Lack of radiological and clinical benefit over two years of low dose prednisolone for rheumatoid arthritis: results of a randomised controlled trial. A randomized study of two long-course prednisolone regimens for nephrotic syndrome in children. Auranofin in the treatment of steroid dependent asthma: a double blind study. Ineffectiveness of cyclosporine as an adjuvant to corticosteroids in the treatment of pemphigus. Controlled trial of azathioprine and plasma exchange in addition to prednisolone in the treatment of bullous pemphigoid. Oral prednisolone followed by inhaled budesonide in newly diagnosed pulmonary sarcoidosis: a double-blind, placebo-controlled multicenter study. Finnish Pulmonary Sarcoidosis Study Group. Double-blind, placebo-controlled study of cyclosporin A as a corticosteroid-sparing agent in corticosteroid-dependent asthma. A controlled trial of early adjunctive treatment with corticosteroids for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. California Collaborative Treatment Group. Neonatal respiratory distress syndrome after repeat exposure to antenatal corticosteroids: a randomised controlled trial. Comparison of short courses of oral prednisolone and fluticasone propionate in the treatment of adults with acute exacerbations of asthma in primary care. The effects of the inhaled corticosteroid budesonide on lung function and bronchial hyperresponsiveness in adult patients with cystic fibrosis.
Evidence for disease modifying activity of low dose corticosteroid treatment in rheumatoid arthritis is contradictory. Studies showing radiological benefit suggest that continued treatment is required to sustain the effect.
                To evaluate the effect of low dose oral prednisolone in early rheumatoid arthritis on disease activity over two years.
                Double blind placebo controlled trial.
                Patients with rheumatoid arthritis, duration <3 years (n = 167), were started on a disease modifying antirheumatic drug (DMARD; sulphasalazine) and allocated by stratified randomisation to prednisolone 7 mg/day or placebo. Primary outcome measure was radiological damage, assessed by the modified Sharp method. Clinical benefit was a secondary outcome. A proactive approach to identifying and treating corticosteroid adverse events was adopted. Patients who discontinued sulphasalazine were offered an alternative DMARD.
                90 of 257 patients eligible for the study refused to participate (more women than men). Of those enrolled, 84% were seropositive for rheumatoid factor, median age 56 years, median disease duration 12 months, female to male ratio 1.8:1. Prednisolone was given to 84 patients; of these 73% continued prednisolone and 70% sulphasalazine at 2 years. Of the 83 patients on placebo, 80% continued placebo and 64% sulphasalazine at 2 years. There were no significant differences in radiological score or clinical and laboratory measures at 0 and 2 years.
                Low dose prednisolone conferred no radiological or clinical benefit on patients maintained on a DMARD over two years. Low dose corticosteroids have no role in the routine management of rheumatoid arthritis treated with conventional disease modifying drugs. Long-course prednisolone regimens have been shown to be more effective than short-course regimens in sustaining remission of nephrotic syndrome in children. However, the most beneficial approach among the long-course regimens remains unknown.
                Seventy-three children with new-onset nephrotic syndrome were allocated at random to the two long-course regimens and followed up for 2 years. Group A was administered prednisolone at a daily dose of 60 mg/m2 for 6 weeks, followed by an alternate-day dose of 40 mg/m2 for 6 weeks (the long daily regimen). Group B was administered the same daily dose for 4 weeks, followed by an alternate-day dose of 60 mg/m2 for 4 weeks, and doses were tapered by 10 mg/m2 every 4 weeks (the long alternate-day regimen).
                Group B had a lower incidence of corticosteroid toxicities than group A during the initial treatment. Kaplan-Meier analysis of the sustained remission rate of the two treatment groups showed a marginally significant difference (P = 0.069) and showed a significant difference when patients were stratified for age of disease onset (P = 0.048). In a subgroup of younger children (<4 years at onset), group B had a greater rate of sustained remission (P < 0.01) and fewer children with frequent relapses (P < 0.05) than group A, whereas in older children (> or =4 years at onset), both groups had similar good sustained remission rates.
                These findings collectively indicate that the long alternate-day regimen may be more beneficial, with less corticosteroid toxicities, than the long daily regimen, and children with younger age at disease onset may be susceptible to relapse and especially benefit from the long alternate-day regimen for sustaining remission of the disease. Long term administration of oral corticosteroids in patients with asthma may be associated with serious side effects. Non-steroidal anti-inflammatory drugs, including gold salts, have been shown to reduce the need for systemic corticosteroid treatment in uncontrolled studies. The effect of oral gold (auranofin) on asthma symptoms, lung function, and the need for oral prednisone treatment was investigated.
                A 26 week randomised, double blind, placebo controlled, parallel group trial of auranofin was performed in 32 patients with moderately severe chronic asthma who required an oral corticosteroid dose of at least 5 mg prednisone a day (or equivalent) or 2.5 mg/day prednisone plus more than 800 micrograms/day inhaled corticosteroids. Auranofin was given orally in a dose of 3 mg twice daily. Asthma symptoms, lung function, and adverse effects were assessed at regular intervals. After 12 weeks of treatment prednisone dosage was tapered down by 2.5 mg every two weeks if the patient was clinically stable. Asthma exacerbations were treated with short courses of high doses of oral steroids.
                Twenty eight of the 32 patients, 13 in the placebo group and 15 in the auranofin group, completed the study. The total corticosteroid reduction achieved after 26 weeks of treatment was significantly greater (4 mg) in the auranofin group than in the placebo group (0.3 mg). The number of exacerbations requiring an increase of steroids was greater in the placebo group (2.1) than in the active group (0.9). A significant increase in FEV1 of 6.4% predicted occurred in the auranofin group during the study and there was a reduction of asthma symptoms such as wheezing and cough. There was no difference between the groups in peak flow measurements or in the number of asthma attacks. The incidence of side effects of auranofin was low, but exacerbations of constitutional eczema were noticeable.
                Auranofin provides an effective adjunct to treatment for steroid dependent asthma, leading to a reduction of oral steroid dose. To compare the effectiveness and the adverse effects of 2 different regimens for the treatment of pemphigus: corticosteroids alone compared with a combination of corticosteroids and cyclosporine.
                Concurrently randomized trial.
                Tertiary care medical center.
                We studied 33 sequential hospitalized patients with newly diagnosed pemphigus vulgaris (n=29) or pemphigus foliaceous (n=4) based on clinical, histological, and immunofluorescence criteria who had not previously been treated with systemic corticosteroids or immununosuppressive drugs. Patients were randomly assigned to treatment with methylprednisolone or prednisolone plus cyclosporine.
                Both groups were treated with similar initial doses of prednisolone (prednisone equivalent, 1 mg/kg), which were increased 50% every 5 to 10 days based on persistence of disease activity. One group was treated in addition with cyclosporine (5 mg/kg).
                Patients were followed up closely for clinical outcome based on time required to control active manifestations of the disease, induction of partial and complete remissions, total amount of corticosteroids administered, frequency of relapses, and development of complications.
                The 2 groups were similar in terms of demographics and baseline disease severity. There was no difference between groups in any of the variables used to measure response to treatment or total amount of corticosteroids administered. Complications were more common in patients who received combination therapy.
                Combination treatment with corticosteroids and cyclosporine, 5 mg/kg, offers no advantage over treatment with corticosteroids alone in patients with pemphigus. Bullous pemphigoid is usually treated with systemic corticosteroids. Side effects are common in elderly patients, justifying the search for adjuvant therapy. This randomized, multicentric unblind study was designed to assess the efficacy of azathioprine or plasma exchange when added to conventional doses of prednisolone. One hundred patients with active disease entered the study. They were randomly allocated to receive 28 days of treatment with oral prednisolone sodium metasulfobenzoate (1 mg/kg per day) either alone or in combination with oral azathioprine (100 to 150 mg/d) or four large-volume plasma exchanges. After 28 days, the prednisolone doses were progressively decreased according to the same strict regimen in the three groups (in combination with oral azathioprine in group 2).
                The clinical results were evaluable in 98 of the 100 patients included in the study. There was no appreciable difference in the percentages of complete remission of the disease in the three therapeutic groups at 28 days (71%, 80%, and 71%, respectively) or at 6 months (42%, 39%, and 29%, respectively). Severe complications were more often observed among patients receiving azathioprine. At 6 months, 14 of 98 patients had died, without any differences noted among the three study groups.
                We conclude that neither azathioprine nor plasma exchange is effective enough to be used routinely as an adjuvant to corticosteroids in the management of bullous pemphigoid. To evaluate the efficacy of oral prednisolone, followed by inhaled budesonide, in patients with newly diagnosed (<3 months) stage I and stage II pulmonary sarcoidosis.
                Double-blind, placebo-controlled, parallel-group, multicenter study.
                Twenty pulmonary medicine departments in Finland.
                One hundred eighty-nine adult patients were randomized to treatment. Patients with erythema nodosum or stage IV sarcoidosis (pulmonary fibrosis), and patients requiring immediate treatment with oral corticosteroids for extrapulmonary lesions or chronic illnesses were excluded.
                The patients received either oral prednisolone for 3 months (20 mg/d for 8 weeks, 15 mg/d for 2 weeks, and 10 mg/d for 2 weeks) followed by inhaled budesonide (Pulmicort Turbuhaler; Astra Draco; Lund, Sweden) for 15 months at 800 microg bid, or placebo tablets followed by placebo inhaler therapy.
                Chest radiographs, lung volumes (FVC), diffusing capacity of the lung for carbon monoxide (D(LCO)), serum angiotensin-converting enzyme (SACE), and beta2-microglobulin at 3-month intervals.
                After 3 months of treatment, radiographic improvements were seen in the active-treatment group when compared to the placebo-treatment group. At 6 months, the difference was still statistically significant. Later, no differences were found. In patients with initial stage I lesions, neither the FVC nor the D(LCO) (the percent predicted mean values) changed during the study, as they were normal from the beginning. In patients with initial stage II disease, the difference in the FVC mean values between the groups also remained unchanged throughout the study. In stage II patients treated for 18 months, but not earlier, the difference in D(LCO) became statistically significant; the largest differences were seen in patients with initial FVC values <80% of predicted and D(LCO) values <75% of predicted. The decrease in SACE in the active-treated stage II patients was significantly larger than in the placebo-treated patients. No difference was observed in adverse events between the active-treated patients and the placebo-treated patients.
                Treatment is not required for patients with stage I disease. An initial treatment with prednisolone followed by long-term inhalation of budesonide is more effective than placebo in patients with stage II disease. Sequential oral and inhaled corticosteroid therapy may be an alternative treatment regimen for stage II sarcoidosis patients, rather than long-term oral corticosteroid therapy alone. Patients with severe asthma who require long-term oral corticosteroid therapy are at risk of unwanted effects. Several immunosuppressive drugs have been assessed as corticosteroid-sparing agents in chronic asthma. We previously showed that cyclosporin A (CsA) administered for 12 wk improved lung function in corticosteroid-dependent patients. We have now investigated the corticosteroid-sparing properties of CsA over a 36-wk period. Following a 4-wk run-in period, 39 corticosteroid-dependent asthmatic patients were randomized to receive CsA (19 patients, initial doses 5 mg/kg/d) or matched placebo (20 patients) for 36 wk. Attempts were then made by a physician ignorant of the trial therapy to reduce their prednisolone dosages at 14-d intervals, provided that a patient's asthma remained stable or improved. Three patients receiving CsA had to be withdrawn from the study before they completed 12 wk of therapy. The remaining 16 patients achieved a statistically significant reduction in median daily prednisolone dosage of 62% (10 to 3.5 mg), compared with a decrease of 25% (10 to 7.5 mg) in the patients taking placebo (p = 0.043). This reduction was most pronounced during the last 12 wk of active therapy. In addition, morning peak expiratory flow rate (PEFR) improved significantly (mean 9.4%, SEM 3.0%) in the active-treatment group but not in the placebo group (p = 0.026 between groups). Predictable changes in renal function and blood pressure, and an increased incidence of hypertrichosis and paresthesia, were observed in the patients treated with CsA, but these did not necessitate withdrawal from the study, and were reversed during a 4-wk run-out period. Thus, low-dose CsA therapy, as compared with placebo, allowed a significant reduction in oral corticosteroid dosages in patients with severe asthma, and also improved lung function. Pneumocystis carinii pneumonia remains a common cause of serious morbidity and mortality in patients with the acquired immunodeficiency syndrome (AIDS). The extensive lung injury that accompanies pneumocystis-associated respiratory failure and the reports of clinical benefit from the use of adjunctive corticosteroids provided the rationale for this prospective multicenter trial.
                A total of 333 patients with AIDS and pneumocystis pneumonia received standard treatment and were randomly assigned to receive either corticosteroids (beginning with the equivalent of 40 mg of prednisone twice daily) or no additional therapy. The primary end points in this unblinded trial were the occurrence of respiratory failure (hypoxemia ratio [partial pressure of arterial oxygen divided by fraction of inspired oxygen] less than 75, intubation, or death), death, and dose-limiting toxicity of the initial standard therapy.
                Of the patients with confirmed or presumed pneumocystis pneumonia (n = 225 and n = 26, respectively), those assigned to treatment with corticosteroids had a lower cumulative risk at 31 days of respiratory failure (0.14 vs. 0.30, P = 0.004) and of death (0.11 vs. 0.23, P = 0.009), as well as a lower risk of death within 84 days (0.16 vs. 0.26, P = 0.026). The frequency of dose-limiting toxicity of the standard therapy was similar in the two treatment groups. Intention-to-treat analyses of the entire cohort confirmed these findings. Clinical benefit could not be demonstrated, however, for patients with mild disease (hypoxemia ratio, greater than 350), equivalent to a partial pressure of oxygen greater than 75 torr on room air. The patients assigned to corticosteroid treatment had an excess of localized herpetic lesions (26 percent vs. 15 percent, P = 0.04) but not of other infections or of neoplasms.
                Early adjunctive treatment with corticosteroids reduces the risks of respiratory failure and death in patients with AIDS and moderate-to-severe pneumocystis pneumonia. Because the adverse effects are few, corticosteroids should be included as part of the initial treatment for persons with AIDS who have moderate-to-severe pneumocystis pneumonia. The efficacy and safety of repeat doses of prenatal corticosteroids remains uncertain. Our aim was to establish whether repeat prenatal corticosteroids given to women at risk of preterm birth can reduce neonatal morbidity without harm.
                In this hospital-based study, 982 women who remained at risk of preterm birth at less than 32 weeks' gestation, 7 or more days after receiving a first course of prenatal corticosteroids, were randomly assigned to receive a repeat intramuscular dose of either 11.4 mg betamethasone (as Celestone Chronodose), or saline placebo. This was repeated every week the woman remained undelivered, at less than 32 weeks' gestation, and at risk of preterm birth. Primary outcomes were occurrence and severity of neonatal respiratory distress syndrome, use and duration of oxygen and mechanical ventilation, and weight, length, and head circumference at birth and hospital discharge. Statistical analyses were on an intention to treat basis. This study is registered as an International Standard Randomised Controlled Trial, number ISRCTN48656428.
                Fewer babies exposed to repeat corticosteroids had respiratory distress syndrome (33%vs 41%; relative risk 0.82, 95% CI 0.71-0.95, p=0.01) and fewer had severe lung disease (12%vs 20%; relative risk 0.60, 95% CI 0.46-0.79, p=0.0003) than those in the placebo group. In keeping with these benefits, babies exposed to repeat corticosteroids needed less oxygen therapy (p=0.03), and shorter duration of mechanical ventilation (p=0.01). Mean weight, length, and head circumference at birth and hospital discharge did not differ between treatment groups. Z-scores for weight (p=0.04) and head circumference (p=0.03) at birth were lower in the babies who received repeat corticosteroids although at the time of hospital discharge Z-scores did not differ between treatment groups (p=0.29 for weight, p=0.48 for head circumference).
                Exposure to repeat doses of antenatal corticosteroids reduces neonatal morbidity. Pending long-term outcome results, the short-term benefits for the babies in our study support the use of repeat doses of corticosteroids in women who remain at risk of very preterm birth 7 or more days after an initial course. Oral corticosteroids used in short courses for acute asthma are regarded as safe, although the frequent use of these drugs may result in patients suffering from systemic side effects. It has become common practice for patients to increase their own inhaled corticosteroid intake when their asthma goes out of control, but it has never been established whether a high dose of inhaled corticosteroid can be as effective as a short course of oral corticosteroid in the treatment of acute exacerbations.
                A multicentre, randomised, double blind, double dummy, parallel group study was undertaken to determine whether the introduction of a high dose of inhaled fluticasone propionate (2 mg daily) is as effective as a short reducing course of oral prednisolone (starting at 40 mg/day and reducing by 5 mg every other day) in the treatment of acute exacerbations of asthma not considered severe enough for admission to hospital but requiring treatment with oral corticosteroid.
                Four hundred and thirteen adult asthmatic subjects who presented to their general practitioner with an acute exacerbation of asthma were recruited in 47 general practices in the United Kingdom. Treatment failures, defined as a reduction in peak expiratory flow (PEF) to below 60% of the patient's best/predicted value on two consecutive occasions or persistent symptoms with no improvement on three consecutive days, occurred in 23% of patients who received oral prednisolone and 27% who received inhaled fluticasone propionate (difference in percentage of treatment failures 4.3, 95% CI -4.1 to 12.8, p = 0.31). In each group 48% were classified as treatment successes, defined as a 10% or greater increase in percentage best/predicted morning PEF. Both treatments were equally well tolerated.
                There is no evidence of a significant difference in efficacy between a reducing dose course of oral prednisolone and high dose inhaled fluticasone propionate in mild exacerbations of asthma which do not require admission to hospital. Bronchial hyperresponsiveness is present in 40-60% of adult patients with cystic fibrosis (CF). Drugs which alter airway hyperresponsiveness have not yet been studied in CF. In this randomized placebo-controlled study, we investigated the effects of an inhaled corticosteroid, budesonide, on lung function and bronchial hyperresponsiveness in adult CF patients, with proven bronchial hyperresponsiveness to histamine. Twelve patients were treated with budesonide, 1600 micrograms day-1, and with placebo during two periods of 6 weeks in a randomized, double-blind, cross-over study. Drug effects were assessed with regard to bronchial hyperresponsiveness to histamine, spirometry and clinical symptom scores. After treatment with budesonide, no significant differences in spirometry were seen, however, bronchial hyperresponsiveness to histamine significantly improved as compared to baseline. Fifty-eight percent of the patients showed at least one doubling-dose increase in PC20 histamine. Daily symptom scores showed small, but statistically significant, improvements in dyspnoea and cough after budesonide treatment. There is increasing evidence suggesting that excessive inflammatory responses contribute to the pulmonary damage that characterizes CF. Treatment with oral corticosteroids improved the clinical course of selected CF patients, but was associated with unacceptable adverse effects. We conclude that daily inhalation of 1600 micrograms day-1 budesonide for 6 weeks induced a small, but significant, improvement in bronchial hyperresponsiveness to histamine, and symptoms of cough and dyspnoea in adult CF patients. Longer observations are needed to establish whether inhaled corticosteroids improve the long term outcome of CF.
Oral corticosteroids at prednisolone-equivalent dose of 1 to 2 mg/kg alternate days appear to slow progression of lung disease in CF; benefit should be weighed against occurrence of adverse events. Risk-benefit analysis of low-dose alternate days corticosteroids is important and the short-term use of oral corticosteroids should be better evaluated.