Postpartum onset anti-MDA5 antibody-positive clinically amyopathic dermatomyositis; case-based review of perinatal onset anti-MDA5 antibody-positive dermatomyositis.

Anti-melanoma differentiation-associated protein 5 (MDA5) antibody positive clinically amyopathic dermatomyositis (CADM) is a subtype of inflammatory myopathy associated with a distinct clinical phenotype, characterized by rapidly progressing interstitial lung disease and limited muscle involvement. Although cases with onset of anti-MDA5 antibody positive CADM during pregnancy or the postpartum period are rare, they present unique challenges due to a potential pregnancy complications and the possible severity of the disease course. We present a case of anti-MDA5 antibody positive CADM that developed during the postpartum period following childbirth without any pregnancy complication. Additionally, we conducted a comprehensive review of case reports and series of similar cases to elucidate the clinical characteristics and outcomes. Our analysis revealed considerable variability in disease presentation, ranging from severe cases requiring multi-targeted therapy to well-controlled cases with less demanding treatments. The scarcity of evidence in this population underscores the importance of accumulating evidence from case series to inform treatment strategies. More precise prediction tools are needed to effectively manage this rare subset of patients.

An overlapping case of IgG4-related disease and systemic lupus erythematosus treated with belimumab: a case-based review.

IgG4-related disease (IgG4-RD) is a systemic condition in which IgG4+ plasma cell infiltration and fibrosis cause organ swelling and lead to diverse clinical manifestations. Although IgG4-RD typically responds to glucocorticoids (GCs), relapse during tapering occurs and an early GC-sparing approach might therefore be beneficial. Systemic lupus erythematosus (SLE) is a chronic inflammatory disease with multiple symptoms that is also treated with GCs as a first-line therapy. Recently, belimumab, a recombinant human IgG-1λ monoclonal antibody that inhibits B-cell activating factor, was approved, but reports of use for IgG4-RD are scarce. Here, we present a rare case of IgG4-RD complicated with SLE which was successfully treated with belimumab. A 67-year-old man was diagnosed with IgG4-RD based on a high serum IgG4 level and histopathological findings. Furthermore, he had pericardial effusion on echocardiography, and laboratory tests revealed thrombocytopenia, autoimmune hemolysis, positive anti-nuclear antibodies, positive anti-DNA antibodies, and hypocomplementemia. These data led to an SLE diagnosis. Treatment was started with prednisolone at 40 mg/day, plus hydroxychloroquine, which initially improved both the SLE and IgG4-RD symptoms. During the GC tapering, belimumab was added and clinical symptoms resolved completely. Our case and the literature review summarize reported rare overlapping cases of IgG4-RD and SLE and suggest that belimumab is a promising candidate for the treatment of IgG4-RD.

Clinical importance of anti-Ro52 antibody for polymyositis and dermatomyositis.

OBJECTIVES: To clarify clinical features of anti-Ro52 antibody (Ab)-positive polymyositis (PM)/dermatomyositis (DM). PATIENTS AND METHODS: We retrospectively examined clinical features and status of anti-Ro52 Ab in patients with PM/DM admitted at the University of Tsukuba Hospital between January 2019 and February 2023. We compared anti-Ro52 Ab-positive and -negative groups. RESULTS: A total of 40 patients were selected and analyzed. Median age at diagnosis was 61.5 (48.8-69.3) years and 34 cases were female. Twenty-three cases were PM and 17 cases were DM (including 6 clinically amyopathic dermatomyositis: CADM). Twenty-two cases were positive for anti-Ro52 Ab, 14 for anti-ARS Ab, and 6 for anti-MDA5 Ab. Interstitial lung disease (ILD) was detected in 29 cases, 9 of which were rapidly progressive. Glucocorticoid (GC)-resistant cardiomyopathy was detected in 6 cases, malignancy in 3 cases, and Sjögren's syndrome (SS) in 4 cases. Of the 22 anti-Ro52 Ab positive cases, only 3 were single-positive and the remaining 19 cases simultaneously had other autoantibodies. Comparing the anti-Ro52 Ab-positive and -negative groups, the frequencies of anti-ARS Ab positivity (63.6% vs. 0%), ILD (95.5% vs. 44.4%), GC-resistant cardiomyopathy (27.3% vs. 0%), concomitant use of immunosuppressants (95.5% vs. 55.6%), and levels of C-reactive protein (CRP) were significantly higher in the anti-Ro52 Ab-positive group (p<0.05). The frequencies of PM/DM, positivity of anti-MDA5 Ab, malignancies, and SS were comparable between groups. CONCLUSION: Anti-Ro52 Ab were frequently positive in PM/DM and anti-Ro52 Ab-positive patients showed significantly higher rates of anti-ARS Ab positivity and ILD, GC-resistant cardiomyopathy, concomitant use of immunosuppressants, and higher levels of CRP. Anti-Ro52 Ab may be useful as a severity marker in PM/DM.

Safety of tacrolimus use during pregnancy and related pregnancy outcomes in patients with systemic lupus erythematosus: A retrospective single-center analysis in Japan.

OBJECTIVE: Tacrolimus is one of the drugs that can be used in pregnancies complicated with systemic lupus erythematosus (SLE), but there are still few reports on its pregnancy outcomes. Although tacrolimus has been reported to cause adverse events, such as increased blood pressure, abnormal glucose metabolism, and susceptibility to infection, there have been no studies on the impact of tacrolimus in SLE pregnancies at these points. We performed a retrospective observational study of pregnancies complicated by SLE at St Luke's International Hospital in Tokyo from April 2003 to August 2021. METHODS: Basic clinical information on SLE, pregnancy outcomes, disease activity before and after pregnancy, laboratory results, blood pressure, blood glucose levels, treatment regimens, and presence of infection was extracted from electronic medical records. We defined overall adverse pregnancy outcomes (APOs) as follows: (1) fetal death after 10 gestational weeks, (2) preterm delivery, (3) delivery due to hypertensive disorders of pregnancy, preeclampsia, or placental insufficiency, or (4) the diagnosis of small for gestational age infants. We also examined whether there was a statistical difference in APO incidence between patients treated with and without tacrolimus. RESULTS: Pregnancy outcomes were obtained for 48 patients with a total of 60 pregnancies complicated by SLE. In 20 (33.3%) of these pregnancies, the patients took tacrolimus, and 28 (46.7%) of the pregnancies had APOs. APO incidence did not statistically differ between the tacrolimus and non-tacrolimus groups in the multivariate analysis (p = 1.00, adjusted OR 1, 95% CI: 0.23-4.39). Multiple regression analyses indicated that tacrolimus use did not significantly affect systolic blood pressure in the third trimester (B = -2.23, p = .74) or blood glucose levels in the first trimester (B = 10.2, p = .056). Incidence of infections did not significantly differ between patients treated with and without tacrolimus in the univariate analysis (10.8% vs. 21.1%, p = .42). CONCLUSION: Tacrolimus did not significantly affect pregnancy outcomes, blood pressure, or glucose levels. Further research is required to confirm its effects in a larger population.

Risk of adverse pregnancy outcomes in Japanese systemic lupus erythematosus patients with prior severe organ manifestations: A single-center retrospective analysis.

BACKGROUND: Systemic lupus erythematosus (SLE) increases the incidence of adverse pregnancy outcomes (APOs). Nevertheless, most of the data on SLE pregnancies were derived from database studies in which details of the pregnancies were unavailable, and no consensus exists on the risk of APO in patients with prior severe organ manifestations. METHODS: SLE patients followed by rheumatologists and gynecologists throughout pregnancy at our institute were retrospectively identified, and their data between April 2003 and December 2020 were reviewed from electronic records. We assigned patients based on the presence of prior severe organ manifestation (renal/neurological manifestation, prior treatment with methylprednisolone pulse therapy/prednisolone 1 mg/kg/day/biological or cytotoxic therapy) and compared the incidence of overall and serious APO (maternal death, pregnancy loss, preterm birth <32 weeks, birthweight <1500 g, Apgar score <7 at 5 min and birth defect). RESULTS: This study included 34 pregnancies in 32 patients; 23 pregnancies in 22 patients were classified as SLE with prior severe organ manifestation. There was no statistical difference in the incidence of overall APO between the two groups (52.2% vs 45.5%, P = 1). Among patients with prior severe organ manifestation, 17.4% had serious APO. A detailed electronic health record search revealed specific causes of APO in all pregnancies with serious APO, except the presence of prior severe organ manifestation. CONCLUSION: The incidence of overall APO in SLE patients was not affected by prior severe organ manifestation. Although the incidence of serious APOs increased in patients with previous severe organ manifestation, there were other risk factors for poor pregnancy outcomes besides prior lupus severity. Therefore, proper management by rheumatologists and gynecologists may enable patients with prior severe organ manifestation to safely deliver healthy babies.

Effect of remission, clinical remission with active serology, and glucocorticoid dosage on the pregnancy outcome of pregnant patients with systemic lupus erythematosus.

BACKGROUND: Remission is a key treatment target in systemic lupus erythematosus (SLE) management. Given the direct correlation between lupus flares and elevated risks of adverse pregnancy outcomes (APOs), securing remission before conception becomes crucial. However, the association between clinical remission with active serology, and the risk of APOs is not thoroughly understood. Additionally, determining the optimal glucocorticoid dosage during pregnancy to mitigate APO risks remains under-researched. This study investigated the risk of APOs in relation to remission/serological activity status in patients in clinical remission/glucocorticoid dosage. METHODS: Pregnant patients with SLE, who were followed up at two Japanese tertiary referral centers, and had their remission status assessed at conception, were included in this study. We categorized the patients into two groups based on whether they achieved Zen/Doria remission at conception and analyzed the APO ratio. We also examined the influence of serological activity in pregnant patients with clinical remission and analyzed the optimal glucocorticoid dosage to minimize the APO ratio. RESULTS: Of the 96 pregnancies included, 59 achieved remission at conception. Pregnant patients who achieved remission showed a significant decrease in the APO ratio compared with those who did not. (overall APO: odds ratio (OR) 0.27, 95% confidence interval (CI) 0.11-0.65, p < 0.01, maternal APO: OR 0.34, 95%CI 0.13-0.85, p = 0.021, neonatal APO: OR 0.39, 95%CI 0.17-0.90, p = 0.028). Conversely, no statistical difference was observed in the APO ratio based on serological activity in pregnant patients with clinical remission. (overall APO: OR 0.62, 95%CI 0.21-1.79, p = 0.37, maternal APO: OR 1.25, 95%CI 0.32-4.85, p = 0.75, neonatal APO: OR 0.83, 95%CI 0.29-2.39, p = 0.73). A glucocorticoid dose of prednisolone equivalent ≥ 7.5 mg/day at conception correlated with increased APO. (overall APO: OR 3.01, 95%CI 1.23-7.39, p = 0.016, neonatal APO: OR 2.98, 95% CI:1.23-7.22, p = 0.016). CONCLUSIONS: Even with active serology, achieving clinical remission can be a clinical target for reducing APOs in patients who wish to conceive. In addition, if clinically feasible, reducing the glucocorticoid dosage to < 7.5 mg/day before conception could be another predictive factor.

A retrospective analysis of the safety of tacrolimus use and its optimal cut-off concentration during pregnancy in women with systemic lupus erythematosus: study from two Japanese tertiary referral centers.

BACKGROUND: Tacrolimus is one of the major treatment options for systemic lupus erythematosus (SLE) and is considered to be a pregnancy-compatible medication. Since little is known about tacrolimus safety during pregnancy complicated by SLE, this study was designed. METHODS: We included SLE pregnant patients who were followed up at two Japanese tertiary referral centers. We performed multivariate logistic regression analysis to assess each adverse pregnancy outcome (APO) risk. Moreover, we assessed the influence of tacrolimus on the APO ratio in pregnant patients with lupus nephritis, and the impact of combined tacrolimus-aspirin therapy on the APO ratio relative to patients exclusively administered tacrolimus. RESULTS: Of the 124 pregnancies, 29 were exposed to tacrolimus. Multivariate analysis showed no statistical difference in APO ratio. (overall APO: adjusted odds ratio [aOR], 0.69; 95% confidence interval [CI], 0.23-2.03; p = 0.50; maternal APO: aOR, 1.17; 95% CI, 0.36-3.83; p = 0.80; neonatal APO: aOR, 1.10; 95% CI, 0.38-3.21; p = 0.86; PROMISSE APO: aOR, 0.50; 95% CI, 0.14-1.74; p = 0.27). Blood pressure and estimated glomerular filtration rate (eGFR) during pregnancy and after delivery did not differ between the two groups. Receiver operating characteristic (ROC) curve showed that tacrolimus concentration > 2.6 ng/ml was related to reduced preterm birth rate. (AUC = 0.85, 95% CI: 0.61-1.00, sensitivity: 93% and specificity: 75%). Regarding effect of tacrolimus on lupus nephritis during pregnancy, tacrolimus showed no increased risk of APO, blood pressure or eGFR during pregnancy and after delivery. (overall APO: OR, 1.00; 95% CI, 0.25-4.08; p = 0.98; maternal APO: OR 1.60, 95% CI, 0.39-6.64; p = 0.51; neonatal APO: OR, 0.71; 95% CI, 0.17-3.03; p = 0.65, PROMISSE APO: OR, 0.50; 95% CI, 0.08-3.22; p = 0.47). Tacrolimus-aspirin combination therapy showed a protective tendency against hypertensive disorders during pregnancy, preeclampsia and low birth weight. CONCLUSIONS: Tacrolimus use during pregnancy with SLE and lupus nephritis showed no significant influence on APO, blood pressure, or renal function; therefore tacrolimus may be suitable for controlling lupus activity during pregnancy. In addition, when using tacrolimus during pregnancy, we should aim its trough concentration ≥ 2.6 ng/ml while paying careful attention to possible maternal side effects of tacrolimus. TRIAL REGISTRATION: Retrospectively registered.

Multidrug-resistant IgA Vasculitis with Gastrointestinal Symptoms Successfully Treated with Intravenous Cyclophosphamide and Maintained with Mycophenolate Mofetil.

We present the case of a 17-year-old woman with IgA vasculitis (IgAV) who presented with relapsing gastrointestinal (GI) symptoms that were refractory to glucocorticoid and combination therapy with cyclosporine A, azathioprine or mycophenolate mofetil (MMF). The patient responded well to remission induction with intravenous cyclophosphamide (IVCY) and was successfully maintained with MMF. Remission induction with IVCY followed by maintenance therapy with MMF was effective in a patient with multidrug-resistant IgAV with GI lesions.

A case report of two systemic lupus erythematosus pregnancies with early placental exposure to belimumab: Case report with review.

Since its approval for the management of systemic lupus erythematosus (SLE), belimumab has been widely used. However, its pregnancy safety profile has been underinvestigated. We present the pregnancy outcomes of two cases of early placental exposure to belimumab and summarise the pregnancy outcomes in previous reports regarding placental exposure to belimumab. Case 1 describes a 27-year-old woman with an 18-year history of SLE and lupus nephritis class III. We introduced belimumab 19 months prior to conception to control her proteinuria and discontinued its use at 5 weeks and 5 days of gestation. Her lupus activity was stable throughout pregnancy, and at 37 weeks and 1 day of gestation, she delivered a healthy girl with no anomaly. At delivery, the girl was small for gestational age, but at the 1-year follow-up, there was no delay in her growth or any serious infection. Case 2 describes a 32-year-old woman with a 15-year history of SLE. We introduced belimumab 9 months prior to conception and discontinued its use at 7 weeks and 1 day of gestation. Although her lupus was well controlled without belimumab, a missed abortion occurred, which was possibly due to foetal factors. Although there is accumulating data on the safety of belimumab use during pregnancy, it seems necessary to cautiously use this medication in pregnant women, until further analyses are conducted.

Effect and safety profile of belimumab and tacrolimus combination therapy in thirty-three patients with systemic lupus erythematosus.

INTRODUCTION/OBJECTIVES: Belimumab combined with mycophenolate mofetil has been proven to be effective for treating systemic lupus erythematosus (SLE) in several randomized controlled trials. Calcineurin inhibitors are also useful in controlling the activity of SLE. However, the safety and effectiveness of belimumab-calcineurin inhibitor combination therapy have not been addressed. Therefore, the current single-center retrospective study aimed to analyze the safety/efficacy profile of belimumab-tacrolimus (B-T) combination therapy in patients with SLE. METHOD: Patients with SLE administered tacrolimus and belimumab during treatment were included in the study. Samples were analyzed for the drug retention rate, SLE flare rate, infection incidence rate, and glucocorticoid-sparing effect of the B-T combination therapy. RESULTS: Thirty-three patients with SLE were treated with B-T combination therapy at our institution. Four patients discontinued treatment due to insufficient response or adverse events. The drug retention rate was over 90% at week 52 and approximately 80% at day 1000. Only one patient developed serious infection. The lupus low disease activity state (LLDAS) achievement ratio was 9.1% on the day of initiation and improved to 64.0% at 52 weeks after initiation. SLE flares were observed in three patients (9.1%) in the first 52 weeks after initiation, and in five patients (15.2%) throughout the study period. A glucocorticoid-reducing effect was also observed in patients treated with B-T combination therapy. CONCLUSIONS: In most patients with SLE, B-T combination therapy is well tolerated with a good efficacy profile and glucocorticoid-reducing effect. Thus, B-T combination therapy represents a feasible option for patients with refractory lupus. Key Points • The safety and effectiveness of belimumab-calcineurin inhibitor combination therapy have not been addressed. • The drug retention rate of belimumab-tacrolimus combination therapy was over 90% at week 52 and around 80% on day 1000 • Almost none of the patients suffered from severe infection after the initiation of belimumab-tacrolimus combination therapy. • Belimumab-tacrolimus combination therapy is efficacious in suppressing lupus activity and achieving LLDAS.

Activation mechanisms of monocytes/macrophages in adult-onset Still disease.

Adult onset Still disease (AOSD) is a systemic inflammatory disorder characterized by skin rash, spiking fever, arthritis, sore throat, lymphadenopathy, and hepatosplenomegaly. Although the etiology of this disease has not been fully clarified, both innate and acquired immune responses could contribute to its pathogenesis. Hyperactivation of macrophages and neutrophils along with low activation of natural killer (NK) cells in innate immunity, as well as hyperactivation of Th1 and Th17 cells, whereas low activation of regulatory T cells (Tregs) in acquired immunity are involved in the pathogenic process of AOSD. In innate immunity, activation of monocytes/macrophages might play central roles in the development of AOSD and macrophage activation syndrome (MAS), a severe life-threating complication of AOSD. Regarding the activation mechanisms of monocytes/macrophages in AOSD, in addition to type II interferon (IFN) stimulation, several pathways have recently been identified, such as the pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs)-pattern recognition receptors (PRRs) axis, and neutrophil extracellular traps (NETs)-DNA. These stimulations on monocytes/macrophages cause activation of the nucleotide-binding oligomerization domain, leucine-rich repeat, and pyrin domain (NLRP) 3 inflammasomes, which trigger capase-1 activation, resulting in conversion of pro-IL-1ß and pro-IL-18 into mature forms. Thereafter, IL-1ß and IL-18 produced by activated monocytes/macrophages contribute to various clinical features in AOSD. We identified placenta-specific 8 (PLAC8) as a specifically increased molecule in monocytes of active AOSD, which correlated with serum levels of CRP, ferritin, IL-1ß, and IL-18. Interestingly, PLAC8 could suppress the synthesis of pro-IL-1ß and pro-IL-18 via enhanced autophagy; thus, PLAC8 seems to be a regulatory molecule in AOSD. These findings for the activation mechanisms of monocytes/macrophages could shed light on the pathogenesis and development of a novel therapeutic strategy for AOSD.

Clinical features and serum cytokine profiles of elderly-onset adult-onset Still's disease.

Recent studies have suggested that the clinical features of elderly-onset adult-onset Still's disease (AOSD) differ from those of young and middle-aged-onset patients, whereas the details remain unclear, and cytokine profiles of elderly-onset AOSD have not been reported. To clarify the clinical features and cytokine profiles of elderly-onset AOSD, we examined patients with AOSD who developed the disease between January 2006 and September 2021. We divided the patients into the young and middle-aged-onset group (aged < 65 years) and the elderly-onset group (aged ≥ 65 years) and compared the groups in terms of patient characteristics, clinical symptoms, laboratory findings including serum interleukin (IL)-6 and IL-18, treatment, and prognosis. A total of 48 patients were examined (10 in the elderly-onset group). In the elderly-onset group, atypical rash was significantly more frequent, typical rash and splenomegaly were significantly less frequent, white blood cell count and neutrophil ratio were significantly higher and serum IL-6 levels were significantly lower. Serum IL-6 showed a significantly negative correlation with age at onset. Treatment and relapse were comparable between the 2 groups, whereas infections were significantly more frequent in the elderly-onset group. The clinical features and cytokine profiles of elderly-onset AOSD might differ from those of young and middle-aged-onset AOSD.

Association of Primary Biliary Cirrhosis-autoimmune Hepatitis Overlap Syndrome with Immune Thrombocytopenia and Graves' Disease.

A 54-year-old woman suffering from pruritus for five years was diagnosed to have Graves' disease and immune thrombocytopenia (ITP) associated with primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome, which was confirmed histologically after a prompt recovery in the platelet count number following steroid therapy. The association between PBC-AIH overlap syndrome and ITP has been rarely reported and the additional association with Graves' disease has not yet been reported. An underlying global derangement of autoimmunity or shared genetic susceptibility was suspected.