Enhanced Antitumor Activity by the Combination of Dasatinib and Selinexor in Chronic Myeloid Leukemia.

BACKGROUND: Chronic myeloid leukemia is a hematological malignancy characterized by the abnormal proliferation of leukemic cells. Despite significant progress with tyrosine kinase inhibitors, such as Dasatinib, resistance remains a challenge. The aim of the present study was to investigate the potential of Selinexor, an Exportin-1 inhibitor, to improve TKI effectiveness on CML. METHODS: Human CML cell lines (LAMA84 and K562) were treated with Selinexor, Dasatinib, or their combination. Apoptosis, mitochondrial membrane potential, and mitochondrial mass were assessed using flow cytometry. Real-time RT-PCR was used to evaluate the expression of genes related to mitochondrial function. Western blot and confocal microscopy examined PINK and heme oxygenase-1 (HO-1) protein levels. RESULTS: Selinexor induced apoptosis and mitochondrial depolarization in CML cell lines, reducing cell viability. The Dasatinib/Selinexor combination further enhanced cytotoxicity, modified mitochondrial fitness, and downregulated HO-1 nuclear translocation, which has been associated with drug resistance in different models. CONCLUSIONS: In conclusion, this study suggests that Dasatinib/Selinexor could be a promising therapeutic strategy for CML, providing new insights for new targeted therapies.

Myositis-Specific and Myositis-Associated Antibodies in Fibromyalgia Patients: A Prospective Study.

Fibromyalgia (FM) is a common rheumatologic disorder characterised by widespread muscular pain. Myalgia is also a common clinical feature in Connective Tissue Disease (CTD), and FM should be studied for the concomitant presence of a CTD. The aim of this study is to evaluate the prevalence of Myositis-Specific and Myositis-Associated Antibodies (MSA/MAA) in a cohort of FM patients. We enrolled 233 consecutive FM patients (defined according to the 2016 criteria) that did not report clinical signs of autoimmune disorders and followed them for at least one year. The patients were tested for MSA/MAA with immunoblotting. FM patients were seropositive for Antinuclear Antibodies (ANA) in 24% of cases, for MSA in 9%, and for MAA in 6%. A specific diagnosis of CTD was made in 12 patients (5.2%), namely, 5 cases of primary Sjögren's Syndrome and 7 of Idiopathic Inflammatory Myopathy. Seropositive patients showed clinical features similar to those who were seronegative at baseline. A CTD diagnosis was associated with ANA positivity (p = 0.03, X2 4.9), the presence of a speckled pattern (p = 0.02, X2 5.3), positivity for MAA (p = 0.004, X2 8.1), and MSA (p = 0.003, X2 9.2). In conclusion, a non-negligible proportion of FM patients may be seropositive for MSA/MAA, and that seropositivity might suggest a diagnosis of CTD.

Systemic Sclerosis and Idiopathic Portal Hypertension: Report of a Case and Review of the Literature.

The presence of liver involvement in systemic sclerosis (SSc) is considered atypical, besides the possible coexistence of other autoimmune hepatic disorders. However, the occurrence of portal hypertension and, more specifically, of the syndromes called idiopathic portal hypertension (IPH) and regenerative nodular hyperplasia (RNH) have been anecdotally reported in the literature for SSc patients. We described a case of SSc woman complicated by IPH; moreover, we reviewed the literature on the topic. A 61-year-old female SSc patient was admitted to our hospital because of the onset of ascites. SSc, as a limited skin subset of disease with anticentromere antibodies, was diagnosed 11 years previously, with no significant visceral involvement. We excluded possible causes of portal hypertension, namely chronic infections, autoimmune hepatic diseases, neoplasia, thrombosis of portal vein, and Budd-Chiari syndrome. Finally, IPH was diagnosed. A review of the literature identified a number of case reports or case series that described IPH in the course of SSc. No specific SSc pattern linked to IPH emerged, even though reports from the literature often described the limited skin subset. Coexistence of prothrombotic states and overlap with other hepatic diseases could facilitate IPH onset. Besides being a rare condition, the onset of IPH in SSc patients is an occurrence that should be taken into account.

A New Method for the Assessment of Myalgia in Interstitial Lung Disease: Association with Positivity for Myositis-Specific and Myositis-Associated Antibodies.

In this study, it was found that myositis-specific and myositis-associated antibodies (MSAs and MAAs) improved the recognition of idiopathic inflammatory myopathies (IIMs) in interstitial lung disease (ILD) patients. The objective of this study is to propose a clinical method to evaluate myalgia in respiratory settings as a possible tool for the recognition of MSA/MAA positivity in ILD patients. We prospectively enrolled 167 ILD patients with suspected myositis, of which 63 had myalgia evoked at specific points (M+ILD+). We also enrolled in a 174 patients with only myalgia (M+ILD-) in a rheumatological setting. The patients were assessed jointly by rheumatologists and pulmonologists and were tested for autoantibodies. M+ILD+ patients were positive for at least one MAA/MSA in 68.3% of cases, as were M-ILD+ patients in 48.1% of cases and M+ILD- patients in 17.2% of cases (p = 0.01 and <0.0001, respectively). A diagnosis of IIM was made in 39.7% of M+ILD+ patients and in 23.1% of the M-ILD+ group (p = 0.02). Myalgia was significantly associated with positivity for MSA/MAAs in ILD patients (p = 0.01, X2: 6.47). In conclusion, myalgia in ILD patients with suspected myositis is associated with MSA/MAA positivity, and could support a diagnosis of IIM. A significant proportion of M+ILD- patients also had MSA/MAA positivity, a phenomenon warranting further study to evaluate its clinical meaning.

"Usual" interstitial pneumonia with autoimmune features: a prospective study on a cohort of idiopathic pulmonary fibrosis patients.

OBJECTIVES: The classification interstitial pneumonia with autoimmune features (IPAF) includes patients with interstitial lung disease (ILD) associated with autoimmune characteristics insufficient to reach classification criteria for a specific autoimmune disease (SAD). These criteria are divided into three domains: clinical, serological and morphological. The latter domain does not include the usual interstitial pneumonia (UIP) pattern, which is deemed not to be significantly associated with SAD. Therefore, the enrolment of these patients is more difficult, requiring at least one item from both of the other domains. The objective of this study is to evaluate the rate of progression towards SAD of a cohort of UIP patients satisfying only one IPAF domain (we called this group "UIPAF") compared with classic idiopathic pulmonary fibrosis (IPF). METHODS: We prospectively enrolled IPF patients with radiologic and/or histologic UIP pattern, followed jointly by rheumatologists and pulmonologists from January 2017 to January 2021, with a minimum follow-up of 12 months. RESULTS: We enrolled 190 IPF patients, 38 (20%) of whom were classified as UIPAF. IPF and UIPAF patients were similar for general characteristics, severity and prognosis, at presentation and at annual check-up. However, 28.9% of UIPAF patients progressed towards SAD, compared with 2% of IPF patients (χ2=30.4, p≤0.0001). CONCLUSIONS: The association between a single clinical or serological domain of IPAF and UIP pattern is predictive for the development of a SAD if compared with isolated UIP. ILD can be the first manifestation of SAD, even with a UIP pattern, therefore, the morphological domain of IPAF criteria could be removed.

Clinical, morphological features and prognostic factors associated with interstitial lung disease in primary SjÓ§gren's syndrome: A systematic review from the Italian Society of Rheumatology.

OBJECTIVE: To evaluate the prevalence, clinical presentation, serological and morphological features of, and therapeutic options for Interstitial Lung Disease (ILD) in primary Sjögren's Syndrome (pSS). METHODS: Pubmed was searched between February 1996 and December 2018 using a combination of MESH terms related to pSS and ILD. Selected works were subjected to blind evaluation by two authors and a senior author in case of disagreement. The work followed PRISMA guidelines and was registered on PROSPERO (CRD42018118669). RESULTS: About 20% of pSS patients have ILD, with a 5-y survival of 84% and a need for supplemental oxygen in the 11-33% range. A significant proportion of ILD patients are seronegative without sicca syndrome. ILD seems to be associated with higher levels of Lactic Dehydrogenases and positivity for Anti-Ro52k. The prevalent pattern in High Resolution Computed Tomography is Nonspecific Interstitial Pneumonia (NSIP), but all other patterns can be present. No difference in mortality was found between patients with NSIP and Usual Interstitial Pneumonia patterns. Amyloidosis and primary lung lymphoma can be observed in about 10% of pSS patients. CONCLUSION: The recognition of pSS underlying an ILD can be challenging in seronegative patients with no or mild sicca symptoms. A complete diagnostic assessment, including minor salivary glands and, in some cases, lung biopsy, should be performed on all patients at risk. A better recognition of the clinical or serological markers of ILD progression in these patients is warranted to drive the physicians to an early diagnosis and an effective treatment.

Clinical, serological and radiological features of a prospective cohort of Interstitial Pneumonia with Autoimmune Features (IPAF) patients.

BACKGROUND: The term Interstitial Pneumonia with Autoimmune Features (IPAF) describes patients with Interstitial Lung Diseases (ILDs) and clinical or serological features of autoimmune diseases insufficient to reach a specific classification of a Connective Tissue Disease (CTD). Currently, retrospective studies on IPAF patients have proven to be heterogeneous in general characteristics, outcomes and High-Resolution Computed Tomography (HRCT) pattern. This study aims to describe for the first time the clinical, serological and radiological features of a prospective cohort of IPAF patients. This cohort is then compared to a group of patients with Idiopathic Pulmonary Fibrosis (IPF). MATERIAL AND METHODS: From 626 consecutive ILD patients evaluated, 45 IPAF and a comparison cohort of 143 IPF patients were enrolled. All patients underwent clinical assessment with rheumatologic and respiratory evaluation, HRCT, Pulmonary Function Tests and Nailfold Videocapillaroscopy. RESULTS: The IPAF patients had a predominance of female gender (62.12%) with a median age of 66 years. The most common findings were: Nonspecific Interstitial Pneumonia (NSIP, 68.89%), Antinuclear Antibody positivity (17.77%) and Raynaud Phenomenon (31.11%). In comparison with IPF, IPAF patients showed younger age, better performances in Pulmonary Function Tests, less necessity of O2 support and predominance of female sex and NSIP pattern. DISCUSSION: This is the first report of a prospective cohort of IPAF patients. IPAF patients seem to have a less severe lung disease than IPF. IPAF criteria probably need to be revisited and validated, but their capacity to recruit patients with incomplete forms or early onset of CTD could be useful for further research.

State of the art in interstitial pneumonia with autoimmune features: a systematic review on retrospective studies and suggestions for further advances.

The term interstitial pneumonia with autoimmune features (IPAF) has been proposed to define patients with interstitial lung disease (ILD) associated with autoimmune signs not classifiable for connective tissue diseases (CTDs). This new definition overcomes previous nomenclatures and provides a uniform structure for prospective studies through specific classification criteria.This work evaluates the characteristics of IPAF patients reported in the literature, to highlight potential limits through a comparative analysis and to suggest better performing classification criteria.Four retrospective studies on the IPAF population have been considered. The study subjects differed in age, sex, smoking habit, ILD pattern and outcomes. Another important difference lies in the diverse items considered in the classification criteria. The retrospective design of the studies and the absence from some of them of a rheumatologist clearly involved in the diagnosis may have influenced the data, but current IPAF criteria seem to include a rather heterogeneous population. To overcome these discrepancies, this review suggests a limitation in the use of single items and the exclusion of extremely specific CTD criteria. This should avoid the definition of IPAF for those diseases at different stages or at early onset. The investigation of a functional or morphological cut-off of pulmonary involvement would be useful.

Present and future of biologic drugs in primary Sjögren's syndrome.

INTRODUCTION: Primary Sjögren's (pSS) syndrome is a chronic, autoimmune, and systemic disease characterized by xerostomia, xerophthalmia, muscle pain and fatigue. The disease may be complicated by a systemic involvement, such as a pulmonary fibrosis or the development of lymphoma which severely worsens the prognosis. Actually, there are no recommendations for the management of pSS. However, recent advances in the understanding of its pathogenesis have uncovered some pathways that have potential as therapeutic targets. Areas covered: In this review, the authors present the biologic drugs potentially valuable to the treatment of pSS in light of its physiopathology with a 'bird's eye' view of future prospects. The authors took into account relevant studies published from 2004 to 2016. Expert opinion: Biological treatment in pSS is a promising opportunity to potentially control disease activity and prevent its complication. Currently, inhibition of B-cell and IL-17 pathways seem to be the most promising avenues. New achievements in the knowledge of pSS pathophysiology are necessary in order to try to simultaneously predict the predominant pathogenic pathway, the kind of patients at major risk to develop a more severe disease, and the appropriate biological therapy to use.

Tumoral calcinosis of the spine in the course of systemic sclerosis: report of a new case and review of the literature.

We report here a case of a 62-year-old Caucasian woman, suffering from diffuse cutaneous systemic sclerosis (SSc), who developed a tumoural calcinosis (TC) localised in the left side of the neck around the cervical spine that caused severe pain and motion impairment, without involvement of regional neurological structures. A review of the literature on this issue (based on PubMed database) allowed us to identify 35 previously described cases of TC in para-vertebral area in the course of SSc. The main characteristics of these patients have been summarised.

Autologous fat grafting in the treatment of fibrotic perioral changes in patients with systemic sclerosis.

Autologous fat tissue grafting (AFTG) has been successfully used in the treatment of different sclerotic conditions, including localized scleroderma. Patients with advanced systemic sclerosis (SSc)-related perioral thickening and mouth opening limitation are candidates for this therapeutic approach. AFTG of the lips was performed to improve mouth opening in patients with SSc. We enrolled in the study 20 female patients with diffuse SSc (median age 35 ± 15 years and 11 ± 10 years of disease duration). Two-milliliter fractions of autologous fat drawn from trochanteric or periumbilical areas were injected in eight different sites around the mouth. Baseline and after-treatment mouth opening changes were assessed by measuring interincisal distance and oral perimeter, while skin hardness was tested by digital durometer. Pre- and posttreatment modifications of microvascular architecture were assessed by counting capillaries in the inferior lip videocapillaroscopy (VC) images and by scoring the microvascular density (MVD) in anti-CD34/CD31 immunohistochemical (IH) stained perioral skin biopsy sections. Similarly, histological sections were examined to evaluate dermoepidermic junction (DEJ) modifications. Three months after treatment, both the interincisal distance and oral perimeter significantly increased (p < 0.001). At the same time, a significant skin neovascularization became evident, both considering the VC images (p < 0.001) and MVD scores in IH sections (p < 0.0001). Finally, some skin histological aspects also improved, as shown by the significant changes in DEJ flattening scores (p < 0.0001). The present study suggests that, in patients with SSc, AFTG can improve mouth opening and function, induce a neovascularization, and partially restore the skin structure.

Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis.

Digital ulcers (DUs) are a rather frequent and invalidating complication in systemic sclerosis (SSc), often showing a very slow or null tendency to heal, in spite of the commonly used systemic and local therapeutic procedures. Recently, stem cell therapy has emerged as a new approach to accelerate wound healing. In the present study, we have tentatively treated long-lasting and poorly responsive to traditional therapy SSc-related DUs by implantation of autologous adipose tissue-derived cell (ATDC) fractions. Fifteen patients with SSc having a long-lasting DU in only one fingertip who were unresponsive to intensive systemic and local treatment were enrolled in the study. The grafting procedure consisted of the injection, at the basis of the corresponding finger, of 0.5-1 ml of autologous ATDC fractions, separated by centrifugation of adipose tissue collected through liposuction from subcutaneous abdominal fat. Time to heal after the procedure was the primary end point of the study, while reduction of pain intensity and of analgesic consumption represented a secondary end point. Furthermore, the posttherapy variation of the number of capillaries, observed in the nailfold video capillaroscopy (NVC) exam and of the resistivity in the digit arteries, measured by high-resolution echocolor-Doppler, were also taken into account. A rather fast healing of the DUs was reached in all of the enrolled patients (mean time to healing 4.23 weeks; range 2-7 weeks). A significant reduction of pain intensity was observed after a few weeks (p < 0.001), while the number of capillaries was significantly increased at 3- and 6-month NVC assessment (p < 0.0001 in both cases). Finally, a significant after-treatment reduction of digit artery resistivity was also recorded (p < 0.0001). Even with the limitations related to the small number of patients included and to the open-label design of the study, the observed strongly favorable outcome suggests that local grafting with ATDCs could represent a promising option for the treatment of SSc-related DUs unresponsive to more consolidated therapies.