LETTERS
1250
To the Editor:
After carefully reading the letter by GonzBlez-Gay et al, we offer the following response. The findings in their epidemiologic study in an area of northwestern Spain from 1981 to 1990 confirm the low incidence of GCA in Mediterranean countries (1,2). The highest incidence rates of GCA have been reported in northern Europe (3,4) and in Minnesota (5,6), in 2 populations of the same ethnic background. A lower incidence has been observed in Italy (l), Israel (2), Spain, and in North American blacks in Tennessee (7). Interestingly, in parallel, a lower frequency of the DR4 gene has been reported in North American blacks (5.7%) and in Mediterranean populations (8.2% in Italy, 10.4% in Spain, 7.0% in Ashkenazi Jews in Israel), compared with Scandinavian and North American whites (15.0% and 15.8%, respectively) (8). It is likely that genetic factors may influence the risk of GCA in different populations, even if some additional influence of environmental factors cannot be excluded. In our epidemiologic study we also, using the Armitage test for linear trend (9), examined trends in GCA incidence by sex, evaluating incidence rates over the time periods 1980-1982, 1983-1985, and 19861988 (data not reported in the article). We observed a statistically significant reduction in total GCA incidence (P < 0.01) during the 9-year study period, and a significant decrease in incidence was also noted in the separate groups of men and women ( P < 0.01 for both groups). The statistical analysis of our data was limited by the small number of patients identified over short periods of time. A reduced awareness of the diagnosis of GCA might explain the reduction in incidence rates over time. This is unlikely, however, since in the last few years of our study period, awareness increased because physicians at the Reggio Emilia Hospital (in particular, in the Departments of Rheumatology, Internal Medicine, Ophthalmology, and Neurology) and private practitioners were involved in our epidemiologic study and were therefore trained in GCA diagnosis. Our data may therefore indicate a real decline in the incidence of GCA in Reggio Emilia over the 9-year study period. Machado et a1 (6) also observed a declining incidence of GCA in men during the period 1970-1985, in Olmsted County, Minnesota. We reported a positive temporal artery biopsy result in only 46% of our GCA patients who had clinical evidence of GCA. As outlined in our article, we believe this low incidence of temporal artery biopsy positivity could be explained by the low mean length of the biopsy specimens analyzed. Noltorp and Svensson (4) also reported a histologic diagnosis of GCA in only 50% of their patients who had the clinical features of the disease. The mean length of the biopsy specimens in their study (0.6 cm) was very similar to that in ours (0.5 cm), and contrasted with the larger specimens obtained in the Olmsted County study (10) and by GonzBlez-Gay and colleagues (5.4 cm and 3 cm, respectively). We believe the criteria used in our study for a diagnosis of probable GCA ( 5 ) were sufficiently selective for diagnosis. In none of our patients was the diagnosis of GCA
modified during the followup period (mean duration 64 months), making possible errors in the diagnosis unlikely. We agree with GonzBlez-Gay et a1 that temporal artery biopsy should be carried out in all patients with suspected GCA. However, from a practical point of view, the biopsy result in a patient with clinical evidence of “classic” GCA would not alter the decision to initiate steroid therapy. Carlo Salvarani, MD Pierluigi Macchioni, MD Luigi Boiardi, MD Lorenzo Lodi, MD Italo Portioli, MD Rheumatology Unit, USL N9 Reggio Emilia, Italy 1. Salvarani C, Macchioni PL. Zizzi F, Mantovani W, Rossi F,
2. 3.
4.
5. 6.
7. 8.
9. 10.
Castri C, Capozzoli N, Baricchi R, Boiardi L, Chiaravalloti F, Portioli I: Epidemiologic and immunogenetic aspects of polymyalgia rheumatica and giant cell arteritis in Northern Italy. Arthritis Rheum 34:351-356, 1991 Friedman G, Friedman B, Benbassat J: Epidemiology of temporal arteritis in Israel. Isr J Med Sci 18:241-244, 1982 Bengtsson B-A, Malmvall B-E: The epidemiology of giant cell arteritis including temporal arteritis and polymyalgia rheumatica: incidences of different clinical presentations and eye complications. Arthritis Rheum 24:899-904, 1981 Noltorp S, Svensson B: High incidence of polymyalgia rheumatica and giant cell arteritis in a Swedish community. Clin Exp Rheumatol 9:351-355, 1991 Huston KA, Hunder GG, Lie JT, Kennedy RH, Elveback LR: Temporal arteritis: a 25-year epidemiologic, clinical, and pathologic study. Ann Intern Med 88:162-167, 1978 Machado EBV, Michet CJ, Ballard DJ, Hunder GG, Beard CM, Chu CP, O’Fallon M: Trends in incidence and clinical presentation of temporal arteritis in Olmsted County, Minnesota, 195G198.5. Arthritis Rheum 31:745-749, 1988 Smith CA, Fidler WJ, Pinals RS: The epidemiology of giant cell arteritis: report of a ten-year study in Shelby County, Tennessee. Arthritis Rheum 26:1214-1219. 1983 Piazza A, Olivetti E, Griffo RM, Rendine S , Amoroso A, Barbanti M, Caruso C, Conighi C, Conte R, Favoino B, Galliano L, Luciani G, Magri D, Martinetti M, Mattiuz PL, Menicucci A, Misefari V , Moro L. Purpura M, Savi M: The distribution of HLA antigens in Italy. Gene Geography 3: 141164, 1989 Armitage P: Tests for linear trends in proportions and frequencies. Biometrics I1:375-386, 1955 Hall S , Lie JT, Kurland LT, Persellin S, O’Brien PC, Hunder GG: The therapeutic impact of temporal artery biopsy. Lancet 11:1217-1222, 1983
Interactions between antibodies and chondrocytes To the Editor: A recent article in Arthritis and Rheumatism by Drs. Takagi and Jasin (1) concerns idiotype-specific interaction between anticollagen antibodies and the membranes of chondrocytes from bovine articular cartilage. The interaction is potentially important in the pathogenesis of collagen autoimmunity, since there was enhancement of chondrocyte metalloprotease secretion following exposure to cytokines
1251
LETTERS
(phytohemagglutinin-activated blood mononuclear cell preparations). One comment made by the authors concerned their failure to detect nonspcw’jic binding of IgG to the chondrocytes, leaving the impression that only specific interaction would affect the metabolism of these cells. We would like to register disagreement on this matter, since we have issued several reports on nonspecific interactions of IgG with chondrocytes (also from bovine articular cartilage). In the concentration range of 0.1 to 5.0 mg/ml, we detected binding of both monomeric and heat-aggregated IgG to confluent monolayers (10-14 days old), which led to increased metalloprotease secretion. We also found increased output of superoxide anion and suppression of proteoglycan synthesis due to interaction with heat-aggregated (not monomeric) IgG (2-5). Using rosetting and enzyme-linked immunosorbent assay techniques, we have recently noted that Fc receptors are absent immediately after isolation of bovine chondrocytes by collagenase, but are detectable after 10 days’ culture, both on the monolayers and after resuspension of the cells by trypsin treatment (unpublished data). Evidently, the collagenase treatment damages or destroys Fc receptors, which regenerate after several days in culture. Since Tagaki and Jasin reported using chondrocytes fresh from the collagenase treatment (or after a period of just 24 hours of incubation), this may explain why they observed no binding of heat-aggregated IgG. It appears, therefore, that catabolic reactions of chondrocytes can be provoked either by idiotype-specific binding of IgG to the membrane, or by Fc-mediated nonspecific binding. A major difference between the two would be that the latter event relates not just to collagen autoimmunity but to any type of joint inflammation that results in immune complexes being liberally deposited in the surface layers of cartilage (6,7). We believe that this may be an important mechanism for cartilage degradation in inflammatory arthritis. T. D. V. Cooke. FRCS(C) R. A. Scudamore, PhD Qiieen’s University Kingston, Ontcirio, Ccincrder I . Takagi T . Jasin HE: Interactions between anticollagen antibodies and chondrocytes. Arthritis Rheum 35:224-230. 1992 2. U n o K. Cooke TDV. Scudamore RA: Interaction of cultured chondrocytes with heat-aggregated immunoglobulin. Trans Orthop Res Soc 14381. 1989 3. Saura R, Cooke TDV. Scudamore RA. Satsuma S: Matrixdegrading activity of chondrocytes stimulated by heat-aggregated IgG (abstract). Arthritis Rheum 33 (suppl 9):S53, 1990 4. Cooke D, Saura R. Uno K. Scudamore A: Interactions of immunoglobulins and chondrocytes. J Rheumatol Suppl 18: I I 4 116, 1991
5. Saura R, Cooke TDV. Scudamore RA: Superoxide anion generation by chondrocytes following stimulation by heat-aggregated IgG. Orthop Trans 15:177-178, 1991 6. Sumi M. Maeda M, Cooke TDV: Deleterious interactions of immune complexes with tibia1 cartilage of antigen-induced arthritic rabbits. 11. Chondrocyte degradation. Clin Orthop 212: 260-274. 1986 7. Trujillo PE. Mannik M: IgG is bound by antigen-antibody bonds
and some IgG and albumin are bound by intermolecular disulfide bonds to cartilage in rheumatoid arthritis and osteoarthritis. Rheumatol Int I1:225-234, 1992
Reply To the Editor: We thank Drs. Cooke and Scudamore for their comments. We are surprised that our colleagues interpreted our work as showing “idiotype-specific interaction between anticollagen antibodies and the membranes of chondrocytes. . .” We have emphasized in these studies the specificity of the different antisera used for the cartilage collagen types. Nowhere in the text of our article do we mention the term idiotype, and we certainly do not claim that our work addresses this issue directly or indirectly. Similarly, Drs. Cooke and Scudamore interpreted our failure to detect binding of heat-aggregated human IgG to chondrocytes as a failure to reproduce their findings dealing with enzyme secretion mediated by IgG. Since we failed to show that freshly isolated cells bind aggregated IgG, we have not pursued this line of investigation any further. It is our opinion that the sentence addressing this matter in the Discussion section is straightforward, and in no way can be interpreted as “. . . leaving the impression that only specific interaction would affect the metabolism of these cells.” We only argue that our observations cannot be explained on the basis of nonspecific interactions. As a matter of fact, one of us (HEJ) has authored several papers dealing with the increase in cartilage matrix degradative capacity mediated by nonspecijic mediators such as cytokines (1,2) and bacterial endotoxin (3). We agree that our seemingly disparate results are due to the different experimental conditions, i.e., fresh versus cultured chondrocytes. However, we disagree on the interpretation of the results as mentioned by Cooke and Scudamore. It is unlikely that the absence of IgG binding is due to digestion of the Fc receptors by collagenase, for the following reasons: I ) The collagenase we used has low protease activity, and it was used with 10% fetal calf serum containing a vast excess of protease inhibitors; 2) The cells were allowed to recover for 24 hours at 37°C which, given the rapid turnover rate of the Fc receptors, would constitute sufficient time to regenerate them; and 3) Our studies and those by Von der Mark et al (4) indicate that collagen receptors are regenerated as early as IS minutes after collagenase treatment. We would suggest that freshly isolated chondrocytes retain a phenotype similar to that of resident chondrocytes in articular cartilage, and that the appearance of Fc receptors after 1&14 days of low-density culture on plastic surfaces is due to dedifferentiation (5,6).
Toshitaka Takagi, MD. PhD Hugo E. Jasin, MD University of Arkansas for Medical Sciences Little Rock. A R I . Jasin H E , Dingle JT: Human mononuclear cell factors mediate cartilage matrix degradation through chondrocyte activation. J Clin Invest 68:571-581. 1981
1252
2. Krakauer T, Oppenheim JJ, Jasin HE: Human interleukin 1 mediates cartilage matrix degradation. Cell Immunol 91:92-99, 1985 3. Jasin HE: Bacterial lipopolysaccharides (LPS) induce cartilage matrix degradation through chondrocyte activation. J Clin Invest 72:20142019, 1983 4. Von der Mark K, Mollenhauer J , Haffle M, van Menxel M, Muller PK: Role of anchorin CII in the interaction of chondrocytes with extracellular collagen, Articular Cartilage Biochemistry. Edited by K Kuettner, R Schleyerbach, VC Hascall. New York, Raven Press, 1986 5 . Mayne R, Vail MS, Mayne PM, Miller EJ: Changes in the type of collagen synthesized as clones of chick chondrocytes grow and eventually lose division capacity. Proc Natl Acad Sci U S A 73:167&1678, 1976 6. Benya PD, Shaffer JD: Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30:215-224. 1982
Reduce serum uric acid levels before withdrawing antihyperuricemic therapy in patients with tophaceous gout To the Editor: McCarthy and coworkers have described progression of tophi on radiography of 9 patients and progression of tophi on physical examination of 7 patients during antihyperuricemic therapy in a group of 39 patients with gout (McCarthy GM, Barthelemy CR, Veum JA, Wortmann RL: Influence of antihyperuricemic therapy on the clinical and radiographic progression of gout. Arthritis Rheum 34: 14891494, 1991). They found no correlation between radiographic progression and mean serum urate concentration. The results of antihyperuricemic therapy, thus seem disappointing. However, the mean serum urate level in the 9 patients with radiographic progression, as given in Table 5 of their article, is 7.1 mg% ([ 1 x 6.8 + 3 x 6.1 + 5 x 7.81 f 9), and the mean serum urate level in the 7 with clinical progression, as given in Table 4, is 8.2 mg% (0.48 mmoles/ liter), during therapy. During the 10 years of followup, the serum urate concentration was measured only as deemed necessary, e.g., a range of 2-13 and an average of 6 determinations per patient in 10 years (see page 1490). Although all but 2 of the 39 patients had decreased excretion of uric acid, only 9 patients were treated with uricosuric drugs and 30 were treated with allopurinol. There are several causes for the disappointing results. I ) Allopurinol was not the drug of choice for most patients with decreased uric acid excretion. 2) The markedly elevated serum urate level points to poor compliance. 3) The evaluation visits were too fewhot frequent enough. 4) The urate levels were not lowered sufficiently. The authors refer to my reported experience with discontinuation of hyperuricemic agents in 10 patients with tophaceous gout (Cast LF: Withdrawal of longterm antihyperuricemic therapy in tophaceous gout. Clin Rheumatol 6:70-73, 1987; reference 5 in McCarthy’s article). During the therapy in those patients, all tophi had disappeared clinically, osseous tophi had shown radiographic regression, and serum urate levels had reached a mean of 5.6 mg% (0.30 mmolesfiiter), a concentration much lower than reached in McCarthy’s group.
LETTERS My recommendations are that patients with tophaceous gout should be evaluated every 3 months and have their antihyperuricemic therapy adjusted until all tophi have disappeared clinically and the serum urate concentration has become normal. Preferably, a level below 5.6 mg% (0.30 mmoles/liter) should be reached before antihyperuricemic therapy is withdrawn.
L. F. Cast, MD University Hospital Leiden. The Netherlands
To the Editor: Contrary to Dr. Cast’s suggestion, allopurinol therapy was the antihyperuricemic agent of choice in the majority of our patients. Although allopurinol is clearly indicated for use in individuals whose hyperuricemia results from urate overproduction, it is equally effective in lowering serum urate concentrations in those whose hyperuricemia results from underexcretion. In addition, it has the potential advantages of single daily dosage, fewer interactions with other drugs, and less frequent incidents of intolerance. Furthermore, it may be used in patients with impaired renal function ( I ,2). Our study reported the consequences of management of gout in a Veterans Administration Medical Center population managed by several practitioners over a prolonged period of time. It was not a precisely designed therapeutic trial. We agree that the results of antihyperuricemic therapy in this unique population appear disappointing overall, and attribute that to poor compliance. However, we reemphasize the lack of correlation between radiographic progression of gouty lytic lesions or erosions and the mean serum urate concentration. This resulted in radiographic progression in some patients with mean serum urate concentrations within the normal range, whereas others with chronically elevated mean serum urate concentrations did not have radiographic progression of disease. Clearly, more frequent assessment of individual compliance should improve outcome. We have absolute confidence that if serum urate concentrations can be maintained at or below 5.6 mg/dl, tophi will resolve and gout will be “cured.”
Geraldine M. McCarthy, MB, MRCPI Robert L. Wortmann, MD Medical College of Wisconsin Milwaukee, WI 1. Wortmann RL: Management of hyperuricemia, Arthritis and
Allied Conditions. Eleventh edition. Edited by DJ McCarty. Philadelphia, Lea & Febiger, 1989 2. Kelley WN, Fox IH, Palella TD: Gout and related disorders of purine metabolism, Textbook of Rheumatology. Third edition. Edited by WN Kelley, E D Harris Jr, S Ruddy, CB Sledge. Philadelphia, WB Saunders, 1989
1250
To the Editor:
After carefully reading the letter by GonzBlez-Gay et al, we offer the following response. The findings in their epidemiologic study in an area of northwestern Spain from 1981 to 1990 confirm the low incidence of GCA in Mediterranean countries (1,2). The highest incidence rates of GCA have been reported in northern Europe (3,4) and in Minnesota (5,6), in 2 populations of the same ethnic background. A lower incidence has been observed in Italy (l), Israel (2), Spain, and in North American blacks in Tennessee (7). Interestingly, in parallel, a lower frequency of the DR4 gene has been reported in North American blacks (5.7%) and in Mediterranean populations (8.2% in Italy, 10.4% in Spain, 7.0% in Ashkenazi Jews in Israel), compared with Scandinavian and North American whites (15.0% and 15.8%, respectively) (8). It is likely that genetic factors may influence the risk of GCA in different populations, even if some additional influence of environmental factors cannot be excluded. In our epidemiologic study we also, using the Armitage test for linear trend (9), examined trends in GCA incidence by sex, evaluating incidence rates over the time periods 1980-1982, 1983-1985, and 19861988 (data not reported in the article). We observed a statistically significant reduction in total GCA incidence (P < 0.01) during the 9-year study period, and a significant decrease in incidence was also noted in the separate groups of men and women ( P < 0.01 for both groups). The statistical analysis of our data was limited by the small number of patients identified over short periods of time. A reduced awareness of the diagnosis of GCA might explain the reduction in incidence rates over time. This is unlikely, however, since in the last few years of our study period, awareness increased because physicians at the Reggio Emilia Hospital (in particular, in the Departments of Rheumatology, Internal Medicine, Ophthalmology, and Neurology) and private practitioners were involved in our epidemiologic study and were therefore trained in GCA diagnosis. Our data may therefore indicate a real decline in the incidence of GCA in Reggio Emilia over the 9-year study period. Machado et a1 (6) also observed a declining incidence of GCA in men during the period 1970-1985, in Olmsted County, Minnesota. We reported a positive temporal artery biopsy result in only 46% of our GCA patients who had clinical evidence of GCA. As outlined in our article, we believe this low incidence of temporal artery biopsy positivity could be explained by the low mean length of the biopsy specimens analyzed. Noltorp and Svensson (4) also reported a histologic diagnosis of GCA in only 50% of their patients who had the clinical features of the disease. The mean length of the biopsy specimens in their study (0.6 cm) was very similar to that in ours (0.5 cm), and contrasted with the larger specimens obtained in the Olmsted County study (10) and by GonzBlez-Gay and colleagues (5.4 cm and 3 cm, respectively). We believe the criteria used in our study for a diagnosis of probable GCA ( 5 ) were sufficiently selective for diagnosis. In none of our patients was the diagnosis of GCA
modified during the followup period (mean duration 64 months), making possible errors in the diagnosis unlikely. We agree with GonzBlez-Gay et a1 that temporal artery biopsy should be carried out in all patients with suspected GCA. However, from a practical point of view, the biopsy result in a patient with clinical evidence of “classic” GCA would not alter the decision to initiate steroid therapy. Carlo Salvarani, MD Pierluigi Macchioni, MD Luigi Boiardi, MD Lorenzo Lodi, MD Italo Portioli, MD Rheumatology Unit, USL N9 Reggio Emilia, Italy 1. Salvarani C, Macchioni PL. Zizzi F, Mantovani W, Rossi F,
2. 3.
4.
5. 6.
7. 8.
9. 10.
Castri C, Capozzoli N, Baricchi R, Boiardi L, Chiaravalloti F, Portioli I: Epidemiologic and immunogenetic aspects of polymyalgia rheumatica and giant cell arteritis in Northern Italy. Arthritis Rheum 34:351-356, 1991 Friedman G, Friedman B, Benbassat J: Epidemiology of temporal arteritis in Israel. Isr J Med Sci 18:241-244, 1982 Bengtsson B-A, Malmvall B-E: The epidemiology of giant cell arteritis including temporal arteritis and polymyalgia rheumatica: incidences of different clinical presentations and eye complications. Arthritis Rheum 24:899-904, 1981 Noltorp S, Svensson B: High incidence of polymyalgia rheumatica and giant cell arteritis in a Swedish community. Clin Exp Rheumatol 9:351-355, 1991 Huston KA, Hunder GG, Lie JT, Kennedy RH, Elveback LR: Temporal arteritis: a 25-year epidemiologic, clinical, and pathologic study. Ann Intern Med 88:162-167, 1978 Machado EBV, Michet CJ, Ballard DJ, Hunder GG, Beard CM, Chu CP, O’Fallon M: Trends in incidence and clinical presentation of temporal arteritis in Olmsted County, Minnesota, 195G198.5. Arthritis Rheum 31:745-749, 1988 Smith CA, Fidler WJ, Pinals RS: The epidemiology of giant cell arteritis: report of a ten-year study in Shelby County, Tennessee. Arthritis Rheum 26:1214-1219. 1983 Piazza A, Olivetti E, Griffo RM, Rendine S , Amoroso A, Barbanti M, Caruso C, Conighi C, Conte R, Favoino B, Galliano L, Luciani G, Magri D, Martinetti M, Mattiuz PL, Menicucci A, Misefari V , Moro L. Purpura M, Savi M: The distribution of HLA antigens in Italy. Gene Geography 3: 141164, 1989 Armitage P: Tests for linear trends in proportions and frequencies. Biometrics I1:375-386, 1955 Hall S , Lie JT, Kurland LT, Persellin S, O’Brien PC, Hunder GG: The therapeutic impact of temporal artery biopsy. Lancet 11:1217-1222, 1983
Interactions between antibodies and chondrocytes To the Editor: A recent article in Arthritis and Rheumatism by Drs. Takagi and Jasin (1) concerns idiotype-specific interaction between anticollagen antibodies and the membranes of chondrocytes from bovine articular cartilage. The interaction is potentially important in the pathogenesis of collagen autoimmunity, since there was enhancement of chondrocyte metalloprotease secretion following exposure to cytokines
1251
LETTERS
(phytohemagglutinin-activated blood mononuclear cell preparations). One comment made by the authors concerned their failure to detect nonspcw’jic binding of IgG to the chondrocytes, leaving the impression that only specific interaction would affect the metabolism of these cells. We would like to register disagreement on this matter, since we have issued several reports on nonspecific interactions of IgG with chondrocytes (also from bovine articular cartilage). In the concentration range of 0.1 to 5.0 mg/ml, we detected binding of both monomeric and heat-aggregated IgG to confluent monolayers (10-14 days old), which led to increased metalloprotease secretion. We also found increased output of superoxide anion and suppression of proteoglycan synthesis due to interaction with heat-aggregated (not monomeric) IgG (2-5). Using rosetting and enzyme-linked immunosorbent assay techniques, we have recently noted that Fc receptors are absent immediately after isolation of bovine chondrocytes by collagenase, but are detectable after 10 days’ culture, both on the monolayers and after resuspension of the cells by trypsin treatment (unpublished data). Evidently, the collagenase treatment damages or destroys Fc receptors, which regenerate after several days in culture. Since Tagaki and Jasin reported using chondrocytes fresh from the collagenase treatment (or after a period of just 24 hours of incubation), this may explain why they observed no binding of heat-aggregated IgG. It appears, therefore, that catabolic reactions of chondrocytes can be provoked either by idiotype-specific binding of IgG to the membrane, or by Fc-mediated nonspecific binding. A major difference between the two would be that the latter event relates not just to collagen autoimmunity but to any type of joint inflammation that results in immune complexes being liberally deposited in the surface layers of cartilage (6,7). We believe that this may be an important mechanism for cartilage degradation in inflammatory arthritis. T. D. V. Cooke. FRCS(C) R. A. Scudamore, PhD Qiieen’s University Kingston, Ontcirio, Ccincrder I . Takagi T . Jasin HE: Interactions between anticollagen antibodies and chondrocytes. Arthritis Rheum 35:224-230. 1992 2. U n o K. Cooke TDV. Scudamore RA: Interaction of cultured chondrocytes with heat-aggregated immunoglobulin. Trans Orthop Res Soc 14381. 1989 3. Saura R, Cooke TDV. Scudamore RA. Satsuma S: Matrixdegrading activity of chondrocytes stimulated by heat-aggregated IgG (abstract). Arthritis Rheum 33 (suppl 9):S53, 1990 4. Cooke D, Saura R. Uno K. Scudamore A: Interactions of immunoglobulins and chondrocytes. J Rheumatol Suppl 18: I I 4 116, 1991
5. Saura R, Cooke TDV. Scudamore RA: Superoxide anion generation by chondrocytes following stimulation by heat-aggregated IgG. Orthop Trans 15:177-178, 1991 6. Sumi M. Maeda M, Cooke TDV: Deleterious interactions of immune complexes with tibia1 cartilage of antigen-induced arthritic rabbits. 11. Chondrocyte degradation. Clin Orthop 212: 260-274. 1986 7. Trujillo PE. Mannik M: IgG is bound by antigen-antibody bonds
and some IgG and albumin are bound by intermolecular disulfide bonds to cartilage in rheumatoid arthritis and osteoarthritis. Rheumatol Int I1:225-234, 1992
Reply To the Editor: We thank Drs. Cooke and Scudamore for their comments. We are surprised that our colleagues interpreted our work as showing “idiotype-specific interaction between anticollagen antibodies and the membranes of chondrocytes. . .” We have emphasized in these studies the specificity of the different antisera used for the cartilage collagen types. Nowhere in the text of our article do we mention the term idiotype, and we certainly do not claim that our work addresses this issue directly or indirectly. Similarly, Drs. Cooke and Scudamore interpreted our failure to detect binding of heat-aggregated human IgG to chondrocytes as a failure to reproduce their findings dealing with enzyme secretion mediated by IgG. Since we failed to show that freshly isolated cells bind aggregated IgG, we have not pursued this line of investigation any further. It is our opinion that the sentence addressing this matter in the Discussion section is straightforward, and in no way can be interpreted as “. . . leaving the impression that only specific interaction would affect the metabolism of these cells.” We only argue that our observations cannot be explained on the basis of nonspecific interactions. As a matter of fact, one of us (HEJ) has authored several papers dealing with the increase in cartilage matrix degradative capacity mediated by nonspecijic mediators such as cytokines (1,2) and bacterial endotoxin (3). We agree that our seemingly disparate results are due to the different experimental conditions, i.e., fresh versus cultured chondrocytes. However, we disagree on the interpretation of the results as mentioned by Cooke and Scudamore. It is unlikely that the absence of IgG binding is due to digestion of the Fc receptors by collagenase, for the following reasons: I ) The collagenase we used has low protease activity, and it was used with 10% fetal calf serum containing a vast excess of protease inhibitors; 2) The cells were allowed to recover for 24 hours at 37°C which, given the rapid turnover rate of the Fc receptors, would constitute sufficient time to regenerate them; and 3) Our studies and those by Von der Mark et al (4) indicate that collagen receptors are regenerated as early as IS minutes after collagenase treatment. We would suggest that freshly isolated chondrocytes retain a phenotype similar to that of resident chondrocytes in articular cartilage, and that the appearance of Fc receptors after 1&14 days of low-density culture on plastic surfaces is due to dedifferentiation (5,6).
Toshitaka Takagi, MD. PhD Hugo E. Jasin, MD University of Arkansas for Medical Sciences Little Rock. A R I . Jasin H E , Dingle JT: Human mononuclear cell factors mediate cartilage matrix degradation through chondrocyte activation. J Clin Invest 68:571-581. 1981
1252
2. Krakauer T, Oppenheim JJ, Jasin HE: Human interleukin 1 mediates cartilage matrix degradation. Cell Immunol 91:92-99, 1985 3. Jasin HE: Bacterial lipopolysaccharides (LPS) induce cartilage matrix degradation through chondrocyte activation. J Clin Invest 72:20142019, 1983 4. Von der Mark K, Mollenhauer J , Haffle M, van Menxel M, Muller PK: Role of anchorin CII in the interaction of chondrocytes with extracellular collagen, Articular Cartilage Biochemistry. Edited by K Kuettner, R Schleyerbach, VC Hascall. New York, Raven Press, 1986 5 . Mayne R, Vail MS, Mayne PM, Miller EJ: Changes in the type of collagen synthesized as clones of chick chondrocytes grow and eventually lose division capacity. Proc Natl Acad Sci U S A 73:167&1678, 1976 6. Benya PD, Shaffer JD: Dedifferentiated chondrocytes reexpress the differentiated collagen phenotype when cultured in agarose gels. Cell 30:215-224. 1982
Reduce serum uric acid levels before withdrawing antihyperuricemic therapy in patients with tophaceous gout To the Editor: McCarthy and coworkers have described progression of tophi on radiography of 9 patients and progression of tophi on physical examination of 7 patients during antihyperuricemic therapy in a group of 39 patients with gout (McCarthy GM, Barthelemy CR, Veum JA, Wortmann RL: Influence of antihyperuricemic therapy on the clinical and radiographic progression of gout. Arthritis Rheum 34: 14891494, 1991). They found no correlation between radiographic progression and mean serum urate concentration. The results of antihyperuricemic therapy, thus seem disappointing. However, the mean serum urate level in the 9 patients with radiographic progression, as given in Table 5 of their article, is 7.1 mg% ([ 1 x 6.8 + 3 x 6.1 + 5 x 7.81 f 9), and the mean serum urate level in the 7 with clinical progression, as given in Table 4, is 8.2 mg% (0.48 mmoles/ liter), during therapy. During the 10 years of followup, the serum urate concentration was measured only as deemed necessary, e.g., a range of 2-13 and an average of 6 determinations per patient in 10 years (see page 1490). Although all but 2 of the 39 patients had decreased excretion of uric acid, only 9 patients were treated with uricosuric drugs and 30 were treated with allopurinol. There are several causes for the disappointing results. I ) Allopurinol was not the drug of choice for most patients with decreased uric acid excretion. 2) The markedly elevated serum urate level points to poor compliance. 3) The evaluation visits were too fewhot frequent enough. 4) The urate levels were not lowered sufficiently. The authors refer to my reported experience with discontinuation of hyperuricemic agents in 10 patients with tophaceous gout (Cast LF: Withdrawal of longterm antihyperuricemic therapy in tophaceous gout. Clin Rheumatol 6:70-73, 1987; reference 5 in McCarthy’s article). During the therapy in those patients, all tophi had disappeared clinically, osseous tophi had shown radiographic regression, and serum urate levels had reached a mean of 5.6 mg% (0.30 mmolesfiiter), a concentration much lower than reached in McCarthy’s group.
LETTERS My recommendations are that patients with tophaceous gout should be evaluated every 3 months and have their antihyperuricemic therapy adjusted until all tophi have disappeared clinically and the serum urate concentration has become normal. Preferably, a level below 5.6 mg% (0.30 mmoles/liter) should be reached before antihyperuricemic therapy is withdrawn.
L. F. Cast, MD University Hospital Leiden. The Netherlands
To the Editor: Contrary to Dr. Cast’s suggestion, allopurinol therapy was the antihyperuricemic agent of choice in the majority of our patients. Although allopurinol is clearly indicated for use in individuals whose hyperuricemia results from urate overproduction, it is equally effective in lowering serum urate concentrations in those whose hyperuricemia results from underexcretion. In addition, it has the potential advantages of single daily dosage, fewer interactions with other drugs, and less frequent incidents of intolerance. Furthermore, it may be used in patients with impaired renal function ( I ,2). Our study reported the consequences of management of gout in a Veterans Administration Medical Center population managed by several practitioners over a prolonged period of time. It was not a precisely designed therapeutic trial. We agree that the results of antihyperuricemic therapy in this unique population appear disappointing overall, and attribute that to poor compliance. However, we reemphasize the lack of correlation between radiographic progression of gouty lytic lesions or erosions and the mean serum urate concentration. This resulted in radiographic progression in some patients with mean serum urate concentrations within the normal range, whereas others with chronically elevated mean serum urate concentrations did not have radiographic progression of disease. Clearly, more frequent assessment of individual compliance should improve outcome. We have absolute confidence that if serum urate concentrations can be maintained at or below 5.6 mg/dl, tophi will resolve and gout will be “cured.”
Geraldine M. McCarthy, MB, MRCPI Robert L. Wortmann, MD Medical College of Wisconsin Milwaukee, WI 1. Wortmann RL: Management of hyperuricemia, Arthritis and
Allied Conditions. Eleventh edition. Edited by DJ McCarty. Philadelphia, Lea & Febiger, 1989 2. Kelley WN, Fox IH, Palella TD: Gout and related disorders of purine metabolism, Textbook of Rheumatology. Third edition. Edited by WN Kelley, E D Harris Jr, S Ruddy, CB Sledge. Philadelphia, WB Saunders, 1989
