Sumber Penggunaan Steroid Jangka Panjang pada Kasus Reumatologi Anak

Steroid

Rheumatologic disorders.13.
Juvenile idiopathic arthritis
Pediatric Vasculitis
Dermatomyositis Scleroderma
Systemic lupus erythematosus
Rheumatic fever
Corticosteroids are one of the most important classes of anti-inflammatory
and immune modulators in a physician’s arsenal to help treat a variety of conditions.
They also have significant adverse effects with short- and long-term use and,
therefore, need to be prescribed judiciously. This article briefly reviews the uses and
adverse effects of corticosteroids.1
Corticosteroids are used widely for their immunosuppressant and anti-
inflammatory properties. They may be used individually or in combination with other
drugs and are prescribed in both short and long courses depending on the condition
being treated and the response of the patient. The adverse effects from short-course
use have been described recently and include changes in mood and behaviour,
vomiting and sleep disturbance. Long-course use of corti- costeroids may lead to
additional side effects. Many of the side effects are reversible if the medication is
stopped, while others may be permanent.2
Although endogenous corticosteroids have both miner- alocorticoid and
glucocorticoid effects, common synthesized steroids are used primarily for their
glucocorticoid ef- fects. Glucocorticoid receptors, found in cells throughout the body,
are nonspe- cific. Therefore, corticosteroid use is associated with a broad array of
both therapeutic and adverse effects.4
 Nevertheless, the effects of corticosteroids can be classified into two general
categories: glucocorticoid (intermediary metabolism, inflammation, immunity, wound
healing, myocardial, and muscle integrity) and mineralocorticoid (salt, water, and
mineral metabolism).12
Kegunaan Steroid
Corticosteroids have been used to treat a wide range of diseases, including
allergic, dermatologic, gastrointestinal, and hematologic/oncologic disorders; some
infectious diseases; organ transplant; renal disease; and respiratory and rheumatologic
disorders. In some cases, such as acute asthma exacerbations, a short course of oral
corticosteroids is used for 3 to 5 days. In other situations, patients need to take
corticosteroids for much longer, sometimes months to years. In general, if someone
has been receiving systemic corticosteroids for less than 10 to 14 days, it is deemed
safe to vaccinate him or her, including with live viral vaccines, per the Red Book.1
Mekanisme Kortikosteroid
The anti-inflammatory effects of GCS are explained by three broad molecular
mechanisms: the decreased expression of pro-inflammatory genes (trans-repression),
the increased expression of anti-inflammatory genes (trans-activation), and non-
genomic mechanisms. Trans- repression is thought to be mainly due to direct interac-
tions between GRα and pro-inflammatory transcription factors such as the activator
protein-1 (AP-1) and NF-κB [24]. Trans-activation is explained by the interaction of
GRα to specific target DNA sequences, named gluco- corticoid-responsive elements
(GRE). Among the genes activated by GRα through GRE with anti-inflammatory
functions, there are the mitogen activated protein kinase phosphatase-1, the
glucocorticoid inducible leucine zip- per and tristetraprolin. In addition, the activated
GRα can also reduce inflammation at the post-transcriptional (altering mRNA
stability), translational (affecting protein synthesis) and post-translational levels
(altering protein processing, modification or degradation).5
Efek samping Kortikosteroid
ADVERSE EFFECTS WITH SHORT-TERM USE = adverse effects of short courses
of corticosteroids (<14 days). The most serious adverse effect was infection due to
immunosuppression, which occurred less than 1% of the time. The most common
infection was again due to varicella. The more common adverse effects of short
courses of corticosteroids included vomiting, behavior changes, and sleep
disturbances, in order of decreasing frequency. Vomiting was associated with larger
doses of corticosteroids and was noted, in particular, with use of oral prednisolone.
The higher the dose, the more likely the patient would experience vomiting. This was
the leading cause of patient nonadherence to corticosteroid treatment. A similar dose
effect was seen with behavioral changes (anxiety, hyperactivity, and ag- gressive
behavior), with these changes seen more frequently with higher doses of
corticosteroids. almost one-third of children experienced blood pressure elevation and
weight gain.1
ADVERSE EFFECTS WITH LONG-TERM USE
There are many adverse effects due to long-term use of corticosteroids, defined as
continued use of oral or intravenous corticosteroids for more than 14 days. With
several important exceptions, most of these effects are reversed or partly reversed
with discontinuation of the corticosteroid medication. However, cataract forma- tion,
earlier development of atherosclerotic disease, and bone abnormalities (osteoporosis
and osteonecrosis) are, in general, unchanged by stopping med- ication. The adverse
effects of long-term corticosteroid use are many and include the aforementioned
osteoporosis and cataract formation, in addition to hypothalamic-pituitary-adrenal
(HPA) axis suppression, cushingoid appearance with weight gain, diabetes,
cardiovascular disorders, elevation of cholesterol level, immunosuppression,
behavioral changes (such as aggressive behavior, inattentiveness, mood swings, and
sleep disturbances), gastrointestinal prob- lems (gastritis and gastrointestinal
bleeding), and skin manifestations (skin thinning, ecchymoses, acne, and striae).
Finally, growth suppression is a problem that is unique to the pediatric population.1
 The main side effects of CS in the pediatric population in- clude growth
impairment, pubertal disorders, and hirsutism. In adults, the main side effects include
acne, delayed cicatrization, the possible appearance of glaucoma, and posterior
cataract, and increase the risk of bone fracture. At any age, the use of CS is associated
with an increased risk of diabetes, hypertension, and virus reactivation.
The three most commonly observed ADRs associated with long-course oral
corticosteroids were weight gain, growth retardation and cushingoid features.2
Terapi Streoid pada SLE
Glucocorticoids (GCs) are the mainstay of treatment of SLE as induction therapy and
to manage acute flares and have dramatically improved the prognosis of severe SLE.
Thus, survival rates have increased from 50% at 3 years in the 1950s (Jessar, 1953) to
92% at 10 years in recent series (Cervera, 2003). GC regimens vary from low dose
(0.1-0.2 mg prednisone/kg/day or equivalent) to moderate (0.2-0.5 mg/kg/day) or
high (0.5-1 mg/kg/day) dose, according to the type of organ involvement, as
discussed below. Of note, these dosages of GCs based on body weight and especially
the high dose of 1mg/kg/day are not evidence-based.6
Indikasi dosis denyut MP pada SLE
It is well assumed that MP pulses, due to their higher potency and faster
mechanism of action compared to oral prednisone, are indicated in those patients with
severe manifestations of SLE in whom a rapid effect is necessary. However, they
might not be limited to this clinical scenario. The rapidity and potency of action make
MP pulses at doses 125–250 mg/day for three days is ideal to deal with many
moderate lupus flares, like arthritis, skin rashes, and pericarditis, and also for
recurrent or non-responding mild flares. Thus, MP pulses may contribute to avoid
high-dose prednisone and to promote a faster tapering, reducing the cumulative GC
dose and thus the short and long-term side effects of oral prednisone.7
Rekomendasi EULAR
Table 3 shows how starting doses of GCs vary among the different guidelines, from
0.3 to 2 mg/kg/day for patients with severe, renal or extra-renal involvement
[51,52,54–56], or whenever the administration of MP pulses during induction therapy
is not possible [54]. Even though the recent 2019 EULAR recommendations do not
provide a specific tapering scheme, they recommend avoiding an initial dose of 1
mg/kg/day of prednisone and highlight the importance of using early MP pulses and
immunosuppressants in order to spare oral GCs [4], with some significant
recommendations: in cases of mild to moderate disease, start with prednisone doses
≤0.5 mg/kg/day, with “gradual tapering”; in cases of severe or organ-threatening
disease, MP pulses (250–1000 mg/day) for 1–3 days are suggested, followed by
prednisone 0.5–0.7 mg/kg/day “with tapering” [4]. Recommended MP doses vary
from 250 mg/day to 1000 mg/day for 3 days when a flare is diagnosed [54]. Again,
there is no agreement on its use during induction, often being reserved for severely
active patients who do not achieve a sufficient response after initial high doses of
prednisone.7
Terapi Kortikosteroid pada JIA
Corticosteroid therapy is traditional treatment for patients with SJIA who have
systemic manifestations [1]. It is usually initiated soon after diagnosis because rapid
onset is often necessary for stabilization of severe disease.9
Systemic corticosteroids (often given as a high-dose ‘pulse‘ of 30mg/kg daily
intravenous methylprednisolone for three days followed by a weaning course of oral
prednisolone starting between 1–2mg/kg daily) are pri- marily used in the treatment
of children with polyarticular or sys- temic disease; oligoarticular disease can usually
be managed with targeted joint injections.10
Terapi Steroid pada Henoch-Schönlein purpura
Henoch-Schönlein purpura is a self-limiting condi- tion, usually resolving within 6 to
8 weeks, but com- plications might arise.4 Renal involvement occurs in 37% of cases;
only 1% of cases result in end-stage renal failure.1,2 Sixty-six percent of children
experience gastrointestinal symp- toms such as abdominal pain (44%), intestinal
bleeding (22%), or intus- susception.11
Terapi Steroid pada Henoch-Schönlein purpura dengan komplikasi renal
Although little is known about disease-modifying treatment of HSP, corticosteroids
have been suggested owing to their immunosuppressive properties and their
usefulness in treating otherchildhood vasculitides. Four randomized, double-blind,
placebo-controlled trials have assessed the effectiveness of corticosteroids in
preventing HSP nephritis. Prednisone (1 mg/kg daily for 2 weeks followed by a 2-
week weaning period, or 2 mg/kg daily for 1 week plus a 1-week weaning period)
resulted in no reduction in the severity of hematuria, proteinuria, or urine protein–to–
urine creatinine ratio.6,12,14 A 2009 Cochrane meta-analysis that evaluated 3 of
these studies (N=569) determined that prednisone did not prevent the development of
kidney disease at 1 month, 3 months, 6 months, or 1 year after the onset of HSP. In a
2012 study, Jauhola and colleagues16 investigated the long-term renal outcomes of
steroids through reassessing 138 of 171patients a mean of 7.7 years after their
treatment in one of the above-mentioned randomized controlled trials (RCTs). They
reported no long-term renal protective effects of prednisone (1 mg/kg daily for 2
weeks plus a 2-week weaning period) versus placebo, determined by urinalysis and
blood pressure.
Pediatric therapies for established severe HSP nephritis include cor- ticosteroids,
immunosuppressants, angiotensin-converting enzyme inhibitors, plasma exchange,
and tonsillectomy. In a systematic review, Zaffanello and Fanos17 evaluated 34
English publications that assessed the effectiveness of these various treatment options
using end-stage renal disease, increasing proteinuria, and increasing serum creatinine
as end points. Although studies have provided evidence for the effectiveness of the
above- mentioned treatments, the lack of prospective RCTs, the small sam- ple sizes
of studies (ranging from N = 3 to N = 56), and the heterogenenity in severity of renal
disease cloud the findings. Therefore, the ideal treatment regimen, including the role
of corticosteroids for children with severe HSP nepritis, remain inconclusive.
Terapi Steroid pada Henoch-Schönlein purpura dengan purpura dan atralgia
A small body of literature speaks to the role of corticosteroid in treateing pupura and
atralghia symptoms
Monitoring penggunaan steroid jangka panjang pada penyakit reumatologi
anak
Before initiating long-term systemic corticosteroid therapy, a thorough history and
physical examination should be performed to assess for risk factors or pre-existing
condi- tions that may potentially be exacerbated by GC therapy, such as diabetes,
dyslipidemia, CVD, GI disorders, affective disorders, or osteoporosis. At a minimum,
baseline measures of body weight, height, BMD and blood pressure should be
obtained, along with laboratory assessments that include a complete blood count
(CBC), blood glucose values, and lipid profile (Table 5). In children, nutritional and
pubertal status should also be examined.14
In general, patients receiving long-term systemic cortico- steroids should be
monitored at least every 6 months, and children younger than 2 years should be
monitored every 3 months.1
BMD dan Risiko Fraktur pada Anak
In adults, a single BMD assessment can help predict the likelihood of fracture due to
age-related osteoporosis. In children with GC-induced osteoporosis, however, this
relationship is not as evident. Therefore, experts have recommended serial BMD
assessments in at-risk children as well as in those displaying evidence of growth
failure. Since BMD results need to be carefully interpreted in relation to the child’s
gender, age, height, and weight, as well as the underlying disease requiring GC
therapy, referral to a specialist for assessment of bone symptomatology and BMD
changes is recommended. At the same time, the bone health assessment of a child on
chronic GC therapy needs to be extended beyond BMD in order to identify risk
factors as well as early manifestations of osteoporosis. As such, bone health
monitoring in pediatric chronic GC users includes an evaluation of calcium and
vitamin D intake, back pain, physical activity, and disease-related risk factors for
attenuated bone mineral accrual and bone loss (such as chronic inflammation and
disuse). A spine radiograph should be considered in at-risk children with a prior
history of vertebral fractures, back pain, chronic GC exposure (> 3 months), poorly-
controlled inflammatory disease, significantly impaired mobility, or reductions in
spine BMD Z-scores on serial measurements.14
Osteonecrosis
patients using high-dose GC therapy or those treated with GCs for prolonged periods
should be evaluated for joint pain and decreased range of motion at each visit [58].
Magnetic resonance imaging should be considered in adult or pediatric patients
presenting with these signs or symptoms.14
Supresi Adrenal
Based on current evidence, experts recommend that physicians be aware of the risk of
AS in patients receiving supraphysiological GC doses for >2 weeks, those who have
received multiple courses of oral steroids totaling >3 weeks in the last 6 months, or in
patients presenting with symptoms of AS (including growth failure in children). If AS
is suspected, biochemical testing of the HPA axis should be considered after GC
treatment has been reduced to a physiologic dose. Given the ease and practicality of a
first morning cortisol measurement, it should be consi- dered for the initial screening
of patients at risk for AS. The insulin tolerance test (ITT) is the definitive test for
evaluation of the HPA axis, but performing this test is complicated and risky for
patients since insulin is administered to achieve hypoglycemia. The ITT is
contraindicated in children secondary to the risks of hypoglycemia on the pediatric
brain. Therefore, in the setting of a normal morning cortisol result and the pres- ence
of AS symptoms, the low-dose adrenocorticotropic hormone (ACTH) stimulation test
should be performed to confirm the diagnosis since it is a sensitive and specific test
for AS.14
Pertumbuhan pada Anak
For children receiving GC therapy, growth should be monitored every 6 months
(ideally by using stadiometry measurements) and measurements should be plotted on
an appropriate growth curve (Table 5). If, after 6 months, growth velocity appears to
be inadequate, the physician should consider all possible etiologies, including AS, as
well as referral to an endocrinologist.14
Hiperglikemia / Diabetes
All patients should be educated about the classic signs and symptoms of
hyperglycemia (polyuria, polydipsia, unexplained weight loss) so that they are
screened for steroid-induced diabetes if symptoms arise. In children presenting with
symptoms suggestive of diabetes, FPG should be performed. If FPG is not diagnostic
of diabetes in those with symptoms, OGTT is recommended. The diagnostic criteria
for diabetes in children are the same as for adults [38]. More frequent screening of
glucose parameters should be considered in children who are at potentially higher risk
of developing hyperglycemia or diabetes, such as transplant recipients, obese patients,
or those with conditions such as ALL or nephrotic syndrome. Annual OGTT is
recommended in children who are very obese and/or who have multiple risk factors
for type 2 diabetes since this test may be associated with higher detection rates.14

12. McKay LI, Cidlowski JA. Physiologic and Pharmacologic Effects of

Corticosteroids. In: Kufe DW, Pollock RE, Weichselbaum RR, et al., editors.
Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.
Available from: https://www.ncbi.nlm.nih.gov/books/NBK13780/
https://www.ncbi.nlm.nih.gov/books/NBK13780/