Rheumatoid arthritis: Can low-dose corticosteroids be used long-term? Latest roundup

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Rheumatoid arthritis (RA) is an autoimmune disease with erosive arthritis as the main clinical manifestation, with a high disability rate, and it is of great significance
to select scientific and effective therapeutic drugs for timely treatment of RA patients.
The existing therapeutic drugs for RA include antirheumatic drugs (DMARDs), biologics and targeted small molecule therapeutics, and the research and development of other drugs has also made great progress, and the application concept of glucocorticoids (GC) as a common treatment for RA has also ^changed1
.

GC is a rapidly effective and desirable drug, and its combination with DMARDs can control disease activity and slow bone destruction in RA patients faster than DMARDs alone, but its risk-benefit ratio has been controversial
。 In this paper, Tore K.
Kvien, Professor of Rheumatology at the University of Oslo School of Medicine, Norway, and Frank Buttgereit, Senior Advisor and Associate Director of the Department of Rheumatology and Clinical Immunology at the Charité School of Medicine at the University of Berlin, agreed based on the latest evidence on the use of low-dose GC maintenance therapy in patients with RA, that GC bridging therapy should be used in early RA to initiate treatment with DMARDs, taking into account the recommendations of the European Union Against Rheumatism (EULAR).
Then, if the condition allows, the dose should be gradually reduced, and the GC
should be stopped within 3 months of treatment as soon as possible.

Long-term use of glucocorticoids does more harm than good

1.
Why is the use of GC for maintenance therapy in RA treatment not supported?

The anti-inflammatory activity of GC relieves joint pain and stiffness, improves joint function, slows imaging progression, and reduces bone loss
when used early in the disease.
However, GC treatment can cause a large number of adverse reactions, most of which are related to dose and exposure time, mainly due to increased cardiovascular events, increased incidence of diabetes, bone loss and osteoporosis
.

Tore K.
Kvien's main concern is that patients with adverse events may occur
without a clear tapering plan when starting GC-bridging therapy (used to initiate or alter traditional synthetic DMARDs until they show efficacy).
Cross-sectional studies show that the problem of GC medication irregularities is still prominent in ^China3, in order to further standardize the use of GC in RA patients, patients should be introduced in detail to the role of GC and possible adverse reactions, and specific stop reduction plans should be formulated to avoid long-term ^use1
.

2.
Is the GC tapering treatment strategy effective in clinical practice?

There is very limited
evidence to support that long-term glucocorticoid use does more harm than good.
CareRA and IMROVED studies have shown that the efficacy persists
in most patients after GC is tapered and discontinued.
A recent ARCTIC study in Norway of RA patients (course < 2 years) treated with biologic DMARDs showed that the GC dose of patients was gradually reduced from baseline <b12>prednisone 15 mg/day to 2.
5 mg/day at 7 weeks of treatment after adjusting the treatment regimen under close monitoring, but it is important to note that most patients received ultrasound-guided GC intra-articular injection, suggesting that this therapy may help reduce systemic GC use
。

Overall, individually, some patients who do not respond well to DMARDs and present with extra-articular or systemic manifestations require aggressive treatment with GC, and adverse events
associated with GC therapy should be closely monitored.
In terms of population, early diagnosis, early use of DMARDs, and treatment according to standard treatment strategies, along with enhanced follow-up, will greatly reduce the proportion of
patients requiring GC maintenance therapy.

Long-term treatment with very low doses of glucocorticoids is beneficial if used correctly

EULAR's RA guidelines recommend that short-term use of GC should be considered when initiating or changing traditional synthetic DMARDs with different dosage regimens and routes of administration, but tapering as soon as possible
.
In contrast, the 2021 American College of Rheumatology (ACR) RA guidelines conditionally recommend not using GC for 3 months as bridging therapy for conventional synthetic DMARDs (level of evidence: very low).

Frank Buttgereit scholars believe that in addition to the cost-effectiveness of GC, there are three reasons to support the use of GC in maintenance therapy for patients with RA, even at very low doses of GC (ideally < 5 mg/day).

1.
In the maintenance therapy of patients with RA, what is the effect of GC low-dose versus gradual tapering?

A recent SEMIRA study comparing the effect of low-dose GC (prednisone 5 mg/day) and taper tapering on disease activity and safety in RA patients showed that the mean change in activity-erythrocyte sedimentation rate (DAS28-ESR) in 28 patients in the low-dose GC-treated group was -0.
08 (difference 0.
61, p<0.
001)<b10> compared with the GC-tapering group (0.
54).
In terms of safety, more patients experienced adverse events in the GC-reduced group (5%) compared with the low-dose GC treatment group (3%)
.
It can be seen that the use of prednisone 5mg/day maintenance therapy can better and safer control of disease, and very low-dose GC therapy has obvious and specific efficacy
.

2.
What are the benefits or harms of long-term use of low-dose GC therapy in elderly RA patients?

For elderly patients, the GLORIA study evaluated the effect of prednisone 5 mg/day versus placebo treatment on disease activity and safety in patients with active RA aged ≥ 65 years, and showed that disease activity decreased rapidly after 3 months of treatment in patients in the prednisone group, and after 2 years, the mean DAS28 (p<0.
0001) lower and joint injury progression was 1.
7 points lower (p=0.
003)
in the prednisone group compared with the placebo group.
In terms of safety, adverse events occurred in patients in both the GC group (60%) and placebo (49%), but most were not serious, mainly infections
.
It can be seen that the benefits and harms of low-dose GC therapy in elderly patients with active RA are comparable
.
Therefore, for most patients with RA, including older patients, the risks associated with low-dose GC therapy are acceptable and some are preventable and manageable
.

3.
What are the limitations of observational studies on the risk-benefit ratio of GC treatment?

Scholars point out that some of the results of GC toxicity are not rigorous, one reason is that there are few randomized controlled trials, and the trial time is short, and the sample size is small, and it is impossible to draw firm conclusions
about GC toxicity related to therapeutic doses.
On the other hand, observational studies tend to have low data quality and high risk of bias, making it difficult to distinguish between increased disease activity and GC in certain treatment side effects
.
Therefore, studies on GC toxicity need to be carefully interpreted
.

conclusion

Tore K.
Kvien and Frank Buttgereit agree that the use of bridging therapy in early RA to initiate treatment with DMARDs should be initiated with reference to EULAR's recommendations, and then tapering as the condition allows, and GC should be stopped
within 3 months of treatment as soon as possible.
Also, GC should be avoided
in patients who achieve clinical remission.
However, given individual heterogeneity, patients who do not achieve remission with DMARDs and nonsteroidal anti-inflammatory drugs (NSAIDs), have low disease mobility, or do not have satisfactory levels of joint functional activity require aggressive treatment
with GC.
Chinese RA guidelines recommend that patients with moderate/high disease activity be treated with traditional synthetic DMARDs plus GC for rapid symptom control, that adverse effects should be closely monitored during treatment, and that glucocorticoids are not recommended alone or in long-term high-doses3
.
In addition, preventive measures such as instructing patients to consume a low-sodium, high-potassium, high-protein diet, limiting high-fat and high-sugar diets, and supplementing vitamin D and calcium should be taken to avoid cardiovascular complications and serious adverse events
such as osteoporosis caused by GC therapy.

References:

1.
Nan Yiyang, Lin Hongju, Yuan Lin.
Research progress of glucocorticoids in the treatment of rheumatoid arthritis[J].
World Latest Medical Information Digest, 2018, 18(62):75-76+79.
DOI:10.
19613/j.
cnki.
1671-3141.
2018.
62.
034

2.
Buttgereit F, Kvien TK.
Controversies in rheumatology: Maintenance therapy with low-dose glucocorticoids in rheumatoid arthritis[J].
Rheumatology (Oxford).
2022 Jun 17:keac355.
doi: 10.
1093/rheumatology/keac355.
Epub ahead of print.
PMID: 35713511.

3.
2018 Guidelines for the diagnosis and treatment of rheumatoid arthritis in China[J].
Chinese Journal of Internal Medicine, 2018, 57(04):242-251.