|Year : 2016 | Volume
| Issue : 3 | Page : 151-157
Juvenile idiopathic arthritis with myelofibrosis
Ishrat Hussain Dar, Omar Farooq, Samia Rashid Mir, Sabina Yusuf Bhat
Department of Medicine, Govt. Medical College, Srinagar, Jammu and Kashmir, India
|Date of Web Publication||14-Dec-2016|
Ishrat Hussain Dar
Associate Professor, Department of Medicine, Government Medical College, Srinagar - 190 010, Jammu and Kashmir
Source of Support: None, Conflict of Interest: None
Juvenile idiopathic arthritis (JIA) is the most common chronic arthropathy of children. JIA comprises a heterogeneous group of several disease subtypes that are characterized by the onset of arthritis before the age of 16 years and has symptoms lasting for at least 6 weeks. Childhood myelofibrosis (MF) is rare with variable outcome reported in literature. MF with myeloid metaplasia is defined as a myeloproliferative disorder characterized by leukoerythroblastosis, tear drop erythrocytes, extramedullary hematopoiesis, and varying degrees of MF. It may be idiopathic or secondary to a large number of conditions. Autoimmune MF has been commonly reported in association with systemic lupus erythematosus. MF presenting as cytopenias has been reported in immune mediated disorders such as rheumatoid arthritis, ulcerative colitis, primary biliary cirrhosis, polyarteritis nodosa, and Sjogren's syndrome. A case of MF in a 14 year old boy who presented with anemia, pancytopenia, splenomegaly, and oligo articular arthritis is described which as per the literature falls into the rarest of cases to be found. This case is only the second reported case of MF associated with JIA in world literature, the only previous case being reported by Jain et al. in 2005 from India.
Keywords: Bone marrow transplantation, juvenile idiopathic arthritis, myelofibrosis, splenomegaly
|How to cite this article:|
Dar IH, Farooq O, Mir SR, Bhat SY. Juvenile idiopathic arthritis with myelofibrosis. Saudi J Health Sci 2016;5:151-7
| Introduction|| |
Juvenile idiopathic arthritis (JIA) is defined as arthritis of unknown etiology that manifests itself before the age of 16 years and persists for at least 6 weeks, while excluding other known conditions. The incidence and prevalence of JIA varies from 2 to 20 and 16-150 per 100,000.  The clinical symptoms of JIA can be quite variable. Several symptoms that are the characteristic of arthritis are not necessarily diagnostic of JIA and may have multiple etiologies that can be differentiated with careful examination of patient history. The disease may develop over days or sometimes weeks, thereby making the diagnosis difficult at the time of presentation. Bone marrow fibrosis can arise as a result of a wide range of neoplastic and nonneoplastic disorders.
| Case Report|| |
A 14-year-old male boy (a product of nonconsanguineous marriage, 5 th in birth order with normal developmental history and milestones) was admitted for the evaluation of joint pains and easy fatigability of 7 years duration in our hospital. Historically, the boy had started with pain in both knee joints gradual in onset, deep diffuse, moderate in intensity associated with swelling of both knee joints without redness or warmth, aggravated by movement, relieved temporarily with analgesics without any history of trauma, fever, rash, and preceding diarrheal or respiratory illness. This persisted for 6 months when he developed pain and swelling of a similar nature in both ankle joints following which he noticed inability to move around (due to pain) that left him practically bed bound leading to stiffness of both knee and ankle joints. Simultaneously, the patient noticed increasing fatigue on accustomed exertion which later on increased to near exertion at rest or ordinary physical activity and the family members noticed him to be turning increasingly pale. This was unassociated with any fever, rash (diffuse or localized), loss of blood from any orifice, easy bruisability, or bleeding from the gums. No history of oral ulcers, photosensitivity, involvement of small joints of the hands, nail abnormalities, myalgias, back pain or stiffness, photophobia, redness, soreness or grittiness of eyes, diminution of vision, pain abdomen or passage of blood and/or mucus with stools, intercurrent infections or chronic drug intake was found. No past history of any hospitalization or exposure to any toxin was evident. Occupation wise the boy helped his parents and siblings at their shop with light duties as he was unable to do heavy work. His family denied any history of psoriasis or systemic lupus erythematosus (SLE) in any of their family members. Examination revealed a lean, pale, thin boy [Figure 1]a with a body weight of 30 kg and height of 1.50 m (body mass index 13.33 kg/m 2 ). Vitals revealed a blood pressure of 100/60 mmHg (as seen by a pediatric cuff) and a radial pulse of 100/min, regular without any radio femoral delay. No pedal edema, cyanosis, jaundice or lymphadenopathy, oral ulcers, thyromegaly, petechiae, rash, or purpura were noted. No bony tenderness, gibbus, kyphoscoliosis, or limb length discrepancy was found. All joints except knee and ankle were in good range of motion and had no swelling or deformity. Both knees were swollen right greater than the left with mild valgus deformity [Figure 1]b. No atrophy of muscles around knees, and no tenderness on palpation were elicited. However, bogginess was present in suprapatellar pouch and bulge sign was positive [Figure 1]c. Range of motion showed restricted flexion with normal extension and rotation. Ligaments around the knee were intact though the strength of muscles around the knee joints was normal. Both ankles were swollen without deformities or nodule [Figure 1]d. No tenderness on palpation was elicited, and the range of motion was normal. Chest, cardiovascular, and the central nervous system were normal. Abdominal examination revealed a palpable, enlarged, nontender spleen 3 cm below the left costal margin. Investigations revealed Hb of 6.8 g% with pancytopenia, reticulocyte count of 0.9%, and erythrocyte sedimentation rate of 64 mm/1 st h. Peripheral blood film revealed marked red cell hypochromia with mild anisocytosis and mild red cell polychromasia. Biochemical investigations such as liver function tests, kidney function tests, blood sugar, electrolytes, thyroid function tests, uric acid, and urine examination were all normal. HLA B27, rheumatoid factor (RF), and ANA-IFA (by Hep 2) were all negative. Hb electrophoresis showed normal quantities of HbA and HbA2. Direct antiglobulin test, HIV I and II, anticyclic citrullinated peptide antibodies were negative, and serum 25(OH) D 3 levels were 38 ng/ml (sufficient). C-reactive protein was elevated. Iron studies (fasting) showed serum iron 9.27 umol/L (10-28.3), ferritin 429.56 ng/ml (15-240), and total iron binding capacity 51.5 umol/L (45-80). Electrocardiogram revealed sinus tachycardia. Ultrasonography (USG) of the abdomen showed mild splenomegaly, without ascites, para aortic lymphadenopathy, or portal hypertension. Upper gastrointestinal endoscopy revealed antral erosive gastritis. Slit lamp examination showed no evidence of uveitis. X-ray chest, cervical spine, knees, ankles, elbows, hands (including wrists) were normal [Figure 2]a-f. USG of the knee and ankle joints demonstrated the presence of fluid in both joint spaces [Figure 3]a-d. Bone marrow aspiration from the iliac crest showed mild relative erythroid hyperplasia with normal marrow cells, bone dust, and possible cellular marrow fibrosis [Figure 4]a and b. The hematoxylin and eosin from trephine biopsy showed cellular marrow with patchy fibrosis and hypoplasia. The findings were consistent with cellular bone marrow fibrosis [Figure 4]c and d. A diagnosis of JIA (oligo articular type) with myelofibrosis (MF) was made. The patient refused a bone marrow transplant and biological therapy citing cost considerations and was started on steroids, disease modifying anti rheumatologic drugs (DMARDs) and supplements. He continues to be on regular follow-up till date with marginal improvement.
|Figure 1: The facial features, swollen knee and ankle joints of the patient (a-d)|
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|Figure 2: The X-rays of the chest, wrists/hands, knees, ankle joints and the cervical spine in the patient (a-f)|
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|Figure 3: Ultrasonography of the knee and ankle joints demonstrating presence of fluid in both joint spaces (a-d)|
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|Figure 4: Bone marrow aspiration from the iliac crest showed mild relative erythroid hyperplasia with normal marrow cells, bone dust and possible cellular marrow fi brosis (a and b). The H and E from trephine biopsy showed cellular marrow with patchy fibrosis and hypoplasia. The findings were consistent with cellular bone marrow fibrosis (c and d)|
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| Discussion|| |
JIA is a chronic, autoimmune, inflammatory joint disease. It is the most common rheumatic disease in children and adolescents. It is defined as 'persistent arthritis' of unknown etiology that begins before the age of 16 years and persists for at least 6 weeks and is diagnosed after excluding other known causes of arthritis.  The occurrence of chronic arthritis in children has been described since the 1800's. Still, an English Pediatrician described 22 children from hospital for sick children, Great Ormond Street that had chronic arthritis. It is still believed that 12 of these children had distinctive features of rheumatoid arthritis.  Since this report, many additional children have been described with rheumatoid arthritis, and it has become obvious that the disease we now call JIA or juvenile rheumatoid arthritis (JRA) is a particularly unpredictable and heterogeneous disease group. The International League of Associations for Rheumatology classification of JIA is as under: 
- Systemic arthritis if there is arthritis in 1 or more joints with, or preceded by, fever of at least 2 weeks' duration. Signs or symptoms must have been documented daily for at least 3 days and accompanied by 1 or more of the following: Evanescent rash, generalized lymphadenopathy, hepatosplenomegaly, and serositis
- Oligoarthritis is if there is arthritis affecting 1-4 joints during the first 6 months
- Polyarthritis (RF-negative) if there is RF negative arthritis affecting 5 or more joints during the first 6 months of disease
- Polyarthritis (RF-positive) if there is RF-positive arthritis affecting 5 or more joints during the first 6 months of disease
- Psoriatic arthritis if there is arthritis and psoriasis, or arthritis and at least 2 of the following: Dactylitis, nail pitting, onycholysis, and/or family history of psoriasis (in a first-degree relative)
- Enthesitis-related arthritis if there is arthritis and/or enthesitis with at least 2 of the following: Presence or history of sacroiliac joint tenderness with or without inflammatory lumbosacral pain; presence of HLA B27 antigen; onset of arthritis in a male over 6 years of age; acute (symptomatic) anterior uveitis; history of ankylosing spondylitis, enthesitis-related arthritis, sacroiliitis with inflammatory bowel disease, Reiter's syndrome, or acute anterior uveitis in a first-degree relative
- Undifferentiated arthritis is diagnosed if there is arthritis that does not fulfil criteria in any of the above categories or that fulfils criteria for 2 or more of the above categories.
The cause of JIA is unknown. It is suspected that environmental factors such as viral infections may trigger the condition in genetically susceptible children. However, it is unusual for more than one child in a family to have arthritis (as in our case).  Polyarticular joint disease has a multifactorial etiology, and it may present as a viral illness or can be the beginning of a chronic disease. Moreover, its underlying etiological process can be infectious or postinfectious with a rheumatological disease or a manifestation of systemic disease. This disease may evolve over days or sometimes weeks, thereby making the diagnosis difficult at the time of presentation. Joint swelling occurs commonly at the knees in oligoarticular JIA and may be the presenting symptom. Examination of affected joints may reveal edema. Synovial effusions and thickening are frequent findings. Thus, to accurately diagnose JIA, the first step is to exclude arthritis with known etiologies.  JIA is a diagnosis of exclusion; Lyme disease, leukemia, infection of bone or joint, psoriasis, inflammatory bowel disease, streptococcal infection, bleeding disorder, and vasculitis must be ruled out as causes of joint disease. One case of JIA in association with pulmonary hemosiderosis has been described in a Malaysian child.  Children with systemic JIA may first be thought to have an acute infectious disease or septicemia. However, the presence of arthritis and/or a rheumatoid rash helps to establish an accurate diagnosis of systemic JIA. In contrast, laboratory tests may be of little value in diagnosing systemic JIA. Fever in children with infectious diseases is of the septic type; this type of fever is clinically more confusing and typically does not repetitively return to the baseline each day, as does the fever associated with JIA. That is, the diagnostic symptom of systemic JIA is a high spiking fever, which may occur at any time of the day but is commonly present in the late afternoon to evening in conjunction with rash. Morning stiffness, limp, limited movement, limb length discrepancy, uveitis, and rheumatoid nodules are other diagnostic factors for JIA. USG of the affected joints is often abnormal early in the course of disease and is useful in identifying joints for corticosteroid injection. USG can be an important positive or negative finding if diagnosis is questionable. Magnetic resonance imaging (MRI) is indicated in patients with monoarticular disease to rule out pigmented villonodular synovitis or synovial hemangiomas. MRI can be used to monitor cartilage injury. Laboratory tests neither rule in nor rule out JRA: The diagnosis essentially is clinical. However, the laboratory studies can be used to provide evidence of inflammation, support the clinical diagnosis of JIA, monitor toxicity of therapy, and better understand the pathogenesis of the disease. 
MF with myeloid metaplasia may be primary or idiopathic or secondary to a large number of conditions.  Infections, metastasis and primary hematological malignancy such as acute megakaryocytic leukemia, chronic granulocytic leukemia, acute myeloid leukemia, acute lymphoid leukemia, hairy cell leukemia, Hodgkin's disease, myeloma, carcinoma, and transitional myeloploliferative syndromes are more frequently causative. Other conditions uncommonly associated with secondary MF are metabolic such as renal osteodystrophy, chronic renal failure, and hyperparathyroidism, bone disease such as osteopetrosis, Paget's disease, osteomalacia, SLE, and systemic sclerosis.  One each reported case of MF in association with dermatomyositis, rheumatoid arthritis, Sjogren's syndrome, and JIA have been reported in literature. ,,, This case is only the second reported case of MF associated with JIA in world literature the only previous case being reported by Jain et al. in 2005 from India.  The disease has been attributed to other systemic immune disorders such as JRA, primary biliary cirrhosis, ulcerative colitis, and idiopathic thrombocytopenic purpura. 
The initial signs and symptoms of MF are cachexia with profound fatigue, marked weight loss, drenching night sweats with low grade fever, marked pallor, and splenomegaly  as was seen in our case as well. Some patients report huge splenomegaly giving rise to an intra-abdominal mass effect causing a dragging sensation in the left hypochondrium, early satiety, diarrhea, and peripheral edema of multifactorial origin. Complete blood count (CBC) reveals anemia with or without pancytopenia, an increased or decreased white cell count and/or platelet count. A normal CBC does not exclude the diagnosis. Anemia is because of ineffective hematopoiesis, erythroid hypoplasia, replacement of normal marrow tissue with collagen fibrosis, and/or hypersplenism. The white blood cell count and platelet count may be increased due to clonal myeloproliferation or decreased as a consequence of sequestration in the spleen. Lactate dehydrogenase increase is attributed to deficient hematopoiesis. Peripheral blood smear shows myelophthisis with leukoerythroblasts and tear drop-shaped red cells. Myelophthisis is due to intramedullary sinusoidal hematopoiesis in bone marrow and myeloid metaplasia of the spleen resulting in disruption of the normal physiological process that release cells at appropriate maturation.  Bone marrow aspiration frequently results in a dry tap (as in our case) and core biopsy often demonstrates patchy medullary fibrosis (as in our case), dysplastic megakaryocytic hyperplasia, osteosclerosis, and dilatation of marrow sinusoids with intravascular hematopoiesis. Cytogenetic studies of bone marrow help in excluding chronic myeloid leukemia.  The primary pathogenic mechanism is a clonal stem cell disorder that leads to ineffective erythopoiesis, dysplastic megakaryocytic hyperplasia, and an increase in the ratio of immature granulocytes to total granulocytes. This is accompanied by reactive MF and extramedullary hematopoiesis in the spleen in multiple organs. The stromal reaction of the bone marrow is a reactive process mediated by the cytokines released by the monoclonal cells. Both monocytes and megakaryocytes have been implicated as the source of nosogenic cytokines that augment fibroblast proliferation (platelet derived growth factor and calmodulin), collagen synthesis (transforming growth factor-β), angiogenesis (vascular endothelial growth factor and basic fibroblast growth factor), and osteogenesis (transforming growth factor-β and basic fibroblast growth factor). , Marrow fibrosis leads to the distortion of marrow sinusoids permitting entry of immature hematopoietic stem cells into sinusoids and then their lodgment into the sites of extramedullary hematopoiesis.  Complications such as portal hypertension with ascites or variceal bleed occur due to increased portal flow as a result of marked splenomegaly. Extramedullary hematopoiesis may occur at lymph nodes causing lymphadenopathy, serosal surfaces leading to pleural effusion and ascites, lungs causing pneumonia such as illness, urogenital system causing hematuria, and involvement of the paraspinal and epidural spaces leading to compression of the spinal cord and nerve roots, severe musculoskeletal and joint pain not responsive to nonsteroidal antiinflammatory drugs (NSAIDs). The corresponding radiologic features include osteosclerosis, hypertrophic osteoarthropathy, and periostitis.  Median survival in patients with MF associated with JIA ranges from 3.5 to 5.5 years but marked variability exists among individual cases depending upon the presence of various prognostic factors. Complete remission has been seen in some reported rare cases. Advanced age, leukocytosis, circulating blasts, increased granulocyte precursors, thrombocytopenia, pancytopenia, abnormal karyotype, and presence of hypercatabolic symptoms are associated with a poor prognosis. Causes of death in patients with MF are infections, thrombohemorrhagic events, leukemic transformation, and heart failure. 
Management of patients particularly children with MF in association with JIA is difficult with a variable outcome. A conservative approach should be tried first before going for advanced forms of therapy. Patients with incident or suspected JIA should be managed by a specialist rheumatology multidisciplinary team. Physical and occupational therapy is encouraged in conjunction with medicines. Patients are motivated to participate in activities such as swimming and cycling. Weight-bearing activities are indicated. Moist heat can be a helpful adjunct modality to address pain and stiffness.
Corticosteroids and androgens have been useful in alleviating anemia but the response is often suboptimal in with advanced disease, transfusion dependent anemia, massive splenomegaly, and karyotype abnormalities.  Hyroxyurea, cladribine, and interferon alpha are helpful in patients with leukocytosis, thrombocytosis, and/or organomegaly. Thalidomide due to its antiangiogenic properties has been shown to have a 20% response rate with poor tolerability when used singly but in combination with corticosteroids the tolerability is good with 70% response rate in improving anemia and thrombocytopenia. Corticosteroids have a special role in patients with MF in conjunction with autoimmune diseases. Kar et al. and Rizzi et al. describe three cases each of primary autoimmune MF where treatment with steroids (prednisolone) resulted in improvement with complete response as defined by normalization of blood counts and partial resolution of fibrosis on bone marrow examination after 4 months to 1 year of treatment. , Similar results have been seen by Pullarkat et al. in their study and treatment of autoimmune MF with steroids.  Our case did not respond to steroid therapy despite 4 months of treatment with prednisolone. Other drugs such as imatinib mesylate, anagrelide, suramin, and perfinidone have been tried with little or no success. , Splenectomy is useful in drug recalcitrant cases with mass-related constitutional symptoms, overt portal hypertension, and progressive anemia requiring repeated multiple transfusions. Complications associated with splenectomy are perioperative bleeding, infection, and thrombosis. Splenic irradiation transiently relives pain and decreases spleen size without any impact on anemia. It may lead to prolonged cytopenias in 25% patients with unpredictable myelosuppressive toxicity unrelated to the dose of irradiation. A subsequent splenectomy is associated with increased perioperative bleeding. Therefore, splenic irradiation should be done only in patients where spenectomy is contraindicated.  Allogenic bone marrow transplant and allogenic hematopoietic stem cell transplant is potentially curative and is the treatment of choice in young patients as in our case.  Bone marrow transplant was offered to our patient who refused it citing cost considerations. Autologous stem cell transplantation is a promising modality to produce a desired clinical response with alleviation of symptoms, reduction in spleen size, freedom from blood transfusion, and/or regression of bone marrow fibrosis.  Regarding the management of arthritis, the treatment options vary from NSAIDs, corticosteroids, DMARDs to biologic agents. Corticosteroids are useful as adjunctive agents. During active disease, especially in polyarticular JIA, low-dose corticosteroid therapy allows time for second-line agents to take effect. Oral corticosteroids can also be useful in systemic and enthesitis-related subtypes. Intra-articular corticosteroid injections are preferred when a limited number of joints are affected. Also indicated in other subtypes, when there is persistent inflammation in a few joints despite systemic therapy, or when contractures are evident due to active disease. Radiographic assistance may be necessary for injecting some joints. The procedure can be undertaken with the administration of entonox or general anesthetic to the child. Adverse effects from intra-articular injections are low. Relief can last beyond 6 months. Patients with systemic JIA may occasionally require intravenous corticosteroids for overwhelming systemic inflammation or more serious complications such as macrophage activation syndrome or pericarditis.
In case of failure with NSAIDs and intra-articular steroid injections with triamcinolone hexacetonide, methotrexate that may be started weekly at a very low-dose (10 mg/m 2 ) orally the effectiveness of which was shown by Giannini et al. and Woo et al. , The maximum effective dose of methotrexate (15-20 mg/m 2 ) was established by Ruperto et al. in the Pediatric Rheumatology International Trials Organization trial.  Three antitumor necrosis factor agents (anti-TNF) agents namely etanercept, infliximab, adalimumab have been so far tested in polyarticular JIA with comparable efficacy and safety.  Other novel drugs in the pipeline for the treatment of JIA are golimumab, certolizumab, abatacept, tocilizumab, and canakinumab.  Rilonacept a recombinant fusion protein of interleukin-1 receptor protein components and the Fc portion of a human immunoglobulin administered once weekly at 2.2-4.4 mg/kg/week by subcutaneous injection is undergoing phase II trial with promising results after 42 weeks. 
A thorough review of the side effects of biologic therapy has been recently reported and the Food and Drug Administration in 2008 issued a black box warning about a possible association between the use of TNF blockers and development of lymphoma and other cancers in children and young adults with JIA and Crohn's disease but a clear causal relationship could not be established.
Most reports of JIA describe an aggressive course with high mortality though some reports describe a less aggressive course with spontaneous remission. ,
- About 40-60% of patients achieve remission or inactive disease
- However, outcome is variable depending on disease subtype
- Early detection and aggressive treatment has also contributed to improved outcomes
- Oligoarticular disease appears to have the best prognosis, with better functional outcome
- A greater proportion of patients with RF-positive and systemic-onset subtypes continue to have active disease after several years
- Juvenile idiopathic onset-associated uveitis is the most common extra-articular manifestation and can lead to visual impairment if disease is poorly controlled.
| Conclusion|| |
This case amply illustrates the pitfalls associated with the diagnosis of anemia and arthritis in the very young people who need a detailed analysis of their symptom complex. All anemias are not iron deficiency or megaloblastic anemias and all arthritis are not to be labeled as rheumatoid arthritis. A detailed evaluation is always needed to come to a conclusion as has been documented in this case.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3], [Figure 4]