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The relationship to rheumatoid arthritis of its so-called variants.

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Arthritis and Rheumatism
DECEMBER, 1958
VOL. I, NO. 6
The Relationship to Rheumatoid Arthritis of
Its So-Called Variants
By CURFUER
MCEWEN,MORRISZIFP, PHILIPCARMEL,DOMENICK
DITATA
AND
MARTIN TANNER
The principal manifestations of certain
syndromes presumed to be variants of
rheumatoid arthritis are reviewed and
the results of serologic studies presented.
The entities investigated were ankylosing spondylitis, Still's disease, psodatic arthritis, the arthritis of ulcerative
colitis and Reiter's syndrome. Serologic
observations suggested that Still's syndrome is truly juvenile rheumatoid
arthritis but that the other variants may
be separate diseases.
Es passate in revista le manifestationes
principal de certe syndromes que presumitemente es variantes de arthritis
rheumatoide. Le resultatos de studios
serologic es presentate. Le entitates investigate es spondylitis ankylosante,
morbo de Still, arthritis psoriatic, le
arthritis de colitis ulcerative, e syndrome
de Reiter. Le\ constatationes serologic
suggere que le morbo de Still es de
facto un forma juvenil de arthritis rheumatoide, durante que le altere variantes
es plus probabilemente morbos separate.
I
N THE CLASSIFICATION of rheumatic diseases adopted by the American Rheumatism Association in 1941* ankylosing sponclylitis and Still's
disease are listed as variants of rheumatoid arthritis.' Many physicians in
the United States and England also consider arthritis accompanying psoriasis
and that accompanying ulcerative colitis to be variants of rheumatoid
arthritis; indeed, psoriatic arthritis was so listed in the classification prepared
by a committee" of the New York Rheumatism Association in 1940.* By a
smaller group Reiter's disease is also suspected of being a modified form of
rheumatoid arthritis. In Europe, on the other hand, these types of joint
disease (with the usual exception of Still's disease) are thought by most
rheumatologists to be distinct from rheumatoid arthritis. At the time the
From the Department of Medicine and the Rheumatic Diseases Study Group, New York
University College of Medicine, the Third Medical Division, BeUeoue Hospital Center,
the New York Veterans Administration Hospital, and the Brooklyn Outpatient Clinic and
Medical Diuision, New York Regbnul Ofice, Veterans Administration.
Aided by grants from tlre Nutionul Institute of Arthritis and Metabolic Diseases, U.S.P.H.S.
(A-l431(Cl), 2A-S064(C) 6 (CS) ( A ) , A-679(C3) ), The Arthritis and Rheumatism
Foundation and the New York State Chapter of The Lrtlrritis nnd Rheumatism Foundation.
One of the authors ( M . 2.) is Senior Intwstigatm, Arthritis nnd Rheumatism Foundation.
*The senior author was a member of the committees of Imth the New York Rheumatism
Association and the American Rheumatism Association which drew lip these classifications.
481
482
MCEWEN, ZIFi!',
CARMEL,
DITATA AND TANNER
American Rheumatism Association's committee for the adoption of a classification of arthritis was deliberating, there was considerable doubt in the minds
of some members of the committee that ankylosing spondylitis and arthritis
accompanying psoriasis should be considered variants of rheumatoid arthritis. In the case of psoriatic arthritis these doubts prevailed, and it was
separately listed. In the case of ankylosing spondylitis, however, pathologic
studies had revealed histologic lesions similar to those of characteristic rheumatoid arthritis?~~
and the majority opinion was that it should be considered
merely a special form of the latter.
Now, in the light of advancing knowledge of clinical, pathologic and
other laboratory aspects of rheumatic diseases, it is timely to reconsider the
question of the relationship of these forms of joint disease to rheumatoid
arthritis. This paper is written for that purpose. The various clinical, radiologic
and pathologic similarities and differences will be reviewed briefly, and
particular attention will be devoted to information provided by results of
sheep erythrocyte agglutination tests in the various types of joint diseases
under discussion. In this paper the abbreviation S.E.A. will be used to
designate the hemagglutination test in general.
RESULTS O F
S.E.A. TESTS
Still's Disease
Stillj originally considered the disease of children which subsequently bore
his name to be distinct from childhood and adult rheumatoid arthritis. Today,
however, it is rather generally agreed that Still's disease is merely rheumatoid
arthritis occurring in children. Nevertheless, this opinion has not beell accepted by
and various differences have been pointed out. Among these
may be mentioned the more frequent occurrence of high fever and severe
systemic and visceral manifestations, the occurrence in some patients of a
rather distinctive maculopapular cmiption,n the extremely common involvement of the cervical spine,Rthe frequency of comparative freedom from pain
in spite of marked swelling, the great rarity of subcutaneous nodules and
the differences in character of such nodules when they do occur.lo On the
whole, however, the clinical features of Still's disease are similar to those
of adult rheumatoid arthritis, and the gross and histologic changes in the
joints are essentially the ~arne.~Jl'~:'
In the present study the sheep erythrocyte agglutination test was done
with serum from 31 patients with Still's disease. The method used for these
tests (and for those to be reported throughout this paper) was that of ZifE,l4
using the euglobulin fraction of the test sera for both direct agglutination
and the more sensitive inhibition technic. Twenty-four of the patients were
under the age of sixteen years, and seven were adults past the age of
twenty-five. In all, the arthritis had begun before the age of twelve years.
The results of the tests on these patients are shown in table 1.
It is seen that 58 per cent of the children gave positive tests by direct
agglutination and that all but one (95.8 per cent) were positive by the more
sensitive inhibition technic. Of the seven adults, four were positive by agglu-
483
RHEUMATOID ARTHRITIS AND ITS SO-CALLED VARIANTS
TABLEl.-Results
of Sheep Erythrocyte Agglutinution and Inhibition Tests in
Juvenile Rheumatoid Arthritis
Negative
Age group
Children
Adultst
Total
Number of
Patients
24
7
31
Agglutination
Positive
Number
Number
Per cent
10
14
4
58
3
13
18
57
58
Negative
Number
lo
1#
2
Inhibition
Positive
Number
Per cent
23
6
29
95.8
80.
93.5
OTiter in this patient, sick less than one year and tested only once, was 7 by agglutination
and 14 by inhibition; a somewhat equivocal result.
t Disease started in childhood but test performed after patients had reached adulthood.
Atypical history in this patient.
tination and six by inhibition. Considering children and adults together, more
than half were positive by agglutination and 93.5 per cent by inhibition, It
should be noted also that the adult who was negative by the inhibition
technic had originally had an attack of rheumatic fever with polyarthritiq,
carditis and chorea at the age of eight. Several years later, however, the
joint disease returned and this time gradually assumed a character which
lead to the diagnosis of Still’s disease. The S.E.A. test was first performed
when she was 26 years old, by which time her arthritis was chronic though
mild. The one child recorded as negative in table 1 had been ill less than a
year, and the single test performed gave a borderline negative result.
Ankylosing Spondylitis
The view that ankylosing spondylitis is rheumatoid arthritis involving the
sacroiliac joints and spine, which is so widely held in the United States, is
based chiefly on the relatively common occurrence of peripheral joint involvement like that of rheumatoid arthritis in many spondylitic patients,11J5-18
and on early reports of pathologic similarities in the two types of joint
disea~e.3>*J1J0-1~
More recently, however, pathologic studies of bone and
joint tissues obtained by biopsy at various stages in the development of
ankylosing spondylitis have shown features which were considered distinct
from those of rheumatoid arthritis.20-24In spite of the official acceptance of
the term rheumatoid spondylitis by the American Rheumatism Association,
there are many rheumatologists in the United States who doubt that the
Marie-Striimpell type of ankylosing spondylitis is a variant of rheumatoid
arthritis, and, as has been already noted, this doubt is very commonly held
in Europe. In general there are three points of view regarding the relationship: first, that ankylosing spondylitis is a variant of rheumatoid art h r i t i ~ , ~ ~ l l . 1 6 - 1 8 , 2 6 - second,
86
that they are distinct disease
and third, that “true” ankylosing spondylitis involving only sacroiliac joints
and spine, with or without involvement of hips and shoulders, is a distinct
disease, but that when more peripheral joints are affected the disease is
rheumatoid arthritis with involvement of the spine.
Favoring the view that ankylosing spondylitis is distinct from rheumatoid
arthritis is the sharp difference in the frequency with which me ! and
484
MC EWEN, ZIFF, CARMEL, DI TATA A N D TANNER
TABLE2.--Results
of Sheep Erythrocyte Agglutination and lnhibition Tesfs
in Ankylosing Spondylitis
T y p e of case
Number of
Pntients
Without peripheral
joint involvement
With peripheral
joint involvement
Atypical
Total
Negative
Agglutination
Positive
Per cent
Number
Number
92
91
1
1.1
18
10'
18
10
119
0
0
1
0
0.8
120
0
Negative
Number
Inhibition
Positive
Number
Per cent
91
1
1.1
18
10
119
0
0
1
0
0
0.8
'Seven of these patients had ulcerative colitis.
women are affected by the two diseases; for ankylosing spondylitis affects
approximately nine men for every woman, whereas rheumatoid arthritis
occurs two or three times as often ill women as in men. Other important
differences are the lack of subcutaneous nodules in ankylosing spondylitis,
and the relative rarity with which classic rheumatoid arthritis affects sarroiliac joints and any part of the spine except that of the cervical region.
Furthermore, even when involvement of other parts of the spine occurs in
patients with rheumatoid arthritis, the sacroiliacs usually are unaffected, and
there rarely is restriction of chest expansion."g A fourth significant difference
is the commonly observed tendency for the hip joint in ankylosing spondylitis
to become rapidly immobile again due to soft-tissue contracture following
arthroplasty, in contrast to the sustained mobility after such operations in
rheumatoid arthritis. Other distinguishing features which are somewhat less
convincing but which are frequently cited are the differences in response to
therapy. Chrysotherapy, for example, is rather generally considered to be of
little if any value in ankylosing spondylitis, in contrast to its reported usefulness in rheumatoid arthritis. Conversely, x-ray therapy and phenylbutazone
are widely regarded as helpful in ankylosing spondylitis, yet of no, or cornparatively little, value in rheumatoid arthritis.
We have applied the sheep erythrocyte agglutination test in the study of
120 patients with ankylosing spondylitis, with the results shown in table 2.
In 92 of these patients involvement was limited to the sacroiliac joints and
spine with or without involvement of the shoulders or hips. In 18 there was,
in addition, involvement of more peripheral joints. Ten patients were considered to have atypical spondylitis using the criteria of Sharp.53 As the
table shows, only one patient gave a positive test, and this was a man with
characteristic ankylosing spondylitis without involvement of peripheral joints.
Psoriatic Arthritis
Opinions with regard to the relationship between rheumatoid arthritis and
arthritis accompanying psoriasis are, as in the case of ankylosing spondylitis,
of three general types. According to one view arthritis with psoriasis is a
special form of joint disease which is distinct from rheumatoid arthriti~.'~*"-~~
At the other extreme is the concept that, barring some patients with degenerative joint disease or other obviously coincidental arthritis, all such cases are
examples of rheumatoid arthritis occurring in patients with
RHEUMATOID ARTHRITIS AND ITS SO-CALLED VARIANTS
TABLE3.-Results
T y p e of diaeane
of
485
Sheep Erythroqte Agglutination und lnhibition Tests in
Arthritis Accompanying Psorhis
Number of
Patients
Negative
Number
Agglutination
Positive
Number
Per cent
Negative
Number
Inhibition
Positive
Number
Per cent
With involvement of
distal inter51
50
lo
2
51
lo
2
phalangeals
Without involvement
of distal interphalangeals
25
25
0
0
25
0
0
76
75
1
1.3
76
1
1.3
Total
'This is the same patient whose titer on a single occasion was 14 by agglutination and
7 by inhibition, an equivocal result.
In view of the fact that joint disease occurs in patients with psoriasis too
frequently to be explained by coincidence," this view carries with it the
belief that psoriasis and rheumatoid arthritis, for some reason, tend to occur
together. Thirdly, there is the compromise opinion that, whereas most cases
are indeed examples of rheumatoid arthritis in patients who also have
psoriasis, there is a separate entity with very definite features, which should
be considered psoriatic arthritis or a r t h r ~ p a t h y . Among
~ ~ - ~ ~ the special features described as characteristic of the latter type of joint disease are:
involvement of the distal interphalangeal joints of fingers and toes (which
are rarely the site of rheumatoid arthritis), psoriasis of the nails, asymmetiic
rather than symmetric involvement of joints, the peculiar type of bone
destruction, the tendency for the arthritis and the skin lesions to flare and
subside together, the greater frequency in men than in women, the comparatively poor response to corticosteroid therapy, the relative lack of osteoporosis
and of muscular atrophy in many patients, the absence of subcutaneous
nodules, and certain pathologic differences in the joint lesions, notably the
lack of pannus and, in late stages, fibrous replacement of normal joint structures with only mild inflammatory rea~tion.'*"~*~~*~
The authors have had the opportunity to perform sheep erythrocyte agglutination and inhibition tests on sera from 76 patients with psoriasis and
arthritis (table 3). In 51 of these patients there was "characteristic" involvement of the distal interphalangeal joints of the fingers and often of the toes,
with psoriatic changes in the nails. Approximately half of these patients also
had involvement of other joints as well. The remaining 25 patients had
arthritis in various joints without involvement of the distal interphalangeals.
As is shown in table 3, only one of these patients gave a positive S.E.A. test,
and the result in this instance was equivocal. This patient had characteristic
involvement of the distal interphalangeal joints. None of the patients without
distal interphalangeal involvement was positive.
Arthritis Accompanying Ulceratioe Colitis
Although it has been reportedRgthat arthritis is the most common complication of ulcerative colitis outside the intestinal tract, comparatively little
has been written about it. HenchRSfound 60 instances of arthritis among
486
M C EWEN, ZIFF, CARMEL, DI TATA AND TANNER
TABLE&--Results of Sheep Erythrocyte Agglutination and Znhibition Tests in
Arthritis Accompanying Ukeratit;e Cok%
Type of disease
Peripheral joint
involvement
Spondylitis
Total
Number of
Patients
15
7
22
Negative
Agglutination
Positive
Inhibition
Positive
Number
Per cent
Number
Number
Per cent
Negative
Number
15
0
0
0
15
0
0
7
7
22
0
0
0
0
0
0
0
22
1,500 patients with ulcerative colitis, a frequency of 4 per cent. In other
series, figures up to 20 per cent have been reported, but most authors place
The opinion of Short,
the frequency at from 4 per cent to 7 per cent.Do-loU
Bauer and Reynolds” that this form of joint disease is probably merely
rheumatoid arthritis occurring in patients with ulcerative colitis is rather
generally held. Hench!””and Ansell and Bywaters:’
on the other hand, have
cited evidence supporting their view that this type of arthritis is distinct and
a manifestation of ulcerative colitis. The liistologic lesions in synovial biopsies
are similar to those of rheumatoid arthritis,llft’Ubut clinically the close temporal relationship between attacks of colitis and of arthritis, and the improvement in arthritis following colectomy suggest an etiologic relationship
between the articular and intestinal lesions.
In the present series 22 patients with ulcerative colitis and arthritis have
been studied. In 15 the joints involved have been peripheral ones, and there
has been close parallelism between episodes of colitis and arthritis. Seven
patients, however, had quite characteristic ankylosing spondylitis. In six of
these, colitis preceded arthritis by brief periods but in the other, a young
woman, spondylitis had preceded the colitis by six years. As is shown in table
4, the S.E.A. tests were negative in all of these patients by both agglutination
and inhibition methods.
Reiter’s Disease
During recent years there has been an increasing interest in the form of
arthritis associated with “nonspecific urethritis” and conjunctivitis, to which
attention was drawn by Fiessinger and Leroyl”l and by Reiter1(J2in 1916 and
first reported in the American literature by Bauer and Engleman in 1942.1°”
While this “triad has been emphasized, many patients also have diarrhea
as an early symptom, and others present keratodermia blennorrhagica,
balanitis or other lesions. It would be inappropriate for the purposes of this
paper to discuss the various theories as to the nature of the disease, its relationship to dysenteric arthritis, or the validity of including under the heading
of Reiter’s disease the relatively large number of cases in which either urethritis or conjunctivitis may be lacking.l0’112 On the other hand, it is appropriate
to note that these cases are sometimes considered to be examples of rheumatoid arthritis. As was remarked at the start of this paper, fully developed
Reiter’s disease is not held by many to be related to rheumatoid arthritis.l12
On the other hand, since the reference by Hench and Boland1I3 to cases of
rheumatoid arthritis precipitated by acute genital gonorrhea ( “postgonor-
487
RHEUMATOID ARTHRITIS AND ITS SO-CALLED VARIANTS
rhea1 rheumatoid arthritis”) some examples of ‘Xeiter’s disease” undoubtedlv
are so diagnosed, especially when conjunctivitis is absent or goes unnoticed.
For this reason patients with arthritis similar to that of Reiter’s disease following urethritis but without conjunctivitis were included in the series on
whom sheep erythrocyte agglutination tests were done.
Data on 41 patients are shown in table 5, of whom 21 presented the full
picture of Reiter’s disease with or without diarrhea or keratodermia blennorrhagica, and 20 had wholly comparable arthritis following diarrhea or nongonococcal urethritis but lacked conjunctivitis and keratodermia. It will be
seen that a positive S.E.A. test was obtained in only one patient, a man with
the full picture of Reiter’s disease including keratodermia blennorrhagica.
Summary of Restrlts of Sheep Erythrocyte Agglutination Tests
Before summarizing the results of sheep erythrocyte agglutination tests in
the various forms of arthritis discussed thus far, it will be useful to present
our experience with this test in patients with rheumatoid arthritis and in
controls. The data are shown in table 6. All patients with rheumatoid arthritis in this table had classic involvement of peripheral joints with or without involvement of the cervical spine but with no clinical or radiographic
evidence of spondylitis elsewhere nor of sacroiliac damage. The controls
included a large number of apparently normal people of various ages, as well
as patients with degenerative joint diseases, gout, rheumatic fever and miscellaneous nonrheumatic diseases.
TABLE
5.-Results
of
Number of
Patients
Manifestations
Urethritis and
arthritis
Above two pliis
eye involvement
Above three plus
keratodcrma
blennorrhagica
Total
Sheep Erythrocyte Agglutiriation and Inhibition Tests
in Reiter’s Disease
Nemtive
Agglutination
Positive
Inhibition
Positive
Number
Per cent
Number
Number
Per cent
Negative
Number
209
20
0
0
20
0
0
16
16
0
0
16
0
0
5
41
4
40
1
1
-
4
1
-
40
1
2.4
2.4
OOne of these patients had severe diarrhea and no urethritis.
TABLE0.-Results of Sheep Eqthrocyte Agglutination and Inhfbition Tests in
Rheumatoid Arthritis and Controls
Groups tested
~~
~
Rheumatoidarthritis
Controls
Whole Serum
Agglutination
Number of
Patients
% Positive
-
Euglobulin Fraction
Agglutination
Inhibition
Niimter of
Number of
Patients
Yo Positive
Patients
Positive
~~
103
104
78
13
144
342
88
2
140
321
96.4
3.7
‘Osteoarthritis, gout, rheumatic fever, miscellaneous nonrheumatic diseases and normal
individuals.
388
MC EWEN, ZIFP, CARMEL, DI TATA AND TANNER
TABLE7.--Resultu
of
Sheep Erythrocyte Agglutination Inhibition Tests
Various Arthritides and Crintrnls
Disease
Rheumatoid arthritis
Juvenile rheumatoid arthritis
(children only)
Ankylosing spondylitis
Psoriatic arthritis
Arthritis accompanying
ulcerative colitis
Reiter's disease
Systemic lupus erythematosus
Controls'
iti
Number of
Patients
Number
Positive
Per cent
Positive
140
135
96.4
24
23
1
1
95.8
0
1
0.0
2.4
28.0
3.7
119
76
22
41
18
32 1
5
12
0.8
1.3
'Osteoarthritis, gout, rheumatic fever, miscellaneous nonrheumatic diseases and normal
individuals.
Whole serum was used for agglutination tests in 103 rheumatoid arthritic
patients and 104 controls. The euglobulin fraction was tested by the agglutination method14 in 144 rheumatoid arthritic patients and in 342 controls,
and by the inhibition methodI4 in 140 rheumatoid arthritic patients and in
321 controls. It will be seen in table 6 that the positive results increased
progressively from 78 per cent using whole serum to 88 per cent using the
euglubulin fraction for agglutination, and to 96 per cent using the euglobulin
fraction for testing by the inhibition technic. Conversely, the number of
what were taken to be false positive results in the control patients decreased
appreciably from 13 per cent to 2 per cent when the euglobulin fraction was
used instead of whole serum for agglutination, and rose merely to 3.7 per
cent when the very highly sensitive inhibition technic was employed.
The results shown in tables 1 to 6 are summarized in table 7. Here only
the results obtained by the inhibition technic using the euglobulin fraction
of the serum are shown, since this method was the most discriminatory. The
sharp difference between the results in patients with classic rheumatoid arthritis and Still's disease on the one hand and those with ankylosing spondylitis, arthritis accompanying psoriasis, arthritis accompanying ulcerative colitis,
and Reiter's disease on the other hand, is striking. Table 7 also includes
results obtained in 18 patients with systemic lupus erythematosus. It is not
the purpose of this paper to discuss this disease and, furthermore, the number
of cases is not large; nevertheless, they are included in the table for comparison because this is the only group of patients in our series to date, save
for those with straightforward adult rheumatoid arthritis and Still's disease,
with a higher percentage of positive agglutination and inhibition tests than
the controls.
DISCUSSION
It was mentioned at the beginning of this paper that one of the important
reasons for listing ankylosing spondylitis as a variant of rheumatoid arthritis
in the classification adopted by the American Rheumatism Association in
1941 was the pathologic similarity reported by a number of observers3~4~11,1"-'B
RHEUMATOID ARTHRITIS AND ITS SO-CALLED VARIANTS
489
between the lesions in the latter disease and those in peripiheral and apophyseal joints of patients with spondylitis. More recently, however, a number of pathologic studies of ankylosing spondylitis have concluded that the
gross and histologic characteristics are difierent from those of rheumatoid
a r t h i t i s , 2 u 14 In any case, most pathologists who have made a special study
of arthritis now emphasize the frequent inconclusiveness of histologic criteria
in attempting to distinguish among various types of joint diseases."Ld.114-11T
Thus, this argument for considering the diseases the same no longer has the
weight it once did.
Turning to a consideration of the clinical and radiologic features, one finds
the differences between classic rheumatoid arthritis and the Marie-Striimpell
type of ankylosing spondylitis to be striking. Indeed the only clinical reason
for considering them the same would appear to be the peripheral joint involvement which occurs in some patients with ankylosing spondylitis. It is
in this connection that the results of the sheep erythrocyte agglutin,'i t'ion
tests are of particular interest, because they were negative in 119 of 120
patients with ankylosing spondylitis irrespective of the presence or absence
of peripheral joint involvement.
The situation with regard to the arthritis which accompanies psoriasis is
similar. Both pathologically and clinically there is now strong evidence that
at least those cases with characteristic involvement limited to distal interphalangeal joints represent a disease which is distinct from rheumatoid
arthritis. As in the case of ankylosing spondylitis, the principal reason for
considering this form of joint disease merely rheumatoid arthritis occurring
in patients who also have psoriasis is the large number of cases in which
involvement of some or all joints does closely resemble that of rheumatoid
arthritis. Here again the results of the S.E.A. tests are of particular interest,
because, with a single exception, they were consistently negative in the 76
patients studied, irrespective of the presence or absence of distal interphalangeal joint involvement.
Philosophic consideration of the problem posed by patients with psoriasis
and arthritis is consistent with these S.E.A. results. As has been pointed out
by Short, Bauer and Reynolds, I the relationship between psoriasis and
arthritis cannot be merely one of coincidence. Furthermore, there is an
increasing agreement with the point of view of Hench,h:' Bauer, Bennett
and ZellerH" and others, that the cases with distinctive involvement limited
to distal interphalangeal joints do differ from rheumatoid arthritis. If, then,
one accepts the existence of a separate arthritic entity in some patients with
psoriasis, it does not appear logical to conclude that, nevertheless, the majority of cases of arthritis occurring in psoriatics represents merely an unexplained tendency for psoriasis and rheumatoid arthritis to occur in the
same patients. Rather, it would be more probable that rheumatoid arthritis
and psoriasis would occur in the same patient no more often than would be
expected on the h x i s of chance.
The number of p,itieiits with arthritis ilccoI1~p:ln~i1lgulcerative colitis
reported here is rather small. Nevertheless, the consistently negative results
warrant the suggestion that this type of joint disease, too, is distinct from
490
MCEWEN, ZIFF, CARMEL, DITATA AND TANNEA
rheumatoid arthritis. Certainly this interesting form of arthritis has received
much less attention than it deserves; further studies in a larger series of
patients are in progress.
The questions raised by Reiter’s disease are different, for the most part,
from those discussed in relation to the other arthritides which are the subject
of this paper because there is no large body of opinion linking it with rheumatoid arthritis. Of special interest are patients with indolent arthritis: clinically similar to that of typical Reiter’s disease (and consistent also with that
of rheumatoid arthritis ) which follows urethritis, but which is not associated
with conjunctivitis or keratodermia blennorrhagica and not responsive to
antibiotic therapy even though gonococci may have been cclltured from the
urethral exudate. The data presented indicate that the great majority of
patients of this type do not give a positive sheep erythrocyte agglutination
test even when done by the inhibition method. It is suggested that in this
type of case the diagnosis of atypical Reiter’s disease be considered before
one of “postgonorrheal rheumatoid arthritis” is made.
The results of the S.E.A. tests in the patients with Still’s diseuse in this
series are, of course, completely in keeping with the almost universally accepted view that this form of joint disease is rheumatoid arthritis occurring
in children. The term “Still’s disease” was used throughout this pitper merely
so as not to “beg the question” before the data were given. The evidence
from all sources is overwhelming that the disease is truly juvenile rheumatoid
arthritis, and the latter is the preferred term.
Comment must be made on differences between results of S.E.A. tests
repcrted here and those obtained by some other investigators. Other writers
have reported positive results in from 0 to 61 per cent of children with
juvenile rheumatoid arthritis,55J1*.122
ccmpared with the 96 per cent presented
here. it will be noted, however (table l ) ,that the latter result was obtained
using the highly sensitive inhibition test and the euglobulin fraction of serum,
and with sensitized sheep erythrocytes as the agglutinable particle. Ccnversely, although most workers have obtained negative results in patients
with ankylosing spondylitis and arthritis accompanying psoriasis comparable
to the results in the present series, a few have reported positive tests in up to
Again it must be pointed out that
more than 50 per cent of cases.55J1H-122
different technics have been employed and that in the authors’ hands the
use of the euglobulin fraction rather than whole serum for the test with
sensitized sheep erythrocytes has been found to eliminate a considerable
niimber of false positive results (table 6 ) .
It must be emphasized that it would be untenable to make decisions regarding the interrelationships of these various joint diseases solely on the
basis of a laboratory test, the full significance of which is not known. In the
opinion of the ;iuthors, however, the results cf the sheep erythrocyte agslutination tests which havc: lwcn reported in this paper do have considerable
weight when considered in relation to the available clinical, patholcgic and
mcliologic evidence. One might reasonably question also the wisdom of attempting to separate these arthritides from rheumatoid arthritis since the
latter is itself a somewhat ill-defined concept which has gradually emerged
RHEUMATOID ARTHRITIS A N D ITS SO-CALLED VARIANTS
491
over more than a century of slowly sharpening clinical and pathologic understanding. The definition of rheumatoid arthritis is largely a clinical one, and
probably must remain so until its cause and pathogenesis are known, or
until a diagnostic test is developed which can be universally accepted as
valid. Whether some technic based on the mechanism underlying the sheep
erythrocyte agglutination test may prove to be usable in this way it is too
early to predict. Meanwhile most physicians will agree that even on purely
clinical grounds the concept of rheumatoid arthritis is sufficiently definite to
establish it as an entity. In the opinion of the authors, that concept can and
should be still further sharpened by separating from it ankylosing spondylitis,
arthritis accompanying psoriasis and ulcerative colitis, and Reiter’s disease.
Finally, it is of interest to point out that at just the time when confusion
regarding the relationship of rheumatoid arthritis to its so-called variants
appears to be approaching clarification, new confusion has emerged regarding its relationship to systemic lupus erythematosus, polyarteritis nodosa
and others of the “collagen diseases.”123
SUMMARY
AND CONCLUSIONS
In this paper a number of joint diseases which have been thought to be
special forms or variants of rheumatoid arthritis have been discussed, and
the clinical, pathologic and radiologic features which support such a relationship and those which raise doubts have been briefly reviewed. Particular
attention has been devoted to results of sheep erythrocyte agglutination tests
done by the inhibition technic on the euglobulin fraction of sera to be tested.
On the basis of these data it is concluded that Still’s disease is truly
juvenile rheumatoid arthritis, but that ankylosing spondylitis, Reiter’s disease,
arthritis accompanying psoriasis, and arthritis accompanying ulcerative colitis
are distinct from rheumatoid arthritis.
ACKNOWLEDGhlENTS
The authors acknowledge with thanks the help given by the following physicians who
contributed sera and data for some of the patients with psoriatic arthritis, ulcerative colitis
and juvenile rheumatoid arthritis: Dr. Barbara Ansell, British Postgraduate Medical School,
London; Dr. Alfred J. Bollet, Wayne University College of Medicine, Detroit; Drs. Joseph
L. Hollander and Ralph A. Jessar, University of Pennsylvania College of Medicine, Philadelphia; Dr. Ann Kuttner, Department of Pediatrics, New York University College of
Medicine, New York; Dr. Frank Schmid, Northwestern University College of Medicine,
Chicago; Dr. John W. Sigler, Henry Ford Hospital, Detroit.
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Currier McEwen, M.D., D.Sc. (Hon.), Associate Professor of
Medicine and Chairman, Rheumatic Diseases Study Group,
New York University College of Medicine, New York, N. Y .
Morris Zifl, M.D., Ph.D., Professor of Medicine, Department
of Internal Medicine, University of Texas Southwestern
Medical School, Dallas, Tex.
Philip D. Carmel, M . D., Attending Rheamatologist, Lutheran
Medical Center, Brooklyn; Attending Physician, Veterans’
Out-Patient Depnrtment, Veterans’ Hospital, New York;
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Brooklyn, N. Y .
Domenick DiTata, M.D., Chief, Arthritis Clinic, Medical
Division, New York Regional Office, Veterans Administration,
New York, N . Y.
Martin Tanner, Senior Research Assistant, Department of
Medicine, New York University College of Medicine, New
York, N. Y.
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