Ayumi Okuyama

Lymphomatoid granulomatosis and diffuse alveolar damage associated with methotrexate therapy in a patient with rheumatoid arthritis

We report on a patient of rheumatoid arthritis (RA) who sequentially developed an axillary mass and a fatal interstitial pneumonia during a 2-year course of methotrexate (MTX) therapy. Autopsy revealed a systemic lymph node involvement and the diagnosis of Epstein–Barr virus (EBV)-related lymphoproliferative disease (LPD) with the features of lymphomatoid granulomatosis was made. The lung tissue specimens revealed a typical diffuse alveolar damage (DAD), and small nodules consisting of atypical B lymphocytes showing positive staining for EBV were sparsely recognized only in basal lungs. This is the first report of a RA patient receiving MTX therapy sequentially developing MTX-associated lymphomatoid granulomatosis and DAD.

Fcγ receptor IIIb polymorphism and use of glucocorticoids at baseline are associated with infusion reactions to infliximab in patients with rheumatoid arthritis

Objective Infusion reaction is a major adverse event in patients with rheumatoid arthritis (RA) treated with infliximab. The possible factors including Fcγ receptor (FcγR) polymorphism associated with the development of infusion reactions in patients with RA receiving infliximab were prospectively examined. Methods 96 patients with RA were enrolled and scheduled to receive infliximab at a dose of 3 mg/kg at weeks 0, 2 and 6 and every 8 weeks thereafter. Genetic polymorphisms for FcγR were examined in FCGR3A 176F/V and FCGR3B NA1/2 alleles by allele-specific PCR analysis. Results An infusion reaction was observed in 17 patients (18%) during 52 weeks of treatment with infliximab. The FCGR3B NA1/NA1 genotype was found in 75% of the patients with infusion reactions and in only 37% of those without (p=0.01), whereas the FCGR3A 176F/V genotype was equally distributed in the patients with or without infusion reactions. Glucocorticoids were used in 53% of the patients who developed an infusion reaction and in 80% of those without an infusion reaction (p=0.02). A multivariable logistic regression model showed that the FCGR3B NA1/NA1 genotype and use of glucocorticoids at baseline could be used as independent predictive factors for infusion reactions (OR 6.1 (95% CI 1.9 to 24.3) and OR 0.26 (95% CI 0.08 to 0.84), respectively). The presence of anti-infliximab antibody during infliximab treatment was also associated with infusion reactions. Conclusion FCGR3B NA1/NA1 genotype, use of glucocorticoids and the presence of anti-infliximab antibody accounted for nearly all patients with RA who developed infusion reactions.

Clinicopathologic investigation of methotrexate-induced lymphoproliferative disorders, with a focus on regression

Abstract Although recent accumulative data reveal the clinicopathogenesis of regression in methotrexate-induced lymphoproliferative disorders (MTX-LPDs), the precise understanding including this category remains controversial. In this study, we analyzed 62 patients with MTX-LPD. Forty-three patients showed regression (Reg group), with high rates of Hodgkin lymphoma (HL) and LPD (90 and 88%, respectively). Among the 43 patients of the Reg group, 14 patients (33%) relapsed. The median duration before relapse in the Reg group was 10.6 months. Although the difference of OS between the Reg and Non-Reg groups was not significantly different, relapse-free patients in the Reg group had a superior overall survival (OS). MTX duration had a significant impact on Epstein–Barr virus (EBV) infection (p = .00131). Furthermore, EBV infection was significantly related to clinical manifestations, including spleen invasion, in the regression phenomenon. Some human leukocyte antigens (HLA) alleles might affect MTX-LPD development via EBV infection, although A*2402 and DRB1*0405 might be affected as fundamental factors.

Corticosteroid-free treatment of tocilizumab monotherapy for microscopic polyangiitis: a single-arm, single-center, clinical trial

Abstract Objectives: To assess the efficacy of tocilizumab (TCZ) monotherapy for the remission induction of microscopic polyangiitis (MPA) in a prospective single-arm, single-center, cohort, pilot study. Methods: Eligible patients were aged between 20 and 80 years and were newly diagnosed with MPA according to Watts’ classification algorithm. Seven patients received 8 mg/kg of intravenous TCZ fortnightly for the first 2 months (5 courses), and monthly for the next 10 months (10 courses). One year after TCZ monotherapy, the patients were followed-up without any treatment. The protocol did not permit the use corticosteroids or any other immunosuppressants. Complete remission (CR) was defined as the Birmingham Vasculitis Activity Score of 0 at two consecutive visits made at least a month apart. Results: CR was achieved in two of six patients (33.3%) at 6 months and three patients (50.0%) at 12 months. Two patients were withdrawn: one because of inefficacy at 6 weeks and the other because of flare at 6 months. One patient voluntarily withdrew after CR at 3 months. Four patients (66.7%) could be kept drug-free after 1 year of TCZ without relapse for 6–15 months at the last visit. Conclusion: TCZ monotherapy may be an alternative treatment strategy in some patients with MPA.

Corticosteroid- and cyclophosphamide-free treatment of anti-neutrophil cytoplasmic antibody-associated vasculitis using tocilizumab

the 4 exhibited fi brinoid necrosis in the glomerular capillaries (Figure 1B). Immunofl uorescence and electron microscopy revealed no immune or electron-dense deposits. No fi ndings supporting systemic rheumatoid vasculitis such as hypocomplementemia or extremely high RF were observed. Therefore, we diagnosed the condition as ANCA-associated vasculitis (AAV) complicated by RA. Tocilizumab was initially started at 8 mg/kg/month for RA; after that, systemic symptoms such as fever abated markedly, and polyarthralgia diminished gradually. After 1 year of tocilizumab treatment, serum creatinine levels decreased from 101 to 80 μ mol/L (1.14 to 0.90 mg/dL; GFR MDRD , 62 mL/min/1.73 m 2 ) with no proteinuria. Serum MPO – ANCA and RF levels returned to normal, and repeated renal biopsies demonstrated histological remission according to the absence of active vasculitis. Mononeuritis multiplex improved according to a test of nerve conduction velocity. Interstitial pneumonia did not change after this treatment. Thus, we successfully treated a patient with AAV complicated by RA using tocilizumab without the use of corticosteroids or cyclophosphamide. Several reports have suggested that tocilizumab alleviates small-vessel vasculitis regardless of renal involvement [2 – 4]. On the other hand, tocilizumab-induced immune complex glomerulonephritis or leukocytoclastic vasculitis has been reported in cases of RA [5,6]. However, these factscould not be denied using tocilizumab against AAV. As there are several reports on D-penicillamine-induced AAV, there is a possibility of bucillamineinduced AAV in this case. However, there are no case reports of bucillamine-induced AAV in the literature, and only a few cases of hypersensitivity vasculitis by bucillamine are described in the investigator ’ s brochure. There is a report that ANCA seroconversion could not be induced by penicillamine [7]. In addition, in this case, AAV developed after the cessation of bucillamine. Therefore, it is unlikely that bucillamine might cause AAV in this case. Rituximab may also be a suitable option for systemic vasculitis with RA [8]. However, concomitant corticosteroids are necessary with rituximab for remission induction therapy. Tocilizumab has strong anti-infl ammatory eff ects and may be an alternative to corticosteroids for the treatment of systemic vasculitis. Moreover, tocilizumab normalized serum MPO – ANCA and RF levels in our Mod Rheumatol, 2015; 25(5): 810–811

The aggressive clinical courses of Hodgkin lymphoma primarily diagnosed as methotrexate-induced non-specific lymphoproliferative disorder in patients with rheumatoid arthritis

Recently, attention has been focused on methotrexate-induced lymphoproliferative disease (MTX-LPD), and atypical phenotypes are occasionally documented. We encountered two patients with rheumatoid arthritis (RA) who were diagnosed with non-specific LPD (LPD-nos). Biopsy samples were not obtained during the initial examination when the LPD development was discovered, and the patients achieved a complete response after MTX cessation (case 1) or steroid pulse therapy (case 2). However, the tumors flared up 1.5 years later, and LPD-nos was determined following biopsies of the lymph node (LN, case 1) and liver (case 2). Prednisolone was subsequently administered instead of chemotherapy; however, multiple masses, including in the spine (case 1), and severe icterus with liver dysfunction (case 2) were exacerbated within a few months. Although the re-biopsy of LN proved the presence of HL and radiation followed by aggressive chemotherapy rescued the patient (case 1), the superficially accessible biopsy site was not found, and autopsy finally revealed HL (case 2). In both cases, the underlying pathogenesis along with the B symptoms and laboratory abnormalities suggested MTX-LPD, HL in particular. Therefore, even if the pathological diagnosis does not confirm the specific LPD subtype, the administration of aggressive chemotherapy should be considered if the LPD activity flares severely.

Successful treatment with tocilizumab monotherapy for Takayasu arteritis developing during infliximab therapy in a patient with ulcerative colitis

Abstract A 23-year-old female patient with ulcerative colitis (UC) who had been successfully treated with infliximab (IFX) plus 5-aminosalicylated acid (5-ASA) developed Takayasu arteritis (TAK). She refused to take glucocorticoids to treat TAK. IFX was discontinued, and 8 mg/kg of tocilizumab (TCZ) was added to 5-ASA. Her symptoms such as fever and chest pain disappeared within a week along with serum CRP. TCZ was administered every 2 weeks for 2 months and monthly thereafter. After 1-year treatment of TCZ monotherapy, arterial wall thickening also improved. In addition, UC has been in remission without any gastrointestinal symptoms. TCZ monotherapy is effective for TAK and might not compromise UC.

Efficacy and tolerability of six-week extended dosing interval with tocilizumab therapy in a prospective cohort as remission maintenance in patients with rheumatoid arthritis

Abstract Objectives: To prospectively evaluate the efficacy and tolerability of a six-week extended dosing interval with tocilizumab (TCZ) in patients with rheumatoid arthritis (RA) in sustained remission. Methods: Patients who received over six doses of intravenous TCZ in clinical remission (disease activity score [DAS] 28 – erythrocyte sedimentation rate [ESR] ≤ 2.6) maintained over 3 months between December 2013 and December 2015 were included. Flare was defined as DAS28-ESR >3.2 at two consecutive visits. Results: Twenty-five patients were enrolled; 87.5% achieved clinical remission at week 54 after six-week extension and 95.5% achieved a van der Heijde modified total Sharp score (ΔmTSS) ≤0.5. The Health Assessment Questionnaire Disability Index (HAQ-DI) did not increase during 54 weeks. HAQ-DI at baseline and ΔDAS28-ESR at week six positively correlated with increase in DAS28-ESR at week 54. ΔSwollen joint count at week six positively correlated with ΔmTSS at week 54. A total of 12 adverse events occurring in 10 patients did not lead to cessation of TCZ except for one case of recurrent lymphoproliferative disorder at week five. Conclusion: A six-week extended dosing interval of TCZ for patients with RA in sustained remission is proposed as an acceptable treatment option for maintaining efficacy and tolerability.

THU0576 Tocilizumab Mono-Therapy for Polymyalgia Rheumatica ∼ A Single-Center, Open, Single-Arm Trial

Background Polymyalgia rheumatica (PMR) is a chronic inflammatory rheumatic disease that mainly affects the elderly. Corticosteroids (CSs) are a definite mainstay for the treatment of PMR; however, their use is associated with severe, serious clinical complications, such as osteoporotic fractures, diabetes, hyperlipidemia, cardio-cerebral vascular events, and glaucoma. Therefore, CS-free treatment strategies may be necessary for some patients with PMR. Interleukin-6 (IL-6) may be involved in the pathogenesis of PMR; furthermore, some case reports have already shown the efficacy of tocilizumab (TCZ), an anti-IL-6 receptor antibody, in the treatment of patients with PMR who had been intolerant or refractory to glucocorticoids [1, 2, 3]. Objectives To assess the efficacy and safety of TCZ monotherapy for PMR Methods Thirteen PMR patients (3 males, 10 females) diagnosed by the 2012 ACR/EULAR classification criteria between Jan 2013 and Feb 2015 were enrolled after obtaining a written informed consent. TCZ (8 mg/kg) was administered biweekly for the first 2 months (5 infusions) and every 4 weeks for subsequent 24 weeks. ESR, CRP, visual analog scale (VAS) assessment of the patients global health, and PMR activity score were prospectively measured every 4 weeks and were evaluated at week 24 and 52. Remission was defined as a PMR activity score less than 1.5 as proposed by Leeb [4]. Results Baseline patient characteristics revealed various comorbidities in 11 of the patients; hypertension in seven, hyperlipidemia in five, diabetes mellitus in three, osteoporotic vertebral fractures in two, history of angina pectoris in one, history of brain infarction in one, history of hematemesis due to NSAID ulcer in one, and glaucoma in one patient. At week 24, nine patients achieved low disease activity as per the PMR activity score criteria, including three in remission. Two patients discontinued TCZ because of no response: one at week 6 and the other at week 16. Two patients discontinued TCZ due to adverse events [Editor 1]; pulmonary infiltrate at week 8, pemphigoid at week 50. The nine remaining patients achieved remission at week 52. There were no serious adverse events [Editor 2] except for pemphigoid during the 52-week treatment period. Conclusions TCZ monotherapy was effective in most (nine out of 13 [Editor 1]) PMR patients, although the response was not as rapid as that to CSs. TCZ monotherapy may be a good alternative therapy to CSs for the elderly with various comorbidities. References Unizony S, et al.: Arthritis Care Res 2012; 64(11):1720–1729 Macchioni P, et al.: Aemin Arthritis Rheum 2013; 43(1): 113–118 Toussirot E, et al.: J Rheumatol 2016 43(1): 249–251 Leeb BF, et al.: Arthritis Rheum 2007; 57(5): 810–815 Disclosure of Interest K. Chino: None declared, A. Shibata: None declared, A. Okuyama: None declared, T. Kondo: None declared, J. Kikuchi: None declared, R. Sakai: None declared, H. Takei: None declared, K. Amano Grant/research support from: Chugai Pharmaceutical Co. Ltd.

AB0530 Efficacy and Safety of Multi-Target Therapy Using a Combination of Cyclophosphamide and Tacrolimus in Patients with Refractory Lupus Nephritis: A Prospective, Single-Arm, Open-Label Study of 13 Patients

Background Pulsed cyclophosphamide (pCYC) for lupus nephritis (LN) has limited effects in some cases; mycophenolate mofetil is an off-label pharmaceutical agent in Japan. Objectives To assess the effectiveness of multi-target therapy with pCYC and tacrolimus (Tac) for treating LN, including refractory cases. Methods We have done a prospective, single-arm, open-label study at our center (UMIN4893). Thirteen patients with active LN were enrolled. Prednisolone was started at 1 mg/ kg/day, aiming to reduce the dose to 10 mg/day after 6 months. Intravenous cyclophosphamide was administered as per the Euro-Lupus protocol (500 mg biweekly for 3 months). The trough concentration of Tac was adjusted to 5–10 ng/ml as per National Health Insurance. Complete remission (CR) was defined as a spot urine protein/creatinine (UPCR) ratio of <0.5 g/gCr and normal eGFR or eGFR improvement as per EULAR/ERA-EDTA recommendations and KDIGO guidelines. Results The mean age was 41.5 years (male:female =2:11); UPCR, 3.4 g/gCr; serum creatinine, 1.00 mg/dl; C3, 44.8 mg/dl (90.0–140.0 mg/dl); and C4, 5.7 mg/dl (18.0–30.0 mg/dl). One, eight and three patients belonged to Classes III, IV, and IV + V, respectively, and one had no data. Eleven out of the 13 patients completed the treatment protocol; 2 patients withdrew. The CR at 6 months was 69.2% (n=9/13). Side effects, including infections, did not increase as compared to conventional therapy with pCYC, except a transient increase in serum creatinine with Tac. Conclusions Multi-target therapy such as pCYC and Tac can be a therapeutic option for refractory LN. Disclosure of Interest R. Sakai: None declared, A. Shibata: None declared, K. Chino: None declared, T. Kondo: None declared, A. Okuyama: None declared, H. Takei: None declared, K. Amano Grant/research support from: Astellas, Chugai, Pfizer, Tanabe-Mitsubishi, Consultant for: Zenyaku Kogyo, Paid instructor for: Chugai, Pfizer, Santen, Tanabe-Mitsubishi, Speakers bureau: AbbVie, Actellion, Astellas, Bristol-Myers-Squibb, Chugai, Diichi-Sankyo, Eisai, Pfizer, Tanabe-Mitsubishi