Corticosteroid Therapy

Introduction

The discovery and introduction of corticosteroid therapy by Philip Hench in the late 1940s and early 1950s was a seminal advance in the treatment of inflammatory diseases, including rheumatoid arthritis (RA). Prior to the introduction of steroids, RA therapy was dominated by poorly effective and toxic therapies (aspirin and gold salts). The glucocorticoid compounds became well known for their impressive and rapid clinical efficacy in a variety of inflammatory clinical disorders.

The mechanisms underlying the efficacy of the corticosteroids are multiple and may include alterations in capillary permeability (possibly from decreased expression of adhesion molecules), inhibition of prostaglandins and leukotrienes, reduction in lysosomal proteolytic enzyme release, decreased circulating lymphocytes, monocytes, basophils and eosinophils and modulation of cytokine secretion (e.g., decreased IL-1, IL-6, IL-8; increased IL-10) production.

Although a variety of glucocorticoid preparations are available for clinical use, prednisone and prednisolone are most popular in the treatment of RA, primarily because of their short duration of action and their relatively low mineralocorticoid effects. Low doses of prednisone (i.e., 5-10 mg/day) are commonly used acutely to manage new-onset joint swelling and stiffness while the patient’s evaluation continues and also for acute flares of disease activity. Chronic low-dose prednisone therapy is commonly used (in 44% to 75% of cases) in RA patients with established disease.

Low-dose oral corticosteroids are commonly used in patients with new-onset RA or for flares of disease as “bridge therapy,” in which they are used to provide immediate relief and restoration of function while awaiting the onset of disease-modifying antirheumatic drug (DMARD) effects, which may take weeks to months. Hence, after 3 to 6 months of bridge therapy, prednisone therapy may be slowly withdrawn. Some patients, especially those who have used higher doses of steroids for longer periods of time may experience steroid withdrawal, that may manifest as increased arthralgias, myalgias, aching, stiffness, fatigue and mood changes.

There is some evidence to suggest that tapering may not always be necessary in the short term. The SEMIRA trial compared the strategies of tapering oral glucocorticoids or continuing low dose glucocorticoid therapy. The trial recruited a total of 259 patients with low RA disease activity (DAS28-ESR ≤3.2) 4-6 weeks before randomization who were on tocilizumab and 5-15 mg daily of glucocorticoids for ≥24 weeks (with daily prednisone 5 mg for ≥4 weeks). Patients continued taking tocilizumab but were randomized (1:1) to taper prednisone to reach 0 mg on week 16 or to continue prednisone 5 mg for 24 weeks. At week 24, changes in DAS28-ESR were greater in the tapered prednisone group (0.54; 95% CI 0.35 to 0.73) than in the continued prednisone group (-0.08; 95% CI, -0.27 to 0.12) (P <0.0001). These results suggest that continuing low-dose glucocorticoid therapy may provide better disease control than tapering, although the safety and efficacy of this strategy beyond 6 months of treatment is not known.

Although corticosteroids are most often used in early RA (see Steroids in Early RA below), evidence of efficacy in established RA is emerging. The GLORIA trial assessed the safety and efficacy of low-dose add-on prednisolone in elderly (≥65 years of age; mean age at baseline 72 years) patients with long established disease (mean disease duration at baseline ≥10 years). A total of 451 patients were randomized (1:1) to receive prednisolone 5 mg/day or placebo for 2 years, in addition to continuing their current antirheumatic therapy. Patients in the prednisolone group showed significant improvements in the benefit endpoints of DAS28 score (0.37 points lower than with placebo; 95% confidence limit [CI], 0.23) (P <0.0001) and Sharp/van der Heijde score (1.7 points lower than with placebo; 95% CL, 0.7) (P = 0.003). However, patients who received prednisolone also had a significantly increased relative risk of experiencing ≥1 adverse event of special interest, including serious events, glucocorticoid-specific events and discontinuation-causing events, with 60% experiencing such events compared to 49% of patients who received the placebo (adjusted relative risk 1.24; 95% CL, 1.04). Thus, the long-term use of low-dose prednisolone in elderly patients with established RA shows definite efficacy benefits with a moderate safety tradeoff.

Corticosteroids are dramatically effective when used acutely but may be hazardous when used chronically. For these reasons, steroids should be avoided, weaned, or used at the lowest possible dose (e.g., as in the SEMIRA trial above) after their introduction. Adverse events ascribed to corticosteroids are numerous and need to be reviewed in every patient receiving them (Table 10-1). The long-term use of these drugs, even at low doses, may be associated with significant reversible and irreversible toxicities. The frequency of steroid toxicity is proportional to the dose and duration of therapy. Therefore, patients should be counseled about potential toxicities, especially if chronic use is intended.

Corticosteroid use may be associated with an increased appetite, weight gain, central obesity, glucose intolerance or hyperglycemia, hypercholesterolemia, osteopenia, osteoporosis, avascular necrosis of bone, capillary fragility and ecchymoses, striae, hyperhidrosis, hirsutism, blurred vision, cataracts, glaucoma, sleep disturbance, emotional lability, depression, edema, hypertension, peptic ulcer disease, growth retardation (in children), menstrual irregularities, muscle weakness, suppression of the hypothalamic-pituitary axis, poor wound healing, cutaneous anergy to recall antigens and an increased risk of infection. Because of the risk of steroid-induced osteoporosis, patients started on chronic low-dose (or higher-dose) corticosteroids should be started on supplemental calcium (1,200-1,500 mg/day) and vitamin D (400 U qd). Sustained use of these agents merits baseline and intermittent bone density assessments and consideration of anti-osteoporosis therapy.

While uncontrolled inflammation is an independent risk factor for infection, the additional use of steroids may further increase the number of serious infectious events (e.g., pneumonia, sepsis, septic arthritis, tuberculosis). Even low-dose prednisone (5-10 mg/day) has been associated with increased rates of serious infectious events in RA patients.

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Steroids in Early RA

Corticosteroids are an attractive option for many patients with new-onset inflammatory arthritis since they are rapid acting and may be used intraarticularly or systemically, and since the dose may be titrated to achieve meaningful control while evaluation continues. For those patients with early inflammatory oligoarthritis (not yet diagnosed as RA), there are limited data to suggest that a brief course of high-dose oral or intraarticular steroids may be beneficial. In one study, early-onset (<12 weeks’ disease duration) inflammatory oligoarthritis patients were given a single high dose of intraarticular or intramuscular corticosteroid, resulting in 50% of the patients achieving sustained remission after a single dose. Predictors of persistent disease included symptom duration >12 weeks, rheumatoid factor (RF) and the presence of the shared epitope genotype.

Historically, low-dose prednisone (≤10 mg/day) has been viewed to be rapidly anti-inflammatory and palliative but unable to yield any long-term structural benefits. For those diagnosed with early RA, several studies have tested the utility or disease-modifying effects of corticosteroids. The results of these trials strongly argue against palliative-only effects of steroids by consistently showing that the use of corticosteroids in early RA may be associated with less radiographic progression and articular erosions over time.

In the COBRA trial, early RA (<2 years) patients receiving a combination regimen of methotrexate (MTX), sulfasalazine (SSZ) and high-dose prednisolone (initially 60 mg/day, slowly lowered over 6 weeks to 7.5 mg/day) did significantly better than those on monotherapy with SSZ alone. Although the clinical benefits were lost after MTX and prednisolone were withdrawn, a long-term radiographic benefit was seen between groups even 5 years later.

In 1995, Kirwan reported radiographic and clinical benefits in 128 early RA patients (<2 years) taking prednisolone (7.5 mg daily) or placebo for 2 years. Data from 106 patients showed that the prednisolone group had less radiographic progression (0.72 vs 5.37 Larsen Units) and fewer new erosions (22.1% vs 45.6%) compared with those on placebo. Van Everdingen and associates have also shown a radiographic benefit for steroid therapy in early RA. In this 2-year study, 81 DMARD-naïve, early RA patients (<1 year) received either placebo or prednisone (10 mg/day). The prednisone group improved in only a few variables (tender joint count and grip strength) at 12 and 24 months. However, there was less radiographic progression in the prednisone (16 van der Heidje-Sharp units) vs placebo (29 Units) groups (Figure 10-1). It should be noted that although there was significantly less radiographic deterioration in those on prednisone, both groups showed significant radiographic deterioration during this 2-year study. The magnitude of steroid benefit was disappointing if one considers recent results with more potent therapies wherein radiographic change over time averages <2 Sharp units per year. Furthermore, there have been trials that show no benefit from early steroid therapy in early RA patients.

These data suggest that corticosteroid therapy is most effective and appropriate in three scenarios of early inflammatory arthritis:

• New-onset early (<12 weeks) undifferentiated inflammatory arthritis in which high-dose (oral or intraarticular) corticosteroids (up to 140 mg methylprednisolone) can be given in very early arthritis patients with the hope of inducing remission
• New-onset RA for which prednisone can be used as symptomatic therapy (usually in doses of 5-10 mg/day) in the first few weeks while the workup and symptoms evolve
• Early-aggressive RA for which prednisone can be used as adjuvant therapy (usually part of a DMARD combination regimen) for those deemed to have aggressive disease or with flares of disease; as disease activity abates, steroids can be tapered.

Intraarticular corticosteroids are occasionally used when one or a few joints are inflamed and symptomatic. As stated earlier, a single large dose of intraarticular steroid may yield long-term remission in a patient with new-onset inflammatory monoarthritis or oligoarthritis. Intraarticular corticosteroid injections are indicated in those with initial monoarthritis or acute focal flares of one or few joints, or those who are disabled by synovitis in one joint despite effective systemic therapy. Steroid joint injections should be avoided in those with neuropathic joints or neuropathic/referred pain when the inflamed joint is infected or with an overlying cellulitis. The use of short-term rest, immobilization and topical ice may improve the success of injection. The benefits of intraarticular corticosteroids have never been adequately studied in early RA patients. The outcome of such injections is highly variable but appears to be most effective initially and less effective with subsequent or repeated injections.

Pulse corticosteroid therapy is rarely, if ever, indicated in the management of RA. Pulse therapy is administered as three daily IV infusions of methylprednisolone 1000 mg. Pulse therapy is usually reserved for those with life-threatening complications, such as vasculitis, severe cytopenia, or pericardial tamponade. Some investigators have studied the clinical benefits of pulse steroid regimens when initiating gold or MTX therapy and demonstrated rapid-onset, short-term, clinical improvement. However, long-term results show no advantage for those given pulse steroids and thus their use is not recommended.

In summary, the clinician must weigh the potential clinical and radiographic benefits of corticosteroids against their well-known and predictable toxicities. The choice of dose, duration and route of administration needs to be tailored to the patient’s needs. Moreover, preventive strategies to limit the risk of infection, diabetes, hypertension and steroid-induced osteoporosis must be considered. Although corticosteroids may be dramatically effective acutely, they may be hazardous when used chronically, especially in high doses.

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