Steroid-sparing Agent In Patients Research Articles

Relapses of pain syndrome in patients with polymyalgia rheumatica during reduction of glucocorticoid therapy

An analysis of causes leading to pain recurrence in patients with polymyalgia rheumatica (PR) after tapering down the dose of glucocorticosteroids (GCS) is presented. True exacerbations resulting from the main disease recurrence and pseudo-exacerbations when the resumption of pain syndrome is not due inflammation but because of other causes – steroid myopathy or chronic adrenal insufficiency (AI) are identified. The experience of using tocilizumab, an inhibitor of interleukin-6 receptors, as steroid-sparing agent in patients with PR is considered. The factors contributing to pain syndrome development, which can mimic exacerbations of PR (associated myofascial pain, vitamin D deficiency, etc.) are indicated. The methodology for AI diagnosis in patients receiving GCS therapy is discussed in detail. Recommendations for the rational AI therapy including acute cases are given.

A Randomized Open-Labeled Trial of Methotrexate as a Steroid-Sparing Agent for Patients With Generalized Myasthenia Gravis.

Background and PurposeTwo clinical trials assessing the steroid-sparing effect of methotrexate (MTX) yielded conflicting results. Our objective was to investigate whether MTX would show a steroid-sparing effect in the treatment of generalized myasthenia gravis (MG) patients who fitted Myasthenia Gravis Foundation of America (MGFA) Class II and Class III.MethodsWe performed an 18-month prospective, randomized, open-labeled trial of prednisone combined with MTX 10 mg orally every week versus prednisone alone in 40 recently diagnosed MG patients of MGFA Class II and Class III between July 2014 and July 2018. The primary endpoint was the prednisone area under the dose–time curve (AUDTC) from months 3 to 18. Secondary endpoints included changes of the Quantitative Myasthenia Gravis Score (QMG), the Myasthenia Gravis Activity of Daily Living Score (MG-ADL), initial time of prednisone reduction, the median prednisone daily dose in each month, adverse events, and treatment failures in each group.ResultsForty participants were included; among those, 5 individuals withdrew. A total of 35 participants completed 18 months of follow-up (18 in prednisone+MTX, 17 in prednisone group). Combined use of MTX reduced the month 3–18 prednisone AUDTC (prednisone+MTX 5,663.44 ± 1,678.08 mg, prednisone 6,683.94 ± 678.08 mg, p = 0.03, 95% confidence interval -1916.01 to -124.98). The initial times of prednisone reduction were 4.34 ± 1.44 months in the prednisone+MTX group and 5.56 ± 2.05 months in the prednisone group (p = 0.04, 95% CI -2.41 to -0.03). The median daily prednisone dose was significantly lower in the prednisone+MTX group at month 6 and months 9–18. No significant differences were found in QMG and MG-ADL scores between the two groups. No serious drug-related adverse events were observed in both groups.ConclusionsThis study provides evidence that MTX has the steroid-sparing ability in generalized MG patients of MGFA Class II and Class III.Clinical Trial Registration http://www.chictr.org.cn/showproj.aspx?proj=10563 identifier ChiCTR-IPR-15006081.

Tocilizumab in Giant Cell Arteritis: A Real-Life Retrospective Study.

This study aims to evaluate (1) the efficacy and safety of tocilizumab (TCZ) as a steroid-sparing agent in patients with giant cell arteritis (GCA) and (2) the usefulness of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) in the follow-up and to detect disease activity. We retrospectively evaluated 12 patients with GCA treated with TCZ (8 mg/kg/mo). Pre- and posttherapy data about clinical signs and symptoms, laboratory results, FDG-PET imaging study, and the mean glucocorticoid (GC) dose were used to assess disease activity. Tocilizumab achieved complete disease remission in all patients. Mean FDG-PET-detected standard uptake value decreased from 2.05 ± 0.64 to 1.78 ± 0.45 ( P = .005). In 2 patients in whom temporal arteries color Doppler sonography examination was consistent with temporal arteritis, the hypoechoic halo disappeared after TCZ treatment. Mean GC dose was tapered from 26.6 ± 13.4 mg/d to 3.3 ± 3.1 mg/d ( P < .0001). One-half of the patients discontinued GC therapy. Three patients experienced severe adverse reactions and had to stop TCZ therapy. In accordance with previous reports, TCZ is an effective steroid-sparing agent for GCA, although careful monitoring of adverse drug reactions is needed. 18F-fluorodeoxyglucose positron emission tomography could be used to monitor disease activity in TCZ-treated patients, but prospective studies are needed to confirm these data.

AB0707 Tocilizumab as a therapeutic option for rhupus patients refractory to conventional therapy

BackgroundDiagnosis of Rhupus bases on the combination of inflammatory symmetrical erosive polyarthritis and clinical features of SLE. For patients whose disease is resistant to or dependent on corticosteroids, methotrexate (MTX)...

Safety and efficacy of mizoribine in patients with connective tissue diseases other than rheumatoid arthritis

The objective of this study was to examine the safety and efficacy of mizoribine (MZR), an inhibitor of inosine monophosphate dehydrogenase, in patients with connective tissue diseases (CTDs) other than rheumatoid arthritis. We identified all patients who had ever been treated with MZR for CTDs at our institution during the period from January 2001 to May 2011. A retrospective review of medical records was performed to evaluate safety and efficacy of MZR. A total of 63 patients (13 induction and 50 maintenance therapy with MZR) were included. During 70.2 patient-years of follow-up, only one patient required discontinuation of MZR due to an adverse event. Doses of PSL were significantly decreased at last follow-up in both the induction (45.2 ± 15.6 vs. 8.4 ± 5.7 mg/day, p < 0.01) and the maintenance group (12.4 ± 7.6 vs. 9.3 ± 6.4 mg/day, p < 0.01). MZR appears to be a safe and well-tolerated steroid-sparing agent in patients with CTDs.

Effect and Safety of Mycophenolate Mofetil in Chronic Pulmonary Sarcoidosis: A Retrospective Study

Background: Treatment of chronic pulmonary sarcoidosis (CPS) is challenging and often requires long-term therapy with systemic corticosteroids and supplementary use of steroid-sparing agents. Objective: To examine the efficiency and safety of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with CPS. Methods: We conducted a retrospective study of patients with biopsy-proven pulmonary sarcoidosis, who were treated with MMF and systemic corticosteroids for >6 months between 2004 and 2010. Corticosteroid dose, pulmonary function parameters and radiological and clinical follow-up before and after treatment with MMF were assessed. Results: Ten patients received MMF for >6 months. MMF was introduced due to side effects (5/10 patients) and due to an inadequate response to prior therapy (5/10 patients). Median duration of treatment with MMF was 31 months (range 8-66). Therapeutic MMF plasma trough levels of 1-3 mg/l were reached with daily doses of 1,722 ± 440 mg MMF. Daily corticosteroid dose could be significantly reduced from 14.3 ± 13.3 to 6.5 ± 2.3 mg prednisolone during treatment. During follow-up, pulmonary function, symptoms and radiological signs improved in 4 patients, while 6 patients remained stable. Median change in FVC was +8.5 % (range -2 to 16). No severe adverse events that were related to combined immunosuppressive therapy occurred. Conclusion: This study indicates that the addition of MMF to corticosteroids is a viable and safe treatment option in CPS. MMF allows a significant reduction of maintenance corticosteroids to levels <10 mg/day while preserving a stable or improved clinical condition.

Pediatric Systemic Lupus Erythematosus: More Than a Positive Antinuclear Antibody

Based on strong research evidence and consensus, the most common disease manifestations at diagnosis of pSLE are constitutional symptoms, arthritis, and malar rash. Based on some research evidence and consensus, patients with pSLE tend to have major organ system involvement (renal/central nervous system) and a greater disease burden compared with adults. Despite these findings, mortality is low. Based on some research evidence and consensus, the diagnosis of pSLE is unlikely if the ANA is negative, and most patients with SLE have a positive ANA at a titer ≥1:160. Based on strong research evidence, both MMF and cyclophosphamide can be used for induction therapy in class III and IV lupus nephritis. Based on strong research evidence, patients with SLE and anticardiolipin antibodies or LA have a two and six times greater risk of venous thrombosis, respectively, compared with patients with SLE without antiphospholipid antibodies. Based on strong research evidence, patients with pSLE have a higher risk for subclinical atherosclerosis when there is weight-adjusted prednisone use, azathioprine use, increasing age, male gender, high BMI, abnormal creatinine clearance, and elevated lipoprotein(a) levels.

Peripheral neuropathy in patients on long-term triazole antifungal therapy

Triazole antifungal drugs are the mainstay of treatment for patients with chronic pulmonary aspergillosis and are often used as steroid-sparing agents in patients with allergic aspergillosis. Peripheral neuropathy (PN) is a rare but reported side effect of triazole therapy in the acute management of invasive fungal infections, but its incidence during long-term triazole treatment for chronic aspergillosis is unknown. The goal of this study was to determine the incidence of PN in this context. A retrospective cohort study was carried out to collect data on all patients with chronic aspergillosis commenced on long-term triazole therapy at the National Aspergillosis Centre in Manchester between 2007 and 2010. Two hundred and twenty-two patients were commenced on triazole therapy. Ten percent developed PN after an average of 4 months. Seventeen percent of patients taking itraconazole, 9% taking voriconazole and 3% taking posaconazole developed PN. This is the first report of posaconazole-induced PN. Twenty-two episodes of PN presented as numbness or tingling in the extremities, while four episodes presented as predominant leg weakness. The majority of cases were axonal, length-dependent neuropathies that recovered after triazole medication was discontinued. Two patients had non-progressive but irreversible PN. Two patients were diagnosed with mononeuropathies. A 10% incidence of PN was observed for patients commenced on triazole therapy for chronic aspergillosis. Patients on long-term triazole therapy should be monitored for neurological symptoms. If PN is suspected, diagnosis should include nerve conduction studies, exclusion of other causes and consideration of dose reduction or cessation of therapy.

An international, phase III, randomized trial of mycophenolate mofetil in myasthenia gravis

This prospective, randomized, double-blind, placebo-controlled, phase III trial assessed the efficacy, safety, and tolerability of mycophenolate mofetil (MMF) as a steroid-sparing agent in patients with myasthenia gravis (MG). Patients with acetylcholine receptor antibody-positive class II-IVa MG (MG Foundation of America [MGFA] criteria) taking corticosteroids for at least 4 weeks were randomized to MMF (2 g/day) or placebo for 36 weeks. The primary endpoint was a composite measure defined as achievement of minimal manifestations or pharmacologic remission (MGFA post-intervention status), with reduction of corticosteroid dose on a set schedule. Secondary endpoints included disease severity, quality-of-life scores, and safety. A total of 44% of MMF-treated (n = 88) and 39% of placebo-receiving (n = 88) patients achieved the primary endpoint (p = 0.541). Improvements in mean quantitative MG, MG activities of daily living, and 36-item Short-Form health survey scores were similar in both groups. Numbers of adverse events were similar in both groups. The most commonly reported adverse events in the MMF-treated group were headache (12.5%) and worsening of MG (11.4%), and in the placebo group, worsening of MG (20.5%) and diarrhea (10.2%). Initiation of mycophenolate mofetil (MMF) treatment was not superior to placebo in maintaining myasthenia gravis (MG) control during a 36-week schedule of prednisone tapering. There were no significant differences in the primary or secondary endpoints between the study groups. MMF was well tolerated and adverse events were consistent with previous studies. Experience from this large, international, multicenter, phase III study employing full MG Foundation of America guidelines will aid the design of future MG studies.

Steroid-dependent Crohn's disease.

Placebo controlled trials have demonstrated that a tapering course of corticosteroids is an effective therapy for active Crohn's disease. A population-based study of 109 patients with Crohn's disease undergoing their first course of corticosteroids showed that, at the end of one year, 44% of patients were steroid responsive, 36% were steroid dependent and 20% were steroid refractory. Side effects occur frequently during a four-month tapering course of corticosteroids, including moon face, acne, infection, ecchymoses, hypertension, hirsutism, petechial bleeding and striae. More serious side effects occur with long term use, including hypertension, diabetes, infection, osteonecrosis, osteoporosis, myopathy, cataracts, glaucoma and psychosis. Low dose corticosteroids, alternate-day corticosteroids and mesalamine (5-aminosalicylate) are not effective steroid-sparing agents in patients with Crohn's disease. Controlled ileal release budesonide, 6 mg/day, is an effective steroid-sparing agent, but it does result in some decrease in adrenal function. Azathioprine, 6-mercaptopurine and methotrexate are all effective steroid-sparing agents, as is the humanized, anti-tumour necrosis factor monoclonal antibody, CDP571. A preliminary, uncontrolled study has suggested that the mouse/human chimeric monoclonal antibody infliximab may also be steroid sparing. Surgical resection is an effective strategy to reduce steroid use in the short to intermediate term, but postoperative reoccurrence of Crohn's disease occurs frequently. Given the morbidity associated with prolonged corticosteroid use, medical and surgical treatment strategies to reduce steroid use should be employed routinely.

Inhibition of methylprednisolone elimination in the presence of clarithromycin therapy

Background: Macrolide antibiotics have long been used as steroid-sparing agents in patients with severe steroid-dependent asthma. Their efficacy and their propensity to potentiate glucocorticoid adverse effects have been attributed in part to their ability to delay glucocorticoid clearance. Objective: We sought to determine whether clarithromycin, a newer macrolide antibiotic, can alter the pharmacokinetic profile of oral glucocorticoids and thereby increase the risk of steroid-induced adverse effects. Methods: An open-label study in a paired design (before and after treatment) was conducted in a hospital-based outpatient clinic. Participants were 6 adult patients (mean age, 30 years) with mild-to-moderate asthma. Prednisone (40 mg/1.73 m 2) and methylprednisolone (40 mg/1.73 m 2) were given as single randomized doses on consecutive study days before and on days 8 and 9 of a clarithromycin (500 mg twice daily) course. Twelve-hour pharmacokinetic profiles with measurement of plasma methylprednisolone and prednisolone levels were taken before and after clarithromycin therapy. Results: Clarithromycin therapy resulted in a 65% reduction of methylprednisolone clearance and significantly higher mean plasma methylprednisolone concentrations compared with preclarithromycin concentrations but had no significant effect on prednisolone clearance or mean prednisolone plasma concentrations. Conclusions: Clinicians must be aware of potential drug interactions that could place patients at increased risk for steroid-induced adverse effects. Such an effect has been demonstrated between clarithromycin and methylprednisolone, two drugs that may be administered concomitantly in asthma. To avoid potential steroid-enhancing effects, prednisone should be substituted for methylprednisolone during prolonged courses of clarithromycin therapy. (J Allergy Clin Immunol 1999;103:1031-5.)

Effect of intravenous immunoglobulin on steroid consumption in patients with severe asthma: A double-blind, placebo-controlled, randomized trial

Background: There is a significant group of patients with severe asthma who require chronic use of systemic steroids for control of their disease. These patients are at risk for severe side effects from oral steroids. Intravenous immunoglobulin (IVIG) has immunomodulatory properties, and a few open-label trials have suggested its possible benefit in individuals with severe asthma. Objective: This study was designed to assess the potential benefit of IVIG as a steroid-sparing agent in patients with severe asthma. Methods: Thirty-eight immunocompetent steroid-requiring patients with severe asthma were randomly enrolled in a double-blind, placebo-controlled trial of IVIG. Results: Of the 38 patients enrolled, 28 patients completed the study. A significant reduction in oral steroid requirement was observed in both the IVIG-treated (n = 16) and the placebo-treated (n = 12) patients. Further exploration of the results showed that IVIG, but not placebo, had a significant steroid-sparing effect in patients requiring high doses of oral steroids (ie, >2000 mg in the year before the study). Within this subgroup, IVIG treatment (n = 9) resulted in a significant decrease in oral steroid requirement, with a median of 16.4 mg/day during the pretreatment period to 3 mg/day during the treatment phase ( P = .0078). No significant decrease in oral steroid requirement was observed in placebo-treated patients (n = 8) within this subgroup. Objective and subjective parameters of the patients’ asthma were unchanged in spite of the steroid tapering achieved in the group treated with IVIG. Conclusion: IVIG may be a useful steroid-sparing agent in patients with severe asthma requiring high doses of oral steroids. (J Allergy Clin Immunol 1999;103:810-5.)

Methotrexate as a steroid sparing agent for asthma in adults.

Sustained oral corticosteroid use can lead to complications, so there is interest in identifying agents that can reduce oral steroid use in people with asthma. Methotrexate has attracted attention as a possible steroid sparing agent in patients with chronic oral steroid dependent asthma. The objective of this review was to assess the effects of adding methotrexate to oral corticosteroids in adults with stable asthma who are dependent on oral corticosteroids. The Cochrane Airways Group trials register and reference lists of identified articles were searched. Randomised trials of the addition of methotrexate compared with placebo in adult steroid dependent asthmatics. Duration of therapy needed to be at least 12 weeks. Trial quality was assessed and data extraction was carried out by two reviewers independently. Study authors were contacted for missing information. Ten trials involving a total of 185 people were included. Study design and quality, corticosteroid dosages and outcomes varied widely. There was a reduction in oral corticosteroid dose favouring methotrexate in parallel trials (weighted mean difference -4.1 mg per day, 95% confidence interval -6.8 to -1.3) and also in cross-over trials (weighted mean difference -2.9 mg per day, 95% confidence interval -5.9 to -0.2). There was no difference between methotrexate and placebo for forced expiratory volume in one minute (weighted mean difference 0.12 litre, 95% confidence interval -0.21 to 0.45). Hepatotoxicity was a common adverse effect with methotrexate compared to placebo (odds ratio 6.9, 95% confidence interval 3.1 to 15.5). Methotrexate may have a small steroid sparing effect in adults with asthma who are dependent on oral corticosteroids. However, the overall reduction in daily steroid use is probably not large enough to reduce steroid-induced adverse effects. This small potential to reduce the impact of steroid side-effects is probably insufficient to offset the adverse effects of methotrexate.

Parenteral triamcinolone acetonide: an alternative corticosteroid for the treatment of asthma.

Corticosteroids are effective in reducing the airway inflammation and controlling the symptoms of asthma. Many patients with chronic, severe asthma are steroid-dependent, requiring daily oral corticosteroids. Although corticosteroids may be effective, many patients suffer from their intolerable side effects. Various medications have been used as steroid-sparing agents in patients who suffer from the side effects of long-term high-dose steroids. While drugs like methotrexate and cyclosporine are promising, none have clearly been shown to be beneficial in most patients with asthma. The long-acting parenteral steroid triamcinolone acetonide has been tested by various investigators in these patients for over 20 years. Intramuscular triamcinolone appears to beneficial, with no significant increase in adverse effects.

Prolonged Use of Methotrexate for Sarcoidosis

To determine the safety and efficacy of methotrexate as a steroid-sparing agent in patients with symptomatic sarcoidosis, a nonrandomized interventional study of patients with chronic sarcoidosis treated with methotrexate for at least 2 years was performed. Efficacy was assessed for all patients after 2 years of treatment. Toxicity was assessed for all patients receiving therapy for the entire time (a total of 150 patient-years). Patients were treated in a subspecialty ambulatory clinic at a university hospital. Patients with biopsy-confirmed sarcoidosis who had persistent symptoms and who were eager to avoid or reduce corticosteroid therapy were selected for study. A total of 50 patients completed at least 2 years of methotrexate therapy. Patients were treated with oral methotrexate once a week. Dosage was adjusted based on the patient's white blood cell count. Clinical response was measured in the affected organ, including the lung (measurement of vital capacity), skin (regression of skin lesions), and central nervous system (magnetic resonance imaging). Also noted was the initial and subsequent dosage of prednisone used as therapy for sarcoidosis. Improvement in vital capacity or other affected symptomatic organ was noted in 33 of 50 treated patients. Corticosteroids were discontinued in an additional six patients who remained stable with clinical or symptomatic improvement. The major toxic effects noted in 150 patient-years of therapy were hepatic (six patients), leukopenia requiring hospitalization (one patient), and cough (one patient). Forty-one liver biopsy procedures were performed in 33 patients. Of these, six demonstrated significant changes related to methotrexate that led to drug discontinuation. Methotrexate is a well-tolerated therapeutic agent with significant steroid sparing and efficacy for the treatment of chronic symptomatic sarcoidosis.

Low-dose methotrexate treatment in elderly patients with bullous pemphigoid.

Various treatments have been used for elderly patients with bullous pemphigoid. The most common is moderate-dose to high-dose prednisone, either alone or in combination with other oral or topical agents. The aim of this study was to evaluate the efficacy of low-dose methotrexate as a steroid-sparing agent in patients with bullous pemphigoid. METHODS. A retrospective chart review of 34 patients with bullous pemphigoid seen from 1989 through the first half of 1993 was conducted. The diagnosis of bullous pemphigoid was confirmed by direct or indirect immunofluorescence microscopy, or salt-split skin sections. Eight of 34 elderly (> 60 years old) patients with therapy-resistant bullous pemphigoid received low-dose weekly methotrexate (average, 5 to 10 mg) in combination with oral prednisone. Patients who received combination therapy required significantly lower (p < or = 0.02) doses of prednisone to control their disease at 1 month compared with baseline doses. In this elderly patient population the side effect profile of the methotrexate was acceptable and well tolerated. We therefore recommend methotrexate and low-dose corticosteroid as first-line combination therapy for selected elderly patients with bullous pemphigoid.

Low-dose oral methotrexate in refractory inflammatory bowel disease

The purpose of this study was to evaluate the efficacy and safety of low-dose weekly, oral methotrexate in patients with steroid-dependent or steroid-refractory inflammatory bowel disease (IBD). Oral methotrexate was given weekly at 15 mg/week. The primary criterion of response was based on steroid withdrawal. Of the 10 patients with Crohn's disease, daily prednisone dosage dropped from a mean of 37 +/- 9.6 mg to 8.3 +/- 2.1 mg/day (P < 0.02); two had a complete withdrawal and four a partial response (< 7.5 mg/day). In the eight patients with ulcerative colitis, daily prednisone dose dropped from a mean of 26.3 +/- 3.2 mg/day to 12.7 +/- 2.0 mg/day (P < 0.001); three had a partial response. Adverse effects due to methotrexate were mild in both groups. We conclude that oral methotrexate may be useful and reasonably safe as a steroid-sparing agent in patients with refractory IBD.

Pancytopenia Following Low-Dose Methotrexate Therapy

Drs Shupack and Webster¹have refreshed our awareness of the risk-benefit considerations for methotrexate therapy for nononcological disorders by means of their pertinent and timely description, in this issue ofTHE JOURNAL, of two patients who developed pancytopenia following low-dose methotrexate therapy for psoriasis. Six additional cases of methotrexate-related bone marrow suppression²are also reviewed. Their report is particularly relevant in view of the See also p 3594. increasing use of methotrexate therapy for rheumatoid arthritis^3,4and extra-articular manifestations of rheumatoid arthritis, including vasculitis.⁵In addition, low-dose methotrexate has been investigated as a steroid-sparing agent in patients with severe asthma.⁶ Methotrexate is a highly effective therapy for patients with severe disabling psoriasis that is resistant to conventional topical therapy and photochemotherapy with methoxsalen and ultraviolet-A irradiation (PUVA). The drug is administered orally or intramuscularly in a weekly dosage of 7.5 to 15 mg. As a