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Rheumatology Advance Access originally published online on July 10, 2007
Rheumatology 2007 46(9):1385-1387; doi:10.1093/rheumatology/kem163
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© The Author 2007. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

EDITORIALS

The Rheumatoid nodule: peripheral or central to rheumatoid arthritis?

J. Highton, P. A. Hessian1 and L. Stamp2

Medicine, Medical and Surgical Sciences, University of Otago, Dunedin School of Medicine,1Physiology Department, University of Otago, Otago School of Medical Sciences, PO Box 913, Dunedin and 2Senior Lecturer and Consultant Rheumatologist, University of Otago, Christchurch School of Medicine, Christchurch Hospital, Christchurch, New Zealand

Correspondence to: Prof. John Highton. E-mail: john.highton{at}stonebow.otago.ac.nz

When asked as a medical student how to treat a patient with rheumatoid arthritis (RA) who was not doing well the immediate answer was gold. The question was not hard since a flick through a short textbook prior to the clinic had not indicated many alternatives. How should the modern medical student answer this question? What might be the best of many treatment options for an individual patient? At least in the case of the newer biological agents their use is based on some understanding of the basic processes involved in the pathogenesis of RA. Can we therefore apply this understanding in making a choice of treatment? Unfortunately any current review of the pathogenesis of RA reveals a situation at least as complex as the therapeutic choices. This has lead Cornelia Weyand [1] to suggest that one way forward would be to develop a string theory of autoimmunity. A corollary might be that there is a minimum requirement of a rheumatoid lesion to cause tissue destruction. Identifying this requisite might get us to the core mechanism of rheumatoid pathogenesis with other mechanisms serving as disease modifiers and amplifiers, thereby explaining the heterogeneity of the disease. One rheumatoid lesion that deserves attention for this reason is the nodule as it seems to be ‘more simple’ than the synovial lesion.

An essential feature of the rheumatoid nodule, as with the joint lesion, is tissue destruction. So what cells are in the rheumatoid nodule, and what cellular interactions and cytokines are necessary for extra-articular tissue damage to occur? Arguably even more important to deciphering the minimal lesion of RA is what is absent from the nodule that is present in the inflamed synovial joint lining.

The most prominent cells in the nodule belong to the monocyte/macrophage (Mph) lineage. Mph migrate from the vascular periphery of the nodule towards the central palisade layer [2]. A distinctive feature of Mph entering some nodules is release of the MRP-8/MRP-14 heterodimer, labelling them as newly arrived, activated macrophages [3, 4]. Migrating Mph accumulate in the palisade interspersed with fibroblasts. The result it is not unlike the thickened synovial lining layer with both containing activated Mph and fibroblasts. Both the palisade and the synovial lining vary in thickness probably reflecting the level of Mph recruitment. However, there are also important differences between the nodule and the synovial lesion. In particular, there are critical differences between the dermal fibroblast in the nodule and the specialized fibroblast like synoviocyte (FLS). The latter is adapted to the production of hyaluronan, and also has prominent expression of VCAM-1 and decay accelerating factor [5]. The FLS is known to make a major contribution to pathogenic mechanisms in the joint [6]. For example, it is a source of matrix metalloproteinase (MMP)-1 and MMP-3. In comparison, we know little of the dermal fibroblast in the palisade, whether it interacts with adjacent activated Mph, and if together they are responsible for tissue destructive mechanisms such as production of MMPs as occurs in synovial membrane.

T lymphocytes, like Mph, are present in both the nodule and synovial membrane in similar proportions. Both CD4 and CD8 subtypes are present in the nodule. T lymphocytes tend to accumulate around vessels and in the area immediately outside the palisade. In this same area there are cells with characteristics that suggest they may be dendritic cells [7]. This would place T lymphocytes and dendritic cells together indicating the potential to interact. One way that such interactions are evident in the synovial membrane is the formation of interacting aggregates of cells containing T lymphocytes, B lymphocytes and dendritic cells. Up to 25% of synovial membranes contain such higher order follicle-like structures. These lymphoid aggregates and complex immune structures are not seen in the nodule. In keeping with this, B lymphocytes and follicular dendritic cells are also absent from the rheumatoid nodule.

Does the absence of organized lymphoid structures containing B lymphocytes in the nodule mean that the lesion lacks the cells, cellular interactions, chemokines and cytokines necessary to orchestrate the formation of complex structures such as lymphoid follicles? We have recently shown that two pulmonary rheumatoid nodules had associated lymphoid aggregates containing both B lymphocytes and T lymphocytes. In some cases germinal centres containing follicular dendritic cells were present [8]. This suggests that the nodule is capable of generating the signals necessary to attract B lymphocytes and to orchestrate the formation of more complex immunological structures. In keeping with this, we have preliminary evidence to suggest that nodules produce chemokines, such as CCL21, CXCL12 and CXCL13, capable of attracting B and T lymphocytes. There is also expression of other cytokines relevant to lymphoid follicles, including B-cell-activating factor of the tumour necrosis factor (TNF) family (BAFF/BlysS) and a proliferation-inducing ligand (APRIL), two potent B lymphocyte activating molecules normally expressed by myeloid cells (unpublished observations). These observations suggest that complex lymphoid structures may be absent from the subcutaneous rheumatoid nodule because of the characteristics of the subcutaneous tissue rather than failure of the nodule to produce the necessary cellular interactions, cytokines and chemokines.

A further point of interest concerning the lymphoid structures observed at the periphery of the lung nodules is the recent report that tuberculous granulomas also had peripheral lymphoid follicles [9]. The suggestion was that the main immune reaction between host and Mycobacteria occurs at the periphery of the granuloma rather than centrally, a suggestion that might therefore warrant consideration in the rheumatoid nodule as well, given the similar appearances.

Of course, the absence of B cells does not mean that the nodule is not the product of mechanisms ultimately mediated by antibodies. The most durable view of the pathogenesis of the nodule is that it is a lesion mediated by immune complexes. In his comprehensive review of the rheumatoid nodule in 1990, Ziff concluded that inflammation and destruction in the nodule was mediated by Mph activated by immune complexes [10]. Subsequent evidence has shown that Mph can be activated to produce TNF via interaction with FcRIII [11] and that FcRIII is expressed by Mph within nodules [12]. Another antibody-mediated mechanism that now warrants investigation in the nodule is anti-CCP antibodies. Antibodies to CCP are likely to be a mechanism adding to tissue injury in RA through interaction with citrullinated proteins such as fibrin in the rheumatoid joint [13]. It seems likely that this could also be true of fibrin in the nodule and citrullination of filaggrin within epithelial cells could also be relevant. In these situations, the potential exists for anti-CCP antibodies to contribute to inflammation and damage in the nodule.

Despite a dispersed lymphocyte population without aggregation into more organized structures, we have shown that the nodule has a cytokine profile similar to that in the synovial membrane. This includes the presence of IFN-{gamma} but not IL-2 or IL-4 [14]. Both TNF and IL-1 can be demonstrated to be present and are produced by cultured nodule tissue [15]. This data would suggest that the nodule might be a Th1 lesion with similarities to the synovial membrane. There is also data suggesting that the population of T cells in the nodule may be oligoclonal [16] and that nodule T cells may migrate through synovial inflammatory sites [17].

Animal models have helped define the contribution of T cells to the pathogenesis of arthritis. For the rheumatoid nodule, the SKG mouse model of arthritis is most relevant [18]. In this model, 10–20% of animals develop subcutaneous necrobiotic nodules. The arthritis in this animal model has been shown to be driven by T cells producing IL-17 [19]. T cells producing IL-17 are increasingly implicated in the pathogenesis of several autoimmune diseases including RA. Our own analysis suggests that IL-17 is not produced in the nodule [20]. This identifies what may be a key difference between the nodule and synovial membrane and demonstrates that in at least one lesion of RA that inflammation and tissue destruction may occur without involvement of IL-17.

The fact that TNF is produced in the nodule and that it is an immune-driven necrotizing granuloma raises further questions. Another granuloma relevant to RA and treatment with anti-TNF agents is the TB granuloma that holds latent TB infection in check [21–23]. These granulomas are dynamic structures that rely on persisting effective T-cell immunity and recruitment of Mph to maintain the granuloma. Consequently, reduction of T-cell immunity or interference with other critical factors such as TNF, can result in loss of structure in the ganuloma and re-awakening of infection [24–27]. Since the rheumatoid nodule has a Th1-like cytokine profile including production of IFN-{gamma} and TNF [14, 15], it shares features with the Tb granuloma. Despite this, the Tb granuloma can break down with anti-TNF treatment while the available prospective data suggests that resolution of nodules does not occur [28]. Indeed, there are reports of new subcutaneous and pulmonary nodules developing during anti-TNF therapy [29–31]. Furthermore, anti-TNF therapy does not result in any histological change within subcutaneous rheumatoid nodules [32]. Overall, the data suggests that TNF plays a less fundamental role in sustaining tissue-damaging inflammation in the nodule than in the Tb granuloma or in the rheumatoid synovial lesion. The reason is not clear but data suggesting production of lesser amounts of TNF in the nodule than in the synovial membrane might be in keeping with these clinical and experimental observations [15] although multiple other explanations are possible.

The natural expectation of any highly successful treatment of RA such as anti-TNF therapy is that it would suppress the principal clinical lesions of the disease and ideally lead to resolution of both articular and extra-articular lesions. The disappearance of both together has been documented with D-penicillamine and hydroxychloroquine [33] and sulphasalazine [34]. Nodules will also shrink when injected with steroids [35, 36]. It would be beneficial to know which of the newer biological therapies might sufficiently address the core pathogenic mechanisms of RA to eradicate nodules as well as synovitis. The available data suggest that anti-TNF therapy does not achieve this ideal. Another biological approach to the treatment of RA has been B-cell depletion therapy (BCDT) [37]. The mechanism by which BCDT ameliorates RA remains in contention. However, there is some data to support the simplest interpretation that it works through depletion of auto-antibodies. The improvement in RA is paralleled by a fall in RF and recrudescence occurs when RF levels rise again [38]. Documenting the effect of BCDT on nodules is clearly of relevance to the hypothesis that nodules are driven by mechanisms dependent upon auto-antibodies.

In conclusion, the rheumatoid nodule is a much-ignored lesion in RA. This is despite the fact that it is a lesion that is destructive of tissue, a key feature shared with the joint lesion. Tissue destruction occurs in the typical subcutaneous lesion despite the lack of lymphocyte aggregation and organization into follicles and in the absence of B lymphocytes and probably IL-17. Could this usually peripherally situated lesion be central to understanding which are the core lesions of RA leading to tissue destruction, and which are additional amplification mechanisms? Definition of the seemingly simpler and less diverse inflammatory mechanisms leading to tissue destruction in the rheumatoid nodule might be one way of addressing the increasing complexity of RA pathogenic mechanisms and getting to the centre of the matter.

The authors have declared no conflicts of interest.

References

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Accepted 14 May 2007


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