- Email: [email protected]
Arthropathy in haematological disorders in children
Indian Journal of Rheumatology 2012 May Volume 7, Number 1 (Suppl); pp. 44–51
Review Article
Arthropathy in haematological disorders in children Deepti Suri1, Sapna Oberoi2
ABSTRACT Haematological disorders, both benign and malignant, may present with osteoarticular complaints. Overlapping rheumatological symptoms can easily mislead the treating physician away from the underlying haematological illness. Suspecting and diagnosing the primary blood disorder is crucial in these patients. In this article, we review the spectrum of haematological disorders commonly associated with arthropathy, their clinical presentation and management. We will further highlight the common diagnostic pitfalls that will help the treating clinician in managing such children. Keywords: Arthritis, blood disorders, children, haematological, musculoskeletal manifestations, rheumatological manifestations
INTRODUCTION Musculoskeletal pain is a common complaint, affecting 10–20% of school age children.1,2 Although, most of these complaints are benign in nature, they pose an important diagnostic challenge for a clinician. The differential diagnosis of arthritis is much broader in children than in adults. Many haematological disorders have been associated with rheumatological symptoms.3 These diseases are close mimics of each other and it is always not easy for a paediatrician to differentiate one from the other. Haematological disorders can present for the first time with rheumatological symptoms or more commonly musculoskeletal manifestations and autoimmune phenomenon may develop later on during the course of haematological disorders.3 The concept of this review is to provide the overview of various haematological illnesses which can be associated with arthropathy in children and to highlight the potential diagnostic clues. The review, however, does not elaborate on the haematological complications that may occur in patients with already established rheumatological conditions.
1
Haematological disorders that present with rheumatological symptoms can be broadly divided into benign and malignant.
BENIGN DISORDERS Sickle cell disease Sickle cell disease (SCD) is a group of inherited haemoglobinopathies in which a defective form of haemoglobin is produced. Musculoskeletal manifestations are seen not only in the homozygous state, but also in compound heterozygous states like HbSC disease and sickle-beta thalassemia.4 Sickle haemoglobin polymerizes in deoxygenated states, distorts red cells into rigid sickle shapes which in turn block microcirculation and cause ischaemia and infarction. Sickle cell disease typically presents in childhood with haemolytic anaemia and intermittent crises.5 Hand–foot syndrome (dactylitis) is typically seen in children between 6 months and 2 years of age and may be the
Assistant Professor, Division of Allergy Immunology, 2Senior Resident, Paediatric Haematology Oncology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Correspondence: Dr. Deepti Suri, email: [email protected]
doi: 10.1016/S0973-3698(12)60028-4
Arthropathy in haematological disorders
first manifestation of the disease.6 Classical presentation is that of a young child with inconsolable crying due to pain with diffuse, symmetric, tender, and warm swelling of the hands, feet, or both. Fever may be present with significant peripheral blood leukocytosis and elevated C-reactive protein. Swelling usually lasts for 1–3 weeks. Radiographs are initially normal; however, it may show marrow densities, lytic areas or periosteal elevation later.7 Osteomyelitis becomes an important differential diagnosis and must always be kept in mind while evaluating these children. Analgesics, anti-inflammatory agents, and hydration form the main stay of therapy.4,8 Sickle-cell arthropathy, caused by microvascular ischaemia and synovial infarctions, usually affects large joints. Severe oligo- or polyarthralgia and transient joint swelling lasting for up to 3 weeks may occur. Knees are, by far, the most commonly involved joints, but elbows, ankles, and other joints can also be involved.8,9 Small, non-inflammatory synovial effusions are commonly associated with bone infarcts. These effusions are often associated with other manifestations of sickle cell crises. It must be remembered that reactionary joint effusions associated with vaso-occlusive crisis are more common than septic arthritis in patients with SCD. As the joints feel warm and tender, septic arthritis, acute gout and haemarthrosis should be excluded. Joint aspirate is typically yellow, non-inflammatory, sterile, and free of crystals. Treatment of associated crisis remains the main stay of therapy.8,9 Septic arthritis and osteomyelitis affecting long bones are serious complications of SCD seen in about 7–17% and 18–61% patients, respectively.10,11 Infarction and necrosis of the medullary bone acts as a nidus for bacterial overgrowth. Hyposplenism, secondary to multiple splenic infarcts, resulting in impaired opsonisation and activation of alternate complement pathways, further predisposes to infections.4 Salmonella species is the leading cause of such infections in patients with SCD, followed by Staphylococcus aureus, gram-negative enteric bacilli, Mycobacterium tuberculosis, and Mycobacterium ulcerans.12 Osteomyelitis is most commonly seen in the diaphysis of long bones (femur, tibia, and humerus) while septic arthritis affects hip, knee, and shoulder joints. As the presenting features of osteomyelitis are similar to those of painful bone crisis due to infarction, a high index of suspicion is important to carry out appropriate investigations.13,14 Despite newer imaging modalities such as magnetic resonance imaging (MRI) and bone scan, the diagnosis of osteomyelitis still depends on clinical judgement and positive blood or bone culture in a patient with SCD.6,7,15 Third generation cephalosporins remain the drug of choice for empirical therapy. Avascular necrosis (AVN) of the bone occurring due to infarction of epiphysis is the most disabling musculoskeletal
Review Article
45
complication of SCD. The estimated prevalence in children younger than 15 years is 3% which increases to 40% by mid-50s.16,17 Head of femur is the commonest site followed by humeral head, tibial condyles, ribs, and spine.14 Pain at rest, limited range of motion and limping are the common clinical findings at presentation of AVN affecting femoral head.17 Radiographs taken at the time of acute bone pain do not show changes of infarction. Later, radiographs may show mottled attenuation of epiphysis, sclerosis near the joint margin, subchondral lucent areas, flattening/collapse of the articular surfaces and secondary osteoarthritis.7 Technetium pyrophosphate bone scans or MRI can detect infarction quite early, even before the development of detectable aseptic necrosis.17,18 Bone scintigraphy may show initial photopaenia, but as the bone revascularises, uptake may return to normal or may even be increased. T2-weighted MR scanning shows high-signal intensity.17,18 Early treatment can be attempted with the prevention of weight bearing or with coring or osteotomy of the femoral head to allow healing without the resultant distortion of bone.19–21 But failure rates can be as high as 50%.20 Once articular breakdown has been established, replacement of the femoral head with a prosthesis or total hip replacement is the treatment of choice. Other less common musculoskeletal manifestations of SCD include bone erosions, gout, bony ankylosis of the spine and hip joint, sacroiliatis, pathological fracture, and inflammation, oedema and necrosis of the muscles.
Thalassemias The thalassemias are a group of congenital disorders in which synthesis of one or other of the globin chains is reduced. Management of these disorders has improved considerably in the last couple of decades, and now 50–68% thalassemia major patients survive to adulthood.22,23 Those with suboptimally treated disease may have significant joint pathology. Musculoskeletal problems not only occur due to marrow hyperplasia resulting from ineffective erythropoiesis, iron overload and its associated endocrinopathies, but also are the significant side effect of chelation therapy.24 Medullary expansion gives long bones a characteristic squared appearance. Coarsening of the trabecular pattern of the bone, osteoporosis, and cortical thinning are common.24 Children with thalassemia often present with backache, leg pains, and recurrent fractures secondary to osteoporosis. About 50% patients of thalassemia major suffer from osteoporosis, in spite of adequate treatment.25 Fractures are seen in the long bones and are reported to occur in 38–41% of
46
Indian Journal of Rheumatology 2012 May; Vol. 7, No. 1 (Suppl)
patients.26,27 Prevention and treatment of early bone loss is the best form of management. Adequate calcium and vitamin D intake, appropriate iron chelation, along with regular transfusions since early infancy may help in prevention. Treatment of osteoporosis, once established, includes treatment of underlying endocrinopathies, iron overload and calcium and vitamin D supplementation.28 Bisphosphonates especially pamidronate and zolendronate have shown promising results in improving the bone marrow density in controlled trials.29–31 In thalassemia major patients, arthropathy affecting small joints can also result secondary to iron deposition in the synovium, as seen in idiopathic haemochromatosis. Profound growth disturbance from premature fusion of the growth plate (particularly of the proximal humerus and distal femur) also occurs in 10–15% of thalassemia major patients, but is significantly reduced with regular transfusions.32 Deferiprone, an orally active iron chelator, is known to cause arthropathy. The incidence ranges from 4% to 15% in European patients to 41% among Indian children.33–36 Symptoms vary from mild non-progressive symptoms to severe erosive arthritis. Large joints, typically the knees, are involved. Children present with inability to squat, difficulty in climbing up and down stairs, wrist pain while writing, and ankle pain while doing daily activities. Radiographic changes include joint effusions, patellar breaking and subchondral flattening of the femoral condyles. Mild symptoms can be controlled with non-steroidal anti-inflammatory drugs (NSAID) and by reducing the dose of deferiprone. Moderate to severe symptoms warrant temporary stoppage of drug until symptoms resolve completely. Rechallenge with deferiprone can be done subsequently with reduced doses followed by slow increments. Reappearance of symptoms warrants permanent stoppage of the drug.34–36 Deferoxamine, used for iron chelation, can also lead to rachitic bone changes and genu valgum in young children, especially when used in higher doses.37 Metaphyseal changes are seen particularly in the vertebrae and they can lead to disproportionate short trunk.38,39 Children on deferoxamine should be regularly monitored for these complications as the changes are irreversible. Chronic small joint arthritis in patients with thalassemia major should also arouse a suspicion of rheumatoid arthritis, as it has been reported more commonly in these patients than in the general population (4.4% vs. 0.3%).40 Thalassemia minor (trait) remains a common and usually silent disorder. In a blinded study comparing 80 cases of thalassemia minor with control patients, 52% of cases had musculoskeletal symptoms compared with 54% of controls. Arthralgia of the wrist and shoulders was most common, and three patients had a short-lived arthritis.41
Suri and Oberoi
Haemochromatosis Hereditary haemochromatosis (HH) is a genetically determined disorder in which mutations in the HFE gene or the TFR2 gene cause increased intestinal iron absorption. The classic triad of the disease includes skin hyperpigmentation, diabetes mellitus and hepatomegaly. Arthropathy is an important manifestation of haemochromatosis which is often misdiagnosed.42 The most common presenting symptom of arthritis is twinges of the pain upon flexing the small joints of the hand, particularly the second and third metacarpophalangeal joints.43 Radiologically, subchondralarthropathy and chondrocalcinosis are the most common findings. Chondrocalcinosis (radiographic calcification in hyaline and/or fibrocartilage) of the knee, wrist, hip, and spine can be seen in up to a third of patients due to deposition of calcium pyrophosphate dihydrate crystals.44 Treatment with regular phlebotomies and iron chelation generally has little effect upon the clinical, radiological or histological progression of the arthropathy. Additional treatment options for arthritis may include the use of analgesics, NSAIDs and intra-articular glucocorticoids.42
Haemophilic arthropathy Haemophilia is a group of congenital disorders of blood coagulation due to the deficiency of factor VIII (haemophilia A) or factor IX (haemophilia B). Mechanical factors play an important role as evident by the onset of haemarthrosis with weight bearing, frequent bleeding into lower limb joints and by the more severe involvement of limbs on the dominant side. Joint disease is the major cause of morbidity in haemophiliacs and is found in up to 90% of severely affected patients.45 Joint damage classically starts as acute haemarthrosis, followed by chronic synovitis which culminates to degenerative arthritis.46 Acute haemarthrosis generally first occurs when a child begins to crawl and walk. Knees, ankles and elbows are most affected. Pain is accompanied by objective clinical findings of warmth, a tense effusion, tenderness, limitation of motion, and a joint that is often held in a flexed position. It is an important differential diagnosis in a young child presenting with monoarthritis. The symptoms are abrupt and usually not associated with other systemic complaints. A careful family history may clinch the diagnosis. Prompt and early factor replacement along with RICE (rest, immobilisation, cold compressions, and elevation) therapy is crucial to decrease the long-term complications of acute haemarthrosis. Bleeding may continue, cyclically in target joints into adulthood. Recurrent haemarthrosis, particularly in patients
Arthropathy in haematological disorders
with severe haemophilia, leads to disabling arthropathy. Chronic synovitis leads to progressive joint damage, cartilage destruction and the range of motion becomes severely restricted. Fibrous ankylosis may ensue. Subluxation, joint laxity and mal-alignment are consequences.47 Primary prophylactic treatment from early years of life rather than demand factor replacement markedly reduces the risk of chronic arthropathy.48 Vigorous and prolonged treatment of bleeding into a target joint with factor replacement can also help in the healing of the joint. If medical therapy fails, arthroscopic or radioactive synovectomy may reduce the bleeding and prevent the progression of early joint disease.49 Failure of aggressive medical therapy and synovectomy will either need total joint replacement or ankylosis of the joint depending upon the joint involved.47
MALIGNANT DISORDERS Leukaemic arthritis Leukaemia is an important differential diagnosis in children presenting with osteoarticular complaints. Musculoskeletal complaints can occur in 15–30% of acute lymphocytic leukaemia patients at disease onset. Arthritic presentation of leukaemia is more common in children than in adults. The reported incidence varies between 12% and 65% among paediatric acute leukaemia patients and 4–13% among adult cases.50 Classical leukaemic arthritis occurs because of synovial infiltration by blast cells. The other proposed mechanisms include; reactive joint inflammation secondary to the leukaemic process in the marrow of adjacent bones, thrombocytopaenic haemorrhage into the joint and synovitis due to immune complex formation.50 Leukaemic patients are also at a higher risk for septic arthritis from bacterial and fungal infections which occurs due to underlying immune-compromised state attributable to their disease per se and chemotherapy. The most worrisome aspect of leukaemic arthritis for the bedside clinician is the fact that it can masquerade other nonmalignant conditions especially juvenile idiopathic arthritis (JIA) resulting in a delay in the diagnosis and treatment. Further, treatment initiated for these benign conditions including glucocorticoids can mask the underlying malignancy.51,52 Although similar in presentation, some subtle clinical features can distinguish leukaemic arthritis from JIA (Table 1). Nocturnal pain awaking the child from sleep, pain out of proportion to joint swelling, bone tenderness, pain and tenderness in the metaphyseal location away from the joint are typical of leukaemia. Symptoms are insidious to begin with
Review Article
47
Table 1 Red flag signs of leukaemic arthritis • • • • • • • • • •
Explosive onset of symptoms Excruciating pain rendering the patient bed-bound Night pains awaking the child from sleep Pain around the joint rather than in the joint Absence of recognisable pattern of joint involvement Severe pallor Petechiae, lymphadenopathy, hepatosplenomegaly Leucopaenia with lymphocytic preponderance Absence of polymorphonuclear response Thrombocytopaenia
and pain is usually not severe enough to render a child bed-bound in JIA. The child may have acute joint pain in leukaemia but in JIA the children usually report a diffuse dull aching discomfort over a joint especially more in the morning hours. Presence of fever, lymphadenopathy and hepatosplenomegaly may not always contribute much in differentiating the two sets of conditions.53 Peripheral blood count showing severe anaemia, leucopaenia with relative lymphocytic predominance and thrombocytopaenia are subtle clues towards malignancy.52,54 Increased awareness of the arthritic presentation of leukaemia can guide the treating physician to request for a bone marrow examination early in the course of the disease. This is mandatory for arriving at the correct diagnosis especially in patients with atypical clinical pattern, nocturnal pain, and prominent systemic features, especially before embarking on corticosteroid therapy. Arthropathy can also be observed in chronic myeloid leukaemias (CML), chronic myelomonocytic leukaemias (CMML) and large granular lymphocytic leukaemia but the incidence is far less in children as compared to adults. Hyperleukocytosis in patients with CML can cause partial or total occlusion of microcirculations, resulting in AVN of the head of femur.55
Lymphoma Bone involvement is seen in 10–20% of paediatric non-Hodgkin lymphoma especially in diffuse large B-cell lymphoma, Burkitt lymphoma and anaplastic large cell lymphoma.56–58 Femur, pelvis, tibia, humerus and spine are commonly involved. Majority of the children present with bone pain and swelling. Radiological features include the presence of lytic or sclerotic lesion which is usually associated with a breach in the underlying cortex. Bone biopsy proves the diagnosis of underlying lymphoma. Patients with non-Hodgkin lymphoma may rarely present with polyarticular or oligoarticular arthritis.59 Immune-complex-mediated
48
Indian Journal of Rheumatology 2012 May; Vol. 7, No. 1 (Suppl)
Suri and Oberoi
Table 2 Arthropathy associated with haematological disorders or their treatment Haematological disorders and drugs
Arthritic manifestations
Sickle cell disease
Dactylitis, avascular necrosis, osteomyelitis, septic arthritis, bone infarctions, joint effusions, sickle cell arthropathy, gout
Thalassemia major
Osteoporosis, fractures, back pain, chronic polyarthritis due to iron overload, intervertebral disc degeneration, deferiprone-related arthropathy, deferoxamine-related bone changes
Haemophilia
Haemarthrosis, chronic haemophilic arthropathy
Haemochromatosis
Chronic small joint polyarthritis
Acute leukaemia
Leukaemic arthropathy, gout, septic arthritis, osteomyelitis
Chronic leukaemias
Gout, polyarthritis, avascular necrosis, rheumatoid arthritis
Lymphoma
Bone pain, fracture, polyarthritis
Myelodysplastic syndrome
Seronegative arthritis, relapsing polychondritis
Multiple myeloma
Thoraco-lumber pain, pathological fractures, osteoporosis
Drugs • Steroids • Interferon • G-CSF • Antithymocyte globulin • Bisphosphonates
Osteoporosis, myopathy, avascular necrosis Arthralgia, myalgia, arthritis Bone pains, arthralgia Serum sickness, avascular necrosis Osteonecrosis of jaw
G-CSF = granulocyte colony stimulating factor.
synovial inflammation is the proposed mechanism rather than direct infiltration of the synovium as seen in leukaemias.
features like fatigue, anaemia, deranged renal functions, hypercalcaemia, and weight loss generally help in making diagnosis.
Myelodysplastic syndrome
Drug-induced arthropathy
Myelodysplastic syndrome (MDS) is a clonal haematopoietic stem cell disorder characterised by progressive peripheral cytopaenias and bone marrow failure. Autoimmune manifestations including seronegative arthritis, rheumatoid arthritis, relapsing polychondritis, haemolytic anaemias, vasculitis as well as positive anti-nuclear antibodies and rheumatoid factor have been reported in 13–30% of patients with MDS.60 These can be present at the time of diagnosis or may appear as the disease progresses. Although these manifestations usually respond to steroids, but MDS with concurrent autoimmune manifestations has been shown to be less responsive to cytotoxic chemotherapy.61
Arthropathy or athralgias can occur due to the drugs used to treat haematological disorders (Table 2). Arthropathy is an important complication of deferiprone, an oral iron chelator used in thalassemics, as mentioned above. Granulocyte colony stimulating factor (G-CSF) is a haematopoietic growth factor which upregulates the production of neutrophils. It is used in congenital neutropaenia, primary prophylaxis of chemotherapy-induced neutropaenia and for the mobilisation of peripheral blood stem cells. Bone pains can occur in 10–20% of patients on G-CSF therapy especially those on higher doses.63 They are commonly observed in the sternum, pelvis and/or lower back and tend to occur 1–2 days prior to the increase in circulating neutrophils. Pain can be controlled in most patients with non-narcotic analgesics. Arthralgias are commonly observed following interferon (IFN) therapy. IFN is also implicated in causing symmetric polyarthritis in some studies. Stopping of IFN, with or without the addition of anti-inflammatory agents, usually results in the remission of arthritis.64 Long-term steroid therapy and anti-thymocyte globulin therapy in aplastic anaemia can cause AVN of the bone.65 Bisphosphonates used in the treatment of osteoporosis can also lead to osteonecrosis.66
Multiple myeloma and POEM syndrome Multiple myeloma and POEM syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) are monoclonal plasma cell disorders seen in older adults. Bone pain, particularly in the back and chest, is present at the time of diagnosis in approximately 60% of the patients.62 It can be the first manifestation of the disease. Associated
Arthropathy in haematological disorders
DIAGNOSTIC OVERVIEW Physicians evaluating children with musculoskeletal symptoms must always be aware that many haematological conditions can present with rheumatic symptoms and signs. High index of suspicion is therefore important to reach the correct diagnosis. Careful history, recognition of the pattern of joint disease and physical examination are of utmost importance. Hepatomegaly, splenomegaly, lymphadenopathy, petechiae, abnormal blood counts, presence of paraprotein, and lytic radiological lesions are to be approached with caution and should prompt relevant investigations. Extreme pain out of proportion to joint swelling, poor response to glucocorticoids and disease-modifying anti-rheumatic drugs should alert one to search for an alternative diagnosis. Underlying leukaemia can be easily excluded by doing a bone marrow examination in children who present with arthritis. The important clues to leukaemia include acute onset of arthritis, pain disproportionate to physical findings, pain around the joint rather than in the joint, night pains, lymphadenopathy, petechiae, hepatomegaly, splenomegaly, sternal tenderness, point tenderness in diaphyseal region and subtle blood count clues. Starting steroids in such a patient will delay the diagnosis of leukaemia and may confer poorer prognosis by delaying the therapy of leukaemia. Symmetrical polyarthritis can rarely be a presenting feature of the underlying occult malignancies such as nonHodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, lung cancer, and gastrointestinal tract cancer. Children with haemophilia may present with noninflammatory monoarticular arthritis. History of other bleeding manifestations, family history, and trauma may or may not be evident. It is always important to consider this differential in a child presenting with monoarticular arthritis; a diagnostic joint aspirate can aggravate bleeding in the case of haemophiliac arthropathy. Avascular necrosis can occur in a couple of haematological conditions such as SCD, patients on long-term steroids, following immunosuppressive therapy in aplastic anaemia and bisphosphonates treatment for osteoporosis, inherited or acquired thrombophilic states and in children presenting with hyperleucocytosis. Thus, it is important to consider them in differential diagnosis while evaluating the children with suspected AVN. Dactylitis presenting in childhood has several differentials with SCD being one of the commonest. The other important causes include infections such as tuberculosis, brucellosis, streptococcal, and staphylococcal infections, psoriatic arthritis and HLA-B27 associated spondyloarthropathies. Children with SCD, leukaemias, lymphomas, and those on long-term steroids and chemotherapy are prone for
Review Article
49
developing septic arthritis as well as osteomyelitis due to their underlying immunocompromised state. These children may not mount classical signs of inflammation. It is always crucial to look for any bone infections in the presence of prolonged fever in such children. Children with certain rheumatological disorders such as rheumatoid arthritis, systemic lupus erythematosis, dermatomyositis, polymyositis, Sjogren’s syndrome, and scleroderma are at increased risk of developing lymphomas, lung cancer, skin cancer, and other lymphoproliferative malignancies. Underlying immune dysregulation and use of immunosuppressive agents are the proposed mechanisms. This should always be kept in mind while treating and following these patients to avoid the delay in the diagnosis of malignancy.
SUMMARY Haematological disorders must always be considered in the differential diagnosis of children presenting with rheumatological complaints. Awareness on the part of the clinician about these manifestations can enable early recognition and diagnosis. Malignancy should always be considered and excluded in children presenting with musculoskeletal symptoms.
CONFLICT OF INTEREST None.
REFERENCES 1. 2.
3.
4. 5.
Goodman JE, McGrath PJ. The epidemiology of pain in children and adolescents: a review. Pain 1991; 46: 247–64. Malleson PN, Beauchamp RD. Rheumatology: 16. Diagnosing musculoskeletal pain in children. CMAJ 2001; 165: 183–8. Ehrenfeld M, Gur H, Shoenfeld Y. Rheumatologic features of hematologic disorders. Curr Opin Rheumatol 1999; 11: 62–7. Almeida A, Roberts I. Bone involvement in sickle cell disease. Br J Haematol 2005; 129: 482–90. Kaur M, Das GP, Verma IC. Sickle cell trait & disease among tribal communities in Orissa, Madhya Pradesh & Kerala. Indian J Med Res 1997; 105: 111–6.
50
Indian Journal of Rheumatology 2012 May; Vol. 7, No. 1 (Suppl)
6.
Kim SK, Miller JH. Natural history and distribution of bone and bone marrow infarction in sickle hemoglobinopathies. J Nucl Med 2002; 43: 896–900. Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia. Radiographics 2001; 21: 971–94. Schumacher HR, Andrews R, McLaughlin G. Arthropathy in sickle-cell disease. Ann Intern Med 1973; 78: 203–11. de Ceulaer K, Forbes M, Roper D, Serjeant GR. Non-gouty arthritis in sickle cell disease: report of 37 consecutive cases. Ann Rheum Dis 1984; 43: 599–603. Balogun RA, Obalum DC, Giwa SO, Adekoya-Cole TO, Ogo CN, Enweluzo GO. Spectrum of musculo-skeletal disorders in sickle cell disease in Lagos, Nigeria. J Orthop Surg Res 2010; 5: 2. Bahebeck J, Atangana R, Techa A, Monny-Lobe M, Sosso M, Hoffmeyer P. Relative rates and features of musculoskeletal complications in adult sicklers. Acta Orthop Belg 2004; 70: 107–11. Burnett MW, Bass JW, Cook BA. Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 1998; 101: 296–7. Stark JE, Glasier CM, Blasier RD, Aronson J, Seibert JJ. Osteomyelitis in children with sickle cell disease: early diagnosis with contrast-enhanced CT. Radiology 1991; 179: 731–3. Jean-Baptiste G, De Ceulaer K. Osteoarticular disorders of haematological origin. Baillieres Best Pract Res Clin Rheumatol 2000; 14: 307–23. Rifai A, Nyman R. Scintigraphy and ultrasonography in differentiating osteomyelitis from bone infarction in sickle cell disease. Acta Radiol 1997; 38: 139–43. Ware HE, Brooks AP, Toye R, Berney SI. Sickle cell disease and silent avascular necrosis of the hip. J Bone Joint Surg Br 1991; 73: 947–9. Gupta R, Adekile AD. MRI follow-up and natural history of avascular necrosis of the femoral head in Kuwaiti children with sickle cell disease. J Pediatr Hematol Oncol 2004; 26: 351–3. Frush DP, Heyneman LE, Ware RE, Bissett GS 3rd. MR features of soft-tissue abnormalities due to acute marrow infarction in five children with sickle cell disease. AJR Am J Roentgenol 1999; 173: 989–93. Washington ER, Root L. Conservative treatment of sickle cell avascular necrosis of the femoral head. J Pediatr Orthop 1985; 5: 192–4. Hungerford DS. Response: the role of core decompression in the treatment of ischemic necrosis of the femoral head. Arthritis Rheum 1989; 32: 801–6. Neumayr LD, Aguilar C, Earles AN, Jergesen HE, Haberkern CM, Kammen BF, et al. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment. J Bone Joint Surg Am 2006; 88: 2573–82.
7. 8. 9.
10.
11.
12. 13.
14.
15.
16.
17.
18.
19.
20.
21.
Suri and Oberoi
22. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000; 355: 2051–2. 23. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004; 89: 1187–93. 24. Voskaridou E, Terpos E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 2004; 127: 127–39. 25. Origa R, Fiumana E, Gamberini MR, Armari S, Mottes M, Sangalli A, et al. Osteoporosis in beta-thalassemia: clinical and genetic aspects. Ann NY Acad Sci 2005; 1054: 451–6. 26. Vogiatzi MG, Macklin EA, Fung EB, Vichinsky E, Olivieri N, Kwiatkowski J, et al. Prevalence of fractures among the thalassemia syndromes in North America. Bone 2006; 38: 571–5. 27. Vogiatzi MG, Macklin EA, Fung EB, Cheung AM, Vichinsky E, Olivieri N, et al. Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Miner Res 2009; 24: 543–57. 28. Anapliotou ML, Kastanias IT, Psara P, Evangelou EA, Liparaki M, Dimitriou P. The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches. Clin Endocrinol (Oxf) 1995; 42: 279–87. 29. Mamtani M, Kulkarni H. Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review. Osteoporos Int 2010; 21: 183–7. 30. Voskaridou E, Terpos E, Spina G, Palermos J, Rahemtulla A, Loutradi A, et al. Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia. Br J Haematol 2003; 123: 730–7. 31. Perifanis V, Vyzantiadis T, Vakalopoulou S, Tziomalos K, Garypidou V, Athanassiou-Metaxa M, et al. Treatment of betathalassaemia-associated osteoporosis with zoledronic acid. Br J Haematol 2004; 125: 91–2; author reply 3–4. 32. Basanagoudar PL, Gill SS, Dhillon MS, Marwaha RK. Premature epiphyseal fusions in beta thalassaemia. Acta Orthop Belg 2010; 76: 114–9. 33. Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003; 102: 1583–7. 34. Panigrahi I, Marwaha RK, Das RR. Long-term response to deferiprone therapy in Asian Indians. Ann Hematol 2010; 89: 135–40. 35. Choudhry VP, Pati HP, Saxena A, Malaviya AN. Deferiprone, efficacy and safety. Ind J Pediatr 2004; 71: 213–6. 36. Cohen AR, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F. Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 2000; 108: 305–12.
Arthropathy in haematological disorders
37. Naselli A, Vignolo M, Di Battista E, Garzia P, Forni GL, Traverso T, et al. Long-term follow-up of skeletal dysplasia in thalassaemia major. J Pediatr Endocrinol Metab 1998; 11(Suppl 3): 817–25. 38. De Virgiliis S, Congia M, Frau F, Argiolu F, Diana G, Cucca F, et al. Deferoxamine-induced growth retardation in patients with thalassemia major. J Pediatr 1988; 113: 661–9. 39. Brill PW, Winchester P, Giardina PJ, Cunningham-Rundles S. Deferoxamine-induced bone dysplasia in patients with thalassemia major. AJR Am J Roentgenol 1991; 156: 561–5. 40. Pliakou XI, Koutsouka FP, Damigos D, Bourantas KL, Briasoulis EC, Voulgari PV. Rheumatoid arthritis in patients with hemoglobinopathies. Rheumatol Int 2011. 41. Arman MI, Butun B, Doseyen A, Bircan I, Guven A. Frequency and features of rheumatic findings in thalassaemia minor: a blind controlled study. Br J Rheumatol 1992; 31: 197–9. 42. Ines LS, da Silva JA, Malcata AB, Porto AL. Arthropathy of genetic hemochromatosis: a major and distinctive manifestation of the disease. Clin Exp Rheumatol 2001; 19: 98–102. 43. Sinigaglia L, Fargion S, Fracanzani AL, Binelli L, Battafarano N, Varenna M, et al. Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload. J Rheumatol 1997; 24: 1809–13. 44. Adamson TC 3rd, Resnik CS, Guerra J Jr, Vint VC, Weisman MH, Resnick D. Hand and wrist arthropathies of hemochromatosis and calcium pyrophosphate deposition disease: distinct radiographic features. Radiology 1983; 147: 377–81. 45. Molho P, Rolland N, Lebrun T, Dirat G, Courpied JP, Croughs T, et al. Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France. The French Study Group. [email protected]. Haemophilia 2000; 6: 23–32. 46. Rodriguez-Merchan EC. Pathogenesis, early diagnosis, and prophylaxis for chronic hemophilic synovitis. Clin Orthop Relat Res 1997; 343: 6–11. 47. Carvajal Alba JA, Jose J, Clifford PD. Hemophilic arthropathy. Am J Orthop (Belle Mead NJ) 2010; 39: 548–50. 48. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535–44. 49. Rodriguez-Merchan EC. Radionuclide synovectomy (radiosynoviorthesis) in hemophilia: a very efficient and single procedure. Semin Thromb Hemost 2003; 29: 97–100. 50. Evans TI, Nercessian BM, Sanders KM. Leukemic arthritis. Semin Arthritis Rheum 1994; 24: 48–56. 51. Gupta D, Singh S, Suri D, Ahluwalia J, Das R, Varma N. Arthritic presentation of acute leukemia in children: experience from a tertiary care centre in North India. Rheumatol Int 2010; 30: 767–70.
Review Article
51
52. Suri D, Ahluwalia J, Sachdeva MU, Das R, Varma N, Singh S. Arthritic presentation of childhood malignancy: beware of normal blood counts. Rheumatol Int 2011; 31: 827–9. 53. Marwaha RK, Kulkarni KP, Bansal D, Trehan A. Acute lymphoblastic leukemia masquerading as juvenile rheumatoid arthritis: diagnostic pitfall and association with survival. Ann Hematol 2010; 89: 249–54. 54. Jones OY, Spencer CH, Bowyer SL, Dent PB, Gottlieb BS, Rabinovich CE. A multicenter case-control study on predictive factors distinguishing childhood leukemia from juvenile rheumatoid arthritis. Pediatrics 2006; 117: e840–4. 55. Hughes C, Patterson K, Murray M. Avascular necrosis of the femoral head in childhood chronic myeloid leukaemia. Br J Haematol 2007; 139: 1. 56. Mody GM, Cassim B. Rheumatologic features of hematologic disorders. Curr Opin Rheumatol 1996; 8: 57–61. 57. Qureshi A, Ali A, Riaz N, Pervez S. Primary non-hodgkin’s lymphoma of bone: experience of a decade. Ind J Pathol Microbiol 2010; 53: 267–70. 58. Haddy TB, Keenan AM, Jaffe ES, Magrath IT. Bone involvement in young patients with non-Hodgkin’s lymphoma: efficacy of chemotherapy without local radiotherapy. Blood 1988; 72: 1141–7. 59. Birlik M, Akar S, Onen F, Ozcan MA, Bacakoglu A, Ozkal S, et al. Articular, B-cell, non-Hodgkin’s lymphoma mimicking rheumatoid arthritis: synovial involvement in a small hand joint. Rheumatol Int 2004; 24: 169–72. 60. Castro M, Conn DL, Su WP, Garton JP. Rheumatic manifestations in myelodysplastic syndromes. J Rheumatol 1991; 18: 721–7. 61. George SW, Newman ED. Seronegative inflammatory arthritis in the myelodysplastic syndromes. Semin Arthritis Rheum 1992; 21: 345–54. 62. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78: 21–33. 63. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (2). N Engl J Med 1992; 327: 99–106. 64. Nesher G, Ruchlemer R. Alpha-interferon-induced arthritis: clinical presentation treatment, and prevention. Semin Arthritis Rheum 1998; 27: 360–5. 65. Marsh JC, Zomas A, Hows JM, Chapple M, Gordon-Smith EC. Avascular necrosis after treatment of aplastic anaemia with antilymphocyte globulin and high-dose methylprednisolone. Br J Haematol 1993; 84: 731–5. 66. Hansen T, Kunkel M, Weber A, James Kirkpatrick C. Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 2006; 35: 155–60.
Review Article
Arthropathy in haematological disorders in children Deepti Suri1, Sapna Oberoi2
ABSTRACT Haematological disorders, both benign and malignant, may present with osteoarticular complaints. Overlapping rheumatological symptoms can easily mislead the treating physician away from the underlying haematological illness. Suspecting and diagnosing the primary blood disorder is crucial in these patients. In this article, we review the spectrum of haematological disorders commonly associated with arthropathy, their clinical presentation and management. We will further highlight the common diagnostic pitfalls that will help the treating clinician in managing such children. Keywords: Arthritis, blood disorders, children, haematological, musculoskeletal manifestations, rheumatological manifestations
INTRODUCTION Musculoskeletal pain is a common complaint, affecting 10–20% of school age children.1,2 Although, most of these complaints are benign in nature, they pose an important diagnostic challenge for a clinician. The differential diagnosis of arthritis is much broader in children than in adults. Many haematological disorders have been associated with rheumatological symptoms.3 These diseases are close mimics of each other and it is always not easy for a paediatrician to differentiate one from the other. Haematological disorders can present for the first time with rheumatological symptoms or more commonly musculoskeletal manifestations and autoimmune phenomenon may develop later on during the course of haematological disorders.3 The concept of this review is to provide the overview of various haematological illnesses which can be associated with arthropathy in children and to highlight the potential diagnostic clues. The review, however, does not elaborate on the haematological complications that may occur in patients with already established rheumatological conditions.
1
Haematological disorders that present with rheumatological symptoms can be broadly divided into benign and malignant.
BENIGN DISORDERS Sickle cell disease Sickle cell disease (SCD) is a group of inherited haemoglobinopathies in which a defective form of haemoglobin is produced. Musculoskeletal manifestations are seen not only in the homozygous state, but also in compound heterozygous states like HbSC disease and sickle-beta thalassemia.4 Sickle haemoglobin polymerizes in deoxygenated states, distorts red cells into rigid sickle shapes which in turn block microcirculation and cause ischaemia and infarction. Sickle cell disease typically presents in childhood with haemolytic anaemia and intermittent crises.5 Hand–foot syndrome (dactylitis) is typically seen in children between 6 months and 2 years of age and may be the
Assistant Professor, Division of Allergy Immunology, 2Senior Resident, Paediatric Haematology Oncology Unit, Department of Paediatrics, Advanced Paediatrics Centre, Postgraduate Institute of Medical Education and Research, Chandigarh, India. Correspondence: Dr. Deepti Suri, email: [email protected]
doi: 10.1016/S0973-3698(12)60028-4
Arthropathy in haematological disorders
first manifestation of the disease.6 Classical presentation is that of a young child with inconsolable crying due to pain with diffuse, symmetric, tender, and warm swelling of the hands, feet, or both. Fever may be present with significant peripheral blood leukocytosis and elevated C-reactive protein. Swelling usually lasts for 1–3 weeks. Radiographs are initially normal; however, it may show marrow densities, lytic areas or periosteal elevation later.7 Osteomyelitis becomes an important differential diagnosis and must always be kept in mind while evaluating these children. Analgesics, anti-inflammatory agents, and hydration form the main stay of therapy.4,8 Sickle-cell arthropathy, caused by microvascular ischaemia and synovial infarctions, usually affects large joints. Severe oligo- or polyarthralgia and transient joint swelling lasting for up to 3 weeks may occur. Knees are, by far, the most commonly involved joints, but elbows, ankles, and other joints can also be involved.8,9 Small, non-inflammatory synovial effusions are commonly associated with bone infarcts. These effusions are often associated with other manifestations of sickle cell crises. It must be remembered that reactionary joint effusions associated with vaso-occlusive crisis are more common than septic arthritis in patients with SCD. As the joints feel warm and tender, septic arthritis, acute gout and haemarthrosis should be excluded. Joint aspirate is typically yellow, non-inflammatory, sterile, and free of crystals. Treatment of associated crisis remains the main stay of therapy.8,9 Septic arthritis and osteomyelitis affecting long bones are serious complications of SCD seen in about 7–17% and 18–61% patients, respectively.10,11 Infarction and necrosis of the medullary bone acts as a nidus for bacterial overgrowth. Hyposplenism, secondary to multiple splenic infarcts, resulting in impaired opsonisation and activation of alternate complement pathways, further predisposes to infections.4 Salmonella species is the leading cause of such infections in patients with SCD, followed by Staphylococcus aureus, gram-negative enteric bacilli, Mycobacterium tuberculosis, and Mycobacterium ulcerans.12 Osteomyelitis is most commonly seen in the diaphysis of long bones (femur, tibia, and humerus) while septic arthritis affects hip, knee, and shoulder joints. As the presenting features of osteomyelitis are similar to those of painful bone crisis due to infarction, a high index of suspicion is important to carry out appropriate investigations.13,14 Despite newer imaging modalities such as magnetic resonance imaging (MRI) and bone scan, the diagnosis of osteomyelitis still depends on clinical judgement and positive blood or bone culture in a patient with SCD.6,7,15 Third generation cephalosporins remain the drug of choice for empirical therapy. Avascular necrosis (AVN) of the bone occurring due to infarction of epiphysis is the most disabling musculoskeletal
Review Article
45
complication of SCD. The estimated prevalence in children younger than 15 years is 3% which increases to 40% by mid-50s.16,17 Head of femur is the commonest site followed by humeral head, tibial condyles, ribs, and spine.14 Pain at rest, limited range of motion and limping are the common clinical findings at presentation of AVN affecting femoral head.17 Radiographs taken at the time of acute bone pain do not show changes of infarction. Later, radiographs may show mottled attenuation of epiphysis, sclerosis near the joint margin, subchondral lucent areas, flattening/collapse of the articular surfaces and secondary osteoarthritis.7 Technetium pyrophosphate bone scans or MRI can detect infarction quite early, even before the development of detectable aseptic necrosis.17,18 Bone scintigraphy may show initial photopaenia, but as the bone revascularises, uptake may return to normal or may even be increased. T2-weighted MR scanning shows high-signal intensity.17,18 Early treatment can be attempted with the prevention of weight bearing or with coring or osteotomy of the femoral head to allow healing without the resultant distortion of bone.19–21 But failure rates can be as high as 50%.20 Once articular breakdown has been established, replacement of the femoral head with a prosthesis or total hip replacement is the treatment of choice. Other less common musculoskeletal manifestations of SCD include bone erosions, gout, bony ankylosis of the spine and hip joint, sacroiliatis, pathological fracture, and inflammation, oedema and necrosis of the muscles.
Thalassemias The thalassemias are a group of congenital disorders in which synthesis of one or other of the globin chains is reduced. Management of these disorders has improved considerably in the last couple of decades, and now 50–68% thalassemia major patients survive to adulthood.22,23 Those with suboptimally treated disease may have significant joint pathology. Musculoskeletal problems not only occur due to marrow hyperplasia resulting from ineffective erythropoiesis, iron overload and its associated endocrinopathies, but also are the significant side effect of chelation therapy.24 Medullary expansion gives long bones a characteristic squared appearance. Coarsening of the trabecular pattern of the bone, osteoporosis, and cortical thinning are common.24 Children with thalassemia often present with backache, leg pains, and recurrent fractures secondary to osteoporosis. About 50% patients of thalassemia major suffer from osteoporosis, in spite of adequate treatment.25 Fractures are seen in the long bones and are reported to occur in 38–41% of
46
Indian Journal of Rheumatology 2012 May; Vol. 7, No. 1 (Suppl)
patients.26,27 Prevention and treatment of early bone loss is the best form of management. Adequate calcium and vitamin D intake, appropriate iron chelation, along with regular transfusions since early infancy may help in prevention. Treatment of osteoporosis, once established, includes treatment of underlying endocrinopathies, iron overload and calcium and vitamin D supplementation.28 Bisphosphonates especially pamidronate and zolendronate have shown promising results in improving the bone marrow density in controlled trials.29–31 In thalassemia major patients, arthropathy affecting small joints can also result secondary to iron deposition in the synovium, as seen in idiopathic haemochromatosis. Profound growth disturbance from premature fusion of the growth plate (particularly of the proximal humerus and distal femur) also occurs in 10–15% of thalassemia major patients, but is significantly reduced with regular transfusions.32 Deferiprone, an orally active iron chelator, is known to cause arthropathy. The incidence ranges from 4% to 15% in European patients to 41% among Indian children.33–36 Symptoms vary from mild non-progressive symptoms to severe erosive arthritis. Large joints, typically the knees, are involved. Children present with inability to squat, difficulty in climbing up and down stairs, wrist pain while writing, and ankle pain while doing daily activities. Radiographic changes include joint effusions, patellar breaking and subchondral flattening of the femoral condyles. Mild symptoms can be controlled with non-steroidal anti-inflammatory drugs (NSAID) and by reducing the dose of deferiprone. Moderate to severe symptoms warrant temporary stoppage of drug until symptoms resolve completely. Rechallenge with deferiprone can be done subsequently with reduced doses followed by slow increments. Reappearance of symptoms warrants permanent stoppage of the drug.34–36 Deferoxamine, used for iron chelation, can also lead to rachitic bone changes and genu valgum in young children, especially when used in higher doses.37 Metaphyseal changes are seen particularly in the vertebrae and they can lead to disproportionate short trunk.38,39 Children on deferoxamine should be regularly monitored for these complications as the changes are irreversible. Chronic small joint arthritis in patients with thalassemia major should also arouse a suspicion of rheumatoid arthritis, as it has been reported more commonly in these patients than in the general population (4.4% vs. 0.3%).40 Thalassemia minor (trait) remains a common and usually silent disorder. In a blinded study comparing 80 cases of thalassemia minor with control patients, 52% of cases had musculoskeletal symptoms compared with 54% of controls. Arthralgia of the wrist and shoulders was most common, and three patients had a short-lived arthritis.41
Suri and Oberoi
Haemochromatosis Hereditary haemochromatosis (HH) is a genetically determined disorder in which mutations in the HFE gene or the TFR2 gene cause increased intestinal iron absorption. The classic triad of the disease includes skin hyperpigmentation, diabetes mellitus and hepatomegaly. Arthropathy is an important manifestation of haemochromatosis which is often misdiagnosed.42 The most common presenting symptom of arthritis is twinges of the pain upon flexing the small joints of the hand, particularly the second and third metacarpophalangeal joints.43 Radiologically, subchondralarthropathy and chondrocalcinosis are the most common findings. Chondrocalcinosis (radiographic calcification in hyaline and/or fibrocartilage) of the knee, wrist, hip, and spine can be seen in up to a third of patients due to deposition of calcium pyrophosphate dihydrate crystals.44 Treatment with regular phlebotomies and iron chelation generally has little effect upon the clinical, radiological or histological progression of the arthropathy. Additional treatment options for arthritis may include the use of analgesics, NSAIDs and intra-articular glucocorticoids.42
Haemophilic arthropathy Haemophilia is a group of congenital disorders of blood coagulation due to the deficiency of factor VIII (haemophilia A) or factor IX (haemophilia B). Mechanical factors play an important role as evident by the onset of haemarthrosis with weight bearing, frequent bleeding into lower limb joints and by the more severe involvement of limbs on the dominant side. Joint disease is the major cause of morbidity in haemophiliacs and is found in up to 90% of severely affected patients.45 Joint damage classically starts as acute haemarthrosis, followed by chronic synovitis which culminates to degenerative arthritis.46 Acute haemarthrosis generally first occurs when a child begins to crawl and walk. Knees, ankles and elbows are most affected. Pain is accompanied by objective clinical findings of warmth, a tense effusion, tenderness, limitation of motion, and a joint that is often held in a flexed position. It is an important differential diagnosis in a young child presenting with monoarthritis. The symptoms are abrupt and usually not associated with other systemic complaints. A careful family history may clinch the diagnosis. Prompt and early factor replacement along with RICE (rest, immobilisation, cold compressions, and elevation) therapy is crucial to decrease the long-term complications of acute haemarthrosis. Bleeding may continue, cyclically in target joints into adulthood. Recurrent haemarthrosis, particularly in patients
Arthropathy in haematological disorders
with severe haemophilia, leads to disabling arthropathy. Chronic synovitis leads to progressive joint damage, cartilage destruction and the range of motion becomes severely restricted. Fibrous ankylosis may ensue. Subluxation, joint laxity and mal-alignment are consequences.47 Primary prophylactic treatment from early years of life rather than demand factor replacement markedly reduces the risk of chronic arthropathy.48 Vigorous and prolonged treatment of bleeding into a target joint with factor replacement can also help in the healing of the joint. If medical therapy fails, arthroscopic or radioactive synovectomy may reduce the bleeding and prevent the progression of early joint disease.49 Failure of aggressive medical therapy and synovectomy will either need total joint replacement or ankylosis of the joint depending upon the joint involved.47
MALIGNANT DISORDERS Leukaemic arthritis Leukaemia is an important differential diagnosis in children presenting with osteoarticular complaints. Musculoskeletal complaints can occur in 15–30% of acute lymphocytic leukaemia patients at disease onset. Arthritic presentation of leukaemia is more common in children than in adults. The reported incidence varies between 12% and 65% among paediatric acute leukaemia patients and 4–13% among adult cases.50 Classical leukaemic arthritis occurs because of synovial infiltration by blast cells. The other proposed mechanisms include; reactive joint inflammation secondary to the leukaemic process in the marrow of adjacent bones, thrombocytopaenic haemorrhage into the joint and synovitis due to immune complex formation.50 Leukaemic patients are also at a higher risk for septic arthritis from bacterial and fungal infections which occurs due to underlying immune-compromised state attributable to their disease per se and chemotherapy. The most worrisome aspect of leukaemic arthritis for the bedside clinician is the fact that it can masquerade other nonmalignant conditions especially juvenile idiopathic arthritis (JIA) resulting in a delay in the diagnosis and treatment. Further, treatment initiated for these benign conditions including glucocorticoids can mask the underlying malignancy.51,52 Although similar in presentation, some subtle clinical features can distinguish leukaemic arthritis from JIA (Table 1). Nocturnal pain awaking the child from sleep, pain out of proportion to joint swelling, bone tenderness, pain and tenderness in the metaphyseal location away from the joint are typical of leukaemia. Symptoms are insidious to begin with
Review Article
47
Table 1 Red flag signs of leukaemic arthritis • • • • • • • • • •
Explosive onset of symptoms Excruciating pain rendering the patient bed-bound Night pains awaking the child from sleep Pain around the joint rather than in the joint Absence of recognisable pattern of joint involvement Severe pallor Petechiae, lymphadenopathy, hepatosplenomegaly Leucopaenia with lymphocytic preponderance Absence of polymorphonuclear response Thrombocytopaenia
and pain is usually not severe enough to render a child bed-bound in JIA. The child may have acute joint pain in leukaemia but in JIA the children usually report a diffuse dull aching discomfort over a joint especially more in the morning hours. Presence of fever, lymphadenopathy and hepatosplenomegaly may not always contribute much in differentiating the two sets of conditions.53 Peripheral blood count showing severe anaemia, leucopaenia with relative lymphocytic predominance and thrombocytopaenia are subtle clues towards malignancy.52,54 Increased awareness of the arthritic presentation of leukaemia can guide the treating physician to request for a bone marrow examination early in the course of the disease. This is mandatory for arriving at the correct diagnosis especially in patients with atypical clinical pattern, nocturnal pain, and prominent systemic features, especially before embarking on corticosteroid therapy. Arthropathy can also be observed in chronic myeloid leukaemias (CML), chronic myelomonocytic leukaemias (CMML) and large granular lymphocytic leukaemia but the incidence is far less in children as compared to adults. Hyperleukocytosis in patients with CML can cause partial or total occlusion of microcirculations, resulting in AVN of the head of femur.55
Lymphoma Bone involvement is seen in 10–20% of paediatric non-Hodgkin lymphoma especially in diffuse large B-cell lymphoma, Burkitt lymphoma and anaplastic large cell lymphoma.56–58 Femur, pelvis, tibia, humerus and spine are commonly involved. Majority of the children present with bone pain and swelling. Radiological features include the presence of lytic or sclerotic lesion which is usually associated with a breach in the underlying cortex. Bone biopsy proves the diagnosis of underlying lymphoma. Patients with non-Hodgkin lymphoma may rarely present with polyarticular or oligoarticular arthritis.59 Immune-complex-mediated
48
Indian Journal of Rheumatology 2012 May; Vol. 7, No. 1 (Suppl)
Suri and Oberoi
Table 2 Arthropathy associated with haematological disorders or their treatment Haematological disorders and drugs
Arthritic manifestations
Sickle cell disease
Dactylitis, avascular necrosis, osteomyelitis, septic arthritis, bone infarctions, joint effusions, sickle cell arthropathy, gout
Thalassemia major
Osteoporosis, fractures, back pain, chronic polyarthritis due to iron overload, intervertebral disc degeneration, deferiprone-related arthropathy, deferoxamine-related bone changes
Haemophilia
Haemarthrosis, chronic haemophilic arthropathy
Haemochromatosis
Chronic small joint polyarthritis
Acute leukaemia
Leukaemic arthropathy, gout, septic arthritis, osteomyelitis
Chronic leukaemias
Gout, polyarthritis, avascular necrosis, rheumatoid arthritis
Lymphoma
Bone pain, fracture, polyarthritis
Myelodysplastic syndrome
Seronegative arthritis, relapsing polychondritis
Multiple myeloma
Thoraco-lumber pain, pathological fractures, osteoporosis
Drugs • Steroids • Interferon • G-CSF • Antithymocyte globulin • Bisphosphonates
Osteoporosis, myopathy, avascular necrosis Arthralgia, myalgia, arthritis Bone pains, arthralgia Serum sickness, avascular necrosis Osteonecrosis of jaw
G-CSF = granulocyte colony stimulating factor.
synovial inflammation is the proposed mechanism rather than direct infiltration of the synovium as seen in leukaemias.
features like fatigue, anaemia, deranged renal functions, hypercalcaemia, and weight loss generally help in making diagnosis.
Myelodysplastic syndrome
Drug-induced arthropathy
Myelodysplastic syndrome (MDS) is a clonal haematopoietic stem cell disorder characterised by progressive peripheral cytopaenias and bone marrow failure. Autoimmune manifestations including seronegative arthritis, rheumatoid arthritis, relapsing polychondritis, haemolytic anaemias, vasculitis as well as positive anti-nuclear antibodies and rheumatoid factor have been reported in 13–30% of patients with MDS.60 These can be present at the time of diagnosis or may appear as the disease progresses. Although these manifestations usually respond to steroids, but MDS with concurrent autoimmune manifestations has been shown to be less responsive to cytotoxic chemotherapy.61
Arthropathy or athralgias can occur due to the drugs used to treat haematological disorders (Table 2). Arthropathy is an important complication of deferiprone, an oral iron chelator used in thalassemics, as mentioned above. Granulocyte colony stimulating factor (G-CSF) is a haematopoietic growth factor which upregulates the production of neutrophils. It is used in congenital neutropaenia, primary prophylaxis of chemotherapy-induced neutropaenia and for the mobilisation of peripheral blood stem cells. Bone pains can occur in 10–20% of patients on G-CSF therapy especially those on higher doses.63 They are commonly observed in the sternum, pelvis and/or lower back and tend to occur 1–2 days prior to the increase in circulating neutrophils. Pain can be controlled in most patients with non-narcotic analgesics. Arthralgias are commonly observed following interferon (IFN) therapy. IFN is also implicated in causing symmetric polyarthritis in some studies. Stopping of IFN, with or without the addition of anti-inflammatory agents, usually results in the remission of arthritis.64 Long-term steroid therapy and anti-thymocyte globulin therapy in aplastic anaemia can cause AVN of the bone.65 Bisphosphonates used in the treatment of osteoporosis can also lead to osteonecrosis.66
Multiple myeloma and POEM syndrome Multiple myeloma and POEM syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, skin changes) are monoclonal plasma cell disorders seen in older adults. Bone pain, particularly in the back and chest, is present at the time of diagnosis in approximately 60% of the patients.62 It can be the first manifestation of the disease. Associated
Arthropathy in haematological disorders
DIAGNOSTIC OVERVIEW Physicians evaluating children with musculoskeletal symptoms must always be aware that many haematological conditions can present with rheumatic symptoms and signs. High index of suspicion is therefore important to reach the correct diagnosis. Careful history, recognition of the pattern of joint disease and physical examination are of utmost importance. Hepatomegaly, splenomegaly, lymphadenopathy, petechiae, abnormal blood counts, presence of paraprotein, and lytic radiological lesions are to be approached with caution and should prompt relevant investigations. Extreme pain out of proportion to joint swelling, poor response to glucocorticoids and disease-modifying anti-rheumatic drugs should alert one to search for an alternative diagnosis. Underlying leukaemia can be easily excluded by doing a bone marrow examination in children who present with arthritis. The important clues to leukaemia include acute onset of arthritis, pain disproportionate to physical findings, pain around the joint rather than in the joint, night pains, lymphadenopathy, petechiae, hepatomegaly, splenomegaly, sternal tenderness, point tenderness in diaphyseal region and subtle blood count clues. Starting steroids in such a patient will delay the diagnosis of leukaemia and may confer poorer prognosis by delaying the therapy of leukaemia. Symmetrical polyarthritis can rarely be a presenting feature of the underlying occult malignancies such as nonHodgkin lymphoma, Hodgkin lymphoma, neuroblastoma, lung cancer, and gastrointestinal tract cancer. Children with haemophilia may present with noninflammatory monoarticular arthritis. History of other bleeding manifestations, family history, and trauma may or may not be evident. It is always important to consider this differential in a child presenting with monoarticular arthritis; a diagnostic joint aspirate can aggravate bleeding in the case of haemophiliac arthropathy. Avascular necrosis can occur in a couple of haematological conditions such as SCD, patients on long-term steroids, following immunosuppressive therapy in aplastic anaemia and bisphosphonates treatment for osteoporosis, inherited or acquired thrombophilic states and in children presenting with hyperleucocytosis. Thus, it is important to consider them in differential diagnosis while evaluating the children with suspected AVN. Dactylitis presenting in childhood has several differentials with SCD being one of the commonest. The other important causes include infections such as tuberculosis, brucellosis, streptococcal, and staphylococcal infections, psoriatic arthritis and HLA-B27 associated spondyloarthropathies. Children with SCD, leukaemias, lymphomas, and those on long-term steroids and chemotherapy are prone for
Review Article
49
developing septic arthritis as well as osteomyelitis due to their underlying immunocompromised state. These children may not mount classical signs of inflammation. It is always crucial to look for any bone infections in the presence of prolonged fever in such children. Children with certain rheumatological disorders such as rheumatoid arthritis, systemic lupus erythematosis, dermatomyositis, polymyositis, Sjogren’s syndrome, and scleroderma are at increased risk of developing lymphomas, lung cancer, skin cancer, and other lymphoproliferative malignancies. Underlying immune dysregulation and use of immunosuppressive agents are the proposed mechanisms. This should always be kept in mind while treating and following these patients to avoid the delay in the diagnosis of malignancy.
SUMMARY Haematological disorders must always be considered in the differential diagnosis of children presenting with rheumatological complaints. Awareness on the part of the clinician about these manifestations can enable early recognition and diagnosis. Malignancy should always be considered and excluded in children presenting with musculoskeletal symptoms.
CONFLICT OF INTEREST None.
REFERENCES 1. 2.
3.
4. 5.
Goodman JE, McGrath PJ. The epidemiology of pain in children and adolescents: a review. Pain 1991; 46: 247–64. Malleson PN, Beauchamp RD. Rheumatology: 16. Diagnosing musculoskeletal pain in children. CMAJ 2001; 165: 183–8. Ehrenfeld M, Gur H, Shoenfeld Y. Rheumatologic features of hematologic disorders. Curr Opin Rheumatol 1999; 11: 62–7. Almeida A, Roberts I. Bone involvement in sickle cell disease. Br J Haematol 2005; 129: 482–90. Kaur M, Das GP, Verma IC. Sickle cell trait & disease among tribal communities in Orissa, Madhya Pradesh & Kerala. Indian J Med Res 1997; 105: 111–6.
50
Indian Journal of Rheumatology 2012 May; Vol. 7, No. 1 (Suppl)
6.
Kim SK, Miller JH. Natural history and distribution of bone and bone marrow infarction in sickle hemoglobinopathies. J Nucl Med 2002; 43: 896–900. Lonergan GJ, Cline DB, Abbondanzo SL. Sickle cell anemia. Radiographics 2001; 21: 971–94. Schumacher HR, Andrews R, McLaughlin G. Arthropathy in sickle-cell disease. Ann Intern Med 1973; 78: 203–11. de Ceulaer K, Forbes M, Roper D, Serjeant GR. Non-gouty arthritis in sickle cell disease: report of 37 consecutive cases. Ann Rheum Dis 1984; 43: 599–603. Balogun RA, Obalum DC, Giwa SO, Adekoya-Cole TO, Ogo CN, Enweluzo GO. Spectrum of musculo-skeletal disorders in sickle cell disease in Lagos, Nigeria. J Orthop Surg Res 2010; 5: 2. Bahebeck J, Atangana R, Techa A, Monny-Lobe M, Sosso M, Hoffmeyer P. Relative rates and features of musculoskeletal complications in adult sicklers. Acta Orthop Belg 2004; 70: 107–11. Burnett MW, Bass JW, Cook BA. Etiology of osteomyelitis complicating sickle cell disease. Pediatrics 1998; 101: 296–7. Stark JE, Glasier CM, Blasier RD, Aronson J, Seibert JJ. Osteomyelitis in children with sickle cell disease: early diagnosis with contrast-enhanced CT. Radiology 1991; 179: 731–3. Jean-Baptiste G, De Ceulaer K. Osteoarticular disorders of haematological origin. Baillieres Best Pract Res Clin Rheumatol 2000; 14: 307–23. Rifai A, Nyman R. Scintigraphy and ultrasonography in differentiating osteomyelitis from bone infarction in sickle cell disease. Acta Radiol 1997; 38: 139–43. Ware HE, Brooks AP, Toye R, Berney SI. Sickle cell disease and silent avascular necrosis of the hip. J Bone Joint Surg Br 1991; 73: 947–9. Gupta R, Adekile AD. MRI follow-up and natural history of avascular necrosis of the femoral head in Kuwaiti children with sickle cell disease. J Pediatr Hematol Oncol 2004; 26: 351–3. Frush DP, Heyneman LE, Ware RE, Bissett GS 3rd. MR features of soft-tissue abnormalities due to acute marrow infarction in five children with sickle cell disease. AJR Am J Roentgenol 1999; 173: 989–93. Washington ER, Root L. Conservative treatment of sickle cell avascular necrosis of the femoral head. J Pediatr Orthop 1985; 5: 192–4. Hungerford DS. Response: the role of core decompression in the treatment of ischemic necrosis of the femoral head. Arthritis Rheum 1989; 32: 801–6. Neumayr LD, Aguilar C, Earles AN, Jergesen HE, Haberkern CM, Kammen BF, et al. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment. J Bone Joint Surg Am 2006; 88: 2573–82.
7. 8. 9.
10.
11.
12. 13.
14.
15.
16.
17.
18.
19.
20.
21.
Suri and Oberoi
22. Modell B, Khan M, Darlison M. Survival in beta-thalassaemia major in the UK: data from the UK Thalassaemia Register. Lancet 2000; 355: 2051–2. 23. Borgna-Pignatti C, Rugolotto S, De Stefano P, Zhao H, Cappellini MD, Del Vecchio GC, et al. Survival and complications in patients with thalassemia major treated with transfusion and deferoxamine. Haematologica 2004; 89: 1187–93. 24. Voskaridou E, Terpos E. New insights into the pathophysiology and management of osteoporosis in patients with beta thalassaemia. Br J Haematol 2004; 127: 127–39. 25. Origa R, Fiumana E, Gamberini MR, Armari S, Mottes M, Sangalli A, et al. Osteoporosis in beta-thalassemia: clinical and genetic aspects. Ann NY Acad Sci 2005; 1054: 451–6. 26. Vogiatzi MG, Macklin EA, Fung EB, Vichinsky E, Olivieri N, Kwiatkowski J, et al. Prevalence of fractures among the thalassemia syndromes in North America. Bone 2006; 38: 571–5. 27. Vogiatzi MG, Macklin EA, Fung EB, Cheung AM, Vichinsky E, Olivieri N, et al. Bone disease in thalassemia: a frequent and still unresolved problem. J Bone Miner Res 2009; 24: 543–57. 28. Anapliotou ML, Kastanias IT, Psara P, Evangelou EA, Liparaki M, Dimitriou P. The contribution of hypogonadism to the development of osteoporosis in thalassaemia major: new therapeutic approaches. Clin Endocrinol (Oxf) 1995; 42: 279–87. 29. Mamtani M, Kulkarni H. Bone recovery after zoledronate therapy in thalassemia-induced osteoporosis: a meta-analysis and systematic review. Osteoporos Int 2010; 21: 183–7. 30. Voskaridou E, Terpos E, Spina G, Palermos J, Rahemtulla A, Loutradi A, et al. Pamidronate is an effective treatment for osteoporosis in patients with beta-thalassaemia. Br J Haematol 2003; 123: 730–7. 31. Perifanis V, Vyzantiadis T, Vakalopoulou S, Tziomalos K, Garypidou V, Athanassiou-Metaxa M, et al. Treatment of betathalassaemia-associated osteoporosis with zoledronic acid. Br J Haematol 2004; 125: 91–2; author reply 3–4. 32. Basanagoudar PL, Gill SS, Dhillon MS, Marwaha RK. Premature epiphyseal fusions in beta thalassaemia. Acta Orthop Belg 2010; 76: 114–9. 33. Cohen AR, Galanello R, Piga A, De Sanctis V, Tricta F. Safety and effectiveness of long-term therapy with the oral iron chelator deferiprone. Blood 2003; 102: 1583–7. 34. Panigrahi I, Marwaha RK, Das RR. Long-term response to deferiprone therapy in Asian Indians. Ann Hematol 2010; 89: 135–40. 35. Choudhry VP, Pati HP, Saxena A, Malaviya AN. Deferiprone, efficacy and safety. Ind J Pediatr 2004; 71: 213–6. 36. Cohen AR, Galanello R, Piga A, Dipalma A, Vullo C, Tricta F. Safety profile of the oral iron chelator deferiprone: a multicentre study. Br J Haematol 2000; 108: 305–12.
Arthropathy in haematological disorders
37. Naselli A, Vignolo M, Di Battista E, Garzia P, Forni GL, Traverso T, et al. Long-term follow-up of skeletal dysplasia in thalassaemia major. J Pediatr Endocrinol Metab 1998; 11(Suppl 3): 817–25. 38. De Virgiliis S, Congia M, Frau F, Argiolu F, Diana G, Cucca F, et al. Deferoxamine-induced growth retardation in patients with thalassemia major. J Pediatr 1988; 113: 661–9. 39. Brill PW, Winchester P, Giardina PJ, Cunningham-Rundles S. Deferoxamine-induced bone dysplasia in patients with thalassemia major. AJR Am J Roentgenol 1991; 156: 561–5. 40. Pliakou XI, Koutsouka FP, Damigos D, Bourantas KL, Briasoulis EC, Voulgari PV. Rheumatoid arthritis in patients with hemoglobinopathies. Rheumatol Int 2011. 41. Arman MI, Butun B, Doseyen A, Bircan I, Guven A. Frequency and features of rheumatic findings in thalassaemia minor: a blind controlled study. Br J Rheumatol 1992; 31: 197–9. 42. Ines LS, da Silva JA, Malcata AB, Porto AL. Arthropathy of genetic hemochromatosis: a major and distinctive manifestation of the disease. Clin Exp Rheumatol 2001; 19: 98–102. 43. Sinigaglia L, Fargion S, Fracanzani AL, Binelli L, Battafarano N, Varenna M, et al. Bone and joint involvement in genetic hemochromatosis: role of cirrhosis and iron overload. J Rheumatol 1997; 24: 1809–13. 44. Adamson TC 3rd, Resnik CS, Guerra J Jr, Vint VC, Weisman MH, Resnick D. Hand and wrist arthropathies of hemochromatosis and calcium pyrophosphate deposition disease: distinct radiographic features. Radiology 1983; 147: 377–81. 45. Molho P, Rolland N, Lebrun T, Dirat G, Courpied JP, Croughs T, et al. Epidemiological survey of the orthopaedic status of severe haemophilia A and B patients in France. The French Study Group. [email protected]. Haemophilia 2000; 6: 23–32. 46. Rodriguez-Merchan EC. Pathogenesis, early diagnosis, and prophylaxis for chronic hemophilic synovitis. Clin Orthop Relat Res 1997; 343: 6–11. 47. Carvajal Alba JA, Jose J, Clifford PD. Hemophilic arthropathy. Am J Orthop (Belle Mead NJ) 2010; 39: 548–50. 48. Manco-Johnson MJ, Abshire TC, Shapiro AD, Riske B, Hacker MR, Kilcoyne R, et al. Prophylaxis versus episodic treatment to prevent joint disease in boys with severe hemophilia. N Engl J Med 2007; 357: 535–44. 49. Rodriguez-Merchan EC. Radionuclide synovectomy (radiosynoviorthesis) in hemophilia: a very efficient and single procedure. Semin Thromb Hemost 2003; 29: 97–100. 50. Evans TI, Nercessian BM, Sanders KM. Leukemic arthritis. Semin Arthritis Rheum 1994; 24: 48–56. 51. Gupta D, Singh S, Suri D, Ahluwalia J, Das R, Varma N. Arthritic presentation of acute leukemia in children: experience from a tertiary care centre in North India. Rheumatol Int 2010; 30: 767–70.
Review Article
51
52. Suri D, Ahluwalia J, Sachdeva MU, Das R, Varma N, Singh S. Arthritic presentation of childhood malignancy: beware of normal blood counts. Rheumatol Int 2011; 31: 827–9. 53. Marwaha RK, Kulkarni KP, Bansal D, Trehan A. Acute lymphoblastic leukemia masquerading as juvenile rheumatoid arthritis: diagnostic pitfall and association with survival. Ann Hematol 2010; 89: 249–54. 54. Jones OY, Spencer CH, Bowyer SL, Dent PB, Gottlieb BS, Rabinovich CE. A multicenter case-control study on predictive factors distinguishing childhood leukemia from juvenile rheumatoid arthritis. Pediatrics 2006; 117: e840–4. 55. Hughes C, Patterson K, Murray M. Avascular necrosis of the femoral head in childhood chronic myeloid leukaemia. Br J Haematol 2007; 139: 1. 56. Mody GM, Cassim B. Rheumatologic features of hematologic disorders. Curr Opin Rheumatol 1996; 8: 57–61. 57. Qureshi A, Ali A, Riaz N, Pervez S. Primary non-hodgkin’s lymphoma of bone: experience of a decade. Ind J Pathol Microbiol 2010; 53: 267–70. 58. Haddy TB, Keenan AM, Jaffe ES, Magrath IT. Bone involvement in young patients with non-Hodgkin’s lymphoma: efficacy of chemotherapy without local radiotherapy. Blood 1988; 72: 1141–7. 59. Birlik M, Akar S, Onen F, Ozcan MA, Bacakoglu A, Ozkal S, et al. Articular, B-cell, non-Hodgkin’s lymphoma mimicking rheumatoid arthritis: synovial involvement in a small hand joint. Rheumatol Int 2004; 24: 169–72. 60. Castro M, Conn DL, Su WP, Garton JP. Rheumatic manifestations in myelodysplastic syndromes. J Rheumatol 1991; 18: 721–7. 61. George SW, Newman ED. Seronegative inflammatory arthritis in the myelodysplastic syndromes. Semin Arthritis Rheum 1992; 21: 345–54. 62. Kyle RA, Gertz MA, Witzig TE, Lust JA, Lacy MQ, Dispenzieri A, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003; 78: 21–33. 63. Lieschke GJ, Burgess AW. Granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor (2). N Engl J Med 1992; 327: 99–106. 64. Nesher G, Ruchlemer R. Alpha-interferon-induced arthritis: clinical presentation treatment, and prevention. Semin Arthritis Rheum 1998; 27: 360–5. 65. Marsh JC, Zomas A, Hows JM, Chapple M, Gordon-Smith EC. Avascular necrosis after treatment of aplastic anaemia with antilymphocyte globulin and high-dose methylprednisolone. Br J Haematol 1993; 84: 731–5. 66. Hansen T, Kunkel M, Weber A, James Kirkpatrick C. Osteonecrosis of the jaws in patients treated with bisphosphonates—histomorphologic analysis in comparison with infected osteoradionecrosis. J Oral Pathol Med 2006; 35: 155–60.