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Accelerated nodulosis during methotrexate therapy for juvenile rheumatoid arthritis
698
Muzaffer et aL
The Journal of Pediatrics May 1996
Accelerated nodulosis during methotrexate therapy for juvenile rheumatoid arthritis M o h a m m e d A. Muzaffer, MBCHB, FRCP(c), Rayfel Schneider, MBBCh, FRCP(c), Bonnie J. Cameron, MD, FRCP(c), Earl D. Silverman, MD, FRCP(c), a n d Ronald M. Laxer, MD, FRCP(c) From the Division of Rheumatology, Departments of Pediatrics, Immunology, and Medicine, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada
We describe two patients with rheumatoid factor-positive, polyarticular-onset juvenile rheumatoid arthritis in whom accelerated nodulosis developed during methotrexate therapy. Although they had only a few nodules at diagnosis, the nodules increased in number and size 3 to 4 months after the start of methotrexate therapy in both patients. The nodules regressed after withdrawal of methotrexate therapy in one patient and were arrested with the addition of hydroxychloroquine in the other. Physicians treating patients with methotrexate for juvenile rheumatoid arthritis must be aware of this extraarticular side effect. (J Pediatr 1996;128:698-700) Juvenile rheumatoid arthritis, the most common form of chronic arthritis in children, is divided into three subtypes based on the pattern of onset within the first 6 months of disease: systemic, pauciarticular, and polyarticular. Rheumatoid nodules occur almost exclusively in patients with rheumatoid factor-positive, polyarticular JRA, which comprises only 5% to 10% of all cases of JRA. 1 These nodules are found most commonly on extensor surfaces (e.g., over the olecranon, ulna, Achilles tendon) and at sites of frequent mechanical irritation and may also, rarely, develop in visceral organs. They may be single or multiple, freely mobile or fixed, and soft or firm and may vary in size ranging from microscopic to several centimeters in diameter. 2 These nodules may regress once a remission has been achieved. 3 Children with RF-positive polyarticular JRA are at great risk of having severe erosive joint disease, and therefore aggressive medical treatment should be instituted early. Methotrexate is a potential disease-remitting drug, which has been shown in a placebo-controlled, randomized trial to be effective and safe for the treatment of children with JRA. 4 Recently, "accelerated nodulosis," the development of a large number of nodules during a short time, has been recognized as a complication of methotrexate therapy in adults with rheumatoid arthritis. 57 To date, this complication has Submitted for publication Nov. 8, 1995; accepted Jan. 26, 1996. Reprint requests: Ronald M. Laxer, MD, FRCP(C), Professor of Pediatrics and Medicine, Head, Division of Rheumatology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/72374
not been reported in children with JRA. We now report two children with RF-positive polyarticular JRA in whom nodulosis developed during methotrexate therapy. CASE REPORTS Case 1. A 13fi-year old girl had polyarthfitis at presentation. Initial laboratory investigations revealed the presence of RF (640 1U) and antinuclear antibody (1/80) and an elevation of the erythrocyte sedimentation rate (89 mrn/hr). A diagnosis of RF-positive ANA ESR JRA RF
Antinuclear antibodies Erythrocyte sedimentation rate Juvenile rheumatoid arthritis Rheumatoid factor
polyarticular JRA was made. Initial treatment consisted of naproxen, low doses of prednisone, and intraarticular corticosteroid injections. Intramuscular gold therapy was added, and during this therapy, asymptomatic subcutaneous nodules developed over the elbow, fifth finger, knee, both Achilles tendons, and the first metatarsophalangeal joint, with no other extraarticular manifestations. Gold therapy was stopped after 1 year because of lack of efficacy. Methotrexate was started at a dose of 7.5 mg/wk. Within 4 months, multiple painful subcutaneous nodules erupted over both elbows, the proximal interphalangeal and metacarpophalangeal joints, both knees, the heel pads, and both Achilles tendons. The nodules were associated with functional disturbance. She required additional intraarticular corticosteroid injections and an increase in the dosage of methotrexate to 10 mg/wk. However, further acceleration of nodulosis (36 nodules in total) was observed, and the nodules were associated with pain and discomfort that limited joint movement. There were no other extraarticular manifestations or symptoms suggestive of methotrexate toxicity. The methotrexate was discontinued, and the patient was started on a regimen of hydroxychloro-
The Journal of Pediatrics Volume 128, Namber 5, Part 1
quine, 200 mg twice a day for 2 months, followed by a reduction to 300 mg/day. The prednisone dose was increased from 10 to 20 rag/day. After these changes, a reduction in the number and size of nodules was observed, leaving only four asymptomatic nodules over the proximal interphalangeal joints of the fight hand. The patient's joint symptoms waxed and waned with the use of nonsteroidal antiinflammatory drugs, hydroxychloroquine, prednisone, and periodic intraarticular corticosteroid injections. Therapy with methotrexate, 7.5 mg/wk, was restarted, and after 3 months of follow-up (while also receiving hydroxychloroquine) the patient had no adverse effects. Case 2. A 15-year-old girl had symmetric polyarthritis at presentation. Small nodules (each measuring <0.5 cm) were detected on both elbows, but there were no other extraarticular manifestations. Laboratory investigations showed the presence of RF (>1280 IU) and antinuclear antibody (1/80), a raised ESR (35 mm/hr), and mild anemia. A diagnosis of RF-positive polyarticular JRA was made. She improved slightly with naproxen treatment but required prednisone, 10 mg/day, for symptom control. Two months after the diagnosis, hydroxychloroquine therapy, 200 mg twice a day, was started for 1 month and then was reduced to 300 mg/day. However, a 3-month trial was without benefit and hydroxychloroquine therapy was discontinued. Seven months after the diagnosis of JRA, methotrexate, 7.5 mg/wk, was added to the therapeutic regimen. Three months later, more subcutaneous nodules developed on both elbows and over the left Achilles tendon. During the next few months the nodules increased in size and number, particularly over the first metatarsophalangeal joints. Because the nodules were associated with only minimal discomfort and the ~hritis remained active, the dose of methotrexate was gradually increased to 15 mg/ wk, and, in addition, hydroxychloroquine therapy, 300 mg/day, was restarted in an effort to minimize nodulosis. There was no further increase in the number of nodules, even though the dosage of methotrexate was further increased to 20 mg/wk, at which point the patient's arthritis showed significant improvement.
DISCUSSION Methotrexate has now b e c o m e widely used in the treatment of JRA. The toxic effects of methotrexate in children are usually mild, and side effects generally resolve with dose reduction. 8-1° Recently the rapid development of a large n u m b e r of nodules, termed "accelerated nodulosis," has been recognized as a complication of methotrexate therapy in adults treated for rheumatoid arthritis. 5-7 In a double-blind comparative study of methotrexate and azathioprine in patients with refractory rheumatoid arthritis, 8% of patients treated with methotrexate had accelerated nodulosis despite good clinical response of polyarthritis. 5 However, in no patient treated with azathioprine did nodulosis develop. 5 In both of our patients, accelerated nodulosis developed 3 to 4 months after the start of methotrexate therapy. These nodules were similar in distribution and size to those reported in adults with nodulosis. In one patient, the addition of hydroxychloroquine to the therapeutic regimen led to sta-
Muzaffer et al.
699
Figure. Case 2. Two nodules developed during methotrexate treatment: one nodule over the left first metatarsopbalangeal joint and another over the first metatarsal head. The lesion over the fifth toe resulted from minor trauma. bilization in the development of nodulosis, which allowed for an increased dose of methotrexate with no other side effects. In the other patient, tender nodules developed and became even more symptomatic when the dose o f methotrexate was increased to 10 mg/wk; it was then necessary to stop the methotrexate therapy. Within 6 months of the cessation of methotrexate therapy, regression of the nodulosis was observed. The exact mechanisms of methotrexate-induced nodulosis are unknown. Whether the development of accelerated nodulosis during methotrexate therapy is a drug-related side effect or is part of the natural history of the rheumatoid disease remains unclear. If the nodules resulted from the underlying disease, it would be predicted that they would continue once methotrexate therapy was stopped. However, the frequent regression when therapy with the drug is stopped and frequent recurrence on rechallenge suggest that nodulosis is a drug-related effect rather than a manifestation of the natural history of the disease. 5' 6 It has been suggested that stabilization of accelerated nodulosis can be achieved with the addition of hydroxychloroquine to the methotrexate regimen. C o m b e et al. Jj added hydroxychloroquine to methotrexate therapy in four patients with rheumatoid arthritis in w h o m methotrexate-in-
700
Muzaffer et aL
duced accelerated nodulosis developed. Three to ten months after the addition of hydroxychloroquine, the nodules had either stabilized or regressed despite the continuation of methotrexate therapy. In one of our cases the addition of hydroxychloroquine allowed us to increase the dose of methotrexate without further development of nodulosis. The mechanism whereby the addition of hydroxychloroquine resuits in stabilization of accelerated nodulosis is not known. The combination of methotrexate and hydroxychloroquine has also been used to reduce liver enzyme abnormalities resulting from methotrexate toxicity. ~2 Nodulosis has developed in only 1.5% of our total JRA patient population that has been treated with methotrexate (unpublished data), in contrast to the 8% to 10% incidence noted in adult series of patients with rheumatoid arthritis. 5 However, both of our patients came from the unique subgroup of patients in whom RF has been detected, who are predominantly female, and whose disease usually starts after the age of 10 years. The clinical features of this subgroup of patients are most similar to those of adult rheumatoid arthritis. Immunogenetic studies have also shown that these patients are very much like those with adult rheumatoid arthritis, with a predominance of H L A - D R 4 positivity.13 Accelerated nodulosis developed in 10% (2/20) of our patients with RF-positive polyarticular JRA who were treated with methotrexate (unpublished data), which is very similar to adult incidence figures. All physicians involved in the management of children with RF-positive arthritis who are receiving methotrexate therapy should be aware of the potential for the development of accelerated nodulosis. Whether or not to stop methotrexate therapy in the face of accelerated nodulosis must be decided by the patient and physician together. We suggest that unless the nodules are painful or interfere with the patient's usual activities, methotrexate therapy should be continued, particularly if the arthritis has improved. The role of
The Journal of Pediatric~ May 1996
hydroxychloroquine in reversing (or even preventing) this complication deserves further study. REFERENCES
1. Cassidy JT, Petty RE. Textbook of pediatric rheumatology. 3rd ed. Philadelphia: WB Saunders, 1995:133-223. 2. Kaye BR, Kaye RL, Bobrove A. Rheumatoid nodules. Am J Med 1984;76:279-92. 3. Englert HJ, Hughes GRV, Walport MJ. Sulphasalazine and regression of rheumatoid nodules. Ann Rheum Dis 1987: 46:244-5. 4. Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexatc in resistant juvenile rheumatoid arthritis. N Engl J Med 1992: 320:1043-9. 5. Kersteins Pit JSM, Boerbooms AMT, Jeurissen MEC. Fast JH, Assmann KJM, van de Putte LBA. Nodulosis during low-dosc methotrexate therapy for rheumatoid arthritis. J Rheumatol 1992; 19:867-71. 6. Segal R, Caspi D, Tishler M, Fisher B, Yaron M. Accelerated nodulosis and vasculitis during methotrexate therapy for rheumatoid arthritis. Arthritis Rheum 1988;31:1182-5. 7. Abu-Shakra M, Nicol P, Urowitz MB. Accelerated nodulosis, pleural effusion and pericardial tamponade during methotrexate therapy. J Rheumatol 1994;21:934-7. 8. Wallace CA, Blayer WA, Sherry DD, Salmonson KL, Wedgwood RJ. Methotrexate toxicity in juvenile rheumatoid arthritis. Arthritis Rheum 1989;32:677-81. 9. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J PEDIATR1992;120:468-73. 10. Rose CD, Singsen BH, Eichenfeld AH, Goldsmith DP, Athreya BH. Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. J PEDIATR1990;117:653-9. 11. Combe B, Guttierrez M, Anaya J-M, Sany J. Possible efficacy of hydroxychloroquine on accelerated nodulosis during methotrexate therapy for rheumatoid arthritis [letter]. J Rheumatol 1993 ;20:755-6. 12. Fries JF, Singh G, Lenert L, Furst DE. Aspirin, hydroxychloroquine, and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis. Arthritis Rheum 1990:33:1611-9. 13. De Inocencio J, Giannini EH, Glass DN. Can genetic markers contribute to the classification of juvenile rheumatoid arthritis? J Rheumatol 1993;20:(suppl 40):12-8.
Muzaffer et aL
The Journal of Pediatrics May 1996
Accelerated nodulosis during methotrexate therapy for juvenile rheumatoid arthritis M o h a m m e d A. Muzaffer, MBCHB, FRCP(c), Rayfel Schneider, MBBCh, FRCP(c), Bonnie J. Cameron, MD, FRCP(c), Earl D. Silverman, MD, FRCP(c), a n d Ronald M. Laxer, MD, FRCP(c) From the Division of Rheumatology, Departments of Pediatrics, Immunology, and Medicine, University of Toronto, Hospital for Sick Children, Toronto, Ontario, Canada
We describe two patients with rheumatoid factor-positive, polyarticular-onset juvenile rheumatoid arthritis in whom accelerated nodulosis developed during methotrexate therapy. Although they had only a few nodules at diagnosis, the nodules increased in number and size 3 to 4 months after the start of methotrexate therapy in both patients. The nodules regressed after withdrawal of methotrexate therapy in one patient and were arrested with the addition of hydroxychloroquine in the other. Physicians treating patients with methotrexate for juvenile rheumatoid arthritis must be aware of this extraarticular side effect. (J Pediatr 1996;128:698-700) Juvenile rheumatoid arthritis, the most common form of chronic arthritis in children, is divided into three subtypes based on the pattern of onset within the first 6 months of disease: systemic, pauciarticular, and polyarticular. Rheumatoid nodules occur almost exclusively in patients with rheumatoid factor-positive, polyarticular JRA, which comprises only 5% to 10% of all cases of JRA. 1 These nodules are found most commonly on extensor surfaces (e.g., over the olecranon, ulna, Achilles tendon) and at sites of frequent mechanical irritation and may also, rarely, develop in visceral organs. They may be single or multiple, freely mobile or fixed, and soft or firm and may vary in size ranging from microscopic to several centimeters in diameter. 2 These nodules may regress once a remission has been achieved. 3 Children with RF-positive polyarticular JRA are at great risk of having severe erosive joint disease, and therefore aggressive medical treatment should be instituted early. Methotrexate is a potential disease-remitting drug, which has been shown in a placebo-controlled, randomized trial to be effective and safe for the treatment of children with JRA. 4 Recently, "accelerated nodulosis," the development of a large number of nodules during a short time, has been recognized as a complication of methotrexate therapy in adults with rheumatoid arthritis. 57 To date, this complication has Submitted for publication Nov. 8, 1995; accepted Jan. 26, 1996. Reprint requests: Ronald M. Laxer, MD, FRCP(C), Professor of Pediatrics and Medicine, Head, Division of Rheumatology, Hospital for Sick Children, 555 University Ave., Toronto, Ontario M5G 1X8, Canada. Copyright © 1996 by Mosby-Year Book, Inc. 0022-3476/96/$5.00 + 0 9/22/72374
not been reported in children with JRA. We now report two children with RF-positive polyarticular JRA in whom nodulosis developed during methotrexate therapy. CASE REPORTS Case 1. A 13fi-year old girl had polyarthfitis at presentation. Initial laboratory investigations revealed the presence of RF (640 1U) and antinuclear antibody (1/80) and an elevation of the erythrocyte sedimentation rate (89 mrn/hr). A diagnosis of RF-positive ANA ESR JRA RF
Antinuclear antibodies Erythrocyte sedimentation rate Juvenile rheumatoid arthritis Rheumatoid factor
polyarticular JRA was made. Initial treatment consisted of naproxen, low doses of prednisone, and intraarticular corticosteroid injections. Intramuscular gold therapy was added, and during this therapy, asymptomatic subcutaneous nodules developed over the elbow, fifth finger, knee, both Achilles tendons, and the first metatarsophalangeal joint, with no other extraarticular manifestations. Gold therapy was stopped after 1 year because of lack of efficacy. Methotrexate was started at a dose of 7.5 mg/wk. Within 4 months, multiple painful subcutaneous nodules erupted over both elbows, the proximal interphalangeal and metacarpophalangeal joints, both knees, the heel pads, and both Achilles tendons. The nodules were associated with functional disturbance. She required additional intraarticular corticosteroid injections and an increase in the dosage of methotrexate to 10 mg/wk. However, further acceleration of nodulosis (36 nodules in total) was observed, and the nodules were associated with pain and discomfort that limited joint movement. There were no other extraarticular manifestations or symptoms suggestive of methotrexate toxicity. The methotrexate was discontinued, and the patient was started on a regimen of hydroxychloro-
The Journal of Pediatrics Volume 128, Namber 5, Part 1
quine, 200 mg twice a day for 2 months, followed by a reduction to 300 mg/day. The prednisone dose was increased from 10 to 20 rag/day. After these changes, a reduction in the number and size of nodules was observed, leaving only four asymptomatic nodules over the proximal interphalangeal joints of the fight hand. The patient's joint symptoms waxed and waned with the use of nonsteroidal antiinflammatory drugs, hydroxychloroquine, prednisone, and periodic intraarticular corticosteroid injections. Therapy with methotrexate, 7.5 mg/wk, was restarted, and after 3 months of follow-up (while also receiving hydroxychloroquine) the patient had no adverse effects. Case 2. A 15-year-old girl had symmetric polyarthritis at presentation. Small nodules (each measuring <0.5 cm) were detected on both elbows, but there were no other extraarticular manifestations. Laboratory investigations showed the presence of RF (>1280 IU) and antinuclear antibody (1/80), a raised ESR (35 mm/hr), and mild anemia. A diagnosis of RF-positive polyarticular JRA was made. She improved slightly with naproxen treatment but required prednisone, 10 mg/day, for symptom control. Two months after the diagnosis, hydroxychloroquine therapy, 200 mg twice a day, was started for 1 month and then was reduced to 300 mg/day. However, a 3-month trial was without benefit and hydroxychloroquine therapy was discontinued. Seven months after the diagnosis of JRA, methotrexate, 7.5 mg/wk, was added to the therapeutic regimen. Three months later, more subcutaneous nodules developed on both elbows and over the left Achilles tendon. During the next few months the nodules increased in size and number, particularly over the first metatarsophalangeal joints. Because the nodules were associated with only minimal discomfort and the ~hritis remained active, the dose of methotrexate was gradually increased to 15 mg/ wk, and, in addition, hydroxychloroquine therapy, 300 mg/day, was restarted in an effort to minimize nodulosis. There was no further increase in the number of nodules, even though the dosage of methotrexate was further increased to 20 mg/wk, at which point the patient's arthritis showed significant improvement.
DISCUSSION Methotrexate has now b e c o m e widely used in the treatment of JRA. The toxic effects of methotrexate in children are usually mild, and side effects generally resolve with dose reduction. 8-1° Recently the rapid development of a large n u m b e r of nodules, termed "accelerated nodulosis," has been recognized as a complication of methotrexate therapy in adults treated for rheumatoid arthritis. 5-7 In a double-blind comparative study of methotrexate and azathioprine in patients with refractory rheumatoid arthritis, 8% of patients treated with methotrexate had accelerated nodulosis despite good clinical response of polyarthritis. 5 However, in no patient treated with azathioprine did nodulosis develop. 5 In both of our patients, accelerated nodulosis developed 3 to 4 months after the start of methotrexate therapy. These nodules were similar in distribution and size to those reported in adults with nodulosis. In one patient, the addition of hydroxychloroquine to the therapeutic regimen led to sta-
Muzaffer et al.
699
Figure. Case 2. Two nodules developed during methotrexate treatment: one nodule over the left first metatarsopbalangeal joint and another over the first metatarsal head. The lesion over the fifth toe resulted from minor trauma. bilization in the development of nodulosis, which allowed for an increased dose of methotrexate with no other side effects. In the other patient, tender nodules developed and became even more symptomatic when the dose o f methotrexate was increased to 10 mg/wk; it was then necessary to stop the methotrexate therapy. Within 6 months of the cessation of methotrexate therapy, regression of the nodulosis was observed. The exact mechanisms of methotrexate-induced nodulosis are unknown. Whether the development of accelerated nodulosis during methotrexate therapy is a drug-related side effect or is part of the natural history of the rheumatoid disease remains unclear. If the nodules resulted from the underlying disease, it would be predicted that they would continue once methotrexate therapy was stopped. However, the frequent regression when therapy with the drug is stopped and frequent recurrence on rechallenge suggest that nodulosis is a drug-related effect rather than a manifestation of the natural history of the disease. 5' 6 It has been suggested that stabilization of accelerated nodulosis can be achieved with the addition of hydroxychloroquine to the methotrexate regimen. C o m b e et al. Jj added hydroxychloroquine to methotrexate therapy in four patients with rheumatoid arthritis in w h o m methotrexate-in-
700
Muzaffer et aL
duced accelerated nodulosis developed. Three to ten months after the addition of hydroxychloroquine, the nodules had either stabilized or regressed despite the continuation of methotrexate therapy. In one of our cases the addition of hydroxychloroquine allowed us to increase the dose of methotrexate without further development of nodulosis. The mechanism whereby the addition of hydroxychloroquine resuits in stabilization of accelerated nodulosis is not known. The combination of methotrexate and hydroxychloroquine has also been used to reduce liver enzyme abnormalities resulting from methotrexate toxicity. ~2 Nodulosis has developed in only 1.5% of our total JRA patient population that has been treated with methotrexate (unpublished data), in contrast to the 8% to 10% incidence noted in adult series of patients with rheumatoid arthritis. 5 However, both of our patients came from the unique subgroup of patients in whom RF has been detected, who are predominantly female, and whose disease usually starts after the age of 10 years. The clinical features of this subgroup of patients are most similar to those of adult rheumatoid arthritis. Immunogenetic studies have also shown that these patients are very much like those with adult rheumatoid arthritis, with a predominance of H L A - D R 4 positivity.13 Accelerated nodulosis developed in 10% (2/20) of our patients with RF-positive polyarticular JRA who were treated with methotrexate (unpublished data), which is very similar to adult incidence figures. All physicians involved in the management of children with RF-positive arthritis who are receiving methotrexate therapy should be aware of the potential for the development of accelerated nodulosis. Whether or not to stop methotrexate therapy in the face of accelerated nodulosis must be decided by the patient and physician together. We suggest that unless the nodules are painful or interfere with the patient's usual activities, methotrexate therapy should be continued, particularly if the arthritis has improved. The role of
The Journal of Pediatric~ May 1996
hydroxychloroquine in reversing (or even preventing) this complication deserves further study. REFERENCES
1. Cassidy JT, Petty RE. Textbook of pediatric rheumatology. 3rd ed. Philadelphia: WB Saunders, 1995:133-223. 2. Kaye BR, Kaye RL, Bobrove A. Rheumatoid nodules. Am J Med 1984;76:279-92. 3. Englert HJ, Hughes GRV, Walport MJ. Sulphasalazine and regression of rheumatoid nodules. Ann Rheum Dis 1987: 46:244-5. 4. Giannini EH, Brewer EJ, Kuzmina N, et al. Methotrexatc in resistant juvenile rheumatoid arthritis. N Engl J Med 1992: 320:1043-9. 5. Kersteins Pit JSM, Boerbooms AMT, Jeurissen MEC. Fast JH, Assmann KJM, van de Putte LBA. Nodulosis during low-dosc methotrexate therapy for rheumatoid arthritis. J Rheumatol 1992; 19:867-71. 6. Segal R, Caspi D, Tishler M, Fisher B, Yaron M. Accelerated nodulosis and vasculitis during methotrexate therapy for rheumatoid arthritis. Arthritis Rheum 1988;31:1182-5. 7. Abu-Shakra M, Nicol P, Urowitz MB. Accelerated nodulosis, pleural effusion and pericardial tamponade during methotrexate therapy. J Rheumatol 1994;21:934-7. 8. Wallace CA, Blayer WA, Sherry DD, Salmonson KL, Wedgwood RJ. Methotrexate toxicity in juvenile rheumatoid arthritis. Arthritis Rheum 1989;32:677-81. 9. Graham LD, Myones BL, Rivas-Chacon RF, Pachman LM. Morbidity associated with long-term methotrexate therapy in juvenile rheumatoid arthritis. J PEDIATR1992;120:468-73. 10. Rose CD, Singsen BH, Eichenfeld AH, Goldsmith DP, Athreya BH. Safety and efficacy of methotrexate therapy for juvenile rheumatoid arthritis. J PEDIATR1990;117:653-9. 11. Combe B, Guttierrez M, Anaya J-M, Sany J. Possible efficacy of hydroxychloroquine on accelerated nodulosis during methotrexate therapy for rheumatoid arthritis [letter]. J Rheumatol 1993 ;20:755-6. 12. Fries JF, Singh G, Lenert L, Furst DE. Aspirin, hydroxychloroquine, and hepatic enzyme abnormalities with methotrexate in rheumatoid arthritis. Arthritis Rheum 1990:33:1611-9. 13. De Inocencio J, Giannini EH, Glass DN. Can genetic markers contribute to the classification of juvenile rheumatoid arthritis? J Rheumatol 1993;20:(suppl 40):12-8.