Beyond Joint Pain: When Arthritis is a Harbinger of Leukaemia

Anamika Bakliwal^1*, Jatin Munjal², Mousumi Kar², Aditi Mittal², Anil Handoo², Rachna Sharma³, Sanjeev Kumar Sharma¹

¹ Department of Haematology-Oncology and Bone Marrow Transplantation, BLK-Max Super Speciality Hospital, New Delhi
² Department of Haematology & Molecular Biology, BLK-Max Super Speciality Hospital, New Delhi
³ Department of Paediatric Intensive Care, BLK-Max Super Speciality Hospital, New Delhi

DOI: https://doi.org/10.62830/mmj2-03-20c

Abstract: Acute lymphoblastic leukaemia (ALL) can present atypically, mimicking rheumatic conditions and causing significant diagnostic delays. This case details a 12-year-old boy initially diagnosed with juvenile idiopathic arthritis (JIA) due to persistent right shoulder and elbow pain and swelling, despite normal initial blood work. Initial evaluation, including physical examination, blood tests (normal complete blood count [CBC], elevated erythrocyte sedimentation rate/C-reactive protein [ESR/CRP]), and even rheumatoid factor positivity, pointed towards JIA. However, escalating nocturnal pain unresponsive to treatment, persistently high acute phase reactants, and bone oedema on magnetic resonance imaging (MRI) ultimately triggered a bone marrow aspiration, revealing a diagnosis of precursor B-cell ALL. This case emphasises the crucial need for high clinical suspicion and thorough investigation, including bone marrow examination, when children present with atypical or treatment-resistant musculoskeletal pain, particularly with features like worsening night pain and bone oedema on imaging, to avoid detrimental delays in diagnosing life-threatening conditions like ALL.

Key words: Leukaemia, Arthritis, Bone Marrow, Biopsy.

Introduction

Acute lymphoblastic leukaemia (ALL) is the most common childhood malignancy, often presenting with fever, pallor, fatigue, and bleeding.1 However, a significant subset of children with ALL may initially exhibit musculoskeletal symptoms, mimicking rheumatic conditions like juvenile idiopathic arthritis (JIA).2 This diagnostic challenge poses a serious risk, as delays in identifying and treating ALL can lead to adverse patient outcomes.3 Musculoskeletal complaints, including bone pain and arthritis, are present in a notable percentage of children with malignancies, highlighting the need for heightened clinical suspicion.4 This case report details the challenging diagnostic journey of a 12-year-old boy whose symptoms initially mimicked JIA, but ultimately revealed an underlying ALL.

Case Report

A 12-year-old boy, with no significant past medical history, presented to a paediatric rheumatology outpatient clinic with a four-week history of severe right shoulder pain and swelling. Notably, he denied any constitutional symptoms such as fever, loss of appetite, fatigue, weight loss, or night sweats. His medical history included a prior episode of bilateral knee pain and swelling that resolved with non-steroidal anti-inflammatory drug (NSAID) treatment, followed by right shoulder pain and swelling that also regressed with NSAID treatment. On physical examination, the patient exhibited swelling, pain, and a restricted range of motion in his right shoulder and elbow joints. Other joint and systemic examinations, including assessment for lymphadenopathy and hepatosplenomegaly, were unremarkable. Initial laboratory tests were surprisingly normal: haemoglobin 11.2 g/dL; white blood cell (WBC) count 8400/mm3; absolute neutrophil count 5820/mm3 ; platelet count 2.86 lakh/microL; erythrocyte sedimentation rate (ESR) 55 mm/h; C-reactive protein (CRP) 105; and lactate dehydrogenase (LDH) 224 U/L. The peripheral blood smear revealed no atypical cells, and serological tests for viral and bacterial aetiologies were negative. Direct radiographs of both hands and feet were also normal. Following the detection of rheumatoid factor positivity, a preliminary diagnosis of migratory JIA was made, and naproxen sodium treatment was initiated. Magnetic resonance imaging (MRI) of the right shoulder unveiled diffuse bone oedema and mild periarticular fluid in the shoulder and elbow joints. An ophthalmological evaluation was conducted to rule out uveitis, which also turned out to be normal. Repeated peripheral blood smears consistently showed no atypical cells. However, the patient's condition did not improve. During follow-up, acute phase reactants remained elevated, and his pain, particularly at night, intensified significantly. His arthritis remained unresponsive to naproxen sodium treatment. Due to the persistent and unsettling joint pain that frequently disrupted his sleep, he was referred to haematology for further evaluation. Despite the continued absence of atypical cells in the peripheral blood smear, the severity of his joint and bony pain prompted a bone marrow aspirate. The bone marrow aspirate yielded a shocking revelation: suggestive evidence of leukaemia, with a staggering 55% blasts. The biopsy further confirmed near-total replacement of the bone marrow by blasts. Flow cytometry analysis identified a cluster of cells within the blast window on the cluster of differentiation 45/side scatter (CD45/SSC) plot. These cells displayed bright expression of cluster of differentiation 10 (CD10) (~97%) along with moderately bright cluster of differentiation 34 (CD34) (~94%), cluster of differentiation 19 (CD19) ( ~96.5%), cytoplasmic cluster of differentiation 22 (cCD22) (~88%), cytoplasmic cluster of differentiation 79a (cCD79a) (~97.2%), cluster of differentiation 58 (CD58) (~99%), human leucocyte antigen – DR isotype (HLA-DR) (~98%), and cluster of differentiation 38 (CD38) (~98%), along with heterogeneous dim expression of cluster of differentiation 20 (CD20) ( ~37.4%). This immunophenotypic profile was highly suggestive of precursor B-cell acute lymphoblastic leukaemia (Pre-B-ALL). Patient was started on BerlinFrankfurt-Münster (BFM) 2009 protocol for ALL, which included steroids, resulting in the complete disappearance of pain in 4–5 days.

Discussion

ALL, the most common childhood malignancy, accounts for around 40% of childhood cancers in individuals under 20 years of age.5 While its precise aetiology remains elusive, environmental, immunological, and genetic factors are believed to play a role.6 Although patients often present with classic symptoms like fever, pallor, fatigue, night sweats, lymphadenopathy, hepatosplenomegaly, and bleeding manifestations, monoarthritis or polyarthritis can be the initial manifestation of leukaemia, posing a significant diagnostic challenge.7,8 When evaluating arthritis in children, a thorough history regarding the number of affected joints, duration and pattern of pain, relationship to daily activity, previous infections, and potential triggering factors is crucial. In cases of monoarthritis, infectious aetiologies like septic arthritis or osteomyelitis should be carefully considered and excluded. In polyarthritis, initial differentials commonly include acute rheumatic fever, systemic and articular JIA, systemic lupus erythematosus, other connective tissue diseases, and vasculitis. Mechanical causes were excluded in our patient, given the absence of trauma history and unremarkable radiographs. The presence of polyarthritis for over six weeks, rheumatoid factor positivity, and persistently elevated acute phase reactants initially suggested inflammatory causes like systemic and articular JIA. However, the possibility of haematological malignancy, though initially considered less likely, remained in the differential diagnosis. Patients with suspected leukaemia presenting with musculoskeletal complaints, but normal baseline complete blood counts (CBCs) and peripheral blood smears, can be mistakenly diagnosed with a rheumatological condition, potentially delaying appropriate treatment.9 Several warning signs can help distinguish between haematologyoncological malignancies and rheumatic diseases. In leukaemia patients, bone pain is often described as deep, disproportionate to the degree of arthritis, worsens at night (independent of joint pain), and may not respond to analgesics.10 In contrast, JIA typically involves multiple joints with morning stiffness, swelling, and milder pain. Furthermore, peripheral blood smears in JIA often show a predominance of neutrophils, while leukaemia may present with lymphocytosis, or, as in our patient's case, even an initial neutrophilic dominance. The absence of morning stiffness has also been suggested as a more robust warning sign for malignancy.11 Stoll et al. emphasised the need to re-evaluate the diagnosis in patients with joint pain that worsens at night and is unresponsive to treatment, particularly in the context of decreasing leucocyte and platelet counts and a significant increase in LDH values.12 Although antinuclear antibody (ANA) positivity is a known indicator of autoimmune diseases, it's not always helpful in excluding malignancies. In our patient, the worsening nocturnal pain and elevated acute phase reactants, despite a consistently normal peripheral blood smear, were crucial factors that prompted further investigation.

Conclusion:

This case report underscores the critical importance of considering malignancy, particularly ALL, in the differential diagnosis of children presenting with persistent musculoskeletal pain, even when initial laboratory findings, including CBCs and peripheral blood smears, appear normal. The patient's progression to severe, night-time bone pain, coupled with elevated acute phase reactants and bone oedema on MRI, ultimately led to the life-saving bone marrow aspirate that revealed the underlying leukaemia. Delayed diagnosis of ALL can have devastating consequences, impacting treatment efficacy and long-term prognosis. Therefore, in patients with atypical JIA, or those presenting with monoarthritis or polyarthritis accompanied by intense night pain, markedly elevated acute phase reactants, and bone oedema on MRI, bone marrow aspiration should be strongly considered before initiating or continuing treatment for presumed rheumatic conditions, even if rheumatoid factor or ANA positivity is present. A high index of suspicion and a thorough diagnostic approach are essential to ensure the timely and accurate diagnosis of ALL, improving the chances of favourable outcomes for these vulnerable patients. Avoidance of steroids till complete diagnosis is made is very crucial, as steroids can mask the diagnosis, further delaying the treatment. In our case, the rheumatologist who had seen the child earlier did not start steroids, which proved extremely beneficial.

Anamika Bakliwal, Jatin Munjal, Mousumi Kar, Aditi Mittal, Anil Handoo, Rachna Sharma, Sanjeev Kumar

Sharma. Beyond Joint Pain: When Arthritis is a Harbinger of Leukaemia. MMJ. 2025, September. Vol 2 (3).

DOI:https://doi.org/10.62830/mmj2-03-20c

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