Page 1207 - Clinical Immunology_ Principles and Practice ( PDFDrive )

CHaPTEr 86 Glucocorticoids 1171

saturation of cytosolic receptors, so any further increase in dose than 14 days in duration. With longer periods of treatment, the
may affect the pharmacodynamics (e.g., receptor off-loading and dose should be reduced gradually to allow the HPA axis to recover,
reoccupancy), receptor synthesis and expression. At these doses, but the rate of reduction is usually faster than for rheumatological
nongenomic effects may deliver additional therapeutic benefit, conditions.
although it remains unclear whether these effects have any direct
therapeutic relevance. Experimental data suggest that these Glucocorticoids in Rheumatoid Arthritis: an Example
differential effects come increasingly into play above ≈100 mg/ GCs are crucially important in the management of RA and are
day (see Table 86.1). Doses of >100 mg of prednisone equivalent used in various dosages at different disease stages. RA is, therefore,
per day are frequently (and successfully) given as initial treatment a useful example to discuss GC therapy in more detail.
for acute or life-threatening exacerbations of connective tissue
diseases, vasculitis, and RA. These doses cannot be administered Low-Dose Maintenance Therapy
over the long term because of their severe adverse effects. In early RA, GC in doses <10 mg are highly effective for relieving
symptoms in patients with active arthritis. Many patients are
Pulse Therapy functionally dependent on this low-dose therapy and continue
22
Pulse therapy involves administration of ≥250 mg prednisone it over the long term. Improvement has been documented not
equivalent per day (usually intravenously) for a short period only in all clinical parameters, including pain scales, joint scores,
(typically 1–5 days, rarely longer). At such high doses, the morning stiffness, and fatigue, but also in acute inflammatory
nongenomic potencies of GCs come into play. It is likely that markers, such as erythrocyte sedimentation rate (ESR) and
these explain the success of very high doses and pulse therapy C-reactive protein (CRP). After 6 months of therapy, the beneficial
in acute exacerbations of immunologically mediated diseases. effects of GCs seem to diminish, but if therapy is then tapered
The immediate effects of very high doses may be additive to the and stopped, patients often experience an exacerbation of
genomic effects mediated by cGCRs. These additional effects symptoms within a few months.
may make a crucial contribution to the therapeutic effect by The disease-modifying properties of GCs were first described
terminating acute exacerbations. Circumstances where very high in 1995, in a 2-year trial of 7.5 mg prednisolone in patients
doses or pulse therapy can be successful include acute episodes who had RA of short or intermediate disease duration and
or particularly severe forms of rheumatic diseases, such as SLE, were treated with NSAIDs (95%) and disease-modifying
23
vasculitis, polymyositis, and RA (see below). antirheumatic drugs (DMARDs) (71%). Nowadays, GCs are
considered to have disease-modifying properties in early RA,
Alternate-Day Regimens but it is less clear whether they inhibit the progression of erosions
Alternate-day regimens were introduced for long-term oral GC in RA of longer duration. A meta-analysis of 15 studies that
therapy with the aim of minimizing undesirable adverse effects, included 1414 patients concluded that GCs given in addition
such as suppression of the hypothalamo–pituitary–adrenal (HPA) to standard therapy can substantially reduce the rate of erosion
24
axis. Instead of daily dosing, a single dose is administered every progression in RA. Another meta-analysis of 70 randomized
other morning, usually in a dose equivalent to or somewhat placebo- or drug-controlled studies found similar effects of
higher than twice the usual daily dose. The idea behind this DMARDs, GCs, and biologicals on radiographic progression
regimen is to allow the HPA axis to remain active by exposing in RA. 25
the body to exogenous GC on alternate days instead of suppressing
it every day. This strategy only works if the HPA axis is still Glucocorticoid Pulse Therapy
active, and, unfortunately, patients often experience breakthrough GC pulse therapy is used to treat some serious complications
symptoms on the second day of treatment. Alternate-day regimens of RA and to induce remission in active disease, for example,
are used rarely these days except in patients with juvenile idio- when initiating second-line antirheumatic treatment. Pulse
pathic arthritis, in whom alternate-day GC regimens cause less therapy with methylprednisolone 1 g/day, dexamethasone 200 mg/
inhibition of body growth. day, or equivalent, given intravenously for 1–3 days, was shown
to be effective in most studies, demonstrating a beneficial effect
Glucocorticoid Withdrawal Regimens that generally lasted for about 6 weeks, albeit with large variations.
Because of their significant adverse effects, GCs are usually reduced This means that it is not wise to apply pulse therapy in active
or stopped as soon as the disease is under control. This needs RA, unless the therapeutic strategy is changed (e.g., DMARD
to be done carefully to avoid a relapse in disease activity and to treatment introduced to maintain the remission induced by pulse
permit recovery of adrenal function. There are no controlled therapy).
comparative studies to support a specific regimen for weaning
patients off GCs, as this process needs to be adjusted according Intraarticular Glucocorticoid Injections
to disease activity, dose/duration of therapy, and clinical response. Intraarticular injections with GCs are often used in RA. The
When patients with RA are treated with up to 10 mg/day of benefit achieved varies, depending on several factors, such as
prednisone, the daily dose can be reduced by 2.5 mg every month the joint treated (size, weight-bearing or non–weight-bearing),
until 5 mg/day is reached. Thereafter, doses can often be reduced inflammatory activity, the volume of synovial fluid in the joint,
by 1 mg per month. When higher doses have been used, a reduc- whether or not synovial fluid was aspirated before the injection,
tion by 5 mg every 1–2 weeks down to 20 mg/day is often well the choice and dose of GC preparation, injection technique,
26
tolerated, followed by further reductions of 1–2.5 mg/day every and whether the joint is rested after the injection. To prevent
2–3 weeks. Addition of immunomodulatory drugs, such as GC-induced joint damage, it is recommended that intraarticular
methotrexate and azathioprine, may allow further dose reductions. GC injections should not be repeated more often than once every
Short courses of GCs for some conditions, such as asthma, may 3–4 weeks, and no more than 3–4 times a year in a weight-bearing
be ceased without tapering if the total treatment course is less joint.