Sustainability in Internal Medicine: A Year-Long Ward-Wide Observational Study.

Population aging and multimorbidity challenge health system sustainability, but the role of assistance-related variables rather than individual pathophysiological factors in determining patient outcomes is unclear. To identify assistance-related determinants of sustainable hospital healthcare, all patients hospitalised in an Internal Medicine Unit (n = 1073) were enrolled in a prospective year-long observational study and split 2:1 into a training (n = 726) and a validation subset (n = 347). Demographics, comorbidities, provenance setting, estimates of complexity (cumulative illness rating scale, CIRS: total, comorbidity, CIRS-CI, and severity, CIRS-SI subscores) and intensity of care (nine equivalents of manpower score, NEMS) were analysed at individual and Unit levels along with variations in healthcare personnel as determinants of in-hospital mortality, length of stay and nosocomial infections. Advanced age, higher CIRS-SI, end-stage cancer, and the absence of immune-mediated diseases were correlated with higher mortality. Admission from nursing homes or intensive care units, dependency on activity of daily living, community- or hospital-acquired infections, oxygen support and the number of exits from the Unit along with patient/physician ratios were associated with prolonged hospitalisations. Upper gastrointestinal tract disorders, advanced age and higher CIRS-SI were associated with nosocomial infections. In addition to demographic variables and multimorbidity, physician number and assistance context affect hospitalisation outcomes and healthcare sustainability.

Role of systemic immunosuppression on subglottic stenosis in granulomatosis with polyangiitis: Analysis of a single-centre cohort.

PURPOSE: Subglottic stenosis (SGS) is a potentially life-threatening manifestation of granulomatosis with polyangiitis (GPA). Endoscopic dilation is effective, but relapses are frequent and the benefit of systemic immunosuppression in this setting is still controversial. We aimed to investigate the role of immunosuppressive treatment on SGS relapse risk. METHODS: This is a retrospective observational study based on review of medical charts among our cohort of patients with GPA. RESULTS: Twenty-one patients with SGS-GPA were identified, with a prevalence of 20% among our entire GPA cohort (n = 105). Compared to patients without SGS, patients with SGS-GPA had an earlier disease onset (mean age 30.2 vs. 47.3 years, p<0.001), and lower BVAS (mean 10.5 vs 13.5; p = 0.018). Five patients didn't receive systemic immunosuppression for SGS and they all (100%) relapsed after the first procedure, while among medical treatment group relapse rate was 44% (p = 0.045). When single treatment regimens are considered, rituximab (RTX) and cyclophosphamide (CYC) yielded a protective role towards the need of subsequent dilation procedure after the first if compared with absence of medical treatment. Patients with SGS and generalized disease, who initially received either a RTX- or a CYC-based induction treatment, and higher cumulative doses of glucocorticoids, showed a delayed median time to SGS relapse (36 vs. 12 months, p = 0.024). CONCLUSIONS: Subglottic stenosis is highly prevalent in patients with GPA and may define a milder systemic disease subset occurring more frequently in younger patients. Systemic immunosuppression provides benefit in preventing recurrence of SGS in GPA patients and regimens based on cyclophosphamide or rituximab might have a non-redundant role in this setting.

Predictors and outcomes of delirium in the emergency department during the first wave of the COVID-19 pandemic in Milan.

BACKGROUND: Respiratory infections can be complicated by acute brain failure. We assessed delirium prevalence, predictors and outcomes in COVID-19 ED patients. METHODS: This was a retrospective observational study conducted at the San Raffaele ED (Italy). Patients age >18 years attending the ED between 26 February 2020 and 30 May 2020 and who had a positive molecular nasopharyngeal swab for SARS-CoV-2 were included. The Chart-Based Delirium Identification Instrument (CHART-DEL) was used to retrospectively assess delirium. Univariable and multivariable logistic regression analyses were used to evaluate delirium predictors. Univariable binary logistic regression analyses, linear regression analyses and Cox regression analyses were used to assess the association between delirium and clinical outcomes. Age-adjusted and sex-adjusted models were then run for the significant predictors of the univariable models. RESULTS: Among the 826 included patients, 123 cases (14.9%) of delirium were retrospectively detected through the CHART-DEL method. Patients with delirium were older (76.9±13.15 vs 61.3±14.27 years, p<0.001) and more frequently living in a long-term health facility (32 (26%) vs 22 (3.1%), p<0.001). Age (OR 1.06, 95% CI 1.04 to 1.09, p<0.001), dementia (OR 17.5, 95% CI 7.27 to 42.16, p<0.001), epilepsy (OR 6.96, 95% CI 2.48 to 19.51, p<0.001) and the number of chronic medications (OR 1.09, 95% CI 1.01 to 1.17, p=0.03) were significant predictors of delirium in multivariable analyses. Delirium was associated with increased in-hospital mortality (adjusted HR 2.16, 95% CI 1.55 to 3.03, p<0.001) and with a reduced probability of being discharged home compared with being institutionalised (adjusted OR 0.39, 95% CI 0.25 to 0.61, p<0.001). CONCLUSIONS: Chart review frequently identified ED delirium in patients with COVID-19. Age, dementia, epilepsy and polypharmacy were significant predictors of ED delirium. Delirium was associated with an increased in-hospital mortality and with a reduced probability of being discharged home after hospitalisation. The findings of this single-centre retrospective study require validation in future studies.

Durable renal response and safety with add-on belimumab in patients with lupus nephritis in real-life setting (BeRLiSS-LN). Results from a large, nationwide, multicentric cohort.

BACKGROUND: Belimumab was recently approved for treatment of lupus glomerulonephritis (LN). AIM: To evaluate renal response and its predictors in LN patients receiving belimumab in real-life. PATIENTS AND METHODS: We considered all patients fulfilling the SLEDAI-2K renal items and/or having estimated glomerular filtration rate (eGFR)≤60 ml/min/1.73 m2, with positive anti-dsDNA and/or low C3/C4 enrolled in the multicentre Italian lupus cohort BeRLiSS (BElimumab in Real LIfe Setting Study), treated with monthly IV Belimumab 10 mg/kg over standard treatment. Primary efficacy renal response (PERR), defined as proteinuria ≤0.7 g/24 h, eGFR≥60 ml/min/1.73 m2 without rescue therapy, was considered as primary outcome. Complete renal response (CRR; proteinuria <0.5 g/24 h, eGFR≥90 ml/min/1.73 m2) was considered as secondary outcome. Prevalence and predictors of PERR were evaluated at 6, 12, 24 months by multivariate logistic regression. RESULTS: Among the 466 SLE patients of BeRLiSS, 91 fulfilled the inclusion criteria, 79 females, median age 41.0 (33.0-47.0) years, median follow-up 22.0 (12.0-36.0) months. Sixty-four (70.3%) achieved PERR, of whom 38.4% reached CRR. Among patients achieving PERR at 6 months, 86.7% maintained response throughout the follow-up. At multivariable analysis, hypertension (OR [95%CI]: 0.28 [0.09-0.89], p = 0.032), high baseline serum creatinine (0.97 [0.95-0.99], p = 0.01) and high baseline proteinuria (0.37, [0.19-0.74], p = 0.005) negatively predicted PERR. Positive predictors of PERR at 12 and 24 months were baseline anti-Sm positivity (OR [95%CI]: 6.2 [1.21-31.7], p = 0.029; 19.8 [2.01-186.7], p = 0.009, respectively) and having achieved PERR at 6 months (14.4 [3.28-63.6]; 11.7 [2.7-48.7], p = 0.001 for both). CONCLUSIONS: Add-on therapy with belimumab led to durable renal response in patients with LN in a real-life setting.

Prognostic Factors and Long-Term Outcome with ANCA-Associated Kidney Vasculitis in Childhood.

BACKGROUND AND OBJECTIVES: ANCA-associated vasculitis is extremely rare in children. We report the clinicopathologic features, long-term outcomes, and prognostic factors of a large pediatric cohort of patients with ANCA-associated kidney vasculitis. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This retrospective study included 85 consecutive patients with kidney biopsy specimen-proven ANCA-associated vasculitis from tertiary referral centers in Italy and Canada. Kidney biopsy specimens were categorized as focal, crescentic, sclerotic, or mixed, according to the Berden classification. The prognostic significance of baseline clinical, laboratory, and histologic findings was analyzed with respect to kidney failure or CKD stage 3-5/kidney failure. RESULTS: A total of 53 patients had microscopic polyangiitis (62%), and 32 had granulomatosis with polyangiitis (38%). Rapidly progressive GN was the most frequent presentation (39%); a third of the patients also had nephrotic-range proteinuria. Kidney biopsy specimens were classified as focal in 21% of the patients, crescentic in 51%, sclerotic in 15%, and mixed in 13%. Remission-induction therapies included cyclophosphamide in 78% of patients. A total of 25 patients (29%) reached kidney failure. The median (interquartile range) time to kidney failure or last follow-up was 35 (6-89) months in the whole cohort, and 73 (24-109) months among the patients who did not reach this outcome. Patients whose biopsy specimens showed sclerotic histology had significantly shorter kidney survival (hazard ratio, 11.80; 95% confidence interval, 2.49 to 55.99) and survival free of CKD stage 3-5 (hazard ratio, 8.88; 95% confidence interval, 2.43 to 32.48), as compared with those with focal/mixed histology. Baseline eGFR, low serum albumin, hypertension, central nervous system complications, and sclerotic histology, which reflected severe kidney involvement, were associated with both kidney failure and CKD stage 3-5/kidney failure at unadjusted analysis; no independent prognostic factors emerged at multivariable analysis. CONCLUSIONS: Children with ANCA-associated kidney vasculitis often have aggressive presentation; a third of such children progress to kidney failure and this usually occurs early during follow-up. A severe clinical presentation is associated with the development of CKD or kidney failure.

PTX3 Intercepts Vascular Inflammation in Systemic Immune-Mediated Diseases.

PTX3 is a prototypic soluble pattern recognition receptor, expressed at sites of inflammation and involved in regulation of the tissue homeostasis. PTX3 systemic levels increase in many (but not all) immune-mediated inflammatory conditions. Research on PTX3 as a biomarker has so far focused on single diseases. Here, we performed a multi-group comparative study with the aim of identifying clinical and pathophysiological phenotypes associated with PTX3 release. PTX3 concentration was measured by ELISA in the plasma of 366 subjects, including 96 patients with giant cell arteritis (GCA), 42 with Takayasu's arteritis (TA), 10 with polymyalgia rheumatica (PMR), 63 with ANCA-associated systemic small vessel vasculitides (AAV), 55 with systemic lupus erythematosus (SLE), 21 with rheumatoid arthritis (RA) and 79 healthy controls (HC). Patients with SLE, AAV, TA and GCA, but not patients with RA and PMR, had higher PTX3 levels than HC. PTX3 concentration correlated with disease activity, acute phase reactants and prednisone dose. It was higher in females, in patients with recent-onset disease and in those with previous or current active vasculitis at univariate analysis. Active small- or large- vessel vasculitis were the main independent variables influencing PTX3 levels at multivariate analysis. High levels of PTX3 in the blood can contribute to identify an increased risk of vascular involvement in patients with systemic immune-mediated diseases.

ANCA-associated vasculitis in childhood: recent advances.

Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitides are rare systemic diseases that usually occur in adulthood. They comprise granulomatosis with polyangiitis (GPA, Wegener's), microscopic polyangiitis (MPA) and eosinophilic granulomatosis with polyangiitis (EGPA, Churg-Strauss syndrome). Their clinical presentation is often heterogeneous, with frequent involvement of the respiratory tract, the kidney, the skin and the joints. ANCA-associated vasculitis is rare in childhood but North-American and European cohort studies performed during the last decade have clarified their phenotype, patterns of renal involvement and their prognostic implications, and outcome. Herein, we review the main clinical and therapeutic aspects of childhood-onset ANCA-associated vasculitis, and provide preliminary data on demographic characteristics and organ manifestations of an Italian multicentre cohort.

Deconstructing IgG4-related disease involvement of midline structures: Comparison to common mimickers.

OBJECTIVE: A series of destructive and tumefactive lesions of the midline structures have been recently added to the spectrum of IgG4-related disease (IgG4-RD). We examined the clinical, serological, endoscopic, radiological, and histological features that might be of utility in distinguishing IgG4-RD from other forms of inflammatory conditions with the potential to involve the sinonasal area and the oral cavity. METHODS: We studied 11 consecutive patients with erosive and/or tumefactive lesions of the midline structures referred to our tertiary care center. All patients underwent serum IgG4 measurement, flow cytometry for circulating plasmablast counts, nasal endoscopy, radiological studies, and histological evaluation of tissue specimens. The histological studies included immunostaining studies to assess the number of IgG4 + plasma cells/HPF for calculation of the IgG4+/IgG + plasma cell ratio. RESULTS: Five patients with granulomatosis with polyangiitis (GPA), three with cocaine-induced midline destructive lesions (CIMDL), and three with IgG4-RD were studied. We found no clinical, endoscopic, or radiological findings specific for IgG4-RD. Increased serum IgG4 and plasmablasts levels were not specific for IgG4-RD. Rather, all 11 patients had elevated blood plasmablast concentrations, and several patients with GPA and CIMDL had elevated serum IgG4 levels. Storiform fibrosis and an IgG4+/IgG + plasma cell ratio >20% on histological examination, however, were observed only in patients with IgG4-RD. CONCLUSIONS: Histological examination of bioptic samples from the sinonasal area and oral cavity represents the mainstay for the diagnosis of IgG4-RD involvement of the midline structures.

Juxta-vertebral lesions in granulomatosis with polyangiitis.

OBJECTIVES: To describe the clinical, pathological, serological, and radiological characteristics of juxta-vertebral masses occurring in patients with granulomatosis with polyangiitis (GPA). METHODS: We analyzed the clinical records of patients with juxta-vertebral lesions from our GPA study cohort and reviewed the English literature for other cases of GPA with juxta-vertebral localization. RESULTS: Out of 74 patients in our GPA study cohort, six (8%) had juxta-vertebral lesions. We found 10 cases of juxta-vertebral GPA described in the English literature. Overall, juxta-vertebral lesions were detected at GPA onset in 11/16 (69%) patients, and preferentially occurred on the right side of the spine (12/15 patients, 80%). Fifteen patients (94%) with juxta-vertebral lesions had systemic GPA. Juxta-vertebral lesions were associated with back pain at GPA onset in 8/16 (50%) patients. In all of them juxta-vertebral lesions resolved or improved after treatment. CONCLUSIONS: Preference for the right-anterior side of the spine, increased 18FDG uptake on PET scan, low or absent invasiveness of the surrounding tissues, and occurrence in the context of systemic disease were the main features of juxta-vertebral GPA. Symptomatic lesions showed a better response to immunosuppressive therapies.

Antineutrophil cytoplasmic antibody positivity in IgG4-related disease: A case report and review of the literature.

BACKGROUND: IgG4-related disease (IgG4-RD) is a fibroinflammatory condition characterized by serum IgG4 elevation and tissue infiltration of IgG4-positive plasma cells. Substantial overlap between IgG4-RD and antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitides (AAV) exists in terms of organ involvement and histopathological features. A positive ANCA assay is regarded as a highly specific finding in favor of an AAV, and generally influences away from a diagnosis of IgG4-RD. Recent reports, however, have raised the possibility that some patients with IgG4-RD are ANCA positive, thus suggesting reconsideration of the role of ANCA in the diagnostic workup. In the present work, we describe the first case of concomitant biopsy-proven IgG4-RD and granulomatosis with polyangiitis (GPA), demonstrating antiproteinase 3 (PR3) ANCA of the IgG4 subclass in the patient's serum. We also review the literature in order to provide clinicians with tools for interpreting ANCA positivity in IgG4-RD patients. CASE SUMMARY: A 51-year-old woman was referred for left exopthalmos due to lacrimal gland enlargement and increased serum IgG4 concentration. IgG4-RD was suspected and further imaging studies disclosed multiple pulmonary masses in the right lung. Histological analysis of the left lacrimal gland was diagnostic for IgG4-RD, but lung biopsy showed typical features of GPA. ANCA assay was positive for anti-PR3 antibodies. Further immunofluorescence studies demonstrated anti-PR3 antibodies of IgG1 and IgG4 subclass. Treatment with rituximab induced swift remission of both IgG4-RD and GPA manifestations. We identified 9 other reports of patients with IgG4-RD and positive ANCA in the English literature, 5 cases with biopsy-proven IgG4-RD and 4 cases in whom IgG4-RD was diagnosed presumptively. Four patients had also histological evidence of concomitant AAV. CONCLUSION: The present work demonstrates that ANCA positivity in patients with biopsy-proven IgG4-RD should prompt the exclusion of a concomitant vasculitic process; a positive ANCA does not exclude the diagnosis of IgG4-RD; confirmation through immunoenzymatic assays of the ANCA specificity, clinical-pathological correlation, and histopathological evaluation remain crucial steps for the differential diagnosis between AAV and IgG4-RD.

Nasal mucosa narrow band imaging in granulomatosis with polyangiitis (Wegener granulomatosis): A preliminary study.

BACKGROUND: Narrow band imaging (NBI) endoscopy is a technique that allows for real-time visualization of mucosal and submucosal vascular patterns. OBJECTIVE: Because granulomatosis with polyangiitis (GPA) (Wegener granulomatosis) is an autoimmune disease defined by vascular inflammation, we examined patients with GPA and with NBI to evaluate whether disease-specific mucosal vascular patterns were present. To the best of our knowledge, the use of NBI endoscopy for assessment of an immune system disease such as GPA has never been previously attempted. METHODS: We conducted a prospective observational study by performing an endoscopic evaluation of upper airways with NBI on patients diagnosed with GPA; on patients with symptoms and signs suggestive for GPA, who were scheduled to undergo nasal biopsy to confirm diagnosis; on patients affected by chronic rhinosinusitis with nasal polyps; and on healthy controls. RESULTS: We enrolled 69 patients. NBI vascular patterns in patients with GPA were consistently and recognizably different from healthy mucosal patterns in 53% of our cases. In patients with GPA, biopsy and NBI results were for the most part comparable, except for three cases. CONCLUSION: Nasal mucosa NBI endoscopy can be considered a promising rapid and noninvasive live imaging technique for nasal mucosa GPA that, based on further study, could become a supplementary diagnostic tool in the complex workup of GPA and vasculitis.

Systemic pentraxin-3 levels reflect vascular enhancement and progression in Takayasu arteritis.

INTRODUCTION: Progression of arterial involvement is often observed in patients with Takayasu arteritis (TA) thought to be in remission. This reflects the failure of currently used biomarkers and activity criteria to detect smouldering inflammation occurring within arterial wall. Pentraxin-3 (PTX3) is a soluble pattern recognition receptor produced at sites of inflammation and could reveal systemic as well as localized inflammatory processes. We verified whether the blood concentrations of PTX3 and of C-reactive protein (CRP) in patients with Takayasu arteritis (TA) might reflect vascular wall involvement, as assessed by signal enhancement after contrast media administration, and the progression of arterial involvement. METHODS: A cross-sectional single-centre study was carried out on 42 patients with TA that comprised assessment of PTX3, of CRP and erythrocyte sedimentation velocity (ESR). In total, 20 healthy controls and 20 patients with Systemic Lupus Erythematous (SLE) served as controls. Vascular imaging was carried out by magnetic resonance angiography, doppler ultrasonography and computed tomography angiography. RESULTS: Patients with TA and SLE had higher plasmatic PTX3 and CRP concentrations than healthy controls (P = 0.009 and 0.017, respectively). PTX3 levels did not correlate with those of CRP. Patients with active systemic TA had significantly higher concentrations of CRP but similar levels of PTX3 than patients with quiescent disease. In contrast, patients with vascular inflammation detectable at imaging had higher PTX3 concentrations (P = 0.016) than those in which vessel inflammation was not evident, while CRP levels were similar. The concentration of PTX3 but not that of CRP was significantly higher in TA patients with worsening arterial lesions that were not receiving antagonists of tumor necrosis factor-α or interleukin-6. CONCLUSIONS: Arterial inflammation and progression of vascular involvement influence plasma PTX3 levels in TA, while levels of CRP accurately reflect the burden of systemic inflammation. These results support the contention that PTX3 reflects different aspects of inflammation than CRP and might represent a biomarker of actual arteritis in TA.

Anti-cytokine treatment for Takayasu arteritis: State of the art.

Takayasu arteritis (TA) is a rare and idiopathic large-vessel arteritis typically affecting young women which has important morbidity and mortality. There are no animal models of TA and pathogenesis is still mysterious. Clinical assessment lacks accurate activity indexes and is based on the integration of clinical, laboratory and radiological data. TA rarity has hampered randomized clinical trials and the achievement of high-quality evidence to guide clinical activity. Prevention of vascular progression, with progressive vessel wall remodelling and hyperplasia, is the main therapeutic goal. Medical therapy remains the mainstay of management and comprises traditional immunosuppressive agents and anti-inflammatory drugs, such as steroids and blockers of pivotal cytokines, TNF-α and IL-6. These strategies however only partially limit vascular progression, indicating that local molecular events are involved. Here we discuss recent data suggesting that selected cellular components of TA lesions should be evaluated as novel therapeutic targets.

Diagnostic value of IgG4 Indices in IgG4-related hypertrophic pachymeningitis.

Diagnosis of IgG4-Related Hypertrophic Pachymeningitis (IgG4-HP) relies on meningeal biopsies, because cerebrospinal fluid (CSF) diagnostic biomarkers are lacking. Here, we determined whether IgG4 intrathecal production could distinguish IgG4-HP from other disorders presenting with HP (OHP). In patients with IgG4-HP, the median CSF IgG4 concentration, IgG4 Index and IgG4Loc were significantly higher than in both controls and OHP. CSF IgG4 levels higher than 2.27mg/dL identified 100% of IgG4-HP and 5% of OHP. An IgG4Loc cut-off of 0.47 identified 100% of IgG4-HP and no cases of OHP. Our results support CSF IgG4 quantification and IgG4 Indices as alternatives to meningeal biopsy for the diagnosis of IgG4-HP when this procedure is contraindicated or uninformative.