Systemic Corticosteroids

Normal Hypothalamic-Pituitary-Adrenal-Axis Function

It is important to understand the normal function of the HPA axis in order to better understand the potential for HPA-axis suppression by synthetic CS. For further background information, several reviews are particularly helpful.

The primary stimulus for release of endogenous cortisol originates in the hypothalamus. The tropic hormone is known as corticotropin-releasing factor (CRF). ACTH is subsequently released by the anterior pituitary. ACTH is produced from the prohormone pro-ACTH/endorphin. There are approximately 10 bursts of ACTH release throughout the day. The greatest frequency of these bursts occurs in the early morning hours during a normal sleep cycle. The zona fasciculata of the adrenal cortex is then stimulated to produce and release cortisol. ACTH also stimulates adrenal androgen synthesis. However, ACTH is not significantly involved in the release of the MC aldosterone.

There are three main controls of endogenous cortisol production. These are discussed in the summary ‘HPA axis in a nutshell’ ( Box 13.2 ).

Glucocorticoid Effects ( Table 13.3 )

CS plays an important teleologic role in maintaining adequate blood glucose levels for brain function. Gluconeogenesis generates glucose at the expense of amino acids derived from endogenous proteins. CS also produces peripheral insulin resistance, which impedes glucose absorption by various body tissues. In addition, glycogen storage in the liver is enhanced. Lipid stores are stimulated to undergo lipolysis, generating increased amounts of triglycerides from which to derive energy.

The net effect is a catabolic state that produces carbohydrates at the expense of protein and fat stores. Through gluconeogenesis, proteins from muscle, trabecular bone (especially vertebral and hip), dermal connective tissue, and vascular proteins are metabolized. Lipolysis results in triglyceride release, with additional fat redistribution (lipodystrophy) to body sites that are characteristic of the habitus for Cushing syndrome.

Mineralocorticoid Effects

Aldosterone is the primary endogenous MC hormone. The primary aldosterone effect is sodium reabsorption and resultant water reabsorption at the proximal tubule site in the kidneys. Sodium is exchanged for potassium, which leads to hypokalemia when there is excessive MC effect. ACTH has no direct control on MC production. The primary MC control mechanisms are through the renin–angiotensin system and serum potassium levels. CS with significant MC effects (such as hydrocortisone) have a similar effect on sodium, potassium, and fluid balance as aldosterone ( Table 13.3 ). Long-acting CS (such as dexamethasone and betamethasone) have essentially no MC effect (see Table 13.1 ).

Glucocorticoid Receptor Physiology and Corticosteroid Resistance

There is only one GCR, but a diverse collection of isoforms, which accounts for endogenous glucocorticoid effects as well as the pharmacological effects of synthetic CS (resulting in both beneficial and AE). This cytosolic receptor is expressed throughout tissues, but there is considerable heterogeneity in sensitivity and biological responses. The GCR functions directly as a transcription factor, which upon translocation to the nucleus binds directly to various glucocorticoid responsive elements of multiple genes in DNA. In addition, the ligand–GCR complex can activate other transcription factors, as detailed in the next section. CS exerts its effects through both genomic and nongenomic actions.

Splice variants, translational isoforms, posttranslational modifications, and polymorphisms give a molecular basis for sensitivity of glucocorticoid responsiveness. There are rare cases of hereditary glucocorticoid resistance, in which there are mutations in the GCR gene. In clinical practice, relative resistance at the GCR in otherwise healthy individuals is much more common than previously recognized. In addition, relative resistance is because of altered CS bioavailability, altered ligand binding to GCR, or altered translocation of the activated GCR complex to the nucleus. Conceptually, this resistance could represent a negative feedback system of sorts, with downregulation of GCR after prolonged or high-dose CS therapy.

Corticosteroids and Transcription Factors

There are two well-described transcription factors with a central role in amplification of the inflammatory response ( Fig. 13.2 ). These transcription factors are nuclear factor kappa B (NFκB) and AP-1. NFκB is biologically inactive as long as it is bound to inhibitor kappa B (IκB). Free NFκB translocates to the nucleus, where it induces transcription of numerous cytokines including (1) ‘immunoawakening’ cytokines (interleukin [IL]-1β, tumor necrosis factor [TNF]-α), (2) ‘immunomodulatory’ cytokines (IL-2, IL-8), (3) growth factors, (granulocyte-colony stimulating factor [G-CSF], granulocyte-macrophage colony-stimulating factor [GM-CSF]), (4) adhesion molecules (intercellular adhesion molecule 1 [ICAM-1], E-selectin), (5) receptors (IL-2 receptor), and (6) proinflammatory enzymes (cyclooxygenase-2 [COX-2], phospholipase A ₂ ).

CS reduce the effects of NFκB in two ways. The CS-GCR complex leads to increased IκB formation, leading to subsequent NFκB binding by this inhibitory protein. The GCR/CS complex can also directly bind to NFκB, thus inhibiting this transcription factor. By either means, there can be a dramatic reduction of a wide variety of components of the inflammatory response via this mechanism of CS.

AP-1 consists of either c-jun homodimers or c-jun/c-fos heterodimers, which bind to a common deoxyribonucleic acid (DNA) site, the AP-1 binding site. There is tremendous overlap with the inflammatory response genes induced by AP-1 and NFκB.

In general, transrepression by GCR/CS complex of proinflammatory cytokines (such as IL-1β, TNF-α, interferon regulatory factor 3 [IRF-3]) accounts for most of anti-inflammatory effects of CS. IRF-3 is a member of the interferon regulatory transcription factor family and plays an important role in the innate immune system. In contrast, transactivation by the GCR/CS complex of various regulatory proteins is responsible for most CS AE (such as diabetes, glaucoma). As such, selective glucocorticoid receptor agonist(s) (SEGRA) that favor transrepression were developed as therapeutic agents with reduced AE. However, more recent data show that the transactivation potential of GR is indispensable for its anti-inflammatory properties.

Corticosteroid-Induced Apoptosis

Apoptosis is an orderly process of programmed cell death. The process is a biologically active, noninflammatory sequence of cellular changes that occur with an intact plasma membrane despite nuclear fragmentation. Q13.3 CS can directly induce apoptosis in lymphocytes and eosinophils. CS can induce apoptosis at least in part through downregulation of the CD3 molecule of T cells; this molecule plays an important role in T-cell activation. There can also be an indirect effect on lymphocytes and eosinophils through CS-induced suppression of cytokines essential to cellular survival.

The logical application of these facts is an underlying explanation for CS effects in autoimmune disorders (apoptosis of autoreactive T cells), allergic disorders (apoptosis of eosinophils), and certain neoplastic disorders (apoptosis of malignant T cells). It is doubtful that the ability of CS to induce apoptosis is limited to these cell types.

Pemphigus Vulgaris

The best-studied purely dermatologic indication for systemic CS therapy is pemphigus vulgaris. The emphasis here is high-dose CS therapy, with use of adjunctive ‘steroid-sparing’ immunosuppressive therapy. CS are appropriate at the start of therapy for any relatively severe case of pemphigus vulgaris that has no absolute contraindications to CS use. Adjunctive therapy is generally used with a choice of azathioprine, mycophenolate mofetil, methotrexate, cyclosporine, cyclophosphamide, rituximab, intravenous immune globulin (IVIg), or plasmapheresis. Anti-inflammatory antibiotics, such as the tetracyclines, as well as CS-sparing immunosuppressive medications have been used for milder cases of pemphigus vulgaris and for pemphigus foliaceus. Pulse methylprednisolone as well as rituximab are other options, which may be indicated to attain rapid disease control in more severe cases of pemphigus vulgaris.

Current management includes prednisone doses no greater than 2 mg/kg daily in divided doses. In general, it is reasonable to start prednisone at 1 to 1.5 mg/kg daily, increasing to the above dose range very selectively as indicated for more severe cases of pemphigus vulgaris. Disease control is usually attained by 4 to 6 weeks. Given this adequate disease control, the divided dose should be consolidated into a single daily dose and tapered rapidly to the 40-mg daily range. Azathioprine or related immunosuppressive drugs can be added at the time of prednisone tapering in many cases. For more severe cases it is wise to add the ‘CS-sparing’ agent at the start of therapy. Management of oral involvement needs to be reasonably aggressive, both to limit progression to more serious cutaneous involvement and to maintain adequate fluid and nutrition intake. Juvenile pemphigus vulgaris is overall similar to that just described, with CS doses adjusted for body weight. The challenge of managing paraneoplastic pemphigus has been reviewed by Anhalt.

General Philosophy and Dosing Strategies

Pulse CS therapy has been proposed as a means to rapidly control life-threatening or serious conditions with minimal toxicity, allowing for less aggressive long-term maintenance CS therapy. Typically, 500 to 1000 mg of methylprednisolone (roughly 10–15 mg/kg daily) is given IV over at least 60 minutes. This dose is repeated on a daily basis for 3 to 5 consecutive days. Pulse methylprednisolone is traditionally administered in an inpatient setting, with cardiac and electrolyte monitoring highly recommended. Alternate-day CS or a nonsteroidal immunosuppressive (‘CS-sparing’) drug such azathioprine and cyclosporine is used to maintain the improvement from the pulse IV CS.

Risks of Pulse Intravenous Corticosteroid

Sudden death of presumed cardiac origin is a notable complication of IV pulse CS therapy. Atrial fibrillation has been reported as well. Furthermore, anaphylaxis attributed to pulse IV CS is a potentially life-threatening complication. Acute electrolyte shifts have been postulated to explain the rare cases of sudden cardiac death. Careful potassium infusions may minimize the risk of these potentially serious cardiac AE. Given that the vast majority of cardiac complications have occurred outside of dermatologic settings, some authors have questioned the need for hospitalization and cardiac monitoring for dermatologic purposes. The recent trend for pulse IV CS therapy is administration in an ambulatory setting if there is no significant renal or cardiac disease present.

The suppression of various lymphocyte subsets is greater with pulse CS therapy than with standard doses of oral CS therapy. CS-induced apoptosis likely plays a key role in this greater effect of IV pulse CS therapy. In addition, there appears to be a persistent decrease in natural killer cell activity. Other immunologic effects are qualitatively similar to those of oral administration.

Summary

The overall interest in pulse CS therapy with IV methylprednisolone has waned over the recent decades. This modality should be used only when the severity of the patient’s condition and the lack of response to alternative modes of therapy indicate its appropriateness. Pulse IV methylprednisolone or dexamethasone therapy should be considered experimental and used very selectively in an individualized fashion.