NIH Conference

Systemic Lupus Erythematosus Contrasts and Comparisons Moderator; JOHN L. DECKER, M.D., F.A.C.P.

Discussants: ALFRED D. STEINBERG, M.D.,

M. ERIC GERSHWIN, M.D., WILLIAM E. SEAMAN, M.D., JOHN H. KLIPPEL, M.D., PAUL H. PLOTZ, M.D., and STEPHEN A. PAGET, M.D., Bethesda, Maryland

Systemic lupus erythematosus, a disease capable of exhibiting virtually any clinical manifestation, is discussed in detail and the findings are compared to those in other, presumably systemic lupus erythematosus-related connective tissue diseases. More emphasis has been placed on the clinical features than on the numerous laboratory manifestations. The conference begins and ends with a brief consideration of current concepts of pathogenesis and suggests some future investigational directions.

D R . JOHN L. DECKER*: Some of the manifestations of sys-

temic lupus erythematosus (SLE) will be described, always with attempts to comprehend the pathogenesis of these features. An effort will be made to contrast or compare the findings to those of the other connective tissue diseases; one cannot help being struck by the multitude of clinical factors that tend to form bridges between them. Reviewing the literature and trying to bring together divergent views on various points, it becomes clear that there has been a great need for classification criteria. Often it is most difficult to say whether or not all the patients so labeled in some studies should be regarded as having lupus erythematosus. The problem is compounded by the lupus erythematosus cell preparation, a finding of very high but not perfect specificity; in some instances lupus erythematosus preparation-positive patients were stuffed into the lupus erythematosus pigeonhole regardless of the other features of their illnesses. In any event, an American Rheumatism Association (ARA) committee has produced and, more importantly, tested a set of classification criteria (1) (Table 1). They have shown that positive findings (without other explanation) on any combination of 4 of * Chief, Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases. • An edited transcription of a Combined Clinical Staff Conference at the Clinical Center, Bethesda, Maryland, 10 January 1974, by the National Institute of Arthritis, Metabolism, and Digestive Diseases, National Institutes of Health, U. S. Department of Health, Education, and Welfare. Annals of Internal Medicine 82:391-404, 1975

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the 14 items on this list had a diagnostic specificity of 99% together with a reasonable sensitivity. The criteria are not perfect and probably never will be. They are never to be substituted for a physician's own diagnostic intuition, but they do provide a good check list to be reviewed when suspicions arise, and they do constitute some assurance of the nature of the disease at hand when used to classify a large number of patients. The work was done in the days when antinuclear fluorescence testing was rare and no data on that test were collected. May it, for example, be substituted for a positive lupus erythematosus preparation? As a guess, I suppose that high-titer antinuclear factor of diffuse or rim type might be so substituted; one group found that such a substitution increased the sensitivity of the criteria from 88% to 92% without decreasing their specificity ( 2 ) . This conference begins with a discussion of some of the experimental studies considered pertinent to the pathogenesis of the disease and turns to a description of the features manifested by patients with it. Why Does Autoimmunity Develop?

Dr. Alfred D. Steinbergf: Fourscore minus seven years ago it was considered doctrine that an organism would not produce antibodies against its own constituents. This horror autotoxicus (3) has been violated by man and other animals in association with autoimmune disease. It is my task to explain how this might come about in general and in lupus erythematosus in particular, and I will attempt to outline plausible possibilities. THEORETICAL CONSIDERATIONS

An examination of the ontogeny of immune capacity and the system of responding to self- and non-self-antigens must underlie any discussion of the pathogenesis of autoimmunity. Recently, Jerne (4) has put forth an updated version of the clonal selection theory in which he postut Senior Investigator, Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases.

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Table 1. ARA Classification Criteria for Systemic Lupus Erythematosus* Facial erythema Discoid lupus Raynaud's phenomenon Alopecia Photosensitivity Oral or nasal ulcers Arthritis without deformity Lupus erythematosus cells Chronic false-positive serologic test for syphilis Profuse proteinuria Cellular casts Pleuritis /pericarditis Psychosis/convulsions Cytopenia * The presence of any four during any estimated specificity of 99%.

period of

ANIMAL MODELS

observation has an

lates that germ line genes code for antibodies that fit to self-histocompatibility antigen. These antibodies would be present on the surface of cells. In the thymus, bone marrow, and other breeder organs such cells are inactivated during embryonic life, perhaps by exhaustive proliferation. A large number of mutations occur leading eventually to cells after two or three mutations that have surface receptors no longer able to recognize self-antigens. These cells would emerge and be available for proliferation upon exposure to foreign antigen. This theory accounts for the close linkage of immune response genes and histocompatibility antigens ( 5 ) . It also explains the particularly aggressive immune responses of animals against histocompatibility antigens present in other animals of the same species (6). It would predict that immune responses would readily be mounted against antigens that differed in only minor ways from self-antigens. This could explain certain autoaggressive behavior which is manifest clinically in autoimmune diseases. Thus the forbidden clone of lymphoid cells, according to Burnet's (7, 8) earlier theory that escaped censorship, would by appropriate interpretation of Jerne's hypothesis be particularly autoaggressive. Self-reactive clones of cells might arise during embryonic development as a result of some error in the process (still unknown) by which such clones are normally eliminated and lead much later in life to autoimmunity (Table 2 ) . Alternatively, self-reactive clones might regularly arise during embryonic life or later and a postnatal mechanism normally regulate the extent of their proliferation. An abnormality of this postnatal immune regulatory mechanism might then be responsible for autoreactive clones of cells. On the other hand, autoimmunity might develop as a result of altered antigenic exposure (Table 2 ) . The clonal selection theories' explanation of avoidance of autoimmunity has run into difficulty. Thyroglobulin, thought by Burnet to be inaccessible to the developing immune system, has been shown in the circulation of newborn humans and normal adults ( 9 ) . Further, peripheral blood lymphocytes from normal humans, and even human thymocytes, have been found which are able to bind labeled human thyroglobulin (10, 11). Additional postnatal control mechanisms must therefore be operative to prevent proliferation of autoreactive cells. 392

Experimental immunological tolerance can exist in either the thymus population, the bone marrow population, or both. Tolerance in either population will confer tolerance; however, tolerance in the thymus is much more long-lived (12). Thus, self-reactive cells could exist without causing diseases provided one cell population, especially the thymic helper cell, remains tolerant. Furthermore, data are accumulating to suggest that the thymus might regulate immune responses to prevent proliferation of autoreactive clones of cells. Supporting evidence for a regulatory role of the thymus comes from experiments in rodents showing autoimmune phenomena following neonatal thymectomy.

Animal models of human disease have helped to shape our thinking. Chronic bacterial and mycoplasmal infections have been found responsible for arthritis in many animals including swine, goats, cattle, poultry, and rodents. Otherwise healthy strains of mice develop immune complex glomerulonephritis when chronically infected with certain viruses. Antibody, complement, and viral antigens are deposited in a lumpy-bumpy or granular pattern in glomeruli, and virus-antibody-complement complexes can be shown in the circulation (13). In mice, immune complex renal disease has been associated with chronic lymphocytic choriomeningitis (LCM), lactic dehydrogenase virus (LDV), Maloney sarcoma, polyoma, and murine leukemia viruses (13). Other animals have also been affected with nephritis during the course of chronic viral illnesses, as in Aleutian disease of mink, equine anemia, and hog cholera. In some viral infections, such as lactic dehydrogenase, complexes containing virus, antibody, and complement may circulate, and a minority may lodge in the kidney without seriously threatening the animal's health. With others, such as lymphocytic choriomeningitis, severe nephritis may occur. However, only some mouse strains Table 2. Some Possible Mechanisms by Which Autoimmunity Might Develop* A. Abnormality of self-tolerance regulatory processes 1. Abnormal development of the immune system—genetic or acquired (e.g., virus infection of thymus) 2. Postnatal abnormality—genetic or acquired (e.g., loss of thymic suppressor cells) B. Altered antigenic exposure 1. Exposuie to cross-reacting antigens, including antigens in food 2. Altered normal body constituents by combination a. Antigen-antibody complexes b. Antigen-antibody-complement complexes 3. Altered body constituents a. Drug bound to erythrocyte, protein, nucleic acid, etc. b. Altered cell surfaces by viruses, mutations, etc. 4. Alteration in the concentration of antigen required to maintain tolerance 5. Exposure to a previously inaccessible antigen such as spermatozoa * This is not meant to be an exhaustive list. Strictly speaking, virusantivirus immune complex diseases might not be classified as autoimmune diseases even though host participation is required for the expressions of disease.

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develop severe nephritis during the course of chronic lymphocytic choriomeningitis disease while other strains have little kidney disease (13). Therefore even with a defined viral infection leading to immune complex disease, genetic factors apparently can determine whether or not clinical disease will ensue. Of particular interest is the observation that large doses of cyclophosphamide given to mice chronically infected with lymphocytic choriomeningitis lead to prevention of renal disease, provided antiviral antibodies are suppressed (14). In these studies there is no change in the high viral levels in the serum. This is convincing evidence that, first, response to an immunosuppressive agent does not mean that a disease is autoimmune or that it is not due to an exogenous infectious agent; and, second, that host-antibody responses against an exogenous agent can lead to disease without any effect upon the underlying infection. Similar results have been reported in Aleutian disease of mink (15). The implications for chronic glomerulonephritis in man, including lupus erythematosus, are obvious. A model related to viral infection is the chronic allogeneic disease that follows the administration of tolerated immunocompetent cells to a host, leading to both autoimmunity and lymphoproliferative malignancy. Immunological consequences include hyperresponsiveness to certain experimental antigens, apparently through enhanced helper effects. Normal regulatory mechanisms seem inadequate or inoperative in the face of the immunological storm created. Ultimately hemolytic anemia (16), arthritis and myocarditis (17), and immune complex glomerulonephritis ensue (18). Since maternal cells have been found to cross the placenta in mammals (19), this model may have implications for naturally occurring autoimmune disease. Further, different strain combinations lead to different disease manifestations, suggesting a genetic component. Finally, the immunologic storm produced leads to excessive viral proliferation which may play an important role in disease production (20). New Zealand mice develop spontaneously autoimmune disease resembling human lupus erythematosus. The NZB mice develop Coombs-positive hemolytic anemia, membranous glomerulonephritis, and lymphoid infiltration of many organs. The cross NZB-by-NZW leads to a first generation hybrid which develops antinuclear antibodies, lupus erythematosus cells, high titers of antibody to DNA, immune complex glomerulonephritis resembling lupus nephritis, and lymphoid infiltration (21). Large numbers of studies have clearly implicated genetic factors in the autoimmune disease of New Zealand mice. A Gross-type murine leukemia virus is involved in the immune complex glomerulonephritis (22). However, only a minority of the antibody eluted from the kidney reacts with these viral antigens; the greatest reactivity is against nuclear antigens (23), as in the case of human lupus erythematosus. Histological abnormalities of the thymus described several years ago have been recently associated with an early loss of thymic hormone (24). Early in life New Zealand mice hyperrespond to heterologous erythrocytes and serum protein antigens and have impaired ability to become tolerant and maintain tolerance to such antigens as well

as to some nucleic acid antigens (21). They have excessive antibody responses to certain viral infections: for example, lymphocytic choriomeningitis. Later in life they have a loss of recirculating T cells and impaired cellular immunity, which is probably related at least in part to an antibody to thymocytes ( 2 5 , 2 6 ) . Thymus regulatory cells appear to be lost prematurely in New Zealand mice (27), as well as in A / J mice which also develop antinuclear antibodies (28). The loss of such suppressive cells could allow excessive proliferation of lymphoid cells in response to selfor foreign antigens (27). For several years a disease resembling human lupus erythematosus has been observed in dogs. A colony of such dogs has been raised and cell-free extracts used to transmit the disease to other animals. Rats were not affected by such extracts; however, abnormalities were observed in recipient dogs and mice. These consisted of antinuclear antibodies, positive lupus erythematosus cell tests, and in the mice, lymphoma associated with murine leukemia viruses suggesting that a viral agent was influencing the recipients (29). PATHOGENESIS OF LUPUS ERYTHEMATOSUS

To what extent are the abnormalities of the animal model present in humans with lupus erythematosus? Evidence for a genetic contribution or predisposition comes from two sources. One is the study of family members of patients with disease. Several groups have reported the occurrence of lupus erythematosus in family members in the same or different generations and in identical twins (30-32). Other autoimmune diseases or only serologic abnormalities have been observed in family members with increased frequency. Autoimmune abnormalities are seen in families of patients with abnormalities of serum immunoglobulins. Females far outnumber males in the development of lupus erythematosus. In one study of the age incidence of this disease by sex there was an impressive increase in the incidence in females as compared with males only in the second to fourth decades; in other words, between the ages of 10 and 40 years (33). This suggests that a sex hormone may be an important secondary factor. Castration and opposite sex hormone treatment of New Zealand mice failed to alter the greater quantity of anti-DNA antibodies in females (21). Mathematical modeling of human data has related lupus erythematosus to the X chromosome (34). In mice an X-linked immune response gene involving the response to synthetic nucleic acids and to other antigens has been described, and in humans there is evidence that the X chromosome can carry determinants of serum immunoglobulin (35) and antibody (36) levels. Studies of HLA antigens in lupus erythematosus have been conflicting and are likely to remain so until subpopulations of patients with lupus erythematosus can be defined. However, the Gm a gene has been associated with lupus erythematosus (37), and further genetic studies seem appropriate. A number of immunological abnormalities have been described in lupus erythematosus. The thymus, which is so important in regulating the immune system and which is Decker et a'/. • Systemic Lupus Erythematosus

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abnormal in New Zealand mice, has been found also to be histologically abnormal in patients with lupus erythematosus (38). In addition, recent studies suggest premature loss of thymic hormone in patients with lupus erythematosus (39). Patients with lupus erythematosus have been found to hyperrespond to immunization with erythrocyte antigens; in addition to an excessive antibody response, other autoantibodies were detected (40, 41). Patients with lupus erythematosus may even hyperrespond to antigens in food (42). The antilymphocyte antibodies found in lupus erythematosus (43) could potentially alter a large number of immune responses. These antibodies are thought to correlate with disease activity and recently have been found to have specificity for T cells (44). They may be responsible for abnormalities of cellular immunity in patients with lupus erythematosus. A number of chronic infections in man have been associated with autoantibodies. Autoantibodies, especially rheumatoid factor, have also been found after immunization of humans with viral preparations and other vaccines. These observations plus the general failure to isolate organisms from tissues of patients with autoimmune diseases have led to a search for evidence for difficult-toisolate organisms such as mycoplasmas and viruses. Evidence has implicated hepatitis B virus (Australia antigen) in some cases of polyarteritis nodosa. However, the situation is much less clear in lupus erythematosus. Patients with lupus erythematosus have been found to have antibodies to double-stranded RNA and to RNA-DNA hybrids, suggesting possible responses to viral nucleic acids (21). They also have been found to have elevated antibody titers to a large number of viruses. However, some of these findings are related to generalized hypergammaglobulinemia (45) and others could be related to antibodies-to-tissue constituents of the viral cultures. Additional evidence for viral infection is the finding of tubuloreticular or paramyxoviruslike structures in the cells of patients with lupus erythematosus. However, there is considerable doubt that such structures represent viruses (46). Although they are seen more often in lupus erythematosus they are found in other diseases and occasionally in normal people. It is entirely possible that they represent a cellular response to injury, perhaps more common after viral infection. The data to date are compatible with, but do not provide adequate evidence for, chronic viral illness as a cause of lupus erythematosus. The host immune system may be at least as important as any particular virus. MECHANISM OF TISSUE I N J U R Y IN LUPUS ERYTHEMATOSUS

There is no doubt that immune complexes can cause damage and they are a likely explanation for early pathological events in the renal glomerulus and choroid plexus in patients with lupus erythematosus. The DNA-anti-DNA complexes have been implicated in lupus nephritis. However, the sequence of events leading to chronic inflammation is complicated and probably involves a number of mechanisms (47). A number of mediators, some derived from complement components, attract cells which ultimately participate in the inflammatory response. Anti394

bodies to a variety of subcellular cytoplasmic constitutents such as mitochondria, or microsomal or soluble protein components occur in many cases with lupus erythematosus (48) and could play a pathogenetic role in areas of inflammation. Immune complexes of human leukocytes and antinuclear antibodies were found to produce tissue inflammation (49); and delayed cutaneous reactivity to autologous leukocytes has been shown in patients with lupus erythematosus (50). Further, biopsies of skin and kidney of patients with lupus erythematosus show nuclei of some cells in areas of inflammation already coated with gamma globulin, whereas biopsies of normal patients do not. These studies suggest possible mechanisms of tissue inflammation in lupus erythematosus in addition to that caused by deposition of immune complexes. Lymphoid cells and macrophages not specifically sensitized could attack cells that are coated with antibody. Such processes could play a secondary role in some autoimmune processes and a primary role in others. Specifically sensitized T cells appear to be important in polymyositis (51) but probably play a lesser role in lupus erythematosus. Nevertheless, some patients with lupus erythematosus have circulating lymphocytes sensitized to autoantigens (52), and lymphocytes capable of attacking and killing human fibroblasts in kidney cell cultures (53). Certainly antibodies to formed elements in the blood, or their precursors, or both contribute to cytopenias. In view of the great variety of autoantibodies present in lupus erythematosus and the several mechanisms available for producing tissue inflammation and destruction, it is not surprising that clinical disease may occur in almost every organ system in the body. The following discussion will describe the most important clinical manifestations of the autoimmune processes that occur in lupus erythematosus. Renal Manifestations

Dr. M. Eric Gershwin*: A discussion of the renal features of connective tissue disease is best begun with a consideration of lupus erythematosus because it is, on the one hand, the best understood, and yet its renal lesion is the greatest source of morbidity and mortality in the disease. Nephritis is the initial manifestation of lupus erythematosus in about 4% to 8% of patients (54). However, almost 35% of patients have some renal involvement by the end of the first year. The probability of new onset of nephritis decreases the longer a patient has lupus erythematosus. For example the onset of nephritis is uncommon, occurring in less than 15%, after 5 years of lupus erythematosus. Of course, exceptions exist. Renal involvement appears inversely related to age, with younger patients affected earlier and with greater severity. As our diagnostic skills have improved in recent years, more and more cases with mild lupus erythematosus nephritis have been recognized and survival rates have thus steadily ad* Clinical Associate, Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases.

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Table 3. Clinical Features of 1_upus Nephritis Pollak (1964]i

Focal glomerulitis Diffuse proliferative glomerulonephritis Membranous lupus glomerulonephritis

Baldwin (1970)

Patients: Proteinuria *

Blood Urea Nitrogen

no.

mg/100 ml

23

Patients

Proteinuria*

Nephrotic Syndrome*

Hypertension*

Hematuria*

Blood Urea Nitrogen >21*

no. 13/14

3/14

2/12

8/12

2/14

24

24/24

14/24

6/18

13/20

13/24

14

14/14

8/13

4/11

7/11

4/14

4/23

13 ± 3.7

14

47

39/47

29 ± 19.7

7

5/7

10 ± 3.1

* First number = number of patients with feature; second number = number of patients tested.

vanced. Five-year survivals are now estimated at 70% to 80% (54) and the incidence of lupus nephritis at between 50% and 7 5 % of cases with systemic disease (55). Clinical manifestations of lupus nephritis include hypertension, edema, acute and chronic renal failure, hematuria, proteinuria, and nephrotic syndrome. Hypertension correlates best with renal failure and is uncommon in its absence. Renal involvement in lupus erythematosus has been variously classified by both clinicians and pathologists. Severe renal changes are seen in patients with marked nephritis, whereas a normal biopsy would be most likely found in a patient with no or minimally active nephritis. However, the in-between ground is controversial and the use of light and electron microscopy can only attempt to predict or prognosticate. Renal involvement in lupus erythematosus, according to the best criteria available, should be divided into three general groups (Table 3) (56, 5 7 ) : focal glomerulitis, diffuse proliferative glomerulonephritis, and membranous lupus glomerulonephritis. Each of these groups appears to have distinctive features. Earlier it was not thought that these groups evolved from one pattern to another but seemed constant within a given patient throughout the natural course of the individual's disease. However, this point is now considered invalid as histologic patterns can progress during the course of the disease. In focal proliferative lupus nephritis, also known as focal glomerulitis, only a few glomeruli are involved. Histologic changes include proliferation of endothelial and mesangial cells, particularly at the periphery of the glomerular tufts; focal necrosis; and infiltration by polymorphonuclear leukocytes. Electron microscopy reveals only minimally thickened or sometimes perfectly normal basement membrane. Patients with focal glomerulitis may have an active sediment or significant proteinuria but rarely develop chronic azotemia. Diffuse proliferative glomerulonephritis has all of the features of focal glomerulitis, but involvement is more severe with widespread interstitial and tubular inflammation along with more uniform glomerular involvement. Necrosis of glomeruli is much more common as are endothelial cell proliferation and wire-loop lesions. Tubular atrophy is often found in addition to a considerable amount of nuclear fragmentation. Electron microscopy, as ex-

pected, shows deposits of thick granular material either along the endothelial side of the basement membrane, in the basement membrane itself, or, occasionally, on the epithelial side. Immunofluorescence of these deposits has shown the presence of DNA-anti-DNA complexes. Products of fibrinogen breakdown, particularly on the endothelial side, suggest local intravascular coagulation. Renal failure is the rule rather than the exception in this group and azotemia, nephrotic syndrome, hypertension, edema, and hematuria are seen in most. Membranous lupus nephritis resembles idiopathic membranous nephritis with diffuse thickening of capillary walls without neutrophil infiltration or necrosis. Electron microscopy in this pattern shows a fine almost linear deposition of granular material along the epithelial side of the glomerular basement membrane. This material, seen by immunofluorescence, is likewise composed of immunoglobulin and complement. The majority of these patients have nephrotic syndrome and hematuria. In comparison to diffuse proliferative glomerulonephritis, hypertension and azotemia are less common but the overall prognosis is poor. The deposition of antigen-antibody complexes has been shown by immunofluorescence. In lupus nephritis the fluorescent pattern is referred to as "lumpy-bumpy," indicating an inhomogenous localization of complexes in contrast to antibasement membrane (Goodpasture's syndrome) nephritis where the pattern is linear. However, it should be remembered that mere demonstration of immunoglobulin deposition does not justify cause-and-effect statements, as immunoproteins are often found attached to damaged renal parenchyma in other diseases (58). Circulating DNA-anti-DNA complexes have been found in the serums of patients with lupus nephritis (59). However, some patients have very high titers of anti-DNA antibodies and no renal disease, and some with severe nephritis have absent anti-DNA antibodies. The latter groups of patients may have other immune complexes such as anti-RNA-RNA. The former remain a problem that may be accounted for by qualitative antibody characteristics. For example, anti-DNA antibodies that fix complement appear in higher titers in lupus nephritis. Similarly, recent studies indicate that patients with lupus nephritis have precipitating antibodies to DNA which have high avidity in contrast to those without nephritis who lack Decker et a/. • Systemic Lupus Erythematosus

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precipitating antibody to DNA and have low antibody avidity for the nucleic acid (60). Renal involvement in scleroderma is relatively uncommon clinically, although autopsy material indicates that about 60% of patients have either fibrinoid necrosis, thickening of glomerular basement membrane, or hyperplasia of interlobular arteries (61). In other cases, the pathology more closely resembles polyarteritis nodosa ( P A N ) . The most characteristic and dramatic pattern manifests severe parenchymal damage accompanied by acute renal failure, with hypertension and almost certain death within a few months. Treatment is not considered to alter this disastrous chain of events, which may be worsened or induced by steroid administration. The histology resembles malignant nephrosclerosis more than it does lupus erythematosus; its pathogenesis has not been related to the immunologic mechanisms discussed above. Polyarteritis nodosa may more justifiably be considered immunologically mediated. Hypersensitivity angiitis can be produced experimentally by infusion of foreign proteins or drugs. In addition, antigen-antibody complexes can be localized in involved vessels. Renal involvement is common, exceeding 7 5 % in some series (62), with proteinuria and hematuria being characteristic manifestations. As with lupus erythematosus, renal involvement may be the only symptom of polyarteritis nodosa and may herald the disease with acute renal failure. The histology is generally of two types, either a frank polyarteritis or a distinctive form of glomerulonephritis. Both can respond dramatically to corticosteroids providing they are instituted early in the course of the disease. Hypertension is thought to result from the intermittent course with healing and subsequent scarring of at least portions of the renal parenchyma. Unlike lupus erythematosus, no definite antigens have been discovered; although antigenantibody complexes are localized in the vessel wall, a cause-and-effect relationship is not clearly delineated. Clinically, the value of arterial contrast studies has been emphasized, and the risk of gross hemorrhage secondary to needle biopsy of the kidney has been recognized. Hematologic Manifestations

Dr. William E. Seaman*: Anemia is common in lupus erythematosus, but the characteristic hemolytic anemia is not; although the Coombs' test is positive in up to one third of patients, less than 5% have clinical evidence of hemolysis. In patients without renal failure, anemia is usually consistent with the "anemia of chronic disease," which is generally not severe. The erythrocytes are usually normochromic and normocytic, the serum iron is low, and the iron-binding capacity is normal or low (63). A similar anemia is common in patients with active rheumatoid arthritis, in whom there is a moderate decrease in erythrocyte survival with an impairment in the expected bone marrow response to this loss. Iron accumulates in the reticuloendothelial system, including the histiocytes in bone marrow, that is, the so-called "reticuloendothelial block." Erythropoietin levels are relatively low (64), and * Clinical Associate, Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases. 395

the anemia can be partly overcome by the administration of erythropoietin. The anemia may also be improved by the administration of cobalt, which probably stimulates erythropoietin, but cobalt is rarely used because of its toxicity. The anemia regularly responds to improvement in the underlying disease. Iron deficiency anemia may accompany, or be mistaken for, the anemia of chronic disease. In particular, patients with scleroderma may have poor absorption of iron from the intestinal tract. They are also more prone to bleeding from hiatus hernia and from intestinal telangiectases. Rarely, amyloidosis may cause iron malabsorption. There is controversy over the possibility that blood loss due to aspirin therapy plays a role in anemia. In the short run, at least, low-dose aspirin therapy produces an increase in fecal blood loss, but anemia in patients with rheumatoid arthritis does not correlate with the use of aspirin (65, 66). The contribution of aspirin to acute gastrointestinal bleeding is also a matter of debate (67). The incidence of macrocytic and megaloblastic anemias in lupus erythematosus has not been studied. However, patients with lupus erythematosus commonly require medicines that antagonize the absorption or utilization of folate, such as diphenylhydantoin, phenobarbital, oral contraceptives, or isoniazid (68). Azathioprine and cyclophosphamide commonly produce macrocytosis (and sometimes anemia) because of their effects on DNA synthesis (69). Folate deficiency may occur with prolonged hemolytic anemia. In patients with rheumatoid arthritis there appears to be a slight increase in the incidence of macrocytic anemia, primarily due to folate deficiency. Serum folate levels in patients with rheumatoid arthritis are misleading, however, in that they are low in about two thirds of patients, usually without a notable reduction in the erythrocyte folate level and often without accompanying anemia. Alter, Zvaifler, and Rath (70) provided evidence that the low serum folate may in part be due to decreased binding of folate to serum proteins in the presence of aspirin. Patients with psoriatic arthritis are more likely to develop a true folate deficiency because of loss of folate in exfoliated skin. They may also be treated with methotrexate, a direct folate antagonist. Patients with scleroderma may develop macrocytic anemia because of malabsorption of folate or vitamin B 12 due to bacterial overgrowth in the intestine secondary to stasis. Characteristically, an abnormal Schilling test will be corrected after treatment with antibiotics. Aplastic anemia has been reported in lupus erythematosus but appears to be more common in scleroderma (71). Microangiopathic anemia may be seen in either of these diseases, even without hypertension. Sideroblastic anemia may occur in any of the collagen vascular diseases, but is often due to drugs. Leukopenia is characteristic of lupus erythematosus but occurs in Felty's syndrome and in Sjogren's syndrome. In patients with lupus erythematosus, the decrease in lymphocytes is generally greater than the decrease in granulocytes, while the opposite is true of patients with Felty's syndrome. In both, the half-life of circulating granulocytes is de-

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creased, and marrow examination usually shows the myeloid series to be normal or increased. A curious finding in some patients with lupus erythematosus and in most patients with Felty's syndrome is a lack of leukocytosis in response to endotoxin or etiocholanalone, a test that is believed to measure the "marrow granulocyte reserve" (72, 73). This abnormality may also be seen in patients with rheumatoid arthritis or Sjogren's syndrome and does not correlate well with leukopenia, except that it was present in all of the five patients with Felty's syndrome who were tested. A serum factor appears responsible for the abnormality (74). The granulocytes from patients with lupus erythematosus show a decreased capability for phagocytosis that is not due to a serum factor (75). Granulocytes from patients with rheumatoid arthritis show normal phagocytosis, but have impaired chemotaxis, a defect that seems to follow the phagocytosis of rheumatoid complexes (76). This defect is not found in the cells from patients with lupus erythematosus (77), perhaps because of their impaired phagocytosis, but patients with lupus erythematosus have a reduced ability to generate the chemotactic factors that attract leukocytes (78). These defects may play a role in the known susceptibility to infection of patients with lupus erythematosus. In patients with juvenile rheumatoid arthritis or polyarteritis nodosa, the leukocyte count tends to rise in relation to active disease, though about 15% of patients with juvenile rheumatoid arthritis may have leukopenia. In rheumatoid arthritis, the leukocyte count may rise in active disease, but this is a less prominent feature than in juvenile rheumatoid arthritis and is a poor index of disease activity. The eosinophil count is often low in patients with lupus erythematosus. Eosinophilia may occur, but tends to be associated with severe skin disease. Eosinophilia in rheumatoid arthritis is associated with severe systemic manifestations; it is unusual in juvenile rheumatoid arthritis, even in the presence of systemic manifestations. Eosinophilia may be seen in scleroderma but is not particularly associated with visceral involvement. Thrombocytopenia is found in up to one fourth of patients with lupus erythematosus. Severe thrombocytopenia may also be seen in Felty's syndrome, in contrast to rheumatoid arthritis, where the platelet count is elevated in 50% of patients (though usually not greater than 800 000/ mm 3 ), or polyarteritis nodosa, in which marked thrombocytosis may be seen. Karpatkin (79) has found evidence for antiplatelet antibodies in 7 8 % of patients with lupus erythematosus though only 14% of patients were thrombocytopenic. Similar antibodies were noted in 6 5 % of patients with idiopathic thrombocytopenic purpura (ITP), though 96% of these patients were thrombocytopenic. The extent of overlap between lupus erythematosus and chronic idiopathic thrombocytopenic purpura remains controversial. Thrombotic thrombocytopenic purpura has been reported in association with virtually all of the collagen vascular diseases, especially lupus erythematosus, but is uncommon. Patients with lupus erythematosus (and also patients with idiopathic thrombocytopenic purpura) may have disor-

dered platelet function, particularly an abnormality of platelet factor III. Uremia and aspirin therapy can also contribute to abnormal platelet function. Among patients with connective tissue diseases, the presence of a circulating anticoagulant is almost pathognomonic for lupus erythematosus. Such anticoagulants appear to be immunoglobulins (80). They usually block the activation of prothrombin to thrombin or, more rarely, have an effect in the intrinsic pathway (80, 81). Significant bleeding may occur, but is uncommon unless the circulating anticoagulant is accompanied by thrombocytopenia or an actual decrease in prothrombin, both of which occur more commonly in patients with circulating anticoagulants. The partial thromboplastin time and, rarely, the prothrombin time may also be prolonged by the presence of fibrin-split products, in which case the thrombin time is also prolonged. Fibrin-split products are commonly elevated in patients with lupus erythematosus but usually not enough to affect these tests. There is a tendency for the elevation to correlate with active renal diseases (82). In patients with amyloidosis, a specific lack of factor X has sometimes been noted but generally does not cause bleeding (83). Patients with severe nephrotic syndrome may lose significant quantities of factor IX but again bleeding does not generally result. Malignancies of the hematopoietic system, particularly malignant lymphoma, appear to be more common in patients with connective tissue disease (84, 85), especially in patients with Sjogren's syndrome (86). This has led to speculation that such malignancies are due to chronic antigenic stimulation. Dermatologic and Neuropsychiatric Manifestations

Dr. John H. Klippel*: Cutaneous involvement is a major clinical feature and forms the basis of diagnosis of many of the connective tissue disorders. In lupus erythematosus, dermatologic disease is often the presenting manifestation of the illness and ranks second only to articular involvement in the frequency of occurrence (54). Among the protean dermal manifestations of lupus erythematosus the most often observed is the erythematosus blush, typically involving a butterfly facial distribution and commonly accompanied by photosensitivity. The discoid lesion is characterized by chronicity, follicular plugging, scarring, and atrophy (87). Dermal vascular changes include petechiae, purpura, and ecchymoses, as well as ischemic lesions which may progress to necrotic ulcerations or digital gangrene. Mucosal abnormalities consist of hemorrhagic shallow ulcerations and vesicular eruptions of the oral and vulvovaginal mucosa. Also recognized are vesico-bullous lesions, palmar and plantar involvement, hives and angioneurotic edema, localized and diffuse alopecia, and erythema multiform lesions. The confinement of disease to cutaneous alterations has served to separate chronic discoid lupus, morphea and linear scleroderma, and cutaneous polyarteritis from the respective systemic disorders. Whether these forms represent distinct entities or limited progression of the same * Clinical Associate, Arthritis and Rheumatism Branch, National stitute of Arthritis, Metabolism, and Digestive Diseases. Decker et al. • Systemic Lupus Erythematosus

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disease has not been satisfactorily resolved. Immunofluorescence studies have shown immunoglobulin and various complement components along the dermal epidermal junction and within cellular nuclei and the walls of dermal blood vessels in lupus erythematosus (88-90). Similar findings may rarely be observed in the cutaneous vascular lesions of scleroderma and dermatomyositis (91) but lupus erythematosus appears unique in exhibiting these complexes in clinically uninvolved skin. The observations provide an important diagnostic tool in lupus erythematosus and may well be of significance in predicting immune complex deposition in other major organ systems (92). Electron microscopic studies have disclosed tubuloreticular structures within the cytoplasm of the dermal endothelium in lupus erythematosus, scleroderma, and dermatomyositis (93, 94). These structures are regularly seen in circulating lymphocytes and within the microvascular lining of multiple organs of these same diseases. They may represent products of cellular degradation incident to any one of a number of insults such as viral infection. Both the deposition of immune complexes and the presence of tubular endothelial inclusions appear to represent basic pathologic alterations and further knowledge of them may contribute significantly to our understanding of pathogenesis. NEUROPSYCHIATRY

The classification of neuropsychiatry illness in lupus erythematosus has been the subject of two recent reviews (95, 96). In order of decreasing frequency are observed [1] alterations of mental function including organic brain syndromes, affective illnesses, and schizophreniclike disorders; [2] transient or recurrent seizure disorders, the majority of which are generalized motor, although a variety of clinical forms have been described; [3] paralytic disease resulting from either ischemic or hemorrhagic events; [4] tremor, choreoathetoid, and ataxic movement disorders; [5] nuclear and infranuclear cranial neuropathies most frequently related to facial sensory, extraocular movements, and pupillary abnormalities; and finally, [6] peripheral neuropathies usually of a mixed sensory-motor variety. Neuropsychiatric disease is second only to renal disease as a cause of death in lupus erythematosus, with both organic mental syndromes and central neurologic involvement excluding seizures having the most unfavorable prognosis (54). The neuropsychiatric abnormalities of lupus erythematosus appear most similar to those observed in polyarteritis (Table 4) (97). Central neurologic involvement is exceedingly rare in scleroderma, polymyositis, and rheumatoid arthritis, although it may be seen in the advanced stages of scleroderma secondary to renal, pulmonary or cardiac disease (98). Cranial, particularly trigeminal (99), and peripheral neuropathies are seen in all the disorders. The peripheral entrapment syndromes that occur in lupus erythematosus are most frequent in rheumatoid arthritis. Neuropsychiatric illness may occur as a result of factors unrelated to the neuropathologic features of the primary disease. Therapeutic agents currently in use are particularly suspect in providing confusion. The behavioral modifica398

Table 4. Neuropsychiatry: Manifestations of (Connective Tissue Disease*f SLE Disorders of mental function Seizures Paralysis Movement disorders Cranial neuropathies Peripheral neuropathies

PSS

++++ ++ +++ ++ + ++ + + + + ++ + +++ +

PM

RA

+ +

+ +++

* SLE = systemic lupus erythematosus; PAN = polyarteritis nodosa; PSS = progressive systemic sclerosis; PM = polymyositis; RA = rheumatoid arthritis. t Plus signs indicate intensity of manifestation.

tions produced by corticosteroids are well recognized, although they probably assume a minimal role in the production of the psychiatric syndromes in lupus erythematosus (100). The immunosuppressive effects of both corticosteroids and cytotoxic agents increase the likelihood of neurologic infectious processes. Neurologic dysfunction may as well be precipitated by disease processes involving other organ systems including hypertension, renal failure, emboli from endocardial lesions, and the enhanced bleeding tendencies of thrombocytopenia and perhaps circulating anticoagulants. Pathologic observations have failed to identify a characteristic neuropathologic alteration in lupus erythematosus. The principal vascular abnormality appears to be a fibrinoid degeneration of arteriolar and capillary-sized vessels, and these changes when found correlate with corresponding clinical disease (95). However, a true vasculitis with intramural inflammatory cells, as seen in polyarteritis, is rare. Several recent observations suggest the involvement of immune mechanisms in the neurologic disease. Levels of the fourth component of complement in the cerebrospinal fluid in lupus erythematosus are depressed concomitant with the development of acute neurologic illness. The accelerated in-vitro decay of hemolytic activity of this complement factor appears to correlate with clinical disease activity (101). This same relationship to disease activity has also been reported with the occurrence of D N A anti-DNA complexes in the cerebrospinal fluid of lupus erythematosus (102). Immunofluorescence studies have shown diffuse deposits of gamma globulin in the choroid plexus of patients with clinical neurologic disease (103). The pathogenic significance of these observations and their potential interrelationships are important areas for future investigation. Hepatic Manifestations

Dr. Paul H. Plotz*: Liver disease plays a minor role in the connective tissue diseases, but new tests of liver inflammation, new serologic tests, and the wider use of hepatotoxic drugs have generated new relationships to be worked out and new diagnostic problems to be solved. In some of the diseases—ankylosing spondylitis, psoriatic arthritis, Reiter's syndrome, dermatomyositis, and polymyositis—there is no significant liver involvement, and * Senior Investigator, Arthritis and Rheumatism Branch, National Institute of Arthritis, Metabolism, and Digestive Diseases.

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only the abnormal transaminase values due to muscle inflammation may lead to confusion in the latter two illnesses. In rheumatoid arthritis, liver disease does not occur significantly, although the alkaline phosphatase is often elevated. In juvenile rheumatoid arthritis, the early systemic phase may be accompanied by dramatic liver and spleen involvement, although aspirin toxicity may have contributed to some of the reported findings, as Rich and Johnson (104) observed. In Sjogren's syndrome, there appears to be an unusual amount of chronic hepatitis. In polyarteritis nodosa, liver and even gall bladder infarction secondary to arteritis are not rare, and it also appears that the hepatitis B antigen, perhaps in the form of immune complexes, may cause some cases of this disease (105). In one variant of scleroderma, the CRST syndrome (calcinosis, Raynaud's phenomenon, sclerodactylia, and telangiectasia), primary biliary cirrhosis has a significant incidence (106). In the classical description of lupus erythematosus, liver disease of clinical importance is negligible. Hepatomegaly is reported to occur in 20% to 30% of patients and splenomegaly in 10% to 2 0 % , but jaundice in less than 5% and, then, usually with an apparent explanation unrelated to lupus erythematosus. Although liver function tests have been reported as abnormal, the abnormalities probably reflect altered serum proteins, not liver disease. The few biopsies reported have shown minor portal inflammatory and fibrotic changes, fatty infiltration, and rare cases of cirrhosis. In autopsies, the liver is spared except for the occasional presence of hematoxylin bodies. With the description of chronic active hepatitis in young women who have a lupuslike illness, and the recognition that the lupus erythematosus cell preparation may be positive in chronic active hepatitis, the picture became distinctly confused and has remained so. The extrahepatic manifestations in chronic active hepatitis resemble lupus erythematosus. There is sometimes a rash in chronic active hepatitis, and it may be lupuslike, though more often acne is prominent; alopecia and oral ulceration are uncommon. Arthritis, though less common in chronic hepatitis, runs the gamut from classical rheumatoid arthritislike illness to mild arthralgias, as it does in lupus erythematosus; glomerulonephritis and nephrotic syndrome occur less often than in lupus erythematosus. Renal tubular acidosis, usually latent, and the sicca syndrome occur in both illnesses. Antismooth muscle antibody, which is often present in chronic active hepatitis, is absent in lupus erythematosus (107). The early reports of chronic active hepatitis stressed the prevalence of this illness in young women, many of whom had lupuslike extrahepatic features. These patients often seem to have a higher incidence of certain autoantibodies as well. In broader surveys of the population of patients with chronic hepatitis, however, this subgroup appears less distinct. The sex and age predilection are less striking, and serologic abnormalities in the only horizontal survey of a large population of patients with chronic hepatitis turned out to correlate with disease activity (108). There is no reason to believe that chronic active hepatitis is simply viral hepatitis in a patient with lupus erythema-

tosus because the viral illness appears to have an unremarkable course in lupus erythematosus. Curiously, both lupus erythematosus and chronic active hepatitis, even "lupoid" hepatitis, may be drug-induced, though by different drugs. A middle-of-the-road interpretation of this confusion seems sensible for the moment. In both lupus erythematosus and chronic hepatitis much evidence suggests an immunologic pathogenesis. In those cases of chronic hepatitis with prominent extrahepatic features, the resemblance to lupus erythematosus can be striking. The lupus erythematosus cell preparation and various other abnormal immunoglobulins found in both diseases may well just reflect a propensity for autoaggression in these two diseases with common pathogenetic mechanisms. Recently, we have been intrigued by the anicteric hepatitis that aspirin may cause. In addition to the three patients reported in detail (109) we have observed three spontaneous cases on our ward in the Clinical Center this past year, and have induced three others in 12 patients given aspirin in a study protocol. Furthermore, Dr. William E. Seaman has retrospectively reviewed the records of all the patients with lupus erythematosus who had abnormal liver function tests on our ward in the prior 2Vz years. Most of the cases showed a clear relation to the institution of aspirin, often at low or moderate doses. Of the remainder, one was due to viral hepatitis, one to alcohol, and three others to other drugs: isoniazid, azathioprine, and triacetyloleandomycin. Thus, our novel and perhaps jaundiced view of liver disease in lupus erythematosus is as follows: hepatitis, usually anicteric and reversible, is not uncommon in lupus erythematosus and is usually due to drugs, particularly aspirin; the prolonged use of aspirin may lead to liver biopsy changes indistinguishable from chronic active hepatitis; and some patients with chronic hepatitis and prominent extrahepatic manifestations and serologic abnormalities may have been driven from classical lupus erythematosus to "lupoid" hepatitis by drugs, possibly by aspirin. Articular Manifestations

Dr. Decker: The notable bone and joint features of lupus erythematosus can usefully be considered in three parts. I will emphasize the synovitis with its rather limited tendency to produce deformity and say only a word on the other two aspects, subcutaneous nodules and aseptic necrosis. Migratory polyarthralgia is a cardinal symptom of the disease occurring in more than 90% of patients; it is the first symptom in about two thirds of them. Specifying the number who have had observed polyarthritis is more difficult because of the extraordinary transiency of the signs of inflammation in many patients. Particularly about the hands one may see puffy, red, tender joint or tendonsheath swelling appear one morning in a location which was normal the previous day; by the next day all signs and symptoms may have again disappeared. A physician, hearing a retrospective description of this phenomenon from a patient with normal hands, is likely to be a bit Decker et al. • Systemic Lupus Erythematosus

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skeptical, but it does occur. It has, in fact, been recognized for years that the descriptions of past joint symptoms in the disease are likely to be more lurid than one would expect from inspection of the patient (110). These attacks may occur in any diarthrodial joint, including the temporomandibular, but are most frequent in knee, proximal interphalangeal, and metacarpophalangeal joints. Of course, there is also much synovitis and tenosynovitis of lesser intensity and more prolonged course. Presumably it is this type that leads to the hand deformities we have seen in 15 patients; in them severe symptoms were not prominent while persistent low-grade symptoms had been of very extended duration (111). This group represents approximately 5% of our patients and so we regard deformities as uncommon; other series, perhaps including "overlap" patients, mention hand deformities in more than 30% (112). The deformities most often observed were those of ulnar deviation, swan neck change, and flexion subluxation of the thumb metacarpophalangeal joints. The majority of the lesions were reducible in contrast to the situation in rheumatoid arthritis, but the most striking contrast is defined radiologically. Rheumatoid hands with these deformities show innumerable large subchondral erosions, whereas in the lupus erythematosus group erosions are almost invariably absent or minimal. I suspect the ARA criteria (Table 1) would do an even better job of distinguishing the two diseases if the words "arthritis without deformity" were replaced with the words "arthritis without bone erosion"; the latter, in our view, has great discriminatory power. Synovial biopsy studies of lupus erythematosus show mild degrees of inflammation with somewhat more tendency to small vessel vasculitis, and little or no granuloma formation (113). Typically one finds a highly viscous, exudative fluid with complement levels below the often low values in the serum and with leukocyte counts below 5000 cells/mm 3 . Mononuclear cells usually predominate (114). Why modest and apparently nondestructive inflammation of this order should lead to the observed deformities is not clear. Distension and gradual weakening of supporting structures abetted by the natural forces of hand function are presumed to be the explanation. Nodules have also been of interest because, like deformity, they appear both in rheumatoid arthritis and lupus erythematosus. In our experience, the lupus nodule is uncommon and transient, lasting a month or two rather than a year or so, usually at the elbow, and is of no clinical consequence. Histologically two types of change are seen. One is constituted of bona fide hematoxylin bodies, often clumped or massed and surrounded by edematous, mildly inflamed, loose connective tissue. The other more common form is for all intents a rheumatoid nodule with its three-zone structure (115). Dr. Eric Bywaters, a recent visitor to the Clinical Center, tells us that he thinks the central fibrinoid is likely to be rather more of an open lattice work perhaps showing some residual structure rather than the compacted, formless, dense mass that constitutes the center of the typical rheumatoid nodule. 400

Finally, it is not appropriate to dismiss clinically very important aseptic necrosis of bone as due only to high-dose steroid hormone therapy, although the likelihood is high that such treatment is the major cause. Several patients with lupus erythematosus have developed the bone lesion without ever receiving steroids, and, thus, perhaps the disease should be regarded as "predisposing to" and the therapy as "resulting in" aseptic necrosis. The pathogenesis is unknown since pathological examination usually follows the significant events by months or years. It is an extremely common and often highly symptomatic process in the patients with severe lupus renal disease cared for at the Clinical Center. Replacement arthroplasty, especially of the hips, has been a great boon to a number of them. Cardiopulmonary Manifestations

Dr. Stephen A. Paget*: In lupus erythematosus there is involvement of the pericardium, myocardium, and endocardium, either singly or in combination. Cardiac manifestations are more prominent in lupus erythematosus than in the other connective tissue disorders, and at times can be the presenting symptoms (112). Pericarditis is the most common cardiac manifestation in lupus erythematosus both clinically and in necropsy studies. In all the connective tissue disorders there is an obvious discrepancy between the incidence of clinically detectable pericarditis (as well as myocarditis and endocarditis) and the higher incidence of such findings in necropsy studies (112, 116118). Pericarditis is usually transient, can be asymptomatic, and may have no obvious relation to other disease activity. However, during the active phase of inflammation patients may be highly symptomatic, and there are reports of cardiac tamponade and constrictive pericarditis treated with pericardiectomy (112, 118). Pericarditis is also found in progressive systemic sclerosis (PSS) and polyarteritis nodosa but appears to be of somewhat less clinical significance and is more often silent with slowly evolving large pericardial effusions; pericarditis is rare in dermatomyositis (61, 119-122). In rheumatoid arthritis (RA) not only can pericardial friction rubs be detected in up to one third of cases in whom it is specifically sought, and pericardial effusions or thickening be noted in as many as 46% of patients by echocardiogram, but complications such as tamponade and constriction do occur and can reach life-threatening proportions. Only a few cases of rheumatoid pericarditis can be related to the typical rheumatoid granulomata or nodules of rheumatoid arthritis (123-126). Pleuritis, like pericarditis, is an important part of the polyserositis so characteristic of lupus erythematosus. Though of somewhat less clinical significance, pleural effusions and pleuritis in seropositive rheumatoid arthritis patients can be a presenting complaint, especially in men. The characteristics of the pleural and pericardial effusions in rheumatoid arthritis and lupus erythematosus are similar. The differential points separating the effusions in lupus erythematosus and rheumatoid arthritis include the low cell count and polymorphonuclear percentage, the * Clinical Associate, Arthritis and Rheumatism Branch, National stitute of Arthritis, Metabolism, and Digestive Diseases.

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presence of lupus erythematosus cells, and normal glucose in lupus erythematosus. In rheumatoid arthritis high cell counts and polymorphonuclear percentages, the presence of rheumatoid arthritis cells, and low glucose tend to be distinctive; also of note is the occasional presence of cholesterol-rich pericardial effusions in rheumatoid arthritis (127). The clinical diagnosis of myocarditis is a difficult one and is usually based upon the finding of tachycardia out of proportion to body temperature or level of anemia, signs and symptoms of congestive heart failure, cardiomegaly, gallop rhythm or typical ECG changes in the absence of valvular disease, pericardial effusion, or hypertension (116-118). The myocardial lesions noted in lupus erythematosus consist of both fibrinoid degeneration of connective tissue and small-vessel fibrinoid necrosis and inflammatory changes, leading to narrowing of the small arteries with concomitant fine scars suggestive of infarcts or extensive areas of myocardial degeneration (118). Although angiographic evidence of large vessel obstruction of coronary arteries has been obtained in patients with lupus erythematosus sustaining myocardial infarction, the involvement of such vessels is rare; rheumatoid arthritis presents a similar pattern (128J. In the latter, small vessel coronary arteritis is seen in 20% of cases and is considered a manifestation of generalized vasculitis; myocardial necrosis due to that vasculitis is rare. In a large percentage of patients with polyarteritis nodosa, on the the other hand, large-vessel coronary arteritis and concomitant histologically proved myocardial fibrosis and infarcts are commonly found, although symptoms of myocardial infarction and angina pectoris rarely dominate the clinical picture. Congestive heart failure (CHF) appears to be the major clinical manifestation of myocardial ischemia (121). Hypertension is an important contribution to the development of congestive heart failure and is a frequent complication of renal disease in lupus erythematosus, progressive systemic sclerosis, and polyarteritis nodosa (116, 119, 121). In progressive systemic sclerosis the typical myocardial fibrosis, that has been designated scleroderma heart disease, has been found in different degrees and in variable percentages of patients. However, that lesion alone rarely produces significant clinical manifestations. Congestive heart failure in progressive systemic sclerosis is more frequently due to systemic and pulmonary hypertension, pericardial disease, or arterial hypoxemia (119). In dermatomyositis, necrosis, with only minimal inflammatory response, can exist in the myocardium as it does in skeletal muscle (129). The most widely mentioned cardiac lesion in lupus erythematosus is the atypical nonbacterial verrucous endocarditis known as Libman-Sacks endocarditis. Though there have been reports of clinically significant valvular disease due to this lesion, such cases are rare and LibmanSacks endocarditis remains, in general, an autopsy diagnosis. There is a poor correlation between the frequent presence of a systolic murmur and the Libman-Sacks lesion as its cause (130). There has been a suggestion that the

incidence of the Libman-Sacks lesion has been decreasing, presumably because of steroid therapy, but recent reports have shown little change in the incidence which runs to approximately one half of necropsy cases (113, 116-118). The recent wide use of echocardiography, an important noninvasive method of studying valvular and pericardial disease, can be expected to increase our knowledge of the cardiac lesions of connective tissue disease (124). PLEUROPULMONARY FEATURES

Pleuritis and pleural effusions are the most common pulmonary manifestations of lupus erythematosus, found in half of the patients, and are more common than in other connective tissue disorders (112). Pulmonary parenchymal disease specifically related to lupus erythematosus includes an atelectasizing pneumonitis resembling viral pneumonitis in a fifth of the cases and diffuse interstitial lung disease in a much smaller percentage (131). In all the connective tissue diseases, however, bacterial or viral infections can complicate or mimic pleural and parenchymal disease making it difficult to ascribe them to the underlying disease alone. Diffuse interstitial pulmonary disease, primarily manifested by fibrosis, is noted in more than three quarters of patients with scleroderma (61, 131) and less commonly in rheumatoid arthritis and lupus erythematosus. The interstitial disease can often be shown in asymptomatic patients without X-ray changes by a reduction in diffusing capacity (131). Clinically, interstitial pulmonary disease can run the gamut from totally asymptomatic status, despite roentgenologic changes, to markedly decreased exercise tolerance and progressive dyspnea on exertion. In rheumatoid arthritis, pulmonary nodules are seen occasionally and, at times, cavitate, making differential diagnosis difficult (127). In summary, specific connective tissue disease cardiopulmonary features are a frequent cause of morbidity and of concern but are an unusual cause of death save for the pulmonary fibrosis and pulmonary hypertension of scleroderma. Infections, arterial hypertension, and coronary arteriosclerosis constitute a greater threat to these patients than do their more specific lesions. Future Directions

Dr. Steinberg: We will close with a hypothetical synthesis of theories which may be useful as a guide in future efforts. A genetic abnormality may produce malfunction of the regulatory mechanism of the immune system. This could be due to early loss of thymic hormone which activates regulatory cells or to a failure in the regeneration of regulatory cells. It is possible that virus can play a role in either process by [1] passing genetic information, or [2] by infecting the thymus. The loss of normal regulatory function would have two immediate consequences: [1] "normal" antigenic exposure would lead to an excessive response, and [2] antigens to which the person was previously tolerant would become capable of stimulating an immune response. These consequences would lead to disease after a time interval which might be very short or might be several decades. Certain viruses or other organisms, previously tolerated, could lead Decker et a/. • Systemic Lupus Erythematosus

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to an adequate immune response terminating in disease. Chronic antigenic stimulation with external and self-antigens in the absence of adequate regulatory function could lead to an excessive response to both, resulting in hypergammaglobulinemia, autoantibodies, and self-reactive lymphoid cells. Disease would be produced by cellular responses to antigenic determinants of specific organs such as thyroid, salivary glands, or synovium or to organisms in particular tissues, and by immune complexes of one or many host antigens combined with antibody. What then can be said of the future? If lupus erythematosus is caused by an interaction of genetic, viral, and immunologic factors, all three deserve further study. Screening of as many genetic markers as possible might lead to a pattern not currently being recognized; careful subgrouping may be necessary to make sense of the data. Epidemiological approaches could be of great assistance. Further study of a variety of immunologic functions in patients before treatment would be desirable. In-vitro techniques for studying regulation of immune responses in humans might be a first step toward understanding in-vivo immune regulation in lupus erythematosus. Finally, the search for exogenous or endogenous agents should continue. Such agents could be relatively specific or, more likely in my opinion, could be one of several agents operating on fertile genetic and immunologic soil. On the other hand, if lupus erythematosus is an immune deficiency disease in which a cell product is lost prematurely, as is insulin in diabetes mellitus, we should define this missing product and attempt replacement therapy. Restoring patients with thymic hormones would be a pleasant alternative to steroid and cyclophosphamide therapy. These briefly sketched approaches could keep many laboratories busy for some time to come. The brilliant theoretical immunologist, Sir McFarland Burnet, stated as recently as two years ago that "we can neither prevent nor cure autoimmune disease . . . , there is no solution that can be satisfactory even in principle . . . , we can only deal with symptoms as they arise and make an empirical compromise between the needs of the afflicted individual and the resources of the community" (132). Most of us are more optimistic. I hope that within a generation preventive or replacement therapies, or both, will be available.

6. W I L S O N D B , N O W E L L P C : Qualitative studies o n the mixed lymphocyte interaction in rats. J Exp Med 131:391-407, 1970 7. BURNET F M : The Clonal Selection Theory of Acquired Immunity, Cambridge, University Press, 1959 8. BURNET F M : Autoimmune disease. II. Pathology of the immune response. Br Med J 2:720-725, 1959 9. TORRIGIANI

10.

Received 13 November

1974; accepted

• Requests for reprints should be addressed to John L. Decker, M.D., Bldg. 10, R o o m 9N218, National Institutes of Health, Bethesda, M D 20014.

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March 1975 • Annals of Internal Medicine • Volume 82 • Number 3

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EISENBERG

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DUBOIS

EL,

SHERWIN

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Diffuse

interstitial

Systemic lupus erythematosus. Contrasts and comparisons.

Systemic lupus erythematosus, a disease capable of exhibiting virtually any clinical manifestation, is discussed in detail and the findings are compar...
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