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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 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: 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 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.

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