The Art of Discontinuing Glucocorticoids in Rheumatoid Arthritis

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Continuous low-dose glucocorticoid regimens are better than tapering for controlling disease activity in rheumatoid arthritis over a six-month period, show the results of the first double blind clinical trial to evaluate an oral glucocorticoid dose-tapering regimen with stable biological background therapy in rheumatoid arthritis.

But discontinuing glucocorticoids is successful in the majority for the patients and reduces the potential for glucocorticoid associated adverse events in the long term, the researchers say.

While tapering oral corticosteroids is the recommended strategy for patients with low disease activity taking disease modifying antirheumatic drugs, there has been little previous evidence from randomized controlled trials to guide tapering strategies.

Conducting a double-blind randomized controlled trial was essential to address the myths and psychology surrounding discontinuation of low dose glucocorticoid treatment, explained Gerd Burmester, professor of medicine and director of the department of rheumatology and clinical immunology at Charité - University Medicine, and Free University and Humboldt University, Berlin Germany.

“In the real world, once the patients know that glucocorticoids are discontinued, they go to the internet and read all about the ‘dangerous’ withdrawal symptoms, which they then frequently experience,” he said.

“This is completely different in a blinded setting, where they do not know if they are still on drugs or not. Here, they judge their feelings much more objectively.”

The American College of Rheumatology recommendations say that low-dose glucocorticoids may be used in patients who need a bridge until they realize the benefits of DMARD therapy and to control flares, but emphasize that they should be used at the lowest possible dose and for the shortest possible period, ideally less than three months,[i] but many patients continue on glucocorticoids for longer than this.

The lack of standardized glucocorticoid tapering strategies means decisions about when and how to taper are largely based on clinician expertise and patient preference.[ii],[iii]

LACK OF EVIDENCE

The Steroid EliMination In Rheumatoid Arthritis (SEMIRA) trial has attempted to address this lack of evidence.

The trial included 318 patients with low rheumatoid arthritis low disease activity who had been taking tocilizumab and glucocorticoids 5–15 mg per day for 24 weeks or more. The patients were recruited from 39 centers in six countries (France, Germany, Italy, Russia, Serbia, and Tunisia) and were eligible for inclusion if they had received prednisone 5 mg per day for 4 weeks or more and had a Disease Activity Score for 28 joints–erythrocyte sedimentation rate (DAS28-ESR) of 3·2 or less at the day of the start of the study and when assessed 4–6 weeks before.

Patients were randomized to prednisone 5 mg per day for 24 weeks or to tapered prednisone in which the dose was immediately reduced by 1mg/day and then by another 1mg/day every four weeks to reach 0 mg per day by the sixteenth week. All patients continued to be treated with tocilizumab (162 mg subcutaneously every week or 8 mg/kg intravenously every 4 weeks), with or without conventional synthetic DMARDs.

The results, published in The Lancet, showed that all 128 patients assigned to continued prednisone had superior disease activity control compared to the 131 who underwent glucocorticoid tapering.

The mean change in DAS28-ESR over the 24 weeks was 0·54 with tapered prednisone and –0·08 with continued prednisone (difference 0·61 [0·35–0·88]; p<0·0001).

Treatment was deemed successful (defined as low disease activity and confirmed adrenal insufficiency at week 24, and no rheumatoid arthritis flare over the study period) in 99 (77%) patients in the continued-prednisone group versus 85 (65%) patients in the tapered-prednisone group (relative risk 0·83; 95% CI 0·71–0·97).

As well as providing better disease control, continuing glucocorticoids at 5 mg per day for 24 weeks appeared safe. Over the 24-week study period, no patients experienced symptomatic adrenal insufficiency and serious adverse events rates were similar, with events occurring in 5% of the tapered-prednisone group and 3% of the continued-prednisone group.

THE FUTURE

Longer studies are needed, Dr. Burmester said because, “despite the low dosage of 5 mg, in the long run, there may be more cases of cardiovascular events, infections and skin lesions (“cortisone skin”).”

The researchers concluded that continuing low-dose corticosteroids for six months appeared safe and effective and that this might influence treatment guidelines on the optimal timing of withdrawal in patients with rheumatoid arthritis with low disease activity receiving effective biological therapy.

But Burmester emphasized: “Discontinuation is possible in the majority of patients without resulting in a disease flare.

“Using our careful tapering scheme, there was not a single case of a steroid withdrawal syndrome in our patients. Thus, this scheme could serve as a model for general discontinuation also in other disease situations apart from rheumatology.”

The 65% treatment success rate from prednisone tapering might be an important figure to share with patients who may have concerns about coming off corticosteroids, Burmester said. “The data form an essential basis for a shared decision in patient counselling.”

He added: “Glucocorticoids are still an essential part of our treatment armamentarium and act synergistically with our DMARD therapy. It is the art of discontinuation and how to use them wisely.”

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REFERENCES

[i] Singh JA, Saag KG, Bridges SL, Jr, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, McNaughton C, Osani M, Shmerling RH, et al. American college of rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Rheumatol. 2015;2016(68):1–26.

[ii]Volkmann ER, Rezai S, Tarp S, Woodworth TG, Furst DE. We still don’t know how to taper glucocorticoids in rheumatoid arthritis, and we can do better. J Rheumatol 2013; 40: 1646–49.

[iii]Caporali R, Todoerti M, Scire CA, Montecucco C, Cutolo M. Oral low-dose glucocorticoids should be included in any recommendation for the use of non-biologic and biologic disease modifying antirheumatic drugs in the treatment of rheumatoid arthritis. Neuroimmunomodulation 2015; 22: 104–11.