Almost Half of Patients with RA Experience Flare after Glucocorticoid Discontinuation

A study by Johanna Maria Maassen, a PhD candidate at Leiden University Medical Center, The Netherlands, and colleagues found that primary glucocorticoid discontinuation resulted in direct loss of disease control in approximately 40% of patients with early rheumatoid arthritis (RA) and undifferentiated arthritis. This loss occurred despite patients taking conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs). When patients who lost disease control restarted glucocorticoids and discontinued them again, the secondary glucocorticoid discontinuation resulted in flares in 50% of those patients.

Maassen et al. also found standard baseline characteristics, such as age, symptom duration at baseline and Disease Activity Score (DAS), were ineffective for personalizing the duration of temporary glucocorticoid bridging. However, the findings, published May 2021 in the Annals of the Rheumatic Diseases, suggest the DAS at the time of discontinuation may provide guidance for glucocorticoid discontinuation.¹

Maassen et al. conducted a post hoc analysis of two treat-to-target trials—the BeSt and IMPROVED studies—and reported on the outcomes of protocolized discontinuation of glucocorticoids.^2,3

The BeSt Study

In the BeSt (Behandel-Strategieën treatment strategies) study, all 133 patients enrolled in arm 3 initiated treatment with 7.5 mg/week of methotrexate, 2,000 mg/day of sulfasalazine and 60 mg/day of prednisone, which was tapered to 7.5 mg/day over six weeks. If the DAS score remained equal to or below 2.4, prednisone was tapered at week 28 from 7.5 mg/day to 5 mg/day and then to 0 at week 35 (i.e., primary prednisone discontinuation).

By 28 weeks, prednisone had been tapered to 0 in 60% of patients and another 16% of patients were able to have prednisone tapered and discontinued after 28 weeks. In the study, 40% of patients experienced flare (DAS >2.4) after primary prednisone discontinuation. Although 60% of patients did not immediately flare after primary discontinuation, 38% of those who did not experience an immediate flare had to restart prednisone later.

If a patient experienced a flare after or during primary prednisone discontinuation, the investigators had patients restart prednisone at 7.5 mg/day. They then discontinued prednisone a second time if the patient maintained a DAS ≤2.4 for six consecutive months. Of those patients who restarted prednisone, 47% experienced flare after a secondary prednisone discontinuation.

When the investigators evaluated the data using univariable and multivariable logistic regression analyses, they found no differences in characteristics between patients with successful vs. unsuccessful secondary prednisone discontinuation.

IMPROVED Study

The IMPROVED (Induction Therapy with Methotrexate and Prednisone in Rheumatoid Or Very Early Arthritic Disease) study had a treat-to-target DAS of <1.6. Patients were initially treated with a combination of methotrexate, gradually intensified in the first six weeks from 7.5 mg/week to 25 mg/week, and prednisone, 60 mg/day tapered to 7.5 mg/day over six over weeks. The investigators evaluated disease activity every four months. Patients who were in early remission (DAS <1.6) at four months had their prednisone treatment tapered over three weeks and then stopped (i.e., primary prednisone discontinuation).

In 34% of patients in this study (n=610), prednisone discontinuation was never attempted or could not be studied. Primary prednisone discontinuation occurred in 61% of patients who were in remission at four months. An additional 5% of patients attempted delayed primary prednisone discontinuation. Of those patients who attempted primary prednisone discontinuation, 39% experienced flare after primary discontinuation. Of the remaining 61% who did not immediately experience flare, 40% had to restart prednisone when their DAS increased beyond 1.6.

In the event of a disease flare after or during prednisone discontinuation, the investigators had patients restart prednisone at 7.5 mg/day and, if the DAS was again maintained below 1.6 for four months, the dosage of prednisone was tapered and stopped a second and final time (i.e., secondary prednisone discontinuation). In total, 139 patients attempted secondary prednisone discontinuation when they again reached remission, and almost half (49%) flared after the secondary discontinuation.

When the investigators performed a sensitivity analysis of the data from the 175 IMPROVED patients who would have met the inclusion criteria for the BeSt study, they found primary prednisone discontinuation was successful in 46%, followed by immediate flare in 54%.

Interpreting the Data

Previous studies have shown that a combination of glucocorticoids with csDMARDs is more effective in rapidly suppressing disease activity in the initial treatment of early RA than slow-acting csDMARDs alone.⁴ As a result, rheuma­tologists often use glucocorticoids as a bridging therapy in patients with RA. However, the 2021 ACR Guideline for the Treatment of Rheumatoid Arthritis suggests glucocorticoids should be tapered and discontinued as soon as possible.⁵

These investigators found that after initial glucocorticoid discontinuation, approxi­mately 40% of patients experienced a disease flare and had to restart prednisone. These flares occurred even though patients were maintained on as much as 25 mg/week of methotrexate in the IMPROVED trial and methotrexate plus an additional 2,000 mg/day of sulfasalazine in the BeSt trial.

Unfortunately, most baseline charac­teristics the investigators found to be associated with successful glucocorticoid discontinuation in the BeSt study could not be confirmed in the IMPROVED study—and vice versa. However, the investigators did find that a lower DAS both at baseline and the final study visit was a stable and reproducible factor associated with maintenance of disease control after glucocorticoid discontinuation. They also noted that being a man in the IMPROVED study was associated with successful primary discontinuation. The authors conclude their paper by suggesting alternative, effective treatments are likely available if the rheumatologist is considering discon­tinuation of glucocorticoids.

Nilanjana Bose, MD, MBA, a rheumatologist with Lonestar Rheumatology, Houston, expresses surprise at the high dose of glucocorticoids described in the paper. She typically prescribes a starting dose of 5–10 mg/day of prednisone in conjunction with DMARD therapy, a practice that stands in marked contrast to the higher dose of 60 mg/day used in both studies. She then tapers patients off glucocorticoids a few weeks after initiating treatment with the DMARD. Not only does she not see the relapse rate described in the paper, but she is also surprised by how high the relapse rates were in both studies. Dr. Bose agrees with the conclusions of the paper that every patient is different and no rules exist for determining when a glucocorticoid taper will be successful.

“You go with your gut feeling,” Dr. Bose says, describing her approach. She also emphasizes the importance of optimizing the DMARD dose. In her experience, if the taper is done correctly, patients will not experience flare. However, she does warn her patients that they may experience a flare when they taper off glucocorticoids. She prescribes prednisone for patients to keep at home to help them recover from flares.

Lara C. Pullen, PhD, is a medical writer based in the Chicago area. 

References

1. Maassen JM, SObrin RDS, Bergstra SA, et al. Glucocorticoid discontinuation in patients with early rheumatoid and undifferentiated arthritis; a post-hoc analysis of the BeSt and IMPROVED studies. Ann Rheum Dis. 2021 Sep;80(9):1124–1129.
2. Goekoop-Ruiterman YPM, de Vries-Bouwstra JK, Allaart CF, et al. Clinical and radiographic outcomes of four different treatment strategies in patients with early rheumatoid arthritis (the BeSt study): A randomized, controlled trial. Arthritis Rheum. 2005 Nov;52(11):3381–3390.
3. Heimans L, Wevers-deBoer KVC, Visser K, et al. A two-step treatment strategy trial in patients with early arthritis aimed at achieving remission: The IMPROVED study. Ann Rheum Dis. 2014 Jul;73(7):1356–1361.
4. Onuora S. Rheumatoid arthritis: Methotrexate and bridging glucocorticoids in early RA. Nat Rev Rheumatol. 2014 Dec;10(12):698.
5. Fraenkel L, Bathon JM, England BR, et al. 2021 American College of Rheumatology guideline for the treatment of rheumatoid arthritis. Arthritis Care Res (Hoboken). 2021 Jul;73(7):924–939.