Increased plasma levels of Gas6 and its soluble tyrosine kinase receptors Mer and Axl are associated with immunological activity and severity of lupus nephritis.

OBJECTIVES: Growth arrest-specific 6 (Gas6) and its receptors have been shown to play a crucial role in the homeostasis of the innate immune system by regulating apoptosis and inflammation. We aimed to verify whether an impairment of this system is associated with systemic lupus erythematosus (SLE) disease activity and with lupus nephritis (LN). METHODS: Plasma Gas6 and the soluble cleaved form of the receptors MerTK (sMer) and Axl (sAxl) concentrations were measured in n=59 SLE patients (n=44 with nephritis, 75%) and analysed in relationship to clinical and laboratory data. RESULTS: Patients with LN were characterised by higher Gas6 (19.0 ng/mL [16.8-24.5] vs. 16.5 ng/mL [13.89-18.91]; p=0.03) and sAxl plasma levels than those without LN (31.36 ng/mL [25.1-41.4] vs. 20.2 ng/mL [15.6-30.7]; p=0.03); conversely sMer plasma concentrations were similar between groups. All the three biomarkers studied were directly correlated to creatinine and daily proteinuria, being inversely related to creatinine clearance. 39 patients had a proteinuria level of <0.5 mg/day, 14 between 0.5 and 3.5 mg/day and 5 had ≥3.5 g/day; Gas6, sAxl and sMer plasma concentrations significantly increased for increasing degree of proteinuria (test for trend p=0.0002; p=0.02; p=0.009, respectively).These correlations were confirmed in multiple linear regression analysis models accounting for gender, age, disease duration and concomitant treatment. CONCLUSIONS: Plasma Gas6, sAxl and sMer concentrations are associated with the severity of LN in patients affected by SLE. The excess cleavage of TAM receptors might contribute to LN pathogenesis.

Overlapping polyclonal lymphoproliferative disorders.

Multicentric Castleman disease (MCD) is a rare clinical entity characterized by a polyclonal lymphoid proliferation, leading to generalized lymphadenopathy, organomegaly and systemic symptoms. It has been reported in association with either other monoclonal or polyclonal lymphoid disorders, such as POEMS syndrome and immunoglobulin (Ig)G4-related disease. We present a patient showing a variant of MCD, sharing common features with POEMS syndrome and associated with the proliferation of IgG4-producing plasma cells.

Association between rheumatic diseases and cancer: results from a clinical practice cohort study.

The association between cancer and immune-mediated rheumatic conditions is controversial, especially as far as polymyalgia rheumatica (PMR) is concerned. Furthermore, no clinical feature has been shown to be suggestive of a paraneoplastic rheumatic syndrome. With the present study, we aim to address both these issues. The study population comprised N = 1750 patients, including N = 100 with PMR, who attended our tertiary immuno-rheumatology clinic between January 1, 2005 and November 30, 2012. A rheumatic disease was deemed paraneoplastic if cancer had been diagnosed in the 2 years preceding or following its onset. The probability of a significant association between a specific rheumatic disease and cancer was evaluated by computing the odds ratio (OR): N = 702 patients with osteoarthritis serving as controls. Furthermore, clinical features distinguishing paraneoplastic rheumatic diseases were searched for by univariate and multivariate analysis. Sjogren's syndrome (SS) [OR 3.6 (CI 95% 1.7-7.5)], PMR (OR 5.1 CI 95% 2.9-8.9), dermatomyositis/polymyositis [OR 12.09 (CI 95% 2.6-55.8)] and vasculitis [OR 3.70 (CI 95% 1.81-7.52)] are associated with cancer. At multivariate analysis, older age is associated with cancer among SS patients (p = 0.03), while in the PMR group, older age, male gender, and ≥6 tender joints are independent predictors of paraneoplastic PMR (p < 0.0004). Cancer frequently either heralds or follows rheumatic manifestations, including PMR. Older age, male gender and a more extensive joint involvement should be considered red flags for paraneoplastic PMR.

Testosterone Plasma Concentration is Associated with Insulin Resistance in Male Hypertensive Patients.

Background: Low testosterone levels are a common finding among men with Type 2 Diabetes Mellitus (T2DM) and are inversely related to insulin resistance. Whether this relationship holds true in patients with hypertension, but normal glucose tolerance or prediabetes, is unclear. Methods: We recruited 87 male outpatients with essential arterial hypertension, aged 35-70 years. Anthropometric data were collected, an Oral Glucose Tolerance Test (OGTT) performed, and the homeostasis model assessment of insulin resistance (HOMA-IR) score calculated. Follicle-Stimulating Hormone, Luteinizing Hormone, testosterone, Sex Hormone-Binding-Globulin and free-testosterone were measured. The concentrations of sex hormones were compared between normoglucotolerant, prediabetic and diabetic patients. Non-parametric tests were applied as appropriate to verify differences among groups, while multiple linear regression was used to predict the variability of testosterone and free-testosterone. Results: Total serum testosterone concentration was significantly lower in T2DM in comparison to normoglucotolerant subjects (p<0.01) and was inversely related to body mass index (r=- 0.25, p<0.01), waist circumference (r=- 0.27, p<0.01), pre and post-OGTT plasma glucose (r=- 0.4, p<0.0001 and r=- 0.29, p<0.01, respectively), pre and post-OGTT plasma insulin (r=- 0.42, p<0.0001 and r=- 0.42, p<0.0001) and HOMA-IR (r=- 0.46, p<0.0001). Similar associations were observed for free testosterone; HOMA-IR was related to testosterone and free-testosterone even in patients with normal glucose tolerance (r=- 0.47, p<0.01 and r=- 0.34, p<0.05, respectively). At multivariate analysis HOMA-IR was the only variable associated to testosterone (p<0.001) and free-testosterone (p<0.05) plasma concentration. Conclusions: In males with hypertension, the link between insulin sensitivity and hypothalamic-pituitary-gonadal axis is maintained along the entire spectrum of glucose tolerance.

Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib.

BACKGROUND AND AIMS: Response to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy. RESULTS: 442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p<0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115-1.290, p<0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108-1.322, p<0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373-0.763, p=0.001). The combination of RD-CLIP score (CLIP score multiplied by RDW) ≥ 70 and no treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734-0.882), positive predictive value of 86.4% and negative predictive value of 83.3%), compared with CLIP (AUC=0.642) or BCLC score alone (AUC=0.579). RD-CLIP score ≥ 35 and no treatment-related diarrhoea had an AUC of 0.787 for predicting 12-month survival. METHODS: Patients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib. CONCLUSION: The novel prognostic index of CLIP score combined with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib.

Profiling the patients visiting the emergency room for musculoskeletal complaints: characteristics and outcomes.

Non-traumatic musculoskeletal complaints are often dealt with by emergency room (ER) physicians. We aimed to quantify how many patients with such complaints have conditions requiring immediate recognition and treatment, versus specialist referral, versus primary care. We retrieved the clinical records of all the patients admitted to the ER department of our hospital along 1 year. Pediatric (age <14 years) and obstetrics/gynecology cases were excluded. Data from all patients visiting the ER for non-traumatic musculoskeletal complaints were classified as follows: true emergencies (i.e., conditions associated with high morbidity/mortality risk), urgencies (i.e., conditions requiring prompt referral to a specialist), and non-urgent conditions (to be dealt with in primary care). Out of 54,915 patients evaluated in the ER of our hospital, 1652 patients complained of non-traumatic musculoskeletal symptoms (3.0 %): Back pain accounted for 944/1652 ER visits (57.1 %), including 6 emergencies (0.6 %) and 105 urgent conditions (11.1 %). Among the remaining 708 patients (42.9 %) who presented with complaints concerning a peripheral joint, true emergencies were 2/708 (0.3 %) while 210/708 were urgent conditions (29.7 %). Although patients who present to ER physicians with musculoskeletal complaints have rarely true emergencies, many of them are in need of urgent treatment and prompt specialist referral.