Page 1208 - Clinical Immunology_ Principles and Practice ( PDFDrive )

1172 ParT TEN Prevention and Therapy of Immunological Diseases

KEY CONCEPTS and growth hormone production, induce muscle wasting, and
2
Glucocorticoid (GC) Therapy in Rheumatoid modulate RANKL/OPG, NF-κB, and AP-1 signaling in bone.
All of these changes lead to enhanced osteoclast function and
Arthritis (RA) lifespan and thus to increased bone resorption. Consequently,
Our view of the risk–benefit ratio of low-dose GC has shifted in recent markers of bone resorption are often increased in patients treated
2
years: with GCs. However, reduced bone formation as a result of
• GCs can now be considered as disease-modifying antirheumatic drugs, reduced osteoblast function is likely to be a more important
especially in early RA. effect of GCs on skeletal health. Oral doses of prednisone as low
• Adverse effects of low-dose GCs are less abundant and less severe as 2.5 mg/day have been shown to suppress serum osteocalcin, a
than previously suggested, and some (e.g., osteoporosis) can be well marker of bone formation. Histologically, mean wall thickness
managed.
• The goal of antirheumatic treatment in early RA is to induce remission is reduced, reflecting the reduced amount of bone replaced in
of disease by aggressive management: GCs are part of this aggressive each remodeling unit. In vitro, osteoblasts and their precursors
strategy. are highly GC responsive. Here, the predominant effect is to
promote osteoprogenitor proliferation, lineage commitment,
and osteoblast differentiation, resulting in the formation of
bone nodules of increased size and numbers. However, GCs
also inhibit type I collagen expression and reduce preosteoblastic
replication. Finally, GCs promote apoptosis of osteoblasts and
osteocytes. The inhibitory effects of GCs on bone formation
Adverse Effects may partly be a result of downregulation of insulin-like growth
Studies of GC toxicity tend to be retrospective and observational. factor 1 (IGF-1) expression by osteoblasts. Fortunately, we now
This can make it difficult to differentiate unfavorable outcomes have effective strategies for the prevention and treatment of
attributable to GCs from those occurring as a result of the GC-induced osteoporosis, using calcium, vitamin D, and specific
underlying disease or other comorbidities. Furthermore, there osteotropic agents, such as bisphosphonates or parathyroid
is a strong selection bias for GC use, as physicians are more hormone. 28
inclined to use them in patients with more severe disease. Fre-
quent, but less serious, adverse effects (e.g., skin thinning, Osteonecrosis
Cushingoid appearance) may be of great concern to patients, Osteonecrosis has long been considered an important consequence
whereas more debilitating toxicities, such as osteoporosis, cata- of high-dose GC use. In a Japanese study of femoral head
racts, and GC-induced hypertension, may initially go unrecognized osteonecrosis, 35% of cases were related to GC treatment. Higher
or be asymptomatic. Interpretation of toxicity data is further average dose may be a more important predictor of avascular
confounded by the use of GCs at variable points in the disease necrosis of bone compared with cumulative dose. Osteonecrosis
course, limited data defining “threshold” doses for particular is particularly noted in SLE but rarely occurs in patients with
adverse events, and the fact that toxicity reports cover a hetero- RA receiving low-dose therapy, affecting <3% of patients.
geneous group of GC-treated diseases. Osteonecrosis rarely occurs in patients with SLE on prednisone
Compared with other antirheumatic agents, GCs have a low doses <20 mg/day.
incidence of short-term symptomatic toxicity, and patients rarely
discontinue therapy for this reason. Despite >60 years of use, Myopathy
we still lack robust data on the longer-term toxicities of GCs As with osteonecrosis, GC-induced myopathy is rare in
from large randomized controlled trials with long-term follow-up. patients receiving low-dose GCs. In small studies, myopathy
The most common GC toxicities are summarized below. appears more closely associated with fluorinated GC prepara-
Some progress has been made by formulating recommenda- tions, such as triamcinolone, than with prednisone. Notably,
tions on which adverse effects of GC treatment should be myopathy has been reported after only 3 months’ treatment with
monitored in RA, how to monitor them, and how often. Two triamcinolone 8 mg/day. In general, myopathy attributable to
levels of monitoring GC adverse events have been proposed: (i) prednisone only occurs after higher doses and longer durations of
for routine clinical practice, details are given on how to identify treatment.
adverse events in a systematic and practical way, and this should
result in preventive and therapeutic measures to minimize the Cardiovascular Adverse Effects
risks of GC therapy; and (ii) for clinical trials, recommendations GC-induced hypertension seems to be, at least in part, mediated
have been made on how to accurately assess the frequency and via fluid retention (as a result of mineralocorticoid effects); it
severity of a wider range of adverse events. 27 is dose related and less likely with medium-dose or low-dose
therapy. Individual variation in susceptibility and other factors,
Osteoporosis such as the starting level of blood pressure, dietary salt intake,
Glucocorticoid-induced osteoporosis (GIOP) is the most impor- functional renal mass, associated diseases, and drug therapy, may
tant potential complication of prolonged GC therapy. Chronic also play a role.
GC treatment results in rapid and profound reductions in bone Another troublesome potential toxicity of low-dose GC is
mineral density, with most bone loss occurring during the first the development of premature atherosclerotic vascular disease.
6–12 months of treatment. 2,28 This has proven difficult to investigate: studies evaluating the
GIOP initially affects trabecular bone, but cortical bone is also effects of GCs on lipids and atherosclerosis in patients with RA
affected with more chronic use, at such sites as the femoral neck. have yielded mixed results, with some studies suggesting that
Precisely how GCs affect bone remains obscure. GCs decrease GCs may, in fact, reverse unfavorable lipid changes. At present,
calcium absorption, increase renal calcium loss, diminish sex there is no evidence of a strong association between low-dose