Residual burden of liver disease after HCV clearance in hemophilia: a word of caution in the era of gene therapy.

Ruling out advanced fibrosis/cirrhosis is mandatory for persons with hemophilia (PWH) who are candidates for gene therapy. However, clinical evaluation and noninvasive tests (NITs) may be inaccurate after hepatitis C virus (HCV) clearance. We conducted a prospective hepatological screening to detect advanced fibrosis/cirrhosis in PWH after HCV clearance. Any risk factor of chronic liver damage was registered by using biochemical data, liver stiffness measurement (LSM), and ultrasound (US). A pre/post-HCV clearance analysis was conducted prospectively in a subgroup of patients who underwent LSM, US, and NITs for fibrosis. We evaluated 119 patients (median age, 53 years; range, 36-87 years) with a previous HCV infection (hemophilia A, n = 108; hemophilia B, n = 11). Ninety-six (81%) presented at least 1 potential risk factor of chronic liver damage. Metabolic risk factors were the most prevalent, with 51 patients (44%) having US steatosis. In 21 patients (18%), clinical, biochemical, liver morphology, and/or LSM were suggestive of advanced fibrosis/cirrhosis. Furthermore, 10 patients (8%) had esophageal varices and 3 (3%) had hepatocellular carcinoma. In 57 patients included in the prospective analysis, LSM and NITs were reduced after HCV clearance (P < .05), but US signs specific of cirrhosis remained unchanged. Overall, 23 of 80 patients (29%) with LSM <10 KPa had at least 1 US sign suggestive of advanced fibrosis/cirrhosis. A similar proportion (18%) was observed for LSM <8 KPa. Overall, risk factors of chronic liver damage are frequent after HCV clearance, but changes in LSM and NITs after clearance may be inaccurate to rule out advanced fibrosis/cirrhosis. A specific diagnostic workup is warranted to evaluate liver health in PWH in the era of gene therapy.

Exploring the prevalence and clinical impact of fibromyalgia syndrome in patients with shoulder diseases: a cross-sectional study.

OBJECTIVES: Fibromyalgia (FM) is a musculoskeletal syndrome characterised by widespread chronic pain often associated with systemic manifestations such as mood disturbances, persistent fatigue, unrefreshed sleep, and cognitive impairment, substantially impacting patients' health-related quality of life. Based on this background, this study aimed to evaluate the prevalence of FM syndrome in patients referring to an outpatient clinic in a central orthopaedic institute for a painful shoulder. The demographic and clinical characteristics of patients fulfilling the criteria for FM syndrome were also correlated with the severity of symptoms. METHODS: Consecutive adult patients referring to the shoulder orthopaedic outpatient clinic of the ASST Gaetano Pini-CTO, Milan, Italy, to undergo a clinical evaluation were assessed for eligibility in an observational, cross-sectional, monocentric study. RESULTS: Two hundred-one patients were enrolled: 103 males (51.2%) and 98 females (48.8%). The mean age ± standard deviation (SD) of the patients was 55.3 ± 14.3 years in the whole population. Of all the patients, 12 (5.97%) fulfilled the 2016 FM syndrome criteria based on the FM severity scale (FSS). Of these, 11 were females (91.7%, p=0.002). The mean age (SD) was 61.3 (10.8) in the positive criteria sample. Patients with positive criteria had a mean FIQR of 57.3 ± 16.8 (range 21.6-81.5). CONCLUSIONS: We found that FM syndrome is more frequent than expected in a cohort of patients referring to a shoulder orthopaedic outpatient clinic, with a prevalence rate (6%) more than double that of the general population (2%).

Disease-modifying anti-rheumatic drugs improve the cardiovascular profile in patients with rheumatoid arthritis.

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.

Successful Chemical Synovectomy in a Patient with Acquired von Willebrand Syndrome with Chronic Synovitis Due to Recurrent Knee Hemarthrosis: A Case Report.

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.

Transmembrane Protein TMEM230, a Target of Glioblastoma Therapy.

Glioblastomas (GBM) are the most aggressive tumors originating in the brain. Histopathologic features include circuitous, disorganized, and highly permeable blood vessels with intermittent blood flow. These features contribute to the inability to direct therapeutic agents to tumor cells. Known targets for anti-angiogenic therapies provide minimal or no effect in overall survival of 12-15 months following diagnosis. Identification of novel targets therefore remains an important goal for effective treatment of highly vascularized tumors such as GBM. We previously demonstrated in zebrafish that a balanced level of expression of the transmembrane protein TMEM230/C20ORF30 was required to maintain normal blood vessel structural integrity and promote proper vessel network formation. To investigate whether TMEM230 has a role in the pathogenesis of GBM, we analyzed its prognostic value in patient tumor gene expression datasets and performed cell functional analysis. TMEM230 was found necessary for growth of U87-MG cells, a model of human GBM. Downregulation of TMEM230 resulted in loss of U87 migration, substratum adhesion, and re-passaging capacity. Conditioned media from U87 expressing endogenous TMEM230 induced sprouting and tubule-like structure formation of HUVECs. Moreover, TMEM230 promoted vascular mimicry-like behavior of U87 cells. Gene expression analysis of 702 patients identified that TMEM230 expression levels distinguished high from low grade gliomas. Transcriptomic analysis of patients with gliomas revealed molecular pathways consistent with properties observed in U87 cell assays. Within low grade gliomas, elevated TMEM230 expression levels correlated with reduced overall survival independent from tumor subtype. Highest level of TMEM230 correlated with glioblastoma and ATP-dependent microtubule kinesin motor activity, providing a direction for future therapeutic intervention. Our studies support that TMEM230 has both glial tumor and endothelial cell intracellular and extracellular functions. Elevated levels of TMEM230 promote glial tumor cell migration, extracellular scaffold remodeling, and hypervascularization and abnormal formation of blood vessels. Downregulation of TMEM230 expression may inhibit both low grade glioma and glioblastoma tumor progression and promote normalization of abnormally formed blood vessels. TMEM230 therefore is both a promising anticancer and antiangiogenic therapeutic target for inhibiting GBM tumor cells and tumor-driven angiogenesis.

Inflammatory interactions between degenerated intervertebral discs and microglia: Implication of sphingosine-1-phosphate signaling.

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.

Fibromyalgia and Shoulder Surgery: A Systematic Review and a Critical Appraisal of the Literature.

Fibromyalgia is a common musculoskeletal syndrome characterized by chronic widespread pain and other systemic manifestations, which has demonstrated a contribution to higher postoperative analgesic consumption to other surgeries such as hysterectomies and knee and hip replacements. The aim of this review is to search current literature for studies considering the impact of fibromyalgia on clinical outcomes of patients undergoing shoulder surgery. A systematic literature review was conducted in PubMed/Medline, Embase, and ClinicalTrials.gov in February 2019. Studies were selected based on the following participants, interventions, comparisons, outcomes, and study design criteria: adult patients undergoing surgery for shoulder pain (P); diagnosis of fibromyalgia (I); patients without fibromyalgia (C); outcome of surgery in terms of pain or analgesic or non-steroidal anti-inflammatory drugs consumption (O); case series, retrospective studies, observational studies, open-label studies, randomized clinical trials, systematic reviews and meta-analyses were included (S). Authors found 678 articles, of which four were found eligible. One retrospective study showed that patients with fibromyalgia had worse clinical postoperative outcomes; two retrospective studies reported a higher opioid prescription in patients with fibromyalgia and one prospective observational study found that a higher fibromyalgia survey score correlated with lower quality of recovery scores two days after surgery. The scarce and low-quality evidence available does not allow confirming that fibromyalgia has an impact on postoperative outcomes in shoulder surgery. Future studies specifically focusing on shoulder surgery outcomes may help improvement and personalization of the management of patients with fibromyalgia syndrome (PROSPERO 2019, CRD42019121180).

Efficacy and Metabolic Effect on Serum Lipids of Apremilast in Psoriatic Arthritis: A Case Report.

Psoriatic arthritis (PsA) is a chronic immune-mediated disease manifesting as joint inflammation with functional impairment associated with psoriasis. Recently, PsA has emerged as a systemic disease with several comorbidities, such as cardiovascular diseases and metabolic disorders. Apremilast is a targeted synthetic disease-modifying anti-rheumatic drug (tsDMARD) directed against phosphodiesterase 4 (PDE4) with demonstrated efficacy and safety in PsA and psoriasis. We report the case of a patient with PsA manifesting as arthritis, dactylitis, mild psoriasis and a significantly reduced health-related quality of life (HRQoL). Treatment with apremilast in association with methotrexate led to a quick improvement of joint and skin involvement with a stable amelioration of HRQoL. Furthermore, we observed a persistent favorable shift of serum lipid profile. Our observations suggest that apremilast is effective in controlling mild skin and joint involvement, including dactylitis, and suggest a potentially advantageous metabolic effect in patients with PsA.

Main Oral Manifestations in Immune-Mediated and Inflammatory Rheumatic Diseases.

Oral manifestations are frequent in patients with rheumatic diseases. The aim of this review is to offer readers practical advice concerning the onset, diagnosis and treatment of the main oral manifestations encountered in rheumatological and dental clinics. Signs and symptoms such as oral hyposalivation, xerostomia, temporomandibular joint disorders, periodontal disease, and dysphagia may be the first expression of a number of rheumatic diseases. Some of these manifestations are aspecific and very frequent, such as oral aphthosis, which can be the first manifestation in patients with systemic lupus erythematosus; some are potentially dangerous, such as jaw claudication during the course of giant cell arteritis; and some are very rare but peculiar, such as strawberry-like gingivitis in patients with granulomatosis with polyangiitis. Other oral manifestations are due to adverse reactions to disease-modifying anti-rheumatic drugs. Oral alterations in rheumatic diseases are frequently overlooked in clinical practice, but their prompt recognition not only allows the local lesions to be appropriately treated, but also makes it possible to identify an underlying systemic disease.

Total Joint Arthroplasty in Patients with Inflammatory Rheumatic Diseases.

Since its introduction, total joint arthroplasty (TJA) has improved the quality of life of patients with degenerative joint disorders. In the last decades, a number of conventional and biological disease-modifying antirheumatic drugs have become available for the treatment of patients with inflammatory rheumatic diseases (IRD), leading to a reduction in the need to undergo TJA. However, TJA is still frequently performed in IRD patients. Both rheumatologists and orthopedics should be aware that patients with IRD have a peculiar perioperative risk profile due to disease-related, patient-related, and surgery-related risk factors. On the basis of current evidence, TJA is a safe procedure for IRD patients as long as an accurate risk stratification and a multidisciplinary approach are applied. We here describe the current strategies for an appropriate surgical management of osteoarthritis in IRD patients and the fascinating opening perspectives that surgeons and clinicians may expect in the future.

Successful sequential therapy with rituximab and belimumab in patients with active systemic lupus erythematosus: a case series.

OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Perioperative Management of Patients with Inflammatory Rheumatic Diseases Undergoing Major Orthopaedic Surgery: A Practical Overview.

Patients with inflammatory rheumatic diseases often need orthopaedic surgery due to joint involvement. Total hip replacement and total knee replacement are frequent surgical procedures in these patients. Due to the complexity of the inflammatory rheumatic diseases, the perioperative management of these patients must envisage a multidisciplinary approach. The frequent association with extraarticular comorbidities must be considered when evaluating perioperative risk of the patient and should guide the clinician in the decision-making process. However, guidelines of different medical societies may vary and are sometimes contradictory. Orthopaedics should collaborate with rheumatologists, anaesthesiologists and, when needed, cardiologists and haematologists with the common aim of minimising perioperative risk in patients with inflammatory rheumatic diseases. The aim of this review is to provide the reader with simple practical recommendations regarding perioperative management of drugs such as disease-modifying anti-rheumatic drugs, corticosteroids, non-steroidal anti-inflammatory drugs and tools for a risk stratification for cardiovascular and thromboembolic risk based on current evidence for patients with inflammatory rheumatic diseases.

Detection of early endothelial damage in patients with Raynaud's phenomenon.

OBJECTIVES: Raynaud's phenomenon (RP) can be the first manifestation of systemic sclerosis (SSc) or other connective tissue diseases (CTDs), often preceding an overt disease by years. It is not known if markers of endothelial damage are detectable in those RP patients who subsequently develop a CTD. METHODS: We studied 82 RP patients at their first evaluation to correlate the levels of endothelial markers with the subsequent development of an overt disease 36months later. We measured plasma levels of tissue-type plasminogen activator (t-PA) and von Willebrand factor (vWF), two markers of endothelial damage, and interleukin-6 (IL-6), a pro-inflammatory cytokine. Thirty sex- and age-matched healthy subjects (HS) served as controls. RESULTS: At baseline, 67 patients showed capillaroscopic normal pattern (CNP) and 15 patients, of which 11 were very early SSc, had capillaroscopic scleroderma pattern (CSP). Plasma levels of t-PA, vWF and IL-6 were higher in patients with CNP (p=0.0001) than in HS and even much higher in patients with CSP (p=0.0001). In patients with CNP and RP of recent onset (<18months), vWF plasma levels were higher when autoantibodies were present (p=0.020). After 36months, among 48 RP patients with CNP who remained in follow-up, 24 were diagnosed as primary and 24 as secondary RP. In secondary RP, basal levels of t-PA, IL-6 and particularly vWF were higher than in primary RP (p=0.005, p=0.004, p=0.0001 respectively) and HS (p=0.0001 for all). CONCLUSIONS: Our findings indicate that markers of endothelial damage are elevated in RP patients who subsequently develop SSc or other CTDs, even in the absence of capillaroscopic abnormalities.

The Adipose Mesenchymal Stem Cell Secretome Inhibits Inflammatory Responses of Microglia: Evidence for an Involvement of Sphingosine-1-Phosphate Signalling.

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.

Prothrombotic biomarkers in patients with rheumatoid arthritis: the beneficial effect of IL-6 receptor blockade.

OBJECTIVES: The pro-inflammatory cytokine interleukin (IL)-6 is involved in the pathogenesis of both rheumatoid arthritis (RA) and cardiovascular events. We evaluated the correlation of prothrombotic biomarkers, in particular those of thrombin generation, with inflammatory and clinical parameters in RA patients treated with tocilizumab, an IL-6 receptor (IL-6R) inhibitor. Naïve and maintenance patients were compared. METHODS: We studied 15 RA patients undergoing tocilizumab infusions at a University Outpatient Clinic. Eight received tocilizumab for the first time and were evaluated at baseline. Seven were in maintenance therapy (9 to 77 months). All 15 patients were evaluated four weeks after the last administration of tocilizumab. At each time, we assessed disease activity score 28 (DAS28), erythrocyte sedimentation rate (ESR) and plasma levels of C-reactive protein (CRP), IL-6, soluble (s)IL-6R, tumour necrosis factor-alpha (TNF-alpha), prothrombin fragment F1+2 and fibrin fragment D-dimer. Forty healthy subjects served as basal controls. RESULTS: At baseline, RA patients showed a moderate-to-high disease activity and median ESR of 51 mm/1(st) hour (interquartile range 25-63). Plasma levels of CRP (p=0.0001), IL-6 (p=0.043), sIL-6R (p=0.003), TNF-alpha (p=0.0001), F1+2 (p=0.0001) and D-dimer (p=0.002) were higher than those of healthy controls. After four weeks we observed reduction of DAS28 (p=0.0001), ESR (p=0.0001), CRP (p=0.014), TNF-alpha (p=0.006), F1+2 (p=0.009) and D-dimer (p=0.04). No differences were observed between naïve and maintenance patients. CONCLUSIONS: The reduction of prothrombotic biomarkers parallels the reduction of inflammatory parameters and clinical symptoms in RA patients treated with tocilizumab, both four weeks after the first administration and during maintenance therapy.

Mesenchymal stem cells: potential for therapy and treatment of chronic non-healing skin wounds.

Wound healing is a complex physiological process including overlapping phases (hemostatic/inflammatory, proliferating and remodeling phases). Every alteration in this mechanism might lead to pathological conditions of different medical relevance. Treatments for chronic non-healing wounds are expensive because reiterative treatments are needed. Regenerative medicine and in particular mesenchymal stem cells approach is emerging as new potential clinical application in wound healing. In the past decades, advance in the understanding of molecular mechanisms underlying wound healing process has led to extensive topical administration of growth factors as part of wound care. Currently, no definitive treatment is available and the research on optimal wound care depends upon the efficacy and cost-benefit of emerging therapies. Here we provide an overview on the novel approaches through stem cell therapy to improve cutaneous wound healing, with a focus on diabetic wounds and Systemic Sclerosis-associated ulcers, which are particularly challenging. Current and future treatment approaches are discussed with an emphasis on recent advances.

Gene expression profile analysis of human mesenchymal stem cells from herniated and degenerated intervertebral discs reveals different expression of osteopontin.

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.

Choosing treatment options for patients with relapsed/refractory multiple myeloma.

Multiple myeloma (MM) is a clonal plasma cell disorder that is still incurable using conventional treatments. Over the last decade, advances in front-line therapy have led to an increase in survival, but there are still some doubts in the case of relapsed/refractory disease. We searched the PubMed database for articles on treatment options for patients with relapsed/refractory MM published between 1996 and 2013. These treatments included hematopoietic cell transplantation (HCT), rechallenges using previous chemotherapy regimens, and trials of new regimens. The introduction of new agents such as the immunomodulatory drugs (IMIDs) thalidomide and lenalidomide, and the first-in-its-class proteasome inhibitor bortezomib, has greatly improved clinical outcomes in patients with relapsed/refractory MM, but not all patients respond and those that do may eventually relapse or become refractory to treatment. The challenge is therefore to select the optimal treatment for each patient by balancing efficacy and toxicity. To do this, it is necessary to consider disease-related factors, such as the quality and duration of responses to previous therapies, and the aggressiveness of the relapse, and patient-related factors such as age, comorbidities, performance status, pre-existing toxicities and cytogenetic patterns. The message from the trials reviewed in this article is that the new agents may be used to re-treat relapsed/refractory disease, and that the sequencing of their administration should be modulated on the basis of the various disease and patient-related factors. Moreover, our understanding of the pharmacology and molecular action of the new drugs will contribute to the possibility of developing tailored treatment.

Autoantibodies to coagulation factors: from pathophysiology to diagnosis and therapy.

Autoantibodies may develop against coagulation factors altering their function or promoting their rapid clearance. In non-congenitally deficient patients, they are usually in association with autoimmune diseases, malignancies, pregnancy or advanced age. The possible development of coagulation factor autoantibodies should be considered when a patient presents with bleeding symptoms without any prior bleeding diathesis. The most common disorder associated with coagulation factor autoantibodies is acquired factor VIII deficiency, which is characterized by hemorrhages involving soft tissues, muscles and skin; hemarthroses are less frequent than in the inherited form. Acquired deficiencies of von Willebrand factor and factor XIII due to autoantibodies are emerging conditions. Autoantibodies to the other coagulation factors may be associated with a wide spectrum of clinical manifestations ranging from minimal or no bleeding to life-threatening conditions. The diagnostic approach begins with global coagulation tests: prothrombin time (PT) and activated partial thromboplastin time (aPTT). In case of prolonged times, mixing studies (typically using normal plasma in a 1:1 proportion) should be performed. Specific factor and inhibitor assays, assessment of lupus anticoagulant and eventually enzyme immunoassays for specific anti-factor antibodies complete the evaluation. A prompt diagnosis of specific coagulation factor inhibitors is mandatory for starting an appropriate treatment aimed at overcoming the deficient factor, in case of bleeding, and, if possible, at the suppression of the autoantibody's production.