Ankylosing
Spondylitis
ByJan Tore
Gran and Gunnar Husby
INDEX WORDS: Ankylosing spondylitis; seronegative spondylarthropathy; women; gender; sex differences.
A
NKYLOSING spondylitis (AS) is a chronic inflammatory disease whose main symptoms are caused by arthritis of the sacroiliac joints (SIJ). The disorder frequently involves spinal and extraspinal joints and entheses. Ocular and cardiac tissues are less often affected. Etiological and pathogenetic mechanisms of AS apparently include both environmental and genetic factors, and an association with the human leukocyte antigen HLA-B27 has been firmly established.‘** Although earlier reports on AS provided some hints of disease occurrence among women, AS has traditionally been regarded as a male disorder. More recent studies on blood donors3 and population surveys4Vshave, however, clearly shown that females constitute a substantial proportion of the AS population. This review adresses clinical, radiological, and laboratory manifestations of AS among women as compared with men with special emphasis on those reports designed to highlight possible differences between the sexes. SEX RATIO IN AS
The most frequently quoted sex ratio in AS is 10: 1 in favor of men, a figure conceivably deriving from West’s study in 1949 whose estimate was based on hospitalized cases of AS in Bristol, England.6 Contemporary reports’-” also noted a striking male dominance, although these studies were often performed at military or veterans’ hospitals and were thus subjected to a biased selection of patients. Less attention was paid to those surveys reporting sex ratios between 4.4 and 3 .7 . ‘l-l3 As early as 1944 and 195 1 Fletcher and Parr presented patient data on AS where women accounted for 47% and 43%, respectively, of total cases.14V15 These studies were based on hospitalized cases of AS, reflecting the referral of a symptomatic population. Accordingly, such estimates are greatly influenced by the nosocomial threshold of AS which may be, for various reasons, different in men and women. Based on the results of studies of presumed healthy blood donors, in 1975, Calin and Fries3 Seminars in Arthritis andRheumatism,
in Women
suggested a sex ratio in AS approaching 1. In this study, a remarkably high incidence of AS among HLA-B27 negative blood donors was observed. Such studies with exceptionally high prevalences (20% to 25%) of AS among blood donors3V16 have been the subject of much debate. Other investigations’7*‘*V’9 have found a much lower frequency of AS among blood donors. To some extent, variations in the interpretation of SIJ roentgenograms may be responsible for this discrepancy. It is also uncertain if healthy blood donors are representative of the general population. Our own epidemiological survey of AS indicated a 6.7% prevalence of AS among HLA-B27 positive individuals.’ Recent population studies of AS4V5 have been unable to confirm the impression gained from some blood donor studies3 that the prevalence of AS in the two sexes was similar, reporting a significant male dominance with a ratio of 4-6: 1. UNDERESTIMATION
OF AS IN WOMEN
The reasons for the presumed underestimation of AS among women are unclear. Perusal of available literature fails to show a consistent opinion as to why such underestimation has occurred. Table 1 summarizes some proposals that have been presented. The tradition of regarding AS as a disease almost exclusively of men is a major factor for this underestimation. Another explanation is the reluctance to expose female reproductive organs to radiation, hence missing the opportunity to obtain a definite diagnosis. Also, the threshold for seeking medical advice because of pain or stiffness of the back might be higher in women than in men. Young men, in physically active From the Department ofRheumatology. Central Hospital ofdust-Agder, Arendal, and the Department of Rheumatology, University Hospital of Troms$ Norway. Jan Tore Gran, MD: Head of the Department of Rheumatology, Central Hospital of Aust-Agder. Arendal; Gunnar Husby, MD: Professor and Head of the Department of Rheumatology, University Hospital of Tromsb Norway. Address reprint requests to Jan Tore Gran, MD: Revmatologisk avdeling, Aust-Agder Sentralsjukehus, 4800 Arendal. Norway. o 1990 by W.B. Saunders Company. 0049-0172/90/1905-0006g5.00/0
Vol 19, No 5 (April), 1990: pp 303-3 12
303
GRAN AND HUSBY
304
Table
1.
Possible
Underestimation
Explanations
of the Prevalence
for admittance to hospitals and medical institutions, contributing to the underestimation of AS in women. Underestimation attributable to the difficulty of diagnosing AS in women must also be considered. If the disease runs a milder and less progressive course in women, the diagnosis could be overlooked. Furthermore, a higher frequency of peripheral arthritis among women could further confuse the diagnosis. Some workers have suggested that the evidence of AS must be overwhelming before this diagnosis is entertained in women.2’ The clinical expression of AS in men and women will be presented in more detail later.
for the of AS in Women
1. Tradition of regarding AS as a disease of men. 2.
Fear of exposing female pelvic organs to radiation.
3.
A higher threshold back pain and/or
4.
for seeking medical advice for stiffness
in
women.
More benign disease course with less disabling symptomatology
5.
More peripheral alternative
6.
in women. arthritis in women
suggesting
diagnoses.
Less pronounced
roentgengraphic
changes in
women. 7.
Slower development
of radiographic
features
in
women. 8.
Sacroiliitis misdiagnosed
as osteitis condensans
ilii. LIMITATIONS
Surveys
Cntena
Ml?fl
Year
for AS
Women
Fletchert4
1944
32
36
88
1953
60
0
Hart and Robinsor?
1959
30
0
90 100
Pohl and Treibe?
1962
62
0
100
McBryde
1973
13
0
?
1974
17
0
100
and McCollum3’
1974
7
0
Rome
Nasseh et alz3
1975
30
0
New York
Jeannet
1975
31
0
Rome
Swezey
et a?
et a?
AS
Sacrorlritrson Roentgenogram
Tyson et al*’
Mach3’
FEMALE
of AS in Women
No. of patients
Survey Authors
2.
ON
This review will focus primarily on 20 studies that analyze the clinical and radiological manifestations and prognosis of AS in women (Table 2). These publications cover a time span of more than 40 years, the first by Fletcher in 194414 and the last one by Kidd et al in 1988.22 As will be discussed later, no clear picture of the natural history of AS in women, as opposed to men, has emerged. The controversies reported are due in part to different study designs. The number of women included in these reports
occupations, might be more likely to find back pain a limiting factor in their employment, and cause them to seek medical advice. This would result in a higher prevalence of undiagnosed AS in the female population. To some extent, the general impression gained from population surveys of joint and back complaints speaks against such a hypothesis. According to these surveys2’ women generally report symptoms of the locomotor system more often than men. On the other hand, women may have an increased threshold Table
OF REPORTS
100 100 50
Men
._
._ _
Hill et aI3
1976
23
0
78
_~
Resnick et al5’
1976
18
80
Rome
100
100
Levitin et a13”
1976
27
0
Rome
100
Molony and Thompsor?
1979
8
0
New York
100
Goodman
1980
12
0
Marks et a?’
1983
25
25
New York
100
Jevleva et alz6
1984
60
New York
78
50
Gran et al”
1984
50
82
New York
100
100
Gran et al’*
1985
44
82
New York
100
100
McKenna
1986
62
61
New York
1988
35
70
New York
100
100
et a?’
et alz5
Kidd et al’*
New York
75 100
305
varies substantially, from 723 to 6224V25;only six surveys report data on more than 40 women. 2’,2e28 Furthermore, the lack of diagnostic criteria in 7 of 20 studies14,21*24*29-32 renders evaluation of the data virtually meaningless. Four of these14*2’*24V29 studies were performed before the promulgation of criteria for diagnosing AS. However, some of the reports24929*31 provide careful descriptions of patients allowing a definitive diagnosis of AS to be established in retrospect. Surprisingly, 12 studies21*23V24929*37 did not include male patients for clinical and radiological comparisons. When male controls were included, it is not always possible to determine whether the same selection criteria were used. It is difficult to establish a definite diagnosis of AS by clinical criteria alone38V39; thus, radiological sacroiliitis (SI) is regarded as mandatory for the diagnosis.40 Nevertheless, six reports 14,21Y26*32*34,35 have included cases diagnosed as AS but lacking the characteristic radiological features. In addition, two other surveys25”0 failed to present information regarding radiological manifestations. Thus, 8 out of 20 reports may have included patients whose back pain was noninflammatory in origin. Ankylosing spondylitis is a chronic rheumatic disease whose severity and stage of progression is largely dependent on disease duration. Because of inherent difficulties in obtaining female cases, very few reports have matched male and female cases for disease duration. Consequently, serious difficulties arise when features such as age at onset, disease outcome, and prevalence of extraarticular manifestations are compared.4’ Ankylosing spondylitis traditionally has been classified as a disease within the spondyloarthropathy complex.42 Some favor the view that these interrelated conditions should be categorized as one disease showing a diversity of clinical manifestations.43 Because important differences among the various spondyloarthropathies exist they should be separated when studies involving clinical and radiological comparisons are conducted. We advocate that patients afflicted with psoriasis, inflammatory bowel diseases (IBD), and Reiter’s disease should be excluded when features of primary AS are discussed. For example, the spondylitis of psoriasis is rather mild and nonprogressive,” and the clinical features of Reiter’s syndrome are frequently dominated by
peripheral arthritis. 45Similarly, the arthritis associated with IBD may be quite different from that of AS.4b Consequently, serious biases may be introduced when such disorders are included in the male or female AS groups. Moreover, as patients with juvenile onset AS are more prone to develop peripheral arthritis than those with adult onset AS4’ perhaps younger patients should be investigated separately. In particular, hip involvement and mode of disease onset are different in juvenile and adult onset AS.47Y48 Of the 20 studies reviewed, only six reports have excluded cases with seronegative arthropathies other than primary AS, and most do not contain information about inclusion of juveniles (Table 3). Therefore, the majority of the studies consist of patients suffering from various disorders within the spondyloarthropathy complex. To facilitate objective evaluation, criteria for disease severity and progression should be used; unfortunately, this assessment was not routinely done. Moreover, as a single examination of a patient with a chronic disease which fluctuates provides a limited impression of the disease, prospective studies using serial examinations are preferred. This is particularly important when estimating the prevalence of remitting clinical features such as peripheral arthritis and acute anterior uveitis (AAU). Too few studies were prospective. Most surveys were based on cases referred to rheumatological institutions and therefore do not represent the general AS population.49*s0It may be assumed that primarily patients with persistent or progressive disease will be followed at academic centers. The impact of referral bias in producing a cohort with more severe disease could be overcome partly by studying patients selected through population surveys, and those cared for by general and specialist practitioners Table 3. Other Seronegative Spondyloarthiopathies Included in Surveys of AS in Women Number of studies JAS
IBD
PSOR
Reiter’s Disease
Exclusion of
7
12
10
9
Inclusion of
6
3
3
3
No information
7
5
7
8
Abbreviations:
JAS,
IBD, Inflammatory
Juvenile
ankylosing
spondylitis;
bowel disease; PSOR, Psoriasis.
306
GRAN AND HUSBY
on an outpatient basis, in addition to those admitted to referral hospitals. All these factors should be taken into consideration when the results of the actual 20 reports are interpreted.
mous with peripheral arthritis whereas others required the presence of soft tissue swelling. With respect to hip involvement, Wilkinson and Bywaters” found hip arthritis in 35% of men and 20% of women. The corresponding percentages observed by Kidd et al** were 29% and 9%‘. The results of those studies contrast sharply with that of Marks et a14’ who found that hip and shoulder involvement occurred slightly but not significantly more often in women. Studies limited to female AS (Table 4) have demonstrated a prevalence of peripheral arthritis between 23%, and 75%. Two surveys including men and women 25*52have reported a significantly higher incidence of peripheral arthritis in women. In another study by Wordsworth and Mowat women had significantly more peripheral joint disease than men, but of 20 cases with peripheral arthritis eight had psoriasis. Three reports.22.28.4’ including our own, did not show any difference with respect to peripheral joint disease. The occurrence of erosive peripheral arthritis demonstrated roentgenographically appears infrequent in both sexes with AS. In contrast, erosions leading to joint destruction are regularly observed in rheumatoid arthritis (RA). Understanding the basis of this difference may provide insight into the pathogenesis of both disorders.
CLINICAL EXPRESSION OF AS IN WOMEN
Ankylosing spondylitis is usually regarded as a disease of young adults, the average age at onset being between 24 and 26 years.5’ The average age at onset of women with AS was between 22 The onset of symptoms and 38 years. 2’*29V31,36*37 before age 30 was found in 92%32 and 46%30 of cases in two studies. In contrast, according to Mach3’ only 12% of women developed symptoms before age 3 1. Two reports comparing men and women concluded that AS started 2 and 4 years later in women. Our study of female AS** did not show any difference in age at disease onset, 23 to 24 years in both sexes. A recent survey by Kidd et a122supported our report. Furthermore, although the initial symptoms of AS are difficult to define in a retrospective study, the impression from various reports is that men and women manifest similar symptomatology. It is often said that women with AS more often exhibit arthritis of the peripheral joints. Evaluation of this observation is difficult because of varying definitions of “peripheral joint affection.” In some reports, joint complaints were synonyTable 4. The Frequency
of Peripheral
Peripheral joint involvement
SLJVIey Authors
Year
Men
Women
Arthritis
in Men and Women
HIP rwolvement (%I Men
Women
Tyson et al”
53
Hart and Robinsor? Swezey et a?
59 74
Mach3’ Nasseh et ai33
74 75
30
-
Hill et al35
76
57
-
Resnick et a16’ Molony and Thompsor?
76 79
41
83$ 50
-
22t 13
18
24
Goodman
et a?’
-
28’
42
23
‘t 57
80
-
75
83§
17
28
Gran et aI”
85
29
29
McKenna
86
52
87
88
47
34
Kidd et aI” *Radiological
changes in 5%
tRadiological
changes
$Radiological
changes
in 50%
of females
$Figures given for adult cases of AS
Shoulder wolvement I%) Men
Women
Disease duration (yrs) Men
45
Women 7
3t
12
Marks et a?’
et alz5
With AS
_
0
29
9
21
15 _.
_
17
14
15
18
16
13 17 12
35
AS IN WOMEN
307
Limitation of spinal ‘mobility in female AS patients ranged from 74% to 100% (Table 5). Comparing men and women, no significant difference in restriction of spinal motion has been firmly established.**~*s To our knowledge, no studies were specifically designed to study possible differences in mortality rates of AS in men and women. In chronic diseases such as AS, however, morbidity may be more relevant than mortality. While it is generally accepted that AS runs a milder course in women, who are less likely to develop severe spinal deformities than men,21~29~32 this statement is based more on impressions than on objective data. In their study of 36 female and 164 male patients with AS, Spencer et als4 found no significant difference in overall disease severity between the sexes, although significantly more women than men belonged to functional class III (Steinbrocker), 25% versus 9% respectively. According to Marks et a14i 8% of both men and women with AS were unemployed because of their disease. More recently, Kidd et al** found that 57% of men and 7 1% of women with AS had not modified their daily life or employment related activities substantially. In our series of 126 individuals with AS,*’ 11% of men and 23% of women were permanently retired from work
before the age of pension. As more men than women were on temporary sick leave, the frequency of employment at the time of examination was the same. Thus, there is no convincing evidence that women with AS suffer more impairment in work ability than men. It may be argued that the similar disease severity observed in men and women with AS is a result of patient selection. As most surveys were based on hospitalized cases, the women included might represent the severe cases of AS. This would be true if a higher threshold for hospital admittance existed for the women than the men. Our own population survey’ did not detect a significant number of undiagnosed mild cases of female AS. RADIOLOGICAL FEATURES OF FEMALE AS
Cervical spine involvement in AS is a controversial subject. Resnick et al’* noted that isolated cervical spine abnormalities are more frequent in female than male AS (31% versus 4%), a difference that did not reach statistical significance. Marks et a14’ likewise found a higher frequency of radiological manifestations in the cervical spine in women than in men. Among 60 women with AS presented by Tyson et al.*i 41 (68%) had cervical spine involvement but only 25% had
Table 5. Age at Onset, Acute Anterior Uveitis, and Restriction of Spinal Mobility in Patients
Age at onset (y~sl Authors
Man
Women
Fletcher14
36
38
Tyson et al”
-
25
Hart and Robinson”
22
With AS Acute anterior w&tie (%)
Men
Restriction of spinal mobility 1%)
Women
Men
Women
0
-
-
13
-
-
-
23
-
-
5
-
-
-
0
-
Pohl and Triebe?
-
Swezey et alz3
-
Mach3’
-
-
-
57 24
-
100 -
Nasseh et al33
-
22
-
19
-
94
Jeannet et al34
38
-
19
-
94
Hill et al35
-
-
27
-
30 -
-
Resnick et al5’
31
87 -
Levitin et a13’
-
30
-
22
-
Molony and Thompson3’
-
22
-
13
-
Goodman et a13*
-
22
-
Marks et a14’ Grar?’ McKenna et alz5
23 -
Kidd et alz2
25
-
-
74 -
17
-
4
40
-
24
24
24
-
26
19
76 -
90 -
24
24
31
67
54
-
100 -
GRAN AND HUSBY
308
Table 6. Radiological
Authors
Manifestations
in Surveys of Women
SIJ ankylosis
Frequency of bambooing
Symphysis pubis involvement
CerVlCal spine involvement
Disease duratton
(%I
(%)
1%)
(%)
(%)
(yrs)
11
25
43
40
17
23
13
5
19
85
85
85
77
Tyson et al” Hart and Robinson” Pohl and Triebe? McBryde
and McCollum”
With AS
Frequency of spinal involvement
0
7
15
18
Mach3’ Swezey
et alz3
-
Jeannet
et al34
-
Goodman
et a13’
86
286 51
17
25”
l38% of those with radiological sacroiliitis.
radiological evidence of such involvement (Table 6). In their study of 222 patients with AS, Wilkinson and Wright found the cervical spine to be affected in 51% of men and 44% of women.” The impact of such radiological features upon cervical mobility has not been adequately studied. Relatively little is known about the frequency of atlantoaxial and subaxial dislocations in women with AS, and fractures of the cervical spine has rarely, if ever, been described. As radiological changes of the dorso-lumbar spine regularly postdate those of the SIJ, their presence will depend on the duration of AS.55 Unfortunately, the majority of studies lacked information regarding disease duration. Our results27 indicated that spinal involvement was more frequent among men (75%) than women (44%), and a similar difference (81% versus 56%) was noted by Resnick et a152 (Table 7). Jeanette et al34 and Hart and Robinson,29 reported that 5 1% and 40%, respectively, of female AS patients had involvement of the spine. Our women with AS had an average disease duration of 15 years; the prevalence of spinal changes in the study by Kidd et a122 was 31% (disease duration 15 years) confirming our estimate. Table 7. Radiological
SIJ ankylosis
Frequency of spinal involvement
Men
Women
Men
Women
Men
Resnicks’
-
-
81
56
-
Gran”
28
16
75
44
14
Kidd”
39
23
58
31
surprisingly,
spinal
in Surveys of Men and Women
Frequency of bambooing (%)
(%)
1%) Authors
Manifestations
Rather
mobility
was similar
in both sexes.** Thus, processes other than those seen on roentgenogram must be involved in determining spinal motion. Ankylosis is regarded as the end point of the inflammatory process in AS. Both SIJ and spinal ankylosis tended to be more frequent among our male patients. 27 Only 7% of our female AS cases had bambooing of the spine,27 a frequency corresponding to that of 5% reported by Pohl and Freiber.24 These estimates contrast sharply with those of others23’30 who demonstrated ankylosis in the overwhelming majority of cases. However, their findings were based on small numbers of patients, subjected to errors of selection bias. In general, the prevalence of bambooing, severe flexion deformities and ankylosis of the SIJ appears low. Many investigators have reported a high prevalence (1 1YE to 61%) of arthritis of the pubic symphysis in women with AS (Tables 6 and 7). We detected such changes in 9% of our women patients, but in none of our men.27 However, in two large series”,54 arthritis of the pubic symphysis was demonstrated more often in men than in women.
Symphysls publs involvement (%I
women
Men
7
0
With AS
Cervical spine Involvement (%I
Disease duration (vrs)
Women
Men
Women
Men
Women
61
55
69
21
15
14
15
18
16
9
309
HLA-B27
AND LABORATORY FEATURES IN WOMEN WITH AS
As tissue antigens are inherited in an autosoma1 codominant fashion, one would not expect a difference in the frequency of HLA-B27 in men and women with AS unless the pathogenesis of AS in the two sexes was different. Several reports show a significant association between B27 and female AS,32,34,3597 and a similar frequency of this antigen in the two sexes.28 One report23 noted a lower prevalence of B27 in female AS, but this study included patients with other seronegative arthropathies known to have a lower frequency of B27.56s57Moreover, that study23 was in blacks, who in general possess HLA-B27 less frequently than whites.s8*s9No study has compared disease manifestations in B27 negative and B27 positive AS in women. Information regarding laboratory measures of disease activity in female versus male AS is sparse, probably because most reports were retrospective. In our survey the mean erythrocyte sedimentation rate (ESR) and immunoglobulin A (IgA) levels were similar in men and women with AS.28 However, the C-reactive protein (CRP) was elevated in 66% of men in contrast to 35% of women, a statistically significant difference. Our results were based on a single examination and need confirmation. EXTRA-ARTICULAR
MANIFESTATIONS
IN
FEMALE AS
In one study,21 systemic manifestations such as weight loss, anorexia, and exhaustion were usually absent in female AS patients. According to Marks et a141AAU occurs ten times more often in women (40%) than in men with AS (4%). We are aware of only one other study that detects such a high frequency of AAU in women (Table 5). And, the low incidence of AAU in their male cases41 is at variance with fo_ previous studies. 60 Three other surveys 22.25.28 cusing on the prevalence of AAU failed to detect any differences between men and women. Cardiac manifestations are encountered in 4% to 43% of patients with AS,6’-63including conduction disturbances and aortic insufficiency. In two reports, aortic insufficiency was detected in 3% of women with AS,33V34 but no cardiac abnormalities were found by another investigator.29 Study-
ing 292 men and 60 women with AS, Bernstein and Broth in 1949 found clinical cardiac disease in 4% and 5% of patients, respectively.64 The prevalence of secondary amyloidosis and nervous system manifestations in unselected groups of female AS patients is unknown. PREGNANCY AND SEX HORMONES IN WOMEN WITH AS
Wilkinson and Bywaters” found that only three out of seven AS patients improved during pregnancy. In a retrospective study, @tensen et a165evaluated the influence of pregnancy on the course of AS in 87 pregnancies of 50 patients. Ankylosing spondylitis had no harmful effects on pregnancy, the fetus, or the newborn. Remission of AS occurred in 20% of pregnancies, exacerbation in 24% and 55% did not experience any change of disease activity. Some of the patients also suffered with psoriasis. In a subsequent prospective study, @tensen and Husby66 found that the majority of women with RA improved during pregnancy, whereas those with primary AS exacerbated while pregnant. Again, pregnancies were uneventful and children were healthy.66 The majority of women develop the initial symptoms of AS between the ages of 20 and 35 years,28 the years with the greatest childbearing potential. In a study of 200 AS patients, Simpson and Stevenson” noted that only 5 of 42 women observed the first symptoms of AS during pregnancy. In the retrospective study of @ensen et a1,65 20% of AS patients related their disease onset to pregnancy. Their findings suggest that pregnancy has no inductive effect on the development of AS. Why AS is one of the few inflammatory rheumatic diseases with a clear excess of males is unknown. No occupational or social factors that might explain this predilection have been defined. It is tempting to suggest that endocrine factors might be involved in the pathogenesis of this disease. However, a recent study found no differences in plasma sex steroid concentrations in AS males and sex and age matched controls.67 CONCLUSION
An increasing awareness that AS frequently affects women has led to a re-evaluation of the traditionally quoted sex ratio of 1O:l in favor of
GRAN AND HUSBY
310
men. Based on recent population surveys a more accurate ratio appears to be 4 to 5: 1. Although not fully defined, the natural history of primary AS in women appears similar to that in men. To facilitate early recognition of AS in women, clinicians must maintain a high index of suspicion. Although divergent data on the extent and frequency of radiological manifestations of female AS has been published, present knowledge indicates more pronounced and widespread radiographic changes in men. Before any firm conclusions regarding clinical, radiological, and laboratory features of female AS can be reached, well-designed and executed studies are needed. Suggestions for future studies are given in Table 8. Information must be acquired prospectively on a sufficient number of patients meeting appropriate diagnostic criteria. Investigations should include members of both
Table
8.
Proposed
Requirements
for Future
Studies
of AS in Women 1. Sufficient 2.
number of women
patients.
Men included for comparison.
3.
New York Criteria for AS.
4.
Exclusion of patients spondyloarthropathies
with other seronegative and juvenile cases of AS.
5.
Criteria for disease severity.
6.
Patient groups representative
for the entire AS
population. 7.
Follow-up
8.
Setter definitions thropathy,
and senal assessments. of terms such as arthralgia,
ar-
arthritis.
sexes that are matched for age of onset, disease duration, and disease activity and severity. Patients should be selected from the general population, rather than from specialty institutions, and studied longitudinally for several years.
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a
11. Wilkinson M, Bywaters EGL: Clinical features and course of ankylosing spondylitis. As seen in a follow-up of 222 hospital referred cases. Ann Rheum Dis 17:209-229, 1958 12. Simpson NRW, Stevenson CJ: An analysis of 200 cases of ankylosing spondylitis. Br Med J 1:214-216, 1949 13. Tanberg A: Initial symptoms in spondylarthritis lopoietica. Rheumatism 6:127-132, 1950
anky-
14. Fletcher E: Ankylosing spondylitis. Lancet 1:754-756, 1944 15. Parr LJA, White P. Shipton E: Some observations on 100 cases of ankylosing spondylitis. Med J Aust 2:544-549. 1951 16. Cohen LM, Mittal KK, Schmid FR, et al: Increased risk for spondylitis stigmata in apparently healthy HLAW27 men. Ann Intern Med 84: l-7, 1976 17. Christiansen FT. Hawkins BR, Dawkins RL, et al: The prevalence of ankylosing spondylitis among B27 positive normal individuals-A reassessment. J Rheumatol 6:7 13. 718, 1979 18. Chappel R, Muylle L, Mortier G, et al: Risque de dtvelopper une spondylarthrite ankylosante chez des personnes “en bonne saute” porteuses de I’antigtne HLA B27. Acta Rheumat 3:319-328, 1979 19. Thorel JB, Cavelier B, Bonneau JC, et al: Etude dune population porteuse de [‘antigene HLA 827 comparee a celle d’une population ttmoin non B27 a la recherche de la spondylarthrite ankylosante. Rev Rheumat 45:275-282. 1978 20. Lawrence JS: Rheumatism in populations. London, UK, Heinemann Medical, 1977, pp 32-67 21. Tyson TL, Thompson WAL, Ragan C: MariiStrdumpell spondylitis in women. Ann Rheum Dis 12:40-2, 1953 22. Kidd B, Mullee M, Frank A, et al: Disease expression of ankylosing spondylitis in males and females. J Rheumatol 15:1407-1409, 1988 23. Swezey RL, Zucker LM, Terasaki PI: Reduced prevalence of HLA antigen w27 in Black females with ankylosing spondylitis. J Rheumatol 1:260-262, 1974 24. Pohl W, Treiber W: Morbus Bechterew beim weiblithen Geschlecht: Munch Med Wochenschr 104:674-678, 1962 25. Mckenna F, Hickling P, Brophy T, et al: Ankylosing
311
spondylitis in women and men: A comparative study. Br J Rheumatol2569, 1986 26. Jevleva LV, Akimova TF, Mylov NM: Bechterew’s diseasein women. Stand J Rheumatol52:13-151984 (suppl) 27. Gran JT, Husby G, Hordvik M, et al: Radiological changes in men and women with ankylosing spondylitis. Ann Rheum Dis 43570-575, 1984 28. Gran JT, astensen M, Husby G: A clinical comparison between males and females with ankylosing spondylitis. J Rheumatol 12:126-129.1985 29. Hart FD, Robinson KC: Ankylosing spondylitis in women. Ann Rheum Dis 18:15-23.1959 30. McBryde AM, McCollum DE: Ankylosing spondylitis in women. The disease and its prognosis. N C Med J 34134-37, 1973 3 1. Mach J: Zum Vorkommen der Spondylarthritis ankylopoetica beim weiblichen Geschlecht. Beitr Orthop 21:241247,1974 32. Goodman CE, Lange RK, Waxman J, et al: Ankylosing spondylitis in women. Arch Phys Med Rehabil 61:167170,198O 33. Nasseh G, Sandan T, Bitter T: La pelveospondylite rhumatismale (spondylite ankylosante) chez la femme (etude clinique et radiologique de 3 1 cas) Med Hygiene 1143:554557,1975 34. Jeannet M, Saudan T, Bitter T: HLA27 in female patients with ankylosing spondylitis. Tissue Antigens 6:262264.1975 35. Hill HFH, Hill AGS, Bodmer JG: Clinical diagnosis of ankylosing spondylitis in women and relation to presence of HLA B27. Ann Rheum Dis 35:267-270,1976 36. Levitin PM, Gough WW, Davis JS: HLA B27 antigen in women with ankylosing spondylitis. JAMA 235:26212622,1976 37. Molony J, Thompson R: Ankylosing spondylitis in women. A review of 8 cases. J Irish Med Assoc 72:236-237, 1979 38. Gran JT: An epidemiological survey of the signs and symptoms of ankylosing spondylitis. Clin Rheumatol 4:161169,1985 39. Baron M, Zendel I: HLA-B27 testing in ankylosing spondylitis: an analysis of the pretesting assumptions. J Rheumatol l&631-636,1989 40. Bennet PM, Wood PHN: Population studies of the rheumatic diseases, in Bennet PM, Wood PHN, (eds): Exe Med Found, Amsterdam. Int Congr Ser 148:456, 1966 41. Marks SH, Barnett M, Calin A: Ankylosing spondylitis in women and men: A case-controlled study. J Rheumatol 10:624-628, 1983 42. Wright VA: Unifying concept for thespondyloarthropathies. Clin Orthoped Rel Res 143:8-14, 1979 43. K&s E: Syndrome or disease? Use of eponym or symptom-related name? Stand J Rheumatol 32:240-241, 1980 (suppl) 44. Hanly JG, Russel HL, Gradman DD: Psoriatic spondylarthropathy-A long term prospective study. Ann Rheum Dis 47:386-393.1988 45. Calin A: Reiter’s syndrome: Epidemiology and immunogenetics. Stand J Rheumatol32:178-183, 1979 (suppl)
46. Moll JMH: Inflammatory bowel disease. Clin Rheum Dis 11:87-111, 1985 47. Calin A, Elswocd J: The natural history of juvenileonset ankylosing spondylitis: A 24-year retrospective casecontrol study. Br J Rheumatol27:91-93, 1988 48. Jacobs JC, Johnston AD, Berdon WE: HLA-27 associated spondyloarthritis and enthesopathy in childhood. J Pediatr 100:521-528.1982 49. Gran JT, Husby G: Ankylosing spondylitis: A comparative study of patients in an epidemiological survey, and those admitted to a department of rheumatology. J Rheumatol 11:788-793, 1984 50. Gran JT, Hordvik M, Husby G: Rocntgenological features of ankylosing spondylitis. A comparison between patients attending hospital and cases selected through an epidemiological survey. Clin Rheumatol3:467-472, 1984 51. Carette S, Graham D, Little H, et al: The natural disease course of ankylosing spondylitis. Arthritis Rheum 26:186-190, 1983 52. Resnick D, Dwosh IL, Goergen TG, et al: Clinical and radiographic abnormalities in ankylosing spondylitis: A comparison between men and women. Radiology 119:293-299, 1976 53. Wordsworth BP, Mowat AG: A review of 100 patients with ankylosing spondylitis with particular reference to socio-economic effects. Br J Rheumatol25: 175- 180, 1986 54. Spencer DH, Park WM, Dick HM, et al: Radiological manifestations in 200 patients with ankylcsing spondylitis: correlation with clinical features and HLA B27. J Rheumatol 6:305-315, 1979 55. Gran JT, Husby G, Hordvik M: Spinal ankylosing spondylitis: a variant form of ankylosing spondylitis or a distinct disease entity. Ann Rheum Dis 44:368-371, 1985 56. Huaux JP, Fiasse R, Le Bruyere M, et al: HLA B27 in regional enteritis with and without ankylosing spondylitis or sacroiliitis. J Rheumatol3:60-63,1977 (suppl) 57. Mallas EG, Mackintosh P, Asquith P, et al: Histocompatibility antigens in inflammatory bowel disease. Their clinical significance and their association with arthropathy with special reference to HLA-B27. Gut 17:906-9 10, 1976 58. Gofton JP: Epidemiology, tissue type antigens and Bechterew’s syndrome (ankylosing spondylitis) in various ethnical populations. Stand J Rheumatol 32:166-168, 1980 (suppl) 59. Gran JT, Mellby AS, Husby G: The prevalence of HLA-B27 in northern Norway. Stand J Rheumatol 13:173176.1984 60. Hart FD: Clinical features and complications, in Moll JMH (ed): Ankylosing Spondylitis. Edinburgh, Churchill Livingston, 1980, p 63 61. Graham DC, Smythe HA: The carditis and aortitis of ankylosing spondylitis. Bull Rheum Dis 16:171-174, 1958 62. Kinsella TD, Johnson LG. Sutherland RI: Cardiovascular manifestations of ankylosing spondylitis. Can Med AssosJ 111:1309-1311,1974 63. Sukenik S, Pras A, Buskila D, et al: Cardiovascular manifestations of ankylosing spondylitis. Clin Rheumatol 6:588-592, 1987 64. Bernstein L, Broth OJ: Cardiac complications in
312
spondylarthritis ankylopoietica. Acta Med Stand 135:185194,1949 65. Gstensen M, Romberg 8, Husby G: Ankylosing spondylitis and motherhood. Arthritis Rheum 25:140-143, 1982 66. @stensen M, Husby G: A prospective clinical study of
GRAN AND HUSBY
the effect of pregnancy on rheumatoid arthritis and ankylosing spondylitis. Arthritis Rheum 26: I 155-I 159, 1983 67. Chevallard M, Angelini M, Ambrosi 9, et al: Sex hormone concentrations in male patients with ankylosing spondylitis: A preliminary report. Clin Rheumatol 6:609610. 1987
Spondylitis
ByJan Tore
Gran and Gunnar Husby
INDEX WORDS: Ankylosing spondylitis; seronegative spondylarthropathy; women; gender; sex differences.
A
NKYLOSING spondylitis (AS) is a chronic inflammatory disease whose main symptoms are caused by arthritis of the sacroiliac joints (SIJ). The disorder frequently involves spinal and extraspinal joints and entheses. Ocular and cardiac tissues are less often affected. Etiological and pathogenetic mechanisms of AS apparently include both environmental and genetic factors, and an association with the human leukocyte antigen HLA-B27 has been firmly established.‘** Although earlier reports on AS provided some hints of disease occurrence among women, AS has traditionally been regarded as a male disorder. More recent studies on blood donors3 and population surveys4Vshave, however, clearly shown that females constitute a substantial proportion of the AS population. This review adresses clinical, radiological, and laboratory manifestations of AS among women as compared with men with special emphasis on those reports designed to highlight possible differences between the sexes. SEX RATIO IN AS
The most frequently quoted sex ratio in AS is 10: 1 in favor of men, a figure conceivably deriving from West’s study in 1949 whose estimate was based on hospitalized cases of AS in Bristol, England.6 Contemporary reports’-” also noted a striking male dominance, although these studies were often performed at military or veterans’ hospitals and were thus subjected to a biased selection of patients. Less attention was paid to those surveys reporting sex ratios between 4.4 and 3 .7 . ‘l-l3 As early as 1944 and 195 1 Fletcher and Parr presented patient data on AS where women accounted for 47% and 43%, respectively, of total cases.14V15 These studies were based on hospitalized cases of AS, reflecting the referral of a symptomatic population. Accordingly, such estimates are greatly influenced by the nosocomial threshold of AS which may be, for various reasons, different in men and women. Based on the results of studies of presumed healthy blood donors, in 1975, Calin and Fries3 Seminars in Arthritis andRheumatism,
in Women
suggested a sex ratio in AS approaching 1. In this study, a remarkably high incidence of AS among HLA-B27 negative blood donors was observed. Such studies with exceptionally high prevalences (20% to 25%) of AS among blood donors3V16 have been the subject of much debate. Other investigations’7*‘*V’9 have found a much lower frequency of AS among blood donors. To some extent, variations in the interpretation of SIJ roentgenograms may be responsible for this discrepancy. It is also uncertain if healthy blood donors are representative of the general population. Our own epidemiological survey of AS indicated a 6.7% prevalence of AS among HLA-B27 positive individuals.’ Recent population studies of AS4V5 have been unable to confirm the impression gained from some blood donor studies3 that the prevalence of AS in the two sexes was similar, reporting a significant male dominance with a ratio of 4-6: 1. UNDERESTIMATION
OF AS IN WOMEN
The reasons for the presumed underestimation of AS among women are unclear. Perusal of available literature fails to show a consistent opinion as to why such underestimation has occurred. Table 1 summarizes some proposals that have been presented. The tradition of regarding AS as a disease almost exclusively of men is a major factor for this underestimation. Another explanation is the reluctance to expose female reproductive organs to radiation, hence missing the opportunity to obtain a definite diagnosis. Also, the threshold for seeking medical advice because of pain or stiffness of the back might be higher in women than in men. Young men, in physically active From the Department ofRheumatology. Central Hospital ofdust-Agder, Arendal, and the Department of Rheumatology, University Hospital of Troms$ Norway. Jan Tore Gran, MD: Head of the Department of Rheumatology, Central Hospital of Aust-Agder. Arendal; Gunnar Husby, MD: Professor and Head of the Department of Rheumatology, University Hospital of Tromsb Norway. Address reprint requests to Jan Tore Gran, MD: Revmatologisk avdeling, Aust-Agder Sentralsjukehus, 4800 Arendal. Norway. o 1990 by W.B. Saunders Company. 0049-0172/90/1905-0006g5.00/0
Vol 19, No 5 (April), 1990: pp 303-3 12
303
GRAN AND HUSBY
304
Table
1.
Possible
Underestimation
Explanations
of the Prevalence
for admittance to hospitals and medical institutions, contributing to the underestimation of AS in women. Underestimation attributable to the difficulty of diagnosing AS in women must also be considered. If the disease runs a milder and less progressive course in women, the diagnosis could be overlooked. Furthermore, a higher frequency of peripheral arthritis among women could further confuse the diagnosis. Some workers have suggested that the evidence of AS must be overwhelming before this diagnosis is entertained in women.2’ The clinical expression of AS in men and women will be presented in more detail later.
for the of AS in Women
1. Tradition of regarding AS as a disease of men. 2.
Fear of exposing female pelvic organs to radiation.
3.
A higher threshold back pain and/or
4.
for seeking medical advice for stiffness
in
women.
More benign disease course with less disabling symptomatology
5.
More peripheral alternative
6.
in women. arthritis in women
suggesting
diagnoses.
Less pronounced
roentgengraphic
changes in
women. 7.
Slower development
of radiographic
features
in
women. 8.
Sacroiliitis misdiagnosed
as osteitis condensans
ilii. LIMITATIONS
Surveys
Cntena
Ml?fl
Year
for AS
Women
Fletchert4
1944
32
36
88
1953
60
0
Hart and Robinsor?
1959
30
0
90 100
Pohl and Treibe?
1962
62
0
100
McBryde
1973
13
0
?
1974
17
0
100
and McCollum3’
1974
7
0
Rome
Nasseh et alz3
1975
30
0
New York
Jeannet
1975
31
0
Rome
Swezey
et a?
et a?
AS
Sacrorlritrson Roentgenogram
Tyson et al*’
Mach3’
FEMALE
of AS in Women
No. of patients
Survey Authors
2.
ON
This review will focus primarily on 20 studies that analyze the clinical and radiological manifestations and prognosis of AS in women (Table 2). These publications cover a time span of more than 40 years, the first by Fletcher in 194414 and the last one by Kidd et al in 1988.22 As will be discussed later, no clear picture of the natural history of AS in women, as opposed to men, has emerged. The controversies reported are due in part to different study designs. The number of women included in these reports
occupations, might be more likely to find back pain a limiting factor in their employment, and cause them to seek medical advice. This would result in a higher prevalence of undiagnosed AS in the female population. To some extent, the general impression gained from population surveys of joint and back complaints speaks against such a hypothesis. According to these surveys2’ women generally report symptoms of the locomotor system more often than men. On the other hand, women may have an increased threshold Table
OF REPORTS
100 100 50
Men
._
._ _
Hill et aI3
1976
23
0
78
_~
Resnick et al5’
1976
18
80
Rome
100
100
Levitin et a13”
1976
27
0
Rome
100
Molony and Thompsor?
1979
8
0
New York
100
Goodman
1980
12
0
Marks et a?’
1983
25
25
New York
100
Jevleva et alz6
1984
60
New York
78
50
Gran et al”
1984
50
82
New York
100
100
Gran et al’*
1985
44
82
New York
100
100
McKenna
1986
62
61
New York
1988
35
70
New York
100
100
et a?’
et alz5
Kidd et al’*
New York
75 100
305
varies substantially, from 723 to 6224V25;only six surveys report data on more than 40 women. 2’,2e28 Furthermore, the lack of diagnostic criteria in 7 of 20 studies14,21*24*29-32 renders evaluation of the data virtually meaningless. Four of these14*2’*24V29 studies were performed before the promulgation of criteria for diagnosing AS. However, some of the reports24929*31 provide careful descriptions of patients allowing a definitive diagnosis of AS to be established in retrospect. Surprisingly, 12 studies21*23V24929*37 did not include male patients for clinical and radiological comparisons. When male controls were included, it is not always possible to determine whether the same selection criteria were used. It is difficult to establish a definite diagnosis of AS by clinical criteria alone38V39; thus, radiological sacroiliitis (SI) is regarded as mandatory for the diagnosis.40 Nevertheless, six reports 14,21Y26*32*34,35 have included cases diagnosed as AS but lacking the characteristic radiological features. In addition, two other surveys25”0 failed to present information regarding radiological manifestations. Thus, 8 out of 20 reports may have included patients whose back pain was noninflammatory in origin. Ankylosing spondylitis is a chronic rheumatic disease whose severity and stage of progression is largely dependent on disease duration. Because of inherent difficulties in obtaining female cases, very few reports have matched male and female cases for disease duration. Consequently, serious difficulties arise when features such as age at onset, disease outcome, and prevalence of extraarticular manifestations are compared.4’ Ankylosing spondylitis traditionally has been classified as a disease within the spondyloarthropathy complex.42 Some favor the view that these interrelated conditions should be categorized as one disease showing a diversity of clinical manifestations.43 Because important differences among the various spondyloarthropathies exist they should be separated when studies involving clinical and radiological comparisons are conducted. We advocate that patients afflicted with psoriasis, inflammatory bowel diseases (IBD), and Reiter’s disease should be excluded when features of primary AS are discussed. For example, the spondylitis of psoriasis is rather mild and nonprogressive,” and the clinical features of Reiter’s syndrome are frequently dominated by
peripheral arthritis. 45Similarly, the arthritis associated with IBD may be quite different from that of AS.4b Consequently, serious biases may be introduced when such disorders are included in the male or female AS groups. Moreover, as patients with juvenile onset AS are more prone to develop peripheral arthritis than those with adult onset AS4’ perhaps younger patients should be investigated separately. In particular, hip involvement and mode of disease onset are different in juvenile and adult onset AS.47Y48 Of the 20 studies reviewed, only six reports have excluded cases with seronegative arthropathies other than primary AS, and most do not contain information about inclusion of juveniles (Table 3). Therefore, the majority of the studies consist of patients suffering from various disorders within the spondyloarthropathy complex. To facilitate objective evaluation, criteria for disease severity and progression should be used; unfortunately, this assessment was not routinely done. Moreover, as a single examination of a patient with a chronic disease which fluctuates provides a limited impression of the disease, prospective studies using serial examinations are preferred. This is particularly important when estimating the prevalence of remitting clinical features such as peripheral arthritis and acute anterior uveitis (AAU). Too few studies were prospective. Most surveys were based on cases referred to rheumatological institutions and therefore do not represent the general AS population.49*s0It may be assumed that primarily patients with persistent or progressive disease will be followed at academic centers. The impact of referral bias in producing a cohort with more severe disease could be overcome partly by studying patients selected through population surveys, and those cared for by general and specialist practitioners Table 3. Other Seronegative Spondyloarthiopathies Included in Surveys of AS in Women Number of studies JAS
IBD
PSOR
Reiter’s Disease
Exclusion of
7
12
10
9
Inclusion of
6
3
3
3
No information
7
5
7
8
Abbreviations:
JAS,
IBD, Inflammatory
Juvenile
ankylosing
spondylitis;
bowel disease; PSOR, Psoriasis.
306
GRAN AND HUSBY
on an outpatient basis, in addition to those admitted to referral hospitals. All these factors should be taken into consideration when the results of the actual 20 reports are interpreted.
mous with peripheral arthritis whereas others required the presence of soft tissue swelling. With respect to hip involvement, Wilkinson and Bywaters” found hip arthritis in 35% of men and 20% of women. The corresponding percentages observed by Kidd et al** were 29% and 9%‘. The results of those studies contrast sharply with that of Marks et a14’ who found that hip and shoulder involvement occurred slightly but not significantly more often in women. Studies limited to female AS (Table 4) have demonstrated a prevalence of peripheral arthritis between 23%, and 75%. Two surveys including men and women 25*52have reported a significantly higher incidence of peripheral arthritis in women. In another study by Wordsworth and Mowat women had significantly more peripheral joint disease than men, but of 20 cases with peripheral arthritis eight had psoriasis. Three reports.22.28.4’ including our own, did not show any difference with respect to peripheral joint disease. The occurrence of erosive peripheral arthritis demonstrated roentgenographically appears infrequent in both sexes with AS. In contrast, erosions leading to joint destruction are regularly observed in rheumatoid arthritis (RA). Understanding the basis of this difference may provide insight into the pathogenesis of both disorders.
CLINICAL EXPRESSION OF AS IN WOMEN
Ankylosing spondylitis is usually regarded as a disease of young adults, the average age at onset being between 24 and 26 years.5’ The average age at onset of women with AS was between 22 The onset of symptoms and 38 years. 2’*29V31,36*37 before age 30 was found in 92%32 and 46%30 of cases in two studies. In contrast, according to Mach3’ only 12% of women developed symptoms before age 3 1. Two reports comparing men and women concluded that AS started 2 and 4 years later in women. Our study of female AS** did not show any difference in age at disease onset, 23 to 24 years in both sexes. A recent survey by Kidd et a122supported our report. Furthermore, although the initial symptoms of AS are difficult to define in a retrospective study, the impression from various reports is that men and women manifest similar symptomatology. It is often said that women with AS more often exhibit arthritis of the peripheral joints. Evaluation of this observation is difficult because of varying definitions of “peripheral joint affection.” In some reports, joint complaints were synonyTable 4. The Frequency
of Peripheral
Peripheral joint involvement
SLJVIey Authors
Year
Men
Women
Arthritis
in Men and Women
HIP rwolvement (%I Men
Women
Tyson et al”
53
Hart and Robinsor? Swezey et a?
59 74
Mach3’ Nasseh et ai33
74 75
30
-
Hill et al35
76
57
-
Resnick et a16’ Molony and Thompsor?
76 79
41
83$ 50
-
22t 13
18
24
Goodman
et a?’
-
28’
42
23
‘t 57
80
-
75
83§
17
28
Gran et aI”
85
29
29
McKenna
86
52
87
88
47
34
Kidd et aI” *Radiological
changes in 5%
tRadiological
changes
$Radiological
changes
in 50%
of females
$Figures given for adult cases of AS
Shoulder wolvement I%) Men
Women
Disease duration (yrs) Men
45
Women 7
3t
12
Marks et a?’
et alz5
With AS
_
0
29
9
21
15 _.
_
17
14
15
18
16
13 17 12
35
AS IN WOMEN
307
Limitation of spinal ‘mobility in female AS patients ranged from 74% to 100% (Table 5). Comparing men and women, no significant difference in restriction of spinal motion has been firmly established.**~*s To our knowledge, no studies were specifically designed to study possible differences in mortality rates of AS in men and women. In chronic diseases such as AS, however, morbidity may be more relevant than mortality. While it is generally accepted that AS runs a milder course in women, who are less likely to develop severe spinal deformities than men,21~29~32 this statement is based more on impressions than on objective data. In their study of 36 female and 164 male patients with AS, Spencer et als4 found no significant difference in overall disease severity between the sexes, although significantly more women than men belonged to functional class III (Steinbrocker), 25% versus 9% respectively. According to Marks et a14i 8% of both men and women with AS were unemployed because of their disease. More recently, Kidd et al** found that 57% of men and 7 1% of women with AS had not modified their daily life or employment related activities substantially. In our series of 126 individuals with AS,*’ 11% of men and 23% of women were permanently retired from work
before the age of pension. As more men than women were on temporary sick leave, the frequency of employment at the time of examination was the same. Thus, there is no convincing evidence that women with AS suffer more impairment in work ability than men. It may be argued that the similar disease severity observed in men and women with AS is a result of patient selection. As most surveys were based on hospitalized cases, the women included might represent the severe cases of AS. This would be true if a higher threshold for hospital admittance existed for the women than the men. Our own population survey’ did not detect a significant number of undiagnosed mild cases of female AS. RADIOLOGICAL FEATURES OF FEMALE AS
Cervical spine involvement in AS is a controversial subject. Resnick et al’* noted that isolated cervical spine abnormalities are more frequent in female than male AS (31% versus 4%), a difference that did not reach statistical significance. Marks et a14’ likewise found a higher frequency of radiological manifestations in the cervical spine in women than in men. Among 60 women with AS presented by Tyson et al.*i 41 (68%) had cervical spine involvement but only 25% had
Table 5. Age at Onset, Acute Anterior Uveitis, and Restriction of Spinal Mobility in Patients
Age at onset (y~sl Authors
Man
Women
Fletcher14
36
38
Tyson et al”
-
25
Hart and Robinson”
22
With AS Acute anterior w&tie (%)
Men
Restriction of spinal mobility 1%)
Women
Men
Women
0
-
-
13
-
-
-
23
-
-
5
-
-
-
0
-
Pohl and Triebe?
-
Swezey et alz3
-
Mach3’
-
-
-
57 24
-
100 -
Nasseh et al33
-
22
-
19
-
94
Jeannet et al34
38
-
19
-
94
Hill et al35
-
-
27
-
30 -
-
Resnick et al5’
31
87 -
Levitin et a13’
-
30
-
22
-
Molony and Thompson3’
-
22
-
13
-
Goodman et a13*
-
22
-
Marks et a14’ Grar?’ McKenna et alz5
23 -
Kidd et alz2
25
-
-
74 -
17
-
4
40
-
24
24
24
-
26
19
76 -
90 -
24
24
31
67
54
-
100 -
GRAN AND HUSBY
308
Table 6. Radiological
Authors
Manifestations
in Surveys of Women
SIJ ankylosis
Frequency of bambooing
Symphysis pubis involvement
CerVlCal spine involvement
Disease duratton
(%I
(%)
1%)
(%)
(%)
(yrs)
11
25
43
40
17
23
13
5
19
85
85
85
77
Tyson et al” Hart and Robinson” Pohl and Triebe? McBryde
and McCollum”
With AS
Frequency of spinal involvement
0
7
15
18
Mach3’ Swezey
et alz3
-
Jeannet
et al34
-
Goodman
et a13’
86
286 51
17
25”
l38% of those with radiological sacroiliitis.
radiological evidence of such involvement (Table 6). In their study of 222 patients with AS, Wilkinson and Wright found the cervical spine to be affected in 51% of men and 44% of women.” The impact of such radiological features upon cervical mobility has not been adequately studied. Relatively little is known about the frequency of atlantoaxial and subaxial dislocations in women with AS, and fractures of the cervical spine has rarely, if ever, been described. As radiological changes of the dorso-lumbar spine regularly postdate those of the SIJ, their presence will depend on the duration of AS.55 Unfortunately, the majority of studies lacked information regarding disease duration. Our results27 indicated that spinal involvement was more frequent among men (75%) than women (44%), and a similar difference (81% versus 56%) was noted by Resnick et a152 (Table 7). Jeanette et al34 and Hart and Robinson,29 reported that 5 1% and 40%, respectively, of female AS patients had involvement of the spine. Our women with AS had an average disease duration of 15 years; the prevalence of spinal changes in the study by Kidd et a122 was 31% (disease duration 15 years) confirming our estimate. Table 7. Radiological
SIJ ankylosis
Frequency of spinal involvement
Men
Women
Men
Women
Men
Resnicks’
-
-
81
56
-
Gran”
28
16
75
44
14
Kidd”
39
23
58
31
surprisingly,
spinal
in Surveys of Men and Women
Frequency of bambooing (%)
(%)
1%) Authors
Manifestations
Rather
mobility
was similar
in both sexes.** Thus, processes other than those seen on roentgenogram must be involved in determining spinal motion. Ankylosis is regarded as the end point of the inflammatory process in AS. Both SIJ and spinal ankylosis tended to be more frequent among our male patients. 27 Only 7% of our female AS cases had bambooing of the spine,27 a frequency corresponding to that of 5% reported by Pohl and Freiber.24 These estimates contrast sharply with those of others23’30 who demonstrated ankylosis in the overwhelming majority of cases. However, their findings were based on small numbers of patients, subjected to errors of selection bias. In general, the prevalence of bambooing, severe flexion deformities and ankylosis of the SIJ appears low. Many investigators have reported a high prevalence (1 1YE to 61%) of arthritis of the pubic symphysis in women with AS (Tables 6 and 7). We detected such changes in 9% of our women patients, but in none of our men.27 However, in two large series”,54 arthritis of the pubic symphysis was demonstrated more often in men than in women.
Symphysls publs involvement (%I
women
Men
7
0
With AS
Cervical spine Involvement (%I
Disease duration (vrs)
Women
Men
Women
Men
Women
61
55
69
21
15
14
15
18
16
9
309
HLA-B27
AND LABORATORY FEATURES IN WOMEN WITH AS
As tissue antigens are inherited in an autosoma1 codominant fashion, one would not expect a difference in the frequency of HLA-B27 in men and women with AS unless the pathogenesis of AS in the two sexes was different. Several reports show a significant association between B27 and female AS,32,34,3597 and a similar frequency of this antigen in the two sexes.28 One report23 noted a lower prevalence of B27 in female AS, but this study included patients with other seronegative arthropathies known to have a lower frequency of B27.56s57Moreover, that study23 was in blacks, who in general possess HLA-B27 less frequently than whites.s8*s9No study has compared disease manifestations in B27 negative and B27 positive AS in women. Information regarding laboratory measures of disease activity in female versus male AS is sparse, probably because most reports were retrospective. In our survey the mean erythrocyte sedimentation rate (ESR) and immunoglobulin A (IgA) levels were similar in men and women with AS.28 However, the C-reactive protein (CRP) was elevated in 66% of men in contrast to 35% of women, a statistically significant difference. Our results were based on a single examination and need confirmation. EXTRA-ARTICULAR
MANIFESTATIONS
IN
FEMALE AS
In one study,21 systemic manifestations such as weight loss, anorexia, and exhaustion were usually absent in female AS patients. According to Marks et a141AAU occurs ten times more often in women (40%) than in men with AS (4%). We are aware of only one other study that detects such a high frequency of AAU in women (Table 5). And, the low incidence of AAU in their male cases41 is at variance with fo_ previous studies. 60 Three other surveys 22.25.28 cusing on the prevalence of AAU failed to detect any differences between men and women. Cardiac manifestations are encountered in 4% to 43% of patients with AS,6’-63including conduction disturbances and aortic insufficiency. In two reports, aortic insufficiency was detected in 3% of women with AS,33V34 but no cardiac abnormalities were found by another investigator.29 Study-
ing 292 men and 60 women with AS, Bernstein and Broth in 1949 found clinical cardiac disease in 4% and 5% of patients, respectively.64 The prevalence of secondary amyloidosis and nervous system manifestations in unselected groups of female AS patients is unknown. PREGNANCY AND SEX HORMONES IN WOMEN WITH AS
Wilkinson and Bywaters” found that only three out of seven AS patients improved during pregnancy. In a retrospective study, @tensen et a165evaluated the influence of pregnancy on the course of AS in 87 pregnancies of 50 patients. Ankylosing spondylitis had no harmful effects on pregnancy, the fetus, or the newborn. Remission of AS occurred in 20% of pregnancies, exacerbation in 24% and 55% did not experience any change of disease activity. Some of the patients also suffered with psoriasis. In a subsequent prospective study, @tensen and Husby66 found that the majority of women with RA improved during pregnancy, whereas those with primary AS exacerbated while pregnant. Again, pregnancies were uneventful and children were healthy.66 The majority of women develop the initial symptoms of AS between the ages of 20 and 35 years,28 the years with the greatest childbearing potential. In a study of 200 AS patients, Simpson and Stevenson” noted that only 5 of 42 women observed the first symptoms of AS during pregnancy. In the retrospective study of @ensen et a1,65 20% of AS patients related their disease onset to pregnancy. Their findings suggest that pregnancy has no inductive effect on the development of AS. Why AS is one of the few inflammatory rheumatic diseases with a clear excess of males is unknown. No occupational or social factors that might explain this predilection have been defined. It is tempting to suggest that endocrine factors might be involved in the pathogenesis of this disease. However, a recent study found no differences in plasma sex steroid concentrations in AS males and sex and age matched controls.67 CONCLUSION
An increasing awareness that AS frequently affects women has led to a re-evaluation of the traditionally quoted sex ratio of 1O:l in favor of
GRAN AND HUSBY
310
men. Based on recent population surveys a more accurate ratio appears to be 4 to 5: 1. Although not fully defined, the natural history of primary AS in women appears similar to that in men. To facilitate early recognition of AS in women, clinicians must maintain a high index of suspicion. Although divergent data on the extent and frequency of radiological manifestations of female AS has been published, present knowledge indicates more pronounced and widespread radiographic changes in men. Before any firm conclusions regarding clinical, radiological, and laboratory features of female AS can be reached, well-designed and executed studies are needed. Suggestions for future studies are given in Table 8. Information must be acquired prospectively on a sufficient number of patients meeting appropriate diagnostic criteria. Investigations should include members of both
Table
8.
Proposed
Requirements
for Future
Studies
of AS in Women 1. Sufficient 2.
number of women
patients.
Men included for comparison.
3.
New York Criteria for AS.
4.
Exclusion of patients spondyloarthropathies
with other seronegative and juvenile cases of AS.
5.
Criteria for disease severity.
6.
Patient groups representative
for the entire AS
population. 7.
Follow-up
8.
Setter definitions thropathy,
and senal assessments. of terms such as arthralgia,
ar-
arthritis.
sexes that are matched for age of onset, disease duration, and disease activity and severity. Patients should be selected from the general population, rather than from specialty institutions, and studied longitudinally for several years.
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