The role of steroid in rheumatic diseases

Rachmat Gunadi Wachjudi

Lahir di Garut, 16-1-1955Pendidikan SD-SMA : Garut Dokter umum: FK UNSRI Palembang Internist: FK UNPAD Bandung Konsultan Reumatologi : FK UI

Jakarta Clinical Rheumatology &

Osteoporosis training Arthritis foundation of WA

Pekerjaan: Staf Reumatologi RS Dr Hasan

SadikinOrganisasi Profesi IDI, IRA, PAPDI, PEROSI,

PERALMUNI, IPS, ISS

The Role of Corticosteroid in Rheumatic Diseases

Rationale&Therapeutic principles

INTRODUCTION

Corticosteroid use is one of the most important and controversial subjects in rheumatology.

The dramatic anti-inflammatory effects of corticosteroids were first described in the setting of treating rheumatoid arthritis (RA). This unexpected discovery by Philip Hench resulted in Nobel price in 1950.

Long-term supraphysiologic therapy produced devastating side effects led to polarized views of the role of corticosteroids in the pathogenesis & therapy of rheumatic diseases.

Hench PS etal. Proc Staff Meet Mayo Clin 24:181, 1949Hench PS etal. Arch Intern Med 85:545,1950

Steroids the Sleaziest of Drugs

Steroids are fast catching up with

antibiotics as the most abused class of drugs in doctor's black bag.

High doses of corticosteroids and other immunosuppressive agents cause AIDS

Mohammed Ali Al-Bayati Ph.D

Corticosteroid Physiology Essential for normal development &

maintenances of homeostasis during both basal and stress conditions.

Represent one of the most important products of the hypothalamic – pituitary – adrenal (HPA) axis & the central response system.

Regulate a broad array of metabolic and central nervous system (CNS) functions

Potent anti-inflammatory actions.

Cortisol Secretion

Anti-inflammatory actions of corticosteroids

Corticosteroid inhibitory effect

Role in Rheumatic diseasesMost of the desired clinical effects of GC

treatment in rheumatic patients are mediated by transrepression.

These include:1. Reduction of clinical signs & symptoms of

inflammation by reducing synthesis of enzymes involved in the biosynthesis of prostaglandin E2 and pro inflammatory cytokines, such as IL1 & TNF – alpha.

2. Retardation of the radiological progression in rheumatoid arthritis

Major Rheumatic Diseases

Osteoarthritis Rheumatoid

Arthritis Systemic Lupus

erythematosus Systemic Sclerosis Spondyloarthropat

hies

Poly-Dermatomyositis

Crystal - Induced Arthritis

Septic Arthritis Vasculitis

Joint Swelling inflammation

What happens in inflammation? Associated with the production of cytokines (TNF & IL1,

IL6) stimulate HPA axis and corticosteroid production feedback suppression of cytokine production & the inflammatory response.

Inadequate corticosteroid production amplify

inflammatory mechanisms & concomitant tissue injury.

Defects in this bidirectional feedback loop between CNS & peripheral inflammatory pathways and/or tissue resistance to the actions of corticosteroids are suspected to contribute to several rheumatic disorders including RA.

Wilder RL. Annu Rev Immunol, 13:307,1995

Chrousos GP. N Engl J Med 332:1351,1995

Glucocorticoid Use in Daily Practice

. GC dosages in different clinical conditions is essentially empirical

. High activity & severity need higher doses

. The rationale is:a/ Higher doses increase cGCR saturation in a dose

dependant manner which intensifies the therapeutically relevant, genomic actions.

b/ Non genomic action of GCs increasingly come into play with increasing dosage

Standardized nomenclature for glucocorticoid doses and glucocorticoid treatment regimens.

Terminology

Dosage Clinical application

Genomic actions (receptor saturation

Nongenomic actions

Low dose <=7.5 Maintenance therapy for many rheumatic diseases

+(<50%) ?

Medium dose >7.5 to <=30 Initially given in primary chronic rheumatic diseases

++ (>50% to <100%)

(+)

High dose >30 to <= 100 Initially given in subacute rheumatic diseases

++(+)(almost 100%)

+

Very high dose >100 Initially given in acute and/or potentially life-threatening exacerbations of rheumatic diseases

+++([almost] 100%) ++

++

Pulse therapy >=250 for one or a few days

+++(100%) +++

Short Acting Preparations (t1/2 < 12 h)

Drug Anti-inflam. Salt retaining Preapartions & dose

Cortisol 1 1.0 5 mg tablet 100 mg/vial (i.m., i.v) Topical; enema

Cortisone 0.8 0.8 5 mg tablet 25 mg/vial (i.m)

Intermediate Acting Preparations (t1/2 = 12 -36 h)

Prednisone 4 0.8 -

Prednisolone 5 0.3 5, 10 mg tablet 20 mg/vial (i.m, intrarti)

Methylprednisolone

5 0 0.5, 1.0 gm inj. for i.m. or slow i.v.

Triamcinolone 5 0 4 mg Tab., 10, 40 mg/ml for i.m. & intrarticular inj.

Therapeutic principles

Dose selection empiric; Needs frequent evaluation Single dose: No harm Few days therapy unlikely to be harmful Incidence of side effects related to duration of

therapy Use is only palliative (except replacement therapy) Inter-current illness: Dose is doubled Abrupt cessation of prolonged high dose leads to

adrenal insufficiency (contraindicated)

Steroids in RA

. Attractive options for many patients with new-onset inflammatory arthritis since they are rapid acting and may be used intra articularly or systemically & since the dose may be titrated to achieve meaningful control while evaluation continues.

. Dramatically effective when used acutely but may be hazardous when used chronically. For these reasons, steroids should be avoided, weaned or used at the lowest possible dose after their introduction.

. Adverse events are numerous. The long term use of these drugs, even at low doses, may be associated with significant reversible & irreversible toxicities.

. The frequency of toxicity is proportional to the dose & duration of therapy.

Corticosteroids therapy is most effective and appropriate in three scenarios of early inflammatory arthritis.

1/ New onset early (<12 weeks) undifferentiated inflammatory arthritis in which oral, IM or IA steroids can be given in very early patients with the hope of inducing remission.

2/ New – onset RA for which prednisolone can be used as symptomatic therapy (usually in doses of 5-20 mg/day) in the first few weeks while the workup & symptoms evolve.

3/ Early – aggressive RA for which prednisone can be used as adjuvant therapy (usually part of DMARD combination regimen) where in high – dose prednisone (60 mg/day) acutely is followed chronically by 5-10mg daily

Acute Gout

Intraarticular Corticosteroids

Indicated in:1/ Patients with new onset inflammatory

monoarthritis2/ Acute focal flares of one or few joints3/ Patients disabled by synovitis in one joint despite

effective systemic therapyShould be avoided in:1/ Neuropathic joints2/ Infected joint or overlying cellulitisMost effective initially and less effective with

repeated injections.

Preparation

Methyl Prednisolone Triamcinolone: 40 mg/ml or 10 mg / ml

Knee joint

AnteriolateralInferiopatellarApproach

TibialPlateau

PatellarTendon

PatellaLateral SuprapatellarBursa

Joint Swelling - Synovial EffusionArthrocentesis and Injection therapy

Subacromial bursa

De Quervain’s tenosynovitis

Trigger finger

Plantar fasciitis

Pulse Corticosteroid Therapy

. Indicated in severe Lupus

. 3 daily IV infusions of 1000 mg methyl prednisolone

. Reserved for life threatening complications as nephritis, vasculitis, severe cytopenias, pericardial tamponade.

. Concomitant Cyclophosphamide

Lupus nephritis (WHO III)

Vasculitis

Adverse reactions (1/2)

Metabolic toxicity: Iatrogenic Cushing’s syndrome Hyperglycaemia, glycosuria, diabetes Myopathy (negative nitrogen balance) Osteoporosis (vertebral compression fracture) Retardation of growth (children) Hypertension, oedema,CCF Avascular necrosis of femurThe frequency of steroid toxicity is proportional to the dose

and duration of therapy

Avascular bone-necrosis

Adverse reactions (2/2)

• HPA axis suppression• Behavioral toxicity: Euphoria, psychomotor

reactions, suicidal tendency • Ocular toxicity: steroid induced glaucoma,

posterior subcapsular cataract.

• Others:– Superinfections– Delayed wound healing– Steroid arthropathy– Peptic ulcer– Live vaccines are dangerous

Contraindications

Infections Hypertension with CCF Psychosis Peptic ulcer Diabetes mellitus Osteoporosis Glaucoma Pregnancy : (prednisolone preferred)

Precautions during therapy

Following examinations of the patient to be done before, during and after steroid therapy

Body weightX-ray of spineBlood glucoseExamination of the eyeB.P.

Information >>> Judgement

New Glucocorticoid Receptor Ligands

1/ Time-release tablets:Already availabe in USA. Taken by night to optimize suppression of proinflammatory cytokines.

2/ Liposomes:small molecules 100nm in size, used as carrier system for GC.Reported in mice to accumulate selectively at site of inflammation.

Metselaar JM etal. A&R 2003,48:2059

3/ Glycyr-rhetinic acid:Inhibits 11 beta hydroxysteroid dehydrogenase thus increases level & action of endogenous GC.

4/ Nitrosteroids:Aromatic molecules which links a conventional GC drug with nitric oxide (NO). enhance anti-inflammatory effect & induces less osteoporosis than CG in animal models.

Paul – Clark MJ. Prox Natl Acad Sci USA 2002, 99:1677

5/ Selective glucocorticoid receptor agonists (SERGAs): Transrepression >> Transactivation

Schackett etal. Proc Natt Acad Sci USA, 2004, 101:227

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