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Rheumatoid arthritisAn infection.

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Rheumatoid Arthritis-An Infection ?
NFECTiON was one of the first theories on the cause of rheumatoid arthritis, but other possible etiologies have gained greater prominence in
the past two decades. A reappraisal of the infective hypothesis at this time
seems appropriate, however, and initially should emphasize a distinction
between an infectious disease and a disease of microbiological causation.
The use of the word “infectious” implies ready communication from one
individual to another and this is clearly not the case in rheumatoid arthritis.
However, a number of diseases are not infectious in the usual sense of the
word but are of microbiological causation and this is particularly so when
host resistance or genetic predisposition are cofactors, as in several neoplasias of mice, cytomegalic inclusion disease, subacute bacterial endocarditis
and actinomycosis. in an increasing number of microbiological infections,
“latency” of the responsible agent is assuming increasing importance and,
as yet, is ill-underst0od.l
Classical rheumatoid arthritis has currently yielded few clues to its causation though a recent assessment of population surveys by Lawrence2 suggested that three etiologic factors were present in patients with rheumatoid
arthritis, one of which was entirely environmental. It was thought that
rheumatoid arthritis might be a sequel to benign polyarthritis in genetically
susceptible individuals and the seasonal incidence of benign polyarthritis
suggested respiratory infection as a factor.
In subacute polyarthritis unassociated with rheumatoid factor, rheumatoid
nodules, or the typical symmetrical deformities of rheumatoid arthritis, the
clinical manifestations may mimic the so-called incomplete Reiter’s syndrome.
In the extensive experience of both Harkness3 and Csonka: comprising 103
and 185 cases respectively, ocular manifestations were absent in over 50
per cent of individuals in whom genital infection was complicated by arthritis. The majority of these patients, therefore, did not have ocular complaints to indicate the correct diagnosis. If the patient is reticent about his
genito-urinary tract symptoms, or, if these symptoms are overlooked because they antedated the arthritis or are minimal, the patient may be diagnosed as a case of “probable rheumatoid arthritis.” In the experience of the
writer, individuals with such a diagnosis are quite often found to have
had a recent genito-urinary infection which suggests an infective etiology to
their arthritis.
In considering ankylosing spondylitis, there is strong evidence to support
the contention that an infective origin is contributory in a proportion of
cases. Romanus,6 in Sweden, studied 117 patients with spondylitis and conFrom. the Depa&mmt of M ~ d i c i w Vancower
General Hospital, and the Univezsity of
British Columbia, Vancouusr, Canada
~ E V M A T I S M VOL.
No. 2 (APRIL), 1963
cluded that prostato-vesiculitis was an etiologic factor. An English followup study of 20 patients,6 who had previously had urethritis complicated by
arthritis, revealed that four subsequently developed spondylitis. Elsewhere
in England an analysis of cases with “atypical spondylitis” showed that 20
were attributable to the sequellae of the urethritis-arthritis syndrome.7 The
relationship of genital infection to spondylitis was further investigated by
applying defined, though partially subjective, criteria for the diagnosis of
chronic prostatitis.s A high incidence of chronic prostatitis (83 per cent)
was found in 54 patients with spondylitis in contrast to an incidence of
33 per cent in 86 cases of rheumatoid arthritis. The subject was fully discussed in an editorial in the British Medical Journal in 19609 and the following opinion was expressed: “Such findings as these go far to prove that
the relationship between chronic urogenital infection and ankylosing spondylitis is a true one, but they cannot be taken to have established an
etiological connection.” The importance of discovering the cause of nongonococcal urethritis was stressed and a plea made for increased research
in this field.
Juvenile rheumatoid arthritis m a y present in early life as a generalized
systemic disease with a septic fewr and no joint symptoms. The clinical
state resembles closely a severe infection, and the occasionaI onset of the
disease within the first few weeks of life is suggestive of an infective origin.1°
Agammaglobulinemic subjects, in whom immediate hypersensitivity is absent and delayed hypersensitivity is depressed to a variable degree, have a
remarkably high incidence of rheumatoid arthritis and connective tissue diseases. This well-established observation conforms to the hypothesis of an
infective origin of these diseases more readily than to other etiologic
The rheumatoid factor has sometimes been regarded as evidence for the
immunologic causation of rheumatoid arthritis. However, rheumatoid factorlike substances have resulted from immunization of rabbits with Escherichin
coli,12 and rats with streptococci.13Recently, 50 per cent of patients with subacute bacterial endocarditis were found to have rheumatoid factor-like substances in their serum.14 Moreover, rheumatoid factor-like substances have been
demonstrated in the sera of patients with syphilis,16 leprosy,16 tuberculosis,17
rubella,18 infective hepatitislDand other viral diseases.*OI2lPopulation studies
have shown that more patients have rheumatoid factor without arthritis
than rheumatoid factor with arthritis;22 thus the most common cause of
rheumatoid factor is not rheumatoid arthritis. The suggestion that rheumatoid factor is a by-product of certain types of antigenic stimulation, particularly long-continued stimulation, would seem to be the most reasonable
hypothesis.23 The fluorescent experiments of Me110rs~~
seem merely to show
that these by-products are manufactured in the vicinity of the rheumatoid
lesions; they do not necessarily have any etiologic significance. Furthermore, the abnormal globulins causing cold agglutination in Eaton agent
pneumonia show that an infective agent can cause unusual immune by-products. Vaughan and
in a recent discussion of the biological significance
of the rheumatoid factor, stressed the possible role of microorganisms in
its production.
Although recent investigations on the pathogenesis of human connective
tissue diseases have stressed abnormal immune responses as probably of
etiologic significance, these manifestations of hypersensitivity or autoimmunity may represent secondary events to primary infections. Thus autoimmune phenomena are demonstrable as a sequel to infective hepatitis26 and
pulmonary tubercul~sis.~~
The observation that lupus erythematosus, a disease characterized by varied autoimmune phenomena, can be induced by
hydralazine and hydantoin derivatives2s and remit when these drugs are
withdrawn would seem to suggest the importance of inciting agents and to
infer that the autoimmune reactions may be of secondary nature. In considering the pathogenesis of the lesions of immediate hypersensitivity, the
inflammatory properties of antigen-antibody complexes have been stressed.29
However, the naturally occurring human disease in which this pathogenetic
mechanism probably operates is acute glomerulonephritis and, etiologically,
there is general agreement that the 8-hemolytic streptococcus is the primary
cause of this disease, so that the immune complexes are presumably secondary
to the initiating streptococcal infection. The pathogenesis of the lesions of
delayed hypersensitivity is not understood but, amongst the other speculaX” hypothesis. Should this
tions, Lawrence30 has suggested the “self
theory prove a satisfactory explanation for the manifestations of delayed
hypersensitivity, the nature of “X” becomes of prime importance. Lawrence
noted the predilection of intracellular parasites for the production of deX” immune reaction operates in
layed sensitivity and thus, if the “self
the connective tissue diseases, either a virus or a PPLO present possible
candidates for “X.”
No infective agent has been demonstrated in cases of rheumatoid arthritis
and t h i s fact has been used to argue against the infectious agent hypothesis.
The exceptional difficulties of isolating some well-known infectious agents
should, however, caution against such a viewpoint. The viruses of infective
hepatitis, the common cold, rubella, and infectious mononucleosis defied
for years, or still defy, the attempts of virologists to isolate them. Thirteen
years elapsed between the isolation of the Eaton agent of primary atypical
pneumoniasl and the development of satisfactory methods for its
a further 4 years passed before this “virus”was found to be a pleuropneumonia
organism.33 In discussing infectious synovitis of chickens, Adler
“Primary isolation of mycoplasma from the joint exudate is often unsuccessful
and it is necessary to resort to blind passages in enrichment media. In soma
instances the organism was not recovered until twenty culture passages
in an artificial medium.” For decades the viral hypothesis of the causation
of cancer was unpopular, yet, following the introduction of the technic
of inoculation of newborn animals by Grossa5 and the tissue culture procedures of Stewart and Eddy,36 a viral etiology of much cancer appears
probable. The vertical transmission of an infective agent from parent to
offspring, as emphasized by Cross in the causation of leukemia, may account
ior some of the “genetic” factors in the production of arthritis and the connective tissue diseases. Furthermore, a recent familial study of rheumatoid
arthritis has indicated that spouses of patients may show evidence of rheumatoid disease more commonly than control spouses.37
While it is quite possible that viruses may be responsible for human
arthritis, there is currently little, even indirect, evidence that this is the
case. Arthritis has occurred following various viral infections;ss the number
of reported cases is small and the types of arthritis seem remote from the
problem of rheumatoid arthritis, although in one report39 rheumatoid-like
arthritis did follow “viral” infection in 14 individuals. The author40 and
other.^^^,^^ have failed repeatedly to demonstrate any suggestion of a virus
causing non-gonococcal urethritis or Reiter’s syndrome. As mentioned above,
however, our very limited knowledge of viral latency should be a stimulus
for continued virologic activity in rheumatic disease research.
There is, however, quite an abundance of circumstantial evidence relating pleuropneumonia-like organisms ( PPLO ) to arthritis, because infection
with these agents frequently causes arthritis in both mammals and birds;
moreover, in mice, certain types of PPLO infection produce pathologic lesions very similar to rheumatoid arthritis43 In humans, however, no confirmed
direct evidence has been obtained to relate PPLO to any type of arthritis.
Nevertheless, most of the past work on human PPLO, particularly that related
to their significance in genital infection, was done before two distinct humzn genital PPLO types were recognized. Since Shepard’s descriptioix4*
with recent c~nfirmation,~~
of T-strain PPLO, it is necessary to consider the
possibility that commensal and pathogenic human PPLO may co-exist and
that the former may obscure the understanding of the latter organisms,
which are more difficult to culture-an analogous situation t o chronic respiratory disease in chickens.4° The usual in vitro sensitivity of PPLO to the
broad spectrum antibiotics does not exclude them from human rheumatology
because streptomycin- and tetracycline-resistant PPLO are known to ocC L I ~ . ~ In
~ , ~ addition,
it is quite possible that a situation analogous to the
streptococcal causation of rheumatic fever might exist and might explain
the resistance of the arthritis to antibiotics.
The propensity of PPLO to remain latent not only confuses the pathogenesis of the diseases caused by the organisms, but might favor their
etiologic role in human arthritis. This feature has been stressed by Klieneberger-Nobel49 as follows : “In disease caused by organisms of the pleuropneumonia group, Koch‘s third postulate, the production of the natural disease by inoculation of culture grown from the lesions, is rarely fulfilled.
It IS my opinion that unless a second factor is present, which may be a
breakdown in the defence mechanism of the host, an unspecific adjuvant
or another infective agent, disease will not develop . . Study of the various
animal diseases shows that in the natural disease caused by organisms of the
PPLO group the period between contamination with the organisms and the
onset of the disease, usually called ‘incubation period‘ cannot be defined,
There is first a latent infection of undetermined duration and later on the
explosive outbreak of disease, due to a second factor. In pleuropneumonia of
cattle and goats we know little about this factor, which may be environmental,
or the disposition of the animal. In agalactia of sheep and goats, fatigue,
parturition and lactation are responsible for the onset. In rats and mice, infection depends on the simultaneous application of unspecific material such
as agar, exudates of various descriptions, diphtheria toxin, tissue cells, cancer transplants or on the application or presence of a second infective agent
such as a virus, rickettsia or a toxoplasma.” The fluctuating course of rheumatoid arthritis and the role of precipitating factors might be explained by
a causative organism whose relationship to the host varied from the p3thogenic to the commensal, depending on extraneous circumstances.
In all infectious diseases the reaction of the body to the agent determines
much of the pathology which results, but it is the infective agent which
is the ultimate culprit. The lesions of tuberculosis are determined largely
by hypersensitivity but the disease is still caused by the tubercle bic:ll~s.
The lymphocytic choriomeningitis virus appears to be quite innocuous t o
immunologically tolerant mice and, therefore, the disease in mice is largely
due to the reaction of the body against the virus;50nevertheless, the virus
is still the ultimate cause of the lymphocytic choriomeningitis.
It is clear that no direct evidence supports the contention that rheumatoid
arthritis is an infection, nevertheless there is sufficient indirect evidence
to warrant renewed efforts in the search for a microbioIogica1 causation.
1. Walker, D. L,;Hanson, R. P., and
Evans, A S.: Symposium on Latency
and Masking in Viral and Rickettsia1
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2. Lawrence, J. S.: Quoted in report of
symposium OR Genetics and Rheumatic Diseases. Brit. Med. J. 1:627,
3. Harkness, A. H.: Non-gonococcal Urethritis, Edinburgh, E. & S. Livingstone Ltd. 1950. p. 102.
4. Csonka, G. W.: The course of Reiter’s
syndrome. Brit. Med. J. 1:1088, 1958.
5. Romanus, R.: Pelvo-spondylitis ossificans in the male. Acta med. scandinav. 145: suppl. 280, 1953.
6. Ford, D. K.: Natural history of arthritis following venereal urethritis. Ann.
Rheumat. Dis. 12:177, 1953.
7. Sharp, J.: Differential diagnosis of ankylosing spondylitis. Brit. Med. J. 1:
975, 1957.
8. Mason, R. M., Murray, R. S., Oates,
J. K., and Young, A. C.: Prostatitis
and ankylosing spondylitis. Brit. Med.
J. 1:748, 1958.
9. Editorial: Ankylosing spondylitis and
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1:865, 1960.
10. Good, R. A., Venters, H., Page, A. R.,
and Good, T. A.: Diffuse connective
tissue diseases in childhood. Lancet
81: 192, 1961.
11. -, Zak, S. J., Condie, R. M., and
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of patients with agammaglobulinemia
and hypogammaglobulinemia. Pediat. Clin. N. Amer. 7:397, 1960.
12. Abruzzo, J. L., and Christian, C. L.:
Induction of rheumatoid factor-like
substances in rabbits. Arth. & Rheumat. 4:103, 1961.
13. Svartz, N.: Recent studies on the rheumatoid factor. Acta rheumat. scandinav. 7:5, 1960.
14. Williams, R. C., and Kunkel, H. G.:
Rheumatoid factor, complement, and
conglutinin aberrations in patients
with subacute bacterial endocarditis.
J. Clin. Invest. 41:666, 1962.
15. Pelteer, A., and Christian, C. L.: The
presence of rheumatoid factor in
sera of patients with syphilis. Arth.
& Rheumat. 2:1, 1959.
16. Cathcart, E. S., Williams, R. C., Ross,
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17. Singer, J. M., Peralta, F. M., Lyons, H.
D., and Plotz, C. M.: Presence of
“serologically active macroglobulins”
in sera of some patients with active
pulmonary tuberculosis. Arth. &
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18. Johnson, R. E., and Hall, A. P.: Rubella
arthritis: report of cases studied by
latex tests. New England J. Med. 258:
743, 1958.
19. Ziff, M.: The agglutination reaction in
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5:644, 1957.
20. Dresner, E., and Trombly, P.: The latex
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21. tiinton, N. A., and Garfield Kelly, H.:
Interpretation of the significance of
a positive sensitized sheep cell agglutination test in the differential
diagnosis of rheumatic disorders.
Canad. M. A. J. 85:638, 1961.
22. Ball, J., and Lawrence, J. S.: Epidemiology of the sheep ccll agglutination test. Ann. Rheumat. Dis. 20:235,
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24. I\lellors, R. C., Nowoslawski, A,, and
Korngold, L.: Rheumatoid arthritis
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25. Vaughan, J. H., and Butler, V. P.: Current status of the rheumatoid factor.
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26. Mackay, I. R., and Larkin, L.: The
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to human tissue antigens. Australasian
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28. Hollry, H. L.: Drug therapy and the
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29. Weigle, W. 0.:
Fate and biological action of antigen-antibody complexes.
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30. Lawrence, H. S.: Homograft sensitivity.
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31. Eaton, M. D., Meekeljohn, G., and
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Barile, M. F.: Growth on artificial
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34. Adler, H. E.: Arthritis in chicks caused
by a mycoplasma. Lab. Invest. 8:
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35. Gross, L.: Pathogenic properties and
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37. Schmid, F. R., and Slatis, 11.: Increased
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42. Csonka, G. W., and Furness, G.: A
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turkeys caused by an antibiotic-resistant PPLO. Vet. Med. 52:305, 1957.
48. Osborne, 0. H., Mataney, C. F., and
Pomeroy, B. S.: The effects of antibiotics on the infectious sinusitis agent
of turkeys: the in vivo development
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79:581, 1960.
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between age at inoculation and outcome of infection. J. Immunol. 86:
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D e n y K . Ford, M.D., Associate Professor, Director of C a m dian Arthritis and Rheumatism Society Research Unit, 0 3 prtment of Mediciw, Uniuersity of British Columbia, Vancouuer, B.C., Canada
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arthritis, infectious, rheumatoid
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