D in the study of synovial fluid. One recent development has been the

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1 CURRENT COMMENT A Speculation on the Pathogenesis of Joint Inflammation in Rheumatoid Arthritis By NATHAN J. ZVAIFLER URING THE PAST FEW YEARS there has been a renewal of interest D in the study of synovial fluid. One recent development has been the demonstration of unusual inclusion bodies within the leukocytes present in inflammatory effusions. While not exclusively limited to rheumatoid arthritis, the phenomenon appears to be most frequent and pronounced in this disease. Immunofluorescent technics disclose both 7s and 19s gamma globulin in these inc1usions.l It has been shown that lysis of washed cells containing inclusions releases measurable amounts of rheumatoid factor into the surrounding media. This has led to the suggestion that the inclusions represent particles of aggregated gamma globulin and rheumatoid faotor which have been phagocytized by the leukocytes in the synovial effusion. Earlier in vitro experiments by Schmidt had shown that phagocytosis of preformed complexes of heat aggregated gamma globulin and rheumatoid factor can occur.:! Astorga and Bollet have reproduced inclusion body cells in vitro by incubating normal leukocytes with rheumatoid factor and FII precipitates and have shown that lysosomal enzymes are released from normal leukocytes following phagocytosis3 Electron microscope studies of the inclusions by Zucker-Franklin suggest that the material within the cytoplasm of neutrophiles is surrounded by a unit membrane, and the lysosomes of the cell coalesce with the substance in the kacuole forming lyso-phagos~mes.~ It is tempting to postulate that joint inflammation in rheumatoid arthritis is a consequence of the interaction of an altered gamma globulin molecule with rheumatoid factor in the synovial fluid. The product of this interaction, the inclusion body, is phagocytized by leukocytes with the consequent release of hydrolytic enzymes from the leukocyte lysosomes. These potent enzymes could produce joint tissue injury directly as suggested by Wei~sman,~ or initiate the release of a number of pharmacologically active substances, such as kinim6 What is lacking to complete this story is the identification of the altered gamma globulin, presumably an antibody in combination with its specific antigen, which is unique to rheumatoid arthritis. To date no specific antigen, capable of initiating or perpetuating rheumatoid arthritis has been found. The observations of Malinin and his associates may be pertinent to this point.7 These workers, applying histochemical technics to the study of the inclusion cell, have found that an almost invariable accompaniment of the inclusion body is the presence of small, oval, basophilic, Feulgen-positive particles. These small particles were demonstrated in the cytoplasm of leukocytes and lying free in the synovial fluid. They were not seen in synovial fluids from patients with joint diseases other than rheumatoid arthritis. The l&tochemical characteristics of these particles suggest a DNA-protein com- 289 ARTHRITIS AND RHEUMATISM, VOL. 8, No. 2 (APRIL), 1965

2 290 NATHAN J. ZVAIFLER plex. One possible interpretation of these findings provides an attractive theory for the pathogenesis of the joint inflammation in rheumatoid arthritis. The theory proposed suggests that the joint inflammation in rheumatoid arthritis is not necessarily the result of a specific initiating event, but rather that the rheumatoid patient provides a unique milieu in which any insult capable of producing joint inflammation could set into motion a self perpetuating series of events. This situation might occur if the synovial tissues contained rheumatoid factor and an antibody directed against a constant by-product of inflammation. Does such an antibody exist? It has been shown that the antinuclear antibodies which are present in systemic lupus erythematorus are not unique to this disease. A significant percentage of patients with rheumatoid arthritis have this material present in their serum, although usually in lesser amounts than in SLE.8,g In a recent report antinuclear factors were found to be present in the majority of rheumatoid synovial effusions studiecl.1 Several workers have even suggested that if the test system is made sensitive enough antinuclear antibodies can be demonstrated in the sera of a variable number of normal subjects A natural consequence of inflammation is the disruption, disintegration, and death of leukocytes. In the course of this process considerable degeneration of leukocyte nucleoprotein occurs. This altered nuclear material could represent an antigen which is a constant by-product of inflammation and the function of antinuclear antibody may be to facilitate its disposal. It would be attractive to speculate that this normal response to inflammation is distorted by the presence of rheumatoid factor in the synovial membrane or fluid of the patient. If these conditions exist then one could envision the initiation of a self perpetuating cycle of inflammation, nuclear degeneration, and the interaction of altered nuclear material with antinuclear antibody. This complex in the presence of rheumatoid factor results in the inclusion body. Phagocytosis of the inclusion body would produce disruption of leukocyte lysosomes. One of the many lysosomal enzymes which would be liberated is DNAase which could act upon the nucleus of the engulfing leukocyte, thus supplying a new source of nuclear material to complete the cycle (fig. 1). The phagocytosis of immune complexes requires complement and may account for the observed low values for hemolytic complement in the synovial fluid of patients with rheumatoid arthritis.14 The scheme proposed resembles superficially the chain reaction suggested by Seegmiller, to explain the acute attack of gouty arthriti~. ~ Several mechanisms of action for colchicine have been postulated by assuming that it blocks some point in the cycle. Similarly, many of the agents available for the treatment of rheumatoid arthritis can be regarded as possible impediments in the above outlined sequence of events. To be effective a drug could act to: 1. Decrease vascular permeability or limit leukocyte migration to the site of inflammation. 2. Interfere with the reaction of antinuclear antibody and altered nuclear material.

3 I'ATHOGENESIS OF JOINT INFLAMMATION 291?.) I NFL AM MAT I ON LYSOSOMAL DISRUPT ION PHAGOCY TOSlS NUCLEAR DEG ENE R AT I 0 N ANTIGEN - ANTIBODY +ANTI NUCLEAR ANT I BODY COMPLEX /+ R HF~F:4: I D INCLUSION BODY Fig Interrupt the interaction of the antigen-antibody complex with rheumafoid factor. 4. Impair phagocytosis by polymorphonuclear cells. 5. Protect leukocyte lysosomes against disruption. 6. Prevent the action of DNAase on the leukocyte nucleus. 7. Limit the release of pharmacologically active substances, or neutralize the effects of those which have been liberated. An analysis of some of the known effects of several of the antirheumatic agents show that they could act at several steps in the proposed scheme. The ghcocorticoids are noteworthy in this regard. They have been demonstrated to decrease vascular permeability, impair leukocyte migration, interfere with phagocytosislg and stabilize lysosomal membranes.lt Another agent which has interesting pharmacologic properties is chloroquine. This drug has been shown to selectively bind to deoxyribose nucleic acid and to prevent both its interaction with antinuclear antibody1s and its enzymatic digestion by DNAase.lg Large amounts of the drug are concentrated in white blood cells. The principal intracellular localization of chloroquine is in the nuclear and lysosomal fractions.20 Evidence has been presented to show that chloroquine can stabilize lysosomes against a variety of injuries.17j0 The effects of gold salts are not well understood. Gerber has shown that they block the sulfhydryldisulfide interchange in the gamma globulin molecule.21 This interchange occurs when gamma globulin is denatured and also presumably plays a role in its acquisition of immunologic specificity.22 Stabilization of the sulfhydryldisulfide interchange might thereby impair antigen antibody combination. The lysosomes of macrophages have been shown to be stabilized by the in vitro addition of gold saltsz3 All of the commonly employed antirheumatic agents, gold salts, chloroquine, salicylates, phenylbutazone and cortisol, have been shown to decrease the permeability of rabbit synovial membrane.24 It iy interesting to note that while any of these demonytrated actions of the antirheumatic drugs could be impediments to the proposed self perpetuating

4 292 NATHAN J. ZVAIFLER cycle, none have been shown to effect the cause of the disease. This is in keeping with the clinical observation that joint inflammation may be suppressed by their use, but rheumatoid arthritis is seldom cured by drug therapy. The scheme proposed has several virtues: It is consistent with a large number of recent observations. It assigns to rheumatoid factor an intimate role in the pathogenesis of rheumatoid arthritis, not relegating it to a secondary position as an interesting by-product of the disease. It offers an explanation for the self perpetuating nature of this chronic progressive illness. It provides an alternative to the requirement of a single etiology for rheumatoid arthritis; for a variety of insults could produce the same end result in a proper- Iv prepared individual. It views the drugs presently used to treat rheumatoid arthritis as impediments to a self perpetuating chain of events rather than as specifics directed at the cause, or causes, of the disease. The concept which has been presented is probably over simplified and has many shortcomings, but objections to, or verifications of, the scheme can be tested by appropriate experiments. It is with the hope of provoking interest, study and criticism, that this hypothesis has been advanced. 1. Hollander, J. L., Rawson, A. J., Restifo, R. A,, and Lassier, A. J.: Studies on the pathogenesis of rheumatoid joint inflammation. Arth. & Rheumat. 7: 314, Parker, R. L., and Schmid, F. R.: Phagocytosis of particulate complexes ot gamma globulin and rheumatoid factor. J. Imm. 88:519, Astorga, C., and Bollet, A. J.: Diagnostic specificity and possible pathogenetic significance of inclusion body cells in synovial fluid. Arth. & Rheumat. 7:288, Ziicker-Franklin, D.: Electron microscope study of cytoplasmic inclusions in leukocytes of patients with rheumatoid arthriti5. Arth. & Rheumat. 7: 760, Weissman, G., Barland, P., and Weidermann, G.: Role of lysosomes in streptolysin S induced arthritis. Clin. Res. 12:240, Goldfinger, S., Melmon, K. L., Webster, 51. E., Sjoerdsma, A., and Seegmiller, J. E.: The presence of a kinin-peptide in inflammatory synovial ehsions. Arth. & Rheumat. 7:311, Malinin, T. I., Pekin, T. J., Zvaifler, N. J., and Bauer, H.: Intracytoplasmic and Intracellular Particles in Rheumatoid Synovial Fluids. Arth. & REFERENCES Rheumat. 7:743, Alexander, W. L., Breniner, J. M., Duthie, J. J. R.: Incidence of the antinuclear factor in human sora. Ann. Rheum. Dis. 19:338, Hijmans, W.: Validity of serologic tests. In: The Epidemiology of Chronic Rheumatism. Phila., Pa., F. A. Davis, 1963, p Barnett, E. F., Bienstock, J., and Block, K. J.: Antinuclear factors in synovial fluid: possible participants in the rheumatoid inclusion body. Arth. & Rheumat. 7:726, Cammarata, R. L. F., Rodnan, G. P., Fennell, R. H., Astello, R. J., and Creighton, A. S.: Serologic reactions and serum protein concentration in the aged. Arth. & Rheumat. 7:297, Nienhuis, R. L. F., Mandema, E., and Jans, Z.: Population studies of rheumatic disease on a coastal island, Part 11-antinuclear factors and antithyroid antibodies. Ann. Rheum, Dis. 22:430, Laffin, R. J., Bardawil, W. A., Pachas, W. N., and McCarthy, J. S.: Immunofluorescent studies on the occurrence of antinuclear factor in normal human serum. Am. J. Path, 45: 465, 1964.

5 PATHOGENESIS OF JOINT INFLAMMATION Pekin, T. J., and Zvaifler, N. J.: Hemolytic complement in synovi 11 fluid. J. Clin. Invest. 43:1372, Setginiller, J. E., and Howell, R. R.: Old and new concepts of acute gouty arthritis. Arth. & Rheumat , Favour, C. V.: The cellular response to inflammation and its modification by glucocorticoids. Inflammation and diseases of connective tissue. Phila., Pa., W. R. Saunders, 1961, p Weissman, G.: Labilization and stabilization of lysosomes. Fed. Proc. 23: 1038, Stollar, D., and Levine, L.: Antibodies to denatiired deoxyribose nucleic acid in lupus erythematosus serum V. Mechanism of DNA-antiDNA inhibition by chloroquine. Arch. Biochem. 101:335, Kurnick, N. B., and Radcliffe, I. E.: Reaction between DNA and quinacrine and other antimalarials. J. Lab. Clin. Med. 60:669, Zvaifler, N. J.: The subcellular 1ocaliz:- tion of chloroquine and its effects on lysosonial disruption. Arth. & Rheumat. 7:760, Gcrber, D. A.: Role of the sulfhydryl groups in the denaturation of human gamma globulin. J. Iinin. 92:885, Karush, F.: The role of disulfide bonds in the acquisition of immunologic specificity. J. Pediat. 60:105, Persellin, R. H., Smiley, J. D., Ziff, M.: Mechanism of action of gold salts. Arth. & Rheumat. 6:787, Sharp, G. W. G.: Effect of certain antirheumatic compounds on the permeability of synovial membrane in the rabbit. Ann. Rheum. Dis. 2250, 1963.