Clin Rheumatol DOI 10.1007/s10067-014-2594-2

CASE BASED REVIEW

Spinal non-Hodgkin’s lymphoma mimicking a flare of disease in a patient with ankylosing spondylitis treated with anti-TNF agents: case report and review of the literature Sara Monti & Nicola Boffini & Marco Lucioni & Marco Paulli & Carlomaurizio Montecucco & Roberto Caporali

Received: 24 March 2014 / Accepted: 25 March 2014 # Clinical Rheumatology 2014

Abstract We report the case of a 52-year-old man with longstanding HLAB27-positive ankylosing spondylitis treated with anti-tumour necrosis factor (TNF) alpha therapy who was admitted to our rheumatology department complaining of increasing lumbar and buttock pain radiating to the posterior thigh, associated with numbness in the leg, gait disturbance and low-grade fever. The clinical picture was initially interpreted as a flare of disease but was not responsive to treatment. A contrast-enhanced spinal MRI was performed with evidence of a diffuse signal abnormality involving the sacroiliac joints and the spine, with evidence of spondylodiscitis of L5 and with a lesion causing L5-S1 root compression and infiltrating the iliopsoas muscle. These findings confirmed the possibility of a reactivation of disease associated with an infectious process. The most frequent causes of infectious spondylodiscitis were excluded, and a biopsy was then performed. Histological analysis revealed a high-grade B-cell non-Hodgkin’s lymphoma of the spine. This case highlights how a differential diagnosis of low back pain with neurological symptoms can be particularly troublesome in ankylosing spondylitis and that continuous vigilance is warranted in patients treated with long-term immunosuppressive therapies.

Keywords Ankylosing spondylitis . Anti-TNF alpha . Lymphoma . Spondylodiscitis S. Monti (*) : N. Boffini : C. Montecucco : R. Caporali Divisione di Reumatologia, IRCCS Fondazione Policlinico S. Matteo, Università di Pavia, Pz.le Golgi 3, Pavia, PV 27100, Italy e-mail: [email protected] M. Lucioni : M. Paulli Divisione di Anatomia Patologica, IRCCS Fondazione Policlinico S. Matteo, Università di Pavia, Pz.le Golgi 3, Pavia, PV 27100, Italy

Introduction Ankylosing spondylitis (AS) is a chronic inflammatory disorder mainly affecting the axial skeleton, the entheses and, occasionally, the peripheral joints. AS generally affects young patients between 20 and 40 years. The prevalence of AS is reported to be between 0.1 and 1.4 % with men being more often affected than women with a ratio of roughly 3:1. There is a strong genetic predisposition with an association with HLAB27. Clinical features characteristically include inflammatory back pain, stiffness and limitation of spinal mobility and chest expansion. Extra-articular manifestations include anterior uveitis and, less commonly, cardiac and pulmonary involvement. Persistent axial involvement can eventually lead to structural and functional impairment with osteoproliferation and ankylosis [1, 2]. The mainstay of treatment for AS is represented by non-steroidal anti-inflammatory agents (NSAIDs) and physiotherapy. In the latest years, new therapeutic options with tumour necrosis factor (TNF) blockers have become available with substantial improvement of pain, function, disease activity and radiologic progression. Longterm efficacy and safety of anti-TNF agents has been reported [1], although controversy exists on the potential predisposing effect on lymphoproliferative disorders associated with longstanding immunosuppression, and continued vigilance is warranted. This topic has been extensively studied in patients with rheumatoid arthritis (RA) with evidence that the increased risk of lymphoma can be attributed more to the disease itself than to treatment [3]; on the other hand, lymphoproliferative disorders have been seldom reported in patients with AS, whether treated with anti-TNF agents or not. We hereby report the case of a patient with AS treated with anti-TNF alpha agents who developed a non-Hodgkin’s lymphoma of the spine, mimicking a flare of disease complicated by an infectious process.

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Case report A 52-year-old man with long-standing HLAB27-positive AS was admitted to our rheumatology department complaining of increasing buttock pain radiating to the posterior thigh, associated with numbness in the leg and gait disturbance. AS was diagnosed in 1994 and treated with Salazopyrin, NSAIDs and physiotherapy with good initial response. During the following years, the disease progressed with diffuse spinal involvement, increasing stiffness and kyphosis. In 2003, a combination therapy with anti-TNF alpha agents (infliximab 5 mg/kg every 8 weeks) and intramuscular methotrexate 10 mg/weekly was started. Stable disease remission was achieved up to 2011. The patient had no peripheral arthritis, no complaint of inflammatory back pain and negative inflammatory markers without signs of extra-articular involvement. Clinimetric scores confirmed good disease control with a Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) of 1; Ankylosing Spondylitis Metrology Index (BASMI) was 4, Ankylosing Spondylitis Functional Index (BASFI) 1.9, and general health (GH) 80; Health Assessment Questionnaire (HAQ) scored 0.8, and pain assessment on a visual analogue scale (VAS) was 1. Methotrexate was stopped at the beginning of 2011 with persistent remission. In May 2011, an attempt to extend the interval between infliximab infusions to 10 weeks was made with good disease control until December 2011, when intense right buttock pain and peripheral arthritis occurred. The symptoms were interpreted as an exacerbation of AS but were not controlled by shortening the infliximab infusion intervals to 8 weeks again. No clinical response was obtained with infliximab infusions every 6 weeks in association with methotrexate. In March 2012, a switch to a different anti-TNF agent (golimumab 50 mg/ monthly) was tried, without the expected results and progression of the right buttock pain to frank sciatica. Inflammatory markers were markedly raised (erythrocyte sedimentation rate (ESR) 70 mm/h and C-reactive protein (CRP) 9 mg/dl); BASDAI was 6.4 and BASMI 7. A low-resolution spinal MRI was performed to exclude compressive myelopathy and was not significant. Sciatic pain was not controlled by conventional analgesic therapy, and only mild relief was achieved with intramuscular steroids. The patient developed low-grade fever and was admitted to our department. The initial physical examination revealed normal vital signs, cardiopulmonary and abdominal findings. There was a deficit in dorsiflexion of the right foot with dysesthesia in the leg and foot, perimalleolar oedema of the right ankle, hypotrophic thigh muscles and positive Lasègue’s sign. Digitopression of L3-L4-L5 spinous processes was painful. Laboratory tests showed a normal full blood count (in particular, WBC 9,670/mm3 with normal differential), CRP 1.4 mg/ dl, ESR 33 mm/h, normal renal and hepatic function. AntiTNF therapy with golimumab was interrupted while awaiting

for a clearer clinical picture. Arterial and venous echocolordoppler of the legs, abdominal ultrasound and Xrays of the foot and ankle were normal. The first spinal MRI taken 2 months earlier was re-evaluated with a confirmed lack of root compression, justifying the patient’s symptoms. A new contrast-enhanced spinal MRI was then performed and showed diffuse signal abnormality: hyperintense on T2weighted and short tau inversion recovery (STIR) images and hypointense on T1, with peripheral contrast enhancement, involving the sacrum, right sacroiliac joint, L5 vertebral body and L5-S1 intervertebral disc, extending to the pedicles of L1, L2 and L3. The lesion completely surrounded the right L5 nerve root and the intracanalicular portion of S1, extending to the soft tissues around the sacrum with infiltration into the right iliopsoas muscle (Fig. 1). The findings could be suggestive of active AS, with bone oedema of the sacroiliac joints and spine, complicated by an infectious process causing spondylodiscitis, given the rapidity of onset with no signs of such lesion 2 months earlier, the extension into the adjacent muscular structures and the immunosuppressive treatment with anti-TNF alpha agents. Subsequent investigations, including haemocultures, Widal-Wright serodiagnosis, IGRA and PPD tests, to exclude tuberculosis (TB) infection were all negative. The patient was not anymore febrile, but sciatic pain, gait disturbances and elevated inflammatory markers were still evident. A paravertebral CT-guided needle biopsy was performed. Cultures from a bioptic material resulted negative, but cytologic findings were suggestive of a lymphoproliferative disorder. The patient was referred to the neurosurgery department for a diagnostic surgical biopsy. While awaiting for the procedure, the patient developed acute urinary retention and saddle anaesthesia due to cauda equina syndrome that required surgical nerve root decompression with partial benefit. Histologic analysis of the specimens confirmed the diagnosis of high-grade B-cell non-Hodgkin’s lymphoma (NHL) (Fig. 2). The patient is still undergoing an intensive polychemotherapy regimen (hyper-CVAD, rituximab and intrathecal methotrexate) in association with radiotherapy with initial response and resolution of sciatic pain and gait disturbances.

Discussion Several systemic autoimmune diseases, including RA and Sjögren’s syndrome, are associated with an increased risk of lymphoproliferative disorders [4]. Long-lasting inflammatory disease activity with persistent B cell proliferation and immune dysregulation represent potentially predisposing factors. However, these data are not confirmed for the AS group, which seems to lack an intrinsic increased risk of lymphoma [5, 6]. The effect of immunosuppressive therapies on the risk of lymphoma remains a matter of debate; conflicting data have

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Fig. 1 Contrast enhancement MRI showing diffuse signal abnormality, hypointense on T1, hyperintense on T2-weighted and STIR images, with peripheral contrast enhancement, involving the sacrum, right sacroiliac

joint, L1-L3 pedicles, L5 vertebral body, L5-S1 intervertebral disc and surrounding the right L5 and S1 root then extending to the soft tissues around the sacrum with infiltration into the right iliopsoas muscle

been published on increased rates of malignancies associated with anti-TNF agents. Case reports have indicated that a rare

but fatal lymphoma (e.g. hepatosplenic) may occur in patients treated with combined thiopurine-TNF alpha inhibitors

Fig. 2 Histological findings. a Diffuse marrow substitution by medium-large size cell infiltration (haematoxylin-eosin, ×10). b CD20 immune stain reaction reveals B cell derivation (LSAB, ×10)

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therapy [7]. Randomized controlled trials (RCTs) have generally provided consistent evidence of efficacy and safety of TNF inhibitors in different rheumatic diseases, including AS [8–11]. Several meta-analyses of RCTs have pooled together safety data from multiple anti-TNF agents, with the advantage of increasing the statistical power to detect changes in the risk of rare events like lymphoproliferative disorders [7, 12]. Nannini et al. [8] reported no cases of malignancy in AS patients treated with etanercept in five randomized placebo-controlled trials. Safety data from 18 randomized trials involving 8,808 RA patients treated with anti-TNF over an average of 0.8 years did not identify a significant increase in the risk of lymphoma, even in the case of combination therapy with methotrexate (OR 1.26; 95 % confidence interval (CI) 0.52–3.06) [13]. Recently, a longterm safety analysis including 23,458 patients exposed to adalimumab in 71 clinical trials in RA, juvenile idiopathic arthritis, AS, psoriatic arthritis, psoriasis and Crohn’s disease was published [14]. The overall malignancy rates were comparable to those expected for the general population; the incidence of lymphoma was increased in patients with RA compared to the general population (standardized incidence ratio (SIR)=2.74; 95 % CI 1.83–3.93), but still within the expected range for RA patients not exposed to anti-TNF therapies. When analysing these data, it could be argued that RCTs may be limited by relatively short duration of exposure to treatment, strict selection criteria and limited patient number and may not represent the general population of patients encountered in clinical practice. Several large observational studies have also assessed the issue of lymphoproliferative disorders and anti-TNF therapies. Data from a Swedish register of patients with RA suggested an increased risk of lymphomas in the anti-TNF group compared to patients treated with traditional disease-modifying anti-rheumatic drugs (DMARDs) (RR 4.9; 95 % CI 0.9–26.2). The authors postulated that the increased risk could be partly explained by higher, longstanding disease activity in the anti-TNF-treated group, leading to some degree of channeling bias [7, 15]. Wolfe and Michaud [16] did not find an increased risk of lymphoma associated with anti-TNF alpha monotherapy or in combination with methotrexate in a large RA cohort of 19,562 patients with 89,710 personyears of follow up. Results from the 3-year prospective French RATIO registry found no significant increase in the risk of lymphoma in patients receiving anti-TNF therapy for spondyloenthesoarthritis [6]. Mariette et al. [17] performed a systematic review and meta-analysis on the risk of malignancies associated with TNF inhibitors in usual clinical practice, analyzing safety data from registries and prospective observational studies including patients with RA, psoriatic arthritis and AS. Treatment with anti-TNF agents was not associated with an increased risk of all-site malignancy, except for skin cancer, with a pooled estimate of 0.95 (95 % CI 0.85–1.05). Pooled estimates on the risk of lymphoma deriving from five RA registries [two US registries (NDBRD [18] and CORRONA [19]), the Swedish (ARTIS [20]), the regional Italian registry (LORHEN [3, 21])

and the French one (RATIO [6])] revealed an increased risk of lymphoma compared to the general population (SIR=2.55; 95 % CI 1.93–3.17). However, consistent with the previous reports, TNF inhibitors did not show an increase in the risk of lymphoproliferative disorders when compared to RA patients treated with classic DMARDs, with a risk estimate of 1.1 (95 % CI 0.70–1.51). There was also no evidence suggesting that a longer duration of exposure to anti-TNF agents increases the risk of developing malignancy. Persistent efficacy and safety of anti-TNF alpha agents (infliximab and etanercept) up to 8 years of continuous treatment in patients with AS has been reported [22, 23]. Data from the Spanish registry BIOBADASER also confirmed a better safety profile of anti-TNF therapy in patients with AS compared to RA, with longer drug survival and lower rates of adverse events [24]. From the previously mentioned evidence, lymphoproliferative disorders do not seem to represent a specific concern in large cohorts of AS patients treated with biologics. Sporadic case reports described the association between lymphomas and AS [25–27]. Rarely, cases of Hodgkin and nonHodgkin’s lymphomas have been described in AS patients treated with etanercept [28–30]. To our knowledge, there are no reported cases of spinal NHL in patients with AS, especially following therapy with anti-TNF agents. Non-Hodgkin’s lymphoma of the spine is uncommon, accounting for only 9 % of spinal epidural tumours. Controversy exists on the origin of the pathological tissue from paraspinal, vertebral or retroperitoneal structures. Lower limb weakness, localized back pain and bladder dysfunction are the most common triad of presentation [31] and were eventually reported by our patient. Differential diagnosis was challenging in this case as several conditions could lead to similar clinical presentations in a patient with AS. A disease flare was suggested by the clinical picture at presentation and was also suggested by the radiologist due to the presence of bone oedema and sacroiliitis on MRI. Relapse after interrupting treatment with anti-TNF alpha is relevant in AS, although re-administration is usually successful [1]. This was not the case of our patient, even after intensifying the therapeutic scheme and switching to a different biological agent. Vertebral fractures either spontaneous or following minor trauma are possible, especially in long-standing AS. Sometimes, they can be associated with haematomas presenting as delayed spinal cord compression [32]. Aseptic spondyodiscitis is a rare complication of established AS and may be associated with neurological complications due to bone instability or granulation tissue growing from the epidural space. Histological analysis is usually diriment, showing fibrosis, reactive bone formation without inflammatory lesions [33]. Infectious spondylodiscitis was also a possible concern, given the increased susceptibility to infections, especially TB, associated with anti-TNF therapy. TNF alpha released from macrophages plays a crucial role in protecting the host against intracellular agents and in the maintenance and

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formation of granulomas in mycobacterial infections [34, 35]. Clinical picture of infectious spondylodiscitis can be similar to our case, usually presenting as a sub-acute illness characterized by back pain typically worsening during the night, spinous process tenderness, sciatic nerve root irritation and fever only in about one half of the cases [36, 37]. In conclusion, our case emphasizes the importance of careful differential diagnosis in patients with AS treated with antiTNF drugs, presenting with symptoms suggestive of an acute exacerbation of the disease. The possibility of an infectious process or, though rare, lymphoproliferative disorders should always be taken into account to avoid incongruous treatments and additional risks for the patient.

Disclosures None. Informed consent was acquired prior to inclusion of clinical data in the paper.

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