Arthropathy in haematological disorders in children
ARTHROPATHY IN HAEMATOLOGICALDISORDERS IN CHILDREN
Musculoskeletal pain is a common complaint, affecting 10–20% of school age children. The differential diagnosis of arthritis is much broader in children than in adults. Many haematological disorders have been associated with rheumatological symptoms.
HAEMATOLOGICAL DISORDERS THAT PRESENT WITH RHEUMATOLOGICALSYMPTOMS CAN BE BROADLY DIVIDED INTO BENIGN ANDMALIGNANT.BENIGN DISORDERS MALIGNANT DISORDERS Sickle cell disease Leukaemic arthritis Thalassemias Lymphoma Haemochromatosis Myelodysplastic Haemophilic syndrome arthropathy Multiple myeloma and Drug-induced POEM syndrome arthropathy
SICKLE CELL DISEASE Musculoskeletal manifestations are seen both in the homozygous state, and compound heterozygous states like HbSC disease and sickle-beta thalassemia. Sickle haemoglobin polymerizes in deoxygenated states, distorts red cells into rigid sickle shapes which in turn block microcirculation and cause ischaemia and infarction.
HAND–FOOT SYNDROME (DACTYLITIS) Typically seen in children between 6 months and 2 years of age. 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. Osteomyelitis becomes an important differential diagnosis and must always be kept in mind while evaluating these children.
SICKLE-CELL ARTHROPATHY Caused by microvascular ischaemia and synovial infarctions. Affects large joints. Severe oligo- or polyarthralgia and transient joint swelling lasting for up to 3 weeks may occur.
Knees are the most commonly involved joints, but elbows, ankles, and other joints can also be involved. Small, non-inflammatory synovial effusions are commonly associated with bone infarcts.
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.
SEPTIC ARTHRITIS AND OSTEOMYELITIS Affects long bones in about 7–17% and 18–61% patients, respectively. 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
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. Third generation cephalosporins remain the drug of choice for empirical therapy.
AVASCULAR NECROSIS (AVN) Occurs due to infarction of epiphysis. The estimated prevalence in children younger than 15 years is 3% which increases to 40% by mid-50s. Head of femur is the commonest site followed by humeral head, tibial condyles, ribs, and spine.
Radiographs taken at the time of acute bone pain do not show changes of infarction. Radiographs may show mottled attenuation of epiphysis, sclerosis near the joint margin, subchondral lucent areas, flattening/collapse of the articular surfaces and secondary osteoarthritis.
Technetium pyrophosphate bone scans or MRI can detect infarction quite early, even before the development of detectable aseptic necrosis. Bone scintigraphy may show initial photopaenia, but as the bone revascularises, uptake may return to normal or may even be increased.
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.
THALASSEMIAS Musculoskeletal problems occur due to :1. Marrow hyperplasia resulting from ineffective erythropoiesis.2. Iron overload and its associated endocrinopathies.3. Side effect of chelation therapy.
Medullary expansion gives long bones a characteristic squared appearance. Coarsening of the trabecular pattern of the bone, osteoporosis, and cortical thinning are common. Children with thalassemia often present with backache, le pains, and recurrent fractures secondary to osteoporosis.
About 50% patients of thalassemia major suffer from osteoporosis, in spite of adequate treatment. Fractures are seen in the long bones and are reported to occur in 38–41% of patients.
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.
Bisphosphonates especially pamidronate and zolendronate have shown promising results in improving the bone marrow density in controlled trials.
In thalassemia major patients, arthropathy affecting small joints can also result secondary to iron deposition in the synovium. 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.
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.
Chronic small joint arthritis in patients with thalassemia major should also arouse a suspicion of rheumatoid arthritis, It has been reported more commonly in these patients than in the general population (4.4% vs. 0.3%).
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
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.
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
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
HAEMOPHILIC ARTHROPATHY Joint disease is the major cause of morbidity in haemophiliacs and is found in up to 90% of severely affected patients. Joint damage classically starts as acute haemarthrosis, followed by chronic synovitis which culminates to degenerative arthritis.
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.
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.
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. Failure of aggressive medical therapy and synovectomy will either need total joint replacement or ankylosis of the joint depending upon the joint involved.
MALIGNANT DISORDERS Leukaemic arthritis Musculoskeletal complaints can occur in 15–30% of acute lymphocytic leukaemia patients at disease onset. The reported incidence varies between 12% and 65% among paediatric acute leukaemia patients and 4–13% among adult cases.
Classical leukaemic arthritis occurs because of synovial infiltration by blast cells.1. The other proposed mechanisms include; Reactive joint inflammation secondary to the leukaemic process in the marrow of adjacent bones,2. Thrombocytopaenic haemorrhage into the joint .3. synovitis due to immune complex formation.
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.
RED FLAG SIGNS OF LEUKAEMIC ARTHRITIS1. Explosive onset of symptoms2. Excruciating pain rendering the patient bed-bound3. Night pains awaking the child from sleep4. Pain around the joint rather than in the joint5. Absence of recognisable pattern of joint involvement6. Severe pallor7. Petechiae, lymphadenopathy, hepatosplenomegaly8. Leucopaenia with lymphocytic preponderance9. Absence of polymorphonuclear response10. Thrombocytopaenia
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. Peripheral blood count showing severe anaemia, leucopaenia with relative lymphocytic predominance and thrombocytopaenia are subtle clues towards malignancy.
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.
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.
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.
MYELODYSPLASTIC SYNDROME 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.
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.
It can be the first manifestation of the disease. Features like fatigue, anaemia, deranged renal functions, hypercalcaemia, and weight loss generally help in making diagnosis.
DRUG-INDUCED ARTHROPATHY 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
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.
Long-term steroid therapy and anti-thymocyte globulin therapy in aplastic anaemia can cause AVN of the bone. Bisphosphonates used in the treatment of osteoporosis can also lead to osteonecrosis.
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 Physicians evaluating children with musculoskeletal symptoms must always be aware that many haematological conditions can present with rheumatic symptoms and signs. Careful history, recognition of the pattern of joint disease and physical examination are of utmost importance.
Hepatomegaly, splenomegaly, lymphadenopathy, p etechiae, 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.