clinical aspects of juvenile and adult ankylosing …

British Journal of Rheumatology 1983;22(suppl 2):104-109

CLINICAL ASPECTS OF JUVENILE AND ADULTANKYLOSING SPONDYLITIS

BY JOHN J. CALABRO

SUMMARY

Ankvlosing spondyhtis (AS) is a heterogeneous and systemic rheumatic disorder that is characterized primarily byinflammation of the spine and sacroiliac joints Consequently, back pain is a frequent presenting complaint althoughthe disease can begin with peripheral arthritis as well as acute anterior uveitis. Unlike men. however, women appearto have milder or atypical AS that may go unrecognized for years. Moreover, the presentation in children rests on therecognition of two distinct subgroups that may be indistinguishable from juvenile chronic polyarthritis. The morefrequent subgroup includes primarily teenage boys who present initially with an asymmetric peripheral pauciarthntisthat most often affects lower-limb joints. Only some years later does sacroiliitis evolve, and, much later still, backcomplaints or other clinical and radiographic features typical of AS. A second subgroup includes mostly girls with apolyarticular onset that is subsequently characterized by cervical fusion, micrognathia, acute anterior uveitis.sacroiliitis. spondyhtis. and rheumatoid-like hands that persist into adulthood.

KEY WORDS: Ankylosing spondyhtis. Juvenile ankylosing spondyhtis. Acute anterior uveitis. Sacroiliitis, differentialdiagnosis. HLA-B27

ANKYLOSING spondylitis (AS) is a heterogeneous and systemic rheumatic disorder characterizedprimarily by inflammation of the spine and sacroiliac joints. Consequently, back pain is a frequentpresenting symptom, although the disease can begin in peripheral joints and in rare instances even withacute anterior uveitis (1).

AS is the prototype of the seronegative spondarthritides which also include Reiter's syndrome andother forms of reactive arthritis due to Yersinia, Salmonella, Shigella and other organisms, psoriaticarthritis, enteric arthritis or the arthritis of chronic inflammatory bowel disease, and certain forms ofjuvenile rheumatoid arthritis (JRA) or juvenile chronic polyarthritis (JCP) as the English prefer to callit (1^1). It is now widely accepted that these disorders are bound together by a common thread and thatthey have little in common with classic rheumatoid arthritis, although they may occasionally coexist ormimic it. especially in their initial presentations (1). Consequently, the former designation of thesedisorders as 'rheumatoid variants' should be abandoned.

The seronegative spondarthritides are unified by a number of common features (1-4). Theseinclude (a) negative tests for rheumatoid factors, (b) absence of rheumatoid nodules, (c) peripheralarthritis, (d) radiologic evidence of sacroiliitis, with or without spondylitis, (e) clinically-interrelatedmucocutaneous, ocular, genital, and gastrointestinal manifestations, (f) a tendency for these disordersto cluster in families, and (g) the frequent association with the inherited antigen HLA-B27.

In the evolution of AS, genetic factors are clearly important (1). Recent experience indicates,however, that environmental or exogenous factors are central to the aetiology and pathogenesis ofAS (5). Moreover, both genetic and exogenous factors are critical to our understanding of theepidemiology of AS (5-8). Of relevance, in this regard, are reports in which active spondylitis andacute anterior uveitis have been associated with the presence of Klebsiella pneumoniae in stoolcultures (6-8).

EpidemiologyThe frequent association between AS and psoriasis, Reiter's syndrome, ulcerative colitis, and

regional enteritis has, until recently, gone unexplained. It now appears that among these disorders,patients with the B27 antigen are the ones who are primarily destined to develop AS. For example, ithas been calculated that the risk for developing AS is 40 times greater in ulcerative colitis patientscarrying the B27 than in those without the antigen (1).

Estimates of the prevalence of AS throughout the world vary widely (1). Certain racial andgeographic groups have an inordinately high frequency of spondylitis. For example, approximately 6%of the Haida Indians in British Columbia have evidence of either sacroiliitis or spondylitis (9). Instriking contrast. African and American Blacks have a very low incidence of the disorder (10). Asmight be anticipated, the prevalence of the B27 antigen is much higher in North American HaidaIndians and much lower in Blacks than in Caucasians.

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CALABRO: CLINICAL ASPECTS 105

The frequency of subjects with B27 who will develop AS has been expressed by two divergentviews, one European (11. 12). the other American (13, 14). Based on currently accepted populationprevalence figures for AS in England, it has been suggested that only 5% of men and 0.6% of womenwith the B27 will develop AS (11). These findings are comparable to those in a report from Hungaryusing basically clinical survey methods and radiographs only when AS was suspected (12). In theHungarian survey, AS was found in 2.9% of males and 0.6% of females who were B27 positive.

Based on two American surveys of B27 positive blood or tissue donors, it has been estimated thatAS will develop in 20% of both men and women with the B27 (13, 14). In one American survey (13),evaluation by postal questionnaires and pelvic radiography of 78 B27 positive blood donors selectedfrom a group of apparently healthy subjects disclosed 14 or 18% who satisfied the criteria for AS. Theprevalence of AS was similar in both sexes. Comparison with 126 B27 negative controls matched forrace, sex. and age failed to yield a single case of AS. In the other American survey (14), evidence forAS was determined by clinical radiologic, and ophthalmologic examinations in apparently healthy B27positive men, aged 18 or over, selected from a tissue-donor population. Back pain and stiffness,restricted lumbar flexion and chest expansion, sacroiliac erosions and sclerosis, and ophthalmologicsequelae of anterior uveitis were found more often in the 24 men of the B27 group than in a controlgroup of 31 men lacking the antigen.

In addition to AS. B27 positive subjects are also predisposed to develop recurrent acute anterioruveitis, and Reiter's syndrome, as well as reactive arthritis. They are also predisposed to psoriasis andpsoriatic arthritis, although the correlation of B27 to these latter disorders is less striking than with theothers (1).

Modes of onsetThe early diagnosis of AS rests on the recognition of three distinct modes of onset (1, 15). Most

cases present with back pain, usually of the lumbar spine and sacroiliac joints, but occasionally of thecervical or thoracic spine. However, in 20-30% of cases, disease begins in peripheral joints, oftenasymmetrically and primarily in knees, hips, ankles, and heels. Recurrent acute attacks of anterioruveitis are the sole presenting manifestation in about 2% of cases.

Early systemic manifestations may include fever, fatigue, anorexia, weight loss, anaemia, andacute anterior uveitis (16). The febrile pattern is typically intermittent with a daily rise and fall tonormal. The fever is usually low-grade but occasionally maybe high, reaching levels of 40.5°C (105°F).

Course of diseaseWhatever the mode of onset, recurrent or persistOnt back pain, often nocturnal and of varying

intensity, is an eventual complaint, as is early morning stiffness that is usually relieved by activity.Patients automatically ease back pain or paraspinal muscle spasm by adopting a bent-over or flexedposition. Consequently, in the untreated patient, some degree of kyphosis is a common sequela.Diffuse costovertebral involvement is usual and may soon lead to diminished chest expansion.

Peripheral synovitis occurs frequently in the course of AS. It is often transient but may becomechronic in as many as 25% of patients (16). The arthritis is usually asymmetric, involving only one or afew large joints, such as hips, knees, or shoulders. Only rarely are the small joints of the hand and footinvolved

Systemic manifestationsWhile acute anterior uveitis is an uncommon presenting feature. 30% of patients are eventually

affected by this ocular inflammation. Attacks of iritis are usually self-limiting, subsiding within a fewweeks but recurrences are common. Rarely are attacks protracted or severe enough to cause loss ofvision.

Neurologic manifestations may result from compression radiculitis or sciatica, cord damage fromvertebral fracture or subluxation. and the cauda equina syndrome. The latter may produce impotency,nocturnal incontinence of urine, poor stream, diminished bladder and rectal sensation, and absence ofankle jerks

Cardiovascular manifestations include cardiomegaly, angina, pericarditis, aortic insufficiencyfrom aortitis. and conduction disturbances. Aortic insufficiency develops in about 3% of patients andusually but not always in a background of severe spinal involvement. Conduction disturbances aremore common, usually disclosed on routine electro- or echocardiography and rarely cause symptoms.

Chest pain that is usually inspiratory and dyspnoea on exertion may result from severe involve-ment of the costovertebral joints. A rare pulmonary manifestation of AS consists of apical or upperlobe fibrosis. occasionally with cavitation that may be mistaken for tuberculosis, and sometimescomplicated by infection with Aspergillus.




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106 PATHOGENESIS OF HLA-B27 ASSOCIATED DISEASES

Survival and prognosisConflicting reports on survival in AS have appeared recently (17, 18). Of 151 Canadian war

veterans observed prospectively since 1947, survival was found to be 61%, significantly less thanexpected, except for a subgroup not treated with radiotherapy (17). Another survey disclosed thatsurvivorship of males was no different than that of the general population, while that of females wasreduced (18). The course and prognosis of AS were examined in two groups, one treated in the 1950s,the other in the 1970s. While the overall prognosis was better in the second group, believed to be theresult of general improvement in patient management, there were, nevertheless, patients with rapidlyprogressive disease and deformity (19).

With early diagnosis, adequate management, and patient compliance, a satisfactory functionalcapacity can be maintained in most patients who lead full and productive lives (16). The prognosis isbleakest for patients who develop progressive arthritis of the spine, hips or knees, for those withunderlying ulcerative colitis and regional enteritis, and for those with secondary amyloidosis.

Juvenile ankylosing spondylitisWhile juvenile AS may begin with back complaints, it is far more frequent for children to present

initially with only peripheral arthritis (20-23). Only some years later do sacroiliac abnormalities evolveand much later still, the development of back complaints and other clinical and radiographic featurescharacteristic of AS.

Our experience confirms the observations reported by others (20, 21, 24). During the past 20years, we have studied 22 children, nine of whom have been reported previously (22). There were 20boys and two girls whose onset of arthritis occurred between 2 and 15 years of age. Peripheral arthritis,primarily of the lower-limb joints, antedated back complaints by 1-12 years in 20 patients. In only twopatients, both teenage boys, were the initial complaints in the low back.

Of the 20 children with onset limited to peripheral joints, only five developed sacroiliac changes onradiography within a year. In the remaining 15, the time lag from the onset of peripheral arthritis tounequivocal sacroiliac radiographic changes or back complaints ranged from 1 to 12 years, with a meanof 6 years.

Four of the five patients who developed sacroiliac radiographic changes within one year also hadasymptomatic restriction of the chest cage (less than 2.5 cm) during the same period. This provided anearly clue to evolving spondylitis rather than JCP, since costovertebral involvement is usually not afeature of the latter. Synovial fluid analysis may also prove useful in differentiating juvenile AS fromJCP, as noted in eight of eight children so tested. Levels of synovial fluid complement proved to behigher than those in JCP, even in the prespondylitic stage when only peripheral arthritis was present.Of all laboratory tests, HLA typing was of the greatest value, since the B27 antigen was present in 20(91%) of our 22 patients, a test that was not available in the initial years when these patients were firstbeing evaluated. None of the 22 patients have had either rheumatoid factor or antinuclear antibodies.

Currently, all 22 patients are in the American Rheumatism Association functional classes I and IIand therefore capable of all ordinary activity. AS continues to be active in 12 patients while 10 are inremission. Five patients have had acute anterior uveitis but none the chronic form of anterior uveitisseen in pauciarticular JCP A family history of AS or another spondarthritic disorder was obtained in 10of the 22 cases.

Spondylitis in femalesFemales with AS appear to have either milder or atypical disease that may go unrecognized for

years (1, 25. 26). Moreover, spondylitis in females may evolve more slowly than in males so thattypical clinical and radiographic features may take an average of 10 years to appear (25). Radiographicdifferences in women include a greater frequency of cervical spine abnormalities, a greater frequencyfor combined cervical and sacroiliac changes with sparing of the intervening thoracic and lumbar spine,and more frequent and severe osteitis pubis.

I would also like to acknowledge an uncommon, yet unique form of spondylitis first described byArnett and associates (26). Peripheral and cervical involvement dominates this clinical subset thatprimarily affects girls and young adult women. Their disease course is characterized by rheumatoid-likehands and limitation of neck motion from cervical apophyseal fusion that progresses into adulthood. Inaddition to correlation with the HLA-B27 antigen, cervical apophyseal fusion is also associated withacute anterior uveitis, micrognathia. sacroiliitis, and spondylitis. Early recognition may be difficult,since spondylitic features may be overshadowed by prominence of peripheral arthritis includingrheumatoid hand deformities.




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Early diagnosisIn order to differentiate AS from other causes of back pain, saeroiliac X-ray examination and the

HLA-B27 were explored as two screening tests for their relative potential values to the practisingclinician (27). It was concluded that saeroiliac radiography was the discriminator of choice because ofgreater specificity as well as other practical considerations. Ultimately, a definite diagnosis of ASdepends on X-ray confirmation, since symmetrical sacroiliitis eventually occurs even in patientspresenting only with peripheral arthritis (Fig. 1). The classical 'bamboo' spine with its prominentsyndesmophytes and diffuse paraspinal ligamentous calcification (Fig. 2) is a late manifestation foundonly in a minority of patients with severe, progressive disease (28).

FIG. 1.—X-ray examination of pelvis discloses pseudowidening of the saeroiliac joints from subchondral erosions andsclerosis lhat arc more prominent on the iliac side.

Many physicians find AS difficult to diagnose. Except for the childhood subgroups, all that isneeded for early diagnosis is the usual approach of all clinicians—a careful history, including that of thefamily, and physical examination, as well as a critical interpretation of pertinent laboratory and X-rayfindings.

X-ray examination of saeroiliac jointsThe saeroiliac joint is one of the most challenging articulations for the radiologist, especially in

children (29). It is customary to include frontal and oblique projections in the preliminary examina-tion. Supplementary views may include anteroposterior erect, stereophotogrammetry, craniocaudalaxial projection, tomography, computed tomography, and scintigraphy (29). Each of these techniquesmay be beneficial in early cases in which routine radiographs appear to be normal or equivocal.However, with supplemental approaches, the skill and experience of the interpreter are extremelyimportant.

Sacroiliitis is not unique to AS and related spondarthritides (29). It may be disclosed in patientswith psoriasis or chronic inflammatory bowel disease in the absence of saeroiliac, spine, or peripheraljoint complaints. It may also occur in juvenile and adult rheumatoid arthritis, Behget's syndrome,Whipple's disease, relapsing polychondritis, crystal-induced synovitis from both gout and pseudogout,




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108 PATHOGENESIS OF HLA-B27 ASSOCIATED DISEASES

FIG. 2—Classical bamboo' spine with prominent syndesmophytes, diffuse paraspinal ligamentous calcification, andfused sacroiliac joints in advanced ankylosing spondylitis.

osteoarthritis, alkaptonuna (ochronotic arthropathy), pustulotic arthro-osteitis, and acute or chronicinfections of the sacroiliac joints (29). X-ray abnormalities of the sacroiliac joints may be found infamilial Mediterranean fever, hyperparathyroidism, Paget's disease, Gaucher's disease, osteitis con-densans ilii,-paraplegia, tuberous sclerosis, fluorosis, occupational acroosteolysis from vinyl chloridepoisoning, and traumatic lesions of the sacroiliac joints (29). The sacroiliac area is often tender onpalpation (trigger points) in fibrositis (fibromyalgia), but the joints are normal on X-ray examina-tion (30). Benign tumours, including osteoid osteoma (31), as well as both primary and secondarymalignancies, may also affect the sacroiliac joints. The major congenital anomaly of the sacroiliacjoints is sacrococcygeal agenesis (29). It is frequently combined with anomalies of the lower thoracicand upper lumbar spine.

REFERENCES

1 Calabro JJ. The spondylarthropathies: An overview. ScandJ Rheumatol 1980;9(suppl 32):21-4.2. Wright V. Family studies implicating genetic factors in rheumatic diseases. Ann Rheum Dis 1975;34(suppl 1):

24-6.3. Wright V Seronegativc polyarthritis: a unified concept. Arthritis Rheum 1978:21:619-33.4. Wright V A unifying concept for the spondyloarthropathies. Clin Orthop 1979:143:8-14.5. Kass E The pathogenesis of ankylosing spondylitis. Ann Clin Res 1975:7:237—43.6 Ebringer RW. Cawdell DR. Cowling P. Ebnnger A. Sequential studies in ankylosing spondylitis: association of

Klebsiella pneumoniae with active disease. Ann Rheum Dis 1978:37:146—51.




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7. Cowling P. Ebringer R. Ebringer A. Association of inflammation with raised serum IgA in ankylosingspondylitis. Ann Rheum Dis 1980;39:545-9

8. Ebringer R. Cooke D, Cawdell DR. Cowling P, Ebringer A. Ankylosing spondylitis: Klebsiella and HLA-B27.Rheumatol Rehabil 1977;16:190-6.

9. Gofton JP, Chalmers A. Price GE. Reeve CE. HL-A27 and ankylosing spondylitis in B.C. Indians. 3 Rheumatol1975;2:314-8.

10. Chalmers IM. Ankylosing spondylitis in African blacks. Arthritis Rheum 1980;23:1366-70.11. Brewerton DA. James DCO. The histocompatibility antigen (HL-A27) and disease. Semin Arthritis Rheum

1975;4:191-207.12 Gomor B. Gyodi E, Bakos L. Distribution of HLA-B27 and ankylosing spondylitis in the Hungarian population.

J Rheumatol 1977;4(suppl 3):33-5.13. Calin A, Fries JF, Schurman D, Payne R The close correlation between symptoms and disease expression in

HLA-B27 positive individuals. J Rheumatol 1977;4:277-81.14. Cohen LM. Mittal KK, Schmid FR, Rogers LF, Cohen KL. Increased risk for spondylitis stigmata in apparently

healthy HL-A W27 men. Ann Intern Med 1976;84:l-7.15. Maltz BA, Sussman P, Calabro JJ. Peripheral arthritis as an initial manifestation of ankylosing spondylitis.

Arthritis Rheum 1969;12:680-l.16. Calabro JJ. An appraisal of the medical and surgical management of ankylosing spondylitis. Clin Orthop

1968:60:125-48.17. Kaprove RE, Little AH, Graham DC. Rosen PS Ankylosing spondylitis: survival in men with and without

radiotherapy. Arthritis Rheum 1980;23:57-61.18. Carter ET, McKenna CH. Brian DD, Kurland LT. Epidemiology of ankylosing spondylitis in Rochester,

Minnesota, 1935-1973. Arthritis Rheum 1979;22:365-70.19. Lehtinen K. Clinical and radiological features of ankylosing spondylitis in the 1950s and 1976 at the same

hospital. Scand J Rheumatol 1979;8:57-61.20. Bywaters EGL. Ankylosing spondylitis in childhood. Clin Rheum Dis 1976;87:387-96.21. Rosenberg AM, Petty RE. A syndrome of seronegative enthesopathy and arthropathy in children. Arthritis

Rheum 1982;25:1041-7.22. Calabro JJ, Katz RM, Maltz BA. Ankylosing spondylitis. J Pediatr 1969;75:912-3.23. Calabro JJ, Gordon RD, Miller KA. Bechterew's syndrome in children: diagnostic criteria. Scand J Rheumatol

1980;9(suppl 32):45-624. Schaller JG. Ankylosing spondylitis of childhood onset. Arthritis Rheum 1977;20(suppl):398-401.25. Jeannet M, Saudan Y, Bitter T. HL-A27 in female patients with ankylosing spondylitis. Tissue Antigens

1975;6:262^(.26. Arnett FC, Bias WB, Stevens MB. Juvenile-onset chronic arthritis, clinical and roentgenographic features of a

unique HLA-B27 subset. Am J Med 1980;69:369-76.27. Grahame R, Kennedy L, Wood PHN. HL-A27 and the diagnosis of back problems. Rheumatol Rehabil

1975;14:168-72.28. Calabro JJ. Diagnosis of low back pain. In: Stanton-HicksM, Boas RA.eds. Chronic low back pain. New York:

Raven Press 1982;39-57.29. Bellamy N, Park W, Rooney PJ. What do we know about the sacroiliac joint? Semin Arthritis Rheum

1983;12:282-313.30. Yunus M, Masi AT, Calabro JJ, Miller KA, Feigenbaum SL. Primary fibromyalgia (fibrositis): clinical study of

50 patients with matched normal controls. Semin Arthritis Rheum 1981;11:151-71.31 Cohen MD, Harrington TM, Ginsburg WW. Osteoid osteoma; 95 cases and a review of the literature. Semin

Arthritis Rheum 1983;12:265-81.

DISCUSSION

Kass: In juvenile chronic polyarthritis, I would like to underline the importance of a family history.At our hospital in Oslo, for many years, before the discovery of HLA-B27, we introduced the term'indirect Bechterew's disease'. We applied this diagnosis particularly to young patients with a diseasepattern compatible with juvenile chronic polyarthritis and then examined the parents clinically andwith radiographs for Bechterew's syndrome. It was not unusual to find cases compatible with adiagnosis of Bechterew's disease in the parents. Frequently, the child also developed Bechterew'sdisease in later years.

Another comment, Prof. Calabro, you mentioned angina pectoris as one of the symptoms. I wouldlike to remind you all, that angina-like pains could be a misinterpretation of the chest-wall pains thatfrequently occur in these patients.

Calabro: Yes, I agree, it could be due to a component of secondary fibrositis or secondarycostochondritis, which are common forms of non-articular rheumatism. There is also costochondraltenderness and that is why physical examination is so important in distinguishing that from true angina.




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