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Inhibitor development affects about 30% of patients with severe haemophilia A (HA) and results from different environmental and genetic risk factors. Previously, we identified the missense variant rs3754689 in the LCT gene linked with this predisposition. Since rs3754689 variant is benign and is located in a conserved haplotype region, we hypothesized that the association signal captured by this variant is located in coinherited, neighbouring genes.To identify novel genetic risk factors associated with inhibitor development in coding regions of R3HDM1, UBXN4, CXCR4, MCM6, DARS and miR128-1 genes.Targeted sequencing was performed in 246 severe HA patients (72 with and 174 without inhibitor): 181 previously and 65 newly enrolled.Forty-one common and 152 rare variants passed the quality control. Logistic regression analysis of common variants identified rs3754689 and four additional variants (.011 P .047; FDR ranging .2-.38). Logistic regression analysis performed only in the 220 Italian patients showed similar results (.004 P .05; FDR ranging .12-.22). Three of these variants (rs3213892 and rs3816155 in the LCT intron 13 and rs961360 in the R3HDM1 intron10-exon11 junction) may affect the expression of UBXN4 and R3HDM1, respectively. Rare variants did not show association with inhibitor development. Identified variants were not replicated in the multi-ethnic SIPPET cohort of 230 severe HA patients.Due to the limited sample size that may be responsible of the high FDR values, we could not confirm with certainty the analysed association. Further evaluation of the expression levels of analysed genes will confirm or not their role in inhibitor development.

Hemophilia A and B are rare X‐linked inherited bleeding disorders caused by complete or partial deficiency in or the absence of coagulation factors VIII and IX. Recurrent joint bleeding (hemarthrosis) is the most frequent clinical manifestation of severe hemophilia. Unless appropriately managed, even subclinical hemarthrosis can lead to the development of hemophilic arthropathy, a disabling condition characterized by joint remodelling, chronic pain, and a reduced quality of life, and eventually requires joint replacement. Given the lack of specific treatments to reduce blood‐induced synovitis, the prevention of bleeding is pivotal to the maintenance of joint health. Prophylactic coagulation factor replacement therapy using extended half‐life recombinant drugs has significantly improved patients' quality of life by reducing the burden of intravenous injections, and the more recent introduction of nonreplacement therapies such as subcutaneous emicizumab injections has improved treatment adherence and led to the greater protection of patients with hemophilia A. However, despite these advances, chronic arthropathy is still a significant problem. The introduction of point‐of‐care ultrasound imaging has improved the diagnosis of acute hemarthrosis and early hemophilic arthropathy, and allowed the better monitoring of progressive joint damage, but further research into the underlying mechanisms of the disease is required to allow the development of more targeted treatment. In the meantime, patient management should be based on the risk factors for the onset and progression of arthropathy of each individual patient, and all patients should be collaboratively cared for by multidisciplinary teams of hematologists, rheumatologists, orthopedic surgeons, and physiotherapists at comprehensive hemophilia treatment centers.

BackgroundCoronavirus disease 2019 (COVID-19) caused by SARS-CoV-2 infection is associated with disorders affecting the peripheral and the central nervous system. A high number of patients develop post-COVID-19 syndrome with the persistence of a large spectrum of symptoms, including neurological, beyond 4 weeks after infection. Several potential mechanisms in the acute phase have been hypothesized, including damage of the blood-brain-barrier (BBB). We tested weather markers of BBB damage in association with markers of brain injury and systemic inflammation may help in identifying a blood signature for disease severity and neurological complications.MethodsBlood biomarkers of BBB disruption (MMP-9, GFAP), neuronal damage (NFL) and systemic inflammation (PPIA, IL-10, TNFα) were measured in two COVID-19 patient cohorts with high disease severity (ICUCovid; n=79) and with neurological complications (NeuroCovid; n=78), and in two control groups free from COVID-19 history, healthy subjects (n=20) and patients with amyotrophic lateral sclerosis (ALS; n=51). Samples from COVID-19 patients were collected during the first and the second wave of COVID-19 pandemic in Lombardy, Italy. Evaluations were done at acute and chronic phases of the COVID-19 infection.ResultsBlood biomarkers of BBB disruption and neuronal damage are high in COVID-19 patients with levels similar to or higher than ALS. NeuroCovid patients display lower levels of the cytokine storm inducer PPIA but higher levels of MMP-9 than ICUCovid patients. There was evidence of different temporal dynamics in ICUCovid compared to NeuroCovid patients with PPIA and IL-10 showing the highest levels in ICUCovid patients at acute phase. On the contrary, MMP-9 was higher at acute phase in NeuroCovid patients, with a severity dependency in the long-term. We also found a clear severity dependency of NFL and GFAP levels, with deceased patients showing the highest levels.DiscussionThe overall picture points to an increased risk for neurological complications in association with high levels of biomarkers of BBB disruption. Our observations may provide hints for therapeutic approaches mitigating BBB disruption to reduce the neurological damage in the acute phase and potential dysfunction in the long-term.

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting about 0. 5-1% of the adult population and manifesting as persistent synovitis, systemic inflammation and production of autoantibodies. Patients affected by RA not only experience chronic disease progression, but are also burdened by a 1.5-fold increased cardiovascular (CV) risk, which is comparable to the risk experienced by patients with type 2 diabetes mellitus. RA patients also have a higher incidence and prevalence of coronary artery disease (CAD). Although RA patients frequently present traditional CV risk factors such as insulin resistance and active smoking, previous studies have clarified the pivotal role of chronic inflammation-driven by proinflammatory cytokines such as interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha)-in accelerating the process of atherosclerosis and impairing the coagulation system. Over the last years, a number of studies have shown that disease-modifying anti-rheumatic drugs (DMARDs) reducing the inflammatory state in general improve the CV risk, however some drugs may carry some apparent negative effects. Thus, RA is a model of disease in which targeting inflammation may counteract the progression of atherosclerosis and reduce CV risk. Clinical and experimental evidence indicates that the management of RA patients should be tailored based on the positive and negative effects of DMARDs on CV risk together with the individual traditional CV risk profile. The identification of genetic, biochemical and clinical biomarkers, predictive of evolution and response to treatment, will be the next challenge for a precision approach to reduce the burden of the disease.

Introduction At the beginning of the coronavirus disease 2019 (COVID-19) pandemic, controversial data were reported concerning angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) that induced a number of physicians to stop using them in patients with COVID-19. Although large-scale studies have ruled out this concern, it is common experience that patients with COVID-19 taking ACE inhibitors or ARBs are at increased risk of death. The aim of this study was to investigate the reasons for this apparently high mortality rate. Methods During the first wave of the pandemic, we conducted a field study of 427 consecutive patients with COVID-19 upon their admission to the emergency department of a hospital in one of the most severely hit cities in northern Italy, and 30 days later. The disease was defined as being mild, moderate or severe on the basis of clinical, laboratory and imaging data, and a multivariate model was used to analyse the determinants of mortality. Results Within 30 days of admission, 31.6% of the patients treated with ACE inhibitors or ARBs and 15.2% of those not treated with these drugs had died. Multivariate analysis showed that the determinants of mortality were age (p = 0.0001), hypertension (p = 0.0120) and diabetes (p = 0.0129), whereas ACE inhibitors or ARBs had no effect on mortality. There was no significant difference between the patients treated with ACE inhibitors and those treated with ARBs. Conclusion The apparently increased mortality of patients with COVID-19 receiving long-term treatment with ACE inhibitors or ARBs is not due to the drugs themselves, but to the conditions associated with their use.

Thrombocytopenia is a common feature of antiphospholipid syndrome (APS) and rarely requires treatment. Here we present the case of a 71-year-old man hospitalized for severe immune thrombocytopenia (ITP) secondary to APS and concomitant SARS-CoV-2 infection. The patient was successfully treated with systemic corticosteroids, intravenous immunoglobulins, and plasma exchange (PEX). Few data are published on the use of plasma exchange in the treatment of thrombocytopenia in non-catastrophic APS. In the setting of acute infection when immunosuppressive therapies might be contraindicated, plasma exchange may be considered an effective therapeutic option. SARS-CoV-2 infection may be a trigger for a relapse of immune thrombocytopenia.

Acquired von Willebrand syndrome (AVWS) is a rare, non-hereditary bleeding disorder related to heterogeneous medical conditions such as hematological malignancies and cardiovascular and autoimmune diseases. We describe the clinical course of a 62-year-old man with polycythemia vera who experienced post-traumatic knee and leg swelling due to hemarthrosis. He was treated at another center with low molecular weight heparin due to misdiagnosed deep vein thrombosis further exacerbating the ongoing bleeding. At our center, he was diagnosed with AVWS with reduced von Willebrand factor (VWF):GPIbR plasma activity and loss of high molecular weight multimers (HMWM). He was treated with compressive bandages with resolution. Five months later, on clinical recurrence of knee and leg swelling, knee ultrasound scan showed the presence of chronic synovitis and a hemorrhagic Baker's cyst with signs of rupture. The treatment consisted of chemical synovectomy with rifampicin and steroids preceded by systemic replacement therapy using plasma-derived factor VIII-VWF concentrate. At the end of the treatment cycle, our patient reported complete resolution of knee pain and restoration of joint range of motion and function. Ultrasound evaluation confirmed complete resolution of knee capsule distension and Baker's cyst. Hemarthrosis is an anecdotal presentation of AVWS and chemical synovectomy was successful in treating this complication. A multidisciplinary approach allowed an effective management of this rare complication.

Biomarkers are used for diagnosis, risk stratification and medical decisions. Copeptin and mid-regional proadrenomedullin (MR-proADM) are markers of stress and endothelial function, respectively, which have been studied in pneumonia, sepsis and septic shock. This study aimed to assess whether copeptin and MR-proADM could predict coronavirus disease 2019 (COVID-19) in-hospital outcomes, that is multi-system complications, length of stay and mortality.Copeptin and MR-proADM were assessed at admission in 116 patients hospitalized with COVID-19. Data were retrospectively extracted from an online database. The primary endpoint was in-hospital mortality. The secondary endpoints were in-hospital complications, the composite outcome 'death, or admission to intensive care unit, or in-hospital complications', and length of stay. The predictive power was expressed as area under the receiver operator characteristic curve (AUROC).Copeptin was increased in non-survivors (median 29.7 [interquartile range 13.0-106.2] pmol/L) compared to survivors (10.9 [5.9-25.3] pmol/L, p 0.01). The AUROC for mortality was 0.71, with a hazard ratio of 3.67 (p 0.01) for copeptin values 25.3 pmol/L. MR-proADM differentiated survivors (0.8 [0.6-1.1] nmol/L) from non-survivors (1.5 [1.1-2.8] nmol/L, p 0.001) and yielded a AUROC of 0.79 and a hazard ratio of 7.02 (p 0.001) for MR-proADM values 1.0 nmol/L. Copeptin and MR-proADM predicted sepsis (AUROC 0.95 and 0.96 respectively), acute kidney injury (0.87 and 0.90), the composite outcome (0.69 and 0.75) and length of stay (r = 0.42, p 0.001, and r = 0.46, p 0.001).Admission MR-proADM and copeptin may be implemented for early risk stratification in COVID-19-hospitalized patients to help identify those eligible for closer monitoring and care intensification.

COVID-19 spread in two pandemic waves in Italy between 2020 and 2021. The aim of this study is to compare the first with the second COVID-19 wave, analyzing modifiable and non-modifiable factors and how these factors affected mortality in patients hospitalized in Internal Medicine wards. Consecutive patients with SARS-CoV-2 infection and dyspnea requiring O

Joint bleeding is a common condition for people with hemophilia and, if untreated, can result in hemophilic arthropathy. Ultrasound imaging has recently emerged as an effective tool to diagnose joint recess distension caused by joint bleeding. However, no computer-aided diagnosis tool exists to support the practitioner in the diagnosis process. This paper addresses the problem of automatically detecting the recess and assessing whether it is distended in knee ultrasound images collected in patients with hemophilia. After framing the problem, we propose two different approaches: the first one adopts a one-stage object detection algorithm, while the second one is a multi-task approach with a classification and a detection branch. The experimental evaluation, conducted with $483$ annotated images, shows that the solution based on object detection alone has a balanced accuracy score of $0.74$ with a mean IoU value of $0.66$, while the multi-task approach has a higher balanced accuracy value ($0.78$) at the cost of a slightly lower mean IoU value.

Play Access is an Android assistive technology that replaces touchscreen interaction with alternative interfaces, enabling people with upper extremity impairments to access mobile games, and providing alternative means of playing mobile games for all. We demonstrate the use of Play Access to support physical therapy for children with haemophilia, with the goal of preventing long-term mobility impairments. To achieve this, we modified Play Access to enable the use of body movements, recognized using wearable sensors, as an alternative interface for playing games. This way, Play Access makes it possible to use existing Android games as exergames, hence better targeting patients’ interest.

Hemophilia is an inherited bleeding hematological disorder characterized by the partial or complete deficiency of clotting factor VIII or IX. Hemophilic arthropathy is the consequence of repeated joint bleeding (hemarthrosis) and its management is based on the prevention of acute bleeding through the administration of the deficient clotting factor concentrate or non-factor therapies. In addition, the management of acute and chronic pain is pivotal in hemophilic arthropathy in order to restore function and allow rehabilitation of the joint.We conducted a qualitative review of the literature regarding current and emerging strategies for pain treatment in hemophilic arthropathy. This review considers systemic and local pharmacological and non-pharmacological interventions for acute and chronic pain management.In hemophilic arthropathy, pain management is based on analgesics such as paracetamol, which represents the first choice for acute and chronic pain in adults and children, in association with opioids for adults. Non-steroidal anti-inflammatory drugs inhibit platelet function, so that the currently preferred drugs are short courses of cyclooxygenase 2 inhibitors. Local treatment with intra-articular injections of corticosteroids is an option for refractory cases and physiotherapy has an important role after hemarthrosis and for the long-term management of chronic pain for both pediatric and adult patients.The management of pain in hemophilia requires more standardization. Meanwhile, the safest drugs should be used at the lowest effective dosage and for periods as short as possible. For the non-pharmacological management of pain in these patients, a multidisciplinary team including hematologists, orthopedic surgeons, rheumatologists, and physiotherapists is warranted.

The pathophysiology of the severe complications of COVID-19 is still unclear. We report preliminary data providing evidence of complement activation in patients with COVID-19 with different degrees of respiratory failure.

Background Severe coronavirus disease 2019 (COVID‐19) is characterized by an increased risk of thromboembolic events, with evidence of microthrombosis in the lungs of deceased patients. Objectives To investigate the mechanism of microthrombosis in COVID‐19 progression. Patients/Methods We assessed von Willebrand factor (VWF) antigen (VWF:Ag), VWF ristocetin‐cofactor (VWF:RCo), VWF multimers, VWF propeptide (VWFpp), and ADAMTS13 activity in a cross‐sectional study of 50 patients stratified according to their admission to three different intensity of care units: low (requiring high‐flow nasal cannula oxygenation, n = 14), intermediate (requiring continuous positive airway pressure devices, n = 17), and high (requiring mechanical ventilation, n = 19). Results Median VWF:Ag, VWF:RCo, and VWFpp levels were markedly elevated in COVID‐19 patients and increased with intensity of care, with VWF:Ag being 268, 386, and 476 IU/dL; VWF:RCo 216, 334, and 388 IU/dL; and VWFpp 156, 172, and 192 IU/dL in patients at low, intermediate, and high intensity of care, respectively. Conversely, the high‐to‐low molecular‐weight VWF multimers ratios progressively decreased with increasing intensity of care, as well as median ADAMTS13 activity levels, which ranged from 82 IU/dL for patients at low intensity of care to 62 and 55 IU/dL for those at intermediate and high intensity of care. Conclusions We found a significant alteration of the VWF‐ADAMTS13 axis in COVID‐19 patients, with an elevated VWF:Ag to ADAMTS13 activity ratio that was strongly associated with disease severity. Such an imbalance enhances the hypercoagulable state of COVID‐19 patients and their risk of microthrombosis.

The etiology of intervertebral disc degeneration is largely unknown, but local neuroinflammation may exert a crucial role through activation of cells as microglia and pro-inflammatory cytokines production. We aimed to compare the effect of degenerated and normal intervertebral disc microenvironment on microglial cells and the potential role of sphingosine-1-phosphate, a pro-inflammatory sphingolipid, in their crosstalk. Human degenerated intervertebral discs (Pfirrmann grade IV) were obtained at surgery for spondylolisthesis. Normal intervertebral discs were collected from cadaveric normal lumbar spines. Normal and degenerated-intervertebral discs were kept in culture to obtain media conditioning. Then, microglial cells were cocultured with conditioned media and viability, proliferation, migration, chemotaxis, and inflammatory gene expression were evaluated. The results demonstrate that conditioned media from degenerated intervertebral discs activate microglial cells, increasing chemotaxis, migration, and pro-inflammatory mediators release to a great extent than normal discs. In addition, we show that the administration of sphingosine-1-phosphate to normal intervertebral disc/microglia coculture mimicked degenerative effects. Interestingly, sphingosine-1-phosphate content in conditioned media from degenerated discs was significantly higher than that from normal ones. In addition, FTY720, a functional antagonist of sphingosine-1-phosphate, potently inhibited the effect of degenerated intervertebral discs on microglial inflammatory factor transcription and migration. Our data report, for the first time, that sphingosine-1-phosphate is involved as signal in the microenvironment of human degenerated intervertebral discs. Sphingosine-1-phosphate signaling modulation by FTY720 may induce beneficial effects in counteracting microglial activation during intervertebral disc degeneration.

BackgroundSevere acute respiratory syndrome coronavirus 2 is a recently discovered pathogen responsible of coronavirus disease 2019 (COVID-19). The immunological changes associated with this infection are largely unknown.MethodsWe evaluated the peripheral blood mononuclear cells profile of 63 patients with COVID-19 at diagnosis and the presence of association with inflammatory biomarkers and 28-days mortality.ResultsLymphocytopenia was present in 51 of 63 (80.9%) patients. This reduction was mirrored also on CD8+ lymphocytes (128 cells/μL), natural killer cells (67 cells/μL) and natural killer T cells (31 cells/μL). Monocytes were preserved in total number but displayed a subpopulation composed mainly of cells with a reduced expression of both CD14 and HLA-DR. A direct correlation was found between serum values of IL-6 and the frequency of Th2 lymphocytes (R=0.17; p=0.04) but not with the monocytes count (R=0.01; p=0.60). Patients who died in the 28 days from admission (N=10, 15.9%), when compared to those who did not, displayed lower mean values of CD3+ (p=0.028) and CD4+ cells (p=0.042) and higher mean percentages of CD8+/CD38+/HLA-DR+ lymphocytes (p=0.026).ConclusionsThe early phases of COVID-19 are characterized by lymphocytopenia, predominance of Th2 lymphocytes and less immunocompetent monocytes, which include atypical mononuclear cells.eTOC-At diagnosis patients with COVID-19 have lymphocytopenia-Monocytes with both normal or altered scatter properties display a reduced expression of CD14 and HLA-DR in most of COVID-19 patients-Patients who die in the 28 days from admission have lower values of CD3+ and CD4+ cells and higher percentages of activated CTL cells compared to those who survive

Despite the recent advances in surgical techniques, the percentage of painful shoulder arthroplasties is still high (more than 10%). The causes of residual pain after shoulder arthroplasty, and the resulting treatment solutions, are many and different. The most common complications of shoulder prosthesis are infections, aseptic loosening, modular components disassembling, metal hypersensitivity, and instability. There are also implant-related complications such as glenoid wear in hemiarthroplasty, rotator cuff tear in anatomical total shoulder arthroplasty, scapular notching, and acromion fracture in reverse shoulder arthroplasty. Several of these complications can be avoided with a careful selection of the implants, a proper surgical technique and a precise implant positioning. The execution of a more accurate preoperative planning and the possible use of patient-specific implants are expected to translate into better clinical results in the future. We provide the reader with recent evidence on the causes and therapeutic options of this condition.

[Background] Respiratory failure is a key feature of severe Covid-19 and a critical driver of mortality, but for reasons poorly defined affects less than 10% of SARS-CoV-2 infected patients., [Methods] We included 1,980 patients with Covid-19 respiratory failure at seven centers in the Italian and Spanish epicenters of the SARS-CoV-2 pandemic in Europe (Milan, Monza, Madrid, San Sebastian and Barcelona) for a genome-wide association analysis. After quality control and exclusion of population outliers, 835 patients and 1,255 population-derived controls from Italy, and 775 patients and 950 controls from Spain were included in the final analysis. In total we analyzed 8,582,968 single-nucleotide polymorphisms (SNPs) and conducted a metaanalysis of both case-control panels., [Results] We detected cross-replicating associations with rs11385942 at chromosome 3p21.31 and rs657152 at 9q34, which were genome-wide significant (P, [Conclusions] We herein report the first robust genetic susceptibility loci for the development of respiratory failure in Covid-19. Identified variants may help guide targeted exploration of severe Covid19 pathophysiology., The IKMB's core facilities received infrastructure support by the Deutsche Forschungsgemeinschaft (DFG) Cluster of Excellence "Precision Medicine in Chronic Inflammation" (PMI, EXC2167). The project also received support through a philanthropic donation by Stein Erik Hagen and Canica AS. L.V. was funded by the Fondazione IRCCS Ca’ Granda «COVID-19 Biobank» research grant. This work was also supported by the Ministero dell’Istruzione, dell’Università e della Ricerca – MIUR project "Dipartimenti di Eccellenza 2018 – 2022" (n° D15D18000410001) to the Department of Medical Sciences, University of Torino. The IKMB authors received financial support from the UKSH Foundation "Gutes Tun!" (special thanks to Alexander Eck, Jenspeter Horst and Jens Scholz) and the German Federal Ministry of Education and Research (BMBF; grant ID 01KI20197). HLA-Typing was performed and supported by the Stefan-MorschStiftung. M.A.H was supported by the Spanish Ministry of Science and Innovation ‘JdC fellowship IJC2018-035131-I.

Background Patients with severe hemophilia A may develop inhibitors against factor VIII (FVIII) in around 30% of cases. Recently, the introduction of non-replacement therapies such as emicizumab, a FVIII-mimicking agent administered as a subcutaneous injection, has revolutionized the treatment of patients with inhibitors. However, although rarely, some patients may develop antibodies against this drug. If neutralizing, these antibodies interfere with the activity of the drug, making it ineffective. Mim8 (Novo Nordisk®) is a novel experimental FVIII-mimetic human bispecific antibody that has a similar function as emicizumab, by bridging activated FIX (FIXa) and FX to activate FX, although with a different molecular structure compared to emicizumab. It is currently in phase II clinical trial for subcutaneous treatment of patients with hemophilia A with or without FVIII inhibitors (1, 2). It is currently unknown whether the antibodies developed against emicizumab by patients with hemophilia A could cross-react with Mim8. Aim Our aim was to study the cross-reactivity of anti-emicizumab antibodies developed by patients with hemophilia A against Mim8 with an in-house detection method. Methods We studied the serum of three patients who developed anti-emicizumab antibodies. Plasma from one patient with persistent inhibiting antibodies was collected both during the treatment (thus also containing emicizumab at steady-state levels) and two years after treatment discontinuation due to inefficacy (neutralizing persistent antibodies). Plasma from two patients who developed transient antibodies against emicizumab were also tested in the course of treatment with emicizumab (non-neutralizing transient antibodies). The plate was coated both with emicizumab and with Mim8 provided by the pharmaceutical companies for research purposes. Plasma samples, diluted 1/20, were loaded into the coated wells and incubated 90 min at 37°C. The cross-reactivity to Mim8 was evaluated also by using the affinity purified anti-emicizumab IgG, which was loaded at 5 ug/mL. A properly adapted ELISA method already described (3) was used as reference assay. Then, biotinylated-emicizumab (1.5 ug/mL) or biotinylated-Mim8 (at 2 and 4 ug/mL) were added and the plate incubated 1 hour at 37°C. Moreover, a competition test was performed by using a mixture of biotinylated-emicizumab (1.5 ug/mL) and an excess of Mim8 (at 4, 8 and 40 ug/mL) in the detection phase. Results The Mim8 molecule - either alone, or matched with emicizumab - used both in the capture phase and in the detection phase did not bind to neither patient's plasma antibodies nor to anti-emicizumab purified IgG, which were instead revealed with the reference assay. The binding of the anti-emicizumab antibodies to biotinylated-emicizumab was not inhibited by the addition of Mim8, even at 40 ug/mL. Conclusions Our in-house method showed that anti-emicizumab antibodies do not react with Mim8 in vitro. Observational studies to test whether Mim8 can be used safely in patients with anti-emicizumab antibodies are needed to confirm our findings in vivo as well. References 1. Østergaard et al. A FVIIIa-mimetic bispecific antibody (Mim8) ameliorates bleeding upon severe vascular challenge in hemophilia A mice. Blood. 2021;blood.2020010331. doi:10.1182/blood.2020010331. 2. Valsecchi C et al. J Thromb Haemost. 2021;19(3):711-718. Disclosures Peyvandi: Roche: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

INTRODUCTION: Emicizumab is a humanised bispecific monoclonal antibody, which replaces the function of factor VIII (FVIII) by bridging activated factor IX and factor X. Emicizumab is approved for prophylaxis of patients with Hemophilia A (HA), both with and without inhibitors. Real-world data on the efficacy and safety of emicizumab were recently reported from a few hemophilia treatment centers, but more data are needed to assess the efficacy and safety of emicizumab in comparison to standard prophylactic treatment. OBJECTIVE: To evaluate the safety and efficacy of emicizumab prophylaxis in a single cohort of patients with HA, with and without inhibitors. METHODS: We performed an observational prospective study including patients affected with HA, with and without inhibitors, switched to emicizumab prophylaxis in the post-marketing era. Data regarding inhibitor status, Annualized Bleeding Rate (ABR), cause of bleeding, type and location of bleeds, Emicizumab Plasmatic Concentration [Emi] and activated partial thromboplastin time (aPTT) were collected for each patient. Hemophilia Joint Health Scores (HJHS) and General Health Visual Analogue Scale (GH-VAS) were collected by trained physiotherapists before switching to emicizumab and 12 months after treatment start. RESULTS: A total of 22 patients, 21 with severe and 1 with moderate HA, were enrolled. Twenty patients were without inhibitor against FVIII and 2 adults with inhibitor were previously treated with bypassing agents. All patients started emicizumab prophylaxis with a loading dose of 3 mg/kg once weekly for 4 weeks, followed by a maintenance dosage of 1.5 mg/kg weekly. Within the children cohort, 3 were Previously Untreated Patients (PUPs) and 2 were previously treated with FVIII without developing inhibitor. The ABR showed a reduction of 74% in the entire cohort, as reported in Table 1. When stratifying for age groups, the ABR reduction was 70% for adults and 100% for children. Within the adults, the zero-bleeding patients increased from 2 to 11 patients (from 12 to 64%, respectively). In the adult cohort, 6 patients experienced 11 bleeding events over a mean follow-up of 300 days. Five out of 11 events were experienced in 6 months by a single patient who developed anti-drug antibodies (ADA) against emicizumab around the 5 th week ([Emi] 31.7 ug/ml). The prophylaxis with emicizumab was interrupted due to the treatment failure, which occurred despite spontaneous ADA clearance. Another patient developed ADA around the 9 th week ([Emi] 28.3 ug/ml), but without associated bleedings in up to 14 weeks of follow-up (minimum [Emi] 17 ug/ml). Of the remaining 5 adults who experienced bleedings during emicizumab prophylaxis, one patient developed spontaneous soft tissue bleeding, another one developed a spontaneous hemarthrosis in his target joint and the remaining 3 patients experienced post-traumatic joint bleedings, 2 out of 3 bleedings were in target joints. The analysis of the number of total joint bleedings before and after switching stratified for spontaneous and post-traumatic, revealed a reduction in target joint bleedings of 73% and a reduction of spontaneous and post-traumatic bleeding of 80% and 43%, respectively. All events were managed in outpatient clinic and required only a single infusion of FVIII concentrate. The plasmatic concentrations of emicizumab at steady state were within previous reported normal range for all patients, with exception of the two patients who developed ADA. Interestingly, steady state concentration was higher in children than in adults (median [Emi] 64.9 ug/ml and 49.85, respectively). The HJHS and GH-VAS scores at baseline and after 12 months of emicizumab prophylaxis available in 6 adults showed improvement in joint health and self-perceived global health, as shown in Figures 2 and 3. No thrombotic events were reported in the entire cohort. DISCUSSION: We report our Milan single center experience on the use of emicizumab prophylaxis in children and adults with HA, with and without inhibitors. Our experience shows a good efficacy of emicizumab both in children and adults, with few post-traumatic bleedings occurring mainly in target joints of adult patients. In addition, physician's and self-assessed scores revealed an improvement of patient's joint health after 12 months of emicizumab prophylaxis. Figure 1 Figure 1. Disclosures Peyvandi: Roche: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria.

Introduction Emicizumab is a recombinant, humanized, bispecific antibody restoring the function of missing activated factor VIII (FVIII) by bridging activated FIX (FIXa) and zymogen factor X (FX), medicating the activation of FX. Emicizumab is approved in several countries, at the doses of 1.5 mg/kg once weekly, 3 mg/kg every 2 weeks or 6 mg/kg every 4 weeks, for the prophylaxis of bleeding episodes in patients with hemophilia A with and without inhibitors. The drug has shown a good efficacy either during registration studies as well as in real-world experiences and was well tolerated without significant side effects. The development of neutralizing anti-emicizumab antibodies has been reported in very few cases which frequently required the switch to other products due to inefficacy of the prophylaxis. Patients maintaining a plasma concentration range of the drug within 30-80 ug/ml did not show significant bleeds. However, real life experiences bring the need of personalization of the drug dose. A recent case series presented at ISTH 2021 from Malaysian authors evaluated the efficacy of a dose of emicizumab between 1.7 and 1.9 mg/kg every 4 weeks, showing that even at a lower dose than that approved could be effective for the prevention of bleeding events. Here we report the case of an adult patient with moderate hemophilia A with inhibitor who developed an anti-emicizumab antibody which reduced the concentration of the drug by 50%. Despite that the patient did not report bleeding events in a follow-up period of 18 weeks. Treatment with emicizumab requires further evaluation to understand the best dose for the prevention of bleeding. Case report A 74 years old patient with moderate hemophilia A (FVIII 1-3%) followed at our Center had history of high-titer inhibitor (maximum titer 20 BU). The patient was treated on-demand with plasma-derived FVIII concentrates, when, in Jul 2000, he developed a neutralizing anti-FVIII antibody requiring treatment with activated prothrombin complex concentrates (Feiba). In Nov 2020 the patient was hospitalized for traumatic brain hemorrhage treated with plasma-derived FVIII (inhibitor titer < 5 BU) and subsequently, for the recurrence of inhibitor, with activated prothrombin complex concentrates. In Feb 2021 the patient started prophylaxis with emicizumab at the initial dose of 3 mg/kg once weekly (loading dose), followed by a maintenance dose of 1.5 mg/kg. The patient underwent periodic blood withdrawal for monitoring drug plasma concentration. In Apr 2021 (week 10) drug concentration showed a slight decrease from initial levels, from 39.1 ug/ml (week 5) to 28.3 (week 10) and a weak positivity for an anti-emicizumab antibody was detected. At the following test (week 15) positivity for the anti-emicizumab antibody was confirmed, witnessed by the consistent reduction in drug plasma concentration up to 20.9 ug/ml. During the following weeks, until week 22, drug plasma concentrations were stable (range 17.0-19.4 ug/ml) and positivity for anti-emicizumab antibody remained, as shown in the table. The results of partial Thromboplastin Time (PTT) were consistent with the drug plasma concentrations during the observation period, in which the patient did not developed any bleeding event. Conclusion This case report may corroborate the hypothesis of the efficacy of a reduced dose of emicizumab in patients with hemophilia A. Close laboratory monitoring in patients in prophylaxis with emicizumab is warranted for the evaluation of drug plasma concentration and the prompt detection of anti-drug antibodies, particularly if patient show a reduced therapeutic efficacy. However, in the absence of bleeding events, positivity for anti-emicizumab antibodies should not bring to sudden drug discontinuation. Indeed, in the view of the above, a lower drug plasma concentration than standard might be effective in the prevention of bleeding. 1. Tang ASO et al. July 2021. Efficacy of Reduced-dose Emicizumab in Haemophilia A with Inhibitors: Real World Experience in East Malaysia. ISTH 2021. Figure 1 Figure 1. Disclosures Peyvandi: Takeda: Consultancy, Honoraria; Sobi: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Roche: Consultancy, Honoraria.

Cardiovascular (CV) comorbidities are a frequent extra-articular manifestation of rheumatoid arthritis (RA). Cardiovascular disease (CVD) with accelerated atherosclerosis is a major cause of morbidity and mortality in patients with RA. Subclinical CVD may be present since the early phase of RA. Not only traditional but also non-traditional CV risk factors are involved in the pathogenesis of RA-related CVD. Due to the lack of specifically designed randomized clinical trials, it is still unclear which tools to use to perform CV risk assessment, how to interpret the results and which interventions are appropriate in RA patients both to prevent and to manage CVD. Based on the available evidence, we propose a practical approach.

The term “precision medicine” has been introduced in recent years to describe an approach based on the individual differences in genes, environment, and lifestyle for tailoring the best personalized management for each patient, in contrast to “imprecision medicine,” in which treatment and prevention of diseases are developed for the average person. Precision medicine is a growing field and currently has some limitations: some of the technologies requested are in the early stages of development; some are not easily available on a large scale (e.g., genetic biomarkers) or are very expensive; furthermore, researchers will need to collect a huge bulk of genetic, serological, biochemical, and diagnostic data (“big data”) to set up new tools; finally, doctors and health-care providers need specific training on how to use these new tools appropriately. Although appropriate tools to put personalized medicine in practice in autoimmune disorders are still lacking, preliminary results are promising. In this chapter, we report the current evidence regarding personalized medicine, with a focus on rheumatoid arthritis as a prototype example.

The etiology of autoimmune diseases is the result of a complex interaction of the immune system with environmental and genetic factors, although the underlying mechanisms are not completely understood. A number of autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus, show a striking female predominance. Sexual dimorphism in autoimmunity can be explained at least in part by the role of sex hormones in the regulation of the immune system, whose cells express estrogen and androgen receptors. Furthermore, other mechanisms such as epigenetics may be involved in this multifaceted scenario. The rupture of this complex balance may contribute to the development of autoimmune diseases. In this chapter, we will focus on the effects of sex hormones and prolactin on the pathogenesis and development of autoimmunity.

Central nervous system (CNS) inflammation is primarily driven by microglial cells which secrete proinflammatory cytokines and undergo proliferation upon activation, as it occurs in neurodegenerative diseases. Uncontrolled or prolonged CNS inflammation is potentially harmful and can result in cellular damage. Recently, many studies have focused on human adipose tissue as an attractive source of cytokines with immunosuppressive properties that potentially modulate inflammation. Our study aimed to evaluate if different methods of human tissue collection could affect adipose mesenchymal stem cell (ADSC)-derived cytokine secretion and investigate the effects of ADSC secretome in modulating microglia activation and the possible implication of sphingosine-1-phosphate (S1P) in these effects. Our results demonstrate that the conditioned medium (CM) of ADSCs isolated by two different processing methods (lipoaspirate and Lipogems) significantly inhibited the lipopolysaccharide (LPS)-induced effects on microglia activation, including microglial expression of CD68, cytokine secretion, proliferation, and migration. Pulse studies with radiolabeled sphingosine demonstrated that LPS treatment of resting microglia induced a significant increase of both cellular and extracellular S1P. Moreover, and of relevance, FTY720, a functional antagonist of S1P receptor, inhibited the multiple LPS-induced proinflammatory effects on microglia, and S1P suppressed the anti-inflammatory effect of ADSC-CM. This suggests that LPS-mediated microglial activation is countered by ADSC-CM through the modulation of sphingosine kinase/S1P signalling.

Lipid metabolism derangement contributes to increased cardiovascular risk in Rheumatoid Arthritis (RA). It is still debated whether and how tocilizumab, an interleukin-6 receptor inhibitor used in active RA, impacts cardiovascular risk. We studied the effect of tocilizumab on the regulation of macrophage cholesterol homeostasis, measuring patient serum ability to respectively load (cholesterol loading capacity, CLC) and discharge (cholesterol efflux capacity, CEC) cells with cholesterol. Patients with RA (n = 8) were studied before and after 4 and 12 weeks of tocilizumab treatment. CLC was measured by a fluorimetric assay of intracellular cholesterol content in human macrophages and CEC was measured for the three main pathways, mediated by the transporters Scavenger Receptor class B-type I (SR-BI), ATP binding cassette-G1 (ABCG1) and -A1 (ABCA1) in specific cell models. After 12 weeks of tocilizumab treatment, serum LDL cholesterol levels were increased, while CLC was reduced. HDL cholesterol levels were unchanged, but CEC was significantly ameliorated for the SR-BI and ABCG1 pathways with respect to baseline. Tocilizumab reduces LDL pro-atherogenic potential despite increasing their serum levels and increases HDL protective activity in RA. The data of our pilot study suggest that tocilizumab regulates lipoprotein function in selected patient populations and lay the groundwork for future larger studies.

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by the presence of autoantibodies and a variable spectrum of clinical manifestations and disease severity. The 2019 criteria for SLE classification by the American College of Rheumatology and European League against Rheumatism define ANA positivity by immunofluorescence or by an equivalent solid-phase assay as the entry criterion (1). However, the prevalence of ANA positivity and the reliability of solid-phase assays in SLE are still a matter of controversy (2). Furthermore, the significance of ANA negativisation during follow-up is uncertain (3).Objectives:Our aim was to retrospectively analyse data on the frequency of ANA seroconversion during the follow-up in a cohort of SLE patients with renal involvement.Methods:Adult patients independent of age at SLE onset with a follow-up duration of at least 36 months starting from January 2009 (for standardization of ANA measurement) and with at least one ANA measurement per year were included in this retrospective longitudinal study. Data on demographic, clinical and laboratory characteristics of the study population are reported in table 1. ANA have been measured with Hep2 cell immunofluorescence assay.Table 1.Demographic, clinical and laboratory baseline characteristics of the 121 patients suffering from systemic lupus erythematosus (SLE).DemographicsGender,%F (n)93 (112)Age in years,mean±SD41.6±12.6Clinical featuresAge at SLE onset in years,mean±SD28.0±11.9SLE duration in years,mean±SD13.8±9.5SLEDAI,median (min-max)4 (0 – 27)Laboratory profileSerum creatinine mg/dL,median (min-max)0.8 (0.4 – 2)24h urine protein g/24h,median (min-max)0.5 (0 – 13.8)ANA,%pos (n)93 (112)Anti-ENA,%pos (n)49 (59)Anti-dsDNA,%pos (n)43 (51)Results:A total of 121 SLE subjects with renal involvement were enrolled. Mean follow-up ± standard deviation (SD) was 8 ± 2 years. Ten subjects (8.3%) with positive ANA at the beginning resulted ANA negative at the end of the follow-up. These subjects had different initial ANA titres: 1:1280 (n=1), 1:640 (n=2), 1:320 (n=2), 1:160 (n=3) and 1:80 (n=2); 48 subjects (39.7%) showed a decrease in ANA titre. Of the 9 patients (7.4%) that were negative at the beginning of follow-up, 6 remained negative, whereas 3 showed ANA positivity at the end of the follow-up with ANA titres 1:160 (n=2) and 1:320 (n=1). No differences between subjects with and without ANA titre variations in terms of age (p=0.551), disease duration (p=0.786), SLEDAI at the beginning (p=0.453) and at the end of follow-up (p=0.169) were observed. ANA negativisation and titre variations at the end of follow-up did not correlate with any of the treatments taken during follow-up, including a history of cyclophosphamide (p=0.788).Conclusion:In our cohort of patients with SLE and renal involvement, 10% of patients experienced negativisation and around 40% of patients showed a decrease in ANA titre during follow-up, independent of disease characteristics and previous treatment. Further studies are warranted to clarify the underlying mechanisms and clinical significance of ANA seroconversion and titre variation in SLE patients. However, based on our results, ANA positivity seems to be a relatively stable parameter further supporting its use as an entry classification criterion for SLE.References:[1]Aringer M et al. Arthritis Rheumatol. 2019; 71(9):1400-1412.[2]Pisetsky DS et al. Autoimmun Rev. 2019; 18(12):102400.[3]Frodlund M et al. Clin Exp Immunol. 2019. Epub ahead of print.Disclosure of Interests:None declared

Background:IL-10 plays a key role in systemic lupus erythematosus (SLE) pathogenesis, promoting B-cell response. IL10 is mainly secreted by regulatory T-cells, but follicular helper T-cells (TFH), also produce it. We previously identified a subset of CCR6+IL-7R+T-cells in human tonsils providing IL-10-dependent B-cell help. These CCR6+T-cells were able to produce IL-10, inducing IgG production.Objectives:to investigate a possible role of CD4+CCR6+IL7R+T-cells in SLE pathogenesis.Methods:37 patients fulfilling the ACR criteria for SLE have been included. Disease activity was assessed by 2k-SLEDAI. PBMC were analyzed by flow cytometry, using specific lineage markers. CCR6+IL7R+T-cells purified from total PBMC of SLE patients or healthy donors (HD) were co-cultured with autologous CD20+B-cells. IL-10, Il-17, total IgG and anti-dsDNA antibodies titers in patients serum and culture supernatants were assessed by ELISA. Embedded sections of lymph nodes from 8 SLE patients were analyzed by immunofluorescence (IF).Results:IL10 levels were significantly higher in SLE patients (Fig 1A). CD4+CCR6+IL7R+T-cells were significantly increased in SLE, in particular in those with higher disease activity and higher IL10 levels. CD4+CCR6+IL7R+T-cells levels associated with anti-dsDNA positivity. CCR6+IL7R+T-cells of SLE patients induced production of IgG and anti-dsDNA IgG (in anti-dsDNA + patients) from autologous B-cells, providing spontaneous help for autoantibody productionex vivo(Fig 1B-C). The IF study of lymph nodes of SLE patients showed that IL-10-producing CCR6+T-cells were highly abundant and co-localized with B-cells at follicle margins.Fig 1Conclusion:our study revealed a novel population of extra-follicular B-helper T-cells, which produce IL-10 and could play a prominent pathogenic role in SLE. Further studies will clarify if this potentially pathogenic cell population might represent a possible future therapeutic target.References:[1]Facciotti F. J Allergy Clin Immunol. 2016; Geginat J. Semin Immunol. 2019; Tsokos GC. Nat Rev Rheumatol. 2019Tab 1:SLE patients characteristics(n=37)DemographicsFemale/Male, n37/5Age, years, median (IQR)44 (38-49)Disease duration, years, median (IQR)19 (11-26)Lab testsANA86%*anti-dsDNA (%)46% medium/high titre41%Disease activity and clinical manifestations SLEDAI-2K, median (min-max)3.5 (0-24) Moderate/high activity19%Ongoing therapyPrednisone dose mg/day, median (IQR)7,5 mg (2,5 – 20)hydroxychloroquine78%Immunosuppressants87%Fig 2Disclosure of Interests: :Maria Gerosa: None declared, Federica Facciotti: None declared, Paola Larghi: None declared, Roberto Bosotti: None declared, Chiara Vasco: None declared, Nicola Gagliani: None declared, Chiara Cordiglieri: None declared, Elsa Rottoli: None declared, Alessandra Emiliana Penatti: None declared, Lorenza Maria Argolini: None declared, Bhavna Karnani: None declared, Yasushi Kobayashi: None declared, Mauro Bombaci: None declared, Jan Piet Van Hamburg: None declared, Roberta Gualtierotti: None declared, Stefano Gatti: None declared, Sara Torretta: None declared, Lorenzo Pignataro: None declared, Sander W. Tas: None declared, Roberto Caporali Consultant of: AbbVie; Gilead Sciences, Inc.; Lilly; Merck Sharp & Dohme; Celgene; Bristol-Myers Squibb; Pfizer; UCB, Speakers bureau: Abbvie; Bristol-Myers Squibb; Celgene; Lilly; Gilead Sciences, Inc; MSD; Pfizer; Roche; UCB, Sergio Abrignani: None declared, Massimiliano Pagani: None declared, Fabio Grassi: None declared, Pier Luigi Meroni: None declared, Richard Flavell: None declared, Jens Geginat: None declared

Background Cardiovascular (CV) disease is the leading cause of premature death among Systemic Lupus Erythematosus (SLE) patients1. Several studies have analysed the incidence of CV events in SLE patients. However, the majority of them have been conducted in American and North European countries 2–7. At the best of our knowledge, no studies in Italy have considered cumulative incidence and incidence rate of CV events in Italy. Objectives The present study is devoted to estimate the incidence of a first ever CV event in Italian lupus patients from five rheumatologic tertiary units from North, Centre and South Italy and to search for features associated with and potentially causative of the detected differences. Methods Clinical charts of SLE patients consecutively admitted to five Italian rheumatologic centres from November 1 st 2000 and December 31 st 2016 were retrospectively studied. Patients selected were free of CV events at baseline. CV cumulative incidence was evaluated as the proportion of patients who experienced a new CV event over the follow up period. CV incidence rate was expressed as the number of events in the cohort divided by the total number of years at risk. Our incidence was compared with that detected in the Italian general population and those reported in SLE cohorts from other countries. Results The median duration of follow-up was 6 years (IQR=3–11). During the observational period, 39(cumulative incidence=7.6%) of the 511 patients had a first CV event with an incidence rate of 10.4/1000 person-years i.e. 12 times higher than in the general population. The CV cumulative incidence detected in our Italian cohort was similar to that reported in the Spanish cohort, but lower than those from North European and American cohorts. The Italian cohort differed from other SLE cohorts in some traditional risk factors (smoke, hypertension, dyslipidemia) and treatment with aspirin and hydroxychloroquine.(table1) Conclusions Our study confirmed the increased CV risk in SLE compared with the general population. However, the incidence of CV events in our SLE series was lower than that detected in North European and American lupus cohorts. These disparities could be ascribed to the differences in the prevalences of traditional CV risk factors among the distinct cohorts. Nevertheless, our CV cumulative incidence was very similar to that detected in the Spanish cohort, despite their higher frequency of traditional risk factors. For this evidence, the geographic (Mediterranean) origin deserve to be considered. On the other hand, the slight difference detected between our series and Baltimore cohort2(where patients were examined every 3 months) underlines the need of a strict follow-up of the SLE patient. References [1] Cervera R, et al. Medicine (Baltimore)2003. [2] Magder LS, Petri M. Am J Epidemiol2012. [3] Bertoli AM, et al. Lupus2009. [4] Bartels CM, et al. J Rheumatol2014. [5] Gustafsson J, et al. Arthritis Res Ther2009. [6] Hermansen M-L, et al. Rheumatol Oxf Engl2017. [7] Fernandez-Nebro A, et al. Medicine (Baltimore)2015. Disclosure of Interest None declared

Background Previous study from our group have pointed out a lower number of cardiovascular (CV) events in Italian patients with Systemic Lupus Erythematosus (SLE) than in North European and American ones. This study aims to assess the incidence of the first CV event in a large, multicenter, Italian cohort of patients with SLE and search for differences in disease and traditional risk factors among distinct cohorts. Methods Clinical charts of SLE patients consecutively admitted to five Italian rheumatologic centres from November 1 st 2000 and December 31 st 2015 were retrospectively studied. Patients selected were free of CV events at baseline. CV incidence rate was expressed as the number of events in the cohort divided by the total number of years at risk. CV cumulative incidence were evaluated as the proportion of patients who experienced a new CV event over the follow up period. Our incidence was compared with that detected in the Italian general population and those reported in SLE cohorts from other countries. Results The median duration of follow-up was 6 years (IQR=3–11). During the observational period, 37(cumulative incidence=7.2%) patients had a first episode of CV event with an incidence rate of 10.1/1000 person-years i.e 12 times higher than in the general population. The CV incidence rate and cumulative incidence detected in our Italian cohort was lower than those from North European and American cohorts. The Italian cohort differed from other SLE cohorts in some traditional risk factors (smoke, hypertension, dyslipidemia) and treatment with aspirin and hydroxychloroquine. Conclusion Our results confirmed that Italian lupus patients suffer a high incidence of CV disease compared with general population. However, this incidence was lower than that detected in North European and American lupus cohorts

Inflammatory joint disorders such as rheumatoid arthritis and spondyloarthritis are chronic systemic diseases with an immune-mediated pathogenesis. They may be associated with neutrophilic dermatoses, particularly pyoderma gangrenosum, Sweet’s syndrome and hidradenitis suppurativa [1–3].

Objectives The sparing effect of hemiplegia in rheumatic diseases has been described, but reports on systemic sclerosis (SSc)-spectrum disorders are unusual. SSc-spectrum disorders are complex diseases of unknown origin characterized by multisystem involvement, skin and organ fibrosis, microvascular alterations, and immunologic abnormalities. We describe two cases of patients with hemiplegia who developed Raynaud׳s phenomenon and skin fibrosis of the non-paretic limb. Methods Clinical, laboratory, and investigation findings of two cases with hemiplegia who developed scleroderma spectrum disorders of the non-paretic limb are presented. A review of the medical literature was performed in PubMed for all articles in English. Results A total of 46 reports from 1935 to 2012 were identified, especially on osteoarthritis and rheumatoid arthritis. Only two case reports on patients with SSc describe asymmetric SSc skin involvement and unilateral acro-osteolysis on x-ray images of the non-paretic limb. By contrast, we report the first description of capillaroscopic microvascular changes in patients with hemiplegia and asymmetric SSc skin involvement. Conclusions Our cases point out the potential role of a "cross-talk" between the nervous system and the skin in SSc-spectrum disorders and suggest future directions for research in studies of pathogenesis.

Gene expression analysis provides an effective methodology to identify clinically relevant genes implicated in intervertebral disc (IVD) pathology. The analysis of gene profile in mesenchymal stem cells (MSCs) from human herniated IVD (H-IVD) and degenerated IVD (D-IVD) has not yet been investigated. We present in this study a characterization of MSCs isolated from clinically categorized H-IVD and D-IVD disc samples. H-IVD-MSCs and D-IVD-MSCs showed multipotent mesenchymal differentiation ability, expressing positivity for adipogenic, osteogenic, and chondrogenic markers with an immunophenotypical profile representative of MSCs. FACS analyses revealed a higher expression of CD44 in D-IVD-MSCs compared to H-IVD-MSCs. Gene expression profile revealed that most genes under investigation displayed large variations and were not significantly different in the two types of analyzed IVD-MSCs. Conversely, the gene expression of osteopontin (OPN), a protein involved in bone matrix mineralization and extracellular matrix destruction, was found markedly increased (more than 400-fold) in D-IVD-MSCs compared to H-IVD-MSCs. Moreover, the OPN protein expression was detectable only in D-IVD-MSCs, and its levels were directly related with D-IVD severity. These findings suggest that an abnormal expression of OPN in D-IVD-MSCs occurs and plays a pivotal role in the pathophysiological process of human disc degeneration. We speculate that the regulation of the OPN pathway might be a therapeutic target to counteract disc degeneration.

In patients with Raynaud’s phenomenon (RP), the role of medical history, capillaroscopy, and autoantibodies in order to provide an early diagnosis of connective tissue disease (CTD) were examined. 115 consecutive adults with uni-, bi-, or triphasic colour changes of the fingers were studied. RP was bilateral in 92.7% of patients. The middle finger was significantly more affected. A lack of association between fingers affected by RP and fingers with capillary abnormalities was observedOR=0.75(0.34–1.66). RP with the cyanotic phase had a higher risk at capillaroscopy to have hemorrhagesOR=4.46(1.50–13.30) and giant capillariesOR=24.85(1.48–417.44). The thumb and triphasic involvement have an OR of 1.477 and 1.845, respectively. RP secondary to systemic sclerosis (SSc) had greater value of VAS pain (p=0.011). The presence of anti-centromere antibodies was significantly associated with a higher risk of SSc (p<0.001). 44.3% of subjects had uniphasic blanching of the fingers, and among these, 27% was diagnosed as having an overt or suspected CTD. Markers of a potential development of CTDs include severe RP symptoms, positive autoantibodies, and capillary abnormalities. These data support the proposal to not discharge patients with uniphasic blanching of the fingers to avoid missing the opportunity of an early diagnosis.

Altered control of T follicular helper (Tfh) cells can lead to generation of autoantibodies and autoimmune manifestations. Signaling pathways that selectively limit pathogenic responses without affecting the protective function of Tfh cells are unknown. Here we show that the ATP-gated ionotropic P2X7 receptor restricts the expansion of aberrant Tfh cells and the generation of self-reactive antibodies in experimental murine lupus, but its activity is dispensable for the expansion of antigen-specific Tfh cells during vaccination. P2X7 stimulation promotes caspase-mediated pyroptosis of Tfh cells and controls the development of pathogenic ICOS+ IFN-γ–secreting cells. Circulating Tfh cells from patients with systemic lupus erythematosus (SLE) but not primary antiphospholipid syndrome (PAPS), a nonlupus systemic autoimmune disease, were hyporesponsive to P2X7 stimulation and resistant to P2X7-mediated inhibition of cytokine-driven expansion. These data point to the P2X7 receptor as a checkpoint regulator of Tfh cells; thus, restoring P2X7 activity in SLE patients could selectively limit the progressive amplification of pathogenic autoantibodies, which deteriorate patients’ conditions.

Rheumatoid arthritis and spondyloarthritis are inflammatory joint disorders with an autoimmune pathogenesis and systemic involvement. The skin is one of the most frequently affected extraarticular sites with a number of manifestations or distinct diseases, including common conditions, such as rheumatoid nodules and psoriasis, and rare diseases like neutrophilic dermatoses. The latter are clinically characterised by polymorphic lesions, including pustules, bullae, abscesses, papules, nodules, plaques and ulcers, and histologically by neutrophil-rich inflammatory infiltrates. Inflammatory joint disorders and neutrophilic dermatoses share a number of pathophysiological features related to their cytokine overexpression profile. Moreover, any organ system can be potentially involved in neutrophilic dermatoses, giving rise to the concept of neutrophilic disease. Among the extracutaneous manifestations of neutrophilic disease, joint involvement is regarded as the most common. It is not associated with erosions and disability and usually responds to treatment for skin involvement, consisting of systemic corticosteroids and, in refractory cases, immunosuppressants or biologics. Arthritis may also be the initial manifestation of rheumatoid arthritis or spondyloarthritis, which has a chronic or recurrent course and requires a continuous treatment with synthetic or biologic disease-modifying anti-rheumatic drugs. If not properly treated, they may be associated with disability and reduced quality of life. Skin lesions occurring during the course of rheumatoid arthritis and spondyloarthritis require a multidisciplinary approach envisaging the collaboration of dermatologists and rheumatologists in order to achieve early diagnosis and treatment. Several biomarkers may help the clinician in the differential diagnosis of arthritis while histology is pivotal for the correct classification of the skin disease. However, in some cases, only regular follow-up allows a definite diagnosis. In this review article, we focus on the prototypic neutrophilic dermatoses like pyoderma gangrenosum, Sweet's syndrome, hidradenitis suppurativa and their syndromic forms as well as on their articular involvement, providing a simple approach for their diagnosis and therapy.

B cells play an important role in the initiation and progression of systemic lupus erythematosus (SLE). Accordingly, B cell-targeted therapy has been suggested as a new rational approach for treating lupus. Belimumab, a human monoclonal antibody directed against B lymphocyte stimulator (BLyS), was reported as the first biological treatment effective in reducing mild-to-moderate SLE disease activity by using different scoring systems and endpoints. Conversely clinical trials with rituximab, a chimeric monoclonal antibody directed against the CD20 expressed by B cells, have failed to achieve primary endpoints in spite of a number of reports showing its beneficial effects. Anecdotal reports have described the sequential use of rituximab and belimumab as a more effective treatment than using the individual drugs alone, without compromising safety.We report a case series of three patients with active SLE refractory to conventional therapies, who underwent treatment with rituximab followed by belimumab as maintenance therapy.We observed a beneficial effect after sequential treatment with rituximab and belimumab. All patients achieved long-standing remission and could reduce or discontinue corticosteroids. Concomitantly, after rituximab administration we observed a rise in BLyS levels, which were dramatically reduced after belimumab introduction.The modulation of plasma BLyS kinetics in patients undergoing sequential treatment with rituximab and belimumab may represent a possible rationale behind the effectiveness of this combined therapy.