Clin Rheumatol DOI 10.1007/s10067-014-2697-9

CASE BASED REVIEW

T cell ALL presenting as seropositive rheumatoid arthritis: case report and review of the literature on seropositive paraneoplastic arthritis Catherine E. Handy & Glenda Robles & Uzma Haque & Brian Houston

Received: 21 May 2014 / Accepted: 23 May 2014 # Clinical Rheumatology 2014

Abstract We present the case of a 61-year-old female with an acute onset of polyarthritis involving the wrists, hands, knees, and ankles. Associated systemic symptoms included fever, weight loss, and lymphadenopathy. Serologic workup revealed positive rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP) antibodies. Radiograph imaging of her bilateral hands and wrists showed erosive joint disease and lymph node, and bone marrow biopsy confirmed a diagnosis of T cell lymphoblastic leukemia. Our case demonstrates a unique clinical phenotype of paraneoplastic arthritis and is only the second reported case of RF, anti-CCPpositive arthritis related to a hematological malignancy. We review the only three published cases of seropositive paraneoplastic arthritis. In each case, systemic symptoms or a poor response to steroid treatment triggered additional workup. These cases highlight the importance of careful clinical assessment and vigilance to rule out secondary causes of inflammatory arthritis, even in patients with seropositive erosive arthritis. Keywords Arthritis . Paraneoplastic arthritis . Seropositive arthritis C. E. Handy (*) Department of Medicine, Johns Hopkins Hospital, 1830 East Monument Street, Suite 920, Baltimore, USA e-mail: [email protected] G. Robles Department of Pathology, Johns Hopkins Hospital, Baltimore, MD, USA U. Haque Department of Rheumatology, Johns Hopkins Hospital, Baltimore, MD, USA B. Houston Department of Cardiology, Johns Hopkins Hospital, Baltimore, MD, USA

Introduction Rheumatologic disorders including inflammatory myopathies, arthritides, Raynaud’s phenomenon, scleroderma, and lupus-like syndromes can present as paraneoplastic processes [1]. Paraneoplastic arthritis is theorized to result from cross reactivity of autoantibodies, direct effect of the neoplasm, or by an unknown underlying cause contributing to both diseases [1]. Paraneoplastic arthritis occurs more frequently in elderly patients, can precede cancer diagnosis by up to 1 year, progresses rapidly, and usually responds to treatment of the underlying malignancy [1]. Joint involvement tends to be asymmetric, oligo or polyarticular, with knee, ankle, hand, and wrist joints being most commonly involved [2].

Case presentation A 61-year-old African-American female with a past medical history of hypertension presented to our emergency department with abrupt onset of neck swelling, dysphagia, and diffuse joint pain and swelling over the course of a few weeks. She was diagnosed with angioedema related to an ACEinhibitor and discharged home on a course of steroids and a new antihypertensive regimen. Over the next 4 weeks, her dysphagia improved but she had persistent neck swelling and worsening joint pain, unresponsive to non-steroidal antiinflammatory medications and oral steroids. She also noted decreased appetite, generalized fatigue, and an unintentional 20-lb weight loss. Her generalized weakness and joint pain were progressive and debilitating, and she re-presented to our emergency department for further evaluation. Her past medical history was significant for osteoarthritis of bilateral knees. During the initial evaluation of knee pain about 10 years prior to current presentation, she had a laboratory workup that showed normal ESR, negative ANA, and

Clin Rheumatol

Fig. 1 Radiographic views of the left and right wrists, respectively. Tiny cystic changes versus erosions were noted in the scaphoid bone of the right wrist and triquetrum and scaphoid bones of the left wrist; 92× 76 mm (300×300 DPI)

evidence of moderate degenerative arthritis on knee X-rays. She was treated with physical therapy, joint injections, and NSAIDS with some improvement. Eventually, she underwent elective bilateral knee replacement in 2006 and 2008 with improvement in her symptoms afterwards. She noted no previous history of adenopathy, pleuritis, pericarditis, ulcers, or rashes. She had no animal exposure or insect bites. She denied any fever, visual, gastrointestinal, or upper respiratory complaints. She had a remote history of tobacco use but no alcohol or illicit drug use. She had no other relevant family or personal history of rheumatologic or oncologic disease. On presentation, she had a temperature of 38.8 °C, pulse of 105/min, blood pressure of 128/78 mmHg, and 22 respirations Fig. 2 Axillary lymph node biopsy specimen with hematoxylin and eosin staining at ×40 magnification showing malignant immature proliferating T cell origin lymphocytic cells (a, black arrow) which were also present on bone marrow biopsy (b, also hematoxylin and eosin staining at ×40 magnification). To determine cell-type origin, CD3 staining of the bone marrow biopsy was done and was strongly positive suggesting T cell origin (c, ×10 magnification); 150× 94 mm (300×300 DPI)

per minute and oxygen saturation was 98 % on room air. On physical exam, she had tender palpable submental, supraclavicular, and posterior occipital lymphadenopathy, up to 3 cm in size. She had active synovitis of bilateral wrists, left first and second MCP, right first and second MCP, right third, bilateral knees, and left ankle. There was no tenderness over her long bones or spine. No skin rash was noted. On initial laboratory investigation, her white blood cell count was 2,810/mm3, hemoglobin 9.1 g/dL, hematocrit 28 %, and platelets of 342,000/mm3. Her creatinine was 0.8 mg/dL. Urinalysis had 1+ protein, with no cells, bacteria, or crystals. HIV, EBV, blood, and urine cultures were all negative. Her uric acid level was 4.2 mg/dL. Antinuclear antibody test was 1:80, ESR 122 mm/h, and CRP 7.1 mg/ dL. Rheumatoid factor (RF) and anti-cyclic citrullinated protein (anti-CCP) were elevated at 1,148 IU and 242 U respectively. Radiographs of her hands and wrists showed cystic changes versus delicate erosions in the carpal bones and cysts in the left ulnar styloid (Fig. 1). She was treated with an empiric course of intravenous antibiotics and NSAIDs without improvement. CT imaging of the neck through pelvis showed bulky diffuse lymphadenopathy. Axillary lymph node biopsy showed a T cell lymphoblastic leukemia (confirmatory pathology seen in Fig. 2). Immunohistochemical staining was positive for CD3, CD5, CD7, and BCL2 and negative for CD20, CD10, CD8, CD4, and BCL6. She was transferred to oncology and started on hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, and dexamethasone) chemotherapy. Unfortunately, her disease was refractory to three different chemotherapy regimens. Repeat bone marrow biopsies were positive for significant disease and she continued to have

Clin Rheumatol Table 1 Published cases of RF and CCP-positive paraneoplastic arthritis with clinical features of arthritis and clinical outcomes Malignancy

Age

Sex

Duration of symptoms preceding cancer diagnosis (months)

Location of synovitis

Reference

Lung adenocarcinoma Lymphomatoid granulomatosis Pancreatic cancer T cell ALL

45 40 58 61

F M M F

3 3–4 2 1–2

Elbows, MCP, PIP, knees Knees, ankles, wrists No synovitis Wrists, MCP, knees, ankle

[4] [5] [6]

prominent joint symptoms with synovitis and pain. She died 8 months after diagnosis.

Discussion Solid tumors are most commonly associated with paraneoplastic arthritis, lung cancer being the most often associated malignancy [3]. While seronegative paraneoplastic arthritis is well described in literature, to our knowledge, there have been only three case reports of paraneoplastic inflammatory arthritis with RF and anti-CCP positivity. The first case reported was a 45-year-old woman with a 3-month history of swelling and stiffness of multiple small joints of the hands and feet, and synovitis of the elbows, MCPs, PIPs, and knee joints. On further workup, she was found to have pleural effusions and mediastinal and hilar adenopathy and was ultimately diagnosed with adenocarcinoma of the lung [4]. The second case was a 40-year-old man who presented with symmetric, diffuse polyarthritis and a maculopapular rash. Symptoms initially responded to steroid therapy but later worsened and skin biopsy led to the diagnosis of lymphomatoid granulomatosis [5]. The third case was a 58-year-old man who presented with 8 weeks of arthralgia involving the hands, wrists, single elbow, shoulders, neck, and back. He showed an initial response to steroids but then had recurrence of symptoms along with abdominal pain, weight loss, and a poor appetite and was found to have metastatic pancreatic cancer [6]. All three cases, summarized in Table 1, were seropositive for RF and antiCCP antibodies, and none were reported to have erosive joint disease. All of these cases, including ours, were found to have late stage malignancies with unsuccessful treatment of the malignancy and articular symptoms. Our patient presented with both high-titer RF and anti-CCP levels as well as delicate carpal erosions and met the 2010 RA criteria for rheumatoid arthritis (RA) [7]. While RF positivity is relatively nonspecific, anti-CCP antibodies are highly specific for RA and predict erosive disease [8]. These antibodies are formed against citrullinated peptides that are exposed to the immune system after peptidylarginine deiminase (PAD) enzymes convert target peptides from dying cells to citrullinated peptides in inflamed joints [8]. Specific

peptidylarginine deiminase enzymes have been shown to be upregulated in malignant solid tumors and lymphomas and in patient’s serum producing citrullinated peptides associated with tumorgenesis [9]. Citrullinated peptides due to overexpression of PAD enzymes in malignant tissue could potentially provide the antigenic stimulation leading to anti-CCPpositive paraneoplastic arthritis. Erosive disease associated with paraneoplastic arthritis has never been described in the literature. Our case demonstrates a unique clinical phenotype and is the second case of RF, anti-CCP-positive arthritis related to hematological malignancy. The rapid onset of polyarthritis, associated constitutional symptoms, and bulky lymphadenopathy triggered additional workup in our patient. Given the close temporal relationship between the onset of arthritis and lymphadenopathy, explosive and rapid progression of symptoms, and poor response to NSAIDs and steroids, we believe that our case represents paraneoplastic arthritis. Unfortunately, our patient had an aggressive malignancy, poorly responsive to treatment, and thus, we cannot establish if the arthritis would have responded to successful treatment of underlying cancer. Our case illustrates the need for careful clinical assessment and vigilance to rule out secondary causes of inflammatory arthritis, even in patients with anti-CCPpositive erosive arthritis.

Disclosures None

References 1. Racanelli V, Prete M, Minoia C, Favoino E, Perosa F (2008) Rheumatic disorders as paraneoplastic syndromes. Autoimmun Rev 7:352–358 2. Kisacik B, Onat AM, Kasifoglu T et al (2014) Diagnostic dilemma of paraneoplastic arthritis: case series. Int J Rheum Dis. doi:10.1111/ 1756-185X.12277 3. Mok CC, Kwan YK (2003) Rheumatoid-like polyarthritis as a presenting feature of metastatic carcinoma: a case presentation and review of the literature. Clin Rheumatol 22:353–354 4. Larson E, Etwaru D, Siva C, Lawlor K (2011) Report of anti-CCP antibody positive paraneoplastic polyarthritis and review of the literature. Rheumatol Int 31:1635–1638 5. Raja R, Lamont D, Yung A, Solanki K (2010) A can of red herrings. Int J Rheum Dis 13:e46–e50

Clin Rheumatol 6. Kumar S, Sethi S, Irani F, Bode BY (2009) Anticyclic citrullinated peptide antibody-positive paraneoplastic polyarthritis in a patient with metastatic pancreatic cancer. Am J Med Sci 338:511–512 7. Kay J, Upchurch KS (2012) ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford) 51(Suppl 6):vi5–vi9

8. van Venrooij WJ, van Beers JJ, Pruijn GJ (2011) Anti-CCP antibodies: the past, the present and the future. Nat Rev Rheumatol 7:391–398 9. Chang X, Han J, Pang L, Zhao Y, Yang Y, Shen Z (2009) Increased PADI4 expression in blood and tissues of patients with malignant tumors. BMC Cancer 9:1471–2407, 9-40

T cell ALL presenting as seropositive rheumatoid arthritis: case report and review of the literature on seropositive paraneoplastic arthritis.

We present the case of a 61-year-old female with an acute onset of polyarthritis involving the wrists, hands, knees, and ankles. Associated systemic s...
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