Realistic guidelines of corticosteroid therapy in rheumatic disease

Seminars in Arthritis and Rheumatism

NOVEMBER

VOL. XI, NO. 2

Realistic

Guidelines of Corticosteroid in Rheumatic Disease

1981

Therapy

By Elayne K. Garber, Peng Thim Fan, and Rodney Bluestone

INCE the early steroid trials of Hench in 1948’ in patients with rheumatoid arthritis, glucocorticosteroids have occupied a major position in the armamentarium of antirheumatic therapy. A wide spectrum of rheumatic diseases with varied pathogenetic mechanisms currently are treated with corticosteroids. Their efficacy, especially in life-threatening illnesses, has been well established.2” Over the years, much has been written about corticosteroids. There is a multitude of general reviews,7*7’ some with an emphasis on pharmacology,8-“.s5 others on the mechanisms of action’2-‘6 and tissue effects of glucocorticoids,‘7*56 and still others have dealt with the antiinflammatory and immunosuppressive effects. ‘8-2’*74Excellent reviews of the side effects are readily available.22m25 Many clinical considerations in the use of corticosteroid therapy have been stressed in past reviews. These, however, have either dealt with broad general guidelines29l30 or been limited to the implementation’0*“v’9,27*3’ and/or withdrawa17~9*26~2* of particular steroid regimens. In spite of more than 30 yr of extensive pharmacologic use, few reviews have addressed solely the clinical considerations of corticosteroid therapeutics in rheumatic disease. A comprehensive review, designed to be a practical guide to the clinical use of steroids in rheumatic disease, is currently indicated. Irrespective of the rheumatic disease being treated, or its severity, the clinician should carefully consider the following questions before corticosteroid treatment is begun: (1) What can corticosteroids be expected to accomplish? (2) Which regimen should be implemented? (3) When and how is a tapering schedule begun and

when should these specific drugs be stopped? and (4) How is alternate-day therapy achieved? This review will separately discuss each of these important aspects of corticosteroid therapy. A logical approach should be based on what we currently understand about the pharmacology and efficacy of glucocorticoids. In practice, the clinician attempts to maximize the antiinflammatory and immunosuppressive effects of corticosteroids and minimize the exogenous suppression of the hypothalamicpituitary-adrenal (HPA) axis as well as other more deleterious side effects. Since these two goals are contradictory, a successful regimen requires a thorough understanding of the degree of inflammation of the disease under treatment so that the administered drugs can be carefully tailored to its needs.

S

CHEMISTRY, STRUCTURE, AND PREPARATIONS

All steroid compounds have a common carbon skeleton. Modifications of the structure of the naturally-secreted adrenal hormone, cortisol, results in the synthetic analogs. The most frequently used glucocorticoids are diagrammed in Fig. 1. Certain structural groups are essential for preservation of biologic action. The circled

From the Medical and Research Services, Wadsworth Veterans Hospital Center, Los Angeles, Calif. Supported in part by Medical and Research Services, Wadsworth VA Hospital Center, Los Angeles, Calif Address reprint requests to Elayne K. Garber. M.D., Rheumatology Section (69//l I I J), Wadsworth VA Hospital Center, Wilshire and Sawtelle Boulevards, Los Angeles, Calif 90073. 0 1981 by Grune & Siratton. Inc. 0049-0172/81/l 102-0001$05.00/0

Seminars in Arthritis and Rheumatism, Vol. 1 1, No. 2 (November), 198 1

231

232

GARBER,

FAN,

AND

BLUESTONE

Fig. 2. Structures which are essential to antiinflammatory activity. (Reprinted with permission from Med C/in North Am 57:1158,1973.)

Fig. 1. Commonly indicate the structural the other molecules.

used glucocorticoids. differences between

differences in potency and duration of action. For example, the addition of the 1,2 double bond to the steroid nucleus accords prednisolone a fourfold increase in antiinflammatory action. Other changes, i.e., the 16 a-methyl and 9 01fluoride additions, give dexamethasone much less salt retaining activity but more antiinflammatory properties. Table 1 may serve as a guide to selection of preparations on the basis of their antiinflammatory potency and their mineralocorticoid activity.

The arrows cortisol and

areas in Fig. 2 are sites that cannot be altered without complete loss of glucocorticoid activity. The presence of a hydroxyl group at the number 11 carbon is imperative. Therefore, cortisone must be converted in vivo by hepatic enzymes to hydrocortisone (cortisol) before it is biologically active. The same is true of the necessity to convert prednisone to prednisolone in vivo. It then becomes obvious why only the 1 I-B-hydroxl compounds are employed for topical or intraarticular use. The antiinflammatory action of cortisone injected into a joint is minimal compared with the effect of hydrocortisone intraarticular-

ABSORPTION AND METABOLISM

The site of glucocorticoid absorption is probably in the upper jejunum. Peak plasma levels occur in approximately 30 min-2 hr depending upon the bioavailability of the drug (gastric emptying time, dissolution characteristics of the drug and the ability to penetrate the gastrointestinal membrane).32 Certain steroid-drug interac-

1Y. Minor differences in structure between cortisol and the synthetic analogs result in striking Table 1. Glucocorticoid

Preparations* Approximate

Antiinflammatory Potency

Hydrocortisone Cortisone

Equivalent

Sodium-

Plasma

Biologic

Dose

Retaining

Half-Life

Half-life

(mg)

POtWlCy

IminI

1

20

2+

90

(hr)

B-12

0.8

25

2+

30

8-12

Prednisone

4

5

1+

60

12-36

Prednisolone

4

5

1+

200

12-36

Methylpradnisolone

5

4

0

180

12-36

Triamcinolone

5

4

0

300

12-36

Betamethasone

20-30

0.6

0

100-300

36-54

Dexamethasone

20-30

0.75

0

100-300

36-54

‘Data compiled from references 7, 9, and 10.

STEROID

THERAPY

IN RHEUMATIC

DISEASE

tions are important. For instance, concurrent antacid administration has no significant effect on prednisolone levels attained following the administration of prednisone.j3 Thus, one may utilize antacids with steroids without concern about therapeutic interference. However, simultaneous use of corticosteroids and salicylates results in lower blood salicylate concentrations than expected since the renal clearance of salicylates is increased after corticosteroid administrathen to monitor tion.34 It would be judicious serum salicylate concentrations in a patient concomitantly taking steroids, especially while steroids are being withdrawn. Eighty percent of the circulating cortisol is bound to an cy globulin, transcortin (corticosteroid-binding globulin-CBG). When the capacity of CBG is exceeded, binding takes place with albumin. It is this albumin-bound portion along with the free steroid that diffuses into the extravascular fluids bathing tissue cells. The synthetic analogs bind CBG to a lesser degree than cortisol; they are less extensively bound to plasma albumin and diffuse more completely into the tissues. This, in part, accounts for the greater antiinflammatory potency of the synthetic analogs. The ability of steroids to bind to albumin has clinical import. Hypoalbuminemia due to liver disease,3sm37 nephrotic syndrome3* and/or other disease conditions3’ results in less protein-binding of prednisolone. These hypoalbuminemic disease states are sometimes associated with an increased frequency of corticosteroid side effects. The Boston Collaborative Drug Study3’ found that when the serum albumin concentration was less than 2.5 g/ 100 ml, the frequency of steroid side effects was doubled. Some authors claim that the increased free (unbound) prednisolone levels are responsible for the toxicity.3537,4”A nomogram depicting the inverse linear relationships between albumin and prenisolone levels has been devised; the reduction of 1 g/d1 of albumin produces a prednisolone concentration increment of 50 ng/ml.4” It is felt that the increased incidence of toxicity of highly-bound drugs (i.e., prednisolone) in the nephrotic syndrome is due to fluctuations of the unbound level between doses.3” Therefore, our practice is to slightly reduce the total steroid dosage in

233

hypoalbuminemic rheumatic disease patients to minimize side effects. The glucocorticoids are metabolized in the liver where they are irreversibly reduced and conjugated with glucuronic acid and then they are excreted by the kidney. The fact that steroid metabolism proceeds by hepatic enzyme induction was substantiated when prednisolonetreated rheumatoid arthritis (RA) patients suffered clinical relapse after they were given phenobarbitone in therapeutic dosages which resulted in decreased prednisolone half-lives.4’ The effect of liver disease on glucocorticoid metabolism remains controversial. Some observers claim impaired conversion of prednisone to prednisolone in the presence of active liver this disease.37,42 Others have not substantiated finding.43”s Delayed clearance of prednisolone in patients with active liver disease has also been demonstrated.36,37.42 This latter finding has clinical relevance since a decreased clearance rate of prednisolone has been found to be a factor in the development of corticosteroid side effects.46 The choice of steroid preparation in liver disease is not dogmatic. Some feel that the poor conversion of prednisone to prednisolone is compensated for by a delayed prednisolone clearance from the circulation.8’42 We utilize prednisolone in rheumatic disease patients with active liver disease to avoid any problems with conversion that might exist, however, we use a slightly lower dose to avoid increased toxicity from decreased clearance rates and decreased albumin binding. The plasma half-life of cortisol-that is, the time elapsed before one-half the concentration of steroid disappears from the circulation, is approximately 80-90 min. The synthetic analogs have longer plasma half-lives than cortisol (Table I). Although the steroids physically disappear from the bloodstream by 100-300 min, their biologic effects initiated at the tissue level persist for a number of hours or days. Their biologic potency at the tissue level is called the biologic half-life. This represents the duration of antiinflammatory action and is based on the duration of pituitary-adrenal suppression following a single dose of a glucocorticoid equivalent in antiinflammatory activity to 50 mg of prednisone. Thus, cortisol is a relatively short acting steroid characterized by a return of ACTH

234

GARBER, FAN, AND BLUESTONE

activity by 12 hr, whereas, dexamethasone, long acting compound, suppresses ACTH more than 48 hr (Table 1). HYPOTHALAMIC-PITUITARY-ADRENAL

a for

(HPA)

AXIS SUPPRESSION AND RECOVERY It is recognized that exogenous glucocorticoids suppress the HPA axis and that abrupt withdrawal of chronic steroids may lead to Addisonian crisis.5’*57 No matter what the dosage, the time of day when the steroid is given influences the degree of suppression. For instance, physiologic dosages of corticosteroids (i.e., 0.5 mg of dexamethasone) completely suppress ACTH release if given at midnight. However, when the same dose is given in the a.m., no suppression occurs.48 Thus, when giving a consolidated steroid dose, it is our practice to give it in the morning to best simulate the normal cortisol diurnal pattern. Overall, the two major questions to be addressed are (1) What is the minimum duration of therapy and dosage necessary to cause HPA axis suppression and (2) how long does it take after glucocorticoids are withdrawn for the HPA axis to recover? HPA AXIS SUPPRESSION

The natural order of HPA axis suppression takes the following pattern: First, the hypothalamus, next the pituitary and last, the adrenal cortex. Thus, the most sensitive indices of steroid-induced HPA axis suppression are the insulin-induced hypoglycemia and metyrapone tests followed in decreasing order of sensitivity by the lysine-vasopressin test and finally the ACTH test.4g Some workers have found that the response of plasma cortisol to synthetic ACTH does not differ materially from the response to insulin-induced hypoglycemia. These investigations, however, either did not delineate the duration of steroid therapy” or were done on untreated normal subjects.59 Thus, they are difficult to extrapolate to the clinical situation involving the corticosteroid treated rheumatic disease patient. The major difficulty in determining the minimum time and dosage required for suppression lies in the variability of the method of HPA axis testing, steroid doses and duration of therapy

encountered from study-to-study. Nevertheless, some broad interpretations are possible. Probably one of the earliest proofs that steroids affect the HPA axis comes from the demonstration of a consistent reduction in adrenal weight in patients who received cortisone for 5 days or more.‘r In another study, a blunted plasma I7hydroxycorticosteroid response after ACTH infusion was found in patients on 20-30 mg of prednisone for 5-l 3 days.‘* Two of these patients were on 20 mg of prednisone for 7 days and one patient was on 30 mg for 5 days. Other investigators have recorded decreased pituitary ACTH responsiveness by metyrapone testing in subjects treated with 100 mg daily of cortisol for 3 days.53 Combining most of the data, it appears that the earliest one may expect some biochemical changes in the HPA function would be 1 wk after beginning daily therapy with 20 mg or more of prednisone. In contrast to the above studies, other authors have demonstrated normal pituitary reserve by metyrapone testing in patients receiving 3-l 5 mg of prednisolone or its equivalent daily for l-35 mo. Here there were no abnormal results from metyrapone tests until the patient had been on continuous corticosteroid treatment for 15 mo, and there were no normal results after 35 mo continuous therapy. Thus, the time period to alter pituitary reserve in patients receiving less than 20 mg of prednisone daily is variable and cannot be easily pinpointed. A precise correlation between the clinical and biochemical status of the HPA system does not exist. Some reports attest that pituitary-adrenal unresponsiveness does not necessarily indicate that surgical stress will prove hazardous.60 Several investigators have stated their skepticism of the true clinical prevalence of adrenal suppression following long-term corticosteroid use.61*62In practice, however, it is our inclination to interpret any biochemical evidence of HPA dysfunction as a warning signal. We would rather be overly cautious and, if necessary, overtreat, with “steroid-coverage” during stress than risk potential catastrophe. Thus, if a patient has been on 20 mg of prednisone (or greater) for 1 wk we assume that the patient has some degree of HPA axis dysfunction and automatically give supplemental steroids during surgical procedures and other stressful situations.

DISEASE

235

HPA AXIS RECOVERY

similar to what occurs in people totally adrenalectomized for the treatment of Cushing disease.68,69 Four subgroups have been characterized: Type I-symptomatic and biochemical evidence of HPA suppression. Type Il-recrudescence of the disease for which the drug was originally prescribed. Type III-dependence upon corticosteroids, either physical or psychological, with demonstrably normal HPA function and no recrudescence of unqerlying disease. Type IV-biochemical evidence of HPA suppression without symptoms and without recurrence of underlying disease.” When evaluating HPA system recovery in corticosteroid-treated patients, the biochemical data should be used as a guide to the clinical situation. We do not consider a patient’s HPA axis “recovered” from steroid suppression until the rapid ACTH test gives a proper (twofold) serum cortisol response. We consider a suboptima1 cortisol response an indicator of incomplete HPA recovery and, therefore, an indicator of possible clinical danger.

STEROID THERAPY IN RHEUMATIC

Recovery of the HPA axis following corticosteroid therapy occurs in the same order as that of suppression: first the hypothalamus, next the pituitary and finally the adrenals.63 There is considerable individual variation in the rate of recovery. Both the dose and the duration of therapy seem to modulate this process. Recovery is slower if patients have received greater than 1.5 mg daily of prednisone or if they have taken the drug for more than 18 rno.‘j4 The natural history of pituitary-adrenal recovery following long-term corticosteroid therapy has been delineated by Graber and co-workers.6s Eight patients with Cushing disease and six patients who had received glucocorticoids for l-10 yr were studied. There were 4 phases of recovery: Phase l-during the first month, plasma ACTH and 17-hydroxy-corticosteroid concentrations were low. Phase 2Auring the second through fifth months, plasma ACTH leveis were supernormal while 17-hydroxycorticoid levels were low. Phase 3-during the sixth to ninth months, plasma 17-hydroxycorticoid levels were normal but in the face of high ACTH values. Phase 4--by 9 mo both ACTH and 17-hydroxycorticoid concentrations were normal with normal metyrapone testing as well. Unfortunately, the clinical aspects of HPA axis recovery are not as clearly defined as the biochemical data. Patients may be able to undergo “stress” much sooner than the biochemical information would imply.66.67 For instance, responsiveness to stress, as measured by pyrogen testing, may recover much earlier than 12 mo. In one study, purified lipopolysaccharide from Salmonella abortus-equi was injected intravenously into healthy subjects and subjects who had been on corticosteroids from 1 mo to 8 yr. Their plasma cortisol levels were then measured. It took 5 mo recovery time for patients who had been on 50 mg or more of cortisol daily. Patients on 20 mg or less of cortisol had normal pyrogen stress tests 24 hr after the drug was stopped.66,67 The gap between the clinical and biochemical picture of HPA axis recovery is exemplified by the corticosteroid withdrawal syndrome. This is an objective syndrome characterized by fever, anorexia, nausea, lethargy, arthralgias, desquamation of the skin, weakness and weight loss,

STEROIDS’ EFFECT ON INFLAMMATION AND IMMUNITY

Virtually every stage of the inflammatory and immunologic response is affected by glucocorticoids to varying degrees. It is important, therefore, to identify which effects are actually observed with in vivo administration. This will put into perspective what effects we may reasonably expect clinically with steroid administration. INFLAMMATION

The acute inflammatory response is depicted in Fig. 3. The various ways in which corticosteroids modify the normal inflammatory process are numbered within this diagram and they are correspondingly listed in Table 2. Microvasculature Glucocorticoids oppose an increase in capillary permeability (number 1 of Fig. 3 and Table 2), thereby decreasing the leakage of cells and fluids into an inflammatory 10cus.‘~ The most likely mechanism for this is that steroids have a vasoconstrictive effect on capillary beds.76.77 Steroids also have been shown to protect the

236

GARBER,

Fig.

3.

Principal

mechanisms

of the

inflammatory

endothelial lining of capillaries and venules in experimental thrombocytopenia induced in rabserum sickness, bits.78 In animals developing cortisone impeded the transit of immune complexes from the circulation across the walls Table (1)

2.

Corticosteroids:

Antiinflammatory

Microvasculature:

i

Permeability

Capillary

Blood

Endothelial tect

Flow

Swelling,

Pro-

Lining

Immune

Complex

Across

Passage

Basement

Mem-

branes (2)

1 Migration

Neutrophils:

To Inflammatory

Site

1 Adherence ?1 * Mononuclear

1 Bacterial

Killing Bone

Marrow

1 Exit; (3)

To Endothelium

Phagocytosis,

Release;

1 Margination

Monocytopenia,

Cells:

Lymphope-

nia Response

To MIF

Bactericidal

And

And

MAF

Fungicidal

Activity (4)

Mediators:

?

Antagonize

Kallikrein-Kinin

System Inhibit

Histamine

By Mast

Stimulated Affect

Synthesis

Cells

71 Prostaglandin

Release

From

Cells

Complement

Synthe-

sis Or Catabolism

?

Stabilize branes

Lysosomal

(After

Ryan

and

AND

BLUESTONE

Majno.“)

of glomerular loops and inhibited the development of glomerulonephritis.79 Thus, in man, corticosteroids may alter the inflammatory process by preventing the passage of immune complexes across basement membranes. Neutrophils

Effects

Capillary

reaction

FAN,

Mem-

The most readily achieved effects of glucocorticoid administration are associated with leukocytes.74 In this regard, the movement, traffic or distribution of neutrophils is sensitive to the effects of steroids while the actual functional performances of these cells are relatively resistant. Thus, corticosteroids exert their major influence by decreasing leukocyte accumulation at an inflammatory site (number 2 of Fig. 3 and Table 2). This has been demonstrated using both and the plastic the Rebuck8c*3 skin-window skin-chamberB4 techniques. Accelerated release of neutrophils from the marrow and decreased egress to the tissues accounts for the neutrophilic leukocytosis seen 4-6 hr after steroids are given.19.74.83 The blood neutrophil half-life is increased with prednisone administration.” Both steroid inhibition of granulocyte adherence8s~87 and granulocyte chemotaxis88-90 contribute to the interference of leukocyte accumulation at an inflammatory site. Corticosteroids in vivo have been shown to reduce neutrophil phagocytosis,” however, suprapharmacologic dosages are required. In general, the literature has not supported steroid alteration of granulocyte func-

STEROID THERAPY IN RHEUMATIC

tion with the exception of decreased nitroblue terazolium reduction9’ and decreased granulocyte adherence.8sm87 Therefore, the major effects of steroids on the neutrophils’ role in inflammation are to reduce their accumulation at the inflammatory site. Mononuclear

237

DISEASE

Cells

Glucocorticoids have a wide spectrum of effects on human mononuclear cells (number 3 of Table 2, Fig. 3). As is the case with neutrophils, the major effect lies with cell traffic. When administered to animals93,94 or man’9,95 corticosteroids cause a profound lymphopenia and monocytopenia, which is maximal at 4-6 hr following administration, with a return to normal by 24 hr. This phenomenon is consistently seen after each and every dose of glucocorticoid, whether given as a single dose or given repetitively over months to years.96 Furthermore, the same degree of lymphopenia/monocytopenia is achieved after 15-20 mg as that seen after 80-100 mg of prednisone.74 The reduction in mononuclear cells is not due to cell lysis. Like the guinea pig and monkey, man is a corticosteroid-resistant species.97 The transient lymphopenia is a result of preferential depletion of the recirculating portion of the intravascular lymphocyte ~001.~~ This depletion of lymphocytes results in redistribution out of the intravascular compartment into other peripheral lymphoid organs, mainly the bone marrow.99 The role of the spleen in this shunting process has not been firmly established.‘OO There is a greater decrease in circulating thymus-derived (T) lymphocytes compared to bone-marrow-derived (B) lymphocytes, although both populations are diminished.“’ A redistribution phenomenon most likely also accounts for the monocytopenia and eosinopenia seen after corticosteroid administration.‘” This redistribution process appears to be mediated by steroid-induced alterations in the surface characteristics of these cells.74 The net result of the changes in cell traffic is that fewer cells gather at the inflammatory site and, therefore, there is a reduced propensity for tissue necrosis. Furthermore, many immunologic functions (to be discussed under humoral and cellular immunity) require a complex interaction between lymphocytes and monocytes. Since steroids limit the

free access of these subpopulations of cells to each other, the net interactions are profoundly influenced. During an inflammatory response, monocytes and macrophages react to a variety of mediators by becoming biologically more active. They phagocytize and destroy target tissues by attaching to them via C, and F, receptors. They also release a number of enzymes which potentiate the inflammatory response. In animals, steroids interfere with the macrophage’s ability to respond to soluble mediators such as macrophage migration inhibitory factor (MIF) or macrophage activating factor (MAF).20,‘02 In high doses (50 mg of prednisone every 12 hr for 6 doses), steroids impair human monocyte bactericidal and fungicidal activity.‘03 Corticosteroids depress the phagocytic activity of the reticuloendothelial system in guinea pigs by suppressing the macrophages’ ability to recognize IgG or C,-coated erythrocytes.201’04 Physiologic concentrations administered in vitro inhibited macrophage secretion of elastase, collagenase, and plasminogen activator.‘05 Thus, both macrophage function and movement are altered by glucocorticoids. From a functional standpoint the monocyte is a much more steroid sensitive cell than the neutrophil.74 Mediators

Certain substances (i.e., kinins, histamine, and prostaglandins) play a significant role in the regulation of vascular responses and resultant inflammatory tissue injury (number 4 of Table 2, Fig. 3). How steroids affect their participation in the inflammatory response remains uncertain. Some studies have suggested that glucocorticoids antagonize the kinin system,“” but others have given conflicting reports.‘07 Hydrocortisone depletes mast cell histamine stores.‘8,20 Corticosteroids reportedly decrease the amount of prostaglandins released from stimulated cells, i.e. transformed mouse fibroblasts,‘08.‘09 but not all studies have confirmed this finding.“’ Although low levels of complement compounds have been found in animals receiving high doses of cortisone, ‘I’ it is not known whether the drug affects complement synthesis or catabolism in man.“* Glucocorticoids in vitro inhibit lysosomal enzyme release,‘13 but the significance of this in the in vivo inflammatory state is unclear.“4

238

Tissue Repair

Glucocorticoids inhibit the reparative mechanisms that follow tissue necrosis. The healing of surgical wounds and the development of granulation tissue is inhibited by corticosteroids in human subjects as well as in experimental animals when given in moderate or large amounts within the first 2-3 days after injury.23 The basic mechanism is decreased collagen formation. Glucocorticoid inhibition of collagen synthesis has been demonstrated in several in vitro studies.1’59”6 Depending on the source of the fibroblasts, steroids may either inhibit or stimulate growth.“7*1’8 Although epithelialization is not directly affected by steroids, the inhibition of the fibrous scar, which is the scaffold for advancing epithelial cells, leads to incomplete healing even at this level.” Overall, corticosteroids exert their antiinflammatory effects by decreasing the availability of inflammatory cells, by interfering with the functions of these cells when they reach the inflammatory site and by suppressing the noncellular components of the inflammatory response. Even the clinical manifestations of the inflammatory mechanisms are probably altered by steroids. Hydrocortisone inhibits pyrogen release from human leukocytes in vitro.“’ This explains the suppression of fever that is seen in many steroid

GARBER, FAN, AND BLUESTONE

treated patients suffering from infections other acute inflammatory processes.

or

HUMORAL IMMUNITY

The normal humoral-antibody response (Fig. 4) involves the passage of a soluble antigen through the circulation down to the medulla of a lymph node where it is taken up by macrophages. Through as yet undetermined mechanisms involving “helper” influences from T cells, a message is passed on to B-lymphocytes which proliferate into antibody-producing cells. Within 14 days of initial contact with an antigen, a low intensity short duration “primary response” is seen. This consists initially of IgM antibodies followed by IgG antibodies. On second and subsequent contacts with the antigen, a much more extensive and greater intensity “secondary response” occurs with IgG antibody production lasting many months or years. IgM antibodies are also produced but for the same duration and at the same intensity as in a primary response. The magnitude of the humoral resonse to antigens is modulated by inhibitory influences from T “suppressor” cells. Steroids’ Effects on Humoral Immunity

Although glucocorticoids are used extensively in the treatment of antibody-mediated disease,

Fig. 4. Humoral Antibody Response. Primary Response: Plasma cell precursors at medullsry cords and cortico-medullary junction proliferate into antibody-producing cells. Secondary Response: Plasma cells proliferate in germinal centers es well, greatly augmenting IgG antibody production. (After Turk.“‘) (Reprinted with permission from Rheumstology. Postgraduate Medicine for the Internist (1980). page 26.Y

STEROID

THERAPY

IN

RHEUMATIC

239

DISEASE

their exact role with respect to the humoral immune system is poorly understood.‘*’ Steroids mnterfere with the passage of immune complexes ,‘cross basement membranes79 and they inhibit the immune clearance of sensitized erythro;,ytes.‘04 However, beyond these effects, their .!bility to modify the humoral process is not ,bverwhelming. Possible ways in which cortico:teroids alter humoral immunity are listed in Table 3. .‘Jerum lmmunoglobulin

(Ig) Concentrations

Both animal12’ and human’22,‘23 studies have !>hown decreased serum Ig concentrations after corticosteroid administration. In man, however, these reductions have been small. Two to three (weeks after 96 mg of methylprednisolone for 3 to .i days, 86% of normal volunteers had a mean decrease in IgG of 22%; 43% had a mean decrease in IgA of 16%; and only 14% had a decrease in IgM of 6%. It was speculated that ..hese alterations in Ig concentrations were due to :In increased catabolism during drug administra.ion and by a decreased synthesis during and for .1 variable time after drug administration. Other nvestigations, however, have not found altered serum Ig concentrations in corticosteroid treated patients.‘24 The true clinical significance of these reductions in Ig serum levels when they do occur remains unkown. Immunoglobulin

Synthesis

The antibody producing ceils’ ability to synthesize Ig may be reduced with steroid use. The experimental work in support of this effect an Ig synthesis is delineated in Table 3. Using an in vitro system of pokeweed mitogen-stimulated Ig production, peripheral blood lymphocytes from normal volunteers receiving 48.5 mg of methylprednisolone, showed a consistent decrease in Ig and total protein synthesis.‘*’ This alteration in Ig production was not due to an increase in suppressor cells, but to hyporesponsive B cells. They had an intrinsic defect in their ability to respond to T helper lymphocytes with Table I. lmmunoglobulin II.

lmmunoglobulin

Concentrations: Synthesis:

3.

Corticosteroids:

Ig biosynthesis. In another investigation, decreased total IgG synthesis rates by human bone marrow was documented in immune thrombocytopenic patients treated with prolonged high dose steroids.‘26 Primary

Antibody

Response

The “primary antibody response” is normal in steroid-treated patients. For example, rheumatoid arthritis (RA) patients treated with multiple intravenous pulses of 1 g of methylprednisolone had normal primary antibody responses to keyhole limpet hemocyanin ( KLH).‘24 Secondary

Antibody

Response

The secondary antibody response probably also remains intact. A normal rise in antibody titers to the secondary antigens tetanus and typhoid have been found in steroid treated RA patients.‘24 In summary, any ability of corticosteroids to alter the humoral immune system is probably minimal. Perhaps glucocorticoids modify Ig synthesis at the cellular level and perhaps this is reflected in slight reductions in Ig serum levels. However, at the present time, the clinical relevance, if any, of these minor effects on humoral immunity remains uncertain. CELLULAR

IMMUNITY

The normal cell-mediated immune response (Fig. 5) involves several stages: (1) immune recognition; (2) immune activation; (3) lymphocyte proliferation, and (4) effector function. Initially, probably in a peripheral site, a tissuefixed antigen must be ‘recognized’ by macrophages. The macrophages play an essential role in presenting the antigen to the T-lymphocyte. Once this is accomplished, these “sensitized” activated T-cells pass down to the local lymph node where they proliferate in the paracortical areas. Within 4 days these immunologically active lymphocytes leave the lymph node. Some go on to other lymph nodes to propagate themselves. Some become long-lived “memory cells” Humoral

lmmunosuppression

?I

Serum

lg Levels

In Vivo

1

B Lymphocyte

lg And

1

B Lymphocyte

Responsiveness

1

IgG Synthesis

By Bone

Protein

Marrow

Synthesis

In Vitro

240

GARBER, FAN, AND BLUESTONE

capable of responding specifically to the same antigen upon reexposure. Others circulate as effector T-lymphocytes able to initiate a series of specific and nonspecific responses. These effector T-cells release “lymphokines,” soluble proteins such as MIF or MAF that act nonspecifically to create a milieu of local inflammation. The effector T-cells may lead to macrophage activation. The macrophage become larger and have increased capacity to kill or inhibit the replication of a variety of organisms and tumor cells. These effector lymphocytes may also become killer (K) cells capable of direct and antibody-dependent cytotoxicity. In the latter process, K cells attach via their F, receptors to antibody-bound targets and lyse the cells.

Steroids’

Effects On Cellular

rect suppression of certain immunologic functions. Such is the case with high dose steroidinduced suppression of deiayed cutaneous hypersensitivity to tuberculin. Here anergy results from decreased recruitment of monocyte-macrophages, and not from inhibition of lymphocyte function.74

tmmune

Recognition

Corticosteroids alter the normal traffic of mononuclear cells and thus decrease their access to antigen (number 1 of Fig. 5 and Table 4). Although there are fewer macrophages to “present the antigen” to the T-lymphocyte, immune recognition proceeds normally.” tmmune

Immunity

Activation

Once the macrophages reach the antigen, there is normal immune activation resulting in “sensitized” T lymphocytes (number 2 of Fig. 4 and Table 4).

Glucocorticoids have a wide range of effects on various aspects of cell-mediated immunity (Table 4). With cellular immunity, as with the acute inflammatory process, the major thrust of their actions is redirection of cellular traffic. How they accomplish this redistribution of cells is unknown.‘** Corticosteroids deplete the circulation of more T than B lymphocytes.“’ Furthermore, they preferentially deplete the circulation of the subset of T-cells that functions as helper cells in immunoregulation of human B lymphocytes. These helper cells are identified by the ability of their F, receptors to fix IgM (T,). On the other hand, suppressor cells or those T lymphocytes with F, receptors for IgG (T,) remain in the bloodstream.921’29 The limited free access of cell subpopulations to each other results in an indi-

Lymphocyte

Proliferation

Lymphocyte proliferation is probably decreased with steroid therapy (number 3 of Fig. 5 and Table 4). Both in vivo and in vitro corticosteroids decrease mitogenic blastogenesis in vitro.95,‘30-‘32 In vivo hydrocortisone administration diminishes antigenic blastogenesis in vitro.95 The fact that steroids impair lymphocyte proliferation is further exemplified by the autologous mixed lymphocyte reaction (MLR). This in vitro normally consists of T-lymphocyte response proliferation upon exposure to autologous irradiated B-cells. Physiologic concentrations of

Antigen Peripheral

Site

b

“Se”SUiZ~d”

T-lymphocyte propagates in other lymph nodes

Fig. 5. Cell Mediated immune Response. (Reprinted with permission for Rheumatology. Postgraduate Medicine for the Internist (1980). page 28.-j

STEROID THERAPY IN RHEUMATIC

Table 4.

Corticosteroids:

1. lmnwne reccg”lric”7

241

DISEASE

Immunosuppressive

Redstributwn

of mmmucle81

Effects

cells traffic

1 Access to B”flgen 2.

,mm”n*

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steroids in vitro cause a profound decrease in this T-lymphocyte proliferation.‘33 The effect of steroids on MLRs involving unrelated (allogeneic) cells remains controversial.‘3”m’3hAn exciting and intriguing explanation for the steroid suppression of generalized lymphocyte proliferation is the finding that glucocorticoids inhibit a factor probably produced by mononuclear cells that controls lymphocyte proliferation. Pharmacologic concentrations of dexamethasone in vitro have been shown to inhibit the production of T-cell growth factor (TCGF), a substance which stimulates clonal expansion of activated T-cells. If TCGF is added back to the steroid-treated cultures, normal lymphocyte proliferation in response to mitogens, antigens or MLRs occurs.‘37m’39 Ejtctor

Function

Lymphocytes have normal lymphokine production when exposed to glucocorticoids (number 4 of Fig. 5 and Table 4). However, the macrophage’s response to these mediators is diminished.‘9.96 Corticosteroids are capable of lessening the ability of lymphocytes to kill antibody-coated targets (antibody-dependent cellular cytotoxicity (ADCC).14’ However, the demonstration of this ADCC suppression in vitro depends on the selection of both the target cell and the effector celli Therefore, it is uncertain whether the direct inhibition of ADCC is a clinically relevant mechanism of steroid action.14’ There is also controversy as to whether glucocorticoids inhibit the generation of cytotoxic lymphocytes in vitro and/or reduce the activity of sensitized killer cells.‘35~‘36~‘40~‘42 Thus, known aspects of glucocorticoid effects on cell-mediated immunity are complicated. Steroids probably only mildly effect lymphocyte proliferation and effector function. The most

profound influence on cell-mediated responses is the limited access of cell subpopulations to one another. Consequently, the net cell-cell interactions is markedly changed. Overall, the majority of the immunosuppressive actions of steroids are directed more toward the cell-mediated rather than the humoral limb of the immune system.‘43.‘44 The translation of the antiinflammatory and immunosuppressive properties of corticosteroids to the clinical situation is difficult and involves answering the following question: What can steroids

be expected to accomplish?

Glucocorticoids cannot be expected to “cure” any disease process for many reasons. They are unable to remove the injurious agent or antigen from the body. They do little to impede the humoral immune process and probably only moderately effect cell-mediated immunity. Thus, corticosteroids’ main efficacy is not in eradicating the initiating event, but instead, is in reducing the net tissue injury. In general, the clinician can anticipate the greatest benefit from therapy when the corticosteroids are implemented to suppress inflammation. The inflammatory event will be modified irrespective of whether it is provoked by an immunologic or nonimmunologic stimulus. After the administration of steroids, one can inevitably expect less evidence of apparent tissue injury: less cutaneous erythema, warmth ulceration or swelling; reduced joint effusions and pain; less proteinuria, pyuria, hematuria or cast spillage. The clinician can also expect a generalized improvement in the systemic manifestations of the disease process with improvement in the erythrocyte sedimentation rate (ESR) and attenuation of fever and general malaise. Keeping in mind steroids’ main actions, it then becomes evident why glucocorticoids are given in certain disease states. The allergic diseases represent the full blown expression of mast cell degranulation with histamine release, kallekrein-kinin system activation and resultant vasodilatation, tissue edema and wheal and flare reaction. Glucocorticoids modify all of these inflammatory processes. Thus, corticosteroids are used in angioneurotic edema, severe drug reactions/contact dermatitis, urticaria, and serum sickness. A further expression of the use of steroids to modulate disruption of blood

242

GARBER. FAN, AND BLUESTONE

pulmonary edema and alveolar cell damage is the administration of pharmacologic doses of methylprednisolone is “shock lung syndrome.“‘45 Blood dyscrasias may be the consequence of antibody-mediated red cell destruction. Although steroids do not prevent the antibody production, nor its attachment to target tissue, they interfere with the splenic removal of antibody-coated targets. Therefore, glucocorticoids are the first-line therapy for acquired and autoimmune hemolytic anemia and idiopathic thrombocytopenia purpura. Several gastrointestinal diseases represent local acute inflammatory reactions coupled with mucosal granuloma formation. The monocyte is the primary cell involved in the formation of granulomata. Corticosteroids reduce local tissue damage, hyperemia, and pus formation. Furthermore, they decrease recruitment of monocyte-macrophages. It follows then that systemic or local steroids are utilized in regional enteritis. The body’s response to organ transplantation is probably the ultimate expression of cellular immunity. There is the possibility that steroids suppress ADCC, the generation of cytotoxic cells and their killer activity in the clinical situation. Thus, suprapharmacologic doses of glucocorticoids are administered to prevent transplantation rejection based on the rationale that the drug will diminish inflammation and hopefully also attenuate cell-mediated immune destruction. vessels,

readily each regimen’s potential.

limitation

as well as its

DAILY HIGH DOSE

Daily high dose therapy implies the use of greater than 15 mg of prednisone or its equivalent a day. This treatment schedule given over an extended period of time has the greatest antiinflammatory and immunosuppressive potency, but also the greatest amount of long-term undesirable side effects such as Cushing syndrome (Fig. 6), osteoporosis, myopathy (Fig. 7), and cataracts. There is a significant correlation between acute psychiatric reactions and steroid dosage, most reactions experienced when the dose exceeds 80 mg per day.‘46,‘47 As previously noted, patients taking daily high dose steroids for longer than 1 wk will inevitably have HPA axis suppression. After each prednisone dose, there is a transient neutrophilia that returns to baseline by the the cutaneous next morning.‘48 Concomitantly, inflammatory response (measured by Rebuck skin window technique) is reduced and the

STEROID REGIMENS

There are four ways to give corticosteroids: high and low daily doses, high dose intravenous “pulses,” and alternate-day dose. The choice of regimen is based on an understanding of both the nature of the rheumatic disease process and the efficacy of each steroid modality. The decision to use a particular regimen represents a trade-off between that regimen’s benefits and adverse side-effects. As the disease process comes under control, the clinician switches from one regimen to another, always aiming at lowering the risk of steroid-induced morbidity. Thus, the clinician must be armed with the knowledge of each regimen’s actions on the HPA axis, as well as its effect on the inflammatory, humoral and cellular immune processes so that one may recognize

Fig. 6. A 50-y-old female who received 20-30 mg of prednisone daily for 2 yr with Cushing syndrome manifested by centripetel obesity, hirsutism, and striae.

STEROID THERAPY IN RHEUMATIC

DISEASE

Fig. 7. Biopsy proven steroid-induced proximal myopathy in a patient after 1 yr of 40 mg of prednisone daily. Right deltoid biopsy showed Type II fiber atrophy without any cellular infiltrate.

neutrophil half-life is prolonged. A direct correlation exists between the dose of prednisone given and the degree of neutrophil half-life prolongation. This neutrophil half-life prolongation indirectly reflects the neutrophils’ exclusion from inflammatory sites. Thus, 60 mg of prednisane has greater antiinflammatory efficacy than 15 mg of prednisone. Furthermore, if the same total prednisone dosage is given in divided doses throughout the day, a greater reduction in neutrophil response is achieved than with single dose therapy. Therefore, divided as opposed to single dosing of equivalent steroid amounts has greater antiinflammatory activity. For example, RA patients required a 20% larger prednisolone amount as a single daily dose to obtain the same therapeutic response as that achieved with four divided daily doses.‘49 Lymphopeniay3 and monocytopenia’48 occur with chronic steroid use. A transient depression is seen after each dose, with return to baseline values by 24 hr. Chronic steroid treatment results in depression of certain cell mediated lymphocyte functions.‘50 In the clinical situation, patients on 40 mg of prednisone/day will have their tuberculin reactivity suppressed after 1 mo of therapy. Patients receiving chronic corticosteroids at a dose of greater than 15 mg/day will be very unlikely to retain intermediate-strength tuberculin reactivity.‘5’

243

daily have increased susceptibility to infections.‘9.‘s2 Definite proof of this clinical observation is hard to document because of the difficulty in finding reasonable clinical control groups to compare with patients treated with corticosteroids. Furthermore, the specific diseases for which the steroids are utilized as well as the generalized debilitation of the host predispose and contribute to an increased frequency of infections. The overall infection rate, for example, in patients with SLE is significantly higher than in those with RA. Infection rate and number of disseminated infections increase in lupus patients with increasing doses of corticosteroids and decreasing renal function.‘s3 Recognizing the limitations of clinical studies, some infections (listed below) are thought to be more frequent and possibly more severe in steroid-treated patients. Certainly, the duration of steroid therapy contributes to the threat of infection.‘54 The host defect in defense against infection induced by corticosteroids is broad and spans the inflammatory and immune systems. Thus, an infectious complication in a steroidtreated patient may be caused by both usual as well as unusual and opportunistic pathogens. One may encounter any of the following infections in the steroid treated patient:‘9,23.‘80 Bacterial-Staphylococcus, gram-negatives, listeria, tuberculosis;‘55 Fungal-Monilia, aspergillus, nocardia, cryptococcus. Viral-Varicella, herpes zoster (Fig. 8); vaccinia, cytomegalovirus, herpes simplex, variola; Parasites-Malaria, amoeba, strongyloides, pneumocystis carinii, toxoplasma.

lnfectiom

It is not surprising, therefore, that patients treated with greater than 20 mg of prednisone

Fig. 8. Herpes zoster in a patient with SLE receiving daily high dose corticosteroids.

244

GARBER. FAN, AND BLUESTONE

PULSE

METHYLPREDNISOLONE

“Pulse” methylprednisolone therapy involves giving 1 g of methylprednisolone (MPS) intravenously on 1 or 3 days consecutively. The methylprednisolone is usually mixed with 50 ml of 5% dextrose and water and given as an infusion over 45 min. The “pulse” is given slowly to avoid abrupt potassium and fluid shifts that could lead to acute hypo- or hypertension, central nervous system changes, peripheral edema and/or congestive heart failure. Sudden deaths have followed direct methylprednisolone boluses into veins. A few overwhelming and fatal infections have occurred in rheumatic disease patients in close proximity to their pulse therapy.‘56 Usually, however, this mode of therapy has few significant side effects. Transient symptoms include a metallic taste, flushing, weakness and arthralgias/arthritis. This form of therapy may be abruptly withdrawn, since it is generally felt that this intensified short course of steroids does not cause HPA axis suppression. One g of methylprednisolone given to normal volunteers produces an increased neutrophil count much greater than that seen with 80 mg and that stays elevated for up to 72 hr after infusion. Neither phagocytosis nor intracellular killing by peripheral leukocytes is impaired with the “pulse.“‘57 A profound but transient lymphopenia occurs after 1 g of MPS intravenously.“‘~” Three

consecutive infusions do not produce any greater decrease of circulating lymphocyte subpopulations or total counts than a single 1 g pulse. Furthermore, the magnitude is not different from that following 60 mg of prednisone orally.‘2’ Decreased mitogen responsiveness of peripheral lymphocytes occurs after 1 g of MPS, but again, there is no difference between various steroid doses’57 including 50 mg, 1 g or 3 consecutive I g doses of MPS.ls8 Normal cutaneous delayed hypersensitivity and normal primary and secondary antibody responses to specific antigens have been encountered after both 1 or 3 daily 1 g i.v. doses of MPS.12’ Suprapharmacologic steroid dosages given in the form of “pulses” compared to high dose daily therapy have several advantages. The “pulse” has fewer long-term side effects, but at the same time has equivalent immunosuppression and perhaps greater antiinflammatory action. DAILY

LOW

DOSE

Low dose chronic therapy involves ingestion, each morning, of from 2 to 15 mg of prednisone. Although steroid side-effects are generally less severe than those seen with daily high dose therapy, many of the same sequelae such as Cushing syndrome and avascular necrosis (Fig. 9) will become apparent if low-dose treatment is continued for several years. This form of therapy partially spares the HPA axis, particularly if the

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8/24/71

Fig. 9. Evolution of evescular necrosis of the femoral head in a patient taking 15 mg of prednisone per day over a 2-y period.

STEROID THERAPY IN RHEUMATIC

DISEASE

dose is less than 5 mg daily. One study found no incidence of HPA axis suppression of insulinhypoglycemia testing in 13 patients with rheumatoid or psoriatic arthritis treated for up to 40 mo with 5-10 mg of prednisolone daily.“’ In another study, blunting of the serum cortisol response to ACTH occurred in some arthritic or asthmatic patients on up to 15 mg of prednisane daily for up to 19 yr. However, none of these patients had complete adrenal suppression.‘hO Because the HPA axis is not completely intact in some patients taking low doses of the drug, it is our practice to automatically implement supplemental corticosteroids during periods of unusual stress such as general anesthesia. The minimal risks of the supplemental steroids are much more acceptable than the risk of death in the anesthetized adrenal-suppressed patient. The antiinflammatory and immuosuppressive effects of low dose steroid therapy are less than with high-dose therapy. There is less neutrophilia with low-dose therapy and, consequently, probably less antiinflammatory activity than seen with high dose steroids. Patients on daily low-dose steroids tend to retain their intermediate-strength tuberculin reactivity,15’ and they tend not to have serious infections. This is especially true if patients are taking less than 5 mg prednisone daily. If the corticosteroid dosage is given in divided doses throughout the day, there is increased antiinflammatory and immunosuppressive potency compared to single dose therapy.‘9.‘49 Unfortunately, however, many of the advantages of the single low dose chronic regimen are lost. Greater HPA axis suppression results’59 if the steroids are given in divided doses. It is our policy, therefore, to avoid the potential side effects of split dose corticosteroid therapy. When we give low dose corticosteroids, we give them as a single a.m. dose. ALTERNATE-DAY

Alternate-day steroid administration involves giving the steroid dose as one morning dosage every 48 hr. This form of therapy has many advantages. Reduced side effects have been documented using this regimen in patients with a variety of diseases.‘(” Children receiving alternate-day therapy have relatively normal linear growth rates when compared to children receiv-

245

ing daily steroids.261’62.‘63 Some investigators have not found any infectious complications in their rheumatic disease patients on alternate-day prednisone.” With few expectionslh4 preservation of the HPA axis has been demonstrated by insulin-induced hypoglycemia testing in rheumatic disease patients’65*‘66 and by cortisol secretion rates in asthmatics”’ initially placed on alternate-day therapy. However, when patients are being transferred over from a daily to an alternate-day regimen, one can expect a slower HPA axis recovery time. Patients on alternate-day therapy may not require increased steroid coverage for periods of stress, but in general, as is the case with low dose steroids, it is safer to give supplemental steroids to cover surgery and general anesthesia. The effects of alternate-day steroid usage on inflammation and immunity are interesting. Neutrophilia, monocytopenia and reduced Rebuck skin window responses of monocytes is seen on the “on” day when prednisone is given. In contrast, on the day “off’ prednisone, the leukocyte counts, inflammatory responses and neutrophil half-life are normal.‘48 Similarly, granulocyte adherence is inhibited on the “on” day concomitant with a prolonged granulocyte intra-vascular half-life, but adherence returns to normal on the “off’ day when neutrophilic halflife is normal.” With every 48-hr cycle, a transient lymphocytopenia ocurs within 4--6 hr after drug administration with a return to normal counts by the next morning.‘68 Diminished cellular immunity on the day the steroid is given, but not on the day off steroid is also found.‘hx~‘“9 Although not substantiated by all authors,“’ most have found preservation of cutaneous delayed hypersensitivity in patients on alternateday steroid therapy.‘5’,‘68 Normal antibody responses to specific antigens have also been seen.‘72 Thus, alternate-day steroids modulate the inflammatory and immune processes with minimal, if any, adverse side effects. Now that all the regimens have been reviewed, it becomes clear what can be expected from each method of administering steroids. Daily high dose therapy can be expected to suppress the cumulative effects of both the inflammatory and immunologic processes. “Pulse” methylprednisolone administration can be anticipated to deliver a short intensified

246

antiinflammatory barrage. Low dose chronic therapy can be expected to participate as adjunctive therapy in maintaining an already suppressed inflammatory or immunologic process at a subclinical level. When given as the initial therapy, low dose corticosteroids can be anticipated to suppress only mild inflammatory and immunologic reactions. Alternate-day therapy can be expected to intermittently suppress cell availability or function, thus, prophylactically preventing the re-expression of a quiet and suppressed, but potentially active disease process. Our second question regarding steroid therapeutics may now be addressed: Which steroid regimen should be implemented? When there is life-threatening or fulminant systemic illness, then the most potent steroid regimen, daily high dose therapy, must be used. Among rheumatic diseases, such a setting occurs with polymyositis; SLE nephritis, hemolytic anemia, thrombocytopenia, or cerebritis; polyarteritis nodosa; and temporal arteritis. Sufficient quantities of steroids are mandatory to bring the disease activity under rapid control. “Pulse” methylprednisolone therapy might be implemented in the following situations: (1) Overwhelming disease activity; (2) ‘Desperation time’ when all other forms of therapy have failed; (3) Disease relapse on conventional oral steroid doses; (4) As a ‘steroid-sparing’ measure to prevent an increase or permit a decrease in the daily oral steroid regimen: and (5) To contain disease activity until other slower acting agents take effect. The clinician will encounter most of these situations when treating patients with SLE cerebritis and nephritis,4*‘73 polyarteritis nodosa, ‘74other systemic necrotizing vasculitides and severe unremitting RA. Pulse methylprednisolone has also been used in rapidly progressive idiopathic glomerulonephritis.‘75-‘77 When an inflammatory condition cannot be controlled with less toxic therapy, then low dose steroids are utilized. Such is the case with RA or mixed connective tissue disease (MCTD) when the polyarthritis is unremitting and unresponsive to more conventional modes of therapy. When the disease is still present but the acceleration has been checked, then low dose steroids are implemented to continually prevent full-blown disease expression. For instance, low dose

GARBEA, FAN, AND BLUESTONE

chronic therapy is utilized to keep SLE nephritis or cerebritis in check once remission has been induced. Low dose steroids are never implemented in life-threatening situations. When long-term steroid usage is anticipated in a disease where the activity is already under control, then alternate-day therapy is implemented. This regimen is used to prevent disease reacceleration. It is utilized to minimize undesirable side effects. Alternate-day therapy is never used in rheumatic diseases to induce remission. When the clinician anticipates eventual steroid withdrawal, then alternate-day therapy is implemented to facilitate the transition toward complete discontinuation of steroids. GENERAL GUIDELINES

Considerations Before Corticosteroid Use The seriousness of the underlying disorder must be evaluated. If the rheumatic disease process can be managed with less toxic agents, then corticosteroids should not be employed. If the process is limited to the skin, then topical rather than systemic steroids may suffice. Intraarticular corticosteroids for the management of localized arthritis are preferable to systemic steroids. Usually it is the unremitting activity and severity of the rheumatic disease which dictate the need for glucocorticoid therapy. Even in the face of the known hazards of steroid therapy, when a patient is critically ill with a necrotizing systemic vasculitis, corticosteroid therapy cannot be withheld. The clinician, however, should be aware of any predisposition a patient may have to any of the known glucocorticoid side effects:29 diabetes mellitus, osteoporosis, peptic ulcer/gastritis, tuberculosis, hypertension, psychological difficulties. If long-term therapy is anticipated, certain adjuvants may be used early to diminish undesirable side effects. For example, restriction of sodium intake may reduce the fluid retention and hypertension of long-term use; increasing both calcium and Vitamin D intake may help prevent the development of osteoporosis; and antacid or cimetidine implementation may expedite the healing of gastroduodenal lesions :n patients taking steroids. If long-term therapy is anticipated, one should aim for eventual alter-

STEROID THERAPY IN RHEUMATIC

nate-day therapy once the disease activity is held in check. The clinician must always try to find the minimum effective steroid dose. This optimum dosage minimizes adverse side effects but at the same time keeps the disease under control. Once the decision has been made to administer glucocorticoids for any rheumatic disease, the choice of preparations is easy. Long acting drugs which will lead to prolonged suppression of the HPA axis e.g. bethamethasone and dexamethasone, arc avoided. Because of the high mineralocorticoid properties of cortisol and cortisone, these agents are also not used. Prednisone and prednisolone are the most commonly used oral preparations, Methylprednisolone is reserved for intravenous use. especially with “bolus” theraPY.

Steroid

Supplementation

During Stress

If patients are taking corticosteroids or have an inadequate response to a short pulse of exogenous ACTH, they are given 100 mg of cortisone acetate intramuscularly or 100 mg of hydrocortisone sodium succinate intravenously the night before surgery and then 100 mg of hydrocortisane intravenously every 8-12 hr on the day of surgery.28 Depending on the degree of ‘physiologic stress’ during the first few postoperative days, the total hydrocortisone dose may be reduced by fifty percent and then gradually tapered, or the patient may be placed back on the original steroid regimen. Hydrocortisone and cortisone are used as supplementation because they possess adequate mineralocorticoid activity but only suppress the HPA axis for 8812 hr. When and How to Reduce Steroids

Surgery We do not perform the ACTH stimulation test on patients currently receiving corticosteroids.‘%iRO Supplemental steroid coverage for surgery is automatically given if they have taken steroids for over a week. The risk of high-dose short-term sterqids to cover the stress of surgery is minimal. Patients who have received corticosteroids in the past year but are not on the drug at the time of operation are given an ACTH challenge. HPA axis recovery time is variable from individual to individual and the adrenals are the last of the HPA axis to recover. It has been shown that an unsatisfactory response to the intravenous ACTH test correlates with an inadequate adrenal response to surgery.“’ Conversely, a preoperative satisfactory response to exogenous corticotrophin corresponds to normal plasma cortisol levels throughout surgery.‘** ACTH

247

DISEASE

Test

After a base-line plasma cortisol determination, 250 PLgof synthetic ACTH (cosyntropin) are given intramuscularly and a repeated plasma cortisol is obtained 30-60 min later. An increment in plasma cortisol of greater than 6 Kg/ 100 ml and a maximum cortisol level greater than 20 pg/lOO ml is normal. When this response has been reached, the physician can assume that pituitary-adrenal recovery is complete.**

When to taper. The decision to reduce the daily steroid dosage is reached: (I) When the disease activity is controlled; (2) when antirheumatic long acting agents are added to the patient’s regimen providing a steroid-sparing effect and the disease is held “in check;” or (3) when the ravages of steroid side effects are so overwhelming that reduction in dosage is mandatory. For instance, temporal arteritis can usually be controlled by high dose prednisone therapy. Once the Westergren sedimentation rate has returned to normal, the daily dose of prednisone may be tapered. Methotrexate given intravenously in polymyositis has proved to be a steroid-sparing agent;ls3 its use allows a tapering of steroids without exacerbation of the myositis. Collapsed vertebral bodies (Fig. IO) and cataracts are two consequences of steroid therapy which often dictate a reduction in steroid dosage as soon as possible. How to taper. The rate of steroid reduction is influenced by: (I) How long the patient has been on steroids; (2) what the underlying disease and its clinicial activity are; (3) whether steroids are the only agents used; and (4) from what dosage level the tapering is initiated. For example, one might proceed more slowly if the patient had been on steroids for years rather than a few weeks or months. One would proceed with extreme caution in tapering when dealing with a widespread potentially lethal necrotixing vasculitis, whereas chronic polyarthritis might not

248

GARBER. FAN, AND BLUESTONE

daily dose by 1 mg every 3 wk until a 5 mg total dose is reached and; finally, reduce by 0.5 mg every mo until the patient is totally weaned from steroids. Complete withdrawal may take more than a year and can be tedious. At all times it is the delicate balance between disease suppression and disease reactivation which determines the pace at which one proceeds. How Is Alternate

Fig. 10.

Steroid-induced

vertebral

body collapse.

cause as much trepidation. It is comforting when reducing steroid dosage to know that other immunosuppressive or antiinflammatory agents are being utilized and are effective in controlling the disease. If one begins tapering steroids from 40 mg of prednisone daily, then initially one does not have to go as slowly as from a starting level of 10 mg daily. If a patient has been on steroids for only a few weeks, the prednisone dosage can be dropped from 40 mg to 10 mg the first week, then 10 mg to zero the second week. On the other hand, for patients who have been on long-term steroid therapy, the following rules are advised: Daily Prednisone > 40 mg 20-40 1O-20 5-10 <5 Example: daily for manner: mg daily mg every

Dose

Decrement 10mg 5 2.5 1 0.5

A patient taking 30 mg of prednisone 2 yr can be withdrawn in the following Reduce the dose by 5 mg/wk until 20 is reached; then reduce the dose by 2.5 2 wk until 10 mg daily; decrease the

Day-Therapy

Achieved?

Alternate day conversion is attempted: (1) Once disease activity is controlled; (2) once anti-rheumatic long acting agents have been added to the regimen providing a steroid-sparing effect and the disease is held “in check”; or (3) once deleterious side effects are so over whelming that steroids must be reduced. To minimize side effects alternate-day corticosteroids should be used as early as possible in the course of the disease. There are several ways to convert daily to alternate-day therapy. Two important reminders are not to go too quickly, for disease activity will relapse and try to make the patient as comfortable as possible with nonsteroidal antiinflammatory drug supplements on the day “off’ prednisone. An effective way to convert to alternate-day therapy is to double the daily steroid dose on the first day and then reduce the dosage on the alternate day.27 For example, if a patient is on 40 mg of prednisone, give 80 mg on day I and 40 mg on day 2. Then begin to taper the alternate 40 mg/day dose to zero. The previous guidelines on the size of the decrement to use also apply to this process. An example of conversion to alternate-day treatment in a patient who has received 40 mg prednisone daily for 6 mo or less would be: 1st week: 80-40-80-30-80-25-80; 2nd week: 20-80-l 5-80-I 2.5-80-I 0; 3rd and 4th week: gradually reduce 80-l 0 to 80-O. Another form of conversion from daily prednisone to alternate-day treatment involves incremental increases and decreases of 5 mg. In our experience, this method is not as effective as the first. For example: 1st week: 40-45-35-50-3055-25; 2nd week: 55-25-60-20-60-20-65; 3rd week: 15-65~15-70-10-70-10; 4th week: 755-75-5-80-O-80. The rapidity with which these dosage changes

249

STEROID THERAPY IN RHEUMATIC DISEASE

can be made depends on the duration of previous daily therapy and the adequacy of control of the underlying disease activity. The conversion process can be difficult and time consuming but if one goes slowly in changing the dosage, one can usually effect the transition from daily to alternate-day therapy with ease and confidence. When the alternate-day regimen has been achieved. slow and cautious reduction of the total steroid dosage is continued in an attempt to use the minimum dose that will effectively suppress the spontaneously fluctuating level of underlying disease activity.

When Should

Steroids

Be Discontinued?

Steroids should be terminated when the disease process can be controlled with less toxic agents. For example, the fever, malaise and peripheral neuropathy of rheumatoid vasculitis are frequently controlled with high dose corticosteroids.‘X4.‘85 Usually, however, other long-acting agents such as penicillamine are added to the takes effect regimen. Once the penicillamine (after a few months), the steroid dosage is reduced. If the penicillamine completely suppresses disease activity, then the corticosteroids are eventually stopped. When remission of disease activity has been induced and/or there is no evidence of ongoing disease activity, then corticosteroid therapy may be terminated. For instance, eosinophilic fasciitis, a syndrome of unknown etiology characterized by skin induration, hypergammaglobulinemia and peripheral eosinophilia, is corticosteroid responsive.‘8h~‘9’ If the skin returns to normal consistency and the laboratory parameters revert to normal either spontaneously or due to steroid treatment, then the prednisone dosage is tapered and eventually withdrawn totally. As previously discussed with regard to the HPA axis, unless a patient has received “pulse” therapy or therapy for less than a week, steroid treatment should not be abruptly halted. The clinician may confidently terminate steroids in a patient receiving either low dose or alternate-day therapy especially if the dosage is less than 5 mg once a day or on alternate days. Select rheumatic diseases are discussed in the following sections to illustrate each of the ways corticosteroids are used. They serve as proto-

types of dosage adjustments and timing and can be extrapolated to other clinical settings. Temporal

(Giant Cell) Arteritis

Temporal arteritis is a serious disorder of the elderly characterized by local symptoms (temporal headache, blindness, jaw claudication) and/ or generalized systemic reactions (fever, anemia, malaise, weight Ioss).‘~*~‘~~ Hallmarks of this disorder are a rapid sedimentation rate and histologic evidence of granulomatous vasculitis. Corticosteroids are implemented as described in Table 5 to arrest the disease and prevent vascular complications. Initial doses are 45-60 mg of prednisone antiinflammatory daily.19(’ For the maximum effect, the steroid is given in divided doses (20 mg every 8 hr) throughout the day. This divided dose schedule is continued until all symptoms are gone and the laboratory tests return to normal (usually 2-4 wk). Once the disease is brought under control, the total dosage is consolidated to a morning dose. If the Westergren erythrocyte sedimentation rate (ESR) remains in the normal range, a program of gradual prednisone reduction is initiated. Thus, the total prednisone dose may be tapered to 40 mg within a 2-wk period as long as the sedimentation rate is normal. From this point, the weekly decrements should not be greater than 10% of the daily dose. If the ESR temporarily rises, or if the patient has mild symptoms e.g., musculoskeletal aches and pains, further reductions of prednisone are interdicted. Subsequent tapering should proceed at a slower pace with smaller decrements. If there is any recrudescence of fever, severe headache or visual

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GARBER, FAN, AND BLUESTONE

symptoms, the prednisone amount is increased up to 60 mg a day. Maintenance therapy becomes the minimum dose of daily steroid necessary to keep the ESR normal and the patient asymptomatic. The minimum duration of corticosteroid therapy necessary to suppress the arteritis remains controversial. Some physicians recommend prednisone therapy for at least 2 yr.‘97”98 A proportion of patients appear to need low prednisone doses for several years or more to control musculoskeletal symptoms. In some patients, however, the daily prednisone dose may be slowly reduced and discontinued altogether after 1-2 yr.

Polyarteritis

Nodosa

Polyarteritis nodosa (PAN) is a progressive necrotizing vasculitis involving small and medium muscular arteries.‘99 Although daily corticosteroids have prolonged survival,2m the addition of an immunosuppressive agent has further improved prognosis.20’~203 Once the diagnosis is established, patients are given high dose prednisone (1 mg/kg/day) (Table 6). Cytotoxic agents are added initially if hypertension or renal involvement is present, and later if side effects from steroids are severe or if there has been no slowing of the disease progression within 3-4 wk.‘04 “Pulse” therapy is also empirically used in patients with PAN.‘74 This form of treatment can be the initial antiinflammatory ‘blast’ delivered to the systemically ill patient. If renal function rapidly deteriorates or if the patient is in danger of losing gangrenous digits while on high dose prednisone, then “pulse” becomes the therapeutic intervention, the temporizing measure until cytotoxic therapy takes hold. If there Table 6. Steroid Usage in PAN

is difficulty in reducing the daily prednisone dose even once the cytotoxics become effective, “pulse” can be used to further suppress disease activity, allowing for an overall decrease in the daily prednisone regimen. In all instances, the “pulse” is administered in the same manner. One gram of methylprednisolone is given as an infusion in 5% dextrose and water over 45 min. This “pulse” is given on 3 consecutive days. The clinician must wait 3-7 days before assessing the effectiveness of the “pulse.” This can be gauged by any improvement in renal function or sediment, any change in laboratory parameters (anemia or elevated ESR), or any overall improvement in the patient’s constitutional symptoms. The “pulse” may be given as is needed (but usually not more than once a week) to curtail disease activity. Polymyalgia

Kheumatica

Polymyalgia rheumatica is a diffuse muscular stiffness and aching affecting the neck, shoulder and pelvic girdle in elderly patients. It is characterized by a rapid sedimentation rate (Westergren ESR greater than 50 mm/hr).‘92~‘98~205 Low dose corticosteroids are used not only therapeutically but diagnostically in patients with polymyalgia rheumatica.“’ With lo-15 mg of prednisone given in the the symptoms are extraordinarily morning, responsive, clearing completely in a day or two after beginning treatment. Once the ESR has normalized and the symptoms have abated, the clinician may begin to reduce the total prednisone dosage. One can usually effectively taper the dose by I mg every 223 wk down to a 5 mg maintenance level if one carefully follows the sedimentation rate. Some patients may require low prednisone doses for many years while others will be able to be slowly weaned off prednisone therapy altogether. Systemic

Lupus Erythematous

Nephritis

Once a remission has been induced in SLE patients with glomerulonephritis by corticosteroids alone or in combination with immunosuppressives, the steroid dose may be reduced. With SLE nephritis, the clinician anticipates the need for long-term disease suppression, yet he or she wants to minimize untoward side effects. Because SLE nephritis is not accompanied by

STEROID THERAPY IN RHEUMATIC

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constant daily symptoms, the patient can easily tolerate an alternate-day schedule. Thus, once disease activity is under control, the transition to alternate-day therapy is begun. In a patient taking 30 mg of prednisone a day, the switch is immediately made to 60 mg on day I and 30 mg on day 2. If the renal function and urinary sediment along with serologic parameters remain stable, then the prednisone dose on day 2 is tapered to zero over a few months. Likewise, the 60 mg prednisone dose is gradually reduced as the disease activity dictates. If at any time the renal function deteriorates, the alter-

nate day regimen is abandoned and the patient is returned to high dose divided prednisone therapy. The alternate day regimen is utilized in SLE nephritis to prevent exacerbation of the potentially agressive inflammatory process and at the same time to facilitate the transition toward complete discontinuation of steroids. ACKNOWLEDGMENT The authors thank Carol Zinsmeister for her excellent secretarial assistance and John D. Forbess for his encouragement and helpful comments in the preparation of this manuscript.

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