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Arthropathy in thalassaemia patients receiving deferiprone
References 1 Schlitt HJ, Raddatz G, Steinhoff G, Wonigeit K, Pichlmayr R. Passenger lymphocytes in human liver allografts and their potential role after transplantation. Transplantation 1993; 56: 951-55. 2 Schlitt HJ, Kanehiro H, Raddatz G, et al. Persistence of donor lymphocytes in liver allograft recipients. Transplantation 1992; 56: 1001-07. 3 Starzl TE, Demetris AJ, Trucco M, et al. Systemic chimerism in human female recipients of male livers. Lancet 1992; 340: 876-77. 4 Starzl TE, Demetris AJ, Trucco MT, et al. Chimerism and donorspecific non-reactivity 27 to 29 years after kidney allotransplantation. Transplantation 1993; 55: 1272-77. 5 Demetris AJ, Murase N, Fujisaki S, Fung JJ, Rao AS, Starzl TE. Hematolymphoid cell trafficking, microchimerism, and GVH reactions after liver, bone marrow, and heart transplantation. Transplant Proc 1993; 25: 3337-44. 6 Qian S, Demetris AJ, Murase N, Rao AS, Fung JJ, Starzl TE. Murine liver allograft transplantation: tolerance and donor cell chimerism.
Hepatology (in press). 7
Larsen CP, Austyn JM, Morris PJ. The role of graft-derived dendritic
Arthropathy in thalassaemia patients receiving deferiprone
The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.
Lancet 1994; 343: 1471-72
The disadvantages of parenteral desferrioxamine led to a search for safe, orally active chelating agents for patients with iron-loading anaemias.1 One such alternative, deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, L1), is associated with arthralgias and arthritis and possibly with induction of systemic lupus erythematosus (SLE).2,3 We describe arthropathy in three deferiprone-treated patients. Sixteen patients with transfusion-dependent homozygous betathalassaemia have been treated with deferiprone, 75 mg/kg per day, for 1-3 years (mean 900, SD 300-0, range 360-1308 days), in a study approved by the Toronto Hospital for Sick Children. 3-8 months after the start of therapy, three patients aged 17, 20, and 27 years complained of severe bilateral knee pain at rest worsening with exertion, morning stiffness, and joint warmth and swelling. One patient also reported similar symptoms in the fingers and wrists of both hands. Examination revealed knee effusions, slight loss of full flexion, stress pain, and joint line tenderness; no other signs or symptoms consistent with SLE were observed. Although no patient had had a positive antinuclear factor (ANF) before therapy, the titre was positive ( > 80) at presentation of joint symptoms in all
leukocytes in the rejection of vascularized organ allografts. Ann Surg 1990; 212: 308-15. Bein G, Gläser R, Kirchner H. Rapid HLA-DRB1 genotyping by nested PCR amplification. Tissue Antigens 1992; 39: 68-73. 9 Ciccone E, Pende D, Viale O, et al. Evidence of a natural killer (NK) cell repertoire for (allo) antigen recognition: definition of five distinct NK-determined allospecificities in humans. J Exp Med 1992; 175: 709-18. 10 Schlitt HJ, Hundrieser J, Ringe B, Pichlmayr R. Donor-type microchimerism associated with graft rejection eight years after liver transplantation. N Engl J Med 1994; 330: 646-47. 8
Klinik für Abdominal-und Transplantationschirurgie (H J Schlitt, J Hundrieser, M Hisanaga, K Wonigeit, Prof R Pichlmayr), and Klinik für Thorax-, Herz-, und Gefäßchirurgie (K Uthoff, M Karck, T Wahlers) Medizinische Hochschule Hannover, D-30623 Hannover,
Germany Correspondence to: Dr Hans
J Schlitt
three, and in one, the titre persists
at over 80. Rheumatoid factor anti-histone and anti-DNA and antibodies were negative. (RF) Knee radiographs showed thalassaemic changes, joint effusions, and minor degenerative changes in the patellofemoral joint of one patient. Magnetic resonance imaging confirmed effusions, with no evidence of synovial hypertrophy or cartilage abnormalities. Aspiration of synovial fluid revealed a sterile transudate without inflammatory cells, and low concentrations of deferiprone uncomplexed to iron. Arthroscopy showed mild synovial hypertrophy and hyperplasia, with iron staining. Synovial biopsy revealed mild synovial lining cell proliferation and extensive iron deposition, without evidence of an inflammatory or allergic reaction. Intra-articular steroids were administered in two patients (with total relief of symptoms in one patient and partial relief in the second) who continued deferiprone without worsening of symptoms; symptoms resolved spontaneously in the third patient during continued treatment. Rheumatological examination was normal in the thirteen symptom-free patients. Before the start of deferiprone, ANF was positive in four, and RF was positive in five; both ANF and RF have remained positive in three of these patients during long-term administration. Anti-DNA and anti-histone antibodies remain
negative. The efficacy of deferiprone has exceeded expectations the past 3 years. Adverse effects have included acute reversible neutropenia or agranulocytosis, and, commonly, arthralgias of the large joints. Frequencies for arthralgias of 33% and 38%, respectively, have been reported in studies from the UK and India in patients on 100 mg/kg daily.4,s In patients in the UK, symptoms included generalised joint pain, swelling, and muscle stiffness; curiously, in one patient, finger pain occurring before treatment was reported as relieved during deferiprone administration. In most patients in all clinical trials, symptoms have resolved after drug withdrawal or dose reduction, with or without administration of non-steroidal anti-inflammatory agents. Spontaneous resolution has also been reported during continued deferiprone administration. While arthralgias appear temporally related to administration of deferiprone, similar complaints in thalassaemia patients have been reported without ironchelating therapy. Symmetrical arthralgias, sterile noninflammatory effusions, osteopenia, bony deformities, and microfractures secondary to marrow expansion were frequently observed in thalassaemia patients before is of regular transfusions.6 There programmes of and clinical evidence to the role experimental support iron in thalassaemic and other osteoarthropathies. over
1471
synovial membranes by free radicals, for catalysed by iron, example, is the likely first event in the inflammation of rheumatoid arthritis, a disease whose activity may be aggravated by iron overload and possibly relieved by iron-chelating therapy.7,8 We hypothesise that deferiprone induces joint symptoms via similar mechanisms. All three patients with symptoms had massively increased tissue iron stores, as reflected by a mean initial hepatic iron concentration approximately forty times normal (21-5 [5’4] mg/g dry weight tissue, normal <0-5), which was higher than that of our symptom-free patients (15-0 [9.6]). Similarly, in the Indian trials, very high serum ferritin concentrations were reported in most patients with symptoms.5 In such heavily iron-loaded patients, an effective chelator should shift substantial iron from tissue (primarily liver) stores to other body compartments. By contrast with the stable 3:1 complexes formed by desferrioxamine and iron, the bidentate chelator deferiprone may form 1:1 or 2:1 Fenton-active complexes with synovial iron. Experimental evidence suggests that this is especially likely at low concentrations of deferiprone relative to iron,9 as we detected in the synovial fluid of our three affected patients. Incomplete complexation may result in the formation of catalytic iron, which in turn accelerates the formation of hydroxyl radical that can peroxidise synovial membranes, as proposed in the pathophysiology of rheumatoid arthritis.7 Alternatively, or in addition, deferiprone may have worsened underlying osteoarthropathy in our patients, all of whom had been managed with irregular transfusions in their early course. The reported symptoms, signs, and findings on synovial aspiration and biopsy in patients with thalassaemic osteoarthropathy6 are similar to those observed in our three affected patients. There is no evidence that deferiprone actually induces SLE. The one Indian fatality2 might have been due to high-dose methylprednisolone. Although the frequency of elevated titres of ANF and RF in deferiprone-treated patients is often cited as support for drug-induced SLE, transfusion-dependent, desferrioxamine-treated patients show a similar frequency of positive ANF and RF.1O Drug-induced SLE is unlikely without other symptoms or the presence of anti-histone antibodies, which were absent throughout over 400 patient-months in this study. Future trials of deferiprone will show the frequency of arthropathy in larger numbers of patients. Peroxidation of
1472
This work was supported by the Medical Research Council of Canada, the Ontario Thalassemia Foundation, the Ontario Ministry of Health (NFO, GK), the Arthritis Society of Canada (RML), and the Cooley’s Anemia Foundation (MB). Presented in abstract form at the American Society of Hematology, Anaheim, December, 1992. We thank Marc Giacomelli for helpful discussion.
References 1 2
3
Brittenham GM. Development of iron-chelating agents for clinical use. Blood 1992; 80: 569-74. Mehta J, Singhal S, Revankar R, Walvalkar A, Chablani A, Mehta BC. Fatal systemic lupus erythematosus in patient taking oral iron chelator L1. Lancet 1991; 337: 298. Berdoukas VA. Anti-nuclear antibodies in patients taking L1. Lancet
1991; 337: 672. 4
5
Al-Refaie FN, Wonke B, Hoffbrand AV, Wickens DG, Nortey P, Kontoghiorghes GJ. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassaemia major. Blood 1992; 80: 592-99. Agarwal MB, Gupte SS, Viswanathan C, et al. Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusiondependent thalassaemia: Indian trial. Br J Haematol 1992; 82: 460-66.
6
7
8
9
Gratwick GM, Bullough PG, Bohne WHO, Markensen AL, Peterson CM. Thalassemic osteoarthropathy. Ann Intern Med 1978; 88: 494-501. Blake DR, Hall ND, Bacon PA, Dieppe PA, Halliwell B, Gutteridge JMC. The importance of iron in rheumatoid disease. Lancet 1981; ii: 1142-44. Magaro M, Zoli A, Altomonte L, et al. Iron chelation in rheumatoid arthritis: clinical and laboratory evaluation. Ann Rheum Dis 1990; 49: 268-69. Hershko C, Link G, Pinson A, Peter HH, Dobbin P, Hider RC. Iron mobilization from myocardial cells by 3-hydroxypyridin-4-one chelators: studies in rat heart cells in culture. Blood 1991; 77:
2049-53. 10 Berkovitch
M, Laxer RM, Matsui D, et al. Analysis of adverse rheumatologic effects of iron chelators in patients with homozygous beta thalassemia. Blood 1992; 80 (suppl 1): 7A.
Department of Pediatrics, Hospital for Sick Children (M Berkovitch MD, R M Laxer MD, G Koren MD, R Inman MD, N F Olivieri MD); Department of Medicine, University of Toronto, Toronto Hospital (R M Laxer, N F Olivieri); Department of Pathology, University of Toronto, Mount Sinal Hospital (K P H Pritzker MD), Toronto, Ontario; and McCalg Center for Joint Injury and Arthritis Research (M J Fritzler MD), University of Alberta, Calgary, Alberta, Canada Correspondence to: Dr Nancy Olivieri, Haemoglobinopathy Program, Hospital for Sick Children, 555 University Avenue, Toronto, Canada M5G1X8
Hepatology (in press). 7
Larsen CP, Austyn JM, Morris PJ. The role of graft-derived dendritic
Arthropathy in thalassaemia patients receiving deferiprone
The iron chelator deferiprone (L1) reduces tissue iron stores in iron-loaded patients. Three of sixteen patients treated with deferiprone developed joint pain and swelling without evidence of systemic lupus erythematosus (SLE). Articular cartilage, synovial hypertrophy and iron deposition, and synovial lining cell proliferation, with no inflammatory or allergic reaction, were observed on synovial exploration and biopsy. Symptoms resolved partly or completely during continued drug administration. We hypothesise that deferiprone-induced shifts of iron to synovium resulted in tissue damage, accelerated by free-radical formation during incomplete complexation of iron and this bidentate chelator. This deferiprone-associated symptom complex is not associated with drug-induced SLE, and does not progress in severity during continued therapy.
Lancet 1994; 343: 1471-72
The disadvantages of parenteral desferrioxamine led to a search for safe, orally active chelating agents for patients with iron-loading anaemias.1 One such alternative, deferiprone (1,2-dimethyl-3-hydroxypyrid-4-one, L1), is associated with arthralgias and arthritis and possibly with induction of systemic lupus erythematosus (SLE).2,3 We describe arthropathy in three deferiprone-treated patients. Sixteen patients with transfusion-dependent homozygous betathalassaemia have been treated with deferiprone, 75 mg/kg per day, for 1-3 years (mean 900, SD 300-0, range 360-1308 days), in a study approved by the Toronto Hospital for Sick Children. 3-8 months after the start of therapy, three patients aged 17, 20, and 27 years complained of severe bilateral knee pain at rest worsening with exertion, morning stiffness, and joint warmth and swelling. One patient also reported similar symptoms in the fingers and wrists of both hands. Examination revealed knee effusions, slight loss of full flexion, stress pain, and joint line tenderness; no other signs or symptoms consistent with SLE were observed. Although no patient had had a positive antinuclear factor (ANF) before therapy, the titre was positive ( > 80) at presentation of joint symptoms in all
leukocytes in the rejection of vascularized organ allografts. Ann Surg 1990; 212: 308-15. Bein G, Gläser R, Kirchner H. Rapid HLA-DRB1 genotyping by nested PCR amplification. Tissue Antigens 1992; 39: 68-73. 9 Ciccone E, Pende D, Viale O, et al. Evidence of a natural killer (NK) cell repertoire for (allo) antigen recognition: definition of five distinct NK-determined allospecificities in humans. J Exp Med 1992; 175: 709-18. 10 Schlitt HJ, Hundrieser J, Ringe B, Pichlmayr R. Donor-type microchimerism associated with graft rejection eight years after liver transplantation. N Engl J Med 1994; 330: 646-47. 8
Klinik für Abdominal-und Transplantationschirurgie (H J Schlitt, J Hundrieser, M Hisanaga, K Wonigeit, Prof R Pichlmayr), and Klinik für Thorax-, Herz-, und Gefäßchirurgie (K Uthoff, M Karck, T Wahlers) Medizinische Hochschule Hannover, D-30623 Hannover,
Germany Correspondence to: Dr Hans
J Schlitt
three, and in one, the titre persists
at over 80. Rheumatoid factor anti-histone and anti-DNA and antibodies were negative. (RF) Knee radiographs showed thalassaemic changes, joint effusions, and minor degenerative changes in the patellofemoral joint of one patient. Magnetic resonance imaging confirmed effusions, with no evidence of synovial hypertrophy or cartilage abnormalities. Aspiration of synovial fluid revealed a sterile transudate without inflammatory cells, and low concentrations of deferiprone uncomplexed to iron. Arthroscopy showed mild synovial hypertrophy and hyperplasia, with iron staining. Synovial biopsy revealed mild synovial lining cell proliferation and extensive iron deposition, without evidence of an inflammatory or allergic reaction. Intra-articular steroids were administered in two patients (with total relief of symptoms in one patient and partial relief in the second) who continued deferiprone without worsening of symptoms; symptoms resolved spontaneously in the third patient during continued treatment. Rheumatological examination was normal in the thirteen symptom-free patients. Before the start of deferiprone, ANF was positive in four, and RF was positive in five; both ANF and RF have remained positive in three of these patients during long-term administration. Anti-DNA and anti-histone antibodies remain
negative. The efficacy of deferiprone has exceeded expectations the past 3 years. Adverse effects have included acute reversible neutropenia or agranulocytosis, and, commonly, arthralgias of the large joints. Frequencies for arthralgias of 33% and 38%, respectively, have been reported in studies from the UK and India in patients on 100 mg/kg daily.4,s In patients in the UK, symptoms included generalised joint pain, swelling, and muscle stiffness; curiously, in one patient, finger pain occurring before treatment was reported as relieved during deferiprone administration. In most patients in all clinical trials, symptoms have resolved after drug withdrawal or dose reduction, with or without administration of non-steroidal anti-inflammatory agents. Spontaneous resolution has also been reported during continued deferiprone administration. While arthralgias appear temporally related to administration of deferiprone, similar complaints in thalassaemia patients have been reported without ironchelating therapy. Symmetrical arthralgias, sterile noninflammatory effusions, osteopenia, bony deformities, and microfractures secondary to marrow expansion were frequently observed in thalassaemia patients before is of regular transfusions.6 There programmes of and clinical evidence to the role experimental support iron in thalassaemic and other osteoarthropathies. over
1471
synovial membranes by free radicals, for catalysed by iron, example, is the likely first event in the inflammation of rheumatoid arthritis, a disease whose activity may be aggravated by iron overload and possibly relieved by iron-chelating therapy.7,8 We hypothesise that deferiprone induces joint symptoms via similar mechanisms. All three patients with symptoms had massively increased tissue iron stores, as reflected by a mean initial hepatic iron concentration approximately forty times normal (21-5 [5’4] mg/g dry weight tissue, normal <0-5), which was higher than that of our symptom-free patients (15-0 [9.6]). Similarly, in the Indian trials, very high serum ferritin concentrations were reported in most patients with symptoms.5 In such heavily iron-loaded patients, an effective chelator should shift substantial iron from tissue (primarily liver) stores to other body compartments. By contrast with the stable 3:1 complexes formed by desferrioxamine and iron, the bidentate chelator deferiprone may form 1:1 or 2:1 Fenton-active complexes with synovial iron. Experimental evidence suggests that this is especially likely at low concentrations of deferiprone relative to iron,9 as we detected in the synovial fluid of our three affected patients. Incomplete complexation may result in the formation of catalytic iron, which in turn accelerates the formation of hydroxyl radical that can peroxidise synovial membranes, as proposed in the pathophysiology of rheumatoid arthritis.7 Alternatively, or in addition, deferiprone may have worsened underlying osteoarthropathy in our patients, all of whom had been managed with irregular transfusions in their early course. The reported symptoms, signs, and findings on synovial aspiration and biopsy in patients with thalassaemic osteoarthropathy6 are similar to those observed in our three affected patients. There is no evidence that deferiprone actually induces SLE. The one Indian fatality2 might have been due to high-dose methylprednisolone. Although the frequency of elevated titres of ANF and RF in deferiprone-treated patients is often cited as support for drug-induced SLE, transfusion-dependent, desferrioxamine-treated patients show a similar frequency of positive ANF and RF.1O Drug-induced SLE is unlikely without other symptoms or the presence of anti-histone antibodies, which were absent throughout over 400 patient-months in this study. Future trials of deferiprone will show the frequency of arthropathy in larger numbers of patients. Peroxidation of
1472
This work was supported by the Medical Research Council of Canada, the Ontario Thalassemia Foundation, the Ontario Ministry of Health (NFO, GK), the Arthritis Society of Canada (RML), and the Cooley’s Anemia Foundation (MB). Presented in abstract form at the American Society of Hematology, Anaheim, December, 1992. We thank Marc Giacomelli for helpful discussion.
References 1 2
3
Brittenham GM. Development of iron-chelating agents for clinical use. Blood 1992; 80: 569-74. Mehta J, Singhal S, Revankar R, Walvalkar A, Chablani A, Mehta BC. Fatal systemic lupus erythematosus in patient taking oral iron chelator L1. Lancet 1991; 337: 298. Berdoukas VA. Anti-nuclear antibodies in patients taking L1. Lancet
1991; 337: 672. 4
5
Al-Refaie FN, Wonke B, Hoffbrand AV, Wickens DG, Nortey P, Kontoghiorghes GJ. Efficacy and possible adverse effects of the oral iron chelator 1,2-dimethyl-3-hydroxypyrid-4-one (L1) in thalassaemia major. Blood 1992; 80: 592-99. Agarwal MB, Gupte SS, Viswanathan C, et al. Long-term assessment of efficacy and safety of L1, an oral iron chelator, in transfusiondependent thalassaemia: Indian trial. Br J Haematol 1992; 82: 460-66.
6
7
8
9
Gratwick GM, Bullough PG, Bohne WHO, Markensen AL, Peterson CM. Thalassemic osteoarthropathy. Ann Intern Med 1978; 88: 494-501. Blake DR, Hall ND, Bacon PA, Dieppe PA, Halliwell B, Gutteridge JMC. The importance of iron in rheumatoid disease. Lancet 1981; ii: 1142-44. Magaro M, Zoli A, Altomonte L, et al. Iron chelation in rheumatoid arthritis: clinical and laboratory evaluation. Ann Rheum Dis 1990; 49: 268-69. Hershko C, Link G, Pinson A, Peter HH, Dobbin P, Hider RC. Iron mobilization from myocardial cells by 3-hydroxypyridin-4-one chelators: studies in rat heart cells in culture. Blood 1991; 77:
2049-53. 10 Berkovitch
M, Laxer RM, Matsui D, et al. Analysis of adverse rheumatologic effects of iron chelators in patients with homozygous beta thalassemia. Blood 1992; 80 (suppl 1): 7A.
Department of Pediatrics, Hospital for Sick Children (M Berkovitch MD, R M Laxer MD, G Koren MD, R Inman MD, N F Olivieri MD); Department of Medicine, University of Toronto, Toronto Hospital (R M Laxer, N F Olivieri); Department of Pathology, University of Toronto, Mount Sinal Hospital (K P H Pritzker MD), Toronto, Ontario; and McCalg Center for Joint Injury and Arthritis Research (M J Fritzler MD), University of Alberta, Calgary, Alberta, Canada Correspondence to: Dr Nancy Olivieri, Haemoglobinopathy Program, Hospital for Sick Children, 555 University Avenue, Toronto, Canada M5G1X8