Immunosuppressive Therapy in Rheumatic Disease

Symposium on Rheumatic Diseases

Immunosuppressive Therapy in Rheumatic Disease Bernard Pirofsky, M.D.,* and Emil J. Bardana, Jr., M.D.**

Over the past two decades evidence has accumulated suggesting that aberrations in immune function are commonly present in a number of rheumatic disorders. A logical extension of these observations has been the development of therapeutic modalities designed to modify immunologic reactivity, in order to treat rheumatoid diseases. This review will summarize the mode of action of various agents employed in immunologic modification, the therapeutic and toxic potentials of such treatments, basic principles for their employment and the results of clinical trials in many of these disease states.

MODE OF ACTION OF IMMUNOLOGICALLY ACTIVE AGENTS Current therapeutic approaches are restricted largely to gross depression of immunologic function. Neither selectivity of action nor reliable methods of immune stimulation have been developed. The phrase "immunosuppressive therapy" is an apt description of our current capability. The ability to inhibit immune function is inclusive and nonspecific. In order to turn off or reduce the action of one clone of cells, we frequently depress or inactivate the entire immune apparatus and even inactivate the total reticuloendothelial system. This biologic sequence is understandable if we examine the pharmacology of these agents. Almost all available therapies exert their effect by interfering with the rate of growth of rapidly dividing cells. Accordingly, they are not specifically directed against immune function. Their action as immunosuppressants is a reflection of the sensitivity of rapidly growing clones of lymphocytes, presumably stimulated by continuous anti genic exposure. We can therefore antiCipate that all chemotherapeutic approaches Professor of :Vledicine and Head, Division of Immunology, Allergy and Rheumatology, University of Oregon Health Sciences Center, Portland, Oregon , '::Associate Professor of Medicine, Division of Immunology, Allergy and Rheumatology, University of Oregon Health Sciences Center, Portland, Oregon Medical Clinics of North America- Vo!. 61, No. 2, March 1977

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BERNARD PIROFSKY AND EMIL J. BARDANA, JR.

for malignancies will be immunosuppressive. Malignant cells, particularly the leukemias and the lymphomas, and other rapidly growing normal tissues such as the reticuloendothelium, the basal layer of the skin, and the gastrointestinal mucosa will also be susceptible to this inhibitory action. This becomes readily apparent when adverse reactions are examined. A large variety of growth-inhibiting agents are available. The more common groups of agents in use, with their mode of action, are summarized in Table 1. All of these materials, with the exception of antilymphocyte antisera and penicillamine, are active by virtue of depressing rapidly growing lymphocytes leading to a nonselective, generalized immunosuppression. Both humoral and cell mediated immune function are effected. Table 1. Representative Immunosuppressive Drugs and Their Postulated Mechanism of Action. CLASS

Ionizing radiation

DRUG

X-Ray ;l2P

POSTULATED MECHANISM OF ACTION

Ionization of atoms producing free radicals leading to scission of DNA chain preventing DNA synthesis.

Alkylation

HN' Chlorambucil Cyclophosphamide

Compound radicals reacting with 2 or more molecules. Function by cross-linking 2 or more DNA chains, preventing replication. Immediate or latent action depending on metabolite production.

Corticosteroids

Prednisone Methylprednisolone

Mode of action unknown. May suppress DNA and RNA synthesis, alter size of intracellular DNA pool, or be lympholytic.

Alkaloids

Vincristine Colchicine

Higher plant products. Damage or destroy cells during mitosis. May bind protein subunits of cell microtubules.

Antimetabolites

Azaserine Azathioprine Cytosinarabinoside Methotrexate

Resemble but are not identical to natural enzyme substrate. Compete for binding sites on enzyme molecule leading to feedback inhibition. Involve glutamine, purines, pyrimadines, and folic acidcontrolled methylation.

Enzyme degradation

Asparaginase

Depletion of amino acid required for some rapidly growing cells.

Antibiotics

Mitomycin C Chloramphenicol

May function as antimetabolite blocking M-RNA, in alkylation cross-linking DNA and as RNA inhibitor.

Cytotoxic antisera

Antithymocyte antisera

Cytotoxic destruction of lymphocytes, mainly T cells.

Antibody modification

Penicillamine

Degradation of IgM into inactive monomeric components.

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421

Selectivity in immunosuppression is highly desirable, but unfortunately not generally available. Several new agents such as oxisuran,78 a presumed T cell suppressant, are being evaluated for this purpose. Therapeutic stimulation of lymphocytes is also highly desirable. If selective stimulation of T suppressor cells can be accomplished, the humoral arm of immune reactivity can be selectively depressed. Experimental studies employing levamisole62 and transfer factors! are currently in progress in this regard.

THERAPEUTIC PRINCIPLES The large number of therapeutic agents employed for immunosuppression clearly indicates that the ideal drug is not yet available. Accordingly, the clinician should become skilled in the use of a limited number of drugs and develop clear principles of use needed to obtain desired therapeutic effects. Table 2 summarizes some of the pertinent information concerning several of the more common drugs utilized. One major source of confusion is therapeutic specificity, Le., whether a specific drug is indicated for a specific disease, or whether immunosuppression induced by one of many drugs is acceptable. In the latter circumstance, the clinician can choose the best drug for that particular patient relative to the state of the disease requiring therapy. For example, is methotrexate the therapy of choice in dermatomyositis, azathioprine in systemic lupus erythematosus, and cyclophosphamide in rheumatoid arthritis? Alternatively, can all of these agents be used to induce therapeutic immunosuppression in any immunologically mediated disorder? The latter viewpoint appears to be more rational. Accordingly, the diagnosis should not dictate the choice of drug. Rather, the specific characteristics of the patient, the state of disease and the variables of the drug must be evaluated in the selection of the optimum agent. This can only be accomplished by having a complete understanding of the drugs being considered. Certain pharmacologic characteristics are important. The rapidity of action and route of administration of the immunosuppressive agent can be crucial. Methotrexate has a rapid therapeutic action with its effect apparent within 36 hours. Accordingly, it is best employed in order to obtain quick action, but is poorly suited for maintenance therapy. It can be administered orally, intramuscularly, or intravenously. Oral administration of azathioprine, chlorambucil and cyclophosphamide involve long latency periods with therapeutic effects apparent after 1 to 3 weeks. These are excellent maintenance drugs, but are poorly suited for immediate therapeutic responses. Chlorambucil is not available for parenteral usage. Azathioprine can be given intravenously but is difficult to obtain. Cyclophosphamide is available for intramuscular or intravenous usage. When employed parenterally at high doses, therapeutic effects may be seen within several days; however, toxicity is often very marked in this circumstance. High dose corticosteroids can be used by all routes and have a rapid therapeutic effect.

$4.47

$16.55/100 $9.93

$12.27

1-2.5 mg/kg body wt Divided dose

1-2 mg/kg body wt Divided dose $20.45/100

50 mg tabs 100 mg vial

50 mg tabs 100-500 mg vials

Induction Maintenance

Moderate 1-3 weeks

Long 1-3 weeks Induction Maintenance

Slow 2-3 weeks

Slow 2-3 weeks

PO, IV

Imuran

AZATHIOPRINE

"Note: IV and IM preparations are substantially more expensive than the oral agents.

Monthly average oral therapeu tic cos t

$7.45/100

2 mg tabs

Dose preparations

"Cost of Drug/lOO tablets

Induction Maintenance

Therapeutic use

0.1 mg/kg body wt Single dose

Long 1-3 weeks

Persistence of therapeutic/ toxic effect when stopped

Average maintenance dose

Slow 2-3 weeks

PO, IM, IV

PO

Drug route

Speed of therapeutic action

Cytoxan

Leukeran

CYCLOPHOSPHAMIDE

Trade Name

CHLORAMB UC IL

$4.20

$17.50/100

5-10 mg/day x 3 Repeat Q 1-4 weeks Single dose

2.5 mg tabs 5,50 mg vials

Induction

Moderate 1-4 weeks

Rapid 24-36 hours

PO, IM, IV

Methotrexate

PTEROYLGLUTAMIC ACID

AMINO METHYL

Table 2. Clinical Use of Common Immunosuppressive Drugs

$2.00

$2.00/100

5-60 mg Single dose

1-50 mg tabs, various parenterals

Induction Maintenance

Short 1-3 days

Rapid 12-72 hours

PO; various IM, IV preparations

I-rednisone

PREDNISONE

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IMMUNOSUPPRESSIVE THERAPY IN RHEUMATIC DISEASE

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The long-acting or short-acting nature of the agent employed is also fundamental in the long-term management of patients under immunosuppression. After a change in dosage, sufficient time must elapse to observe the effects of the change before additional changes are made. As a general rule, when azathioprine, chlorambucil, and cyclophosphamide are being employed orally, a 2 to 3 week period is required for evaluation of the effects of a dosage. Additional changes prior to this time can be cumulative and dangerous. All therapeutic agents have undesirable side effects and immunosuppressive drugs are not an exception. The clinician must be aware of these toxic manifestations, and their potential danger must be considered in the choice of drug for individual subjects. In the patient with liver disease, it would be foolish to choose a drug with known hepatotoxicity such as methotrexate. Both cyclophosphamide and azathioprine are also hepatotoxic, although to a lesser extent. In contrast, chlorambucil very rarely induces liver damage. These problems will be reviewed in greater detail below. It is axiomatic that an optimal therapeutic effect requires the administration of appropriate dosages. This cannot be accomplished by starting a patient on a predetermined therapeutic schedule and rigidly adhering to the dose in the face of therapeutic failure. The clinician must be prepared to adjust the dosage until either a therapeutic effect is observed or toxic manifestations become apparent. The same principle is applicable when a therapeutic response develops. The clinician is then obliged to progressively reduce the therapy to determine the minimum dosage to maintain the induced remission. Corticosteroids appear to occupy a unique role in relationship to immunosuppressive therapy. Many immunosuppressive agents exhibit minimal therapeutic benefit when administered alone. However, when 10 to 15 mg of prednisone daily is given concomitant with immunosuppression at the start of therapy, remissions are generally seen. At that stage, the corticosteroids can be slowly reduced and eventually discontinued while the remission is maintained with immunosuppressive drugs. These observations would seem to suggest that the simultaneous usage of multiple immunosuppressive agents would be beneficial. It is possible to devise combined therapies such as MOPP and COPP as employed in the treatment of the lymphomas. This approach is generally not required. The majority of immunologically mediated rheumatoid diseases respond promptly and satisfactorily to a single immunosuppressant supplemented by low dose corticosteroids. Accordingly, it is unnecessary to assume the increased toxicity inherent in the use of multiple combined therapies.

ADVERSE SIDE EFFECTS The potential dangers of immunosuppressive therapy have been widely discussed. This has led to a general reluctance to use such drugs, frequently depriving patients of potentially life-saving medication or

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BERNARD PIROFSKY AND EMIL J. BARDANA, JR.

condemning them to a limited, painful, debilitated existence. Rheumatologists appear to be blessed by a therapeutic armamentarium characterized by great toxicity. Salicylates, nonsteroidal anti-inflammatory drugs, gold, and corticosteroids are highly toxic drugs with an encyclopedic list of undesirable side effects. Clinicians have accepted the limitations imposed by these toxicities for many years. In comparison, immunosuppressive therapy is frequently smooth and uneventful. It is obvious that the clinician must have a frank discussion with the patient in order to explain the potential toxicity and benefits of all available therapies, in order to choose the most appropriate drug or combination. When viewed in this light, immunosuppressive therapy will occupy an important role in the management of a select group of subjects. Toxicity from immunosuppressive therapy falls into four major categories. Table 3 summarizes the major side effects of the more common drugs employed. Toxicity Resulting from Interference with Rapid Cell Growth The reticuloendothelium, gastrointestinal mucosa and basal layer of the skin are particularly susceptible, in view of their rapid growth rate. Gastrointestinal intolerance is common with azathioprine and cyclophosphamide, less common with methotrexate, and almost never seen

Table 3.

Frequency of Adverse Side Effects':' of Common Immunosuppressive Drugs

CHLORAMBUCIL

CYCLOPHOSPHAMIDE

AZATHIOPRINE

3+

3+

2+

3+

0

2+

2+

2+

2+

4+

rare

2-i-

2,

3,

0

0

2+

2+

2+

4+

Rash/fever

rare

rare

2+

1+

0

Oral ulcers

0

0

0

4+

()

Alopecia

0

4+

1+

2+

0

AZQspermia

0

4+

0

0

0

Annovulation

0

4+

0

0

0

Hemorrhagic cystitis

0

4+

0

0

0

Bone marrow depression Susceptibility to

infection Hepatic toxicity Gastrointestinal

intolerance

METHOTREXATE

PRF.DNISONE~

( )neogenesis "·Toxicity scored from 0 to 4+ by increasing frequency.

Frequent side effects limited to corticosteroids: Aseptic necrosis, osteoporosis, cataract formation, activation of diabetes, poor wound healing, fluid retention, potassium depletion, hypertension, myopathy.

IMMUNOSUPPRESSIVE THERAPY IN RHEUMATIC DISEASE

425

with chlorambucil. Alopecia reflects involvement of the basal layer of the skin. It is very common with cyclophosphamide, rare with azathioprine and methotrexate and not observed with chlorambucil. Bone marrow depression is a major danger but should not be exaggerated. In contrast to malignancy, immunologically mediated diseases generally respond to these drugs at dose levels that do not induce significant marrow depression. The clinician should routinely follow platelet, reticulocyte and total granulocyte counts in order to effectively monitor bone marrow function. If marrow depression occurs, recovery is generally prompt with azathioprine and less rapid with chlorambucil, cyclophosphamide, and methotrexate. Prolonged marrow depression is very rare. Cyclophosphamide has the distressing ability to depress ovocyte and sperm cell growth, a side effect not seen with the other agents. Methotrexate administered orally frequently induces ulcers of the buccal mucosa, an effect not seen with intermittent parenteral therapy. Idiosyncratic Reactions As with any drug, idiosyncratic reactions can occur at any time during immunosuppressive therapy. Fever and skin rashes are not infrequent with azathioprine. There is a prompt lysis of fever when the drug is discontinued. These reactions are less common with other agents. Toxicity Resulting from Interference with Immune Function Manipulating an important homeostatic mechanism such as the immune response may be potentially dangerous. There are two major sequelae which have received great attention, but inadequate experimental study. An increased susceptibility to infection is possible. In practical terms, acute infectious disease in the absence of bone marrow depression, is very rare. In contrast, major problems with chronic, opportunistic types of infection are not uncommon. In particular, Pneumocystis carinii and tuberculous and cryptococcal meningitis may develop. On the basis of our experience, prolonged high dose corticosteroids appear to be more hazardous in this regard. Chemical immunosuppression is less dangerous, but a distinct contributing factor. It is interesting that antilymphocyte antisera exhibits little if any tendency to increase infectious susceptibility.77 Potential dangers of malignancy have received the greatest attention. It is theorized that interference with the surveillance function of the immune apparatus may permit malignancies to surface.!5 The concept is supported by an increased incidence of malignancy observed in renal transplant patients under heavy immunosuppression. 69 Extrapolating these observations to medical cases receiving immunosuppression may not be entirely justified. The oncogenic effects of the foreign graft and the host response to reject it must be given consideration. A survey by Worthington of 3000 medically immunosuppressed patients has not confirmed an increased incidence of malignancy, and at least one additional group has not observed an increased incidence of malignancy.85 In addition, evidence is accumulating that similar uremic patients maintained under renal dialysis without immunosuppression also exhibit an

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BERNARD PIROFSKY AND EMIL J. BARDANA, JR.

increased incidence of malignancy.69 A recent study in our laboratory clarifies this relationship. Using azathioprine and antilymphocyte antisera alone and in combination was shown to greatly increase the spread and incidence of virus-induced murine leukemia. However, the same animals receiving the same immunosuppressive therapy and followed for two years, without inoculation of murine leukemia virus, did not demonstrate an increased incidence of spontaneous malignancy?9 This study more closely duplicates clinical conditions and suggests that immunosuppression is not oncongenic and does not increase the developsuppressive therapy could adversely affect the severity of the malignant process. It should also be emphasized that corticosteroids are potent immunosuppressants and even salicylates depress cell-mediated immunity.4:l Accordingly, if the clinician is concerned that immunosuppressive drugs may increase the danger of malignancy, it is irrational to avoid drugs such as azathioprine and cyclophosphamide and employ high dose corticosteroids. If the concept of immune surveillance is accepted, we must assume an equal danger of neoplasia if equivalent degrees of immunodepression are induced by whatever mechanism. Semantics frequently enter into the problem and must be avoided. A drug is not safe because it is "anti-inflammatory," therapeutic because it is "chemotherapeutic," and dangerous because it is "immunosuppressive." Most of the drugs employed fit all three categories. A misunderstanding of these principles can lead to ridiculous situations. We have seen a patient in whom azathioprine was discontinued because "immunosuppression" was dangerous in the presence of leukemia, and 6mercaptopurine substituted because it was "chemotherapeutic." It is very difficult to clarify the relationship, if any, between malignancy and immunosuppressive therapy as employed in rheumatoid disease. It should be remembered that many of these diseases are associated with variable degrees of depression in cellular immunity. This in itself will theoretically enhance the development of malignancy.15 Accordingly, the respective roles of the disease and the therapies must be considered. Unfortunate anecdotes without adequate studies can totally distort this relationship. A recent letter incriminating azathioprine in the development of reticulum cell sarcoma in a patient with Sjogren's syndrome illustrates this problem. s6 The authors neglected to mention the high incidence of this malignancy in these patients, recognized long before immunosuppressive therapy was developed. Other Side Effects The individual drugs available have a variety of other side effects which can be detrimental. A simple listing of these adverse reactions, when steroids are discussed, would overwhelm this review. Aseptic necrosis, osteoporosis, growth retardation, cataract formation, gastrointestinal distress and weight gain are particularly disturbing and frequently debilitating. Methotrexate may induce hepatotoxicity, and similar but less frequent liver involvement is noted with cyclophosphamide and azathioprine. Cyclophosphamide may induce severe, life-threatening hemorrhagic cystitis.

IMMUNOSUPPRESSIVE THERAPY IN RHEUMATIC DISEASE

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It is apparent from the above review that the choice of which immunosuppressant should be employed depends on the condition of the patient and the experience with the specific drugs. In general, long-term therapy is best maintained with oral chlorambucil, azathioprine, or cyclophosphamide. On the basis of cost and freedom from toxicity, chlorambucil is superior, followed by azathioprine and then by cyclophosphamide. Methotrexate is best restricted to parenteral usage in the early treatment to induce rapid therapeutic responses. Corticosteroids appear to be the most dangerous group of drugs with the greatest number of side effects and should be used for their synergistic effect and for their rapid action during initiation of therapy or treatment of relapse. Long-term, high dose corticosteroid therapy should be avoided, if one of the other immunosuppressive agents can maintain the remission.

RESULTS OF CLINICAL TRIALS Systemic Lupus Erythematosus Immunosuppressive drugs have been employed for over a decade in the management of this disease. 5 • 11 Despite their continued utilization, many clinicians continue to doubt their efficacy.so.9s The majority of reports dealing with immunosuppressive drugs have been confined to renal, central nervous system, and cardiopulmonary involvement, characterized by a high patient morbidity and mortality.16. 26. 28. 29. 50. 52. 53. 89-92 The protective effects of immunosuppressive therapy on the progression of nephritis in the NZB/NZW murine model has encouraged similar approaches in man. 45 . 73 The initial uncontrolled studies generally concluded that either azathioprine,3.32.47.52.66 cyclophosphamide,t7.37.46.49.83 or chlorambucil,33.87 in combination with steroids, resulted in therapeutic benefits which exceeded either drug given alone. A definite steroid-sparing effect was also claimed by many investigators. Unfortunately, recent randomized studies have failed to resolve the controversy which surrounds the use of these drugs. Sztejnbok reported favorable responses with azathioprine in a randomized group of patients with a spectrum of abnormalities in systemic lupus erythematosus.92 Nineteen patients treated with conventional doses of prednisone were compared to 16 individuals managed with prednisone and azathioprine (2.5 mg per kg per day). Six of the control patients died during the 3 year study, whereas none given azathioprine succumbed. Seven of the patients treated with azathioprine were able to discontinue prednisone, compared to only 2 of the control patients. The mean maintenance dose of prednisone in the treated and control groups was 5.8 mg per day and 14.7 mg per day, respectively. Favorable responses were also observed with cyclophosphamide in a controlled, short-term study of patients with lupus nephritis. 89 Subsequent randomized studies by the same group compared cyclophosphamide, azathioprine, and placebo in lupus nephritisYo. 91 Cyclophosphamide was found to have a more beneficial effect on urine sediment, proteinuria, and serum complement in one studY,90 and on symptomatic improvement and levels of DNA antibody in another study.91

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BERNARD PIROFSKY AND EMIL J. BARDANA, JR.

Cade carefully studied 50 patients, all but one of whom had diffuse proliferative glomerulonephritis. l6 Four treatment groups were devised on the basis of their chronological order of presentation. Patients were similar with regard to their clinical and laboratory parameters. One group received high dose prednisone, one group azathioprine alone, one azathioprine and heparin, and one azathioprine plus prednisone. Patients on regimens containing azathioprine did remarkably well. Of the 15 patients treated with prednisone alone, only two survived, with a mean survival of 19 months. Mean survival in the groups treated with azathioprine ranged from 29 to 41 months. The most severe complications occurred in the groups treated with prednisone; the group which did best was that treated with azathioprine alone. Donadio found azathioprine to be of no value when used with prednisone as compared to prednisone alone. 28 ,29 In this randomized study, 9 patients with diffuse glomerulonephritis treated with high dose prednisone were compared with 7 treated with azathioprine plus large doses of prednisone. Renal biopsy was performed before and after 6 months of therapy. Both clinical activity and renal histopathology were equally well controlled in both groups. This study concluded that azathioprine added little to high dose prednisone. 28 In a follow-up report 30 months later, one patient in the group receiving prednisone had renal failure, but renal function was unchanged in all others. However, three patients in the prednisone group had been treated with cyclophosphamide or azathioprine for flares in their renal disease. Renal tissue was not reexamined in the follow-up report. 29 Donadio recently reported on 39 patients with systemic lupus erythematosus and progressive glomerulonephritis treated with either prednisone alone or combined prednisone and cyclophosphamide. No difference was seen in the two groups at the end of 6 months. After 24 months, fewer individuals showed renal progression among those treated with cyclophosphamide and prednisone than among the group treated with prednisone aloneYo Fries reported unfavorable results with cyclophosphamide in a randomized 16 week trial of a rather heterogeneous group of patients with renal and nonrenal systemic lupus erythematosus, and others with polymyositis. 41 One group of patients received prednisone, the other cyclophosphamide in small doses (1 mg per kg per day). Ten of the 22 patients with similar forms of lupus nephritis were randomized into two groups of five and all those receiving cyclophosphamide were treatment failures. Hahn reported similar results in a group of 24 patients with various forms of "life threatening" systemic lupus erythematosus. 5 She compared the therapeutic effects of prednisone at 60 mg daily initially to azathioprine at 3 to 4 mg per kg per day with prednisone in a randomized study. During a mean follow-up period of 18 to 24 months, there were no significant differences in outcome as assessed by the numbers of deaths, renal and extrarenal manifestations, and immunologic parameters. There was no evidence of a steroid-sparing effect by azathioprine. Though neither of the latter two studies was designed to evaluate the efficacy of immunosuppressive therapy in lupus nephritis, each study did arrive at negative conclusions in this respect. Hahn compared three steroid-treated patients with focal glomerulonephritis to five

IMMUNOSUPPRESSIVE THERAPY IN RHEUMATIC DISEASE

429

similarly involved individuals treated with combined therapy. However, focal glomerulonephritis is generally associated with a relatively good prognosis and would reduce the probability of recognizing differences of one treatment modality over another, particularly in the small sample studied. In the group with diffuse glomerulonephritis, 3 of 6 patients in the group treated with prednisone alone had membranous glomerulonephritis, whereas all 5 patients treated with prednisone and azathioprine had membranoproliferative changes. Lacking comparable renal parameters it is virtually impossible to select matched controls on the basis of the poorly quantifiable cardiopulmonary and hematologic features of systemic lupus erythematosus. Decker investigated cyclophosphamide or azathioprine with low dose corticosteroid therapy in 38 patients with diffuse glomerulonephritis.26 The authors concluded there was only marginal benefits obtained by cytotoxic agents in controlling systemic lupus erythematosus, though it was noted that no lupus-related deaths, renal or otherwise, occurred in the 12 patients treated with cyclophosphamide. Renal failure was noted to be twice as frequent in patients treated with prednisone alone as it was when cyclophosphamide or azathioprine was added to the regimen. In addition, a major defect in the study was the lack of classification of diffuse nephritis initially found into either membranous or proliferative types. There were no follow-up biopsies to clarify improvements in histopathology. The most convincing evidence for the therapeutic efficacy of azathioprine (and we suspect this would apply equally to other cytotoxic drugs) in diffuse proliferative glomerulonephritis is provided in the reports by Hayslett and his associates. 52, 53 Though these studies were not controlled, the histopathological documentation is unsurpassed in the literature, and the treatment regimen was designed specifically to maximize synergism of the cytotoxic drug with steroid, while avoiding complications accruing from either. Eight of 16 patients initially studied had diffuse proliferative glomerulonephritis established by biopsy prior to therapy. Repeat biopsy was performed after 24 to 36 months of combined treatment with prednisone (20 mg per day) and azathioprine (2.3 mg per kg per day). All but one had previously been treated with prednisone alone for one to 11 months without clinical improvement. In 7 of the 8 individuals there was obvious improvement in the necrotic and proliferative histologic lesions, with transformation to the more indolent form of membranous change after combined therapy. Such transformation has not been documented with exclusive steroid treatment. 52 The second report by the same group documents significant critical indices which determine prognosis and response to therapy in any given group of patients.53 Thirty-one individuals with lupus glomerulonephritis characterized by subendothelial deposits were treated with azathioprine and prednisone as outlined above, and biopsies were done again 1 to 2 years after the start of treatment. At the end of follow-up, which averaged 40 months, 12 patients demonstrated no clinical evidence of renal disease while 8 manifested a stable course with normal renal function and asymptomatic proteinuria. Eleven patients demonstrated continued clinical deterioration. Among those patients who

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BERNARD PIROFSKY AND EMIL J. BARDANA, JR.

improved or remained stable, 5 showed complete disappearance of deposits, associated with marked reduction in the intraglomerular proliferation. In an additional 11 patients, dissolution of subendothelial deposits was associated with subepithelial deposits characteristic of membranous nephropathy. In the nonresponders, subendothelial deposits persisted or increased in number. Clinicians who remain skeptical as to the role of immunosuppressive drugs in the treatment of systemic lupus erythematosus will not be convinced unless the pitfalls prevalent in previous studies can be scrupulously avoided. In addition to prospective, randomized design, future investigators must avoid: (1) arriving at any conclusions after too short a follow-up period; (2) comparing relatively unmatched patients in the vast spectrum of systemic lupus erythematosus; (3) utilizing small numbers of patients however well matched; (4) failing to keep patients in the prescribed treatment category, e.g., adding some immunosuppression to the group receiving steroids alone; (5) either employing inadequate doses of cytotoxic drugs, or blindly adhering to high levels destined to induce toxicity; (6) utilizing continuous high dose steroids which abrogate the principal purpose of the cytotoxic agent; (7) selecting patients with advanced, irreversible disease; and (8) failing to obtain reliable baseline renal biopsies with precise definition of histopathology with which to compare histologic changes after an adequate treatment interval. Characterization of renal involvement appears to offer the most accessible and reliable method of staging and evaluating therapeutic efficacy in a disease so protean as systemic lupus erythematosus. Despite the contrary observations of earlier studies,2 it has become increasingly apparent that the character of the histologic lesion, and its prognosis cannot be predicted accurately from the usual tests of kidney function or light microscopy.4. 8. 13. 19,22,53,55 Many investigators have proposed that subendothelial electron-dense deposits are noted only with very active clinical and histopathologic disease irrespective of the initial light microscopic pattern. B, 31, 34, 53 If all patients with systemic lupus erythematosus, irrespective of renal parameters, were subjected to renal biopsy at the time of diagnosis, subendothelial deposits might be used to stage the disease, initiate immunosuppressive therapy, select matched controls, and avoid the bias which would be introduced by depending on tests of renal function as the sole rationale for biopsy. Until such data are available, it is the opinion of the authors that immunosuppressive drugs can be invaluable adjuncts in the treatment of some patients with systemic lupus erythematosus." In this respect, it is of interest to note that many outspoken skeptics still continue to employ these drugs in this framework.

Rheumatoid Arthritis A significant number of patients with rheumatoid arthritis (estimated at 5 to 20 per cent) experience severe progression of disease despite adequate conventional treatment.2:J As a result, wide variety of immunosuppressive agents have been utilized including azathioprine, nitrogen mustard, cyclophosphamide, chlorambucil, and methotrexate. 25 Methotrexate has been used principally in psoriatic arthritis.'2 Azarabine

IMMUNOSUPPRESSIVE THERAPY IN RHEUMATIC DISEASE

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has also recently been found to be effective in the treatment of refractory psoriatic arthritis. 64 There have been some favorable uncontrolled reports using chlorambucil in the treatment of rheumatoid arthritis.27 The cytotoxic drugs most widely employed in the treatment of this disease are azathioprine and cyclophosphamide.2 1. 24, 25. 39, 40. 51. 94. 96 Fostick treated 108 patients with cyclophosphamide in an uncontrolled study.39.40 All patients treated had severe active disease that had been unresponsive to conventional therapy. Complete remission was noted in 29 patients. Forty-five individuals entered partial remission, 21 responded clinically, but without change in sedimentation rate, and 13 failed to improve. Eighteen patients were able to discontinue corticosteroid therapy. These observations were confirmed by a randomized study of 48 patients sponsored by the Cooperating Clinics of the American Rheumatism Association. 21 This study also compared the effects of conventional doses of cyclophosphamide (50 to 150 mg per day) with a low dose regimen (5 to 15 mg per day). This study indicated a distinct reduction in disease activity, using the higher dose regimen, as judged by grip strength, number of inflamed joints, duration of morning stiffness, and walking speed. Sedimentation rate was a poor indicator of improvement. An interesting feature of this study was the observation that serial x-ray films indicated minimal new erosions in patients receiving cyclophosphamide at 100 mg per day. There was a small group of patients who had received cyclophosphamide for as long as 5 years with continued suppression and excellent control of disease. 21 Townes reported similar results in a double blind crossover study of 24 patients. 94 Eleven patients who completed nine months of treatment on cyclophosphamide (average dose, 1.8 mg per kg per day) demonstrated significant decrease in painful or swollen joints, morning stiffness and increase in grip strength when compared to 11 patients on placebo. After crossover, significant improvement was observed in patients switched to cyclophosphamide, and deterioration was noted over several months in most patients switched to the placebo. This study did not confirm improvement in erosive joint disease. Several well controlled, double blind crossover studies have demonstrated significant improvement in patients with rheumatoid arthritis treated with azathioprine. 51 , 68. 96 The additional benefit of reducing maintenance corticosteroids was also noted. In one study, 49 patients had been taking prednisone for at least 6 months in doses ranging from 5 to 20 mg daily.68 The mean steroid requirement after one year of combined therapy was reduced 36 per cent in those on azathioprine. Steroid dosage was unchanged in patients taking placebo. In another study, definite amelioration in clinical parameters such as involved joint count and grip strength was noted in patients receiving azathioprine at 2 to 2.5 mg per kg per day.96 A recent unique study by Currey and his associates compared azathioprine, cyclophosphamide, and gold under double blind conditions in 121 patients with relatively early rheumatoid arthritis.24 Over a period of 18 months, azathioprine and cyclophosphamide produced clinical improvement comparable to that achieved with gold. Concomitant reduc-

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tion of corticosteroids was facilitated by immunosuppressive drugs, but not with gold. After a 12 to 18 month follow-up, patients treated with azathioprine and cyclophosphamide showed less deterioration radiologically than the group treated with gold. Drug management was easiest with azathioprine, but cyclophosphamide was marginally the more effective drug. This study concluded that if long-term hazards of malignancy and mutagenesis prove acceptable, immunosuppressive agents might provide a useful alternative to gold therapy relatively early in the course of the disease. Rheumatoid vasculitis poses a difficult therapeutic challenge in that the condition may be aggravated or, as some believe, precipitated by corticosteroid therapy.6o,63 Accentuation of the vasculitis process is considered part of a so-called malignant rheumatoid syndrome.1O Chlorambucil has been used in at least 9 patients with this disorder, and 6 experienced remission. 58 , 84, 93 In 5 of the latter instances the alkylating agent was given with penicillamine, which is reported to produce therapeutic improvement. 56 Polymyositis and Dermatomyositis The efficacy of treatment in these conditions is difficult to evaluate because of the spontaneous exacerbations and remissions that may occur. Controlled studies of immunosuppressive therapy have not appeared. Most investigators believe that steroid therapy is beneficiaF and Pearson has observed that patients with coexisting malignancy may show shorter periods of steroid responsiveness than those with uncomplicated disease. 75 It has become increasingly apparent that a proportion of adult patients with these conditions either respond poorly to steroids, or require maintenance therapy with prohibitive doses. Improvement has been observed when steroid therapy is supplemented with weekly injections of methotrexate in amounts of 25 to 50 mg. 67 ,68 As a result of these observations, other investigators have reported continued or similar improvement with methotrexate therapy.l, 72 In the authors' experience, azathioprine has proved equally effective in doses of 2 to 2.5 mg per kg per day, and is a much easier drug to manage. Concomitant steroid therapy can be reduced to minimal doses and, at times, be maintained in an alternate day pattern. Benson and Aldo have reported similar experiences with azathioprine.9 Findlay has mentioned, without elaborating details, some promising results with cyclophosphamide therapy in the surprising incidence of dermatomyositis among the Bantu tribe of the TransvaaP8 Other studies with cyclophosphamide were not as encouraging.41 Antilymphocyte serum has been utilized in a small number of patients with some benefits by several investigators/6, HS Scleroderma The evaluation of treatment in this disorder has been very difficult because of the slowly progressive nature of its course, the occasional spontaneous remissions which are seen, and the unavailability of objective parameters on which to assess clinical improvement. No single

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drug or combination of agents has proved to be of value in adequately controlled studies. The frequent association of scleroderma with other autoimmune disease, and particularly the similarities shared with mixed connective tissue disease, suggest the possibility of an immunologic abnormality in its pathogenesis. 5 Corticosteroids have been ineffective, and their use has generally been restricted to rapidly progressive pulmonary involvement or disabling myositis. Immunosuppressive drugs have also been disappointing in the treatment of this disease. Apart from isolated case reports, Jensen treated 21 patients in various stages of scleroderma with azathioprine.57 Eight patients were reportedly improved and two promptly suffered relapse upon cessation of therapy. The authors frankly discuss the difficulties in evaluating their results and their inability to unequivocally establish the efficacy of the drug in this disorder. Chlorambucil was utilized by Mackenzie in the treatment of 11 cases of progressive scleroderma. 65 Improvement was noted in all cases as judged by increased range of motion, decreased sclerosis of skin, healing of skin ulcers and improvement in radiologic abnormalities. Six to 12 months of therapy were required before signs of improvement were noted. This apparent success suggests that expanded controlled studies should be undertaken to confirm these results. The lack of confirmatory data over the past few years suggests these preliminary impressions may have been premature. Several reports of successful renal transplantation in patients with scleroderma with renal failure have offered some element of encouragement in a usually desperate situation. IS. 59. SI Renal involvement with associated azotemia and hypertension is a strong indicator of poor prognosis, with death usually occurring within 6 months. Periarteritis Nodosa Corticosteroids are traditionally considered to be the most effective therapy for periarteritis nodosa. In one of the larger studies, 130 patients with periarteritis nodosa were treated with corticosteroids. Forty-eight per cent of the patients treated with steroids survived five years, whereas only 13 per cent of untreated subjects survived 5 years.42 Although treatment with corticosteroids has been associated with limited success, high doses and prolonged therapy are often required. Treatment with azathioprine and cyclophosphamide, with or without corticosteroids, may ultimately prove superior, but as yet this has not been studied conclusively. Melam and Patters on described a 17 year old boy with periarteritis nodosa who had received up to 80 mg of prednisone daily without response. After institution of azathioprine, the boy went into a remission which lasted for at least 11 months.71 Over a period of 3 years, 15 biopsyproven cases of periarteritis nodosa were seen at the University of Oregon Health Sciences Center, and patients were treated with prednisone and azathioprine. 44 Prednisone was initially started at 60 mg daily and tapered to maintenance levels of 5 to 20 mg daily. Azathioprine was given at 2 to 2.5 mg per kg per day. Eight patients had hypertension and 9 had renal involvement. Fourteen patients survived a

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mean observation period of 26 months (ranging from 6 to 42 months). Three patients were considered to have a complete remission, 11 underwent considerable functional improvement with some evidence of residual renal failure and peripheral neuropathy. One fatality occurred with progressive pulmonary involvement. All but two patients required maintenance immunosuppression. 44 An unpublished addendum to this preliminary report is the fact that survivors hip has remained unchanged after 5 years of follow-up. Similar results with azathioprine and steroids were reported by Claman in a 54 year old woman with a systemic necrotizing vasculitis. 20 There are two preliminary reports6. 77 of therapeutic responses of periarteritis nodosa to antithymocyte antisera. Wegener's Granulomatosis Wegener's granulomatosis is an especially serious disorder characterized by areas of granulomatous necrosis in the upper and lower respiratory tract, vasculitis involving both arteries and veins, and focal glomerulonephritis.99 The disease is poorly understood, but electron microscopy of renal tissue has occasionally shown electron dense deposits in a pattern suggestive of immune complexes. Immunosuppressive therapy is the treatment of choice. A variety of drugs has been utilized in association with corticosteroids. Initial reports involved successful treatment with chlorambucil,54.70 but similar success has been achieved with cyclophosphamide,48,74 5-fiuorouracil and methotrexate,97 and azathioprine. 3. ·14 The largest series was reported by Wolff and involved 18 patients treated with cyclophosphamide. 99 All but four patients were also treated with corticosteroids. Long-lasting remissions were achieved in 12 of 14 patients with generalized disease, and in 4 patients with limited disease. All patients with glomerular disease had marked improvement in renal function with frequent disappearance of proteinuria and normalization of renal histopathology.35 The same group recently reported 2 patients with Wegener's granulomatosis who were in complete remission after cyclophosphamide therapy, but who had end-stage renal failure. Renal transplantation was successfully carried out, and neither patient had clinical evidence of recurrent glomerulonephritis 10 and 28 months following transplantation. 36

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