Juvenile rheumatoid arthritis with myelofibrosis with myeloid metaplasia
http://www.100md.com
《美国医学杂志》
Department of Pediatrics, All India Institute of Medical Sciences, New Delhi, India
Abstract
Myelofibrosis with myeloid metaplasia is defined as a myeloproliferative disorder characterized by leukoerythroblastosis, tear drop erythrocytes, extramedullary hematopoesis and varying degree of myelofibrosis. It may be idiopathic or secondary to a large number of conditions. Here is a rare case of myelofibrosis occurring in a patient with juvenile rheumatoid arthritis.
Keywords: Myelofibrosis; Myeloid metaplasia; Juvenile rheumatoid arthriti
Myelofibrosis with myeloid metaplasia is classified broadly as a chronic myeloid disorder and more specifically as a chronic myeloproliferative disease. The primary pathogenetic mechanism is a clonal stem-cell disorder that leads to ineffective erythropoiesis, dysplastic-megakaryocytic hyperplasia,and an increase in the ratio of immature granulocytes to total granulocytes. This clonal myeloproliferation is characteristically accompanied by reactive myelofibrosis and by extramedullary hematopoiesis in spleen or in multiple organs. Myelofibrosis with myeloid metaplasia may be primary or idiopathic or secondary to large number of other conditions.[1] Idiopathic myelofibrosis is rare in childhood with a variable outcome reported in literature. Most reports describe an aggressive course and a high mortality although few cases have been reported with a less aggressive course and even spontaneous regression.[2],[3] Here we present the unusual case of an eight-year-old boy who was initially diagnosed as rheumatoid factor (RF) positive polyarticular juvenile rheumatoid arthritis on the basis of clinical signs and symptoms and investigations and one and a half year later also found to be suffering from myelofibrosis with myeloid metaplasia. The pathogenesis, diagnosis, clinical features and therapeutic options in myelofibrosis with myeloid metaplasia have also been discussed.
Case Report
An eight-year-old male child initially presented to the pediatric rheumatology clinic of a tertiary care hospital with complaints of low-grade fever and pain in multiple joints of 2 months duration. He was investigated and a diagnosis of polyarticular juvenile rheumatoid arthritis (JRA) with positive rheumatoid factor (RF) was made. He was started on naproxen and later advised methotrexate but did not take it and was lost to follow up for some time. He returned after 3 months with increasing joint stiffness for which he was treated with three doses of pulse dexamethasone therapy. The child was again lost to follow up and returned one and a half years later with increasing joint pains and progressive pallor for one year and fever and inability to walk for the last two months. On examination, he had severe pallor, icterus, few petechiae and features suggestive of congestive cardiac failure. Chest and cardiovascular examination was normal except for evidence of hyperdynamic circulation. Abdominal examination revealed massive splenomegaly (22 cm below costal margin) and hepatomegaly (7 cm below costal margin,13 cm span with normal smooth surface). Examination of the joints revealed no features of acute inflammation but there was restriction of movement at all major synovial joints with flexion contractures in both knee joints. Left hip joint was dislocated. On consulting his previous records, it was found that he had a hepatomegaly of 2 cm and splenomegaly of 5 cm at the time of initial presentation. On investigating the child, we found pancytopenia with a hemoglobin of 5.2 gm/dl, TLC of 1700/ cumm, DLC of N30L70, platelet count of 20,000/ cumm and reticulocyte count < 1%. Peripheral smear showed microcytic hypochromic anemia with poikilocytosis with neutropenia and thrombocytopenia with occasional metamyelocytes and nucleated red cells. Previous reports (at the time of initial presentation) were hemoglobin 8.1gms/dl, TLC 11,900/ cumm, DLC N74L24E02 and platelets 350,000/ cumm. Liver and renal function tests were within normal limits. Bone marrow aspiration was dry and biopsy revealed reduced cellularity and increased reticulin fibers suggestive of grade III myelofibrosis with erythroid predominance. The child needed repeated blood and platelet transfusions and was unable to maintain his hemoglobin and platelet count within normal limits. The treatment options available to us at this stage were very limited. Bone marrow transplantation could not be considered because of cost constraints. We added weekly oral methotrexate but 3 weeks after its addition, the child had an episode of intracerebral bleed with a platelet count of 10,000/cumm. Daily oral prednisolone at the dose of 2 mg/Kg was added at this time. After adding prednisolone the blood and platelet requirement came down and from 2 weeks after the addition of prednisolone, he did not require any more transfusions. Prednisolone was tapered to 1 mg/Kg/d at discharge and to 0.5mg/Kg/d after 15 days. His last blood counts 3 months after discharge are hemoglobin 11.2 gm/dl, TLC 10,700/ cumm, DLC N52L46M2 and platelets 210,000/ cumm.
Discussion
Primary myelofibrosis is also called agnogenic myelofibrosis with myeloid metaplasia. The common causes of secondary myelofibrosis are malignancies like acute megakaryocytic leukemia, chronic granulocytic leukemia, acute myeloid leukemia, acute lymphoid leukemia, hairy cell leukemia, Hodgkins disease, myeloma, carcinoma and transitional myeloproliferative syndromes Other conditions uncommonly associated with secondary myelofibrosis are metabolic causes like renal osteodystrophy, chronic renal failure, hyperparathyroidism; bone disease like osteopetrosis, Paget's disease and osteomalacia and connective tissue diseases such as Systemic Lupus Erythromatosis and systemic sclerosis.[4] One case each of dermatomyositis, rheumatoid arthritis and Sjogren's syndrome in association with myelofibrosis have also been reported in literature.[5],[6],[7] However, we did not come across any report of association of juvenile rheumatoid arthritis with myelofibrosis in our search of literature.
Initial signs and symptoms of myelofibrosis are cachexia (profound fatigue, weight loss, night sweats, and low-grade fever), pallor and marked splenomegaly. Intraabdominal mass effect from organomegaly may also be responsible for the characteristic presence of early satiety, diarrhea, and peripheral edema. Laboratory studies reveal anemia, an increased or decreased white cell count, an increased or decreased platelet count, a leftward shift in the granulocyte count, and increased levels of lactate dehydrogenase. Anemia is present because of ineffective hematopoiesis, erythroid hypoplasia, the replacement of normal hematopoietic tissue with collagen fibrosis and hypersplenism. The white cell count and platelet count may be increased due to clonal myeloproliferation or decreased as a consequence of sequestration in the spleen. The increase in lactate dehydrogenase level is attributed to deficient hematopoiesis. Peripheral smear typically shows myelophthisis of the blood, a condition characterized by the presence of leukoerythroblasts (immature granulocytes and nucleated red cells) and teardrop-shaped red cells. Myelophthisis occurs because of intramedullary sinusoidal hematopoiesis in the bone marrow and myeloid metaplasia of the spleen with disruption of the normal processes, which in the bone marrow are responsible for release of cells at appropriate maturation. Bone marrow is not easily aspirated often resulting in a dry tap. Findings in the core biopsy specimen are medullary fibrosis, dysplastic-megakaryocytic hyperplasia, osteosclerosis, and dilatation of marrow sinusoids accompanied by intravascular hematopoiesis. Cytogenetic studies of the bone marrow are helpful in excluding the possibility of chronic myeloid leukemia, another chronic myeloid disorder.[4]
Pathogenesis-The primary defect lies at the level of the pluripotent hematopoietic stem cell which undergoes trilineage (granulocytic, erythroid and megakaryocytic) monoclonal proliferation. The stromal reaction of the bone marrow is a reactive process mediated by the cytokines released by these monoclonal cells. Both megakaryocytes and monocytes have been implicated as sources of the nosogenic cytokines that may augment fibroblast proliferation (platelet-derived growth factor and calmodulin), collagen synthesis (transforming growth factor b), angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor) and osteogenesis (transforming growth factor b and basic fibroblast growth factor).[8],[9] Extramedullary hematopoiesis that occurs in this condition was previously attributed to rekindling of quiescent hematopoietic stem cells in sites of former embryonic hematopoiesis including spleen by a myelostimulatory factor. It is now believed that marrow fibrosis leads to distortion of marrow sinusoids permitting entry into sinusoids of immature hematopoietic stem cells that are then washed into peripheral blood and lodge in the sites of extramedullary hematopoiesis.[1]
Complications such as portal hypertension with ascites or variceal bleeding may occur due to increased portal flow resulting from marked splenomegaly. Extramedullary hematopoiesis may also occur at lymph nodes, resulting in lymphadenopathy; serosal surfaces, leading to pleural effusion and ascites; the lungs, causing a pneumonia-like process; the urogenital system, causing hematuria and paraspinal and epidural spaces, leading to compression of the spinal cord and nerve roots. Severe musculoskeletal and joint pain not responsive to nonsteroidal anti-inflammatory drugs may also be present. The corresponding radiologic features may include osteosclerosis, hypertrophic osteoarthropathy, and periostitis.[4]
Median survival is seen to be 3.5 to 5.5 yr but marked variability exists depending on the presence of various prognostic factors. Complete remission has also been reported in some cases. Advanced age, leucocytosis, circulating blasts, increased number of granulocyte precursors, thrombocytopenia, abnormality in karyotype and presence of hypercatabolic symptoms are associated with a poorer prognosis.[10] The principal causes of death in patients with myelofibrosis are infection, thrombohemorrhagic events, heart failure and leukemic transformation.
In view of the highly variable outcome of myelofibrosis in children, conservative management should always be tried first. Androgen and corticosteroids are useful in alleviating the anemia but the response is often seen to be suboptimal in patients with advanced disease, transfusion-dependent anemia, massive splenomegaly and karyotype abnormalities.[4] However, in the present case a good response to prednisolone was seen despite presence of massive splenomegaly and transfusion dependent anemia. Hydroxyurea is helpful in patients with leukocytosis, thrombocytosis, or organomegaly. Interferon-alfa and cladribine are also useful for the above indication. Thalidomide has been evaluated in myelofibrosis with myeloid metaplasia for its antiangiogenic properties singly and in combination with corticosteroids. As a single agent it showed poor tolerability and only 20% response rate but in combination with prednisolone it showed good tolerability with 70% response rate in improvement of anemia and thrombocytopenia. Many other drugs like imatinib mesylate, anagrelide, suramin and perfenidone have also been tried but not proved useful.[11],[12] Etanercept, a soluble tumor necrosis factor receptor may benefit by thwarting constitutional symptoms in patients with myelofibrosis with myeloid metaplasia. Splenectomy has a role in drug-recalcitrant cases with mass-related constitutional symptoms, overt portal hypertension and progressive anemia requiring repeated transfusions. It might be associated with complications like perioperative bleeding, infection and thrombosis. Splenic irradiation is transiently helpful in relieving pain and decreasing the spleen size but has no effect on anemia. It may lead to prolonged cytopenia in upto 25 percent cases and is also associated with unpredictable myelosuppressive toxicity not correlating with the doses of radiation. Subsequent splenectomy, if required, is associated with increased preioperative bleeding. Hence this option should be reserved for patients in whom splenectomy can not be done.[13] Allogeneic bone marrow transplantation as well as allogeneic hematopoietic stem cell transplantation may be potentially curative and can be considered in young patients with a poor prognosis.[14] Autologous Stem-Cell Transplantation is an upcoming modality, which has the potential to produce a clinical response in the form of alleviation of symptoms, reduction in spleen size, freedom from dependence on red-cell transfusion, or regression of bone marrow fibrosis.[15]
Methotrexate has been reported to be useful in a case of dermatomyositis with myelofibrosis in ameliorating the autoimmune symptoms as well as improving the hematologic findings.[5] Corticosteroids have also got a special role in patients with myelofibrosis in conjunction with autoimmune diseases. Complete remission of hematologic findings has been reported in a case of Systemic Lupus Erythematosis with myelofibrosis.[16] In the present case, the child was first started on weekly oral methotrexate at a dose of 10 mg/m2, but after three weeks child had intracerebral bleed. We added prednisolone at the dose of 2 mg/Kg/d, which was gradually tapered to 0.5 mg/Kg/d and methotrexate was continued. Patient has been in sustained remission in follow-up for the last six months.
References
1. Tefferi A. Myelofibrosis with myeloid metaplasia. NEJM 2000, 342: 1255-1265.
2. Sah A, Minford A, Parapia L A. Spontaneous remission of juvenile idiopathic myelofibrosis. Br J Haematol 2001; 112: 1083-1090.
3. Sekhar M, Prentice H G, Popat U, Anderson D, Janmohammed R, Roberts I et al. Idiopathic myelofibrosis in children. Br J Haematol 1996; 93: 394-397.
4. McCarthy DM. Fibrosis of the bone marrow: content and causes. Br J Haematol 1985; 59: 1-7.
5. Tsuji G, Maekawa S, Saigo K, Nobuhara Y, Nakamura T, Kawano S et al. Dermatomyositis and myelodysplastic syndrome with myelofibrosis responding to methotrexate therapy. Am J Hematol 2003; 74(3): 175-178.
6. Ros Exposito S, Rodriguez Moreno J, Campoy Reolid E, Roig Escofet D. Idiopathic myelofibrosis associated with rheumatoid arthritis. Med Clin (Barc) 1994; 102(7): 277
7. Marie I, Levesque H, Cailleux N, Lepretre S, Duval C, Tilly H, Courtois H. An uncommon association: Sjogren's syndrome and autoimmune myelofibrosis. Rheumatology (Oxford) 1999; 38(4): 370-371.
8. Castro-Malaspina H, Gay RE, Jhanwar SC et al. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood 1982; 59: 1046-1054.
9. Kimura A, Katoh O, Hyodo H, Kuramoto A. Transforming growth factor-beta regulates growth as well as collagen and fibronectin synthesis of human marrow fibroblasts. Br J Haematol 1989; 72: 486-491.
10. Kvasnicka HM, Thiele J, Werden C, Zankovich R, Diehl V, Fischer R. Prognostic factors in idiopathic (primary) osteomyelofibrosis. Cancer 1997; 80: 708-719.
11. Yoon SY, Li CY, Mesa RA, Tefferi A. Bone marrow effects of anagrelide therapy in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 1999; 106: 682-688.
12. Mesa R A, Teffari A, Elliott M A, Call T G, Schroeder G S, Yoon SY et al. A phase II trial of perfenidone, a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia. Br J Haematol 2001; 114: 111-113.
13. Elliott M A, Chen M G, Silverstein M N, Teffari A. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol 1998;103: 505-511.
14. Guardiola P, Esperou H, Cazals-Hatem D et al. Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. Br J Haematol 1997; 98: 1004-1009.
15. Anderson JE, Deeg HJ, Tefferi A et al. Effective treatment of myelofibrosis by autologous peripheral blood stem cell transplantation (PBSCT). Blood 1999; 94: (Suppl 1): 396a-396a.
Abstract
16. Daly H M, Scott G L. Myelofibrosis as a cause of pancytopenia in systemic lupus erythematosis. J Clin Path 1983; 36: 1219-1222.(Jain Vandana, Maheshwari )
Abstract
Myelofibrosis with myeloid metaplasia is defined as a myeloproliferative disorder characterized by leukoerythroblastosis, tear drop erythrocytes, extramedullary hematopoesis and varying degree of myelofibrosis. It may be idiopathic or secondary to a large number of conditions. Here is a rare case of myelofibrosis occurring in a patient with juvenile rheumatoid arthritis.
Keywords: Myelofibrosis; Myeloid metaplasia; Juvenile rheumatoid arthriti
Myelofibrosis with myeloid metaplasia is classified broadly as a chronic myeloid disorder and more specifically as a chronic myeloproliferative disease. The primary pathogenetic mechanism is a clonal stem-cell disorder that leads to ineffective erythropoiesis, dysplastic-megakaryocytic hyperplasia,and an increase in the ratio of immature granulocytes to total granulocytes. This clonal myeloproliferation is characteristically accompanied by reactive myelofibrosis and by extramedullary hematopoiesis in spleen or in multiple organs. Myelofibrosis with myeloid metaplasia may be primary or idiopathic or secondary to large number of other conditions.[1] Idiopathic myelofibrosis is rare in childhood with a variable outcome reported in literature. Most reports describe an aggressive course and a high mortality although few cases have been reported with a less aggressive course and even spontaneous regression.[2],[3] Here we present the unusual case of an eight-year-old boy who was initially diagnosed as rheumatoid factor (RF) positive polyarticular juvenile rheumatoid arthritis on the basis of clinical signs and symptoms and investigations and one and a half year later also found to be suffering from myelofibrosis with myeloid metaplasia. The pathogenesis, diagnosis, clinical features and therapeutic options in myelofibrosis with myeloid metaplasia have also been discussed.
Case Report
An eight-year-old male child initially presented to the pediatric rheumatology clinic of a tertiary care hospital with complaints of low-grade fever and pain in multiple joints of 2 months duration. He was investigated and a diagnosis of polyarticular juvenile rheumatoid arthritis (JRA) with positive rheumatoid factor (RF) was made. He was started on naproxen and later advised methotrexate but did not take it and was lost to follow up for some time. He returned after 3 months with increasing joint stiffness for which he was treated with three doses of pulse dexamethasone therapy. The child was again lost to follow up and returned one and a half years later with increasing joint pains and progressive pallor for one year and fever and inability to walk for the last two months. On examination, he had severe pallor, icterus, few petechiae and features suggestive of congestive cardiac failure. Chest and cardiovascular examination was normal except for evidence of hyperdynamic circulation. Abdominal examination revealed massive splenomegaly (22 cm below costal margin) and hepatomegaly (7 cm below costal margin,13 cm span with normal smooth surface). Examination of the joints revealed no features of acute inflammation but there was restriction of movement at all major synovial joints with flexion contractures in both knee joints. Left hip joint was dislocated. On consulting his previous records, it was found that he had a hepatomegaly of 2 cm and splenomegaly of 5 cm at the time of initial presentation. On investigating the child, we found pancytopenia with a hemoglobin of 5.2 gm/dl, TLC of 1700/ cumm, DLC of N30L70, platelet count of 20,000/ cumm and reticulocyte count < 1%. Peripheral smear showed microcytic hypochromic anemia with poikilocytosis with neutropenia and thrombocytopenia with occasional metamyelocytes and nucleated red cells. Previous reports (at the time of initial presentation) were hemoglobin 8.1gms/dl, TLC 11,900/ cumm, DLC N74L24E02 and platelets 350,000/ cumm. Liver and renal function tests were within normal limits. Bone marrow aspiration was dry and biopsy revealed reduced cellularity and increased reticulin fibers suggestive of grade III myelofibrosis with erythroid predominance. The child needed repeated blood and platelet transfusions and was unable to maintain his hemoglobin and platelet count within normal limits. The treatment options available to us at this stage were very limited. Bone marrow transplantation could not be considered because of cost constraints. We added weekly oral methotrexate but 3 weeks after its addition, the child had an episode of intracerebral bleed with a platelet count of 10,000/cumm. Daily oral prednisolone at the dose of 2 mg/Kg was added at this time. After adding prednisolone the blood and platelet requirement came down and from 2 weeks after the addition of prednisolone, he did not require any more transfusions. Prednisolone was tapered to 1 mg/Kg/d at discharge and to 0.5mg/Kg/d after 15 days. His last blood counts 3 months after discharge are hemoglobin 11.2 gm/dl, TLC 10,700/ cumm, DLC N52L46M2 and platelets 210,000/ cumm.
Discussion
Primary myelofibrosis is also called agnogenic myelofibrosis with myeloid metaplasia. The common causes of secondary myelofibrosis are malignancies like acute megakaryocytic leukemia, chronic granulocytic leukemia, acute myeloid leukemia, acute lymphoid leukemia, hairy cell leukemia, Hodgkins disease, myeloma, carcinoma and transitional myeloproliferative syndromes Other conditions uncommonly associated with secondary myelofibrosis are metabolic causes like renal osteodystrophy, chronic renal failure, hyperparathyroidism; bone disease like osteopetrosis, Paget's disease and osteomalacia and connective tissue diseases such as Systemic Lupus Erythromatosis and systemic sclerosis.[4] One case each of dermatomyositis, rheumatoid arthritis and Sjogren's syndrome in association with myelofibrosis have also been reported in literature.[5],[6],[7] However, we did not come across any report of association of juvenile rheumatoid arthritis with myelofibrosis in our search of literature.
Initial signs and symptoms of myelofibrosis are cachexia (profound fatigue, weight loss, night sweats, and low-grade fever), pallor and marked splenomegaly. Intraabdominal mass effect from organomegaly may also be responsible for the characteristic presence of early satiety, diarrhea, and peripheral edema. Laboratory studies reveal anemia, an increased or decreased white cell count, an increased or decreased platelet count, a leftward shift in the granulocyte count, and increased levels of lactate dehydrogenase. Anemia is present because of ineffective hematopoiesis, erythroid hypoplasia, the replacement of normal hematopoietic tissue with collagen fibrosis and hypersplenism. The white cell count and platelet count may be increased due to clonal myeloproliferation or decreased as a consequence of sequestration in the spleen. The increase in lactate dehydrogenase level is attributed to deficient hematopoiesis. Peripheral smear typically shows myelophthisis of the blood, a condition characterized by the presence of leukoerythroblasts (immature granulocytes and nucleated red cells) and teardrop-shaped red cells. Myelophthisis occurs because of intramedullary sinusoidal hematopoiesis in the bone marrow and myeloid metaplasia of the spleen with disruption of the normal processes, which in the bone marrow are responsible for release of cells at appropriate maturation. Bone marrow is not easily aspirated often resulting in a dry tap. Findings in the core biopsy specimen are medullary fibrosis, dysplastic-megakaryocytic hyperplasia, osteosclerosis, and dilatation of marrow sinusoids accompanied by intravascular hematopoiesis. Cytogenetic studies of the bone marrow are helpful in excluding the possibility of chronic myeloid leukemia, another chronic myeloid disorder.[4]
Pathogenesis-The primary defect lies at the level of the pluripotent hematopoietic stem cell which undergoes trilineage (granulocytic, erythroid and megakaryocytic) monoclonal proliferation. The stromal reaction of the bone marrow is a reactive process mediated by the cytokines released by these monoclonal cells. Both megakaryocytes and monocytes have been implicated as sources of the nosogenic cytokines that may augment fibroblast proliferation (platelet-derived growth factor and calmodulin), collagen synthesis (transforming growth factor b), angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor) and osteogenesis (transforming growth factor b and basic fibroblast growth factor).[8],[9] Extramedullary hematopoiesis that occurs in this condition was previously attributed to rekindling of quiescent hematopoietic stem cells in sites of former embryonic hematopoiesis including spleen by a myelostimulatory factor. It is now believed that marrow fibrosis leads to distortion of marrow sinusoids permitting entry into sinusoids of immature hematopoietic stem cells that are then washed into peripheral blood and lodge in the sites of extramedullary hematopoiesis.[1]
Complications such as portal hypertension with ascites or variceal bleeding may occur due to increased portal flow resulting from marked splenomegaly. Extramedullary hematopoiesis may also occur at lymph nodes, resulting in lymphadenopathy; serosal surfaces, leading to pleural effusion and ascites; the lungs, causing a pneumonia-like process; the urogenital system, causing hematuria and paraspinal and epidural spaces, leading to compression of the spinal cord and nerve roots. Severe musculoskeletal and joint pain not responsive to nonsteroidal anti-inflammatory drugs may also be present. The corresponding radiologic features may include osteosclerosis, hypertrophic osteoarthropathy, and periostitis.[4]
Median survival is seen to be 3.5 to 5.5 yr but marked variability exists depending on the presence of various prognostic factors. Complete remission has also been reported in some cases. Advanced age, leucocytosis, circulating blasts, increased number of granulocyte precursors, thrombocytopenia, abnormality in karyotype and presence of hypercatabolic symptoms are associated with a poorer prognosis.[10] The principal causes of death in patients with myelofibrosis are infection, thrombohemorrhagic events, heart failure and leukemic transformation.
In view of the highly variable outcome of myelofibrosis in children, conservative management should always be tried first. Androgen and corticosteroids are useful in alleviating the anemia but the response is often seen to be suboptimal in patients with advanced disease, transfusion-dependent anemia, massive splenomegaly and karyotype abnormalities.[4] However, in the present case a good response to prednisolone was seen despite presence of massive splenomegaly and transfusion dependent anemia. Hydroxyurea is helpful in patients with leukocytosis, thrombocytosis, or organomegaly. Interferon-alfa and cladribine are also useful for the above indication. Thalidomide has been evaluated in myelofibrosis with myeloid metaplasia for its antiangiogenic properties singly and in combination with corticosteroids. As a single agent it showed poor tolerability and only 20% response rate but in combination with prednisolone it showed good tolerability with 70% response rate in improvement of anemia and thrombocytopenia. Many other drugs like imatinib mesylate, anagrelide, suramin and perfenidone have also been tried but not proved useful.[11],[12] Etanercept, a soluble tumor necrosis factor receptor may benefit by thwarting constitutional symptoms in patients with myelofibrosis with myeloid metaplasia. Splenectomy has a role in drug-recalcitrant cases with mass-related constitutional symptoms, overt portal hypertension and progressive anemia requiring repeated transfusions. It might be associated with complications like perioperative bleeding, infection and thrombosis. Splenic irradiation is transiently helpful in relieving pain and decreasing the spleen size but has no effect on anemia. It may lead to prolonged cytopenia in upto 25 percent cases and is also associated with unpredictable myelosuppressive toxicity not correlating with the doses of radiation. Subsequent splenectomy, if required, is associated with increased preioperative bleeding. Hence this option should be reserved for patients in whom splenectomy can not be done.[13] Allogeneic bone marrow transplantation as well as allogeneic hematopoietic stem cell transplantation may be potentially curative and can be considered in young patients with a poor prognosis.[14] Autologous Stem-Cell Transplantation is an upcoming modality, which has the potential to produce a clinical response in the form of alleviation of symptoms, reduction in spleen size, freedom from dependence on red-cell transfusion, or regression of bone marrow fibrosis.[15]
Methotrexate has been reported to be useful in a case of dermatomyositis with myelofibrosis in ameliorating the autoimmune symptoms as well as improving the hematologic findings.[5] Corticosteroids have also got a special role in patients with myelofibrosis in conjunction with autoimmune diseases. Complete remission of hematologic findings has been reported in a case of Systemic Lupus Erythematosis with myelofibrosis.[16] In the present case, the child was first started on weekly oral methotrexate at a dose of 10 mg/m2, but after three weeks child had intracerebral bleed. We added prednisolone at the dose of 2 mg/Kg/d, which was gradually tapered to 0.5 mg/Kg/d and methotrexate was continued. Patient has been in sustained remission in follow-up for the last six months.
References
1. Tefferi A. Myelofibrosis with myeloid metaplasia. NEJM 2000, 342: 1255-1265.
2. Sah A, Minford A, Parapia L A. Spontaneous remission of juvenile idiopathic myelofibrosis. Br J Haematol 2001; 112: 1083-1090.
3. Sekhar M, Prentice H G, Popat U, Anderson D, Janmohammed R, Roberts I et al. Idiopathic myelofibrosis in children. Br J Haematol 1996; 93: 394-397.
4. McCarthy DM. Fibrosis of the bone marrow: content and causes. Br J Haematol 1985; 59: 1-7.
5. Tsuji G, Maekawa S, Saigo K, Nobuhara Y, Nakamura T, Kawano S et al. Dermatomyositis and myelodysplastic syndrome with myelofibrosis responding to methotrexate therapy. Am J Hematol 2003; 74(3): 175-178.
6. Ros Exposito S, Rodriguez Moreno J, Campoy Reolid E, Roig Escofet D. Idiopathic myelofibrosis associated with rheumatoid arthritis. Med Clin (Barc) 1994; 102(7): 277
7. Marie I, Levesque H, Cailleux N, Lepretre S, Duval C, Tilly H, Courtois H. An uncommon association: Sjogren's syndrome and autoimmune myelofibrosis. Rheumatology (Oxford) 1999; 38(4): 370-371.
8. Castro-Malaspina H, Gay RE, Jhanwar SC et al. Characteristics of bone marrow fibroblast colony-forming cells (CFU-F) and their progeny in patients with myeloproliferative disorders. Blood 1982; 59: 1046-1054.
9. Kimura A, Katoh O, Hyodo H, Kuramoto A. Transforming growth factor-beta regulates growth as well as collagen and fibronectin synthesis of human marrow fibroblasts. Br J Haematol 1989; 72: 486-491.
10. Kvasnicka HM, Thiele J, Werden C, Zankovich R, Diehl V, Fischer R. Prognostic factors in idiopathic (primary) osteomyelofibrosis. Cancer 1997; 80: 708-719.
11. Yoon SY, Li CY, Mesa RA, Tefferi A. Bone marrow effects of anagrelide therapy in patients with myelofibrosis with myeloid metaplasia. Br J Haematol 1999; 106: 682-688.
12. Mesa R A, Teffari A, Elliott M A, Call T G, Schroeder G S, Yoon SY et al. A phase II trial of perfenidone, a novel anti-fibrosing agent, in myelofibrosis with myeloid metaplasia. Br J Haematol 2001; 114: 111-113.
13. Elliott M A, Chen M G, Silverstein M N, Teffari A. Splenic irradiation for symptomatic splenomegaly associated with myelofibrosis with myeloid metaplasia. Br J Haematol 1998;103: 505-511.
14. Guardiola P, Esperou H, Cazals-Hatem D et al. Allogeneic bone marrow transplantation for agnogenic myeloid metaplasia. Br J Haematol 1997; 98: 1004-1009.
15. Anderson JE, Deeg HJ, Tefferi A et al. Effective treatment of myelofibrosis by autologous peripheral blood stem cell transplantation (PBSCT). Blood 1999; 94: (Suppl 1): 396a-396a.
Abstract
16. Daly H M, Scott G L. Myelofibrosis as a cause of pancytopenia in systemic lupus erythematosis. J Clin Path 1983; 36: 1219-1222.(Jain Vandana, Maheshwari )