Pathogenesis of Rheumatoid Arthritis

EDWARP D. HARRIS, Jr., M.D. New Brunswick, New Jersey

Many tvpes of cells are activ?ted and transformed i,n rheumatoid synovium, thereby coritributing to amplification of the dlseati pro- cess. The immune response in rheumafoid arthritis is probably Initi- ated by arl aritigen, although there is some evidence that anticoi- lagen antibodies develop in response to tissue destruction, after rheumatoid arthritis has evolved clinically. Early inflammation in the syndvium is characterized by a striking vascular proliferation, oc- currihg in req~~Ise to angiogefiesis kctors released by activated macrophages. Generalized activation of macrophages and lympho- cytes typical of the immune reaction in the synovium generates an- tibody production, including production of rheumatoid factor. Data suggest tha’t immune complexes de#qsited within cqtilage attract pplym&phonuclear leukocytes, which then release enzymes onto t!e cariilage surface. Many produ+ of inflamnjat/on act as media- tors, driving proliferation of tiynoyial cells. Stellate cells, macro- phages, and fibroblasts have t+n f@und along !he pannus/cartilage junction; by various interactions, these cpntribute to destruction of carti!age and bone.

Studies of the pathogenesis of rheumatoid arthritis continue to focus on one recurring fact: there are an enormous number of different types of cells.and pathways of communication among cells that aie activated in this disease. Despite this confluence of stimuli, rheumatoid arthritis occa- sionally goes’ into remission spontaneously or in response to treatment. The inference from this is an optimistic one: that apparently minor inter- ventions affecting a few crucial mediators of inflammation or restoring a few inhibitory pathways in and around the joints may be suffidient to re- store a balance leading to remission.

In this review, I shall direct special attention to the various steps of amplification of the rheumatoid process, and to the many ways that one inflammatory or proliferative process affects others. I shall consider the following components of rheumatoid arthritis: (1) etiology and genetic predisposition; (2) early inflammatidn in synovium; (3) immune response in synovium; (4) polymorphonuclear leukocyte activaiion; and (5) synovial proliferation. More detailed discussions of the pathogenesis of this condi- tion can’be found in other sources [1,2].

From the University of Medicine and Dentistry of New Jersey-Rutgers Medical tid’tool, New Brunswick, New Jersey. Requests for reprints should be addressed to Dr. Edward D. Harris, Jr., UMDNJ-Rutgers Medical School, Academic Health Science Center, CN 19, New Brunswick, New Jersev OSSO3.

ETIQLQGY AND GENETIC PREDISPOSITION

The hope of finding a single infectious agent responsible for the cause of rheumatoid arthritis, similar to the discovery of streptococci as the cause of rheumatic fever, has become increasingly slim. In fact, it seems more likely that many different stimuli are responsible for triggering the condi-

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tion in individuals with specific immunogenetic suscepti- bility.

Stastny [3] first noted the association between rheuma- toid arthritis and products of the human immune response gene, HLA-DRA. There is a fourfold to sixfold increased risk of rheumatoid arthritis developing if DR4 is present. This is a relatively weak association compared with the very strong risk (approximately 140) associated with HLA- 827 and ankylosing spondylitis. Moreover, HLA-DR2 has a reduced prevalence in patients with rheumatoid arthritis; if present, it may be associated with less severe disease as well as with a more favorable response to treatment with gold salts or d-penicillamine [4].

All observations point to the likelihood that the immune response in rheumatoid arthritis is initiated by an antigen. What is its source? The possible role of viruses has re- ceived much attention, particularly in light of a greater appreciation of the chronicity of viral infections and the ability of many viruses to persist in human cells for years.

Epstein-Barr virus has been postulated as a causative agent. Patients with rheumatoid arthritis have a higher titer of antibody against Epstein-Barr virus nuclear anti- gens than do patients without the disorder (51. Lympho- cytes from rheumatoid patients lack T-suppressor lym- phocyte activity directed against the polyclonal activation of B lymphocytes that follows infection in vitro of these cells by Epstein-Barr virus (6,7]. In contrast to this sup- porting data, there is no evidence from comparisons of patients with rheumatoid arthritis and control subjects that infection with Epstein-Barr virus occurs before the onset of the disease.

Parvovirus infection as the initial cause of rheumatoid arthritis has received recent support. Simpson et al [6] derived a transmissible agent from rheumatoid synovial tissue that resulted in severe multisystem disease or death when injected into neonatal mice. The infective agent was tentatively identified as a parvovirus. Antisera developed against the virus (named RA-1) were reactive in enzyme-linked immunosorbent assay tests with syno- vial extracts from 13 of 14 patients with rheumatoid arthri- tis but not with extracts from eight patients with osteo- arthritis.

The difficulty in assigning a causative role to a certain virus is the possibility that the virus is a mere “passenger,” finding better growth conditions in the highly vascular rheumatoid synovium. More specialized research, includ- ing examinations of many tissues using sensitive probes for specific viral DNA or RNA, will be essential in deter- mining whether a particular agent is the cause of, or merely a secondary accompaniment to, the rheumatoid synovitis.

Is it possible that endogenous components of the human body can become antigens and serve as a chronic stimulus to the immune response? There are ample data in rats and mice that an immune response to collagen is

genetically determined. Models of collagen-induced ar- thritis exist in the rat, mouse, and primate. Antibodies to the five major genetic types of collagen have been dem- onstrated in the serum and synovial fluid of patients with rheumatoid arthritis. However, there was nothing specific about the collagen types to which antibodies had devel- oped nor about the type of arthritis that developed [9]. Most of the reactivity could be accounted for by antibody cross-reacting with epitopes present on all five collagen types. Although anticollagen antibody titers were gener- ally lower in patients without rheumatoid arthritis, they were significant.

At present, it is most consistent with current data to con- clude that anticollagen antibodies develop in response to destruction of connective tissue after rheumatoid arthritis has evolved. Once formed, these antibodies may partici- pate in forming immune complexes within the joint, lead- ing to an accentuation of the inflammatory response. Sup- porting this concept is the finding that antibody titers are invariably higher against the denatured rather than the native collagens [9,10], suggesting that the immune sys- tem has reacted to breakdown products of collagen that are denatured after degradative proteinase attack on the native substrate. Although patients with rheumatoid arthri- tis and the HLA-DR3 type may be more likely to have anti- gen antibodies at higher titers than similar patients with other DR types, current data obtained from sensitive en- zyme-linked immunosorbent assays do not confirm any significant association between the presence of anticol- lagen antibodies and any DR- or DQ-HLA type [lo].

EARLY SYNOVIAL INFLAMMATION

Biopsies of synovium in patients who have early synovitis and are proven later to have rheumatoid arthritis show edema, perivascular infiltration with mononuclear cells, and a striking accumulation of new blood vessels. It is this vascular proliferation that must precede cellular prolifera- tion. Without angiogenesis, a proliferative synovitis cannot develop. Angiogenesis factors released by activated mac- rophages have been demonstrated [ll], and probably play a crucial role in generating the synovial inflammation. Especially in areas associated with aggregates of lympho- cytes, there are small blood vessels in rheumatoid syno- vium identical to the high endothelial venules of lymph node paracortex [12]. These venules are known to be the site of lymphocyte diapedesis from blood to tissues, and have endothelial cells ranging from 12 to 15 microns in diameter. The cells are plump, have a thick perivascular sheath, stain positively for nonspecific esterase activity, and have ribonuclease-labile metachromasia [12].

These types of vessels and endothelial cells are found in nonrheumatoid synovitis as well as in rheumatoid arthri- tis and may represent endothelial cells that are respond- ing to substances released by lymphocytes or macro- phages. The response may permit accelerated adhesion

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of lymphocytes to the endothelium with subsequent mi- gration to perivenule sites where, clustered among acces- sory cells, the lymphocytes become activated and the synovium becomes a lymphoid organ. Such modified ven- ules may permit the exit of lymphocytes back into the vas- culature. Moreover, it can be speculated that this recircu- lation could facilitate “spread” of the rheumatoid process to extra-articular sites.

Studies with fluorescent antibodies to laminin (a glyco- protein component of vascular basement membranes) have shown that new vessel formation (angiogenesis) is most prominent in the subintimal tissue, where it must support the synovial cell proliferation in this area [13].

THE SYNOVIAL IMMUNE RESPONSE

stimulation with soluble recall antigens [21]. Anergic pa- tients had an increased number of T8+ and DR+ cells in peripheral blood, increased numbers of T4+ cells and DR+ cells in synovium, and less reactive skin tests against antigens such as purified protein derivative. Non- anergic patients had a normal ratio of T8-t to T4+ lym- phocytes in peripheral blood, relatively acellular synovium with few T lymphocytes, and normal dermal responses to antigens. It is interesting that cellular and dermal anergy was reversed toward normal after leukapheresis [22], par- alleling a short-lived beneficial clinical response. The ex- planation of this is not clear but it may be related to depletion of “committed” lymphocytes from tissues by leukapheresis and replacement subsequently by naive cells capable, for a time, of response to recall antigens.

It is now generally agreed that the synovial immune re- sponse is incompletely mirrored by lymphocytes in the peripheral circulation. The most striking change in mono- nuclear cell surface antigens in peripheral blood of pa- tients with rheumatoid arthritis is not a consistent altera- tion in the ratio of T8+ to T4+ cells but an increase in la+ antigens on lymphocytes, an index of their activated state [14,15]. Activated 6 lymphocytes (B blasts) in peripheral blood correlate with disease activity in rheumatoid arthri- tis. Similarly, an increased expression of Fc receptors on peripheral blood monocytes in rheumatoid arthritis has been measured [16] and is an index of their activated state.

In rheumatoid synovium, there is a state of generalized activation of both monocyte/macrophages and lympho- cytes that accumulate there. In “transitional” areas, there is a mixture of strongly DR+ macrophage-like cells [17,18] and lymphocytes. Many of the DR+ cells are “in- terdigitating” or “stellate” cells with long cell processes extending to contact lymphocytes. It is very possible that the presumed antigen in rheumatoid arthritis is processed by these activated accessory cells and presented along with class II mixed histocompatibility antigens to T4+ cells that undergo clonal proliferation and a primary amplifica- tion of the immune response. “Lymphocyte-rich” foci in synovium have high concentrations of T4+ cells and may have functional characteristics similar to germinal centers in lymph nodes [19]. B lymphocytes are relatively sparse in cell populations eluted from rheumatoid synovial mem- branes [18]. This finding may be related in part to the fact that B lymphocytes are induced to undergo rapid differen- tiation to plasma cells. A consistent increase in the ratio of T8+ to T4+ lymphocytes is found in rheumatoid synovial fluid when compared with rheumatoid synovial tissue [20]; the functional significance of this, if any, is unknown but may be related to selective retention of T4+ cells in the synovium at sites of intense immunologic activity.

This activated immune response generates antibody production. One subset of antibodies is rheumatoid factor. The role of rheumatoid factor in the pathogenesis of rheu- matoid arthritis and the relationship of rheumatoid factor to disease manifestations are reviewed elsewhere [23,24]. Debate still continues as to whether (1) rheuma- toid factor induces active disease by its presence in blood and tissues; or (2) titers of rheumatoid factor mirror dis- ease activity; or (3) perhaps by accelerating clearance of immune complexes, rheumatoid factors are pratective. There seems to be little doubt, however, that immune complexes, many of which contain rheumatoid factors, play major roles in amplification of the immune response and its translation into inflammation.

Most provocative of recent data are those suggesting that the deposition of immune complexes within superfi- cial layers of avascular hyaline cartilage and menisci serves as a chemotactic force drawing in the proliferative synovitis that destroys cartilage by progressive invasion. Following the identification of immunoglobulin and com- plement (and thus by inference, immune complexes) [25], convincing data have been presented to indicate that immune complexes trapped within collagenous tissues are able to activate complement [26]. In addition to serv- ing as a chemoattractant for the synovial cells, the im- mune complexes in cartilage may attract polymorphonu- clear leukocytes to the cartilage surface in rheumatoid patients. A selective adherence of polymorphonuclear leukocytes to rheumatoid cartilage compared with control cartilage has been demonstrated in vitro [27]; the carti- lage-bound immune complexes could serve as a surface for the polymorphonuclear leukocytes to bind to in the act of reverse endocytosis and release of their granules con- taining hydrolytic enzymes onto the cartilage surface.

POLYMORPHONUCLEAR LEUKOCYTES-AMPLIFIERS OF INFLAMMATION

There is growing evidence suggesting that several sub- groups of rheumatoid patients can be identified by the state of responsiveness of their lymphocytes in vitro after

More than one billion polymorphonuclear leukocytes may be drawn into the joint cavity of the knee in a rheumatoid patient with moderately active disease [28]. Without

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means for egress from the inflammatory sites, these cells eventually die and are lysed within this synovial “sink.”

Polymorphonuclear leukocytes are a major source of amplification of the inflammatory condition within the joint. Many chemotactic stimuli for these cells have been identi- fied; two of the most potent are the C5a fragment of com- plement and leukotriene B+ Once they are in the joint space, neutrophils are activated by phagocytosis (or frus- trated phagocytosis against surfaces) and other stimuli. An increment in cytosolic free calcium initiates activation, leading to active phosphorylation of cellular proteins and eventual translation of these events into the inflammatory functions of the cell: aggregation, degranulation, and su- peroxide anion generation [29].

Leukotriene B4 can be considered a prototype of the inflammatory amplifiers found in synovial fluid and gener- ated by neutrophils. Activation signals release arachidonic acid from phospholipids in the cell membranes. Further oxidation and other enzymatic actions yield prosta- glandins, thromboxanes, and leukotrienes [30]. These agents act as autacoids, i.e., mediators produced locally by resident and newly arriving cells in the joint fluid. Leu- kotriene B4 has been demonstrated in the synovial fluid of rheumatoid patients [31]. Once produced and released by neutrophils, leukotriene B4 is rapidly deactivated (half-life equal to 3 to 4 minutes) [32]. Its effects are to enhance vascular permeability for polymorphonuclear leukocytes, attract them into the inflammatory sites, and augment degranulation. The leukotrienes act additively, if not syn- ergistically, with prostaglandins and products of comple- ment activation to amplify this inflammation.

An interesting recent observation suggests that the immunochemical composition of immune complexes, as well as their size, is of importance in determining their capability to directly activate neutrophils [33]. Certain rheumatoid factors may modulate activation responses by neutrophils to immune complexes. Another regulating ef- fect on neutrophils that may occur after phagocytosing by rheumatoid factor and immune complexes may be a sup- pressive one upon neutrophil chemotaxis [34] and motility [351.

Although it is not known what initiates the process, it is known that multiple inflammatory pathways are activated within synovial fluid in addition to activation of neutrophils (see [2] and [23] for review). Some examples follow:

1. The clotting system is activated through Hageman factor. Fibrin deposition on the surface of synovium is prominent in many cases of rheumatoid arthritis. lntrasynovial hemorrhage, clot, and necrosis may be the genesis of rice bodies in rheumatoid arthritis.

2. In the presence of high-molecular-weight kinino- gen, prekallikrein is processed by Hagemen factor frag- ment to kallikrein, which, in turn, transforms kininogen to bradykinin.

3. Kallikrein can activate plasminogen to plasmin. In

addition to its fibrinolytic capabilities, plasmin can activate various steps in the classical complement system, can activate Hageman factor, and can activate neutral metal- loproteinases.

All of these pathways interact at many points. Indeed, it is surprising that, once triggered, the inflammatory path- ways do not continue uncontrolled and unabated. Too little is known about the normal factors responsible for turning off these various pathways of inflammation.

It is often said that nonsteroidal anti-inflammatory drugs do not affect the progression of underlying disease in rheumatoid arthritis. This is probably not true, but it cannot be disproven because it would be unethical to withhold nonsteroidal anti-inflammatory drugs from these patients. However, the probabilities are high that since the prolifer- ative lesion in rheumatoid arthritis is driven by inflamma- tory mediators generated within synovial fluid, suppres- sion of synovial inflammation is also likely to retard the development of proliferative synovitis.

SYNOVIAL PROLIFERATION

In no other kind of inflammation is there such heterogene- ity as in rheumatoid synovitis. As mentioned earlier, prod- ucts of inflammation drive synovial proliferation. Interleu- kin 1, its close biologic cousins, and platelet-derived growth factors (which have analogues expressed as gene products of many cells, including malignant ones) are probably of great importance as mediators of synovial proliferation. A molecule similar to interleukin 1 has been identified in synovial fluid from inflammatory synovitis by use of affinity chromatography and an assay for the ability to stimulate proliferation of murine lymphocytes in re- sponse to phytohemagglutinin [36].

lnterleukin 1 induces synovial fibroblasts to produce large amounts of interstitial collagenase and prosta- glandins [37,38]. In addition, it probably induces new col- lagen and proteoglycan biosynthesis by connective tissue cells, has a mitogenic effect upon synovial cells, and has effects on cartilage chondrocytes similar to its impact upon synovial cells.

Platelet-derived growth factor is an equally potent autocoid with varied forms synthesized by many types of cells [39]. Released from microclots formed during angio- genesis in the proliferative lesion, this substance may stimulate the proliferation of adjacent synovial cells. Platelet-derived growth factor has a primary structure homologous to that of products of oncogenes [40], a fact that may help explain the extraordinary proliferation of active rheumatoid synovium at local sites within the joint.

An additional polypeptide, not yet fully characterized, has been found in culture media from stimulated human peripheral blood monocytes [41]. This substance, “syno- vial activator,” appears to be different from interleukin 1 and connective tissue activating peptides, but until struc- tural data have been reported, it cannot be ruled out that

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Figure 1. Scanning electron photomicrograph of cytoplas- mic extensions of a stellate cell from rheumatoid synovium. The cell has been cultured on a substratum of type 1 col- lagen. Thin filaments extend from these extensions to the collagen. It is these extensions that react with specific anti- body to rheumatoid synovial collagenase 1441. (Original magnification x 7,680; bar = 5 fl)

synovial activator is not an aggregate of interleukin 1 di- mers, or factors similar to and of the same genetic lineage as interleukin 1.

When rheumatoid synovial cells are dissociated by pro- teinases, washed, and allowed to adhere to surfaces of culture dishes, many different types of cells are found. Many are macrophage-like, whereas others have pheno- types and surface markers characteristic of fibroblasts. A third variety (found in 10 to 40 percent of adherent cells in culture) are stellate cells with long dendritic extensions of cytoplasm radiating from the main cell body (Figure 1) [42]. These cells do not have Fc receptors nor do they produce lysozyme, so they appear not to be macro- phages.

Substances such as interleukin 1 that induce collagen biosynthesis in synovial cell cultures also lead to a stellate appearance of many cells in culture [43]. Immunolocaliza- tion studies with a monospecific antibody to human rheu- matoid synovial collagenase have shown that these cells contain large amounts of collagenase (compared with other adherent cells) and release enzyme into culture media. If the cells are cultured on a substratum of col- lagen, collagenase protein released by the dendritic ex- tensions of the cells binds to the collagen, leaving an exact “footprint” of the dendritic process if the cell is re- moved from the culture plate [44].

SYMPOSIUM ON DICLOFENAC SODIUM AND INFLAMMATORY DISEASE-HARRIS

As more careful evaluations of the pannus/synovial junction and the surrounding pannus tissue are made, even more heterogeneity of this area is being recognized. For example, mast cells replete with characteristic gran- ules have been observed [45-471. It is interesting to spec- ulate upon functional involvement of these cells at that site. Mast cell heparin can stimulate invasion of capillary endothelial cells in vitro and may therefore have a role in angiogenesis [48]. It is also possible that heparin, through its effect as a potential “second messenger” on synovial and bone cells [49], may amplify the effects of hormones such as parathyroid hormone that regulate connective tis- sue turnover.

Although the striking paucity of neutrophils at the pannus/cartilage border relative to their high concentra- tions in synovial fluid has been observed, recent morpho- logic studies have shown “pockets” of neutrophils at the invasive junction-in particular at shallow, narrow areas of pannus [47,50]-perhaps reflecting early stages of car- tilage destruction. In subchondral areas of erosion by the rheumatoid process, osteoclasts and chondroclasts have been noted [51]. It is likely that these cells are induced to form by lymphokines and monokines generated by the in- flammatory lesion in synovium.

COMMENTS

Many cells are activated and transformed in rheumatoid synovium. Whether in response to immune complexes localized in cartilage or to depletion from cartilage of inhib- itors of angiogenesis or proteinases, the synovium devel- ops a polarized attack on cartilage and bone. Both are destroyed by multiple types of cells. It is the interaction among the cell types that amplifies the response among the many different types of cells. At one moment along any pannus/cartilage junction there may be multiple foci dominated by different cell types: polymorphonuclear leu- kocytes (unusual), stellate cells, macrophages, or fibro- blasts. I agree, too, with Fassbender et al [52] that it is likely that the histomorphology of the same area must vary with time. Pockets of invasive cells are very likely replaced by more vascular granulation tissue; the cycle may be repeated until the cartilage and subchondral bone are destroyed.

In conclusion, this review has focused on the heteroge- neity of the rheumatoid process and the many steps in which amplification occurs. It follows that there are multi- ple possible entry points for specific therapy. Since rheu- matoid arthritis occasionally goes into spontaneous re- mission, perhaps very subtle regulatory enhancement may be sufficient to shut down the entire process. The more we learn about pathophysiology, the more likely it is that effective therapies will be discovered and used in the care of patients with rheumatoid arthritis.

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51. Bromley M, Woolley DE: Chondroclasts and osteoclasts at sub- chondral sites of erosion in the rheumatoid joint. Arthritis Rheum 1984; 27: 968-975.

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i0 April 26, 1666 The Americas Journal of Medicine Volume 86 (suppl 48)

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