mTORC2 contributes to systemic autoimmunity.

The development of many systemic autoimmune diseases, including systemic lupus erythematosus, is associated with overactivation of the type I interferon (IFN) pathway, lymphopenia and increased follicular helper T (Tfh)-cell differentiation. However, the cellular and molecular mechanisms underlying these immunological perturbations remain incompletely understood. Here, we show that the mechanistic target of rapamycin complex 2 (mTORC2) promotes Tfh differentiation and disrupts Treg homeostasis. Inactivation of mTORC2 in total T cells, but not in Tregs, greatly ameliorated the immunopathology in a systemic autoimmunity mouse model. This was associated with reduced Tfh differentiation, B-cell activation, and reduced T-cell glucose metabolism. Finally, we show that type I IFN can synergize with TCR ligation to activate mTORC2 in T cells, which partially contributes to T-cell lymphopenia. These data indicate that mTORC2 may act as downstream of type I IFN, TCR and costimulatory receptor ICOS, to promote glucose metabolism, Tfh differentiation, and T-cell lymphopenia, but not to suppress Treg function in systemic autoimmunity. Our results suggest that mTORC2 might be a rational target for systemic autoimmunity treatment.

Angiotensin-converting enzyme (ACE and ACE2) imbalance correlates with the severity of cerulein-induced acute pancreatitis in mice.

Angiotensin-converting enzyme (ACE) and its effector peptide angiotensin II (Ang II) have been implicated in the pathogenesis of pancreatitis. Angiotensin-converting enzyme 2 (ACE2) degrades Ang II to angiotensin-(1-7) [Ang-(1-7)] and has recently been described to have an antagonistic effect on ACE signalling. However, the specific underlying role of ACE2 in the pathogenesis of severe acute pancreatitis (SAP) is unclear. In the present study, the local imbalance of ACE and ACE2, as well as Ang II and Ang-(1-7) expression, was compared in wild-type (WT) and ACE2 knock-out (KO) or ACE2 transgenic (TG) mice subjected to cerulein-induced SAP. Serum amylase, tumour necrosis factor-α, interleukin (IL)-1ß, IL-6 and IL-10 levels and histological morphometry were used to determine the severity of pancreatitis. In WT mice, pancreatic ACE and Ang II and serum Ang II expression increased (P < 0.05), while pancreatic ACE2 and Ang-(1-7) and serum Ang-(1-7) levels were also significantly elevated (P < 0.05) from 2 to 72 h after the onset of SAP. However, the ratio of pancreatic ACE2 to ACE expression was significantly reduced (from 1.46 ± 0.09 to 0.27 ± 0.05, P < 0.001) and paralleled the severity of pancreatitis. The Ace2 KO mice exhibited increased levels of tumour necrosis factor-α, IL-1ß, IL-6, multifocal coagulative necrosis and inflammatory infiltrate, and lower levels of serum IL-10 and pancreatic Ang-(1-7) (4.70 ± 2.13 versus 10.87 ± 2.51, P < 0.001) compared with cerulein-treated WT mice at the same time point. Conversely, Ace2 TG mice with normal ACE expression were more resistant to SAP challenge as evidenced by a decreased inflammatory response, attenuated pathological changes and increased survival rates. These data suggest that the ACE2-ACE imbalance plays an important role in the pathogenesis of SAP and that pancreatic ACE2 is an important factor in determining the severity of SAP.

Ulinastatin activates the renin-angiotensin system to ameliorate the pathophysiology of severe acute pancreatitis.

BACKGROUND AND AIM: Ulinastatin is a drug used effectively to alleviate symptoms and improve the pathophysiology of various types of pancreatitis. However, the molecular mechanism responsible for its action remains unknown. Therefore, we further explore the therapeutic effects of ulinastatin and investigate possible molecular pathways modulated by this drug in the development of severe acute pancreatitis (SAP). METHODS: SAP mouse model was created by administering intraperitoneal injections of cerulein and lipopolysaccharide. Pancreatic injury was assessed by performing biochemical and histological assays and by measuring the inflammatory response of the pancreas. Specifically, we examined changes in the expression of components of the rennin-angiotensin system (RAS), including angiotensin-converting enzyme (ACE)-angiotensin II (Ang II)-angiotensin type 1 receptor (AT-1R), and ACE2-Ang-(1-7)-Mas receptor. RESULTS: When SAP mouse models were treated with ulinastatin at a dosage of 50,000 U/kg body weight, we found, through biochemical and histopathological analyses, that the pancreatic injury was significantly ameliorated. Administration of ulinastatin to SAP mice led to increased expression of ACE2, Ang-(1-7), and Mas receptor, decreased expression of serum Ang II and pancreatic AT-1R, and no alterations in the expression of pancreatic ACE and Ang II when compared to cerulein-treated control group that did not receive ulinastatin. CONCLUSIONS: This study shows that ulinastatin has differential effects on the two axes of the RAS during SAP. Our results further suggest that upregulation of components of the ACE2-Ang-(1-7)-Mas pathway might be an important mechanism contributing to the therapeutic role of ulinastatin in alleviating pancreatitis-associated symptoms.

CD8 T cell-derived perforin regulates macrophage-mediated inflammation in a murine model of gout.

OBJECTIVES: Gout is characterized by hyperuricemia and recurrent inflammatory episodes caused by intra-articular crystal deposition of monosodium urate (MSU). There is a clear relationship between gout and metabolic syndrome. Recent evidence indicates that perforin plays a role in regulating glucose homeostasis and provides protection in diet-induced non-alcoholic steatohepatitis models. However, the impact of perforin on immune inflammation in gout remains unclear. METHODS: We induced acute gout models in both wild-type (WT) mice and Prf1null mice by administering intra-articular injections of MSU crystals. We compared the ankle joint swelling and the histological score between the two groups. Furthermore, we investigated underlying mechanisms through in vitro co-culture experiments involving CD8 T cells and macrophages. RESULTS: In this study, Prf1null mice showed significantly more pronounced ankle swelling with increased inflammatory cell infiltrations compared with WT mice 24 h after local MSU injection. Moreover, MSU-induced Prf1null mice exhibited increased accumulation of CD8 T cells but not NK cells. Perforin-deficient CD8 T cells displayed reduced cytotoxicity towards bone marrow-derived M0 and M1 macrophages and promoted TNF-α secretion from macrophage. CONCLUSIONS: Perforin from CD8 T cells limits joint inflammation in mice with acute gout by downregulating macrophage-mediated inflammation. Key Points • Perforin deficiency increased swelling in the ankle joints of mice upon MSU injection. • Perforin deficiency is associated with increased immune cell recruitment and severe joint damage in gout. • Perforin regulated CD8 T cell accumulation in gout and promoted CD8 T cell cytotoxicity towards M0 and M1 macrophages. • CD8 T cell-derived perforin regulated pro-inflammatory cytokine secretion of macrophage.

Systematic analysis for clinical characteristics and outcomes of IgG4-related disease patients during the COVID-19 pandemic.

BACKGROUND: To systematically describe clinical characteristics and investigate factors associated with COVID-19-related infection, hospital admission, and IgG4-related disease relapse in IgG4-RD patients. METHODS: Physician-reported IgG4-RD patients were included in this retrospective study. Using multivariable logistic regression analysis to determine factors for primary outcome (COVID-19-related IgG4-RD relapse) and secondary outcome (COVID-19-related infection and hospital admission). Covariates included age, sex, body mass index, smoking status, comorbidities, IgG4-RD clinical features, and treatment strategies. RESULTS: Among 649 patients, 530 had a diagnosis of COVID-19, 25 had COVID-19-related hospital admission, and 69 had COVID-19-related IgG4-RD relapse. Independent factors associated with COVID-19 infection were age (OR, 0.98; 95% CI, 0.96-1.00), body mass index (1.10, 1.03-1.18), and tofacitinib (0.34, 0.14-0.79). Further analysis indicated that age (1.10, 1.03-1.16), coronary heart disease (24.38, 3.33-178.33), COVID-19-related dyspnea (7.11, 1.85-27.34), pulmonary infection (73.63, 16.22-4615.34), and methotrexate (17.15, 1.93-157.79) were associated with a higher risk of COVID-19-related hospital admission. Importantly, age (0.93, 0.89-0.98), male sex (0.16, 0.03-0.80), ever/current smoking (19.23, 3.78-97.80), COVID-19-related headache (2.98, 1.09-8.17) and psychiatric symptoms (3.12, 1.07-9.10), disease activity before COVID-19 (1.89, 1.02-3.51), number of involved organs (1.38, 1.08-1.76), glucocorticoid dosage (1.08, 1.03-1.13), and methotrexate (5.56, 1.40-22.08) were strong factors for COVID-19-related IgG4-RD relapse. CONCLUSIONS: Our data add to evidence that smoking and disease-specific factors (disease activity, number of involved organs, and specific medications) were risk factors of COVID-19-related IgG4-RD relapse. The results highlight the importance of adequate disease control with b/tsDMARDs, preferably without using methotrexate and increasing glucocorticoid dosages in the COVID-19 era. Key Points • COVID-19-related infection or hospital admission were associated with known general factors (age, body mass index, specific comorbidities and methotrexate) among IgG4-RD patients. • Smoking and disease-specific factors (disease activity, number of involved organs and specific medications) were associated with higher odds of COVID-19-related IgG4-RD relapse. • The results highlight the importance of adequate disease control with b/tsDMARDs, preferably without using methotrexate or increasing glucocorticoid dosages.

Severe acute pancreatitis is associated with upregulation of the ACE2-angiotensin-(1-7)-Mas axis and promotes increased circulating angiotensin-(1-7).

BACKGROUND/OBJECTIVES: Angiotensin-converting enzyme 2 (ACE2), its product angiotensin-(1-7) and its receptor Mas may counteract the adverse effects of the ACE-angiotensin receptor II-AT(1) axis in many diseases. We examined the expression of these novel components of the rennin-angiotensin system in an experimental mouse model of severe acute pancreatitis (SAP). METHODS: SAP was induced by six intraperitoneal injections of caerulein, and mice were sacrificed at 2, 12, 24, 48 and 72 h post disease-induction (normal control group mice were sacrificed at 2 h post disease-induction). Tissue and blood were collected for biochemical detection, gene and protein expression by qRT-PCR and western blot analysis, enzyme-linked immunosorbent assay and immunohistology detection. RESULTS: Pancreatic ACE2 gene and protein expression, plasma and pancreatic angiotensin-(1-7) levels and Mas receptor gene and protein expression were significantly increased (p < 0.05) following SAP induction compared with the normal control group. CONCLUSIONS: Severe acute pancreatitis is associated with upregulation of the ACE2-angiotensin-(1-7)-Mas axis and promotes increased circulating angiotensin-(1-7). These results support the presence of an ACE2-angiotensin-(1-7)-Mas axis in pancreatitis.

Foxo3 Promotes the Differentiation and Function of Follicular Helper T Cells.

Follicular helper T cells (Tfhs) are essential for germinal center (GC) B cell maturation and antibody development. However, the intrinsic mechanisms that regulate Tfh differentiation are largely unknown. Here, we demonstrate that the frequencies of Tfhs and GC B cells, as well as interleukin-21 (IL-21) and anti-ovalbumin (OVA) antibodies, are markedly decreased in forkhead box O3 (Foxo3) knockout mice immunized with OVA. Using mixed bone marrow chimeras and lymphocyte-repopulated Rag1-/- mice proves that wild-type (WT), but not Foxo3-deficient T cells provoke GC B cell maturation and antibody production. Deficiency of Foxo3 inhibits inducible T cell co-stimulator (ICOS)-induced Tfh differentiation. Chromatin immunoprecipitation assay results suggest that Foxo3 is able to bind to the IL-21 promoter and regulate IL-21 secretion. In conclusion, our study unveils a critical role of Foxo3 in the regulation of Tfh differentiation and IL-21 production. Modulating Foxo3 activity may be beneficial for enhancing or preventing antibody-mediated immune responses.

Angiostrongylus cantonensis: effect of combination therapy with albendazole and dexamethasone on Th cytokine gene expression in PBMC from patients with eosinophilic meningitis.

To determine how combination therapy with albendazole and dexamethasone changed cytokine responses in peripheral blood mononuclear cells (PBMC) in patients with eosinophilic meningitis caused by Angiostrongylus cantonensis (EOMA), we measured mRNA levels of Th2 (IL-5, IL-4 and IL-10) and Th1 (IL-2 and IFN-gamma) cytokines with reverse transcription polymerase chain reaction (RT-PCR). Forty-three patients were divided into three groups: group 1 (pre-treatment, 13 patients), group 2 (7 days post-treatment, 14 patients), and group 3 (30 days post-treatment, 16 patients). Peripheral eosinophil counts were also measured. EOMA patients showed higher levels of Th2 cytokines, including IL-5 and IL-10, and peripheral eosinophil counts, but no changes in IL-4 or Th1 cytokines. Combination therapy reduced IL-5 mRNA expression and peripheral eosinophil counts to control levels, but increased IL-10, IL-2, and IFN-gamma mRNA expression, and did not change IL-4 levels. These data suggest that systemic Th2 cytokine responses, especially IL-5, and peripheral eosinophil counts increased in EOMA patients. Combination therapy with albendazole and dexamethasone can shift the cytokine responses from Th2 to Th1 dominance, which may be a therapeutic mechanism.

Serum-soluble TRAIL: a potential biomarker for disease activity in myositis patients.

OBJECTIVES: Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is a member of the TNF super-family, which is involved in the regulation of immune response and pathogenesis of autoimmune diseases, including polymyositis (PM) and dermatomyositis (DM). In this study, we examined the level and origin of serum-soluble TRAIL (sTRAIL) in patients with PM and DM and analyzed its association with disease activity and clinical features. METHOD: 11 PM patients, 33 DM patients, and 20 healthy controls were enrolled in this study. Clinical features were recorded when admitted, and disease activity was evaluated by myositis disease activity assessment visual analogue scale (MYOACT). TRAIL expression in muscle tissues was detected by immunohistochemistry. Serum sTRAIL levels were measured by enzyme-linked immunosorbent assay. The expression of membrane TRAIL (mTRAIL) and its receptors, including DR4 and DR5, on circulating T cells was analyzed by flow cytometry. RESULTS: TRAIL was expressed in infiltrated inflammatory cells in muscle tissues from patients. The serum sTRAIL level was markedly increased in patients and was positively correlated with the disease activity. Serum sTRAIL was decreased after therapy in patients and was specifically higher in patients with dysphagia, but lower in patients with autoantibody Jo-1 positive. The frequency of mTRAIL and its receptors on circulating T cells from patients were significantly elevated than that from healthy controls. CONCLUSIONS: The serum sTRAIL could be a biomarker for evaluating the disease activity of PM and DM, and targeting the generation of TRAIL in T cells might be a potential approach in the treatment of PM and DM.

[Clinical study of the impact of a history of chronic diseases on the mortality of patients with multiple organ dysfunction syndrome in the elderly].

OBJECTIVE: To analyze the clinical feature of multiple organ dysfunction syndrome in the elderly (MODSE) and study the impact of a history of chronic diseases on the mortality of patients with MODSE. METHODS: Altogether 331 cases with MODSE were prospectively analyzed in 4 tertiary-level teaching hospitals in Beijing and Tianjin cities from March 2002 to January 2005. RESULTS: In our investigation,the primary etiology of MODSE was severe infection (27.2%), shock (24.5%), major operation (22.1%), cardiopulmonary resuscitation (CPR) (11.2%), severe trauma (7.2%), or severe pancreatitis (6.6%) in order of frequency. The incidence rate of dysfunction in cardiovascular system, lung, brain, gastrointestinal system, kidney, coagulation system and liver was 72.2%, 94.6%, 74.6%, 83.1%, 77.9%, 76.1%, 77.6% respectively. The mortality rates in the group with dysfunction of lung, brain, cardiovascular and gastrointestinal system were higher than those with the normal organ function. The mortality rate of patients with brain dysfunction ranked the highest (74.1%). Seventy-eight point five percent of patients with MODSE had a history of chronic diseases, and in average with two chronic diseases. The mortality rate of patients with chronic diseases was higher than those without chronic diseases (68.1% vs. 54.9%, P=0.039). With the increase in number of failing organs, mortality was getting higher. CONCLUSION: Infection is the most common primary cause, lung and gastrointestinal system are the most affected organs in multiple organ dysfunction, and the mortality rate of patients with brain dysfunction is the highest. The mortality rate of patients with chronic diseases is higher than those without chronic diseases. Early intervention of primary diseases and chronic diseases and prompt control of infection play a key role in preventing deterioration of patients with MODSE.

[Clinical observation on 25 cases of severe angiostrongyliasis cantonensis].

OBJECTIVE: To summarize the clinical features of severe angiostrongyliasis cantonensis (AC) patients. METHODS: Clinical data on symptoms, physical signs, auxiliary examination and prognosis of 25 severe AC patients hospitalized in June-Sept 2006 were analyzed. RESULTS: Epidemiologically, all cases had eaten uncooked fresh water snails. One of the early symptoms was fever (16 cases, 64.0%), including 8 cases with low-grade fever, 7 cases with mid-range fever, and 1 case high fever. Nervous system manifestation: (1) All cases had headache, entire headache (56.0%) or partial (44.0%), especially in occipitalis. (2) Patients had distinct degree neck rigidity, with negative pathologic reflex; 12 cases had nausea and vomiting (48.0%). (3) 20 cases (80.0%) had skin paresthesia, 5 had severe pain and hyperalgia on skin; 3 cases with skin numbness, and 2 with thermohypesthesia. (4) 11 cases (44.0%) appear distinct degree depraved vision; 3 cases had photophobia, 5 with blur vision, 1 each with diplopia, defect of field vision or bug sign, respectively. (5) Nasolabial groove became shallow and distortion of commissure in 4 cases (16.0%), and 2 cases (8.0%) couldn't close up eyelid. (6) 4 cases had sustained or curative tinnitus. Laboratory examination showed that eosinophilic granulocytes increased in both peripheral blood and cerebrospinal fluid. Skull MRI for 14 cases revealed linear enhancement in local meninx or abnormal enhancement in cerebral parenchyma. Chest CT examination in 7 cases showed nodule shadow and spot flaky ground-glass shadow in lungs. One and 3 months after being discharged from hospital, 12 patients (48.0%) still had sequelaes--7 cases had tingling sensation on skin, 1 case had temperature sensation dysfunction on the skin of chest and abdomen, 3 cases had headache occasionally, and 1 case still had defect of field vision. CONCLUSION: Central nervous system has been impaired in the angiostrongyliasis cantonensis patients who may need a longer convalescent period.

Exogenous leptin protects rat models of sodium taurocholate­induced severe acute pancreatitis through endocrinal and immunological pathways.

Acute pancreatitis (AP) is a common non­bacterial disease compromising pancreatic tissues. Adipocyte­derived leptin is closely associated with the severity and clinical outcome of pancreatitis. The potential protective effects of exogenous leptin administration on a rat model of severe AP (SAP) remain to be elucidated, and were examined in the present study. Male Wistar rats were divided into a sham operation group (SO), SAP model group (SAP) and leptin group (LEP). Each group was divided into three sub­groups by observation time (24, 48 and 72 h). The SAP models were prepared by retrograde injection of 6% sodium taurocholate into the pancreatic­bile duct. Following model establishment, exogenous leptin was intraperitoneally injected into mice at 50 mg/kg in the LEP group. Subsequently, serum amylase, lipase and glucose levels at particular time­points were analyzed using a fully­automatic biochemical analyzer, and serum levels of tumor necrosis factor (TNF)­α and interleukin (IL)­10 were detected using an enzyme­linked immunosorbent assay. The pathological changes in pancreatic tissues were observed using hematoxylin and eosin staining, and the pancreatic expression of the long form of the leptin receptor (OB­Rb) was detected and evaluated using Nest­polymerase chain reaction analysis. The mortality rates of the model rats were compared between the groups. Following the administration of exogenous leptin, the serum level of amylase in the LEP group was significantly decreased at 48 h, compared with that in the SAP group, with serum lipase levels decreased at 48 and 72 h, and blood glucose levels decreased at 72 h. Regarding the serum inflammatory factors, the level of TNF­α in the LEP group was significantly lower, compared with that in the SAP group at 24 h; whereas no significant difference was observed in the serum level of IL­10 between the two groups. Regarding the pathological changes in the pancreas, the tissues in the LEP group showed significantly alleviated pancreatic inflammation. In addition, the pancreatic expression of OB­Rb in the LEP group was significantly higher, compared with that in the SAP group at 24 and 48 h. No significant difference in 3­day mortality rates were observed between the SAP group and the LEP group. Taken together, exogenous leptin administration regulated inflammatory factors and the expression of OB­Rb at the early stage of AP, which exerted protective effects by through the immunological and endocrinal pathways.

A scoring system for assessing the severity of acute diarrhea of adult patients.

BACKGROUND: Diarrhea is frequently seen in developed and developing countries, and severe diarrhea is characterized by the high risk of death. Thus, it is very important to assess the severity of diarrhea early. We conducted a multi-center study to identify risk factors for the severity of diarrhea in adult patients and formulate an adult diarrhea state score (ADSS) for out-patient clinicians. METHODS: A total of 219 adult patients with acute diarrhea were divided into two groups: 132 patients with mild diarrhea and 87 with severe diarrhea. Logistic regression was used to determine risk factors for the severity of diarrhea. The risk factors were assessed and an ADSS was formulated. Receiver operating characteristic (ROC) analysis was made to evaluate the diagnostic accuracy of ADSS, and the Kappa test was used to confirm the diagnostic reliability. RESULTS: Five risk factors for evaluating the severity of diarrhea in adults included age (P<0.05), axillary temperature (P<0.01), mean arterial pressure (P<0.01), white blood cell count (WBC; P<0.01), and WBC in stool (P<0.01). The area under the ROC curve for ADSS was 0.958 when the cut off value was 4 (a sensitivity of 0.909; a specificity of 0.874), and the Kappa value was 0.781 (P<0.05). CONCLUSION: The risk factors associated with the pathogenic condition of diarrhea were identified, quantified and formulated into an ADSS, which has high diagnostic accuracy and reliability for the early identification of patients with severe acute diarrhea.

The ACE2-angiotensin-(1-7)-Mas axis protects against pancreatic cell damage in cell culture.

OBJECTIVE: Angiotensin-converting enzyme 2 (ACE2), its product angiotensin-(1-7), and its receptor Mas have been shown to moderate the adverse effects of the ACE-angiotensin II-AT1 axis in many diseases. The aim of this study was to determine whether the ACE2-Ang-(1-7)-Mas axis could have similar effects in a cell culture model of pancreatic damage. METHODS: AR42J cells were stimulated with 10 nmol/L cerulein to simulate acute pancreatitis. ACE2, Ang-(1-7), Mas receptor, and PI3K/AKT pathway were measured by quantitative real-time polymerase chain reaction and Western blot analysis. RESULTS: ACE2 and Mas receptor protein levels in AR42J cells were significantly increased (P < 0.05) between 30 minutes and 6 hours postdisease induction compared with the control group. Mas receptor gene expression was significantly increased (P < 0.05) at 2 hours postdisease induction, and Ang-(1-7) was increased at 6 hours. Treatment with Ang-(1-7) in AR42J cells increased IL-10, decreased IL-6 and IL-8, and reduced the damage to pancreatic cells. Levels of IL-6 and IL-8 in AR42J cell culture were increased significantly after treatment with A779. Moreover, Ang-(1-7) increased the concentration of PI3K/AKT pathway and eNOSin AR42J cells. CONCLUSIONS: ACE2-angiotensin-(1-7)-Mas axis significantly inhibits pancreatitis in response to decreased inflammatory factors by the activation of endothelial nitric oxide synthase and NO signaling pathways.

A rare case of diffuse pulmonary nodules in a patient with adult-onset Still's disease.

Adult-onset Still's disease (AOSD) is a multisystemic inflammatory disorder, but pulmonary involvement is rare. We herein describe the case of a woman diagnosed with AOSD; treatment resolved her symptoms, but nine days later she was admitted with pyrexia and a productive cough. A chest X-ray revealed diffuse pulmonary nodules and patchy shadows. A high-resolution chest computed tomography scan confirmed diffuse infiltration in the pulmonary parenchyma, signs of alveolar nodules, distribution along the lobule center, several areas of tree-in-bud patterns, and bilateral pleural effusion. The patient was treated with high doses of corticosteroids, which rapidly reduced the size of her diffuse pulmonary nodules and dramatically improved her pleural effusion.

The new use of an ancient remedy: a double-blinded randomized study on the treatment of rheumatoid arthritis.

Rheumatoid arthritis (RA) is the most common chronic inflammatory disease with unknown causes and unknown cures in Western medicine. This double-blinded study aimed to investigate the efficacy and safety of a widely used traditional Chinese medicine (Paeoniflorin (PAE) plus cervus and cucumis polypeptide injection (CCPI) using disease-modifying antirheumatic drugs (DMARD) as a control (methotrexate (MTX) plus leflunomide (LEF)). Patients were randomly assigned to one of the three groups: PAE + CCPI, MTX + LEF, and MTX + LEF + CCPI. The primary end point was the American College of Rheumatology 20% improvement response criteria (ACR20). The secondary end point was that of adverse effect frequencies and the speed of onset action. Our results showed that more patients in the CCPI-containing groups responded to the ACR20 during early treatment. After six months, ACR20 showed no significant difference among the three treatments. The maximum improvement in the two DMARD groups was significantly higher than that in the PAE + CCPI group (p < 0.01). CCPI made the onset action of the DMARD therapy 4.6 times faster. PAE + CCPI had significantly lower adverse event incidences than the two DMARD groups. These results indicate that PAE + CCPI appear to be a more acceptable alternative to DMARDs when patients cannot use DMARDs. CCPI appears to be a beneficial add-on to DMARDs that makes the onset of action faster, especially when patients need to relieve RA symptoms as soon as possible. Although not as effective as DMARDs, PAE appears to be a safer option to substitute DMARDs for long-term RA treatment when DMARD toxicity is an issue.

The identification of risk factors for critically ill patients with acute fever and formulation of activation criteria to alert outpatient clinic doctors.

RATIONALE, AIMS AND OBJECTIVES: Acute fever is the most common early clinical symptom of many critical illnesses with a high mortality rate. It is necessary to identify patients with severe acute fever early and accurately. The aim of this study is to identify risk factors for critically ill outpatients with acute fever and formulate activation criteria of adult fever state score (AFSS) to alert outpatient clinic doctors. METHODS: Retrospectively, 357 adult patients with acute fever were divided into two groups: 180 patients with a severe state and 177 patients with a mild state. Logistic regression was used to determine risk factors for the severe state. Risk factors were weighted and an AFSS was formulated. A receiver operating characteristic (ROC) analysis of weighted cumulative scores was performed to evaluate the diagnostic accuracy of AFSS, and the kappa test was used to confirm diagnostic reliability. A χ(2) -test for trend was applied to determine the relevance between AFSS and admission rate and in-hospital mortality. A Kruskal-Wallis test was used to examine the relationship between AFSS and length of stay. RESULTS: Risk factors for state included: old age, long fever course, past medical history, abnormal temperature, abnormal respiratory rate, abnormal heart rate, abnormal mean arterial pressure and abnormal peripheral white blood cell count. The area under the ROC curve of AFSS was 0.964 and ≥8 points predicted severe state; the Kappa value was 0.801. With an increase in score, there was an increase in admission rate, mortality rate and length of stay. The forecast performance of AFSS was superior to the modified early warning score. CONCLUSIONS: The AFSS has high diagnostic accuracy and reliability for the early identification of patients with severe acute fever.