• Introduction
• Which drugs are available?
• Which section of the rheumatic process do antirheumatic drugs combat?
• The group of nonsteroidal anti-inflammatory drugs (NSAIDs)
• The group of 'basic therapeutics'
• The group of immunosuppressives/cytostatics
• The group of drugs containing cortisone
• When can the drugs be discontinued?
• Which recent developments should be considered?
• Drug therapy - Summary
• Tables

Introduction

Drugs are employed in the treatment of rheumatic illnesses for three main reasons:

• to prevent lasting damage to joints and organs as well as to prevent any further complications from the illness
• to ease discomfort
• to shorten or, if possible, to cure the underlying illness.

Only certain specific forms of paediatric rheumatic arthritis (= joint inflammation) allow the cause of the illness to be determined and therefore enable a therapy effective against the cause of the illness to be provided, e.g. the prescription of antibiotics for borrelia arthritis. The cause(s) of rheumatic illnesses in the narrower sense, such as juvenile idiopathic arthritis (JIA), remain unknown. It was for this reason that the name 'juvenile idiopathic arthritis' was proposed internationally for JIA in 1999, since 'idiopathic' means the same as saying 'cause unknown'. Even though there is currently no etiological treatment for JIA, we still have a wide range of drugs effective against the disease itself. Therefore, as a general rule, a satisfactory solution can be found for every child affected. Drug treatment is required for most children, because (amongst other reasons) physiotherapy cannot be carried out satisfactorily in the absence of drugs owing to the pain involved; incorrect joint positions caused by pain and inflammation would get worse and would lead to defective positions; and in particular, the risk of joint dysfunctions and organ damage resulting from inflammation would increase.

 

Drugs produced desirable (in this case, the antirheumatic effect sought after) and undesirable effects (often referred to as 'side effects'). This often causes concern for both parents and children, and for good reason. The package insert included with the drugs and anxious enquiries from relatives, friends, neighbours or even the chemist ("Does your child really have to take such powerful drugs?") do not exactly go a long way towards setting their minds at rest. Another factor is the generally extended duration of the treatment. It is hardly surprising, therefore, that although patients are happy to participate in all the other therapeutic procedures, such as physiotherapy, occupational therapy or working with support devices, they frequently have major reservations about beginning drug therapy.

 

Certain essential requirements exist to ensure a successful drug therapy with as few side effects as possible.

• The preparations and drug adjustments must be selected by a doctor with experience in paediatric rheumatology. Treatment by a specialist should ensure that the drugs are always administered appropriately and are selected according to the latest medical knowledge.

• The parents (and the child, if age permits it) should be informed of the effects of the drugs used, including any undesirable effects. As part of this process, parents and patients should also be told that any serious or long-term harm caused by drug treatment or by taking drugs for a period of several years can almost always be minimised by regular visits to the doctor (see below).

• There must be a trusting and reliable cooperation between parent/child, the paediatric rheumatologist and the paediatrician or GP. The parents must share their daily observations of their children with the doctors so that the latter can evaluate the effects and side effects of the treatment. The parents are responsible for the important task of giving the child the drugs regularly in accordance with the prescription plan, looking out for desirable and undesirable effects and informing the doctor immediately of anything that strikes them as unusual.

This makes it possible to ensure that the drug treatment is being administered appropriately and generally speaking allows severe undesirable effects to be avoided; major problems or long-term harm caused by drug treatment are rare. In this regard, it is important to take the drugs in the correct dosage and at the recommended times, and to carry out regular medical tests, including laboratory tests (blood count, liver and kidney function, level of inflammation, urine status). For this reason we place particular emphasis on giving parents and children detailed information on times, dosages, potential undesirable effects and medical tests required in the form of a written prescription plan. This plan also provides information on the procedure to follow in certain situations such as holiday trips, outbreaks of chickenpox or operations.

to top 

Antirheumatic drugs are divided into several groups (Table 6): nonsteroidal anti-inflammatory drugs (NSAIDs), the 'basic therapeutics' (also called disease modifying drugs) in the narrower sense; immunosuppressives/cytostatics, which are basic therapeutics in the wider sense; cortisone preparations; newer substances that are still in the testing phase; and 'alternative' drugs, often better referred to as 'complementary' (i.e. additional) drugs. The drugs in each of these groups merit a discussion in terms of how they work, how they are used, and the undesirable effects they can have.  We should start off by saying that each individual drug may be encountered under several different names: Whenever a pharmaceutical firm introduces a new drug, it holds a patent over that drug that lasts for a number of years. During that time, no other firm is entitled to manufacture or sell that drug, i.e. the drug is available under one name only. For example, leflunomide is sold uniquely under the name Arava® (the small 'R' indicates that the name is proprietary and was chosen for marketing purposes). After the patent on this drug has run out, other firms will be entitled to manufacture and/or sell it. These firms will then select their own names for what is the same substance. To take another example, the nonsteroidal antirheumatic diclofenac was distributed by its original manufacturer under the name Voltaren®. Since then, diclofenac has been sold by 'copycat firms' under more than 30 different proprietary names. These 'copycat preparations' with the same active ingredient are referred to as 'generic medicaments'. The copycat firms have not spent anything on research and development for these preparations and generally distribute them more cheaply than the firm that originally developed the preparation. It can be assumed that the copycat preparations or generic medicaments will have the same effectiveness as the original preparation.

to top 

A simplified account of how juvenile idiopathic arthritis and other rheumatic illnesses develop is provided in Figure 7. One or more 'triggers' (one example that comes to mind here is viruses) can cause the immune system (the body's natural defence system) of vulnerable people to flare up in a pattern of continuous inflammation. As a consequence, the typical clinical signs of inflammation – swelling, a sensation of heat, pain and restriction in movement – occur, sometimes in joints. It would be beneficial if drugs or treatment strategies existed that took effect right at the start of the illness' chain of development (Fig. 7), i.e. to combat the cause of the illness itself. Since the identity of this trigger or these triggers of illness is still only a matter of conjecture (see above; e.g. viruses) and we cannot change people's individual disposition (Fig. 7), no etiological treatment currently exists. However, in the majority of cases, with the help of the drugs available today, the underlying rheumatic illness can be controlled. These substances work in the illness process as follows: analgesics such as paracetamol work purely symptomatically (at the far right of the illness' chain of development in Fig. 7, not shown in the diagram). Nonsteroidal anti-inflammatory drugs work to combat inflammation. 'Basic therapeutics' and immunosuppressives/cytostatics are designed to retune the immune system ('immunomodulating' effect) and thereby inhibit the subsequent rheumatic inflammation process. Cortisone preparations work on both the immune system and the inflammation process directly. TNF inhibitors inhibit TNF (tumour necrosis factor ), which has a potent inflammatory effect. 

to top 

What does the term nonsteroidal anti-inflammatory drugs (NSAIDs) mean?

NSAIDs represent a group of drugs that work directly to reduce inflammation. The term 'nonsteroidal' is intended to differentiate them from cortisone preparations (= 'steroids'). They can lower fever and relieve pain even in small doses and are therefore one of the most frequently prescribed drugs in general (e.g. Aspirin®). The NSAIDs listed in Table 7 have been used in paediatric rheumatology.

to top 

How do nonsteroidal anti-inflammatory drugs work?

Their inflammation-inhibiting effect occurs principally because they inhibit the accumulation of prostaglandins within the body. Prostaglandins are substances, similar to hormones, that the body needs in order to trigger inflammation reactions, amongst other reasons. If the body's own production of prostaglandins is reduced, the inflammation reaction also decreases. NSAIDs inhibit prostaglandin production by inhibiting the enzyme cyclooxygenase (abbr. COX). Enzymes are protein molecules that accelerate the biochemical reactions in our body; without enzymes, the various biochemical reactions in our body would occur so slowly that life would be impossible. Cyclooxygenase is needed for the production of prostaglandin. Cyclooxygenase 1 (COX-1) is chiefly involved in the production of prostaglandins in 'functional tissues' such as the gastrointestinal tract, the kidneys and blood platelets (thrombocytes). The prostaglandins involved in inflammation reactions, on the other hand, are produced through the effect of cyclooxygenase 2 (COX-2).  Conventional NSAIDs inhibit both COX-1 and COX-2.  Numerous undesirable effects of NSARs (see below), particularly on the gastrointestinal tract, are caused by COX-2 inhibition.  A particular advantage of the more recent selective COX-2 inhibitors (selective in this context means that the substances almost exclusively inhibit COX-2, and not COX-1) is that undesirable side effects on the gastrointestinal tract are rarer. Owing to undesirable side effects on the cardiac circulatory system in adults, some of the COX-2 inhibitors already approved for adults, such as Rofecoxib (Vioxx®), have been withdrawn from the market. At this point in time, no COX-2 selective NSAID has been approved for children's use.  The effect of NSAIDs begins shortly after they have been taken. The maximum effect is reached after two or more hours, depending on the preparation. The best way to obtain the desirable long-term effects are to take the correct dose of the drug at regular intervals.

to top 

When are nonsteroidal anti-inflammatory drugs administered?

NSAIDs are generally administered as soon as the rheumatic joint inflammation has been diagnosed. They therefore represent the first and foremost drugs used in the treatment of juvenile idiopathic arthritis.

to top 

What should be borne in mind when taking nonsteroidal anti-inflammatory drugs?

Small children are more likely to accept drugs in syrup form. In Germany, the preparations indometacin (Indopaed®) and ibuprofen (e.g. Ibuflam®) are available in this form (Table 7; as at summer 1999).  Naproxen syrup (Proxen®) must currently be obtained via Switzerland. The main advantage of drugs in syrup form is that they can be dosed precisely per kilogram of bodyweight. So that parents can measure the correct dose of syrup, they are issued with a 2-millilitre or 5-millilitre syringe, which they can use to extract the required amount from the bottle, e.g. 1.5 millilitres or 3 millilitres. NSAID tablets or -capsules, on the other hand, are generally produced for adults. Thus, they can only be administered in multiples of single capsules; for example, a 25 mg capsule of indometacin administered to a small child with a bodyweight of 12 kg would represent the entire daily amount prescribed, if not more, so only one tablet could be administered daily and the dose could not be spread out evenly throughout the day.

 

Many NSAIDs are inactivated relatively quickly by the body. These preparations are referred to as having a short 'half-life'. The half-life is the time after which half the amount of the drug taken has been broken down or expelled by the body. Drugs with short half-lives, e.g. Aspirin®, need to be taken at more frequent intervals (usually 3 to 4) spread throughout the day in order to maintain a sufficiently high concentration of the drug in the bloodstream for it to take effect. Preparations with longer half-lives, on the other hand, need to be given only once or twice per day (e.g. Proxen®).

to top 

Which undesirable effects may be experienced?

We cannot give a complete list of the undesirable effects of NSAIDs here; we recommend that you consult the package insert, the 'Red List' (the pharmaceutical index of the German Pharmaceutical Industry Association) or the relevant literature. Instead, we will give a few of the major side effects and how to deal with them, by way of example. The undesirable effects for different NSAID substances are similar and there are few variations between preparations, although the effects of any individual drug can vary from one child to another. Intolerance to a specific nonsteroidal anti-inflammatory drug does not necessarily mean, therefore, that none of the other NSAIDs will be tolerated either. If undesirable effects are encountered, it may thus be worth switching to another preparation.  By far the most frequent undesirable effects of NSAIDs are manifested in the form of problems in the gastrointestinal tract, extending from queasiness, nausea and stomach aches to peptic ulcers. These risks primarily affect older people. All NSAIDs can cause stomach problems of this nature and should thus never be taken on an empty stomach; instead, they should be taken directly after meals, with a pot of yoghurt or a glass of milk if required.  The antithrombotic ('blood-thinning') effect of NSAIDs, especially Aspirin®, is used therapeutically as a prophylaxis against thromboses, e.g. following operations. This effect is achieved by inhibiting or impairing cyclooxygenase 1 in the blood platelets (cf. above COX-1/2; blood platelets = thrombocytes). This can lead to an increased tendency to bleed. Warning signs of this in children are nosebleeds or an above-average number of 'bruises' on the shins. It is particularly important to look out for this effect in the run-up to operations, for example if the tonsils are being taken out. NSAIDs must be discontinued one week before the date of the operation. - Selective COX-2 inhibitors have no antithrombotic effect.  The analgesic (=pain-relieving) effect of NSAIDs can mean that, for example, in the event of inflammation of the middle ear, no pain is felt in the initial stages of the inflammation, and the illness is not diagnosed until a more advanced stage, at which damage has already occurred to the eardrum or the ossicles. Children being treated with NSAIDs who suffer from infections of the upper respiratory tract ('colds') should therefore have their ears examined at an early stage.  NSAIDs can also produce sensations of dizziness and tinnitus, particularly in higher doses. The undesirable effects on the central nervous system include tiredness and headaches. Attacks of cramp are symptomatic of poisoning and can occur when the dose is too high. Depending on the symptoms, the drug can be discontinued, the dose can be lowered or the patient can be switched to another preparation.  All other undesirable effects of NSAIDs are comparatively rare. These effects include an increase in the frequency of asthma attacks in children suffering from asthma, a decrease in the number of red and/or white blood corpuscles, and allergic reactions, visible in the form of skin rashes. Rashes provoked by sunlight when Naproxen (Proxen®) is being taken generally make it necessary to discontinue the drug.

Vor allem in höherer Dosierung können die NSAR Schwindelgefühl und Ohrensausen verursachen. Zu den unerwünschten Wirkungen auf das zentrale Nervensystem gehören Müdigkeit und Kopfschmerzen. Krampfanfälle stellen ein Vergiftungssymptom dar, das bei Überdosierung auftreten kann. Je nach Symptomatik können Absetzen, Dosisverminderung oder Umsetzen auf ein anderes Präparat erforderlich werden.

Alle anderen unerwünschten Wirkungen der NSAR sind vergleichsweise selten. Dazu gehören Begünstigung von Asthmaanfällen bei Kindern, die unter Asthma leiden, Verminderung der roten und/oder weißen Blutkörperchen, allergische Reaktionen, erkennbar an Hautausschlägen. Durch Sonnenlicht begünstigte Hautausschläge unter Naproxen (Proxen®) machen im allgemeinen Absetzen des Medikamentes erforderlich.

to top 

what does 'basic therapeutics' mean?

'Basic therapeutics' are also referred to as 'long-term antirheumatics' or 'disease-modifying drugs'. As shown in the highly simplified diagram in Figure 7, the immune system represents the point of application for basic therapeutics. These drugs therefore take effect more at the 'basis' of the disease process, as compared with NSAIDs (hence the name 'basic therapeutics'). We expect a correspondingly deeper effect from basic therapeutics on the rheumatic inflammation process.  Two elements shared by all basic therapeutics are the fact that they have a delayed action, most not coming into effect until after 2-3 months; and the fact that they act solely on rheumatic pain, and not on other kinds of pain like headaches (as NSAIDs such as Aspirin® do). The therapy is successful in approximately 2/3 of patients. Therapeutic adjustment of basic therapeutics requires special experience and is therefore generally reserved for the paediatric rheumatologist or the Specialist Clinic.

to top 

Which basic therapeutics are recognised? (cf. Table 8)

The principal basic therapeutics in the narrower sense used today remain chloroquine/hydroxychloroquine and sulfasalazine; gold and D-penicillinamine are still used only infrequently (Fig. 7, Table 8).  In the broader sense, immunosuppressives/cytostatics can also be classified as basic therapeutics (see below).

to top 

When are basic therapeutics administered?

We use basic therapeutics whenever the effect of NSAIDs is insufficient to control the disease activity properly, i.e. predominantly for progressive polyarthritis, but also for persistent oligoarthritis. As a general rule in this situation, treatment with NSAIDs is continued rather than stopped.

to top 

Are there subgroup-specific guidelines governing the use of "basic therapeutics in the narrower sense"?

We proceed on the principle that basic therapeutics can work for all subgroups (beginning forms, progressive forms; see above) of juvenile idiopathic arthritis.  We use chloroquine and hydroxychloroquine (Resochin®/Quensyl®) predominantly for ANA-positive oligoarthritis, whereas sulfasalazine appears to be most effective for HLA-B27- positive children. These preparations are not used to treat systemic juvenile idiopathic arthritis ("Still's syndrome"), since they can not only cause the disease to advance, but can also provoke serious complications such as "macrophage activation syndrome" (MAS).

to top 

Which undesirable effects should be looked out for with basic therapeutics?

Once again, we do not propose to provide a complete list of all known undesirable effects here, but merely to state the more important ones by way of example (cf. NSAIDs). More information can be found in the package insert; alternatively, your doctor will be ready to discuss the effects with you.  If antimalarial medication (chloroquine/hydroxychloroquine) is taken, undesirable effects are relatively rare. Effects that can occur are a lightening in hair colour, skin rashes, increased light sensitivity of the skin, gastrointestinal problems and changes in the blood count. In children already prone to outbreaks, these outbreaks can be exacerbated, so these children should be exempted from treatment with antimalarial medication. The most serious risk, which however occurs extremely rarely, is of undesirable effects on the retina that can lead to permanent damage to vision. We therefore recommend that children receive special ophthalmological tests once every 3-6 months, and we generally limit the duration of the therapy to 2-3 years. Thanks to these precautionary measures we have never witnessed an incident of damage to the retina. Accumulation of (hydroxy-)chloroquine in the cornea is not noticed by the child him- or herself, does not lead to any loss of vision and disappears once the therapy has ended.  There is also a risk of problems in the gastrointestinal tract during treatment with sulfasalazine (Azulfidine®). In addition, changes to the blood count, skin rashes, side effects on the central nervous system such as headaches or disturbances in perception and disruptions to kidney function are also possible. If a drop in sperm count occurs, this will rectify itself after the preparation has been discontinued.

to top 

What is meant by immunosuppressives/cytostatics?

Another therapeutic option is offered by immunosuppressives/cytostatics, which are 'basic therapeutics' in the broader sense. For paediatric rheumatology, this group comprises the drugs listed in Table 9. Immunosuppressives provide their antirheumatic effect by 'suppressing', i.e. slowing down, the immune system, which unarguably plays a crucial role in the emergence of inflammatory rheumatic illnesses (Figure 7).  As with 'basic therapeutics' in the narrower sense (see above), they provide their effect only after a period of weeks or months.

to top 

Which immunosuppressives/cytostatics are used in paediatric rheumatology?

The substance with the best ratio of desirable to undesirable effects is currently methotrexate. It has been used, in combination with azathioprine (Imurek®), in paediatric rheumatology for over 35 years. Ciclosporin A (Sandimmun®), a drug developed for use for organ transplants, has also been used in paediatric rheumatology for several years. Other, newer preparations used include leflunomide (Arava®) and mycophenolate mofetil (CellCept®). Methotrexate and azathioprine are approved for use in paediatric and aadolescent rheumatology, and ciclosporin is approved for the treatment of rheumatic iridocyclitis. - The choice of which drug is used is made based on their effectiveness and tolerability for each individual patient. Chlorambucil and cyclophosphamide (Leukeran®, Endoxan®) are cytostatics in the narrower sense and are classified as alkylating substances. They work by binding with the DNA ('genes') in the cell nucleus. By inhibiting cell growth they work primarily on rapidly growing tissue such as the hematopoietic system and the immune system. Their main field of application is in cancer therapy. Leukeran® and Endoxan®, mentioned above, are among the strongest antirheumatic drugs. However, their use is restricted to a small number of severe illness-related problems owing to their potential carcinogenic effect (see below).

to top 

When are immunosuppressives/cytostatics used?

Methotrexate (MTX) and azathioprine are used in the treatment of systematic JIA where basic therapeutics in the narrower sense, such as sulfasalazine, cannot be used for as long as 'systemic' symptoms like fever and/or rashes occur (see above). They are also used for progressive forms of polyarthritis or even severely progressive forms of oligoarthritis if basic therapeutics such as chloroquine are not sufficiently effective. For rheumatoid-factor-positive polyarthritis, which has a tendency to destroy joints as the illness progresses, we now primarily use MTX as a general rule as it gives better results. For rheumatic iridocyclitis (inflammation of the iris), immunosuppressives, particularly methotrexate, azathioprine and ciclosporin A are used, if treatment with cortisone eye-drops and ointment fails to produce the required effect.  The main field of application for chlorambucil is in treating amyloidosis, a severe complication of highly inflammatory progressive forms of JIA. Children with systemic JIA are the most at risk from amyloidosis. Amyloidosis can lead to dysfunctions and eventually to organ failure, particularly of the kidneys. Limited treatment with chlorambucil can more often than not result in the prognosis for children with amyloidosis being significantly improved. We use cyclophosphamide to treat collagenosis where the organs are severely affected and for systemic vasculitis (=rheumatic disease of the blood vessels). For JIA, cyclophosphamide is reserved for the treatment of special problems such as accompanying vasculitis (=inflammation of the blood vessels) or very serious progressive iridocyclitis.

to top 

Do successful results of therapy continue after immunosuppressives have been discontinued?

Unfortunately, it is not uncommon for rheumatic inflammation to flare up again once these drugs have been discontinued ('relapse'). For this reason we never discontinue a drug abruptly: we prefer to discontinue treatment gradually over a period of months, and often introduce a replacement drug as part of the therapy while the old drug is still being taken.

to top 

Which undesirable effects should be looked out for with immunosuppressives/cytostatics?

Here too, we cannot list all the known undesired effects in their entirety, but we can provide a brief description of certain major effects by way of example (further information can be obtained from the treating doctor, the package insert or the 'Red List'.). The most significant undesirable effects are related to the principal effect of this preparation, namely the 'suppression' (braking) of cell growth. Rapidly growing tissue such as the immune system and hematopoietic bone marrow are particularly affected by this. Inhibition of the immune system can thus result in an increased risk of infection, or a risk that infections will develop more seriously. As a consequence of the effect on the bone marrow, a reduction in the number of red and white blood cells and the platelets can occur. Since the doses used in rheumatology are somewhat lower than those used in cancer therapy, this problem is not of major importance. By reducing the dosage or by temporarily stopping the medication, combined with antibiotic or antiviral treatment if an infection is suspected (acyclovir/Zovirax® for chickenpox or shingles), such situations can usually be brought under control. The important part is to identify such complications in good time.  When taking MTX, problems in the gastrointestinal tract, such as nausea or stomach aches, are encountered on a not infrequent basis. Since the weekly dose is usually given in one day, these problems are usually confined to a certain space of time. A particular problem with MTX is the  growing feeling of revulsion felt by approx. 1/3 of children, which can be so pronounced that it can be necessary to discontinue the drug. Measures such as administering MTX in liquid form (from MTX ampoules originally designed to be injected) in orange juice, simultaneously administering ondansetron (a drug against nausea) or subcutaneous administration can help to reduce the feelings of revulsion. - Regular liver function tests in the blood must be carried out owing to potential effects on the liver. If the ban on alcohol during MTX therapy is observed, however, permanent damage to the liver is very rare. Drugs in liquid form, including those made from plants, can contain alcohol,    This situation must be discussed with the treating doctor on a case-by-case basis. During long-term MTX therapy (lasting several years), thought should be given to having a histological liver examination carried out occasionally, although this is no longer a general recommendation owing to the better results obtained from long-term observation. Persistent coughing can, on the other hand, indicate the presence of side effects on the lungs, which are rare. NSAIDs (see above) can boost the concentration of methotrexate in the blood and thereby increase both desired and undesired effects. NSAIDs should therefore be given a certain time before methotrexate is administered.  Azathioprine (e.g. Imurek®) can also cause gastrointestinal troubles and an increase in liver and pancreas values. Rarely (in approx. 3 people in 1000), a congenital hypersensitivity to azathioprine is observed due to a congenital lack of the enzyme TPMT (thiopurine methyltransferase) (enzyme = protein molecule that accelerates biochemical reactions in the body). TPMT is responsible for inactivating azathioprine. If TPMT levels are insufficient, excessively high levels of azathioprine remain in the body, which can lead to undesirable effects. This manifests as early as when the drug is being introduced: the children develop fever, nausea and possibly even a drop in the number of red and/or white blood cells and/or platelets. Once azathioprine has been discontinued these symptoms disappear. For this reason, we use a specialist laboratory to examine the TPMT levels of all children who have been prescribed azathioprine before their therapy begins. If their TPMT levels are not sufficiently high, we will not administer azathioprine therapy.  The most significant undesired effect of ciclosporine A is a disturbance of kidney function, including potential kidney failure, and an increase of blood pressure. This risk can be minimised by regularly testing blood pressure, 'kidney values' and the concentration of the drug in the bloodstream. The dosages of ciclosporin A used in rheumatology are already relatively low. As soon as the 'kidney value' for the level of creatinine in the blood becomes excessively high, we diminish the daily dose of ciclosporine A or discontinue the drug altogether. Other unpleasant effects of ciclosporin A include increased growth of body hair, overgrowth (hyperplasia) of the gums, dysfunctions in the gastrointestinal tract or paraesthesia (a burning sensation) in the hands and feet. It should be borne in mind that when certain drugs such as erythromycin (e.g. Paediathrocin®) are taken concurrently, the concentration of ciclosporine in the blood and thus the side effects can be increased.  Lefluonamide (Arava®) can lead to increased blood pressure, problems in the gastrointestinal tract such as diarrhoea, nausea or vomiting, loss of hair or headaches. In addition, as for the other immunosuppressives, regular tests must be carried out on the blood count and liver values. If undesirable effects manifest, the daily dosage of leflunomide is lowered. If this fails to resolve the problem, the drug is discontinued. Owing to its long half-life (cf. NSAIDs) of approx. 14 days, leflunomide remains in the body for a long time. If required, the drug cholestyramine can be administered to force the intestines to purge the drug from the body.  As with other immunosuppressives, mycophenolate mofetil (MMF) (CellCept®) also carries an increased risk of infection, changes to the blood count and blood platelets, dysfunctions in the gastrointestinal tract, disturbances to kidney function, changes in blood pressure and headaches. As with all other antirheumatic drug therapies, the undesirable side effects can generally be identified early or in time by regular medical and laboratory testing, so that appropriate countermeasures can be introduced.  Long-term consumption of immunosuppressives/cytostatics is associated with a certain degree of risk of contracting malignant illnesses such as leukaemia. This risk increases in proportion to the total quantity of substances taken and primarily exists in relation to the cytostatic drugs chlorambucil and cyclophosphamide  If the total quantity of chlorambucil taken is limited (approx. 500 mg/m2 body surface), the risk can be significantly reduced. With methotrexate, such complications are extremely rare. The same applies to the use of azathioprine in paediatric rheumatology. This problem exists similarly for ciclosporine A, leflunomide and MMF. Prior to any use of immunosuppressives/cytostatics, these questions must be discussed with the parents, as well as with the children, if age permits it.

to top 

Can immunosuppressives/cytostatics affect sexual functions?

Immunosuppressives/cytostatics should not be taken during pregnancy owing to the danger of deformities in the unborn child. Female rheumatism patients of childbearing age and being treated with immunosuppressives/cytostatics should not become pregnant. Contraception measures should be discussed with the treating doctor in good time, preferably before the therapy begins. Patients should wait a minimum of six months after these drugs have been discontinued before trying to become pregnant. The same applies for male patients, who must not attempt to conceive children whilst undergoing treatment with immunosuppressives/cytostatics and may not try to conceive until at least six months after these drugs have been discontinued. - In men, and more rarely in women, a potential consequence of long-term therapy with chlorambucil (Leukeran®) or cyclophosphamide (Endoxan®) is permanent sterility, i.e. it may be impossible to have children after the therapy.

to top 

Tumour necrosis factor alpha-blocking substances – a new group of antirheumatics

'Tumor necrosis factor alpha' (TNFα) is what is known as a cytokine. Cytokines are messengers in the immune system, similar to hormones, that pass information between cells. Drugs that are designed to work against specific cytokines are referred to as anticytokines. These drugs have been available for several years now. They are often extraordinarily effective and are one of the most important therapeutic advances in antirheumatic therapy of the past few decades. They are consistently very expensive in comparison to conventional medication, which is due to their complicated structure (protein molecules) and, therefore, their complicated manufacturing process. Etanercept, for example, is currently about one hundred times as expensive as methotrexate.

 

The cytokine TNFα plays an important role in the development of rheumatic inflammations. If the effect of TNFα is decreased, the inflammatory reaction becomes less severe. The TNFα antagonists currently available in antirheumatic therapy are etanercept (Enbrel®), adalimumab (Humira®) and infliximab (Remicade®). This drug group is also referred to under the term 'biological drugs', abbreviated as 'biologicals'. This term refers to the protein structure of the anticytokines but also to their target point of application within the immune system, namely to act as antagonists to TNFα. In paediatric and adolescent rheumatology etanercept (Enbrel®) has been approved for use for antirheumatic therapy for polyarthritis when treating JIA. For the other two preparations that are already used in adult rheumatology, approval for use in children is expected within the next one to two years. These drugs are protein molecules that have proven to be very effective primarily in non-systemic cases with high rheumatic inflammatory activity. 'Non-systemic' means that the   fever attacks and skin rashes observed in systemic JIA are not present. These drugs have, on the other hand, proven to be less effective in treating systemic JIA.. Although success rates of 70-80% are achieved when using etanercept to treat JIA with polyarthritis, this figure drops to approx. 30% for systemic JIA.

to top 

Are the TNFα-blocking substances taken orally or injected?

As mentioned above, the anti-TNFα-blocking substances have a protein structure. When proteins are taken via the mouth ('orally'), they are broken down into their composite elements by digestive enzymes in the stomach and then in sections of the intestines. Etanercept, adalimumab and infliximab would therefore not be effective if taken orally.  They must therefore be injected – etanercept subcutaneously (i.e. under the skin) once to twice a week; adalimumab also subcutaneously, although only once a fortnight; infliximab, on the other hand, is administered as an intravenous infusion once every 4-6 weeks.

to top 

What are the differences that still need to be looked out for between the different TNFα-blocking substances?

Etanercept (Enbrel®) differentiates itself from the other two substances by virtue of its different mechanism of action. Each etanercept molecule is composed of two TNFα receptors, practically identical to those found in the human body, and these TNFα receptors are bound to each other by means of an immunoglobulin. Receptors are antenna-like structures used by cells to receive signals. The TNFα molecule, which we need to survive, thus works by seeking out the TNFα receptor on the surfaces of a cell and fitting into it in the same way a key fits into a lock. This 'key-lock' contact generates a signal that tells the cell nucleus to begin manufacturing inflammation molecules. If etanercept (and therefore TNFα receptors) is injected into the body, some of the TNFα molecules that would otherwise have triggered inflammation reactions on the surface of the immune cells (see above,  key-lock contact) are intercepted, and the inflammation reaction therefore does not occur or occurs to a much lesser extent.

 

Adalimumab (Humira®) and infliximab (Remicade®), which as mentioned above have not yet been approved for use in paediatric rheumatology, are monoclonal antibodies that target TNFα and inhibit its effect. 'Monoclonal' means that all the antibodies were produced from the same cell line and therefore have an identical molecular structure.

to top 

Which undesirable effects should be looked out for with TNFα-blocking substances?

As for all drugs, hypersensitivity may be experienced, primarily at the injection site for etanercept and adalimumab and as a general reaction for infliximab (since it is administered intravenously). The most significant undesirable effect of this drug group is the increased risk of infection. Prior to beginning any treatment with these substances, the presence of tuberculosis must be ruled out. It is important to note that minor infections can become serious infections if they are not noticed and addressed in good time. In practice, this chiefly involves interrupting or at least reducing anti-TNFα therapy during feverish infections. The treating doctor must decide on the course of action to follow in each case. He or she will also determine whether antibiotics should be administered in addition. As with immunosuppressives, no inoculations must take place during treatment with TNFα-blocking substances. Changes in the blood count and increases in the level of liver enzymes are occasionally observed, so regular tests of the blood count, including platelets, and the liver values must be carried out during treatment with TNFα-blocking substances. Rarely, autoimmune reactions will occur where autoantibodies are produced. In isolated cases, treatment can lead to the development of multiple sclerosis. Patients in families with a history of multiple sclerosis should not be treated with these drugs. Only long-term observation will make it possible to say in the absence of any doubt whether TNFα-blocking substances increase the risk of contracting malignant diseases. The effects of TNFα inhibitors on pregnancy are not yet sufficiently well known, so these drugs should be taken only if it has been conclusively established that the patient is not pregnant.

to top 

Cortisone – why are people often reluctant to accept the therapy?

Cortisone preparations are frequently used in excessively high dosages in treating rheumatic illnesses in children, which leads not only to major undesirable effects but also to a relapse in the illness if an attempt is made to reduce the dosage. The initial intention is therefore generally not to provide a high-dosage therapy over an extended period of time.  Anyone who has witnessed the suffering experienced by children with highly active systemic juvenile idiopathic arthritis – attacks of fever, chills, shortness of breath, intense pain and stiff joints – will understand the fact that cortisone preparations are used in this situation, since they work astoundingly quickly in making these severe symptoms disappear. Owing to the known undesirable effects of long-term cortisone therapy (see below), the intention from the beginning is always to reduce the high initial cortisone dosage to an uncontroversial tolerable dosage after a maximum of four to six weeks. As is generally known, however, this is often not sufficient, since even when the dosage is reduced relatively cautiously the symptoms of the illness can recur just as strongly as before at cumulative dose which is still high. The dose of cortisone must then be increased once more, frequently to a higher daily dose than before, so that the symptoms of the illness can once more be controlled. From a broader view, this higher cortisone dose must often then be given for a long time in order to prevent any further relapses of the illness. It is at this point that the children experience the dreaded side effects of cortisone, including arrested growth, weight gain, osteoporosis, etc. (see below).  It is also a question, in such cases of severe illness in which there is usually no way forward without using cortisone preparations, of finding treatments that do not 'automatically' lead to long-term high-dosage cortisone therapy. The use of certain therapeutic procedures can often lead to solutions (see below).  Cortisone and related substances are vital hormones that the human body produces in the adrenal cortex. Cortisone has numerous effects, including immunosuppressive and strong anti-inflammatory effects (Figure 7), which explains the good effectiveness of these preparations in treating inflammatory-rheumatic illnesses. Taking them for an excessive length of time and in excessive doses does, however, inevitably lead to further effects: bone decalcification (osteoporosis), excess weight, increased body hair, high blood pressure, muscle weakness, susceptibility to infection, cataracts, glaucoma and – of particular danger to children – growth dysfunctions (dwarfism).

to top 

Should cortisone preparations be avoided because of their undesirable effects?

Cortisone preparations still play an important role in drug therapy against rheumatism. In certain situations we still cannot do without them. If they are used carefully and tailored to the problem and if precautions are taken, effective cortisone preparations are by no means always accompanied by significant undesirable effects.

to top 

In which pharmaceutical form can cortisone preparations be administered?

One way is via 'systemic' administration, where the cortisone preparation is given either orally as a tablet (into the gastrointestinal tract) or as a subcutaneous injection under the skin, intramuscularly or even intravenously. There is also a special form of intravenous therapy known as 'pulse therapy' (see below). A distinction should be drawn between this and 'local' therapy, in which the preparation is applied only to a specific area. This includes treatment of the eyes with cortisone drops and ointment and injections directly into the joint (e.g. Lederlon®).

to top 

In which illness situations do we systematically use cortisone?

These situations are predominantly progressions in which it is necessary to treat significant systemic disease activity, e.g. incapacitating attacks of fever combined with chills or if the heart is significantly affected. Highly inflammatory clinical pictures with severe joint swellings and joint pain may additionally render the use of cortisone necessary if other measures are not sufficiently effective (Table 9).  A rare complication of rheumatic illnesses during childhood is 'macrophage activation syndrome' (MAS). This is a severe clinical picture, which may be triggered by viruses or by drugs (cf. above) involving a reduction in the number of red and white blood cells and blood platelets (thrombocytes), an increase in liver values and consciousness disturbances. This condition must be treated with cortisone preparations (amongst other treatments) as quickly as possible. When an accumulation of fluid (oedema) occurs at the point where vision is sharpest ('macula lutea', Latin for 'yellow spot') in a patient suffering from chronic rheumatic iridocyclitis (known as a 'cystitic macular oedema'), there is a risk of permanent damage and restricted vision. In this situation, it is necessary to act without delay and the condition is systematically treated with cortisone preparations.  As a bridge until the effect of a recently commenced therapy with 'basic therapeutics' and/or immunosuppressives is felt, we can use infusion pulse therapy. This involves giving high doses of methylprednisolone as a short injection on three successive days or with one day's interval between each administration. If required, the 'cortisone pulse' can be repeated after four weeks. In our experience, this procedure has few side effects.

to top 

What are the chances of minimising the threat of undesirable effects during longer-term systemic cortisone therapy?

There is an advantage in keeping the amount of cortisone administered as low as possible, preferably to a level that can be administered as a morning dose. If the illness situation permits it, treatment should not be begun with a high cortisone dose. Instead, attempts should be made to treat the illness with the low dose sought after right from the beginning. This is especially likely to be successful if treatment with a 'long-term antirheumatic', e.g. methotrexate, is begun at the same time (long-term antirheumatics have a 'cortisone-sparing effect'). The time until the delayed action of the long-term antirheumatic (see above) takes effect can be bridged using cortisone pulse therapy if required ('bridge treatment', see above). The quantity administered daily for longer-term treatment should where possible be considerably below 0.2 mg/predisone/kg bodyweight. The frequency and severity of the undesirable effects can be further reduced if cortisone does not have to be given daily and if instead the double daily dosage can be given every second day, with a cortisone-free day separating the two dosage days. Here it must be added that these measures designed to reduce side effects also diminish the effectiveness of the cortisone therapy and are therefore not always possible. Attention should be paid to different levels of cortisone sensitivity from one patient to another.

to top 

When do we need local cortisone therapy?

The more locally an inflammation process occurs, the more 'local' the treatment should be as well. 'Local' in this sense means that the drug is not administered via the mouth/gastrointestinal tract or by intravenous, subcutaneous or intramuscular injection, and that it does not affect the entire organism. Rather, the drug is applied only to a single part of the body, either externally, e.g. eye drops or eye ointment, or as an injection directly into the joint ('intra-articular'). Systemic cortisone treatment has, with a few exceptions, not produced significant results in the treatment of rheumatic inflammation of the iris (iridocyclitis) (Table 9). Instead, cortisone eye-drops or  -eye ointment are used, and are dosed by the ophthalmologist based on the diagnostic findings observed in each patient following observation with a slit lamp.  For swollen joints, particularly when physiotherapy has reached an impasse, impressive results can often be achieved by treating with an injection of a special cortisone preparation (triamcinolone hexacetonide = Lederlon®) into the joint.

to top 

Is local cortisone therapy free from side effects?

Unfortunately, even local cortisone therapy carries a risk of undesirable effects (for the side effects observed during systemic administration, see above.). In the eyes, an increase in the internal pressure ('glaucoma') and/or an opacity in the lens ('cataract') can develop. In addition, treatment with cortisone eye ointment and/or eye drops makes the eye more prone to infection; fortunately, infectious complications are rare in practice.  The risk of infection is also the main problem when administering cortisone into joints, although if the correct procedure is followed and sterile conditions are observed, actual infections are extremely rare. Scarlike changes to the skin at the injection site can occur when taking triamcinolone-hexacetonide owing to damage to the subcutaneous fatty tissue, which we expect to see in 3-5% of cases. These changes however disappear as years go on. With injections of triamcinolone-hexacetonide into joints, calcium deposits in the joint and local growth dysfunction are also observed.

to top 

When can the drugs be discontinued?

The rule of thumb is that antirheumatic therapy should be continued for a period of 3-6 months after the signs of illness have disappeared, including the normalisation of the lab inflammatory levels. In order to avoid relapses, treatment is discontinued gradually over a period of months rather than abruptly. Only one drug is ever reduced at a time – never two at once. Otherwise, if a relapse occurred, there would be no way of telling which of the drugs was responsible. If the child remains free of symptoms for two years without taking medication, this is referred to as a 'remission'. This means that the patient may now have recovered from the illness.

to top 

Which other forms of therapy should be considered?

In addition to a combination of 'basic therapeutics' and/or immunosuppressives, which are also being used increasingly in paediatric rheumatology, the new therapies of intravenously administered immunoglobulins and autologous bone marrow transplantation should be mentioned.  For combinations of two or more 'basic therapeutics' or immunosuppressives, a stronger antirheumatic effect is expected without additional side effects. This has often been confirmed in practice. Corresponding controlled drug studies such as those carried out in adult rheumatology have not yet been carried out for children, however.  Immunoglobulins are administered approximately once every four weeks by infusion. The effect – like that of 'basic therapeutics' – can be assessed only after several months. Acute intolerance reactions are among the known side effects. Immunoglobulins are proteins obtained from blood plasma and blood donors. There is therefore a certain risk that infections, particularly viral infections, may be transferred. Technically processing the preparations before use means, however, that according to present knowledge this danger is very slight.  'Autologous bone marrow transplantation' is founded on the consideration that the immune system and its cells play an important role in the development of rheumatic inflammations (Fig. 7).  The bone marrow is where the various blood cells (red and white cells, platelets) are produced. In autologous bone marrow transplantation for the treatment of rheumatic illnesses, the existing bone marrow is destroyed using drugs and new bone marrow is created using exclusively bone marrow stem cells that have been previously harvested from the patient's own blood. The expectation is that the immune cells responsible for the underlying rheumatic inflammation will be destroyed and that therefore this will practically cause a recovery from the rheumatic illness. The treatment carries an acute and massive risk of infection during the weeks after the patient's own bone marrow has been destroyed and until new, functional bone marrow has been constructed from the patient's own reinserted bone marrow stem cells. The new bone marrow no longer contains the morbid immune cells. The possibility of these cells redeveloping later cannot be completely excluded. In addition to the acute danger of infection (see above), there are concerns that – in the same way as following cytostatic therapy – severe consequential complications may develop years after the event. Initial reports on rheumatic children treated in this way are very encouraging. However, there have also unfortunately been deaths following acute complications. In its current form, this treatment can therefore be recommended only for children with very severe, life-threatening rheumatic illnesses. There is however hope that the treatment's tolerability will be further improved in the foreseeable future.

to top 

Drug therapy - Summary

As of yet there is no treatment for the cause of JIA. We do however have a wide range of effective drugs that – as part of a total treatment plan (specific physiotherapy, occupational therapy, provision of support devices, etc.) - can bring successful results for the vast majority of children. The drugs should however be adapted to each individual patient and above all administered by an experienced paediatric rheumatologist. When drawing up the long-term prognosis, which for the majority of children will be good, care should be taken to ensure that the risk of side effects from the drug therapy is less significant than the illness itself. More information is available here.

to top 

Table 6

Drugs for therapy against juvenile idiopathic arthritis

• Nonsteroidal antI-inflammatory drugs (NSAIDs)
• 'Basic therapeutics'
• Immunosuppressives/cytostatics
• TNF a inhibitors
• Cortisone preparations
• Drugs in the test phase
• 'Complementary' pharmaceutical

to top 

Table 7

Nonsteroidal anti-inflammatory drugs (NSAIDs) used in paediatric rheumatology

to top 

Table 8

'Basic therapeutics': Basic therapeutics in the narrower sense must be distinguished from immunosuppressives/cytostatics. The chemical names are given followed by examples of proprietary names in brackets.

* drugs still used, but rarely

to top 

Table 9

Corticosteriods for JIA – when? Systemically:

• when nonsteroidal anti-inflammatory drugs, basic therapeutics or TNFα inhibitors do not work sufficiently well in the treatment of systemic JIA or severe polyarthritic progress
• for severe progressions: e.g. four-weekly intravenous pulse therapy as a bridge therapy until recently introduced 'basic therapeutics' take effect instead of continuous cortisone therapy
• bfor macrophage activation syndrome (MAS) (see text)
• in certain specific situations for rheumatic iridocyclitis
• for cystic macular oedema (see text)
• intravenous pulse therapy for acute outbreaks of posterior synechiae*
• interruption of a persistent outbreak of iridocyclitis using pulse therapy
• pre-operatively

Locally:

• intra-articularly (=into the joint) -

• as eye drops/ointment for iridocyclitis

* 'posterior synechia' = adhesions between the iris and the lens surface behind it

to top 

Figure 7

Caption for Figure 7

Where do the drugs work? Highly simplified diagram of the development of a rheumatic joint inflammation:  still ultimately unknown disease-triggering substances ('triggers', e.g. viruses in the environment cause an abnormal regulation in the immune system of people with the relevant disposition ('disposition' is determined by e.g. HLA-B27 or a family history of suffering from 'dandruff/psoriasis'). This leads to persistent inflammatory reactions. These cause swelling, a sensation of heat, pain and functional restrictions in joints. In terms of therapy, we can intervene at the end of this chain by applying cold compresses, analgesics and physiotherapy ('symptomatic therapy'). Nonsteroidal anti-inflammatory drugs (NSAIDs) work to inhibit inflammation. 'Basic therapeutics' (BT), including immunosuppressives/cytostatics (IS) work on the immune system and are designed to have a positive effect on the abnormal regulation. TNFα inhibitors are designed to target TNFα, a cytokine with strong inflammation-inducing properties (anti-TNFα). Cortisone preparations (CS) are strong inflammation inhibitors but also have immunomodulating effects. More detailed information is available in the 'Download' -  area under 'Pharmacotherapy'.

to top