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Modern Rheumatology Case Reports

A case of acute diffuse large B cell lymphoma in an anti-human T-cell leukaemia virus type 1-
positive rheumatoid arthritis patient treated with methotrexate, who died

Naomi Yoshida, Gen Sugiyama, Suzuna Sugi, Koki Satake, Daisuke Wakasugi, Satoshi Yamasaki, Yutaro Mihara, Kotaro Matsuda, Hiroaki Ida, Koichi Ohshima, Rin Yamaguchi & Munetoshi Nakashima

To cite this article: Naomi Yoshida, Gen Sugiyama, Suzuna Sugi, Koki Satake, Daisuke Wakasugi, Satoshi Yamasaki, Yutaro Mihara, Kotaro Matsuda, Hiroaki Ida, Koichi Ohshima, Rin Yamaguchi & Munetoshi Nakashima (2019): A case of acute diffuse large B cell lymphoma in an anti-human T-cell leukaemia virus type 1-positive rheumatoid arthritis patient treated with methotrexate, who died, Modern Rheumatology Case Reports, DOI: 10.1080/24725625.2019.1702493
To link to this article: https://doi.org/10.1080/24725625.2019.1702493
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MODERN RHEUMATOLOGY CASE REPORTS
CASE REPORT
A case of acute diffuse large B cell lymphoma in an anti-human T-cell leukaemia virus type 1-positive rheumatoid arthritis patient treated with methotrexate, who died
Naomi Yoshidaa, Gen Sugiyamab, Suzuna Sugia, Koki Satakea, Daisuke Wakasugia, Satoshi Yamasakia, Yutaro Miharac, Kotaro Matsudac, Hiroaki Idad, Koichi Ohshimac, Rin Yamaguchie and
Munetoshi Nakashimaa
aDivision of Rheumatology, Kurume University Medical Center, Kurume, Japan; bDivision of Gastroenterology, Kurume University Medical Center, Kurume, Japan; cDepartment of Pathology, Kurume University School of Medicine, Kurume, Japan; dDivision of Respirology, Neurology, and Rheumatology, Department of Medicine, Kurume University School of Medicine, Kurume, Japan; eDivision of Pathology, Kurume University Medical Center, Kurume, Japan

ARTICLE HISTORY
Received 23 August 2019
Accepted 26 November 2019

KEYWORDS
Rheumatoid arthritis; methotrexate; lymphoproli- ferative disease; human
T-cell leukaemia virus type 1; diffuse large B-cell lymphoma

Introduction
Rheumatoid arthritis (RA) is an autoimmune disorder presenting with overgrowth of articular synovial tis- sue and destruction of cartilage and bone [1]. Early diagnosis and treatment are desirable to prevent loss of locomotive ability [1–3]. Hence, the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR) RA classification criteria were introduced in 2010, thereby allowing the diag- nosis of RA at an early stage [2]. EULAR recommen- dations for the management of RA were also published at the same time and were updated till 2016 [3,4], which recommend methotrexate (MTX) as the initial disease-modifying anti-rheumatic drug (DMARD) to treat RA, and biologics as second phase DMARDs. With these treatment strategies, the prog- nosis of RA has dramatically improved.
There are adverse effects associated with treat- ment are serious issues in treating RA [5].

Lymphoproliferative disease (LPD) is one of the ser- ious adverse events caused by MTX [6], which was previously called MTX-related LPD, but it is now called immunosuppressive drug-associated LPD (IDR- LPD) because it has been revealed that other immunosuppressive drugs including biological prod- ucts can also cause LPD [6]. The LPD caused by immunosuppressive drugs has been classified as “other iatrogenic immunodeficiency-associated lym- phoproliferative disorders” in the fourth edition of the WHO classification of hematopoietic/lymphoid tissue tumours in 2008 [6]. Importantly, some cases of LPD in patients with RA treated with MTX achieve remission only by discontinuation of MTX. However, there have been cases of LPD that do not improve after withdrawal of MTX and therefore require chemotherapy [7,8].
Human T-cell leukaemia virus type 1 (HTLV-1) is a retrovirus that mainly infects CD4-positive T cells [9].

CONTACT Munetoshi Nakashima [email protected] Division of Rheumatology, Kurume University Medical Center, 155-1 Kokubu-machi, Kurume 839-0863, Japan
© 2019 Japan College of Rheumatology

The virus is involved in the development of adult T-cell leukaemia/lymphoma (ATLL) and HTLV-1- associated myelopathy (HAM)/tropical spastic para- paresis (TSP) [10–12]. HTLV-1 endemic areas include the Caribbean countries, South America, Central Africa, and the southwestern region of Japan [13]. HTLV-1-infected patients are at a higher risk of developing neoplasms probably due to suppressed immunity by infection [14]. Although the precise pathophysiology of anti-tumour immune suppression remains unclear, recent reports implicate that HTLV-1 infection causes changes in the population and func- tions of lymphocytes and dendritic cells [15].
Here, we report a fatal case of rapidly progressive diffuse large B-cell lymphoma (DLBCL) in a HTLV-1 positive patient with RA who had been treated with MTX.

Case presentation
A 70-year-old woman, who was diagnosed with RA at 54 years of age and had been treated with MTX for 16 years, was admitted to our hospital for fever and jaundice. Her RA had been in remission due to the MTX treatment (10 mg/week). Her c-glutamyl transpeptidase (cGTP) level was elevated slightly for one year before the admission; however, the results of other examinations for liver function had been in the normal range, and both abdominal computed

tomography and ultrasonography did not reveal any abnormalities two months before the admission.
She rapidly lost visual acuity of her right eye, and was diagnosed with right optic neuritis by magnetic resonance imaging (MRI) one month before the admission. She was treated with two courses of intravenous methylprednisolone pulse therapy (500 mg) for 3 days, followed by an oral treatment of prednisolone (PSL) (30 mg/day). Despite these treat- ments, her visual acuity did not improve. Her blood tests after the pulse therapy revealed a decreased platelet level (41,000/lL) and a mild increase in lac- tate dehydrogenase (LDH) levels (381 U/L). The dose of PSL was tapered to 20 mg/day three weeks after the pulse therapy (Figure 1).
She was admitted to our hospital for fever and jaundice. Her chest and abdominal physical examina- tions did not reveal any abnormalities. No palpable cervical, axillary, and inguinal superficial lymph nodes were found. Her blood tests showed anaemia and severe thrombocytopenia (Table 1). Biochemical analyses indicated liver dysfunction with bilirubine- mia. Her C-reactive protein (CRP) level was elevated. Serological tests for hepatitis B virus, hepatitis C virus, and cytomegalovirus were negative (Table 1). Examination of her anti-Epstein-Barr virus (EBV) anti- body titre suggested a prior EBV infection. Abdominal ultrasonography revealed numerous swellings of lymph nodes in the hepatic portal

Figure 1. Outline of the clinical course. Methotrexate (MTX) at a dose of 10 mg/week was administered to treat rheumatoid arthritis. Steroid pulse therapy was performed for the treatment of optic neuritis. A slight increase in lactate dehydrogenase (LDH) level and a decrease in platelet count were noted at this time. When the patient was treated with prednisolone (PSL; 20 mg), she developed a fever and jaundice. Ceftriaxone was then orally administered with 20 mg of PSL. On October 11, a malignant lymphoma was suspected because numerous lymph nodes were enlarged in the hepatic portal centre as shown by abdominal ultrasonography and soluble interleukin-2 receptor levels increased to 37,234 U/mL. She died on October 13. mPSL, methylprednisolone.

Table 1. Laboratory data on admission.
Haematology Biochemistry Serological test Infection
aFerritin and sIL2-R determined on the 3rd admission day. bHTLV-1 positive determined after death.
RBC red blood cells, Hb haemoglobin, Hct Haematocrit, MCV: mean corpuscular volume, WBC white blood cells, Neut neutrophils, Lympho lympho- cytes, Mono monocytes, Eosino eosinophils, PLT platelets, PT prothrombin time, APTT activated partial thromboplastin time, TP total protein, Alb albumin, T. Bil total bilirubin, D. Bil direct bilirubin, LDH lactate dehydrogenase, AST aspartate aminotransferase, ALT alanine aminotransferase, ALP, alkaline Phosphatase,c-GTP: c-glutamyl transpeptidase, ChE cholinesterase, AMY amylase, BUN blood urea nitrogen, Cre creatinine, CRP C-reactive protein, RF rheumatoid factor, ACPA: anti-citrullinated peptide antibodies, ANA: antinuclear antibody. MPO myeloperoxidase, PR3 proteinase 3, ANCA anti-neutrophil cytoplasmic antibodies, sIL-2R soluble interleukin-2 receptor, HBsAg hepatitis B surface antigen, HBcAb anti hepatitis B core antibod- ies., HAAb Hepatitis A Virus antibodies, EBV Epstein-Barr virus, VCA virus capsid antigen, EBNA EBV nuclear antigen, CMV cytomegalovirus, HSV Herpes Simplex Virus, HTLV-1/2 Human T-cell leukaemia virus type 1.

Figure 2. Abdominal ultrasonography. (A) Enlargement of the lymph nodes at the hepatic portal centre (circle). (B, C) Enlargement of both adrenal glands. Right: 31.3 × 19.3 mm (B). Left: 37.8 × 34.7 mm (C) (arrows).
region (Figure 2). There was no dilatation of the bile duct, and no stones or tumour. Swellings of the spleen and adrenal gland were also observed. All of the medications, except the 20 mg/day of PSL, were discontinued for their possible adverse effects. Ceftriaxone (2 g/day) was started for suspected sep- sis. Platelet transfusions (10 units) were performed on the 1st and 3rd hospitalisation days. She was then diagnosed with disseminated intravascular coagulation for haemorrhage in her subcutaneous and mucous membrane, and nafamostat (200 mg/ day) was started on the 3rd hospitalisation day. Her general status worsened rapidly, and she died on 5th hospitalisation day (Figure 1). Malignant lymph- oma was suspected for her diagnosis, because of remarkable elevation of soluble interleukin-2 recep- tor (sIL-2R) (37,234 U/mL) and a positive test for anti- HTLV-1 antibody in her sera, which was found to be positive after her death. We also confirmed that the antibodies against all of the examined antigens (gag p19, gag p24, env gp46, env gp21) were positive in her stocked sera by using INNO-LIA HTLV I/II Score (Fujirebio 80627). After her death, we confirmed that there was no family history of ATLL, HAM/TSP, HTLV- 1 associated uveitis.

Autopsy findings
An autopsy was performed after we obtained per- mission from her family. No abnormal findings were observed in her head by autopsy imaging using computed tomography. A macroscopic examination showed enlargement of multiple organs including the liver, spleen, adrenal glands, and systemic lymph nodes. Histological analyses showed invasion of atypical lymphocytes in multiple lymph nodes, the bone marrow, liver, spleen, both lungs, both kidneys, stomach, pancreas, gallbladder, bilateral adrenals, bilateral ovaries, uterine body, and epicardium. Among them, diffuse lymphocyte infiltration was remarkable in the liver with extensive hepatocellular necrosis. Most of her spleen was occupied by invad- ing atypical lymphocytes. The infiltrating lympho- cytes had large nuclei with fine granular chromatin and relatively clear nucleoli. Immunohistochemical analysis revealed that the lymphocytes stained posi- tive for CD20, but negative for CD3, CD4, CD8, CD10, CD56, bcl-2, bcl-6, MUM-1, and TIA-1 (Figure 3). In situ hybridisation study revealed that these infiltrat- ing lymphocytes were negative for EBV infection. The pathological diagnosis was DLBCL, and a clinical

Figure 3. Histological findings. Haematoxylin and eosin staining revealed that heterozygous lymphocytes had large, fine granular chromatin and relatively clear nucleoli (A) (400×; scale bar, 20 lm). Immunostaining revealed that the lymphocytes stained positive for CD20 (E) (200×; scale bar, 50 lm), and negative for CD3 (B) (200×; scale bar, 50 lm), CD4 (C) (200×; scale bar, 50 lm), CD8 (D) (200×; scale bar, 50 lm), CD10, CD56, bcl-2, bcl-6, MUM-1, and TIA-1. The cells also tested negative for EBV (F) (200×, scale bar, 50 lm).

Table 2. Reported cases of LPD onset and autopsy in rheumatoid arthritis patients.

LPD: Lymphoproliferative disorder, EBV: Epstein-Barr virus, HL: Hodgkin lymphoma, DLBCL: Diffuse large B-cell lymphoma, RA: Rheumatoid arthritis, MTX: Methotrexate, ETN: Etanercept, DAD: Diffuse alveolar damage, AML: Acute myeloid leukaemia, HTLV-1: Human T-cell leukaemia virus type 1, N.D.: Not described.

diagnosis of IDR-LPD was made because of her med- ical history of MTX treatment for RA.

Discussion
MTX is recommended as the initial treatment for RA. Biologics or Janus kinase (JAK) inhibitors are used as the second phase treatment when the effect of MTX is insufficient [3]. MTX treatments potentially can cause adverse effects including interstitial pneumo- nia and infectious diseases such as pneumocystis pneumonia [16]. It is also known that LPD often appears during treatments with DMARDs including MTX [6]. Although the pathophysiology of the devel- opment of LPD is unknown, it has been reported that LPD sometimes regresses by discontinuation of MTX [7,17]. Previous reports have shown that reacti- vation of EBV is involved in the development of some IDR-LPDs [18–20]; however, the virus was negative in the lesion of our present case.

There have been 3 studies reporting the results of autopsies of patients with RA plus IDR-LPD (Table 2 [PubMed search with RA þ LPD þ Autopsy]). Kameda
et al. have reported patients with RA treated with
MTX who simultaneously developed EBV-related LPD and diffuse alveolar damage [21]. In their case, the patient died eight months after the onset of LPD. Tokuhira et al. reported a patient with RA who developed acute myeloid leukaemia with multiline- age dysplasia complicated with EBV-associated T-cell LPD without the use of MTX [22], who died 5 weeks after the onset of LPD. Tokuhira et al. also reported a case of EBV-positive Hodgkin lymphoma compli- cated in a patient with RA treated with MTX [23], who died after a week despite the treatment with cyclophosphamide for LPD. However, HTLV-1 was not tested in all these cases. Our case progressed rapidly in 5 days after hospitalisation and died. We initially thought that the patient had ATLL, which is a poor prognostic lymphoma with rapid progression caused by HTLV-1 infection [24]. Serological test for

anti HTLV-1 antibody revealed that she was a HTLV-1 carrier; however, her diagnosis of lymphoma was DLBCL but not ATLL.
The 5-year survival rate of patients with IDR-LPD has been reported to be about 80%, and an aggres- sive and rapid clinical course is unusual [19]. CT and ultrasonography examination performed several months before the liver dysfunction did not show lymphadenopathy in the present case, which high- lights that the growth of lymphoma had been rapid in this case. We speculated that there may have been risk factors that made the lymphoma more aggressive in our case. It has been reported that the high disease activity of RA is a distinct risk factor for LPD in RA, regardless of the dose of MTX [7], but RA was in remission in our case. Other reports sug- gested that the presence of monoclonal immuno- globulin heavy chains in patients aged 70 years and older as well as DLBCL are poor prognostic factors in IDR-LPD [19]. In this case, two of these risk factors (old age and DLBCL) were found.
We also considered the possibility that the HTLV-1
infection accelerated the progression of her DLBCL. Among HTLV-1 carriers, 6–7% of males and 2–3% of females develop ATLL 20–30 years after the infection [9]. On the other hand, persistent infection of HTLV- 1 causes immunosuppression and increases the risk for the development of neoplasms other than ATLL [14]. DLBCL was diagnosed in our case of RA with HTLV-1 infection. DLBCL is the most frequent lymph- oma among non-Hodgkin lymphomas [25], and is more frequent in immune-deficient patients than in the normal immune population [26]. Moreover, Suefuji et al. reported that the 5-year survival rate of patients with early B cell lymphoma was less in HTLV-1 carriers (49%) than in non-carriers (78%) [27]. They argued that B cell lymphoma develops more due to dysfunction of cytotoxic T cells (CTLs), an important subset of T cells for an anti-tumour immune response, because the number of CTLs is decreased in HTLV-1 carriers [27]. Beltran et al. reported that EBV-positive DLBCL in HTLV-1 carriers is identified earlier with lower disease activity, and therefore responds better to therapy compared to that in EBV-negative patients [28], consistent with the results of our case.
These epidemiological investigations on increased
risk of tumours in HTLV-1 carriers imply a link between HTLV-1 and immune suppression. One of the most important factors is a higher HTLV-1 pro- viral load (PVL) in peripheral blood mononuclear cells (PBMCs) from asymptomatic carriers (ACs), which is the independent risk factor for ATL as well as HAM/TSP [29]. However, Iwanaga et al. emphasise the effect of HTLV-1 PVL magnitude on ATLL pro- gression rather than anti-tumour immunity. Recent

cell based research may contribute to the under- standing of the mechanisms of impairment of anti- tumour immunity in HTLV-1 infection. Kattan et al. revealed that the high CTL avidity correlates with low PVL [30]. The authors argue that the quality of CTL is necessary for the efficient control of HTLV-1 in vivo, but we think it is also possible that the high PVL dampens the lytic activity of CTL, an important cell in anti-tumour immunity. Another plausible mechanism that may cause anti-tumour immunity suppression in HTLV-1 carriers is an augmentation of regulatory T cells (Tregs). It is known that ATLL cells are usually positive for CD4, CD25, CCR4, and Forkhead box P3 (Foxp3), a master regulator of Tregs [31,32]. It is important that the percentage of
CD4þFoxp3þ cells in peripheral blood is higher in
HTLV-1 infected population than in uninfected one [33]. Toulza et al. identified CCL22 produced by HTLV-1-infected PBMCs as the chemokine that main- tains the high frequency of CD4þ Foxp3þ T cells in
HTLV-1 infected individuals [34]. Dendritic cells (DCs)
are antigen-presenting cells and are also critical role player in the anti-tumour immunity [35]. Nascimento et al. found that the DC maturation was impaired in HTLV-1 infected patients, but not in non-infected donors [36]. These recent studies suggest that HTLV-
1 infection alters anti-tumour immunity, however, most of these reports do not emphasise the roles of HTLV-1 infection in anti-tumour immunity. This is probably due to insufficient evidence, both in clinical and basic, to support this hypothesis. Further clinical and basic research is required to address what the main pathophysiology of possible suppression of anti-tumour immunity is in ATLL and other tumours in HTLV-1 carriers: natural background (e.g. genet- ical) or HTLV-1 per se.
Unfortunately, we could not conclude pathologic- ally, whether the optic nerve lesion was a lymphoma or not, because the patients family did not permit examination of the central nervous system (CNS). Autopsy imaging analysis of her head by computed tomography did not determine the pathological diagnosis. However, we think that it is possible that her optical involvement was the initial symptom of lymphoma, because her visual loss was not improved by steroid therapy, which is supposed to be effective to treat optic neuritis. There is a report about a primary CNS lymphoma that developed with symptoms of optic neuritis [37]. In the report, the authors concluded that it is difficult to distinguish lymphoma from optic neuritis by MRI [37]. There is also a case report of an HTLV-1 carrier, in whom pri- mary CNS T cell lymphomas developed [38]. Despite these reports, primary CNS lymphoma is found only in 2% of primary CNS tumours [39]. It usually appears in the elderly or in immune deficient

patients such as HIV-infection, immunosuppressive therapy after transplantation or autoimmune dis- eases [40].
Overall, we experienced a case of IDR-LPD in a patient with RA treated with MTX. The case implies a possibility that a HTLV-1 infection can result in a rapid development of IDR-LPD by inhibiting anti- tumour immunity. Further evidence with similar cases is required to elucidate the relationship between the progression of IDR-LPD and HTLV- 1 infections.

Patient consent
Since the patient was deceased, we obtained written informed consent from the patient’s family to pub- lish this manuscript.

Ethical Approval
Not Applicable.

Conflict of interest
None.

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