Sustained-release indomethacin in the management of ankylosing spondylitis

Sustained-Release Indomethacin in the Management of Ankylosing Spondylitis

JOHN J. CALABRO, Worcester,

Ankylosing spondylitis is a systemic rheumatic disorder that is characterized by inflammation of the spine, sacroiliac, end large peripheral joints. Although back pain is the most frequent presenting symptom, disease can begin in peripheral joints-especially in children and women-and, rarely, even with acute iritis. Whatever the mode of onset, recurrent back pain that is frequently nocturnal and of varying intensity is an eventual complaint, as is early morning stiffness that is typically relieved by activity. The long-term prognosis is clearly enhanced by early diagnosis and patient education, both of which are central to preventing or minimizing disability. By suppressing articular inflammation, pain, and stiffness, the nonsteroidal anti-inflammatory drugs facilitate exercise and other supportive measures. Currently, among these agents, indomethacin occupies an important place. By virtue of its 12-hour dosage system, sustained-release indomethacin can be prescribed only once or twice daily, providing the anti-inflammatory efficecy of indomethacin while promoting patient compliance.

M.D., F.A.C.P.

Massachusetts

From the University of Massachusetts School and the Division of Rheumatology, ment of Medicine. Saint Vincent Hosoital. ter, Massachusetts.

The introduction of indomethacin in the 1960s brought recognition to a therapeutic class of drugs now known collectively as the nonsteroidal anti-inflammatory drugs [I]. Clearly, its discovery provided the impetus for worldwide research for other comparable agents. As a result, there has been a steady proliferation of nonsteroidal anti-inflammatory drugs in the past two decades. To fully appreciate the impact of this advance, one need only to take a retrospective look at the state of the art of rheumatology in the pre-indomethacin era [2]. lndomethacin became available for clinical trials in November 1961 [3]. Its promise derived from its unique pharmacology as a synthetic, nonsteroidal indole compound with potent analgesic, antipyretic, and anti-inflammatory properties. One of the major difficulties that plagued early clinical trials was the erratic absorption with the tablet formulation of indomethacin. Studies of serum levels in healthy volunteers ultimately led to a change in the formulation of indomethacin from the original unacceptable tablet to the current capsule that has now become an efficacy standard against which many nonsteroidal anti-inflammatory drugs are compared. In 1965, after four years of clinical trials in the United States, indomethacin became available for general prescribing. By then, a great deal of clinical investigation had proved its effectiveness in acute gout as well as moderate to severe osteoarthritis, rheumatoid arthritis, and ankylosing spondylitis [3]. Reappraisals of the long-term use of indomethacin have been published after five years [4], after 10 years [5], after 15 years [6], and only recently after 20 years [7]

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INDOMETHACIN

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Unifying Features of the Seronegative Spondyloarthropathies

the activity or flares of ankylosing spondylitis can be closely correlated with the presence of Klebsiella pneumoniae in stool cultures [17-191. In fact, molecular mimicry between Klebsiella and the HLA-B27 antigen has been suggested, although this concept of cross-reactivity may be restricted to only certain strains of Klebsiella. The rheumatic diseases comprise at least 100 distinct disorders that affect as many as 36 million Americans [20]. Ankylosing spondylitis is the third most common form of chronic arthritis in the United States, affecting as many as three million Americans [21,22]. Although the prevalence of ankylosing spondylitis varies widely throughout the world, it is directly proportional to the frequency with which the 827 antigen occurs in a given population [lo]. Nevertheless, the frequency of the eventual development of ankylosing spondylitis in subjects having the B27 antigen remains unsettled [8]. On the basis of two American surveys, one of B27-positive blood donors [21] and another of B27-positive tissue donors [23], it has been calculated that ankylosing spondylitis will develop in 20 percent of both men and women possessing the antigen. The frequent association between spondylitis and psoriasis, Reiter’s syndrome, ulcerative colitis, and Crohn’s disease has, until recently, defied explanation. It now appears that among these disorders, the patients most apt to eventually have ankylosing spondylitis are those with the B27 antigen. In fact, it has been estimated that the risk of the development of spondylitis is 40 times greater in patients with ulcerative colitis and the B27 antigen than in such patients without the antigen [lo]. In addition to ankylosing spondylitis, B27-positive subjects are also prone to recurrent attacks of acute anterior uveitis (without arthritis or spondylitis) as well as Reiter’s syndrome. They are also predisposed to psoriasis and psoriatic arthritis, although the correlation of B27 to these latter disorders is less striking than with acute anterior uveitis, Reiter’s syndrome, and ankylosing spondylitis

Negative results for IgM rheumatoid factor Absence of subcutaneous (rheumatoid) nodules Inflammatory peripheral arthritis Fioentgenographic evidence of sacroiliitis, with or without spondylitis Clinically interrelated mucocutaneous, ocular, genital, and gastrointestinal manifestations Frequency of enthesopathy’ Tendency to cluster in families Frequent association with the inherited antigen HLA-627 *Characterized clinically by heel pain or other localized areas of tenderness due to inflammation of ligaments, tendons, or fascia and roentgenographically by osseous proliferation and/or erosions at these sites.

Indomethacin, initially marketed as a 25 mg capsule, was soon followed by a 50 mg capsule and more recently a 75 mg sustained-release preparation. This report will focus on the use of sustained-release indomethacin in the management of patients with ankylosing spondylitis. First, however, because of their bearing on management, the classification, epidemiology, pathogenesis, and natural history of ankylosing spondylitis will be reviewed. CLASSIFICATION Ankylosing spondylitis is a heterogeneous and systemic rheumatic disorder that is characterized by inflammation of the axial skeleton (spine and sacroiliac joints) and large peripheral joints [8]. It is the prototype of a group of rheumatic disorders known collectively as the seronegative spondyloarthropathies, which also include enteric arthritis or the arthritis of chronic inflammatory bowel disease (ulcerative colitis and Crohn’s disease), psoriatic arthritis, and Reiter’s syndrome and other forms of reactive arthritis caused by enteric pathogens. It is now universally acknowledged that the seronegative spondyloarthropathies are characterized by a number of unifying features [8-151 (Table I). However, these disorders have little in common with classic rheumatoid arthritis, although they may occasionally mimic it, particularly in their initial presentations. Consequently, the former classification of these disorders as “rheumatoid variants” should be discarded [8]. EPIDEMIOLOGY

[lOI. NATURAL

Ankylosing spondylitis affects three times more men than women and usually begins between the ages of 20 and 40 years. Fewer than 10 percent of cases begin in childhood (juvenile ankylosing spondylitis) and approximately 15 percent after the age of 40 years. Modes of Onset. Ankylosing spondylitis has three distinct modes of onset [8]. The most frequent initial complaint is back pain, usually of the lumbar spine and sacroiliac joints, but occasionally of the cervical or thoracic spine. However, in as many as 30 percent of patients, most of whom are primarily children and women, the disease begins in peripheral joints, often asymmetrically and usually of the knees, hips, ankles, and heels. The time interval between the onset of peripheral arthritis and sacroiliac or back pain may be prolonged to five, 10, or even 15 years, particularly in boys who otherwise have a diag-

AND PATHOGENESIS

The initial 1973 disclosure and subsequent worldwide confirmation of an unusually high frequency of the inherited antigen HLA-B27 both in patients and in asymptomatic first-degree relatives provides overwhelming .evidence of a genetic predisposition in the evolution of ankylosing spondylitis [8]. There are, nevertheless, recent reports suggesting that environmental or exogenous factors are also operative in pathogenesis [14,16]. Of particular relevance, in this regard, are investigations in which

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HISTORY

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Clinical

Tests For Early Detection

T&St

Sacroiliac Chest

compression

expansion

Fingers

to floor

Schober

test

Occiput

to wall

of Ankylosing

INDOMETHACIN

Spondylitis Interpretation

Method

Exert Measure

direct

compression

maximal

chest

over the sacroiliac expansion

joints

at the nipple

line

Patient bends forward with knees extended; distance from fingertips to floor is measured A mark is made on the spine at the level of the iliac crests and then another 10 cm directly above while patient is standing upright. Patient then bends forward maximally and the distance between the two marks is measured Patient places heels and back against wall and tries to touch the wall with the back of the head without raising his chin above carrying level

nosis of pauciatticular juvenile rheumatoid arthritis. Recurrent attacks of acute anterior uveitis (iritis) are the sole presenting manifestation in about 2 percent of cases. Early systemic manifestations may include fever, fatigue, anemia, anorexia, and weight loss [24]. Course of Disease. Whatever the mode of onset, intermittent or persistent back pain is an eventual complaint. Patients automatically ease the back pain and paraspinal muscle spasm by adopting a flexed or bent-over position. Consequently, some degree of kyphosis is common in untreated patients. Diffuse costovertebral involvement is another early manifestation that soon leads to diminished chest expansion. The usual course of ankylosing spondylitis is characterized by remissions and exacerbations that may be mild in some and severe in others. Rarely is the course persistently progressive, resulting in early and severe disability. Peripheral synovitis occurs frequently in the course of ankylosing spondylitis. While often transient, it becomes chronic in as many as 25 percent of patients [25]. Peripheral arthritis is usually asymmetric, involving only one or a few large joints, such as the hips, knees, or shoulders. Rarely are the small joints of the hand and foot involved. Systemic Manifestations. Except for uveitis, which is more apt to occur in B27-positive patients, the frequency of systemic manifestations is comparable in patients with or without the B27 antigen [26]. Consequently, all patients should be monitored for ophthalmologic, neurologic, cardiovascular, or pulmonary involvement, since these are the major extra-articular manifestations observed in ankylosing spondylitis [8,27]. Although acute anterior uveitis is an uncommon presentation of ankylosing spondylitis, 30 percent of patients are eventually affected by this ocular inflammation [8]. Attacks of uveitis are usually short-lived, subsiding within a few weeks, but recurrences are common. Rarely are attacks severe or protracted so as to cause loss of vision. Neurologic abnormalities may result from compression radiculitis or sciatica, from cord damage due to vertebral

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25, 1985

Local tenderness suggests sacroiliac involvement, which can be asymptomatic initially Expansion of 3 cm or less is a clue to early costovertebral involvement Inability to touch close to the floor is evidence of early lumbar involvement Increase of less than 3 cm indicates loss of lumbar flexion

Inability to touch loss of cervical

head to wall signifies extension

fracture or subluxation, and from the cauda equina syndrome. The latter may produce impotence, nocturnal urinary incontinence, poor stream, diminished bladder or rectal sensation, and absence of ankle jerks [28]. Cardiovascular manifestations include cardiomegaly, angina, pericarditis, aortic insufficiency from aortitis, and conduction disturbances [8]. Aortic insufficiency develops in only 3 percent of patients and usually, but not always, in patients with severe spinal involvement. Cardiac conduction disturbances are more frequent; they are usually disclosed on routine electro- or echocardiography and rarely cause symptoms [29]. Chest pain that is usually inspiratoty as well as dyspnea on exertion may result from severe involvement of the costovettebral joints. A rare pulmonary manifestation of ankylosing spondylitis includes apical or upper lobe fibrosis that occasionally progresses to cavitation as well as intercurrent infection with Aspergillus 130-321. EARLY

DIAGNOSIS

Ankylosing spondylitis continues to remain one of the most commonly overlooked causes of back complaints in young people [33]. Yet, all that is required for early diagnosis is the usual approach of all primary physicians-a complete history, including that of the family, and physical examination, as well as a critical interpretation of pertinent laboratory and roentgenographic findings. History and Physical Examination. If a patient complains of back pain, there are three clues in the history that point to ankylosing spondylitis: (1) the back pain has persisted for more than three months; (2) the pain is intermittent, often worse at night; and (3) the pain is accompanied by early morning stiffness that is readily relieved by activity. On physical examination, certain simple tests will disclose typical abnormalities at an early stage (Table II). For example, to unmask local tenderness from sacroiliitis, the sacroiliac joints should be compressed bilaterally (Figure 1). In a surprising number of cases, the patient will not

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spasm. One final check of early lumbar involvement is the Schober test (Table II). If the skin stretches less than 3 cm, the lumbar spine is affected. The occiput-to-wall test will disclose early cervical spine involvement, as will detection of diminished cervical extension, flexion, and lateral bending. With appropriate management, most abnormal measurements will improve or revert to normal. Consequently, in long-term management, these tests should become a routine pat-t of the patient’s examination at each follow-up visit. Laboratory and Roentgenographic Clues. When ankylosing spondylitis is active, the erythrocyte sedimentation rate is elevated in most patients, as are other acutephase reactants, such as serum IgA levels. Tests for rheumatoid factor, such as the latex fixation, give negative results. Consequently, a negative result for rheumatoid factor in a young patient who has only peripheral arthritis should, in fact, suggest the possibility of ankylosing spondylitis or, for that matter, still another of the seronegative spondyloarthropathies. Detection of the HLA-B27 in the patient’s serum is perhaps the best single laboratory clue. Its absence, however, does not preclude a diagnosis of ankylosing spondylitis. The diagnosis of ankylosing spondylitis must be confirmed by roentgenographic examination. In the majority of patients, the earliest changes occur in the sacroiliac joints (Figure 3). It is customary to include frontal and oblique projections in the preliminary examination [8]. Additional studies may include anteroposterior erect, stereophotogrammetry, craniocaudal axial projection, tomography, computed tomography, and scintigraphy. Although each of these latter techniques may be beneficial in cases in which routine x-ray films appear to be normal or equivocal, they are seldom needed. Moreover, with these additional approaches, interpretation depends largely on the skill and expertise of the radiologist [8,34]. Finally, x-ray abnormalities of the sacroiliac joints are not unique to ankylosing spondylitis and related spondyloarthropathies and may be found in a host of other disorders [8,35]. Moreover, the sacroiliac joints are often tender on palpation in fibromyalgia (fibrositis), but the joints are normal on roentgenographic examination [36]. Early changes of the lumbar spine include diffuse vertebral squaring and demineralization (Figure 4). Minimal ligamentous calcification and one or two evolving syndesmophytes may also be noted. The classic “bamboo spine,” with its prominent syndesmophytes and diffuse paraspinal ligamentous calcification of the entire spine, the usual textbook illustration, is not useful in early diagnosis. In fact, it takes an average of IO years to develop and is observed only in patients with progressive disease, a group that comprises fewer than 15 percent of all patients with ankylosing spondylitis. Differential Diagnosis. One of the most important disorders from which ankylosing spondylitis must be distin-

Figure 1. Direct compression is applied to the sacroiliac joints. Local tenderness or gluteal pain will reveal sacroiliitis, which is occasionally asymptomatic early.

Figure 2. A simple test for detection of asymptomatic costovertebral involvement is to measure chest-cage expansion at the nipple line before and after deep inspiration. In ankylosing spondylitis, chest expansion is often 3 cm or less; normal expansion is 6 cm or greater.

previously have reported pain specifically in the sacroiliac joints. To check for early costovertebral involvement, which is frequently asymptomatic, the patient’s chest expansion should be checked (Figure 2). If the maximal expansion is 3 cm or less, a suspicion of ankylosing spondylitis should be aroused since normal chest expansion is 6 cm or greater. To explore for lumbar involvement, the patient should be asked to touch to the floor while keeping the knees extended. Most patients with spondylitis are unable to reach with their fingertips much below knee level. Moreover, on examination of the lumbar spine, the normal lumbar lordosis may be lost because of paraspinal muscle

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INDOMETHACIN

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Figure 4. Lateral x-ray view of the lumbar spine reveals typical early changes including demineralization and squaring of vertebral bodies as well as ligamentous calcification from the third to the fourth lumbar vertebrae (arrow).

on the iliac side.

have disclosed that ankylosing spondylitis is not uncommon in women, as previously believed. In fact, ankylosing spondylitis evolves more slowly in women than in men; typical clinical and roentgenographic features may not become apparent for 10 or more years [8,38]. Ankylosing spondylitis also tends to occur later in life in women, frequently after age 40. Futhermore, the pattern of spinal involvement on roentgenographic examination is often different from that observed in men [39]. Women with ankylosing spondylitis have a higher frequency of cervical spine abnormalities, a greater tendency for combined cervical and sacroiliac changes with sparing of the intervening thoracic and lumbar spine, and more frequent and severe osteitis pubis. Ankylosing spondylitis may also be overlooked when onset occurs in childhood; the condition is often misdiagnosed as pauciarticular juvenile rheumatoid arthritis [40]. Boys between the ages of 10 and 16 are primarily affected. Although juvenile ankylosing spondylitis may begin with back complaints, it is far more frequent for children to present initially with only peripheral arthritis [41451. Only some years later do sacroiliac abnormalities evolve and much later still, the development of back complaints and other clinical and roentgenographic features characteristic of ankylosing spondylitis. Additional clues to evolving ankylosing spondylitis in a child include recurrence of acute (not chronic) anterior uveitis, absence of antinuclear antibodies, and presence of the B27 antigen

guished is herniation of a lumbar disk. This condition is restricted to the spine and has no systemic manifestations such as fatigue, anorexia, or weight loss; all laboratory results, including the erythrocyte sedimentation rate, are normal. The only certain way to diagnose a herniated disk is to confirm the defect with either myelography or computed tomographic scanning. A more difficult differential diagnosis may be presented by the diffuse idiopathic skeletal hyperostosis (DISH) syndrome. The syndrome occurs primarily in men over the age of 50 and may resemble ankylosing spondylitis both clinically and roentgenographically. Patients with the DISH syndrome may have spinal pain, stiffness, and loss of spinal motion that develops insidiously [37]. Characteristic findings on roentgenographic examination include continuous calcification and ossification of the anterolateral aspects of at least four contiguous vertebral bodies, most often in the cervical and lower thoracic regions of the spine. However, in the DISH syndrome, the disk spaces as well as the sacroiliac and apophyseal joints are uninvolved. Moreover, the erythrocyte sedimentation rate is normal and the syndrome is not linked to the 827 antigen. Fibromyalgia (fibrositis) should also be included in the differential diagnosis [36]. This benign disorder, seen most often in young and middle-aged women, is characterized by symmetric tender (trigger) points that occur at multiple sites of the body and are not restricted to the spine. However, the fact that the patient is a woman, should not decrease the suspicion of ankylosing spondylitis as the cause of her back problems. Recent surveys

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INDOMETHACIN

Drug Therapy

SYMPOSIUM-CALABRO

in Ankylosing

Sponclylitis*

lent results achieved by these seemingly undramatic measures must be emphasized. Initial care begins with the appropriate use of nonsteroidal anti-inflammatory drugs to suppress atticular inflammation and discomfort. The drugs listed in Table Ill should be considered first, since these are of proved value in ankylosing spondylitis. Clearly, the task of selecting the most appropriate drug often rests more on tolerance or potential risks than on marginal differences in efficacy

Daily Dosage Drug

Year of U.S. Marketing

Average

1915 1952 1961 1965 1976 1978

49 300 mg 300 mg 100 mg 750 mg 300 mg

1981

75 mg

Salicylates Phenylbutazone+ Oxyphenbutazone+ lndomethacin Naproxen Sulindac Sustained-release indomethacin

Range 3-6 100-400 100-400 25-200 250-l ,000 100-400 75-150

g mg mg mg mg mg

[471. Nonsteroidal Anti-Inflammatory Drugs. By suppressing axial and peripheral joint inflammation, pain, and stiffness, the nonsteroidal anti-inflammatory drugs facilitate exercise and other supportive measures that are the hallmark of treatment in ankylosing spondylitis [48]. Although aspirin or other salicylates may be tried first, they are seldom adequate and in no way comparable to the effectiveness of either indomethacin or phenylbutazone. In fact, in a multicenter comparative trial of 49 patients with ankylosing spondylitis, in which each received six weeks treatment with each of three drugs (aspirin, indomethacin, phenylbutazone), seven, or only 15 percent, showed response to aspirin, in contrast to more than 90 percent efficacy with either indomethacin or phenylbutazone [49]. Indomethacin: One of the earliest reports of indomethacin in moderate to severe ankylosing spondylitis dates back to 1968 [50]. It detailed a five-year clinical trial of the drug in 28 patients. As judged by several criteria, including articular pain, duration of morning stiffness, onset of fatigue, and joint mobility, the overall response to indomethacin was rated as good in 21 patients, fair in five, and poor in two. After receiving indomethacin for an average period of 33 months, 21 of the 28 patients were considered to be in functional class I of the American Rheumatism Association [51]. Only one patient had been so classified prior to the drug trial. The average Westergren erythrocyte sedimentation rate values for all 28 patients decreased during the drug trial from 39 to 26 mm per hour (p ~0.01, Student t test). Consequently, the results of this trial suggest that indomethacin may favorably alter the course of moderate to severe ankylosing spondylitis. Central nervous system and gastrointestinal side effects, frequently transient and generally tolerated upon reduction of the daily dosage, occurred most often after prolonged administration of indomethacin [50]. Four of the eight patients who experienced adverse reactions were taking 200 mg of the drug daily. lndomethacin was discontinued in three patients: in two because of poor response to the drug and in one because of an adverse reaction. In 1981, 18 years after the first patients were entered into this trial back in 1963, it was possible to locate and reassess 14 of the remaining 25 patients [48]. Of the 14, four had had remission and required no further drug therapy. lndomethacin had been discontinued in four patients: in two because of gastrointestinal side effects and in two because of a more favorable effect from another nonste-

mg

‘Drugs listed are the only nonsteroidal anti-inflammatory drugs with Food and Drug Administration approval in the United States +Currently recommended only after other drugs have been tried first. Oxyphenbutazone, while still available, is no longer marketed by Geigy Pharmaceuticals.

cently described by Arnett and associates [46], must also be recognized. Peripheral joint and cervical spine involvement dominates this clinical subset that primarily affects girls. The course of disease is characterized by rheumatoid-like hands and limitation of neck motion from cervical apophyseal fusion that progresses into adulthood. In addition to correlation with the HLA-B27 antigen, cervical apophyseal fusion is also associated with acute anterior uveitis, micrognathia, sacroiliitis, and spondylitis. Early recognition may be difficult because spondylitic features may be overshadowed by prominence of peripheral ar-thritis, including rheumatoid hand deformities. COMPREHENSIVE

MANAGEMENT

Effective management is clearly enhanced by early diagnosis and patient compliance, each of which contribute decisively to preventing or minimizing disability [33,47]. Such an enhanced outlook, however, embraces several components of long-term care that require, first and foremost, the enthusiastic efforts of the patient, which, in turn, are directly related to the encouragement and support of the primary physician. Comprehensive management demands both immediate and long-term objectives [24]. The physician must first relieve the patients joint discomfort with nonsteroidal antiinflammatory drugs, then begin long-range planning to prevent, delay, or correct deformity. Consequently, daily exercises and other supportive measures are vital to maintain proper posture and range of motion. Although patients may need the help of specialists in their long-term care, the primary physician should be in charge-to advise and establish a close and harmonious working relationship with the patient. Therefore, from the outset, the outcome will depend largely on how capable the physician is in educating and motivating the patient. For some patients, a drug regimen augmented by postural training may appear too simple. Consequently, the excel-

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roidal anti-inflammatory drug. The remaining six patients continue to receive indomethacin at an average daily dosage of 100 mg (range 75 to 100 mg) and continue to benefit from its long-term use. In my experience, although the major hazard of prolonged indomethacin use in ankylosing spondylitis has been gastrointestinal bleeding, the frequency of this side effect has been no greater than that observed with aspirin and other conventional drugs used in the treatment of moderate to severe ankylosing spondylitis. For treatment of moderate to severe ankylosing spondylitis, the initial dose of indomethacin is 25 mg given two or three times daily. The dosage of indomethacin can be increased by 25 mg at about weekly intervals until a satisfactory response is obtained or the daily maximum of 200 mg is reached (Table Ill). Most patients require 100 mg daily. However, some patients may need only a single 25 mg capsule on arising, and others with severe back or hip involvement may require as much as 200 mg daily. To avoid gastric upset, patients should be advised to take the capsules with meals or at bedtime with milk or food. Currently, indomethacin ranks as one of two drugs that are most firmly established in the drug therapy of ankylosing spondylitis as indicated by Hill [52] of England in a comprehensive and critical review published in 1980. Moreover, in this review, the fact that indomethacin was compared with eight other drugs introduced more recently for ankylosing spondylitis both in the United States and abroad attests to its place as the standard reference drug in comparative drug trials for ankylosing spondylitis. Sustained-release indomethacin: lndomethacin is now available in three capsule forms: a 25 mg capsule, a 50 mg capsule, and a 75 mg sustained-release form. Sustained-release indomethacin capsules are designed to release 25 mg of the drug initially and the remaining 50 mg over an extended time period. When measured over a 24-hour period, the cumulative amount and timecourse of indomethacin absorption from a single capsule of sustained-release indomethacin are comparable to those of three doses of 25 mg indomethacin capsules given at four- to six-hour intervals. Absorption into the systemic circulation of sustained-release indomethacin continues over an extended period, with 90 percent of the dose absorbed by 12 hours. Sustained-release indomethacin is recommended for all of the indications of the 25 mg and 50 mg capsules of indomethacin except acute gouty arthritis (Table IV). If 75 mg sustained-release indomethacin capsules are used in initiating treatment in active, moderate to severe ankylosing spondylitis, one capsule daily, taken either in the morning or at bedtime, is the usual starting dose in order to observe for patient tolerance. For patients who require 150 mg of indomethacin daily and have demonstrated acceptable tolerance, sustained-release indomethacin may be prescribed as one capsule twice daily (Table Ill). If

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IV

INDOMETHACIN

Approved Indications and Sustained-Release

Conventional lndomethacin Moderate to severe rheumatoid arthritis+ Moderate to severe osteoarthritis Moderate to severe ankylosing spondylitis Acute painful shoulder (bursitis and/or tendinitis) Acute gouty arthritis

SYMPOSIUM-CALABRO

for Conventional Indomethacin*

Sustained-Release lndomethacin Moderate to severe rheumatoid arthritis+ Moderate to severe osteoarthritis Moderate to severe ankylosing spondylitis Acute painful shoulder (bursitis and/or tendinitis)

*Except for patients under 15 years of age because for use in children have not been established. +lncluding acute flares of chronic disease.

safe

conditions

minor adverse effects develop when the dosage is increased to 150 mg daily, the dosage should be reduced rapidly to one that is tolerated and the patient should be observed closely. If severe adverse reactions occur, sustained-release indomethacin should be discontinued. One disadvantage with the use of the 25 mg and 50 mg indomethacin capsules is the need to administer each of these preparations three or four times daily. Alternatively, the newer 75 mg sustained-release form can be given once or twice daily. Consequently, the use of the sustained-release formulation is a more convenient way of prescribing indomethacin and is especially suited for patients who tend to be noncompliant [53]. lndomethacin suppositories (50 mg) are also available and can be administered at bedtime to allay night-time discomfort as well as early morning stiffness. Phenylbutazone and oxyphenbutazone: Most patients initially require 300 or 400 mg of either phenylbutazone or oxyphenbutazone administered three or four times daily, whereas patients with minimal disease activity may need only a single 100 mg tablet either on arising or at bedtime (Table Ill). To screen for rare but serious renal or hematopoietic adverse reactions, including fatal aplastic anemia, a complete blood cell count, platelet count, and urinalysis must be performed weekly for the initial two months of drug therapy and monthly thereafter. Naproxen and sulindac: Naproxen and sulindac are additional drugs with proved efficacy in ankylosing spondylitis. Because of their longer half-life, 13 hours for naproxen and 16 hours for sulindac, they can be given twice daily and are therefore aptly suited for patients who tend to be noncompliant. The daily maximum should not exceed 1,000 mg for naproxen and 400 mg for sulindac (Table Ill). Regardless of the choice, patients should be monitored and warned of potential adverse reactions, particularly those that are common to all nonsteroidal anti-inflammatory drugs (Tables V and VI). Finally, every effort should be attempted to reduce the daily dose to the lowest one

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TABLE

V

VI

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Five Major Classes Effects

of Untoward

Allergic or hypersensitivity Drug idiosyncrasy Overdose Drug interaction Side effects

reaction

Adverse Reactions Common Nonsteroidal Anti-Inflammatory

include nausea with or without vomiting, dyspepsia (including indigestion and heartburn) or epigastric pain, abdominal distress or pain, diarrhea, and constipation. Others are anorexia, bloating, flatulence, proctitis, rectal bleeding, ulcerative stomatitis, intestinal ulceration associated with stenosis and obstruction, and development or aggravation of ulcerative colitis or regional enteritis. Severe toxicity, such as major bleeding, development or reactivation of peptic ulcer, or gastrointestinal perforation, is infrequent. All drugs can induce hepatitis and jaundice. Common mucocutaneous adverse reactions include variable rashes, pruritus, urticaria, and stomatitis. Less frequent side effects include petechiae, ecchymoses, erythema nodosum, photosensitivity, alopecia, and rarely exfoliative dermatitis or toxic epidermal necrolysis [57]. Cornea1 deposits and retinal disturbances, including those of the macula, have been observed with prolonged nonsteroidal anti-inflammatory drug therapy. Blurred vision is a significant symptom that not only necessitates withdrawal of drug but also a thorough ophthalmologic evaluation. Ototoxicity includes ringing in the ears or difficulty with hearing, side effects that are reversible with dosage reduction or discontinuation of the drug. Some of the nonsteroidal anti-inflammatory drugs may aggravate psychiatric disturbances, epilepsy, and parkinsonism, and therefore should be used with considerable caution in patients with these disorders. Headache is a common central nervous system side effect, as are drowsiness, dizziness, confusion, and lightheadedness; patients should therefore be warned about engaging in activities requiring mental alertness or motor coordination. Less common central nervous system side effects include agitation, lethargy, malaise, and depression. Palpitations occur in fewer than 1 percent of patients receiving nonsteroidal anti-inflammatory drugs. Other cardiopulmonary side effects include arrhythmias, congestive heart failure, and pneumonitis [58,59], as well as hypotension, hypertension, and elevation of blood urea nitrogen values. Sodium and fluid retention have been observed with each of these drugs but appear to be more frequent with certain ones, such as phenylbutazone and ibuprofen. All drugs can cause renal toxicity, including the nephrotic syndrome [60-621. Three distinctive forms of renal toxicity can occur with the nonsteroidal anti-inflammatory drugs. The first is acute renal insufficiency, which is related to decreased renal blood flow, and the second is hyperkalemia due to hyporeninemic hypoaldosteronism. These two forms of nephrotoxicity are induced by prostaglandin inhibition. The third form is acute interstitial nephritis, which can evolve with or without proteinuria. Although the development of proteinuria may be a warning sign of toxicity from a nonsteroidal anti-inflammatory drug, it may also be a clue to evolving secondary amyloidosis that is known to occur, although uncommonly, in ankylosing spondylitis. Contraindications and cautions: The nonsteroidal

Drug

to All Drugs

Gastrointestinal upset: nausea, vomiting, dyspepsia, diarrhea, constipation Major gastrointestinal bleeding, ulcer, or perforation Toxic hepatitis Mucocutaneous: skin rash, pruritus, urticaria, alopecia, stomatitis Ocular toxicity: reversible blurring of vision Ototoxicity: reversible ringing in ears and difficulty with hearing Central nervous system toxicity: headache, drowsiness, dizziness, confusion, lightheadedness, agitation, lethargy, malaise, depression Cardiopulmonary toxicity: palpitations, arrhythmias, pneumonitis Sodium and fluid retention: pitting edema of legs, congestive heart failure Renal toxicity: diminished function, interstitial nephritis, papillary necrosis, nephrotic syndrome

possible. Drug withdrawal should be attempted slowly and only after active articular disease has been suppressed for several months. Untoward drug effects: While reactions to drugs are varied, they fall into five major classes [54] (Table V). These include allergic or hypersensitivity reactions, in which symptoms are related to the patient’s immunologic response to standard doses of drug. The most common clinical manifestation is a mild systemic illness closely resembling serum sickness. It begins a few days after initiation of the drug and usually lasts only a few days or weeks, unless the drug is continued. Rarely is there progression to hypersensitivity vasculitis with severe skin and widespread major organ involvement resulting in a fatal outcome. The second is drug idiosyncrasy, which is characterized by an inordinate response to a normal or less than standard dose of a drug. The third is a fairly predictable response to overdose of drug. The fourth is drug interaction, in which unpredictable toxicity evolves when another drug is added, the result of rising levels of free drug because of competition for plasma protein binding sites [55]. All antiinflammatory drugs have this capacity. The fifth includes adverse reactions or side effects. Adverse reactions: The nonsteroidal anti-inflammatory drugs share a common core of side effects unique to all (Table VI). They differ widely, however, in their innate propensity for and frequency of inducing these and other adverse experiences [54,56]. The most frequent side effects occur in the gastrointestinal tract. Adverse reactions 46

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anti-inflammatory drugs are contraindicated in patients who are allergic to aspirin or who have nasal polyps associated with angioedema or a bronchospastic reaction to aspirin or other nonsteroidal anti-inflammatory drugs. Safe conditions for use in children have not been established. Therefore, with the exception of aspirin and tolmetin, which are approved for children, no nonsteroidal anti-inflammatory drug should be prescribed for children 14 years of age or younger except when lack of efficacy or toxicity associated with other drugs warrants the risk. Nor have safe conditions for their prescribing in pregnant and nursing women been established. All nonsteroidal anti-inflammatory drugs should be used with great care in the elderly. All may mask the usual signs and symptoms of infection.

lndomethacin and sustained-release indomethacin drug interactions: In a study of normal volunteers, it was found that long-term concurrent administration of 3.6 g of aspirin per day decreased indomethacin blood levels approximately 20 percent. In normal volunteers receiving indomethacin, the administration of diflunisal decreased the renal clearance and significantly increased the plasma levels of indomethacin. Furthermore, the combined use of indomethacin and diflunisal has been associated with fatal gastrointestinal hemorrhage. Therefore, diflunisal and conventional or sustained-release indomethacin should not be used concomitantly. Clinical studies have shown that indomethacin does not influence the hypoprothrombinemia produced by anticoagulants. However, when any additional drug, including conventional or sustained-release indomethacin, is added to the treatment of patients on anticoagulant therapy, the patients should be observed for alterations of the prothrombin time. When indomethacin is given to patients receiving probenecid, the plasma levels of indomethacin are likely to be increased. Therefore, a lower total daily dosage of indomethacin may produce a satisfactory therapeutic effect. Indomethacin, 50 mg administered three times daily, may produce a clinically relevant elevation of plasma lithium and reduction in renal lithium clearance in psychiatric patients and normal subjects with steady-state plasma lithium concentrations. This effect has been attributed to inhibition of prostaglandin synthesis. As a consequence, when conventional or sustained-release indomethacin and lithium are given concomitantly, the patient should be carefully observed for signs of lithium toxicity. In addition, serum lithium concentrations should be monitored more frequently at the outset of such combination drug treatment. The administration of indomethacin can reduce the natriuretic and antihypertensive effect of furosemide and thiazides in some patients. This response has been attributed to inhibition of renal prostaglandin synthesis by nonsteroidal anti-inflammatory drugs. Therefore, when indomethacin is added to the treatment of a patient receiv-

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ing furosemide or thiazides, or furosemide or thiazides are added to the treatment of a patient receiving indomethatin, the patient should be observed closely to determine if the desired effect of furosemide or thiazides is obtained. Blunting of the antihypertensive effect of beta-adrenoceptor blocking agents by nonsteroidal anti-inflammatory drugs has been reported. Therefore, when these blocking agents are used to treat hypertension, patients should be observed carefully in order to confirm that the desired therapeutic effect has been obtained. lndomethacin blocks the furosemide-induced increase in plasma renin activity. This fact should be kept in mind when plasma renin activity is evaluated in hypertensive patients. Other Antirheumatic Agents. Irradiation of the spine has justifiably come into disrepute as a form of therapy for ankylosing spondylitis [24]. Radiotherapy renders patients with ankylosing spondylitis IO times more susceptible to acute myelogenous leukemia than is the general population 1631. It has been suggested that the risk of leukemia rises sharply as the mean dose to spinal marrow reaches 500 rads [64]. Moreover, in a 1965 survey of more than 14,500 patients with ankylosing spondylitis who had received radiotherapy at some time between 1935 and 1954, 49 had died from acute myelogenous leukemia six to eight, and even as long as 15, years following radiotherapy [65]. More recently, basal cell carcinomas have been reported to occur in the lumbosacral area of a patient who had received radiotherapy for ankylosing spondylitis 22 years previously [66]. It is important, therefore, to continue to examine previous radiation sites carefully since cutaneous neoplasms may develop as long as 50 years later in patients who have undergone irradiation of the spine [66]. Although useful in the treatment of rheumatoid arthritis, none of the slow-acting or remittive antirheumatic agents such as intramuscular gold, the antimalarial drugs, o-penicillamine, and azathioprine is of value in ankylosing spondylitis. All narcotics, strict analgesics, and muscle relaxants lack the anti-inflammatory property needed for effective suppression of ankylosing spondylitis [24]. Consequently, they can be added for short periods as adjunctive treatment for severe articular pain and spasm, but they should never be used as basic drugs in management. Oral adrenocorticosteroids have limited therapeutic value in management. In fact, their long-term use may be risky, predisposing patients to steroid-induced compression fractures of the spine or ischemic necrosis of the femoral head. In the treatment of acute anterior uveitis, topical steroids (and cycloplegics) are usually satisfactory, so that oral corticosteroids are rarely required. The use of intra-articular steroids may also be beneficial, particularly when one or two peripheral joints are more severely inflamed than others, thereby compromising rehabilitation, exercise, and other supportive measures [24]. Supportive Measures. Restoring function or correcting deformity is much more difficult than preventing it. Yet,

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patient must always sit erect, preferably on a chair with a hard, straight back and seat. Although suitable braces may help to maintain good posture, most patients do well without them. Nighttime care: Nighttime is often forgotten in the overall management of arthritis. Not only do patients need adequate hours of rest at night but they must sleep on a firm mattress supported by a rigid board. Consequently, water beds are to be avoided. Moreover, no pillows are to be used under the hips or knees and only a small one, if any, under the neck. Therapeutic exercise: Prescribed by a physician or a qualified associate, exercise must become an intrinsic pat-l of the patient’s daily lifestyle. The use of heat to alleviate stiffness and pain, particularly a warm shower on arising, helps to enhance activity and exercise. Therapeutic exercise must be tailored not only to the degree of spine involvement but also to the patient’s age, strength, and capacity to cooperate. Moreover, exercises must be performed daily and reevaluated periodically as part of the patient’s regular follow-up. Extension of the spine and chest cage stretching are the most important exercises and may be done either standing or lying down. l Spine extension exercise: Lying on the abdomen, the patient stretches the arms out at shoulder level. The patient then raises the head, chest, shoulders, and arms off the bed as far as possible. The patient then relaxes and repeats the exercise 10 to 20 times. l Chest cage expansion: Lying on the back, the patient clasps the hands behind the head. The patient then pulls the elbows to the bed while breathing in deeply, holds the breath in for a count of 10, exhales, and relaxes. The exercise should be repeated 10 to 20 times.

chest expansion. Left, patient faces cbrner while touching opposite walls at shoulder height. Right, patient bends elbotis and leans forward while extending neck (looking up) and breathing in as deeply as possible.

even advanced deformities of the spine or marked limitation of the chest cage will often yield readily to a program of exercise. The objective of all supportive measures, whether they be postural training, therapeutic exercise, or recreational therapy, is to build up muscle groups that oppose the direction of potential deformities and thus to strengthen extensor rather than flexor muscle groups. Finally, regardless of the course of disease, the psychosocial and rehabilitative needs of the patient deserve careful attention in long-range planning [24]. Rest and activity: A proper balance between rest and activity must be provided for each patient. Prolonged bed rest promotes vertebral osteoporosis and should therefore be avoided. For most patients, seven or eight hours of sleep at night is sufficient. When needed, however, short rest periods during the day may help to prevent general fatigue and to counteract the patient’s tendency to “droop” in the late afternoon. The amount of daily rest will depend on the degree of disease activity. Some restrictions may be necessary when the patient has severe fatigue or when the disease flares and becomes more active than usual. Even then, however, the patient should be encouraged to continue daily exercise. Above all, the patient must be encouraged to stay active in order to keep the spine as mobile as possible. Postural training: To prevent the automatic tendency to stoop since it helps to alleviate spinal pain, the patient must always consciously stand as erect as possible and to walk “tall.” Even when picking up objects from the floor, the patient should not bend over but “squat erect.” The

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l Combined exercise for spine extension and chest expansion: Because of its dual objectives, this is an ex-

tremely useful exercise (Figure 5). The exercise is repeated 10 to 20 times and, depending on the need, is performed once, twice, or three times daily. When indicated, exercises that stretch calf and hamstring muscles should also be done. Specific exercises to improve function of hips, shoulders, or other involved peripheral joints may also be prescribed. Recreational activity: Kinesiologic analyses of various sports have determined those most therapeutically useful [67]. For example, swimming, archery, racquettype games, and dancing appear to be suitable for patients, whereas bowling, golfing, and jogging are usually not. Swimming encourages motion of the chest cage, spine, shoulders, and hips. The wedge kick is particularly effective in promoting hip movement. If shoulder motion is limited, the back stroke must be avoided, but the side stroke or a modified breast stroke may be used. Archery aids motion of the chest cage, spine, and shoulders, as do racquet-type sports, such as badminton

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and tennis. Games like dart throwing promote extension and rotation of the spine, shoulder, and hip as well as deep breathing. Dancing enhances both spine extension and chest expansion. This is true of most forms of ballroom dancing, like the fox-trot, waltz, rumba, and swing. Some forms of dancing, however, should be avoided because they require abrupt and extensive twisting motion that may aggravate the spine. These include the twist, the bump, the hustle, and disco dancing. Bowling is contraindicated for patients with marked restriction of spine, shoulder, or hip movement. Jogging and long periods of golf-putting promote forceful flexion of the spine that may be harmful. Using a long putter or restricting golf practice to the driving range is a more practical alternative. Surf-casting may be difficult for persons with marked limitation of the spine and hips. On the other hand, bait-casting, fly-casting, or trolling are encouraged, since they require less physical strain. A case in point of recreational activity inappropriate for ankylosing spondylitis is provided by a 26-year-old man in whom a fixed lumbar kyphosis rapidly developed from IO-speed bicycling [68]. His deformity resulted from riding flexed forward on a IO-speed bicycle for several hours daily when his spondylitis was active. This case serves to remind us that exercise, whether formal or recreational, must be geared to promote extension rather than flexion, thereby opposing the direction of potential deformity. Sexual activity: Ankylosing spondylitis can cruelly sap sexual energy and pleasure. Consequently, patients should discuss openly and freely problems of sexuality induced by their disease. Most forms of sexual intercourse are possible for both men and women even in the presence of flexion deformities of the spine. Men with spondylitis are often reluctant to have intercourse in the top position, because spinal flexion causes back pain and spasm. In this situation, the supine position, in which the man lies flat on his back, may be more comfortable. On the other hand, intercourse with the patient lying on the side might be more suitable in the presence of severe deformity of the back or hip. Surgical Intervention. Reconstructive surgery should

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be contemplated only after all conservative measures have failed. For patients with uncorrectable deformities, whether of the spine, hips, or other joints, surgical correction is now feasible [69]. This requires, however, a very careful assessment, meticulous preoperative planning, and precise attention to operative techniques to assure consistent success without major risk to the patient. Although the technique of lumbar osteotomy is constantly improving, it is still an extensive and delicate procedure that also requires prolonged postoperative care [24,69,70]. Total hip replacement may also provide dramatic results initially, but the subsequent development of bony ankylosis above the prosthesis may result in failure [71]. While spine, hip, or other reconstructive measures are a last resort, correction of vertebral fracture or dislocation are urgent problems because of their potential for nerve root injury or compression of the spinal cord [24].

SURVIVAL AND PROGNOSIS Conflicting reports on survival in ankylosing spondylitis have appeared recently. Of 151 Canadian war veterans observed prospectively since 1947, survival was found to be 61 percent, significantly less than expected, except for a subgroup of patients not treated with radiotherapy [72]. Another survey disclosed that survivorship of males was no different from that of the general population, whereas that of females was reduced [73]. The course and prognosis of ankylosing spondylitis were examined in two groups, one treated in the 195Os, the other in the 1970s [74]. Although the overall prognosis was better in the second group, believed to be the result of general improvement in patient management, there were nevertheless patients with rapidly progressive disease and deformity. The long-term prognosis is bleakest for patients in whom rapidly progressive arthritis of the spine or hips develops, for those with underlying ulcerative colitis or regional enteritis, and for the rare patient in whom secondary amyloidosis develops. Blindness from recurrent anterior uveitis rarely occurs. With early diagnosis, comprehensive management, and patient compliance, a satisfactory functional capacity can be maintained in most patients who are thus able to lead full and productive lives.

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Wise ME: The latent period and its variation in human leukaemia induced by x-rays. Health Phys 1961; 4: 250-266. Court Brown WM, Doll R: Mortality from cancer and other causes after radiotherapy for ankylosing spondylitis. Br Med J 1965; 2: 1327-1332. Good AE, Diaz LA, Bowerman RA: Basal cell carcinomas following roentgen therapy of ankylosing spondylitis. Arthritis Rheum 1980; 23: 1065-1067. Edwards MH, Calabro JJ, Avedon EM, Arje FB, Berryman DL: Therapeutic recreation for the patient with ankylosing spondylitis. Arch Phys Med Rehabil 1966; 47: 77-83. Taylor PW: Ankylosing spondylitis with unusual spinal deformity: a case report. J Rheumatol 1980; 7: 919-922. Simmons EH: Kyphotic deformity of spine in ankylosing spondy-

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litis. Clin Orthop 1977; 128: 65-77. Law WA: Ankylosing spondylitis and spinal osteotomy. Proc R Sot Med 1976; 69: 715-720. William F, Taylor AR, Arden GP, Edwards DH: Arthroplasty of the hip in ankylosing spondylitis. J Bone Joint Surg 1977; 598: 393-397. Kaprove RE, Little AH, Graham DC, Rosen PS: Ankylosing spondylitis. Arthritis Rheum 1980; 23: 57-61. Carter ET, McKenna CH, Brian DD, Kurland LT: Epidemiology of ankylosing spondylitis in Rochester, Minnesota, 1935-1973. Arthritis Rheum 1979; 22: 365370. Lehtinen K: Clinical and radiological features of ankylosing spondylitis in the 1950s and 1976 at the same hospital. Stand J Rheumatol 1979; 8: 57-61.

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