INTRODUCTION — In 1950, 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). Since that time, the exact role of glucocorticoids in the treatment of RA has generated considerable debate.
Glucocorticoids exert both antiinflammatory and immunosuppressive effects via several mechanisms [1] (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 interact with transcription factors and thus affect gene transcription. Glucocorticoids 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, chronic, and pulse), intramuscular, intravenous, 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 by the intraarticular route in the treatment of RA [2]. 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 sicker patients with active rheumatoid arthritis (RA), prednisone is frequently added for a short period to the treatment regimen to rapidly minimize disease activity while awaiting a clinical response to a slower-acting disease-modifying antirheumatic drug (DMARD) [3-6]. 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 [7]. 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
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. However, mood disorders and hyperglycemia may be seen with daily treatment at these relatively low doses, although short-term treatment of early RA with even high-dose prednisone has not been associated with long-term worsening of glucose tolerance [8]. (See "Major side 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 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 substantially inhibits the progression of radiographic joint damage, and this effect is sustained over many years [9,10]. One open-label trial has suggested that lower initial doses of glucocorticoids (prednisone 30 mg daily) may have comparable efficacy to the higher dose used in the classic COBRA regimen [11].
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 [12]. (See 'Efficacy of chronic use' below.)
Short-term use of glucocorticoids has not been directly compared with biologic DMARDs.
Many clinicians employ NSAIDs, glucocorticoids, a traditional DMARD such as methotrexate, and, if needed, a biologic agent for patients with moderate to severe RA.
EFFICACY OF CHRONIC USE — Evidence is conflicting regarding the benefits of chronic glucocorticoid therapy for patients with rheumatoid arthritis (RA). We generally do not use glucocorticoids on a chronic basis without concurrent therapy with a disease-modifying antirheumatic drug (DMARD) or with DMARD combinations (eg, a nonbiologic traditional DMARD and a biologic agent). The main conclusions from randomized trials in which patients received 7.5 to 10 mg/day of prednisone or equivalent were that initial symptomatic benefit may be achieved and sustained for up to two years at the initial dose, and that radiologic progression is reduced with such doses [13-21]. 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 [14]. 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 [15].
●In a randomized trial involving 81 DMARD-naïve patients with RA for less than one year who were assigned to receive either prednisone (10 mg/day) or placebo, greater clinical improvement in multiple measures was seen at six months in the patients treated with prednisone; however, the benefit was sustained only for joint tenderness at 24 months [16]. Radiographic progression was less in the prednisone-treated group, and this advantage persisted for at least three years following the completion of two years of prednisone treatment [22]. Vertebral compression fractures occurred in five and two of the prednisone-treated and placebo-treated patients, respectively.
●Another trial documented radiographic benefit of prednisone in patients treated with a tight-control strategy. 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 (MTX) or placebo plus MTX beginning within one year of disease onset and continuing for two years [20]. Disease activity was assessed monthly to determine whether the dose of MTX should be increased. A second DMARD was added if control was inadequate at a maximum MTX 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 MTX, 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 MTX 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 [23-25]:
●A randomized trial of low-dose glucocorticoid therapy (prednisone 5 mg/day) compared with placebo found that the benefits of chronic glucocorticoid therapy were temporary; improvement in the number of painful joints with prednisone was observed at 12 weeks but not at 24 weeks [26]. Abrupt discontinuation of glucocorticoids resulted in a significant exacerbation of the disease for a period of eight weeks.
●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 [19]. 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 joint damage progression (1.7 points lower) when compared with the group taking placebo after two years of follow-up [27]. Even in this short, two-year trial, 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 [23].
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.
The effects of chronic glucocorticoid use in combination with effective therapy for RA with a nonbiologic or biologic DMARD remain to be determined. An effective DMARD or DMARD combinations (including conventional and biological DMARDs) may provide sufficient improvement so that the maintenance dose of the glucocorticoid may be decreased or discontinued to minimize the potential for adverse effects related to the glucocorticoid [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, while having similar effects on other measures of disease activity [30-33]. 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 [34]. 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 [31].
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) [31]; 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 [35,36]. 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 osteoporosis, skeletal fractures, gastrointestinal bleeding, peptic ulcer disease, diabetes mellitus, infections, cataracts, and impaired hypothalamic-pituitary-adrenal axis response. (See "Major side effects of systemic glucocorticoids".)
In an analysis of serious adverse events following prednisone therapy in RA, the complications were dose-dependent, primarily occurring at doses greater than or equal to 5 mg/day [37]. By comparison, there was no difference in the occurrence of such events between patients taking less than 5 mg/day and the control group. An average prednisone dose between 10 and 15 mg/day correlated most strongly with the development of an adverse event. The relationship between adverse events and cumulative dose (rather than the daily dose) was much weaker. This study was flawed because it used historic matched controls who were never treated with glucocorticoids. However, multiple other studies also found evidence consistent with a dose-response relationship between glucocorticoid use and adverse effects, particularly with respect to bone loss.
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 [38]. In another study of 65 patients treated with an average of 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 [39]. Doses above 5 mg/day also may be associated with an increased long-term risk of fractures [40]. Doses of less than 2.5 mg/day may still confer some increased risk [41]. Significant loss of BMD can occur in as little as three months of glucocorticoid use [42]. (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"):
●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 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 [43]. 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 [44].
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 [45]. 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 [46].
Although intravenous administration is the most popular route for pulse therapy, pulse glucocorticoid therapy can also be given orally or by intramuscular (IM) injection [47-49]. 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 disease remission from weeks 2 to 12, but no significant difference was seen at week 16 [48]. 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 [49]. 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 [44,50]. 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) [51]; 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 [52]. (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 [53].
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 [54]; 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 [52,53,55]. 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 [55]. 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 [51]. 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 [56]. (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 [57]. Studies suggest that glucocorticoids should be used as a bridge between the initiation of traditional (nonbiologic) and biologic disease-modifying antirheumatic drugs (DMARDs) and the therapeutic effect of these slower acting agents and/or for the treatment of acute synovitis [58]. Glucocorticoids may also be used at lower doses in combination with traditional (nonbiologic) and biologic DMARDs to maintain function and to prevent degradation of joints in patients with rheumatoid arthritis. (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 [59]:
●Established hypertension or diabetes mellitus
●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.
Chronic therapy — As noted above, most adverse effects of chronic glucocorticoid therapy are typically seen 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 more than 5 mg/day prednisone equivalent [60], with 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 [51,61,62]. Patients with RA, particularly those on DMARDs, usually do not require higher daily doses for synovitis control. Even lower doses, such as less than 5 mg/day, may be adequate in some patients [28]. In one randomized trial of glucocorticoid tapering in patients with RA and low disease activity or remission, tapering off prednisone 5 mg daily over 16 weeks, compared with continued therapy, was associated with an increase in mean disease activity (0.6 disease activity score in 28 joints-erythrocyte sedimentation rate [DAS28-ESR] difference at 24 weeks), but no tapered patients discontinued the trial due to lack of flare control [63]. However, treatment was considered successful (no more than low disease activity, no RA flare, and no adrenal insufficiency) less often in patients who discontinued glucocorticoid therapy (65 versus 77 percent). Adverse effects occurred in relatively few patients (5 percent of patients discontinuing prednisone and 3 percent of those who continued the medication).
To minimize interference with the normal diurnal hormonal pattern, glucocorticoids are best administered in the morning.
Concurrent initiation of a nonbiologic or biologic DMARD may permit tapering of the glucocorticoid once the patient begins to respond to the DMARD [51]. Once the patient has improved further or after other effective agents have been added, glucocorticoid therapy should be slowly tapered over a period of months as tolerated. If symptoms return upon tapering, it can be assumed that the particular DMARD or combination is inadequate, and a higher dose or alternative therapies should be utilized. (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 the DMARD. Alternatively, pulse intravenous methylprednisolone therapy, usually consisting of three separate infusions of up to 1000 mg of methylprednisolone given at weekly intervals, may rarely be used and may lead to marked but temporary disease suppression. 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 [59,65]:
●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 [59]:
●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 repeated yearly 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 [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 5th to 6th 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 10th to 12th 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
●We primarily use glucocorticoids as a bridge between the initiation and realization of therapeutic effects of disease-modifying antirheumatic drugs (DMARDs) 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 traditional and biologic DMARDs when needed to maintain function and to prevent degradation of joints. We generally 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.)
●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.)
●Evidence is conflicting regarding the 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.)
●The chronic use of low-dose glucocorticoids in RA can cause multiple adverse events, including an increased risk for osteoporosis, skeletal fractures, gastrointestinal bleeding, peptic ulcer disease, diabetes mellitus, infections, cataracts, 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 side effects of systemic glucocorticoids" and "Prevention and treatment of glucocorticoid-induced osteoporosis".)
●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 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".)
●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. Glucocorticoid therapy should be slowly tapered over a period of months, as tolerated, once the patient has improved further or after other effective agents have been added. (See 'Chronic therapy' above.)
●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".)
