INTRODUCTION

Corticosteroid medications are found in the therapeutic armamentarium of most medical specialties. Rheumatologists have had a long relationship with these agents ^1,² since their first demonstrated therapeutic efficacy in rheumatoid arthritis.³ Systemic corticosteroids therapy is the cornerstone of the treatment of acute, active systemic lupus erythematosus (SLE) either alone or in combination with “steroid-sparing” (immunosuppressive) agents.² Despite this, many issues regarding the methods of use of this class of agents remain controversial. Such issues include the appropriate initial dose, route of administration, duration of treatment, acceptable withdrawal algorithm, and impact, prevention, and treatment of the inevitable side effects of prolonged use.

In this review, we incorporate the best evidence available as well as refer to our experience in the University of Toronto Lupus Clinic, a prospective long-term observational cohort study of 35 years duration.⁴ This chapter will review multiple aspects of using systemic corticosteroids in treating SLE. Historical Aspects of Corticosteroids Use in Treating Rheumatic Diseases and SLE

In the early 1920s, Edward Calvin Kendall proposed that rheumatoid arthritis represented a deficiency of adrenal hormone. In the 1930s, Henry L. Mason and others isolated a number of steroid hormones from the adrenal cortex and special interest focused on Compound E, later named cortisol (hydrocortisone). Kendall had suggested that such hormones could be therapeutically useful in rheumatoid arthritis (RA), and research in this area was accelerated during World War II.¹

In 1949, Philip Showalter Hench and associates at the Mayo Clinic obtained sufficient quantities of cortisol to administer it to a patient with rheumatoid arthritis.³ The results of this new treatment were dramatic. RA patients who until then were incapacitated experienced dramatic improvement. So great was the excitement over the new treatment, that the Nobel Prize committee altered its time-honored rule for delaying the award for a number of years after any major discovery, and immediately in 1950 awarded the prize in medicine to Edward Calvin Kendall, Tadeus Reichstein, and Philip Showalter Hench for their “discoveries relating to the hormones of the adrenal cortex, their structure and biological effects.”¹

Soon thereafter, oral corticosteroids were also used to treat SLE. In the early 1960s, Pollak and colleagues ^5,⁶ reported that high doses of oral prednisone helped to prevent or postpone the onset of renal failure. It was not until much later that the long-term side effects became obvious and muted the initial excitement over the therapeutic actions of corticosteroids. Oral corticosteroids became the mainstay of treatment for most clinical manifestations of SLE. Another important development took place in 1976, as Edward Cathcart and his colleagues treated seven SLE patients with diffuse proliferative glomerulonephritis with high-dose intravenous methylprednisolone “pulses.”⁷ This treatment led to a rapid and dramatic improvement in five of seven patients. This treatment regimen had initially been used for acute rejection in renal transplantation with impressive results.^8,⁹ Unfortunately, 30 years later many uncertainties around this treatment approach still exist.

RATIONALE FOR SYSTEMIC CORTICOSTEROIDS USE IN SLE

SLE is characterized by generalized inflammation and excessive autoantibody production. These findings constitute the rationale for the use of systemic corticosteroids in the treatment of SLE for their anti-inflammatory and immunosuppressive actions. The effect of the inflammation on organ dysfunction is indisputable. It has been established that the hypothalamic-pituitary-adrenal (HPA) axis and glucocorticoids in particular play an essential natural role in aborting and limiting inflammation.¹⁰ This natural mechanism of suppression of inflammation is multiplied significantly when treating SLE with pharmacologic doses. The beneficial and therapeutic effects in SLE of administered systemic corticosteroids are likely due first to their anti-inflammatory effects in the short term and later to their immunosuppressive effects through inhibition of antibody synthesis.¹¹

Once steroids have been initiated, one must use objective criteria to measure response to therapy to guide systemic corticosteroid tapering and withdrawal. Currently, four disease activity measures are in use in lupus clinics and in therapeutic trials: SLE Disease Activity Index (SLEDAI-2K),¹² the British Isles Lupus Assessment Group (BILAG),¹³ SLE Activity Measure (SLAM),¹⁴ and European Consensus Lupus Activity Measurement (ECLAM)¹⁵ (see Chapter 2). We recommend using any of the above indices to monitor the disease activity in SLE patients to assess adjusting the systemic corticosteroids dose used. In therapeutic trials, predetermined systemic corticosteroid withdrawal algorithms are sometimes used as outcome measures and are applied irrespective of disease activity. The latter approach with its lack of flexibility is not appropriate for use in daily practice.

Mechanisms of Action

The human glucocorticoid receptor (GR) gene is one locus on chromosome 5_q31-32, and the human GR messenger RNA has alternative splice variants that produce the target proteins.¹⁶ The GR is a member of the steroid-hormone-receptor family of proteins. It binds with high affinity to cortisone, which initiates the dissociation of molecular chaperones, such as heat-shock proteins, from the receptor. The GR are intracellular structures and therefore most of the initial action is contained within the affected cells. In brief, the cortisol–GR complex penetrates the nucleus to bind to the DNA sequence called glucocorticoid-responsive elements. The latter complex initiates the transcription process mediated by RNA polymerase II. The proteins produced are anti-inflammatory proteins,¹⁷ which are discussed below.

Cortisol (hydrocortisone) is the major corticosteroid hormone found in the human adrenal cortex. It is derived from the hydroxylation of cortisone. Systemic corticosteroid agents mimic the endogenous steroid hormones produced in the adrenal cortex, mineralocorticoid (aldosterone), and glucocorticoid (cortisol). Mineralocorticoids are primarily regulated by the renin-angiotensin system and possess salt-retaining properties. Glucocorticoids are primarily regulated by corticotropin (ACTH), and have anti-inflammatory effects as well as metabolic and immunogenic effects on the body. While several corticosteroid agents possess properties of both hormones, fludrocortisone is most commonly used for its mineralocorticoid activity and hydrocortisone, cortisone, prednisone, and prednisolone are used for their glucocorticoid effects (Table 45.1).^18,¹⁹

TABLE 45.1 FORMS AND HALF-LIFE OF STEROIDS

Although the broad mechanisms are known, the cellular pathways affected by the drugs are numerous and complex.²⁰^–²² As mentioned above, the initial therapeutic effects in SLE of administered systemic corticosteroids are likely due first to their anti-inflammatory effects on the cellular mechanism of the immune response and later to their immunosuppressive effects through inhibition of antibody synthesis as effects on humoral immune response.²⁰

Corticosteroids exert their anti-inflammatory effect primarily by inhibiting the production of cytokines and cell-adhesion molecules. Anti-inflammatory effects of systemic corticosteroids include decrease of neutrophil margination, decrease macrophage migration, decrease accumulation of neutrophils at inflammatory sites, inhibition of neutrophil and macrophage phagocytosis, inhibition of production of pro-inflammatory cytokines IL-1 and TNF, inhibition of cycloxygenase-2 (COX-2), induction of expression of lipocortin-1, decrease of T-cell proliferation, and decrease of IL-2 synthesis.²³

On the other hand, corticosteroids block antibody production by a number of mechanisms. Lymphopenia (T cells affected more than B cells and CD4 T cells more than CD8 T cells) may be induced through lymphocyte redistribution (mainly to bone marrow and spleen) and perhaps through enhanced apoptosis.²³ In addition, corticosteroids may inhibit IL-2 synthesis and signaling, inhibit signal transduction events critical for T-cell activation, down-regulate cell surface molecules important for full T-cell activation and function, and inhibit antigen-presenting cell function.²⁴

FORMS AND DELIVERY ROUTES OF SYSTEMIC CORTICOSTEROIDS

The various types of corticosteroids that have been used in rheumatology and their potencies are summarized in Table 45.1. There is no reason to believe that there is a major difference among various oral corticosteroid preparations^11,^25,²⁶; rather it is frequency of dosing and the dose used that determine the clinical effect. Hydrocortisone is the saturated physiologic form of the steroids, whereas prednisone is an unsaturated synthetic. Prednisone is the most frequently used preparation due to its shorter half-life and the availability of tablets in a variety of doses, which makes dose adjustments easy.²⁷ Multiple websites provide instant conversions of corticosteroid dosages. (We recommend www.globalrph.com/corticocalc.htm.)

Topical Corticosteroids

Topical corticosteroid preparations may be used for inflammatory skin rashes without evidence of vasculitis. Formulations include short acting hydrocortisone (0.125% to 1.0%), intermediate-acting products that contain triamcinolone (0.025% to 0.5%), and long-acting formulations with betamethasone (0.01% to 0.1%).

Intrasynovial Therapy with Corticosteroids

In selected patients where the disease activity is limited to the soft tissue and joints, intrasynovial corticosteroid injections can be given. These preparations vary in potency, dosage, and formulations. Examples are methylprednisolone acetate, prednisolone tebutate, dexamethasone acetate, and betamethasone acetate. A local anesthetic is used with intrasynovial corticosteroids to produce immediate pain relief.

For oral delivery, most clinicians prescribe prednisone (North America) or prednisolone (Europe) for the reasons mentioned above. Two dosing schedules are used: daily morning dose or divided dose regimen (two to four times per day). In patients with less active disease, the single daily dose may minimize side effects. Patients with more active disease will require divided dose regimens. In patients who experience significant mineralocorticoid side effects, particularly fluid retention, methylprednisolone (Medrol) may be used instead at a 20% lower dose. However, methylprednisolone is more expensive than prednisone. Patients with liver disease are sometimes unable to metabolize prednisone (which is technically a prohormone) and may be given prednisolone instead (in the same dose as prednisone).^1,^28,²⁹

The typical approach to dosage regimens quoted in the rheumatology literature is based on body weight, which has no scientific basis. Corticosteroid responsiveness is more related to host factors, disease factors, and organ-specific factors. Clinical experience has shown that host responsiveness both in the disease and side effects is variable. Some patients may develop osteonecrosis on as little as 20 mg of prednisone for 6 months, and some never develop this lesion on much higher doses. It has also long been known that RA is much more sensitive as a disease to steroid effects than is SLE. Furthermore, within the spectrum of SLE, some organ systems are more sensitive to steroids (skin, joints, and serous membranes) and some much less sensitive (renal, central nervous system). Each of these factors should be considered (host, disease, and organ) in choosing an appropriate induction dose of prednisone. According to the literature, typical dosages of prednisone follow: low or maintenance dosage, approximately 0.1 to 0.25 mg/kg/d; moderate dosage, approximately 0.5 mg/kg/d; high dosage, 1 to 3 mg/kg/d; and massive (very high) dosage, 15 to 30 mg/kg/d.³⁰

We would recommend that in adults induction doses could be defined as low (1 to 20 mg/d), moderate (20 to 40 mg/d), high (40 to 80 mg/d) and very high (>80 mg/d, which includes oral and intravenous “pulse therapy”/intermittent infusion). These doses are not based on body weight. Based on the past responsiveness of the host and organ involvement, the physician could choose a low, moderate, high, or very high dose as induction therapy. Therapeutic dilemmas occur when a patient does not respond to a high dose of prednisone. The current tendency is to then move to “pulse” therapy in massive doses rather than a lesser increase in dose such as 100 to 200 mg/d of prednisone or methylprednisolone. This dilemma is discussed below.

Intravenous Therapy

Methylprednisolone (trade names Depo-Medrol, Medrol, Solu-Medrol) is prednisolone with a methyl group attached at position 6, to produce a compound that is water soluble. Due to its solubility, this preparation can be given intravenously, and very large doses can be given in a very short time. This drug was used initially in treating diffuse lupus nephritis using the same protocol as in renal transplantation.⁹ This protocol is this still used in treating SLE and other rheumatic diseases in most clinics and hospitals despite the lack of evidence that it is superior to lower doses. In fact, evidence from several small studies suggests that moderate doses (defined by some authors as 500 mg) have equal efficacy and fewer side effects than high doses.³¹^–³⁴ The other advantage of the intravenous treatment is that it can be given intermittently when a flare occurs, rather than keeping patients on very high doses of oral corticosteroids for longer periods. Studies of RA patients showed that low and moderate doses are comparable to the efficacy of high doses, with no difference, for example, in terms of the reduction rate of lymphocytes counts.³⁵^–³⁹ Based on this evidence and our experience from the lupus clinic, if the intravenous “pulse” therapy is chosen as the induction with a very-high-dose approach we would advocate the use of a stepwise increase of the pulse doses, depending on response, rather than beginning with megadoses. The evidence to support this approach includes the following:

1. There have been no randomized clinical trials to support the often-used 1000-mg dose or to determine the appropriate frequency of methylprednisolone infusion in SLE.

2. The reports that have appeared in the literature that compared moderate doses versus high doses did not show any superiority of the high doses and observed a lower infection incidence with moderate doses.³¹^–³⁴

3. The pharmacodynamics and pharmacokinetics of methylprednisolone suggest that a dose of 320 mg may be adequate for full immunosuppressive effects.⁴⁰

The duration of “pulse therapy” typically varies from 3 to 5 consecutive days.⁴³ Again, this is not evidence based, and because patients are usually continued on high doses of prednisone after the pulse there would not seem to be much rationale for the longer course of “pulse therapy.”

Situations in which intravenous pulse therapy might be considered are generally those that have been refractory to treatment with high oral doses of prednisone such as severe lupus nephritis and neuropsychiatric disease, severe refractory thrombocytopenia or hemolytic anemia, and severe vasculitis.