Corticosteroid therapy in inflammatory bowel diseases · disease. Because of this many young pati-ents died of their disease. The introduction of corticosteroids has almost restored

Corticosteroidtherapy in inflammatory bowel diseases

The informed patient

Revised

edition 2012

11th revised edition 2012

U2

Publisher:

Leinenweberstr. 579108 FreiburgGermany

FALK FOUNDATION e.V.

www.falkfoundation.org

© 2012 Falk Foundation e.V.All rights reserved.


Corticosteroidtherapy in inflammatorybowel diseases

Prof. Dr. Tilo Andus

1

Author:Prof. Dr. Tilo AndusKlinik für Allgemeine Innere Medizin, Gastroenterologie, Hepatologie und internistische Onkologie Krankenhaus Bad CannstattKlinikum StuttgartPrießnitzweg 2470374 StuttgartGermany

2

Introduction 5

The natural role and regulation of corticosteroids in the body 7

• Anti-inflammatory properties of corticosteroids 12

• The effect of corticosteroids on metabolism 12

• The effect of corticosteroids on fluid balance 12

Treatment with corticosteroids 13

• Synthetic corticosteroids to im-prove efficacy and tolerance 13

• Different formulations for the treatment of ulcerative colitis 14

• “Topical” corticosteroids 16

• Efficacy in inflammatory bowel diseases 18

• Ulcerative colitis 18

• Pouchitis 20

• Crohn’s disease 21

• Microscopic colitis (collagenous colitis and lymphocytic colitis) 23

3


Contents Page


4

Page

• Endemic sprue / Celiac disease 24

• Tolerance and side effects 24

• Pregnancy and cortisol therapy 28

• Breast feeding and cortisoltherapy 28

Glossary 29

5

Introduction

The discovery of cortisol by E. Kendalland O. Wintersteiner in 1937, and itssynthesis by T. Reichstein for the firsttime in 1938, made it possible for Ph. S.Hench to use this substance for the firsttime in 1948 to treat a patient with arheumatic inflammation of the joint. Cortisol be longs to a class of hormonesknown as corticosteroids (often simplycalled cortisone in everyday speech).Hormones – the word comes from Greek and means “to set in motion” –are the body's own messengers. Theyare generally re leased from specialglands in response to a stimulus andcarried in the blood to their destinationsin the body. Hor mones then control anumber of metabolic processes in theirtarget organs.The rapid and potent anti-inflammatoryeffect of cortisol rapidly established thecorticosteroids as an effective treatmentin cases of acute and chronic inflamma-tion, and also helped its three discov -erers to get the Nobel Prize in 1950.

Even then it became clear that the desired activities of the corticoster oidswere accompanied by unwanted side effects and only gradually people didlearn to avoid these as far as possible,by target ing and limiting the use of corticosteroids.

Introduction

Treatment with corticosteroids was also asignificant advance for patients withinflammatory bowel disease. Even aslate as in the 50s, the life-expectancy of these patients was clearly reducedbecause there was no effective treatmentfor severe acute exacerbations of thedisease. Because of this many young pati-ents died of their disease. The introductionof corticosteroids has almost restored thelife-expectancy of patients with Crohn’sdisease and ulcerative colitis to normalvalues. The challenge today is to use corti-costeroids in such a way that patients alsoenjoy the highest possible quality of life asa result of their use. Meanwhile so-calledtopically active corticosteroids (see page16) are registered for the treatment ofmicroscopic colitis.

“Cortisone fear” is a widespread problem,resulting from inadequate knowledge in the general public and also in many pa -tients with inflammatory bowel disease. Itis therefore the aim of this patient adviceleaflet to present the most importantaspects of treatment with corticosteroidsin a comprehensible manner.

6

Corticosteroids in the body

The natural role and regulation of corticoster -oids in the body

The endogenous hormone cortisol andits precursor cortisone are produced inthe adrenal cortex.

The adrenals, consisting of medulla andcortex, are one of the organs in thebody which act as glands (fig. 1).

Fig. 1: Localization of the adrenals in

relation to the kidneys

Adrenal glands

Kidneys

Urinary bladder

Ureter

7


Cortisol is essential for the body. Theproduction of cortisol in the adrenalglands is stimulated by a controlling hor-mone, the adrenocorticotropic hormone(ACTH) (fig. 2). ACTH is produced in the pituitary gland (hypophysis), a glandwhich is only the size of a cherry stoneand which weighs less than 1g.

The release of ACTH is controlled by a further hormone, the so-called corti-cotrophin releasing hormone (CRH).

Fig. 2: The cortisol control system in the

hypothalamus, hypophysis and

adrenal cortex

ACTH

Cortisol

+

–

–

+

CRH

8

CRH is produced in the mid-brain in thecentral nervous system (hypo thalamus).

In this complicated system, cortisol it -self regulates its own release: high con-centrations of cortisol inhibit its ownrelease.

This type of control is known as a self-regulating feedback mechanism. Nerv -ous and inflammatory stress factors alsohave an effect upon this regulatory loop.

Cortisol is normally secreted in a rhythm

that depends upon the time of day.The greatest amounts are released inthe early morning, smaller amountsbeing produced there after (fig. 3). Onlyin the evening is there a second smallerpeak. Altogether, the adrenal corticesproduce about 8 – 25 mg cortisol perday.

Fig. 3: Diurnal (related to the time of day)

rhythm of blood cortisol levels

18 20 22 0 2 4 6 8 10 12 14 16 18

25

20

15

10

5

0

Time

Plasma cortisol [μg/100ml]


9

Under severe stress, such as seriousillnesses, the body requires more corti-sol. Because of this, the adrenal corticesare able to produce up to 200 – 300 mgper day in such situations.

All corticosteroids, including cortisol, act by “binding” to specific receptors

(re cognition sites) on cells and thenalter ing their metabolism. Thus, for ex -ample, they stimulate the degradation of proteins. Since almost all cells in thehuman body possess this type of recep-tor, corticosteroids also act upon almostall cells.

This multiplicity of activities can bebroad ly divided into three groups:

1. the anti-inflammatory effects,

which are also important for efficacy inthe treatment of inflammatory boweldisease,

2. the metabolic effects (applying to

the general metabolism), which arealso responsible for the occurrence ofside effects and

3. the activities which affect fluid

balance (mineral metabolism).


10

Fig. 4: Inhibition of inflammation by

corticosteroids

Precursorcells in thebone marrow

Inflammatorycells in theblood stream

Increase

Specialization

Migration

to inflammation

Activation

Release of

inflammatory

factors

Inflammatory cells in, forexample, the gut, the joint…

Co

rtic

oste

roid

s

–

–

–

+

+


11


Anti-inflammatory properties of

corticosteroids

The anti-inflammatory effect is due tothe fact that corticosteroids inhibit themultiplication (proliferation) and develop-ment (differentiation) of inflammatorycells in the bone marrow, the migrationof inflammatory cells from the bloodinto the gut and the activation of theseinflammatory cells (fig. 4). Corticoster -oids also have a direct effect upon alltypes of inflammatory cells, as well asthe white blood cells (leukocytes). Inthese, they inhibit the release of inflam-matory hormones, such as the cyto -kines, which stimulate inflammation.

The effect of corticosteroids on

metabolism

The effects upon general metabolismare even more varied. Corticosteroidsaffect the metabolism of the liver, themuscles, the fatty tissues, the bonesand ligaments, and many other organs.

The effect of corticosteroids on fluid

balance

The effect upon fluid balance occursbecause cortisol bears a certain resem-blance to another hormone – aldoster -one – which affects fluid balance by itseffect upon the excretion of minerals inthe kidneys. Like aldosterone, cortisolincreases the retention of sodium andwater in the body.

12

Treatment with corticosteroids


Very soon after cortisol was first used inthe treatment of inflammatory diseases,attempts were made to increase its effi-cacy, and at the same time to reduceunwanted side effects, by chemicalmodifications.

Synthetic corticosteroids to improve

efficacy and tolerance

The development of corticosteroidssuch as prednisone, prednisolone and 6-methyl prednisolone resulted in corti-costeroids with hardly any or with noremaining effect upon mineral metabo-lism whilst at the same time increasingtheir anti-inflammatory efficacy.

Prednisolone and prednisone have ananti-inflammatory activity about fourtimes as great as endogenous cortisoland 6-methyl prednisolone is as muchas five times more effective.

Since all anti-inflammatory and meta -bolic effects are mediated via the samereceptors on the cells it is very difficultto separate the desired effects from the unwanted side effects. In order toachieve progress here, attempts weremade to transport the active substancedirect to the site of inflammation, in

13

order to minimize the systemic effects,produced by circulation in the blood(topically active steroids, see page 16).

Different formulations for the

treatment of ulcerative colitis

Initially, formulations for the treatment of ulcerative colitis were produced thatachieve a high concentration of corti -costeroid only in the bowel, namely in those parts where the inflammation is located. It was possible to achievethis goal in part by the development ofenemas. Relatively high local concentra-tions of corticosteroid can be achievedin the rectum and distal parts of the large bowel through the use of cortico-steroid enemas (fig. 5).

Nevertheless, some of the corticoster -oid applied in this way is absorbedthrough the gut mucosa and leads tounwanted side effects, albeit to a re -duced extent. Corticosteroid foams arejust as effective as the enemas but arepreferred by most patients because oftheir ease of use. In addition, becauseof the consistency and volume of thefoam, most patients are better able tocontain the foam.


14

In more severe cases of disease, how -ever, corticosteroids must be adminis -tered in the form of tablets, capsules, oreven as intravenous injections, in orderto achieve an adequate effect.

Fig. 5: Efficacy of corticosteroid enemas and

foam preparations in the large bowel


Stomach

Small bowel

Large bowel

15

“Topical” corticosteroids

In an effort to preserve the efficacy ofthe corticosteroids whilst reducing theside effects of these substances, so-called “topical” cortico steroids havebeen developed in recent years. Theterm topical means that the activity isexerted predominantly at a local level, at the site of inflammation. The principleof “topical” corticosteroids will now beexplain ed using the example of budeso-nide, which has long been used success -fully in asthma therapy, in the treatmentof acute Crohn’s disease flares withinvolvement of the ileum and/or theascending colon and has been approvedfor rectal therapy of ulcerative colitis aswell as collagenous colitis.

Fig. 6: The uptake and breakdown of

budesonide in the body


Oral budesonide

Heart

Stomach

Liver

Large bowel

Colon ascendens

Small bowel

Ileum

Sigmoid

Anus (Rectum)

Rectalbudesonide

10% systemically

active (active

in the

whole body)

90% broken

down in

the liver

16

Budesonide is a very highly active corti-costeroid. It is rapidly absorbed throughthe intestinal mucosa when adminis -tered orally or rectally after acting at thesite of the inflammation, and is carriedto the liver. Here, in contrast to the corti-costeroids in use hitherto, more than90% of the budesonide is broken downduring the first passage through the liverso that only a small proportion gets intothe body. This means that fewer sideeffects are to be expected (fig. 6).

In order for oral budesonide to arrive atthe site of inflammation in the bowel, itis crucial that it must not be absorbed inthe upper segments of the small boweland thus enters the blood stream. Inother words, in the upper parts of theintestine. As a consequence, a specialcoating must be used to make sure that the active agent is only released at the site of inflammation (particularlyat the boundary between the small andthe large intestine).

It must, however, be noted that, as aresult of these coatings, inflammation in the esophagus, in the stomach and inthe upper parts of the small intestine,such as the duodenum, cannot be treated by these formulations. For thetreatment of diseases in these bowelsegments new budesonide preparationsare under development. It is also truethat in cases of severe disease it maybe necessary to use systemically activecorticosteroids.


17

Efficacy in inflammatory bowel

diseases

In general corticosteroids are currentlythe most effective drugs for the treat-ment of acute exacerbations of inflam-matory bowel diseases (ulcerative colitisand Crohn’s disease). Long term treat-ment with systemically active cortico-steroids should, however, be avoidedwhere possible.

Ulcerative colitis

Mild to moderately active

ulcerative colitis

In mild to moderately active ulcerativecolitis, treatment with 5-aminosalicylicacid (mesalazine) is generally adequate.Occasionally a short course of systemi-cally active corticosteroids (for example40 mg per day of prednisolone), with arapid dosage reduction of 10 mg every 5 days and a halt to corticosteroid treat-ment within 3 weeks, may lead to amore rapid alleviation of the symptoms.As an alternative, a combination therapyconsisting of tablets and enemas orfoam preparations may be applied before.Most patients respond rapidly to thistreatment. Not infrequently, the thera-peutic advantages of systemic cortico-steroid therapy are somewhat reducedby the occurrence of side effects.


18


Left sided ulcerative colitis

In left sided ulcerative colitis, in whichonly the final 50 cm of the large bowelis affected, 5-aminosalicylic acid (mesa -lazine) enemas or foam preparationshave been preferred, and – wherenecessary – corticosteroid foam pre -parations or enemas, because these a chieve the highest concentrations of ac tive substance in the area of the in flam mation. In severe cases, it may benecessary to administer a combinationof 5-aminosalicylic acid (mesalazine) andcorticoster oid rectally, or possibly even acombination of enemas and oral formu-lations (tablets, capsules).

Highly active ulcerative colitis

Highly active ulcerative colitis alwaysrepresents an acute danger to the pa -tient. In these cases it is often unclearwhether tablets can still be effective.On the other hand, enemas and foampreparations are generally unable to beretained for a sufficient period owing tothe severe diarrhea. Because of this, in-patient treatment and the intravenousadministration of high doses of cortico-steroids are necessary in such cases.Additional therapeutic meas ures mustbe introduced according to the severityof the disease.

19

Inactive ulcerative colitis –

mainte nance of remission

On the basis of what we know at pre-sent, corticosteroids should not be usedfor the so-called maintenance of remis-sion (remission = freedom from symp -toms/absence of active disease), sincethey are unable to achieve this, and patients will only be troubled by the pos-sible side effects. First-line agents insuch cases are preparations containingaminosalicylic acid (mesalazine). Thistherapy may reduce the risk of coloncancer.

Patients who do not tolerate mesalazinemay benefit from the probiotic E. coliNissle 1917.

Pouchitis

When, as a result of ulcerative colitis,patients require complete surgical remov -al of the colon, a small bowel reservoir(pouch) can be created in many cases,thus permitting regular passage of stoolthrough the anus.

In some cases, however, the pouch maybecome the site of chronic inflamma -tion. The standard therapy in such casesconsists in the administration of theantibiotic metronidazole. As an alterna -tive, if better tolerated, budesonide canbe used as an enema or foam.


20


Crohn’s disease

Mild to moderately active Crohn’s

disease

Mild to moderately severe attacks ofacute Crohn’s disease can be treatednowadays either with 5-aminosalicylicacid (mesalazine) or corticosteroids.Corticosteroids are more effective than5-aminosalicylic acid. This is also accept -ed for the topical acting corticosteroidbudesonide. For corticosteroids, the 6month therapeutic schedule (tab. 1) forthe treatment of acute Crohn’s diseaseis increasingly being abandoned sincethe majority of patients respond muchmore rapidly to treatment of this sort.Moreover, the rate of side effects forsystemically active corticosteroids isrelatively high.

Tab. 1: Treatment schedule of active Crohn’s

disease using prednisolone as an

example

Weeks Daily dose of prednisolone

1 60 mg2 40 mg3 35 mg4 30 mg5 20 mg6 15 mg7–14 10 mg3–6 months 5–10 mg

21


Depending upon the disease activity, a variable reduction is recommendednowadays.

The “topical” corticosteroid budesonideis also used as an oral preparation in thetreatment of Crohn’s disease. It is takenas a capsule containing pellets that areresistant to gastric juice. Budesonide is then released from the pellets in thesmall bowel and the large bowel andacts directly on the bowel mucosa. After absorption, budesonide will beinactivated in the liver. Best results willbe obtained, if the end of the smallbowel (terminal ileum) will be inflamed.If the rectum is affected, combinationtherapy with enemas or foam prepara -tions or systemically effective corti coster -oids are recommended.

Highly active Crohn’s disease

As in ulcerative colitis, in these caseswe are also dealing with a serious situa-tion requiring in-hospital treatment andadministration of a high dose of cortico-steroids in the form of injections. Ifnecessary, addi tional therapeutic meas -ures must also be taken in such cases.

22

Inactive Crohn’s disease – mainte -

nance of freedom from symptoms

(maintenance of remission)

Corticosteroids are not recommendedfor maintenance of remission.

Microscopic colitis (collagenous

colitis and lymphocytic colitis)

Because cases of microscopic colitis are rare and can only be diagnosed bycareful examination of tissue samplesfrom the colon (they normally cannot be recognized macroscopically atcolonos copy), it often takes time beforethe diagnosis is made. They result inchronic watery diarrhea.

Budesonide as capsules or granules, isagent of choice in both forms of micros-copic colitis – collagenous colitis andlymphocytic colitis. It exhibits good efficacy and few sideeffects. The standard dose is 1 x 9 mg a day or 3 x 3 mg a day. With this treat-ment, the frequency of bowel move-ments improves in about 90 % of pa -tients and, in about 80 % of patients withcollagenous colitis, there is improvementin the collagen deposits that form in the wall of the colon. This is even true in cases in which other therapies, such as 5-aminosalicylic acid, metronidazole


23

or prednisolone have failed.Based on patients’ symptoms, the doseof budesonide can be reduced duringtreatment. Patients, however, must takemedication long-term.

Endemic sprue / Celiac disease

Endemic sprue or celiac disease is achronic inflammatory disorder of thesmall bowel, which is triggered by glu-ten and gliadin, both proteins found ingrains. Patients experience diarrhea,iron and vitamin deficiencies, weightloss and growths in the small bowel.

The standard therapy consists in a dietfree of gluten and gliadin.

In the few cases of endemic sprue orceliac disease that are refractory totherapy, patients have been successfullytreated with prednisolone and, morerecently, with budesonide, a corticoster-oid that is associated with a much lowerrate of side effects.

Tolerance and side effects

Prolonged treatment with systemicallyactive corticosteroids leads to sideeffects which frequently force the dos -age to be reduced or treatment to bediscontinued. The simultaneous appear -ance of a number of visible side effectsof corticosteroids such as weight gain


24

with truncal obesity, moon face, buffalohump, stretch marks on the skin (striae),is also termed Cushing’s syndrome.Possible side effects of corticosteroidsare listed in table 2.

The long list of possible problems associated with corticosteroid treatmentalso underlines how important it is tosearch for new corticosteroids withfewer side effects.


25

Tab. 2: Possible side effects of cortico -

steroids

Possible side effects

of corticosteroids

• Weight gain with truncal obesity, moon face,buffalo hump

• Striae (stretch marks on the skin), ecchymo-ses (small hemorrhages in the skin), acne

• Atrophia of the adrenal cortices• Increase in blood pressure• Osteoporosis (loss of bone) and aseptic

disturbance of blood flow (bone necrosis)• Electrolyte disturbances, for example, lack

of potassium• Cataract and glaucoma• Insomnia, psychosis• Nerve damage• Inflammation of the muscles, muscle wasting• Increased susceptibility to infection (tubercu-

losis, fungal diseases)• Disturbances of growth (in children)

26

In the following section, some of thepossible side effects of corticosteroidswill be described in greater detail, to -gether with advice as to what can bedone for them.

Osteoporosis is a common and potenti-ally severe complication following pro-longed treatment with corticosteroids.Spontaneous fractures may occur. Corti-costeroids inhibit the formation andstim ulate the breakdown of bone by in -hibiting the uptake of calcium in the gutand stimulating the release of parathor-mone (a hormone which promotes thebreakdown of bone). If necessary, calcium and vitamin D must be taken. There is evidence that, compared withsystemic corticosteroids, budesonide ismuch better tolerated than systemiccorticosteroids also with respect to therisk of osteoporosis.

Corticosteroid-induced bone necrosis isa severe disturbance of blood supply to the bone. Fortunately, it is rare. It pre dominantly affects the hip joint andmanifests itself as pain.

Prolonged treatment with corticoster -oids may lead to a atrophia of the adre-nal glands because the endogenous cor-tisol production is suppressed.

It is therefore necessary to avoid break -ing off treatment with corticosteroidssuddenly and to stop them very graduallyby reducing the dose so that the adrenal


27

cortex has sufficient time for regene ra -tion and can itself secrete cortisol again.Strong fatigue or faintness may be typi-cal symptoms for rapid decrease of cor-ticosteroid dosage.

Lens opacities (cataracts) and an in -crease in the internal pressure of theeye (glaucoma) are also rare. In order tobe able to make the diagnosis at an early stage, regular ophthalmological ex -ami nations should be carried out in pa -tients on long-term treatment with corti-costeroids. If necessary, the preparationmust be changed or treatment must bediscontinued.

Suppression of the immune system bycorticosteroids also weakens resistanceto infection. Because of this, when there are palpable masses in the abdo-men, the presence of an abscess (col lec tion of pus) must be excluded be -fore treatment with corticosteroids isstarted.


Pregnancy and cortisol therapy

No increased risk of abortion. The new-born has to be carefully examined by apediatrician, if high dosage of cortico-steroids are used during the last periodof pregnancy. An insufficient treatmentof inflammatory bowel disease could bemore dangerous for both, the motherand the baby, than an adequate cortisoltherapy.

Because of the limited experience withthe drug, there is no general recommen-dation for the administration of budeso-nide during pregnancy.

Breast feeding and cortisol therapy

Cortisol may be excreted into breastmilk and therefore reach the infant.Suppression of the cortisol metabolismseems to be possible. This should becarefully checked by a pediatrician.Permanent damage are not expected.


28

Glossary

Glossary

5-aminosalicylic acid (5-ASA; mesa -

lazine): active constituent of many medicines for the treatment ofinflammatory bowel diseases

Abscess: collection of pus

ACTH: adrenocorticotropic hormone; controlling hormone that stimulatesthe formation and secretion of corti-costeroids. ACTH is produced in thepituitary gland.

Aldosterone: hormone of the adrenal cortex which affects fluid balance

Bone necrosis: severe disturbance of blood supply to the bone withdestruction of bony tissue

Budesonide: topically (locally) acting, potent corticosteroid, which can beadministered in the form of capsules,granules, foam or enemas

Cataract: opacity of the lens of the eye caused by a variety of factors (con -genital or acquired)

Collagenous colitis: type of microscopiccolitis characterized by developmentof a band of collagen fibers over 10 μm in thickness

Colon: large bowel

29

Glossary

Corticosteroids: class of hormones thatare released from the adrenal cortices

Cortisol: hormone belonging to the corticosteroid family, regulates a large variety of metabolic processes

CRH: corticotrophin releasing hor -mone; a controlling hormone whichregulates the secretion of ACTH.CRH is produced in the hypothal -amus.

Crohn’s disease: inflammatory disease of the digestive tract, named after Dr. Burrill B. Crohn, the doctor whofirst described the disease. Commonin the region of the lower ileum (partof the small bowel) and the colon (large bowel).

Cushing’s syndrome: typical clinical picture which is produced by theincrease of cortisol in the plasma andwhich can arise during prolonged and high-dose administration of corti-costeroids

Cytokines: hormones which mediate inflammatory reactions (inflammatorymediators)

Differentiation: further development (specialization) of cells

30

Endemic sprue / Celiac disease: chronic inflammatory disorder of the smallbowel triggered by intolerance tograin proteins

Glaucoma: general term for diseases of the eye in which there is an in -crease in the pressure within the eye

Hormone: a messenger substance produced in the body which regulatesmetabolic processes

Hypothalamus: central nervous region of the mid-brain

Ileum: the lowest section of the small bowel

Immune system: complex system for warding off substances that are foreign to the body

Lymphocytic colitis: type of microscopic colitis characterized by increasednumbers of lymphocytes in the tissuesamples

Microscopic colitis: chronic inflammatory disorder of the colon, which can onlybe diagnosed by microscopic exami-nation of tissue samples obtainedfrom the colon

Migration: movement of inflammatory cells from the blood into the bowel

Glossary

31

32

Osteoporosis: loss of bony tissue through increased destruction of bone and/or reduced formation of bone

Parathormone: hormone which is produced in the parathyroid glands and which, among other things, increases the breakdown of bone

Pouchitis: inflammation of the pouch following surgical removal of thecolon in ulcerative colitis

Proliferation: multiplication of cells

Psychosis: impairment of the state of mind, leads to a change in the whole structure of experience

Remission: the state of being free of symptoms in a chronic disease

Ulcerative colitis: chronic inflammationof the large bowel

Glossary

Further information for patients

with inflammatory bowel

diseases:

– Microscopic colitis – Collagenous and lymphocytic colitis (Bu82e)27 pages

– Ulcerative colitis and Crohn’s diseaseAn overview of the diseases and their treatment (S80e)72 pages

– Diet and Nutrition in Crohn’s Disease and Ulcerative Colitis20 Questions – 20 Answers (S84e)60 pages

– Crohn’s disease and its associated disorders(S85e)44 pagesRevised edition 2012

These brochures can be ordered free of charge

from Falk Foundation e.V. or the local Falk partner.




www.falkfoundation.org

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Corticosteroid therapy in inflammatory bowel diseases · disease. Because of this many young pati-ents died of their disease. The introduction of corticosteroids has almost restored