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A 38-year-old female was referred with a history of fever, polyarthralgia, and bone pain. She was diagnosed with chronic recurrent multifocal osteomyelitis based on imaging and biopsy findings. Non-steroidal anti-inflammatory drugs and bisphosphonate caused no improvement. Then, she developed recurrent diarrhoea and abdominal pain. Genetic testing revealed MEFV mutation. Based on the symptoms and genetic mutation results that emerged during the course of these events, she was diagnosed with familial Mediterranean fever. All symptoms, including bone pain, improved with daily colchicine administration. This case was considered familial Mediterranean fever complicated with a clinical diagnosis of chronic recurrent multifocal osteomyelitis, which is included in the spectrum of pyrine autoinflammatory diseases. Considering this case, patients with chronic recurrent multifocal osteomyelitis with MEFV gene variants may respond to colchicine.

Introduction Abatacept efficacy in older patients with rheumatoid arthritis (RA) has been primarily demonstrated via retrospective comparisons with younger patients. The objective of this study was to compare efficacy of abatacept in older vs. younger patients with RA, and efficacy of abatacept with that of conventional synthetic disease-modifying anti-rheumatic drugs (csDMARDs) in both age groups. Methods This prospective, multicenter, observational study (UMIN000014913) enrolled csDMARD-refractory patients without previous biological DMARD treatment. Abatacept (A) or csDMARDs (C) were administered at the treating physician’s discretion to older (O, ≥ 65 years) and younger (Y, 20–64 years) patients, producing AO, AY, CO, and CY groups. Clinical efficacy after 24 weeks was evaluated using European League Against Rheumatism (EULAR) erythrocyte sedimentation rate response criteria. Results Overall, 202 patients were evaluated. Compared with the CO group, more patients in the AO group achieved a EULAR good or moderate response (p

Objective This study aimed to identify which disease activity parameters may be risk factors for preterm birth (PB) and low birth weight (LBW) in patients with systemic lupus erythematosus (SLE). We also analyzed the extent to which these parameters affected PB and LBW. Methods We collected the SLE Disease Activity Index (SLEDAI), the rate of lupus low disease activity state (LLDAS) attainment, complement levels, and the titer of anti-double stranded DNA (dsDNA) antibody as disease activity parameters. We retrospectively analyzed the associations of these parameters with PB and LBW. Results Sixty pregnancies were included in this study. C3 levels and anti-dsDNA antibody titers at conception were strongly associated with PB ( p = 0.03 and p = 0.01, respectively), whereas C3 and CH50 levels were associated with LBW ( p = 0.02 and p = 0.03, respectively). A logistic regression analysis showed that the cutoff values of C3 and anti-dsDNA antibody for PB were 62.0 mg/dl and 5.4 IU/ml, respectively. The cutoff values of C3 and CH50 for LBW were 87.0 mg/dl and 41.8 U/ml, respectively. The risk of PB or LBW was increased when divided by the cutoff value, and the combination of these cutoff values showed a significantly higher risk of PB and LBW ( p = 0.01 and p < 0.01, respectively). Conclusions PB and LBW are strongly associated with disease activity parameters in patients with SLE. Therefore, strictly monitoring and controlling these disease activity parameters, with or without clinical manifestation, is important for women who want to become mothers.

Recently, mepolizumab, an interleukin (IL)-5 inhibitor, has been indicated for the treatment of eosinophilic granulomatosis with polyangiitis (EGPA) refractory to standard therapies. However, no reports have compared the efficacy of mepolizumab according to symptoms and organ lesions. Herein, we report two cases in which mepolizumab was highly effective in the management of EGPA with lung lesions and otitis media refractory to treatment with multiple immunosuppressive agents. These two cases suggest that mepolizumab is effective in treating pulmonary and ear lesions in EGPA.

Objective To investigate the serum total antibody (immunoglobulin M and immunoglobulin G) titre against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain following BNT162b2 messenger ribonucleic acid (mRNA) coronavirus disease 2019 (COVID-19) vaccination in Japanese rheumatic disease patients undergoing immunosuppressive therapy. Methods The serum antibody titre against SARS-CoV-2 spike protein was analysed in 123 outpatients with rheumatic diseases at Kagawa University Hospital and 43 healthy volunteers who had received 2 doses of the BNT162b2 mRNA vaccine with at least 14 days elapsing since the second dose. Results The antibody titre in rheumatic disease patients was significantly lower than that in healthy subjects (p0.0001). The antibody titres of the 41 patients who received biologics or Janus kinase inhibitors and the 47 patients who received conventional immunosuppressive agents were significantly lower than those of the 35 patients who did not receive immunosuppressive agents (p0.0001 and p0.0001, respectively). In addition, the mean antibody titre of the 43 patients on methotrexate was significantly lower than that of the 80 patients not on methotrexate (p=0.0017). Conclusion Immunogenicity to the BNT162b2 mRNA COVID-19 vaccine in rheumatic disease patients was found to be reduced under immunosuppressive treatment. In particular, methotrexate seems to be associated with a decreased antibody response.

Objective Hydroxychloroquine (HCQ) has been prescribed in Japan only relatively recently and is recommended for the treatment of skin lesions, arthritis and renal lesions according to the Japanese Guideline for the Management of systemic lupus erythematosus (SLE) (2019). However, the associations between the efficacy and safety and the HCQ dose in Japanese SLE patients remain unclear. We investigated the efficacy and safety of different HCQ doses in Japanese SLE patients with a low disease activity who were not receiving immunosuppressants. Methods The disease activity was evaluated using the SELENA-SLEDAI 2011 criteria, the Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) and serum biomarkers. Safety was evaluated via the frequency of adverse events over a period of three months. Results We enrolled 61 SLE patients treated with HCQ and no additional immunosuppressive therapy for more than 3 months. HCQ was administered to 46 patients at the usual dose and to 15 cases at a lower than usual dose. Although the CLASI activity scores decreased significantly in both groups, the magnitude of this decrease was larger in the usual-dose HCQ group than in the low-dose HCQ group. SLEDAI scores and immunological activity were significantly improved only in the usual-dose HCQ group. In addition, changes in the serum complement levels in the usual-dose HCQ group were more dramatic than in the low-dose HCQ group six months after the initiation of HCQ administration. Adverse events were more frequent in the usual-dose HCQ group than in the low-dose HCQ group (30.4% and 13.3%, respectively). Conclusion HCQ therapy is effective for maintenance therapy of SLE patients. The usual dose of HCQ may have some advantage in ameliorating low complement levels.

Background Muscle enzymes are the major noninvasive diagnostic parameters useful in polymyositis/dermatomyositis (PM/DM). Few studies have yet correlated findings on 18F-FDG PET with disease activity in patients with PM/DM. Purpose We evaluated 18F-FDG muscle uptake in patients with PM/DM compared with non-muscular diseases and correlated the results with serum muscle enzymes. Methods A total of 28 patients with untreated PM/DM and 28 control patients with non-muscular diseases were examined with 18F-FDG PET/CT. 18F-FDG uptake was evaluated in 9 proximal skeletal muscle regions bilaterally. The uptake was scored as follows: 0 = less than that of the mediastinal blood vessels, 1 = greater than or equal to that of the mediastinal blood vessels, and 2 = greater than or equal to that of the liver. A score 1 or 2 was considered positive. The mean and maximum standardized uptake values (SUV) were calculated in each muscle and were averaged for all muscle regions. PET findings were correlated with serum muscle enzymes. Results 18F-FDG uptake was observed in 82% of patients with PM/DM and 7% of control patients. The number of positive regions, total score, mean SUVmean, and mean SUVmax in patients with PM/DM were significantly higher than those in the control patients (all P < 0.001). The total score of 2 was the best cut-off value that could discriminate patients with PM/DM from control patients. The total score, mean SUVmean, and mean SUVmax showed significant correlations with creatine kinase (P = 0.047, 0.002, 0.010, respectively) and aldolase (P = 0.036, 0.005, 0.038, respectively). Conclusion 18F-FDG PET/CT using visual and SUV methods demonstrated its usefulness by discriminating PM/DM from non-muscular diseases and correlating with serum muscle enzymes in patients with PM/DM.

Background: Hereditary angioedema (HAE) is an inherited disease characterized by recurrent angioedema without urticaria or pruritus. The most common types of HAE are caused by deficiency or dysfunction in C1 esterase inhibitor (C1-INH-HAE), which has a reported association with systemic lupus erythematosus (SLE). However, not much is known about the clinical manifestations, disease course, and treatment of SLE complicated with C1-INH-HAE.Case presentation: A 31-year-old Japanese woman with a history of swelling of the lips without any specific triggers presented to our institution. She began experiencing swelling of the lips at the age of 14 years. At the age of 20 years, she was diagnosed with C1-INH-HAE on the basis of blood test results showing low C4 and C1 esterase inhibitor activity. At the age of 30 years, she developed malar rash, alopecia, and arthralgia in her hands and elbows. In addition, fever, oral ulcers, and discoid rash on the anterior chest were noted at a follow-up examination 8 months later. Physical examination, laboratory tests, and thorough examination of the organ lesions revealed positive antinuclear antibody, fever, nonscarring alopecia, oral ulcers, malar rash, discoid rash, arthralgia, leukopenia, thrombocytopenia, hypocomplementemia, lupus retinopathy, and nephritis. Based on these findings, she was diagnosed with SLE according to the 2019 European League Against Rheumatism/American College of Rheumatology classification criteria. The patient was initially treated with 20 mg/day prednisolone, and then prednisolone was tapered with the concomitant use of 400 mg/day hydroxychloroquine and 1 mg/day tacrolimus. After the initiation of immunosuppressive therapy, the clinical symptoms associated with SLE improved. At a follow-up examination 7 months later, it was noted that the patient was able to maintain remission of SLE by continuing 7 mg/day prednisolone, 400 mg/day hydroxychloroquine, and 2 mg/day tacrolimus.Conclusions: Our patient presented with a variety of symptoms, including fever and cytopenia in addition to mucocutaneous, joint, ocular, and renal lesions. It is important for physicians to recognize that SLE complicated with C1-INH-HAE can present with various clinical manifestations and organ lesions.

In patients with systemic lupus erythematosus (SLE), a higher frequency of atherosclerotic lesions is associated with poor prognosis. Hydroxychloroquine (HCQ) has been reported to improve the lifespan and the prognosis of dyslipidaemia in patients with SLE, but the mechanism is unclear. We investigated the effect of supplemental HCQ treatment on the levels of serum cytokines associated with atherosclerosis in patients with stable SLE.Patients with SLE who received supplemental HCQ and maintained low disease activity between January 2016 and September 2020 were included in this study. Disease activity was assessed using Safety of Estrogens in Lupus National Assessment-SLE Disease Activity Index, Cutaneous Lupus Erythematous Disease Area and Severity Index, and Lupus Low Disease Activity State. Serum complement titres, anti-dsDNA antibodies, and serum cytokines (adiponectin, resistin, and leptin) were analyzed before and after HCQ treatment.Forty-one patients (4 males and 37 females, mean age 41.3 ± 13.2 years) were included. Serum adiponectin levels were significantly increased after 3 months of HCQ treatment compared to baseline, and serum resistin levels were significantly reduced. The change in serum resistin level after HCQ administration was correlated with a significant reduction in serum TNF-α, interleukin (IL)-6, IL-8, and IL-1RA levels.Supplemental HCQ treatment in patients with SLE improved adipokine levels. HCQ may improve prognosis by controlling disease activity in SLE and reducing risk factors for atherosclerosis. Key Points • Hydroxychloroquine has been reported to improve the prognosis of dyslipidaemia in patients with SLE, but the underlying mechanism is unclear. • In this study, hydroxychloroquine improved adipokine levels in patients with SLE, implicating adipokines as a potential mechanism underlying the benefit of hydroxychloroquine on dyslipidaemia. • Supplemental hydroxychloroquine should be considered in patients with SLE harboring lipid abnormalities and risk factors for atherosclerosis.

We investigated the effect of hydroxychloroquine (HCQ) as an add-on treatment to immunosuppressants on the expression of proinflammatory cytokines in patients with systemic lupus erythematosus. Serum levels of tumor necrosis factor (TNF)-α, interleukin (IL)-2, IL-6, IL-8, vascular endothelial growth factor (VEGF)-A, monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), and interleukin 1 receptor antagonist (IL-1ra) were measured immediately before and 3 months after treatment with oral HCQ. Among the 51 patients enrolled in the study, HCQ treatment led to significantly reduced serum levels of TNF-α, IL-6, IL-8, VEGF-A, IL-1ra, and IL-2 (p

We investigated serum total antibody titers against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor-binding domain after BNT162b2 mRNA vaccination against coronavirus disease 2019 (COVID-19) in Japanese patients taking various immunosuppressive medications for rheumatic disease. In 212 outpatients with rheumatic diseases at Kagawa University Hospital and 43 healthy volunteers (controls), all of whom had received 2 doses of BNT162b2 vaccine, serum antibody titers of SARS-CoV-2 spike protein were analyzed at least 14 days after the second dose. Many of the patients were taking immunosuppressive agents to manage their rheumatic disease. The antibody titers against SARS-CoV-2 spike protein in these patients were significantly lower than those in controls. The analysis of therapeutic agents revealed that the antibody titers in patients treated with rituximab were much lower than those in controls. In patients treated with tacrolimus, baricitinib, azathioprine, mycophenolate mofetil, abatacept, tumor necrosis factor inhibitors, cyclosporine, interleukin-6 inhibitors, methotrexate, or glucocorticoids, antibody titers were moderately lower than those of controls. Interleukin-17 and interleukin-23 inhibitors did not impair the humoral response. In addition, the combination of methotrexate with various immunosuppressive agents reduced titers, although not significantly. In Japanese patients with rheumatic disease, many immunosuppressants impaired the immune response to the BNT162b2 vaccine. The degree of decline in antibody titers differed according to immunosuppressant. When used concomitantly with other immunosuppressants, methotrexate may impair the immune response to the BNT162b2 vaccine. However, immunomodulatory treatments such as interleukin-17 and -23 inhibitors may not attenuate this response in patients with rheumatic disease.

ObjectivesWe investigated the effect of hydroxychloroquine (HCQ) on S100A8 and S100A9 serum levels in systemic lupus erythematosus (SLE) patients with low disease activity receiving immunosuppressants.MethodsSELENA-SLEDAI, Cutaneous Lupus Erythematous Disease Area and Severity Index (CLASI) and serum levels of complement factors, anti-dsDNA antibodies, and white blood cell, lymphocyte, and platelet counts were used to evaluate disease activity, cutaneous disease activity, and immunological activity, respectively. Serum S100A8 and S100A9 were measured at HCQ administration and after 3 or 6 months using ELISA.ResultsS100A8 and S100A9 serum levels were elevated at baseline and the magnitude of decrease from baseline at 3 and 6 months after HCQ administration was greater in patients with renal involvement than in those without (baseline: S100A8, p = 0.034; S100A9, p = 0.0084; decrease: S100A8, p = 0.049; S100A9, p = 0.023). S100 modulation was observed in patients with ( n = 17; S100A8, p = 0.0011; S100A9, p = 0.0002) and without renal involvement ( n = 20; S100A8, p = 0.0056; S100A9, p = 0.0012), and was more apparent in patients with improved CLASI activity scores (improved: S100A8, p = 0.013; S100A9, p = 0.0032; unimproved: S100A8, p = 0.055; S100A9, p = 0.055). No associations were observed for immunological biomarkers.ConclusionHCQ may improve organ involvement in SLE by modulating S100 protein levels, especially in patients with renal or skin involvement.

We examined the effect of biologic disease-modifying anti-rheumatic drugs on the time to pregnancy in patients with rheumatoid arthritis who hope to become mothers. Additionally, we evaluated adverse pregnancy outcomes and risk factors of these drugs. We retrospectively investigated 25 pregnancies of 19 patients who were taking disease-modifying anti-rheumatic drugs. In 15 pregnancies, patients continued biologic disease-modifying anti-rheumatic drugs until conception (group A). In 10 pregnancies, patients discontinued biologic disease-modifying anti-rheumatic drugs and conventional synthetic disease-modifying anti-rheumatic drugs at the time of planning to conceive (group B). We used tumor necrosis factor inhibitors (certolizumab pegol and etanercept) for group A patients. The mean time to pregnancy was shorter in group A than in group B (5.9 ± 3.8 vs 11.0 ± 6.5 months, P = 0.04). The mean birth weight of newborns was lighter in group B than in group A (2446.5 ± 352.4 vs 2969.4 ± 459.9 g, P = 0.007). There were no significant differences in the rates of preterm birth, light-for-date, and premature rupture of the membranes between the groups. In patients with preterm birth or light-for-date newborns, the mean dose of corticosteroids during pregnancy was significantly higher compared with that in those with full-term birth or non-light-for-date newborns (P = 0.02, P

Background Tocilizumab has been shown to be effective for treatment of juvenile idiopathic arthritis (JIA). To our knowledge, this is the first reported case of interstitial lung disease occurring shortly after tocilizumab infusion in a patient with JIA. Case presentation A 14-year-old female patient with polyarticular JIA developed interstitial lung disease after intravenous and subcutaneous administration of tocilizumab. Her condition improved with glucocorticoid therapy. Conclusion Our results suggest that increased interleukin-6 levels in the blood following tocilizumab treatment may be linked to development of interstitial lung disease.

Recently, a unique clinicopathologic variant of multicentric Castleman disease, TAFRO (i.e. thrombocytopenia, anasarca, fever, renal failure or reticulin fibrosis and organomegaly) syndrome, has been identified in Japan. Previous reports have shown that affected patients usually respond to anti-interleukin 6 (IL-6) receptor antibody, but not all patients achieve remission. Here, we present a 62-year-old man meeting the criteria of TAFRO syndrome. Serum, plasma and ascites levels of cytokines, including IL-6 and vascular endothelial growth factor, were markedly elevated. Tocilizumab, an anti-IL-6 receptor antibody, and corticosteroids were initially used to treat the increase in acute inflammatory proteins and the anasarca, resulting in decreased cytokine levels. However, the patient showed a rapidly progressive course of anasarca and ascites, and an increase in acute inflammatory proteins and cytokine levels shortly thereafter. Rituximab, an anti-CD20 antibody, successfully induced remission of disease symptoms and decreased cytokine levels. The patient was successfully treated with rituximab despite being refractory to tocilizumab and corticosteroids. During our patient's clinical course, monitoring cytokine profiles, especially vascular endothelial growth factor, was useful in tracking the disease activity of TAFRO syndrome.

To reveal which disease activity parameters affect low Apgar scores of newborns, which is considered as a predictive parameter for neurological development. We examined retrospectively the data from 42 newborns who were delivered from systemic lupus erythematosus (SLE) mothers from 2006 to 2019. We evaluated whether the disease activity parameters, such as the achievement ratio of lupus low disease activity state (LLDAS), SLE disease activities index (SLEDAI), complement level, titer of anti-double stranded DNA (anti-dsDNA) antibody, therapeutic agents were related with low Apgar scores of newborns. In 42 newborns, adverse pregnancy outcomes, especially preterm birth (16.7%), low birth weight (31.0%) light-for-date (11.9%) were associated with disease activity parameters or prednisolone dose. Apgar scores at 1 minute were related with unachieved LLDAS and the titer of anti-dsDNA antibody at first and third trimester, SLEDAI score and complement level at third trimester, mean prednisolone dose. Apgar scores at 5 minutes were also associated with the titer of anti-dsDNA antibodies at first and third trimester and mean prednisolone dose. Multivariate analysis showed only high titer of anti-dsDNA antibody was significantly associated with low Apgar score at both one minute and 5 minutes. In our retrospective study, high titer of anti-dsDNA antibodies at first and third trimester was a risk factor for low Apgar scores of newborns born to SLE mothers. We considered that high titer of anti-dsDNA antibody influenced on childrens neurological development, therefore, there is a need for long-term follow-up study of SLE offsprings.

Background Antineutrophil cytoplasmic antibodies (ANCA) and Anti-glomerular basement membrane (GBM) antibodies often induce rapidly progressive glomerulonephritis (RPGN). Some reports have demonstrated RPGN with the sequential appearance of ANCA then anti-GBM antibodies, suggesting that ANCA may induce the development of anti-GBM antibodies. Whereas, many reports have shown that the development of ANCA is associated with various infectious diseases, such as non-tuberculous mycobacterial infection. Case presentation A 65-year-old woman with pulmonary non-tuberculous mycobacterial (NTM) infection was monitored without treatment. One year later, serum myeloperoxidase (MPO)- ANCA were elevated (14.1 U/mL (normal value Conclusion This report shows that preceding NTM infection may have induced ANCA and anti-GBM antibodies and caused the development of RPGN.

Background: Connective tissue disease (CTD) often occurs in women of child-bearing age, and flare-ups during pregnancy. Therefore, it is important to manage their disease activities with the treatment which have no influence on fetal growth and development. Among the treatment during pregnancy glucocorticoid is most often used for maintain or control to flare-ups of CTD disease activities. However, prolonged use of glucocorticoid during pregnancy is considered to increase the risk of adverse pregnancy outcomes (APOs) including preterm birth, intrauterine growth restriction, and premature rupture of membrane (PROM) (1, 2). Objectives: The aim of this study is to reveal the dose of glucocorticoid which influences on APOs. Methods: We investigated 164 pregnant patients complicated with CTD from March 2006 to January 2019. All these patients were managed their disease activities throughout pregnancy in our institute. APOs including preterm births, light-for-date (LFD) newborns, PROMs in these pregnant patients were examined retrospectively. We analyzed the association between APOs and the incidence or mean dose of glucocorticoid use during pregnancy. Results: Underlying CTD is Systemic lupus erythematosus (25.3%), Sjogren’s syndrome (24.9%), rheumatoid arthritis (18.1%), Antiphospholipid syndrome (8.8%), mixed connective tissue disease (6.7%), and others. Glucocorticoid was administered in 96 cases, which tended to be earlier gestational week at delivery (37.5±3.0 vs. 38.9±1.5, P Conclusion: Glucocorticoid is often used for CTD patients during pregnancy, however, CTD patients who were treated with continuing high dose of glucocorticoid during pregnancy had high risks for APOs such as preterm birth, low birth weight of newborns, preterm PROM. Our data indicated that the cut-off dose of prednisolone values of preterm birth, LFD, preterm PROM was 7.5 mg, 6.7 mg, 5.0 mg per day respectively. It is important for rheumatologists to pay much attention for these risk of glucocorticoid use to CTD patients who hope to conceive and to manage the disease activity with appropriate dose of glucocorticoid. Recently, many immunosuppressants including biologics have been reported to be available for the safety use during pregnancy, and might be helpful to reduce the risk of APOs by glucocorticoid use. References: [1] Ostensen M, Forger F. How safe are anti-rheumatic drugs during pregnancy? Curr Opin Pharmacol 2013;13:470-5. [2] Gur C, Diav-Citrin O, Shechtman S, et al. (2004) Pregnancy outcome after first trimester exposure to corticosteroids: a prospective controlled study. Reprod Toxicol 18:93-101 Disclosure of Interests: None declared

Background: Some reports revealed that S100A8 and S100A9 proteins were associated with disease activity of lupus nephritis(LN) [1]. However, there have been no reports about the mechanism of additional hydroxychloroquine (HCQ) treatment for systemic lupus erythematosus (SLE) patient with low disease activity. Objectives: To clarify the mechanism of additional HCQ treatment for Japanese SLE patients with low disease activity. Methods: All the 44 patients were enrolled in this study. These patients had been receiving additional oral HCQ sulfate continuously for at least 3 months. These patients had no need for additional immunosuppressants including glucocorticoids, during this study because of their sustained low disease activity for 3 months prior to starting HCQ. Low disease activity was defined as SELENA-SLEDAI score of 8 or less with no activity in major organ systems. As conventional immunological and clinical assessment for SLE disease activity were determined to examine the levels of complement (C3, C4, CH50), anti-dsDNA anti-body, blood cell count, SELENA-SLEDAI and CLASI score. Serum levels of S100A8 and S100A9 reported as novel markers for SLE disease activity[1] were measured using ELISA (CircuLex ELISA Kit, MBL) at the time of HCQ administration as well as 3 months later. In addition, several expressions of cytokines (IFN-α, IFN-γ, TNF-α, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-17, IL-1α, IL-1β, IL-1ra, VEGF, GM-CSF, G-CSF, CCL2, CCL3, CCL4, CXCL) were measured by multiplex assay (Human Luminex assay, R&D systems). Results: We enrolled 44 patients. Prednisolone dose during this study was fixed at the mean of 5.0±2.9 mg per day. SELENA-SLEDAI scores, CLASI scores, anti-dsDNA antibody and serum levels of C3 improved significantly, and serum levels of S100A8 and S100A9 proteins decreased significantly 3 months after additional HCQ treatment. The changes in serum S100A8 and S100A9 levels in SLE patients with LN were more significantly higher than in those without LN. Among these patients, the changes of serum cytokine expressions were measured in 18 patients. The expressions of IFNs were not detected in almost of all patients. Serum levels of TNF-α, IL-6, IL-8, IL-1β, IL-1ra, VEGF, CCL3 and CCL4 decreased significantly 3 months after additional HCQ treatment (Figure1). Seven of 18 SLE patients had a history of LN. These patients have been in sustained complete remission(CR) of LN for over one year(mean duration of CR was 5.0 ± 3.5 years). The reductive effect of additional HCQ treatment on serum S100A9, TNF-α, IL-6 and IL-8 levels was much more apparent in those with history of LN (LN: S100A9, p=0.016, TNF-α, p=0.016, IL-6 p=0.031, IL-8, p=0.031; no LN: S100A9, p=0.065, TNF-α, p=0.083, IL-6 p=0.090, IL-8, p=0.557). The changes of serum S100A8 and S100A9 levels were correlated with those of serum IL-8 and IL-1ra (Figure 2). Conclusion: HCQ could reduce the serum levels of S100 protein and several cytokines in SLE Japanese patients with low disease activity. Recently, some reports showed that novel biomarker including IL-8 or S100 proteins was correlated with severity of LN [1, 2]. Our findings suggest that HCQ treatment without any additional immunosuppressant could reduce the expression of serum S100 proteins, IL-8 and IL-1ra, which were considered to be associated with the improvement of renal and life prognosis. Our data also indicated that S100 protein is closely related to IL-8 or IL-1ra expression in SLE pathogenesis, especially in LN. Farther investigations are needed to more clarify the significance of HCQ treatment in SLE. References [1] P Tantivitayakul, et al. Lupus. 2016(25):38-45. [2] A El-shehaby, et al. J Clin Immunol. 2011(5):848-56. Disclosure of Interests: None declared

Background: Systemic lupus erythematosus (SLE) is an autoimmune disease that occurs in women of childbearing age, and has high risk for adverse pregnancy outcomes (APOs) (1,2). Moreover, it is unclear whether maternal SLE influences the growth and development of children born from SLE mothers. Apgar scores at five minutes is a predictive factor of neurological development of newborns. However, there is no report about the association between maternal SLE and Apgar score of newborns. Objectives: The aim of this study was to identify risk factors for APOs and for low Apgar scores of newborns from SLE mothers. Methods: We investigated 50 SLE patients who were delivered from May 2006 to December 2018 in our institution. We examined retrospectively regarding APOs including spontaneous abortions, preterm births, premature rupture of membranes (PROM), light-for-date (LFD) newborns, and low Apgar scores of newborns. We analyzed the association between disease activity, laboratory findings, treatment agents, and APOs or Apgar scores. Results: As for APOs of SLE mothers, cases with preterm births showed higher SLE disease activity index (SLEDAI) during the first trimester (P = 0.01) and higher titers of anti-double-stranded DNA (anti-dsDNA) antibodies at the time of conception (P Conclusion: In SLE, immunological abnormalities at conception, high SLEDAI and glucocorticoid doses were risk factors for preterm birth and having a LFD newborn. Apgar scores at five minutes were significantly associated with the titer of anti-dsDNA antibodies. Minimizing disease activity before pregnancy may decrease risks for mothers and their newborns. In preconception counseling, it is important for rheumatologists to explain these risk factors to patients with SLE who hope to conceive. There is a need for long-term follow-up studies focusing on the neurological development of children born from SLE mothers. References [1] Clowse ME, Jamison M, Myers E, James AH. A national study of the complications of lupus in pregnancy. Am J Obstet Gynecol 2008;199:127.e1-6. [2] Bundhun PK, Soogund MZ, Huang F. Impact of systemic lupus erythematosus on maternal and fetal outcomes following pregnancy: a meta-analysis of studies published between years 2001–2016. J Autoimmun 2017;79:17-27. Disclosure of Interests: None declared

Background:Connective tissue disease-associated pulmonary hypertension (CTD-PH) is constructed by a variety of pathologies, including cardiac, pulmonary, and vascular involvement, as well as immune abnormalities. Because of its various constructs, it is difficult for many respiratory physicians, cardiologists, and rheumatologists to determine a treatment strategy for CTD-PH. In addition, CTD-PH has different pathologies from iPAH, and there are cases in which immunosuppressive therapy is effective. These suggests that the two PAHs may have different pathogenesis, including inflammation in the pulmonary artery. However, there are not enough biomarkers to distinguish pathologies. On the other hand, it has been reported that various cytokines such as TIMP-1, Interleukin (IL)-6, IL-17, and IL-21 are involved in the pathogenesis of CTD-PH or vasculitis. (1,2) However, the relationship between these cytokine expression and the pathogenesis or treatment of CTD-PH has not been fully clarified.Objectives:To clarify the relationship between cytokine profile and clinical features, change in cytokines and hemodynamics by treatment, association with the effectiveness of immunosuppressive therapy.Methods:Patients suspected PH was included. At the time of cardiac catheterization(RHC), sera in pulmonary pre and post-capillary were collected and TIMP-1, MCP-1, IL-17 and IL-21, IL-12p70 and IL-6 were analyzed by ELISA(ABCAM UK, Ella simple plex USA). The following clinical data were collected: age, gender, underlying disease, complication of interstitial lung disease, treatment (immunosuppressant and pulmonary vasodilator), hemodynamics. Furthermore, we investigated the relationship between cytokines and clinical data.Results:15 cases of CTD-PH, 13 cases of non-CTD-PH, and 6 cases of non-PH were analyzed. (SSc 12 cases, MCTD 7cases, SLE 2 cases, and others 13 cases) 28 cases were diagnosed with PH by RHC. There was a positive correlation between IL-6 and mean pulmonary arterial pressure in all PH case. In addition, MCP-1, IL-6, and TIMP-1 tend to be high in SSc-PH cases. On the other hand, in Non-SSc-PH, IL-12p70 and IL-17 were high. In cases who pulmonary vascular hemodynamics improved by treatment, IL-17, IL-21, and TIMP-1 decreased.Conclusion:Biomarker profiles in pulmonary capillaries may differ depending on the disease. Furthermore, it suggested that IL-17, IL-21 and TIMP-1 may be biomarkers of therapeutic effect.References:[1]Hashimoto-Kataoka T. et al. Proc Natl Acad Sci U S A. 2015 May 19;112(20):E2677-86.[2]Jun Ishizaki et al. Arthritis Res Ther. 2017 Sep 29;19(1):218.Disclosure of Interests:None declared.

Background:It is known that most of ANCA-associated vasculitis (AAV) patients are elderly. A cohort study showed that the mean age of onset was 71.1 years, especially in patients with microscopic polyangiitis (MPA)1). However, the characteristics and prognosis of age-depended AAV patients are still unclear.Objectives:To clarify the differences in age-related characteristics and prognosis between Japanese patients with AAV.Methods:We enrolled 44 patients with AAV who underwent remission induction therapy at our hospital from January 2016 to December 2020. They were divided with under 70 years old group (Results:Mean age were 61.9 ± 9.74 years old in (n=12)≥70 yo (n=32)p valueAge (year)61.9 ± 9.7477.5 ± 4.61< 0.01*Female, n (%)10 (83)28 (87)0.66AAV typeMPA, n (%) / GPA, n (%)6 (50) / 6 (50)26 (81) / 6 (19)0.06Newly diagnosed, n (%)6 (50)27 (84)0.045*ANCA positivity MPO, n (%) / PR3, n (%)11 (92) / 0 (0)30 (94) / 3 (9)1 / 0.55 negative, n (%)1 (8)1 (3)0.48CRP (mg/dl)3.34 ± 4.018.15 ± 6.860.03*eGFR (mL/min)55.8 ± 25.357.7 ± 24.70.93BVAS12.0 ± 8.014.8 ± 6.80.23Remission induction therapyCY, n (%) / RTX, n (%)5 (42) / 7 (58)16 (50) / 16 (50)0.74Maintenance therapy AZA, n (%)7 (58)14 (44)0.50 RTX, n (%)1 (8)6 (19)0.65 others, n (%)2 (17)3 (9)0.60 without IS, n (%)2 (17)9 (28)0.70The p-value was estimated using Fisher’s exact or Wilcoxson rank sum test. yo, years old; AAV, ANCA-associated vasculitis; MPA, microscopic polyangiitis; GPA, granulomatosis with polyangiitis; CY, cyclophosphamide; RTX, rituximab; AZA, azathioprine; IS, immunosuppressants. *pConclusion:There was no difference in remission rate between two groups. Severe infections were observed only in the ≥70 yo group. We suggest that younger AAV patients need attention to relapse after the remission because of lower relapse free survival in References:[1]Sada KE, et al. Arthritis Res Ther 2014; 16: R101.Figure 1.Relapse free survival Relapse free survival was calculated by Kaplan-Meier method and compared by log-rank test. *pDisclosure of Interests:None declared

Background:Recently, there are many reports from Japan about methotrexate associated lymphoproliferative disorder (MTX-LPD). We are investigating the predictive factor of spontaneous regression (SR) in MTX-LPD. On the other hand, FDG-PET/CT is used for diagnosis of LPD including malignant lymphoma. In addition, it was reported that imaging biomarkers such as metabolic tumor volume (MTV) and total lesion glycolysis (TLG) could predict the prognosis of malignant tumor (1, 2). However, there is no report that these imaging biomarkers could predict the SR of MTX-LPD.Objectives:We investigate the usefulness of FDG-PET/CT for predictive factor of SR in MTX-LPD.Methods:We enrolled 24 RA patients who diagnosed MTX-LPD and performed FDG-PET/CT from 2005 to 2019. We divided these cases into spontaneous regression cases (SR group; 15 cases) and cases that treated with chemotherapy after MTX discontinuation (CTx group; 9 cases), and compared the difference as follow subjects between two groups; clinical data including histopathological findings, SUVmax to evaluate malignant tumor activity by FDG-PET/CT, MTV and TLG which refer to metabolically active volume of the tumor segmented FDG-PET/CT. In addition, we analyzed cut off levels, sensitivity and specificity using statistical software JMP.Results:Diffuse large B cell lymphoma (DLBCL) and Hodgkin lymphoma (HL) were 5 and 1 cases in SR group, and 1 and 5 cases in CTx group. In addition, MTV and TLG by FDG-PET/CT was significantly lower in SR group, although SUVmax is no difference between two groups (figure 1). Cut off levels of MTV and TLG were 103.12 ml (sensitivity; 88.9%, specificity; 86.7%) and 361.75 ml (sensitivity; 88.9%, specificity; 86.7%), respectively.Conclusion:We suggested that MTV and TLG were useful for predict of SR in MTX-LPD.References:[1]Chen HH, Chiu NT, Su WC. et al. Prognostic value of whole-body total lesion glycolysis at pretreatment FDG PET/CT in non-small cell lung cancer. Radiology. 2012 Aug;264(2):559-66.[2]Chu KP, Murphy JD, La TH. et al. Prognostic value of metabolic tumor volume and velocity in predicting head-and-neck cancer outcomes. Int J Radiat Oncol Biol Phys. 2012 Aug 1;83(5):1521-7.Figure 1.Comparison of the level of MTV(a) and TLG (b).Disclosure of Interests:None declared

Background:Apremilast, the small-molecule phosphodiesterase (PDE) -4 inhibitor, was approved for the treatment of recurrent oral ulcers associated with Behcet’s disease (BD) in Japan from September 2019, following the success of the phase 3 RELIEF study (1). However, the efficacy of apremilast on domains other than oral ulcers in BD patients is unclear. On the other hand, it has been reported that apremilast may decrease the production of proinflammatory cytokine and increase the production of anti-inflammatory mediators in psoriasis (PS) and psoriatic arthritis (PsA) (2).Objectives:To evaluate the effects and safty of apremilast on clinical symptoms and the changing of serum cytokine expression.Methods:BD patients who had treated with apremilast for active oral ulcers were included in the study. We investigated the improvement rate of oral and genital ulcers, skin lesions, arthritis. In addition, serum cytokines (IFN-γ, IL-10, IL-8, and TNF-α) before and after apremilast treatment were measured using a multiplex immunoassay (Luminex Assay, R&D Systems).Results:Fourteen patients (3 males and 11 females) were enrolled in this study. The mean age was 46.6 ± 13.0 years and the mean duration of disease was 10.2 ± 8.8 years. All patients had active oral ulcers, five had genital ulcers, six had skin lesions, and four had arthritis. Three months after the treatment with apremilast, oral ulcers improved in 13 patients (92.9%). The improvement rates of genital ulcers, skin lesions and arthritis were 60%, 25% and 25%, respectively. Changes in serum cytokines were different from those previously reported in PS. Adverse events were gastrointestinal symptoms such as nausea and diarrhea in 6 patients and sensorineural deafness in 1 patient. Medication was reduced in 2 patients, and discontinued in 1 patient due to nausea and diarrhea.Conclusion:Apremilast is useful not only for oral ulcers, but also for other lesions in BD patients. The effect of apremilast for other domain such as genital ulcers, skin lesions, arthritis was not comparable to that of active oral ulcers. Additionally, BD may have different cytokine profile from PS and PsA.References:[1]Hatemi G, Mahr A, Ishigatsubo Y, et al. Trial of Apremilast for Oral Ulcers in Behcet’s Syndrome. N Engl J Med. 2019;381(20):1918-28[2]Schafer P. Apremilast mechanism of action and application to psoriasis and psoriatic arthritis. Biochem Pharmacol. 2012;83(12):1583-1590Disclosure of Interests:None declared

Background:Previous reports showed that connective tissue disease (CTD) have a high risk for adverse pregnancy outcomes (APOs) such as preterm birth, light-for-date, or preeclampsia1). It was revealed that these APOs were associated with high disease activity or treatment agents, particularly in glucocorticoid2). Some patients, who have no or insufficient preconception care and became unplanned pregnant, exacerbate the underlying disease, and lead to disappointing pregnancy outcomes. Therefore, preconception care and planning for pregnancy is very important to control disease activities and manage the appropriate treatment agents, including glucocorticoid, immunosuppressants, biologics, hydroxychloroquine, and anticoagulants3).Objectives:We investigate whether the presence or absence of preconception care before pregnancy affects clinical disease course and pregnancy outcomes.Methods:We examined 200 CTD women who delivered their newborns in our institution from March 2006 to January 2021. We analyzed the association between preconception care and the clinical course of underlying diseases during pregnancy or pregnancy outcomes.Results:Of all 200 cases, 133 (55.9%) cases had preconception care in our institution, while the others had no or insufficient preconception care. We showed the comparison of treatment agents and pregnancy outcomes between the cases with and without preconception care in Table 1. There was no significant difference in the rate of glucocorticoid use and the mean prednisolone dose during pregnancy between these two groups. However, the rate of increased dose of glucocorticoid or pulse therapy was significantly higher in the cases without preconception care. As for pregnancy outcomes, there was no significant difference in the live birth rate. On the other hand, the gestational weeks at delivery were significantly shorter, and the rate of preterm birth was higher in the cases without preconception care. In addition, the rate of the hospitalization of neonatal intensive care unit (NICU) was also significantly higher in the cases without preconception care.Conclusion:We revealed that preconception care before pregnancy reduced the need for intensified treatment such as increasing dose of glucocorticoid or pulse therapy. The rate of preterm birth and NICU hospitalization was also shown to decrease. Therefore, it is important for our rheumatologists to provide an appropriate preconception care for CTD women of childbearing age and to make a plan for pregnancy.References:[1]Tsuda S, Sameshima A, Sekine M, Kawaguchi H, Fujita D, Makino, et al. Mod Rheumatol 2019:24;1-10.[2]Clowse ME, Magder LS, Petri M. J Rheumaotol 2011;38:1012-1016.[3]Sammaritano LR, Bermas BL, Chakravarty EE, Chambers C, Clowse MEB, Lockshin MD, et al. Arthritis Care Res 2020;72:461-488.Table 1.Comparison of treatment agents and pregnancy outcomes between the cases with and without preconception carePreconception care (+) (n=113)Preconception care (-) (n=89)P valueTreatment agents during pregnancy Glucocorticoid use (n (%))64 (56.6)50 (56.2)1.00 Mean glucocorticoid dose (mg/day)6.3±3.98.4±6.10.09 Dose-up of glucocorticoid (n (%))11 (9.7)26 (29.2) Glucocorticoid pulse therapy (n (%))0 (0)8 (9.0)0.01* Immunosuppressant (n (%))14 (12.5)4 (4.5)0.08 Hydroxychloroquine (n %))7 (6.2)6 (6.7)1.00 Anticoagulant therapy (n (%))21 (18.8)16 (17.8)1.00Pregnancy outcome Spontaneous abortion (n (%))8 (7.1)6 (6.7)1.00 Live birth (n (%))100 (88.5)78 (87.6)1.00 Gestational weeks at delivery (week)38.7±1.437.3±3.50.01* Birth weight of newborn (gram)2888.8±453.72678.4±732.60.25 Adverse pregnancy outcomes (n (%))26 (26.0)28 (35.0)0.20 Preterm birth (n (%))5 (5.0)19 (23.8) Light-for-date (n (%))10 (10.0)9 (11.3)0.81 Hypertensive disorder (n (%))5 (5.0)8 (10.0)0.25 NICU management (n (%))13 (13.0)24 (30.0)Disclosure of Interests:None declared

Background:In systemic lupus erythematosus(SLE), a higher frequency of atherosclerotic lesions is associated with a poor life prognosis (1). Hydroxychloroquine (HCQ) has been reported to improve the prognosis of life and dyslipidemia in SLE (2), and the mechanism has been unclear.Objectives:To determine the effect of HCQ treatment on serum cytokines associated with atherosclerosis in SLE.Methods:SLE patients who received additional HCQ and maintained low disease activity between January 2016 and September 2020 were included in this study. Disease activity was assessed by SLEDAI, CLASI and LLDAS, and serum complement titers, anti-ds-DNA antibodies, serum insulin and serum cytokines (adiponectin, resistin and leptin) were analyzed before and after HCQ treatment.Results:Fifty-four patients (3 males, 51 females, mean age 41.9±12.8 years) were included (Table 1). Thirty-two patients achieved LLDAS at baseline. Serum adiponectin and insulin levels were significantly increased after 3 months of HCQ treatment compared to baseline, and serum resistin levels were significantly lower (Figure 1). Patients with a history of renal disease had greater degree of changes in serum adiponectin and resistin levels. Among SLE patients who did not achieve LLDAS at baseline, those who still did not achieve LLDAS after 3 months had significantly lower serum leptin levels before HCQ treatment than those who achieved it after 3 months.The change of serum resistin levels correlated with those of serum S100A8 levels (r=0.5, p=0.0001).Conclusion:Additional HCQ treatment in SLE patients improves lipid abnormalities. HCQ may improve prognosis by controlling disease activity in SLE and reducing risk factors for atherosclerosis.References:[1]Gregory Katz, et al. Systemic Lupus Erythematosus and Increased Prevalence of Atherosclerotic Cardiovascular Disease in Hospitalized Patients. Mayo Clin Proc. 2019; 94:1436-1443.[2]Laura Durcan, et al. Longitudinal Evaluation of Lipoprotein Parameters in Systemic Lupus Erythematosus Reveals Adverse Changes with Disease Activity and Prednisone and More Favorable Profiles with Hydroxychloroquine Therapy. J Rheumatol. 2016; 43: 745–750.Table 1.Characteristics of SLE patients enrolled in this studyCharacteristicsn=54, no.(%)Female, no(%)51(94)Age, years, mean±SD41.9±12.8Disease duration, years, mean±SD15.1±11.1Past involvementRenal involvement23 (43)NPSLE5 (9)ComplicationAPS10 (19)Dyslipidemia2 (4)Diabetes 1 (2)Concomitant immunosuppressive treatmentsPrednisone No.(%)46 (85) Median Dosage, mg/day (range)5.0 (1-10)Disease activitySLENA-SLEDAI score3.9±2.0 Current skin involvement30 (56) anti-dsDNA positive, no(%)21 (39)low complement, no(%)29 (54)Anti-dsDNA positive means anti ds-DNA titer increases over 12 IU/mlLow complement means any of C3, C4 and CH50 decreases to less 68mg/dl, less 12mg/dl, 30U/ml.APS: Anti-phospholipid antibody syndrome, NPSLE: neuropsychiatric SLE,Disclosure of Interests:None declared

Background:Rituximab(RTX) and Cyclophosphamide(CY) has been indicated for ANCA-associated vasculitis(AAV) as remission induction therapy. However, older age and renal disfunction were independent predictor of treatment related adverse effects in remission induction with CY in recent reports1). Japanese AAV patients are characterized by the predominance of elderly, and the study about comparison of efficacy and safety between RTX and CY in elderly Japanese AAV patients are limited.Objectives:To compare the efficacy and safety between RTX versus CY as remission induction therapy in Japanese AAV patients.Methods:We analyzed 40 cases (20 cases received RTX and 20 cases received CY) who received remission induction therapy in our hospital between January 2016 and August 2019. Clinical and laboratory variables at diagnosis, rates of complete remission(CR) at 6 months, defined as Birmingham Vasculitis Activity Score (BVAS)=0 and prednisone 7.5 mg/day, AAV relapse at 12 months, and adverse effects were investigated.Results:Of 40 patients, mean age was 73.5±9.6 years (6 males and 34 females). Diagnosis of MPA and GPA were 30 cases and 10 cases, respectively. 37 cases (93%) were positive for MPO-ANCA. Treatment regimen was determined by attending physician. Baseline characteristic of each group (RTX group and CY group) are shown in Table1. Baseline charactor, disease activity, organ involvement, and the proportion of patients with relapsing disease were similar in the two treatment groups. At 6 months, there was no difference of remission rate between two groups (RTX: CY = 62%: 44%, p=0.35) (Figure 1). However, mean PSL dosage at 3 months was significantly lower in RTX group (10.0±4.6mg/day) as compared to CY group (15.8±9.5mg/day; p=0.025) (Figure 2). At 12 months, 1 case in CY group and no case in RTX group had relapse. Adverse effects through 12 months are shown in Table 2. 8 infections (30%) in CY group and 7 infections (35%) occurred in RTX group (p=0.64), respectively. 1 case in RTX group had died due to renal failure.Table 1.Comparison of clinical characteristics at baseline between RTX and CY groups.RTX(n=20)CY(n=20)p valueDeath, n (%)1 (5)0 (0)0.50Infections, n (%)7 (35)8 (30)0.46Serious (grade 3), n (%)4 (15)3 (10)0.50Malignancy, n (%)1 (5)0 (0)0.50VTE, n (%)1 (5)0 (0)0.50AMI, n (%)1 (5)0 (0)0.50Leukopenia, n (%)3 (15)3 (10)0.70Necrosis of femoral head, n (%)0 (0)1 (5)0.50Mediastinal emphysema0 (0)1 (5)0.50VTE: venous thrombotic emboli, AMI: acute myocardial infarctionConclusion:We indicated that PSL was tapered more rapidly in RTX group, although there was no difference of remission rate at 6 months and infection at 12 months between RTX and CY therapy. Therefore, remission induction therapy with RTX might be more safety for elderly Japanese AAV patients.References:[1]Little MA, Nightingale P, Verburgh CA, Hauser T, et al. Ann Rheum Dis 2010; 69:1036–1043.Table 2.Adverse effects through 12 months. % = patients with 1 effectsRTX(n=20)CY(n=20)p valueAge, year72.3 ± 11.074.8 ± 8.010.55female, n (%)16 (80)18 (90)0.33AAV type0.14 MPA, n (%)13 (65)17 (85) GPA, n (%)7 (35)3 (15)Newly diagnosis, n (%)7 (35)4 (20)0.24ANCA positivity MPO, n (%)20 (100)17 (85)0.12 PR3, n (%)1 (5)2 (10)0.50 negative, n (%)0 (0)2 (10)0.24 eGFR (mL/min)55.0 ± 29.558.1 ± 21.50.45Organ involvement General, n (%)14 (70)19 (95)0.046* Cutaneous, n (%)1 (5)3 (15)0.30 Eyes, n (%)4 (20)1 (5)0.17 ENT, n (%)5 (25)5 (25)1.00 Pulmonary, n (%)14 (70)15 (75)0.50 Renal, n (%)14 (70)13 (65)0.50 Neurologic, n (%)8 (40)4 (20)0.15BVAS13.8 ± 6.614.1 ± 7.60.73RTX: Rituximab, CY: Cyclophosphamide, ANCA: antineutrophil cytoplasmic autoantibody, AAV: ANCA-associated vasculitis, GPA: granulomatosis with polyangiitis, MPA: microscopic polyangiitis, ENT: Ear, Nose, and Throat, BVAS Birmingham Vasculitis Activity Score, * p Disclosure of Interests:None declared

Background:Lymphoproliferative disorders (LPD) that develop in rheumatoid arthritis (RA) patients treated with MTX (MTX-LPD) is one of the important complications for RA patients. We have previously epidemiologically demonstrated an association between MTX and the development of LPD in RA patients1). MTX-LPD has varied pathologies including various clinical symptom and histological finding. Therefore, we need more information about MTX-LPD. In addition, it is one of the characteristics for MTX-LPD that spontaneous regression (SR) after MTX discontinuation. However, the mechanism of SR is not clarified.Objectives:We collect the information such as clinical symptom and histological finding of MTX-LPD with RA patients, and clarify the clinical features of MTX-LPD. In addition, we investigated the difference between SR cases and cases that treated with chemotherapy after MTX discontinuation (CTx cases).Methods:We enrolled 90 MTX-LPD patients from Kagawa Prefecture, Japan between June 2005 and December 2019. Patients were diagnosed according to American College of Rheumatology (ACR) 1987 classification criteria or ACR/European League Against Rheumatism (EULAR) 2010 classification criteria, and treated with disease modifying antirheumatic drugs (DMARDs) including MTX. We collected as follow information; age, gender, duration of RA, laboratory data (lymphocyte counts and sIL-2R) and treatment of MTX-LPD. In addition, we divided 16 MTX-LPD cases diagnosed histological into two groups (SR:CTx group; n=10:6), and analyzed the histological findings (CD4, CD8, CD163 and CD47) using the staining in immunohistochemistry (IHC) between the two groups. Each positive cell analyzed using virtual viewer soft ImageScope.Results:Characteristics of 90 MTX-LPD patients are as follow; mean age 66.5±11.2 years,63 female, duration of RA 18.5±19.4 years. 65 patients (72.2%) were spontaneously improved by discontinuing MTX. 58 patients (64.4%) were proven MTX-LPD histologically. In these patients, diffuse large B-cell lymphoma (DLBCL) was the most frequent histological type of MTX-LPD (56.9%). Infiltration of CD8 positive lymphocyte in the lesion was significant less in the SR cases than in the CTx cases (Figure 1). However, CD4, CD163 and CD47 positive cells had no significant difference between two groups.Figure 1.CD8 positive lymphocytes in the specimen of lesion using the staining in immunohistochemistry (IHC) between SR and CTxgroup.Conclusion:We revealed clinical features of MTX-LPD with RA patients. In addition, CD8 positive lymphocytes are involved in tumor immunity. In this study, we suggested that the extent of CD8 positive lymphocyte infiltration may predict SR of MTX-LPD. Further study is necessary on revealing the mechanism of SR in MTX-LPD.References:[1]Kameda T. et al. Arthritis Care Res (Hoboken). 2014 Sep;66(9):1302-9.Disclosure of Interests:None declared

Background:Systemic sclerosis (SSc) have various organ involvements including pulmonary hypertension (PH), digital ulcers (DU), and interstitial lung disease (ILD). On the other hand, Nailfold capillary (NFC) abnormalities (enlarged/giant capillaries, fresh or old hemorrhages, avascular areas, ramified/bushy capillaries) detected by capillaroscopy are included in ACR/EULAR classification criteria for SSc as one of important findings. In addition, many studies have reported the relationship between NFC abnormalities and organ involvements (DU, PH) [1][2]. However, there are a few reports about the relationship between NFC abnormalities and ILD.Objectives:We clarify the association with NFC abnormalities and ILD in SSc patients.Methods:We enrolled SSc patients without PH from January 2016 to December 2019 in our institution. SSc patients were diagnosed according to EULAR classification criteria in 2013. ILD was detected by chest CT scans. We assessed severity of ILD with pulmonary function tests (PFT). Abnormal PFT was defined as vital capacity (%VC) or diffusion capacity (DLCO) < 70%. NFC abnormalities were detected with “OptiPiX capillaroscopy Clinic 1.7.x” and the number of capillaries was measured per 1mm in 2nd to 5th fingers of both hand. We defined enlarged and giant capillaries as >30 µm and >50 µm, respectively.Results:We enrolled 59 SSc patients (54 females, 5 males). Mean age is 65.0 ± 8.0 years. Thirty-one patients (52.5%) were complicated with ILD. Mean capillary counts are 6.6/mm. The number of patients with each NFC abnormalities (enlarged capillaries, giant capillaries, microhemorrhages, ramified, avascular areas) are 42, 32, 48, 38, and 33 cases, respectively. Two cases did not have NFC abnormalities. SSc patients with giant capillaries had fewer ILD complications (p Conclusion:We investigated the relationship between NFC abnormalities and ILD conplications in SSc patients. NFC abnormalities are associated with ILD complicacion and severity of ILD. It was suggested that no giant capillary in SSc patients may predict ILD complication. Moreover, no enlarged capillary may predict the severe ILD.References:[1]Valeria Riccieri et al. Systemic sclerosis patients with and without pulmonary arterial hypertension: a nailfold capillaroscopy study. Rheumatology, Volume 52, Issue 8, 1 August 2013, Pages 1525–1528[2]Maurizio Cutolo et al. Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis: A Multicenter, Prospective Cohort Study. Arthritis Rheumatol. 2016 Oct; 68(10): 2527–2539.Disclosure of Interests:None declared

Background:HCQ for SLE in Japan has been administered in many cases after approval. Therefore, the effect of additional administration of HCQ on low disease activity of SLE was considered to be clearer.Objectives:To clarify the effect of HCQ treatment on the control of disease activity in SLE patients.Methods:All SLE patients with low disease activity (LDA) enrolled in this study started additional HCQ treatment from January 2016. All patients with LDA enrolled in this study started HCQ treatment and had been receiving oral HCQ continuously for at least 3 months without using other immunosuppressive treatments or glucocorticoids. Disease activity was evaluated by SLEDAI, CLASI, and LLDAS, and serum complement values, anti-DNA antibodies, and pro-inflammatory cytokines were analyzed as immunological biomarkers before and after HCQ treatment.Results:52 of 100 patients were enrolled in this study (M:F; 4:48, average age; 40.6±13.4). 24 lupus nephritis patients were in sustained remission. 29 patients (56%) achieved LLDAS and 3 patients (6%) achieved clinical remission (CR) before HCQ administration.Of the 20 patients (38%) who did not achieve LLDAS before HCQ administration, the LLDAS achievement rates at 3, 6, and 12 months after additional HCQ were 47%, 59%, and 81% (including 12.5% of CR achievement rates), respectively.Serum levels of MRP8, MRP14, TNF-α, IL-6, VEGF-A, IL-1ra, MIP-1a and IL-2 decreased significantly 3 months after additional HCQ treatment. In addition, serum levels of MRP8, MRP14, TNF-α, IL-6 and IL-2 also decreased significantly 3 months after additional HCQ treatment despite achieving LLDAS or CR. The expressions of IFN-α didn’t decrease significantly in 9 cases that could be detected.The magnitude of the changes in serum MRP8, MRP14, IL-8 and Il-1ra levels in patients with a history of LN was significantly higher than in those without a history of LN. The magnitude of the reduction in serum MCP-1 levels in patients not achieving LLDAS with a history of LN was significantly higher than in those without a history of LN(p=0.046).The change of CLASI activity score was correlated with the change in serum levels of MRP14 and MCP-1 with univariate analysis (MRP14: r=-0.41, p=0.017, MCP-1: r=-0.58, p=0.0006). The change of serum C3 levels had a negative correlation with MCP-1(r=-0.33, p=0.022).The magnitude of the change in serum levels of MRP14, TNF-α, IL-8, MCP-1, MIP-1a and IL-1ra in patients achieving LLDAS were correlated with the change of CLASI activity score with univariate analysis (MRP14: r=-0.49, p=0.041, TNFα: r=0.74, p=0.0038, IL-1ra: r=0.66, p=0.038, MIP-1a: r=0.63, p=0.037, Figure 1). Moreover, the change of serum C3 and C4 levels in them had a negative correlation with the change of serum MCP-1 levels (Figure 2).Figure 1.Correlation between change of CLASI activity scores and serum MCP-1 levels in SLE patients with LLDAS (IL-8: r=0.77,p=,0.0007, MCP-1: r=0.80,p=,0.0001).Figure 2.Correlation between change of serum C3 and C4 levels and serum MCP-1 levels in SLE patients with LLDAS (C3: r=-0.40, p=0.028, C4: r=-0.37, p=0.047).Conclusion:Additional administration of HCQ is useful for cytokine control even in LLDAS-achieved cases, and particularly contributes to the improvement of skin lesion.In addition, regulation of IL-8 and MCP-1 is important for control of renal lesions of SLE, and more control of the activity of SLEThe effect of HCQ on IL-8 and MCP-1 is related to the control of renal lesions in SLE, so that disease activity of more SLE patients might be more controlled disease activity.References:[1]R Wakiya, et al. Hydroxychloroquine modulates elevated expression of S100 proteins in systemic lupus erythematosus. Lupus. 2019;28:826-833Disclosure of Interests:None declared

Background:Recently, several type of biologics such as TNF inhibitors, IL-17 inhibitors, IL-12/23 (p40) inhibitors and IL-23 (p19) inhibitors are approved for PsA. Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) 2015 Treatment Recommendation suggests the treat-to-target strategy for PsA1), however, this recommendation does not indicate how to determine which biologics to use. Recent reports revealed that IL-17 inhibitors were as effective as TNF inhibitors2). On the other hand, based on the Tight Control of Psoriatic Arthritis (TICOPA) study, present treatment strategies for PsA aim to reach on minimal disease activity (MDA)3).Objectives:We investigate the effectiveness of IL-17 inhibitors focusing on MDA achievement which were administered for the Psoriatic Arthritis (PsA) patients in our institution.Methods:We examined 46 patients whom were diagnosed and treated in our institution. We analyzed DAS28-CRP as the evaluation of arthritis and Minimal Disease Activity (MDA) achievement as that of overall disease activity.Results:Biologics were administered in 30 cases (65.2%) of all 46 cases. In 30 cases, 19 cases (63.3%) initiated TNF inhibitors (TNFi) and 7 cases (23.3%) were IL-17 inhibitors (naïve group). In 9 cases, TNFi were switched into Il-17 inhibitors (switch group), 7 cases continued TNFi (TNFi group). Patients characteristics in the cases which could collect the data were shown in Table 1. As for arthritis, DAS28-CRP has significantly improved at fourth weeks in naïve and TNFi group. In switch group, DAS28-CRP has not demonstrated significant improvement, however, IL-17 inhibitors were effective for the cases to which they were initiated for arthritis. As for MDA, 71% and 78% have also achieved MDA at twentieth weeks in both naïve and switch groups. In the TNFi group, 67% have not achieved MDA at twentieth weeks because of no improvement of rash (Figure 1). In switch group, all cases to which IL-17 inhibitors were initiated for either arthritis or rash have achieved MDA, however, 40% of cases which were introduced for both arthritis and rash have not achieved MDA.Table 1.Comparison of clinical characteristics at baseline in 3 groups.Il-17 naïve group (n=7)IL-17 switch group (n=9)TNF group (n=7)p valueAge, year60.7 ± 18.953.8 ± 15.450.7 ± 13.6N.SDisease duration, year20.3 ± 25.817.4 ± 9.59.9 ± 12.4N.SMale, n (%)3 (43)6 (67)5 (71)N.SMTX, n (%)2 (29)4 (44)5 (71)N.SCRP(mg/dl)0.41 ± 0.501.87 ± 3.131.07 ± 1.77N.SSwollen joint count6.7 ± 7.33.6 ± 4.26.2 ± 6.9N.STender joint count6.6 ± 7.02.2 ± 2.66.9 ± 9.0N.SPatient pain VAS55.7 ± 22.347.1 ± 34.935.4 ± 13.6N.SBSA (%)12.5± 17.37.7 ± 14.87.4 ± 7.2N.SBiologics, nSecukinumab: 2Ixekizumab: 5secukinumab: 3Ixekizumab: 5Brodalumab: 1Infliximab: 3Adalimumab:3Etanercept:1TNF: Tumor Necrosis Factor, MTX: Methotrexate, VAS: visual analog scale, BSA: body surface area, N.S: not significantConclusion:In our study, IL-17 inhibitors could bring high rate of MDA achievement for both naïve and switch from TNFi. We suggest that TNFi should be switched into IL-17 inhibitors rapidly in the case of ineffective for TNFi.References:[1]Coates LC, Kavanaugh A, Mease PJ, et al. Arthritis Rheumatol. 2016;68:1060-71.[2]Miyagawa I, Nakayamada S, Tanaka Y. Curr Rheumatol Rep. 2019 20;21:21.[3]Coates LC, Moverley AR, McParland L, et al. Lancet. 2015 19;386:2489-98.Disclosure of Interests:None declared

Background:Pulmonary hypertension associated with connective tissue disease (CTD-PH) has complicated pathology including immune abnormalities, cardiac and pulmonary lesions. Therefore, it is difficult for rheumatologist to manage CTD-PH. We hesitate to use immunosuppressants in addition to pulmonary vasodilators to treat CTD-PH. Although there is a report that the cytokine such as Interleukin (IL)-6, IL-17 and IL-21 are involved in the development of PH1), changes in the hemodynamics of theses cytokines with treatment are not clear.Objectives:We investigate serum cytokine profile and clinical appearance in CTD-PH, and clarify the relationship between change in cytokines and hemodynamics before and after treatment.Methods:14 cases of CTD-PH (8 cases in Scleroderma; SSc-PH group, 4 cases in Mixed connective tissue disease; MCTD-PH group, 2 cases in Systemic lupus erythematosus; SLE-PH group), 6 cases in Other-PH group, and 2 cases of SSc without PH as controls were included. The following clinical data were collected: age, gender, underlying disease, complication of interstitial lung disease, treatment (immunosuppressant and pulmonary vasodilator). Serum samples in pre- and post-capillary before and after treatment were collected during cardiac catheterization examination. Serum cytokines (MCP-1, IL-6, IL-17 and IL-21) of these samples were measured by ELISA (ABCAM, UK).Results:Serum MCP-1, IL-6, and IL-21 levels were higher in SSc-PH group than in the other groups. Conversely, serum IL-17 levels tended to be higher in non-SSc group compared to SSc-PH group. Additionally, serum MCP-1 levels in SSc-PH group decreased in post-capillary as compared to pre-capillary. Furthermore, patients with decreased serum IL-17 and IL-21 levels before and after treatment showed improved pulmonary hemodynamics.Conclusion:SSc-PH had a different cytokine profile compared with non-SSc-PH. We suggested that the serum IL-17 and IL-21 levels effect the hemodynamics in CTD-PH.References:[1]Hashimoto-Kataoka T. et al. Proc Natl Acad Sci U S A. 2015 May 19;112(20):E2677-86.Disclosure of Interests:None declared

Background Systemic lupus erythematosus(SLE) is deeply associated with not only acquired immunity but also innate immunity throughout toll like receptors(TLRs) signalling. Among many TLRs, TLR7 and TLR9 were reported to be closely associated with IFN-α production which contributed the pathogenesis of SLE. On the other hand, several reports demonstrated that S100A8 and S100A9 proteins which was known as one of damage-associated molecular patterns(DAMPs), were associated with disease activity of lupus nephritis. These proteins were also shown to reflect the treatment response by immunosuppressive therapy for SLE. 1 2 However, there is no report about the effect of hydroxychloroquine(HCQ) on S100A8 and S100A9 proteins expression. Objectives To find a new biomarker of treatment with HCQ, we focused on expression of S100A8 and S100A9 proteins in SLE. Methods We enrolled all SLE patients treated with HCQ in the absence of additional immunosuppressive therapy more than 3 months in our institute from Jan 2016 to Dec 2017 Serum levels of S100A8 and S100A9 proteins were measured by ELISA(CircuLex ELISA Kit, MBL) at the screening, 3 months and 6 months after HCQ administration. Disease activity of SLE was measured using the SLENA-SLEDAI 2011 Cutaneous disease activity was evaluated by Cutaneous Lupus Erythematosus Disease Area and Severity Index (CLASI). Immunological activity was examined by the levels of complement (C3, C4, CH50), anti-dsDNA anti-body and counting blood cell. Results 61 patients were enrolled in this study. HCQ was administered 48 cases with usual dose(based on ideal weight), 15 cases with low dose than usual dose (table 1). CLASI was improved by the treatment with HCQ independent of HCQ dose. However, the effect of HCQ on SLENA-SLEDAI and immunological biomarker was shown in the patients treated with usual dose HCQ, not shown in those treated with low dose HCQ. On the other hand, serum levels of S100A8 and S100A9 proteins were significantly elevated in SLE patients with renal lesion(p=0.02). These proteins were significantly decreased by the treatment with HCQ regardless of the HCQ dose(p Conclusions HCQ reduced the expression of serum S100A8 and S100A9 proteins, which reflected SLE disease activity especially in skin lesion. The measurement of S100A8 and S100A9 proteins is novel predictive biomarker for the efficacy of HCQ treatment on skin lesion in SLE patients. References [1] Tyden H, et al. Pro-inflammatory S100 proteins are associated with glomerulonephritis and anti-dsDNA antibodies in systemic lupus erythematosus. Lupus2017;(26):139–149. [2] Tantivitayakul P, et al. Elevated expressions of myeloid-related proteins-8 and -14 are danger biomarkers for lupus nephritis. Lupus 2016;(25):38–45. Disclosure of Interest None declared

Background Myositis-specific autoantibody (MSA) and myositis-associated autoantibody (MAA) are often detected in dermatomyositis (DM) and polymyositis (PM), and are useful diagnostic markers. In addition, autoantibodies are reportedly related to clinical symptoms, including skin findings, muscle symptoms, and interstitial lung disease, and provide information useful for medical treatment. However, the clinical significance of the presence of multiple MSA/MAA and anti-Ro52 autoantibodies has not been determined. Objectives The purpose of our study was to clarify the clinical significance of multiple MSA/MAA and anti-Ro52 autoantibodies. Methods We enrolled 58 patients diagnosed with DM and PM at Kagawa University Hospital. PM and DM were diagnosed according to the Bohan and Peter criteria.1 The patients were analysed for MSA (anti-Mi-2, anti-Jo-1, anti-SRP, anti-PL-7, anti-MDA5, anti-TIF1γ, anti-PL-12, anti-EJ, and anti-OJ) and MAA (anti-RNP, anti-Ku, and anti-PM-Scl) by ELISA (MESACUP anti-ARS, MDA5 and TIF1γ test, MBL, Nagoya, Japan) and Line blot (EUROLINE Myositis Profile 3, EUROIMMUN, Lubeck, Germany). We extracted MSA/MAA(+) and anti-Ro52(+) patients and analysed the association between the presence of multiple MSA/MAA or anti-Ro52 autoantibodies and patients’ clinical features (skin findings such as Gottron papule, heliotrope rash and mechanic’s hand, interstitial lung disease, malignancy, and arthritis). Results 53/58 patients were positive for MSA/MAA, followed by anti-Ro52 (n=27), anti-PL7 (n=12), anti-Jo1 (n=8), anti-PM-Scl75 (n=7), anti-Ku (n=6), anti-SRP (n=4), anti-EJ (n=4), anti-TIF1γ (n=4), anti-MDA5 (n=4), anti-Mi2 (n=3), anti-PL12 (n=1), anti-PM-Scl100 (n=1), and five cases were MSA/MAA(-). Five patients had multiple MSA/MAA (anti-PL-7+anti-Jo-1, anti-PL-7+anti-PL-12, anti-PL-7+anti Ku, anti-Ro52 +anti-Jo1+anti-PM-Scl75, and anti-Ro52 +anti-Jo1+anti Ku). In patients with DM/PM, anti-Ro52(+) patients were complicated by interstitial lung disease (ILD) and had a higher KL-6 value at onset (p Conclusions We hypothesise that the presence of multiple MSA/MAA may be useful for predicting ILD. However, in this study, anti-Ro52 autoantibodies did not correlate with ILD and myositis. Reference [1] Bohan, A., Peter, J.B., 1975. Polymyositis and dermatomyositis (second of two parts). N. Engl. J. Med. 292, 403–407. Disclosure of Interest None declared

Background Connective tissue diseases (CTD) patients have various clinical manifestation including pulmonary hypertension (PH) and digital ulcer (DU). Especially, Raynaud’s phenomenon (RP) is one of the common symptoms. On the other hand, “abnormal nailfold capillaries” are important as the findings that suggest RP associated with CTD. They are included in one of the items of classification criteria for Sclerderma (SSc) in 2013 Classification Criteria for Systemic Sclerosis (ACR/EULAR) 1). Recently, some reports presented the usefulness of nailfold capillaroscopy (NFC) in SSc 2). NFC findings showed enlarged/giant capillaries, fresh or old haemorrhages, avascular areas, ramified/bushy capillaries. These findings are known as “scleroderma pattern” features. Additionally, there are some reports that nailfold capillary density in SSc related with DU, PH and interstitial pneumonia (IP). In this study, we clarify the association between nailfold capillary density and clinical manifestation by analysis of the case in our institution. Objectives To clarify the association between nailfold capillary density and clinical manifestation. Methods We enrolled Japanese SSc patients from May 2016 to May 2017 in our institution. We measured total nailfold capillary count per 1 µm from second to fifth finger by NFC “OptiPiX Capillaroscopy Clinic 1.7.x”. In addition, we investigated relationship with NFC findings and clnical manifestation such as current and previous DU, PH and IP. Results We enrolled 42 SSc patients. Total nailfold capillary counts significantly decreased, especially in SSc patients with, previous DU (ρ=−0.4122, p=0.0054), and PH (ρ=−0.3226, p=0.0023). In addition, there is significant difference between DU and existence of giant capillaries (ρ=0.3019 p=0.0464), existence of avascular areas (ρ=0.4057 p=0.0063). On the other hand, there is no significant difference between IP, PH and other “scleroderma pattern” features. Conclusions Our study revealed that total nailfold capillary counts were associated with PH and DU in SSc patients. We suggest that nailfold capillary density may most predict complications with SSc patients. References [1] Markus Mueller, et al. Relation of Nailfold Capillaries and Autoantibodies to Mortality in Patients With Raynaud Phenomenon. Circulation. 133:509–517, 2016. [2] Maurizio Cutolo, et al. Nailfold Videocapillaroscopic Features and Other Clinical Risk Factors for Digital Ulcers in Systemic Sclerosis. Arthritis & Rheumatology. 68 (10): 2527–2539, 2016. Disclosure of Interest None declared

Background Recently, many connective tissue disease (CTD) patients wish to become a mother because immunosuppressants and biologics enable to improve the outcome of underlying CTD and quality of life respectively. However, Pregnancies in CTD patients often have problems including underlying disease exacerbation, some complications during pregnancy especially in preterm birth, light for date (LFD) and premature rapture of membrane (PROM). Previous study identified that high clinical activities with hypocomplementemia and positive anti-dsDNA antibody were at highest risk for pregnancy loss and preterm delivery in SLE1). It is unclear whether these problems are associated with the activity of underlying CTD or immunosuppressant treatment. Objectives We examine the issue of pregnancy and delivery complicated with CTD by the analysis of the cases in our institution. Methods We investigated the risk factors of preterm birth, LFD (light for dates) and perinatal complication from exacerbation of underlying disease, anti SS-A antibody, antiphospholipid antibody, doses of corticosteroid, immunosuppressants or biologics before pregnancy in 142 cases which were delivered in our institution. Results In 23 among all cases underlying diseases were exacerbated, and these occurred more often in PM/DM (60%), MCTD (33.3%), RA (15.3%) and SLE (13.3%). In SLE, SS, MCTD and PM/DM, preterm births and LFD were closely related to disease exacerbation and dose of corticosteroid, pulse therapy, and these were extracted as risk factors for these perinatal complications. Preterm birth was also associated with low complement (CH50) and high titer of anti-dsDNA antibody, and LFD was associated with high titer of anti-dsDNA antibody before pregnancy. However, there was no significant association with these factors in threatened premature delivery and PROM. In RA, perinatal complications were not influenced by methotrexate and biologics before pregnancy. However, only LFD was related with doses of corticosteroid during pregnancy. Conclusions We extracted disease exacerbation and dose of corticosteroid, pulse therapy during pregnancy and also low complement, high titer of anti-double stranded DNA antibody before pregnancy as risk factors of pregnancy outcomes. In pregnancy complicated with CTD, we need to control the disease activity strictly, however, we should consider the increase or pulse therapy of corticosteroid carefully. References Clowse ME, Maqder LS, et al. The clinical utility of measuring complement and anti-dsDNA antibodies during pregnancy in patients with systemic lupus erythematosus. J Rheumatol. 2011 Jun; 38(6):1012–6. Disclosure of Interest None declared

Background Patients with rheumatoid arthritis (RA) have a high risk for lymphoproliferative disorders (LPDs). An LPD in a patient treated with methotrexate (MTX) is known as MTX-associated LPD (MTX-LPD), which is classified among immunodeficiency-associated lymphoproliferative disorders (ID-LPD) as “other iatrogenic ID-LPD” in the 2008 World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissues (1). We previously reported that MTX is an independent risk factor for LPD onset in Japanese patients with RA (2). In MTX-LPD, MTX withdrawal can result in spontaneous regression of LPD. In addition, limited evidence indicates that Epstein–Barr virus infection is related to spontaneous regression of MTX-LPD. No biomarker has been identified that predicts spontaneous regression of MTX-LPD. Objectives To identify a biomarker that predicts spontaneous regression of MTX-LPD in RA patients. Methods We enrolled RA patients from Kagawa Prefecture, Japan, who developed MTX-LPD during the period from June 2010 through December 2016. RA was diagnosed in accordance with the American College of Rheumatology 1987 classification criteria and was treated with disease-modifying antirheumatic drugs, including MTX. The patients were divided into two groups: those followed-up after discontinuation of MTX alone (MTX withdrawal group) and those who received chemotherapy at 1 month or later after MTX discontinuation (chemotherapy group). The following variables were compared between groups: change in peripheral lymphocyte subsets after MTX discontinuation, serum soluble interleukin-2 receptor, and lymphocyte subsets and Epstein–Barr virus–encoded RNAs in a biopsy specimen from a lesion. Results We enrolled 43 MTX-LPD patients (29 in the withdrawal group and 14 in the chemotherapy group). From among these groups, we selected 32 patients for analysis of changes in peripheral lymphocyte subsets (23 in the withdrawal group and 9 in the chemotherapy group) and 22 for analysis of lymphocyte subsets in a lesion specimen (11 each in the withdrawal group and chemotherapy group). Peripheral lymphocyte counts were significantly higher after MTX discontinuation in the withdrawal group. Analysis of lymphocyte subsets from lesion specimens revealed significantly higher CD8-positive lymphocyte counts in the chemotherapy group than in the withdrawal group. Conclusions Lymphocyte count differed before and after MTX discontinuation, and a higher CD8-positive lymphocyte count in a lesion specimen was associated with spontaneous regression of MTX-LPD. These findings may help identify a predictive marker for MTX-LPD treatment and management. References Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, et al., WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. IARC Press, Lyon, 2008. Association of higher methotrexate dose with lymphoproliferative disorders onset in rheumatoid arthritis patients. Kameda T, Dobashi H, Miyatake N, Inoo M, Onishi I, Kurata N, Mitsunaka H, Kawakami K, Fukumoto T, Susaki K, Izumikawa M, Nakashima S, Shimada H, Takeuchi Y, Haba R, Mano S, Onishi H, Imataki O, Matsunaga T. Arthritis Care Res (Hoboken). 2014 Sep;66(9):1302–9. Disclosure of Interest None declared