THE SERUM FACTOR IN RHEUMATOID ARTHRITIS AGGLUTINATING SENSITIZED SHEEP ERYTHROCYTES A thesis presented for the degree of Doctor of Medicine hy John Ball The Victoria University of Manchester April 1951 ProQuest Number: 13916492 All rights reserved INFORMATION TO ALL USERS The quality of this reproduction is dependent upon the quality of the copy submitted. In the unlikely event that the author did not send a complete manuscript and there are missing pages, these will be noted. Also, if material had to be removed, a note will indicate the deletion. uest ProQuest 13916492 Published by ProQuest LLC(2019). Copyright of the Dissertation is held by the Author. All rights reserved. This work is protected against unauthorized copying under Title 17, United States Code Microform Edition © ProQuest LLC. ProQuest LLC. 789 East Eisenhower Parkway P.O. Box 1346 Ann Arbor, Ml 48106- 1346 "l&.oiq W. 7-51. C O N T E N T S Page Acknowledg ement s Historical introduction Review of literature Part Is An exxppeerriimmeennttaall ssttuuddyy ooff tthhee agglutination of sensitized sheep cells by human s erum 18 A. Technical details of the Rose test 18 B* The modified Rose test 19 (1) The role of heterophil antibody 20 (2) The rble of anti~sheep erythrocyte rabbit serum 29 (a) The effect of increasing the concentration of haemolysin 29 (b) The effect of different batches of haemolysin (3) The duration of the test 36 C. Summary of Part I hi Part II: The clinical trial hh A. Source of clinical material Ljlj. B. General review of results based on single tests h6 C. General review of results based on multiple tests h7 Tka Victoria University of Manchester, | MESJICAL LIBRARY. « « 11 - - QgJLLH^TIori Of V/.'G'-’'fl.ATIKCJ TO ! MiDtCit1 ■” T- I - ii - Page D. Description of the clinical material and results in the non-rheumatoid groups 50 Summary and discussion 67 E. Analysis of the results .in 6*+2 cases of rheumatoid arthritis 73 (1) The distribution of cases according to agglutinin titre 73 (2) The relation of the test to clinical findings 7*+ (a) Psoriatic rheumatoid arthritis? juvenile rheumatoid arthritis and rheumatoid arthritis associated with osteo-arthritis 75 (Id) The relation of the test to sex 75 (c) The relation of the test to age at onset of the disease 76 (d) The relation of the test to duration of disease 77 (e) The relation of the test to nodule formation 78 (f) The relation of the test to X-ray findings 80 (g) The relation of the test to extent of joint involvement 81 (h) The relation of the test to activity of disease 82 (3) Summary and discussion of the results in rheumatoid arthritis 83 F. The relation of the test to clinical course of disease and effects of adrenocorticotrophic hormone (ACTH) 87 iii - iii - Page G. The effect of increasing the sensitivity of the test 90 H- A critical assessment of the test as a diagnostic aid 97 I. General summary of Part II 101 Part III: The nature and significance of the rheumatoid serum factor 105 Discussion 11^ Summary of Part III 118 General simmary 120 Technical appendix 125 Bibliography 131 Reprint of Author’s article in Lancet, IJov 11, 1950 - iv - ACKNOWLEDGEMENTS This investigation was carried out whilst holding, an appointment as Research Assistant in the Pathological Laboratories of the Rheumatism Research Centre at Manchester University. I am deeply indebted to Professor S.La Baker9 the Director of the Centre’s Pathological Laboratories, for. his constant encouragement and advice and to Dr. J.H. Kellgren, the Clinical Director of the Rheumatism Research Centre, for allowing me access to his patients and records and for advice regarding the clinical aspects of the work. I have been fortunate in being able to discuss serological problems with Professor H.B. Maitland to whom I express my sincere thanks for his interest in the work. The electrophoresis diagrams were prepared by Mr. R.G.S. Johns in Professor J.R. Marrack’ Laboratory and it is a pleasure to express my thanks for their ready co-operation. - v - - V - I am indebted to the physicians and surgeons of the Manchester Koyal Infirmary, the University Department of Pediatrics, Monsall Hospital, Crumpsail Hospital, Wrightington Orthopaedic Hospital and the MinersT Clinic at Walkden for kindly providing serum from their patients. My thanks are due to Dr. L. Haddocks whose co-operation greatly facilitated the collection of control sera. I am greatly indebted to Miss F. Bier for her assistance and advice in the presentation of the results of the clinical trial and for typing the thesis. My thanks are also due to Messrs. D. Taylor and R. Finnigan for careful technical assistance during the investigation. HISTORICAL INTRODUCTION The history of medicine teaches us that an insecure and shifting nomenclature indicates an insufficient knowledge of the aetiological agents or "body mechanisms underlying disease states. It also teaches us that superficial similar­ ities are often found in distinct conditions and that apparent ly unconnected disorders may have a common pathological basis. It will be germane to this thesis to illustrate these lessons by brief reference to the history of rheumatic disease. Although gout was known to Hippocrates, the ancients described rheumatic disease under the generic title arthritis. The term 'rheumatism1 arose out of the belief that diseases were expressions of the discharge exteriorly or into the body cavities such as the joints, of faulty "humours11 of which four constituted the human body. Not until the seventeenth century was this medieval concept replaced by accurate clinical observation exemplified in Sydenham's lucid de~ scription of acute rheumatic fever, lumbago and gout. Later 'rheumatism', under the influence of aetiological theory, came to have a broader meaning; any migratory pain in muscle or joint was called rheumatic, and diverse maladies were characterised by the adjective 'gouty*. - 2 - 2 The recognition of new clinical entities sometimes led to confusion. Thus, the term 'ischiadica1, originally clearly under­ stood to mean a painful condition of the hips, was adopted by Cotugno (1770) to describe a syndrome known later as sciatica. Cullen1s (1785) nosological studies, and the clinical demonstration by Scudamore (1827) that tendinous tissue is a common site of rheumatic disease were significant contribu­ tions to our knowledge. Yet the modern reader of Scudamore cannot clearly interpret his descriptions of chronic rheumatism in terms of the many syndromes known today. The truth is that clinical studies at this time were seriously hindered by the absence of a "reliable point of reference with which the aspects of disease might be correlated" (Mettler, 19k7)- With the advent of bacteriology the truly infective artnritides were clearly demarcated as a separate group5 and with this discovery came the realisation that chronic arthritis of known infective origin may present clinically and patho­ logically in a form indistinguishable from either rheumatoid arthritis or osteo-arthritis (Reports 011 Chronic Rheumatic Diseases, 193?)• The creation of cellular pathology by Virchow (18?8) made possible a histological appraach to rheumatic disease5 by 190k Aschoff had described the characteristic cardiac Tbs VieictM Univsvsity af Mane^st:}?, | MES'.CAL L'HRARY, I 3 C0U-2OTIO?? 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