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Remarks on the present state of the rheumatoid arthritis problem
Seminar
on Connective
Remarks
on the Present
Rheumatoid
Arthritis
Tissue State
of the
Problem*
CHARLES RAGAN, M.D. New York, New York
R
ECENT
studies on rheumatoid arthritis have
“atypical” [ 11; “classic” rather than “probable,” according to the proposed diagnostic criteria [I] ; with a positive serologic reaction for the rheumatoid factor rather than with a negative reaction [2] ; men do better than women [ 71. In population studies of patients with classic rheumatoid arthritis, i.e., those patients exhibiting positive “factor” reactions and x-ray changes, the sex incidence approaches 1: 1, in contrast to the usual clinic population ratio of two to three females to one male. In such total population studies, however, patients with joint signs and symptoms (but not necessarily factor-positive or x-ray-positive) have a similar female preponderance [3]. The hereditary aspects of peripheral joint rheumatoid arthritis are not as clear-cut as they appear to be in the spinal variant, MarieStriimpell spondylitis [79]. Peripheral joint rheumatoid arthritis occasionally appears in families have been entwins, and certain countered with a high prevalence of the disease. In three studies the rheumatoid factor has been observed more frequently in siblings [3,7,8] but in one the technic used is considered by some to be too sensitive and consequently non-specific [a]. No conclusive pedigree studies on the disease has been carried out to date. Most students of the disease believe that genetic factors probably play a role in peripheral joint rheumatoid arthritis but one which will not be easy to document. Assessment of therapy has been particularly difficult. An attempt is currently being made in this country to determine the possibility of employing modern methods of therapeutic evaluation in this disease, with its characteristics of chronicity, unpredictable course, and end-
been concentrated in three fairly well delined areas-the clinical disease, the tissues involved, and the serologic reactions observed. Each area has been intensively investigated in relationship to pathogenesis. An evaluation of the current status of this work might prove illuminating. Clinical Studies. The clinical picture of the disease-its natural history [YJ] and its epidemiology [3]-has received a great deal of attention. These efforts on a clinical plane have been fraught throughout with difficulties imposed by the elusive nature of rheumatoid arthritis. The disease when far advanced is apparent even to the novice but in its early or minimal stage is difficult to recognize and to characterize even for the trained specialist. Diagnostic criteria have been proposed but they have serious limitations [4]. Criteria to appraise the rate and intensity of progression of the disorder have been suggested but these also have defects [5,6]. Individual patients have been noted who violate all the criteria, and the frequency with which these patients are encountered has sorely tried the investigator who has chosen to work with rheumatoid arthritis. All dicta promulgated for assessing (1) the presence of the disease, (2) its severity, and (3) its expected course, can be applied only to rheumatoid arthritis in general and not to the individual patient. And, lastly, functional capacity correlates with severity of disease on a statistical but no more precise basis. From these studies certain broad generalizations may however be made. Patients are more likely to have sustained disease if the manifestations of the disease are “typical” rather than * From MAY,
the Department of Medicine, Columbia University College of Physicians and Surgeons, and the Edward Daniels Faulkner Arthritis Clinic of the Presbyterian Hospital, New York, New York. 1959
797
798
Remarks on the Present State of the Rheumatoid Arthritis Problem--Rugan
points so difficult to appraise. In England similar efforts have been made [9] but reservations have been expressed concerning the validity of these trials [ 701. All in all, the relevant clinical studies of rheumatoid arthritis have been tedious and not too rewarding. Although a great mass of data has been accumulated from such studies, we have gained from them but little solid knowledge of the cause of the disease. Connective Tissue Studies. The study of the tissues involved in rheumatoid arthritis, in relation to etiologic mechanisms, has had a long and honorable history. The histopathology of rheumatoid arthritis may be called nondescript. In patients with unequivocal disease the lesions are similar to scar tissue with an element of granulomatous inflammation. In early disease, the specificity of the lesion observed may be questioned. The rheumatoid nodule is considered to be the most characteristic visible lesion but the distinction between the nodule of rheumatoid arthritis and that of rheumatic fever remains a matter of dispute, and the fact that rheumatoid nodules appear in patients with unequivocal systemic lupus erythematosus [ 7 I] tends to lessen the specificity of this so-called specific lesion. It has been proposed on the basis of limited direct evidence, as well as on inferential evidence, that the primary lesion is an arteritis [7573]. But one or another form of arteritis may be encountered in a myriad of disorders and this view, even if correct, can therefore hardly lead to a closer delineation of our knowledge regarding possible pathogenic mechanisms. It has suggested to some the possibility that the disease may be based on hypersensitivity. This train of thought has been fortified by the lack of conclusive evidence of a microbial etiology, by the sustained nature of the disease in many instances, and by the presence of the rheumatoid factor which, it has been suggested, may play the role of an antibody, particularly an autoantibody. The disease affects the connective tissue widely and has loosely been called-with some justification since it involves this tissue primarily-a disease of the connective tissue. In the last decade, interest in this aspect of the problem has stimulated and has led to the support of much work in this previously neglected area. A great deal has been learned about the connective tissue, its cells, amorphous ground substances and fibrillar elements [74]. Ignorance even of the
composition of the connective tissue was so monumental when the work began that our understanding of this aspect of normal tissue has completely occupied the attention of many investigators and they have been able to approach the problem of abnormal states only sporadically. It is hoped that in time an understanding of abnormal conditions will logically follow the elegant work which has so far been done on the composition of normal components. Another aspect of the problem, i.e., the plasticity of this tissue, its genesis, differentiation, turnover and the role it plays in vital processes, has been touched upon even in normal states only in the most superficial fashion [ 751. Suffice it to say, however, that as of now, little knowledge of the pathogenic mechanisms involved in rheumatoid arthritis has evolved from these truly great additions to our general biologic knowledge. The Concept of Autoimmunity in Rheumatoid The autoimmune aspects of the probArthritis. lem have developed in two separate channels. The first consists of attempts to determine the antigenicity of components of homologous connective tissue. These have been unsuccessful to date, and there is a real possibility that isolation procedures may destroy the potential antigenicity of the substances under investigation. The second approach involving the concept of autoimmunity has concerned itself with the possible role of the rheumatoid factor as an antibody. Significant advances have been made in our understanding of the reaction in which this material participates [76]. In brief, and in oversimplified terms, the reaction involves the factor residing in the 19s fraction of gamma globulin (which contains other antibodies) and the reactant material with which the factor reacts. This latter substance is, in the precipitating and some agglutinating systems, an aggregate of 7S gamma globulin; in other agglutinating systems it consists of antibody gamma globulin in combination with its specific antigen -as in an immune precipitate. In other words, the factor reacts with gamma globulin antibody only in the physical state in which gamma globulin exists when it is combined with specific antigen. A soluble complex with a sedimentation constant of 22s apparently is formed, consisting of the factor and non-aggregated gamma globulin. The interpretation of the difference in reactant material in precipitating and agglutinating systems on the one hand and the soluble complex on the other is not clear at this time. AMERICAN
JOURNAL
OF
MEDICINE
Remarks on the Present State of the Rheumatoid Arthritis Problem-&gun The reactant is species-non-specific. Similarities and dissimilarities between the rheumatoid factor and antibodies are frequently reported. Crude attempts made to induce the disease, or to modify it once established, by injecting the factor 1171 or the reactant [78] have so far been unsuccessful. Continued study of the role of the rheumatoid factor in the disease is a lead which must be pursued. At the time of this writing, the thought that this reaction may turn out to be of the Wassermann reaction type and lead us no further towards knowledge of pathogenesis is uppermost in many minds. Thus, in summary, the ideas which have been followed have not, up to now, led to a clear-cut understanding of the pathogenesis of rheumatoid arthritis. The picture, however, is not all black. With the interest which has been aroused by each new development, new investigators have been attracted to the field and it is to be hoped that these new minds will continue to develop fresh approaches. Control of rheumatoid arthritis need not wait upon complete elucidation of the basic mechanisms involved. The demonstration that the process of rheumatic fever was initiated by infection with the Group A hemolytic streptococcus is an example. Antistreptococcal prophylaxis for the prevention of recurrent attacks of rheumatic fever has been eminently successful in curbing that disease, yet we have little more understanding of the subsequent stages of rheumatic fever following the initial streptococcal infection than we have of rheumatoid arthritis. More complete comprehension of the precipitating causes of rheumatoid arthritis, its initiation, and its ability to sustain itself might provide the means whereby the chain of progression of the pathologic process could be broken, As an example of this, there is a clinical oddity which has been recognized for a long time. When the patient with rheumatoid arthritis receives an insult, whether traumatic or infectious (a bout of pneumonia), the symptoms of the disease may abate temporarily. This cannot be satisfactorily explained by an increase in endogenous steroid secretion or other known factors. We have naively considered that the patient with rheumatoid arthritis cannot manage more than one disease at a time but a logical explanation based on knowledge of pathogenicity would obviously be more satisfying. It is still possible, of course, that further understanding of the clinical picture of the disease, its morbid pathology, the characteristics of the MAY, 1959
799
connective tissue or the role of the rheumatoid factor may help to unravel the problem of the pathogenesis of rheumatoid arthritis. Obviously, each of these areas needs continued study. In addition, new investigators recently brought into this field may develop a fresh approach which would fulfill the wish of those who have given categorical funds for the prevention and cure of rheumatoid arthritis. New concepts require an idea, some prior knowledge, and a dash of serendipity. They cannot be bought, but the development of a fresh concept and its pursuit to a successful conclusion can be helped immensely by such funds. Success in this framework would consist of ability to break the chain of progression of events which we know as the disease “rheumatoid arthritis.” Total success would mean ability to prevent the inception of the disorder, but most of us would be quite happy to be able to modify the disease for the benefit of the patient by measures which, in addition to being reliable and relatively non-toxic, would be based logically on an understanding of pathogenic mechanisms. REFERENCES 1. SHORT, C. L., BAUER, W. and REYNOLDS, W. E. Rheumatoid Arthritis. Cambridge, 1957. Harvard University Press. 2. RAGAN, C. The general management of rheumatoid arthritis. J. A. M. A., 141: 124, 1949. 3. LAWRENCE, J. C. Prevalence of rheumatoid arthritis in urban and rural populations in United Kingdom. In: Population Studies in Rheumatoid Arthritis, p. 13. Edited by Kellgren, J. H. Arthritis and Rheumatism Foundation in cooperation with the National Institute of Arthritis and Metabolic Diseases of the U. S. Public Health Service. New York, 1958. 4. ROPES, M. W., BENNETT, G. A., COBB, S., JACOX, R. and JESEAR, R. A. Proposed diagnostic criteria for rheumatoid arthritis. J. Chronic Dis., 5: 630, 1957. 5. STEINBROCKER,O., TRAEGER, C. H. and BATTERMAN, R. C. Therapeutic criteria in rheumatoid arthritis. J. A. M. A., 140: 659, 1949. 6. LANSBURY,J. Quantitation of the activity of rheumatoid arthritis. V. A method for summation of the systemic indices of rheumatoid activity. Am. J. M. SC., 232: 300, 1956. 7. DEBLECOURT,J. J. Hereditary factors in rheumatoid arthritis and ankylosing spondylitis. Ninth International Congress on Rheumatic Diseases, vol. 2, p. 93, 1957. 8. ZIFF, M., SCHMID,F. R., LEWIS, A. J. and TANNER, M. Familial occurrence of the rheumatoid factor. Arthritis B Rheumat., 1: 392, 1958. 9. Long-term results in early cases of rheumatoid
800
10.
11.
12.
Remarks
on the Present State of the Rheumatoid
arthritis treated with either cortisone or aspirin. A third report by the Joint Committee of the Medical Research Council and Nuffield Foundation on clinical trials of cortisone, ACTH and other therapeutic measures in chronic rheumatic diseases. Brit. M. J., 1: 847, 1957. SAVAGE, 0. Criteria for measurement in chronic diseases. Report of a Symposium on Clinical Trials, p. 34. Tonbridge, Kent, England, 1958.
LARSON, D. L. and SHULMAN,L. E. Relation of rheumatoid arthritis to systemic lupus erythematosus. Am. J. Med. (In press.) SOKOLOFF, L., MCCLUSKEY, J. T. and BUNIM, J. J. The vascularity of the early subcutaneous nodules of rheumatoid arthritis. Proceedings of the New York Pathologic Society, November 1952. Bull. NPW York Acad. Med., 29: 733, 1953.
Arthritis
Problem--&gun
13. RAGAN, C. The role of hypersensitivity in the management of rheumatoid arthritis. Ann. Rheumat. Dis. (In press.) 14. CASTOR, W. Approaches to the study of connective tissue. Bull. Rheumat. Dis., 9: 177, 1959. 15. SLACK, H. G. B. Some notes on the composition and metabolism of connective tissue. Am. J. Med., 26: 113,1959. 16. VAUGHAN, J. H. Serum responses in rheumatoid arthritis. Am. J. Med., 26: 596, 1959. 17. VAUGHAN, J. H. and HARRIS, J. Transfusion of rheumatoid factor. Proceedings of the American Rheumatism Association, San Francisco, June, 1958. Arthritis CT Rheumatism, 2: 51, 1959.
18. CHRISTIAN, C. L. Personal communication. 19. MCKUSICK, V. A. Genetic factors in disease of connective tissue. Am. J. Med., 26: 283, 1959.
AMERICAN
JOURNAL
OF MEDICINE
on Connective
Remarks
on the Present
Rheumatoid
Arthritis
Tissue State
of the
Problem*
CHARLES RAGAN, M.D. New York, New York
R
ECENT
studies on rheumatoid arthritis have
“atypical” [ 11; “classic” rather than “probable,” according to the proposed diagnostic criteria [I] ; with a positive serologic reaction for the rheumatoid factor rather than with a negative reaction [2] ; men do better than women [ 71. In population studies of patients with classic rheumatoid arthritis, i.e., those patients exhibiting positive “factor” reactions and x-ray changes, the sex incidence approaches 1: 1, in contrast to the usual clinic population ratio of two to three females to one male. In such total population studies, however, patients with joint signs and symptoms (but not necessarily factor-positive or x-ray-positive) have a similar female preponderance [3]. The hereditary aspects of peripheral joint rheumatoid arthritis are not as clear-cut as they appear to be in the spinal variant, MarieStriimpell spondylitis [79]. Peripheral joint rheumatoid arthritis occasionally appears in families have been entwins, and certain countered with a high prevalence of the disease. In three studies the rheumatoid factor has been observed more frequently in siblings [3,7,8] but in one the technic used is considered by some to be too sensitive and consequently non-specific [a]. No conclusive pedigree studies on the disease has been carried out to date. Most students of the disease believe that genetic factors probably play a role in peripheral joint rheumatoid arthritis but one which will not be easy to document. Assessment of therapy has been particularly difficult. An attempt is currently being made in this country to determine the possibility of employing modern methods of therapeutic evaluation in this disease, with its characteristics of chronicity, unpredictable course, and end-
been concentrated in three fairly well delined areas-the clinical disease, the tissues involved, and the serologic reactions observed. Each area has been intensively investigated in relationship to pathogenesis. An evaluation of the current status of this work might prove illuminating. Clinical Studies. The clinical picture of the disease-its natural history [YJ] and its epidemiology [3]-has received a great deal of attention. These efforts on a clinical plane have been fraught throughout with difficulties imposed by the elusive nature of rheumatoid arthritis. The disease when far advanced is apparent even to the novice but in its early or minimal stage is difficult to recognize and to characterize even for the trained specialist. Diagnostic criteria have been proposed but they have serious limitations [4]. Criteria to appraise the rate and intensity of progression of the disorder have been suggested but these also have defects [5,6]. Individual patients have been noted who violate all the criteria, and the frequency with which these patients are encountered has sorely tried the investigator who has chosen to work with rheumatoid arthritis. All dicta promulgated for assessing (1) the presence of the disease, (2) its severity, and (3) its expected course, can be applied only to rheumatoid arthritis in general and not to the individual patient. And, lastly, functional capacity correlates with severity of disease on a statistical but no more precise basis. From these studies certain broad generalizations may however be made. Patients are more likely to have sustained disease if the manifestations of the disease are “typical” rather than * From MAY,
the Department of Medicine, Columbia University College of Physicians and Surgeons, and the Edward Daniels Faulkner Arthritis Clinic of the Presbyterian Hospital, New York, New York. 1959
797
798
Remarks on the Present State of the Rheumatoid Arthritis Problem--Rugan
points so difficult to appraise. In England similar efforts have been made [9] but reservations have been expressed concerning the validity of these trials [ 701. All in all, the relevant clinical studies of rheumatoid arthritis have been tedious and not too rewarding. Although a great mass of data has been accumulated from such studies, we have gained from them but little solid knowledge of the cause of the disease. Connective Tissue Studies. The study of the tissues involved in rheumatoid arthritis, in relation to etiologic mechanisms, has had a long and honorable history. The histopathology of rheumatoid arthritis may be called nondescript. In patients with unequivocal disease the lesions are similar to scar tissue with an element of granulomatous inflammation. In early disease, the specificity of the lesion observed may be questioned. The rheumatoid nodule is considered to be the most characteristic visible lesion but the distinction between the nodule of rheumatoid arthritis and that of rheumatic fever remains a matter of dispute, and the fact that rheumatoid nodules appear in patients with unequivocal systemic lupus erythematosus [ 7 I] tends to lessen the specificity of this so-called specific lesion. It has been proposed on the basis of limited direct evidence, as well as on inferential evidence, that the primary lesion is an arteritis [7573]. But one or another form of arteritis may be encountered in a myriad of disorders and this view, even if correct, can therefore hardly lead to a closer delineation of our knowledge regarding possible pathogenic mechanisms. It has suggested to some the possibility that the disease may be based on hypersensitivity. This train of thought has been fortified by the lack of conclusive evidence of a microbial etiology, by the sustained nature of the disease in many instances, and by the presence of the rheumatoid factor which, it has been suggested, may play the role of an antibody, particularly an autoantibody. The disease affects the connective tissue widely and has loosely been called-with some justification since it involves this tissue primarily-a disease of the connective tissue. In the last decade, interest in this aspect of the problem has stimulated and has led to the support of much work in this previously neglected area. A great deal has been learned about the connective tissue, its cells, amorphous ground substances and fibrillar elements [74]. Ignorance even of the
composition of the connective tissue was so monumental when the work began that our understanding of this aspect of normal tissue has completely occupied the attention of many investigators and they have been able to approach the problem of abnormal states only sporadically. It is hoped that in time an understanding of abnormal conditions will logically follow the elegant work which has so far been done on the composition of normal components. Another aspect of the problem, i.e., the plasticity of this tissue, its genesis, differentiation, turnover and the role it plays in vital processes, has been touched upon even in normal states only in the most superficial fashion [ 751. Suffice it to say, however, that as of now, little knowledge of the pathogenic mechanisms involved in rheumatoid arthritis has evolved from these truly great additions to our general biologic knowledge. The Concept of Autoimmunity in Rheumatoid The autoimmune aspects of the probArthritis. lem have developed in two separate channels. The first consists of attempts to determine the antigenicity of components of homologous connective tissue. These have been unsuccessful to date, and there is a real possibility that isolation procedures may destroy the potential antigenicity of the substances under investigation. The second approach involving the concept of autoimmunity has concerned itself with the possible role of the rheumatoid factor as an antibody. Significant advances have been made in our understanding of the reaction in which this material participates [76]. In brief, and in oversimplified terms, the reaction involves the factor residing in the 19s fraction of gamma globulin (which contains other antibodies) and the reactant material with which the factor reacts. This latter substance is, in the precipitating and some agglutinating systems, an aggregate of 7S gamma globulin; in other agglutinating systems it consists of antibody gamma globulin in combination with its specific antigen -as in an immune precipitate. In other words, the factor reacts with gamma globulin antibody only in the physical state in which gamma globulin exists when it is combined with specific antigen. A soluble complex with a sedimentation constant of 22s apparently is formed, consisting of the factor and non-aggregated gamma globulin. The interpretation of the difference in reactant material in precipitating and agglutinating systems on the one hand and the soluble complex on the other is not clear at this time. AMERICAN
JOURNAL
OF
MEDICINE
Remarks on the Present State of the Rheumatoid Arthritis Problem-&gun The reactant is species-non-specific. Similarities and dissimilarities between the rheumatoid factor and antibodies are frequently reported. Crude attempts made to induce the disease, or to modify it once established, by injecting the factor 1171 or the reactant [78] have so far been unsuccessful. Continued study of the role of the rheumatoid factor in the disease is a lead which must be pursued. At the time of this writing, the thought that this reaction may turn out to be of the Wassermann reaction type and lead us no further towards knowledge of pathogenesis is uppermost in many minds. Thus, in summary, the ideas which have been followed have not, up to now, led to a clear-cut understanding of the pathogenesis of rheumatoid arthritis. The picture, however, is not all black. With the interest which has been aroused by each new development, new investigators have been attracted to the field and it is to be hoped that these new minds will continue to develop fresh approaches. Control of rheumatoid arthritis need not wait upon complete elucidation of the basic mechanisms involved. The demonstration that the process of rheumatic fever was initiated by infection with the Group A hemolytic streptococcus is an example. Antistreptococcal prophylaxis for the prevention of recurrent attacks of rheumatic fever has been eminently successful in curbing that disease, yet we have little more understanding of the subsequent stages of rheumatic fever following the initial streptococcal infection than we have of rheumatoid arthritis. More complete comprehension of the precipitating causes of rheumatoid arthritis, its initiation, and its ability to sustain itself might provide the means whereby the chain of progression of the pathologic process could be broken, As an example of this, there is a clinical oddity which has been recognized for a long time. When the patient with rheumatoid arthritis receives an insult, whether traumatic or infectious (a bout of pneumonia), the symptoms of the disease may abate temporarily. This cannot be satisfactorily explained by an increase in endogenous steroid secretion or other known factors. We have naively considered that the patient with rheumatoid arthritis cannot manage more than one disease at a time but a logical explanation based on knowledge of pathogenicity would obviously be more satisfying. It is still possible, of course, that further understanding of the clinical picture of the disease, its morbid pathology, the characteristics of the MAY, 1959
799
connective tissue or the role of the rheumatoid factor may help to unravel the problem of the pathogenesis of rheumatoid arthritis. Obviously, each of these areas needs continued study. In addition, new investigators recently brought into this field may develop a fresh approach which would fulfill the wish of those who have given categorical funds for the prevention and cure of rheumatoid arthritis. New concepts require an idea, some prior knowledge, and a dash of serendipity. They cannot be bought, but the development of a fresh concept and its pursuit to a successful conclusion can be helped immensely by such funds. Success in this framework would consist of ability to break the chain of progression of events which we know as the disease “rheumatoid arthritis.” Total success would mean ability to prevent the inception of the disorder, but most of us would be quite happy to be able to modify the disease for the benefit of the patient by measures which, in addition to being reliable and relatively non-toxic, would be based logically on an understanding of pathogenic mechanisms. REFERENCES 1. SHORT, C. L., BAUER, W. and REYNOLDS, W. E. Rheumatoid Arthritis. Cambridge, 1957. Harvard University Press. 2. RAGAN, C. The general management of rheumatoid arthritis. J. A. M. A., 141: 124, 1949. 3. LAWRENCE, J. C. Prevalence of rheumatoid arthritis in urban and rural populations in United Kingdom. In: Population Studies in Rheumatoid Arthritis, p. 13. Edited by Kellgren, J. H. Arthritis and Rheumatism Foundation in cooperation with the National Institute of Arthritis and Metabolic Diseases of the U. S. Public Health Service. New York, 1958. 4. ROPES, M. W., BENNETT, G. A., COBB, S., JACOX, R. and JESEAR, R. A. Proposed diagnostic criteria for rheumatoid arthritis. J. Chronic Dis., 5: 630, 1957. 5. STEINBROCKER,O., TRAEGER, C. H. and BATTERMAN, R. C. Therapeutic criteria in rheumatoid arthritis. J. A. M. A., 140: 659, 1949. 6. LANSBURY,J. Quantitation of the activity of rheumatoid arthritis. V. A method for summation of the systemic indices of rheumatoid activity. Am. J. M. SC., 232: 300, 1956. 7. DEBLECOURT,J. J. Hereditary factors in rheumatoid arthritis and ankylosing spondylitis. Ninth International Congress on Rheumatic Diseases, vol. 2, p. 93, 1957. 8. ZIFF, M., SCHMID,F. R., LEWIS, A. J. and TANNER, M. Familial occurrence of the rheumatoid factor. Arthritis B Rheumat., 1: 392, 1958. 9. Long-term results in early cases of rheumatoid
800
10.
11.
12.
Remarks
on the Present State of the Rheumatoid
arthritis treated with either cortisone or aspirin. A third report by the Joint Committee of the Medical Research Council and Nuffield Foundation on clinical trials of cortisone, ACTH and other therapeutic measures in chronic rheumatic diseases. Brit. M. J., 1: 847, 1957. SAVAGE, 0. Criteria for measurement in chronic diseases. Report of a Symposium on Clinical Trials, p. 34. Tonbridge, Kent, England, 1958.
LARSON, D. L. and SHULMAN,L. E. Relation of rheumatoid arthritis to systemic lupus erythematosus. Am. J. Med. (In press.) SOKOLOFF, L., MCCLUSKEY, J. T. and BUNIM, J. J. The vascularity of the early subcutaneous nodules of rheumatoid arthritis. Proceedings of the New York Pathologic Society, November 1952. Bull. NPW York Acad. Med., 29: 733, 1953.
Arthritis
Problem--&gun
13. RAGAN, C. The role of hypersensitivity in the management of rheumatoid arthritis. Ann. Rheumat. Dis. (In press.) 14. CASTOR, W. Approaches to the study of connective tissue. Bull. Rheumat. Dis., 9: 177, 1959. 15. SLACK, H. G. B. Some notes on the composition and metabolism of connective tissue. Am. J. Med., 26: 113,1959. 16. VAUGHAN, J. H. Serum responses in rheumatoid arthritis. Am. J. Med., 26: 596, 1959. 17. VAUGHAN, J. H. and HARRIS, J. Transfusion of rheumatoid factor. Proceedings of the American Rheumatism Association, San Francisco, June, 1958. Arthritis CT Rheumatism, 2: 51, 1959.
18. CHRISTIAN, C. L. Personal communication. 19. MCKUSICK, V. A. Genetic factors in disease of connective tissue. Am. J. Med., 26: 283, 1959.
AMERICAN
JOURNAL
OF MEDICINE