Glucocorticoids
Joel S. Mindel
Hydrocortisone (cortisol) is the major naturally occurring glucocorticoid in humans. The blood level of hydrocortisone is determined by the rate of pituitary adrenocorticotrophic hormone (ACTH) secretion, which varies in a diurnal fashion. The daily rate of hydrocortisone secretion by the adrenal cortex is approximately 20 to 25 mg/day. The highest level is at approximately 6:00 AM, and the lowest is at approximately midnight. Plasma levels of hydrocortisone fluctuate from a high of approximately 16 μg/100 ml to a low of approximately 4 μg/100 ml.
Patients prescribed a corticosteroid secrete less ACTH. This feedback suppression of the hypothalamus and pituitary gland reduces the pharmacologic effect from the exogenous corticosteroid until the dose exceeds that equivalent to the physiologic hydrocortisone secretion (i.e., exceeds 20 to 25 mg/day). A long-acting corticosteroid, such as dexamethasone, in a dose as low as 0.5 mg suppresses ACTH secretion and the plasma hydrocortisone level for 24 hours.
Hydrocortisone circulates bound to blood proteins. Transcortin is a corticosteroid-binding globulin with a high affinity, but there is relatively little of it. Albumin has a low affinity, but it is in such large quantity that its total binding capacity is high. Only that portion of the corticosteroid dose not bound to these proteins produces a physiologic or pharmacologic effect. As the dose increases, saturating the binding sites, the drug’s effects are enhanced.
MECHANISM OF ACTION
Ophthalmologists use corticosteroids primarily for their anti-inflammatory and immunosuppressive activities. Glucocorticoids can inhibit many aspects of inflammation both by increasing the transcription of anti-inflammatory genes and by decreasing the transcription of proinflammatory genes.1 For example, corticosteroids can reduce the synthesis of proinflammatory agents such as prostaglandins. This can be achieved2,3 by inhibiting the transcription of the genes for phospholipase A2, the enzyme that cleaves arachidonic acid from phospholipids, and COX-2 and by inhibiting the activation of phospholipase A2. Corticosteroids are capable of promoting the release of the phospholipase A2 inhibitor, lipocortin, from leukocytes. It is unclear, however, how important this mechanism is as the serum and plasma levels of metabolites of prostaglandins are not reduced by treatment with large doses of corticosteroids.4 Other mechanisms that have been proposed, for which there is some evidence:
Corticosteroids can increase secretion of leukocyte protease inhibitors, which reduce inflammation.
Interleukin-1 (IL-1) is a proinflammatory cytokine. Levels of IL-1 receptor antagonist can be elevated by glucocorticoid stimulation of its synthesis.
Synthesis of IL-10, a macrophage-secreted anti-inflammatory cytokine, is increased by glucocorticoids.
Glucocorticoids inhibit transcription of the inflammatory cytokines IL-1B, -2, -3, -4, -5, -6, -11, and granulocyte macrophage-colonystimulating factor.
Chemokines attract inflammatory cells to the site of inflammation. Glucocorticoids inhibit transcription of chemokines IL-8, RANTES, MCP-1, MCP-4, MIP-1 α, and eotaxin.
Nitric oxide increases blood flow, enhancing the inflammatory response. Nitric oxide synthase is inducible by some of the proinflammatory cytokines listed previously. Glucocorticoids inhibit their induction.5
Glucocorticoids produce apoptosis (i.e., programmed cell death) of eosinophils and T-cell lymphocytes while increasing the cell life of neutrophils.6 Systemic administration of therapeutic doses of corticosteroids produces lymphocytopenia, eosinophilopenia, decreased lymph node mass, and a relative increase in polymorphonuclear cells.7,8 With prolonged corticosteroid use, an absolute increase in polymorphonuclear cells can occur, producing a leukemia-like picture.
At pharmacologic levels, equivalent to approximately 10-6 M hydrocortisone, lysosomal membranes are stabilized. This effect reduces the release of degradative enzymes and correlates well with the anti-inflammatory activity of corticosteroids.
SYNTHETIC CORTICOIDS
A common feature of the anti-inflammatory corticosteroids is an 11β-hydroxy group. Prednisone does not have this structure and has no anti-inflammatory activity until it is converted in the liver, with approximately 80% efficiency, to prednisolone.9 Patients with hepatic disease may have impaired conversion of prednisone to prednisolone.10 Because of the hydroxylation requirement of prednisone, the permilligram clinical efficacy of oral prednisone is three to four times that of hydrocortisone, whereas the per-milligram clinical efficacy of prednisolone is four to five times that of hydrocortisone.11 It also is why anti-inflammatory eyedrop preparations may contain prednisolone but do not contain prednisone.
Prednisolone may be unique among synthetic corticosteroids in that it competes with endogenous hydrocortisone for protein-binding sites on transcortin.12,13 Prednisolone binds with approximately 2.5 times greater affinity than cortisol and can displace it. Although prednisolone binds albumin with approximately 300 times stronger affinity than hydrocortisone, prednisolone does not displace cortisol. These considerations are important at low prednisone/prednisolone doses because it is only the unbound drug that is pharmacologic active. At low-prednisolone doses, the active unbound drug may be the weaker endogenous corticosteroid, hydrocortisone, that has been displaced from transcortin.
Many corticosteroids have low water solubility. Hence, they are prepared and administered in the form of water-soluble esters such as phosphates and hemisuccinates. In a real sense, these esters are prodrugs and must be hydrolyzed to their free alcohols for their full potency. Dexamethasone disodium phosphate ester is an example.14 The half-life of dexamethasone disodium phosphate ester in blood is approximately 5.4 minutes. The maximum plasma concentration of the free (alcohol) is achieved approximately 10 minutes after intravenous injection.15 The dexamethasone elimination half-life is approximately 210 minutes.
The clearance of corticosteroids from the blood is determined primarily by liver metabolism. This metabolism can be increased by drugs that induce liver enzymes.16 Chronic treatment with diphenylhydantoin can increase prednisolone metabolism by 77% and speed its clearance half-time by 45%. Diphenylhydantoin use can, by similar mechanisms, increase the metabolic inactivation rates of hydrocortisone, dexamethasone, and methylprednisolone by 15%, 51%, and 56%, respectively. In turn, corticosteroids can selectively enhance or decrease liver enzyme syntheses (e.g., the synthesis of transaminases involved in gluconeogenesis are increased, whereas synthesis of butyrylcholinestrase [pseudocholinesterase] is decreased). By day 12, patients receiving prednisone, 50 to 100 mg daily, have a 50% decrease in circulating butyrylcholinestrase activity.17 If the prednisone dosage is reduced to 10 to 15 mg daily, the butyrylcholinestrase level gradually recovers, becoming normal in 30 to 60 days. The activity of erythrocyte acetylcholinesterase is unaffected by corticosteroids. Immunoglobulin synthesis by the liver is variably affected: serum immunoglobulin G (IgG) is reduced, sera immunoglobulin A (IgA) and immunoglobulin M (IgM) are little changed, and serum immunoglobulin E (IgE) is elevated initially but, by 3 weeks of pharmacologic doses, is reduced.18
The plasma concentrations of free and total prednisolone show a diurnal variation when the drug is administered orally.19 Volunteers were given 2 mg prednisolone/10 kg body weight at 6 A.M., noon, 6:00 P.M., and midnight. Depending on the time of day, differences were found in prednisolone bioavailability, plasma concentrations, and clearance rates. The two extremes occurred at noon and 6:00 P.M. The 6:00 P.M. plasma concentration was 60% higher than during the rest of the day. This may explain in part the observation that there is less suppression of adrenal function when corticosteroids are administered in the morning than in the evening.20
The secretion of ACTH and hydrocortisone, the plasma levels of therapeutic corticosteroids, and the variations in intraocular pressure (IOP) all show diurnal phenomena. In addition, plasma glucocorticoid levels maintained above normal may cause an increase in the IOP. Therefore, it is logical to suspect that the normal diurnal secretion of hydrocortisone is responsible for the diurnal fluctuations in IOP. Glucocorticoid receptors have been detected in cultures of human trabecular cells.21 When adrenalectomized patients have had their blood levels of corticosteroids maintained at a constant level, their diurnal variations in ocular pressure did not occur.22
Long-term administration of corticosteroids above physiologic doses results in adrenal gland atrophy and a sustained suppression of the hypothalmic-pituitary-adrenal axis. If withdrawal from corticosteroid treatment is too sudden, the patient may exhibit weakness, fatigue, orthostatic hypotension, hypoglycemia, nausea, arthralgia, and dyspnea; deaths have been attributed to adrenal insufficiency.23 The degree of pituitary-adrenal suppression is not predictable in a given patient. Although certain generalizations can be made relating to the degree and duration of suppression with the dose and duration of corticosteroid treatment, there are many exceptions found when the degree of recovery actually is tested by the administration of ACTH-releasing hormone.24 In general, dosages of prednisone, 40 mg once daily for less than a week, do not result in significant adrenal suppression.25
Once adrenal suppression occurs, full recovery of hypothalamic-pituitary-adrenal function may take as long as 9 months.26 Weaning the patient away from corticosteroids may be required and can begin with rapid reduction to approximately physiologic doses of corticosteroid. For prednisone and prednisolone, the upper limits of doses having physiologic equivalence are approximately 5 mg/day; for dexamethasone, the upper limits of doses are approximately 0.75 mg/day. Tapering down below these doses is best done with a short-acting corticosteroid (e.g., hydrocortisone is better than prednisone or prednisolone, although the latter two drugs frequently are used). Dexamethasone, because of its long action, is best avoided as a weaning drug. An example of a withdrawal program would be to give the weaning drug daily at a dose equivalent to the normal physiologic secretion rate for 1 week and then to decrease the daily dose, at weekly intervals, by one-tenth steps of that dose.
Alternate-day therapy with doses less than 40 mg every other day tends not to produce suppression, even after long periods of treatment.27 In alternate-day therapy, the 2-day total dosage is given as a single dose (e.g., 25 mg prednisone, four times a day, becomes 200 mg prednisone every other day). However, the benefits of every-other-day therapy are lost if long-acting preparations (e.g., dexamethasone) are used. Prolonged alternate-day corticosteroid use eventually may cause the other side effects of daily therapy (e.g., when 25 patients taking daily prednisone for a mean duration of approximately 5 years were compared with 25 patients taking alternate-day therapy, drug-induced osteoporosis was present to a comparable degree in both groups).28 Surprisingly, long-term (i.e., mean 5-year duration) treatment of temporal arteritis may not induce osteoporosis.29,30
There is some evidence that alternate-day oral therapy may, in part, have less toxicity and be less efficacious because there is less drug absorption when large doses are used.31 When volunteers were given oral prednisone 0.2 mg/kg or 0.8 mg/kg, the total plasma prednisolone, the unbound plasma prednisolone, and the protein-bound prednisolone were much less than four times as much for the 0.8 mg/kg dose.
Another approach to avoiding the complications of prolonged corticosteroid use has been pulsed therapy. Experience gained by rheumatologists in treating autoimmune diseases, such as systemic lupus erythematosus, has been applied to ocular inflammatory diseases.32,33 In pulse therapy, a large dose of corticosteroid is given intravenously (e.g., methylprednisolone 1 g) over a short period (e.g., less than 1 hour) and repeated for several days (e.g., for 3 days). The patient then goes for a relatively long period, weeks or months, receiving little or no corticosteroid medication until the pulse therapy is repeated.
OCULAR THERAPY
GENERAL CONSIDERATIONS
Corticosteroids usually are palliative. They attack the results of the disease process and not the causes. The correct corticosteroid dose in a given patient depends on the severity of the disease process and is based on both the clinician’s experience and by a trial-and-error process.
Oral corticosteroids and subconjunctival, sub-Tenon’s, and retrobulbar injections of corticosteroids have been used primarily for treating retrolenticular pathologies. Eyedrops and ointments have been used primarily for conditions of the lids, conjunctiva, cornea, and iris-ciliary body. Parenteral depot preparations may contain carriers, such as polyethylene glycol/myristyl picolinium, that provide prolonged release characteristics. An injection of one of these can give a therapeutic response for 6 or more weeks. Allergic reactions to the myristyl picolinium in a methylprednisolone preparation have been reported.34 The data available on the duration of drug presence in the orbit and its intraocular penetration are largely from animal studies (i.e., quantitative human data are relatively few). When a 5-mg dose of dexamethasone disodium phosphate, a nondepot formulation, was injected peribulbarly in 61 patients, a mean vitreous drug peak of 13 ng dexamethasone/ml was achieved in 6 to 7 hours. The mean serum drug peak of approximately 60 ng/ml was reached 20 to 30 minutes after the injection.35 Oral administration of dexamethasone, 7.5 mg, produced peak vitreous concentrations ranging from 1.7 to 23.4 ng/ml (median, 5.2 ng/ml) within 4 to 10 hours; the peak serum concentrations ranged from 2.5 to 98.1 ng/ml (median, 61.6 ng/ml) and occurred between 1 and 3 hours after ingestion.36
Early studies indicated that topical corticosteroids readily penetrated the cornea. However, as the assay techniques improved, the aqueous humor levels were revised downward. When 50 μl of a 0.1% betamethasone sodium phosphate solution were applied to the cornea, the mean peak level, detected 1.5 to 2 hours later, was 7.7 ng/ml (i.e., 1/13,000 of the original concentration).37 When subjects were given a single 50-μl drop of a commercially available preparation of dexamethasone alcohol 0.1% suspension,38 fluorometholone alcohol 0.1% suspension, prednisolone acetate 1% suspension,39 or prednisolone sodium phosphate 0.5% solution40 just before cataract surgery, the aqueous humor levels of dexamethasone, fluorometholone, and prednisolone were measured. The results are listed in Table 1.
TABLE 1. Mean Concentration of Aqueous Humor Drug (ng/ml) | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Commercially available preparations of corticosteroid eyedrops exist as solutions or suspensions. The drug concentration that is dissolved in the supernatant of a suspension is not altered by shaking it (unless the temperature of the solution becomes elevated). However, the number of drug-containing particles in the supernatant is transiently affected by shaking.41 Different brands, depending on such variables as particle size and particle number, can behave differently. The relative amounts of prednisolone acetate after shaking were compared using drops from two different brands; the respective percent amounts of drug after 0, 10, 20, and 40 shakes (numerator), when compared with the amounts after 20 minutes of shaking on a mechanical rotator (denominator), were for one brand 23%, 53%, 69%, and 82%, respectively, and were for the other brand 5%, 14%, 13%, and 22%, respectively. Because the drug-containing particles can be trapped under the lids and act as a reservoir, prior shaking of the bottle alters the effective dose of a corticosteroid suspension.
SELECTED ENTITIES
Giant Cell Arteritis
Corticosteroids have been the primary treatment for giant cell arteritis. The dose size and frequency have been monitored using relief of symptoms, such as headache, jaw claudication, musculoskeletal pain and malaise, and/or an improvement in laboratory data, such as reduced Westergren erythrocyte sedimentation rate, C-reactive protein level and reactive thrombocytosis, or recovery from anemia.42,43,44 Initially, large doses of corticosteroid are given orally (e.g., 100 to 150 mg/day prednisone) or intravenously (e.g., 1 g [or more] prednisolone disodium phosphate per day). Once the symptoms are reduced and the laboratory study results approach normal levels, the dose of corticosteroid is lowered.
A major goal of corticosteroid treatment is to prevent ischemic infarction of the optic nerves. Vision loss can occur even after the initiation of intravenous corticosteroids,45 but it is rare after 96 hours (i.e., 4 days) of treatment.46 The resultant loss of vision rarely is reversible,47 and in those patients claiming improvement, the course of the disease often was atypical (i.e., one patient had an uncharacteristically slow [months] progression of visual loss to light perception and 20/400 visual acuity before responding to a pulse dose of methylprednisolone 80 mg intravenously followed by 1 month of oral prednisone 100 mg/day).48 However, aggressive therapy can be recommended, if not to salvage the affected eye, then to protect the unaffected one.
The need for continued corticosteroid treatment once the initial signs and symptoms disappear is quite variable, from as short as 1 month’s time to indefinitely.49,50 Relapses frequently occur after treatment is stopped. In one study, one third of patients relapsed,51 75% of these occurring within 3 months; one patient relapsed more than 10 years after stopping treatment. The percentage of CD8 cells has been correlated with disease control: patients with giant cell arteritis treated 6 months with corticosteroids whose CD8 cell counts were lower than one standard deviation from those of control subjects required a higher dose of prednisone, a longer duration of treatment, and were more likely to relapse.52
Because the initial therapeutic response to large doses of corticosteroids is dramatically rapid, usually within 24 hours, some have advocated using this as a diagnostic test rather than the temporal artery biopsy. According to this line of reasoning, the literature indicates that temporal artery biopsy specimen results are negative in 60% to 70% of temporal arteritis suspects.53,54 Because only a minority of patients have a positive biopsy specimen result, the procedure should be reserved for those in whom either the corticosteroid response is rapid but prolonged treatment is medically contraindicated or there is failure to rapidly respond to corticosteroid treatment55 but the physician believes that giant cell arteritis is present.
However, the alternative argument seems more cogent: the temporal artery biopsy results, whether positive or negative, seem correct approximately 95% of the time. Most clinicians would prefer to have a positive biopsy specimen result before committing their patients to the potential complications of long-term corticosteroid treatment53,54 or a negative biopsy specimen result before withholding vision-preserving therapy. When 109 patients with giant cell arteritis or polymyalgia rheumatica or both were followed prospectively for a mean ± standard error period of 68.5 ± 5.4 weeks, 10 patients had fractures develop, five of which were vertebral, and four patients had peptic ulcers develop, two of which perforated.56 But here, too, exists a counter argument. Despite the frequently stated fear of corticosteroid complications, many investigators have found that temporal arteritis and its treatment does not negatively affect longevity.49,51,57
Methotrexate has been used to reduce the need for corticosteroids.58 The investigators’ goal was to control the disease after an initial 2 weeks of large-dose prednisone, with 10 mg prednisone per day or less. Methotrexate was added as a single weekly 10-mg dose at the beginning of treatment. A mean length of 14 weeks was needed for 11 newly diagnosed patients with giant cell arteritis to achieve control on 10-mg prednisone per day and a mean length of 30 weeks before corticosteroids could be withdrawn completely.
Alternate-day therapy also minimizes the side effects of treatment. However, control of the disease is compromised. Three groups of 20 patients with biopsy-proven temporal arteritis were treated after the acute phase of their disease as follows:
Group A: Prednisone 15 mg every 8 hours
Group B: Prednisone 45 mg every morning as a single dose
Group C: Prednisone 90 mg every other morning as a single dose59
After 4 weeks of following this therapy, the patients found the subsequent results in their respective groups:
Group A: Eighteen of 20 patients were asymptomatic with mean hemoglobin (in g/dl) having increased from 11.4 to 14.1 and mean sedimentation rate (mm/hr) having decreased from 96 to 14.
Group B: Sixteen of 20 patients were asymptomatic with mean hemoglobin having increased from 11.3 to 13.3 and mean sedimentation rate having decreased from 94 to 18.
Group C: Six of 20 patients were asymptomatic with mean hemoglobin having increased from 11.3 to 12.5 and mean sedimentation rate having decreased from 96 to 44.
Although statistical analysis confirmed that alternate-day therapy was not as effective, none of these patients experienced an ischemic optic neuropathy or other vasculopathy. The question remains whether some loss of disease control is worth the potential reduction in drug-induced morbidity. This question is best answered on a patient-by-patient basis.
The question of “Can a temporal artery biopsy be positive after prolonged systemic corticosteroid therapy?” is not the same as the more important question of “Will the frequency of finding a positive temporal artery biopsy result be reduced by prolonged corticosteroid therapy?” The answer to both questions is yes. It is possible for the results of the temporal artery biopsy specimen to remain positive (i.e., show signs of inflammatory disease including giant cells) for long periods after initiation of corticosteroid treatment. Positive biopsy specimen results have been reported after 1 month of prednisone 60 mg daily,60 6 weeks of prednisone 30 to 40 mg daily,61 and 6 months of prednisone 30 to 60 mg daily.62 However, there also is evidence to suggest that corticosteroid use results in a rapid reduction in the incidence of positive results of biopsy specimens. When 132 patients were analyzed who were clinically diagnosed as having temporal arteritis and in whom 84 had a positive biopsy specimen result, it was found that the incidence of a positive biopsy result before corticosteroid treatment was 82% but fell to 60% with less than 1 week of therapy and was 10% after 1 week of treatment.63
Optic Neuritis
There are surprisingly few controlled investigations in the literature regarding corticosteroid treatment of optic neuritis.64 Those that exist have had relatively few subjects and have failed to convincingly show efficacy (e.g., retrobulbar injections of a single dose of triamcinolone,65 40 mg, in patients with optic neuritis of less than 10 days’ duration did not result in a significant difference in visual acuity or visual field recovery at 6 months after treatment). Uncontrolled studies have tended to be more enthusiastic.66
The visual loss from a single attack of optic neuritis usually resolves spontaneously. When permanent visual loss occurs, it often is the result of the cumulative effects of recurrent attacks. If a patient is given corticosteroids for his initial attack, he tends to attribute his recovery to the drug. He becomes “hooked” and the physician is under pressure to treat each successive attack with corticosteroids. If the physician does not and the visual recovery is worse than that of the preceding attack, the physician can be accused of withholding a beneficial therapy. However, repeated treatments with corticosteroids, especially if the attacks are close together, can lead to the side effects associated with this class of drugs.
To determine the efficacy of corticosteroid treatment in optic neuritis, a multicenter National Eye Institute-funded investigation was performed by the Optic Neuritis Study Group.67,68,69,70,71,72,73 Unfortunately, there has been a strong tendency to attribute its findings to the different routes of corticosteroid administration (e.g., statements are made such as “Oral steroids are contraindicated in optic neuritis”) rather than to the differences in doses and rates of drug administration. This discussion will focus on the latter two.
Approximately 450 subjects were entered into the study. Subjects were between 18 and 46 years of age and were seen within 8 days of their first known attack of optic neuritis in the affected eye; 31 of 448 subjects were known to have prior optic neuritis in the contralateral eye. None of the subjects were considered to have “probable MS” or “definite MS” and none had had previous treatment with systemic corticosteroids. The investigators focused on the effect of systemic corticosteroids on the rate of recovery of visual function, the final level of visual function recovery, the frequency of optic neuritis recurrences, and the frequency of progression to probable MS and definite MS. The patients were entered into one of three groups. There was a high-dose corticosteroid treatment group that received pulse therapy of intravenous methylprednisolone sodium succinate (molecular weight = 496.53) 250 mg every 6 hours for 3 days followed by oral prednisone 1 mg/kg for 11 more days; a moderate-dose corticosteroid treatment group that received oral prednisone 1 mg/kg/day for 14 days; and an oral placebo-group. The first two treatment groups also received a short oral taper of prednisone 20 mg on day 15 and prednisone 10 mg on days 16 and 18. Assuming that the liver’s conversion rate of prednisone (molecular weight = 348.43) to the active form of the drug, prednisolone (molecular weight = 364.43), occurs with 80% efficacy and that the patients weighed no less than 60 lb or more than 250 lb, the prednisolone-equivalent amount of corticosteroid received by the high-dose/pulsed group during the first 3 days of treatment was 2202 mg, whereas that of the moderate-dose group was 68 to 285 mg (i.e., the high-dose pulsed group received between 8 and 32 times more prednisolone).
The use of corticosteroids increased the early rate of recovery of visual function (e.g., on day 4, the mean visual acuity in the high-dose pulsed prednisolone group had improved from 20/80 at entry to 20/25, whereas the acuity in the placebo-treated group had not changed). However, the use of corticosteroids did not improve the final level of acuity compared with that achieved by spontaneous recovery. Six months after treatment, the acuity in eyes receiving the high-dose pulsed treatment was only minimally better than placebo-treated eyes; by 1 year, there was no significant difference. Moderate dose but neither high-dose pulsed corticosteroid treatment nor placebo treatment significantly increased the risk of a future attack of optic neuritis in the same or the contralateral eye. During the first 2 posttreatment years, 30% of patients taking the moderate dose (68 to 285 mg prednisolone equivalent for the first 3 days) had a second attack compared with 14% taking the high-dose pulsed treatment (2202 mg prednisolone equivalent for the first 3 days) and 16% taking the oral placebo. This significant increase remained at the end of 5 years being, respectively, 41% moderate dose and 25% for both pulsed high-dose and placebo treatments. With regard to the frequency of progression to probable MS or definite MS, high-dose pulsed therapy showed a benefit over both moderate-dose therapy and placebo that persisted for 2 years but was no longer statistically significant by 5 years posttreatment. At 2 years, 7% of the high-dose pulsed corticosteroid treatment group had converted to definite MS, whereas the corresponding figures for placebo and moderate-dose treatments were 16.7% and 14.7%, respectively. Most of the benefit from high-dose pulsed treatment came in those subjects with two or more brain magnetic resonance imaging signal abnormalities; the rate of progression to definite MS in patients with normal scans was too low to be evaluated. However, by the third year posttreatment, there was no significant difference in the incidence of definite MS among the three groups. At 5 years posttreatment, 36% of the 388 study patients who, at entry, were considered to have neither probable MS nor definite MS had converted to the former (27%) or latter (9%). There were no statistically significant differences between the conversion rates of the three treatment groups. These findings suggest an overall beneficial effect that lasts for 2 years with 3 days of high-dose pulsed corticosteroid treatment and raise the possibility that high-dose pulsed treatment should be repeated every 2 years in those patients having all three of these characteristics: optic neuritis, no diagnosis of probable MS or definite MS, and two or more brain plaques seen on magnetic resonance imaging. The complication rate from corticosteroids in these subjects, ages 18 to 46 years, was small. Only two of the 150 subjects receiving high-dose pulsed corticosteroid therapy had possible drug-related significant side effects: the first patient became psychotic and the second patient had pancreatitis develop.
The methodology of the Optic Neuritis Study Group has been criticized. The high-dose pulsed corticosteroid treatment group was not masked or controlled because it was the only one to receive its initial medication intravenously. The one control group in the study received an oral placebo. Thus, only the moderate treatment group, which received its medication orally, was masked and controlled adequately. Patient or physician bias or both could have affected the results reported for the high-dose pulsed group. Another criticism is the failure of the study group to consider a prior attack of optic neuritis in the contralateral eye or a recurrence of optic neuritis in the same or contralateral eye as evidence of probable MS or definite MS. Many, if not most, neurologists and neuro-ophthalmologists would consider a second attack of optic neuritis as justifying the word multiple in multiple sclerosis. The statistical effect of a reclassification of these subjects is not clear.
Predict Glaucoma
Retrospective and prospective studies have assessed the value of the IOP response to corticosteroids as a predictor for developing glaucoma. In one study,74 29 of 134 patients had glaucoma develop 5 to 15 years after being challenged with corticosteroid drops. Nine (26%) of the 29 patients were from the group of 34 patients who had had a high response (16 mmHg or higher) to topical dexamethasone 0.1% drops; 13 (20%) of the 29 were from the group of 66 patients who had had an intermediate response (6 to 15 mmHg), and 7 (21%) of the 29 were from the group of 34 patients who had had a low response (5 mmHg or lower). The author concluded that the test was of little predictive value. However, the overall incidence of glaucoma developing in this study population was so inexplicably high (21.6%) that some problem in the methodology used is suspected. In a retrospective study of 788 subjects who had had their IOP response assessed 5 or more years previously using dexamethasone 0.1%, four times a day for 6 weeks and had been classified by Becker’s criteria, 13% of the high responders had glaucoma develop (i.e., elevated pressures and visual field loss) and an additional 64% had ocular hypertension develop.75 The corresponding figures for intermediate and low responders were as follows: 3% and 0% had glaucoma develop, respectively, and 46% and 2% had ocular hypertension develop, respectively. In another study of 22 normotensive subjects who were high responders (i.e., subjects whose IOPs increased 16 mmHg or greater) and who were followed up 10 or more years, five had IOPs greater than 21 mmHg develop. Two of these five subjects had visual field defects develop.76
The IOP response to corticosteroids may have some value in predicting who will have open-angle glaucoma develop, but there are too many false-positives to justify routine prospective testing using it (i.e., too few of the high responders had glaucoma develop).
Thyroid (Graves) Ophthalmopathy
This is an autoimmune condition in which the orbital tissues exhibit lymphocytic infiltration, increased mucopolysaccharide content, and edema. The extraocular muscles initially become inflamed and swollen and later fibrosis occurs. Diplopia, proptosis, and a compressive optic neuropathy can result. Large doses and prolonged use of systemic corticosteroids can arrest the process. However, once scar tissue forms or optic atrophy has occurred, drug therapy is of no benefit in reversing these problems. The active phase of thyroid ophthalmopathy is self-limited. Functional sequelae can be prevented if the process is controlled by corticosteroids until the active phase burns itself out. This usually takes months to, rarely, years of treatment.
One early report77 of 10 patients with thyroid optic neuropathy found a return of visual acuity to 20/30 or better in all subjects. They were treated with daily oral prednisone, 20 to 120 mg for 1 to 54 months. Subsequent authors have not had as good success. Only 10 of 21 eyes with thyroid optic neuropathy responded, even though doses of prednisone up to 100 mg were used daily for at least 30 days78; these authors noted that if benefit were to occur, visual function began to improve within 1 week of starting treatment. Patients with severe exophthalmos, if acute, also have responded to high-dose systemic corticosteroids. Administering oral prednisone (e.g., 80 mg or more a day) improves approximately half the patients treated.79,80 If patients do not respond, it is either because the dose of corticosteroid is too low or secondary changes have occurred that prevent improvement. However, not all clinicians accept this explanation. The enigma (to some) of why patients do not always respond has led to several immunologic investigations.81
In one study, most patients with acute thyroid ophthalmopathy were found to have a decreased number of thymus-derived lymphocytes that, in vitro, formed rosettes with sheep erythrocytes; these patients responded well to corticosteroids. Those patients who did not respond to treatment were from the minority that did not have a decrease in circulating thymus-derived rosette-forming lymphocytes. In another study, the presence of human leukocyte antigen (HLA)-DR4 was significantly associated with a good response to corticosteroid therapy. Fourteen of 37 patients responding to corticosteroid treatment were HLA-DR4 positive. None of the 20 patients who did not respond to corticosteroids were HLA-DR4 positive.82 Somatostatin receptors occur on lymphocyte membranes and octreotide binds to them. Orbital scintigraphy with (111I n-diethylenetriamine penta-acetic acid-D-Phe1) octreotide has been used to predict which patients will respond to corticosteroids.83 Presumably, there are more lymphocytes present in the orbit during active disease when the condition is responsive to corticosteroids.
Rapid control of the various forms of thyroid ophthalmopathy has been achieved using pulse therapy followed by oral therapy (e.g., 500 mg methylprednisolone intravenously within 30 minutes on days 1 and 2 followed by 40 mg prednisolone daily).84,85,86 Because of potential irreversibility once optic atrophy occurs, even larger initial pulse doses have been advocated for thyroid optic neuropathy (e.g., 1000 mg methylprednisolone daily for 3 days).87
Radiation therapy for thyroid ophthalmopathy has been claimed superior to corticosteroid therapy short term88 but less effective long term.89 In prospective, randomized trials, radiation therapy and oral prednisone were found equivalent 24 weeks posttreatment,90 and combined use of radiation therapy and corticosteroids was found more effective than radiation alone at 6 to 9 months posttreatment.91 Oral corticosteroids appear to be as effective as intravenous immunoglobulin therapy 6 months after initiation of treatment92 and slightly more effective than subcutaneous somatostatin treatment, three times a day, 3 months after initiation of therapy.93
Although controversial, there is some basis to believe that radioactive iodine treatment of hyperthyroidism is associated with an increased risk of developing or exacerbating thyroid ophthalmopathy. In one randomized, prospective, but not masked, study, ophthalmopathy developed or worsened in four of 38 medically (methimazole) treated patients, six of 37 surgically (subtotal thyroidectomy) treated patients, and 13 of 39 iodine-treated patients (p = .02 for the risk of this last group compared with the other two combined).94 Assuming that radioactive iodine results in the release of antigenic agents from damaged cells and that these antigenic agents are the cause of the increased thyroid ophthalmopathy, systemic corticosteroids have been used to try to prevent or attenuate postradioiodine thyroid ophthalmopathy. Prednisone, 0.4 to 0.5 mg/kg/day starting 2 to 3 days after radioiodine and continuing for 1 month, followed by a 2-month taper was associated with improvement or no progression of ophthalmopathy in 145 patients. In 150 patients receiving radioiodine but not oral corticosteroids, 23 (15%) had worsening ophthalmopathy or ophthalmopathy develop 2 to 6 months after treatment.95
Miscellaneous
ALLERGIC CONJUNCTIVITIS. Systemic corticosteroids do not alter the early phase of allergic conjunctivitis (first hour, neutrophil response) but do markedly limit the late-phase (eosinophil) response.96 Topical corticosteroids are effective in the control of conjunctival allergic symptoms.97,98,99
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