170

SEROLOGICAL AGGLUTINATIONAND PRECIPITIN MECHANISMSIN RHEUMATOID ARTHRITIS

By ELLIS DRESNER, M.D., M.R.C.P.,Senior Staff Physician and Rheumatologist, Lemuel Shattuck Hospital, Boston, Massachusetts

Streptococcal AgglutinationIn I929 Cecil and his colleagues observed that

the sera of patients with rheumatoid arthritis hadthe property of agglutinating a specific strain ofhaemolytic streptococcus in high titre, and as thisproperty was not present in the sera of controlsubjects, concluded that it was a specific mani-festation of the disease (Cecil et al., 1929, I931).Later it was found that other strains of haemolyticstreptococcus were also agglutinated by a highproportion of rheumatoid sera, but agglutininswere not found in cases of degenerative or otherarthritis (Nicholls and Stainsby, I93I). Theagglutinins were thought to be antibodies to anon-type-specific haemolytic streptococcal antigen,and their presence in rheumatoid sera was widelyconfirmed (Dawson et al., I932a; Gray andGowen, I931; Kalbak, 1948; Keefer et al., I933;Wainwright, 1934). Soon afterwardsagglutininsactive against R strains of pneumococci (Dawsonet al., I932a and b; Wallis, I946b) and staphylo-cocci (Oker-Blom, 1952a) were also found to bepresent in rheumatoid sera. It is generallyaccepted that the presence of agglutinins is relatedto the duration and severity of the arthritis, about68 per cent. of patients having them at some timein the blood (Cecil and de Gara, I946) and alsoin the synovial fluid (Levinthal, I939).

These observations naturally led to a search forthe presence of other streptococcal antibodies inthe blood in rheumatoid arthritis, but significanttitres of antistreptolysin 0 and antifibrinolysin,though present in proven haemolytic streptococcalinfections and rheumatic fever, could not be foundin rheumatoid arthritis (Myers and Keefer, '934;Myers et al., '935; Perry, 1940; Ouchterlony and.Palmborg, '949; Bunim and McEwen, I940). Anti-hyaluronidase and antihaemolysin (Harris et al.,1950; Faber, 1953), and antistaphylolysin (Oker-Blom and Widholm, 1952) were similarly absent.Oker-Blom (I947a and b; Oker-Blom and

Widholm, 1952), as a result of absorption studies

of rheumatoid sera with streptococci, staphylo-cocci, colloidal aluminium silicate and specificantibacterial immune sera, showed that agglu-tinating activity is specific for neither of the aboveorganisms, and cannot be correlated with theserum concentrations of antibodies to them.

It is clear that the phenomenon of bacterialagglutination in rheumatoid arthritis is non-specific with regard to the organisms agglutinatedand that a bacterial antigen is not involved. Inconfirmation of this, Dawson et al. (1934) noteda tendency of rheumatoid sera to precipitatehaemolytic streptococci in parallel to their abilityto agglutinate them, and Chasis and McEwen(1936) also found non-type-specific precipitins inrheumatoid sera active against crude streptococcalextracts, independently of the presence of agglu-tinins. Further light was thrown on the problemby Wallis (I946a), who showed that rheumatoidsera can agglutinate suspensions of collodionparticles unsensitized with antigen. The collodion-agglutinating factor is often present in highdilution, is not found in normal sera in significantamounts, is thermolabile, and appears to be aglobulin.For some time the properties of streptococcal.

and collodion agglutination were used as diag-nostic tests for rheumatoid arthritis, but havenow been largely abandoned because of theirfailure in about one-third of cases, and technicaldifficulties involved in preparing stable anduniform test preparations.

Sheep Cell AgglutinationIn I940 Waaler observed that sera from patients

with rheumatoid arthritis agglutinated sheep ery-throcytes, previously sensitized with a non-agglutinating amount of haemolytic amboceptor,in about 36 per cent. of cases, whereas less than5 per cent. of non-rheumatoid sera possessed thisproperty. Agglutination did not occur withunsensitized cells, and was therefore not due to

copyright. on July 9, 2021 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.33.378.170 on 1 April 1957. D

ownloaded from

http://pmj.bmj.com/

April 1957 DRESNER: Serological Agglutination and Precipitin Mechanisms in Rheumatoid Arthritis 171

heterophile antibody. The finding of an agglu-tinating factor in some sera against sensitizederythrocytes (' Agglutinationsfordende Substanz ')had been previously noted by Meyer in I922, buthad not been related to rheumatoid arthritis.Then in 1948, Rose and others, whilst testing theserum of a convalescent from rickettsialpox withrheumatoid arthritis for complement fixation,found it to agglutinate sheep erythrocytes treatedwith rabbit antisheep cell amboceptor to a titreI28 times greater than that against unsensitizedcells. This led to the development of a ' differ-ential agglutination test' with the result expressedas the quotient of the sensitized over the unsensi-tized cell titres. A positive result, arbitrarilytaken as a differential titre of i in i6 or greater, waspresent in 8o per cent. of adult rheumatoidsarthritis tested, and in 7 per cent. of controls.A modification of the Rose technique was

devised by Heller et al. (I949) with the resultexpressed as the titre of agglutination of sensitizedcells after prior removal of heterophile antibodyby adsorption with sheep cells. By this methodHeller claimed positive tests in 90 per cent. ofcases of rheumatoid arthritis compared with 6i percent. by the Rose differential technique. Thisgain in sensitivity was at the expense of some lossof specificity, but many workers found it the moreadvantageous method (Ball, 7950).A further modification of the Heller technique

(Heller et al., 1952; Jacobson et al., I953) uses theratio between the differential agglutinating titres oftest sera diluted in 5 per cent. sheep serum and insaline after preliminary absorption of heterophile, aratio of4 to I or higherindicatingapo~itive reaction.

In published reports of tests on rheumatoidsera using the Waaler-Rose or Heller methods ortheir modifications, the proportion of positiveresults varies from about 45 to as high as go percent. in different series. Kellgren (1952) found47 per cent. of his own series of 642 cases gavepositive reactions, whilst Coggeshall (I953), in areview of I,8oo published cases, found an overallpositive percentage of 64. Greenbury et al. (1956)had go per cent. positive tests in 294 cases, andclaim a rise to 95 per cent. in patients with radio-logical lesions. This wide variability in reportedresults is probably partly due to a lack of uni-formity in diagnostic criteria. Results are muchmore frequently positive in unequivocal than inunselected cases (Ball, 1952; Alexander and deForest, I954), but the exclusion of doubtful casesgives a bias suggesting unmerited sensitivity ofthe test. Improvements in technique of per-forming the test are reported to give a higherpercentage of positive results (Boisvert et al.,1956), but sensitivity can be raised only at the

expense of specificity, as for example by increasingthe amount of amboceptor used. An agglutinatingsystem positive in 60-70 per cent. of rheumatoidsis positive in up to 4 per cent. of controls. Falsepositive readings are found most commonly in' atypical' forms of rheumatoid arthritis (Ball,1952). Positive results are rarely obtained inankylosing spondylitis (I.5 per cent.), juvenilerheumatoid arthritis (13.5 per cent.), and psoriaticarthritis (7 per cent.), and almost never in rheu-matic fever (Rose et al., 1948; Scott, 1952; Kell-gren, 1952; Heller et al., 1952; Ball, I952;Alexander and de Forest, 1954; Svartz andSchlossmann, 1950). The reported incidence ofup to 3 per cent. positive tests in osteoarthritis ispossibly due to the inclusion of some cases ofmild or concealed rheumatoid arthritis. Thecondition other than rheumatoid arthritis mostfrequently giving a positive test is systemic lupuserythematosis, in which the incidence, when thestandard methods are used, is possibly as high asin rheumatoid arthritis (Ball, 1952; Svartz andSchlossmann, 1950; Kellgren, 1952), and positivetests occur not infrequently in scleroderma anddermatomyositis (Alexander and de Forest, 1954;Dordick and Wasserman, 1950; Svartz andSchlossmann, 1952). Occasional positive testsare also reported in a variety of miscellaneousconditions (Greenbury et al., 1956). The test isnot, as was originally thought, of value as anindex of disease activity in rheumatoid arthritis,and, once positive, tends to remain so despitevariations in the patient's clinical condition (Pikeet al., 1953) or steroid therapy (Ball, 1952;Alexander and de Forest, 1954; Svartz andSchlossmann, 1950). Positive tests in rheumatoidarthritis are most likely to be found in males;in those with widespread disease of long standing;and especially in the presence of subcutaneousnodules (Kellgren, 1952). Although the test maybecome positive within a few weeks of the onsetof the disease (Ball, 1952; Pike et al., 1953;Jawetz and Hook, '949; Brown et al., '949;Sulkin et al., 1949) it more usually- does so afterabout a year, and its diagnostic value thereforefails in the earliest stages of the illness whenlaboratory confirmation of the diagnosis is mostneeded. When the agglutinating factor is presentin the blood it is also found in the synovial fluid(Jacobson et al., I953, 1956; Svartz and Schloss-mann, I950).

In general, the test as performed by the methodsdescribed has a high degree of specificity forrheumatoid arthritis and those conditions charac-terized histologically by the presence of fibrinoid,with the exception, as Kellgren points out, ofrheumatic fever. Nevertheless, about one-thirdof all cases of arthritis are negative by these

copyright. on July 9, 2021 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.33.378.170 on 1 April 1957. D

ownloaded from

http://pmj.bmj.com/

POSTGRADUATE MEDICAL JOURNAL

methods at any one time, and in seeking toexplain this, Ziff and his colleagues (I954) con-sidered the possible presence in rheumatoidserum of an agglutination inhibitor. Such aninhibitor was found in non-rheumatoid sera, andits partial separation from the agglutinating factorwas achieved by the use of the euglobulin fractionof the serum precipitated by dialysis againstphosphate buffer at pH 6. Agglutinating activityin the euglobulin fraction was 92 per cent. posi-tive, compared with 78 per cent. positive in wholeserum in 83 cases of rheumatoid arthritis, andthe incidence of positive reactions in control serawas reduced from I3 per cent. to 2 per cent.Virtually complete removal of the hypothesizedinhibitor was demonstrated by the finding ofioo per cent. failure to inhibit the agglutinationofknown positive serum by rheumatoid euglobulinfractions, whereas only 5 per cent. of control serabehaved in this way. Thus failure of the euglo-bulin concentrate of rheumatoid serum to inhibitagglutination provides a more sensitive index ofagglutinating activity than does the direct test foragglutination. It is of interest that by the euglo-bulin test 6 out of I2 cases of juvenile rheumatoidarthritis had positive agglutination, an incidencemuch higher than that reported by the standardtests in this condition; and all I2 showed failureto inhibit agglutination. This latter finding canbe interpreted as indicating the test to be positivein all cases. All of ii patients with ankylosingspondylitis and 6 patients with psoriatic arthritiswere negative both as regards the presence ofagglutinator and the absence of inhibitor, insharp contrast to the uniformly positive results inadult and juvenile rheumatoid arthritis, including6 early cases. Although 3 of 7 cases of dis-seminated lupus erythematosis had positive testson their whole sera, in only one was the euglobulinfraction active in causing agglutination and failingto inhibit agglutination in known positive sera,and this particular case had clear evidence ofrheumatoid arthritis in addition to lupus. Useof the euglobulin fraction to reduce the numberof false positive reactions has been confirmed(Bernstock et al., I956). The presence of aserum agglutination inhibitor was also discoveredindependently by Heller et al. (I954) in Cohn'sfraction II. Ziff and his colleagues found inhi-bitor in pooled human gamma globulin whichwas active in vivo in inhibiting the agglutinationreaction, and in causing inhibition of the reactionto reappear in rheumatoid sera (Ziff et al., 1956).Cold precipitation of serum as a means of frac-tionation yields a globulin of high activity (Svartzand Schlossmann, 1955) and appears to be almostas effective as dialysis in removing inhibitor andfactors giving false positive reactions.

Nature of the ReactionThat the reaction is of aetiological importance

in rheumatoid arthritis seems probable because ofits high degree of specificity in the adult andjuvenile forms of the disease and its absence inthe pathologically-related conditions, ankylosingspondylitis and psoriatic arthritis, when serumfractionation techniques are used. The persistenceof the reaction during spontaneous and hor-monally-induced remissions, when other indicesof disease activity have reverted to normal, isadditional evidence that it cannot reasonably bethought to be a non-specific manifestation ofsynovial inflammation.Waaler (I940) considered the rheumatoid factor

to be an intensification of an agglutination activatornormally present in serum, and found it to bethermostable and precipitable with globulin onammonium chloride fractionation. Rose et al.(1948) and Thulin (I955) located it in the beta-gamma globulin fraction by electrophoresis, andHeller et al. (I954) in Cohn's fraction II (gammaglobulin). Robinson et al. (I954) fractionatedserum protein by dialysis against phosphate bufferand found maximum activity in the beta-globulincomponent, but Lamont-Havers (1953) found awater-precipitated gamma globulin to contain theactive factor. The cold-precipitated active frac-tion of Svartz and Schlossmann (1955) is also agamma globulin, but as the result of zone electro-phoresis studies on starch columns Svartz (1956)believes some activity is due also to a fraction inthe beta region. By ethanol precipitation ofserum, Heller et al. (1955) found activity speci-fically in fraction III, predominantly beta globulin,although there is no correlation between beta-globulin concentration and agglutinating activity.By the combined use of a number of fractionationtechniques, Lospalluto and Ziff (I956) havepurified the agglutinating factor more than fivehundredfold over the original serum, and show thepresence of two components with mobilities inthe gamma-globulin range. They have made apreliminary chemical characterization of the factorand also of serum inhibitor, which they show tobe present in all human sera, but in insufficientamounts in rheumatoid sera to modify its agglu-tinating titre. Agglutinating activity is destroyedby bacterial contamination (Jawetz and Hook,1949) and by lyophilization (Robinson et al., 1954),but is otherwise stable for years. Attempts toremove the factor by adsorption on to sensitizedcells have met with little success (Waaler, I940;Pike et al., 1953; Winblad, 1952a), and it is notadsorbed by barium sulphate, asbestos, or filterpaper (Vaughan, I955), but precipitates with thebeta globulin when serum is treated with alu-minium silicate (Thulin, 1955).

172 ,April I957copyright.

on July 9, 2021 by guest. Protected by

http://pmj.bm

j.com/

Postgrad M

ed J: first published as 10.1136/pgmj.33.378.170 on 1 A

pril 1957. Dow

nloaded from

http://pmj.bmj.com/

April I957 DRESNER: Serological Agglutination and Precipitin Mechanisms in Rheumatoid Arthritis I73

The factors causing bacterial and cellularagglutination are distinct, and can be separatedby absorption methods (Pike et al., I949a and b)and by electrophoresis (Thulin, 1955).

Systems other than the sheep cell-rabbit ambo-ceptor can be used to detect agglutination (Wager,1950; Winblad, 1952a; Shichikawa et al., 1956a);horse, ox, goat, cow, chicken and guinea-pig cells,and even washed erythrocyte stroma (Svartz andSchlossmann, I955) can be sensitized with homo-logous rabbit antiserum; or homologous guinea-pig antiserum may be substituted. Pike et al.(I949a and b) state that sensitized rat and humangroup 0 cells do not detect agglutination, butthis is disputed (Wager, 1950; Foz et al., 1954).Rheumatoid serum does not enhance the agglu-tination by normal human or infectious mono-nucleosis sera, or by anti-Rh serum with sensitizedRh-positive cells; it is not an enhancer of non-specific agglutination.The agglutinating factor has many of the

features of an antibody to an unknown antigenicstimulant, such as its location in the antibodyfraction, its stability, and its enhancement bynon-immune serum and pooled human plasma(Winblad, 1952b; Plotz, 1953). The effect 'ofglobulin fractions of normal sera in enhancingagglutination by specific immune sera has beenknown for many years (Pike et al., I949b). Theapparent lack of immunological specificity of thereaction, both as regards the type of cells agglu-tinated and the source of amboceptor, suggeststhat if this is an immune reaction the antibodyconcerned cannot be specific for erythrocytes,which may serve rather as an inert carrier than asthe source of antigen. That this is indeed so wasshown by Heller et al. (1954), who demonstratedthat tannic acid-treated erythrocytes, when coatedwith human serum fraction II, are agglutinatedby active rheumatoid sera. Erythrocytes can, infact, be eliminated from the system entirely asVaughan (1955) has shown that the rheumatoidfactor is active in non-agglutinating systems andcan be adsorbed on the washed immune precipi-tates from the antisera of rabbits immunized withcrystalline egg albumin, although it cannot beadsorbed by barium sulphate. A system con-sisting of Brucella abortus sensitized with a humananti-Brucella serum will also detect the rheuma-toid factor (Foz et al., 1954); and polystyrenelatex particles coated with pooled gamma globulinwill also serve as a carrier mechanism (Plotz andSinger, 1956). Further, sera agglutinating humanfraction II-coated cells will precipitate with pooledhuman serum fraction II, but the reaction isinhibited by excess of fraction II (Epstein et al.,1956). If the agglutinating factor is a com-ponent of an immune precipitin reaction the

antigen must necessarily be a gamma-globulinconstituent common to many species.

Speculation has arisen as to whether theagglutinating factor could be a complement(Meyer in I922 assumed that his' Agglutinations-fordende Substanz' was the third component ofcomplement, the only thermostable componenfthen known), and this role has been recentlyexamined (Hobson and Gorrill, 1952; Gorrilland Hobson, I952). Hobson and Gorrill claimthat the agglutinating factor present in smallamounts in normal sera resides in the fourthcomponent of complement (C4) and that thefirst component (Ci), after heating, inhibits theagglutinating activity of C4. The Ci and C4components of active rheumatoid sera behave inthe same way, but in them the lytic titre of C4is about three times as great as normal. Thiswould inferentially relate the increased lytic titreof C4 to agglutinating activity. Identification oflytic activity with complement is denied by Ball(1952a) and by Bunim (1953), but Shichikawaet al. (I956b and c), although unable to relateagglutinating activity to C3 or C4, found sometentative relationship with Ci. The elevation ofcomplement that occurs in the sera in many con-nective tissue disorders (Wedgewood and Janeway,1953) and in about one-third of cases of rheuma-toid arthritis (Vaughan et al., 1951) is not generallycorrelatable with agglutinating activity of wholeserum. However, the actual fractions of comple-ment elevated in these disorders is not known.A theory that the rheumatoid factor might be

an auto-antibody is rejected by Svartz (1956) onthe grounds that it is not adsorbed with erythro-cytes, whether coated with globulin or not;positive sera do not give a positive antiglobulintest; and steroids fail to lower its titre. Haemagglu-tination is inhibited in vitro by sulphonamides,especially azetazolamide, but only at non-thera-peutic levels. The significance of this finding isnot clear.

ConclusionsIt seems clear that in both the'sensitized sheep

cell and the streptococcal agglutination tests thecells and organisms have no immunological func-tion but serve as inert carriers of a globulinconstituent of serum; in the case of the sheepcells, of a gamma globulin in the amboceptor, andin the streptococci, of a water-soluble pseudo-globulin (Lamont-Havers, I955), possibly a betaglobulin (Oker-Blom, I952b). Cohn fraction IIof serum-gamma globulin-in excess can inhibitagglutination or reduce the titre of a positiveserum, presumably by competition with the rheu-matoid factor for the globulin reactant on thecarrier. This reactant or ' antigen ' is therefore

copyright. on July 9, 2021 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.33.378.170 on 1 April 1957. D

ownloaded from

http://pmj.bmj.com/

174 POSTGRADUATE MEDICAL JOURNAL April I957

a constituent of normal human gamma-globulinand also of the antisera to a wide range of antigenicstimulants.The agglutinating factor or 'antibody' has

been variously located in the beta- and gamma-globulin components of sera fractionated bydifferent methods, and its chemical nature is notyet known although some preliminary data haveaccrued (Lospalluto and Ziff, I956). The evidenceat present is against it being a fraction of comple-ment. The agglutinating factor for streptococciis a euglobulin (Lamont-Havers, 1955) distinctfrom the agglutinating factor for sheep cells.An inhibitor to the sheep-cell agglutinating factoris present in all sera, but in rheumatoid arthritisin amounts too small to reduce the agglutinatingtitre. Its absence is probably of diagnosticsignificance.Tannic acid-treated and fraction II-coated

erythrocytes will absorb both the sheep-cell andstreptococcal factors from serum, but amboceptor-sensitized cells will not, and the sheep-cell factoris not removed by prior absorption of positiveser.im with streptococci. It is clear, therefore,that separate reactors, or different fractions of thesame reactor, are involved in the two tests.

If the. character of the ' antigen ' in humangamma globulin and antisera which reacts withthe abnormal globulin component in the blood ofsubjects with rheumatoid arthritis is elucidated, itmay support the belief that a true immunereaction is concerned, involving an unknowncomponent of the host's connective tissues-possibly of a non-protein nature in combinationwith a constituent of serum protein. Thulin(1955) suggests that, because treatment of rheu-matoid sera with a variety of mucopolysaccharidesand autoclaved synovial tissue reduces or abolishesits titre for agglutinating streptococci, there existsin these sera auto-antibodies reacting with anti-genically active depolymerized mesenchymal poly-saccharides bound to serum proteins. Evidencethat immune reactions of this nature can occur isat present slight, but investigation of the immuno-logical reactivity of tissue polysaccharides is beingpursued (Boake and Muir, 1955; Glynn andHolborrow, 1952; Steffen and Schindler, I955)and seems to offer a likely field for the furtherinvestigation of the pathogenesis of certainrheumatic diseases.

BIBLIOGRAPHYALEXANDER, R., and DE FOREST, G. K. (r954): Amer. J.

Med., x6, 19I.BALL, J. (95o): Lancet ii, 520.BALL J. (x952): Ann. em.is., 11,97.BALL, J. (952a): Lancet, i, 614.BERNSTOCK, L., BEDSON, H. S., and GLYN, J. H. (I956):

Brit. med. J., 1, xi5I.BOAKE, W. C., and MUIR H (Igss): Lancet, ii, 1222.BOISVERT, P. L., BROCiETT, J. B., and DE FOREST, G.

(1956): Yale 7. Biol. Med., 28, 622.

BROWN, R., BUNIM, J. -J., and McEWEN, C. (I949): AnnRheum. Dis., 8, 299.

BUNIM, J. J. (1953): Ibid., 13, 321.BUNIM, J. J., and McEWEN, C. (l940): J. cin. Invest., 19, 75.CECIL, R. L., and DE GARA, P. F. (I946): Amer. 7. med. Sci.,

211, 472.CECIL, R. L., NICHOLLS, E. E., and STAINSBY, W. J. (1929):

Arch. intern. Med., 43, 571.CECIL, R. L., NICHOLLS, E. E., and STAINSBY, W. J. (1931):

Amer. 7. med. Sa., I1I, 12.CHASIS, H., and McEWEN, C. (I936): 7. Immunol., 31, 439.COGGESHALL H. C. (I953): Ann. Rheum. Dis., 12, 321.DAWSON, M. ., OLMSTEAD, M., and BOOTS, R. Hi (1932a):

_. Immunol. 23, I87.DAWSON, M. H., OLMSTEAD, M., and BOOTS, R. H. (1932b):

Ibid., 23, 205.DAWSON, M. H., OLMSTEAD, M., and JOST, E. L. (1934):

Ihid. 27, 335.DORDICK, J. R. and WASSERMAN, M. M. (i950): Amer. 7.

lin. Path., 20, 526.EPSTEIN, W., JOHNSON, A. M., and RAGAN, C. (I956):

Proc. Ann. Meet. A.R.A., Chicago, June I956.FABER, F. (1953): Acta med. Scand., 247, I21.FOZ, A., and BATALLA, E. (I955): Rev. esp. Rheum., 6, 142.FOZ, A., BATALLA, E., and ESPACIO, L. (I954): Rev. Diqgn. biol.(Madr.), 3, 460.GLYNN, L. E., and HOLBORROW, E. J. (1952): Lancet, ii 449.GORRILL, R. H., and HOBSON, D. (1952): Y. path. Bact.,GRA .J., and GOWEN, C. H. (1931): Amer. 7. med. Sci.,

I82, 682.GREENBURY, C. L., HILL, A. G. S., SMITH, R. S., and

GOOD, M. S. (I956): Lancet, i,544.HARRIS, T N HARRIS, S., DANNENBERG, A. R., and

HOLLANDER J. L. (I950): Ann. intern. Med., 32, 917.HELLER G., JACOBSON, A. S., and KOLODNY, M. H.

(I949): Proc. Soc. exper. Biol. & Med., 72, 316.HELLER, G., JACOBSON, A. S., KOLODNY, M. H., and

KAMMERER, W. H. (1954): Y. Immunol., 72, 66.HELLER, G JACOBSON, A. S., KOLODNY, M. H., and

SCHUMAN, R. L. (I952): Ibid., 69, 27.HELLER, G., KOLODNY, M. H., LEPOW, I. H., JACOBSON,

A. S., REVERA, M. E., and MARKS, G. H. (I955): Ibid.,74, 340.

HOBSON, D., and GORRILL R. H. (1952): Lancet, i, 389.JACOBSON, S., KAMMERER, H., and HELLER, G. (1953):

Ann. Rheum. Dis., 22, 321.JACOBSON, A. S., KAMMERER, W. H., WOLF, J., EPSTEIN,

W. V., and HELLER, G. (I956): Amer. Y. Med., 20, 490.JAWETZ, E., and HOOK, E. V. (1949): Proc. Soc. exper. Bsol. &

Med 70, 65o.KALBAI, K. (I948): Acta med. Scand., 230, 8KEEFER, C. S., MYERS, W. K., and OPPEL, T. W. (1933):

7. clin. Invest., I2, 279.KELLGREN, J. H. (1952): Brit. med. 7., i, 1093, II 52.LAMONT-HAVERS, R. W. (1953): Ann. Rheum. Dis., 13, 321.LAMONT-HAVERS, R. W. (1955): Proc. Soc. exper. Biol. &

Med 88, 35.LOSPALLUTO, J., and ZIFF, M. (1956): Proc. Ann. Meeting

A.R.A., Chicago, June I956.LEVINTHAL, W. (1939): Ann. Rheum. Dis., I, 67.MEYER, K. (1922): Ztschr. f. Immun. u. exper. Therap., 33, 283.MILLER, J. E LYNCH, E. R., and LANSBURY, J. (1949):

7. Lab. &t cin. Med., 34, 1216.MYERS, W. K., and KEEFER, C. S. (x934): 7. clin. Invest., 23, 155.MYERS, W. K., KEEFER, C. S., and HOLMES, W. F. (1935):

Ibid., 24, I19.NICHOLLS, E. E., and STAINSBY, W. J. (1931): Ibid., 20, 323.OKER-BLOM, N. (1952a): Ann. Med. exp. Biol. Fenn., 30, 139.OKER-BLOM, N. (1952b): Ibid., 30, 150.OKER-BLOM, N., and WIDHOLM, 0. (1952): Ibid., 30, I44.OUCHTERLONY O., and PALMBORG, G. (1949): Rheumatism,

5, I28.PERRY, C. B. (I940): Ann. Rheum. Dis., 2, 147.PIKE, R. M., SULKIN, S. E., and COGGESHALL, H. C.

(it49a): Y. Immunol., 63, 441.PIKE, R. M., SULKIN, S. E., and COGGESHALL, H. C.

(I9 9b): Ibid., 63, 447.PIKE, R. M., SULKIN, S. E., COGGESHALL, H. C., and

BURDETTE, R. I. (1953): 7. Lab. clin. Med., 42, 88o.PLOTZ, C. M. (1953): Ann. Rheum. Dis., 13, 32I.PLOTZ, C. M., and SINGER, J. (1956): Proc. Ann. Meeting

A.R.A., Chicago, June I956.ROBINSON A. R., STULBERG, C. S and KUYPER, A. C.

(1954): hoc. Soc. exper. Biol. & Mel, 8S, 4.ROSE, H. M., RAGAN, C., PEARCE, E., and LIPMAN, M. 0.

(1948): Ibid 68, I.SCOTT, F. E. 1. (I952): Lancet, i, 392.SHICHIKAWA, K., ASANO, N., ORIHARA, M., MAYEDA, A.,

TAMATANI, Y., and YASUI)A, J. (I956): Acta Rheum.Scand., 2, 34.

SHICHIKAWA, K., et al. (q956b): Ibid., 2, 4S.SHICHIKAWA, K., et al. (i9s6c): Ibid., 2, 55.STEFFEN C., and SCHINDLER, H. (i955): Schwerz. Z. allg.

Path. haht., I8, 287.Bibliography continued on page 192.

copyright. on July 9, 2021 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.33.378.170 on 1 April 1957. D

ownloaded from

http://pmj.bmj.com/

192 POSTGRADUATE MEDICAL JOURNAL April 1957

Clinical examination showed vague tendernessin the right half of the abdomen, maximum in theright iliac fossa. A tender mass was palpable inthe region of McBurney's point about 2 in. indiameter. Temperature was 990 and pulse rate 8o.Laparotomy under general anaesthesia showed a

tumour in the posterior wall of the caecum at thelevel of the ileo-caecal valve. The caecum wasadherent to the posterior abdominal wall. A righthemi-colectomy was carried out with resection ofthe terminal ileum, caecum and ascending colon,and an end-to-end anastomosis was performed.Post-operatively the patient made a satisfactoryrecovery.The specimen (Figs. 3 and 4) showed an ulcer

about r7 in. in diameter with vertical walls, pene-trating deeply into the muscular layer of the bowel.

Further investigations showed no evidence ofamoebiasis or other exciting cause.

Histological examination of both specimensshowed no evidence of malignancy. In the firstpatient there was marked oedema in the sub-mucous layer. The inflammatory processes weremost marked in the depths of the ulcer, suggestingthat the process of penetration was still active andthat an abscess was probably about to form. Thesub-mucous oedema is clearly shown in the section(Fig. 2). In the male patient there was no grossoedema in the sub-mucous layer, but inflammatoryprocesses were rather more active. The ulcer hadnot penetrated so deeply, but the muscle hadactually been partly breached. The histologicalpicture is shown in Fig. 5.

CommentIt will be noted that both these cases were

diagnosed as appendicitis and that the truepathology was only detected at operation. Thisappears to be the usual state of affairs with simpleulcers in the colon. In both specimens it was verynoticeable that the inflammatory process was active

FIG. 5.

in the sub-mucous layer. As Cameron noted, thisis a feature which has been seen by all observersreporting this condition in the past and it would,therefore, seem that the lesion is primarily one ofthe superficial layers in the bowel.

I should like to thank Dr. D. Brewer for themicrophotographs and histological reports andMr. T. F. Dee for Figs. I, 3 and 4.

BIBLIOGRAPHYCAMERON, J. R. (I939), Brit. J. Surg., 269 526.WATTS, G. T. (I955), Postgrad. med.J., 319 414.

Bibliography continued from page 174-Ellis Dresner, M.D., M.R.C.P.

SULKIN, S. E., PIKE, R. M., and COGGESHALL, H. C.(i949): Proc. Soc. exper. Biol. & Med., 70, 475.

SVARTZ, N. (I956): Lancet, ii, 194.SVARTZ, N., and SCHLOSSMANN, K. (i95o): Ann. Rheum.

Dis., 9, 377.SVARTZ, N., and SCHLOSSMANN, K. (1952): Act. med. Scand.,

142, 420.

SVARTZ, N., and SCHLOSSMANN, K. (1955): Ann. Rheum.Ds., I4, I9I.

THULIN, K. E. (i95s): Acta Rheum. Scand., i, 22.VAUGHAN, J. N. (i95s): Ann. Rheum. Dis., 14, 431.VAUGHAN, J. H., BAYLES, T. B., and FAVOUR, C.B. (195I):

Amer. Y. med. Sci., 222, x86.

WAALER, E. (I940): Acta path. et Microbiol. Scand., 17, 172.WAGER, 0. (I950): Ann. Med. exp. Fenn., 28, Suppl. 8.WAINWRIGHT, C. W. (1934): Y. Amer. med. Ass., I03, I357.WALLIS, A. D. (I946a): Amer. 3Y. med. Sd., 212, 7I6.WALLIS, A. D. (1946b): Ibid., 212, 7I8.WEDGEWOOD, R. J. P., and JANEWAY, C. A. (1953): Pediatrcs,

II, 569.WINBLAD, S. (Is92a): Acta med. Scand., 142, 450.WINBLAD, S. (s952b): Ibid., 142, 458.ZIFF, M BROWN, P., BADIN, J., and McEWEN, C. (I954):

Bull. J?heum. Dis., 5, 75.ZIFF, M BROWN, P., LOSPALLUTO, J., BADIN, J. andMcEi EN, C. (I956): Amer. J'. Med., 20, 500.

copyright. on July 9, 2021 by guest. P

rotected byhttp://pm

j.bmj.com

/P

ostgrad Med J: first published as 10.1136/pgm

j.33.378.170 on 1 April 1957. D

ownloaded from

http://pmj.bmj.com/