Randomized double-blind study of the effect of dexamethasone and methylprednisolone pulse in the control of rheumatoid arthritis flare-up: a preliminary study

Introduction

Rheumatoid arthritis (RA) is a chronic inflammatory disease of unknown etiology which involves connective tissues throughout the body, particularly diarthroidal joints and marked by a symmetric peripheral polyarthritis. RA is the most common inflammatory disease of the musculoskeletal system in Iran.1 RA signs and symptoms may vary in severity. Periods of increased disease activity are called ‘flares’. Corticosteroids are the mainstay of severe RA flare-up treatment. Different preparations, doses and ways of administration of these medications are used in the control of RA activity. Pulse therapy with corticosteroids is a common method in the treatment of severe RA flare-up. In corticosteroid pulse therapy supra-pharmacologic doses of corticosteroids are used for one to several days.2 The aim of pulse therapy is to obtain a quicker and stronger efficacy of corticosteroid dosage.2

Methylprednisolone (MP) is the standard corticosteroid for pulse therapy but other corticosteroids such as dexamethasone (DEX) can be used for this purpose. MP is a synthetic corticosteroid with a biologic half-life of 12–36 h, high anti-inflammatory activity (1.25 times that of prednisolone), and low mineralocorticoid effect (glucocorticoid to mineralocorticoid effect of 6 to 1).3 DEX is also a synthetic corticosteroid with a longer biologic half-life (36–72 h), higher anti-inflammatory activity (six times of prednisolone), and a very low mineralocorticoid effect.3 DEX is also very much cheaper than MP. DEX pulse has been used successfully in the treatment of different diseases.4-12 Some published studies have also reported the use of DEX pulse therapy for RA.13, 14

Although glucocorticoid pulse therapy has been used for more than three decades, few clinical trials have been performed in the comparison of different preparations of glucocorticoids in the treatment of different diseases. Although there are no large controlled studies comparing MP and DEX pulse therapy, it appears that the two drugs may be similar in efficacy. Some comparative studies showed that the efficacy of the two drugs is equal in the treatment of optic neuritis, traumatic optic neuropathy, cornea graft rejection, multiple sclerosis, and steroid-resistant nephritic syndrome.15, 14, 16-19 In addition, complications with these two therapies is equal.15, 14, 16-19

Due to the lower price and easy availability of DEX, comparing the efficacy and safety of DEX and MP for pulse therapy of RA flare-up is necessary, but before starting a large study we conducted this preliminary study to test the initial intended effects.

Materials and methods

This randomized double-blind controlled study was performed in the Emam Reza Education Hospital of Tabriz University of Medical Sciences (TUOMS) Iran, from February to July 2012. The study was approved by the ethics committee of the TUOMS and was registered with the Iranian Registry of Clinical Trials (IRCT) with the registration number IRCT201112066975N2. The American College of Rheumatology 2011 criteria20 was used to diagnose RA. RA patients with severely active disease (Disease Activity Score in 28 joints [DAS28] > 5.2), after having the aims of the study explained to them and obtaining written informed consent, were recruited to the study. The exclusion criteria were congestive heart failure, active infection, hypokalemia (K⁺ < 3.5), systolic blood pressure > 180 mmHg or diastolic blood pressure > 100 mmHg, diabetes and pregnancy.

Thirty patients fulfilling the inclusion criteria were randomly allocated to the DEX (n = 14) or MP (n = 16) pulse groups. Randomization was performed by RandList software.1.2 (http://www.randomisation.eu). The patients randomized to the DEX pulse group received intravenous (i.v.) infusions of 120 mg DEX on 3 consecutive days, and the participants included in the MP pulse group received i.v. infusion of 1 g MP (sodium hemisuccinate) on 3 consecutive days. In both groups the drugs were dissolved in 250 mL of 5% dextrose and infused i.v. over 2 h. After pulse therapy, prednisolone 15 mg/day in three divided doses was started in both groups and their disease-modifying antirheumatic drugs (DMARDs) were adjusted according to the disease activity.

The disease activity of all the patients was measured by the DAS28 at baseline, and days 4 (1 day after the intervention) and 30. DAS28 was calculated using tender and swollen joint counts, erythrocyte sedimentation rate (ESR), and the patients' assessment of disease activity (by a visual analogue scale: 0–100 mm). Patients were all evaluated by the same observer who was not aware of randomization until day 30 when the study was completed. Patients were not aware about the treatment type. The primary outcome measures were disease activity, a significant reduction in disease activity (reduction in DAS28 > 1.2) and the number of patients who were in remission (DAS28 < 2.6) or had low disease activity (2.6 ≤ DAS28 < 3.2) on days 4 and 30. The secondary outcome measure was the number of patients who had treatment complications during the pulse therapy. Any complications observed or reported during the therapy were recorded.

Results

Thirty RA patients with severely active disease were randomized to the DEX and MP pulse groups. The demographic and clinical characteristics of the patients in the DEX and MP pulse groups are shown in Table 1. There were no significant differences between the two treatment groups at the time of entry into the study. Excepting one patient, all of the patients completed the study (Fig. 1). The mean DAS28 in DEX and MP pulse groups before treatment was 6.3 and 6.1, respectively. The values of the DAS28 at days 4 and 30 decreased in both groups (Table 2, Fig. 2). Within-group analysis of the patients taking DEX showed that the mean DAS28 fell by 2.4 and 2.6 at days 4 and 30 (P = 0.01 on paired t-test). Between-group analysis showed that the differences in the DAS28 at days 4 and 30, and the number of patients whose DAS28 score reached < 3.2 and 2.6 in the DEX and MP groups were not significant.

Side-effects developed in nine patients in the MP group and five in the DEX group (see Table 3). The most common side-effects were flushing and headaches. Excepting one, all of the adverse effects were classified as mild. One of the patients in the MP pulse group developed hyperglycemia, as a result of which the MP infusion was discontinued. There were no significant differences between the two groups.

Discussion

In our study, all the dexamethasone-treated RA patients responded favorably (decrease in DAS28 > 1.2) and this response continued for 1 month. The side-effects of DEX pulse developed in 35.7% of the patients and were mild in all the cases. In addition, this study showed that the effect and complications of the DEX pulse therapy for severe RA flare-up are similar to the MP pulse. Lashina et al. in a previous study on 31 early RA patients showed that a mega dose of DEX is comparable with MP.15 However, to the best of our knowledge, this study is the first randomized trial aimed at comparing the effects of DEX and MP pulse in patients with severe RA flare-up (DAS28 > 5.2). The main limitation of our study was the small number of patients.

Our study suggests that DEX pulse therapy is a safe and effective treatment for RA flare-up. In addition, treatment with DEX is less expensive than MP. The cost of a 3-day pulse therapy with DEX in Iran is 9.68 US dollars but with MP it goes up to 35.4 US dollars. Although the effect of DEX and MP pulse in control of RA flare-up was equal, in view of easy availability and cost, we recommend DEX pulse.

Conclusion

Dexamethasone pulse therapy may be a safe and effective treatment for RA flare-up. A large double-blind, randomized and controlled trial might further determine the place of DEX pulse therapy in patients with severely active RA in comparison with the standard MP pulse.