May 1971 Vol 30 No 3
`
`READING
`ROOM
`
`the
`umatic Diseases
`
`213
`224
`
`236
`
`243
`
`259
`
`265
`
`271
`
`285
`
`290
`
`294
`
`299
`
`303
`
`307
`
`316
`
`Heberden Oration, 1970 (cid:9)
`Enthesopathy of Rheumatoid and
`Ankylosing Spondylitis (cid:9)
`J. Ball (cid:9)
`Temporal Arteritis in a Large Necropsy Series (cid:9)
`Tendon Involvement in the Rheumatoid Hand
`K. M. Backhouse, A. G. L. Kay, E. N. Coomes, and A. Kates (cid:9)
`Acromegalic Arthropathy (cid:9)
`R. Bluestone, E. G. L. Bywaters,
`M. Hartog, P. J. L. Holt, and S. Hyde (cid:9)
`Anti-DNA Activity in Systemic Lupus Erythematosus
`G. R. V. Hughes, S. A. Cohen, and C. L. Christian (cid:9)
`Ibumin Metabolism in Rheumatoid Arthritis
`F. C. Ballantyne, A. Fleck, and W. Carson Dick (cid:9)
`Immunological Reactivity to Mycoplasma fermentans in Patients
`M. H. Williams and F. E. Bruckner (cid:9)
`with Rheumatoid Arthritis (cid:9)
`Serological Investigations for Evidence of Infectious Aetiology of
`Rheumatoid Arthritis R. W. Chandler, H. Robinson, and A. T. Masi 274
`279
`B. L. J. Treadwell (cid:9)
`Juvenile Gout (cid:9)
`Uric Acid Clearance in Patients with Gout and Normal Subjects
`M, L. Snaith and J. T. Scott (cid:9)
`Amylase Resistance and Insolubility of Ageing Costal Cartilage
`J. K. van der Korst, A. G. W. Lansink, and A. E. M. A.
`van Hooft-Aarnoutse (cid:9)
`Synovial Giant Cells in Rheumatoid Arthritis and Other Joint
`A. K. Bhan and S. Roy (cid:9)
`Diseases (cid:9)
`An Enzyme System in Rat Leucocyte Granules which degrades
`A. J. Anderson (cid:9)
`Insoluble Collagen (cid:9)
`Suppression of Adjuvant-Induced Arthritis in the Rat by
`D. T. Walz, M. J. Di Martino, and A. Misher (cid:9)
`Gold Sodium (cid:9)
`Production of a Chronic Arthritis with Ovalbumin. Its Retention
`in Rabbit Knee Joints
`R. Consden, A. Doble, L. E. Glynn, and A. P. Nind (cid:9)
`Reproducible Polyarthritis in Rats caused by Mycoplasma
`P. C. T. Hannan and B. 0. Hughes (cid:9)
`arthritidis (cid:9)
`Lubrication of Synovial Membrane
`E. L. Radin, I. L. Paul, a A. Swann, and E. S. Schottstaedt (cid:9)
`322
`326
`- (cid:9)
`Heberden Society
`Book Review (cid:9)
`333
`..71-.1.6" (cid:9)
`333
`Notes (cid:9)
`335
`Abstracts (cid:9)
`
`‘ (cid:9))\ (cid:9)
`1 'A 1q4--
`
`JUL
`k
`National. LibrarY1
`)
`\\ of 1\1 iciri
`
`G. Ostberg (cid:9)
`
`liv
`
`i (cid:9)
`
`BRITISH MEDI
`TAVISTOCK
`
`This material (cid:9)
`?pied ....... .........---"10
`atthe NMI and may tie
`Subject US Copyright Laws
`
`Ex. 1039 - Page 1
`
`

`

`Annals of the Rheumatic Diseases
`A journal of clinical rheumatology and connective tissue research
`
`This Journal, founded by the Empire Rheumatism Council, now the Arthritis and Rheumatism
`Council for Research in Great Britain and the Commonwealth, has the support of the
`following organizations: the Heberden Society; the Ligue Internationale contre le Rhumatisme ,
`and the British, European, and American Branches of the Ligue; the American Rheumatism
`Association; the Canadian Rheumatism Association.
`
`Advice to contributors
`Communications This journal exists to publish work
`on all aspects of rheumatology and disorders of connec-
`tive tissue. Laboratory as well as clinical studies are
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`KIDD, C. B. (1965) Brit. J. prey. soc. Med., 19, 4 (Psychia-
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`COPYRIGHT (:) 1971 by the
`Annals of the Rheumatic Diseases
`All rights of reproduction are reserved in respect of
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`Ex. 1039 - Page 2
`
`

`

`Ann. rheum. Dis. (1971), 30, 274
`
`Serological investigations for evidence
`of an infectious aetiology
`of rheumatoid arthritis
`
`ROBERT W. CHANDLER, HARRY ROBINSON, AND ALFONSE T. MASI
`From the Rheumatology Section of the Department of Medicine, University of Tennessee School of Medicine,
`Memphis, Tennessee
`
`The possibility that rheumatoid arthritis (RA) has
`an infectious aetiology has spurred many attempts at
`the identification of such agents. Early work cen-
`tred in a possible relationship of RA and strep-
`tococcal infection was stimulated by the report of
`Cecil, Nicholls, and Stainsby (1930). More recently,
`Mycoplasma have been investigated by isolation and
`serological techniques (Bartholomew, 1967; Barnett,
`Balduzzi, Vaughan, and Morgan, 1966). Also,
`diphtheroid organisms and bacterial L-forms have
`been reported to be associated with RA (Duthie,
`Stewart, Alexander, and Dayhoff, 1967). Transmis-
`sion of a form of arthritis by the inoculation of new-
`born mice with RA synovial membrane extracts has
`been claimed by Warren, Marmor, Liebes, and
`Hollins (1969). Differences in susceptibility of RA
`and normal synovial membrane cell cultures to
`Newcastle disease virus infection have been inter-
`preted as due to a pre-existing infection of the RA
`synovial membrane (Smith and Hamerman, 1968).
`New and varied techniques are being utilized to
`search for 'slow' viruses and other agents in many of
`the connective tissue diseases, but these efforts have
`thus far yielded equivocal or negative results
`(Fresco, 1968; Norton, Velayos, and Robison,
`1970). Sporadic positive reports have not usually
`been confirmed by later investigators. Yet, in spite
`of the contradictory findings in the literature, one of
`the most commonly accepted theories is that an
`infectious agent may trigger a cycle of events which
`leads to RA.
`Our group is currently conducting a long-term
`follow-up study of patients with early RA and other
`connective tissue diseases (Masi, Robinson, and
`Hughen, 1968). Briefly, the criteria for admission of
`a patient into this study are:
`(1) Age less than 45 years;
`(2) First physician diagnosis and referral to study
`within 6 months;
`(3) Residence within the county of Shelby,
`Tennessee.
`
`Normal controls, matched for age, race, and sex,
`have been secured for the study patients. Among the
`many laboratory tests conducted on the patients and
`controls, are serological determinations of infectious
`disease antibody titres on the first blood specimen
`taken. This report is an analysis of the results on our
`first 22 RA patients and controls.
`
`Material and methods
`PATIENT SERA
`Blood specimens taken on the first visit of RA patients to
`our Arthritis Research Programme outpatients clinic
`were used in this study. Sera were separated from the clot
`within 1 to 2 hours and frozen at -20'C. in aliquots with
`portions also lyophilized. The tests described below were
`performed on frozen specimens of recently obtained sera,
`and on lyophilized specimens of those obtained more
`than 3 months before testing. The latex-fixation method
`of Singer and Plotz (1956) was used to test for rheuma-
`toid factor (RE) in RA patients.
`
`CONTROL SERA
`The normal control sera were mostly taken from patients
`of the City of Memphis Hospital fracture clinic and from
`University of Tennessee employees. Matching was done
`by age ( 5 years), sex, and race. One Negro normal
`female served as control for one white RA female; other-
`wise matching was complete. Control sera were treated
`the same as patient sera.
`
`ANTIGENS AND REFERENCE SERA
`These were obtained from commercial sources (Flow
`Laboratories, Rockville, Maryland; Difco Laboratories,
`Detroit, Mich.; Microbiological Associates, Bethesda,
`Md.; and Markham Laboratories, Chicago, Ill.). The
`sources of the various antigens are indicated in Tables
`II, III, and IV.
`
`SEROLOGICAL PROCEDURES
`Most of the agglutination procedures were carried out as
`slide agglutination tests according to the procedures
`recommended by the supplier of the antigens. The
`heterophil test for sheep erythrocyte antibodies was done
`as a tube test (Wintrobe, 1961). The rubella haemag-
`
`Accepted for publication November 4, 1970
`This investigation was supported by USPHS Grant No. 5 ROl AM-12049 from the National Institute of Arthritis and Metabolic Diseases.
`
`This material wascopied
`at the NLM and maybe
`Subject USCopyright Laws
`
`Ex. 1039 - Page 3
`
`

`

`Infectious aetiology of rheumatoid arthritis 275
`
`glutination inhibition (HAI) test was carried out in
`Microtiter equipment (Stewart, Parkman, Hopps,
`Douglas, Hamilton, and Meyer, 1967). The cold agglutin-
`ation titrations were performed by the technique of
`Finland, Peterson, Allen, Samper and Barnes (1945),
`except that all volumes were reduced and Microtiter
`equipment was used. The reading of the cold agglutinin
`titres, after overnight incubation in the cold, was done
`by gently inverting the plates three times and observing
`for clumping on the Microplate reading mirror.
`Complement fixation (CF) was done in Microtiter
`equipment, using two units of antigen, as determined by
`block titrations, and two full units of guinea-pig comple-
`ment (Flow Laboratories, Grade A, Lyophilized)
`(Fiset, 1964). The primary incubation of antigen, serum,
`and complement was for 1 hour at 375C., followed by the
`addition of sensitized sheep erythrocytes. The plates were
`then incubated for 45 min. at 375C. with one agitation
`during this period. All plates were then centrifuged and
`read for haemolysis.
`A serum was recorded as reactive when any level of
`antibody reactivity was observed and not just at the
`accepted diagnostic levels routinely used in the test under
`consideration. RA and control sera were titrated at the
`same time, using single lots of the various biologicals, and
`were read without knowledge of the serum source.
`
`STATISTICAL ANALYSIS
`This was done first by determining if there were signifi-
`cant differences in the proportions of subjects with
`reactive titres between the RA group and the normal
`control group. Secondly, the random 't' test was used
`after logarithmic transformation of the titres, to test
`
`whether there were significant differences between the
`mean titres of the reactive sera in the two groups.
`Geometric mean titres are shown in Tables III and IV.
`The `V test cannot be used when there are less than two
`positive observations per group and such instances are
`identified by dashes in the Tables.
`
`Results
`The characteristics of the RA and control groups
`are shown in Table I. The two groups differed only
`slightly in terms of demographic variables. The RA
`patients had a median duration from the onset of
`the first symptoms of arthritis to the serum collection
`of 5 months (range 6 weeks to 78 months), and a
`median interval from first physician diagnosis to
`serum collection of 2 months (range 2 to 6 months).
`All patients had a diagnosis of either rheumatoid
`arthritis (two classical, thirteen definite, and three
`probable) or juvenile rheumatoid arthritis (three
`definite, one probable) by American Rheumatism
`Association criteria (Ropes, Bennett, Cobb, Jacox,
`and Jessar, 1958; Bywaters, 1968).
`Twelve of the thirty antigens used yielded com-
`pletely non-reactive results with both the RA and
`control sera (Table II).
`Table III (opposite) shows the test results with
`thirteen antigens yielding reactive titres but with no
`significant differences found between the groups.
`Significant differences between the RA and control
`groups were found with the five antigens shown in
`
`Table I Age, sex, and race distributions of new rheumatoid patients and controls
`
`Type of subject (cid:9)
`
`No. of subjects Age (yrs)
`
`New rheumatoid (cid:9)
`
`Normal (cid:9)
`
`22
`
`22
`
`Mean
`
`26.9
`
`24.9
`
`2 Std. Errors (cid:9)
`
`4.62
`
`4.12
`
`Sex (cid:9)
`
`M (cid:9)
`
`3
`
`3
`
`F (cid:9)
`
`19
`
`19
`
`Race
`
`White Negro
`
`14
`
`13
`
`8
`
`9
`
`Table II Twelve antigens yielding all non-reactive titres with new RA patient and normal control sera
`
`Type of antigen
`
`Lymphocytic choriomeningitis (1)*
`Salmonella Ha (2)
`Rickettsial pox (1)
`Heterophil
`Mycoplasma salivarium (3)
`Mycoplasma hominis 1 (3)
`Mycoplasma fermentans (3)
`Mycoplasma orate 2 (3)
`Mycoplasma arthritidis (3)
`Mycoplasma hyorhinis (3)
`Mycoplasma pulmonis (3)
`Mycoplasma laidlawii (3)
`
`Type of test (cid:9)
`
`CF
`Agg.
`CF
`Agg.
`CF
`CF
`CF
`CF
`CF
`CF
`CF
`CF
`
`Titres**
`
`Negative
`Negative
`Negative
`Negative
`Negative
`Negative
`Negative
`Negative
`Negative
`Negative
`Negative
`Negative
`
`• Supplier in parentheses: (I) Markham Laboratories.
`(2) Difco Laboratories.
`3) Microbiological Associates.
`
`•• All negative except for standard positive reference sera.
`CF = complement fixation.
`Agg. = agglutination.
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1039 - Page 4
`
`(cid:9)
`

`

`276 (cid:9) Annals of the Rheumatic Diseases
`
`Table IV. In a comparison of the results with
`Salmonella 1-113 and Hd antigens, it was determined
`that serum antibody titres to the antigens correlated
`significantly (P <0 •01). The Proteus OXK and OX2
`antibody test results did not show any correlation.
`In the Proteus OXK test, the RA patients had a
`significantly lower proportion of reactive titres than
`the normal group, but in terms of reactive titres RA
`patients had a significantly higher mean titre than
`the normal controls. With the Proteus• OX2 test, RA
`patients again had a significantly lower proportion
`of reactive titres than normal subjects, but the mean
`titres of reactive tests in the two groups did not differ
`significantly. In the test for Herpes virus hominis
`antibodies using tissue-culture derived antigen, the
`proportions of reactive titres in the two groups did
`not differ significantly, although the RA patients had
`a significantly higher mean titre.
`
`x 2 tests showed no significant correlations
`between presence or absence of a positive latex-
`fixation test in RA patients and a reactive antibody
`titre to the antigens in Table IV. In addition, no
`significant differences were found by the 't' test in
`reactive mean titres when rheumatoid factor positive
`and negative RA patients were compared. No
`significant associations were found between titres of
`antibodies to antigens in 'Fables 111 and IV and the
`intervals from either onset of symptoms or from
`first medical diagnosis of RA. By the analysis of
`variance test, it was determined that the log titres of
`the serological tests d;d not differ significantly by the
`season of the year in which the serum samples were
`collected.
`
`Discussion
`Our negative results with the Mycoplasma antigens
`
`Table III Thirteen antigens yielding no significant differences in reactions with new rheumatoid and normal
`control sera
`
`Type of antigen
`
`Type
`of
`test
`
`Numbers of subjects
`with reactive titres
`
`22
`new
`rheitmatoidv
`
`22
`
`normals
`
`Salmonella 0 (2)* (cid:9)
`Agg•
`Erysipelothrix insidiosa (2) Agg.
`Leptospira pool-1 (2) (cid:9)
`Agg.
`Leptospira pool-3 (2) (cid:9)
`Agg.
`Agg.
`Cold Agglutinins (cid:9)
`Proteus OX19 (2) (cid:9)
`Agg•
`Brucella abortus (2) (cid:9)
`Agg.
`HAI
`Rubella (4) (cid:9)
`CF
`Psittacosis (1) (cid:9)
`CF
`Mumps (4) (cid:9)
`Mycoplasma orale 1 (3) CF
`CF
`Adenovirus (4) (cid:9)
`CF
`Cytomegalovirus (4) (cid:9)
`
`2
`0
`
`1
`1
`1
`0
`19
`22
`5
`1
`9
`13
`
`1
`2
`0
`0
`
`22
`22
`4
`1
`7
`15
`
`P
`value
`x2
`test
`
`NSt
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`NS
`
`Geometric mean
`reactive tests
`
`titres of
`
`new
`rheumaloids
`
`: 80
`I (cid:9)
`All neg.
`: (cid:9) 16
`: 32
`: 20
`: 160
`All neg.
`: 288
`: (cid:9) 13.2
`:2.3
`:8
`:8
`: (cid:9) 11.6
`
`normals
`
`: 50
`: 50
`: (cid:9) 16
`All neg.
`All neg.
`: 20
`: 20
`: 513
`:8.8
`:2.8
`:4
`: 17.7
`: (cid:9) 10.5
`
`P
`value
`
`test
`
`NS
`
`NS
`NS
`NS
`
`NS
`NS
`
`• Supplier in parenthesis: (1) Markham Laboratories.
`not significant: P (cid:9)
`(2) Difco Laboratories.
`complement fixation.
`(3) Microbiological Associates.
`Agg.
`agglutination.
`(4) Flow Laboratories.
`11AI
`hacmagglutination inhibition.
`Table IV Five antigens yielding statistically significant diJJi•rence.s• in reactions with new rheumatoid and
`control sera
`
`0.05.
`
`t NS
`
`Type of antigen
`
`Type
`of
`test
`
`Numbers of subjects
`with reactive titres
`
`22
`new
`rheumatoids
`
`22
`
`normals
`
`P
`value
`x2
`test
`
`Geometric mean titres of
`reactive tests
`
`New
`rheumatoid,
`
`P
`value
`,t,
`test
`
`< •01
`NS
`< •01
`
`Normals
`
`I :104
`1 : 249
`1 (cid:9) : 70
`1 (cid:9) :116
`1 (cid:9) : 6.4
`
`Salmonella Hb (1)*
`Agg.
`Salmonella Hd (1)
`Agg.
`Proteus OXK (1)
`Agg.
`Proteus OX2 (1)
`Agg.
`Herpes virus hominis (2) CF
`
`0
`1
`7
`5
`12
`
`8
`11
`20
`15
`12
`
`< •01 All neg.
`<•01 1 :320
`<•01
`1 (cid:9) :195
`1 : 70
`< •01
`NS1*
`1 (cid:9) : 17
`
`• Supplier in parentheses: (1) Difco Laboratories.
`(2) Flow Laboratories.
`
`t NS = not significant; P > 0.05.
`CF = complement.
`Agg. = agglutination.
`
`This material was copied
`atthe NMI and may be
`Subject US Copyright Laws
`
`Ex. 1039 - Page 5
`
`

`

`Infectious aetiology of rheumatoid arthritis 277
`
`contrasted with those of Bartholomew (1967), who
`found an increased prevalence of reactive titres in
`the sera of RA patients compared to normal
`controls. His Mycoplasma antigen consisted, how-
`ever, of a mixture of fresh isolates, including those
`from RA, Reiter's syndrome, and systemic lupus
`erythematosus patients. Also, he tested sera from
`chronic advanced RA patients in contrast to the
`newly-diagnosed RA patients in our panel. It would
`be anticipated that any causal relationship of an
`infectious agent with RA would be best identified
`early in the disease. Other investigators have not
`confirmed Bartholomew's results (Barnett and others,
`1966; Sharp, 1970). However, his finding may reflect:
`(1) A progressive susceptibility of certain RA
`patients to infection by Mycoplasma which may be
`related to the duration of the disease;
`(2) The utilization of organisms containing anti-
`gens not found in standard strains from commercial
`sources.
`The data presented here are in contrast to those of
`Smiley and Casey (1969) who report both a lower
`prevalence and a lower geometric mean titre of
`antibodies in RA patients for cell culture derived
`Herpes virus hominis antigen compared with controls.
`In addition they found an even lower proportion of
`H. hominis antibodies in RA patients as compared
`to normal controls using egg-derived antigen. Their
`data also demonstrated that RA patients have a
`reduced capacity for lymphocyte transformation
`when stimulated by H. hominis antigen. They found
`no significant differences between RA patients and
`normal subjects to five other virus antigens, four of
`which are included in our panel of antigens. Our
`results were also negative for these four antigens.
`Our data show that, to a cell-culture derived H.
`hominis antigen, the proportions of reactive anti-
`bodies were equal in early RA and controls, but the
`mean titre was significantly greater in RA patients
`than in controls. Smiley (1970) defined his RA
`patients as having long-standing disease. The selected
`immunological defect in the immune response to
`H. hominis postulated by Smiley and Casey may
`reflect some phenomenon related to duration of
`disease. It is interesting that the recent work of
`Simsarian, Roth, Hopps, Douglas, Williams, and
`Meyer (1970) also shows a reduced prevalence
`of H. hominis antibodies in an undefined panel of
`RA patients. They found, as did Smiley and Casey,
`that the addition of a high titred RF serum to
`positive H. hominis sera from either the RA or the
`control groups, could depress the antibody titre to
`H. hominis. However, neither group presented data
`to show any relationship between the level of H.
`hominis antibody titre and the natural occurrence or
`absence of RF. Our data from new RA patients
`show no correlation between RF and H. hominis
`antibodies.
`
`It is tempting to attribute the low prevalence of
`Salmonella and Proteus OX antibodies in RA to an
`immunological deficiency or hypo-reactivity as
`others have done with other antigens (Epstein and
`Jessar, 1959; Rawson, Abelson, and McCarty, 1961;
`Houba, Adam, Malaeek, and Tesarek, 1964).
`However, there are a number of reports which have
`demonstrated hyper-reactivity (Houba and others,
`1964; Meiselas, Zingale, Lee, Richman, and Siegel,
`1961; Ascari and Gorman, 1969) as well as no
`alteration from the normal immune response in RA
`patients (Shearn, Epstein, and Engleman, 1963;
`Waller, Ellman, and Toone, 1966; Rhodes, Scott,
`Markham, and Monk-Jones, 1969). The possibility
`also exists that the reduced prevalence of Salmonella
`and Proteus OX antibodies in RA might have
`resulted from the induction of immunological
`tolerance by these or related antigens. Immuno-
`logical tolerance may be induced by high doses of
`antigen, best accomplished during the neonatal
`period, or by repeated subimmunogenic doses of
`soluble and relatively nonphagocytizable antigen.
`This tolerance is usually of finite duration but may
`be prolonged by periodic injections of the antigen.
`A slow or defective infectious agent may possibly be
`inducing tolerance to itself and related antigens.
`Such tolerance to virus has been demonstrated in the
`lymphocytic choriomeningitis virus infections in
`mice (Hotchin, 1962).
`The results of Barnett and others (1966), who
`mainly used chronic RA patients, were extended and
`supported by our data which is based on newly-
`diagnosed RA patients and normal controls. Our
`data did not demonstrate a causal relationship
`between the infectious agents studied and RA. The
`data may possibly be consistent with a selected
`immunological alteration during early RA.
`
`Summary
`Using a panel of thirty infectious disease antigens
`and testing sera from 22 newly-diagnosed RA
`patients and 22 controls, no evidence of a causal
`relationship with RA was detected by serological
`means. Of the thirty antigens, 25 showed either no
`reactivity with RA and control sera, or no significant
`differences between the two groups. In contrast to
`other reports in the literature, Herpes virus hominis
`antibodies were found in equal proportions in RA
`patients and controls. Also, we found a significantly
`higher mean antibody titre to H. hominis in early
`RA compared to controls.
`A significantly reduced prevalence of reactive
`titres was found in early RA compared to controls
`using Salmonella Hb and Hd antigens, and Proteus
`OXK and OX2 antigens. The serum reactivity to
`Salmonella Hb and Hd antigens was significantly
`
`This material was copied
`at the NLM and may be
`Subject US Copyright Laws
`
`Ex. 1039 - Page 6
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`

`

`278 Annals of the Rheumatic Diseases
`
`correlated but such correlation did not exist with tions and tolerance in early RA was discussed.
`the Proteus antigens. (cid:9)
`The excellent technical assistance of Mrs. Margaret
`The possibility of selected immunological altera- Dugger is most gratefully acknowledged.
`
`References
`ASCARI, W. Q., AND GoRivtAN, J. G. (1969) Transfusion (Basel), 9, 35 (Hemagglutinating antipenicillin antibodies
`(HAPA). Incidence and significance in four groups of patients).
`BARNETT, E. V., BALDUZZI, P., VAUGHAN, J. H., AND MORGAN, H. R. (1966) Arthr. and Rheum., 9, 720 (Search
`for infectious agents in rheumatoid arthritis).
`BARTHOLOMEW, L. E. (1967) Ann. ,V.Y. Acad. Sci., 143, 522 (Characterization of mycoplasma strains and antibody
`studies from patients with rheumatoid arthritis).
`BYWATERS, E. G. L. (1968) in 'Population Studies of the Rheumatic Diseases', ed. P. H. Bennett and
`P. H. N. Wood, p. 455. Elzevier, Amsterdam.
`CECIL, R. L., Nicmous, E. E., AND SrAmoy, W. J. (1930) Amer. J. Path., 6, 619 (Characteristics of streptococci
`isolated from patients with rheumatic fever and chronic infectious arthritis).
`DUTHIE, J. J. R., STEWART, S. M., ALEXANDER, W. R. M., AND DAYHOPT, R. E. (1967) Lancet, 1, 142 (Isolation of
`diphtheroid organisms from rheumatoid synovial membrane and fluid).
`EPSTEIN, W. L., AND JESSAR, R. A. (1959) Arthr. and Rheum., 2, 178 (Contact-type delayed hypersensitivity in
`patients with rheumatoid arthritis).
`FINLAND, M., PETERSON, 0. L., ALLEN, H. E., SAMPER, B. A., AND BARNES, M. W. (1945) J. clin. Invest., 24, 451
`(Cold agglutinins. I. Occurrence of cold isohemagglutinins in various conditions).
`FISET, P. (1964) `Serological Techniques' in 'Techniques in Experimental Virology, ed. R. J. C. Harris, p. 225.
`Academic Press, London.
`FRESCO, R. (1968) Fed. Proc., 27, 246, abstr. no. 170. (Tubular (myxovirus-like) structures in glomerular deposits
`from a case of lupus nephritis).
`HOTCHIN, J. (1962) Cold Spring Harbor Symp. Quant. Biol., 'Basic Mechanisms in Animal Virus Biology', vol. 27,
`p. 479 (The biology of lymphocytic choriomeningitis infection: virus induced immune disease).
`HOUBA, V., ADAM, M., MAL/AK, J., AND TESAREK, B. (1964) Experientia (Basel), 20, 522 (Delayed hypersensitivity
`and antibody response in rheumatoid arthritis).
`MASI, A. T., ROBINSON, H., AND HUGHEN, M. (1968) Memphis and Mid-South med. J., 43, 359 (The arthritis
`research program survey of newly diagnosed arthritis among residents of Memphis and Shelby County).
`MEISELAS, L. E., ZINGALE, S. B., LEE, S. L., RICHMAN, S., AND SIEGEL, M. (1961) J. clin. Invest., 40, 1872
`(Antibody production in rheumatic diseases. The effect of brucella antigen).
`NORTON, W. L., VELAYOS, E., AND ROBISON, L. (1970) Ann. rheum. Dis., 29, 67 (Endothelial inclusions in
`dermatomyositis).
`PEASE, P. (1969) Ibid., 28, 270 (Bacterial L-forms in the blood and joint fluids of arthritic subjects).
`RAWSON, A. J., ABELSON, N. M., AND MCCARTY, D. J. (1961) Arthr. and Rheum., 4, 463 (The isohemagglutinin
`partition in rheumatoid arthritis).
`RHODES, K., SCOTT, A., MARKHAM, R. L., AND MONK-JONES, M. E. (1969) Ann. rheum. Dis., 28, 104
`(Immunological sex differences. A study of patients with rheumatoid arthritis, their relatives, and controls).
`ROPES, M. W., BENNETT, G. A., COBB, S., JACOX, R., AND JESSAR, R. A. (1958) Bull. rheum. Dis., 9, 175 (1958
`Revision of the diagnostic criteria for rheumatoid arthritis).
`SHARP, J. T. (1970) Arthr. and Rheum., 13, 263 (Mycoplasmas and arthritis).
`SHEARN, M. A., EPSTEIN, W. V., AND ENGLEMAN, E. P. (1963) Proc. Soc. exp. Biol. (N.Y.), 113, 1001 (Antibody
`response to brucella antigen in patients with rheumatoid arthritis).
`SIMSARIAN, J. P., ROTH, H., HOPPS, H. E., DOUGLAS, R. D., WILLIAMS, M. S., AND MEYER, H. M. JR. (1970)
`Arthr. and Rheum., 13, 348 (Serologic and virologic studies in patients with rheumatoid arthritis RA).
`SINGER, J. M., AND PLOTZ, C. M. (1956) Amer. J. Med., 21, 888 (The latex fixation test. I. Application to the
`serologic diagnosis of rheumatoid arthritis).
`SMILEY, J. D. (1970) Personal communication.
`- AND CASEY, H. L. (1969) Arthr. and Rheum., 12, 698 (Decreased CF antibodies in sera and decreased
`lymphocyte transformation to herpes simplex in patients with rheumatoid arthritis) (Abstr.)
`SMITH, C., AND HAMERMAN, D. (1968) Ibid.,11, 842 (Resistance of rheumatoid synovial cells to infection with exogenou
`virus) (Abstr.).
`STEWART, G. L., PARKMAN, P. D., HoPPs, H. E., DOUGLAS, R. D., HAMILTON, J. P., AND MEYER, H. M. JR. (1967)
`New Engl. J. Med., 276, 554 (Rubella-virus hemagglutination-inhibition test).
`WALLER, M., ELLMAN, H. M., AND TOONE, E. C. (1966) Acta rheum. scand., 12, 250 (Brucella immunization in
`patients with seropositive and seronegative rheumatoid arthritis).
`WARREN, S. L., MARMOR, L., LIEBES, D. M., AND HOLLINS, R. (1969) Arch. intern. Med., 124, 629 (An active
`agent from human rheumatoid arthritis which is transmissible in mice).
`WINTROBE, M. M. (1961) 'Clinical Hematology', 5th Ed., p. 1115. Lea and Febiger, Philadelphia.
`
`This material was copied
`atthe NLM and may be
`Subject US Copyright Laws
`
`Ex. 1039 - Page 7
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