GLUCOCORTICOIDS IN ALLERGIC DISEASES

Acta med. scand. Suppl. 500, pp. 43-48, 1969

GLUCOCORTICOIDS IN ALLERGIC DISEASES

by Michael Schwartz

The logical treatment of allergic diseases and allergic reactions in general --to remove the responsible allergen from the patient or the patient from the allergen - is just as correct in theory as it is difficult or impossible to achieve in practice,

In some cases it is possible to “accustom” the body to contact with the compounds against which, usually for unknown reasons, it has formed antibodies, by means of the so-called desensitization therapy, and in this way to prevent or weaken the allergic reaction. There are, however, large gaps in our understanding of this treatment, and in the majority of allergic diseases the results are very poor. It is necessary to acknowledge that so little is known today about the allergic diseases that in by far the majority of cases the treatment is expectant and purely symptomatic. The situation in the allergic diseases does not, therefore, differ greatly from that in the other disorders which are discussed in this symposium.

The allergic diseases which will be discussed in the following are:

Hay fever I Bronchial asthma Vasomotor rhinitis I I the atopic disorders

Resnier ’s prurigo I

These disorders are presumably due to a common genetic constitution and have many features in common (6).

To these may be added: Urticaria and angioneurotic oedema (Quincke) Allergic reactions to drugs Allergic shock Allergic skin diseases Gastro-intestinal allergy

Finally, it is probable that a number of the other disorders and reactions which have been discussed

in this symposium are due to antigen-antibody reactions (certain blood disorders, certain liver diseases, renal and gastro-intestinal diseases), but these are traditionally dealt with under the organs concerned.

The use of the glucocorticoids in allergic disease began in 1949, as soon as cortisone (and ACTH) was introduced. Today -and like Dumas we can say 20 years after - a considerable body of experience has been accumulated concerning the practical clinical applications of these agents in allergic disease. But unfortunately the hope which was raised of obtaining a better aetiological and, especially, patho- genic understanding of these disorders through the action of the corticosteroids has been disappointed.

Today-as was the case 20 years ago -we still speak of the anti-allergic action, which is very considerable, of the glucocorticoids, without knowing what it is we really mean. In contrast to the antihistamines the glucocorticoids have no measurable effect on the urticaria1 cutaneous reaction, which is perhaps manifest most typically in hay fever, and they similarly do not affect the allergic antibodies (reagins) in the blood. On the other hand, the corticosteroids are most effective in asthma, in which the effect of the antihistamines approximates to zero.

It is more reasonable to consider that the often dramatic action which may be achieved with the glucocorticoids in allergic diseases is associated with the anti-inflammatory effects of the agents. Thus the glucocorticoids have a marked suppressive effect on the antigen-antibody reaction of the type “delayed hypersensitivity”. It is then another question of how much is in fact known about the anti-inflammatory action.

One very important feature of the effect of the glucocorticoids on allergic diseases and reactions - of whatever type these may be --is that there is no question of an instantaneous effect. Regardless of whether the patient suffers from asthma, vasomotor

44 Michael Schwartz

rhinitis, or eczema, there is always an interval of up to ten hours following the administration of a full therapeutic dose before the effect begins to be manifest. This is found regardless of the mode of administration (3). There is thus nothing to be gained by using intravenous injections of glucocorticoids in allergic (anaphylactic) shock, where the treatment of choice is still epinephrine.

There would seem to be no difference in the action of the various synthetic glucocorticoids in allergic disease. The latest synthetic glucocorticoids are thus no better than prednisone, which is used by the majority of physicians, including the author. Ad- ministration of the adrenocorticotropic hormone (ACTH) has the same effect as the steroids, but for a number of reasons this form of treatment is no longer used very often. The present writer, who can remember the very dramatic effect of ACTH in the early period when cortisone was in short supply, will not be surprised if it should turn out that the steroid production which is induced by ACTH in the adrenals, in some way or other is found to have a particularly marked anti-allergic effect.

GENERAL LINES I N THE TREATMENT OF ALLERGIC DISEASES

WITH CORTICOSTEROlDS As mentioned, glucocorticoid therapy is generally not the treatment of choice in allergic diseases. In many cases these disorders are quite transient and their course is so harmless that either no treatment or another form of symptomatic treatment is to be prefered.

Steroid therapy is not curative but merely symptomatic, and not unless the symptoms reach a considerable degree of severity should the use of these agents be contemplated.

On the other hand, many of the allergic diseases and reactions are often transient, self-limiting occur- rences, as for example many of the allergic reactions to drugs, and serum sickness. In these conditions there is no great danger that the patient would enter the more dangerous long-term steroid therapy, and in such cases it is not necessary to hesitate too long before initiating steroid therapy. However, it is important to be aware of the spontaneous course of these disorders in order to be able to withdraw the hormones as soon as possible after the spontaneous cure has occurred.

Where the allergic disease is of a chronic nature,

as vasomotor rhinitis, Besnier’s prurigo (which is, however, usually treated with local applications) and that disorder which is of greatest importance, asthma, then the situation is quite different. In all these disorders, the glucocorticoids have an admir- able symptomatic effect which, especially in the case of asthma, one could not do without nowadays. On the other hand, it should be stressed that the more effective such an agent is in a chronic disease, the more difficult it is to withdraw the treatment. Asthma patients are, therefore, particularly common partic- ipants in the group of those receiving long-term corticosteroid therapy, which involves all the risks which will be discussed later in this symposium.

GLUCOCORTICOID THERAPY I N ALLERGIC DISEASES AND REACTIONS

OF SHORT DURATION H a y fever

By far the most common form in Denmark is due to grass pollen and lasts as a rule from a few weeks up to two months, being partly dependent on local conditions.

In severe manifestations, in which conventional treatment with desensitization t antihistamines has proved inadequate, it may be necessary to conteni- plate the use of glucocorticoids. The principle is to give a moderately large dose initially, e. g., prednisone 10mg q.i.d. for two days, and thereafter rapidly to reduce the dose (over two to three days) to 5 mg q. i. d. or less. The dosage must be adjusted to the effect, and it is useful to ascertain the pollen count in the air in order to determine the duration of treatment. Here in Denmark the newspapers do not give reports of the pollen counts, but information obtained from other patients with hay fever may give guidance. Another form of dosage for corticosteroid therapy in hay fever has become accepted during recent years: the use of injections of crystalline suspensions. Good results of the injection treatment of hay fever with methylprednisolone (80mg per dose) have been reported from Den- mark (5). It is possible for the patient to get through the season on very few injections.

Bronchial asthma

Steroid therapy of the acute asthma attack, and also of its most severe manifestation status asthmaticus is the most effective treatment available in this disorder. The rule mentioned previously applies here:

Clircocorticoids in allergic diseases 45

The treatment of choice in urticaria (and allergic angioneurotic oedema) should be the antihistamines rather than the steroids.

one should not use a sledge hammer to crack a nut. In mild attacks other symptomatic therapy should always be tried first, and often this will prove ade- quate. If the attack does not disappear within a reasonable length of time, the patient will often be Serum sickness admitted to hospital, and if this in itself does not bring the attack to an end, then steroid therapy may be considered.

The principle behind the treatment is exactly the same as that in hay fever. The most important points are to begin with a large dose and to keep the duration of treatment short. In the acute attack and in status we usually employ the “old-fashioned” ACTH therapy, beginning with 60 units q. i.d. and rapidly diminishing the dose with withdrawal after eight days.

This standard treatment brings almost every attack of asthma to an end, and has moreover the advantage that it also brings itself to an end. A completely comparable self-limiting course of steroids in acute asthma is recommended by the Medical Research Council in England: 60 mg prednisone on the first day, falling by 5 mg daily until the end of the course after 12 days ( 2 ) .

Short courses of steroid therapy for asthma patients who are to undergo operations, especially in the thorax, generally lead to an improvement in the pulmonary function to the best which can be achieved in that particular patient.

The contra-indications to treatment are the usual: peptic ulcers, heart failure, mental illness, etc., and as usual the contra-indications are not absolute if treatment is really imperative.

Urticaria and (allergic) angioneurotic oedema

In introduction it may be mentioned that the dom- inant inherited form of angioneurotic oedema, which IS due to an absence of the serum inhibitor of C1-esterase, has nothing to do with allergy, and the effect of steroids in these cases is dubious.

The most important thing in these disorders is to clarify the aetiology, which frequently turns out to be a drug of one sort or another, and the duration of the illness is therefore limited if the cause is removed. The principles of steroid therapy are the same as those in hay fever. As a rule steroid therapy must be continued for at least one and often two weeks - but if at all possible, no longer. Month-long courses of steroids in urticaria (so-called “chronic” urticaria) -the aetiology of which is unknown - should only exceptionally be necessary.

This disorder is probably rare nowadays, but prophylactic treatment with 1 ml tetanus antitoxin does lead to occasional cases being admitted to almost every medical department during any year. The dominating symptoms are usually urticaria and angioneurotic oedema, and they almost always disappear rapidly and quite spontaneously. It would have to be an unusually severe case for the physician to be tempted into giving glucocorticoid therapy. The lines to be followed are the same as in urticaria. It will usually be found that just when the decision to use steroids has been taken, the symptoms disappear of themselves.

Allergic shock

Allergic (anaphylactic) shock is a state to be dreaded. In by far the majority of cases, it is the doctor him- self who is an essential factor in the aetiology, as he has prescribed, or injected, the agent which has pro- duced the shock. As mentioned above, there is a considerable latent period before any effect of glucocorticoids is manifest in allergic conditions, and although steroids may have a valuable therapeutic effect in the late sequelae of an antigen-antibody reaction such as, for example, oedema following the use of serum, it is not the steroids which should be considered in the first place. It is epinephrine, antihistamines, and other symptomatic treatment of shock which are required. If it is considered desir- able to give glucocorticoids, they can just as well be given orally in this situation. To start treatment of allergic shock with steroids is to waste precious time.

Allergic reactions to drugs

It is outside the framework of this symposium even to count up the many manifestations of drug allergy. Many forms are dealt with elsewhere in the symposium, for example those occuring in certain blood diseases, liver diseases, peri-arteritis nodosa etc. The most common are probably the dermatological manifestations and several of these, especially exfoliative erythrodermia, may be life-endangering.

Once the diagnosis is established the problem - whether or not to use glucocorticosteroids -must be settled by the course of the illness. Certain con‘

46 Michael Schwartr

ditions e. g. exfoliative erythrodermia - form absolute indications for treatment, and are perhaps among the greatest triumphs attributable to steroid therapy. Other cases, such as those of quiet, transient erythema, are best treated expectantly, possibly with calamine lotion. If it is decided to give glucocorticoid therapy, then full doses should be given, e. g. 40-60-80 mg prednisone daily, with a subsequent gradual slow and tentative reduction. Naturally, the drug suspected of giving rise to the condition must be withdrawn possibly all drugs, if there is any doubt.

These reactions are characteristically acute, often of very dramatic appearance, but as a rule transient. The subjective disturbances: itching, burning in the skin, erythema, oedema, etc. may be considerable. The effect of steroid therapy is generally very satisfactory and of rapid onset. Most frequently it is possible to conclude therapy within a fortnight. On the withdrawal of treatment there seems sometimes to be some “excitement” in the skin again, but this disappears spontaneously without it being necessary to restart the treatment.

The effect of steroids on allergic drug reactions is, as mentioned above, extremely satisfactory on condition that the administration of the allergen ceases. The effect is far more dubious if, for some reason or other, the administration of the drug to which the patient is sensitive is continued. Similarly, it is not to be anticipated that the glucocorticoids will have any particular prophylactic effect when they are given in the hope of permitting the use of drugs to which the patient has previously shown severe reaction. This form of treatment is extremely dangerous and should only be attempted when it is a matter of life or death.

LONG-TERM THERAPY WITH GLUCOCORTICOIDS

IN ALLERGIC DISEASES Bronchial asthma

Asthma is by far the most important of the allergic diseases both with regard to incidence and to severity. The use of glucocorticoids in the treatment of the acute attack has been described in brief above.

Long-term corticosteroid therapy of asthma should be considered when the illness does not permit the patient to lead a normal, or nearly normal, life, and where other therapy has proved to be ineffective.

All studies over the years have unanimously demonstrated the extremely satisfactory results of

such treatment, and there are by now such large groups of patients treated in this manner, who have been observed for sufficiently long periods, for it to be possible to give general and consistent directions for this treatment. The experience gained over the years has proved to be quite uniform from one group of workers to the next (2, 3, 4, 8).

indications fbr long-term steroid thrrap-v in asthma

a) The first prerequisite before starting on a long- term glucocorticoid treatment which may last for years, or even throughout the patient’s life, is that conventional therapy has proved ineffective, or else has had so little effect that the patient is severely handicapped by his illness. If there is any doubt about this then the patient should be observed for a suitable period on conventional therapy. b) A second important consideration is whether steroid therapy will be effective in the particular patient concerned. It is necessary to ensure that the action of the steroids is so marked that it is worth- while taking the risks involved. Useful information in this respect may be gained by ordinary clinical observation, including stethoscopy, but it is better to employ more objective measurements of the pulmonary function, for example examination of the F.E.V. c) The patient (and his doctor!) must understand the principle of the treatment, especially that the steroids are not drugs to be taken against the acute attack in the same way as ephedrine, spray, etc. The patient must follow the doctor’s instructions, and the doctor must be willing constantly to maintain contact with his patient. Asthma patients on long- term steroid therapy in whom there is sudden dete- rioration of the illness run the risk of the attack proving fatal within a few hours. In serious deteri- oration of the illness -as may be seen especially i n acute respiratory tract infections the dose of steroids must immediately be increased to full strength (40-60 nig prednisone), and it is possible to save a great deal of time if the patient is aware of this. I t may take 24-36 hours before the steroid effect again reaches its height. In more severe attacks these patients should always be admitted to hospital (4).

Duration of treatment The final aim of the treatment is to be able to withdraw the steroid therapy. Experience has shown that this is only rarely possible (about 10 O/” of patients)

Clucocorticoids in allergic diseases 41

and that it may represent a risk. Maunsell et al. (4) report that 11 out of 52 patients developed status asthmaticus in connection with attempts to withdraw steroids, and three of them died. In such cases in particular it is important to restart the treatment at once, and not to try to treat the patient expectantly. Patients with rheumatoid arthritis develop joint pain etc. when steroids are withdrawn. Patients with asthma develop bronchial constriction which may well prove fatal.

Apart from this, there is a certain degree of addic- tion associated with steroid therapy which makes it even more difficult to withdraw these drugs.

Dosage of glucocorticoids As in acute asthma, the initial dose should be rela- tively large (40-60 mg prednisone in four divided doses). The dosage is then reduced over a few days to about 20 mg daily, and attempts are made, under the guidance of the effect, to reduce it as far as possible by means of a slow and gradual diminution in dosage. The majority of patients in whom it proves necessary to continue usually end with a dose of 5--15 mg prednisone daily. J t is undesirable to give larger doses, and less than 5 mg daily approaches homeopathy, although there are patients who say that they cannot do without their 2.5 mg every, or every other, day. A dose of steroids which keeps the patient completely symptom-free is in general too large.

Naturally, advantage should at the same time be taken of the effects of other drugs (theophyllamine, spray, etc.).

It may be mentioned that even after many years of treatment the effect of the steroids would seem to remain constant. It is unnecessary to fear that one will be obliged to increase the dose over the years (4).

Effect of treatment On the whole it can be said that there is an excellent effect of long-term steroid therapy in about 60 I)/(, of asthma patients, some effect in about 25 O l i o , and therapeutic failure in only about 5 “/,,-lS o/o of asthma patients.

The effect is more or less uniform regardless of sex and age and also of the duration of the illness.

It is hardly surprising that mild cases react more favourably than severe.

It is of no consequence to the effect of the treatment whether the asthma is due to infection alone (“intrinsic asthma”) or whether there are also con-

vincingly demonstrable external factors which pro- voke the attacks. The risks of fatal asthma on attempts to withdraw therapy and particularly when it is not restarted in full dosage have been described above.

Side-effects of steroid therapy of asthma This question is dealt with elsewhere in the symposium. The incidence is given as about 20°/,, but must vary according to what are understood as side- effects. There would not appear to be any risk of increased tendency to infection, even after a number of years of treatment, and the other side-effects are those which are generally recognized. Many asthma patients have now received treatment for 5-10 years or even longer.

In children an extra complication which may be seen is retardation of growth. After reduction of the dosage or withdrawal of the treatment the children are stated to catch up again. Several authors state that it is necessary to be considerably more reluctant to give steroid therapy to children than to adults.

Inhalation therapy with steroids The writer has no personal experience of this form of treatment. Despite the fact that theoretically there should be certain advantages of this method, it has proved disappointing in the majority of trials. The difficulty lies in, among other things, obtaining a particle size which is not so small as to give merely an absorption effect, and not so large that the drops do not reach the bronchioli (1 ) .

The conclusion must be that long-term steroid therapy in asthma is here to stay. Despite the by no means inconsiderable risks it must be accepted that in many cases this is the only form of treatment which is capable of enabling the patient to live a more or less normal life. As long as we have so little knowledge about the true biochemical basis of asthma, other allergic diseases and the other diseases which have been discussed in this symposium -then it is necessary to be satisfied with symptomatic treatment, and happy that such is available. The price which must be paid -the side-effects -is not to be complained about -it is always expensive to be poor.

Long-term glucocorticoid therapy in other allergic diseases

Of the allergic diseases other than asthma in which the question of long-term therapy may be raised,

48 Michael Schwartz

vasomotor rhinitis, Besnier's prurigo (atopic der- matitis), chronic urticaria and the rare cases of gastro-intestinal allergy may be named.

The symptoms of these diseases must be very dis- turbing, long-lasting and quite intractable to other therapy before steroid treatment for long periods is considered.

The treatment must follow the lines laid down for the treatment of asthma.

Tt is possible to treat one particular form of gastro-intestinal allergy characterized by severe eosinophilia and hyproproteinaemia due to gastro-intestinal loss of protein very effectively with steroids. If it is possible to demonstrate the allergen -which is often milk -then the elimination of this com- pound from the diet is curative. This is another example of the fact that knowledge about the aetiology and pathogenesis of an illness is of greater importance to the patient than the availability of what is, it is true, often an outstanding symptomatic therapy.

DISCUSSlON Dr. Lorenzen: Are there any reasons to be especially careful about treating the acute attack of bronchial asthma with glucocorticoids, as it is known that the treatment will be of very short duration and may lead to a crucial improvement within a very short time?

Is there any investigation which has demonstrated that the lethality of the acute attack of asthma has been reduced since the introduction of the glucocorticoids?

In what way does long-term glucocorticoid therapy affect the course of the illness? Is there any increase in the incidence of such complications as reduced pulmonary function, bronchitis and pneumonia? Has the mortality rate altered as a result of long-term therapy?

Dr. Schwartzr There has probably been little change i n the lethality of asthma, although in certain areas the mortality rate has increased; for example an increase in mortality rate has recently been registered in England. It was thought that the steroids were responsible for the increase, but a very comprehensive investigation revealed that this is probably not the case.

There is no increase in the complications of bronchial asthma in connection with steroid therapy. On the contrary, there would seem to he a reduction in the incidence of bronchitis. Pneumonia is similarly not more common.

1 consider that there is a very real indication for treatment with glucocorticoids i n patients with bronchial asthma, because the patients feel better and have a far greater work- ing capacity. I am in complete agreement with you in that it is precisely because steroid therapy brings the patient out of the acute attack more rapidly that this is such a reasonable therapy. But there is reason to observe the patient for a period before starling therapy. Many attacks of asthma dis-

appear spontaneously soon after the patient has been admitted to hospital.

Dr. Bruun: On the whole I agree with Schwartz, but I would like to make some comments on long-term therapy.

The percentage of patients with bronchial asthma in whom long-term therapy with steroids is necessary has been found in most parts of Europe and the USA to be in the region of 8-16°/0. Where the dosage of the glucocorticoids in long- term therapy is concerned, it is usually possible to manage with very small doses, e.g. 5-7'il mg prednisone daily. This is of great importance, as it means that there is a sharp decrease in the incidence of side-effects.

Dr. Videbrpk: Is there any evidence that corticotrophin is more effective than the glucocorticoids in asthma?

Dr. Schwartz: No, not insofar as I am aware.

Dr. Andersson: Some workers consider that the remission following corticotrophin therapy is of longer duration than that after the glucocorticoids. Moreover the inhibitory action of the glucocorticoids on the adrenal cortical function is avoided. For these reasons I consider that it is an advantage to retain corticotrophin therapy.

Dr. Kierulf: May 1 enquire about the value of using the eosinophilia in the peripheral blood as a parameter in establishing the indications for initiating therapy, and for its maintenance. I agree with Schwartz that it is first and foremost the frequency and severity of the attacks which indicate treatment. The question is whether it is possible to decide from the number of eosinophil leucocytes in the peripheral blood whether the patient is about to develop an attack. Should one carry out regular eosinophil counts?

Dr. Schwartz: There is no doubt that in asthma patients with very severe eosinophilia there are very frequently indications for steroid therapy. The fluctuations in their eosinophilia and asthma run in parallel, so that it is possible to treat them according to either their symptoms or their eosinophilia with the same results.

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REFERENCES Annotation: Aerosol Steroids in Bronchial Asthma. Lancet I: 1412-1413, 1963. Editorial: Corticosteroid Therapy in Asthma. Brit. med. J . I : 1413-1414, 1961. Lowell, F. C.: Allergic disorders. In: Clinical uses of adrenel steroids, ed. Brown, J . & Pearson, Carl M., pp. 152-1 61, 447. McGraw-Hill Book Co., New York, 1962. Maunsell, K . , Bruce Pearson, R . S., & Livingstone, J. L.: Long-term corticosteroid treatment of asthma. Brit. med. J. I : 661-665, 1968. Pallesen, A. E.: Behandling af hlafeber med steroiddepot- praeparatet Depo-Medrol (Metylprednisolon). Ugeskr.

Schwartz, M.: Heredity in Bronchial Asthma. Thesis, Munksgaard, Copenhagen, p. 288, 1952. Walsh, S. D., & Grant, J . W. 8.: Corticosteroids in treatment of chronic asthma. Brit. med. J. 11: 796-802, 1966.

Lag.: 573-576, 128, 1966.

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GLUCOCORTICOIDS IN ALLERGIC DISEASES