The first presentation of a case of nail-patella syndrome newly diagnosed at the onset of rheumatoid arthritis: a case report.

BACKGROUND: Nail-patella syndrome (NPS) is a rare autosomal dominant disorder that is characterized by dysplasia of the nails, hypoplasia and/or dislocation of the patella and the presence of iliac horns. Using the CARE guidelines, we present the first reported case of NPS that was newly diagnosed at the onset of rheumatoid arthritis (RA). CASE PRESENTATION: A 74-year-old man was admitted to our hospital due to an 8-month history of arthralgia in bilateral wrists, elbows and fingers. He had a past history of glaucoma and left patella dislocation that had been operatively recentered at the age of 15 years. Laboratory data showed elevated levels of serum C-reactive protein and rheumatoid factor and an elevated titer of anti-SS-A antibodies, while estimated glomerular filtration rate (eGFR), titers of other antibodies and the results of a urinary test were normal. An X-ray showed deformity of bilateral radial heads and the right elbow, and magnetic resonance imaging (MRI) of his hands showed synovitis and erosion in the multiple swollen joints of the wrists and fingers. In addition to these typical features of RA, he had bilateral thumb nail dysplasia with mild hypoplasia of bilateral patellae and iliac horns as shown by the X-ray. He was diagnosed as having autosomal dominant disorder NPS co-existing with RA and he was treated with methotrexate in combination with an oral Janus kinase (JAK) inhibitor, leading to induction of remission. CONCLUSIONS: We have presented a rare case of NPS that was newly diagnosed at the onset of RA. Clinical and radiographic findings of NPS are highlighted in this case report for diagnosing NPS on the basis of typical manifestations.

Immunosuppressive Treatment for an anti-U1 Ribonucleoprotein Antibody-positive Patient with Pulmonary Arterial Hypertension.

A 34-year-old woman with pulmonary arterial hypertension (PAH) was admitted to the hospital. She had been diagnosed with PAH three years earlier and treated with triple vasodilator therapy. She was positive for anti-U1 ribonucleoprotein antibodies but did not show any other symptoms associated with autoimmune diseases. Corticosteroid and cyclophosphamide therapy was administered, suspecting the involvement of immunological pathophysiology. After 3 weeks, the mean pulmonary artery pressure decreased from 50 to 38 mmHg without any change in the vasodilators. Immunosuppressive therapy was effective in this patient with PAH with an anti-U1 ribonucleoprotein-antibody-positive response and might be an option for patients with these specific features.

Ligneous periodontitis exacerbated by Behçet's disease in a patient with plasminogen deficiency and a stop-gained variant PLG c.1468C > T: a case report.

BACKGROUND: Plasminogen serves as the precursor to plasmin, an essential element in the fibrinolytic process, and is synthesized primarily in the liver. Plasminogen activation occurs through the action of plasminogen activator, converting it into plasmin. This conversion greatly enhances the fibrinolytic system within tissues and blood vessels, facilitating the dissolution of fibrin clots. Consequently, congenital deficiency of plasminogen results in impaired fibrin degradation. Patients with plasminogen deficiency typically exhibit fibrin deposits in various mucosal sites throughout the body, including the oral cavity, eyes, vagina, and digestive organs. Behcet's disease is a chronic recurrent systemic inflammatory disease with four main symptoms: aphthous ulcers of the oral mucosa, vulvar ulcers, skin symptoms, and eye symptoms, and has been reported worldwide. This disease is highly prevalent around the Silk Road from the Mediterranean to East Asia. We report a case of periodontitis in a patient with these two rare diseases that worsened quickly, leading to alveolar bone destruction. Genetic testing revealed a novel variant characterized by a stop-gain mutation, which may be a previously unidentified etiologic gene associated with decreased plasminogen activity. CASE PRESENTATION: This case report depicts a patient diagnosed with ligneous gingivitis during childhood, originating from plasminogen deficiency and progressing to periodontitis. Genetic testing revealed a suspected association with the PLG c.1468C > T (p.Arg490*) stop-gain mutation. The patient's periodontal condition remained stable with brief intervals of supportive periodontal therapy. However, the emergence of Behçet's disease induced acute systemic inflammation, necessitating hospitalization and treatment with steroids. During hospitalization, the dental approach focused on maintaining oral hygiene and alleviating contact-related pain. The patient's overall health improved with inpatient care and the periodontal tissues deteriorated. CONCLUSIONS: Collaborative efforts between medical and dental professionals are paramount in comprehensively evaluating and treating patients with intricate complications from rare diseases. Furthermore, the PLG c.1468C > T (p.Arg490*) stop-gain mutation could contribute to the association between plasminogen deficiency and related conditions.

Infliximab biosimilar-induced lupus nephritis: A case report.

We present a case of microhematuria, proteinuria and hypocomplementemia which developed in a 55-year-old female who was being treated with an infliximab biosimilar for rheumatoid arthritis. Renal biopsy showed lupus nephritis (ISN/RPS classification class IV + V). Treatment with the infliximab biosimilar was discontinued, and treatment with prednisolone, hydroxychloroquine and abatacept was started, resulting in clinical remission of lupus nephritis and RA. Although tumour necrosis factor-α α inhibitors are known to induce production of autoantibodies, symptoms are usually limited to skin involvement or arthritis, and renal complications are rare. Physicians should be aware of the risk of lupus nephritis and carefully monitor patients for the development of renal involvement during treatment with tumour necrosis factor-α inhibitors.

The Association of Grit With Burnout Components (Professional Efficacy, Exhaustion, and Cynicism) Among Academic Rheumatologists: The TRUMP 2 -SLE Study.

OBJECTIVES: There is a high prevalence of burnout among rheumatologists. Grit, which is defined as possessing perseverance and a passion to achieve long-term goals, is predictive of success in many professions; however, whether grit is associated with burnout remains unclear, especially among academic rheumatologists, who have multiple simultaneous responsibilities. Thus, the purpose of this study was to examine the associations between grit and self-reported burnout components-professional efficacy, exhaustion, and cynicism-in academic rheumatologists. METHODS: This cross-sectional study involved 51 rheumatologists from 5 university hospitals. The exposure was grit, measured using mean scores for the 8-item Short Grit Scale (range, 1-5 [5 = extremely high grit]). The outcome measures were mean scores for 3 burnout domains (exhaustion, professional efficacy, and cynicism; range, 1-6; measured using the 16-item Maslach Burnout Inventory-General Survey). General linear models were fitted with covariates (age, sex, job title [assistant professor or higher vs lower], marital status, and having children). RESULTS: Overall, 51 physicians (median age, 45 years; interquartile range, 36-57; 76% men) were included. Burnout positivity was found in 68.6% of participants (n = 35/51; 95% confidence interval [CI], 54.1, 80.9). Higher grit was associated with higher professional efficacy (per 1-point increase; 0.51 point; 95% CI, 0.18, 0.84) but not with exhaustion or cynicism. Being male and having children were associated with lower exhaustion (-0.69; 95% CI, -1.28, -0.10; p = 0.02; and -0.85; 95% CI, -1.46, -0.24; p = 0.006). Lower job title (fellow or part-time lecturer) was associated with higher cynicism (0.90; 95% CI, 0.04, 1.75; p = 0.04). CONCLUSIONS: Grit is associated with higher professional efficacy among academic rheumatologists. To prevent burnout among staff, supervisors who manage academic rheumatologists should assess their staff's individual grit.

Amelioration of nephritis in receptor for advanced glycation end-products (RAGE)-deficient lupus-prone mice through neutrophil extracellular traps.

The receptor for advanced glycation end-products (RAGE) is a pattern recognition receptor that regulates inflammation, cell migration, and cell fate. Systemic lupus erythematosus (SLE) is a chronic multiorgan autoimmune disease. To understand the function of RAGE in SLE, we generated RAGE-deficient (Ager-/-) lupus-prone mice by backcrossing MRL/MpJ-Faslpr/J (MRL-lpr) mice with Ager-/- C57BL/6 mice. In 18-week-old Ager-/- MRL-lpr, the weights of the spleen and lymph nodes, as well as the frequency of CD3+CD4-CD8- cells, were significantly decreased. Ager-/- MRL-lpr mice had significantly reduced urine albumin/creatinine ratios and markedly improved renal pathological scores. Moreover, neutrophil infiltration and neutrophil extracellular trap formation in the glomerulus were significantly reduced in Ager-/- MRL-lpr. Our study is the first to reveal that RAGE can have a pathologic role in immune cells, particularly neutrophils and T cells, in inflammatory tissues and suggests that the inhibition of RAGE may be a potential therapeutic strategy for SLE.

Association of alcohol consumption and fatigue in SLE: A cross-sectional study from Lupus Registry of Nationwide Institution (LUNA) cohort.

OBJECTIVE: Fatigue is one of the most common complaints and is a potentially modifiable issue in systemic lupus erythematosus (SLE). Studies suggest that alcohol consumption has a protective effect against the development of SLE; however, an association between alcohol consumption and fatigue in patients with SLE has not been studied. Here, we assessed whether alcohol consumption was associated with fatigue using lupus patient-reported outcomes (LupusPRO). METHODS: This cross-sectional study, conducted between 2018 and 2019, included 534 patients (median age, 45 years; 87.3% female) from 10 institutions in Japan. The main exposure was alcohol consumption, which was defined as the frequency of drinking [<1 day/month (none group), ≤1 day/week (moderate group), and ≥2 days/week (frequent group)]. The outcome measure was the Pain Vitality domain score in LupusPRO. Multiple regression analysis was performed as the primary analysis after adjusting for confounding factors, such as age, sex, and damage. Subsequently, the same analysis was performed as a sensitivity analysis after multiple imputations (MIs) for missing data (n = 580). RESULTS: In total, 326 (61.0%) patients were categorized into the none group, 121 (22.7%) into the moderate group, and 87 (16.3%) into the frequent group. The frequent group was independently associated with less fatigue compared with none group [ß = 5.98 (95% CI 0.19-11.76), p = 0.04], and the results did not substantially deviate after MI. CONCLUSIONS: Frequent drinking was associated with less fatigue, which highlights the need for further longitudinal studies focusing on drinking habits in patients with SLE.

A young female case of asymptomatic immune-mediated necrotizing myopathy: a potential diagnostic option of antibody testing for rhabdomyolysis.

Anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) immune-mediated necrotizing myopathy (IMNM) is a neuromuscular disorder that presents muscle weakness in proximal extremities and/or the trunk with an elevation of creatine kinase (CK). Young and asymptomatic anti-HMGCR IMNM patients are very rare and a treatment regimen has not been established. The present case, a 17-year-old woman without any muscular symptoms, only showed hyperCKemia that was detected by chance. After close examinations, including a muscle biopsy and antibody search, she was diagnosed as anti-HMGCR IMNM, and initial treatment with methotrexate and continuous intravenous immunoglobulin seemed to be effective. The present case is the unusually young asymptomatic case of anti-HMGCR IMNM. The diagnosis was successfully made, leading to the early introduction of a treatment. Given the course of this case, we believe that the preceding antibody testing is one of the diagnostic option for rhabdomyolysis.

Pharmacologic inhibition of PARP5, but not that of PARP1 or 2, promotes cytokine production and osteoclastogenesis through different pathways.

OBJECTIVES: PARPs, which are members of the poly(ADP-ribose) polymerase superfamily, promote tumorigenesis and tumour-associated inflammation and are thus therapeutic targets for several cancers. The aim of the present study is to investigate the mechanistic insight into the roles PARPs for inflammation. METHODS: Primary murine macrophages were cultured in the presence or absence of the PARP5 inhibitor NVP-TNKS656 to examine the role of PARP5 for cytokine production. RESULTS: In contrast to the roles of other PARPs for induction of inflammation, we found in the present study that pharmacologic inhibition of PARP5 induces production of inflammatory cytokines in primary murine macrophages. We found that treatment with the PARP5 inhibitor NVP-TNKS656 in macrophages enhanced steady-state and LPS-mediated cytokine production through degradation of IκBα and subsequent nuclear translocation of NF-κB. We also found that pharmacologic inhibition of PARP5 stabilises the adaptor protein 3BP2, a substrate of PARP5, and that accelerated cytokine production induced by PARP5 inhibition was rescued in 3BP2-deleted macrophages. Additionally, we found that LPS increases the expression of 3BP2 and AXIN1, a negative regulator of ß-catenin, through suppression of PARP5 transcripts in macrophages, leading to further activation of cytokine production and inhibition of ß-catenin-mediated cell proliferation, respectively. Lastly, we found that PARP5 inhibition in macrophages promotes osteoclastogenesis through stabilisation of 3BP2 and AXIN1, leading to activation of SRC and suppression of ß-catenin, respectively. CONCLUSIONS: Our results show that pharmacologic inhibition of PARP5 against cancers unexpectedly induces adverse autoinflammatory side effects through activation of innate immunity, unlike inhibition of other PARPs.

Grit personality of physicians and achievement of treatment goals in patients with system lupus erythematosus.

OBJECTIVES: Although personality characteristics of patients with SLE affect their disease activity and damage, it is unclear whether those of attending physicians affect the outcomes of patients with SLE. Grit is a personality trait for achieving long-term goals that may influence the decision-making for continuing treatment plans for patients. We aimed to evaluate the relationship between the grit of attending physicians and achievement of treatment goals in patients with SLE. METHODS: This cross-sectional study was conducted at five referral hospitals. The main exposure was 'consistency of interest' and 'perseverance of effort' of the attending physicians, measured by the Short Grit Scale. The primary outcome was achievement of a lupus low disease activity state (LLDAS). The association between physicians' grit score and LLDAS was analysed by generalized estimating equation (GEE) logistic regression with cluster robust variance estimation, with adjustment for confounders. RESULTS: The median (interquartile range) total, consistency and perseverance scores of 37 physicians were 3.1 (2.9-3.6), 3.3 (2.8-3.8) and 3.3 (3.0-3.5), respectively. Among the 386 patients, 154 (40%) had achieved LLDAS. Low consistency score (≤2.75) in physicians was related to LLDAS achievement independently using GEE logistic regression. The score of the question 'I often set a goal but later choose to pursue a different one' was significantly higher in patients achieving LLDAS. CONCLUSIONS: Difficulty of attending physicians to change treatment goals might be related to lower LLDAS achievement in patients with SLE.

Association of one-point glucocorticoid-free status with chronic damage and disease duration in systemic lupus erythematosus: a cross-sectional study.

OBJECTIVE: It is still unclear how glucocorticoids (GCs) affect the long-term clinical course of patients with SLE. The objective of this study is to explore the factors associated with GC-free treatment status. METHODS: Using data from the lupus registry of nationwide institutions, GC dose at registration was compared between short, middle and long disease durations of <5, 5-20 and ≥20 years, respectively. After excluding patients who never used GC, we evaluated the relationship between GC-free status and chronic damage using Systemic Lupus International Collaborating Clinics Damage Index. RESULTS: GC doses at enrolment of the 1019 patients were as follows: GC-free in 101 (10%); 0

CD38 reduces mitochondrial fitness and cytotoxic T cell response against viral infection in lupus patients by suppressing mitophagy.

Infection is one of the major causes of mortality in patients with systemic lupus erythematosus (SLE). We previously found that CD38, an ectoenzyme that regulates the production of NAD+, is up-regulated in CD8+ T cells of SLE patients and correlates with the risk of infection. Here, we report that CD38 reduces CD8+ T cell function by negatively affecting mitochondrial fitness through the inhibition of multiple steps of mitophagy, a process that is critical for mitochondria quality control. Using a murine lupus model, we found that administration of a CD38 inhibitor in a CD8+ T cell-targeted manner reinvigorated their effector function, reversed the defects in autophagy and mitochondria, and improved viral clearance. We conclude that CD38 represents a target to mitigate infection rates in people with SLE.

Potential of a Novel Chemical Compound Targeting Matrix Metalloprotease-13 for Early Osteoarthritis: An In Vitro Study.

Osteoarthritis is a progressive disease characterized by cartilage destruction in the joints. Matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTSs) play key roles in osteoarthritis progression. In this study, we screened a chemical compound library to identify new drug candidates that target MMP and ADAMTS using a cytokine-stimulated OUMS-27 chondrosarcoma cells. By screening PCR-based mRNA expression, we selected 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide as a potential candidate. We found that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated IL-1ß-induced MMP13 mRNA expression in a dose-dependent manner, without causing serious cytotoxicity. Signaling pathway analysis revealed that 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide attenuated ERK- and p-38-phosphorylation as well as JNK phosphorylation. We then examined the additive effect of 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide in combination with low-dose betamethasone on IL-1ß-stimulated cells. Combined treatment with 2-(8-methoxy-2-methyl-4-oxoquinolin-1(4H)-yl)-N-(3-methoxyphenyl) acetamide and betamethasone significantly attenuated MMP13 and ADAMTS9 mRNA expression. In conclusion, we identified a potential compound of interest that may help attenuate matrix-degrading enzymes in the early osteoarthritis-affected joints.

Skeletal muscle heme oxygenase-1 activity regulates aerobic capacity.

Physical exercise has profound effects on quality of life and susceptibility to chronic disease; however, the regulation of skeletal muscle function at the molecular level after exercise remains unclear. We tested the hypothesis that the benefits of exercise on muscle function are linked partly to microtraumatic events that result in accumulation of circulating heme. Effective metabolism of heme is controlled by Heme Oxygenase-1 (HO-1, Hmox1), and we find that mouse skeletal muscle-specific HO-1 deletion (Tam-Cre-HSA-Hmox1fl/fl) shifts the proportion of muscle fibers from type IIA to type IIB concomitant with a disruption in mitochondrial content and function. In addition to a significant impairment in running performance and response to exercise training, Tam-Cre-HSA-Hmox1fl/fl mice show remarkable muscle atrophy compared to Hmox1fl/fl controls. Collectively, these data define a role for heme and HO-1 as central regulators in the physiologic response of skeletal muscle to exercise.

Association of explanatory histological findings and urinary protein and serum creatinine levels at renal biopsy in lupus nephritis: a cross-sectional study.

BACKGROUND: The aim of the present study was to evaluate the association between the histology of active and chronic lesions and urinary protein and serum creatinine (SCr) levels, as common clinical endpoints in clinical trials for lupus nephritis (LN). METHODS: In total, 119 patients diagnosed with LN class III, IV, and V, as defined by the International Society of Nephrology/Renal Pathology Society, between 1990 and 2015, were enrolled in the present study. Multiple regression analysis was performed to explore semi-quantitative histological variables associated with urinary protein and SCr levels. RESULTS: The mean age of the enrolled patients was 45 years, and 79% were female. The mean SCr and mean urinary protein levels at the time of renal biopsy were 0.87 mg/dl and 3.00 g/gCr, respectively. Class IV (71%) was the most common type of LN followed by class III (17%), and class V (13%). Multicollinearity was confirmed between monocellular infiltration (variance inflation factor [VIF] = 10.22) and interstitial fibrosis (VIF = 10.29), and between karyorrhexis (VIF = 4.14) and fibrinoid necrosis (VIF = 4.29). Fibrinoid necrosis and monocellular infiltration were subsequently excluded, and multiple regression analysis revealed that only the urinary protein level was correlated with wire loop lesions (ß-coefficient [ß]: 1.09 and confidence interval [CI]: 0.35 to 1.83), and that the SCr level was correlated with glomerular sclerosis (ß: 1.08 and CI: 0.43 to 1.74). CONCLUSION: As urinary protein and SCr levels were not quantitatively associated with active lesions, they may not accurately reflect the response to remission induction therapy in patients with LN.

Risk Factors for Chronic Damage Accumulation Across Different Onset Eras in Systemic Lupus Erythematosus: A Cross-sectional Analysis of a Lupus Registry of Nationwide Institutions (LUNA).

Chronic damage accumulation affects not only mortality but also quality of life in patients with systemic lupus erythematosus (SLE). Risk factors for chronic damage were explored in SLE through different onset eras. Two hundred forty-five patients at Okayama University Hospital and Showa University Hospital were divided into three groups based on the onset era: a past-onset group (onset before 1995; n=83), middle-onset group (1996-2009; n=88), and recent-onset group (after 2010; n=74). The mean Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index (SDI) score as an index of chronic damage was 1.93, 1.24, and 0.53 in the past-, middle-, and recent-onset groups, respectively. In the pastonset group, the total SDI score was significantly associated with glucocorticoid monotherapy by linear regression analysis (ß-coefficient [ß]=0.63; 95% confidence interval [CI], 0.21-1.05) and C-reactive protein levels (ß=0.67; 95% CI, 0.27-1.07). In the middle-onset group, the total SDI score was significantly associated with the SLE Disease Activity Index at registration (ß=0.09; 95% CI, 0.03-0.12). Reducing the accumulation of chronic damage in SLE patients might be possible with the concomitant use of immunosuppressants and tight control of disease activity.

The CD38/NAD/SIRTUIN1/EZH2 Axis Mitigates Cytotoxic CD8 T Cell Function and Identifies Patients with SLE Prone to Infections.

Patients with systemic lupus erythematosus (SLE) suffer frequent infections that account for significant morbidity and mortality. T cell cytotoxic responses are decreased in patients with SLE, yet the responsible molecular events are largely unknown. We find an expanded CD8CD38high T cell subset in a subgroup of patients with increased rates of infections. CD8CD38high T cells from healthy subjects and patients with SLE display decreased cytotoxic capacity, degranulation, and expression of granzymes A and B and perforin. The key cytotoxicity-related transcription factors T-bet, RUNX3, and EOMES are decreased in CD8CD38high T cells. CD38 leads to increased acetylated EZH2 through inhibition of the deacetylase Sirtuin1. Acetylated EZH2 represses RUNX3 expression, whereas inhibition of EZH2 restores CD8 T cell cytotoxic responses. We propose that high levels of CD38 lead to decreased CD8 T cell-mediated cytotoxicity and increased propensity to infections in patients with SLE, a process that can be reversed pharmacologically.

Deletion of Mir223 Exacerbates Lupus Nephritis by Targeting S1pr1 in Faslpr/lpr Mice.

Objective: The micro RNAs (miRNAs) and their target mRNAs are differentially expressed in various immune-mediated cells. Here, we investigated the role of Mir223 and sphingosine-1-phosphate receptor 1 (S1pr1) in the pathogenesis of systemic lupus erythematosus. Methods: We analyzed miRNA and mRNA profiling data of CD4+ splenic T cells derived from MRL/MpJ-Faslpr /J mice. We performed 3' untranslated region (UTR) luciferase reporter gene assay using human umbilical vein endothelial cells (HUVECs). We generated the B6-Mir223-/-Faslpr/lpr mice and the lupus phenotypes were analyzed. Results: In CD4+ splenic T cells, we identified upregulation of miR-223-3p and downregulation of the possible target, S1pr1 by RNA sequencing of MRL/MpJ-Faslpr /J mice. The transfection with miR-223-3p mimic significantly suppressed a luciferase activity in HUVEC treated with a Lentivirus vector containing 3' UTR of S1pr1. The mRNA levels of S1pr1 were significantly decreased after miR-223-3p overexpression. In B6-Mir223-/-Faslpr/lpr mice, the proportion of CD3+ T cells, CD3+CD4-CD8- cells, B cells, plasma cells, and S1PR1+CD4+ T cells in the spleen was significantly increased compared with that in B6-Mir223+/+Faslpr/lpr mice by flow cytometry. B6-Mir223-/-Faslpr/lpr mice demonstrated the elevation of glomerular and renal vascular scores associated with enhanced intraglomerular infiltration of S1PR1+CD4+ T cells. Conclusion: Unexpectedly, the deletion of Mir223 exacerbated the lupus phenotypes associated with increased population of S1PR1+CD4+ T in spleen and the enhanced infiltration of S1PR1+CD4+ T cells in inflamed kidney tissues, suggesting compensatory role of Mir223 in the pathogenesis of lupus nephritis.