Prednisone / Prednisolone
| Type | Recommendation |
|---|---|
| When to deprescribe | |
| CBR |
We suggest deprescribing decisions be made in consultation with the person and their GP and/or specialist providers to ensure it aligns with their preferences, goals and overall treatment plans. We suggest deprescribing be offered to older people taking long-term oral corticosteroids for:
|
| Ongoing treatment | |
| CBR | We suggest that ongoing treatment with oral corticosteroids may be necessary for some people with autoimmune diseases who experience a relapse after attempts to deprescribe, despite concurrent use of disease-modifying agents. In such cases, we suggest maintaining long-term oral corticosteroids at the lowest effective dose. |
| How to deprescribe | |
| CBR |
We suggest individualising the tapering schedule and adjusting the schedule based on individual preferences, overall risk of withdrawal effects, risk of glucocorticoid-induced adrenal insufficiency, risk of relapse, adverse drug effects, disease activity, the initial dose, and duration of use. In general, we suggest reducing the dose by prednisone equivalent of 10-20% per week; however, some people may require very gradual tapering such as 1 mg every four to eight weeks, especially when approaching physiological glucocorticoid dosing. |
| Monitoring | |
| CBR |
We suggest advising patients to report to their healthcare providers symptoms of potential signs and symptoms of glucocorticoid withdrawal syndrome (e.g. sleep disturbance and mood changes), glucocorticoid-induced adrenal insufficiency (e.g. myalgias, fatigue, and muscle weakness) and recurrence of underlying conditions (e.g. breathlessness for COPD or arthralgias in rheumatoid arthritis). We suggest monthly monitoring of erythrocyte sedimentation rate and C-reactive protein for at least three months, followed by monitoring every six months thereafter. However, this should be tailored based on individual factors such as their preferences, responses and tolerance to deprescribing. |
CBR, consensus-based recommendation
At pharmacological doses, corticosteroids are widely used for their anti-inflammatory and immunosuppressive effects across various conditions [177]. While corticosteroids offer substantial therapeutic benefits, prolonged systemic corticosteroid use is associated with serious adverse effects, including osteoporosis, hypertension, glaucoma, peptic ulcer disease, increased infection risk, worsened glycaemic control, and psychiatric disturbances [177]. However, these effects are dose-dependent and less likely to occur at physiological replacement doses [177].
Refer to the narrative evidence summary, the GRADE Summary of Findings table in the guidelines, and the Technical Report for a complete presentation of the deprescribing evidence based on the GRADE framework (including other factors considered in developing the recommendations).
Older people, particularly those with severe chronic conditions, are frequently prescribed long-term oral corticosteroids. These medications provide rapid symptom relief and help achieve clinical remission, which is a key goal in managing autoimmune or autoinflammatory diseases [177]. Systemic corticosteroids are typically reserved for managing disease flares or as an adjunct therapy to induce remission while awaiting the therapeutic effects of disease-modifying drugs (biologic or synthetic), which have more favourable long-term safety profiles. This process can generally take six to 12 weeks. Once remission or low disease activity is achieved, deprescribing corticosteroids should be considered. A cohort study of older people with inflammatory bowel disease found that 40% were on long-term corticosteroid therapy, despite 24% being in remission or having only mild disease activity [442]. Since long-term corticosteroid use is rarely warranted, especially in respiratory and endocrine conditions, deprescribing should be considered when the disease is stable or in remission [443].
The duration and approach to oral corticosteroid use vary considerably depending on the condition being treated. For instance, polymyalgia rheumatica, a chronic inflammatory condition typically seen in people over the age of 50 years, typically requires treatment with oral corticosteroids for at least 12 months as monotherapy [444]. In some cases, methotrexate can be used as a corticosteroid-sparing agent, while the use of biologic disease-modifying drugs is generally not indicated. A common corticosteroid regimen involves initiating prednisolone at 15 mg daily for four weeks, followed by dose reductions of 2.5 mg every four weeks until reaching 10 mg daily. Subsequently, reductions of 1 mg every four to eight weeks are recommended, depending on the individual's response and tolerability. Regimens lasting less than nine months are generally not advised due to a higher risk of relapse. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) are useful for monitoring disease activity but are not specific markers and should be interpreted alongside the individual's symptoms [444]. Current guidelines recommend monthly monitoring of CRP and ESR during the first three months of treatment, followed by monitoring every two to three months thereafter or as clinically indicated [444].
Chronic glucocorticoid therapy (≥ 3-4 weeks) increases the risk of glucocorticoid-induced adrenal insufficiency, which can occur both after discontinuation and during continued use, even at low doses (≤5 mg prednisolone equivalent) [445]. The risk increases with treatment duration (≥ 3-4 weeks) and higher doses (e.g. >15-25 mg hydrocortisone equivalent: 4-6 mg prednisone/prednisolone, 3-5 mg methylprednisolone, 0.25-0.5 mg dexamethasone) [446]. Symptoms of adrenal insufficiency, such as fatigue, malaise, muscle aches, and low energy, often overlap with those of the underlying inflammatory disease, glucocorticoid withdrawal syndrome, or stress events (e.g. infection). The European Society of Endocrinology/Endocrine Society joint guideline suggests considering the total daily glucocorticoid dose when distinguishing adrenal insufficiency from withdrawal symptoms, as higher doses make adrenal insufficiency less likely [446].
We suggest advising patients to report to their healthcare providers symptoms of potential signs and symptoms of glucocorticoid withdrawal syndrome (e.g. sleep disturbance and mood changes) [446], glucocorticoid-induced adrenal insufficiency (e.g. myalgias, fatigue, and muscle weakness) [446] and recurrence of underlying conditions. It may be helpful to provide examples of common symptoms when encouraging individuals to self-monitor and report symptoms. As some symptoms are non-specific, many individuals may not recognise that they could be indicative of withdrawal syndrome or adrenal insufficiency.
We identified five studies (one RCT and four before-and-after studies) related to prednisolone deprescribing from the systematic review and meta-analysis [447-451] and one retrospective cohort study related to glucocorticoid deprescribing in general [452].
Overall, the included studies investigated glucocorticoid use across various diseases. Although an observational study suggested that deprescribing may reduce hospitalisation rates, the certainty of this evidence is very low. There appears to be an increased risk of disease flare-ups in patients with severe conditions (polymyalgia rheumatica and autoimmune pancreatitis). However, the current evidence is inadequate to inform evidence-based recommendations.
Key study characteristics and results
A narrative summary of each study is provided below, highlighting key characteristics and main findings.
Three studies included people with rheumatoid arthritis.
- Hirata 2021 conducted a before-and-after study that included 36 who had been receiving a stable regimen of prednisolone and methotrexate for more than six months regardless of disease activities [449]. Participants were excluded if they required a long-term glucocorticoid for extraarticular manifestations (e.g. rheumatoid vasculitis or interstitial lung disease). Prednisolone dose was reduced with an increment of methotrexate dose in all participants. After 24 months, the proportion of people using prednisolone reduced by 86.1% (p< 0.0001) while the clinical remission rate increased from 25.0% to 38.9%. Serious adverse events were reported in 2/36 (6%) people which were peritoneal cancer and myelodysplastic syndrome.
- Almayali 2023 conducted an extension study that included patients who previously completed a two-year RCT [451]. In the main RCT, participants with inadequate control of rheumatoid arthritis (DAS28-ESR [Rheumatoid arthritis Disease Activity Score with Erythrocyte Sedimentation Rate] ≥2.60) were randomised to two years of 5mg prednisolone daily or placebo. Participants were excluded if they were already receiving glucocorticoid therapy or if they had other uncontrolled conditions. Among the 96 patients who had been receiving prednisolone for two years, tapering of prednisolone after two years of therapy significantly increased disease activity (DAS-28 score increased from 2.88 ± 1.14 to 3.12 ± 1.15, p=0.04) and 43/96 (45%) of all participants experienced disease flares during tapering. However, there was a small reduction in signs and symptoms of adrenal insufficiency (1.1 ± 1.2 to 0.8 ± 1.3), indicating that withdrawal of low-dose prednisolone could be safe in certain cohorts.
- Goto 2023 conducted a retrospective cohort study that included 122 patients who discontinued glucocorticoids and 126 patients who continued [452]. Patients were included in the analysis if they had a diagnosis of rheumatoid arthritis and received therapeutic intervention. Those who discontinued their glucocorticoids had a significantly lower rate of infection requiring hospitalisation (OR 0.35, 95% CI 0.18, 0.67).
One study included patients with chronic obstructive pulmonary disease (COPD).
- Rice 2000 conducted a blinded placebo-controlled RCT that included 38 men with COPD who had been taking both inhaled beta-agonists and oral prednisolone (> 5mg/day) for at least six months [450]. Participants were included if there had not been any reduction in their prednisolone dose in the past month and if they had a smoking history of at least 20 pack years. Participants were excluded if they had asthma, a history of eosinophilia, a high IgE titer, a strong family history of atopy, or normal or highly (50%) variable spirometry results within the last five years. All eligible participants were randomised to either on-demand dosing (n=18) versus continuation (n=20). At six months, participants in the on-demand group had a significantly lower average daily corticosteroid dose (MD -7.4, 95% CI -12.38, -2.42). However, there were no significant differences between the two groups in terms of the number of participants experiencing at least one exacerbation, exacerbation rate, or number of days until the first exacerbation.
One study included patients with autoimmune pancreatitis.
- Hirano 2015 conducted a before-and-after study that included 21 patients with autoimmune pancreatitis who were clinically and serologically stable [448]. All participants who had received prednisolone for at least three years without clinical relapse with immunoglobulin G < 1600 mg/dL in the past year on maintenance dose ≤ 5mg were included. Participants had their low-dose maintenance prednisolone tapered before complete withdrawal. During the follow-up period (range 19 to 48 months), clinical (n=10/21, 48%) and serological (n=5/21, 24%) relapse occurred. There were two malignancies (gastric cancer and tongue cancer) in two patients who survived after surgical resection. HbA1c levels increased significantly, particularly in patients having clinical or serological relapse (6.16 ± 0.57% and 6.68 ± 0.69%, p = 0.0012), which could be attributed to the resumption of prednisolone.
One study included patients with polymyalgia rheumatica.
- Esselinckx 1977 conducted a before-and-after study that included 18 patients with polymyalgia rheumatica treated with stable doses of prednisolone [447]. Patients with any signs that correlated with giant cell arteritis were excluded. Two participants (11%) died during the follow-up period, one of a bleeding duodenal ulcer and one of ovarian cancer. All participants experienced a recurrence of the underlying condition. In three participants, the relapse was severe and rapid, so within four days, the original dose of prednisolone had been reinstated. Within one week, 12 (67%) participants had relapsed. Two participants relapsed in week two, and one participant relapsed in week 10. Satisfactory symptomatic control was re-established with the reintroduction of oral prednisolone. After the gradual withdrawal, one participant was maintained on a lower dose, one participant was maintained on a higher dose, and in the other participants, the initial dose was resumed. Although two participants were symptom-free, they were described as having a markedly raised erythrocyte sedimentation rate (ESR) so the oral prednisolone therapy was resumed.
In the RCT, prednisolone was gradually tapered by 5mg per week in patients with chronic obstructive pulmonary disease (n=38, low certainty) [450].
The method was not described in the retrospective cohort study related to glucocorticoid deprescribing in patients with rheumatoid arthritis (n=248) [452].
For the other four single-arm studies investigating prednisolone deprescribing, the prednisolone dose was:
- Withdrawn abruptly and gradually titrated at a mean rate of 1mg per month over four to five months (study=1, n=18) [447]
- Tapered by 1mg every 8-10 weeks until complete cessation (study=1, n=21), Individualised (study=1, n=36) [448]
- The dose was tapered over 12 weeks, starting with a baseline dose of 5 mg of prednisolone daily. Every two weeks, a 'prednisolone-free' day was added until complete discontinuation by week 13 (study=1, n=96) [451]
- Prednisolone was gradually reduced up to 1 mg per month while at the same time, the methotrexate dose was gradually increased up to 16 mg per week and up to 4 mg per month for folate (study=1, n=36) [449]
There is no universally established tapering strategy for long-term glucocorticoid therapy, making an individualised approach essential [453]. Current guidelines recommend a slower tapering rate as the dose approaches physiological levels (e.g. 4-6 mg prednisone) [446]. As the dose decreases, the risk of adrenal insufficiency rises, necessitating a slower taper to allow recovery of the hypothalamic–pituitary–adrenal axis that leads to increased adrenocorticotropic hormone levels and the eventual restoration of normal adrenal function and cortisol production [454].