Rheumatic Disorders. Glucocorticoids are used widely in the treatment of a variety of rheumatic disorders and are a mainstay in the treatment of the more serious inflammatory rheumatic diseases, such as systemic lupus erythematosus, and a variety of vasculitic disorders, such as polyarteritis nodosa, Wegener's granulomatosis, Churg-Strauss syndrome, and giant cell arteritis. For these more serious disorders, the starting dose of glucocorticoids should be sufficient to suppress the disease rapidly and minimize resultant tissue damage. Initially, prednisone (1 mg/kg per day in divided doses) often is used, generally followed by consolidation to a single daily dose, with subsequent tapering to a minimal effective dose as determined by the clinical picture.
Although they are an important component of treatment of rheumatic diseases, glucocorticoids are often used in conjunction with other immunosuppressive agents such as cyclophosphamide and methotrexate, which offer better long-term control than steroids alone. The exception is giant cell arteritis, for which glucocorticoids remain superior to other agents. Caution should be exercised in the use of glucocorticoids in some forms of vasculitis (e.g., polyarteritis nodosa), for which underlying infections with hepatitis viruses may play a pathogenetic role. Although glucocorticoids are indicated in these cases, there is at least a theoretical concern that glucocorticoids may complicate the course of the viral infection by suppressing the immune system. To facilitate drug tapering and/or conversion to alternate-day treatment regimens, the intermediate-acting glucocorticoids such as prednisone and methylprednisolone are generally preferred over longer-acting steroids such as dexamethasone.
In rheumatoid arthritis, because of the serious and debilitating side effects associated with chronic use, glucocorticoids are used as stabilizing agents for progressive disease that fails to respond to first-line treatments such as physiotherapy and nonsteroidal anti-inflammatory agents. In this case, glucocorticoids provide relief until other, slower-acting antirheumatic drugs, such as methotrexate or agents targeted at tumor necrosis factor, take effect. A typical starting dose is 5-10 mg of prednisone per day. In the setting of an acute exacerbation, higher doses of glucocorticoids may be employed (typically 20-40 mg/day of prednisone or equivalent), with rapid taper thereafter. Complete relief of symptoms is not sought, and the symptomatic effect of small reductions in dose (decreases of perhaps 1 mg/day of prednisone every 2-3 weeks) should be tested frequently while concurrent therapy with other measures is continued, to maintain the lowest possible prednisone dose. Alternatively, patients with major symptomatology confined to one or a few joints may be treated with intra-articular steroid injections. Depending on joint size, typical doses are 5-20 mg of triamcinolone acetonide or its equivalent.
In noninflammatory degenerative joint diseases (e.g., osteoarthritis) or in a variety of regional pain syndromes (e.g., tendinitis or bursitis), glucocorticoids may be administered by local injection for the treatment of episodic disease flare-up. It is important to use a glucocorticoid that does not require bioactivation (e.g., prednisolone rather than prednisone) and to minimize the frequency of local steroid administration whenever possible. In the case of repeated intra-articular injection of steroids, there is a significant incidence of painless joint destruction, resembling Charcot's arthropathy. It is recommended that intra-articular injections be performed with intervals of at least 3 months to minimize complications.
Renal Diseases. Patients with nephrotic syndrome secondary to minimal change disease generally respond well to steroid therapy, and glucocorticoids clearly are the first-line treatment in both adults and children. Initial daily doses of prednisone are 1-2 mg/kg for 6 weeks, followed by a gradual tapering of the dose over 6-8 weeks, although some nephrologists advocate alternate-day therapy. Objective evidence of response, such as diminished proteinuria, is seen within 2-3 weeks in 85% of patients, and >95% of patients have remission within 3 months. Cessation of steroid therapy frequently is complicated by disease relapse, as manifested by recurrent proteinuria. Patients who relapse repeatedly are termed steroid-resistant and often are treated with other immunosuppressive drugs such as azathioprine or cyclophosphamide. Patients with renal disease secondary to systemic lupus erythematosus also are generally given a therapeutic trial of glucocorticoids.
Studies with other forms of renal disease, such as membranous and membranoproliferative glomerulonephritis and focal sclerosis, have provided conflicting data on the role of glucocorticoids. In clinical practice, patients with these disorders often are given a therapeutic trial of glucocorticoids with careful monitoring of laboratory indices of response. In the case of membranous glomerulonephritis, many nephrologists recommend a trial of alternate-day glucocorticoids for 8-10 weeks (e.g., prednisone, 120 mg every other day), followed by a 1- to 2-month period of tapering.
Allergic Disease. The onset of action of glucocorticoids in allergic diseases is delayed, and patients with severe allergic reactions such as anaphylaxis require immediate therapy with epinephrine. The manifestations of allergic diseases of limited duration—such as hay fever, serum sickness, urticaria, contact dermatitis, drug reactions, bee stings, and angioneurotic edema—can be suppressed by adequate doses of glucocorticoids given as supplements to the primary therapy. In severe disease, intravenous glucocorticoids (methylprednisolone, 125 mg intravenously every 6 hours, or equivalent) are appropriate. In less severe disease, antihistamines are the drugs of first choice. In allergic rhinitis, intranasal steroids are now viewed as the drug of choice by many experts.
Bronchial Asthma and Other Pulmonary Conditions. Corticosteroids frequently are used in bronchial asthma (Chapter 36). Although they sometimes are employed in chronic obstructive pulmonary disease (COPD), particularly when there is some evidence of reversible obstructive disease, data supporting the efficacy of corticosteroids are much less convincing than for bronchial asthma. The increased use of corticosteroids in asthma reflects an increased appreciation of the role of inflammation in the immunopathogenesis of this disorder. In severe asthma attacks requiring hospitalization, treatment with high-dose parenteral glucocorticoids is essential. Symptomatic relief sometimes is very rapid; however, the onset of a maintained response may take up to 6-12 hours. Intravenous administration of 60-120 mg methylprednisolone (or equivalent) every 6 hours is used initially, followed by daily oral doses of prednisone (30-60 mg) as the acute attack resolves. The dose then is tapered gradually, with withdrawal planned for 10 days to 2 weeks after initiation of steroid therapy. In general, patients subsequently can be managed on their prior medical regimen.
Less severe acute exacerbations of asthma (as well as acute flares of COPD) often are treated with brief courses of oral glucocorticoids. In adult patients, 30-60 mg prednisone is administered daily for 5 days; an additional week of therapy at lower doses also may be required. Upon resolution of the acute exacerbation, the glucocorticoids generally can be rapidly tapered without significant deleterious effects. Any suppression of adrenal function usually dissipates within 1-2 weeks. In the treatment of severe chronic bronchial asthma (or, less frequently, COPD) that is not controlled by other measures, the long-term administration of glucocorticoids may be necessary. As with other long-term uses of these agents, the lowest effective dose is used, and care must be exercised when withdrawal is attempted. Given the risks of long-term treatment with glucocorticoids, it is especially important to document objective evidence of a response (e.g., an improvement in pulmonary function tests). In addition, these risks dictate that long-term glucocorticoid therapy be reserved for those patients who have failed to respond to adequate regimens of other medications (Chapter 36).
In many patients, inhaled steroids (see Table 42–4) can either reduce the need for oral corticosteroids or replace them entirely. Many physicians prefer inhaled glucocorticoids over previously recommended oral theophylline in the treatment of children with moderately severe asthma, in part because of the behavioral toxicity associated with chronic theophylline administration. The oral bioavailability of inhaled corticosteroids varies considerably; however, when used as recommended, inhaled glucocorticoids are effective in reducing bronchial hyperreactivity and are less likely to suppress adrenal function than are the oral glucocorticoids. Dysphonia or oropharyngeal candidiasis may develop, but the incidence of such side effects can be reduced substantially by maneuvers that reduce drug deposition in the oral cavity, such as spacers and mouth rinsing or by using corticosteroids with low oral bioavailability. For example, ciclesonide (alvesco, omnaris) and beclomethasone dipropionate (beconase aq, qvar), are inactive compounds that are activated on site by lung esterases; therefore they are less likely to adversely affect the oral cavity (Derendorf et al., 2006). The status of glucocorticoids in asthma therapy is discussed in Chapter 36.
Antenatal glucocorticoids are used frequently in the setting of premature labor, decreasing the incidence of respiratory distress syndrome, intraventricular hemorrhage, and death in infants delivered prematurely. Betamethasone (12 mg intramuscularly every 24 hours for two doses) or dexamethasone (6 mg intramuscularly every 12 hours for four doses) is administered to women with definitive signs of premature labor between 26 and 34 weeks of gestation (Roberts and Dalziel, 2006). Due to evidence of decreased birthweight and adrenal suppression in infants whose mothers were given repeated courses of glucocorticoids, only a single course of glucocorticoids should be administered.
Infectious Diseases. Although the use of immunosuppressive glucocorticoids in infectious diseases may seem paradoxical, there are a limited number of settings in which they are indicated in the therapy of specific infectious pathogens. One dramatic example of such beneficial effects is seen in AIDS patients with Pneumocystis carinii pneumonia and moderate to severe hypoxia; addition of glucocorticoids to the antibiotic regimen increases oxygenation and lowers the incidence of respiratory failure and mortality. Similarly, glucocorticoids clearly decrease the incidence of long-term neurological impairment associated with Haemophilus influenzae type b meningitis in infants and children ≥2 months of age.
A long-standing controversy in medicine is the use of glucocorticoids in septic shock (Sprung et al., 2008). Supraphysiological doses of glucocorticoids had been used routinely as adjunctive therapy in subjects with septic shock associated with gram-negative bacteremia until it was recognized that glucocorticoid therapy in supraphysiologic doses actually increased mortality. Subsequent studies then examined the benefit of somewhat lower doses of glucocorticoids (e.g., 100 mg hydrocortisone every 8 hours) administered to patients early in the course of their disease. In one multicenter randomized placebo-controlled trial, beneficial effects of hydrocortisone plus fludrocortisone were seen only in subjects with adrenal insufficiency as determined by the rapid cosyntropin stimulation test. Although a second large study using hydrocortisone alone failed to demonstrate a beneficial effect regardless of adrenal status, current guidelines suggest that hydrocortisone be used in adult patients with septic shock whose blood pressure fails to respond adequately to fluids and vasopressors (Dellinger et al., 2008).
Ocular Diseases. Ocular pharmacology, including some consideration of the use of glucocorticoids, is discussed in Chapter 64. Glucocorticoids frequently are used to suppress inflammation in the eye and can preserve sight when used properly. They are administered topically for diseases of the outer eye and anterior segment and attain therapeutic concentrations in the aqueous humor after instillation into the conjunctival sac. For diseases of the posterior segment, intraocular injection or systemic administration is required. Generally, ocular use of glucocorticoids should be supervised by an ophthalmologist.
A typical prescription is 0.1% dexamethasone sodium phosphate solution (ophthalmic), 2 drops in the conjunctival sac every 4 hours while awake, and 0.05% dexamethasone sodium phosphate ointment (ophthalmic) at bedtime. For inflammation of the posterior segment, typical doses are 30 mg of prednisone or equivalent per day, administered orally in divided doses.
Topical glucocorticoid therapy frequently increases intraocular pressure in normal eyes and exacerbates intraocular hypertension in patients with antecedent glaucoma. The glaucoma is not always reversible on cessation of glucocorticoid therapy. Intraocular pressure should be monitored when glucocorticoids are applied to the eye for >2 weeks.
Topical administration of glucocorticoids to patients with bacterial, viral, or fungal conjunctivitis can mask evidence of progression of the infection until sight is irreversibly lost. Glucocorticoids are contraindicated in herpes simplex keratitis because progression of the disease may lead to irreversible clouding of the cornea. Topical steroids should not be used in treating mechanical lacerations and abrasions of the eye because they delay healing and promote the development and spread of infection.
Skin Diseases. Glucocorticoids are remarkably efficacious in the treatment of a wide variety of inflammatory dermatoses. As a result, a large number of different preparations and concentrations of topical glucocorticoids of varying potencies are available. A typical regimen for an eczematous eruption is 1% hydrocortisone ointment applied locally twice daily. Effectiveness is enhanced by application of the topical steroid under an occlusive film, such as plastic wrap; unfortunately, the risk of systemic absorption also is increased by occlusive dressings, and this can be a significant problem when the more potent glucocorticoids are applied to inflamed skin. Glucocorticoids are administered systemically for severe episodes of acute dermatological disorders and for exacerbations of chronic disorders. The dose in these settings is usually 40 mg/day of prednisone. Systemic steroid administration can be lifesaving in pemphigus, which may require daily doses of up to 120 mg of prednisone. Further discussion of the treatment of skin diseases is presented in Chapter 65.
Gastrointestinal Diseases. Glucocorticoid therapy is indicated in selected patients with inflammatory bowel disease (chronic ulcerative colitis and Crohn's disease; Chapter 47). Patients who fail to respond to more conservative management (i.e., rest, diet, and sulfasalazine) may benefit from glucocorticoids; steroids are most useful for acute exacerbations. In mild ulcerative colitis, hydrocortisone (100 mg) can be administered as a retention enema with beneficial effects. In more severe acute exacerbations, oral prednisone (10-30 mg/day) frequently is employed. For severely ill patients—with fever, anorexia, anemia, and impaired nutritional status—larger doses should be used (40-60 mg prednisone per day). Major complications of ulcerative colitis or Crohn's disease may occur despite glucocorticoid therapy, and glucocorticoids may mask signs and symptoms of complications such as intestinal perforation and peritonitis.
Budesonide, a highly potent synthetic glucocorticoid that is inactivated by first-pass hepatic metabolism, reportedly exhibits diminished systemic side effects commonly associated with glucocorticoids. Oral administration of budesonide in delayed-release capsules (entocort, 9 mg/day) facilitates drug delivery to the ileum and ascending colon; the drug also has been used as a retention enema in the treatment of ulcerative colitis.
Hepatic Diseases. The use of corticosteroids in hepatic disease has been highly controversial. Glucocorticoids clearly are of benefit in autoimmune hepatitis, where as many as 80% of patients show histological remission when treated with prednisone (40-60 mg daily initially, with tapering to a maintenance dose of 7.5-10 mg daily after serum transaminase levels fall). The role of corticosteroids in alcoholic liver disease is not fully defined; the most recent meta-analysis of previously published reports failed to establish a beneficial role of corticosteroids, even in patients with severe disease (Rambaldi et al., 2008). Further studies are needed to confirm or refute the role of steroids in this setting. In the setting of severe hepatic disease, prednisolone should be used instead of prednisone, which requires hepatic conversion to be active.
Malignancies. Glucocorticoids are used in the chemotherapy of acute lymphocytic leukemia and lymphomas because of their antilymphocytic effects. Most commonly, glucocorticoids are one component of combination chemotherapy administered under scheduled protocols. Glucocorticoids once were frequently employed in the setting of hypercalcemia of malignancy, but more effective agents, such as the bisphosphonates, now are the preferred therapy.
Cerebral Edema. Corticosteroids are of value in the reduction or prevention of cerebral edema associated with parasites and neoplasms, especially those that are metastatic. Although corticosteroids are frequently used for the treatment of cerebral edema caused by trauma or cerebrovascular accidents, controlled clinical trials do not support their use in these settings.
Miscellaneous Diseases and Conditions. Sarcoidosis. Corticosteroids are indicated therapy for patients with debilitating symptoms or life-threatening forms of sarcoidosis. Patients with severe pulmonary involvement are treated with 10-20 mg per day of prednisone, or an equivalent dose of alternative steroids, to induce remission. Higher doses may be required for other forms of this disease. Maintenance doses, which often are required for long periods of time, may be as low as 5 mg/day of prednisone. These patients, like all patients who require chronic glucocorticoid therapy at doses exceeding the normal daily production rate, are at increased risk of secondary tuberculosis; therefore, patients with a positive tuberculin reaction or other evidence of tuberculosis should receive prophylactic antituberculosis therapy.
Thrombocytopenia. In thrombocytopenia, prednisone (0.5 mg/kg) is used to decrease the bleeding tendency. In more severe cases, and for initiation of treatment of idiopathic thrombocytopenia, daily doses of prednisone (1-1.5 mg/kg) are employed. Patients with refractory idiopathic thrombocytopenia may respond to pulsed high-dose glucocorticoid therapy.
Autoimmune Destruction of Erythrocytes. Patients with autoimmune destruction of erythrocytes (i.e., hemolytic anemia with a positive Coombs test) are treated with prednisone (1 mg/kg per day). In the setting of severe hemolysis, higher doses may be used, with tapering as the anemia improves. Small maintenance doses may be required for several months in patients who respond.
Organ Transplantation. In organ transplantation, high doses of prednisone (50-100 mg) are given at the time of transplant surgery, in conjunction with other immunosuppressive agents, and most patients are kept on a maintenance regimen that includes lower doses of glucocorticoids (Chapter 35). For some solid organ transplants (e.g., pancreas), protocols that either withdraw corticosteroids early after transplantation or that avoid them completely are becoming more common (Meier-Kriesche et al., 2006).
Spinal Cord Injury. A meta-analysis of several randomized, controlled trials (Bracken, 2002) demonstrated significant decreases in neurological defects in patients with acute spinal cord injury treated within 8 hours of injury with large doses of methylprednisolone sodium succinate (30 mg/kg initially followed by an infusion of 5.4 mg/kg per hour for 23 hours). One trial showed further improvement with an additional 24 hours of treatment. The ability of corticosteroids at these high doses to decrease neurological injury may reflect inhibition of free radical–mediated cellular injury, as occurs following ischemia and reperfusion. Potential side effects include increased susceptibility to infection and other wound complications.
Diagnostic Applications of Adrenocortical Steroids
In addition to its therapeutic uses, dexamethasone is used as a first-line agent to diagnose hypercortisolism and to differentiate among the different causes of Cushing's syndrome (Arnaldi et al., 2003).
To determine if patients with clinical manifestations suggestive of hypercortisolism have biochemical evidence of increased cortisol biosynthesis, an overnight dexamethasone suppression test has been devised. Patients are given 1 mg of dexamethasone orally at 11 p.m., and cortisol is measured at 8 a.m. the following morning. Suppression of plasma cortisol to <1.8 μg/dL suggests strongly that the patient does not have Cushing's syndrome. Drugs such as barbiturates that enhance dexamethasone metabolism or drugs (estrogens) or conditions (pregnancy) that increase the concentrations of corticosteroid binding globulin can interfere with suppression and compromise the test. The formal dexamethasone suppression test is used in the differential diagnosis of biochemically documented Cushing's syndrome. Following determination of baseline cortisol levels for 48 hours, dexamethasone (0.5 mg every 6 hours) is administered orally for 48 hours. This dose markedly suppresses cortisol levels in normal subjects, including those who have nonspecific elevations of cortisol due to obesity or stress, but it does not suppress levels in patients with Cushing's syndrome. In the high-dose phase of the test, dexamethasone is administered orally at 2 mg every 6 hours for 48 hours. Patients with pituitary-dependent Cushing's syndrome (i.e., Cushing's disease) generally respond with decreased cortisol levels. In contrast, patients with ectopic production of ACTH or with adrenocortical tumors generally do not exhibit decreased cortisol levels. Despite these generalities, dexamethasone may suppress cortisol levels in some patients with ectopic ACTH production, particularly with tumors such as bronchial carcinoids, and many experts prefer to use inferior petrosal sinus sampling after CRH administration to make this distinction.