Secukinumab versus guselkumab in the complete resolution of ustekinumab-resistant psoriatic plaques: The ARROW study.

Interleukin (IL)-23-independent IL-17A production has been suggested to be involved in persistent manifestations of psoriatic disease, including anti-IL-12/23-refractory psoriatic plaques; this study aimed to test this hypothesis by investigating the clinical and molecular effects of direct IL-17A (with secukinumab) versus selective IL-23 inhibition (with guselkumab) in patients with anti-IL-12/23 (ustekinumab)-refractory psoriatic plaques. A 16-week, randomized, open-label, parallel-group, Phase IIa study (ARROW, NCT03553823) was conducted in patients with ≥1 active psoriatic plaque (total clinical score [TCS] ≥6) at screening despite treatment with ustekinumab, and a Psoriasis Area and Severity Index (PASI) score 1-10. Patients were randomized 1:1 to receive secukinumab 300 mg (n = 20) or guselkumab 100 mg (n = 20). Biopsies from one refractory ('target plaque') were obtained at baseline and Week 16. The primary endpoint was the proportion of patients whose ustekinumab-refractory target plaque achieved clear/almost clear status (TCS 0-2) at Week 16. Transcriptomic and histological analyses were conducted on target plaques to determine the molecular effects of direct IL-17A versus selective IL-23 inhibition. At Week 16, target plaque clear/almost clear status was achieved in 60.0% of patients treated with secukinumab versus 40.0% of patients treated with guselkumab (p = 0.1715). Molecular analyses identified that secukinumab modulated a greater proportion of psoriasis disease transcriptome genes (72.1% vs. 48.0%) and resulted in more histological responders (72.2% vs. 53.3%) compared with guselkumab. Secukinumab demonstrated a greater clinical and molecular effect on ustekinumab-refractory psoriatic plaques versus guselkumab. These results are consistent with the hypothesis that IL-23-independent IL-17 mechanisms may be relevant to the inflammation driving refractory manifestations of psoriasis.

Selective up-regulation of the soluble pattern-recognition receptor pentraxin 3 and of vascular endothelial growth factor in giant cell arteritis: relevance for recent optic nerve ischemia.

OBJECTIVE: To assess local expression and plasma levels of pentraxin 3 (PTX3) in patients with giant cell arteritis (GCA). METHODS: Plasma and serum samples were obtained from 75 patients with GCA (20 of whom had experienced optic nerve ischemia in the previous 3 weeks and 24 of whom had experienced symptom onset in the previous 6 months and had no history of optic nerve ischemia) and 63 controls (35 age-matched healthy subjects, 15 patients with rheumatoid arthritis, and 13 patients with chronic stable angina). In 9 patients in whom GCA was recently diagnosed, circulating levels of interleukin-1ß (IL-1ß), IL-2, IL-4, IL-6, IL-7, IL-8, IL-10, IL-12p70, CCL2/monocyte chemotactic protein 1, CCL3/macrophage inflammatory protein 1α (MIP-1α), CCL4/MIP-1ß, CCL11/eotaxin, CXCL9/monokine induced by interferon-γ, CXCL10/interferon-γ-inducible 10-kd protein, tumor necrosis factor α (TNFα), interferon-γ, vascular endothelial growth factor (VEGF), granulocyte-macrophage colony-stimulating factor, and FasL were measured via a multiplexed cytometric assay. PTX3 and VEGF concentrations were assessed by enzyme-linked immunosorbent assay. PTX3 and CD68 expression were determined by immunohistochemistry and immunofluorescence on temporal artery samples. RESULTS: GCA patients with very recent optic nerve ischemia had significantly higher PTX3 and VEGF levels compared to other GCA patients and controls. GCA patients with a disease duration of <6 months had significantly higher PTX3 levels compared to other GCA patients and controls. Immunohistochemistry revealed selective PTX3 expression in the wall of inflamed arteries. CONCLUSION: Our findings indicate that local expression of PTX3 is a feature of vascular inflammation in GCA; elevated circulating levels of PTX3 identify patients with very recent optic nerve ischemia or a recent diagnosis. Optic nerve ischemia is also associated with increased circulating VEGF levels.

Phase I study of non-pegylated liposomal doxorubicin in combination with ifosfamide in adult patients with metastatic soft tissue sarcomas.

OBJECTIVE: The aim of this study was to evaluate the maximum tolerated dose (MTD) and safety of the combination of non- pegylated liposomal doxorubicin (Myocet) and ifosfamide in patients with metastatic soft tissue sarcomas. METHODS: Cohorts of four patients with metastatic soft tissue sarcomas received up to five cycles of intravenous ifosfamide 3000 mg/m2 on days 1- 3 in combination with escalating doses of intravenous Myocet on day 1 every 3 weeks until dose limiting toxicity (DLT) in at least one patient. Starting dose of Myocet was 40 mg/m2 to be escalated through 10 mg/m2 increase up to 80 mg/m2. Toxicity was graded according to the National Cancer Institute Common Toxicity Criteria v3.0 (NCI-CTC v3.0). RESULTS: Ten patients were enrolled in the study and 8 of them received the treatment. Median age was 45 years, 3 patients were male and 5 were female. DLT, consisting of neutropenic fever, was reached in one patient at dose level 2 (Myocet 50 mg/m2). Therefore, the MTD and the recommended phase II dose is 40 mg/m2. CONCLUSIONS: The combination of intravenous Myocet 40 mg/m2 on day 1 and ifosfamide 3,000 mg/m2 on days 1-3 every 3 weeks is safe and feasible; a phase II study is ongoing.

Circulating chromogranin A reveals extra-articular involvement in patients with rheumatoid arthritis and curbs TNF-alpha-elicited endothelial activation.

TNF-alpha plays an important role in the natural history of rheumatoid arthritis (RA), a systemic disease characterized by endothelial activation and synovial involvement with bone erosions. Neuroendocrine signals contribute as well to RA, but their role is poorly understood. We measured in 104 RA patients and in an equal number of sex- and age-matched, healthy controls the blood levels of chromogranin A (CgA), a candidate marker linking the neuroendocrine system to TNF-alpha-mediated vascular inflammation. CgA levels were significantly higher in patients with RA and remained stable over time. High levels of CgA were significantly associated with severe extra-articular manifestations, namely pulmonary fibrosis, rheumatoid vasculitis, serositis, and peripheral neuropathy. RA sera curbed the response of human microvascular endothelial cells to TNF-alpha, as assessed by the expression of ICAM-1, the release of MCP-1/CCL2, and the export of nuclear high-mobility group box 1; the effect abated in the presence of anti-CgA antibodies. The efficacy of the blockade was significantly correlated with the CgA concentration in the serum. The recombinant aminoterminal portion of CgA, corresponding to residues 1-78, had similar inhibitory effects on endothelial cells challenged with TNF-alpha. Our results suggest that enhanced levels of CgA identify patients with extra-articular involvement and reveal a negative feedback loop that limits the activation of endothelial cells in RA.

Management of heart failure with reduced ejection fraction in Europe: design of the ARIADNE registry.

AIMS: The introduction of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor) is likely to change the approach to the management of patients with chronic heart failure with reduced ejection fraction (HFrEF). The Assessment of Real Life Care-Describing European Heart Failure Management (ARIADNE) registry will evaluate patient characteristics, practice patterns, outcomes, and healthcare resource utilization in the outpatient setting across Europe, with the main focus on factors that guide physicians' decisions to start and continue sacubitril/valsartan in patients with HFrEF. METHODS AND RESULTS: ARIADNE, a prospective, observational registry will enrol 9000 ambulatory patients with HFrEF in 23 European countries Supplement 1. The study will describe 4500 patients treated with conventional treatment (including an angiotensin-converting enzyme inhibitor/angiotensin receptor blocker), and 4500 patients started on sacubitril/valsartan. In each country, patients will be enrolled consecutively over an expected period of 12 months, and followed-up for 12 months. The primary objective is to describe the baseline clinical and demographic characteristics of patients with chronic HFrEF, which guide the decision of the treating physician to initiate sacubitril/valsartan or to continue conventional treatment. A co-primary objective is to identify the baseline characteristics that are associated with the likelihood of reaching the target dose of sacubitril/valsartan 97/103 mg twice daily during follow-up. CONCLUSIONS: The ARIADNE registry will provide a comprehensive profile of patients with chronic HFrEF in Europe, will elucidate how management varies between countries, and will help clarify the usage and outcomes associated with use of sacubitril/valsartan in real life.

Conversation galante: how the immune and the neuroendocrine systems talk to each other.

The generation of endogenous adjuvants and the clearance of apoptotic cells occur at the intersection between the neuroendocrine and the immune systems. Recent data suggest that autoimmunity associates with a communication breakdown between the two systems and that events taking place in lymphoid organs and in peripheral inflamed tissues shape the response to tissue damage. Autonomic nerve endings release norepinephrine and acetylcholine, whereas sensitive fibers release neuropeptides. Moreover, nervous endings in the tissues control the secretory activity of neuroendocrine cells, which are distributed in the gut, the pancreas, the lung, the thyroid, the liver, the prostate, the skin. Intracellular enzymes, and in particular the 11 beta-hydroxysteroid dehydrogenase type 1, regulate the availability of active glucocorticoids in inflammatory macrophages and maturing dendritic cells; in turn the rate of active glucocorticoids determine the efficiency of phagocytes in clearing apoptotic cells, possibly influencing the availability of autoantigens. Immune cells release cytokines, which, in turn signal to the central and peripheral nervous system. We learnt from cytokine-neutralizing therapies that the sustained production of pro-inflammatory signals interferes with various neuro-endocrine axes. A better molecular dissection of this finely regulated inter-system cross-talk, in physiological conditions and during self-sustaining inflammatory diseases, might enable more rational therapeutic approaches.

Neuroendocrine modulation induced by selective blockade of TNF-alpha in rheumatoid arthritis.

Tumor necrosis factor-alpha (TNFalpha) is a main actor in the pathogenesis of rheumatoid arthritis (RA), interacting with other molecules in complex mechanisms. The neuroendocrine system is known to be involved and Chromogranin A (CHGA) serum levels are elevated in patients with RA. We evaluated the effect of the selective blockade of TNF-alpha, induced by treatment with anti-TNF-alpha monoclonal antibodies (mAbs), on the serum levels of CHGA and on its correlation with TNF-alpha and TNF-alpha receptors (TNFRs) serum levels. Seven patients with RA have been treated with the anti-TNF-alpha mAb, infliximab. We measured the serum levels of TNF-alpha, its receptors (tumor necrosis factor receptor-I [TNFR-I] and tumor necrosis factor receptor-II [TNFR-II]), and CHGA before and during the treatment. We also measured, as a control, the serum levels of CHGA, TNF-alpha, and soluble TNFRs in 14 patients who were being treated with infliximab, adalimumab, or etanercept and in 20 matching negative controls. The serum levels of TNFR-I and TNFR-II, which are a sensitive marker for the TNF-alpha pathway, correlated with those of CHGA before treatment (Pearson's coefficient, respectively, 0.59 and 0.53). Treatment with anti-TNF-alpha mAb provided a significant clinical response in all patients and the correlation between CHGA and TNFR-I and TNFR-II was no more evident during treatment (respectively, -0.09 and -0.07). TNF-alpha blockade allows a clinical effect in patients with RA and modifies the correlation between CHGA and TNFRs, suggesting that TNF-alpha and CHGA reciprocally interfere in the pathogenesis of RA, through intermediate adaptors, whose identification warrants further studies.

Hypoglycaemia and lactic acidosis in a MALT non Hodgkin's lymphoma.

Hypoglycaemia associated with lactic acidosis is a rare complication of lymphomas; only four cases have been previously reported. Recent studies provide evidence of direct consumption of glucose by the tumour cells, leading to lactic acidosis. We report the case of a 64-year-old patient with a gastric diffuse large B cell non-Hodgkin's lymphoma transformed from an indolent mucosa associated lymphoid tissue (MALT) lymphoma, admitted to our department for acute renal failure due to a tumour lysis syndrome. After recovery from renal failure, she developed severe hypoglycaemia and lactic acidosis refractory to therapy. She died after the onset of shock and coma.

Chromogranin A: a novel factor acting at the cross road between the neuroendocrine and the cardiovascular systems.

Chromogranin A (CHGA) is a secretory protein stored in and released from neurons and cells of the diffuse neuroendocrine system. Cells of the adrenal medulla and adrenergic terminals are a main source of CHGA but also myocardial cells produce it under stress conditions. After secretion, CHGA is cleaved into several biologically active fragments, including vasostatins and catestatin. CHGA and its proteolytic peptides exert a broad spectrum of activities on the cardiovascular system. They act on blood pressure by controlling the vascular tone and the cardiac inotropic and chronotropic function. CHGA revealed to be a sensitive marker of myocardial dysfunction, with a high predictive power of morbidity and mortality in heart failure and ischemic heart disease. In addition, CHGA has been involved in the control of sustained endothelial inflammation and has been shown to be a good marker of persistent vascular inflammation in rheumatologic disorders affecting vessels.

The clinical spectrum of the neurological involvement in vasculitides.

Both the central nervous system (CNS) and the peripheral nervous system (PNS) are major target organs in primary vasculitides. They may either be affected in the setting of systemic vasculitis, potentially involving any other organ, or they may be the sole site of the inflammatory process. In both cases, the clinical pattern of PNS involvement is essentially uniform, presenting as sensory axonal polyneuropathy or mononeuritis multiplex. The damage is related to the ischemic occlusion of the vasanervorum due to small-vessel vasculitis. On the contrary, the range of manifestations of CNS vasculitis is much wider and several pathogenetic mechanisms are implicated, including angiitis of the hemispheres and spinal cord, thrombosis of dural sinuses, stenosis and aneurysms of medium and large arteries, granulomatous meningeal involvement and direct cytokine damage presenting with encephalopathy. Besides, even extracranial noninflammatory vascular disease may induce CNS symptoms, as is the case of carotid stenosis, vena cava syndrome and renovascular hypertension. In this paper we will review the broad spectrum of clinical manifestations of CNS and PNS neuropathy as they occur in primary systemic and non systemic vasculitides.