Malignant cerebral infarction after ChAdOx1 nCov-19 vaccination: a catastrophic variant of vaccine-induced immune thrombotic thrombocytopenia.

Vaccine-induced thrombotic thrombocytopenia with cerebral venous thrombosis is a syndrome recently described in young adults within two weeks from the first dose of the ChAdOx1 nCoV-19 vaccine. Here we report two cases of malignant middle cerebral artery (MCA) infarct and thrombocytopenia 9-10 days following ChAdOx1 nCoV-19 vaccination. The two cases arrived in our facility around the same time but from different geographical areas, potentially excluding epidemiological links; meanwhile, no abnormality was found in the respective vaccine batches. Patient 1 was a 57-year-old woman who underwent decompressive craniectomy despite two prior, successful mechanical thrombectomies. Patient 2 was a 55-year-old woman who developed a fatal bilateral malignant MCA infarct. Both patients manifested pulmonary and portal vein thrombosis and high level of antibodies to platelet factor 4-polyanion complexes. None of the patients had ever received heparin in the past before stroke onset. Our observations of rare arterial thrombosis may contribute to assessment of possible adverse effects associated with COVID-19 vaccination.

Reduction of autophagy and increase in apoptosis correlates with a favorable clinical outcome in patients with rheumatoid arthritis treated with anti-TNF drugs.

BACKGROUND: Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. RESULTS: PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. CONCLUSIONS: Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.

Tissue factor over-expression in platelets of patients with anti-phospholipid syndrome: induction role of anti-ß2-GPI antibodies.

Anti-phospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity. It is well known that in these patients thrombosis may be the result of a hypercoagulable state related to anti-ß2-glycoprotein I (ß2-GPI) antibodies. Moreover, platelets may play a role in thrombotic manifestations by binding of anti-ß2-GPI antibodies. Platelets express tissue factor (TF), the major initiator of the clotting cascade, after activation. We primarily analyzed whether anti-ß2-GPI antibodies may trigger a signal transduction pathway leading to TF expression in human platelets. Platelets from healthy donors were incubated with affinity purified anti-ß2-GPI antibodies for different times. Platelet lysates were analyzed for phospho-interleukin-1 receptor-associated kinase 1 (IRAK), phospho-p65 nuclear factor kappaB (NF-κB) and TF by Western blot. IRAK phosphorylation was observed as early as 10 min of anti-ß2-GPI treatment, with consequent NF-κB activation, whereas TF expression, detectable at 45 min, was significantly increased after 4 h of anti-ß2-GPI treatment. Virtually no activation was observed following treatment with control immunoglobulin IgG. We then analyzed TF expression in platelets from 20 APS patients and 20 healthy donors. We observed a significant increase of TF in APS patients versus control subjects (P < 0·0001). This work demonstrates that anti-ß2-GPI antibodies may trigger in vitro a signal transduction pathway in human platelets, which involves IRAK phosphorylation and NF-κB activation, followed by TF expression. Furthermore, ex vivo, platelets of APS patients showed a significantly increased expression of TF. These findings support the view that platelets may play a role in the pathogenesis of APS, with consequent release of different procoagulant mediators, including TF.

Microparticles and autophagy: a new frontier in the understanding of atherosclerosis in rheumatoid arthritis.

Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process.

Treating lupus patients with antimalarials: analysis of safety profile in a single-center cohort.

This longitudinal retrospective study aims at describing the safety profile and the reasons for discontinuation of antimalarials in patients with systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE), focusing on ocular toxicity. We analyzed the clinical data of 845 SLE and DLE patients; 59% of them were taking antimalarials: 1.4% chloroquine (CQ), 88.5% hydroxychloroquine (HCQ) and 10.1% both. The mean therapy duration was 82.5 ± 77.4 months. At least one side effect was reported by 19.4% of patients, leading to temporary or permanent withdrawal in 9.1% and 10.3% of cases, respectively; 19.3% of patients experienced side effects with HCQ and 8.6% with CQ. In 55.1% of cases, the adverse event was mild or moderate. Ophthalmological alterations were reported by 8.5% but were confirmed by the ophthalmological examination in 5.5% of cases. Retinal alterations were associated with age, disease duration and duration of the antimalarial therapy, but not to drug dose and comorbidities or lupus nephritis. This is the largest monocentric longitudinal study confirming the good safety profile of antimalarials in DLE and SLE patients. The main adverse events during the therapy were mild or moderate, but maculopathy-reported in a low percentage of patients-remains the main cause of treatment withdrawal.

The chronic damage in systemic lupus erythematosus is driven by flares, glucocorticoids and antiphospholipid antibodies: results from a monocentric cohort.

OBJECTIVES: Literature data suggest a significantly higher mortality in patients affected by systemic lupus erythematosus (SLE) developing chronic damage. Therefore, damage prevention is a major goal in the management of SLE patients. In the present study, we assessed damage by means of the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI), in a large cohort of SLE patients. Additionally, we aimed at evaluating its association with demographic and clinical features as well as with disease activity and laboratory findings. PATIENTS AND METHODS: We enrolled consecutive patients affected by SLE diagnosed according to the American College of Rheumatology (ACR) 1997 revised criteria. Chronic damage was determined by SDI calculated at the last examination in all patients with at least six months of follow-up. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K); flare was defined as an increase of SLEDAI-2K ≥ 4 compared with the previous visit. RESULTS: We evaluated 349 SLE patients (M/F 25/324, mean age ± SD 42.7 ± 12.4 years, mean disease duration ± SD 164.9 ± 105.2 months). Among the enrolled patients, 125 (35.8%) showed a SDI ≥ 1 (mean SDI ± SD 1.7 ± 0.9, range 0-5). The musculo-skeletal was the most frequently involved organ/system in SDI score (41/349 patients, 11.7%), with deforming/erosive arthritis in 21/349 (6.0%). The presence of chronic damage was associated with age (P < 0.001), disease duration (P < 0.001), number of flares (P = 0.02) and with the use of glucocorticoids (P = 0.02). The logistic regression analysis revealed the association between neuropsychiatric damage and antiphospholipid syndrome (P = 0.01, OR = 3.9) and between the presence of cardiovascular damage and anti-ß2GPI antibodies (P = 0.01, OR 6.2). CONCLUSIONS: In the present study chronic damage was identified in about one third of SLE patients. The association between SDI and the number of flares claim for a thigh-control of the disease activity in order to prevent the chronic damage. The possible role of antiphospholipid antibodies (aPL) in the development of neuropsychiatric and cardiovascular damage may suggest a more careful assessment of such aPL positive patients.

Antibodies to age-ß2 glycoprotein I in patients with anti-phospholipid antibody syndrome.

Anti-phospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized clinically by arterial and/or venous thromboses, recurrent abortions or fetal loss and serologically by the presence of 'anti-phospholipid antibodies' (aPL). The main target antigen of the antibodies is ß2 glycoprotein I (ß2 GPI). Post-translational oxidative modifications of the protein have been widely described. In this study we aimed to analyse sera reactivity to glucose-modified ß2 GPI (G-ß2 GPI). Sera collected from 43 patients with APS [15 primary APS (PAPS) and 28 APS associated with systemic lupus erythematosus (SLE) (SAPS)], 30 with SLE, 30 with rheumatoid arthritis (RA) and 40 healthy subjects were analysed by an enzyme-linked immunosorbent assay (ELISA) using a G-ß2 GPI. Nine of 15 consecutive PAPS out-patients (60%) and 16 of 28 SAPS (57.1%) showed serum antibodies [immunoglobulin (Ig)G class] against G-ß2 GPI (anti-G-ß2 GPI) by ELISA. The occurrence of anti-G-ß2 GPI was significantly higher in APS patients compared to patients suffering from SLE. No RA patients or control healthy subjects resulted positive for anti-G-ß2 GPI. Of note, aG-ß2 GPI prompted to identify some APS patients (four PAPS and seven SAPS), who were negative in the classical anti-ß2 GPI test. Moreover, in APS patients, anti-G-ß2 GPI titre was associated significantly with venous thrombosis and seizure in APS patients. This study demonstrates that G-ß2 GPI is a target antigen of humoral immune response in patients with APS, suggesting that ß2 GPI glycation products may contain additional epitopes for anti-ß2 GPI reactivity. Searching for these antibodies may be useful for evaluating the risk of clinical manifestations.

Acute longitudinal myelitis following Cryptococcus laurentii pneumonia in a patient with systemic lupus erythematosus.

Central nervous system (CNS) involvement in systemic lupus erythematosus (SLE) is reported in about 50% of patients. Among the neuropsychiatric features of SLE, myelopathy, including acute transverse myelitis (ATM) or acute longitudinal myelitis (ALM), represents an uncommon event. A possible vascular aetiology of SLE myelopathies has been hypothesized and it seems to be much more associated to SLE-associated antiphospholipid syndrome (APS). Furthermore, a possible infectious cause of ATM or ALM in healthy subjects has been described. SLE patients are susceptible to infection due to the disease itself or to the immunosuppressive therapy. Cryptococci non-neoformans have been rarely associated to infections in humans. Here we describe the case of a 47-year-old woman with SLE and Sjögren Syndrome who developed an ALM concurrently with a Cryptococcus laurentii pneumonia. The patient was treated with antimycotics, high doses of glucocorticoids and intravenous immunoglobulins with a significant clinical and radiological improvement. As far as we know, this is the first case of Cryptococcus laurentii infection and ALM in a patient with SLE who later developed a seronegative APS. Even though myelopathy may be considered primarily associated to SLE, a possible role of the infection in ALM development cannot be excluded.

Validation of a disease-specific health-related quality of life measure in adult Italian patients with systemic lupus erythematosus: LupusQoL-IT.

OBJECTIVE: The objective of this paper is to assess the validity of a linguistically validated version of the Lupus Quality of Life (LupusQoL(©)) in Italian patients affected by systemic lupus erythematosus (SLE). METHODS: Consecutive SLE patients completed the Italian version of the LupusQoL(©) and the Short Form (SF)-36. Disease activity was evaluated by the SLE disease activity Index-2000 (SLEDAI-2 K), and chronic damage by the Systemic Lupus International Collaborating Clinics/American College Rheumatology (ACR) Damage Index score (SDI). Internal consistency and test-retest reliability, convergent and discriminant validity were examined. Factor analysis with varimax rotation was performed. RESULTS: A total of 117 Italian SLE patients (M:F 13:104; mean age 40.6 ± 11.6 years, mean disease duration 127.5 ± 94.1 months) were recruited into the study. The Italian version of the LupusQoL(©) demonstrated substantial evidence of convergent validity in these patients when compared with equivalent items of the SF-36. In addition, the LupusQoL(©) discriminated between patients with different degrees of disease activity as measured by the SLEDAI-2 K. SLE patients with higher disease activity (SLEDAI-2K ≥4) showed poor QoL compared with those with lower disease activity (SLEDAI-2K <4), with significant differences in the domains of physical health, planning, burden to others and fatigue (p = 0.001, p = 0.04, p = 0.03, p = 0.04, respectively). The confirmatory factor analysis using the eight domain loadings of the 34 items showed a poor fit (χ(2)/degree of freedom (df) 2.26, χ(2 )= 1128.6 (p < 0.001), root mean square error of approximation (RMSEA) = 0.167; goodness-of-fit index (GFI) = 0.606, comparative fit index (CFI) = 0.649)). Screeplot analysis suggested a five-factor loading structure and confirmatory factor analysis result of which is similar to the eight-factor model. A good internal consistency was observed (Cronbach's α 0.89-0.91). Test-retest reliability was good to excellent between baseline and day 15 (intraclass correlation coefficient (ICC) 0.90-0.98). CONCLUSION: The Italian version of the LupusQoL(©) is a valid tool for adult patients with SLE.

Switching between TNFalpha antagonists in rheumatoid arthritis: personal experience and review of the literature.

OBJECTIVE: To evaluate the clinical response after switching to another TNFalpha antagonist in patients with rheumatoid arthritis (RA) and provide a review of the literature on this topic. METHODS: In this ongoing, longitudinal, observational study we have prospectively collected data of patients starting biological treatments since 2000. The present analysis is restricted to RA patients who switched to another anti-TNFalpha due to lack of efficacy (LaE), loss of efficacy (LoE), or adverse events (AEs) by the end of December 2007. Disease activity score (ESR-based DAS28) was calculated and the clinical response (none, moderate, good) was evaluated according to the European League Against Rheumatism (EULAR) criteria. Clinical remission (DAS28 <2.6) and low disease activity (DAS28

Nucleotide fractional incorporation: a simple metabolic feature potentially related to clinical outcome in colorectal cancer patients.

Among the different investigated biomarkers, cell proliferation has provided valuable information on the clinical outcome of patients with malignant tumors. In the present study, we analyzed the potential relevance of fractional incorporation (FI) of a nucleotide precursor (3H-thymidine, 3H-dT) into DNA of tumor cells, determined on the primary tumor, on long-term clinical outcome of a series of patients with colorectal cancer. Determination of 3H-dT FI was carried out on fresh tumor material obtained at surgery as part of the clinical management of the primary tumor in 28 patients with colorectal cancer. Analysis of the relation between the FI and clinico-pathological characteristics of the tumor showed a trend of an inverse relation between the biomarker and Dukes' stage and no relation with tumor site. At 6 year follow-up, alive patients had a statistically significant higher median FI value (2.4%; range: 1.1-6.5%) than dead patients (1%; range: 0.3-4.5%) (p=0.02). Owing to the simplicity of this inexpensive methodology, the preliminary results of our study would indicate the potential of FI, a metabolic-kinetic parameter, to give prognostic information in colorectal cancer patients.

[Adenomatous tissue in colorectal carcinomas: clinical significance and probable histogenetic implications of morphological differences]. / Tessuto adenomatoso in carcinomi colorettali. Significato clinico e probabili implicazioni istogenetiche di differenze morfologiche.

In this study we tested the hypothesis that colorectal cancers containing adenoma (CCA) could be a different entity from colon cancers without adenoma (CSA). Clinical data, histologic preparations of operative specimens and survival of 210 patients who underwent resective surgery for colorectal cancer were studied. Adenomatous tissue within the cancer was found in 62 of 210 carcinomas (CCA), the other 148 cancers were lacking adenomatous features (CSA). CCA occurred more frequently in female patients (p = 0.003). Synchronous adenomas were detected in the resected colon of 19 out 62 CCA and of 24 out 148 CSA (p = 0.04). CCA showed the extent of intraparietal spread (p = 0.001), grade (p = 0.007) and stage (p = 0.004) lower than CSA. These characteristics also appeared statistically related to size of the cancers. The adenomatous tissue within CCA was tubular in 4 cases, tubulo-villous in 34 and villous in 24 cases. The villous histotype was statistically related to the older age of patients (p < 0.0001), larger cancer size (p = 0.01), presence of synchronous adenomas in the resected colon (p = 0.02) and higher histologic grade of the cancer (p < 0.05). Patients with CCA evidenced a higher 5-year survival rate (p = 0.02). Our results evidence epidemiologic, clinical and pathologic differences between CCA and CSA and suggest a possible double histogenesis of colon cancer.