PRACTI AL THERAPE TIC

Drugs 44 (4): 585-603. 1992 00 12-6667/92/00I0-0585/$09 .50/0 © Adis International Limited. All rights reserved. DRU1192

Ankylosing Spondylitis Current Drug Treatment

Jan Tore Gran and Gunnar Husby Department of Rheumatology, Central Hospital of Aust-Agder, Arendal, and Department of Rheumatology, Deakon's Hospital, Oslo, Norway

Contents 585 587 587 587 590 590

596 596 596 596 597 597 597 598 598 598 599

Summary

Summary I. Objectives of Drug Therapy 2. Drugs Used in AS 2.1 Sulfasalazine 2.2 Other Disease-Modifying Antirheumatic Drugs 2.3 Nonsteroidal Anti-Inflammatory Drugs 2.4 Corticosteroids 2.5 Analgesics 3. Specific Treatment Considerations 3.1 Peripheral Joint Disease 3.2 Enthesopathy 3.3 Psoriasis 3.4 Inflammatory Bowel Disease 3.5 Other Nonarticular Disease Complications 3.6 Special Considerations in Patients Undergoing Surgery 3.7 Special Considerations during Pregnancy and Lactation 4. Conclusions

The administration of drugs constitutes an important component of the therapeutic programme in ankylosing spondylitis (AS). The main objective of initiating such therapy is to reduce pain, stiffness and discomfort. There are at present 3 groups of drugs available for the management of AS. The first group is represented by drugs thought to influence the disease process itself. In this group, sulfasalazine is the only drug which in controlled trials has been shown to suppress disease activity in AS. We recommend the use ofsulfasalazine in patients with high disease activity, with peripheral arthritis and in those with AS of short duration. The second group of drugs includes nonsteroidal anti-inflammatory drugs (NSAIDs), which suppress inflammation without influencing the disease process. These drugs should be administered selectively during periods of high disease activity. Moreover, I drug should be used in appropriate dosage before it is assumed to be inefficient. High doses of NSAIDs may be prescribed before bedtime in patients suffering from severe pain and stiffness during the night. The toxicity profile of NSAIDs includes gastrointestinal and renal side effects. The third group comprises analgesics and muscle relaxants. Such drugs should be used rather frequently in patients with longstanding AS refractory to treatment with NSAIDs.

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Peripheral arthritis and enthesopathy are generally managed by local injections of corticosteroids, while AS complicated by psoriasis or inflammatory bowel disease is treated as primary AS. AS occurring in juveniles is best treated with aspirin and an NSAID, although careful observation is necessary for the development of Reye's syndrome (with aspirin) and gastric irritation (with NSAIDs). When patients with AS undergo surgery, the possibility of silent gastrointestinal bleeding due to the use of NSAIDs and salicylates should not be ignored. Patients treated with oral corticosteroids should receive a bolus injection of soluble corticosteroid prior to surgical intervention. NSAIDs may be administered pre- and postoperatively to relieve stiffness induced by immobility. Rapid treatment of intervening infections and use ofNSAIDs is recommended in AS complicated by renal amyloidosis . During pregnancy and lactation, ibuprofen may be the preferred drug in AS.

Ankylosing spondylitis (AS) is an inflammatory rheumatic disease that is characterised clinically by pain and stiffness of the back, not infrequently accompanied by peripheral arthritis and acute anterior uveitis (Gran 1985). A diagnosis of AS rests on the radiological demonstration of arthritis of the sacroiliac joints, but in about 60% of cases additional radiological changes are found elsewhere in the spine (Gran et al. 1984). A rather characteristic clinical feature of AS is enthesopathy, consisting of inflammation and new bone formation at the sites of attachments ofligaments, tendons andjoint capsules to bone (Ball 1971). Such manifestations are most frequently located at the patellae (knees), calcanea (heels) and the ischial tuberosities (in the hips). In contrast to most other inflammatory rheumatic diseases, males are affected more often than females, in a ratio of 5: I (Gran & Husby 1990). The age of onset of AS is most frequently between 18 and 45 years (Gran 1985). The aetiology of AS remains unknown , but genetic factors are of great importance since more than 90% of cases with AS possess the HLA antigen B27 (Brewerton et al. 1973; Gran & Husby 1992a; Schlosstein et al. 1973). However, as fewer than 2 to 7% of individuals carrying HLA B27 eventually develop AS (Gran et al. 1985; Khan & van der Linden 1990), environmental factors must also be responsible for the development of this rheumatic disorder. Rather recently, inflammation (Mielants

& Veys 1990) and possibly also infections (Ebringer et al. 1979) in the gastrointestinal tract have been suggested to play a role in the aetiopathogenesis of AS (Gran & Husby I992b). AS is a chronic disease but with a highly variable course (Gran 1985). About 5 to 10% of patients will develop total bony ankylosis of the spine (Gran & Husby I992a) with thoracic kyphosis (abnormal convex curvature of the spine), while other patients may experience little impairment of functional capacity. In a small proportion of cases, life-threatening complications develop, such as renal amyloidosis, aortic insufficiencyand cardiac conduction disturbances (Hart 1980). The long term functional outcome in AS appears to be greatly influenced by the patients' motivation and capacity to perform physical exercises (Robinson & Bradley 1957). Performing a daily programme designed by a skilled physiotherapist may reduce the tendency towards malalignment and stiffness of the spine as well as improve the muscular strength necessary to performe various physical activities (Wynn-Parry & Deary 1980). Thus, a comprehensive management of AS, constructed as early as possible in the disease course, includes patient education and the establishment of close cooperation with a physiotherapist trained in AS. However, the administration of drugs also constitutes an important component of the therapeutic programme in AS, and will be addressed in more detail in this review.

587

Treatment of Ankylosing Spondylitis

1. Objectives of Drug Therapy The main objective of initiating drug therapy in AS is to reduce pain, stiffness and discomfort . By ameliorating such symptoms, it is also possible to make the patient capable of performing physical exercises necessary to prevent further deformity and disability . It has not been shown, however, that drugs are capable of preventing the development of serious disease complications such as amyloidosis and aortic incompetence. Furthermore, little is known about the long term effects of drugs on disease progression and development of spinal immobility. Although several drugs have been shown to reduce the inflammatory activity in AS, this may not necessary result in alteration of disease course. Such a paradox may seriously question the role of inflammation in AS. If the inflammatory reaction represented the major factor responsible for evolution of bony ankylosis, an inhibition of this response should lead to prevention of the ossification of the spine.

2. Drugs Used in AS There are at present 3 groups of drugs available for the treatment of AS. The first group is represented by the so-called specific disease-modifying antirheumatic drugs, which are thought to influence the disease process itself. In contrast to rheumatoid arthritis, it is questioned whether such drugs exist at all for the treatment of AS. Unfortunately, no drug has yet been found which consistently both improves systemic disease activity and prevents the development and progression of radiological erosions and bony ankylosis. During recent years, however, much attention has been focused on the possible role of sulfasalazine as a disease-modifying drug in AS. The second group comprises of drugs which in general appear to suppress inflammation and thereby influence pain and stiffness in AS, without interfering with the disease process per se. Such drugs include nonsteroidal anti-inflammatory drugs (NSAIDs) and are widely used in AS. Corticoste-

roids may also be included in this group as their main effect is to suppress inflammation without influencing disease evolution. The third group of drugs employed in AS includes simple analgesics and drugs thought to affect muscle relaxation. 2.1 Sulfasalazine 2.1.1 Pharmacology According to some workers (Ebringer et al. 1979), AS may be triggered by intestinal Gram-negative bacteria such as Klebsiella spp. Also of interest are inflammatory changes in the small bowel mucosa as demonstrated by ileocolonoscopy in patients with AS (Mielants & Veys 1990). These observations may indicate that the gut is directly involved in the aetiopathogenesis of AS, a view that is further supported by the observation that AS is seen more often in patients with inflammatory bowel disorders and vice versa than expected by chance alone (Gran & Husby 1992b). Finally, the effectiveness of sulfasalazine treatment of both ulcerative colitis and Crohn's disease (Dick et al. 1964; Lennard Jones 1983) provided a rationale for deploying this drug in AS. Sulfasalazine has also been shown to exert a favourable effect on another inflammatory rheumatic disease, namely rheumatoid arthritis (Neumann & Grindulis 1984). The drug has also proven effective in reactive arthritis (Mielants et al. 1986; Peliskova et al. 1986). Administered orally, sulfasalazine is cleaved by bacterial enzymes in the colon, yielding 2 major metabolites, 5-aminosalicylic acid and sulfapyridine (Pinals 1988). Aminosalicylic acid is mostly excreted unchanged in the faeces and the therapeutic effect may be excerted in the intestine . Sulfapyridine on the other hand is more readily absorbed, and thus possesses the potential ability to act systemically. 2.1.2 Clinical Use The first study of sulfasalazine in AS was conducted by Amor et al. (1984), but the results of this study appear somewhat difficult to interpret. Eight other trials have been published since then (table

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1),6 of which have been double-blind and placebocontrolled. The impression gained from reviewing the reports on sulfasalazine therapy in AS is somewhat equivocal. Firstly, enough evidence appears to have accumulated to anticipate a future role for sulfasalazine in the drug management of AS. As expressed by reductions of erythrocyte sedimentation rate (ESR), C-reactive protein (CRP) and immunoglobulin A (IgA), most studies have shown a significant suppression of disease activity in patients treated with sulfasalazine compared with placebotreated controls (table II). On the other hand, further studies are warranted before any firm conclusions can be drawn regarding the possible effect of this drug on clinical disease variables such as morning stiffness, night pain and overall well-being (table II). Three trials failed to show any effect of sulfasalazine on chest expansion, but in another 3 chest expansion increased significantly among those actively treated when compared with controls. There has been no consistent trend towards sulfasalazine influencing spinal mobility in AS. Unfortunately, no long term prospective study has yet been conducted to study the possible influence of this drug on development of erosion and bony ankylosis of the spine and sacroiliac joints. In 1990, Ferraz et al. carried out a meta-analysis to assess the efficacy of sulfasalazine in AS. Five

randomised, controlled trials comparing sulfasalazine to placebo were located and assessed methodologically. The pooled results of clinical benefit favouring sulfasalazine over placebo were as follows: duration of morning stiffness reduced by 28.2%; severity of morning stiffness improved by 30.6%; severity of pain alleviated by 26.7%; ESR down 9.2%; IgA decreased 11.7%; and general wellbeing improved 7.1%. The conclusion was that sulfasalazine represented a safe and effective drug in the short term treatment of AS. Conceivably, the most favourable clinical effect of sulfasalazine in AS may be the ability to reduce the activity of peripheral arthritis. Interestingly, a clear association between inflammatory changes in the small bowel demonstrated by ileocolonoscopy and the occurrence of peripheral arthritis in AS has been observed (Mielants & Veys 1990).Thus, bearing in mind the effect of sulfasalazine on ulcerative colitis and Crohn's disease, perhaps the mechanism of sulfasalazine in AS is related to its influence in the gastrointestinal tract. Future studies should be directed at detecting subgroups of patients with AS particularly susceptible to the effects of sulfasalazine. Such individuals may be those not possessing HLA B27, since such patients exhibit both inflammatory bowel changes and peripheral arthritis more often than B27-positive patients (Mielants & Veys 1990).

Table I. Studies of sulfasalazine in ankylosing spondylitis Reference

No. of patients

Amor et a!. (1984) Andrade et al. (1989) Corkill et al, (1990) Davis et al, (1989) Dougados et at, (1986) Feltelius & Hellgren (1986) Fraser & Sturrock (1990) Nissile et al. (1988) Taylor et al, (1991)

60 26 62 28 30 37 20 85 40

Abbreviations: db

Mean disease duration (years)

Maximum dose (g/day)

Duration of study (months)

12.3 8.5 10.0 12.1 9.0 3.8 11.0

2 3 2 2 2 3 40 mg/kg/day 3 2

6 6 12 3 6 3 6 6 12

= double-blind; pc = placebo-controlled; 0 = open;

int

= interventional,

% with peripheral arthritis 0

Study design

db, pc 0

25.0 0 100.0 64.7 15.0

db, db, db, db, int db, db,

pc pc pc

pc pc pc

589

Treatment of Ankylosing Spondylitis

Table II. Stud ies on the effect of sulfasalazine in ankylosing spondylitis (number of stud ies) Variable

Beneficial effect

No effect

Not tested

Laboratory measures ESR CRP IgA

5 3 3

3 2 3

3 2

Peripheral arthritis

3

Symptoms Morning stiffness Night pain Reduction in NSAID use Signs Chest expansion Spinal mobility Radiological progression

Abbreviations : ESR

4

2

2

4 2

1 1

3

4

1

6 1

= erythrocyte sedimentation rate ; CRP = C-reactive protein; IgA

2.1.3 Tolerability The side effects of sulfasalazine therapy in AS do not appear to be different from those seen during treatment of patients with rheumatoid arthritis (table III). Gastrointestinal discomfort and central nervous system (CNS) toxicity seem to represent the major problems associated with sulfasalazine therapy. Other unwanted effects of sulfasalazine not to be overlooked are fever, skin rash, hepatotoxicity and leucopenia . Most adverse reactions during therapy with sulfasalazine tend to develop during the first 3 months of treatment (Jones et al. 1991; McConkey et al. 1980). 2.1.4 Place of Su/fasalazine in AS Therapy Clearly, more studies are warranted before firm conclusions can be drawn regarding the place of sulfasalazine in the therapeutic management of AS. 'At present , it is our strategy to deploy sulfasalazine in all newly diagnosed patients with AS. In patients with longstanding AS, those with high disease activit y (determined by increased levels ofESR, CRP and IgA), and patients with active peripheral arthritis are also suitable for sulfasalazine treatment. On the other hand , patients with disease confined exclusively to the spine and sacroiliac joints, and those with normal ESR have to rely on the bene-

4 3 5 1 1

7 = immunoglobulin A.

ficial effects of physical exercises and the administration of NSAIDs (see section 2.3). A dose of 40 rug/kg/day is recommended.

Table III. Adverse reactions to sulfasalazine (those reported in patients with AS in parentheses) Haematological Megaloblastic anaemia , methaemoglobinaemia. haemolytic anaemia . aplastic anaemia, hypoprothrombinaemia. (leucopenia). agranulocytosis, thrombocytopenia Gastrointestinal Parotitis. pancreatitis. hepatitis. (abnormal liver tests). (nausea)

eNS Vert igo, tinnitus. peripheral neuropathy, ataxia . (headache) . [dizziness]. convulsions. insomnia. (depression), hallucinations Mucocutaneous Stomatitis, Stevens Johnson syndrome. Lyell's syndrome. pruritus. urticaria, photosensitivity Others (Fever), serum sickness. conjunctival and scleral injection, arthralgia, myocarditis. fibrosing alveolitis, eos inophilic pneumonitis, revers ible oligospermia Renal Crystaluria , haematuria, proteinuria, nephrotic syndrome

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Table IV. Studies of penicillamine in the treatment of ankylosing spondylitis

Reference

Bird & St Dixon (1977) Golding (1974) Jaffe (1977) Leca & Camus (1975) Scharf & Nahir (1976) Steven et al. (1985) Tytman et al. (1989

No. of patients

Study design

7 2 5 10 1 17 49

0 0

Efficacy

(+f-) +

0 0 0

+

db. pc 0

+

Abbreviations and symbols : 0 = open; db = double-blind ; pc = placebo-controlled ; + = positive effect demonstrated; - = no effect demonstrated.

2.2 Other Disease-Modifying Antirheumatic Drugs Penicillamine has been tried in a few patients with AS. Golding (1974) reported a favourable effect of penicillamine in 2 patients, and Scharf and Nahir 2 years later noted marked improvement in I patient with AS and severe peripheral arthritis (Scharf & Nahir 1976). On the other hand, Leca and Camus (1975) found no favourable effect of penicillamine in 10 patients treated for 6 months. Similarly, Bird and St Dixon (1977) failed to observe any benefit from penicillamine therapy in 7 cases of AS. We are aware of only I rather large controlled study of this drug in AS (Steven et al. 1985), which did not show penicillamine to be effective (table IV), hence its use cannot be recommended. Furthermore, as far as we know, there have been no controlled trials of antimalarials (e.g. chloroquine), parenteral gold (sodium aurothiomalate) [Hill 1980; Neustadt 1977] or cyclosporin in AS. Treatment with oral gold (auranofin) does not influence the disease manifestations of AS (Grasedyck et al. 1990). Due to its toxicity profile, levamisole is no longer recommended for use in rheumatic diseases (Hill 1980). Methotrexate, now widely used in rheumatoid arthritis and psoriatic arthritis (Black et al. 1964; Scully et al. 1991), has been deployed in a few

patients with AS. Handler (1989) reported favourable results in 3 patients suffering from AS, although the diagnosis of AS in these cases was not appropriately provided. Recently, Ferraz et al. (1991) reported methotrexate treatment of I patient with AS who had failed to respond to NSAIDs and sulfasalazine. Interestingly , because of abdominal discomfort, calcium folinate (leucovorin) 6mg was given 24 hours after intake of methotrexate. Complete resolution of methotrexate-induced adverse effects was obtained after 2 weeks of treatment with calcium folinate, and peripheral arthritis responded favourably to methotrexate. Consequently, calcium folinate rescue may represent a means of overcoming unwanted effects of methotrexate therapy in AS. The need for anti-spondylitic or disease-modifying drugs in AS is indeed urgent. Of particular use would be the development of drugs with a selective activity against the process of bony ankylosis. At present, drug therapy in AS is still, however, highly dependent on NSAIDs. 2.3 Nonsteroidal Anti-Inflammatory Drugs Table V summarises some of the larger trials of NSAIDs currently available for use in AS in most Western countries. Due to the large number of studies and the many different study designs, it appears extremely difficult to conclude which drug is the best with regard to clinical effect. Nor is it easy to firmly establish which drug offers the lowest incidence of unwanted effects. Consequently, the task of selecting the most appropriate drug most often rests on individual patient tolerance and the physician's own experience with a particular NSAID. Although there is little evidence to suggest substantial differences in the effects of various NSAIDs (Brooks & Day 1991), patients sometimes have strong preferences (Wasner et al. 1981). NSAIDs are widely used, and it has been estimated that between 78 and 86% of patients with AS in the UK are taking these drugs (Calin & Elswood 1990). About 50 to 60% of patients report good or excellent pain relief, while 38 to 50% experience favourable effects on stiffness (Calin &

Treatment of Ankylosing Spondylitis

591

Table V. Some double-blind trials of NSAIDs in ankylosing spondylitis

Study drug

Comparator drug

No. of patients

Results

Reference

Dic Eto

Sui Indo Nap/PI Pbz Indo Indo Indo Pbz Open study PI Nap Dic PI Pbz Indo Flu Nap Nap Keto Indo Indo Pbz Pbz PI Indo Dic Indo Nap

62 99 128 30 19 57 26

Dic > Sui Eto = Indo Eto > PI Fen < Pbz Fen = Indo Flu = Indo Flu = Indo Flu = Pbz Effective Indo > PI Indo > Nap Indo > Dic Keto > PI Keto = Pbz Nap = Indo Nap = Flu Pbz = Nap Pbz = Nap Pbz > Keto Pir = Indo Pir = Indo Sui < Pbz Sui = Pbz Sui > PI Sui < Indo Ten = Dic Tol = Indo Tol = Nap

Nahir & Scharf (1980) Bacon (1990) Bacon (1990) Wordsworth et al. (1980) Shipley et al. (1980) Lomen et al. (1986) Good & Mena (1977) Calin & Grahame (1974) Nicolic & Lukacevic (1975) Sturrock & Hart (1974) Peter (1975) Khan (1987) Dorfmann & de Seze (1973) Jessop (1976) Zeidler et al. (1975) Burry & Siebers (1980) van Gerwen et al. (1978) Ansell et al. (1978) Treadwell & Tweed (1975) Tannenbaum et at. (1984) Sydnes (1981) Gengos et al. (1979) Eberl (1974) Liebling et al. (1975) Gibson & Laurent (1980) Mayrhofer et at, (1990) Esdaile et al. (1982) Byron & Steele (1982)

Fen Flu

Ibu Indo

Keto Nap Pbz

Pir Sui

Ten Tol

65 27 262 13 35 30 20 25 25 55 87 120 24 83 23 57 60 34

Abbreviations and symbols: Dic = diclofenac; Eto = etodolac; Fen = fenoprofen; Flu = flurbiprofen; Ibu = ibuprofen; Indo = indomethacin;

Keto = ketoprofen ; Nap = naproxen ; Pbz = phenylbutazone ; Pir = pirox icam; Sui = sulindac; Ten = tenoxicam ; Tol = tolmetin; PI = placebo ; > indicates superior efficacy ; < indicates inferior efficacy; = indicates equivalent efficacy .

Elswood 1990). The most popular NSAID in the UK for use in AS is indomethacin, followed in turn by naproxen, piroxicam, diclofenac and ibuprofen (Calin & Elswood 1990). 2.3.1 Pharmacology The dosage, half-life (table VI), and mechanisms by which NSAIDs act differ slightly between the various drugs presently available . Nevertheless, in general they all exert their effects by inhibiting the inflammatory process in one way or another. Principally they act by inhibiting either the cyclooxygenase activity of the various lipoxygenase enzymes, both of which result in decreased prosta-

glandin production. In addition, NSAIDs have analgesic, antipyretic and platelet-inhibitory actions (Brooks & Day 1991). As stated earlier, they do not have any impact on the disease process itself. Consequently, disease development, as observed radiologically by the evolution of bony ankylosis, appears to be independent of the administration of NSAIDs. This may be an interesting paradox since bony ankylosis is regarded by most workers as the end-stage of long-standing inflammatory activity. Clearly, factors other than inflammation appear necessary for the development of ankylosis of joints and ligaments in AS. Alternatively, this part of the disease process may be de-

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Table VI. Dosage and plasma elimination half-life of some currently available NSAIDs used in ankylosing spondylitis Half-life (h)

Maximum dose (mg/day)

Long plasma half-life (> 12h) Diflunisal Naproxen Phenylbutazone Pirox icam Sulindac Tenoxicam

15 13 72 38 16 60

1000 1000 400 20 400 20

Short plasma half·life «12h) Diclofenac Etodolac Fenoprofen Ibuprofen Indomethacin Ketoprofen Tolmetin

1.3 6.5 2.7 1.7 4.5 1.7 2.0

200 200 3200 2400 200 300 2000

pendant on inflammatory reactions not influenced by NSAIDs. Yet another possibility is a direct transformation process or pathway from normal or noninflammatory tissue to enchondral bone formation (Lussier & de Medicis 1983). 2.3.2 Clinical Use The clinical effect of NSAIDs is mainly amelioration of musculoskeletal pain and stiffness, and reduction of swelling in the peripheral joints. By doing so, an increase in the overall well-being of the patient is obtained. In the spine, increased mobility may favourably influence the functional capacity of the patient. Although marginal differences in efficacy and toxicity exist between the various NSAIDs (Brooks & Day 1991), some general principles in the selection ofa particular agent should be followed. Firstly, the objectives of treatment should be agreed upon with the patient before initiating NSAID administration. In our experience an 'on and off regimen is to be recommended, in which the drug is administered selectively during periods with high disease activity, and stopped during quiescent periods until the next flare occurs. There are no studies that have shown any beneficial effect of continuous

NSAID administration. Moreover, by intermittent use of the drug, the potential toxic effects on the gastrointestinal mucosa may be reduced or avoided. Another clinical advantage of such a drug regimen is that after a long period of NSAID therapy, temporary cessation of the drug offers an opportunity for the patient to test the current efficacy of the drug. For example, if cessation is followed by an exacerbation, the drug is still beneficial. Conversely, if a status quo is experienced after cessation, the drug may no longer be effective, or the disease has run into a natural remission. This may seem rather obvious, but it is not unusual to meet patients, especially the elderly, who have been receiving an NSAID for years and, after cessation of the drug, no increase of disease activity is experienced. Another event often observed in patients with AS is a rather frequent shift from one drug to another. Most often, this is due to a presumed lack of beneficial effect and a wish for a second drug perhaps offering the patient better relief of pain and stiffness. It should be stressed, however, that before abandoning one drug as being inefficient, the drug should be used in appropriate dosage for a long enough period to clearly establish its possible efficacy. A small increase in dosage may result in significant improvement in the patient's well-being. Generally , the drug should be used for at least 6 weeks before another NSAID is selected. Moreover, every attempt should be made to avoid combinations of NSAIDs since there has not been any study yet conducted that has demonstrated synergism among these drugs. An important factor in the medical treatment of AS is the timing of drug administration. As pain and stiffness are often felt most severely during the night and in the early morning, it may be worthwhile to prescribe a relatively high dose of the drug just before bedtime with the second dose given upon awakening. Similarly, when discomfort is worst during the daytime, most of the daily dosage should be given in the morning and afternoon. By administering a drug with a slow absorption late in the evening, an effect on morning stiffness may be obtained. Alternatively, a suppository given at

Treatment of Ankylosing Spondylitis

Table VII. Side effects reported in patients treated with NSAlDs Gastrointestinal Dyspepsia, peptic ulcer, ulcer perforat ion. melena. indigestion, constipation , gastrointestinal upset. nausea, vomiting, diarrhoea . oesophageal ulceration, oesophageal stricture , perforation of colonic diverticulae , pancreatitis, sialadenitis Hepatic Elevation of liver enzymes. fatal hepatic necrosis , granulomatous hepatitis. cholestasis Mucocutaneous Stomatit is. pruritus , urticaria, fixed drug eruption . photosensitivity, alopecia, onycholys is. erythema multiforme, Stevens Johnson syndrome , Lyell's syndrome . Henoch Schenlein 's purpura, thrombocytopenic purpura Renal Renal insufficiency, acute interstitial nephritis, nephrotic syndrome Pulmonary Precipitation of acute asthma, pulmonary oedema, pulmonary infiltrates Haematological Granulocytopenia, agranulocytosis, thrombocytopenia, haemolytic anaemia, aplastic anaemia. alteration of platelet funct ion, prolongation of bleeding time ONS

Headache. dizziness, confusion . depression, drowsiness. anxiety , hallucinations, cognitive dysfuncion, seizures , syncope , paranoia , tinnitus, lightheadedness . agitation , lethargy . malaise, aseptic meningitis Cardiac Heart failure due to sodium and fluid retention, palpitat ions, arrhythm ias, leg oedema. increase of arterial blood pressure in hypertensive patients Others Gynaecomast ia, goitre , epistax is, hypo- and hyperglycaemia. hearing difficulties, reversible blurring of vision

bedtime often relieves both night pain and early morning stiffness. 2.3.3 Tolerability Table VII gives an overview of the various toxic reactions most often encountered in patients treated with NSAIDs. Clearly, the well known occurrence of gastrointestinal side effects represents the single most important factor limiting the usefulness of NSAIDs. In 1984, nearly 1 in 7 Americans was

593

treated with an NSAID (Brooks & Day 1991), and it is thus not surprising that the most prevalent serious drug toxicity in the US is increasingly recognised as gastrointestinal pathology associated with NSAID use (Fries et al. 1991). The main risk factors for gastrointestinal adverse reactions are increased age, use of prednisone, previous gastrointestinal side effects, level of disabil ity and NSAID dose (Fries et a1.1991 ; Johnson & Day 1991). Also, a patient's personalit y and psychological profile may be yet another factor predisposing to the development of NSAID-induced dyspeptic symptoms (Juby & Davis 1991). It has been estimated that approximately 40% of patients using NSAIDs will experience some kind of gastrointestinal adverse reaction (Giercksky et al. 1988; Larkai et al. 1989). The most frequentl y occurring side effects are indigestion and dyspepsia, while 10 to 20% have endoscopicall y visible gastric ulcers (Farah et al. 1988; Larkai et al. 1987). One particular clinical problem of such ulcers is that they are frequently not antedated by dyspepsia (Jorde & Burhol 1987; Larkai et al. 1989). According to Armstrong and Blower (1987), more than half of patients admitted for NSAID-associated bleeding present with lifethreatening bleeding as the first symptom of this adverse reaction . One possible explanation for the observed lack of pain in NSAID-related peptic ulceration is that NSAIDs, being analgesics, conceal ulcer pain (Graham 1991). It should be noted , however, that in a recent study of 94 patients with gastric bleeding, no differences with respect to the occurrence of dyspepsia between NSAID users and nonusers was found (Aabakken et al. 1991). Thus, the results did not support the alleged masking of ulcer symptoms by NSAIDs in bleeding ulcers. All NSAIDs inhibit prostaglandin synthesis, which may lead to increased production of gastric acids. Moreover, gastric mucin production is decreased as is the rate of mucosal cell turnover (Miller s: Jacobson 1979). Thus, all NSAIDs appear capable of inducing gastric ulceration and bleeding (Brooks & Day 1991), more or less regardless of their administration as enteric coated tablets or suppositories.

594

In many patients with AS, the development of gastric side effects clashes with a sustained need for anti-inflammatory drugs. A certain limitation of duodenal ulceration may be obtained by the simultaneous administration of histamine Hj-receptor antagonists such as cimetidine and ranitidine (Stock & Bach 1988), although these drugs do not appear to provide protection against gastric ulceration (Graham 1991). Prevention may be achieved by using the prostaglandin analogue misoprostol in doses of 400 to 800 ~g/day (Graham et al. 1989). Also, omeprazole may reduce the formation of gastric ulcers (Walan et al. 1989). Although NSAIDs share a common core of side effects, they differ somewhat in their innate propensity for inducing toxic reactions. Therefore, some of the individual NSAIDs currently available will be briefly addressed. Phenylbutazone Phenylbutazone was introduced in 1949, and was soon proved effective in most arthritic conditions . Its use now, however, is strictly limited due to its association with severe haematological adverse reactions such as aplastic anaemia and agranulocytosis (Hill 1980). Agranulocytosis tends to develop primarily in younger patients, often after a few days or weeks of therapy (Calabro 1987). Usually, it is readily reversible when the drug is discontinued (Calabro 1987). On the other hand, aplastic anaemia occurs more frequently in the elderly, and is more apt to evolve insidiously after prolonged drug therapy, and is more likely to prove fatal (Calabro 1987). In England alone there have been 16 deaths per million prescriptions of phenylbutazone (Richter 1985). Other side effects include epigastric distress , nausea, vomiting, peptic ulceration, oedema, stomatitis, hepatitis and skin eruptions. In some countries, including Norway, this drug has been totally abandoned. Where it is still available, phenylbutazone 100 to 400 rug/day should be restricted to the most severe cases of AS, in whom all other NSAIDs have proved unsuccessful. Finally, it should be mentioned that phenylbutazone is one of the very few NSAIDs reported to control or inhibit syndesmophyte for-

Drugs 44 (4) 1992

mation and ossification of paraspinal ligaments when administrated continuously (Boersma 1976). Indomethacin Indomethacin was introduced in the US in the 1960s, and has remained the drug of choice in AS for man y rheumatologists (Calabro & Amante 1968). It is effective, but rather frequently accompanied by gastrointestinal side effects (Kinsella et al. 1967). Among elderly patients, indomethacin should also be used with caution due to its association with adverse CNS reactions. Headache , sleeplessness, confusion, anxiety and depression are not infrequently encountered among patients treated with indomethacin. Both CNS toxicity and gastrointestinal adverse reactions are more likely to occur if daily doses exceed 150mg (Kinsella et al. 1967) [the recommended daily dosage of indomethacin is 75 to 100mg]. Headaches often occur immediately after beginning treatment with the drug and usually disappear after a few days of continued use. However, their severity may preclude continuation of indomethacin (Calabro 1987). Due to its unwanted effects on fluid retention and its ability to cause acute renal failure (Brooks et al. 1980), indomethacin is best avoided in patients with established renal failure. A cautionary note should also be made for patients with angina pectoris, as the drug has been reported to induce electrocardiographic abnormalities in such patients (Brooks et al. 1980). Suppositories of indomethacin 50 or 100mg may be administered at bedtime to allay early morning stiffness and night pain. Naproxen Naproxen is another NSAID very frequently used in the treatment of AS. It was marketed in the US in 1976, and is currently available as convetional tablets, suppositories, and enteri c; coated tablets that may reduce the incidence of gastric toxicity (Aabakken et al. 1989). It may be administered orally 2, 3, or 4 times a day. The effect of naproxen in patients with AS has been established by numerous studies, one of which showed it to be

Treatment of Ankylosing Spondylitis

as effective as phenylbutazone (van Gerwen et al. 1978). The most prominent side effects of naproxen are dyspepsia and gastric ulceration . Due its effect on fluid retention, naproxen should be used with caution in patients with renal insufficiency, cardiac failure and/or hypertension. Caution is also recommended in patients with pulmonary disorders, as several cases of pulmonary infiltrates and exacerbation of pre-existing asthma have been reported (Szczeklik et al. 1977). Piroxicam Piroxicam , a potent inhibitor of cyclo-oxygenase, has been available for use in AS since the early 1980s. The most characteristic feature of this NSAID is its long plasma elimination half-life, ranging from 14 to 158 hours (Brogden et al. 1984). Piroxicam is therefore administered once daily, and is aptly suited for patients who tend to be noncom pliant (Calin & Elswood 1990). However, the long half-life may also prolong the duration of side effects, particularly gastrointestinal bleeding. In a large multicentre study in Norway (Husby et al. 1986), piroxicam was given for osteoarthrosis to analyse the frequency of adverse reactions. Unwanted effects were not found to be related to the patients' age, although the clinical consequences may be more severe in the elderly. The incidence of adverse reactions to piroxicam seems to decline with continued therapy (Brogden et al. 1984). Sulindac Sulindac, marketed in the US in 1978, is chemically related to indomethacin but may exhibit a lower incidence of adverse reactions (Brogden et al. 1978; Caruso & Bianchi-Porro 1980; Lanza 1984). The daily dosage is 400mg, given in 2 divided doses. Most important is the relative lack of effect of sulindac on renal blood flow and glomerular filtration (Bunning & Barth 1982; Ciabattoni et al. 1984). However, controversy exist as to whether sulindac really is less nephrotoxic than other NSAIDs (Brater et al. 1984; Roberts et al. 1984). We tentatively suggest, however, that sulindac should be the drug of choice in patients with

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cardiac or renal failure and in patients with hypertension. The clinical efficacy profile is similar to that of other NSAIDs. Ibuprofen Ibuprofen was introduced in the UK in 1967 and in the US in 1974 (Kantor 1979). It is perhaps the drug exhibiting the lowest incidence of toxic drug reactions (Nicolic & Lukacevic 1975). Consequently, in several countries, ibuprofen is approved for nonprescription sale to the general public. Together with ketoprofen, fenoprofen and diclofenac, ibuprofen represents the group of NSAIDs having the shortest plasma half-lives. Diclofenac Diclofenac competes with arachidonic acid for binding to cyclo-oxygenase, resulting in decreased formation of prostaglandins (Small 1989). Chemically, it is the sodium salt of amino phenylacetic acid (Fowler 1979), and the recommended daily dose is 100 to 150 mg. It appears to be as effective as indomethacin or sulindac in treating patients with AS, but possibly induces less gastrointestinal toxicity than aspirin and indomethacin (Small 1989). Etodolac and Flurbiprofen Etodolac is a newer NSAID which may be as effective as indomethacin (Bacon 1990). The effects of flurbiprofen seem comparable to that of phenylbutazone, indomethacin and naproxen (Stubbs & Freeman 1989). 2.3.4 Drug Interactions NSAIDs tend to displace coumarin anticoagulants, sulphonylurea hypoglycaemic agents, anticonvulsants and some antibiotics from proteinbinding sites which may give rise to clinical effects (Brooks et al. 1980). In haemostatic disorders, ibuprofen and indomethacin may be the wisest choice of NSAID (Brooks et al. 1980). However, whenever an NSAID is prescribed along with anticoagulant therapy, the patient must be carefully observed for alterations in prothrombin time.

Drugs 44 (4) 1992

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2.4 Corticosteroids Oral corticosteroids have not been shown to inhibit the disease process in AS. Also of importance is the rather large risk of corticosteroid-induced toxic reactions when treating such a chronic disorder. Moreover, corticosteroids do not appear to be effective in controlling clinical manifestations of AS. In fact, better efficacy has been achieved with both indomethacin and phenylbutazone (Calabro 1968). On the other hand , corticosteroids given as intra-articular injections usually have a remarkable favourable effect on the clinical features of peripheral arthritis (Husby et al. 1975). Such an observation further emphasises the difference between pure inflammation and inflammation leading to bony ankylosis. In severely ill patients, high doses of oral corticosteroids may be administered, but rather abruptly discontinued if favourable responses are not obtained within a reasonably short time (1 to 2 weeks). Occasionally, patients with crippling peripheral joint disease, systemic or renal amyloidosis, and uveitis not responding to topical steroids may benefit from oral corticosteroids. A dramatic response to intravenous injections of methylprednisolone 1000mg (pulse therapy) was reported in patients failing to respond to NSAIDs (Minz et al. 1981). When signs of high disease activity were present , relapses several months after 3 pulses were rarely observed . Another study confirmed these findings of the favourable effects of pulsed therapy in AS, but unfortunately clinical improvement lasted for only I or 2 months (Richter et al. 1983). In our experience, pulse therapy with methylprednisolone rarely provides lasting relief in AS (Nygaard et al. 1987). 2.5 Analgesics Probably due to the widespread use of NSAIDs, 'plain' analgesics have received little attention in the therapeutic management of AS. However, in some patients NSAIDs appear insufficient to minimise pain and stiffness, and concomitant analgesics such as paracetamol (acetaminophen) and dex-

tropropoxyphene should be given. Patients with AS suffer from chronic lifelong pain indeed neccesitating the occasional prescription of analgesics. The risk of drug abuse, addiction and analgesic toxicity should be balanced with improvement of functional capacity obtained through the use of such drugs. At present, some rheumatologists appear too restrictive in their administration of analgesics, somewhat failing to understand completely the burdens of chronic painful disease. Analgesicsshould be given with caution to young patients, and prescribed for short periods only. The objectives of such treatment and the risks of analgesic toxicity should be carefully explained to patients. Principally, analgesics should never be deployed as first-line drugs in the therapeutic management of AS. However, in patients unable to tolerate NSAIDs, these drugs may represent the only alternative for relieving pain and making the patient fit for physical exercises. In a very few patients who suffer from otherwise incurable pain and disability , opiates may be administered. In our experience, drug abuse and addiction appear to be rather rare events among patients afflicted by AS, but the risk must nevertheless be considered .

3. Specific Treatment Considerations 3.1 Peripheral Joint Disease Among juvenile patients with AS, the disease most often starts in the peripheral joints without evidence of axial involvement (Cassidy & Petty I990a). If monoarticular joint disease is present, the condition is best treated with intra-articular injections of a corticosteroid, usually triamcinolone 5 to 20mg depending on joint size. When more than I joint is affected, the administration of an NSAID is indicated. However, contrary to adult patients with AS (Cassidy & Petty 1990b), juveniles may respond to salicylates.Aspirin in amounts sufficient to ensure a plasma concentration of at least 250 mg/L (1.8 mmol/L) should be deployed for I to 3 months before NSAIDs are prescribed (Cassidy & Petty I990a). The major toxic reactions

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to salicylates are tinnitus, hearing loss, Reye's syndrome (rare) and gastric irritation. Unfortunately, there are rather few trials of NSAID therapy performed in juvenile AS. Recommended drugs are tolmetin sodium 25 to 30 mg/ kg/day and indomethacin I to 2 rug/kg/day (Cassidy & Petty 1990b). Disease-modifying antirheumatic drugs are rarely administrated in juvenile AS, because the peripheral arthritis does not lead to destruction or misalignment. In drug-resistant peripheral arthritis, surgical synovectomy should be considered. Adult patients with AS complicated by peripheral arthritis are managed by the administration of NSAIDs and intra-articular triamcinolone injections. In arthritis confined to the knee joint, intra-articular injections of osmic acid (osmium tetroxide) may be used (Nissile 1978). It is our experience that patients with gonarthritis of short duration exhibiting active synovitis with rather large swellings are those who best respond to osmic acid injections. In severe adult polyarticular disease resembling rheumatoid arthritis, remittive agents such as sulfasalazine , gold and antimalarials may be employed. We are, however, not aware of any controlled study that has demonstrated favourable effects of such therapy in patients with AS. Finally , the possible benefits of methotrexate in such cases still await controlled trials . 3.2 Enthesopathy Enthesopathy describes inflammation at the tendinous insertion of bone. Achilles tendinitis, and calcaneal and tarsal periostitis may be troublesome disease manifestations of AS. Such features are initially treated with NSAIDs and supportive measures such as heel pads and orthopaedic shoes. Local injections with corticosteroids are then administrated, although the ir effects have to confirmed by controlled trials. Some patients with calcaneal enthesopathy may benefit from local radiotherapy (Grill et al. 1988). If calcaneal spur formation is visible on x-ray, an orthopedic surgeon should be consulted.

3.3 Psoriasis Psoriasis is commonly accompanied by involvement of the musculoskeletal system (Wright 1980). Most frequently, arthritis develop in the peripheral joints, but also the sacroiliac joints may become involved, thus resembling AS. Unfortunately, we are not aware of any well conducted long term study designed to compare disease outcomes in ' pure' AS and AS associated with psoriasis ; nor is it known whether control of the skin disease may influence the activity of arthritis. There is, however, no clearcut association between the degree of psoriasis and the severity of spondylitic disease. AS associated with psoriasis is managed as primary AS, although a less frequent tendency towards spinal deformities may be anticipated (Alanso et al. 1991 ; Gran & Husby 1984; Gran et al. 1984). 3.4 Inflammatory Bowel Disease The inflammatory bowel disorders ulcerative colitis and Crohn's disease are accompanied by AS in some 2 to 4% of cases (Gran & Husby I992b). In contrast to the peripheral arthritis in such bowel diseases , there is no correlation between activity of intestinal disease and that of the spine (Neumann & Wright 1983). Similarly, surgery of the affected bowel does not ameliorate symptoms of associated AS (Fernandez-Herlihy 1959). Consequently, AS and concomitant inflammatory bowel disease should be treated as 2 separate disorders. It should be noted that asymptomatic sacroiliitis seen in ulcerative colitis and Crohn's disease is not a feature of AS (Gran & Husby 1992b). Although not confirmed , relapse of ulcerative colitis due to diclofenac and naproxen therapy has been reported (Gueller 1987). In B27-negative AS and AS exhibiting peripheral arthritis, the concomitant occurrence of bowel inflammation should always be considered (Mielants & Veys 1990). Such cases may benefit from treatment with sulfasalazine (Mielants & Veys 1985).

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3.5 Other Nonarticular Disease Complications Renal amyloidosis represents one of the most serious and lifethreatening complications of AS (Husby 1980). It is manifested initially by proteinuria (Lance & Curran 1991) which not infrequently progresses into nephrotic syndrome and renal failure. The diagnosis is made by rectal biopsy in which the histological specimen is stained with Congo red to demonstrate the tissue deposits of amyloid (Lance & Curran 1991). In patients with proteinuria, a positive rectal biopsy or subcutaneous fat smear is also highly suggestive of renal amyloidosis (Husby 1992). Unfortunately, there are as yet no means of inhibiting the deposition of amyloid in parenchymatous organs. There are, however, some observations indicating that general suppression of the inflammatory process may retard the development of systemic amyloidosis (Husby 1992). Thus, rapid treatment of intervening infections and use of NSAIDs may be recommended in AS complicated by renal amyloidosis . Renal failure is best managed in cooperation with a nephrologist, and patients with end-stage renal failure should always be considered for renal transplantation (Hartman et al. 1992). However, abnormalities of renal function, the development of proteinuria and the demonstration of casts in urinary specimens should alert the physician to the possibility of analgesic (i.e. salicylate) nephropathy . In England about 40% of patients with analgesic nephropathy had arthritis (Cove-Smith & Knapp 1978). In rare instances, NSAIDs may cause acute interstitial nephritis, papillary necrosis and nephrotic syndrome (Clive & Stoff 1984; Husser! et al. 1979). Cardiac conduction disturbances and aortic insufficiency are best managed by a cardiologist, and patients developing acute anterior uveitis should be seen promptly by an ophthalmologist. Apical fibrocystic disease of the lungs is a very rare complication of AS, but may be associated with fungal (Aspergillus spp.) or bacterial infection requiring appropriate antimicrobial therapy (Crompton et al. 1974).

Drugs 44 (4) 1992

3.6 Special Considerations in Patients Undergoing Surgery The most frequent cause of surgical intervention in AS is the involvement of hip, requiring arthroplasty . Due to AS, these cases may face serious problems postoperatively because physical inactivity increases both pain and stiffness. This stiffness induced by immobility may render physical exercises difficult after surgery for hip prosthesis. Although NSAIDs have not been completely ruled out as putative agents retarding wound healing, it is our current strategy to use such drugs both pre- and postoperatively . No drug is at present available to prevent heterotrophic ossification (i.e. calcification or ossification in adjacent soft tissue) which is not infrequently seen after hip surgery in AS (Delee et al. 1976; Nollen & Slooff 1973,). Indomethacin has been suggested to cause aseptic necrosis of the femoral head (Christiansen & Soos 1981), and should therefore not be used in AS patients with involvement of these joints. However, this association between indomethacin and aseptic necrosis has been disputed by other workers (Bossingham et al. 1978). The surgeon managing patients with AS should also be aware of the possibility of silent gastrointestinal bleeding from use of NSAIDs and salicylates. Before surgery, x-rays of the cervical spine should be obtained to rule out the presence of atlanto-occipital subluxation obstructing the medullary canal (medulla oblongata) [Sharp & Purser 1961 ]. Finally, if unattended, patients using oral corticosteroids may fail to produce an adequate plasma cortisol response to the stress provoked by surgery. A bolus injection of soluble corticosteroid (e.g. methylprednisolone 100 to 200mg) should be administered 12 to 24 hours before orthopaedic intervention. 3.7 Special Considerations during Pregnancy and Lactation Contrary to rheumatoid arthritis, and possibly systemic lupus erythematosus (Lockshin et al. 1984; 0stensen & Husby 1983; Zurier 1983), pregnancy

Treatment of Ankylosing Spondylitis

rarely influences the disease course of AS (Husby et al. 1988).Similarly, the postpartum flare-up often seen in rheumatoid arthritis and perhaps in systemic lupus erythematosus is infrequently observed in AS (Husby et al. 1988). Consequently, pregnant women with AS most often face unchanged clinical problems during pregnancy and lactation. Therefore, the need for adm inistration of drugs has to be dealt with during such periods. The general rule is to deploy the least toxic compounds, preferably in reduced dosage and only for short periods (0stensen & Husby 1985). Teratogenicity from salicylates and NSAIDs has not been proven in humans (0stensen & Husby 1985). However, these drugs have been reported to cause intra- and postpartum bleeding in both mother and in the newborn (Stuart et al. 1982). NSAIDs have also been incriminated as agents causing delayed parturition, and should thus be avoided in late pregnancy (Cecere & Persellin 1981); it is advisable to stop treatment 2 to 4 weeks prior to delivery (0stensen & Husby 1985). During pregnancy, ibuprofen and indomethacin are perhaps the only drugs satisfactorily studied in pregnant women without observable fatal complications (0stensen 1985). During lactation, diclofenac, ketoprofen , ibuprofen, naproxen, mefenamic acid, flufenamic acid and phen ylbutazone may be given without unfavourable effects on the , nursing infant (0stensen 1985). Oral corticosteroids are excreted into breast milk but the importance of this transportation remains unknown (McKenzie et al. 1975).

4. Conclusions The basic drug therapy in AS rests firmly on the administration of NSAIDs. Of drugs possibly influencing the disease course, sulfasalazine appears at present to be the only alternative. However, any effect on AS of such disease-modifying antispondylitic drugs may throw new light on the aetiopathogenesis of this rheumatic disease. Special attention regarding prescription of drugs for AS is to be made during surgery, pregnancy and lactation. Although the treatment of AS is aimed at relieving

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pain and stiffness to allow maintenance of joint function , an important objective is also to avoid undue hazards from various forms of drug treatment.

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Correspondence and reprints: Dr Jan Tore Gran, Department of Rheumatology, Central Hospital of Aust-Agder, 4800 Arendal, Norway.