Hospital Practice

ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20

Current Concepts in Management of Lupus Nephritis Edgar S. Cathcart To cite this article: Edgar S. Cathcart (1977) Current Concepts in Management of Lupus Nephritis, Hospital Practice, 12:5, 59-67, DOI: 10.1080/21548331.1977.11707132 To link to this article: http://dx.doi.org/10.1080/21548331.1977.11707132

Published online: 06 Jul 2016.

Submit your article to this journal

View related articles

Full Terms & Conditions of access and use can be found at http://www.tandfonline.com/action/journalInformation?journalCode=ihop20 Download by: [FU Berlin]

Date: 26 November 2016, At: 13:07

Current Concepts in Management

of Lupus Nephritis EDGAR

s.

cAT H cART

Boston University

Since prognosis seems to vary according to which of several possible types of disease is present, the first step is renal biopsy and histologic classification. Management options thereafter- both conventional (steroid therapy) and investigational (cytotoxic agents plus steroids, thymic hormone replacement, steroid "pulse" therapy)- are discussed in terms of recent clinical results and theoretical mechanisms of action.

Ten years ago, the prognosis for SLE patients with renal involvement was rather grim. Median survival from time of diagnosis was only about :n months. Today, that figure has been extended to about five years or more. Unfortunately, much of this prognostic improvement represents advances in diagnosis rather than therapy or basic etiologic understanding. Lupus nephritis still accounts for about half the deaths that occur in SLE. What has happened is that more and more mild cases of SLE are being recognized, including many with mild renal involvement that might have been missed in an earlier period. Not until 1971, in fact, did a committee of the American Rheumatism Association finally come up with a preliminary, but extensively investigated, set of diagnostic criteria for the disease. The committee's studies indicated that, during a given period of observation, the presence of any four of the 14 criteria listed had an estimated sensitivity for SLE of 88% and an estimated specificity of 99%. More recently, the increasing use of antinuclear antibody testing, tests for DNA-binding capacity, and radioimmunoassays for serum complement levels has also strengthened our ability to detect SLE. But when it comes to identifying lupus nephritis itself (which may occur in as many as so% of patients who meet the "four-or-more" criteria for SLE), definitive diagnosis still requires renal biopsy and light or electron microscopic examination of the specimens. This is so for two reasons. First, although the finding of casts or proteinuria serves to alert the physician to the presence of renal disease, it usually does so only in advanced cases of lupus nephritis, missing the early lesions that lack these flagrant signs; moreover, occasional SLE patients have been found with advanced nephritis but negative urinalysis. Second, and more important, it is now clear that, before one can undertake rational management of the renal lesion or make

statements about its prognosis, one must first determine exactly which of several types is at hand. In recent years, we have learned that, for prognostic purposes, it is useful to separate patients with active lupus nephritis into at least three categories: mild (focal) proliferative glomerulitis, severe (diffuse) proliferative glomerulonephritis, and membranous glomerulonephropathy. In the first type, microscopically evident disease activity is confined to portions of only a few of the glomeruli sampled (for an accurate diagnosis, biopsies must contain no fewer than five glomeruli, preferably about 10). Typically, the basement membrane is only minimally thickened, if at all (photo 1A, page6o). The focal lesions show a proliferation of endothelial and mesangial cells, usually at the periphery of the few glomerular tufts involved, together with swelling, focal necrosis, and infiltration by polymorphonuclear leukocytes (photo 18). By immunofluorescence all glomeruli show prominent mesangial stainings (photo tC). As might be expected, the clinical features of this lesion are generally mild and reversible. There may be microscopic hematuria and slight but significant proteinuria, but rarely do azotemia, hypertension, renal insufficiency, or nephrotic syndrome develop. In diffuse proliferative disease, the microscopic findings are basically those found in focal disease but much more extensive: all or almost all of the glomeruli are swollen and necrotic, and the proliferation of endothelial and mesangial cells is often so severe that many capillaries are completely obliterated (photo 2). In addition, inflammation commonly extends to the tubules and the interstitium. So-

Dr. Cathcart Is Associate Professor of Medicine, Boston University School of Medicine, and Program Director of the Arthntb Section, Boston University Medical Center, Boston. Hospital Practice May 1977

59

called wire-loop lesions (segmental thickening of the glomerular tuft's basement membrane) are frequent; electron microscopy shows thick, granular material deposited along the endothelial side of the basement membrane, in the membrane itself, or (rarely) along the epithelial side of the membrane. Immunofluorescence shows that these deposits contain DNA-anti-DNA complexes. The prognosis for most patients with this lesion is grave; gross hematuria and heavy proteinuria are the rule, as are azotemia, hypertension, edema, renal failure, and nephrotic syndrome. Many clinical features of the third, or membranous, type of lupus nephritis are also those seen in diffuse proliferative disease- namely, gross hematuria, heavy proteinuria, nephrotic syndrome, hypertension, and azotemia; the last two, however, are much less common, and renal failure is rare. Generally, the major problem with patients with this form of disease is protein loss; if that problem can be controlled, the prognosis is relatively good. In the absence of significant endothelial and mesangial cell proliferation, deposits of granular material along the capillary epithelium (photo 3A) are mainly responsible for the characteristic histologic feature of this lesion - an almost uniform thickening of the glomerular capillary walls (photo 38). These deposits, present in all types of lupus nephritis but more numerous and more evenly distributed in this type, contain immunoglobulin and complement. On immunofluorescence, they show a characteristic "lumpy-bumpy" pattern (photo 3C) that helps to distinguish membranous lupus nephritis from antibasementmembrane nephritis (Goodpasture's syndrome), in which the fluorescent pattern is typically smooth and linear. In contrast to the proliferative types of lupus nephritis, the membranous type rarely shows any necrosis or leukocyte infiltration. This classification of lupus nephritis into three basic categories (there may be overlap, of course, of the three in individual cases) dates from about 1970· Recent findings, however, indicate that there may be two more basic types: an early form of glomerular disease that is confined to mesangial cells

6o

Hospibl Practice M11y 19n

Lesions of four tllfJeS of lupw nephritis are shown on these pages, courtesu of Dr. Magda SUlmant, Boston University School of Medicine. In one tvpe, focal proliferative disease, electron microscopy often shows nonnal glomerular basement membrane but electron-dense deposits (arrows) in mesangial areas (lA). By light microscopfl, the same le-

In the third, or membranow, ti/Pe of lupw nephritis, electron microscopy typicall11 reveals large electron-dense deposits (asterisks) that are primarily at subepithelial and Intramembranous sites In the thickened and deformed glomerular caplllarv wall, but mau al1o e:rtend Into the mesanglum (3A). A light microscopy view of a membranous lesion

sion shows most of an affected glomerulus spared but some proliferation and an increase in the mesangial matrix (lB); on immunofluorescence, a focal lesion again shows prominent mesangial involvement (lC). In a second type, diffuse proliferative

disease, glomerular involvement is more extensive: there is solidification of the glomerulus, obliteration of most capillary loops due to marked increases in intrinsic and inflammatory cells, and extensive necrosis in many glomeruli (2).

again shows diffuse basement membrane thickening (3B), which, when subjected to immunofluorescence, manifests the characteristic "lumpy-bumpy" staining pattern that serves to distinguish this lesion from the smooth pallem seen In antlbasement mem-

brane nephritis (3C). A fourth t11pe, interstitial disease, is marked b11 substantial or complete sparing of the glomeruli; immunofluorescence shows bright, granular deposltr along tubular basement membranes and the interstitium (4). Hospital Practice May 1977

61

and an extraglomerular lesion in which disease activity is largely, sometimes completely, confined to the interstitium. To take the extraglomerular lesion first: here, most, if not all, glomeruli sampled appear normal or show only a slight increase in populations of mesangial cells. But among the glomeruli and surrounding the renal tubules, there is widespread mononuclear cell infiltration, with varying degrees of interstitial edema and fibrosis, tubular atrophy, and thickening of tubular basement membranes. Immunofluorescence reve!ils bright, granular deposits of immunoglobulin and complement along tubular basement membranes or in the interstitium (photo 4). Electron microscopy shows numerous interstitiallymphocyt~s and mast cells, and, again, electron-dense deposits in thickened, tubular basement membranes. An interesting fact about this lesion - and a point to which we will return later- is that similar interstitial changes, with comparative sparing of the glomeruli, have been described in acutely rejecting kidney transplants. The mesangial lesion, also called "minimal glomerular changes," is characterized by a proliferation of the scavenger-like mesangial cells in the glomerulus and by deposits of im-

American Rheumatism Association 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 asts Pleuritis, pericarditis Psychosis, convulsions Cytopenia "The presence of any four during any period of observation has an estimated speci.ficity of 99'Yo Color indicates active renal involvement

62.

Hospital Practice May 1cn7

munoglobulin and complement in thickened mesangial matrix and glomerular capillaries. What these changes appear to represent is a developing failure by the mesangial cells to degrade and eliminate the deposits. If so, and since the mesangiallesion appears to be the earliest manifestation of lupus nephritis so far as the glomeruli are concerned, perhaps this is an appropriate place to discuss what is known or believed about the pathogenesis of nephritis in SLE. That lupus nephritis (and SLE) is an "immune complex disease" is not a new idea, of course. Some of the supporting evidence has already been mentioned- namely, immunofluorescent and electron microscopic findings of immunoglobulin and complement in renal biopsies. In addition, it has been demonstrated that gamma globulin eluted from kidney tissue in advanced disease has high concentrations of antinuclear antibodies, suggesting that the gamma globulin there is present in the form of complexes rather than as a result of nonspecific trapping in the damaged tissue. Moreover, some patients with lupus nephritis have been shown to have circulating free DNA at one time and circulating anti-DNA at other times, suggesting that complexes are being formed repeatedly. Finally, in some instances it has been possible to demonstrate DNA within glomerular deposits, a finding tantamount to direct evidence for the presence of the antigen portion of an immune complex. The events leading up to the deposition of immune complexes in the kidneys of (some) SLE patients are unknown. Nevertheless, in formulating approaches to the management of lupus nephritis, certain assumptions about these events are commonly made and acted upon. Generally, the assumptions involve an interplay of infectious, genetic, and immunologic factors. At the risk of oversimplifying, the currently most popular version of this hypothetical interplay can be summarized as follows: The infectious agent is a type C RNA virus, the transmission of which in animals is known to be almost always vertical. Because of a presumed genetic predisposition in the host, the virus is allowed to slip by the immune

surveillance and home in on and replicate or express itself in the thymus. This thymic lesion alters and may eventually destroy T-cell function, either directly or through an autoimmune mechanism. Defective cellular immunity allows further viral replication and dissemination, inducing an escalating humoral response. Immune complexes are formed, circulate, and are deposited. Immune reactions against both viral and host antigens on and in cells spread. Inflammation and clinical disease result. The evidence supporting this thinking is well known. For our purposes, we need review only some of the highlights. First, there are the animal models for lupus - notably, New Zealand mouse disease. This entity is not only clinically and serologically similar to human lupus, it is also clearly inherited and strongly associated with type C viruses. Second, there is no question that B-cell activity in patients with active lupus is deranged, as attested by exceedingly large concentrations of circulating immunoglobulin and DNA antibodies, together with a marked complement depletion. And as far as T -cell activity is concerned, one consistent index of lupus activity is a profound lymphopenia. Let me digress here to discuss an interesting line of investigation currently being pursued at this center and elsewhere concerning the type of lymphopenia seen in active SLE and its possible relationship to a deficiency of a thymic hormone, thymosin. This hormone is known to influence the maturation of lymphocytes c~mmitted to the T-cell pathway. It has been shown that thymosin can act on lymphoid stem cells not previously exposed to the thymus and also on cells that have been exposed. In immunoincompetent "nude" mice, thymosin may be responsible for converting previously unresponsive bone marrow cells into cells that respond to T-cell mitogens and express T-cell surface antigens. In the New Zealand hybrid mouse (NZB/NZW), the administration of thymosin has been shown to enhance depressed T-cell function and to lessen the autoimmune features of the murine model of immune complex renal disease. Is any of this relevant to human lu-

pus? Recently, M.A. Scheinberg and I, at this center, and A.L. Goldstein, from the University of Texas, Calveston, were prompted to find out. We did so after a preliminary study in this laboratory had indicated that patients with active SLE had a significant decrease in the number of spontaneous rosette-forming T cells and an increase in "null" cells (those cells lacking either T orB markers). Accordingly, we first measured the number of peripheral blood T, B, and null cells in a sizable number of subjects - 25 patients with active SLE, 15 with inactive (controlled) SLE, five with rheumatoid arthritis, and z6 healthy controls. A few from each group then re-

ceived zoo to 300 j.Lg of a calf thymosin preparation (a dose we had previously determined was optimal), and lymphocyte counts were repeated. Our findings appear relevant not only to pathogenesis but also to treatment of SLE. As anticipated, the pretreatment percentage of T cells was markedly reduced in active SLE down to a mean of about 39% of the total lymphocyte population, compared to about 6o% in patients with inactive SLE and healthy controls. The null cell population in active SLE was increased - a mean of about 49% vs 23% in inactive disease and about 14% in controls. There was no significant difference in the proportion of B

cells among the various groups. After administration of thymosin, only patients with active SLE showed a significant change: the proportion of T cells among total lymphocytes rose by an average of 16%, and this rise was accompanied by a drop in the absolute number of null cells that averaged about 17%. Our tentative conclusion was that much of the T-celllymphopenia seen in active lupus may be related to the increase in null cells, many of which may simply be immature T cells. Exposure to thymosin, which may be deficient in patients with SLE, clearly alleviated the marked T-cell lymphopenia, perhaps by promoting maturaHospital Practice

Mll)' 1977

63

tion steps otherwise precluded by a thymic lesion. Whether thymic hormone replacement therapy will ever be clinically useful in SLE remains to be proved. Meanwhile, other promising methods of preventing or arresting autoimmune phenomena have emerged within the pasJ few months. As they age, NZB/NZW mice lose precursors of "suppressor" T cells and their ability to produce soluble immune response suppressor (SIRS) factor after expOsure to the mitogen concanavalin-A. Dr. Thomas Waldmann and his associates at NIH decided to treat a colony of NZB/NZW mice with thrice weekly injections of SIRS obtained from young, normal BALB/c or NZB mice. Whereas only 7% of control animals were alive after a full year of study, 93% of the treated mice survived and were free of renal disease. Coincidentally, Dr. Robert Zurier at the University of Connecticut, using a different approach, showed that the continuous administration of prostaglandin E 1 (PGE 1) fully protects NZB/ NZW mice against nephritis during the first year of life. This latter observation is particularly intriguing, since one of the hallmarks of clinical SLE the development of antinuclear and anti-DNA antibodies - was not affected by PGE 1 treatment. At first glance these data appear to contradict our hypothesis that circulating immune complexes are the forerunners of lupus nephritis. But, then, the poet Robert Burns said it better a hundred years ago: '1'he best laid schemes o' mice and men/Gang aft a-gley." In brief, we appear to be entering a new era in which therapeutic intervention in patients with SLE will make it possible to prevent some or all of the steps leading to the deposition of immune complexes in renal tissues. The optimal approach would seem to be threefold: 1) identify genetic markers for the. disease such as specific HLA antigens or immune response (Ir) genes; 2.) isolate and eradicate the causative exogenous agent(s); and 3) repair the primary immunologic (thymic?) lesion. But in the absence of solid evidence supporting the relevance or feasibility of any of the above, we are currently left to operate at a lower level of effectiveness, namely, sup64

Hospital Practice May 1977

In pallent.s with active SLE, the proportion ofT cells in total blood lymphocytes was significantly lower, while that of null cells was significantly higher, compared with the values in those with inactive disease and in healthy controls (left). But after a group of

pression of immune response and inflammatory mechanisms. That brings us to the use of steroids, which are of course both anti-inflammatory and immunosuppressive. Both modes appear to be important in treating SLE -which is another way of saying that we basically do not know which is responsible for clinical improvement. The principal steroid in use today for SLE is prednisone. Because of their well-known side effects, especially when relatively high doses and long-term use are anticipated, the consensus about steroids in SLE is to reserve them for patients with advanced disease. Where does this leave patients with mild nephritis, that is, those with a mesangial or focal proliferative lesion not manifested by significant proteinuria, urinary casts, or evidence of advanced immune cOmplex disease? For such patients, a conservative

program of aspirin ( 1 gm/4 hr) and an antimalarial like hydroxychloroquine sulfate (2.00 mglday) is sometimes undertaken on a wait-and-see basis. For reasons that are unclear, occasional patients appear to benefit from such nonspecific treatment, to which little (less than 15 mglday) or no prednisone may be added, depending on the experience and the preferences of the physician. When there is an adverse change in clinical status - the development of marked urologic abnormalities, for example, or a drop in serum complement and a rise in DNA binding- a renal biopsy should be taken in order to be sure which sort of lesion (focal proliferative vs diffuse proliferative vs membranous nephritis) is present and as an aid to prognosis. In diffuse proliferative disease, for instance, immune complex deposits may be seen in subendothelial, intramembranous, or

patients with active SLE were treated with the thymic hormone, thymosin, the values were normalized, implying that the T-celllymphopenia of active SLE ls related to the increase in null cells, many of which may be immature T cells.

subepithelial sites; subendothelial deposits have been associated with a more severe clinical course than either of the other two. Conversely, biopsies may also be useful in evaluating response to therapy; some investigators have suggested that clinical improvement in severe disease may be accompanied by a migration of the deposits from subendothelial to subepithelial sites. The development of advanced lupus nephritis (usually diffuse proliferative disease)" has traditionally meant turning to the use of steroids. Immediately, the question is: how much? The "correct" answer necessarily varies from patient to patient, but in general terms the choices can be said to come down to these: 1) give an intermediate dose (1 to 2. mg/kg/day of prednisone) right away, then gradually taper and discontinue (if possible) as clinical and laboratory remission is induced; or 2.)

start out with as low a dose as possible (about o. 5 mg/kg/day of prednisone) and monitor for signs of improvement. My own preference is far the second approach, since I believe that the greater the dose the greater the risk of untoward side effects. A question posed in recent years regarding low- vs intermediate-dose steroid is: why not add an immunosuppressive agent like cyclophosphamide or azathioprine to the treatment program and so potentiate the steroid's positive effects while "sparing" the patient from some of its possible ill effects? The proposal was based largely on reports of favorable results with cytotoxic agents in treating New Zealand mouse disease. Although there was concern about the deleterious effects (such as inducing neoplasia or facilitating infection), it is fair to say that the proposal was greeted with some

enthusiasm. Case reports and trials soon followed and now glut the literature. Until recently, however, only three prospective, randomized, and controlled studies involving long-term (at least 18 months) follow-up had been reported, and they offered three different conclusions: 1) that one agent, azathioprine, was of no value when combined with prednisone, 2.) that azathioprine alone was an effective treatment, and 3) that the combination of azathioprine and prednisone had significant value. If that seemed to leave the issue in doubt, more recent findings have only increased the uncertainty, putting this approach, in the opinion of many, even farther back on the investigationa! shelf. First, it now appears that, in mice, long-term administration of azathioprine or cyclophosphamide frequently leads to the development of tumors, particularly lymphomas; this association may have its human counterpart in recent reports of cerebral lymphomas in patients treated with these agents. Second, two recent clinical studies with long-term follow-up suggest that any apparent initial benefit referable to the use of immunosuppressive agents may diminish greatly or disappear altogether in the long run. One study, by B. H. Hahn and coworkers at the Washington University School of Medicine, St. Louis, compared intermediate-dose prednisone alone vs intermediate-dose prednisone plus azathioprine in patients with life-threatening disease (including histologically defined nephritis in most) followed for about 18 to 2.4 months; the group assigned to combination therapy gained no additional benefit. The other study, by J. L. Decker and coworkers at NIH, compared low-dose prednisone, low-dose ·prednisone plus azathioprine, and low-dose prednisone plus cyclophosphamide in patients with diffuse proliferative glomerulonephritis followed for 2.8 months; it found azathioprine minimally effective, cyclophosphamide only slightly more so. All of this is not to say that combining an immunosuppressive agent with steroids in lupus nephritis has been repudiated. Rather, we seem to be roughly in the same position as a few years ago - awaiting the results of Hospital Practice May 1977

65

I Pulse (1 gm bolus, 3 consecutive days) Methylprednisolone pulse therapy In seven SLE patients (given eight courses of treatment) with deteriorating renal function or

carefully controlled studies on the subject, preferably those conducted on a multicenter basis, involving many subjects and using a variety of doses and schedules. In the meantime, therefore, the old low- vs intermediate-dose steroid choice has regained center stage. The first may sometimes give inadequate control of severe disease, the second,

evidence of advanced immune complex disease was associated with a reversal to baseline of creatinine values.

side effects as bad as or worse than moderate disease. One situation in which there may be an alternative, however, is a severe diffuse proliferative glomerulonephritis that manifests an interstitial component. As mentioned earlier, the interstitial lesion in lupus nephritis is characterized by changes similar to those seen in acutely rejecting kidney trans-

As in thymosln administration, methylprednisolQne pulse therapy in seven patients with severe lupu.! nephritis wa.! associated with an apparent redistribution of lymphocytes that reduced the proportion of null cells and alleviated the T -cell deficit.

66

Hospital Practice May 1977

plants. In 1974 a patient with biopsydemonstrated diffuse proliferative glomerulonephritis and a moderate interstitial lesion came under treatment at this center. All signs pointed to a rapid downhill course: he had large amounts of subendothelial deposits, depressed serum complement (C3) levels (less than 55 mg!dl); increased DNA binding (greater than 2.5%); and high urinary protein excretion (9 to 12. gm/day). Serum creatinine levels were rising acutely (1.4 mg!dl, up from 0.9 mg/dl four weeks previously). Because of the rapidly deteriorating renal function, M.A. Scheinberg, B.A. Idelson, W.C. Couser, and I decided to try a form of steroid therapy that had brought some favorable results in the management of kidney transplant rejection - an intravenous "pulse" of methylprednisolone. The pulse would be given as a 1 gm bolus on each of three consecutive days, after which low-dose steroid therapy (less than 40 mg!day) would be withheld as long as ethically possible in order to assess the effects of the pulse therapy. The first few. days and weeks after the pulse were marked by fluctuations in serum creatinine levels and proteinuria. Low-dose prednisone was begun two weeks after the pulse. After four weeks, serum C3 levels and DNA binding had returned to normal, as

had both the percentages and absolute numbers of peripheral blood T and B lymphocytes. Serum creatinine was normal and stayed so for the next 18 months, which were symptom-free. The only remaining abnormality of renal function was proteinuria, 2. 5 to 3-5 gm/day. At 18 months, the patient was readmitted with evidence of renewed immune complex renal disease. Biopsy again showed diffuse proliferative glomerulonephritis, plus more advanced membranous changes, although there was a reduction in the amount of subendothelial deposits. Another pulse was administered, and renal function again rapidly improved. Ten months after the second pulse, serum creatinine levels and urinary protein excretion were within normal limits. The patient is now being maintained on 15 mg/day of prednisone. Because of our initial patient's favorable response, we then pulsed six more patients. Like the first, four of them also had evidence of rapidly deteriorating renal function; the other two were normal in that respect but had abnormal biopsies and depressed serum C3 levels. All five biopsies taken (biopsy was contraindicated in the sixth patient) showed diffuse proliferative disease with prominent subendothelial deposits prior to therapy. Following the pulse, all patients with impaired renal function showed a reversal to normal or baseline function. All but one were started on low-dose prednisone two weeks after intravenous methylprednisolone. The total study group of seven has survived symptomfree for periods ranging from six to 30 months. Of course, these are preliminary, uncontrolled findings in a handful of patients, and one would want more data before forming definite conclusions. Such studies deserve to be repeated, however, not only to establish whether or not the improvement seen in our patients was effected by the pulse therapy but also by including renal biopsies before and after therapy, to help gain an understanding of the mechanism(s) responsible for the improvement. At present one can only speculate about these mechanisms. It has been shown, for example, that short

courses of methylprednisolone can cause a pronounced and sustained decrease in serum IgG, through increased catabolism and decreased synthesis. It is therefore conceivable that pulse therapy in lupus renal crises arrests or even reverses immune complex deposition by inhibiting antiDNA antibody synthesis. Or the explanation may be found in the formation of smaller complexes or in the creation of an excess of antigen over antibody. Or there might be dissociation of larger complexes through increased catabolism of IgG. One might thus expect a redistribution of complexes - from subendothelial sites in the basement membrane to the intramembranous or subepithelial sites associated with a more benign course. Such redistribution has been reported in patients with early diffuse proliferative disease treated with steroids and azathioprine. Pulse therapy might also improve the condition of seriously ill patients by blocking the deleterious effects of circulating lymphotoxins. In normal subjects, high-dose steroids interfere with lymphocyte traffic in the peripheral circulation causing a sudden and profound B-and T-celllymphopenia. In our patients, B-and T-celllymphopenia was evident during the first two or three weeks after pulse therapy, after which it significantly improved. Concomitantly there was a reduction in null cells that correlated well with a

rise in C3 levels and a fall in DNAbinding capacity. Thus, perhaps pulse therapy effects another sort of redistribution, this one of lymphocytes, involving a restoration of the T-cell population (as in thymosin administration) and a removal and ultimate replacement of a clone of antibody-producing B cells. In conclusion, it is to be hoped that the next few years will see significant advances in our ability to manage lupus nephritis. For that to happen, however, I think that one basic ground rule has to be observed: the task should be reserved for the large teaching centers fully capable of taking it on. SLE is a complex, often multisystem disease, and the experience of recent years has shown that, even as we come to grips with one of its lifethreatening features, another may arise to take its place (e.g., the rising incidence of CNS-related deaths in lupus). As far as the renal problem itself is concerned, however, it is now clear that optimal management is possible only after a full diagnostic profile, with all its prognostic implications, has been drawn, and that is possible only where all of the necessary technology is available. Finally, by virtue of the number of patients they treat, large teaching centers also provide the necessary data base for randomized and controlled investigations, especially when carried out cooperatively. 0

Selected Reading Bald win DS et al: The clinical course of the proliferative and membranous forms of lupus nephritis. Ann Intern Med 73:92.9, 1970 Epstein FH et al: Case 2.-1976 (Case Records of the Massachusetts General Hospital). N Engl J Med 294:100, 1976 Phillips PE: The virus hypothesis in systemic lupus erythematosus. Ann Intern Med 83:709, 1975

Decker JL et al: Systemic lupus erythematosus: contrasts and comparisons. Ann Infern Med 82.:391, 1975 Hahn BH, Kantor OS, Osterland CK: Azathioprine plus prednisone compared with prednisone alone in the treatment of systemic lupus erythematosus. Ann Intern Med 83:597, 1975 Decker JL et al: Cyclophosphamide or azathioprine in lupus glomerulonephritis. Ann Intern Med 83:600, 1975 Scheinberg MA, Cathcart ES, Goldstein AL: Thymosin-induced reduction of "null cells" in peripheral blood lymphocytes of patients with systemic lupus erythematosus. Lancet l:42.4, 1975 Cathcart ES et al: Beneficial effects of methylprednisolone "pulse" therapy in diffuse proliferative lupus nephritis. Lancet b62., 1976

Hospital Practice May 1977

67

Current concepts in management of lupus nephritis.

Hospital Practice ISSN: 2154-8331 (Print) 2377-1003 (Online) Journal homepage: http://www.tandfonline.com/loi/ihop20 Current Concepts in Management...
9MB Sizes 0 Downloads 0 Views