1. ARTHROPATHY IN HAEMATOLOGICAL
DISORDERS IN CHILDREN

2.  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.

3. HAEMATOLOGICAL DISORDERS THAT PRESENT WITH RHEUMATOLOGICAL
SYMPTOMS CAN BE BROADLY DIVIDED INTO BENIGN AND
MALIGNANT.
BENIGN DISORDERS MALIGNANT DISORDERS
 Sickle cell disease  Leukaemic arthritis
 Thalassemias  Lymphoma
 Haemochromatosis  Myelodysplastic
 Haemophilic syndrome
arthropathy  Multiple myeloma and
 Drug-induced POEM syndrome
arthropathy

4. 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.

5. 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.

6.  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.

7. 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.

8.  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.

9.  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.

10. 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

11.  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.

12. 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.

13.  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.

14.  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.

15.  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.

16. 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.

17.  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.

18.  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.

19.  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.

20.  Bisphosphonates especially pamidronate and
zolendronate have shown promising results in
improving the bone marrow density in controlled
trials.

21.  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.

22.  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.

23.  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.

24.  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%).

25. 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

26.  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.

27.  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

28.  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

29. 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.

30.  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.

31.  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.

32.  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.

33.  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.

34. 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.

35.  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.

36.  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.

37. RED FLAG SIGNS OF LEUKAEMIC ARTHRITIS
1. Explosive onset of symptoms
2. Excruciating pain rendering the patient bed-bound
3. Night pains awaking the child from sleep
4. Pain around the joint rather than in the joint
5. Absence of recognisable pattern of joint involvement
6. Severe pallor
7. Petechiae, lymphadenopathy, hepatosplenomegaly
8. Leucopaenia with lymphocytic preponderance
9. Absence of polymorphonuclear response
10. Thrombocytopaenia

38.  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.

39.  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.

40.  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.

41. 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.

42.  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.

43. 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.

44. 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.

45.  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.

46. 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

47.  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.

48.  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.

49.  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.

50.  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.

51.  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.

52. 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.

53.  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.