Use of glucocorticoids in the treatment of rheumatoid arthritis

INTRODUCTION — In 1950, Philip Hench and colleagues earned a Nobel Prize in medicine and physiology for discovering the dramatic beneficial effect of cortisone on a patient incapacitated by rheumatoid arthritis (RA) [1]. Since that time, glucocorticoids have been a key medication for the treatment of RA, although the precise role of glucocorticoids continues to generate considerable debate.

Glucocorticoids exert both antiinflammatory and immunosuppressive effects via several mechanisms [2,3] (see "Glucocorticoid effects on the immune system"). Among those pertinent to patients with RA are the following:

●Inhibition of prostaglandin and leukotriene synthesis

●Reductions in macrophage phagocytosis, in interleukin (IL)-1 secretion, and in the number of circulating monocytes

●Inhibition of the release of collagenase and lysosomal enzymes

These effects are mediated by intracellular glucocorticoid receptors that translocate to the nucleus after binding with glucocorticoids, affecting the transcription of thousands of genes by directly binding to DNA at glucocorticoid response elements and by interacting with other transcription factors [3]. Non-genomic glucocorticoid effects may also be mediated by posttranscriptional and posttranslational mechanisms, by physicochemical interactions with biologic membranes, and by binding to membrane-bound glucocorticoid receptors.

Among patients with RA, glucocorticoids may be administered via several different modalities. These include oral (short-term and chronic therapy), intramuscular, intravenous (pulse therapy), and intraarticular routes. (See "Pharmacologic use of glucocorticoids".)

This topic will review the use of glucocorticoids given both short-term and chronically in low doses, given intravenously as pulse therapy over a short period of time, and when administered intraarticularly in the treatment of RA [4]. An overview of the management of RA is discussed separately. (See "General principles and overview of management of rheumatoid arthritis in adults".)

EFFICACY OF SHORT-TERM USE — In patients with more severe, active rheumatoid arthritis (RA), prednisone is frequently added for a short period to the treatment regimen to rapidly reduce disease activity while awaiting a clinical response to a slower-acting disease-modifying antirheumatic drug (DMARD) [5-7]. Moderate doses of glucocorticoids of 10 to 15 mg/day may often have a substantial clinical benefit in patients with RA. Especially when used for short-term (generally <1 month) management of active joint disease, glucocorticoids are more effective than either placebo or a nonsteroidal antiinflammatory drug (NSAID).

Support for the value of short-term (ie, within the first month of therapy) glucocorticoid therapy comes from a year 2003 meta-analysis of 10 studies utilizing random assignment of 320 patients with RA to groups that received glucocorticoids (equivalent to 15 mg of prednisolone or less per day), placebo, or NSAIDs [8]. The significant main results were as follows:

●Prednisolone reduced joint tenderness more than placebo or NSAIDs

●Prednisolone reduced pain more than placebo or NSAIDs

●Prednisolone increased grip strength more than placebo

Glucocorticoid adverse effects are both dose and duration dependent, and short-term use of glucocorticoids in doses less than the equivalent of 15 mg of prednisolone per day is seldom associated with serious adverse effects. Observational studies have suggested a small increase in harms such as serious infections even with very short courses of glucocorticoids at the population level, although for an individual patient the risk is low [9]. Mood disorders and hyperglycemia may be seen with daily treatment at these relatively low doses; however, short-term treatment of early RA with even high-dose prednisone therapy has not been associated with long-term worsening of glucose tolerance [10]. (See "Major adverse effects of systemic glucocorticoids".)

Several clinical trials have suggested benefits of high-dose prednisone therapy in early RA. The Combination Therapy Trial in Early Rheumatoid Arthritis (COBRA) and the Behandel Strategieen (BeSt) trial demonstrated that the addition of higher-dose oral prednisone (60 mg/day, tapering to 7.5 mg/day by week 6 and then stopping after week 12) in combination with other conventional DMARDs leads to more rapid improvement in disease activity and also lower rates of radiographic joint damage, an effect that while small was sustained over many years [11,12]. An open-label trial has suggested that lower initial doses of glucocorticoids (prednisone 30 mg/day) may have comparable efficacy to the higher dose used in the classic COBRA regimen [13].

Clinical experience suggests that glucocorticoids continue to be effective for periods up to six months. Longer-term use is more controversial because of waning effectiveness in controlling symptoms and because of increasing risk of adverse events [14]. (See 'Efficacy of chronic use' below.)

It is notable that the more rapid onset of action of biologic and targeted synthetic DMARDs (eg, janus kinase inhibitors) compared with conventional DMARDs may reduce the need for short-term glucocorticoids. In the BeST trial, patients randomized to higher-dose oral prednisone with methotrexate had similar outcomes at three months to those randomized to infliximab with methotrexate [12].

Many clinicians employ short-term glucocorticoids as bridging therapy when starting a DMARD, particularly in patients who have more severe or disabling symptoms despite NSAIDs. This strategy is embraced in guidelines from the European Alliance of Associations for Rheumatology (EULAR). Guidelines from the American College of Rheumatology also acknowledge the frequent use of glucocorticoids in this setting, although they recommend against routine use of short-term glucocorticoids because of challenges tapering therapy in some patients [15].

EFFICACY OF CHRONIC USE — Evidence is conflicting regarding the benefits of chronic glucocorticoid therapy for patients with rheumatoid arthritis (RA). We do not use glucocorticoids on a chronic basis without concurrent therapy with a disease-modifying antirheumatic drug (DMARD) or combination of DMARDs (eg, a conventional DMARD and a biologic agent), as DMARDs are more potent disease modifiers in the long term. The main conclusions from randomized trials in which patients received 7.5 to 10 mg/day of prednisone or equivalent in addition to DMARDs were that initial symptomatic benefit may be achieved and sustained for up to two years [16-24]. Radiologic progression is also modestly reduced with such doses, although these effects are less clinically relevant in the current era of more effective DMARDs. These conclusions were best demonstrated in three randomized trials:

●One trial included 128 patients with RA of less than two years' duration who were randomly assigned to prednisolone therapy (7.5 mg/day) or placebo; other DMARDs could also be prescribed, although the study is nearly three decades old, only 4 percent of the participants received methotrexate, and biologic therapies were not yet available [17]. Prednisolone was beneficial compared with placebo for reducing pain at up to six months and for reducing disability at up to 15 months. At two years, prednisolone therapy resulted in significantly fewer hand erosions (22 versus 46 percent). Among those initially administered prednisolone, an increase in erosions was seen one year after drug withdrawal [18].

●A two-year, open-label trial of 250 patients with early RA starting a first DMARD (most commonly methotrexate or sulfasalazine) randomized patients to prednisolone 7.5 mg/day or no prednisolone. Improved disease activity was seen in the prednisolone group throughout the two-year study, along with small benefits in radiographic progression [24].

●Another trial documented radiographic benefit of prednisone in patients treated with a tight-control strategy including methotrexate. In this trial, 236 patients with early RA who had not received therapy with either DMARDs or glucocorticoids were randomly assigned to receive prednisone (10 mg/day) plus methotrexate or placebo plus methotrexate beginning within one year of disease onset and continuing for two years [22]. Disease activity was assessed monthly to determine whether the dose of methotrexate should be increased. A second DMARD was added if control was inadequate at a maximum methotrexate dose of 30 mg/week (cyclosporine for the patients initially entered in the trial or adalimumab for the majority of the patients who were subsequently entered in the trial after a change in trial protocol).

After two years, radiologic scores for the patients receiving prednisone showed a statistically significant lower amount of progression compared with those receiving placebo, although the absolute difference was small (difference in Sharp-van der Heijde score of 0.87 units). The prednisone group had more symptomatic benefit during the first three months; this difference was sustained but was not significantly different at the end of two years. In the group receiving prednisone plus methotrexate, there was less need for the additional DMARD (15 versus 41 percent, including cyclosporine in 2 versus 7 patients and adalimumab in 16 versus 42 patients). The prednisone-treated patients experienced fewer adverse events, particularly gastrointestinal upset and elevated liver enzymes, possibly due to the lower average maximal dose of methotrexate in this group (19.7 versus 23.4 mg/week). No vertebral fractures were noted.

It is less clear whether similar efficacy to that seen with 7.5 to 10 mg/day of prednisone can be achieved with doses of 5 to 7 mg/day as the data are mixed [25,26]:

●A dose of 7 mg of prednisolone daily was no better than placebo in preventing radiographic damage in a trial that randomly assigned 167 patients with RA of less than three years' duration (mean of 12 months) to receive sulfasalazine, with either low-dose glucocorticoid therapy or placebo [21]. There were no significant differences at two years between the two groups in the proportions of patients who developed new erosions or in the rate of joint space narrowing. The authors of the study speculated that the standardized use of a DMARD (sulfasalazine) and of alternative DMARDs in those who did not have a good clinical response in either group may have "outweighed any prednisolone effect."

●In a randomized trial including 451 patients aged 65 and older with RA, the addition of prednisolone 5 mg daily to disease-modifying therapy resulted in lower measures of disease activity (0.37 points lower) and small differences in joint damage progression (1.7 points lower) when compared with the group taking placebo after two years of follow-up, although only 14 percent of patients were receiving a biologic therapy [27]. Even in this short, two-year trial, however, patients in the prednisolone arm experienced more adverse events (60 versus 49 percent), which consisted mostly of nonserious infections.

In a nonrandomized prospective study of over 800 patients, prednisone doses of 5 mg/day (or less) did not dramatically affect the rate of radiographic progression [25].

Even lower doses, such as 1 to 4 mg/day continued indefinitely, may be effective in some patients. This potential beneficial effect was shown in a trial in which 31 patients were randomly assigned to continued maintenance therapy of 1 to 4 mg/day of prednisone or to slow dose reduction, decreasing the daily dose by 1 mg every four weeks [28]. At study entry, patients were clinically stable, and practically all were receiving disease-modifying antirheumatic drugs. Withdrawal from the study for lack of efficacy was significantly less frequent in patients maintained on their initial stable prednisone dose (3 of 13 patients versus 11 of 15 patients).

In an analysis of the National Data Bank for Rheumatic Diseases' longitudinal study in the United States of long-term outcomes in RA, in which patients completed questionnaires every six months, the pattern of glucocorticoid use was examined [29]. The study included 12,749 patients, 66 percent of whom had used glucocorticoids to treat their RA at some point in their disease course. The following findings were observed:

●Thirty-six percent of patients were current users of glucocorticoids.

●Among patients who were current glucocorticoid users, approximately 25 percent discontinued this medication within the following year, and approximately two-thirds had discontinued use at five years. Persistent use (more than five years) occurred in approximately one-third of the patients.

●One-quarter of patients in remission or with minimal disease activity continued taking glucocorticoids.

Tapering chronic glucocorticoids — The ability to taper glucocorticoids in many patients who have achieved low-disease activity with DMARD therapy was demonstrated in a randomized trial of 259 patients with RA [30]. This study included patients that had received glucocorticoids for at least 24 weeks but were currently in low-disease activity with tocilizumab and prednisone 5 mg/day. In a double-blind fashion, patients were randomized to continue prednisone 5 mg or taper prednisone by 1 mg every four weeks until off. Treatment success (continued low-disease activity and absence of disease flare over the 24-week study) was more common in those who continued prednisone instead of tapering (77 versus 65 percent), but these numbers also demonstrated that almost two-thirds of patients were able to discontinue prednisone without worsening of disease activity. Furthermore, no symptoms of adrenal insufficiency were reported.

Taken together, the studies demonstrate that chronic glucocorticoids can have beneficial effects on disease activity and may have small effects on damage progression. Effective DMARD or DMARD combinations (including conventional and/or biologic or targeted synthetic DMARDs), however, may often provide sufficient improvement so that glucocorticoids are not required or, if used, can be decreased or discontinued to minimize the potential for adverse effects [6].

Low-dose chronotherapy — A limited number of randomized trials and several other studies have suggested that a modified form of prednisone, which delays release of the drug until approximately four hours after nighttime oral administration, is more effective than standard immediate-release prednisone taken in the morning, or even split-dose prednisone taken on a twice-daily basis, in reducing morning stiffness, with both groups showing similar effects on other measures of disease activity [31-34]. The role of the delayed-release form in clinical practice, for which it is available in some countries, remains uncertain. The modified-release form of the drug was developed in an effort to more effectively reduce morning symptoms by countering the effects of proinflammatory cytokines, including interleukin-6, that are produced late at night [35]. Use of this agent has been termed chronotherapy because of its deliberate timing to address circadian rhythms associated with symptoms and the production of such inflammatory mediators [32].

The efficacy of this agent was examined in a 12-week randomized trial involving 350 patients with active RA, most of whom were receiving traditional DMARDs (eg, methotrexate) [32]; treatment with the modified-release form of prednisone (5 mg) at night resulted in significantly greater clinical improvement in composite measures of disease activity compared with placebo (American College of Rheumatology composite measure for 20 percent improvement [ACR20] of 48 versus 29 percent and ACR50 of 22 versus 10 percent) and in a greater relative reduction from baseline in morning stiffness (55 versus 35 percent).

Further research will be required to establish the value of using delayed-release prednisone over the longer duration of glucocorticoid therapy frequently employed in patients with RA, particularly given its substantially greater cost [36,37]. The relative efficacy, risk, and cost-benefit analysis of chronic use of delayed-release prednisone compared with standard immediate-release prednisone remain to be determined.

RISKS OF CHRONIC USE — The chronic use of low-dose glucocorticoids in rheumatoid arthritis (RA) can cause multiple adverse events. These include an increased risk for infections, osteoporosis, skeletal fractures, gastrointestinal bleeding, peptic ulcer disease, diabetes mellitus, cataracts, cardiovascular events, weight gain, skin changes, and impaired hypothalamic-pituitary-adrenal axis response (see "Major adverse effects of systemic glucocorticoids"). While these effects are dose dependent, even glucocorticoid doses of ≤5 mg/day carry some risk.

Multiple observational studies have demonstrated a dose-dependent increase in the risk of serious infections with glucocorticoids. The risk of infection at doses >10 mg/day is substantially greater than that of biologic therapies and even doses ≤5 mg/day are associated with a small but clinically relevant increase in the risk of infection similar to that seen with biologics [38,39]. Although randomized trials are not powered to assess serious infection risk with low-dose glucocorticoids, a randomized trial of 451 patients with RA who were 65 years or older similarly found that those randomized to prednisone 5 mg/day had a significantly greater risk of all infections and numerically more serious infections [27].

Glucocorticoids are also associated with increased cardiovascular risk, particularly at higher doses. In one study, cardiovascular risk was elevated among those receiving prednisone ≥5 to 9 mg/day [hazard ratio [HR] 1.56 (1.18-2.06)], with an even greater risk in those receiving prednisone ≥10 mg daily [HR 1.91 (1.31-2.79)] [40]. This added risk may be particularly relevant in older patients and those with comorbidities

A prospective, randomized, controlled trial of low-dose prednisone in patients with RA found that patients receiving 10 mg of prednisone per day lost approximately 7 percent of lumbar trabecular bone mineral density (BMD) over 20 weeks versus no change in the placebo group [41]. In another study of 65 patients treated with an average of prednisone 5.6 mg/day, BMD in the lumbar spine and trochanter fell at a rate of 2 and 0.9 percent per year, respectively; these changes were prevented with calcium and vitamin D supplementation, which increased BMD by 0.72 and 0.85 percent per year, respectively [42]. Doses above 5 mg/day also may be associated with an increased long-term risk of fractures [43]. Doses of less than 2.5 mg/day may still confer some increased risk [44]. Significant loss of BMD can occur in as little as three months of glucocorticoid use [45]. (See "Clinical features and evaluation of glucocorticoid-induced osteoporosis", section on 'Epidemiology and risk factors'.)

Bone loss in RA is also proportional to the degree of disability and is inversely proportional to the amount of weightbearing exercise an individual can tolerate. Although difficult to prove, it is likely that the direct effect of prednisone to induce bone loss is partially attenuated if the patient also has greater mobility.

A major goal for patients with RA treated chronically with glucocorticoids is to minimize adverse events. The following factors should be part of the regimen (see "Prevention and treatment of glucocorticoid-induced osteoporosis"):

●Tapering glucocorticoids to the lowest effective dose – Limiting the dose to a maximum of 10 mg/day when treating articular disease and preferably to less than 5 mg/day

●Using other measures to minimize bone loss, such as calcium and vitamin D supplementation, and, in patients in whom long-term use is anticipated, considering bisphosphonate or other glucocorticoid-induced osteoporosis therapy (see "Prevention and treatment of glucocorticoid-induced osteoporosis")

PULSE GLUCOCORTICOIDS — Pulse therapy consists of the administration of high doses of glucocorticoids, generally ≥250 mg prednisolone equivalent over a short period of time, usually one to a few days [46]. No studies exist that directly compare this mode of therapy with a regimen of chronic low-dose oral prednisone. The available studies examining pulse glucocorticoids have been poorly controlled and have consisted of only a small number of patients. As a result, pulse glucocorticoids remain a modality of last resort for the treatment of rheumatoid arthritis (RA).

The utility of pulse glucocorticoid therapy among patients with RA has been limited to the following settings (see "General principles and overview of management of rheumatoid arthritis in adults"):

●The treatment of acute flares

●A therapeutic bridge between the initiation of and response to disease-modifying antirheumatic drugs (DMARDs)

The average duration of response to pulse therapy alone is six to eight weeks, with a significantly prolonged response when combined with DMARDs [47].

The minimum effective dose of methylprednisolone is unknown. The standard "pulse" dose has traditionally been 1000 mg administered intravenously (IV) daily for three consecutive days once monthly, but some evidence suggests that lower doses may be as effective. One study, for example, randomized 36 patients with active RA to standard pulse therapy or 100 mg IV daily for three consecutive days once monthly; there was no statistically significant difference in initial response or in sustained clinical improvement between the two regimens [48]. The therapeutic benefit of a single dose of "pulse" therapy for treatment of active RA appears to be unsatisfactory, and multiple pulse doses would be required to attain a therapeutic benefit [49].

Although intravenous administration is the most popular route for pulse therapy, pulse glucocorticoid therapy can also be given orally or by intramuscular (IM) injection [50-52]. These modes of administration may have variable durations of efficacy. One trial compared patients treated with a single dose of either 500 mg of oral methylprednisolone plus placebo injection or 120 mg of IM methylprednisolone plus a placebo tablet, administered once every four weeks (at weeks 0, 4, and 8), for a total of three doses. IM therapy resulted in better rates of disease remission from weeks 2 to 12, but no significant difference was seen at week 16 [51]. In contrast, another study comparing 1000 mg of IV methylprednisolone, 320 mg of IV methylprednisolone, and 320 mg of IM methylprednisolone found no significant differences with respect to the duration of benefits among the three groups [52]. Thus, the IV and IM routes may be equivalent.

Serious adverse events have been reported with methylprednisolone infusion. These include cardiovascular collapse, hypokalemia, myocardial infarction, possible bone loss, and severe infection, principally occurring in patients with compromised cardiovascular or immune systems [47,53]. In view of the very transient therapeutic benefit, the risk of significant adverse effects, and availability of other effective treatments for active RA, the authors do not use "pulse" glucocorticoids for management of active articular disease in patients with RA.

INTRAARTICULAR THERAPY — Intraarticular glucocorticoids are an important mainstay of the treatment of symptomatic synovitis in patients with rheumatoid arthritis (RA) [54]; such therapy is palliative rather than disease-modifying. Different glucocorticoid preparations may vary in their durations of efficacy, due in part to differences in solubility. One study of glucocorticoid injections into affected knees found that triamcinolone hexacetonide provided longer-lasting local pain relief than hydrocortisone succinate or triamcinolone acetonide [55]. (See "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?".)

Although many investigators do not recommend a formal rest period following joint injection, some studies suggest that rest may be beneficial. In one study of patients with inflammatory knee arthritis, those treated with 24 hours of bed rest following intraarticular glucocorticoid injection had, when compared with patients treated in the ambulatory setting, greater improvement at 12 weeks post-injection in the pain score, stiffness score, knee circumference, 50-foot walking time, and serum C-reactive protein [56].

Intraarticular injections of multiple joints may have advantages over intramuscular injections for patients experiencing a disease flare. In a randomized controlled trial of short-term therapy, polyarticular intraarticular injections were more effective than intramuscular injections in attaining improvement by American College of Rheumatology criteria [57]; they were also associated with fewer adverse events.

Adverse events — Although rare, risks associated with intraarticular injection include tendon rupture, osteonecrosis, acute synovitis (transient postinjection flare which usually resolves within 48 hours), localized skin hypopigmentation, septic arthritis, and systemic effects [55,56,58]. The potential complications of joint aspiration and injection are described in more detail separately. (See "Joint aspiration or injection in adults: Complications".)

An early study reviewed 18 years of experience with intraarticular glucocorticoid injections among 8000 patients who received a total of 235,000 injections [58]. There were 79 cases of osteonecrosis. These events were associated with weightbearing joints that had been injected with large doses of glucocorticoids more frequently than once per month for extended periods of time. As a result, recommendations are that individual joints usually receive no more than four injections yearly [54]. However, monthly injections may initially be warranted in patients with very active synovitis. In such patients, the benefit from suppressing joint inflammation may compensate for the increased risk of toxicity [59]. (See "Joint aspiration or injection in adults: Complications".)

GENERAL APPROACH — Glucocorticoids remain an important therapeutic option in the treatment of rheumatoid arthritis (RA); however, widely accepted criteria for the initiation of glucocorticoid therapy have not been established, and, indeed, specific dosing strategies have not been well studied either for short-term flare management or long-term disease management [60]. Studies suggest that glucocorticoids may be used as a bridge between the initiation of conventional (nonbiologic) or biologic disease-modifying antirheumatic drugs (DMARDs) and realizing the therapeutic effect of these slower acting agents and/or for the treatment of acute synovitis [7]. Glucocorticoids may also be used at lower doses in combination with conventional (nonbiologic) and biologic DMARDs to improve function and symptoms in patients without adequate response to DMARD therapy. Glucocorticoids have some effects on preventing joint damage, although this effect is less relevant given the greater effectiveness of currently available DMARDs for limiting radiographic progression. (See "Initial treatment of rheumatoid arthritis in adults", section on 'Oral glucocorticoids'.)

When deciding whether to initiate glucocorticoid therapy, the following clinical features, which increase the risk of toxicity, should be considered [61]:

●Established hypertension

●Diabetes mellitus or prediabetes

●Preexisting cataract(s) or glaucoma

●Significant risk factors for osteoporosis

Patients should be informed about the risks and benefits of glucocorticoid therapy and about the danger of abrupt cessation of the medication after long-term use. Whether the benefits of therapy with glucocorticoids outweigh the risks associated with these agents ultimately rests upon the judgment of the individual clinician.

Short-term use — Patients with more severe symptoms who have inadequate benefit with or contraindications to NSAIDs may be prescribed glucocorticoids, often at doses of 10 to 15 mg/day. Concurrent initiation of a nonbiologic or biologic DMARD permits tapering of the glucocorticoid once the patient begins to respond to the DMARD [54]. If disease activity increases upon tapering, it can be assumed that the particular DMARD or combination of DMARDs is inadequate, and a higher DMARD dose or alternative DMARDs should be utilized.

Chronic therapy — As noted above, adverse effects of chronic glucocorticoid therapy are greatest at doses of 7.5 to 10 mg/day or higher, but infection risk is increased in patients with RA on DMARD therapy who receive any amount of chronic glucocorticoid therapy. Cardiovascular risk is also increased in patients with RA on ≥5 mg/day prednisone equivalent [40], with added risk of bone loss at lower doses. Thus, when chronic use is anticipated, the dose of glucocorticoids should be tapered as quickly as possible to the lowest effective dose, usually 5 to 10 mg/day of prednisone or its equivalent [54,62,63]. Patients with RA, particularly those on DMARDs, usually do not require higher daily doses for synovitis control. Even doses less than 5 mg/day may be adequate in some patients [28].

To minimize interference with the normal diurnal hormonal pattern, glucocorticoids are best administered in the morning.

Patients on chronic glucocorticoids who achieve low-disease activity with effective DMARD therapy should attempt slow glucocorticoid tapering over a period of months to determine if glucocorticoids can be successfully discontinued and, if not, to find the lowest effective dose [30]. In those who require very low doses of glucocorticoids to maintain remission (ie <5 mg/day), weighing the risks of chronic glucocorticoids versus the risks of the alternative DMARDs being considered is required. (See "Glucocorticoid withdrawal" and "Treatment of rheumatoid arthritis in adults resistant to initial conventional synthetic (nonbiologic) DMARD therapy".)

Chronic therapy using monthly intramuscular (IM) glucocorticoid injections has been tried, but without sustained benefit, as shown in a study that randomly assigned 91 patients with RA and an inadequate response to a DMARD to either IM depomedrone (methylprednisolone acetate; 120 mg) or placebo [64]. Typical glucocorticoid adverse events were more frequent in the depomedrone group, and improved disease activity seen with depomedrone during the first year of treatment diminished subsequently. There was no significant difference in disease activity at the end of two years.

Flares — When a flare of RA occurs, it should be recognized that the underlying DMARD therapy may not be adequate, and steps should be taken to optimize the treatment. Flares of disease may be treated by an increase in the dose of oral glucocorticoid, with the intention of reducing the dose once the flare is under control. For patients on chronic prednisone therapy at less than or equal to 7.5 mg a day, increasing the prednisone to 15 mg a day in a single or divided dose for one to two weeks, then tapering to baseline prednisone dose over another two weeks is often adequate for management of a pauci- or polyarticular flare. For a severe flare, higher doses of 0.5 mg/kg body weight may be necessary, tapered to baseline over approximately four to six weeks. Need for frequent increases of the prednisone dose for flare management should prompt consideration of changing DMARD therapy. Pulse intravenous methylprednisolone therapy may lead to a marked but temporary disease suppression, but given the potential risks, this approach is not recommended. A flare in a single or perhaps two or three joints can sometimes be addressed with intraarticular glucocorticoid injection. (See "General principles and overview of management of rheumatoid arthritis in adults", section on 'Drug therapy for flares'.)

Monitoring parameters — The need for baseline studies to monitor toxicity varies among patients. The following are generally recommended [61,65]:

●Serum glucose.

●Lipid profile.

●Bone mineral density – Bone mineral density (BMD), preferably of the spine and hip, should be measured if it is anticipated that a patient will be treated with glucocorticoids for more than six months [66]. Dual photon x-ray absorptiometry (DXA) is an accurate method for assessing BMD. (See "Overview of dual-energy x-ray absorptiometry".)

BMD testing and prophylactic measures have been underutilized in patients at risk for glucocorticoid-induced osteoporosis. This was illustrated in a review of the medical records of 212 patients who received one year of oral glucocorticoid therapy. Only 21 percent of these patients had documented evidence of BMD testing, and only 31 percent were receiving medication for osteoporosis prevention [67].

Another study showed that patients with RA who were >50 years in age sustained more hip fractures than other groups but were least likely to have effective fracture prevention therapy prescribed [68]. More attention to the prevention and monitoring of possible adverse events of long-term glucocorticoid therapy is warranted. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

Osteoporosis prevention counseling has been underutilized in patients taking glucocorticoids. This was illustrated in a survey-based study in which patients taking oral glucocorticoids were asked to recall whether or not they received osteoporosis prevention counseling and to identify factors associated with the intake of calcium and vitamin D and with the assessment of bone mineral density [69]. Only 36 percent reported receiving osteoporosis prevention counseling. Slightly more than one-half of the study participants were obtaining the recommended amount of calcium. One-third were obtaining the recommended amount of vitamin D, and a similar proportion had received a test of BMD within the preceding year. Effective strategies need to be developed to educate patients regarding this potential complication and strategies for prevention.

Once glucocorticoid therapy is initiated, the following should be assessed or performed at each patient visit [61]:

●The presence of polydipsia, edema, shortness of breath, or visual changes

●Weight gain

●Blood pressure

All patients on chronic therapy (ie, more than six months) at a dose of prednisone above 5 mg/day [66] (or 7.5 mg/day for more than three months [65]) should be treated with calcium (1000 mg/day) and vitamin D (400 to 800 international units/day) supplementation. The BMD should be monitored for as long as the glucocorticoid therapy is continued, and the serum glucose and lipid profile should be periodically reassessed. Patients who continue to lose bone may benefit from the addition of a bisphosphonate or other treatment [65,70]. (See "Prevention and treatment of glucocorticoid-induced osteoporosis".)

In addition to monitoring for the development of toxicities, patients should be assessed for therapeutic benefits from these agents with alterations based upon clinical response. (See "General principles and overview of management of rheumatoid arthritis in adults".)

Patient attitude — The attitudes of 148 patients with RA to oral glucocorticoid treatment were surveyed, and the factors influencing these views and their likely clinical impact were assessed in a study published in 2003 [71]. The majority (68 percent) of the patients were not willing to be treated with an oral glucocorticoid. The patients who were willing to be treated were older and had higher mean erythrocyte sedimentation rates, worse function, and greater use of DMARDs. Many patients refused to participate due to their high level of concern about the adverse effects of glucocorticoid treatment [71].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Rheumatoid arthritis".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Rheumatoid arthritis symptoms and diagnosis (Beyond the Basics)" and "Patient education: Rheumatoid arthritis treatment (Beyond the Basics)" and "Patient education: Disease-modifying antirheumatic drugs (DMARDs) in rheumatoid arthritis (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Goals of therapy – We primarily use glucocorticoids as a bridge between the initiation and realization of therapeutic effects of disease-modifying antirheumatic drugs (DMARDs) in patients with more severe disease and/or for the treatment of acute synovitis. At lower doses (generally <5 to 7.5 mg a day prednisone equivalent), we use glucocorticoids in combination with conventional and biologic DMARDs in patients who have not achieved an adequate response with DMARDs alone, attempting slow glucocorticoid tapering if patients reach low disease activity. We do not use glucocorticoids in the absence of concurrent DMARD therapy. Comorbidities associated with an increased risk of toxicity should be considered when deciding whether to initiate glucocorticoid therapy. Patients should be informed about the risks and benefits of glucocorticoid therapy and about the danger of abrupt cessation of the medication after long-term use. (See 'General approach' above.)

●Short-term glucocorticoids – When used for a period of one month or less, glucocorticoids are more effective than either a placebo or a nonsteroidal antiinflammatory drug (NSAID), and clinical experience suggests that glucocorticoids continue to be effective for periods up to 24 months. (See 'Efficacy of short-term use' above.)

●Long-term glucocorticoids – Evidence is conflicting regarding the risks and benefits of chronic glucocorticoid therapy for patients with RA. Specific management strategies for use of chronic glucocorticoid therapy have been poorly studied. In trials in which patients received 7.5 to 10 mg/day of prednisone or equivalent, there was initial symptomatic benefit that was not sustained at the initial dose, but, with these doses, radiologic progression may be slowed. It is less clear whether similar efficacy can be achieved with doses of 5 to 7 mg/day, but even lower doses, such as 1 to 4 mg/day continued indefinitely, may be effective in some patients. (See 'Efficacy of chronic use' above.)

●Adverse events – The chronic use of low-dose glucocorticoids in RA can cause multiple adverse events, including an increased risk for infections, osteoporosis, skeletal fractures, gastrointestinal bleeding, peptic ulcer disease, diabetes mellitus, cataracts, cardiovascular events, weight gain, skin changes, and impaired hypothalamic-pituitary-adrenal axis response. A major goal for patients with RA treated chronically with glucocorticoids is to minimize adverse events. We try to limit the dose to a maximum of 10 mg/day and preferably to less than 5 mg/day, and we use other measures to minimize bone loss. (See 'Risks of chronic use' above and "Major adverse effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

●Pulse glucocorticoids – Pulse therapy consists of the administration of high doses of glucocorticoids over a short period of time; pulse glucocorticoids remain a modality of last resort for the treatment of RA. The available studies examining pulse glucocorticoids are very limited, and serious cardiovascular adverse events and infections may occur. The utility of pulse glucocorticoid therapy among patients with RA has been limited to the treatment of acute flares and to the use as a therapeutic bridge between the initiation of and response to DMARDs. The average duration of response to pulse therapy alone is six to eight weeks. The authors do not use "pulse" glucocorticoid therapy for management of active articular disease in patients with RA. (See 'Pulse glucocorticoids' above.)

●Intraarticular glucocorticoids – Intraarticular glucocorticoids are frequently helpful for the treatment of symptomatic synovitis in patients with RA; such therapy is palliative rather than disease-modifying. Intraarticular injections of multiple joints may have advantages over intramuscular injections for patients experiencing a disease flare. Although rare, risks associated with intraarticular injection include tendon rupture, osteonecrosis, acute synovitis (transient postinjection flare which usually resolves within 48 hours), septic arthritis, and systemic effects. In general, the frequency of intraarticular injections should be limited to four per year or fewer. (See 'Intraarticular therapy' above and 'Adverse events' above and "Intraarticular and soft tissue injections: What agent(s) to inject and how frequently?" and "Joint aspiration or injection in adults: Complications".)

●Glucocorticoid management – The dose of glucocorticoids should be tapered as quickly as possible to the lowest effective dose when chronic use is anticipated. Glucocorticoids are best administered in the morning to minimize interference with the normal diurnal hormonal pattern. Patients who have been on glucocorticoids long-term should taper glucocorticoids slowly over a period of months, as tolerated, once they have improved or after other effective agents have been added. (See 'Chronic therapy' above.)

●Monitoring – We obtain baseline studies to monitor toxicity, including serum glucose, a lipid profile, and appropriate studies for the prevention and treatment of glucocorticoid-induced osteoporosis. We monitor patients for the presence of polydipsia, edema, shortness of breath, visual changes, weight gain, and changes in blood pressure at each visit following the initiation of glucocorticoids. (See 'Monitoring parameters' above and "Prevention and treatment of glucocorticoid-induced osteoporosis".)

ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Eric Matteson, MD, MPH, who contributed to earlier versions of this topic review.