[Clinical characteristics of patients with rheumatic diseases and abnormal liver function].

Objective: To investigate the clinical characteristics of patients with rheumatic diseases and abnormal liver function, as well as determine the proportion and severity of liver function abnormalities. Methods: Cross-sectional study. Data were collected from patients registered in the Chinese Rheumatism Date Center from 2011 to 2021. The rheumatic diseases analyzed in this study were rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjogren syndrome (SS), ankylosing spondylitis (AS), and gout. Patient data, including demographic characteristics [ such as age, sex, body mass index,(BMI), and smoking history], liver function test results [including alanine aminotransferase (ALT), aspartate aminotransferase, alkaline phosphatase(ALP), and total bilirubin], and use of anti-rheumatic immune drugs and liver-protective drugs, were collected and compared between groups with normal and abnormal liver functions. In addition, the proportions of abnormal liver function were compared between sex and age groups. Results: A total of 116 308 patients were included in this study, including 49 659 with RA, 17 597 with SLE, 9 039 with SS, 11 321 with AS, and 28 692 with gout. The lowest proportion of liver function abnormalities was observed in patients with RA[11.02% (5 470/49 659)], followed by those with SS[17.97% (1 624/9 039)] and AS [18.22% (2 063/11 321) ], whereas patients with SLE [21.14% (3 720/17 597) ] and gout [28.73% (8 242/28 692)] exhibited the highest proportion of these abnormalities. Elevated ALT, mostly classified as grade 1, was the most commonly noted liver function abnormality, whereas elevated ALP was the least common. Some patients who took liver-protective drugs had normal liver function, with the lowest percentage observed in patients with gout [7.45% (36/483) ] and ranging from 21.7% to 30.34% in patients with RA, SLE, SS, and AS. The proportion of liver function abnormalities was higher in males than in females for all disease types [RA: 13.8%(1 368/9 906) vs. 10.3%(4 102/39 753); SLE: 33.6% (479/1 424) vs. 20.0% (3 241/16 173); SS: 25.4%(111/437) vs. 17.6%(1 513/8 602); AS: 20.1%(1 629/8 119) vs. 13.6% (434/3 202); and gout: 29.3% (8 033/27 394) vs. 16.1% (209/1 298)]. In RA, SLE, and AS, the proportions of liver function abnormalities were similar across all age groups. In SS, the proportion of liver function abnormalities increased with age [<40 years: 14.9%(294/1 979); 40-59 years: 18.1%(858/4 741); ≥60 years: 20.4%(472/2 319)], whereas a reversal of this trend was observed in gout [<40 years: 34.9%(4 294/12 320); 40-59 years: 25.5%(2 905/11 398);≥60 years: 21.0%(1 042/4 971)]. Conclusions: The proportions of combined liver function abnormalities in patients with rheumatologic diseases were high, and the utilization rates of liver-protective drugs were low. It is necessary to pay more attention to monitoring patients' liver function, timely administer liver-protective drugs, and optimize liver-protective regimens during the treatment of rheumatic diseases.

[Analysis of differentially expressed microRNA and protein expression profiles carried by exosomes in the plasma of patients with Takayasu's arteritis].

Objective: To detect the microRNAs (miRNAs) and proteins carried by exosomes in the plasma of patients with newly diagnosed Takayasu's arteritis (TAK) and analyze their possible roles in the pathogenesis of TAK. Methods: Ten patients with newly diagnosed TAK from the Department of Rheumatology and Immunology, Peking Union Medical College Hospital were selected during June-November 2020. Five healthy controls were matched with five patients by age and sex. RNA sequencing and protein mass spectrometry were used to detect miRNAs and proteins, respectively, carried by exosomes in the plasma. Differentially expressed miRNAs (DE-miRNAs) and proteins (DEPs) were screened. Thereafter, hierarchical cluster analysis, function, signal pathway, and protein domain enrichment analysis of DE-miRNAs and DEPs were performed. Finally, miRNAs and proteins related to vasculitis and autoimmunity were identified. The possible roles of the miRNAs and proteins in the pathogenesis of TAK were explored. Enumeration data were compared using Fisher's exact probability test or Chi-square test, and a P-value<0.05 was considered significant. Results: Compared with the healthy controls, patients with TAK had 29 DE-miRNAs on their plasma exosomes. Among these DE-miRNAs, miR-101-3p, miR-122-5p, miR-143-3p, miR-185-3p, miR-192-5p, miR-194-5p, miR-19a-3p, miR-19b-3p, miR-20b-5p, miR-21-5p, miR-22-3p, miR-335-5p, miR-34a-5p, miR-3613-5p, miR-548ad-5p, miR-590-3p, and miR-7-5p were upregulated; whereas miR-1249-3p, miR-141-3p, miR-199a-5p, miR-199b-5p, miR-200a-3p, miR-200c-3p, miR-204-5p, miR-29c-5p, miR-335-3p, miR-381-3p, miR-4433b-5p, and miR-584-5p were downregulated. Finally, miR-34a-5p, miR-200c-3p, miR-143-3p, miR-22-3p, and miR-21-5p were identified. Among the 357 DEPs screened, 236 DEPs were upregulated, whereas 121 DEPs were downregulated. Finally, kallikrein B1 (KLKB1), kininogen 1 (KNG1), desmoplakin (DSP) were identified. Conclusion: MiR-34a-5p, miR-200c-3p, miR-143-3p, miR-22-3p, miR-21-5p, KLKB1, KNG1, and DSP carried by exosomes in plasma might participate in the pathogenesis of TAK by regulating vascular physiology, inflammation, autoimmunity, and other processes. They may be biomarkers and therapeutic targets of TAK.

[Recommendations on the diagnosis and treatment of anti-neutrophil cytoplasmic antibody associated vasculitis in China].

Anti-neutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a group of systemic small vasculitis characterized by ANCA positive in serum. Three diseases are included in this group of diseases: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA). In China, standardized diagnosis and treatment of AAV is still lacking. Based on the evidence and guidelines from China and abroad, the Chinese Rheumatology Association formulated the standardization of diagnosis and treatment of ANCA associated vasculitis. The purpose is to standardize the diagnosis of AAV and disease activity assessment, and recommend the treatment strategies.

[Clinical characteristics and pregnancy outcomes of non-criteria obstetric antiphospholipid syndrome].

Objective: To study clinical characteristics and pregnancy outcomes under anti-coagulation therapy of non-criteria obstetric antiphospholipid syndrome. Methods: Patients suspected of obstetric antiphospholipid syndrome(OAPS) were recruited through Chinese Rheumatism Data Center from 2015 to 2019 consecutively. Patients fulfilling 2006 Sydney revised antiphospholipid syndrome criteria were classified as OAPS. Patients fulfilling definition of non-criteria OAPS(NCOAPS) by expert consensus on diagnosis and management of obstetric antiphospholipid syndrome of China were classified as NCOAPS. Clinical characteristics and laboratory results of two groups were compared. Live birth rates and pregnancy outcomes under anti-coagulation therapy were studied. Results: A total of 88 patients were enrolled, including 56 patients (63.6%) as OAPS, 32(36.4%) as NCOAPS. Live births were only reached in 16.1% (9/56) in OAPS patients and 12.5%(4/32) in NCOAPS. Fetal losses after 10 weeks of gestation and pre-eclampsia before 34 weeks were more common in OAPS group compared to NCOAPS group [78.6%(44/56) vs. 18.8%(6/32), P<0.001; 25.0%(14/56) vs. 3.1%(1/32), P=0.020, respectively]. After enrollment, 15 pregnancies were recorded in OAPS, 10 in NCOAPS, all of whom were treated with low-dose aspirin (LDA) combined with low-molecular weight heparin (LMWH). Live birth rates saw dramatic improvements compared to baseline levels in OAPS [16.1% (9/56) vs. 11/15] along with NCOAPS [12.5% (4/32) vs. 7/10]. Conclusion: Though NCOAPS and OAPS patients differ in antiphospholipid antibody spectrum and pattern of pregnancy morbidities, both groups benefit from LDA combined with LWMH treatment, as live birth rates improve. Non-criteria OAPS patients are recommended to receive anti-coagulation therapy during pregnancy.

[Clinical characteristics and risk factors in 118 patients with systemic lupus erythematosus and osteonecrosis].

Objective: To investigate the clinical characteristics and risk factors for osteonecrosis (ON) in patients with systemic lupus erythematosus (SLE). Methods: This is a case-control study. A total of 118 patients diagnosed with SLE complicated with ON (study group) were retrospectively analyzed between 2014 and 2019. Gender, age, and course matched 118 SLE patients without ON were selected as controls. Clinical manifestations, laboratory findings, medical history, and treatments were recorded and analyzed. Results: Among 118 patients, the male to female ratio was 20 to 98 with a median age of 27 years and course of disease 1-168 months. Compared with the control group, the study group presented a longer cumulative duration of glucocorticoid therapy [36.5 (0-168) months vs. 19.0(0-168) months on average, P<0.05], a higher incidence of osteoporosis (29.7% vs. 4.2%, P<0.001), a higher frequency of immune-suppressive therapy (83.9% vs. 64.4%, P=0.035), more organs involveed [median 2 (0-5) vs. 1 (0-4)], and a higher SLE disease activity index (SLEDAI) (14.22±7.40 vs. 11.63±6.11, P<0.05) in univariate logistic regression. The control group had a higher rate of positive Coombs test (39.8% vs. 7.6%, P<0.05). No statistical difference on methylprednisolone (MP) pulse therapy (P>0.05) was observed. Multivariate logistic regression suggested that SLEDAI (OR= 1.070, 95%CI 1.026-1.116, P<0.005), osteoporosis (OR=10.668, 95%CI 3.911-29.103, P<0.001) and a positive Coombs test(OR=0.492, 95%CI 0.266-0.910, P<0.05) were related to the development of ON in SLE patients. Conclusion: A higher disease activity and the presence of osteoporosis are associated with an increased risk of ON in patients with SLE, and positive Coombs test seems a protective factor of ON.

[The 487th case: prominent eyes, headache, blurred vision].

One 51 years old man was admitted to the rheumatology department with a history of prominent eyes, headache and blurred vision for half year. The main manifestations included retrobulbar inflammatory pseudotumor and retroperitoneal fibrosis. He was initially diagnosed as granulomatosis with polyangiitis. Prednisone and cyclophosphamide were administrated and effective. New mass of dura mater and osteosclerosis presented during follow up. Finally Erdheim Chester disease(ECD) was diagnosed by biopsy and pathological examination. Vemurafenib, a v-raf murine sarcoma viral oncogenes homolog B1 (BRAF) inhibitor, 480 mg was given twice a day. The patient's condition is stable and still in follow-up. Although ECD is a rare histiocytosis, clinicians should pay attention to its manifestations and differential diagnoses.

[Use of new diagnostic criteria for reclassification of polyarteritis nodosa].

With the recognition of antineutrophil cytoplasmic antibodies (ANCA)-related vasculitis and widespread vaccination against viral hepatitis B, the prevalence of polyarteritis nodosa (PAN) varied considerably. In our study, patients diagnosed as polyarteritis nodasa (PAN)based on the 1990 American College of Rheumatology(ACR) criteria were reclassified using 2007 European Medicines Agency(EMA) algorithm modified by 2012 Chapel Hill Consensus Conference(CHCC) definitions, aiming to evaluate the new classification criteria for the diagnosis of PAN. A total of 113 PAN patients admitted to Peking Union Medical College Hospital from January 2002 to December 2018 were retrospectively analyzed, who were classified into three subtypes including 9 patients with cutaneous, 80 with classic and 24 Hepatitis B virus (HBV) associated PAN. All patients were reclassified according to 2007 EMA algorithm using CHCC 2012 definitions. As a result, 7 patients were diagnosed as microscopic polyangiitis(MPA) and 19 patients with unclassified vasculitis based on the new classification criteria. The diagnostic rate of PAN was gradually declined as the classification criteria of vasculitides was update. However, there are quite a few PAN patients in China, whom rheumatologists should pay attention to the early diagnosis and treatment.

[Clinical analysis of golimumab in the treatment of severe/refractory cardiovascular involvement in Behcet syndrome].

OBJECTIVE: To explore the effectiveness and safety of golimumab in the treatment of severe/refractory cardiovascular Behcet syndrome (BS). METHODS: We retrospectively analyzed the clinical data of nine patients diagnosed with severe/refractory cardiovascular BS and treated with golimumab from February 2018 to July 2020 in Peking Union Medical College Hospital. We analyzed levels of erythrocyte sedimentation rate (ESR) and high-sensitivity C-reactive protein (hsCRP), imaging findings, and the doses of glucocorticoids and immunosuppressive agents during the period of combined treatment with golimumab. RESULTS: Nine patients were enrolled, including 8 males and 1 female, with a mean age and median course of (37.0±8.6) years and 120 (60, 132) months, respectively. Seven patients presented with severe aortic regurgitation combined with other cardiovascular involvement secondary to BS. Two patients presented with large vessel involvement, including multiple aneurysms and vein thrombosis. Prior to golimumab treatment, seven patients were treated with glucocorticoids and multiple immunosuppres-sants [with a median number of 3 (1, 3) types] while still experienced disease progression or elevated inflammation biomarkers during postoperative period. Eight patients with disease progression, uncontrolled inflammation and history of severe postoperative complications required effective and fast control of inflammation during perioperative period. One patient had adverse reaction with tocilizumab and switched to golimumab during perioperative period. The patients were treated with golimumab 50 mg every 4 weeks, along with concomitant treatment of glucocorticoid and immunosuppressants. After a median follow-up of (16.3±5.6) months, all the patients achieved clinical improvement. Vascular lesions were radiologically stable and no vascular progressive or newly-onset of vascular lesions was observed. The eight patients who experienced cardiac or vascular operations showed no evidence of postoperative complications. The ESR and hsCRP levels decreased significantly [16.5 (6.8, 52.5) mm/h vs. 4 (2, 7) mm/h, and 21.24 (0.93, 32.51) mg/L vs. 0.58 (0.37, 1.79) mg/L (P < 0.05), respectively]. The dose of prednisone was tapered from 35 (15, 60) mg/d to 10.0 (10.0, 12.5) mg/d. No prominent adverse reactions were observed. CONCLUSION: Our study suggests that golimumab is effective in the treatment of severe/refractory cardiovascular BS. Combination immunosuppression therapy with golimumab contributes to control of inflammation, reduction of postoperative complications and tapering the dose of glucocorticoids or immunosuppressants.

[Clinical and prognostic characteristics in patients with eosinophilic granulomatosis with polyangitis].

Objective: To analyze the clinical and prognostic characteristics in patients with eosinophilic granulomatosis with polyangitis (EGPA). Methods: The clinical data of 146 EGPA patients hospitalized in Peking Union Medical College Hospital from 2000 to 2019 were analyzed retrospectively, including clinical manifestations, laboratory results, treatment, complications and outcome at discharge. Birmingham Vasculitis activity score-V3 (BVAS-V3) was used to evaluate disease activity. Results: The ratio of male to female was 1.8∶1 with average age (41.7±16.1) year-old. The median time from disease onset to diagnosis was 18(6, 60) months (0.5~450). The most common clinical manifestations were lung [121(82.9%)] and nose/paranasal sinuses [119(81.5%)] involvement. The positive rate of anti-neutrophil cytoplasmic antibody (ANCA) was 24.7%, mainly peripheral (P)-ANCA/myeloperoxidase (MPO)-ANCA. Compared with ANCA-negative patients, the ANCA-positive patients had a higher incidence of renal involvement and nervous system involvement (66.7% vs. 20.9%, 80.6% vs. 51.8%, P<0.001), fever and optic neuropathy (66.7% vs. 40.9%,8.3% vs. 0, P<0.05), more active disease [median BVAS-V3 25(18,30)vs. 19(14,24),P=0.001] and more elevated erythrocyte sedimentation rate [40.5(20.5,82.8)mm/1h vs. 25.0(13.3,50.8)mm/1h,P=0.006] and C-reactive protein [37.1(11.8,72.9)mg/L vs.13.5(3.4,66.1)mg/L,P=0.036]. More ANCA-negative patients had pleural effusion (20.9% vs. 5.6%, P<0.04) compared with ANCA-negative patients. Pulmonary infection was the most common complication. A total of 12 EGPA patients (8.2%)achieved remission and 6 patients (4.1%)died or discharged themselves from the hospital. Conclusion: EGPA is a rare small vessel vasculitis. The clinical manifestations and outcomes are heterogenous. The mortality rate of EGPA is high.

[Clinical features and risk factors of portal vein thrombosis in 28 patients with antiphospholipid syndrome].

Objective: Portal vein thrombosis (PVT) is a rare and severe clinical manifestation of antiphospholipid syndrome (APS), as well as a predictor of poor prognosis. This study was conducted to explore the clinical features and risk factors of PVT in APS patients. Methods: A total of 123 APS patients diagnosed from 2012 to 2019 were retrospectively enrolled. The diagnosis of PVT was made according to the 2009 American College of Liver Diseases (AASLD) criteria. Clinical and laboratory data were collected. A multivariate (MV) logistic regression model was constructed using a stepwise forward selection procedure among those candidate univariables with P values<0.10. Results: A total of 28 cases with PVT, and 95 control cases without PVT were finally enrolled.The 28 APS-PVT patients included 5 males and 23 females with age range from 17 to 63 years. Clinical manifestations included acute thrombosis in 8 patients, chronic thrombosis in 16, and 4 with portal vein spongiform. As to the involved vessels, single portal vein thrombosis was seen in 20 patients, portal combined with superior mesenteric vein (SMV) and splenic vein in one patient, portal plus SMV in 4 and only SMV in 3 patients. Other manifestations were portal hypertension (16/28), esophageal varices (13/28), spleen infarction (7/28) and gastrointestinal bleeding (4/28). Two antiphospholipid antibodies were positive in 13 cases. Triple positive antibodies were seen in 7 cases. Multivariate logistic regression analysis showed that disease duration less than 0.5 years (OR=72.74, 95%CI 7.50-705.45, P<0.001), hypoalbuminemia (OR=356.45, 95%CI 19.19-6 620.14, P<0.001), and elevated erythrocyte sedimentation rate (ESR)/C-reactive protein (CRP) (OR=14.41, 95%CI 1.49-139.20, P<0.001) were independent risk factors for PVT in APS. Conclusion: PVT is usually misdiagnosed due to insidious onset. Short disease duration, hypoalbuminemia and elevated ESR/CRP are risk factors for PVT in APS. Better understanding, early diagnosis and treatment will improve the clinical outcome.

[Clinical characteristics of 57 patients with polyarteritis nodosa and renal involvement].

Objective: To investigate the clinical characteristics of polyarteritis nodosa (PAN) patients with renal involvement. Methods: PAN patients admitted to the department of rheumatology, department of pediatrics, department of nephrology, general internal medicine department and department of vascular surgery at Peking Union Medical College Hospital from June 2012 to August 2018 were enrolled in this study and were divided into two groups according to renal involvement or not. The clinical characteristics were analyzed. Results: A total of 94 PAN patients were finally enrolled and 57 (60.64%) presented kidney manifestation. The mean age of onset was (37.76±17.40) years old and the interval from onset to diagnosis was 10 (0 to 240) months. Forty patients were misdiagnosed once or more times. In patients with renal involvement, 9 cases suffered from renal ischemia or infarction, 31 with microscopic haematuria, 26 with proteinuria, renal artery or its branch involved in 17 cases, renal vein thrombosis in 1 case, 4 cases with pyeloureterectasis, one case with renal fascia thickening, 33 cases with impaired renal function (serum creatinine>84 µmol/L) including creatinine>140 µmol/L in 10 patients. Renal artery branch stenosis was the most common presentation [9 cases (52.94%)] of renal vascular involvement, other abnormalities including nodular dilatation [4 cases (23.53%)], occlusion [3 cases (17.65%)]. There were significant differences (P<0.05) in the PAN patients with and without renal involvement in the following: age of onset [(33.72±16.13) years vs. (43.97±17.66) years, t(2)=2.901, P=0.005], weight loss(≥4kg since PAN onset) [25(43.86%) vs. 7(18.92%), χ(2)=6.216, P=0.013], elevation of diastolic blood pressure [22(38.60%) vs. 7(18.92%), χ(2)=4.072, P=0.044], acromegaly gangrene [18(31.58%) vs. 21(56.76%), χ(2)=5.859, P=0.015], and gastrointestinal artery involvement [20(35.09%) vs. 6(1.22%), χ(2)=3.993, P=0.046]. Laboratory parameters and the application of glucocorticoid and cyclophosphamide therapies were similar in two groups (all P>0.05). Conclusion: Young PAN patients are more likely to be associated with renal involvement, especially gastrointestinal arteries.

[CYP2C19 genetic polymorphism and monitoring voriconazole plasma concentrations in the treatment and prevention of invasive fungal disease for hematological patients].

Objective: To evaluate the effects of CYP2C19 genetic polymorphism on the plasma concentration of voriconazole in patients with hematological disease and the value of serial monitoring plasma concentrations in the treatment and prevention of invasive fungal disease (IFD). Methods: From January 2016 to December 2016, 65 hematological patients who received voriconazole intravenous administration for the treatment of invasive fungal disease were enrolled in this study. The population CYP2C19 polymorphism of voriconazole were performed using PCR-Pyrosequencing. The trough plasma concentrations of vriconazole (Ctrough) was detected by ultra performance liquid chromatography tandem mass spectrometry. Results: Based on the genotype analysis, 65 subjects were identified as extensive metabolizers' group (30 cases) and poor metabolizers' group (35 cases). The Ctrough of the 65 patients were detected for 169 times totally, and there was a significant difference of Ctrough values between the two groups [0.98(0.38-2.08) mg/L vs 2.19(1.53-4.27) mg/L, z=10.286, P<0.001]. The medium of Ctrough in 65 hematological patients were described. Lack of response to therapy was more frequent in patients with voriconazole levels <1.5 mg/L (50.0%) than in those with voriconazole levels >1.5 mg/L (20.5%) (P=0.052). And the risk of adverse events was more frequent in patients with voriconazole levels >5.5 mg/L (80.0%) than in those with voriconazole levels ≤5.5 mg/L (8.3%) (χ2=11.689, P=0.020). Conclusion: Patients with CYP2C19 wild-type phenotype are extensive metabolizers, their Ctrough of voriconazole are significantly lower than patients with CYP2C19 non-wild-type phenotype (poor metabolizers). Appropriate concentrations of vriconazole can improve the efficacy and safety during treatment.