Spondyloarthropathy
as an Old World Phenomenon
By Bruce M. Rothschild and Robert J. Woods The presence of spine and sacroiliac involvement and the nature and distribution of erosive lesions allowed definitive diagnosis of spondyloarthropathy in the great apes (Gorilla and Pan [chimpanzee]), the lesser ape (Hylobates), and Old World monkeys (Theropithecus, Papio, Cercopithecus, Macaca, Colobus, Presbytis, and Erythrocebus). Analysis of lesional character, distribution, radiological appearance, and sex ratios showed a picture indistinguishable from human spondyloarthropathy. This contrasts with orangutans (Pongo), who lack reactive bone or sacroiliac involvement. A different pathophysiology, as yet undefined, is implied for their erosive arthritis. Limited individual susceptibility to
A
RTHRITIS IS well established as a disease of antiquity in African primates.‘~4 However, the nature of that arthritis has been controversia1.135.6The presence of asymmetrical erosive arthritis with ankylosis in rhesus monkeys (Macaca mulatfu) and baboons (Papio qnocephalus)‘~2~6suggests that spondyloarthropathy might be present. Indeed, Ruffer’ reported “spondylitis” in “sacred monkeys of the ancient temples near Thebes,” and Sokoloff et alx reported similar findings in contemporary Mucaca. The recognition by Ford et al3 of 10 cases of inflammatory arthritis per 2,000 in a Rhesus monkey (Mucaca) breeding colony suggested that this might represent a population phenomenon. Rothschild and Woods9 provided clear documentation that spondyloarthropathy best describes the arthritis found in gorillas. That
From the Arthritis Center of Northeast Ohio, Youngstown, OH; Northeast Ohio Universities College of Medicine, Rootstown, OH; UniversityofAkron, Akron, OH; Carnegie Institute, Pittsburgh, PA; and Ohio State University, Columbus, OH. Supported in part by NIH Division of Diagnostic Resources grant no. RR00919 and National Institute of Arthritis and Musculoskeletal and Skin Disease grant no. AR35736-03. Bruce M. Rothschild, MD: Director, Arthritis Center of Northeast Ohio, Northeast Ohio Universities College of Medicine, and University ofAkron; Robert J. Woods, MA: Ohio State University. Address reprint requests to Bruce M. Rothschild, MD, Arthritis Center of Northeast Ohio, 5701 Market St, Youngstown, OH 44512. Copyright 0 1992 by W.B. Saunders Company 0049-0172192/2105-004$5.00/O
306
spondyloarthropathy in humans (1% to 4%), Old World monkeys (2.4%), and lesser apes (2.4%) contrasts with the high frequency of disease in the great apes (20% to 28%). The wide geographic distribution of this phenomenon suggests an African and perhaps Asian “panendemit.” This natural disease state provides a unique model for in-depth analysis of the contribution of genetic and environmental factors to disease pathophysiology. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Spondyloarthropathy; keys; apes; animal model of arthritis.
mon-
arthritis, affecting 20% of free-ranging and 12% of captive gorillas, was indistinguishable from a human erosive disease of the spondyloarthropathy variety, psoriatic arthritis. The character, distribution, and frequency of spondyloarthropathy in nonhuman Old World primates was therefore surveyed to define the transgenic distribution of the phenomenon. METHODS
The articular skeletons of adult Old World primates were examined from the following collections: American Museum of Natural History (AMNH) (New York, NY), Caribbean Primate Research Center (CPRC) (University of Puerto Rico, San Juan, PR), Carnegie Museum (CM) (Pittsburgh, PA), Cleveland Museum of Natural History (CMNH) (Cleveland, OH), Field Museum of Natural History (FMNH) (Chicago, IL), Florida State Museum (UF and FSM) (Gainesville, FL), Museum of Comparative Zoology (MCZ) (H arvard University, Cambridge, MA), National Museum of Natural History (NMNH) (Washington, DC), University of Washington (PHY) (Seattle, WA), and Wake Forest University (WFU) (WinstonSalem, NC). The macerated (eg, lye- or papain-treated to remove the soft tissues) primate skeletons were surveyed for visible evidence of articular and periarticular joint and spine pathology. With rare exceptions, the postcranial skeletons examined were completely preserved. Each skeletal
Seminars in Arthritis andRheumatism, Vol21, No 5 (April), 1992: pp 306-316
SPONDYLOARTHROPATHY
IN THE OLD WORLD
307
element of all sampled individuals was carefully observed by both authors, with concurrence as to the observation representing an erosion and ruling out artifacts such as postmortem trauma (eg, drawer damage). For purposes of this study, articular surfaces were treated as missing if artifactual damage precluded demonstration of joint disease. The 1,699 Old World primates examined included 99 gorillas (GoriEla), 79 chimpanzees (Pan troglodytes), 54 orangutans (Porzgo pygmeus), 123 gibbons (Hylobates), 237 baboons (Papio), 12 Gelada baboons (Theropithecus), 94 colobus monkeys (Colobus), 74 leaf monkeys (Presbytis), 18 langurs (Nasalis), 361 guenons (Cercopithecus), 371 macaques (Mucaca), 115 Patas monkeys (Erythrocebus), 33 langurs (Qguh-ix), and 26 mangabeys (Cercocebus). The pathological specimens were subjected to radiological examination in the anatomical position in which they would be viewed during in vivo radiology. RESULTS
Peripheral Joint Disease
Erosive disease was found (Table 1) in 2.4% of all Old World monkeys (4.6% of Papio, 16.7% of Theropithecus, 1.1% of Cercopithecus, 3.9% of Colobus, 5.2% of Elythrocebus, 2.2% of Macaca, 3.1% of Presbytis), 2.4% of the lesser ape (Hylobates), and 19% of great apes (28% of
Pan [chimpanzee], 20% of Gorilla, and 9.3% of Pongo [orangutan]). Erosions were marginal
(bare area) and subchondral in distribution (Figs 1 and 2). As used here, the term marginat denotes that zone of metaphyseal bone within the synovial membrane (Fig 1) but extrinsic to the cartilage-lined bone.lozl’ Marginal areas tend to be “indented” in their location and therefore somewhat protected from postmortem artifactual changes.” Subchondral erosions (Fig 2) affect the bone originally covered with cartilage. Approximately 50% of erosions (except in orangutans) were associated with perierosional smooth, billowy, sclerotic new bone formation. No new bone formation was found in any orangutan. Because a 30% to 50% alteration (loss or accretion) in bone must occur before alterations can be detected in routine radiographs,” most of the gross erosions were not detected on radiological examination. Radiological examination of periarticular bone showed maintenance of normal bone density. Osteopenia was notable by its absence. A sclerotic margin was present in approximately 50% of erosions visible on radiographs in all genera with erosive disease (Fig 3) with the exception of orangutans (which manifest no reaction). Even with a quite mutilating form of arthritis (arthritis mutilans), reactive new bone formation and sclerosis are prominent (Fig 3). Axiul Joint Disease
Table 1. Pathology in Old World Primates
hi Cercocebos Cercopithecus Colobus
Total Examined
Afflicted
Animals
26
70
0
0
-
361
63
4
1
100
94
59
4
4
100
Erythrocebus
115
43
6
5
67
Macaca
371
59
8
2
Nasalis
18
55
0
0
~Presbytis
74
52
2
3
Pygathrix
33
25
0
0
Hylobates
64 50 -
123
58
3
2
50
Gorilla
99
79
19
21
85
Pan
79
30
22
28
60
Pongo
54
65
5
9
40
Syndesmophytes (calcification of the annulus fibrosus) and sacroiliac erosions or fusion were present (Table 2) in 2.1% of Old World primates (1.9% of Papio, 8.3% of Theropithecus, 1.1% of Cercopithecus, 2.6% of Elythrocebus, 1.1% of Mucaca), 3.2% of lesser apes (Hylobates), 0% of orangutans, and 6.7% of the other great apes (5.1% of Pan and 8.0% of Gorilla). Sacroiliac fusion (Fig 4) was noted in 3 Pupio (2 bilateral), 1 Macaca (bilateral), 3 Hyfobates (1 bilateral and 2 unilateral), 5 Gorilla (3 bilateral and 2 unilateral), and 1 Pan (unilateral). Sacroiliac erosions (recognized as multiple, small, crater-shaped holes with smooth, rounded edges) were present in 1 Cercopithecus, 1 Colobus, 1 Presbytis, 3 Papio, 3 Pan, and 2 Gorilla. Anulus fibrosus calcification (syndesmophyte formation) was noted (Fig 5) in 3 Pupio, 1
ROTHSCHILD AND WOODS
polyarticular involvement. “Pencil-in-cup” deformity was noted in a distal interphalangeal joint in one individual. Erosive disease in Theroin one individual pithecus was pauciarticular and polyarticular in a second (Fig 6). Erosive arthritis (Tables 2 and 3; Fig 6) in Erythrocebus was pauciarticular in three individuals and polyarticular in one. Erosive disease was pauciarticular (Tables 2 and 3; Fig 6) in Colubus, Presbytis, Cercopithecus, and Macaca. Erosions of the metacarpal phalangeal and proximal and distal interphalangeal joints of a single finger ray and peripheral joint fusion were noted in Macaca. Apes
Fig 1:
(A) Lateral view of Erythrocebus
carpals shows marginal
meta-
erosions (arrowheads)
Arthritis in the lesser ape, Hylobates, was pauciarticular in distribution (Fig 6). The distribution of erosive arthritis in the great apes Pan (chimpanzee) and Gorillay~‘3is delineated in Tables 2 and 3. Erosive disease was symmetrical in 16 of 22 chimpanzees (73%). Pauciarticular
without reactive new-bone formation. The white arrowhead locates a deep erosion, while the black arrowheads identify more subtle erosions. (B) Oblique and posterior views of Etythrocebus elbow show marginal erosions (arrowheads) with minimal new-bone formation.
Theropithecus, 3 Cercopithecus, 2 Macaca, 4 Hylobates, and 1 Gorilla. Such lesions were
frequently associated with zygoapophyseal joint fusion and occasionally with costovertebral joint or symphysis pubis fusion. Sexual Predisposition No sexual predisposition for spondyloarthropathy (Table 1) was noted in Papio, Presbytis, Hylobates, Macaca, or Gorilla (male-female ratio, approximately 1:l). Males were proportionately overrepresented in Colobus, Cercopithecus, Erythrocebus, and Pan (approximately 3:2) and underrepresented in Pongo (approximately 2:3). Monkeys
Erosive disease in Papio was pauciarticular in four individuals and polyarticular in five (Tables 2 and 3). Five to 10 (average, 7) joints (Table 2; Fig 6) were affected in the five individuals with
Fig 2:
Erythrocebus
erosions (arrowheads)
distal
radius
and ulnar
with reactive new bone
formation (A), especially prominant radii in B (arrowhead). Subchondral
in distal erosions
(arrowhead) are prominent in Erythrocebus knee (C). Erosion with reactive new-bone formation (arrowhead) is apparent at the metatarsal most aspect of the calcaneus) joint (D).
(right-
SPONDYLOARTHROPATHY
309
IN THE OLD WORLD
age, 7.5). Wrist, metacarpophalangeal, ankle, metatarsophalangeal, and shoulder joints were predominantly affected. Sacroiliac disease and syndesmophyte formation were notably absent. DISCUSSION
Old World Primates, Exclusive of Orangutans
Fig 3:
Posterior view of Macaca phalanges (A,
Erosive disease, not limited in distribution to a single joint, was found (Table 1; Fig l-3) in 2.4% of Old World monkeys, 3.2% of the lesser ape Hylobates, and 19% of great apes (28% of chimpanzees, 20% of gorillas, and 9.3% of orangutans). Attribution of a single diagnosis to this phenomenon in all affected Old World primates (except orangutans) is predicated upon a major assumption. (The arthritis in orangutans [discussed in detail below] has a number of characteristics that suggest it is different from that of the other African primates.) Anthropomorphizing from human disease, relatively few erosive disorders that are not predominantly monoarticular occur with any frequency within the population. Rheumatoid arthritis (RA) and
B) shows severe erosive arthritis with new bone formation. (C) Posterior-anterior view of Macaca phalanges
shows severe erosive disease with
sclerotic reaction.
(involving less than 5 joints) erosive disease was found in only four individuals (18%). In those chimpanzees with polyarticular disease, nine joints were typically affected (range, 5 to 14). Wrist, metacarpophalangeal, ankle, metatarsophalangeal, and shoulder joints were predominantly affected. Four chimpanzees had sacroiliac erosions or fusion. Erosive disease was pauciarticular in 40% of gorillas. The joints of the toes and fingers were predominantly affected. Sacroiliac erosions or fusion were present in nine gorillas, and spine involvement was present in three. Erosive disease (Tables 2 and 3) in Pongo (orangutans) was pauciarticular (shoulders) in one individual and polyarticular in four (wrists, ankles, and isolated metacarpophalangeal, proximal interphalangeal, or distal interphalangeal joints). Erosive disease was symmetrical in three of five orangutans (60%). Polyarticular disease in orangutans affected five to nine joints (aver-
Fig 4: Posterolateral joint fusion.
view of Macaca sacroiliac
ROTHSCHILD AND WOODS
Fig 5:
Macaca spine with classic syndesmophytes
Zygoapophyseal
producing fusion through the annulus fibrosus.
joint fusion is also present. (A) lateral x-ray image; (B) lateral view. The arrowhead
A marks zygoapophyseal
in
joint fusion.
spondyloarthropathy are the prime candidates.“.‘+‘5 The nature and distribution of the peripheral erosions in Old World primates (except orangutans) was the same in the presence or absence of spine or sacroiliac (axial joint) involvement (Table 2), again suggesting that all were manifestations of a single disease. The nature and distribution of the lesions and occurrence and frequency of spine and sacroiliac involvement (Figs 4 and 5) allow definitive diagnosis of spondyloarthropathy in Papio, Theropithecus, Cercopithecus, Macaca, Colobus, Elythrocebus, Presbytis, Hylobates, Gorilla, and Pan. The presence of annulus fibrosus calcifica-
tion, sacroiliac fusion, or erosions is diagnostic of spondyloarthropathy,9~‘1~15,‘6 in contrast to the solely ligamentous ossification characteristic of diffuse idiopathic skeletal hyperostosis.““’ Peripheral joint fusion, limited in distribution to Macaca, further supports the diagnosis of spondyloarthropathy, as it does in humans.”
The radiological picture of erosions with sclerotic margins and no periarticular osteopenia (Fig 3) is also characteristic of spondyloarthropathy.%11.15~17.
There was no significant variation in frequency of disease (Table 1) among the Old World monkeys or lesser apes. The high frequency in Theropithecus is not statistically significant (only 12 individuals were available for assessment; x’ = 3.33). Although erosive arthritis and spondyloarthropathy were unrepresented in Nasalis, Pygathrix, and Cercocebus, the small number of specimens available for assessment precludes confident exclusion of the disease in those populations. The frequency of disease in Old World monkeys and lesser apes (40/1,467), however, was significantly less than that noted in gorillas and chimpanzees (P < .OOOl; x”). The special susceptibility of gorillas and chimpanzees remains unexplained at this time.
SPONDYLOARTHROPATHY
311
IN THE OLD WORLD
Table 2: Distribution
of Arthritis in Old World Primates Number of Affected
Genus
Axial Joint
Pauciarticular
Polyarticular
n
%
n
%
n
Joints (Polyarticular)
%
Papio
7
64
4
36
5
45
Theropithecus Colobus
1 1
50 25
1 3
50 75
1 0
50 0
Range
Average
5-10.
7
6' -
6* -
Presbytis
1
50
1
50
0
0
-
Cercopithecus
3
75
2
50
0
0
-
Macaca
2
25
7
88
0
0
-
-
Erythrocebus Hylobates
3 2
50 67
3 3
50 100
1 0
17 0
9 -
9 -
Gorilla
9
47
8
40
10
50
5-13
6
Pan
4
18
4
18
18
82
5-14
9
Pongo
0
0
1
20
4
80
5-9
7.5
*Minimal number; hands and feet missing.
we believe this statistically significant observation has biological importance, artifact related to small sample size is of concern. The frequency of involvement of a given joint (Table 4) in the polyarticular subgroup of great apes (none of the lesser apes had polyarticular erosive disease) was indistinguishable from that of humans (P = .115; Fisher’s Exact Test), while monkeys had more frequent metatarsophalangeal joint involvement (P = .006; Fisher’s Exact Test). Monkeys and great apes with polyarticular disease had similar distributions of joint involvement, except for elbow (P = .048; Fisher’s Exact Test) and metatarsophalangeal
An intriguing approach to analysis of primate spondyloarthropathy is to divide the affected animals into groups with pauciarticular and polyarticular disease. Polyarticular erosive disease in Papio and Theropithecus (two genera of baboons) was significantly more common (P = .005; Fisher’s Exact Test) than that noted in the other Old World monkeys and was indistinguishable in frequency (Table 2) from that noted in the great apes, Gorilla and Pan (P = .26; Fisher’s Exact Test). The data base is small, but subsequent examination of other baboons with spondyloarthropathy has shown a polyarticular pattern of erosive arthritis. While
Table 3: Skeletal Distribution
(%I of Erosive Arthritis in Apes and Monkeys Monkeys
Joint Shoulder
Gorilla
Chimpanzee
Orangutan
Hylobates
Baboon
Nonbaboon
(n = 19)
(n = 22)
(n = 5)
(n = 3)
(n = 13)
(n = 24)
5
23
20
25
36
22
20
18
0
25
55
35
Wrist
50
86
80
75
100
30
MCP
70
95
60
25
40
9
PIP
60
55
60
0
10
9
DIP
15
9
40
0
9
4
Elbow
Hip
0
0
0
0
9
0
Knee
15
0
0
50
36
22
Ankle
40
59
40
0
27
13
MTP
50
50
20
0
9
9
Sacroiliac
40
18
0
50
50
30
Spine
15
0
0
50
27
22
Abbreviations:
MCP, metacarpophalangeal;
PIP, proximal interphalangeal; DIP, distal interphalangeal; MTP, metatarsophalangeal.
312
*I---+ > < > * * I L* TAEROPITHECUS
*
>
Wrist Elbow Shoulder
>*
cc
x
* > > >
x
X
>
4
* * * * >
*
HYLOBATES
> >
*
*
*
*
4
L
4
*
*
*
4
*
>>> <
* * * > > *
>
< *
>
1
4
*
*
pattern of erosive arthritis in monkeys and lesser apes. Arrows indicate affected
side (, right); diamonds indicate bilateral disease; an X indicates a missing joint. Each vertical column represents a single animal.
(P = .049; Fisher’s Exact Test) joints (both more frequent in monkeys, perhaps related to brachiation). The distribution of pauciarticular joint disease in baboons (Papio and Theropithecus), nonbaboon monkeys, Hylobates, gorillas, and chimpanzees (Table 5) was indistinguishable (x2 and Fisher’s Exact Test), with the exception of metacarpophalangeal joints (more common in the great apes [x2 = 11.64; P < .OOl]). Although a trend toward increased frequency of proximal interphalangeal joint involvement was noted gorillas and chimpanzees, it did not achieve statistical significance (x2 = 3.27).
Table 4: Distribution
The frequency of involvement of a given joint in monkeys, Hylobates, and human skeletons (Todd Collection) with pauciarticular spondyloarthropathy’6 was also indistinguishable. However, great apes had significantly greater metacarpophalangeal (21% v 73%) (x2 = 8.23; P < .005) and proximal interphalangeal(l8% v 54%) (x2 = 6.51; P < .015) joint involvement than did humans. Perhaps the increased (statistically significant compared with humans) occurrence of metacarpophalangeal and proximal interphalangeal joint involvement in the great apes can be attributed to the “increased articular insult” associated with “knuckle walking.“”
(%) of Polyarticular
Erosions in Apes and Monkeys Monkeys
Orangutan
Gorilla
(n = 4)
(n = 10)
(n = 5)
25
10
28
60
100
0
27
17
60
100
Wrist
100
64
89
100
100
MCP
60
91
100
80
100
PIP
71
73
50
40
100
DIP
40
50
11
20
0
Hip
0
0
6
20
0
Knee
0
18
6
40
100
Ankle
40
73
72
60
0
MTP
20
73
56
20
0
IP
0
64
17
0
0
Sacroiliac
0
37
11
40
100
Spine
0
20
0
40
0
Joint Shoulder Elbow
Abbreviation:
IP, interphalangeal
joints of feet.
Chimpanzee
Baboon (n = 5)
Nonbaboon (n = 1)
SPONDYLOARTHROPATHY
IN THE OLD WORLD
Table 5: Distribution
313
(%) of Pauciarticular
Erosions (%) in Apes and Monkeys Monkeys
Orangutan Joint
(n=
Chimpanzee
1)
(n = 4)
Baboon
Nonbaboon
Hylobates
(n = 8)
(n = 8)
(n = 15)
(n = 4) 25
0
0
17
27
Elbow
0
25
14
33
47
25
Wrist
0
75
43
83
40
75
Shoulder
100
Gorilla
0
75
57
20
7
25
PIP
100
75
43
0
7
0
DIP
0
0
0
0
7
0
Hip
0
0
0
0
0
0
Knee
0
0
14
17
27
50
Ankle
0
0
0
17
20
0
MTP
0
25
29
0
13
0
IP
0
0
14
0
0
0
Sacroiliac
0
50
14
50
13
50
Spine
0
0
13
17
20
25
MCP
Data from Rothschild and Woods.g.13
Differential Diagnosis
The bone remodeling in Old World monkeys, lesser apes, chimpanzees, and gorillas was much more exuberant than that seen in human rheumatoid arthritis’2’x,19 but quite similar to that noted in human spondyloarthropathy.9913~‘6The rarity of periarticular loss of bony density and the tendency to new bone formation in nonhuman Old World primates (except orangutans) contrasts with the periarticular osteopenia and absence of perierosional bone reaction noted in human RA.12,‘8,19The disease in Old World primates is clearly distinguishable from the symmetrical (but axial joint-sparing [except for the junction of first and second cervical verteTable 6: Skeletal Distribution
brae]) distribution that characterizes RA.‘1*14,19,20 The limited number of joints involved in Old World primates (Table 6) is clearly at variance with the involvement of almost every peripheral diarthrodial joint in RA.‘1,15,‘9 The average of 8.6 joints involved (range, 5 to 14) in Old World primates (except orangutans) with polyarticular erosive disease is significantly at variance with the average of 12 joints involved in humans with RA (P < .OOl;t test). The difference in number of affected joints is artificially narrowed because joint groups (involvement of five or one metacarpophalangeal joints is counted the same) are being compared. Patients with RA often have many joints in a given group affected. Persis-
(%) of Erosive Arthritis in Old World Primates and of Symptomatic
Reiter’s Syndrome, Psoriatic Arthritis, and RA in Homo sapiens Apes Joint
Monkeys
Lesser
Great
Shoulder
25
15
Baboon 36
Homo sapiens Other
Reiter’s
Psoriatic
22
13-21
4-23
29-46 26-66
RA
Elbow
25
16
55
35
10-14
1 o-43
Wrist
75
69
100
30
16-34
44-62
64-92
MCP
25
79
40
9
7-46
34-53
70-72
PIP
0
57
10
9
5-31
II-40
40-70
Hip
0
0
9
0
5-28
Knee
50
6
36
22
67-70
Ankle
0
49
27
13
45-65
28-63
3-54
MTP
0
47
9
9
57
33-34
70-72
50
28
50
30
24-65
52
0
Sacroiliac Data from references
9, 19,23, and 40-51.
O-38 27-72
7-12 24-82
-
314
tence of statistical significance, even with grouping, emphasizes the meaningfulness of this observation. The difference in number of involved joints in RA and in spondyloarthropathy is reproducible in all skeletal populations we have examined. The oligoarticular and polyarticular erosive arthritis observed in Old World primates is distinguishable from the predominantly monoartitular disorders gout and infectious arthritis. Although erosions with sclerotic margins often characterize gout or infectious arthritis,“.‘“‘h.“’ the appendicular skeletal distribution of arthritis and spinal involvement clearly distinguish the arthritis of Old World primates from gout or infectious arthritis. No evidence of overgrowth of periosteum adjacent to erosions (so characteristic of gout or amyloidosis)“~‘4’s~“‘*” was present in Old World primates. Amyloidosis, although a recognized complication of Shigella or tuberculosis infections in primates,22 cannot be invoked as the cause of erosive disease in Old World primates because it rarely produces radiologically detectable erosions.“” No such lesions were found in the Old World primates studied. Variety of Spondyloarthropathy
Although human spondyloarthropathy is divisible into several varieties (psoriatic arthritis, Reiter’s syndrome [reactive arthritis], ankylosing spondylitis, and inflammatory bowel diseaserelated arthritis”,2’.24),the frequently asymmetrical distribution of Old World primate sacroiliac and spine involvement eliminates the latter two as diagnostic considerations. The pattern of disease (Table 6) in Old World primates (except orangutans) was similar to that found in gorillas (indistinguishable from human psoriatic arthritis’). Suggestion of a relationship to psoriasis is not new; skin lesions with the gross visual and histologic appearance of psoriasis have been reported in Macaca.25 These psoriatic lesions were described as “erythematous plaques with adherent white scale, spongiform pustules and Munro microabscesses, clinically and histologically indistinguishable from psoriasis.” However, the dermatopathology of Reiter’s syndrome and psoriatic arthritis are similar,‘4’5.2”and transition from one to the other has been reported’4.‘” for both potentially infectious disorders.2h~2”
ROTHSCHILD AND WOODS
Equal representation
in male and female
Papio, Presbytis, Macaca, Hylobates, and Gorilla
(Table 1) is more common with human psoriatic arthritisy.“.‘” and rarely reported in reactive arthritis.3” (Male predominence [3:2] in the other afflicted genera is not statistically distinguishable from a 1:l ratio). Infectious-agent diarrhea-related Reiter’s syndrome or reactive arthritis”~‘“~“~“~~~ may also be responsible for Old World primate spondyloarthropathy. Although chlamydial infections (associated with human venereally transmitted reactive arthritis) have been found in Papio,33 the presence of spondyloarthropathy in monogamous Hylobate?” makes the venereal variety of Reiter’s syndrome unlikely. Although reactive arthritis is commonly pauciarticular,” one source (Salmonella typhimutium) can produce a polyarticular pattern3’ similar to that noted in Papio, Theropithecus, and Pan. Pauciarticular arthritis, reactive arthritis, and Reiter’s syndrome have also been seen as a complication of the human acquired immunodeficiency syndrome (AIDS),3’.‘4 albeit with a distribution pattern quite different from that noted in nonhuman Old World primates. Although AIDS appears to be a relatively new phenomenon (most of the affected animals were collected in the early part of the century), retroviruses (human immunodeficiency virus is a retrovirus) have been implicated in the ctiology of psoriasis.‘i Orangutans
Although orangutans clearly are susceptible to erosive arthritis, the etiology is less clear. Absence of reactive new-bone formation and axial joint disease are at variance with spondyloarthropathy,‘.‘3,‘h while subchondral localization and maintainence of periarticular bone density contrast with RA.‘” The erosive disease in orangutans actually looks quite different from that of other Old World primates. There is no evidence of reactive new-bone formation, no periarticular osteopenia, and no axial disease. The numbers are small, but the disease looks different. Further supporting that perspective is ongoing work on New World monkeys (Rothschild and Woods, data not presented). Several individuals in one genus had an erosive arthritis resembling the spondyloarthropathy seen in
SPONDYLOARTHROPATHY
315
IN THE OLD WORLD
Old World monkeys. Diagnosis of spondyloarthropathy was confidently made, even without evidence of axial disease. We subsequently examined additional animals of that genus and found axial disease. Because the orangutan is considered an extremely “odd” primate,36 perhaps its arthritis is also unique (eg, analagous to Caprine arthritis, a pauciarticular, minimally erosive, lentivirus-related disease of goats4’).
Table 7: Geographic Distribution Spondyloarthropathy
in Old World Primates
SpondyloPrimates
arthropathy*
Africa
+
207 Papio 12 Theropithecus
+
77 C&bus
+
32 Presbytis
+
Borneo
Arabia +
+ +
+
+
337 Macaca
+
+
+
+
Implications
Asia
+
361 Cercopithecus
59 Erythrocebus
+
+
23 Pygathrix +
9 Cercocebus
As spondyloarthropathy is indigenous (“pandemic”) in nonprosimian primates from both Africa and Asia (Table 7), a non-species-specific etiology is suggested. Limited occurrence (0.1% to 5.2%) in humans, lesser apes, and most monkeys contrasts with the high frequency (16% to 28%) noted in gorillas, chimpanzees, and Theropithius. 9~13 This natural disease state provides a unique model for in-depth analysis of the contribution of genetic and environmental factors to disease pathophysiology. Investigation of genetic immunomodumay allow identification of the lating systems38’39 adaptive physiological parameters that determine disease susceptibility.
of
+
+
123 Hylobates Gorillas
+
+
Chimpanzees
+
+ +
Orangutans ‘Spondyloarfhropathydocumented
as present.
ACKNOWLEDGMENT The authors thank Drs Dana E. Austin, Philip Hershkovitz, Nancy Hong, Lyman Jellema, Bruce Latimer, William R. Maples, Guy Musser, D. Patterson, Dwayne Schlitter, Darren Swindler, Richard Thorington, Jean Turnquist, and David Weaver for their assistance in facilitating examination of the collections they curate and Ruth Green and Christine Rothschild for cogent manuscript review.
REFERENCES 1. Bramblett CA: Pathology in the Darajani baboon. Am J Phys Anthropol26:331-340,1968 2. Bywaters EG: Observations on chronic polyarthritis in monkeys. J R Sot Med 74:794-799,198l 3. Ford E, Hird D, Franti C, et al: Analysis of factors associated with sixty cases of chronic arthritis in Rhesus monkeys at the California Primate Research Center. Lab Anim Sci 89:561, 1986 4. Fox H: Chronic arthritis Philos Sot 31:71-149, 1939
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Trans
Am
5. Driesch A: Pathologically altered skeletal remains of baboons from ancient Egypt. Tierarztl Prax 13:367-372, 1985 6. Obeck DK, Toft JD II, Dupuy HJ: Severe polyarthritis in a rhesus monkey: Suggested mycoplasma etiology. Lab Anim Sci 26:613-618, 1976 7. Ruffer MA: Studies in the Palaeopathology of Egypt. Chicago, IL, University of Chicago, 1921, pp 184-193 8. Sokoloff L, Snell KC, Stewart HL: Spinal ankylosis old rhesus monkeys. Clin Orthop 61:285-293,1968
in
9. Rothschild BM, Woods RJ: Spondyloarthropathy gorillas. Semin Arthritis Rheum 18:267-276, 1989
in
10. Martel W, Hayes JT, Duff IF: The pattern of bone erosion in the hand and wrist in rheumatoid arthritis. Radiology 84:204-214,1965 11. Resnick D, Niwayama G: Diagnosis of Bone and Joint Disorders (ed 2). Philadelphia, PA, Saunders, 1989 12. Woods RJ, Rothschild BM: Population analysis of
symmetrical erosive arthritis (1200 years before the present 1263,1988
in Ohio Woodland time). J Rheumatol
13. Rothschild BM, Woods RJ: Reactive in chimpanzees. Am J Primatol85:125-134,
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14. McCarty DJ: Arthritis and Allied Conditions Philadelphia, PA, Lea & Febiger, 1989 15. Rothschild BM: Rheumatology: A Primary Approach. New York, NY, Yorke Medical, 1982
(ed 11). Care
16. Rothschild BM, Woods RJ. Spondyloarthropathy: Erosive arthritis in representative defleshed bones. Am J Phys Anthropol85:125-134,199l 17. Rothschild BM: Diffuse idiopathic skeletal hyperostosis (DISH) and arthritis in an early 20th century geriatric population. Age 14:17-19,199l 18. Rothschild BM, Woods R: Old World spondyloarthropathy: The gorilla connection. Arthritis Rheum 31:934935,1988 19. Rothschild BM, Woods RJ, Ortel W: Rheumatoid arthritis in the buff: Erosive arthritis in representative defleshed bones. Am J Phys Anthropol 1990; 82:441-449, 1990 20. Katz WA: Diagnosis and Management Disease (ed 2). Philadelphia, PA, Lippincott,
of Rheumatic 1989
21. Ortner DJ, Putschar WG: Identification of Pathologic Conditions in Human Skeletal Remains. Washington, DC, Smithsonian, 1981 22. Chapman
WL Jr, Crowell
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ROTHSCHILD AND WOODS
sus monkeys with rheumatoid arthritis Am Vet Med Assoc 171:855-858,1977
and enterocolitis.
J
23. McEwen C, DiTata D, Lingg C, et al: Ankylosing spondylitis and spondylitis accompanying ulcerative colitis, regional enteritis, psoriasis, and Reiter’s disease: A comparative study. Arthritis Rheum 14:291-318, 1971 24. Mielants H, Veys EM, Cuvelier C, et al: Subclinical involvement of the gut in undifferentiated spondyloarthropathies. Clin Exp Rheumatol7:499-504,1989 25. Zanolli MD, Jayo MJ, Jayo JM, et al: Psoriatic plaques in a Cynomolgus monkey (Mucaca fusciculati). Clin Res 36:86A, 1988 (abstr) 26. Vasey FB, Deitz C, Fenske NA, et al: Possible involvement of group A streptococci in the pathogenesis of psoriatic arthritis. J Rheumatol9:719-722,1982 27. Rahman MU, Ahmed S, Schumacher HR, et al: High levels of antipeptidoglycan antibodies in psoriatic and other seronegative arthritides. J Rheumatol 17:621-625, 1990 28. Wallace MR, Garst return of acute rheumatic 26212557-2561, 1989
PD, Papadimos fever in young
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29. Zeidler H: Undifferentiated arthritis and spondyloarthropathy as a major problem of diagnosis and classification. Stand J Rheumatol65:54-62, 1987 (suppl) 30. Hannu TJ, Leirisalo-Repo M: Clinical picture of reactive Salmonella arthritis. J Rheumatol 15:1668-1671, 1988 31. Mielants H, Veys EM: Clinical and radiographic features of Reiter’s syndrome and inflammatory bowel disease related to arthritis. Curr Opin Rheumatol 2:570576,199O 32. Inman RD, Johnston ME, Hodge M, et al: Postdysenteric reactive arthritis: A clinical and immunogenetic study following an outbreak of salmonellosis. Arthritis Rheum 31:1377-1383, 1988 33. Davis P, Stein M, Latif A, et al: Acute arthritis in Zimbabwean patients: Possible relationship to human immunodeficiency virus infection. J Rheumatol 16:346-348, 1989 34. Reveille JD, Conant MA, Duvic M: Human immunodeficiency virus-associated psoriasis, psoriatic arthritis, and Reiter’s syndrome: A disease continuum? Arthritis Rheum 33:1574-1578, 1990
35. Gladman DD: Psoriatic arthritis. Curr Opin Rheumatol2:577-581,199O 36. Schwartz JH: The Red Ape: Orang-utans and Human Origins. Boston, MA, Houghton Mifflin, 1987, pp l-337 37. Cheevers WP, McGuire TC. The lentiviruses: Maedii Visna, caprine arthritis-encephalitis, and equine infectious anemia. Adv Virus Res 34:189-215,198s 38. Heise ER, Cook DJ, Schepart BS, et al: The major histocompatibility complex of primates. Genetica 73:53-68, 1987 39. Lawlor DA, Ward FE, Ennis PD, et al: HLA-A and B polymorphisms predate the divergence of humans and chimpanzees. Nature 335:268-271.1988 40. Bitar E: Le rhumatisme psoriasique au Liban. Rev Rhum Ma1 Osteoartic 47:317-321,198O 41. Dry11 A, Cazalis P, Seze S: Rheumatisme psoriasique. Nouv Presse Med 4:1408-1412, 1975 42. Fletcher DE, Rowley KA: The radiologic features of rheumatoid arthritis. Br J Radio1 25:282-295,1952 43. Kammer GM, Sofer NA, Gison DJ: Psoriatic arthritis: A clinical, immunologic and HLA study of 100 patients. Semin Arthritis Rheum 9:75-97, 1979 44. Kouse M: Clinical observations on Reiter’s disease with special reference to the venereal and non-venereal aetiology. Acta Derm Vener 58:1-36, 1978 (suppl81) 45. Martio J, Kiviniemei P, von Essen R: Early rheumatoid arthritis in the USSR and in Finland. Stand J Rheumato1 9:39-43, 1980 46. Mall JM: The clinical spectrum of psoriatic arthritis. Clin Orthop 143:66-75, 1979 47. Peterson CC Jr, Silbiger ML: Reiter’s syndrome and psoriatic arthritis: Their roentgen spectra and some interesting similarities. Am J Roentgen01 101:860-871, 1967 48. Scarpa R, Oriente P, Pucine A: Psoriatic arthritis in psoriatic patients. Br J Rheumatol23:246-250,1984 49. Serre H, Simon L, Sony J: Le rhumatisme psoriasique. J Agreges 3:265-274, 1970 50. Weissberg DL, Resnick D, Taylor A, et al: Rheumatoid arthritis and its variants: Analysis of scintiphotographic, radiographic, and clinical examinations. Am J Roentgen01 131:665-673, 1978 51. Weldon WV, Scaletter R: Roentgen changes in Reiter’s syndrome. Am J Roentgen01 86:344-350, 1961
as an Old World Phenomenon
By Bruce M. Rothschild and Robert J. Woods The presence of spine and sacroiliac involvement and the nature and distribution of erosive lesions allowed definitive diagnosis of spondyloarthropathy in the great apes (Gorilla and Pan [chimpanzee]), the lesser ape (Hylobates), and Old World monkeys (Theropithecus, Papio, Cercopithecus, Macaca, Colobus, Presbytis, and Erythrocebus). Analysis of lesional character, distribution, radiological appearance, and sex ratios showed a picture indistinguishable from human spondyloarthropathy. This contrasts with orangutans (Pongo), who lack reactive bone or sacroiliac involvement. A different pathophysiology, as yet undefined, is implied for their erosive arthritis. Limited individual susceptibility to
A
RTHRITIS IS well established as a disease of antiquity in African primates.‘~4 However, the nature of that arthritis has been controversia1.135.6The presence of asymmetrical erosive arthritis with ankylosis in rhesus monkeys (Macaca mulatfu) and baboons (Papio qnocephalus)‘~2~6suggests that spondyloarthropathy might be present. Indeed, Ruffer’ reported “spondylitis” in “sacred monkeys of the ancient temples near Thebes,” and Sokoloff et alx reported similar findings in contemporary Mucaca. The recognition by Ford et al3 of 10 cases of inflammatory arthritis per 2,000 in a Rhesus monkey (Mucaca) breeding colony suggested that this might represent a population phenomenon. Rothschild and Woods9 provided clear documentation that spondyloarthropathy best describes the arthritis found in gorillas. That
From the Arthritis Center of Northeast Ohio, Youngstown, OH; Northeast Ohio Universities College of Medicine, Rootstown, OH; UniversityofAkron, Akron, OH; Carnegie Institute, Pittsburgh, PA; and Ohio State University, Columbus, OH. Supported in part by NIH Division of Diagnostic Resources grant no. RR00919 and National Institute of Arthritis and Musculoskeletal and Skin Disease grant no. AR35736-03. Bruce M. Rothschild, MD: Director, Arthritis Center of Northeast Ohio, Northeast Ohio Universities College of Medicine, and University ofAkron; Robert J. Woods, MA: Ohio State University. Address reprint requests to Bruce M. Rothschild, MD, Arthritis Center of Northeast Ohio, 5701 Market St, Youngstown, OH 44512. Copyright 0 1992 by W.B. Saunders Company 0049-0172192/2105-004$5.00/O
306
spondyloarthropathy in humans (1% to 4%), Old World monkeys (2.4%), and lesser apes (2.4%) contrasts with the high frequency of disease in the great apes (20% to 28%). The wide geographic distribution of this phenomenon suggests an African and perhaps Asian “panendemit.” This natural disease state provides a unique model for in-depth analysis of the contribution of genetic and environmental factors to disease pathophysiology. Copyright o 1992 by W.B. Saunders Company INDEX WORDS: Spondyloarthropathy; keys; apes; animal model of arthritis.
mon-
arthritis, affecting 20% of free-ranging and 12% of captive gorillas, was indistinguishable from a human erosive disease of the spondyloarthropathy variety, psoriatic arthritis. The character, distribution, and frequency of spondyloarthropathy in nonhuman Old World primates was therefore surveyed to define the transgenic distribution of the phenomenon. METHODS
The articular skeletons of adult Old World primates were examined from the following collections: American Museum of Natural History (AMNH) (New York, NY), Caribbean Primate Research Center (CPRC) (University of Puerto Rico, San Juan, PR), Carnegie Museum (CM) (Pittsburgh, PA), Cleveland Museum of Natural History (CMNH) (Cleveland, OH), Field Museum of Natural History (FMNH) (Chicago, IL), Florida State Museum (UF and FSM) (Gainesville, FL), Museum of Comparative Zoology (MCZ) (H arvard University, Cambridge, MA), National Museum of Natural History (NMNH) (Washington, DC), University of Washington (PHY) (Seattle, WA), and Wake Forest University (WFU) (WinstonSalem, NC). The macerated (eg, lye- or papain-treated to remove the soft tissues) primate skeletons were surveyed for visible evidence of articular and periarticular joint and spine pathology. With rare exceptions, the postcranial skeletons examined were completely preserved. Each skeletal
Seminars in Arthritis andRheumatism, Vol21, No 5 (April), 1992: pp 306-316
SPONDYLOARTHROPATHY
IN THE OLD WORLD
307
element of all sampled individuals was carefully observed by both authors, with concurrence as to the observation representing an erosion and ruling out artifacts such as postmortem trauma (eg, drawer damage). For purposes of this study, articular surfaces were treated as missing if artifactual damage precluded demonstration of joint disease. The 1,699 Old World primates examined included 99 gorillas (GoriEla), 79 chimpanzees (Pan troglodytes), 54 orangutans (Porzgo pygmeus), 123 gibbons (Hylobates), 237 baboons (Papio), 12 Gelada baboons (Theropithecus), 94 colobus monkeys (Colobus), 74 leaf monkeys (Presbytis), 18 langurs (Nasalis), 361 guenons (Cercopithecus), 371 macaques (Mucaca), 115 Patas monkeys (Erythrocebus), 33 langurs (Qguh-ix), and 26 mangabeys (Cercocebus). The pathological specimens were subjected to radiological examination in the anatomical position in which they would be viewed during in vivo radiology. RESULTS
Peripheral Joint Disease
Erosive disease was found (Table 1) in 2.4% of all Old World monkeys (4.6% of Papio, 16.7% of Theropithecus, 1.1% of Cercopithecus, 3.9% of Colobus, 5.2% of Elythrocebus, 2.2% of Macaca, 3.1% of Presbytis), 2.4% of the lesser ape (Hylobates), and 19% of great apes (28% of
Pan [chimpanzee], 20% of Gorilla, and 9.3% of Pongo [orangutan]). Erosions were marginal
(bare area) and subchondral in distribution (Figs 1 and 2). As used here, the term marginat denotes that zone of metaphyseal bone within the synovial membrane (Fig 1) but extrinsic to the cartilage-lined bone.lozl’ Marginal areas tend to be “indented” in their location and therefore somewhat protected from postmortem artifactual changes.” Subchondral erosions (Fig 2) affect the bone originally covered with cartilage. Approximately 50% of erosions (except in orangutans) were associated with perierosional smooth, billowy, sclerotic new bone formation. No new bone formation was found in any orangutan. Because a 30% to 50% alteration (loss or accretion) in bone must occur before alterations can be detected in routine radiographs,” most of the gross erosions were not detected on radiological examination. Radiological examination of periarticular bone showed maintenance of normal bone density. Osteopenia was notable by its absence. A sclerotic margin was present in approximately 50% of erosions visible on radiographs in all genera with erosive disease (Fig 3) with the exception of orangutans (which manifest no reaction). Even with a quite mutilating form of arthritis (arthritis mutilans), reactive new bone formation and sclerosis are prominent (Fig 3). Axiul Joint Disease
Table 1. Pathology in Old World Primates
hi Cercocebos Cercopithecus Colobus
Total Examined
Afflicted
Animals
26
70
0
0
-
361
63
4
1
100
94
59
4
4
100
Erythrocebus
115
43
6
5
67
Macaca
371
59
8
2
Nasalis
18
55
0
0
~Presbytis
74
52
2
3
Pygathrix
33
25
0
0
Hylobates
64 50 -
123
58
3
2
50
Gorilla
99
79
19
21
85
Pan
79
30
22
28
60
Pongo
54
65
5
9
40
Syndesmophytes (calcification of the annulus fibrosus) and sacroiliac erosions or fusion were present (Table 2) in 2.1% of Old World primates (1.9% of Papio, 8.3% of Theropithecus, 1.1% of Cercopithecus, 2.6% of Elythrocebus, 1.1% of Mucaca), 3.2% of lesser apes (Hylobates), 0% of orangutans, and 6.7% of the other great apes (5.1% of Pan and 8.0% of Gorilla). Sacroiliac fusion (Fig 4) was noted in 3 Pupio (2 bilateral), 1 Macaca (bilateral), 3 Hyfobates (1 bilateral and 2 unilateral), 5 Gorilla (3 bilateral and 2 unilateral), and 1 Pan (unilateral). Sacroiliac erosions (recognized as multiple, small, crater-shaped holes with smooth, rounded edges) were present in 1 Cercopithecus, 1 Colobus, 1 Presbytis, 3 Papio, 3 Pan, and 2 Gorilla. Anulus fibrosus calcification (syndesmophyte formation) was noted (Fig 5) in 3 Pupio, 1
ROTHSCHILD AND WOODS
polyarticular involvement. “Pencil-in-cup” deformity was noted in a distal interphalangeal joint in one individual. Erosive disease in Theroin one individual pithecus was pauciarticular and polyarticular in a second (Fig 6). Erosive arthritis (Tables 2 and 3; Fig 6) in Erythrocebus was pauciarticular in three individuals and polyarticular in one. Erosive disease was pauciarticular (Tables 2 and 3; Fig 6) in Colubus, Presbytis, Cercopithecus, and Macaca. Erosions of the metacarpal phalangeal and proximal and distal interphalangeal joints of a single finger ray and peripheral joint fusion were noted in Macaca. Apes
Fig 1:
(A) Lateral view of Erythrocebus
carpals shows marginal
meta-
erosions (arrowheads)
Arthritis in the lesser ape, Hylobates, was pauciarticular in distribution (Fig 6). The distribution of erosive arthritis in the great apes Pan (chimpanzee) and Gorillay~‘3is delineated in Tables 2 and 3. Erosive disease was symmetrical in 16 of 22 chimpanzees (73%). Pauciarticular
without reactive new-bone formation. The white arrowhead locates a deep erosion, while the black arrowheads identify more subtle erosions. (B) Oblique and posterior views of Etythrocebus elbow show marginal erosions (arrowheads) with minimal new-bone formation.
Theropithecus, 3 Cercopithecus, 2 Macaca, 4 Hylobates, and 1 Gorilla. Such lesions were
frequently associated with zygoapophyseal joint fusion and occasionally with costovertebral joint or symphysis pubis fusion. Sexual Predisposition No sexual predisposition for spondyloarthropathy (Table 1) was noted in Papio, Presbytis, Hylobates, Macaca, or Gorilla (male-female ratio, approximately 1:l). Males were proportionately overrepresented in Colobus, Cercopithecus, Erythrocebus, and Pan (approximately 3:2) and underrepresented in Pongo (approximately 2:3). Monkeys
Erosive disease in Papio was pauciarticular in four individuals and polyarticular in five (Tables 2 and 3). Five to 10 (average, 7) joints (Table 2; Fig 6) were affected in the five individuals with
Fig 2:
Erythrocebus
erosions (arrowheads)
distal
radius
and ulnar
with reactive new bone
formation (A), especially prominant radii in B (arrowhead). Subchondral
in distal erosions
(arrowhead) are prominent in Erythrocebus knee (C). Erosion with reactive new-bone formation (arrowhead) is apparent at the metatarsal most aspect of the calcaneus) joint (D).
(right-
SPONDYLOARTHROPATHY
309
IN THE OLD WORLD
age, 7.5). Wrist, metacarpophalangeal, ankle, metatarsophalangeal, and shoulder joints were predominantly affected. Sacroiliac disease and syndesmophyte formation were notably absent. DISCUSSION
Old World Primates, Exclusive of Orangutans
Fig 3:
Posterior view of Macaca phalanges (A,
Erosive disease, not limited in distribution to a single joint, was found (Table 1; Fig l-3) in 2.4% of Old World monkeys, 3.2% of the lesser ape Hylobates, and 19% of great apes (28% of chimpanzees, 20% of gorillas, and 9.3% of orangutans). Attribution of a single diagnosis to this phenomenon in all affected Old World primates (except orangutans) is predicated upon a major assumption. (The arthritis in orangutans [discussed in detail below] has a number of characteristics that suggest it is different from that of the other African primates.) Anthropomorphizing from human disease, relatively few erosive disorders that are not predominantly monoarticular occur with any frequency within the population. Rheumatoid arthritis (RA) and
B) shows severe erosive arthritis with new bone formation. (C) Posterior-anterior view of Macaca phalanges
shows severe erosive disease with
sclerotic reaction.
(involving less than 5 joints) erosive disease was found in only four individuals (18%). In those chimpanzees with polyarticular disease, nine joints were typically affected (range, 5 to 14). Wrist, metacarpophalangeal, ankle, metatarsophalangeal, and shoulder joints were predominantly affected. Four chimpanzees had sacroiliac erosions or fusion. Erosive disease was pauciarticular in 40% of gorillas. The joints of the toes and fingers were predominantly affected. Sacroiliac erosions or fusion were present in nine gorillas, and spine involvement was present in three. Erosive disease (Tables 2 and 3) in Pongo (orangutans) was pauciarticular (shoulders) in one individual and polyarticular in four (wrists, ankles, and isolated metacarpophalangeal, proximal interphalangeal, or distal interphalangeal joints). Erosive disease was symmetrical in three of five orangutans (60%). Polyarticular disease in orangutans affected five to nine joints (aver-
Fig 4: Posterolateral joint fusion.
view of Macaca sacroiliac
ROTHSCHILD AND WOODS
Fig 5:
Macaca spine with classic syndesmophytes
Zygoapophyseal
producing fusion through the annulus fibrosus.
joint fusion is also present. (A) lateral x-ray image; (B) lateral view. The arrowhead
A marks zygoapophyseal
in
joint fusion.
spondyloarthropathy are the prime candidates.“.‘+‘5 The nature and distribution of the peripheral erosions in Old World primates (except orangutans) was the same in the presence or absence of spine or sacroiliac (axial joint) involvement (Table 2), again suggesting that all were manifestations of a single disease. The nature and distribution of the lesions and occurrence and frequency of spine and sacroiliac involvement (Figs 4 and 5) allow definitive diagnosis of spondyloarthropathy in Papio, Theropithecus, Cercopithecus, Macaca, Colobus, Elythrocebus, Presbytis, Hylobates, Gorilla, and Pan. The presence of annulus fibrosus calcifica-
tion, sacroiliac fusion, or erosions is diagnostic of spondyloarthropathy,9~‘1~15,‘6 in contrast to the solely ligamentous ossification characteristic of diffuse idiopathic skeletal hyperostosis.““’ Peripheral joint fusion, limited in distribution to Macaca, further supports the diagnosis of spondyloarthropathy, as it does in humans.”
The radiological picture of erosions with sclerotic margins and no periarticular osteopenia (Fig 3) is also characteristic of spondyloarthropathy.%11.15~17.
There was no significant variation in frequency of disease (Table 1) among the Old World monkeys or lesser apes. The high frequency in Theropithecus is not statistically significant (only 12 individuals were available for assessment; x’ = 3.33). Although erosive arthritis and spondyloarthropathy were unrepresented in Nasalis, Pygathrix, and Cercocebus, the small number of specimens available for assessment precludes confident exclusion of the disease in those populations. The frequency of disease in Old World monkeys and lesser apes (40/1,467), however, was significantly less than that noted in gorillas and chimpanzees (P < .OOOl; x”). The special susceptibility of gorillas and chimpanzees remains unexplained at this time.
SPONDYLOARTHROPATHY
311
IN THE OLD WORLD
Table 2: Distribution
of Arthritis in Old World Primates Number of Affected
Genus
Axial Joint
Pauciarticular
Polyarticular
n
%
n
%
n
Joints (Polyarticular)
%
Papio
7
64
4
36
5
45
Theropithecus Colobus
1 1
50 25
1 3
50 75
1 0
50 0
Range
Average
5-10.
7
6' -
6* -
Presbytis
1
50
1
50
0
0
-
Cercopithecus
3
75
2
50
0
0
-
Macaca
2
25
7
88
0
0
-
-
Erythrocebus Hylobates
3 2
50 67
3 3
50 100
1 0
17 0
9 -
9 -
Gorilla
9
47
8
40
10
50
5-13
6
Pan
4
18
4
18
18
82
5-14
9
Pongo
0
0
1
20
4
80
5-9
7.5
*Minimal number; hands and feet missing.
we believe this statistically significant observation has biological importance, artifact related to small sample size is of concern. The frequency of involvement of a given joint (Table 4) in the polyarticular subgroup of great apes (none of the lesser apes had polyarticular erosive disease) was indistinguishable from that of humans (P = .115; Fisher’s Exact Test), while monkeys had more frequent metatarsophalangeal joint involvement (P = .006; Fisher’s Exact Test). Monkeys and great apes with polyarticular disease had similar distributions of joint involvement, except for elbow (P = .048; Fisher’s Exact Test) and metatarsophalangeal
An intriguing approach to analysis of primate spondyloarthropathy is to divide the affected animals into groups with pauciarticular and polyarticular disease. Polyarticular erosive disease in Papio and Theropithecus (two genera of baboons) was significantly more common (P = .005; Fisher’s Exact Test) than that noted in the other Old World monkeys and was indistinguishable in frequency (Table 2) from that noted in the great apes, Gorilla and Pan (P = .26; Fisher’s Exact Test). The data base is small, but subsequent examination of other baboons with spondyloarthropathy has shown a polyarticular pattern of erosive arthritis. While
Table 3: Skeletal Distribution
(%I of Erosive Arthritis in Apes and Monkeys Monkeys
Joint Shoulder
Gorilla
Chimpanzee
Orangutan
Hylobates
Baboon
Nonbaboon
(n = 19)
(n = 22)
(n = 5)
(n = 3)
(n = 13)
(n = 24)
5
23
20
25
36
22
20
18
0
25
55
35
Wrist
50
86
80
75
100
30
MCP
70
95
60
25
40
9
PIP
60
55
60
0
10
9
DIP
15
9
40
0
9
4
Elbow
Hip
0
0
0
0
9
0
Knee
15
0
0
50
36
22
Ankle
40
59
40
0
27
13
MTP
50
50
20
0
9
9
Sacroiliac
40
18
0
50
50
30
Spine
15
0
0
50
27
22
Abbreviations:
MCP, metacarpophalangeal;
PIP, proximal interphalangeal; DIP, distal interphalangeal; MTP, metatarsophalangeal.
312
*I---+ > < > * * I L* TAEROPITHECUS
*
>
Wrist Elbow Shoulder
>*
cc
x
* > > >
x
X
>
4
* * * * >
*
HYLOBATES
> >
*
*
*
*
4
L
4
*
*
*
4
*
>>> <
* * * > > *
>
< *
>
1
4
*
*
pattern of erosive arthritis in monkeys and lesser apes. Arrows indicate affected
side (, right); diamonds indicate bilateral disease; an X indicates a missing joint. Each vertical column represents a single animal.
(P = .049; Fisher’s Exact Test) joints (both more frequent in monkeys, perhaps related to brachiation). The distribution of pauciarticular joint disease in baboons (Papio and Theropithecus), nonbaboon monkeys, Hylobates, gorillas, and chimpanzees (Table 5) was indistinguishable (x2 and Fisher’s Exact Test), with the exception of metacarpophalangeal joints (more common in the great apes [x2 = 11.64; P < .OOl]). Although a trend toward increased frequency of proximal interphalangeal joint involvement was noted gorillas and chimpanzees, it did not achieve statistical significance (x2 = 3.27).
Table 4: Distribution
The frequency of involvement of a given joint in monkeys, Hylobates, and human skeletons (Todd Collection) with pauciarticular spondyloarthropathy’6 was also indistinguishable. However, great apes had significantly greater metacarpophalangeal (21% v 73%) (x2 = 8.23; P < .005) and proximal interphalangeal(l8% v 54%) (x2 = 6.51; P < .015) joint involvement than did humans. Perhaps the increased (statistically significant compared with humans) occurrence of metacarpophalangeal and proximal interphalangeal joint involvement in the great apes can be attributed to the “increased articular insult” associated with “knuckle walking.“”
(%) of Polyarticular
Erosions in Apes and Monkeys Monkeys
Orangutan
Gorilla
(n = 4)
(n = 10)
(n = 5)
25
10
28
60
100
0
27
17
60
100
Wrist
100
64
89
100
100
MCP
60
91
100
80
100
PIP
71
73
50
40
100
DIP
40
50
11
20
0
Hip
0
0
6
20
0
Knee
0
18
6
40
100
Ankle
40
73
72
60
0
MTP
20
73
56
20
0
IP
0
64
17
0
0
Sacroiliac
0
37
11
40
100
Spine
0
20
0
40
0
Joint Shoulder Elbow
Abbreviation:
IP, interphalangeal
joints of feet.
Chimpanzee
Baboon (n = 5)
Nonbaboon (n = 1)
SPONDYLOARTHROPATHY
IN THE OLD WORLD
Table 5: Distribution
313
(%) of Pauciarticular
Erosions (%) in Apes and Monkeys Monkeys
Orangutan Joint
(n=
Chimpanzee
1)
(n = 4)
Baboon
Nonbaboon
Hylobates
(n = 8)
(n = 8)
(n = 15)
(n = 4) 25
0
0
17
27
Elbow
0
25
14
33
47
25
Wrist
0
75
43
83
40
75
Shoulder
100
Gorilla
0
75
57
20
7
25
PIP
100
75
43
0
7
0
DIP
0
0
0
0
7
0
Hip
0
0
0
0
0
0
Knee
0
0
14
17
27
50
Ankle
0
0
0
17
20
0
MTP
0
25
29
0
13
0
IP
0
0
14
0
0
0
Sacroiliac
0
50
14
50
13
50
Spine
0
0
13
17
20
25
MCP
Data from Rothschild and Woods.g.13
Differential Diagnosis
The bone remodeling in Old World monkeys, lesser apes, chimpanzees, and gorillas was much more exuberant than that seen in human rheumatoid arthritis’2’x,19 but quite similar to that noted in human spondyloarthropathy.9913~‘6The rarity of periarticular loss of bony density and the tendency to new bone formation in nonhuman Old World primates (except orangutans) contrasts with the periarticular osteopenia and absence of perierosional bone reaction noted in human RA.12,‘8,19The disease in Old World primates is clearly distinguishable from the symmetrical (but axial joint-sparing [except for the junction of first and second cervical verteTable 6: Skeletal Distribution
brae]) distribution that characterizes RA.‘1*14,19,20 The limited number of joints involved in Old World primates (Table 6) is clearly at variance with the involvement of almost every peripheral diarthrodial joint in RA.‘1,15,‘9 The average of 8.6 joints involved (range, 5 to 14) in Old World primates (except orangutans) with polyarticular erosive disease is significantly at variance with the average of 12 joints involved in humans with RA (P < .OOl;t test). The difference in number of affected joints is artificially narrowed because joint groups (involvement of five or one metacarpophalangeal joints is counted the same) are being compared. Patients with RA often have many joints in a given group affected. Persis-
(%) of Erosive Arthritis in Old World Primates and of Symptomatic
Reiter’s Syndrome, Psoriatic Arthritis, and RA in Homo sapiens Apes Joint
Monkeys
Lesser
Great
Shoulder
25
15
Baboon 36
Homo sapiens Other
Reiter’s
Psoriatic
22
13-21
4-23
29-46 26-66
RA
Elbow
25
16
55
35
10-14
1 o-43
Wrist
75
69
100
30
16-34
44-62
64-92
MCP
25
79
40
9
7-46
34-53
70-72
PIP
0
57
10
9
5-31
II-40
40-70
Hip
0
0
9
0
5-28
Knee
50
6
36
22
67-70
Ankle
0
49
27
13
45-65
28-63
3-54
MTP
0
47
9
9
57
33-34
70-72
50
28
50
30
24-65
52
0
Sacroiliac Data from references
9, 19,23, and 40-51.
O-38 27-72
7-12 24-82
-
314
tence of statistical significance, even with grouping, emphasizes the meaningfulness of this observation. The difference in number of involved joints in RA and in spondyloarthropathy is reproducible in all skeletal populations we have examined. The oligoarticular and polyarticular erosive arthritis observed in Old World primates is distinguishable from the predominantly monoartitular disorders gout and infectious arthritis. Although erosions with sclerotic margins often characterize gout or infectious arthritis,“.‘“‘h.“’ the appendicular skeletal distribution of arthritis and spinal involvement clearly distinguish the arthritis of Old World primates from gout or infectious arthritis. No evidence of overgrowth of periosteum adjacent to erosions (so characteristic of gout or amyloidosis)“~‘4’s~“‘*” was present in Old World primates. Amyloidosis, although a recognized complication of Shigella or tuberculosis infections in primates,22 cannot be invoked as the cause of erosive disease in Old World primates because it rarely produces radiologically detectable erosions.“” No such lesions were found in the Old World primates studied. Variety of Spondyloarthropathy
Although human spondyloarthropathy is divisible into several varieties (psoriatic arthritis, Reiter’s syndrome [reactive arthritis], ankylosing spondylitis, and inflammatory bowel diseaserelated arthritis”,2’.24),the frequently asymmetrical distribution of Old World primate sacroiliac and spine involvement eliminates the latter two as diagnostic considerations. The pattern of disease (Table 6) in Old World primates (except orangutans) was similar to that found in gorillas (indistinguishable from human psoriatic arthritis’). Suggestion of a relationship to psoriasis is not new; skin lesions with the gross visual and histologic appearance of psoriasis have been reported in Macaca.25 These psoriatic lesions were described as “erythematous plaques with adherent white scale, spongiform pustules and Munro microabscesses, clinically and histologically indistinguishable from psoriasis.” However, the dermatopathology of Reiter’s syndrome and psoriatic arthritis are similar,‘4’5.2”and transition from one to the other has been reported’4.‘” for both potentially infectious disorders.2h~2”
ROTHSCHILD AND WOODS
Equal representation
in male and female
Papio, Presbytis, Macaca, Hylobates, and Gorilla
(Table 1) is more common with human psoriatic arthritisy.“.‘” and rarely reported in reactive arthritis.3” (Male predominence [3:2] in the other afflicted genera is not statistically distinguishable from a 1:l ratio). Infectious-agent diarrhea-related Reiter’s syndrome or reactive arthritis”~‘“~“~“~~~ may also be responsible for Old World primate spondyloarthropathy. Although chlamydial infections (associated with human venereally transmitted reactive arthritis) have been found in Papio,33 the presence of spondyloarthropathy in monogamous Hylobate?” makes the venereal variety of Reiter’s syndrome unlikely. Although reactive arthritis is commonly pauciarticular,” one source (Salmonella typhimutium) can produce a polyarticular pattern3’ similar to that noted in Papio, Theropithecus, and Pan. Pauciarticular arthritis, reactive arthritis, and Reiter’s syndrome have also been seen as a complication of the human acquired immunodeficiency syndrome (AIDS),3’.‘4 albeit with a distribution pattern quite different from that noted in nonhuman Old World primates. Although AIDS appears to be a relatively new phenomenon (most of the affected animals were collected in the early part of the century), retroviruses (human immunodeficiency virus is a retrovirus) have been implicated in the ctiology of psoriasis.‘i Orangutans
Although orangutans clearly are susceptible to erosive arthritis, the etiology is less clear. Absence of reactive new-bone formation and axial joint disease are at variance with spondyloarthropathy,‘.‘3,‘h while subchondral localization and maintainence of periarticular bone density contrast with RA.‘” The erosive disease in orangutans actually looks quite different from that of other Old World primates. There is no evidence of reactive new-bone formation, no periarticular osteopenia, and no axial disease. The numbers are small, but the disease looks different. Further supporting that perspective is ongoing work on New World monkeys (Rothschild and Woods, data not presented). Several individuals in one genus had an erosive arthritis resembling the spondyloarthropathy seen in
SPONDYLOARTHROPATHY
315
IN THE OLD WORLD
Old World monkeys. Diagnosis of spondyloarthropathy was confidently made, even without evidence of axial disease. We subsequently examined additional animals of that genus and found axial disease. Because the orangutan is considered an extremely “odd” primate,36 perhaps its arthritis is also unique (eg, analagous to Caprine arthritis, a pauciarticular, minimally erosive, lentivirus-related disease of goats4’).
Table 7: Geographic Distribution Spondyloarthropathy
in Old World Primates
SpondyloPrimates
arthropathy*
Africa
+
207 Papio 12 Theropithecus
+
77 C&bus
+
32 Presbytis
+
Borneo
Arabia +
+ +
+
+
337 Macaca
+
+
+
+
Implications
Asia
+
361 Cercopithecus
59 Erythrocebus
+
+
23 Pygathrix +
9 Cercocebus
As spondyloarthropathy is indigenous (“pandemic”) in nonprosimian primates from both Africa and Asia (Table 7), a non-species-specific etiology is suggested. Limited occurrence (0.1% to 5.2%) in humans, lesser apes, and most monkeys contrasts with the high frequency (16% to 28%) noted in gorillas, chimpanzees, and Theropithius. 9~13 This natural disease state provides a unique model for in-depth analysis of the contribution of genetic and environmental factors to disease pathophysiology. Investigation of genetic immunomodumay allow identification of the lating systems38’39 adaptive physiological parameters that determine disease susceptibility.
of
+
+
123 Hylobates Gorillas
+
+
Chimpanzees
+
+ +
Orangutans ‘Spondyloarfhropathydocumented
as present.
ACKNOWLEDGMENT The authors thank Drs Dana E. Austin, Philip Hershkovitz, Nancy Hong, Lyman Jellema, Bruce Latimer, William R. Maples, Guy Musser, D. Patterson, Dwayne Schlitter, Darren Swindler, Richard Thorington, Jean Turnquist, and David Weaver for their assistance in facilitating examination of the collections they curate and Ruth Green and Christine Rothschild for cogent manuscript review.
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