Current Medical Research and Opinion
Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis
Vol. 3, No. 2, 1975
D. M. Grennan, M.B., Ch.R., M.R.C.P.,
John A. Anderson, M .A,, D.Phil.(Oxon),
Alastair C. Kennedy, M. B.,Ch.B.,
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
M.R.C.P.,
William Mitchell, W. CarsonDick, M.D., M.R.C.P., and
W. Watson Buchanan, M.D., F.R.C.P.(Ed. and Glas.) The Centrefor Rheumatic Diseases and University Department of Medicine, Glasgow Royul Infirmary. Glasgow, Scotlandand the Department of Biomathematics, University of Oxford, England
Curr. med. Res. Opin., (1975), 3, 104.
Received: 27th January 1975
Summary A retrospective study is reported of 160patients with dejnite or classical rheumatoid
arthritis, in which changes in haemoglobin concentration were analysed against changes in various routine clinical and laboratory indices of disease activity over a period of’ time. Although statistically significant correlations were found between haemoglobin concentrations and the articular index of joint tenderness, serum albumim concentration, and erythrocyte sedimentation rate at one point in time, significant relationships in changes in haemoglobin concentration were only found with changes in the latter two Iaboratory indices. The signifcant correlations were weak and less important than the cumulative efect of unknown variables in determining haemoglobin level. The study shows that the routine clinics[ and laboratory parameters of disease activity in rheumatoid arthritis are of no value in predicting the haemoglobin concentration. Key words: Arthritis, rheumatoid- haernoglobin levels - blood sedimentation
Introduction The anaemia of rheumatoid arthritis is common, occurring in about 60 % of women and 40 % of men.4.’ 1 Although this anaemia is often mild and may seem unimportant in patients whose ravaged joints may restrict their activity anyway, its possible clinical significance is greatly increased by the increasing part surgery now plays in the management of the established disease. This becomes more apparent when one Reprint requests: Dr. David M. Grennan, Centre for Rheumatic Diseases, 35 Baird Street, Glasgow G4 OEH, Scotland. 104
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D. M. Grennan, John A. Anderson, Alastair C. Kennedy, William Mitchell, W. Carson Dick and W. Watson Buchanan
remembers that the blood loss after an osteotomy of the knee is often sufficient to lower the haemoglobin a further 2 to 3 g. x.12 Previous workers have shown that the anaemia of rheumatoid arthritis is related to the erythrocyte sedimentation rate,’ 3,1 7 other acute phase reactants,’ 3 serum albumin and a 2 globulin,17 serum iron,’7 disease duration in female^,^ and clinical disease activity.8 However, the degree of this relationship between the haemoglobin level and the various clinical and biochemical parameters of disease severity seems less securely documented than perhaps is warranted by the emphasis placed upon it by most current rheumatological texts.’ Thus, to our knowledge, in no study has the haemoglobin level been related to a validated, graded, assessment of disease activity, and in none has the change in haemoglobin level during the course of the disease been related to the change in clinical and biochemical parameters of clinical activity. In this study we have attempted to define the relevance of each of the routinely used disease parameters in influencing haemoglobin change during the course of the disease and to see if any one changing parameter or group of parameters would enable us to predict a change in haemoglobin concentration. s2v7
Method This was a retrospective survey of 160 patients with ‘definite’ or ‘classical’ rheumatoid arthritis, as defined by the criteria of the American Rheumatism Association,15 who had been seen at the Centre for Rheumatic Diseases more than once over a period of time and in whom the various clinical and biochemical indices had been recorded. Forty eight of these patients were male and the mean age of the group studied was 52.6 years (range 22 to 73 years). In none was there overt evidence of disease of any other major system and in particular in none was the blood urea elevated. Clinical assessment methods included : an articular index of joint tenderness,l functional grade and X-ray stage.’ 6 Laboratory parameters included : haemoglobin, erythrocyte sedimentation rate (Westergren units), serum albumin measured by a bromocresol green dye binding method, serum globulin measured by the difference between serum albumin and total serum protein measured by a buiret method, and the reciprocal of the rheumatoid factor titre measured by a latex particle agglutination method.10 The biochemical indices and functional index were analysed in 160 patients, and in a sub-group of 80 patients the articular index ofjoint tenderness and X-ray stage were also considered. The changes in each parameter for each patient from one time of observation to the next were calculated and the results analysed by multiple pairwise regression analysis of change in haemoglobin against change in each of these parameters and against the time interval between consecutive intervals at which the observations were made. Regression analyses was also carried out of haemoglobin values as against the values of each of the other parameters at the time of the first clinic visit. The mean and standard error of the mean of the intervals at which patients were seen was 2.65 years k0.19 and the mean and standard error of the mean of the total period over which they were followed was 4.98 years 0.13. 105
Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
Results As can be seen in Tables I and 11, only the regression of change in serum albumin concentration and erythrocyte sedimentation rate (E.S.R.)against change in haemoglobin are statistically significant. However, there is a considerable variation about the regression line and it can be seen that the standard deviation of the basic distribution of the changes in haemoglobin is 1.84 which only reduces to 1.82 after allowing for the erythrocyte sedimentation rate, the most significant regression value. Table I. Regression analysis of changes in haemoglobin on changes in other parameters in 160 patients.
Haernoglobin Slope on
Standard error
F value
Significance
Standard deviation
E.S.R. Albumin Globulin Functional grade Interval
0.0041 0.19 0.042 0.190
20.713 32.163 0.395 2.220
l/lOoo ljlOo0
1.82
N.S. N.S.
1.84 1.92 1.93
0.044
0.143
N.S.
1.88
-0.01888 1.10 -0.0266 -0.283 0.0167
Table 11. Regression analysis ofchanges in haemoglobin on changes in articular index and X-ray grade in sub-group of 80 patients
Haemoglobin Slope on
Standard error
F value
Significance
Standard deviation
Articular index X-ray grade
--0.0123
0.0142
0.74
N.S.
2.05
-0.6141
0.4935
1.55
N.S.
1.87
When haemoglobin values were analysed against the other values at the time of the first clinic visit (Table III), it can be seen that a statistically significant association was found between the haemoglobin and the articular index of joint tenderness, serum albumin concentration and the erythrocyte sedimentation rate. Again there was a considerable variation about the regression line. Table 111. Regression analysis of haemoglobinagainst other parametersat time of first clinic visit ~
Haemoglobin Slope
106
~
~
~
~
F value
Significance
Standard deviation
0.0251 -0.0346
0.0041 0.0109
38.15 9.99
1/1m
ljloo
1.61 I .71
0.701 1 I .0457 -0.3399
0.2745 0.5697 0.2417
6.52 3.37 1.98
1/100 N.S. N.S.
1.74 5.48 1.76
0.1123
0.2109
0.28
N.S.
1.82
OI1
E.S.R. Articular index Albumin Globulin X-ray grade Functional grade
~
Standard error
--
D. M. Grennan, John A. Anderson, Alastair C . Kennedy, William Mitchell, W. Carson Dick and W. Watson Buchanan
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
Discussion In this study we attempted to determine the value of various routine clinical and laboratory parameters in rheumatoid arthritis in predicting the haemoglobin concentration. The haemoglobin concentration was found to correlate significantly with the articular index of joint tenderness, serum albumin concentration and erythrocyte sedimentation rate, and a significant relationship was found in the change in haemoglobulin concentration over a period of time and the latter two laboratory parameters. However, statistically significant relationships were weak and only accounted for a small fraction of the variation in change in haemoglobin level. In other words the cumulative effect of other variable factors, which were not recorded, far outweigh in importance the factors which were considered. To a clinician this is perhaps not surprising when one considers the multiplicity of factors which may cause anaemia in a patient with rheumatoid arthritis, e.g. diminished dietary intake of iron due to anorexia and chronic gastro-intestinal blood loss due to salicylate therapy. None of the patients in the present study gave a history of melaena, and although faecal occult blood tests may have given some indication of subclinical gastro-intestinal blood loss they are frequently positive in patients on salicylates who are not anaemic and do not constitute a routine test at a busy rheumatic diseases out-patient clinic. None of the patients in the present study had overt iron deficiency anaemia as judged by the mean corpuscular haemoglobulin concentration and by blood film appearances. The fact that the changes in neither of the two clinical parameters of disease activity - the articular index of joint tenderness and the functional grade - were significantly related to change in haemoglobin concentration perhaps conflicts with the current concept of a close relationship between clinical arthritis activity and the degree of anaemia. It could be argued that neither of these two clinical indices alone is sensitive enough to detect small changes in severity of arthritis, and neither alone may be fully representative of disease activity over a period of time. Both are subject to relatively rapid change, especially the articular index of joint tenderness, which has been found an extremely useful parameter in short-term clinical trials of antirheumatic drugs.3 However, it may not reflect the overall disease activity over a period of time as well as laboratory indices, such as the serum albumin concentration and the erythrocyte sedimentation rate which change more slowly and are of little value in short-term clinical therapeutic trials.9 In conclusion, the results of this retrospective study indicate that no one clinical or laboratory parameter of disease activity can be expected to predict the haemoglobin value in a patient with rheumatoid arthritis.
Acknowledgment The authors wish to thank the Arthritis and Rheumatism Council for generous financial support. One of as (ACK) was a Medical Research Council Clinical Research Fellow, and another (W.M.) a fourth year Medical Student at Glasgow University and in receipt of a Carnegie Student Research Grant.
107
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Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis
References 1. Boyle, J. A,, and Buchanan, W. W., (1971). “Clinical Rheumatology”, p. 155. Blackwell Scientific Publications, Oxford and Edinburgh. 2. Copeman, W. S. C., (1964). “Textbook of the Rheumatic Diseases”, p. 182. Livingstone, Edinburgh and London. 3. Deodhar, S. D., Dick, W. C., Hodgkinson, R., and Buchanan, W. W., (1973). Measurement of clinical response to anti-inflammatory drug therapy in rheumatoid arthritis. Quart. J. Med., 42, 387-401. 4. Empire Rheumatism Council, (1950). Report of Scientific Advisory Committee. Ann. rheum. Dis., 9, Suppl., 86. 5. Gibberd, F. B., (1966). The haemoglobin level in patients with rheumatoid arthritis. Acta. rheum. Scand.. 12, 122-134. 6. Hill, A. G. S., and Greenbury, C. C.,(1959). Marrow iron in rheumatoid arthritis. Ann. rheum. Dis., 18, 57. 7. Hollander, J. L., and McCarty, D. J., (1972). “Arthritis and Allied Conditions”, p. 343. Lea and Febiger, Philadelphia. 8. Jeffrey, M. R., (1953). Some observations on anaemia in rheumatoid arthritis. Blood, 8,502. 9. Lee, P., Jasani, M. K., Dick, W. C., and Buchanan, W. W.,(1973). Evaluation of a functional index in rheumatoid arthritis. Scand. J. rheum., 2., 71-77. 10. MacSween, R. N. M., Hughes, H., Breen, C., Kitchen, P.,Cathcart,B., and Buchanan, W. W., (1974). A comparative study of some commercially available tests for rheumatoid factor. J. clin. Path., 27,368-371. 11. Nilsson, F., (1948). Anaemia problems in rheumatoid arthritis. Acta. med.Scand., Suppl.,210. 12. Pattison, E., Protheroe, K., Pringle, R. M., Kennedy, A. C., and Dick, W. C., (1973). Reduction in haemoglobin after kneejoint surgery. Ann. rheum. Dis.. 32,582. 13. Richmond, J., Gardner, D. L., Roy, L. M. H., and Duthie, J. J. R., (1956). Nature of anaemia in rheumatoid arthritis 111. Changes in the bone marrow and their relation to other features of the disease. Ann. rheum. Dis.. 15,217. 14. Ritchie, D. M., Boyle, J. A., McInnes, J. M., Jasani, M. K., Dalakos, T. G., Grieveson, P., and Buchanan, W. W., (1968). Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Quart. J. Med., 37,393. 15. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A., (1959). Revision of diagnostic criteria for rheumatoid arthritis. Arthr. rheum., 2, 16. 16. Steinbrocker, O., Traeger, C. H., and Batterman, R. C., (1949). Therapeutic criteria in rheumatoid arthritis. J. Amer. med. Ass., 140, 659. 17. Strandberg, O., (1966). Haematological data and clinical activity of the rheumatoid diseases. Acta. med. Scand., 180, Suppl. 454,13.
108
Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis
Vol. 3, No. 2, 1975
D. M. Grennan, M.B., Ch.R., M.R.C.P.,
John A. Anderson, M .A,, D.Phil.(Oxon),
Alastair C. Kennedy, M. B.,Ch.B.,
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
M.R.C.P.,
William Mitchell, W. CarsonDick, M.D., M.R.C.P., and
W. Watson Buchanan, M.D., F.R.C.P.(Ed. and Glas.) The Centrefor Rheumatic Diseases and University Department of Medicine, Glasgow Royul Infirmary. Glasgow, Scotlandand the Department of Biomathematics, University of Oxford, England
Curr. med. Res. Opin., (1975), 3, 104.
Received: 27th January 1975
Summary A retrospective study is reported of 160patients with dejnite or classical rheumatoid
arthritis, in which changes in haemoglobin concentration were analysed against changes in various routine clinical and laboratory indices of disease activity over a period of’ time. Although statistically significant correlations were found between haemoglobin concentrations and the articular index of joint tenderness, serum albumim concentration, and erythrocyte sedimentation rate at one point in time, significant relationships in changes in haemoglobin concentration were only found with changes in the latter two Iaboratory indices. The signifcant correlations were weak and less important than the cumulative efect of unknown variables in determining haemoglobin level. The study shows that the routine clinics[ and laboratory parameters of disease activity in rheumatoid arthritis are of no value in predicting the haemoglobin concentration. Key words: Arthritis, rheumatoid- haernoglobin levels - blood sedimentation
Introduction The anaemia of rheumatoid arthritis is common, occurring in about 60 % of women and 40 % of men.4.’ 1 Although this anaemia is often mild and may seem unimportant in patients whose ravaged joints may restrict their activity anyway, its possible clinical significance is greatly increased by the increasing part surgery now plays in the management of the established disease. This becomes more apparent when one Reprint requests: Dr. David M. Grennan, Centre for Rheumatic Diseases, 35 Baird Street, Glasgow G4 OEH, Scotland. 104
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
D. M. Grennan, John A. Anderson, Alastair C. Kennedy, William Mitchell, W. Carson Dick and W. Watson Buchanan
remembers that the blood loss after an osteotomy of the knee is often sufficient to lower the haemoglobin a further 2 to 3 g. x.12 Previous workers have shown that the anaemia of rheumatoid arthritis is related to the erythrocyte sedimentation rate,’ 3,1 7 other acute phase reactants,’ 3 serum albumin and a 2 globulin,17 serum iron,’7 disease duration in female^,^ and clinical disease activity.8 However, the degree of this relationship between the haemoglobin level and the various clinical and biochemical parameters of disease severity seems less securely documented than perhaps is warranted by the emphasis placed upon it by most current rheumatological texts.’ Thus, to our knowledge, in no study has the haemoglobin level been related to a validated, graded, assessment of disease activity, and in none has the change in haemoglobin level during the course of the disease been related to the change in clinical and biochemical parameters of clinical activity. In this study we have attempted to define the relevance of each of the routinely used disease parameters in influencing haemoglobin change during the course of the disease and to see if any one changing parameter or group of parameters would enable us to predict a change in haemoglobin concentration. s2v7
Method This was a retrospective survey of 160 patients with ‘definite’ or ‘classical’ rheumatoid arthritis, as defined by the criteria of the American Rheumatism Association,15 who had been seen at the Centre for Rheumatic Diseases more than once over a period of time and in whom the various clinical and biochemical indices had been recorded. Forty eight of these patients were male and the mean age of the group studied was 52.6 years (range 22 to 73 years). In none was there overt evidence of disease of any other major system and in particular in none was the blood urea elevated. Clinical assessment methods included : an articular index of joint tenderness,l functional grade and X-ray stage.’ 6 Laboratory parameters included : haemoglobin, erythrocyte sedimentation rate (Westergren units), serum albumin measured by a bromocresol green dye binding method, serum globulin measured by the difference between serum albumin and total serum protein measured by a buiret method, and the reciprocal of the rheumatoid factor titre measured by a latex particle agglutination method.10 The biochemical indices and functional index were analysed in 160 patients, and in a sub-group of 80 patients the articular index ofjoint tenderness and X-ray stage were also considered. The changes in each parameter for each patient from one time of observation to the next were calculated and the results analysed by multiple pairwise regression analysis of change in haemoglobin against change in each of these parameters and against the time interval between consecutive intervals at which the observations were made. Regression analyses was also carried out of haemoglobin values as against the values of each of the other parameters at the time of the first clinic visit. The mean and standard error of the mean of the intervals at which patients were seen was 2.65 years k0.19 and the mean and standard error of the mean of the total period over which they were followed was 4.98 years 0.13. 105
Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
Results As can be seen in Tables I and 11, only the regression of change in serum albumin concentration and erythrocyte sedimentation rate (E.S.R.)against change in haemoglobin are statistically significant. However, there is a considerable variation about the regression line and it can be seen that the standard deviation of the basic distribution of the changes in haemoglobin is 1.84 which only reduces to 1.82 after allowing for the erythrocyte sedimentation rate, the most significant regression value. Table I. Regression analysis of changes in haemoglobin on changes in other parameters in 160 patients.
Haernoglobin Slope on
Standard error
F value
Significance
Standard deviation
E.S.R. Albumin Globulin Functional grade Interval
0.0041 0.19 0.042 0.190
20.713 32.163 0.395 2.220
l/lOoo ljlOo0
1.82
N.S. N.S.
1.84 1.92 1.93
0.044
0.143
N.S.
1.88
-0.01888 1.10 -0.0266 -0.283 0.0167
Table 11. Regression analysis ofchanges in haemoglobin on changes in articular index and X-ray grade in sub-group of 80 patients
Haemoglobin Slope on
Standard error
F value
Significance
Standard deviation
Articular index X-ray grade
--0.0123
0.0142
0.74
N.S.
2.05
-0.6141
0.4935
1.55
N.S.
1.87
When haemoglobin values were analysed against the other values at the time of the first clinic visit (Table III), it can be seen that a statistically significant association was found between the haemoglobin and the articular index of joint tenderness, serum albumin concentration and the erythrocyte sedimentation rate. Again there was a considerable variation about the regression line. Table 111. Regression analysis of haemoglobinagainst other parametersat time of first clinic visit ~
Haemoglobin Slope
106
~
~
~
~
F value
Significance
Standard deviation
0.0251 -0.0346
0.0041 0.0109
38.15 9.99
1/1m
ljloo
1.61 I .71
0.701 1 I .0457 -0.3399
0.2745 0.5697 0.2417
6.52 3.37 1.98
1/100 N.S. N.S.
1.74 5.48 1.76
0.1123
0.2109
0.28
N.S.
1.82
OI1
E.S.R. Articular index Albumin Globulin X-ray grade Functional grade
~
Standard error
--
D. M. Grennan, John A. Anderson, Alastair C . Kennedy, William Mitchell, W. Carson Dick and W. Watson Buchanan
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
Discussion In this study we attempted to determine the value of various routine clinical and laboratory parameters in rheumatoid arthritis in predicting the haemoglobin concentration. The haemoglobin concentration was found to correlate significantly with the articular index of joint tenderness, serum albumin concentration and erythrocyte sedimentation rate, and a significant relationship was found in the change in haemoglobulin concentration over a period of time and the latter two laboratory parameters. However, statistically significant relationships were weak and only accounted for a small fraction of the variation in change in haemoglobin level. In other words the cumulative effect of other variable factors, which were not recorded, far outweigh in importance the factors which were considered. To a clinician this is perhaps not surprising when one considers the multiplicity of factors which may cause anaemia in a patient with rheumatoid arthritis, e.g. diminished dietary intake of iron due to anorexia and chronic gastro-intestinal blood loss due to salicylate therapy. None of the patients in the present study gave a history of melaena, and although faecal occult blood tests may have given some indication of subclinical gastro-intestinal blood loss they are frequently positive in patients on salicylates who are not anaemic and do not constitute a routine test at a busy rheumatic diseases out-patient clinic. None of the patients in the present study had overt iron deficiency anaemia as judged by the mean corpuscular haemoglobulin concentration and by blood film appearances. The fact that the changes in neither of the two clinical parameters of disease activity - the articular index of joint tenderness and the functional grade - were significantly related to change in haemoglobin concentration perhaps conflicts with the current concept of a close relationship between clinical arthritis activity and the degree of anaemia. It could be argued that neither of these two clinical indices alone is sensitive enough to detect small changes in severity of arthritis, and neither alone may be fully representative of disease activity over a period of time. Both are subject to relatively rapid change, especially the articular index of joint tenderness, which has been found an extremely useful parameter in short-term clinical trials of antirheumatic drugs.3 However, it may not reflect the overall disease activity over a period of time as well as laboratory indices, such as the serum albumin concentration and the erythrocyte sedimentation rate which change more slowly and are of little value in short-term clinical therapeutic trials.9 In conclusion, the results of this retrospective study indicate that no one clinical or laboratory parameter of disease activity can be expected to predict the haemoglobin value in a patient with rheumatoid arthritis.
Acknowledgment The authors wish to thank the Arthritis and Rheumatism Council for generous financial support. One of as (ACK) was a Medical Research Council Clinical Research Fellow, and another (W.M.) a fourth year Medical Student at Glasgow University and in receipt of a Carnegie Student Research Grant.
107
Curr Med Res Opin Downloaded from informahealthcare.com by York University Libraries on 12/29/14 For personal use only.
Relationship between haemoglobin and the other clinical and laboratory parameters in rheumatoid arthritis
References 1. Boyle, J. A,, and Buchanan, W. W., (1971). “Clinical Rheumatology”, p. 155. Blackwell Scientific Publications, Oxford and Edinburgh. 2. Copeman, W. S. C., (1964). “Textbook of the Rheumatic Diseases”, p. 182. Livingstone, Edinburgh and London. 3. Deodhar, S. D., Dick, W. C., Hodgkinson, R., and Buchanan, W. W., (1973). Measurement of clinical response to anti-inflammatory drug therapy in rheumatoid arthritis. Quart. J. Med., 42, 387-401. 4. Empire Rheumatism Council, (1950). Report of Scientific Advisory Committee. Ann. rheum. Dis., 9, Suppl., 86. 5. Gibberd, F. B., (1966). The haemoglobin level in patients with rheumatoid arthritis. Acta. rheum. Scand.. 12, 122-134. 6. Hill, A. G. S., and Greenbury, C. C.,(1959). Marrow iron in rheumatoid arthritis. Ann. rheum. Dis., 18, 57. 7. Hollander, J. L., and McCarty, D. J., (1972). “Arthritis and Allied Conditions”, p. 343. Lea and Febiger, Philadelphia. 8. Jeffrey, M. R., (1953). Some observations on anaemia in rheumatoid arthritis. Blood, 8,502. 9. Lee, P., Jasani, M. K., Dick, W. C., and Buchanan, W. W.,(1973). Evaluation of a functional index in rheumatoid arthritis. Scand. J. rheum., 2., 71-77. 10. MacSween, R. N. M., Hughes, H., Breen, C., Kitchen, P.,Cathcart,B., and Buchanan, W. W., (1974). A comparative study of some commercially available tests for rheumatoid factor. J. clin. Path., 27,368-371. 11. Nilsson, F., (1948). Anaemia problems in rheumatoid arthritis. Acta. med.Scand., Suppl.,210. 12. Pattison, E., Protheroe, K., Pringle, R. M., Kennedy, A. C., and Dick, W. C., (1973). Reduction in haemoglobin after kneejoint surgery. Ann. rheum. Dis.. 32,582. 13. Richmond, J., Gardner, D. L., Roy, L. M. H., and Duthie, J. J. R., (1956). Nature of anaemia in rheumatoid arthritis 111. Changes in the bone marrow and their relation to other features of the disease. Ann. rheum. Dis.. 15,217. 14. Ritchie, D. M., Boyle, J. A., McInnes, J. M., Jasani, M. K., Dalakos, T. G., Grieveson, P., and Buchanan, W. W., (1968). Clinical studies with an articular index for the assessment of joint tenderness in patients with rheumatoid arthritis. Quart. J. Med., 37,393. 15. Ropes, M. W., Bennett, G. A., Cobb, S., Jacox, R., and Jessar, R. A., (1959). Revision of diagnostic criteria for rheumatoid arthritis. Arthr. rheum., 2, 16. 16. Steinbrocker, O., Traeger, C. H., and Batterman, R. C., (1949). Therapeutic criteria in rheumatoid arthritis. J. Amer. med. Ass., 140, 659. 17. Strandberg, O., (1966). Haematological data and clinical activity of the rheumatoid diseases. Acta. med. Scand., 180, Suppl. 454,13.
108
