Factors associated with 25-hydroxyvitamin D level in Chinese hospitalized patients with systemic lupus erythematosus: a retrospective cohort study.

We aimed to investigate the factors associated with vitamin D deficiency and changes in 25 (OH)D levels, as well as the impact of those changes on disease activity and renal function among SLE patients. This retrospective cohort study was based on the medical records of SLE patients hospitalized between 2010 and 2021. We collected relevant information from this patient population. Logistic regression analysis was employed to determine the factors associated with vitamin D deficiency and increased 25 (OH)D levels, and we calculated the odds ratios (ORs) and 95% confidence intervals (CIs) accordingly. At baseline, among the 1257 SLE patients, the median and interquartile range of 25 (OH)D levels were 14 (9, 20) ng/ml, with 953 (75.8%) patients exhibiting 25 (OH)D deficiency (< 20 ng/ml). The presence of 25 (OH)D deficiency was found to be associated with renal involvement and a high glucocorticoid (GC) maintenance dose. Among the 383 patients who were followed up for an average of 18 months, an increase of at least 100% in 25 (OH)D levels was positively associated with a decreased GC maintenance dose and vitamin D3 supplementation, with adjusted odds ratios(OR) (95% confidence interval [CI]) of 2.16 (1.02, 4.59) and 1300 (70, 22300), respectively. Furthermore, an increased level of 25 (OH)D was significantly associated with a decrease in the Disease Activity Index 2000 score and the urinary protein/creatinine ratio. Patients with SLE have low vitamin D levels, especially those with impaired kidney function. Increased 25 (OH)D levels can be achieved through supplementation with high doses of vitamin D3 and are associated with improvements in disease activity and the urinary protein/creatinine ratio.

Clinical significance of HScore and MS score comparison in the prognostic evaluation of anti-MDA5-positive patients with dermatomyositis and interstitial lung disease.

OBJECTIVES: To evaluate the clinical significance of the HScore and MS score in the prognosis of anti-melanoma differentiation-associated gene 5 (MDA5) positive patients with dermatomyositis (DM) and interstitial lung disease (ILD). METHODS: The clinical features as well as HScore and MS score were compared between the survivors (n = 61) and nonsurvivors (n = 36) among 97 anti-MDA5-positive DM-ILD patients. Potential prognostic factors were analysed. RESULTS: Compared with survivors, nonsurvivors had significantly older age, tended to be male, and had a significantly higher frequency of fever at disease onset, higher levels of aspartate transaminase, lactate dehydrogenase, and serum ferritin, as well as higher values of HScore and MS score but had a significantly lower frequency of arthritis at disease onset. Multivariate analysis revealed that age ≥50 years [hazard ratio (HR) = 2.70, p = .040, 95% confidence interval (CI) 1.05-6.97)], male gender (HR = 3.20, p = .017, 95% CI 1.23-8.28), and higher HScore (HR = 3.72, p = .003, 95% CI 1.56-8.86) were independent risk factors for mortality. Patients with more risk factors had significantly poorer survival (p < .001). CONCLUSIONS: Older age, high HScore, and male gender are risk factors for poor survival among anti-MDA5-positive DM-ILD patients, suggesting the potential role of macrophage activation in the pathogenesis.

Liver damage in primary biliary cirrhosis and accompanied by primary Sjögren's syndrome: a retrospective pilot study.

INTRODUCTION: Primary biliary cirrhosis (PBC) and primary Sjögren's syndrome (pSS) have been referred to as "generalized autoimmune epithelitis". Indeed, the pathogenic mechanisms, clinical features, and optimal therapeutic approaches for them are not yet fully defined. MATERIAL AND METHODS: A retrospective analysis was carried out on clinical data obtained from 302 inpatients newly diagnosed with PBC, pSS, or the coexistence of PBC and SS between May 2011 and December 2014. Forty-two patients with abnormal hepatic function were divided into the PBC group (n = 17), the coexistent group (PBC accompanied by SS, n = 13), and the pSS group (n = 12). Their clinical symptoms, laboratory data, and pathological features were collected and analyzed when they were first diagnosed. The clinical and laboratory data were collected at 0, 1, and 3 months after treatment. RESULTS: Of the 42 patients with abnormal liver function, 4 were male and 38 were female patients. Compared with the patients in the PBC group, the patients in the other 2 groups were more likely to have an elevated erythrocyte sedimentation rate (ESR) and serum immunoglobulin G (IgG) levels. Abnormal serum immunoglobulin M levels (IgM) were more frequent in the PBC group. Corticosteroids were effective in normalizing elevated liver enzyme levels in patients with SS and in those with coexistent conditions. CONCLUSIONS: This pilot study suggests that patients with PBC, pSS, and PBC/SS coexistence and having liver function abnormality share similar symptoms, but have different pathogenesis and prognosis.

Umbilical cord mesenchymal stem cells transplantation in patients with systemic sclerosis: a 5-year follow-up study.

OBJECTIVE: To assess the long-term safety and efficacy of umbilical cord mesenchymal stem cells transplantation (UMSCT) in patients with systemic sclerosis (SSc). METHODS: Forty-one patients with moderate to severe SSc underwent UMSCT at the Affiliated Drum Tower Hospital of Nanjing University Medical School from 2009 to 2017. In this study, we conducted a longitudinal and retrospective analysis and compared the clinical and laboratory manifestations before and after UMSCT. The main outcome of the study was overall survival. We evaluated changes in the modified Rodnan Skin Score (mRSS), as well as the changes in the pulmonary examination by using high-resolution computed tomography (HRCT) and ultrasound cardiogram (UCG). Additionally, we assessed the Health Assessment Questionnaire-Disability Index (HAQ-DI) and the severity of peripheral vascular involvement during the first year after treatment. RESULTS: The overall 5-year survival rate was 92.7% (38 out of 41 patients). Following UMSCT, the mean mRSS significantly decreased from 18.68 (SD = 7.26, n = 41) at baseline to 13.95 (SD = 8.49, n = 41), 13.29 (SD = 7.67, n = 38), and 12.39 (SD = 8.49, n = 38) at 1, 3, and 5 years, respectively. Improvement or stability in HRCT images was observed in 72.0% of interstitial lung disease (ILD) patients. Pulmonary arterial hypertension (PAH) remained stable in 5 out of 8 patients at the 5-year follow-up. No adverse events related to UMSCT were observed in any of the patients during the follow-up period. CONCLUSION: UMSCT may provide a safe and feasible treatment option for patients with moderate to severe SSc based on long-term follow-up data. The randomized controlled study will further confirm the clinical efficacy of UMSCT in SSc. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00962923. Key Point • UMSCT is safe and effective for SSc patients.

Eltrombopag in severe immune thrombocytopenia secondary to connective tissue disease: a report of 17 patients and literature review.

To assess the remission rate of eltrombopag in the treatment of severe immune thrombocytopenia (ITP) secondary to connective tissue disease (CTD) and to explore factors related to drug efficacy in the context of literature reports, seventeen CTD patients accompanied with severe ITP treated with eltrombopag between June 2019 and February 2021 were included, with their follow-up information recorded. Combined with literature review, patients were divided into two groups depending on whether the treatment was effective or not to determine efficacy-related factors. Totally, 7 patients with systemic lupus erythematosus, 6 with Sjögren's syndrome, and 4 with undifferentiated connective tissue disease were enrolled. The median duration of eltrombopag treatment was 8 weeks, and the median time to response was 4 weeks. Twelve (70.6%) patients responded to eltrombopag. Patients with higher serum white blood cell counts, lower serum triglyceride levels, or previously received multiple immunosuppressants achieved a better efficacy (p < 0.05), while those with megakaryocytopenia in bone marrow tended to have lower remission rate (p = 0.08). By using pooled data including literature reported cases, we demonstrated that evidence of leukopenia, megakaryocytopenia, and being treated with fewer prior immunosuppressants were still associated with poor remission (p < 0.05). Meanwhile, there was a trend indicating the primary disease might affect the treatment efficacy (p = 0.06). Eltrombopag is a viable option for treating severe ITP secondary to CTDs, yet it may be less effective for patients with leukopenia, megakaryocytopenia, and being treated with fewer prior immunosuppressants. Key Points • Eltrombopag provides an alternative to the current treatment of CTD-ITP. • White blood cell levels, bone marrow megakaryocyte counts, and prior use of immunosuppressants may affect the efficacy of eltrombopag.

Development of Clinical Decision Models for the Prediction of Systemic Lupus Erythematosus and Sjogren's Syndrome Overlap.

OBJECTIVE: To explore the clinical features of patients with systemic lupus erythematosus and Sjögren's syndrome overlap (SLE-SS) compared to concurrent SLE or primary SS (pSS) patients, we utilized a predictive machine learning-based tool to study SLE-SS. METHODS: This study included SLE, pSS, and SLE-SS patients hospitalized at Nanjing Drum Hospital from December 2018 to December 2020. To compare SLE versus SLE-SS patients, the patients were randomly assigned to discovery cohorts or validation cohorts by a computer program at a ratio of 7:3. To compare SS versus SLE-SS patients, computer programs were used to randomly assign patients to the discovery cohort or the validation cohort at a ratio of 7:3. In the discovery cohort, the best predictive features were determined using a least absolute shrinkage and selection operator (LASSO) logistic regression model among the candidate clinical and laboratory parameters. Based on these factors, the SLE-SS prediction tools were constructed and visualized as a nomogram. The results were validated in a validation cohort, and AUC, calibration plots, and decision curve analysis were used to assess the discrimination, calibration, and clinical utility of the predictive models. RESULTS: This study of SLE versus SLE-SS included 290 patients, divided into a discovery cohort (n = 203) and a validation cohort (n = 87). The five best characteristics were selected by LASSO logistic regression in the discovery cohort of SLE versus SLE-SS and were used to construct the predictive tool, including dry mouth, dry eye, anti-Ro52 positive, anti-SSB positive, and RF positive. This study of SS versus SLE-SS included 266 patients, divided into a discovery cohort (n = 187) and a validation cohort (n = 79). In the discovery cohort of SS versus SLE-SS, by using LASSO logistic regression, the eleven best features were selected to build the predictive tool, which included age at diagnosis (years), fever, dry mouth, photosensitivity, skin lesions, arthritis, proteinuria, hematuria, hypoalbuminemia, anti-dsDNA positive, and anti-Sm positive. The prediction model showed good discrimination, good calibration, and fair clinical usefulness in the discovery cohort. The results were validated in a validation cohort of patients. CONCLUSION: The models are simple and accessible predictors, with good discrimination and calibration, and can be used as a routine tool to screen for SLE-SS.

Association Between Mycophenolate Mofetil Use and Subsequent Infections Among Hospitalized Patients with Systemic Lupus Erythematosus: A Nested Case-Control Study.

INTRODUCTION: The association between mycophenolate mofetil (MMF) and infection in patients with systemic lupus erythematosus (SLE) has not been clarified. This study evaluated the degree and factors in effect of MMF use on infection in patients with SLE. METHODS: A hospitalized-based observational study was conducted to collect medical records on patients with SLE during 2010-2021. A nested case-control study was performed among 3339 patients with SLE, including 1577 cases and 1762 controls by whether they developed any type of infection. The exposure of MMF use was determined within 1 year before diagnosed infection or the end of follow-up. Logistic regression was used to estimate the odds ratio (OR) and 95% confidence interval (CI) for association between MMF and subsequent infection. RESULTS: MMF was significantly associated with the risk of overall infection (adjusted OR 1.90, 95% CI 1.48-2.44) and different types of infections, including bacterial infection (adjusted OR 2.07, 95% CI 1.55-2.75), viral infection (adjusted OR 1.92, 95% CI 1.23-3.01), and opportunistic infection (adjusted OR 2.13, 95% CI 1.31-3.46). The top three risks of specific types of infections were bacteremia/septicemia, urinary tract infection/pyelonephritis, and herpes zoster. Stratification analysis showed risk of overall infection increased especially in MMF users with age over 55 years, diabetes, central nervous system involvement, and thrombocytopenia. Moreover, the risk of infection increased with increasing dosage and duration of MMF use. Additionally, the combination of MMF with CYC and other immunosuppressants significantly increases the risk of infections compared to using a single one. CONCLUSIONS: MMF use is associated with various type of infections in patients with SLE, particularly in those with longer use, older age, complications with comorbidities, and concomitant use of CYC or other immunosuppressants.

Efficacy and Safety of CMAB008 Compared with Innovator Infliximab in Patients with Moderate-to-Severe Rheumatoid Arthritis Receiving Concomitant Methotrexate: A Randomized, Double-blind, Multi-center, Phase III Non-inferiority Study.

OBJECTIVES: The aim of this work is to verify the non-inferior efficacy and safety of CMAB008 compared with innovator infliximab in rheumatoid arthritis patients combined with methotrexate. METHODS: We conducted a randomized, double-blinded, parallel, positive control design, multicenter study, with a stable dose of methotrexate. Patients were enrolled randomly with a ratio of 1:1 to receive intravenously CMAB008 3 mg/kg or innovator infliximab 3 mg/kg at weeks 0, 2, 6, 14, 22 and 30. The primary efficacy endpoint was American College of Rheumatology 20% improvement criteria (ACR20) response rate at week 30. The non-inferiority was established if the lower limit of the one-sided 97.5% confidence interval (CI) for the difference was more than - 15% and the equivalence was established if the two-sided 95% CI was within ± 15% in an exploratory equivalence analysis. The secondary endpoints included other efficacy assessment parameters, as well as immunogenicity, safety, and pharmacokinetics. RESULTS: In the full analysis population (FAS), 110 (57.6%) of 191 patients in the CMAB008 group and 120 (62.2%) of 193 patients in the innovator infliximab group reached the primary outcome of ACR20 at week 30. The differences of the rates were - 4.6% and the lower limit of one-sided 97.5% confidence interval was - 14.29%, not less than the lower limit of the non-inferiority margin (- 15%); so CMAB008 was non-inferior to innovator infliximab. Further, CMAB008 was equivalent to innovator infliximab both in FAS (difference - 4.6%, 95% CI - 14.29% to 5.12%) and PPS (difference - 3.3%, 95% CI - 13.18% to 6.62%). The efficacy, safety, immunogenicity, and pharmacokinetics are highly similar between CMAB008 and innovator infliximab. CONCLUSIONS: Non-inferior efficacy of CMAB008 to innovator infliximab is illustrated with similar early and lasting therapeutic effects, and the equivalence is further demonstrated. CMAB008 is well tolerated and has semblable safety compared with the innovator infliximab. TRIAL REGISTRATION NUMBER: NCT03478111.

Double allogenic mesenchymal stem cells transplantations could not enhance therapeutic effect compared with single transplantation in systemic lupus erythematosus.

The clinical trial of allogenic mesenchymal stem cells (MSCs) transplantation for refractory SLE patients has shown significant safety and efficacy profiles. However, the optimum frequency of the MSCs transplantation (MSCT) is unknown. This study was undertaken to observe whether double transplantations of MSCs is superior to single transplantation. Fifty-eight refractory SLE patients were enrolled in this study, in which 30 were randomly given single MSCT, and the other 28 were given double MSCT. Patients were followed up for rates of survival, disease remission, and relapse, as well as transplantation-related adverse events. SLE disease activity index (SLEDAI) and serologic features were evaluated. Our results showed that no remarkable differences between single and double allogenic MSCT were found in terms of disease remission and relapse, amelioration of disease activity, and serum indexes in an SLE clinical trial with more than one year followup. This study demonstrated that single MSCs transplantation at the dose of one million MSCs per kilogram of body weight was sufficient to induce disease remission for refractory SLE patients.

Characteristics of Hearing Loss in Patients with Systemic Lupus Erythematosus.

OBJECTIVE: To investigate the clinical characteristics of hearing loss (HL) in patients with systemic lupus erythematosus (SLE) and its related factors. METHODS: Ninety-one hospitalized SLE patients and thirty healthy controls were enrolled. All subjects completed pure tone audiometry (PTA), extended high frequency audiometry (EHFA) and distortion product otoacoustic emission (DPOAE) to assess hearing function. SLE patients were divided into two groups according to the presence or absence of HL, and the risk factors of HL were determined by multivariate logistic regression. RESULTS: The incidence of HL was 27.47% in SLE patients, significantly higher than in the control group (3.3%) and most cases were mild-to-moderate, bilateral and predominantly sensorineural. Compared with the control group, the hearing thresholds of SLE patients increased significantly in the middle and high frequencies starting from 2000 Hz. Even though the PTA test results were normal, the EHFA test results showed significant differences in hearing impairment between SLE patients and normal controls. For patients with abnormal PTA results, the signal-to-noise ratio (SNR) in DPOAE was markedly reduced, and the pass rate was also decreased. The Systemic Lupus International Collaborating Clinics Damage Index (SDI, OR 9.13) and secondary Sjögren's syndrome (sSS, OR 8.20) were identified as independent associated factors for HL, and there was no difference in PTA and EHFA at all frequencies between hydroxychloroquine users and non-users. CONCLUSIONS: HL is not rare in SLE patients, and EHFA can help identify early hearing impairment. Having a high SDI score and secondary Sjögren's syndrome may predict the presence of HL in SLE.

Efficacy of allogeneic mesenchymal stem cell transplantation in patients with drug-resistant polymyositis and dermatomyositis.

OBJECTIVE: To assess the safety and clinical efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in a small-scale pilot study with 10 patients with drug-resistant polymyositis (PM) or dermatomyositis (DM). METHODS: A single-arm trial involving 10 patients with DM/PM who were either refractory to standard treatment, or had severe systemic involvement. All patients consented and underwent allogeneic MSCT. Clinical and laboratory manifestations were compared before and after MSCT. RESULTS: Improvements were seen in serum creatine kinase (CK), CK-MB, patient global assessment by visual analogue scale and muscle strength by manual muscle test in all patients, as well as improvement in interstitial lung disease in selected patients. Improvement in chronic non-healing skin ulcers was noted in one patient. Clinical responses were also seen in patients undergoing a second MSCT for recurrence of disease. CONCLUSION: MSCT appears safe and effective in drug-resistant patients with DM/PM. Larger-scale studies including a control group receiving standard treatment are needed to assess the long-term efficacy of allogeneic MSCT in refractory patients with DM/PM.

Umbilical cord mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus.

OBJECTIVE: Umbilical cord (UC)-derived mesenchymal stem cells (MSCs) have shown marked therapeutic effects in a number of diseases in animal studies, based on their potential for self-renewal and differentiation. No data are available on the effectiveness of UC MSC transplantation (MSCT) in human autoimmune disease. This study was undertaken to assess the efficacy and safety of allogeneic UC MSCT in patients with severe and treatment-refractory systemic lupus erythematosus (SLE). METHODS: We conducted a single-arm trial that involved 16 SLE patients whose disease was refractory to standard treatment or who had life-threatening visceral involvement. All of the patients gave consent and underwent UC MSCT. Clinical changes were evaluated before and after transplantation using the SLE Disease Activity Index (SLEDAI), measurement of serum antinuclear antibody (ANA), anti-double-stranded DNA (anti-dsDNA) antibody, serum complement C3 and C4, and albumin levels, and assessment of and renal function. Evaluation of potential mechanisms of MSCT effects focused on the percentage of peripheral blood Treg cells and serum levels of cytokines. RESULTS: From April 2007 to July 2009, a total of 16 patients with active SLE were enrolled and underwent UC MSCT. The median followup time after MSCT was 8.25 months (range 3-28 months). Significant improvements in the SLEDAI score, levels of serum ANA, anti-dsDNA antibody, serum albumin, and complement C3, and renal function were observed. Clinical remission was accompanied by an increase in peripheral Treg cells and a re-established balance between Th1- and Th2-related cytokines. Significant reduction in disease activity was achieved in all patients, and there has been no recurrence to date and no treatment-related deaths. CONCLUSION: Our findings indicate that UC MSCT results in amelioration of disease activity, serologic changes, and stabilization of proinflammatory cytokines. These data provide a foundation for conducting a randomized controlled trial of this new therapy for severe and treatment-refractory SLE.

Influence of SLCO1B1 521T>C, UGT2B7 802C>T and IMPDH1 -106G>A Genetic Polymorphisms on Mycophenolic Acid Levels and Adverse Reactions in Chinese Autoimmune Disease Patients.

INTRODUCTION: Mycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking. METHODS: This study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 -118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 -106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects. RESULTS: SLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 -106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029). CONCLUSION: For Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 -106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.

Factors associated with event-free survival in Chinese patients with Takayasu's arteritis.

OBJECTIVES: To investigate long-term outcomes of Takayasu's arteritis (TA) and explore the predictive factors associated with poor prognosis. METHODS: We performed a retrospective study on consecutive TA patients admitted to the Nanjing Drum Tower Hospital during the period from July 2010 to March 2019. Potential factors contributing to adverse outcomes, including death, vascular complications, and vascular stenosis aggravation were assessed by Cox regression analysis. RESULTS: Seventy-one individuals were enrolled, in which 90.1% were female. The mean onset age was 29.44 ± 11.75 years, and mean follow-up time was 3.42 ± 2.38 years. Adverse outcomes were observed in twenty-five (35.2%) patients, and the 1-, 5-, and 8-year event-free survival was 94.2%, 61.8%, and 29.8% respectively. Univariable Cox regression revealed that pulmonary hypertension (PH) (HR 4.13), high total cholesterol levels (HR 4.49), high LDL cholesterol levels (HR 5.14), and low-dose cyclophosphamide (CTX) treatment (HR 0.53) were associated with adverse outcomes. Among them, only CTX treatment remained significant in multivariable Cox regression analysis (HR 0.62). Interestingly, compared to those ineffective to CTX, the responders had higher immunoglobulin A levels (p < 0.05) but lower CRP levels (p < 0.05). CONCLUSIONS: Even with vigorous therapy, a large proportion of TA patients may present adverse outcomes along with the development of disease. Low-dose CTX treatment is helpful for a better prognosis. Key Points • The prognosis of Takayasu's arteritis is still poor. • Application of low-dose cyclophosphamide in high-risk patients helps to improve the outcome. • Abnormal lipid profiles may contribute to the development of this disease, which also deserves attention.

Allogenic mesenchymal stem cells transplantation in refractory systemic lupus erythematosus: a pilot clinical study.

OBJECTIVE: To determine the safety and efficacy of allogeneic mesenchymal stem cell transplantation (MSCT) in refractory systemic lupus erythematosus (SLE). METHODS: A total of 15 patients with persistently active SLE underwent MSCT. Outcome was evaluated by changes in the SLE disease activity index (SLEDAI), serological features (anti-nuclear antibodies and anti-double-stranded DNA (anti-dsDNA)), renal function and percentage of peripheral blood regulatory T cells. RESULTS: From 11 March 2007 to 4 November 2008, 15 patients with persistently active SLE were enrolled and underwent MSCT. The mean follow-up period was 17.2+/-9.5 months. A total of 13 patients have been followed for more than 12 months. All patients clinically improved following treatment with mesenchymal stem cells with a marked decrease in the SLEDAI score and 24 h proteinuria. At 12-month follow-up, SLEDAI scores decreased from 12.2+/-3.3 to 3.2+/-2.8 and proteinuria decreased from 2505.0+/-1323.9 to 858.0+/-800.7 mg/24 h (all p<0.05, by paired t test, n=12). At 1-year follow-up in 13 patients, 2 had a relapse of proteinuria, while the other 11 continue to have decreased disease activity on minimal treatment. Anti-dsDNA levels decreased. Improvement in glomerular filtration rate was noted in two patients in which formal testing was performed. Non-renal-related manifestations also improved significantly. No serious adverse events were reported. CONCLUSION: Allogeneic MSCT in patients with refractory lupus resulted in amelioration of disease activity, improvement in serological markers and stabilisation of renal function. MSCT appears beneficial in treatment of patients with SLE refractory to conventional treatment options.

Clinical significance of non-thyroidal illness syndrome on disease activity and dyslipidemia in patients with SLE.

OBJECTIVES: Nonthyroidal illness syndrome (NTIS), also known as low triiodothyronine (T3) syndrome, frequently affects patients with systemic lupus erythematosus (SLE) and may affect lipid metabolism. Dyslipidemia is highly prevalent and associated with the long-term prognosis of SLE. The aim of the present study was to explore the clinical significance of NTIS on disease activity and dyslipidemia in patients with SLE. METHODS: Clinical and laboratory data were collected retrospectively from 223 patients with SLE. The correlation between free triiodothyronine (FT3), SLE disease activity, and lipid profiles were estimated. The correlation coefficient (r) was calculated using a Pearson's regression model. Univariate and multivariate logistic regression analyses were performed to identify the risk factors for dyslipidemia in SLE. RESULTS: Serum FT3 levels were negatively correlated with the levels of 24 h urine protein (UP), blood urea nitrogen (BUN), creatinine (Cr) and SLE disease activity index (SLEDAI) (all p < 0.001) in NTIS patients but not in euthyroid patients. ApoB/ApoA1 was significantly correlated with SLEDAI (p < 0.01) in NTIS patients and CRP (p < 0.001) and ESR (p < 0.01) in euthyroid patients. A multivariate analysis revealed that only FT3 exhibited an independent negative association with dyslipidemia (P = 0.01; OR = 0.48; 95% CI 0.27-0.85). CONCLUSION: NTIS frequently occurs in patients with SLE. Low FT3 is associated with disease activity in SLE patients complicated with NTIS. Low FT3 is an independent risk factor for dyslipidemia in patients with SLE.

Severe thrombocytopenia in connective tissue diseases: a single-center review of 131 cases.

To analyze the clinical characteristics of severe thrombocytopenia in patients with various connective tissue diseases (CTDs), one hundred thirty-one consecutive CTD patients with blood platelet count less than 20 × 109/L on admission, which was ascribed to the nature of diseases, during January 2011 to June 2015 in our department were enrolled and checked for their survival status in September 2015. The patients were categorized based on background diseases or therapeutic effects, and compared with clinical features, treatment strategies, and long-term outcomes among the groups. Cumulative survival rates were estimated using Kaplan-Meier analysis. Of the patients, 88.5% were female. The most frequently seen background diseases were primary Sjögren's syndrome (pSS) (53.4%) and systemic lupus erythematosus (SLE) (40.5%). Age on admission for SLE patients (36.7 ± 14.1 years) was much younger than that for other patients (44.4 ± 15.4 years for pSS and 46 ± 16.1 years for other CTDs, p < 0.05). Ninety-six cases accompanied with various bleeding symptoms, which were more common in pSS patients than in SLE patients (80.0% vs. 64.2%, p < 0.05). Glucocorticoids and/or intravenous immunoglobulin were applied as initial therapy with an overall response rate of 36.6%. For patients failed to respond, immunosuppressive drugs were added and the other 22.8% benefited from the treatment. Compared to those ineffective to the aforementioned drugs, patients with therapeutic effects had significantly high immunoglobulin G levels. Twenty patients with refractory diseases accepted mesenchymal stem cell transplantation (MSCT) with a total effective rate of 65.0%. Eleven patients died after the follow-up for a mean time of 27.7 months, of which 7 were associated with hemorrhage. There was no difference in the survival rate among different background diseases. However, compared with those who did not gain remission, patients achieved partial or complete remission had better cumulative survival rates (p < 0.01). In conclusion, among various CTDs, severe thrombocytopenia often occurs in patients with SLE or pSS. Early response to the treatments, but not the background disease, is an important predictor of long-term prognosis. For patients with refractory thrombocytopenia, MSCT may provide an alternative therapeutic strategy.

NUDT15 R139C Variants Increase the Risk of Azathioprine-Induced Leukopenia in Chinese Autoimmune Patients.

The aim of this study was to investigate the influence of NUDT15 R139C, thiopurine S-methyltransferase (TPMT), and 6-TGN on azathioprine (AZA) induced leukopenia in Chinese autoimmune patients. Among 87 enrolled patients, 23 (26.4%) had leukopenia. The NUDT15 R139C variant was associated with leukopenia (p = 1.86 × 10-7; OR: 7.59; 95% CI: 3.16-18.21). However, TPMT genotype was not shown to be correlated with the incidence of leukopenia (p = 0.95). There was no significant difference of 6-TGN concentration between patients with or without leukopenia (p = 0.15) and no association was found in patients with NUDT15 R139C variants alleles (p = 0.62). Finally, we found that the range of 6-TGN concentrations in autoimmune diseases was much lower than the established 6-TGN monitoring range for inflammatory bowel diseases. Therefore, the variant of NUDT15 R139C is strongly associated with AZA-induced leukopenia in Chinese patients with various autoimmune diseases such as systemic lupus erythematosus, Sjögren's syndrome, etc.

NUDT15 R139C variation increases the risk of azathioprine-induced toxicity in Chinese subjects: Case report and literature review.

INTRODUCTION: Azathioprine (AZA) is widely used as an immunosuppressive agent, and its efficacy has been recommended by many clinical studies. However, leukopenia, the most common toxicity, still restricts its clinical applications. Recent studies found that NUDT15 R139C polymorphism is strongly associated with AZA-induced leukopenia in Koreans. However, the follow-up studies available are all limited to inflammatory bowel disease (IBD). Here, we report a case of a Chinese patient with Sjögren syndrome (SS) with wild-type TPMT*3C who was diagnosed with AZA-induced severe toxicity due to NUDT15 mutation based on clinical and laboratory characteristics. CASE PRESENTATION: A 22-year-old Chinese woman with SS developed severe leukopenia after AZA administration for 21 days. Detection of 6-thioguanine nucleotides (6-TGN) showed that the erythrocyte concentration had beyond the monitoring range, indicating that severe leukopenia might be caused by AZA. Furthermore, gene sequencing showed that NUDT15 R139C (poor metabolizer) homozygosity might explain this adverse event. Based on the evidence, AZA administration was immediately stopped and supportive treatments provided, and the patient eventually recovered. CONCLUSION: In this report, we first provide detailed clinical and laboratory characteristics of AZA-induced leukopenia in a patient with SS with a mutant NUDT15 R139C genotype (TT allele) and normal TPMT activity. This case indicates that NUDT15 R139C and TPMT*3C genotypes, and more importantly, 6-TGN levels, should be routinely monitored for those administered with AZA to predict and prevent AZA-induced toxicity.