au: VMiedical AYT
`ofAustralia
`
`February 3, 1986
`Vol. 144, No. 3
`
`
`
`JOURNAL OF THE AUSTRALIAN MEDICAL ASSOCIATION
`
`
`WCALTLLOR
`McALITA SC)
`
`
`
`LEADING ARTICLES) jiversity
`
`Relinquishing ‘mothers: [)r..
`THERAPEUTICS
`
`Single-dose therapy in the
`Gordon Parker.
`Aa i
`Compliance with asthmathe
`managementof urinary tract
`
`in paediatric practice.
`infections. Judith A. Whitworth __136
`
`
`Side-effects of corticosteroid
`David R. Lines
`
`# agents. J. Paul Seale,
`Bicycle accidents.
`
`Douglas Cohen 2 ===414
`. PRUE te As aalete l9eeeaecaec
`
`Informational needs for the
`
`- effective prevention of accidents
`MEDICAL MISCELLANY
`in childhood. Graham Vimpani,
`Frederick Ill of Germany.
`John Pearn, Jerry Moller_____——115
`James H. Leavesley_ i143
`
`ORIGINAL ARTICLES
`CASE REPORTS
`Psychological disability in women
`Child cyclist injuries: a
`whorelinquish a baby for
`prospective study.
`adoption. John T. Condon____117
`Christopher J. Armson,
`Effects of intervention on
`Clifford W. Pollard.
`medication compliancein children
`Pathological rupture of the spleen
`with asthma. Nerida A. Smith,
`in transforming non-Hodgkin’s
`J. Paul Seale, Philip Ley, John Shaw,
`lymphoma. JamesD.Griffiths,
`Peter U, Bracs2.4. 4g
`Jue Chong Ding, Surender K. Juneja,
`Intrapulmonary coin lesions: the
`Robert J.S. Thomas, John J. Martin,
`changingpatterns.
`lan AzCooperaaoa
`146
`David B. Francis,
`A case of uridine diphosphate
`Paul V. Zimmerman________——122
`galactose-4-epimerase
`Glucagon and ureteric calculi.
`deficiency detected by neonatal
`David R. Webb,
`lan N. Nunn,
`screening for galactosaemia.
`Donald McOmish, William S.C. Hare 124
`Francis G. Bowling,
`Effective palliation of melanoma
`David K.B. Fraser, Alan E. Clague,
`with procarbazine and radio-
`Alan Hayes, Darryl J. Morris____150
`therapy given by a low-dose
`Acute, severe hepatitis due to
`fractionation schedule.
`Coxiella burneti infection.
`P. Grantley Gill, Richard L. Abbott,
`Raymond P. Kelly, David J. Byrnes,
`Ash Ahmad, Joan Zeicmanis___126
`denniferTurnerweSY
`Major hepatic resection for
`neoplasia: the Concord Hospital
`H Boua iVed ES
`DEPARTMENTS,
`experience. Patrick C. Cregan,
`
`John W. Hollinshead, David J. Gillett 128
`Notice Board Madisan
`
`| Meetings or
`
`158
`Obituaries; «.:
`Q
`
`159
`Book Reviews
`LETTERS TO THE EDITOR:
`163
`
`signe nner
`vier
`ieee
`eR eae es
`MA
`sce berE>
`
`
`
`POINT OF VIEW
`Psychiatry, compensation and
`rehabilitation. Fiona K. Judd,
`Graham D. Burrows__1:3
`
`a Registered by Australia Post. Publication No. NBG 0038.
`
`
`
`JANSSEN EXHIBIT 2069
`Mylan v. Janssen IPR2016-01332
`
`JANSSEN EXHIBIT 2069
`Mylan v. Janssen IPR2016-01332
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`

`Therapeutics|139
`THE MEDICAL JOURNAL OF AUSTRALIA Vol. 144 February 3, 1986
`
`ste
`This material may be protected by Copyright law (Title 17 U.S. Code)
`
`Side-effects of corticosteroid agent
`
`ABSTRACT Anti-inflammatory cortico-
`teroid drugs are powerful therapeutic agents
`for a wide range of disorders. However, they
`lo have recognized side-effects, most of
`which are related to the dose and the duration
`of therapy. Thus, short courses of even high
`doses of corticosteroid drugs have very few
`adverse effects. A detailed knowledge of the
`long-term side-effects of corticosteroid agents
`and their incidence will assist the physician
`in making informed judgements on the poten-
`tial benefits of treatment with these drugs.
`(Med J Aust 1986; 144: 139-142)
`
`F
`
`he developmentofcorticosteroid agents
`represented a major advance in the
`treatment of numerous inflammatory
`diseases of varying causes; regrettably,
`their
`widespread use must be tempered by an
`appreciation of their side-effects, which occur
`commonly. As with any potent
`therapeutic
`agents, the prescribing of corticosteroid therapy
`should be guided by a careful consideration of
`its perceived benefits and potential risks. This
`article will
`review the unwanted effects of
`systemically administered anti-inflammatory
`corticosteroid agents.
`the complications of
`In general, any of
`corticosteroid agents are related to the dose and
`the duration of therapy.’ Thus, mostof the well
`known problems will arise only during long-
`term treatment. Onthe other hand, remarkably
`few. adverse effects are associated with short
`courses of corticosteroid drugs,
`even in
`relatively high doses! In view of this clear
`distinction, short-term andlong-termtreatments
`will be considered separately.
`\
`Since prednisone, prednisolone
`and
`methylprednisolone are the most commonly
`usedcorticosteroid agents, most ofthe available
`clinical data on side-effects concern these drugs.
`Sound reasonsexist for the administration of one
`of these agents in preference to the more potent
`corticosteroid drugs, such as dexamethasone and
`betamethasone. Prednisone, prednisolone and
`its methyl analogue have less mineralocorticoid
`activity than doescortisol, so their propensity
`to retain sodium and water will be less than that
`of cortisol. In addition, their biological half-lives
`are of intermediate duration (12-36 hours),
`allowing a once-a-day dosage
`regimen.
`Furthermore, a patient’s daily requirements can
`easily be obtained from the rangeofthe available
`tablets and this facilitates the process oftitrating
`dosage against disease to find the minimum dose
`
`
`the disease.that will control In contrast,
`“Fifth article in an occasional series on therapy with
`corticosteroid agents.
`
`Department of Pharmacology, The University
`of Sydney, NSW 2006.
`J. Paul Seale, PhD, FRACP, Associate Professor in
`Clinical Pharmacology.
`Mark R. Compton, BSc, Research Assistant.
`Reprints will not be available from the authors. The
`series of articles on corticosteroid therapy will be
`published later in booklet form.
`
`J. Paul Seale and Mark R. Compton
`
`although dexamethasone and betamethasone are
`virtually devoid of mincralocorticoid activity,
`they have much longer biological half-lives
`(36-54 hours) which are responsible for their
`profound suppression of the hypothalamic—
`pituitary—adrenalaxis. Also, the available tablet
`strengths do notallow for the samefinetitration
`of minimal daily dosage that is possible with
`prednisone and prednisolone.
`
`Short-term therapy
`Dosesof up to 100 mg of prednisone a day may
`be taken for three weeks or less without any
`great risk ofthe occurrence of adverseeffects.
`Occasionally, patients may notice weight gain,
`mild fluid retention, insomnia or mood changes
`(euphoria, depression or,
`rarely, psychosis).
`Adverse psychiatric reactions are morelikely to
`occur in patients with pre-existing psychological
`problems.2. The metabolic
`actions of
`corticosteroid drugs may lead to hyper-
`glycaemia,
`to ketoacidosis in diabetic indi-
`viduals
`and to hypokalaemia. Superficial
`punctuate ulcerations ofthe gastric mucosa and
`associated haemorrhage may also occur!
`However, these effects are reversed when the
`drugs are discontinued. A rare but serious
`complicationof the intravenous administration
`of corticosteroid drugs in asthmatic patients is
`the development of anaphylactoid reactions;
`these may be difficult to differentiate from an
`exacerbation of asthma?
`Short courses of high-dose corticosteroid
`agents may producetransient abnormalities of
`the hypothalamic—pituitary—adrenal axis such as
`reduced basal plasma concentrations of cortisol,
`diminished adrenal gland responsesto adreno-
`corticotrophin (ACTH) and blunted responses
`to insulin-induced hypoglycaemia.* Two days
`after the administration of prednisolone (25 mg
`twice a dayfor five days), the cortisol responses
`of 10 normal mento both the induction of hypo-
`glycaemia and the administration of synthetic
`ACTH were reduced to about one-half their
`previouslevels. In a studyof seven patients with
`chronic airflow obstruction, who were given
`prednisolone (20 mg twice a day for three
`weeks), basal plasmacortisol and plasma ACTH
`concentrations were suppressed at
`the com-
`pletion of treatment but returned to normal
`values within four days. Thus, it is evident that
`corticosteroid therapy can affect hypothalamic—
`pituitary—adrenal function within a few days of
`its commencement, even though the dysfunction
`usually disappears rapidly once treatment has
`been ceased.
`that patients
`Since these findings suggest
`theoretically may be at risk if they encounter
`stress within a few days of the abrupt discon-
`tinuation of corticosteroid therapy,
`it may be
`preferable to withdraw an agent gradually over
`five to seven days. For some inflammatory
`disorders,
`it may be necessary to reduce the
`
`dosage of a corticosteroid drug over a longer
`period of time to prevent recrudescenceof the
`disease. Whetever possible, once-a-day
`regimens should be prescribed, since they are
`more likely to result in rapid recovery of the
`hypothalamic—pituitary-adrenal
`axis when
`corticosteroid therapy is ceased.6
`Awarenessof the transient disturbances which
`mayoccur with short-term courses of cortico-
`steroid agents will ensure that these potent drugs
`are used safely and effectively.
`
`Long-term therapy
`It is with prolongedtreatment that the unwanted
`effects, well known both to medical practitioners
`and to the lay public, are likely to be encoun-
`tered. In general,
`the lower the maintenance
`dose of a corticosteroid agent, the less the risk
`of side-effects.
`In adults, it is likely that daily doses in excess
`of 10 mg ofprednisone will eventually lead to
`some side-effects.’ It
`is probable that even
`smaller daily doses (for example, 7.5 mg of
`prednisone),
`if taken in the long term, are
`associated with complications in the elderly
`Thus, it is not possibleto stipulate a daily dose
`at whichthe risk of side-effects is non-existent.
`Hypertension
`salt-retaining properties of
`Although the
`prednisone and prednisolone are less than those
`of cortisol, these synthetic corticosteroid agents
`maystill cause hypernatraemia, fluid retention
`and hypertension. In addition, other mechan-
`isms, such as the enhancementof the vasocon-
`strictor effects of endogenous substances and
`increased concentrations of renin substrate? have
`been postulated as contributing to the hyper-
`tensive effects of glucocorticoid hormones.
`These effects are probably related to the dose
`since long-term low-dose therapy does notcarry
`any appreciable risk. In a study of 129 patients
`with chronic airflow obstruction who were tak-
`ing prednisone or prednisolone (mean daily dose
`+ SD, 6.7 + 3.3 mg for 9.7 + 5.5 years) and
`66 patients with rheumatoid arthritis who were
`taking prednisone or prednisolone (8.4 + 2.7 mg
`for 8.4 +2.7 years),
`there was a small,
`statistically significant increase in systolic blood
`pressure without a
`significant
`increase in
`diastolic blood pressure.’ However, multiple
`regression analysis showed that an increased
`systolic blood pressure level correlated with age
`and blood pressure before therapy, which
`suggested that
`these factors were the main
`determinants of increases in systolic blood
`pressure. It was concluded that low doses of
`prednisone or prednisolone are not important
`causes of hypertension.
`In the elderly, the incidence of elevated blood
`pressure maybehigher. Fifteen of 100 patients
`(aged 69 years or more) who were taking pred-
`nisolone (12.5 mg a day orless) for an average
`of 4.8 years developed hypertension (defined as
`
`

`

`[Therapeutics
`February 3, 1986 Vol. 144 THE MEDICAL JOURNAL OF AUSTRALIA
`a diastolic blood pressure of greater
`than
`5 mmHgora systolic blood pressure ofgreater
`than 180 mmHg), compared with three of 100
`age-matched and sex-matched controls. The
`precise mechanisms by whichelderlypatients
`develop hypertension, and other side-effects of
`corticosteroid therapy, such as osteoporosis,
`more
`readily than others have not been
`elucidated. One possible contributoryfactor may
`be the increased plasma concentration of
`unbound corticosteroid drug due to the lower
`serum albumin level
`in the elderly."
`Electrolyte disturbances
`Since prednisone and prednisolone retain some
`mineralocorticoid activity,
`they increase the
`distal renal tubular reabsorption of sodium in
`exchange
`for potassium, hydrogen and
`ammonium ions which may lead to hypernat-
`raemia and hypokalaemia in someindividuals.!2
`In large doses, corticosteroid drugs may cause
`hypokalaemic alkalosis. However, alkalosis may
`develop in somepatients without any evidence
`of potassiumdepletion, suggesting that increases
`in serum bicarbonate levels may be a direct
`cffect of corticosteroid therapy.!?
`Osteoporosis
`Patients who receive prolonged therapy with
`greater than physiological doses ofcorticosteroid
`agents tend to develop some degree of osteo-
`porosis. Glucocorticoid agents decrease bone
`formation owing to a direct inhibition of osteo-
`blastic
`activity and they
`increase bone
`resorption, which leads to loss of bone —
`preferentially that of trabecular bone in the spine
`and
`ribs! Bone
`resorption occurs
`as
`a
`consequence of secondary hyperparathyroidism,
`which is caused by corticosteroid-induced
`hypercalciuria and inhibition of enteral calcium
`absorption? Not all patients develop osteo-
`porosis, but postmenopausal womenand elderly
`or immobilized patients are at high risk of this
`complication. Since current pharmacological
`approaches at best halt, rather than reverse,
`corticosteroid-induced osteoporosis, one should
`aim to detect
`this problem before serious
`complications such as compression fractures of
`the vertebral column have occurred. While the
`reliable detection of carly changes requires
`sophisticated techniques
`such as photon
`absorptiometry, plain x-rayfilms of the spine
`may also provide useful
`information. Once
`patients at risk have beenidentified, prophylaxis
`with vitamin D and calcium supplements, or
`vitamin D and hydrochlorothiazide therapyif
`hypercalciuria
`is present,
`should
`be
`considered.'? Since no proofyet exists that such
`a programmeofprophylaxis is effective, therapy
`should be embarked upon in preference to
`witnessing the
`relentless progression of
`osteoporosis
`in
`susceptible individuals.
`Alternate-day treatment, which reduces the
`incidence of some of
`the
`side-effects of
`corticosteroid drugs, would appear to have no
`advantage over daily use in terms of
`the
`development of osteopenia.'4
`Cutaneous effects
`Easybruising, purpura and ecchymoses, which
`are quite commonin older patients on long-term
`
`corticosteroid treatment, typically involve the
`face and neck, the extensor surfaces of the arms
`and the hands andthe areas below the knees.
`Although the mechanism is not clearly under-
`stood,
`it
`is
`thought
`to be related to the
`diminished phagocytosis of extravasated blood
`and changes in connective tissue.!2 Hirsutism has
`been reported in approximately 10% ofpatients
`and depends on the duration of treatment.5
`Acneiformlesionsthat affect the face and upper
`trunk may occur in a minority of patients on
`long-term therapy.!?
`Growth impairment
`In children,
`long-term use of corticosteroid
`agents inhibits linear bone growth and epi-
`physeal closure, reducing skeletal growth. To
`facilitate the early detection of growth retarda-
`tion it is essential that regular measurements of
`height and weight are plotted on percentile
`charts. Fortunately, accelerated growth backto
`the child’s height percentile usually follows the
`cessation of corticosteroid therapy as the ad-
`ministration of corticosteroid drugs also inhibits
`epiphyseal closure. However, this growth catch-
`up maynot occur after long-term use of high-
`dose corticosteroid therapy,
`leaving the child
`permanently stunted.
`If
`single doses of
`prednisone or prednisolone, which have a
`relatively short biological half-life, are taken in
`the morning, this regimenisleast likelyto affect
`the maximalsecretion of growth hormdnein the
`early hours of the morning.'¢
`Glucose intolerance
`impair carbohydrate
`Glucocorticoid agents
`metabolism by increasing hepatic gluconeo-
`genesis and by decreasing the utilization of
`glucose by various tissues.'? Fasting blood
`glucose concentrations are within normal ranges
`in most patients who are taking corticosteroid
`drugs but usually some reduction in the ability
`to respond to a glucose load is present, with a
`pattern in a glucose tolerance test
`that
`is
`indicative of insulin resistance. This impairment
`of glucose tolerance is greatest when cortico-
`steroid treatment begins and the response
`improves
`considerably during long-term
`therapy.'7 The developmentof overt diabetes is
`unusual except in individuals with pre-existing
`abnormal results of a glucose tolerancetest.
`Corticosteroid-induced diabetesis usually mild
`and can be managed along conventional lines
`bydietary measures, the administrationoforal
`hypoglycaemic agents and the judicious use of
`insulin, if necessary. It is frequently reversible
`on cessation of corticosteroid therapy, although
`the reversalofthe diabetic state maytake several
`months.!8
`Aseptic necrosis of the femoral head
`Theuse ofcorticosteroid agents is one of many
`factors which maypredispose patients to the
`developmentof aseptic necrosis of the femoral
`head. Among the numerous theories that are
`advancedas a basis for this unusual complica-
`tion of corticosteroid therapy,
`the currently
`favoured explanation is that fat microemboli
`occlude subchrondral end-arterioles and lead to
`bone-cell death!® The typical
`radiological
`appearanceis that of a lucent area betweenthe
`
`i490
`
`collapsed bone and the overlying cartilage.
`During a 10-year period, six patients (who
`represented approximately 1% ofall patients in
`one study who were receiving corticosteroid
`drugs for pulmonary diseases) developedaseptic
`necrosis of the femoral head.!9 A typical patient
`had been receiving greater than physiological
`dosesof corticosteroid drugs for more than three
`months, and more often for years. Recipients
`of renal transplants have an increased incidence
`of aseptic necrosis of bone, presumably as a
`long-term sequela of corticosteroid treatment,
`In a recent Australian survey, six of 52 renal
`transplantrecipients who survived for more than
`10 years developed aseptic necrosis of bone
`which involved otherjoints in addition to the
`hip2° A reviewofthe literature suggests that
`high doses ofcorticosteroid agents in the first
`month after transplantation were associated with
`an increased prevalence of aseptic necrosis.2°
`Patients with other disorders such as hyperuri-
`caemia, alcoholism, hyperlipidaemia or poly-
`cythaemia, who alsotake corticosteroid drugs,
`may be at greater risk of developing aseptic
`necrosis than those without these disorders.1?
`Peptic ulceration
`Support for the theorythat corticosteroid drugs
`lead to the developmentofpeptic ulceration has
`waxed and waned overthe years. The widely
`accepted clinical notion that
`there was an
`association was dispelled in 1976 by Conn and
`Blitzer, when they reviewed 42 randomized con-
`trolled trials and foundthat there was no sig-
`nificant
`relationship between corticosteroid
`therapy and peptic ulceration unless the drug
`was taken for more than 30 days or in large
`doses! The burning question has been
`rekindled recently by Messer et al., who
`reviewed 71 controlled trials in which patients
`were randomized to receive corticosteroid
`therapyor non-steroidal therapyforat least four
`days.?? The incidence ofpeptic ulcers was 1.8%
`in the corticosteroid-treated group compared
`with 0.8% in control patients2? Thus, current
`evidence suggests a small but significant associa-
`tion between corticosteroid therapy and peptic
`ulceration. However,
`in view of
`this
`low
`incidenceit is illogicalto institute prophylactic
`therapy — with antacids or with histamine
`H,-receptor antagonists — in all patients who
`are receiving corticosteroid drugs. If a patient
`is sufficiently unlucky as to develop an ulcer
`during corticosteroid treatment, he or she should
`be managed with conventional therapy. In the
`absence of convincing evidence that “steroid
`ulcers” are resistant to therapy,
`there are no
`compelling reasons to discontinue corticosteroid
`treatment unlesslife-threatening complications
`of the ulcer have supervened.
`Symptomsof gastrointestinal intolerance such
`as dyspepsia and nausea may occur,
`in which
`case antacid therapy is useful. It is important
`to choose agents such as aluminiumhydroxide,
`magnesiumtrisilicate and magnesium hydroxide
`whichdonotappearto affect the absorption of
`prednisolone.23
`Pancreatitis
`Acute pancreatitis is a rare but serious compli-
`
`

`

`Therapeutics|14
`THE MEDICAL JOURNAL OF AUSTRALIA Vol. 144. February 3, 1986
`
`
`
`
`the onset of
`cation of corticosteroid therapy,
`whichis not related to the dose, duration or type
`of corticosteroid drug that is used. In a review
`of 112 patients with drug-induced pancreatitis.
`corticosteroid agents were the most common
`offenders, being implicated in 51 cases2*
`Myopathy
`Corticosteroid myopathy presents as weakness
`and wasting in the proximal
`limb and girdle
`musculature. Although the dosage of cortico-
`steroid agent has frequently been high and
`sustained over many months,
`there does not
`appearto be goodcorrelation betweenthe total
`dose, the duration oftreatment, the paticnt’s age
`or sex andthe severity of the myopathy. Since
`the incidence is higher with the fluorinatedcorti-
`costeroid drugs such as triamcinolone?> such
`agents should not be used in the long term.
`Patients usually recover within a few weeks of
`the cessation of the corticosteroid therapy.
`Oculareffects
`Although an increase in intraocular pressureis
`more commonwith the topical administration
`of corticosteroid preparations, it can also occur
`with systemic corticosteroid agents but onlyafter
`months oryears of treatment.2° The risk, which
`appearsto be genetically determined, is greatest
`in individuals with myopia or diabetes. The
`proposed mechanisminvolves increased produc-
`tion of aqueous humour and swelling of the
`collagen in the trabecular meshwork in the
`drainage angle of the anterior chamber, leading
`to an increased resistance to aqueous outflow2®
`Increases in intraocular pressure are usually
`reversible if corticosteroid therapy is ceased.
`Posterior subcapsular cataracts have been
`documentedin patients who are receiving long-
`termcorticosteroid therapy. The usual minimum
`time required for the onset of cataracts is one
`year of
`treatment with at
`least
`10 mg of
`prednisone a day.2° There is some evidence to
`suggest that this complication is more common
`in children and in patients with rheumatoid
`arthritis. In viewof these ocular complications,
`it is prudentforall patients who are being treated
`with long-term corticosteroid therapy to undergo
`regular ophthalmological examinations.
`Raised intracranial pressure
`A small proportion of patients, usually children
`or young women, develop papilloedema and
`signs of raised intracranial pressure when their
`corticosteroid dosage is being reduced. This
`syndromehas been designatedeither as “benign
`intracranial hypertension” or as “‘pseudotumour
`cerebri”. The usual treatmentis to increase the
`corticosteroid dose temporarily to relieve the
`symptoms and then to attempt a more gradual
`withdrawal 27
`Infections
`Corticosteroid drugs impair cell-mediated im-
`munity by decreasing the numberofcirculating
`lymphocytes and monocytes, by blocking the
`sensitization of lymphocytes to antigen and by
`inhibiting the responsiveness of monocytes to
`the chemotactic factors that are elaborated by
`lymphocytes.28 Antibody formation and turnover
`are not affected significantly by corticosteroid
`drugs.
`In spite of the recognized effects of
`
`corticosteroid agents and experimental studies
`that have demonstrated an increased risk of
`infection with
`numerous
`agents
`in
`corticosteroid-treated animals, it has been more
`difficult to document the degree of increased
`susceptibility in clinical studies? Nevertheless,
`it is generally agreedthat patients whoarc taking
`long-termcorticosteroid drugs are predisposed
`to bacterial
`(mycobacteria,
`staphylococcus,
`listeria). viral (herpes, cytomegalovirus), fungal
`(candida,
`cryptococcus)
`and parasitic
`(toxoplasma, pneumocystis) infections.?® In the
`case oftuberculosis, preventive measures should
`be taken.
`In patients with positive results of
`Mantoux skin tests to intermediate strength
`tuberculin (5 TU), but normal chest radiograph
`films. modest doses of corticosteroid agents
`(10-15 mg of prednisolone a day) do not appear
`to carry an increased risk of tuberculosis.?°
`Therefore, such individuals do not benefit from
`prophylactic therapy with isoniazid. However,
`if patients have radiological features that are
`consistent with inactive pulmonarytuberculosis,
`they warrant treatment with two drugs suchas
`isoniazid and ethambutol or rifampicin° The
`physician should bealert to the possibility of
`both commonand unusual infections in patients
`who are receiving corticosteroid agents, par-
`ticularly if these are combined with other
`immunosuppressant drugs.
`Adrenal suppression
`In treating inflammatorydiseases with cortico-
`steroid agents, it is common to begin with high
`doses to obtain some measure ofcontrol. There-
`fore, the dose is reduced, according to indices
`of disease activity, until a satisfactory mainten-
`ance dose is reached. Ultimately it may be
`possible to cease the administration of cortico-
`steroid therapy altogether, in which case certain
`guidelines should be observed. It is generally
`accepted that derangement ofadrenal function
`occurs after a few days of high-dose cortico-
`steroid therapy. In contrast to the rapid recovery
`after treatment that is limited to two to three
`weeks,
`long-term daily therapy with cortico-
`steroid drugs may suppress hypothalamic—
`pituitary—adrenal function for up to nine months
`after the cessation of treatment.3! Therefore, it
`is important to keep the daily maintenance dose
`as
`low as possible or
`to use alternate-day
`therapy2? because both of these strategies —
`particularly the latter — minimize the chances
`of blunting the
`stress
`response of
`the
`hypothalamic-pituitary—adrenal axis.
`Since the recoveryof the adrenal cortex lags
`behind that ofthe pituitary, one can usually as-
`sume that full integrity has been restored when
`the adrenal gland can mount an adequate
`secretory response of cortisol
`to synthetic
`ACTH:3' Therefore, the following approach for
`the withdrawal ofcorticosteroid therapy is sug-
`gested3! First, wean the patient to “‘physio-
`logical’ doses of a corticosteroid agent (such
`as 20 mg of hydrocortisone or 5 mg of pred-
`nisone) to be taken for one to two months; then
`halve the dose for the next one to two months;
`and then determine the morning plasmacortisol
`concentration, omitting the morning dose of
`
`corticosteroid agent on the day of plasma
`sampling. A morning cortisol concentration of
`greater than 0.28 mol/L (10 pg/l00mL) indi-
`cates that basal hypothalamic—pituitary—adrenal
`function has recovered. Adrenal reserve is then
`assessed by a tetracosactrin (ACTH) stimulation
`test. If the morning plasmacortisol level is less
`than 0.28 pmol/L CO ug/l00 mL),
`then
`corticosteroid treatment should be continued for
`another one to two months before another
`morning plasma sample is collected.
`In most circumstances, a justifiable alternative
`to these diagnostic tests of adrenal functionis
`to administer
`supplemental corticosteroid
`therapy during physiological stress (such as
`accidents, surgical procedures, febrile illnesses,
`repeated vomiting or dehydration) for a year
`after the medication is discontinued. Depending
`upon the clinical urgency, therapy can be given
`parenterally or by mouth in a daily dose that
`is equivalent to 200-400 mg of hydrocortisone.*!
`A syndromecalled “steroid pseudorheuma-
`tism’, which is distinct from simple adrenal
`insufficiency, has been recognized in patients
`whotake their corticosteroid therapyerratically
`or whose dosage is
`reduced abruptly.
`It
`is
`characterized by fever,
`anorexia, malaise,
`myalgia andarthralgia.' These symptoms resolve
`after increasing the dose of corticosteroid agent:
`a more gradual reduction of corticosteroid drugs
`prevents their recurrence.
`
`I
`
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