LETTERS TO THE EDITOR
G . VREUGDENHIL*, A . J. G . SWAAKt
'Department of Internal Medicine, Division of Haematology, Sint Radboud University Hospital, Nijmegen, The Netherlands fDepartment of Rheumatology, Dr Daniel de Hoed Cancer Centre, Rotterdam, The Netherlands Accepted 12 November 1991 1. Boyd B, Lappin TRJ. Erythropoietin deficiency in the anaemia of chronic disorders. Eur J Haemalol 1991;46:198-201. 2. BoydHK, Lappin TRJ, Bell L. Evidence for impaired erythropoietin response to anemia in rheumatoid disease. Br J Rheumatol 1991;30:255-9. 3. Hansen TM, Hansen HE, Birgens HS, Hohund B, Lorenzen 1. Serum ferritin and the assessment of iron deficiency in rheumatoid arthritis. Scand J Rheumatol 1983;12:353-9. 4. Vreugdenhil G, Bolks CAM, Van Eijk HG, Swaak AJG. Anaemia of chronic disease: diagnostic significance of erythrocyte and serological parameters in iron deficient rheumatoid arthritis patients. Br J Rheumatol 1990;29:105-10. 5. Baer AN, Dessypris EN, Goldwasser E, Krantz SB. Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol 1987 ;66:559-64. 6. Vreugdenhil G, Wognum AW, Van Eijk HG, Swaak AJG. Anaemia in rheumatoid arthritis, the role of iron, vitamin B12 and folic acid deficiency and erythropoietin responsiveness. Ann Rheum Dis 1991;49:93-8. 7. Vreugdenhil G, Kontoghiorghes GJ, Van Eijk HG, Swaak AJG. Impaired erythropoietin responsiveness to the anaemia in rheumatoid arthritis. A possible inverse relationship with iron stores and effects of the oral ironchelator, l,2-dimethyl-3 hydroxypyrid-4-one. Clin Exp Rheumatol 1991; 9:35-^0. 8. Biemond P, Van Eijk HG, Swaak AJG, et al. Iron metabolism from ferritin by superoxide derived from stimulated polymorphonuclear leucocytes. Possible mechanisms in inflammation diseases. J Clin Invest 1984,73:1576-9. 9. Blake DR, Lunec J, Ahern M, et al. Effect of intravenous iron dextron on rheumatoid synovitis. Ann Rheum Dis 1985;44:183-«. 10. Cartwright GE. The anemia of chronic disorders. Semin Hemalol 1966;3:351-75. 11. Hantzschel H, Otto W, Arnold S, et al. A comparison of prednisolone with azathioprine and prednisolone with intramuscular gold in rheumatoid arthritis. Clin Rheumatol 1988,7:181-7.
12. Vreugdenhil G, Kroos M, Lowenberg B, Van Eijk HG, Swaak AJG. Impaired iron uptake and transferrin binding by erythroblasts in anaemia of rheumatoid arthritis. Br J Rheumatol 1990;29:335-9. 13. Birgegard G, Hallgren R, Caro J. Serum erythropoietin in rheumatoid arthritis and other inflammatory arthritis. Relationship to anemia and the effect of anti-inflammatory treatment. Br J Haematol 1987;65:479-83. 14. Tauchi T, Ohyatik JH, Fujeda H, Lin KY, Ohyashiki K, Toyama K. Correction of anaemia in rheumatoid arthritis by recombinant human erythropoietin. Br J Rheumatol 1990;29:235-6. 15. Pincus T, Olsen NJ, Russell J, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990;89:161-8. 16. Maury CPJ. Anemia in rheumatoid arthritis. Role of cytokines. Scand J Rheumatol 1989;18:3-5. 17. Clibon U, Bonewold L, Cara J, et al. Erythropoietin fails to reverse the anemia in mice continuously exposed to tumor necrosis factor alpha in vivo. Exp Hematol 1990;18:438-41 Oral Tolerance and Collagen Arthritis
SIR—I read with interest Norman Staines' discussion of oral tolerance and collagen arthritis [1]. I enjoyed the clarity of his presentation on the concept of oral tolerance and its potential application in humans. However, I was concerned with the suggestion that this be applied to the collagen model of arthritis. The collagen model is not a model of rheumatoid arthritis! The subchondral erosions, periosteal reaction and tendency to joint osseous function [2] are features quite distinct from those noted in rheumatoid arthritis [3-5]. The collagen model of arthritis, however, shares those features with primate spondyloarthropathy [3,6-8]. While this similarity would suggest that the collagen model of arthritis would be an excellent model for assessment of therapy for spondyloarthropathy, we have noted a peculiar dichotomy. Cathcart et al. [2] reported predominant involvement of knees and ankles in collageninduced arthritis in New World monkeys. They particularly noted sparing of the shoulder joints. We have identified spontaneously occurring spondyloarthropathy in New World monkeys (Rothschild and Woods, submitted). Presence of sacroiliac erosions and syndesmophytes allowed unequivocal diagnosis [3,6-9]. Peripheral joint erosions were present in elbow, wrist, shoulder, metacarpal and metatarsal phalangeal joints, and less commonly in the knees. As patterns of joint involvement have proven quite reproducible, even across species lines [4—8], a suspicion was raised that the collagen arthritis model may not actually be an appropriate model for spondyloarthropathy. Cathcart et al. [2] further examined the question of susceptibility to collagen induction of arthritis in two important New World monkey genera, Cebus (Capuchin) and Saimiri (squirrel monkeys). They found that Saimiri were highly susceptible to collagen induction of arthritis, while no arthritis could be induced in Cebus. The complete post-cranial skeletons of 178 Cebus and 136 Saimiri were surveyed for visible evidence of articular and periarticular joint and spine pathology. All animals had been freeranging in their native habitat. Peripheral and axial joint erosions and fusion were present in Cebus but absent in Saimiri. Capuchin monkeys {Cebus) (resistant to collageninduced arthritis) naturally developed spondyloarthropathy, while squirrel monkeys {Saimiri) (susceptible to collagen-induced arthritis) were unaffected in the wild. While the collagen arthritis model elicits a spondylo-
Downloaded from http://rheumatology.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 24, 2015
saw a rise in serum Epo and a decline of serum ferritin after iron chelation [7] while no change occurred in RA activity. The question is whether rises in-serum Epo of this magnitude contribute to the Hb rise although one expects a decline in serum Epo if Hb rises through other mechanisms. Recombinant human Epo (r-Hu-Epo) was shown to be effective in anaemia of RA if high dosages are used [14,15]. In these studies ferritin levels decreased while no significant effects occurred on RA activity. So iron chelators and r-Hu-Epo share the effects of improving the anaemia without affecting RA activity. Although these are short term studies, one could argue that ferritin can only be regarded as a parameter of iron stores. In conclusion it is clear that ferritin levels may reflect both disease activity and iron stores in RA. Therefore it remains difficult to interpret the inverse correlation between serum ferritin and serum Epo. Since in ACD other factors like cytokines [16] may be involved. Moreover, it has been shown that TNFa blocks the effects of r-Hu-Epo [17]. Nevertheless the ACD seems to be responsive to excess exogenous Epo. Therefore further in vitro studies with respect to the possible influence of iron stores on Epo metabolism are warranted because in vivo the masking effects on this relationship due to RA activity can hardly be eliminated.
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arthropathy-like disorder, it may well represent a pathophysiology different from that of the natural state. Extreme caution should probably be considered in any application of collagen arthritis model data to human application. B. M. ROTHSCHILD
Arthritis Center of Northeast Ohio, Northeastern Ohio Universities, College of Medicine, 5701 Market Street, Youngstown, OH, USA Accepted 20 September 1991
TABLE I Polymylagia Rheumatoid arthritis Controls rheumatica Overlap No. of patients Mean age (years)
THT MHT
20
14
30
24
69.4 3 (15%) 9 (45%)
71.6 2 (14%) 5 (36%)
72.3 3 (10%) 6 (20%)
78.6 2 (8%) 2 (8%)
THT, thyroglobulin haemagglutation test; MHT, microsomal haemagglutation test.
Hypothyroidism and Thyroid Antibodies in Polymyalgia Rheumatics SIR—The large number of polymyalgia rheumatica patients studied by Bowness et al. [1] lends further support to an increased incidence of hypothyroidism in this condition. We have studied the incidence of thyroid disease and thyroid antibodies in a small group of patients with polymyalgia rheumatica as part of a study looking at rheumatoid arthritis presenting after the age of 65. As in other series [2,3] we found that some elderly rheumatoids present with an acute onset, often with shoulder involvement. Some of these have features of both rheumatoid arthritis and polymyalgia rheumatica. These have been called an
overlap group. The incidence of thyroid antibodies in these groups is presented in Table I. Ten of the 20 polymyalgia rheumatica patients had thyroid antibodies detected. Nine of these had a TSH performed and it was normal in eight. One patient had an undetectable TSH and raised free T4 but was on thyroid replacement for hypothyroidism. In this study we have reported thyroid antibodies as being present even though the titre was low in three of the 10 polymyalgic patients. This may explain the high incidence compared with Bowness et al. [1], although our numbers are small. We have, however, compared this incidence with elderly rheumatoid subjects and normal nursing home controls. It is of some interest that those rheumatoids who also fulfilled criteria for polymyalgia rheumatica [4] had an incidence of thyroid antibodies between the rheumatoid and polymyalgic group. We have recently evaluated a further 47 patients with polymyalgia rheumatica and found nine (19%) with thyroid antibodies. Although this is a lower incidence than our initial small study, it is still higher than our control group. We feel that our results, in a prospective study, lend further support to an association between polymyalgia rheumatica and autoimmune thyroid disease. I. STEWART*, J. RIDWAYI
* Department of Rheumatology, tResearch Immunologist, Victoria Hospital, Blackpool FY3 8NR Accepted 6 December 1991 1. Bowness P, Shotliff K, Middlemiss A, Myles AB. Prevalence of hypothyroidism in patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol 1991 ;30:349-51. 2. Corrigan AB, Robinson RG, Tereny TR, Dick-Smith JB, Walters D. Benign rheumatoid arthritis of the aged. Br Med J 1974;i:444-6. 3. Healey LA. Rheumatoid arthritis in the elderly. Clins Rheum D« 1986;12(1): 173-9. 4. Bird HA, Esselinck W, Dixon AS, Mowat AG, Wood PH. An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis 1979;38:434-9.
Downloaded from http://rheumatology.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 24, 2015
1. Staines NA. Oral tolerance and collagen arthritis. BrJRheumatol 1991;30(Suppl2):40-3. 2. Cathcart JE, Hayes KC, Gonnerman WA, Lazzari AA, Franzblau C. Experimental arthritis in a nonhuman primate. I. Induction by bovine type II collagen. Lab Invest 1986;54:26-31. 3. McCarthy DJ. Arthritis and allied conditions. 11th ed. Philadelphia: Lea and Febiger, 1989. 4. Rothschild BM, Woods RJ, Ortel W. Rheumatoid arthritis in the buff: erosive arthritis in representative defleshed bones. Am J Physical Anthropol 1990;82:441-9. 5. Rothschild BM, Turner KR, DeLuca MA. Symmetrical erosive peripheral polyarthritis in the Late Archaic Period of Alabama. Science 1988 ;241:1498-501. 6. Rothschild BM, Woods RJ. Spondyloarthropathy: erosive arthritis in representative defleshed bones. Am J Physical Anthropol 1991 ;85:125-34. 7. Rothschild BM, Woods RJ. Spondyloarthropathy in gorillas. Semin Arthritis Rheum 1989;18:267-76. 8. Rothschild BM, Woods RJ. Reactive erosive arthritis in chimpanzees. Am J Primatol 1991 ;25:49-56. 9. Resnick D, Niwayama G. Diagnosis of bone and joint disorders. 2nd ed. Philadelphia: Saunders, 1988.
G . VREUGDENHIL*, A . J. G . SWAAKt
'Department of Internal Medicine, Division of Haematology, Sint Radboud University Hospital, Nijmegen, The Netherlands fDepartment of Rheumatology, Dr Daniel de Hoed Cancer Centre, Rotterdam, The Netherlands Accepted 12 November 1991 1. Boyd B, Lappin TRJ. Erythropoietin deficiency in the anaemia of chronic disorders. Eur J Haemalol 1991;46:198-201. 2. BoydHK, Lappin TRJ, Bell L. Evidence for impaired erythropoietin response to anemia in rheumatoid disease. Br J Rheumatol 1991;30:255-9. 3. Hansen TM, Hansen HE, Birgens HS, Hohund B, Lorenzen 1. Serum ferritin and the assessment of iron deficiency in rheumatoid arthritis. Scand J Rheumatol 1983;12:353-9. 4. Vreugdenhil G, Bolks CAM, Van Eijk HG, Swaak AJG. Anaemia of chronic disease: diagnostic significance of erythrocyte and serological parameters in iron deficient rheumatoid arthritis patients. Br J Rheumatol 1990;29:105-10. 5. Baer AN, Dessypris EN, Goldwasser E, Krantz SB. Blunted erythropoietin response to anaemia in rheumatoid arthritis. Br J Haematol 1987 ;66:559-64. 6. Vreugdenhil G, Wognum AW, Van Eijk HG, Swaak AJG. Anaemia in rheumatoid arthritis, the role of iron, vitamin B12 and folic acid deficiency and erythropoietin responsiveness. Ann Rheum Dis 1991;49:93-8. 7. Vreugdenhil G, Kontoghiorghes GJ, Van Eijk HG, Swaak AJG. Impaired erythropoietin responsiveness to the anaemia in rheumatoid arthritis. A possible inverse relationship with iron stores and effects of the oral ironchelator, l,2-dimethyl-3 hydroxypyrid-4-one. Clin Exp Rheumatol 1991; 9:35-^0. 8. Biemond P, Van Eijk HG, Swaak AJG, et al. Iron metabolism from ferritin by superoxide derived from stimulated polymorphonuclear leucocytes. Possible mechanisms in inflammation diseases. J Clin Invest 1984,73:1576-9. 9. Blake DR, Lunec J, Ahern M, et al. Effect of intravenous iron dextron on rheumatoid synovitis. Ann Rheum Dis 1985;44:183-«. 10. Cartwright GE. The anemia of chronic disorders. Semin Hemalol 1966;3:351-75. 11. Hantzschel H, Otto W, Arnold S, et al. A comparison of prednisolone with azathioprine and prednisolone with intramuscular gold in rheumatoid arthritis. Clin Rheumatol 1988,7:181-7.
12. Vreugdenhil G, Kroos M, Lowenberg B, Van Eijk HG, Swaak AJG. Impaired iron uptake and transferrin binding by erythroblasts in anaemia of rheumatoid arthritis. Br J Rheumatol 1990;29:335-9. 13. Birgegard G, Hallgren R, Caro J. Serum erythropoietin in rheumatoid arthritis and other inflammatory arthritis. Relationship to anemia and the effect of anti-inflammatory treatment. Br J Haematol 1987;65:479-83. 14. Tauchi T, Ohyatik JH, Fujeda H, Lin KY, Ohyashiki K, Toyama K. Correction of anaemia in rheumatoid arthritis by recombinant human erythropoietin. Br J Rheumatol 1990;29:235-6. 15. Pincus T, Olsen NJ, Russell J, et al. Multicenter study of recombinant human erythropoietin in correction of anemia in rheumatoid arthritis. Am J Med 1990;89:161-8. 16. Maury CPJ. Anemia in rheumatoid arthritis. Role of cytokines. Scand J Rheumatol 1989;18:3-5. 17. Clibon U, Bonewold L, Cara J, et al. Erythropoietin fails to reverse the anemia in mice continuously exposed to tumor necrosis factor alpha in vivo. Exp Hematol 1990;18:438-41 Oral Tolerance and Collagen Arthritis
SIR—I read with interest Norman Staines' discussion of oral tolerance and collagen arthritis [1]. I enjoyed the clarity of his presentation on the concept of oral tolerance and its potential application in humans. However, I was concerned with the suggestion that this be applied to the collagen model of arthritis. The collagen model is not a model of rheumatoid arthritis! The subchondral erosions, periosteal reaction and tendency to joint osseous function [2] are features quite distinct from those noted in rheumatoid arthritis [3-5]. The collagen model of arthritis, however, shares those features with primate spondyloarthropathy [3,6-8]. While this similarity would suggest that the collagen model of arthritis would be an excellent model for assessment of therapy for spondyloarthropathy, we have noted a peculiar dichotomy. Cathcart et al. [2] reported predominant involvement of knees and ankles in collageninduced arthritis in New World monkeys. They particularly noted sparing of the shoulder joints. We have identified spontaneously occurring spondyloarthropathy in New World monkeys (Rothschild and Woods, submitted). Presence of sacroiliac erosions and syndesmophytes allowed unequivocal diagnosis [3,6-9]. Peripheral joint erosions were present in elbow, wrist, shoulder, metacarpal and metatarsal phalangeal joints, and less commonly in the knees. As patterns of joint involvement have proven quite reproducible, even across species lines [4—8], a suspicion was raised that the collagen arthritis model may not actually be an appropriate model for spondyloarthropathy. Cathcart et al. [2] further examined the question of susceptibility to collagen induction of arthritis in two important New World monkey genera, Cebus (Capuchin) and Saimiri (squirrel monkeys). They found that Saimiri were highly susceptible to collagen induction of arthritis, while no arthritis could be induced in Cebus. The complete post-cranial skeletons of 178 Cebus and 136 Saimiri were surveyed for visible evidence of articular and periarticular joint and spine pathology. All animals had been freeranging in their native habitat. Peripheral and axial joint erosions and fusion were present in Cebus but absent in Saimiri. Capuchin monkeys {Cebus) (resistant to collageninduced arthritis) naturally developed spondyloarthropathy, while squirrel monkeys {Saimiri) (susceptible to collagen-induced arthritis) were unaffected in the wild. While the collagen arthritis model elicits a spondylo-
Downloaded from http://rheumatology.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 24, 2015
saw a rise in serum Epo and a decline of serum ferritin after iron chelation [7] while no change occurred in RA activity. The question is whether rises in-serum Epo of this magnitude contribute to the Hb rise although one expects a decline in serum Epo if Hb rises through other mechanisms. Recombinant human Epo (r-Hu-Epo) was shown to be effective in anaemia of RA if high dosages are used [14,15]. In these studies ferritin levels decreased while no significant effects occurred on RA activity. So iron chelators and r-Hu-Epo share the effects of improving the anaemia without affecting RA activity. Although these are short term studies, one could argue that ferritin can only be regarded as a parameter of iron stores. In conclusion it is clear that ferritin levels may reflect both disease activity and iron stores in RA. Therefore it remains difficult to interpret the inverse correlation between serum ferritin and serum Epo. Since in ACD other factors like cytokines [16] may be involved. Moreover, it has been shown that TNFa blocks the effects of r-Hu-Epo [17]. Nevertheless the ACD seems to be responsive to excess exogenous Epo. Therefore further in vitro studies with respect to the possible influence of iron stores on Epo metabolism are warranted because in vivo the masking effects on this relationship due to RA activity can hardly be eliminated.
213
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BRITISH JOURNAL OF RHEUMATOLOGY VOL. XXXI NO. 3
arthropathy-like disorder, it may well represent a pathophysiology different from that of the natural state. Extreme caution should probably be considered in any application of collagen arthritis model data to human application. B. M. ROTHSCHILD
Arthritis Center of Northeast Ohio, Northeastern Ohio Universities, College of Medicine, 5701 Market Street, Youngstown, OH, USA Accepted 20 September 1991
TABLE I Polymylagia Rheumatoid arthritis Controls rheumatica Overlap No. of patients Mean age (years)
THT MHT
20
14
30
24
69.4 3 (15%) 9 (45%)
71.6 2 (14%) 5 (36%)
72.3 3 (10%) 6 (20%)
78.6 2 (8%) 2 (8%)
THT, thyroglobulin haemagglutation test; MHT, microsomal haemagglutation test.
Hypothyroidism and Thyroid Antibodies in Polymyalgia Rheumatics SIR—The large number of polymyalgia rheumatica patients studied by Bowness et al. [1] lends further support to an increased incidence of hypothyroidism in this condition. We have studied the incidence of thyroid disease and thyroid antibodies in a small group of patients with polymyalgia rheumatica as part of a study looking at rheumatoid arthritis presenting after the age of 65. As in other series [2,3] we found that some elderly rheumatoids present with an acute onset, often with shoulder involvement. Some of these have features of both rheumatoid arthritis and polymyalgia rheumatica. These have been called an
overlap group. The incidence of thyroid antibodies in these groups is presented in Table I. Ten of the 20 polymyalgia rheumatica patients had thyroid antibodies detected. Nine of these had a TSH performed and it was normal in eight. One patient had an undetectable TSH and raised free T4 but was on thyroid replacement for hypothyroidism. In this study we have reported thyroid antibodies as being present even though the titre was low in three of the 10 polymyalgic patients. This may explain the high incidence compared with Bowness et al. [1], although our numbers are small. We have, however, compared this incidence with elderly rheumatoid subjects and normal nursing home controls. It is of some interest that those rheumatoids who also fulfilled criteria for polymyalgia rheumatica [4] had an incidence of thyroid antibodies between the rheumatoid and polymyalgic group. We have recently evaluated a further 47 patients with polymyalgia rheumatica and found nine (19%) with thyroid antibodies. Although this is a lower incidence than our initial small study, it is still higher than our control group. We feel that our results, in a prospective study, lend further support to an association between polymyalgia rheumatica and autoimmune thyroid disease. I. STEWART*, J. RIDWAYI
* Department of Rheumatology, tResearch Immunologist, Victoria Hospital, Blackpool FY3 8NR Accepted 6 December 1991 1. Bowness P, Shotliff K, Middlemiss A, Myles AB. Prevalence of hypothyroidism in patients with polymyalgia rheumatica and giant cell arteritis. Br J Rheumatol 1991 ;30:349-51. 2. Corrigan AB, Robinson RG, Tereny TR, Dick-Smith JB, Walters D. Benign rheumatoid arthritis of the aged. Br Med J 1974;i:444-6. 3. Healey LA. Rheumatoid arthritis in the elderly. Clins Rheum D« 1986;12(1): 173-9. 4. Bird HA, Esselinck W, Dixon AS, Mowat AG, Wood PH. An evaluation of criteria for polymyalgia rheumatica. Ann Rheum Dis 1979;38:434-9.
Downloaded from http://rheumatology.oxfordjournals.org/ at University of Iowa Libraries/Serials Acquisitions on July 24, 2015
1. Staines NA. Oral tolerance and collagen arthritis. BrJRheumatol 1991;30(Suppl2):40-3. 2. Cathcart JE, Hayes KC, Gonnerman WA, Lazzari AA, Franzblau C. Experimental arthritis in a nonhuman primate. I. Induction by bovine type II collagen. Lab Invest 1986;54:26-31. 3. McCarthy DJ. Arthritis and allied conditions. 11th ed. Philadelphia: Lea and Febiger, 1989. 4. Rothschild BM, Woods RJ, Ortel W. Rheumatoid arthritis in the buff: erosive arthritis in representative defleshed bones. Am J Physical Anthropol 1990;82:441-9. 5. Rothschild BM, Turner KR, DeLuca MA. Symmetrical erosive peripheral polyarthritis in the Late Archaic Period of Alabama. Science 1988 ;241:1498-501. 6. Rothschild BM, Woods RJ. Spondyloarthropathy: erosive arthritis in representative defleshed bones. Am J Physical Anthropol 1991 ;85:125-34. 7. Rothschild BM, Woods RJ. Spondyloarthropathy in gorillas. Semin Arthritis Rheum 1989;18:267-76. 8. Rothschild BM, Woods RJ. Reactive erosive arthritis in chimpanzees. Am J Primatol 1991 ;25:49-56. 9. Resnick D, Niwayama G. Diagnosis of bone and joint disorders. 2nd ed. Philadelphia: Saunders, 1988.
