003;48:594–601. 25. Foxwell B, et al. Efficient adenoviral infection with IkappaB alpha reveals that macrophage tumor necrosis factor alpha production in rheumatoid arthritis is NFkappaB dependent. Proc Natl Acad Sci USA 1998;95:8211–8215. 26. Brennan F, Foey A. Cytokine regulation in RA synovial tissue: role of T cell/ macrophage contact–dependent interactions. Arthritis Res 2002;4:S177–S182. 27. Duke O, Panayi GS, Janossy G, Poulter LW. An immunohistological analysis of lymphocyte subpopulations and their microenvironment in the synovial membranes of patients with rheumatoid arthritis using monoclonal antibodies. Clin Exp Immunol 1982;49:22–30. 28. Klimiuk PA, Goronzy JJ, Bjornsson J, Beckenbaugh RD, Weyand CM. Tissue cytokine patterns distinguish variants of rheumatoid synovitis. Am J Pathol 1997;151:1311–1319. 29. Schroder AE, Greiner A, Seyfert C, Berek C. Differentiation of B cells in the nonlymphoid tissue of the synovial membrane of patients with rheumatoid arthritis. Proc Natl Acad Sci USA 1996;93:221–225. 30. Berek C, Kim HJ. B-cell activation and development within chronically inflamed synovium in rheumatoid and reactive arthritis. Semin Immunol 1997;9:261–268. 31. Wagner UG, et al. The role of CD8þ CD40Lþ T cells in the formation of germinal centers in rheumatoid synovitis. J Immunol 1998;161:6390–6397. 32. Takemura S, et al. Lymphoid neogenesis in rheumatoid synovitis. J Immunol 2001;167:1072–1080. 33. Stott DI, Hiepe F, Hummel M, Steinhauser G, Berek C. Antigen-driven clonal proliferation of B cells within the target tissue of an autoimmune disease. The salivary glands of patients with Sjogren’s syndrome. J Clin Invest 1998;102:938–946. 34. Sims GP, Shiono H, Willcox N, Stott DI. Somatic hypermutation and selection of B cells in thymic germinal centers responding to acetylcholine receptor in myasthenia gravis. J Immunol 2001;167:1935–1944. 35. Park Y, Kang YM, Butterfield J, Detmar M, Goronzy JJ, Weyand CM. Thrombospondin 2 Functions as an Endogenous Regulator of Angiogenesis and Inflammation in Rheumatoid Arthritis. Am J Pathol 2004;165:2087–2098. 36. Davis LS, et al. Inflammation, immune reactivity, and angiogenesis in a severe combined immunodeficiency model of rheumatoid arthritis. Am J Pathol 2002;160:357–367. 37. Klimiuk PA, Yang H, Goronzy JJ, Weyand CM. Production of cytokines and metalloproteinases in rheumatoid synovitis is T cell dependent. Clin Immunol 1999;90:65–78. 38. Kang YM, et al. CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med 2002;195:1325–1336. 39. Setoguchi K, et al. Suppression of T cell responses by chondromodulin I, a cartilagederived angiogenesis inhibitory factor: therapeutic potential in rheumatoid arthritis. Arthritis Rheum 2004;50:828–839. 40. Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM. T cell activation in rheumatoid synovium is B cell dependent. J Immunol 2001;167:4710–4718. Goronzy & Weyand Rheumatoid arthritis 70 Immunological Reviews 204/2005 41. Goronzy JJ, Weyand CM. B cells as a therapeutic target in autoimmune disease. Arthritis Res Ther 2003;5:131–135. 42. Zinkernagel RM. Localization dose and time of antigens determine immune reactivity. Semin Immunol 2000;12:163–171; discussion 257–344. 43. McHeyzer-Williams LJ, Driver DJ, McHeyzer-Williams MG. Germinal center reaction. Curr Opin Hematol 2001;8:52–59. 44. Cyster JG. Leukocyte migration: scent of the T zone. Curr Biol 2000;10:R30–R33. 45. Fu YX, Chaplin DD. Development and maturation of secondary lymphoid tissues. Annu Rev Immunol 1999;17:399–433. 46. Tumanov AV, et al. Dissecting the role of lymphotoxin in lymphoid organs by conditional targeting. Immunol Rev 2003;195:106–116. 47. Ruddle NH. Lymphoid neo-organogenesis: lymphotoxin’s role in inflammation and development. Immunol Res 1999;19:119–125. 48. Drayton DL, Chan K, Lesslauer W, Lee J, Ying XY, Ruddle NH. Lymphocyte traffic in lymphoid organ neogenesis. differential roles of LTalpha and LTalphabeta. Adv Exp Med Biol 2002;512:43–48. 49. Cuff CA, Schwartz J, Bergman CM, Russell KS, Bender JR, Ruddle NH. Lymphotoxin alpha3 induces chemokines and adhesion molecules: insight into the role of LT alpha in inflammation and lymphoid organ development. J Immunol 1998;161:6853–6860. 50. Szekanecz Z, Kim J, Koch AE. Chemokines and chemokine receptors in rheumatoid arthritis. Semin Immunol 2003;15:15–21. 51. Loetscher P, Moser B. Homing chemokines in rheumatoid arthritis. Arthritis Res 2002;4:233–236. 52. Muller G, Lipp M. Concerted action of the chemokine and lymphotoxin system in secondary lymphoid-organ development. Curr Opin Immunol 2003;15:217–224. 53. Shi K, et al. Lymphoid chemokine B cellattracting chemokine-1 (CXCL13) is expressed in germinal center of ectopic lymphoid follicles within the synovium of chronic arthritis patients. J Immunol 2001;166:650–655. 54. Bradfield PF, et al. Rheumatoid fibroblastlike synoviocytes overexpress the chemokine stromal cell-derived factor 1 (CXCL12), which supports distinct patterns and rates of CD4þ and CD8þ T cell migration within synovial tissue. Arthritis Rheum 2003;48:2472–2482. 55. Bofill M, Akbar AN, Amlot PL. Follicular dendritic cells share a membrane-bound protein with fibroblasts. J Pathol 2000;191:217–226. 56. Lindhout E, van Eijk M, van Pel M, Lindeman J, Dinant HJ, de Groot C. Fibroblast-like synoviocytes from rheumatoid arthritis patients have intrinsic properties of follicular dendritic cells. J Immunol 1999;162:5949–5956. 57. Cancro MP. Peripheral B-cell maturation: the intersection of selection and homeostasis. Immunol Rev 2004;197:89–101. 58. Seyler TM, et al. Biological functions of BLyS and APRIL in rheumatoid synovitis. Arthritis Rheum 2003;48:S457. 59. Seshasayee D, Valdez P, Yan M, Dixit VM, Tumas D, Grewal IS. Loss of TACI causes fatal lymphoproliferation and autoimmunity, establishing TACI as an inhibitory BLyS receptor. Immunity 2003;18:279–288. 60. Page G, Miossec P. Paired synovium and lymph nodes from rheumatoid arthritis patients differ in dendritic cell and chemokine expression. J Pathol 2004;204:28–38. 61. Zheng B, Han S, Takahashi Y, Kelsoe G. Immunosenescence and germinal center reaction. Immunol Rev 1997;160:63–77. 62. Scotet E, et al. T cell response to Epstein–Barr virus transactivators in chronic rheumatoid arthritis. J Exp Med 1996;184:1791–1800. 63. Scotet E, et al. Frequent enrichment for CD8 T cells reactive against common herpes viruses in chronic inflammatory lesions: towards a reassessment of the physiopathological significance of T cell clonal expansions found in autoimmune inflammatory processes. Eur J Immunol 1999;29:973–985. 64. Grubeck-Loebenstein B, Berger P, SaurweinTeissl M, Zisterer K, Wick G. No immunity for the elderly. Nat Med 1998;4:870. 65. Albright JF, Albright JW. Aging, Immunity, and Infection. Totowa: Human Press, 2003. 66. Centers for Disease Control and Prevention (U.S.). Natl Vital Statistics Report 1998 Natl Vital Statistics Reports 1998;47:26–36. 67. Fry TJ, Mackall CL. Current concepts of thymic aging. Springer Semin Immunopathol 2002;24:7–22. 68. Haynes BF, Markert ML, Sempowski GD, Patel DD, Hale LP. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu Rev Immunol 2000;18:529–560. 69. Jendro MC, GantenT,MattesonEL, Weyand CM, Goronzy JJ. Emergence of oligoclonal T cell populations following therapeutic T cell depletion in rheumatoid arthritis. Arthritis Rheum 1995;38:1242–1251. 70. Szakal AK, Aydar Y, Balogh P, Tew JG. Molecular interactions of FDCs with B cells in aging. Semin Immunol 2002;14:267–274. 71. Hodes RJ, Hathcock KS, Weng NP. Telomeres in T and B cells. Nat Rev Immunol 2002;2:699–706. 72. Koetz K, Bryl E, Spickschen K, O’Fallon WM, Goronzy JJ, Weyand CM. T cell homeostasis in patients with rheumatoid arthritis. Proc Natl Acad Sci USA 2000;97:9203–9208. 73. Goronzy JJ, Weyand CM. Aging, autoimmunity and arthritis: T-cell senescence and contraction of T-cell repertoire diversity – catalysts of autoimmunity and chronic inflammation. Arthritis Res Ther 2003;5:225–234. 74. Kong FK, Chen CL, Six A, Hockett RD, Cooper MD. T cell receptor gene deletion circles identify recent thymic emigrants in the peripheral T cell pool. Proc Natl Acad Sci USA 1999;96:1536–1540. 75. Douek DC, et al. Changes in thymic function with age and during the treatment of HIV infection. Nature 1998;396:690–695. 76. Ponchel F, et al. Dysregulated lymphocyte proliferation and differentiation in patients with rheumatoid arthritis. Blood 2002;100:4550–4556. 77. Hazenberg MD, et al. Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med 2000;6:1036–1042. 78. Hazenberg MD, Borghans JA, de Boer RJ, Miedema F. Thymic output: a bad TREC record. Nat Immunol 2003;4:97–99. 79. Goronzy JJ, Weyand CM. Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol 2001;22:251–255. 80. Schonland SO, et al. Premature telomeric loss in rheumatoid arthritis is genetically determined and involves both myeloid and lymphoid cell lineages. Proc Natl Acad Sci USA 2003;100:13471–13476. 81. Weyand CM, Goronzy JJ. Stem cell aging and autoimmunity in rheumatoid arthritis. Trends Mol Med 2004;10:426–433. 82. Itoh K, et al. Clonal expansion is a characteristic feature of the B-cell repetoire of patients with rheumatoid arthritis. Arthritis Res 2000;2:50–58. 83. Johnson SA, Cambier JC. Ageing, autoimmunity and arthritis: Senescence of the B cell compartment – implications for humoral immunity. Arthritis Res Ther 2004;6:131–139. Goronzy & Weyand Rheumatoid arthritis Immunological Reviews 204/2005 71 84. Papadaki HA, Kritikos HD, Valatas V, Boumpas DT, Eliopoulos GD. Anemia of chronic disease in rheumatoid arthritis is associated with increased apoptosis of bone marrow erythroid cells: improvement following anti-tumor necrosis factor-alpha antibody therapy. Blood 2002;100: 474–482. 85. Kochi Y, et al. Analysis of single-nucleotide polymorphisms in Japanese rheumatoid arthritis patients shows additional susceptibility markers besides the classic shared epitope susceptibility sequences. Arthritis Rheum 2004;50:63–71. 86. Chapman A, et al. CD11bþCD28– CD4þ human T cells: activation requirements and association with HLA-DR alleles. J Immunol 1996;157:4771–4780. 87. Okamoto Y, Douek DC, McFarland RD, Koup RA. Effects of exogenous interleukin-7 on human thymus function. Blood 2002;99:2851–2858. 88. Moulias R, et al. Age-related increase in autoantibodies. Lancet 1984;1:1128–1129. 89. Goldrath AW, Bevan MJ. Low-affinity ligands for the TCR drive proliferation of mature CD8þ T cells in lymphopenic hosts. Immunity 1999;11:183–190. 90. Viret C, Wong FS, Janeway CA Jr. Designing and maintaining the mature TCR repertoire: the continuum of self-peptide: self-MHC complex recognition. Immunity 1999;10:559–568. 91. Schonland SO, et al. Homeostatic control of T-cell generation in neonates. Blood 2003;102:1428–1434. 92. Chamberlain WD, Falta MT, Kotzin BL. Functional subsets within clonally expanded CD8(þ) memory T cells in elderly humans. Clin Immunol 2000;94:160–172. 93. Schwab R, et al. Expanded CD4þ and CD8þ T cell clones in elderly humans. J Immunol 1997;158:4493–4499. 94. Naylor K, et al. The Influence of Age on T Cell Generation and T Cell Receptor Diversity (Submitted) 95. Fitzgerald JE, et al. Analysis of clonal CD8þ T cell expansions in normal individuals and patients with rheumatoid arthritis. J Immunol 1995;154:3538–3547. 96. Hingorani R, et al. Oligoclonality of V beta 3 TCR chains in the CD8þ T cell population of rheumatoid arthritis patients. J Immunol 1996;156:852–858. 97. Schmidt D, Martens PB, Weyand CM, Goronzy JJ. The repertoire of CD4þ CD28– T cells in rheumatoid arthritis. Mol Med 1996;2:608–618. 98. Waase I, Kayser C, Carlson PJ, Goronzy JJ, Weyand CM. Oligoclonal T cell proliferation in patients with rheumatoid arthritis and their unaffected siblings. Arthritis Rheum 1996;39:904–913. 99. Martens PB, Goronzy JJ, Schaid D, Weyand CM. Expansion of unusual CD4þ T cells in severe rheumatoid arthritis. Arthritis Rheum 1997;40:1106–1114. 100. Wagner UG, Koetz K, Weyand CM, Goronzy JJ. Perturbation of the T cell repertoire in rheumatoid arthritis. Proc Natl Acad Sci USA 1998;95:14447–14452. 101. Barthlott T, Kassiotis G, Stockinger B. T cell regulation as a side effect of homeostasis and competition. J Exp Med 2003;197:451–460. 102. Gleeson PA, Toh BH, van Driel IR. Organspecific autoimmunity induced by lymphopenia. Immunol Rev 1996;149: 97–125. 103. Campisi J. Cellular senescence as a tumorsuppressor mechanism. Trends Cell Biol 2001;11:S27–S31. 104. Effros RB. Loss of CD28 expression on T lymphocytes: a marker of replicative senescence. Dev Comp Immunol 1997;21:471–478. 105. Vallejo AN, Bryl E, Klarskov K, Naylor S, Weyand CM, Goronzy JJ. Molecular basis for the loss of CD28 expression in senescent T cells. J Biol Chem 2002;277:46940–46949. 106. Monteiro J, Batliwalla F, Ostrer H, Gregersen PK. Shortened telomeres in clonally expanded CD28– CD8þ T cells imply a replicative history that is distinct from their CD28þCD8þ counterparts. J Immunol 1996;156:3587–3590. 107. Warrington KJ, Vallejo AN, Weyand CM, Goronzy JJ. CD28 loss in senescent CD4þ T cells: reversal by interleukin-12 stimulation. Blood 2003;101:3543–3549. 108. Warrington KJ, Takemura S, Goronzy JJ, Weyand CM. CD4þ, CD28– T cells in rheumatoid arthritis patients combine features of the innate and adaptive immune systems. Arthritis Rheum 2001;44:13–20. 109. Appay V, et al. Characterization of CD4(þ) CTLs ex vivo. J Immunol 2002;168: 5954–5958. 110. Griffiths GM, Alpert S, Lambert E, McGuire J, Weissman IL. Perforin and granzyme A expression identifying cytolytic lymphocytes in rheumatoid arthritis. Proc Natl Acad Sci USA 1992;89:549–553. 111. Schirmer M, Vallejo AN, Weyand CM, Goronzy JJ. Resistance to apoptosis and elevated expression of Bcl-2 in clonally expanded CD4þCD28- T cells from rheumatoid arthritis patients. J Immunol 1998;161:1018–1025. 112. Vallejo AN, Schirmer M, Weyand CM, Goronzy JJ. Clonality and longevity of CD4þCD28null T cells are associated with defects in apoptotic pathways. J Immunol 2000;165:6301–6307. 113. Zhang X NT, Goronzy JJ, Weyand CM. Breakdown in the compartmentalization of central and effector memory CD4 T cells in rheumatoid arthritis (submitted). 114. Goronzy JJ, Weyand CM. T-cell regulation in rheumatoid arthritis. Curr Opin Rheumatol 2004;16:212–217. 115. Yen JH, et al. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med 2001;193:1159–1167. 116. Nakajima T, et al. De novo expression of killer immunoglobulin-like receptors and signaling proteins regulates the cytotoxic function of CD4 T cells in acute coronary syndromes. Circ Res 2003;93:106–113. 117. Namekawa T, et al. Killer cell activating receptors function as costimulatory molecules on CD4þCD28null T cells clonally expanded in rheumatoid arthritis. J Immunol 2000;165:1138–1145. 118. Moretta L, Biassoni R, Bottino C, Mingari MC, Moretta A. Human NK-cell receptors. Immunol Today 2000;21:420–422. 119. Snyder MR, et al. Formation of the killer Ig-like receptor repertoire on CD4þCD28null T cells. J Immunol 2002;168:3839–3846. 120. Snyder MR, Weyand CM, Goronzy JJ. The double life of NK receptors: stimulation or co-stimulation? Trends Immunol 2004;25:25–32. 121. Snyder MR, Lucas M, Vivier E, Weyand CM, Goronzy JJ. Selective activation of the c-Jun NH2-terminal protein kinase signaling pathway by stimulatory KIR in the absence of KARAP/DAP12 in CD4þ T cells. J Exp Med 2003;197:437–449. 122. SnyderMR,NakajimaT,LeibsonPJ,WeyandCM, Goronzy JJ. Stimulatory killer Ig-like receptors modulate T cell activation through DAP12-dependent and DAP12-independent mechanisms. J Immunol 2004;173: 3725–3731. 123. Raulet DH, Vance RE, McMahon CW. Regulation of the natural killer cell receptor repertoire. Annu Rev Immunol 2001;19:291–330. 124. Martin MP, et al. Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J Immunol 2002;169:2818–2822. 125. Groh V, Bruhl A, El-Gabalawy H, Nelson JL, Spies T. Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci USA 2003;100:9452–9457. 126. Raulet DH. Roles of the NKG2D immunoreceptor and its ligands. Nat Rev Immunol 2003;3:781–790. Goronzy & Weyand Rheumatoid arthritis 72 Immunological Reviews 204/2005 127. Ruth JH, et al. Fractalkine, a novel chemokine in rheumatoid arthritis and in rat adjuvant-induced arthritis. Arthritis Rheum 2001;44:1568–1581. 128. Nanki T, et al. Migration of CX3CR1-positive T cells producing type 1 cytokines and cytotoxic molecules into the synovium of patients with rheumatoid arthritis. Arthritis Rheum 2002;46:2878–2883. 129. Sawai H, Park YW, Roberson J, Goronzy JJ, Weyand CM. Dominance of Stimulatory Signals in the Rheumatoid Synovial Microenvironment – A Role for FractalkineCX3CR1 Interactions (In press). 130. Goronzy JJ, et al. Prognostic markers of radiographic progression in early rheumatoid arthritis. Arthritis Rheum 2004;50:43–54. 131. Liuzzo G, et al. Perturbation of the T-cell repertoire in patients with unstable angina. Circulation 1999;100:2135–2139. 132. Pasceri V, Yeh ET. A tale of two diseases: atherosclerosis and rheumatoid arthritis. Circulation 1999;100:2124–2126. 133. Rittner HL, Zettl A, Jendro MC, BartzBazzanella P, Goronzy JJ, Weyand CM. Multiple mechanisms support oligoclonal T cell expansion in rheumatoid synovitis. Mol Med 1997;3:452–4

ARTICLE TWO

APA

(American Psychological Assoc.)

References

Emery, P., & Suarez-Almazor, M. E. (2003). Rheumatoid arthritis. American Family Physician, 68(9), 1821-1823

Rheumatoid Arthritis PAUL EMERY, University of Leeds, Leeds. United Kingdom MARIA E. SUARLZ-ALM,\ZOR, M.I)., Baylor College of Medidne, Houston, Texas This is one in a series of chapters excerpted from Clinical Evidence Concise, published by the BMJ Publishing Group, Tavistock Square, London, United Kingdom. Clinical Evidence Concise (S published in print twice a year and is updated monthly online. Each topic is revised every eight months, and users should view the most up-to-date version at www.clinica'evidence. com. If you are interested in contributing to Clinical Evidence, please contact Claire Folkes (cfo!kes@ bmjgroup.com). The complete text for this topic is also available in HTML and PDF format through the AFP Web site at www. aaf p. org/afp/ 200311 OVbritish. html. This series is part of the AfP's CME. See "Clinical Quiz" on page 1707. What are the effects of treatments? BENEFICIAL Antimalarials. One systematic review has found that hydroxychloroquine reduces disease activity and joint inflammation compared with placebo in people with rheumatoid arthritis. We found insufficient evidence about effects on functional status. One systematic review found no consistent difference in the effectiveness between antimaJarials and other disease-modifying antirheumatic drugs (DMARDs). Early Intervention with DMARDs. One systematic review and one additional randomized controlled triai (RCT) found that early DMARDs {oral gold, intramuscular gold, hydroxychloroquine, methotrexate, minocycline) significantly improved radiologic progression, swollen joint counts, and quality of life scores at 12 to 60 months compared with delayed treatment. Methotrexate. One systematic review has found that methotrexate reduces joint inflammation and radiologic progression, and improves functional status compared with placebo in people with rheumatoid arthritis. One systematic review and subsequent RCTs have found no consistent differences in efficacy between methotrexate versus leflunomide, parenteral gold, or etanercept. MinocycUne. RCTs have found that minocycline improves control of disease activity compared with placebo. We found no RCTs comparing minocycline versus other DMARDs. Short-Term Low-Dose Oral Corticosteroids. One systematic review has found that lowdose oral corticosteroids taken for several weeks significantly reduce disease activity and joint inflammation compared with placebo. Sulfasalazine. Systematic reviews have found that sulfasalazine versus placebo for six months significantly reduces disease activity and joint inflammation. We found inadequate evidence on radiologic progression and functional status. One systematic review found no consistent differences between sulfasalazine and other DMARDs. Another systematic review of observational studies and RCTs found that over five years people were less likely to continue sulfasalazine than methotrexate. LIKELY TO BE BENEFICIAL Auranofin (less Effective Than Other DMARDs). One systematic review has found that auranofin (oral goid) versus placebo reduces disease activity and joint inflammation, but found no evidence on radiologic progression or long-term functional status. Limited evidence from RCTs suggests that auranofin is less effective than DMARDs. Leflunomide (Long-Term Safety Unclear). One systematic review has found that leflunomide versus placebo reduces disease activity and joint inflammation, improves functional status and health related quality of life, and decreases radiologic progression. We found no good evidence on long-term adverse effects. We found no consistent evidence of a difference in clinical efficacy between leflunomide and methotrexate or sulfasalazine. ^^ij^ g This clinical content conforms to AAEP criteria for evidence-based continuing medical education •^^ (EB CME). EB CME is clinical content presented with practice recommendations supported by evidence that has been systematically reviewed by an AAFP-approved source. The practice recommendations in this activity are available at www.dinicalevidence.com/lpBinCE/lpextdll?f=temptates8ifn=main-h.htm&2.0. NOVEMBER 1,2003 / VOLUME 68, NUMBER 9 www.aafp.org/afp AMERICAN FAMILY PHYSICIAN 1821 Treatment with Several DMARDs Combined. One systematic review and subsequent RCTs have found that combining certain DMARDs is more effective than using individual drugs alone. However, the balance between benefit and harm varies among combinations. Tumor Necrosis Factor Antagonists (LongTerm Safety Unclear). RCTs have found that tumor necrosis factor antibodies {etanercept and infliximab) significantly improve symptoms, and reduce long-term disease activity and joint inflammation compared with piacebo. One RCT found no significant difference between etanercept and methotrexate for quality of life at one year. Short-term toxicity is relativeiy low, but iong-term safety is less clear. TRADE OFF BETWEEN BENEFITS AND HARMS Azathioprine. One systematic review has found that azathioprine versus placebo reduces disease activity in the short term {16 weeks to six months). We found no evidence on radioiogic progression or long-term functional status. A high level of toxicity limits the usefulness of azathioprine. Cyclosporin. One systematic review has found that cyclosporin taken for a minimum of four months significantly reduces disease activity and joint inflammation, improves functional status, and may decrease the rate of radiologic progression compared with methotrexate. One RCT found no significant difference between parenteral gold versus cyclosporin for radioiogic joint damage or seif assessment of change in disease activity at 36 months. A very high frequency of toxicity limits the usefulness of cyclosporin. Cyclophosphamide. One systematic review has found that cyclophosphamide significantly reduces disease activity and joint inflammation compared with piacebo at six months. It also may reduce the rate of radioiogic progression, but evidence was iimited. We found no evidence of its effect on iongterm functional status. Severe toxicity limits its usefuiness. Long-Term Low-Dose Oral Corticosteroids. One systematic review and one subsequent RCT have found Lhat low-dose orai corticosteroids taken for at least three months significantiy reduce pain, joint inflammation, and functional status compared with piacebo. However, iong-term use is associated with considerabie adverse effects. Parenteral Cold. One systematic review has found that parenterai gold reduces disease activity and joint inflammation, and slows radioiogic progression compared with piacebo in people with rheumatoid arthritis. We found no evidence on long-term functional status. One systematic review and one RCT indicate increased withdrawals because of toxicity. RCTs found no significant differences in clinical efficacy between parenteral gold and methotrexate or cyclosporin at one to three years. Penicillamine. One systematic review has found that penicillamine reduces disease activity and joint inflammation compared with placebo at four to six months. We found no evidence about effects of peniciilamine on radiologic progression or long-term functionai status. One systematic review has found no consistent difference between penicillamine versus other DMARDs. Common and potentially serious adverse effects limit the usefulness of penicillamine. Definition Rheumatoid arthritis is a chronic inflammatory disorder. It is characterized by a chronic polyarthritis that primarily affects the peripheral joints and related periarticuiar tissues. It usualiy starts as an insidious symmetric polyarthritis, often with nonspecific systemic symptoms. Diagnostic criteria include arthritis lasting longer than six weeks (although evidence suggests that 12 v^^eeks is more specific), positive rheumatoid factor, and radiologic damage.' Incidence/Prevalence Prevaience ranges from 0.5 to 1.5 percent of the popuiation in industrialized coun- 1822 AMERICAN FAMILY PHYSICIAN www.aafp.org/afp VOLUME 68, NUMBER 9 / NOVEMBER 1,2003 Clinical Evidence Concise Rheumatoid arthritis occurs more frequently in women than men (2.5:1 ).^-^ The annual incidence in women was recently estimated at 36 per 100,000 and in men at 14 per 100,000.^ Etiology/Risk Factors The evidence suggests that the cause is multifactorial in people with genetic susceptibility.'' Prognosis The course of rheumatoid arthritis is variable and unpredictable. Some people experience flares and remissions, and others have a progressive course. Over years, structural damage occurs, leading to articular deformities and functional impairment. About one half of people will be unabie to work within 10 years.'' Rheumatoid arthritis shortens iife expectancy." SEARCH DATE: July 2002 Adapted with permission from Emery F, SuarezAlmazor ME. Rheumatoid arthritis. Clin Evid Concise 2003:10:274-6. Paul Emery has undertaken lectures and consulting work for Pharmacia, Aventis, Schering-Plough, and Wyeth. REFERENCES 1. Arnett FC, Edv^/orthy SM, Bloch DA, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1987;31:315-24, 2. Lawrence RC, Helmick CG, Arnett FC, et al. Estimates of the prevalence of arthritis and selected musculoskeletal disorders in the United States. Arthritis Rheum 1998;41:778-81. 3. Symmons DP, Barrett EM, Bankhead CR, et al. The incidence of rheumatoid arthritis in the United Kingdom: results from the Norfolk Arthritis Register. BrJ Rheumatol 1994;33:735-9. 4. Winchester R, Dwyer E, Rose S, The genetic basis of rheumatoid arthritis: the shared epitope hypothesis. Rheum Dis Ciin North Am 1992;18:761-83. 5. Yeiin E, Henke C, Epstein W. The work dynamics of the person with rheumatoid arthritis. Arthritis Rheum 19S7;30:507-12. 6. Mutru 0, Laakso M, Isomaki H, et al. Ten year mortality and causes of death In patients with rheumatoid arthritis. BMJ 1985:290:1797-9,

ARTICLE 3

APA

(American Psychological Assoc.)

References

Veronesi, J. (2003). Defenses gone awry: rheumatoid arthritis. Rn, 66(8), 46-54 8p.

Rheumatoid arthritis Rheumatoid arthritis can lead to progressive joint destruction, deformity, and disabiiity uniess patients receive early, aggressive treatment. Do you know the interventions that can arrest the progression of this disease? ie. Lifelong. Debilitating. Relentless. Those are just a few of the words used to describe rheumatoid arthritis (RA), an autoimmune disease that affects about 2.1 million U.S. patients.' RA is the second most common form of aithritis, behind only osteoarthritis, which affects more than 20 million patients.^ RA involves inflammation of the synovium, the thin tissue lining the joints that produces joint lubricant and nutrients for cartilage." This inflammation causes pain, stiffness, and swelling, and can eventually lead to joint damage and loss of function. RA can also caase systemic symptoms, including malaise, low-grade fever, and weight loss, and sometimes affects the lungs and heart.'' JAMES VERONESI is director of nursing systems and resources at Penn State Milton S. Hershey Medical Center in Hershey. Pa. STAFF EDITOR: Jeff Bauer Although RA can begin at any time, most patients experience symptoms and are diagnosed between the ages of 20 and 40.^ Women are diagnosed vrith RA two to three times as often as men, which suggests that hormones may play a role in the disease.** While about 1% - 2% of whites are affected by RA, the pi'evalence is higher among Native Americans, affecting 3.5% - 5.3%." For some patients, RA is mild or moderate and characterized by periods of flares and remissions. However, for others it involves irreversible joint damage, possible deformity, and progressive disability.^ That's not all: Patients viith RA whose symptoms persist longer than two years have a life span that's 10 -15 years shorter than that of people vrithout RA.'' There is no known cure for RA, but early treatment can reduce the likelihood of a patient suffering permanent disability. By having a better underetanding of this disease, you can help ensure that patients get the treatment they need and remain as active and productive as possible. The body attacking its own joints The immune system plays a key role in the development of RA, although the exact mechanism is not clearly understood.^ An xmknown trigger causes rheumatoid factor antibody (an IgM antibody) to develop against the body's naturally occurring antibody, immunoglobulin G (IgG). IgG, in turn, is transformed into an antigen. Rheumatoid factor antibodies then combine with these IgG antigens to form antigen-antibody complexes. These complexes are deposited in the synAUGUST 2003 Vol. 66, No.8 www.rnweb.com JAMES F. VERONESi, RN, MSN, CNAA, CHE ovium and stimulate immune cells, particularly T-tymphocytes and macrophages, to enter the synovial fluid, where normally there are very few cells. Once inside the synovial fluid, these inflammatory cells release two cytokines—^tumor necrosis factor (TNF) and interleukin-l— that lead to synovitis."' This inflammation causes the warmth, redness, swelling, and pain associated with RA." As the disease pi'ogresses, the cells of the synovium grow and divide abnoi-mally and form a mass known as pannus that invades and erodes joint soft tissue, cartilage, and bone.'''' Pannus can scar and shorten tendons and ligaments, leading to lax ligaments, joint subluxation, and contractui'es, as well as bone spurs and osteophytes.^ Surrounding muscles, ligaments, and tendons that support and stabilize the joint become weak and unable to function properly. Genetic predisposition appears • • KEY WORDS rheumatoid arthntis [RA] synovitis pannus rheumatoid nodules nonsteroidal anti-inflammatory drugs [NSAlDs] disease-modifying antirheumatic drugs CDMARDs) biologic response modifiers (BRMs] Worn down - i ^ cartilage i/f^ and narrowed •y , joint space ¡l,,,.^— Inflammatory cells —- Joint swelling - Growth of synovial membrane that invades the bone www.rnweb.com Vol, 66, No, 8 AUGUST 2003 RN to be a factor in the development of RA.^ Patients who have a I'elative with an immune system disorder have an increased risk of developing the same or anothei* immune system disorder.'' Most patients who develop RA have a class II human leukocyte antigen, subgi-oup DR4 (HLA-DR4), which is inherited.*' Nevertheless, genetics are not believed to be solely responsible for the development of RA.^ Some researchers theorize that an environmental agent, such as a virus, chemical compound, or radiation, triggers the disease in patients who are genetically predisposed to it; however, no specific agent has been identified."*'^ An insidious onset of pain and stiffness For about 80% of patients, the onset of RA is slow and insidious, with symptoms developing gradually.^ Periods of exacerbation and remission are common. Symptoms vary considerably from one patient to another, however, and it's difficult to identify a sj3ecific set of symptoms common to all patients vrith RA. Moming stiffness in the joints that lasts for at least one hour", pain, joint tendemess, and fatigue are frequent complaints. Most patients typically present with an initial complaint of stiffiiess and joint tendemess that increases in frequency and intensity over weeks to months. The stiffness and tendemess typically affect distal phalangeal joints. Although any joint can be affected by RA, the proximal interphalangeal (PIP), metacarpophalangeal (MCP), and metatarsophalangeal joints, as well as those of the vmsts, shoulders, elbows, knees, and ankles, are commonly affected."* Unlike osteoarthritis, RA usually affects joints bHaterally. The number of affected joints will vary, but RA almost always involves thi'ee or more."* Patients vrith RA typically can move theii" inflamed joints, but experience deep discomfort."* Not all symptoms are articular (joint-related). RA patients may also experience fatigue, malaise, anorexia, weight loss, and occasional fever.^ These symptoms can precede joint-related symptoms by weeks or months.'' Less common effects are anemia, neck pain, and diy eyes and mouth (sicea complex).'' About 25% of patients develop rheumatoid nodules, bumps under the skin that tend to foi-m in areas of pressure such as the elbow but can be found anywhere, including the heart and lungs."* Rare but more serious complications of RA include non-Hodgkin's lymphoma, pericardial or pleural effusions, pericarditis, coronary arteritis, pulmonary fibrosis, and nodular lung disease.^ Patients may experience mild peripheral neuropathy, Felt/s syndrome (enlargement of the spleen), rheumatoid vascuütLs, and Sjogren's syndi-ome.'' Diagnosis is based primarily on symptoms There's no single test or combination of tests that's definitive for diagnosing RA. Diagnosis is based primarily on physical examination and the patient's description of symptoms. Because RA can be difficult to differentiate from other rheumatic diseases, the American College of Rheumatology created diagnostic criteria based on an analysis of RA patients and control subjects with other rheumatic diseases. (See the box on page 49.) Four of the seven criteria must be present for a diagnosis of RA. While they're not conclusive, laboratory studies can still be useful in recognizing RA. Patients are frequently tested for complete blood count (CBC), rheumatoid factor, erythrocyte sedimentation rate (ESR), antinuclear antibody (ANA), and C-ï'eactive protein.^ The white blood cell count (WBC) is typically normal, but may be slightly elevated. The platelet count is frequently elevated. Typically, a highei" platelet count indicates more severe disease. Rheumatoid factor is present in 70% - 90% of patients with RA, but is also found in patients with other diseases.'' The ESR is typically elevated. ANA is positive in 20% - 30%> of RA patients, and is more common among patients viith nonarticular symptoms.'' Creactive protein is a marker of systemic inflammation that's used to monitor the course of RA and responsiveness to therapy .•* Laboratory analysis of the synovial fluid is invaluable in determining the extent of disease. As RA pi'ogi'esses, the synovial fiuid in affected joints becomes less clear, and the WBC becomes mm-kedly elevated (>50,000).' Systemic WBC can be elevated, but is usually only mñdly so. X-rays taken during the first six months of disease typically show only soft-tissue swelling and periarticular osteoporosis."* As the disease gets worse, i-adiographic findings may include narrowing of the joint space and erosion of the joint margin.'* In advanced disease, fusion of bones in the wiist may be observed.*" Early and aggressive treatment is essential RA was once viewed as a relatively haiTnless disorder that did not require aggressive treatment; AUGUST 2003 Vol.66, No. 8 www.rnweb.com RN today, RA is I'ecognized as a condition that can produce profound debilitation. As a result, early and aggressive intervention to arrest the progression of the disease and prevent irreversible joint damage is now the prefeiTed method of treatment.''' Ti'eatment typically involves a combination of phai'- macologic and nonpharmacologic methods. Nonpharmacologic treatments for RA include rest, exei'cise, therapeutic heating and cooling, physical and occupational therapy, and the use of assistive devices. The primary role of physical and occupational therapy is to evaluate patients and develop an appropriate exercise program that they can follow on theh" OWTI. Because fatigue is a symptom of RA, any program should pi-ovide for a balance of rest (for the joints and the body as a whole) and exercise. Resting the affected joints allows inflammation to decrease. Because of the risk of joint contractures over time, relaxing by lying supine is preferred to pi-olonged sitting. General rest becomes critical as the tUsease progresses to an advanced stage. Patients should rest as needed, but with the goal of developing an increased tolerance for activity. Patients may find it helpful to take frequent short breaks throughout the day to mitigate the effects of fatigue. Part of the patient's exercise progi-am should include passive range-of-motion and isometric exercises, which help to preser\'e joint motion, muscular strength, and endurance. Hydrotherapy is an effective isometric exercise. Because ofthe buoyancy of water, hydrothei-apy enables a patient to do isometric exercises with no more stress on the joint than that of active range-of-motion exercises.'^ Patients should monitor Is it rheumatoid arthritis? Because rheumatoid arthritis (RA) can be difBcult to differentiate from other rheumatic diseases, the American College of Rheumatology developed the following guidelines for standardizing the diagnosis of RA. These criteria are based on an analysis of more than 5(X) patients—half with R A, half with other rheumatic diseases. For a diagnosis of RA, a patient's signs and symptoms must satisfy at least foiu' of the seven criteria, and patients with criteria 1- 4 must have had these symptoms for at least six weeks. Criteria 1. Morning stiffness 2. Arthritis of three or more joint areas 3. Arthritis of hand joints 4. Symmetric arthritis 5. Rheumatoid nodules 6. Serum rfieumatoid factor 7. Radiographie changes Expianation Morning stiffness in and around the joints, lasting at least one hour before maximum improvement At least three joint areas simultaneously have had soft tissue swelling or fluid (not bony overgrowth alone] observed by a physician. The possible areas are the right or left proximal interphalangeal [PIP], metacarpophalangeal (MCP), wrist, elbow, knee, ankle, and metatarsophalangeai (MTP) joints. At least one area swollen (as defined above) in a wrist MCP, or PIP joint Simultaneous involvement ofthe same joint areas (as defined in critehon 2] on both sides ofthe body, (Bilateral involvement of PlPs, MCPs, or MTPs is acceptable without absolute symmetry.] Subcutaneous nodules, over bony prominences or extensor surfaces, or in juxta-articular regions, observed by a physician Abnormal amounts of serum rheumatoid factor Radiographie changes typical cf RA on pcsteraanterior hand and wrist radiographs, which must include erosions or unequivocal bcny decaldficaticn localized in, cr mcst marked adjacent to, the involved joints [Ostecarthritis changes alone do net qualify.) Source: American College of Rheumatology, "1987 oriteria for the classification of acute arthritis of rheumatoid arthritis." 1988. www.rheumatology.org/research/ctassification/ra.html (5 May 2003]. their progress with the prescribed exercise program and should stop doing any exet'cise that produces increased pain one houi' after the exercise has been completed.'^ Heat and cold therapies are used for their muscle-relaxing and analgesic effects; since neither type of therapy affects the progression of RA, the choice of heat or cold is subjective.'' Moist heat is generally preferred over dry heat. and can be applied by sitting in a bathtub of warm water. Patients whose finger joints are affected may find that warmed paraffin dips I'elieve joint stiffness. Many patients find it easier to perfoiTn exei'cises after applying heat to the affected joints. Assistive devices are most beneficial for patients whose symptoms involve the large joints, such as the knee oi' hip. For patients with less severe disease, the use of www.rnweb.com Vol.66, No,8 AUGUST 2003 an elevated toilet seat, safety bars, and lai'ge handles on utensils may reduce the level of discomfort associated with activities of daily living (ADLs). For patients who have difficulty walking, a cane or walker may be beneficial. Splinting is useful to prevent conti'actures but is not effective with all joints. For example, the elbow and shoulder lose motion so rapidly that splinting may not be effective for pi'eserving function. To preserve function, splints should be applied for the shortest I)eriod of time possible and must keep the joint aligned in the most effective position. The longer a patient uses splints, the more dependent the joint becomes on them. Casts should not be used because they could cause permanent joint stiffness.'* To help reduce the pain associated with RA, the physician may suggest the use of a transcutaneous electrical nei"ve stimulation (TENS) unit. When applied to the area of pain, the TENS unit pi-ovides small electrical stimulations to nerve endings beneath the skin in the painful area. These electrical stimulations work by blocking pain messages to the brain.' Various choices for drug therapy There are several classes of drugs used in the treatment of RA, including nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, and disease-modifying antirheumatic drugs (DMARDs).^ Because cartilage damage and bony erosions frecjuently occur within the first two years of RA's onset, rheumatologists now move more aggressively to the use of DMARDs.^ More recently, a category of medications known as biologic response modifiers (BRMs) have been used to help arrest the disease. A chart highlighting all four classes of drugs, how long they take to work, and their side effects appears in the box on page 51. NSAIDs are typically used first-line to treat the pain and infiammation of RA, but they do not alter the progression of the tlisease or prevent joint damage.^ The traditional NSAIDs (aspirin, ibu]Jï'ofen, others) inhibit the cyclooxygenase enzymes COX~1 and COX-2. COX-1 leads to the development of prostaglandins that protect the gastric mucosa and promotes normal clotting, while COX-2 is induced by cytokines and causes an inflammatory response. The newer NSAIDs that selectively block the COX-2 enzyme, such as celecoxib (Celebrex) and rofecoxib (Vioxx), may be preferred over traditional, non-selective NSAIDs because they are less likely to be toxic to the GI tract.'* No one NSAID has been found to be more effective than another for treating RA," so the choice for an individual patient is based on clinician and patient preference.^ A patient who does not respond favorably to a particulai' NSAID within three weeks should receive a trial of an alternate NSAID.'' Corticosteroids work quickly and are well known for their antiinflammatory effect, but they can cause serious side effects, including osteoporosis, muscle weakness, diabetes, hyjiertension, and increased risk of infection, particularly if they are taken in high doses or over a long period. They can be administered orally or injected directly into a joint. When prescribed, they are typically used as adjunctive therapy with other drugs, including DMARDs. This allows the corticosteroid dose to be kept lower than would be required in monotherapy.'" Some rheumatologists recommend starting patients on lowdose corticosteroids (for example, prednisone 5-1 0 mg daily PO) until the slower-acting DMARD begins to work."* Developing a regimen in this manner will minimize the side effects typically seen with higher doses of steroids. In some cases, steroids may be needed only dtiring periods of acute exacerbation of R A. While both NSAIDs and corticosteroids can help alleviate symptoms, only DMARDs can alter the course of KA and reduce the risk of its long-term outcomes.'^ DMARDs work by suppressing lymphocyte destruction of the synovial membrane. However", they are relatively slow-acting, requiring one to six months to achieve maximum effect; therefore, to prevent joint damage, treatment with DMARDs should begin within three months of diagnosis.'* DMARDs that are used for RA include methotrexate (Kheumatrex), hydroxychloroquine (Plaquenñ), sulfasalazine (Aziilfidine), leflunomide (Arava), azathioprine (Imuran), injectable gold salts (Myochrysine, Solganal), and Dpenicillamine (Depen, Cuprimine). DMARDs are potent medications, and each has potentially serious side effects that require close monitoiing.^ BRMs are a relatively new intervention for RA. This class of drug targets specific chemicals involved in the immune response pathway that actually leads to the development of RA. There are two types of BRMs: TNF inhibitors and interleuMn blockers. TNF is a cytokine that plays a major role in the inflammation associated with RA.* TNF inso AUGUST 2003 Vol. 66, No.8 www.rnweb.com Medications used to treat rheumatoid arthritis Drugs Effects Time to maximum effect Side effects Nonsteroidal anti-inflammatory drugs (NSAIDs) Aspinn. ibuprofen (Advil, Moîrin IB, others], COX-2 inhibitore such as celecoxib (Celebrex) and rofecoxib (Vioxx), others Reduces inflammation and pain 1 - 2 weeks Gl symptoms, ulcers, fluid retention, kidney and liver damage (rare) Corticosteroids Prednisone (Deltasone, Orasone), meihylprednJsolone (MedroO, others Reduces inflammaticn, suppresses the immune system Varies, usually rapid Osteoporosis, mood changes, fluid retention, weight gain, hypertension, cataracts, onset or worsening of diabetes, muscle weakness, increased risk of infection Disease-modifying antirtieumatic drugs (DMARDs) Hydroxychloroquine [Plaquenil], sulfasalazine [Azulfidine], methotrexate [Rheumatrex). injectable gold salts [Myochrysine, SolganaO, azathioprine Omuran], D-penicillamine (Depen, Cuprimine], leflunomide (Arava], others Reduces inflammation and pain, suppresses the immune system, prevents joint and cartilage destruction 1 - 6 months Hydroxychloroquine: Rash, diarrhea, retinal toxicity Sulfysalazine: Rash, myelosuppression, Gl symptoms Methotrexate: Gl symptoms, stomatitis, rash, alopecia, myelosuppression, hepatotoxicity, pulmonary toxicity Injectable gold salts: rash, stomatitis, myelosuppression, thrombocytopenia, proteinuria Azathioprine: Myelosuppression, hepatotoxicity, flulike illness, Gl symptoms, nausea, elevated liver function tests D-penicillamine: Rash, stomatitis, dysgeusia (distorted sense of taste), myelosuppression Lefíunomide: Hash, alopecia, Gl symptcms, hepatotoxicity; risk of birth defects/ fetal death Biologic response modifiers (BRMs) Etanercept [Enbrel), infliximab (Remicade), anakinra (Kineret) Reduces inflammation by blocking the action of proteins that trigger inflammation 1 - 2 weeks Injection site reactions, headache, increased risk of infection [including sepsis or tuberculosis) I'i? Sources: 1. American College of Rheumatology Ad Hoc Comrnittee on Clinical Guidelines. "Guidetines for the management of rheumatoid arthritis." 1996. wvw.rheumatology.org/research/guidelines/ra-mgmt/ra-mgmthtml (9 May 2003). 2. Matsumoto, A K., & Bathon, J. "Rheumatoid arthritis treatments." 2003. www.hopkins-arthritis.org/Fheumatoid/rheum_treat.html (9 May 2003). 3. National Institute of Arthritis and Muscuioskeletal and Skin Diseases. "Medications commonly used to treat rheumatoid arthritis." 1999. www.niams.nih.gov/hi/topics/arthritis/drugs.pdf (9 May 2003). 4. National Institute of Arthritis and Muscuioskeletal and Skin Diseases. "New arthritis drugs for rheumatoid arthritis and osteoarthritis." 2002. www.niams.nih.gov/hi/topios/arthritis /arthrdrugs.htm (9 May 2003]. hibitors work by blocking the action of TNF, deactivating it before it causes inflammation." Two drugs in this class are etanercept (Enbrel) and infliximab (Remieade). A newer type of BRM speciflcally targets intei'leiikin-1. Anakinra (Kineret) was the first drug of this type approved for treating RA.'^ Interletikin-1 is a protein found in excess in the joint space of patients with RA, and it stimulates the production of additional haiTTiful cytokines. By targeting interleukin-1, anakinra prevents the release of these additional chemicals responsible for inflammation. Injection site reactions are the most common side effect from BRMs, but serious and sometimes fatal infections, including sepsis and tuberculosis, have been rewww.rnweb.com Vol.66, No.8 AUGUST 2003 RN ported among patients receiving TNF inhibitors.^ For patients with significant joint destruction who don't beneflt from other therapies, sui'geiy may be necessaiy. This may consist of synovectomy, arthrodesis {joint ñision), or total joint replacement.*^ Joint replacement may offer the patient the best option, paiticutarly when there is a loss of function and intractable pain. Helping patients cope with pain, limitations Nursing cai'e focuses on helping patients manage the chronic pain, impaired mobility, and psychological effects that are associated with RA. Not smprisingly, daily joint pain and loss of function can affect patients' ability to perform ADLs and care for themselves, limit their opportunities for work and recreation, and lead to depression.'' Ade(ïuate pain management is crucial. If pain isn't adequately controlled, patients are likely to refrain from exercise and other activities, thus increasing their risk of developing joint contractures and further loss of function. To help patients control theii" pain, educate them about their medications—explain why each medication has been pi-escribed, how to take it properly, and what side effects to expect. If their physician recommends use of a TENS unit, patients will need to be taught how to use it properly. Also, teach patients how to apply heat and cold safely and effectively. For example, they should place a banier between ice and sMn to avoid tissue damage. You can educate patients about other methods of pain management, including biofeedback and relaxation techniques such as deep breathing and meditation.' Maintaining mobility is a very important ti'eatment goal. Teach patients that they can reduce the early morning stiffness associated with RA by taking a warm bath or shower after lising. Assess and reinforce patients' knowledge of the therapy and exercise regimens prescribed by their physical and occupational therapists. If patients' pain and stiffness interferes with their self-care and ADLs, look for ways to address those symptoms. For example, tell patients to use both pharmacological and non-phaiTnacological pain relievers befoi'e beginning selfcare and to proceed at a pace that's comfoitable foi' them and doesn't induce further pain. Teach patients to take frequent rest periods during acute exacerbations of disease to minimize fatigue.''^ Along with physical and occupational therapists, you play an important role in evaluating a patient's need for assistive devices. If your patient cannot afford devices that can gi-eatly aid in her care and activity, refer her to the social services professionals who can help her obtain such devices. Most patients with RA experience some degree of depression, anxiety, and feelings of helplessness.'* When combined with pain and physical discomfort, patients' feelings of fear, anger, and fi-ustration can increase their stress overall' Refer your patients to support groups, such as those sponsored by the Aithiitis Foundation (800-283-7800), or to counseling to address these issues.* Patients with depression may beneflt from drug therapy.^ RA is a serious condition that must be treated aggressively to maintain patients' functional status and minimize pain. With advances in drug therapies and other treatments comes a new hope that the effects of this debilitating condition can be slowed oi' even prevented. As that search continues, nurses play an essential role in administei*ing interventions and seeking ways to improve the quahty of these patients' lives. D REFERENCES 1, National Institute of Arthritis and Musculoskeletal and Skin Diseases, "Questions and answers about arthritis pain." 2001. www.niams .nih.gov/hi/topics/arthritis/arthpain.intm [ U May 2003]. 2, Batiion, J. "Rheumatoid arthritis: Patiiophysiology." 2003, www.hopkins-artiiritis.org/rheum atoicl/rheum_ciin_path.htmi [14 May 2003], 3, Tierney. L M,, McPhee, S, J., & Papadakis, M. A. [Eds.]. (2003], Current medical diagnosis and treatment 2003 [42nd ed.], Stamford, CT: Lange Medical Books/McGraw-iHill, 4, Browning, M A, (2001]. Rheumatoid artiiritis: A primary care approach, J Am Acad Nurse Pract 13&1 399. 5, National institute of Arthritis and Muscuioskeletal and Skin Diseases. "Handout on iiealth: Rheumatoid arthritis," 1999, www.niams nih.gov/iii/topics/arthritis/raiiandout,iitm (14 May 2003]. 6, Matsumoto, A, "Rheumatoid arthritis: Clinical presentation," 2003, www.iiopkins-arthritis.org /rheumatoid/rheum_ciin_pres,iitml [14 May 2003], 7, American College of Rheumatology, "Guideiines for the management of rheumatoid arthritis," 1996, www.rheumatoiogy.org/research /guidelines/ra-mgmt/ra-mgmlhtml (14 May 2003]. 8, Matsumoto, A, K,, & Bathon, J. "Rheumatoid arthritis: Treatments," 2003, www.iiopkinsarthritis,org/rheumatoid/rheum_treat,html [14 May 2003], 9, Johns Hopkins University, Division of Rheumatology. "Osteoarthritis: Treatments," 2003. vvww,hopkins-arthritis,org/osteo/osteo _treaihtml(14May2003], 10, Arthritis Foundation. "Corticosteroids," 2003. www arthritis.org/conditions/DrugGuide /about_corticosteroids,asp (14 May 2003], 11, American Coiiege of Rheumatology, "Preliminary FDA approval of Enbrel (etaneroept]." 1998, vvww,rheumatology,org/research/hotline /etanercepthtmi. (14 iVlay 2003]. 12, National Institute of Arthritis and Musculoskeieta! and Skin Diseases, 'New arthritis drugs for rheumatoid artiiritis and osteoarthntis." 2002, www,niams.nih.gov/hi/topics/arthritis /arthrdrugs.htm [14 May 2003]. 13, Ignatavidus, D. D. (2001]. Rheumatoid arthritis and the older adult. Genatr Nurs. 22QI 139, S2 AUGUST 2003 Vol, 66, No, 8 www,rnweb,com RN/Drexel University Home Study Program Continuing Education Test #694 2C0NTACTH0URS "Defenses gone awry: Rheumatoid arthritis" OBJECTIVES After reading the article you should be able to: 1. Identify signs and symptoms of rheumatoid arthritis (RA). 2. Discuss nursing and medical management of RA. 3. Develop a teaching plan for a patient with RA. Circle the one best answer for each question below. Transfer your answers to the card that follows page 90. Save this sheet to compare your answers with the explanations you'll receive. Or, take the test online at www.rnweb.com. 1. Rheumatoid arthritis (RA) affects approximately how many patients in the United States? a. 1.3 million. b. 1.7 million. c. 2.1 million. d. 2.7 million. 2. RA involves inflammation of the: a Tendons. b. Ligaments. c. Muscles. d. Synovium. 3. Which of the following is a systemic symptom of RA? a. Higfi-grade fever. b. Increased appetite. c. Maiaise. d. Weight gain. it. Which of the following is a characteristic of RA? a. Patients expenence symptoms and are diagnosed between the ages of 40 and 60. b. Men are diagnosed two to three times as often as females. c. The prevalence is higher in Native Americans. d. It is a curabie disease. Which of the following is a characteristic of how RA affects joints? a. Joints are almost always affected uniiateraliy. b. Patients are unable to move their inflamed joints. c. Usuaily one to two joints are affected. d. Stiffness and tenderness typically affeot the distal phalangeal joints. 6. Which of the following is a rare but more serious complication ofRA? a. Diabetes insipidus. b. Acute renal faiiure. c. Non-Hodgkin's lymphoma. d. Thyroid storm. 7. Approximately what percentage of patients with RA have a slow and insidious onset of disease, with gradual symptom development? a. 20%. b. 40%. C. 60%. d. 80%. 8. About what percentage of patients develop rheumatoid nodules? a. 25%. b. 35%. C. 45%. d. 55%. 9. All of the following laboratory tests are useful in recognizing RA EXCEPT: a. Antinuclear antibody. b. C-reactive protein. c. Erythrocyte sedimentation rate. d. Alkaline phosphatase. 10. All of the following are nonpharmacologic treatments for RA EXCEPT: a. Exercise b. Use of heat or cold therapies. C- Resting the affected joints. d. Prolonged sitting. 11. When should a patient with RA stop exercising? a. If there's increased pain one hour after exercising. b. If no pain occurs after exercise. c. If the pain decreases after exercise. d. If the pain remains the same after exercise. 12. Which of the following is correct conceming the use of splinting? a. Casts are more effective than splints b. Splints should be used for an extended period of time, c. Splints are effective in preserving elbow and shouider function. d. Splinting is not effective in preventing contractures with all joints. 13. Which of the following is a criterion for diagnosing RA? a. Evening stiffness. b. Asymmetric arthrilis. c. Arthritis of foot joints. d. Presenoe of rheumatoid nodules. 14. Which class of drugs is typically used first-line to treat pain and inflammation? a. Biologic response modifiers [BRMs]. b. Corticosteroids. c. Immunosuppressants. d. Nonsteroidal anti-infiammatory drugs CNSAIDs). 15. Which cla5s of drugs can alter the course of RA and reduce the risk of its long-term outcomes? a. BRMs. b. Corticosteroids. c. Disease-modifying antirheumatic drugs [DMARDs), d. NSAIDs, 16. Which class of drugs targets specific chemicals involved in the immune response pathway that leads to the development of RA? a. BRMs. b. Corticosteroids, c. DMARDs. d. immunosuppressants. 17. What is the time to maximum effect for DMARDs? a. Five to seven days. b. One to two weeks. c. Three weeks. d. One to six months. 18. Wbich of tbe following is an adverse effect of BRMs? a. Cataracts. b. Injection site reactions. c. Mood changes. d. Osteoporosis. Credit will be granted for this unit through August 2005 It was prepared by Marilyn Herbert-Ashton, RN. BC. MS. Approved for Texas type 1