Dr. Chit SoeAssociate Professor

Consultant Physician & Rheumatologist

Use of Steroid in Rheumatology

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Long Term Steroid

• The millennium brings with it the 50th anniversary of Hench’s discovery that corticosteroids might be used to treat rheumatoid arthritis.

• Attitudes towards such use have waxed and waned since then.

• Initial hope that steroids might dramatically alter the long term course of the disorder gave way to a recognition of serious adverse effects, that accompany high dose treatment.

• The use of low dose corticosteroids in arthritis remains highly controversial.

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• A recent survey in general practice found that 1.4% of patients aged over 54 were using corticosteroids at a mean dose of 8mg daily

• Although rheumatologists claim to use less the audit had found use (as great as 80%).

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Reasons

• in an attempt to modify the progression of structural disease.

• “bridge” to suppress inflammation while other disease modifying drugs take effect or

• to combat acute flares of the disease

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Clinical Courses of RA

Adapted from: Henderson, Edwards, Pettipher. Mechanisms and Models in Rheumatoid Arthritis.© 1995 Academic Press Limited.

Chronic Progressive

ChronicIntermittent

Acute Onset

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Th1 cell

IFN -γ

TNF-α

IL-2

Activated Th1 Cell in Rheumatoid Arthritis

Smith JB, Haynes MK. Ann Intern Med. 2002;136:908-922

Feldmann M, Brennan FM, Maini RN. Annu Rev Immunol. 1996;14:397-440.

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Regulation of Gene Expression by

Glucocorticoids• Following ligand binding, HSP90 and several

other of the associated proteins dissociate, and the GR is directed into the nucleus where it can interact with specific DNA sequences within the regulatory regions of affected genes.

• These short DNA sequences that are recognized by the activated glucocorticoid receptor are termed glucocorticoid-responsive elements (GREs)

• and provide specificity to the induction of gene transcription by glucocorticoids.

• The currently acknowledged consensus GRE DNA sequence is GGTACAnnnTGTTCT,

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Improve symptom

• A Dutch trial comparing prednisolone 10 mg daily with placebo as an adjunct to intramuscular gold reported clinical improvement in both groups over 12 weeks;

• this was greatest among those trearted with prednisolone.

• The Arthritis and Rheumatism Council trial randomised 128 patients to prednisolone 7.5 mg daily or placebo in additon to non-steroidal and disease modifying agents.

• Symptomatic benefit was maintained for only 6-9 months of the two year follow up.

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Meta-analysis

• A meta-analysis of the effectiveness of low dose corticosteroidsa in rheumatoid arthritis based on 9 of 34 studies identified in a rigorous search strategy

• compared the effectiveness of prednisolone to either placebo or active drug controls (aspirin, chloroquine, or deflazacort).

• Although corticosteroids tended to be better at reducing the number of tender or swollen joints and the number of erythrocyte sedimentation rate, these differences were not significant.

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Retard Erosion!!

• Whether corticosteroids attenuate the progression of erosive damage is also unresolved.

• In the Arthritis and Rheumatism Council study showed prednisolone had a pronounced and significant (p<0.004) effect on the development of hand erosions in patients with rheumatoid arthritis of less than two year’s duration.

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• Gotzsche and Johansen report a further meta-analysis comparing prednisolone at a dose of 2.5-15 mg daily with palacebo or non-steroidal anti-inflammatory drugs

• They show that at these dose prednisolone is much more effective than non-steroidal drugs at improving joint tenderness, pain, and grip strength.

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Concern

• To the practising rheumatologist the great disincentive to using short term low dose prednisolone is not concern about lack of anti-aiflammatory effect

• but the worry that stepping treatment down may be difficult, with the consequence

• that the patient is exposed to the risk of adverse effects.

CPT

Corticosteroid Pulse Therapy

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Corticosteroid Pusle Therapy in Active Rheumatiod Arthritis

By Bas L.A.M. Weusten, Johannes W.G.Jacobs, and Johnnes W.J.Bijisma• In an attempt to reduce the frequent and

potentially servere side effects of long-term oral steroid therahy, the intermittent intravenous administration of high doses of corticosteroids (corticosteroid pulse therapy, CPT) was introduced.

• CPT was reported to be effective against renal allograft rejection.

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• Later reports showed that patients with idiopathic glomerulomephritis and glomerulonephritis associated with systemic lupus erythematous respond well to this from of treatment.

• In the course of the past decade,CPT also has been used to treat rheumatoid arthritis (RA).

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Different Regimens (For Acute Flare Up)

• Many studies of the efficacy of (different regimens of) CPT in RA have been performed

• 1,000 mg of methylprednisolone intravenously in 10 RA patients once a month for 6 consecutive months

• Tender joint counts, walking time, and grip strength improvement were still apparent more than 7 months after the last corticosteriod infusion.

• CPT did not influence the progression of erosions followed radiologically

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• Forster et al reported long-lasting clinical improvement in their RA patients after a regimen of

• 1,000 mg of methylprednisolone given on 3 alternate days and 1,000 mg intravenously on 3 consecutive days

• The benefit lasted more than 1 year • erythrocyte sedimentation rate and C-

reactive protein level, was of shorter duration (about 2 weeks)

• whereas methylpredisolone is metabolized and excreted within a few days

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CPT IN CONJUNTION WITH DISEASE-MODIFYING

ANTIRHEUMATIC DRUG THERAPY(Bridging)• Neumann et al investigated the

possibility of maintaining the clinical improvement induced by intiating (new) diseasemodifying antirheumatic drug (DMARD) therapy concomitantaly.

• They found that a regimen of 3 *1,000mg methylpredisolone intravenously on alternate days,

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• If started simultaneously with a new DMARD, was able to bridge the gap between the start and effect of at least two different DMARDs: D-penicillamine and sulphasalazine.

• In 1988, a similar effect of CPT in conjunction with sodium aurothiomalate was demonstrated.

• In contrast, we found that CPT (3x1,000 mg methylperdnisolone) is unable to bridge the gap between the start and the effect of azathioprine.

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COMPARISON OF THE EFFICACY OF DIFFERENT

REGIMENS OF CPT• After intial reports on the efficacy of high-dose

intravenous CPT, several investigators studied the effects of reduced doses of methylpred-nisolone.

• Radia and Frust compared the efficacies of a single dose of 1,000 mg of methylprednisolone given intravenously,

• 320 mg of methylprednisolone administered intravenously,

• and 320 mg of methylprednisolone given intramuscularly.

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• Shipley et al claimed a significantly better response to a single intravenous 1,000-mg dose of methylprednisolone than to 500 mg and 40 mg.

• Dexamethasone (200 mg),given via an intravenous infusion on alternate days over a 5-day period was also tried.

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• They found that 85% of patients treated with 1,000 mg of methylprednisolone considered the therapy worthwhile,

• compared with only half the patients receiving lower dosages.

• Several authors have compared high-dose oral prednisolone with intravenous methylprednisolone.

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• In conclusion, different regimens of CPT are of clinical benefit for patients with severe, intractable RA.

• As for bridging the gap between the start and effect of a newly introduced DMARD, the effect of low-dose or oral CPT has not been proved,

• Recommended regimens consisting of three 1,000-mg doses of methylprednisolone.

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SIDE EFFECTS OF CPT

• sudden death, infections, hypersensitivity, osteonecrosis of the femoral head, and multiple other complications

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ON

• Flattening or deformity of the femoral head was assumed to be possible ON, but only when seen in conjunction with a normal joint space was it considered incontrovertible ON.

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Short-term ComplicationsAttributable to CPT

(n=90)Increase in diastolic blood pressure(> 10 mm Hg) 44 (51%)Hyperglycemia (> 6.0 mmol/L) orglucosuria 14 (16%)Facial flushing 12 (14%)

Headache 10 (12%)Bitter taste 9 (10%)Vertigo 5 (6%)Palpitations/tachycardia 5(6%)Urinary tract infections 4 (5%)Euphoria 4 (5%)Tiredness/malasie 2(2%)Insomnia 2 (2%)Erythema/urticaria 2 (2%)Jitteriness/fear 2 (2%)Hypokalemia 2 (2%)

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Long term

• TB

• Osteoporosis

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• (9) Systemic steroid therapy may have an important early

• role in establishing control of synovitis or bridging disease

• control between different DMARD therapies but long-term

• use is not justified. (grade of recommendation B)

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• When using corticosteroids• in RA, osteoporosis prevention should always be

considered• following the National Osteoporosis Society/RCP

guidelines [92].• The recent NICE technology appraisal for the secondary• prevention of osteoporosis [94] gives clear guidance on

treatment• thresholds after fragility fracture and is due to report

shortly on• primary prevention.

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Recent Developments in the Therapy of patients withSevere Systemic Lupus

ErythematosusDimitrios T.Boumpas,M.D.Long-term follow-up of patients

participation in these controlled trials suggest that toxicity is low and benefit outweigh the risk.

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EBM

• The Cochrane Controlled Trial Registry, MEDLINE, and EMBASE were searched for RCTs of treatment for DPLN.

• All available RCTs of patients with biopsy-proven DPLN were included, and data were extracted for overall mortality, end-stage renal disease, doubling of serum creatinine level, relapse, major infection, herpes zoster infection, ovarian failure, malignancy, and bladder toxicity.

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• Twenty-five of 920 articles identified were eligible RCTs and were included.

• The majority compared cyclophosphamide or azathioprine plus steroids versus steroids alone.

• cyclophosphamide combined with steroids remains the best option to preserve renal function

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Other Use

• Systemic use also in – Vasculitis– Dermatomyositis

• Local Injection– Joint-(RA, OA, Gout)– Soft tissue- (Painful arc,

tennis elbow, carpal tunnel)

• Local application– Psoriasis

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Equivalent doses of steroid.This table takes no account of

mineralocorticoid activity effects, nor dose it take account of variations in

duration of action (BNF)Prednisolone 5 mg= Betamethasone 750 microgram= Cortisone acetate 25 mg= Deflazacort 6 mg= Dexamethasone 750 micrograms= hydrocortisone 20 mg= Methylprednisolone 4 mg= Triamicinolone 4 mg= methasone 750 micrograms= hydrocortisone 20 mg= Methylprednisolone 4 mg= Triamicinolone 4 mg

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• The relatively high mineralocorticoid activity of cortisone and hydrocortisone, and the resulting fluid retention, make them unsuitable for disease suppression on a long-term basis.

• However, they can be used for adrenal replacement therapy

• hydrocortisone is preferred because cortisone requires conversion in the liver to hydrocortisone.

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• Betamethasone and dexamethasone have very high gluococorticoid activity in conjunction with insignificant mineralocorticoid activity.

• This makes them particularly suitable for high-dose therapy in conditions where fluid retention would be a disadvantage (e.g. cerebral oedema).

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STEROIDTREATMENT CARD

• I am a patient on STEROID treatment which must not be stopped suddenly.

• If you have been taking this medicine for more than three weeks, the dose should be reduced gradually when you stop taking steroids unless your doctor says otherwise.

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• Read the patient information leaflet given with the medicine.Always carry this card with you and show it to anyone who treats you (for example a doctor, nurse, pharamacist or dentist).

• For one year after you stop the treatment, you must mention that you have taken steriods.

•If you become ill, or if you come into contact with anyone who has an infectious disease, consult your doctor promptly. If you have never had chickenpox, you should avoid close contact with people who have chickenpox or shingles. If you do come into contact with chickenpox, see your doctor urgently.

• Make sure that the information on the card is kept up to date.

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Summary

• Steroid reduce symptoms• Steroid reduce disease progression• Low dose long term- methylprednisolone 7.5-

15mg / OD CM• Pulse- methylprednisolone 1000mg in 100 ml

NS in 1 hr alternate day for 3 dose• Beware of side effects• Educate to use steroid card

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