Azathioprine plus prednisone in treatment of pemphigoid.

Twenty-five patients taking part in a controlled trial to compare azathioprine plus prednisone with prednisone alone in the treatment of pemphigoid were followed up for three years. Results showed that the addition of azathioprine 2.5 mg/kg body weight daily reduced the total maintenance dose of prednisone needed by about 45%, with no increase in serious side effects or mortality. The suggestion that azathioprine might increase the risk of disseminated malignancy in elderly patients was not supported. We conclude that in future trials the combination of azathioprine with prednisone should be used as the standard treatment for comparison.     

Beclomethasone dipropionate in asthma.

Beclomethasone dipropionate aerosol therapy can replace or diminish systemic corticosteroid therapy in the majority of asthmatics. In a clinical trial of 41 patients with perennial asthma, the 10 who had not required long-term corticosteroid therapy improved symptomatically and in pulmonary function. Of the 31 who had required prolonged systemic corticosteroid therapy 12 were able to discontinue oral prednisone therapy, 15 were able to decrease the maintenance dose of prednisone and only 4 were unable to decrease the dose; all maintained satisfactory lung function and some showed improvement. Discontinuation of systemic corticosteroid therapy was accomplished more readily in patients whose daily maintenance dose was less than 15 mg and who had been taking the drug for less than 3 years. Side effects consisted of a "dry throat" in seven patients, two of whom had throat infections with Candida albicans. Recurrence of rhinitis after discontinuation or reduction of systemic corticosteroid therapy was noted in 11 patients.     

Azathioprine in Ulcerative Colitis: Final Report on Controlled Therapeutic Trial

Eighty patients, all of whom were suffering from a frank clinical attack of ulcerative colitis, were admitted to the trial. The attack was treated with a standard course of corticosteroids and the patients were immediately placed on treatment with either azathioprine in a dose of 2·5 mg/kg body weight or dummy tablets. The trial tablets were continued for one year while the patients were maintained under regular clinical, sigmoidoscopic, histological, haematological, and biochemical surveillance. If a patient relapsed during such maintenance treatment he or she was treated with a further course of corticosteroids without interrupting maintenance treatment.In the treatment of an actual attack of ulcerative colitis the results in the attacks which brought the 80 patients into the trial show that no benefit came from the addition of azathioprine to a standard course of corticosteroid therapy.Patients admitted in their first attack of ulcerative colitis showed no benefit from the one-year maintenance treatment with azathioprine, the benefits of which were confined to patients admitted in a relapse of established disease. Even in these the difference between the treated group and the control group failed to reach statistical significance, but the difference was big enough to suggest that there is a prima facie case for regarding azathioprine as of some benefit in this group of patients.     

Recovery of Adrenocortical Function during Long-term Treatment with Corticosteroids

The recovery of adrenocortical function during very slow withdrawal of corticosteroids was studied in a homogeneous group of patients suffering from sarcoidosis. All patients had been treated with gradually decreasing doses of prednisone for at least two years. The initial dose had been 40 mg. daily in all cases. Determination of the cortisol production rate and of plasma fluorogenic corticosteroids was done under basal conditions and after tetracosactrin stimulation. There was good correlation between cortisol production rate and plasma fluorogenic corticosteroids throughout all the tests. Cortisol production rate and plasma fluorogenic corticosteroids started to rise when the dosage of prednisone was lowered to 7·5 mg. daily and reached normal values when the dosage was reduced to 2·5 mg. The response to tetracosactrin began to increase at the same dosage level, but was not normal at 2·5 mg., or when prednisone treatment was stopped. At a dosage level of 7·5 mg. of prednisone plasma fluorogenic corticosteroids already showed a nyctohemeral rhythm.It may be calculated that even very low dosages of prednisone given during the last stage of a treatment schedule enhance total corticosteroid activity beyond the normal level, which would account for their therapeutic value.     

EFFECTIVENESS OF ANTACIDS IN REDUCING DIGESTIVE DISTURBANCES IN PATIENTS TREATED WITH PREDNISONE AND PREDNISOLONE

To appraise the efficiency of complemental antacid administration in preventing and reducing digestive disturbances during prolonged treatment with prednisone and prednisolone, 100 patients with active rheumatoid arthritis who were maintained on combined antacid and prednisone or prednisolone therapy for periods of one year or longer, were studied clinically and roentgenographically. Antacid therapy consisted of 300 mg. of dried aluminum hydroxide gel and 50 mg. of magnesium trisilicate taken with each 2.5 mg. dose of the steroids.Digestive symptoms, such as indigestion, heartburn, sour eructations, gnawing epigastric distress and the like, were experienced by 18 per cent of patients during treatment with prednisone or prednisolone combined with antacids. Among patients who had been maintained on the steroids without antacids beforehand, the incidence of digestive complaints was reduced from 38 per cent to 17 per cent by the addition of alkali therapy, and the severity of the distress decreased in others.Active peptic ulcers were detected roentgenographically in three of the 100 patients. In two instances the ulcers were asymptomatic and in two instances they were considered as reactivations of previously healed lesions. The incidence of active ulcers in this series was substantially lower than that reported by several investigators among patients treated with prednisone and prednisolone without the concomitant administration of alkalis. The size of dosage and individual susceptibility appeared to be important factors in the development of digestive disturbances from steroids.Results of the study indicated that the complemental use of antacids with each divided dose of steroid is highly effective in reducing the frequency and severity of digestive symptoms during prednisone and prednisolone administration. The low incidence (3 per cent) for roentgenographically demonstrable active lesions in the series suggests that the addition of acid-neutralizing agents during prolonged treatment with these steroids may afford at least partial protection against the development and reactivation of peptic ulcers.     

Use of antilymphocyte globulin after cadaveric renal transplantation

Antilymphocyte globulin (A.L.G.) was prepared by injecting fresh frozen splenic cells subcutaneously into horses. The IgG fraction of the serum was concentrated by a batch technique using diethylaminoethanol-Sephadex. Fourteen patients given this material by intramuscular injection after cadaveric renal transplants, in addition to azathioprine and prednisone, had less evidence of rejection compared with patients previously treated with azathioprine and prednisone only, despite a reduction of the mean daily prednisone dose from 65 to 45 mg. Toxicity, especially local reaction, fever, and hypotension, limited the amount of A.L.G. that was given.     

Co-trimoxazole and Azathioprine: A Safe Combination

Ninety-four patients receiving immunosuppressive therapy with azathioprine and prednisone after human cadaver kidney transplantation developed urinary tract infections and were treated with co-trimoxazole or another antibiotic in a controlled randomized prospective trial. The incidence of leucopenia in the group treated with co-trimoxazole (10·6%) was not significantly different from that in the group treated with other antibiotics (23·6%). Leucopenia when it occurred did so soon after transplantation at a time when the function of the renal transplant was poor in relation to the dosage of azathioprine given. In all cases the temporary withdrawal of azathioprine relieved the leucopenia despite continuation of the co-trimoxazole treatment. This study did not provide any evidence that co-trimoxazole plus azathioprine was a more potent cause of leucopenia than azathioprine alone.     

Vasoactive intestinal peptide inhibits TNF-α-induced apoptotic events in acinar cells from nonobese diabetic mice submandibular glands

Introduction

In systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents.

Methods

Data on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS).

Results

A total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose ≥ 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties.

Conclusions

Despite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.     

Randomised controlled trial of azathioprine withdrawal in ulcerative colitis.

OBJECTIVE--To determine whether azathioprine can prevent relapse in ulcerative colitis. DESIGN--One year placebo controlled double blind trial of withdrawal or continuation of azathioprine. SETTING--Outpatient clinics of five hospitals. SUBJECTS--79 patients with ulcerative colitis who had been taking azathioprine for six months or more. Patients in full remission for two months or more (67), and patients with chronic low grade or corticosteroid dependent disease (12) were randomised separately. 33 patients in remission received azathioprine and 34 placebo; five patients with chronic stable disease received azathioprine and seven placebo. MAIN OUTCOME MEASURE--Rate of relapse. Relapse was defined as worsening of symptoms or sigmoidoscopic appearance. RESULTS--For the remission group the one year rate of relapse was 36% (12/33) for patients continuing azathioprine and 59% (20/34) for those taking placebo (hazard rate ratio 0.5, 95% confidence interval 0.25 to 1.0). For the subgroup of 54 patients in long term remission (greater than six months before entry to trial) benefit was still evident, with a 31% (8/26) rate of relapse with azathioprine and 61% (17/28) with placebo (p less than 0.01). For the small group of patients with chronic stable colitis (six were corticosteroid dependent and six had low grade symptoms) no benefit was found from continued azathioprine therapy. Adverse events were minimal. CONCLUSIONS--Azathioprine maintenance treatment in ulcerative colitis is beneficial for at least two years if patients have achieved remission while taking the drug. Demonstration of the relapse preventing properties of azathioprine has implications for a large number of patients with troublesome ulcerative colitis, who may benefit from treatment with azathioprine.     

Where do we stand with IPF treatment?

Despite receiving ‘weak no’ recommendations in the updated guidelines on treating patients with Idiopathic Pulmonary Fibrosis (IPF), two key treatment options are pirfenidone and N-acetylcysteine (NAC), and both are used in clinical practice. The efficacy of pirfenidone is supported by a number of Phase III trials as well as a Cochrane meta-analysis. Tolerability data are also provided by clinical trials and a long-term extension phase of these studies. Pirfenidone is approved in Europe for the treatment of patients with mild-to-moderate IPF. NAC-based therapy has no such approval, but is commonly used to treat patients. A Phase III trial suggested some benefit of the NAC, prednisone and azathioprine regimen for IPF patients, but the study had many limitations. A further study to investigate this regimen, compared with a placebo alone arm, was recently stopped due to increased mortality in the triple-therapy arm. Discussion of these data and recent findings highlight the importance of a further update to the existing guidelines, so that IPF specialists can provide the most up-to-date advice and treatment to patients in clinical practice.     

Controlled trial of azathioprine in chronic ulcerative colitis.

A double-blind controlled trial of azathioprine in a dose of 2-2.5 mg/kg body weight over six months was conducted among 44 patients with active chronic ulcerative colitis. Three patients treated with placebo did not complete the trial because their disease became so severe that colectomy was performed. Among patients who completed the trial the mean dose of prednisolone necessary to control the disease decreased in those treated with azathioprine and those treated with placebo; the reduction was greater among those who took azathioprine (p less than 0.001). Activity of the disease apparently improved in both treatment groups but a significant (p less than 0.001) trend was observed only in those patients treated with azathioprine. No serious side effects from azathioprine occurred during the trial but seven of 24 patients had to stop the drug because of nausea. Azathioprine may have a role in the treatment of a few patients wih troublesome chronic colitis for whom conventional drug treatment is ineffectual, or for whom continuous systemic corticosteroid treatment is needed to control symptoms, and for whom surgical treatment is inappropriate.     

High frequency of corticosteroid and immunosuppressive therapy in patients with systemic sclerosis despite limited evidence for efficacy

Introduction

In systemic sclerosis (SSc) little evidence for the effectiveness of anti-inflammatory and immunosuppressive therapy exists. The objective of this study was to determine the extent to which SSc patients are treated with corticosteroids and immunosuppressive agents.

Methods

Data on duration and dosage of corticosteroids and on the type of immunosuppressive agent were analyzed from 1,729 patients who were registered in the German Network for Systemic Scleroderma (DNSS).

Results

A total 41.3% of all registered SSc patients was treated with corticosteroids. Corticosteroid use was reported in 49.1% of patients with diffuse cutaneous SSc and 31.3% of patients with limited cutaneous SSc (P < 0.0001). Among patients with overlap disease characteristics, 63.5% received corticosteroids (P < 0.0001 vs. limited cutaneous SSc). A total 16.1% of the patients received corticosteroids with a daily dose ≥ 15 mg prednisone equivalent. Immunosuppressive therapy was prescribed in 35.8% of patients. Again, among those patients with overlap symptoms, a much higher proportion (64.1%) was treated with immunosuppressive agents, compared with 46.4% of those with diffuse cutaneous SSc sclerosis and 22.2% of those with limited cutaneous SSc (P < 0.0001). The most commonly prescribed drugs were methotrexate (30.5%), cyclophosphamide (22.2%), azathioprine (21.8%) and (hydroxy)chloroquine (7.2%). The use of these compounds varied significantly between medical subspecialties.

Conclusions

Despite limited evidence for the effectiveness of corticosteroids and immunosuppressive agents in SSc, these potentially harmful drugs are frequently prescribed to patients with all forms of SSc. Therefore, this study indicates the need to develop and communicate adequate treatment recommendations.     

Azathioprine in Ulcerative Colitis: An Interim Report on a Controlled Therapeutic Trial

This interim report on a controlled therapeutic trial of azathioprine in ulcerative colitis deals with the first 40 patients to complete a one-year period of maintenance treatment with azathioprine or with dummy tablets. The patients all suffered from classical ulcerative colitis and were in an actual attack of the disease at the time of admission. The attack was treated with a standard corticosteroid regimen and the patients were assigned at random to maintenance treatment with real or dummy azathioprine tablets, using a stratified design. The treatment and control groups were closely similar at the beginning of the trial.The effect of treatment has been assessed on the basis of the number of relapses of the disease occurring during the one-year trial period, supplemented by an assessment of the sigmoidoscopic picture and of the histological findings on serial rectal biopsy. In the patients receiving azathioprine the disease ran a more favourable course than in the control group. After the attack had been treated 11 of the 20 patients on azathioprine were symptom-free throughout the rest of the one-year trial period compared with only 5 out of 20 in the control group. The only three patients classed as failures were all in the control group. These differences just fail to reach conventional levels of statistical significance.Azathioprine is not dramatically successful but may still be a useful addition to the medical treatment of ulcerative colitis, particularly if conventional medical treatment is ineffective and there are reasons for wishing to avoid radical surgery. In the dose used azathioprine was virtually free from undesirable side effects.     

Complications of systemic corticosteroid therapy for problematic hemangioma.

Systemic corticosteroid therapy has been used to treat hemangiomas for 30 years; yet, there are no studies of possible complications. We reviewed the database of the Vascular Anomalies Center at the Boston Children's Hospital and gathered information on short- and long-term side effects in children who were given systemic corticosteroids for problematic hemangiomas. In addition, a questionnaire regarding early and late consequences was sent to the families of children who were treated with corticosteroids from 1983 to 1997. Of 300 patients with hemangiomas, 80 children were identified as having received a full course of systemic corticosteroids for problematic tumors. Complete data were collected on 62 of these children. The response rate to the questionnaire was 78 percent (n = 62 of 80). The initial dose of corticosteroid varied from 2 to 3 mg/kg/ day. Duration of therapy ranged from 2 to 21 months (mean, 7.9 months; median, 6.5 months). The follow-up interval from the cessation of therapy ranged from 6 months to 15 years (mean, 4 years; median, 3 years). Short-term complications included cushingoid facies (n = 44; 71 percent), personality changes (n = 18; 29 percent), gastric irritation (n = 13; 21 percent), fungal (oral or perineal) infection (n = 4; 6 percent), and diminished gain of height (n = 22; 35 percent) and weight (n = 26; 42 percent). A total of 91 percent of children who had diminished gain of height (n = 20) returned to their pretreatment growth curve for height by 24 months of age. One child, who was treated at another institution with a dose of 20 mg/kg/day for 6.5 months that was slowly tapered over 18 months, was petite 6 years after ending therapy. Another child treated with an initial dose of 2 mg/kg/day for 5 months was smaller than predicted at the age of 6 years, but she was born prematurely and was on ventilatory support for respiratory distress. Three children treated with the standard dose and duration were at a low percentile for weight 4, 5, and 10 years after the cessation of therapy. Statistical analysis showed a correlation between diminished gain of height with duration of therapy and age at initiation of treatment. One child had corticosteroid myopathy that resolved with cessation of therapy. We found no evidence for immunologic suppression, i.e., there was no increase in the number of bacterial infections during corticosteroid administration. In conclusion, systemic corticosteroids can be safely given to treat endangering hemangiomas in infants at doses of 2 to 3 mg/kg/day, which are slowly tapered and stopped before the age of 1 year. Short-term side effects were minor and transient, and no serious long-term complications occurred.     

Reticulum Cell Sarcoma after Renal Homotransplantation and Azathioprine and Prednisone Therapy

Two patients developed reticulum cell sarcomata after they had been treated with azathioprine and prednisone in the course of cadaveric renal transplantation. Both had terminal widespread herpes simplex virus infection.Immunosuppressive therapy could be responsible for an increased risk of malignant lymphomata either directly or by facilitating infection with oncogenic viruses.     

SYSTEMIC LUPUS ERYTHEMATOSUS—Results of Treatment with Triamcinolone

Twenty-nine patients with systemic lupus erythematosus were treated with a new synthetic unsaturated prednisolone derivative, triamcinolone, for as long as 11 months. This hormone is 1.3 times as powerful as prednisone and 4.4 times more potent than hydrocortisone as an anti-inflammatory agent. The average dose for beginning therapy in cases of mild systemic lupus erythematosus was 20.6 mg. a day. The average maintenance dose used to control mild exacerbations of the disease was 26.0 mg. a day. There was no evidence of sodium retention or potassium loss.Sixteen patients had upper gastrointestinal x-ray studies before and during therapy with triamcinolone. There was no evidence of peptic ulceration except in one patient who was receiving 96 mg. a day. Nine patients had gastric analysis with histamine before and during therapy. No significant changes were noted in results of these tests, even in the patient who had an ulcer. No abnormal increase in uropepsin was noted in cases in which this factor was tested.The pattern of clinical improvement closely paralleled that obtained by previous treatment with older steroids. There was a disappearance of all the clinical and laboratory abnormalities produced by the disease, with the exception of long standing renal involvement. A major difference between triamcinolone and other steroids was a tendency to progressive gradual loss of weight, partly owing to fluid loss. Cushingoid appearance produced by other steroid therapy did not disappear.The cutaneous side effects, particularly Cushingoid appearance, hirsutism and striae were more pronounced than with older steroids. The most serious side effect was muscle weakness which appeared in six patients, all women, in from four to thirty-two weeks after starting triamcinolone. The profound muscle weakness, most pronounced in the quadriceps group, gradually cleared after several weeks of therapy with another steroid.Fourteen patients had received prior steroid therapy with all the older anti-inflammatory hormones and seven of them were better controlled and felt better with triamcinolone.     

Systemic lupus erythematosus; results of treatment with triamcinolone

Twenty-nine patients with systemic lupus erythematosus were treated with a new synthetic unsaturated prednisolone derivative, triamcinolone, for as long as 11 months. This hormone is 1.3 times as powerful as prednisone and 4.4 times more potent than hydrocortisone as an anti-inflammatory agent. The average dose for beginning therapy in cases of mild systemic lupus erythematosus was 20.6 mg. a day. The average maintenance dose used to control mild exacerbations of the disease was 26.0 mg. a day. There was no evidence of sodium retention or potassium loss. Sixteen patients had upper gastrointestinal x-ray studies before and during therapy with triamcinolone. There was no evidence of peptic ulceration except in one patient who was receiving 96 mg. a day. Nine patients had gastric analysis with histamine before and during therapy. No significant changes were noted in results of these tests, even in the patient who had an ulcer. No abnormal increase in uropepsin was noted in cases in which this factor was tested. The pattern of clinical improvement closely paralleled that obtained by previous treatment with older steroids. There was a disappearance of all the clinical and laboratory abnormalities produced by the disease, with the exception of long standing renal involvement. A major difference between triamcinolone and other steroids was a tendency to progressive gradual loss of weight, partly owing to fluid loss. Cushingoid appearance produced by other steroid therapy did not disappear. The cutaneous side effects, particularly Cushingoid appearance, hirsutism and striae were more pronounced than with older steroids. The most serious side effect was muscle weakness which appeared in six patients, all women, in from four to thirty-two weeks after starting triamcinolone. The profound muscle weakness, most pronounced in the quadriceps group, gradually cleared after several weeks of therapy with another steroid. Fourteen patients had received prior steroid therapy with all the older anti-inflammatory hormones and seven of them were better controlled and felt better with triamcinolone.     

Cell-mediated Immune Responses in Chronic Liver Diseases

Studies of the cell-mediated response to liver antigens, using the leucocyte migration test, in 163 patients with various liver disorders showed that abnormal responses were almost confined to active chronic hepatitis (53% abnormal), primary biliary cirrhosis (64%), and cryptogenic cirrhosis (29%). The test was also abnormal in five out of seven patients with jaundice due to drug hypersensitivity and in one patient with acute infectious hepatitis at a time when mitochondrial antibodies were present in the serum. More of those with active chronic hepatitis on prednisone or azathioprine had normal tests than of those who were untreated, and in 8 out of 10 examined serially during therapy there was an accompanying improvement in leucocyte migration. Abnormal responses to salivary gland or kidney antigens were also found in nearly half of those with features of Sjögren''s syndrome or renal tubular acidosis as part of a multisystem involvement—this, though occurring in cryptogenic cirrhosis, was found with greater frequency in active chronic hepatitis and primary biliary cirrhosis. These cell-mediated immune responses, perhaps triggered by the initial damage to the liver from viral or other agents, may be responsible both for the perpetuation of the liver disease and, because of common surface antigens, for the damage to other organs.     

Effect of Several Drugs on Gastric Potential Difference in Man

Measurement of gastric mucosal potential difference was used to study the effect on the gastric mucosal barrier in six volunteer subjects of several drugs known to provoke ulcers. Potential differences were also recorded in nine patients with rheumatoid arthritis being treated with long-term aspirin and five patients on long-term prednisone. Unbuffered aspirin and ethanol “broke” the barrier as shown by a rapid fall in potential difference. The effects of aspirin were dose related, with 600 mg causing a greater reduction than 300 mg. The effects of aspirin and ethanol given together were additive and caused the greatest fall in potential difference. Sodium acetylsalicylate did not alter the normal potential difference. Indomethacin, phenylbutazone, and prednisone all failed to cause any change in potential difference. The patients on long-term aspirin and prednisone had readings within the normal range and responded the same as normal subjects to an acute challenge. These studies show that aspirin and ethanol will damage the gastric mucosal barrier but that indomethacin, phenylbutazone, and prednisone do not.     

High versus "low" dose corticosteroids in recipients of cadaveric kidneys: prospective controlled trial.

Corticosteroids have the major role in the immunosuppressive treatment of patients who have received renal transplants. Despite their extensive use there is still debate about the appropriate dose that will prevent rejection of the renal allograft with the least morbidity. From March 1979 to November 1981 a randomised controlled trial of high (33 patients) v low oral dose (34 patients) of prednisolone along with azathioprine was conducted in recipients of first cadaveric transplants who had received a blood transfusion within six months of transplantation. The main difference in outcome between the two groups was a high incidence of some infections in the high dose group. Patient mortality, graft survival, transplant function, and number of rejection episodes were indistinguishable in the two groups, but rejection episodes tended to occur later in the high dose group. These findings suggest that the use of lower doses of corticosteroids soon after cadaveric renal transplantation does not jeopardise graft survival and results in lower patient morbidity.