Search

SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life-threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndrome spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult-onset Still’s disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in the COVID-19 pandemic.

Purpose To evaluate the post- coronavirus disease-19 (COVID-19) outcome of thyroid function in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-related thyrotoxicosis. Methods This was a single-center prospective study involving 29 patients (11 females, 18 males; median age 64 years, range: 43–85) with thyrotoxicosis diagnosed after hospitalization for COVID-19 and then followed-up for a median period of 90 days (range: 30–120) after hospital discharge. At follow-up, patients were evaluated for serum thyrotropin (TSH), free-thyroxine (FT4), free-triiodiothyronine (FT3), TSH receptor antibodies (TRAb), thyroglobulin antibodies (TgAb), thyroperoxidase antibodies (TPOAb) and ultrasonographic thyroid structure. Results After recovery of COVID-19, serum TSH values significantly increased (P

SARS-CoV-2 infection is characterized by a protean clinical picture that can range from asymptomatic patients to life threatening conditions. Severe COVID-19 patients often display a severe pulmonary involvement and develop neutrophilia, lymphopenia, and strikingly elevated levels of IL-6. There is an over-exuberant cytokine release with hyperferritinemia leading to the idea that COVID-19 is part of the hyperferritinemic syndromes spectrum. Indeed, very high levels of ferritin can occur in other diseases including hemophagocytic lymphohistiocytosis, macrophage activation syndrome, adult onset Still's disease, catastrophic antiphospholipid syndrome and septic shock. Numerous studies have demonstrated the immunomodulatory effects of ferritin and its association with mortality and sustained inflammatory process. High levels of free iron are harmful in tissues, especially through the redox damage that can lead to fibrosis. Iron chelation represents a pillar in the treatment of iron overload. In addition, it was proven to have an anti-viral and anti-fibrotic activity. Herein, we analyse the pathogenic role of ferritin and iron during SARS-CoV-2 infection and propose iron depletion therapy as a novel therapeutic approach in COVID-19 pandemic.

OBJECTIVES: This study aims to investigate if short-term topical treatment with cetylated fatty acid (CFA) cream reduces the detrimental effects of early and advanced knee osteoarthritis (OA). PATIENTS AND METHODS: The study included 113 patients (32 males, 81 females; median age 70.0 years; 95% CI: 69.0 to 71.4 years) with knee OA diagnosed according to American College of Rheumatology classification criteria. Each patient underwent knee X-rays, followed by a CFA topical treatment (two applications per day for one week). Before and after the treatment, patients completed a Western Ontario and McMaster Universities Osteoarthritis Index questionnaire. All knee X-rays were classified according to Kellgren-Lawrence scale. RESULTS: After one week of treatment, decreased Western Ontario and McMaster Universities Osteoarthritis Index overall scores and sub-scale scores were observed in the whole cohort (p

Summary Nuclear interferon-inducible protein 16 (IFI16) and anti-IFI16 antibodies have been detected in subjects with several rheumatic diseases, often correlating with disease severity, and in this study we investigated their prevalence and clinical associations in psoriatic arthritis (PsA) compared to psoriasis (Pso). We tested sera and synovial fluids of patients with PsA for IFI16 protein levels by capture enzyme-linked immunosorbent assay (ELISA) and for anti-IFI16 immunoglobulin (Ig)G and IgA by ELISA, protein radio-immunoprecipitation and immunoprecipitation-Western blot of IgG. Sera from patients with Pso and healthy subjects were used as controls, and in a subgroup of patients with PsA we also studied sera after treatment with etanercept. IFI16 was detectable in the sera of 66% of patients with Pso, 46% with PsA and 19% of controls. Among PsA cases, 51% of IFI16-positive cases had elevated levels of C-reactive protein (CRP) compared to 31% of patients with undetectable IFI16. Anti-IFI16 of both IgG and IgA isoforms were detected with significantly higher frequency in PsA and Pso compared to healthy controls, with higher IgG titres in patients with elevated C-reactive protein (CRP) (P = 0·015). Immunoprecipitation confirmed the presence of anti-IFI16 IgG antibodies and these preferentially recognized epitopes outside the N-terminus of the protein. Lastly, IFI16 was detected in one of seven and anti-IFI16 in three of seven synovial fluids from patients with PsA. Therefore, IFI16 and anti-IFI16 are detectable in serum and synovial fluid of PsA patients, especially in cases of elevated CRP.

Background Serum anti-mitochondrial antibodies (AMA) are the hallmark of primary biliary cholangitis (PBC) and are identified also in systemic sclerosis (SSc) patients with limited variant and serum anti-centromere antibodies (ACA). Indirect immunofluorescence (IIF) shows the cytoplasmic pattern that characterizes AMA positivity, but it is usually performed when a suspect of PBC is already present. Protein-immunoprecipitation (IP) and IP-Western Blot (WB) have the advantage of 1) identify AMA in an early screening phase, before the onset of PBC and liver function abnormalities; 2) detect the proteins that constitute the pyruvate dehydrogenase complex (PDC) complex (the subunits E1α, E1β, E2/E3, and E3BP) which seem to be associated to different risk of PBC onset. Objectives To determine the prevalence and clinical significance of the PDC complex subunits in AMA positive SSc patients with and without PBC. Methods Sera from 279 consecutive patients with rheumatic disease (146 with SSc, 77 with undifferentiated connective tissue disease –UCTD-, and 56 with polymyositis/dermatomyositis -PM/DM) were tested by protein-IP for the screening of serum autoantibodies. In 58/279 (21%) sera we report a complete or partial protein-IP pattern of 75-50-40-34kD bands corresponding to the 4 proteins of the PDC complex recognized by AMA. In these sera we performed IIF and IP-WB to confirm the identity of these bands, by using established protocols. Clinical charts were used to analyze clinical and laboratory data for possible statistical correlation. Results In 15/58 (26%) patients with protein-IP AMA pattern we confirm a diagnosis of PBC, and all of them had a diagnosis of SSc without additional rheumatic disease. Their expression of the PDC subunits is variable by IP-WB (Figure panel A), but this variability is not associated with specific clinical and laboratory features. In the 42/58 (72%) cases with AMA protein-IP pattern but without clinical and histological evidence of PBC, the E2 component of the PDC was detected in all except one patient, while the expression of the other proteins of the PDC was significantly less represented, i.e. E3BP in 14/42 (33%), E1β in 13/42 (31%), E3 in 6/42 (14%), and E1α in 4/42 (10%) patients. The IIF analysis on Hep2 cells of AMA positive samples also shows different patterns of expression, which spans from cytoplasmic positive staining with a reticular pattern in AMA positive sera for all the PDC proteins recognized by AMA, to cytoplasmic speckled pattern in cases with incomplete expression of PDC antigens (Figure panel B). So far, no specific clinical correlation was identified in these patients, as they did not have a diagnosis of PBC or other autoimmune liver disease or manifested elevated liver function tests. Conclusion The expression of the PDC antigenic components is variable both in SSc patients with AMA positive PBC and in SSc patients AMA positive without PBC or altered liver function tests, but we could not identify a clinical significance of this variability. It may be necessary to maintain a strict follow-up of these patients and to perform longitudinal studies to determine the prognostic value of this variable expression of PDC components in the onset of PBC. References [1] Fujimoto M, et al. Arthritis Rheum. 1995Jul; 38(7): 985-9 [2] Ceribelli A, et al. J Immunol Methods. 2018Jan; 452: 1-5 Disclosure of Interests Angela Ceribelli: None declared, Natasa Isailovic: None declared, Carolina Gorlino: None declared, Elena Generali: None declared, Maria De Santis: None declared, Giacomo Maria Guidelli: None declared, Marta Caprioli: None declared, Piercarlo Sarzi-Puttini: None declared, Minoru Satoh: None declared, Carlo Selmi Grant/research support from: AbbVie, Janssen, MSD, Novartis, Pfizer, Consultant for: AbbVie, Alfa-Sigma, Biogen, Bristol-Myrs Squibb, Celgene, Eli-Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB, Speakers bureau: AbbVie, Alfa-Sigma, Biogen, Bristol-Myrs Squibb, Celgene, Eli-Lilly, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, UCB

Background: Baricitinib is an oral selective JAK1/2 inhibitor recently approved in the EU for the treatment of rheumatoid arthritis (RA). No real-life data are available about its efficacy and safety. Objectives: To investigate the efficacy and safety profiles of baricitinib in a real-life setting. Methods: We performed a multicenter prospective observational study on adult RA patients starting JAK inhibitors between 12/2017 and 12/2018. Demographic and clinical data as well as laboratory values and adverse events were collected at baseline and after 12 and 24 weeks. Disease activity was measured by DAS28-CRP at baseline, after 12 and 24 weeks. Results: We obtained data from 150 patients with RA (women 116 – 77.3%; median age 60 years, inter-quartile range IQR 54-68; median disease duration 10 years, IQR 4-18) treated with baricitinib 2 or 4 mg QD, however only 2/150 (1.3%) at the reduced dosage. At the time of database lock 95/150 (63%) patients have completed the 12 weeks follow-up, 38/150 (25%) patients have completed the 24 weeks follow-up. Baricitinib was started after at least one conventional synthetic DMARD in all 148/150 cases (99%), being in all of cases methotrexate, while was started prior to a biologic DMARD in 57 (38%) patients. It was prescribed as a second line in 17/93 (18%) patients, third in 27 (29%), fourth or higher in 49 (53%). Baricitinib was prescribed as monotherapy in 57/150 (38%) patients, while combined with methotrexate in 65/150 (43%), at a median dosage of 15 mg/week. Oral corticosteroids were used by 105/150 (70%) patients, at a median dosage of 5 mg/day. Mean DAS28-CRP at baseline was 4.92 (standard deviation 1.22), with 65 (43.3%) patients having a DAS28-CRP>5.1. At both 12 and 24 weeks, a significant reduction of disease activity scores was observed (DAS28-CRP mean 3.07, SD 1.36, and 2.85, SD 1.35, respectively; p values Conclusion: In our real-world dataset, baricitinib is effective in reducing RA disease activity, after 12 weeks, being generally well-tolerated with few severe adverse events. Disclosure of Interests: Giacomo Maria Guidelli: None declared, Elena Generali: None declared, Chiara Bazzani: None declared, Roberto Gorla: None declared, Garifallia Sakellariou: None declared, Massimiliano Limonta: None declared, Maria Sole Chimenti: None declared, Roberto Perricone: None declared, Edoardo Conticini: None declared, Bruno Frediani: None declared, nicola boffini: None declared, Lorenzo Dagna Consultant for: Prof Lorenzo Dagna received consultation honoraria from Abbvie, Amgen, Biogen, Bristol-Myers Squibb, Celltrion, Novartis, Pfizer, Sanofi-Genzyme, and SOBI., Marta Riva: None declared, Maria Rosa Pozzi: None declared, Rosa Daniela Grembiale Grant/research support from: BMS, Consultant for: JANSSEN, CELGENE, Speakers bureau: PFIZER, JANSSEN, BMS, NOVARTIS, Teodora Serban: None declared, Gerolamo Bianchi Consultant for: Alfa-Sigma, Amgen, BMS, Celgene, Medac, UCB, Speakers bureau: Abbvie, Abiogen, Alfa-Sigma, Amgen, BMS, Celgene, Carlo Selmi Grant/research support from: Abbvie, Janssen, MSD, Novartis, Pfizer, Consultant for: Abbvie, Alfa-Sigma, Biogen, BMS, Celgene, Eli-Lilly, GSK, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, YCB, Speakers bureau: Abbvie, Alfa-Sigma, Biogen, BMS, Celgene, Eli-Lilly, GSK, Janssen, Merck Sharp and Dohme, Novartis, Pfizer, Roche, Sanofi-Genzyme, YCB

Background Systemic sclerosis (SSc) is an autoimmune fibrotic disease characterised by variable clinical manifestations based on the predominant organ involvement. With the exceptions of acute fulminant myocarditis with pericardial effusion and heart failure, myocardial involvement in SSc is clinically silent until arrhythmias appear, while representing the major cause of sudden death or atrio-ventricular (AV) blocks in SSc. There are no reliable screening algorithm to discriminate myocardial involvement nor established treatments. Objectives To identify early/clinically silent myocardial involvement in SSc and define a possible treatment. Methods We used Holter electrocardiography (ECG) to investigate our cohort of patients with SSc (n=221, all fulfilling the ACR classification criteria) for ventricular ectopic beats (VEB)/AV blocks/unexplained tachycardia as sensitive signs of myocardial involvement. In 24 patients (women 23%–95.8%, anti-centromere-ACA 16%–66.6%, anti-topoisomerase-aScl70 3%–12.5%, anti-RNA polimerase III 3%–12.5%, anti-Ku 2%–8.3%, limited skin disease-lSSc 12%–50%, diffuse skin disease 5%–20.8%, sine scleroderma 7%–29.2%, median age 66.5 years, IQR 57.8–72.5), never treated with anti-fibrotic agents, we performed heart magnetic resonance (hMR) searching for myocardial oedema (on T2 STIR sequences, using the signal ratio between myocardium and skeletal muscle with a cut-off value of ≥1.9 for oedema) or fibrosis (presence of any late gadolinium enhancement (LGE) with intramyocardial or subepicardial pattern). Patients with myocardial oedema at hMR were treated with mycophenolate mofetil (MFM) 2 g/day or with azathioprine (AZA) 100 mg/day and underwent a control hMR after six months. Results In 10/24 (42%) of the SSc cases with Holter ECG alterations (8 VEB, 1 tachycardia, 1 type II AV block) we observed SSc myocardial involvement at hMR. In more detail, 6 patients had myocardial oedema at T2 STIR sequences (including cases as follows: 1 aScl70-positive with lSSc and lung fibrosis, 2 ACA-positive with lSSc, 3 ACA-positive sine scleroderma), and 4 only fibrosis (1 Scl70-positive with lSSc and lung fibrosis, 1 ACA-positive with lSSc, 1 ACA-positive sine scleroderma, 1 anti-Ku-positive sine scleroderma). At 6 months of medical treatment, myocardial oedema disappeared in 3 patients treated with Aza and in 1 treated with MFM, the additional 2 patients are still receiving MFM treatment at the time of analysis. Conclusions We observed that 42% of patients with SSc and minor arrhythmias on 24 hour Holter ECG have clinically silent myocardial involvement at hMR; those with potential reversible disease (oedema rather than fibrosis) favourably respond to immunosuppressants. Detectable serum ACA and the absence of skin involvement are over-represented in this subgroup of patients. Disclosure of Interest None declared

Background Psoriatic arthritis (PsA) often affects women of reproductive age. Secukinumab (SEC), a monoclonal antibody against interleukin-17A is effective in contrasting the progression of articular and cutaneous manifestations of PsA but has not been extensively studied in pregnancy, despite 84 cases of accidental exposure reported with reassuring safety outcomes. Objectives To evaluate the maternal and fetal outcomes in women with PsA exposed to SEC during pregnancy. Methods During a 10 months observational period, we enrolled 6 patients, treated by SEC 150 mg subcutaneously every month after weekly induction. All of them stopped the treatment by the time pregnancy test turned positive. All women had previously been counselled about contraceptive methods adoption and the potential risk of becoming pregnant during SEC administration, signing an informed consent. We collected demographic and clinical data of both patients and babies, with a peculiar focus on maternal-fetal safety issues. APGAR scores at 1 min (APGAR1) and 5 min (APGAR5) from delivery were recorded. Results We observed 6 pregnancies from 6 mothers (4 of European, 1 Asian and 1 Latin-American ethnicity). Patient mean age at conception was 336±131 months; disease duration, 62±27 months; pre-conceptional exposure, 46±9 weeks; the (estimated) post-conceptional exposure 7±2 weeks. No major gestational complications were reported. One mother consulted the Emergency Department for a syncopal episode, but after a routine evaluation and an observation of 6 hours, was discharged; her pregnancy was otherwise unremarkable. Four girls (mean weight: 3170±200 g) and 2 boys (mean weight: 3460±60) were born. Mean gestational age was 38±2 weeks; 3 vaginal deliveries (1 oxytocine-induced for scarce dilation) and 3 caesarean sections were observed. The APGAR scores were above 8, excepting for an APGAR1 of 6 (born with caesarean section), then turned on 10 at APGAR5. Results are summarised on table 1. DAPSA, for the whole population, was under 4 (remission) at conception, and remained stable after delivery. Conclusions The present study, despite the limited number of observations, represents the first report on pre-conceptional exposure to SEC. The available data, due to the lack of controlled studies, place the drug’s use on FDA “B” category. Of note, SEC failed to cause teratogenicity, when administered throughout the whole pregnancy in a study conducted on primates (Cynomolgus monkeys). The limited knowledge on human beings suggests, nevertheless, not to administer SEC during pregnancy, unless a clear benefit overwhelm the potential risk. SEC, in conclusion, seems to have an acceptable safety profile, even when accidentally taken in the very first pregnancy phase. Reporting the cases of pregnancy exposures, as recommended by the ongoing Producer’s policy, is the only way that would allow to confirm, or reject, this statement. A long-term follow-up of the mother and the offspring health, similarly, is needed. References [1] Mouyis MA, et al. J Rheumatol2017;44:1. [2] Skorpen CG, et al. Ann Rheum Dis2016;75(5):795–810. [3] Warren R, et al. P2134 25th EADVC2016, Vienna (AUT). [4] Cosentyx® Core Data Sheet. Version 1.1. Disclosure of Interest None declared

Background Skin psoriasis affects 3% of the general population and as much as 20%–40% of patients will develop psoriatic arthritis (PsA), with the two conditions representing a clinical and immunological continuum within a prototype for chronic inflammation. Different from most rheumatic diseases, no serum autoantibody is associated with PsA, and there are currently no biomarkers for an early diagnosis and prediction of PsA onset in psoriasis, frequently causing a delayed diagnosis. Monozygotic twins discordant for psoriasis/PsA represent a unique setting to investigate the influence of environmental and stochastic factors on disease phenotype. Through a high-throughput proteomic analysis (SomaLogic) we have previously identified a set of 13 proteins differentially expressed in the serum of monozygotic twins discordant for psoriatic disease. Objectives To validate serum proteomic biomarkers of psoriatic disease using commercially available ELISA in monozygotic twins and in unrelated patients with psoriasis or PsA. Methods Our study included sera from our cohort of monozygotic twins previously described and from 70 unrelated patients with psoriatic disease (psoriasis without PsA 34%–49%, PsA with/without psoriasis 36%–51%; women 46%, median age 52 years, interquartile range 41–59) followed at Humanitas Research Hospital, and 25 healthy subjects (52% women, median age 52 years, IQR 44–62). Candidate serum proteomic biomarkers obtained by SomaLogic analysis were validated using commercially available ELISA kits and proteins are herein anonymized due to a pending patent request. Results We found a significant correlation between SomaLogic results in monozygotic twins and ELISA results in unrelated psoriatic cases in the serum levels of 2 proteins (figure 1), which are involved in inflammatory and immune response, and one has been previously reported in psoriatic plaques. Four proteins showed a significantly different expression between psoriasis and PsA versus controls, in particular two proteins have a potential role in disease pathogenesis, as protein #1 acts as cell-surface receptor and regulates differentiation, proliferation and survival of dendritic cells, while protein #2 is involved in regulation of UV radiation-induced apoptosis and protein folding. Conclusions Two serum proteomic biomarkers, previously identified in a cohort of monozygotic twins discordant for psoriatic disease, can discriminate psoriatic disease, thus representing potential biomarkers of disease and possibly playing a pathogenetic role in disease. Disclosure of Interest None declared

Granulomatosis with polyangiitis, formerly known as Wegener's granulomatosis or disease, is a systemic, necrotizing small-vessel vasculitis, belonging to the group of anti-neutrophil cytoplasm antibody vasculitis. The therapeutic strategy includes, in most cases, corticosteroids associated, at least in severe forms of the disease, with immunosuppressive agents: cyclophosphamide and rituximab to induce remission, methotrexate, azathioprine and mycophenolate mofetil to prevent relapses. Intravenous immunoglobulins represent an alternative adjuvant therapy. We described 5 cases of patients with granulomatosis with polyangiitis treated with monthly high-dose intravenous immunoglobulins (500 mg/kg/daily for 3 consecutive days for 9 months). No patients experienced adverse reactions, and 4 patients (80%) achieved a complete remission after 9 courses of this therapy, which was maintained also 3 months later, although we are unable to determine whether improvement in outcomes was a direct result of the IVIG. We also discussed the beneficial effects of intravenous immunoglobulins in patients suffering from granulomatosis with polyangiitis, reporting the previously published data.

Background Systemic sclerosis (SSc) is characterized in virtually all patients by anti-nuclear antibodies (ANA) with anti-centromere (ACA), anti-topoisomerase I (ant-Scl70), and anti-RNA polymerase III antibodies identifying patient subgroups. However, there are no reliable biomarkers predicting SSc susceptibility and internal organ involvement. Objectives We aimed to identify serum protein biomarkers associated with SSc and interstitial lung disease (ILD), using a highly multiplexed proteomic technology. Methods We analyzed serum samples of 3 patients with SSc and ILD (2 limited SSc: one ANA positive and one anti-Scl70 positive, and one diffuse SSc anti-Scl70 positive), 3 patients with SSc and no ILD (ACA positive limited SSc), and 4 healthy controls. All subjects were women and age matched. Serum proteomics profiling was performed using the SOMAscan platform (SomaLogic, Inc., Boulder, CO, USA). Statistical analysis included Student9s t-test and were performed using the SomaSuite software (SomaLogic, Boulder, CO, USA). Results Proteomic analysis identified 33 proteins which differentiate SSc from HC and 9 proteins which differentiate SSc patients with and without ILD. Compared to healthy controls, SSc cases showed an altered expression of proteins involved in extracellular matrix formation and cell-cell adhesion, angiogenesis, and lymphocyte recruitment, activation, and signaling, while an overall inhibition of neutrophil function was noted. An interferon and IL-1 signatures were also found. Patients with SSc and ILD manifested increased protein levels related to intracellular signaling and cell cycle, along with an increase of monocyte chemoattractants and ligands for the leukocyte adhesion compared to SSc without ILD. We further observed a decrease in B cell stimulating factor and IL-22 signaling in SSc with ILD. Conclusions Serum proteomic profiles can differentiate SSc from healthy controls and SSc patients with and without ILD; moreover, our results identify biomarkers with a putative pathogenetic significance. Disclosure of Interest None declared

Systemic sclerosis (SSc) is a rare autoimmune disease, characterized by vasculopathy and fibrosis of the skin and internal organs. This disease is still considered incurable and is associated with a high risk of mortality, which is related to fibrotic events. An early diagnosis is useful for preventing complications, and targeted therapies reduce disease progression and ameliorate patients’ quality of life. Nevertheless, there are no validated biomarkers for early diagnosis with predictive prognostic value. Exosomes are membrane vesicles, transporting proteins and nucleic acids that may be delivered to target cells, which influences cellular behavior. They play important roles in cell–cell communication, both in physiological and pathological conditions, and may be useful as circulating biomarkers. Recent evidences suggest a role for these microvesicles in the three main aspects related to the pathogenesis of SSc (immunity, vascular damage, and fibrosis). Moreover, exosomes are of particular interest in the field of nano-delivery and are used as biological carriers. In this review, we report the latest information concerning SSc pathogenesis, clinical aspects of SSc, and current approaches to the treatment of SSc. Furthermore, we indicate a possible role of exosomes in SSc pathogenesis and suggest their potential use as diagnostic and prognostic biomarkers, as well as therapeutic tools.

Rituximab is a human/murine monoclonal antibody targeting the CD20 antigen on B-lymphocytes surface. Although it has been licensed for treatment of non-Hodgkin's lymphoma, nowadays it is also a novel therapy for autoimmune diseases, such as rheumatoid arthritis and systemic lupus erythematosus. Despite the increasing evidence regarding the safety and efficacy of rituximab in these conditions, many cutaneous adverse events have been reported. Here, we describe the case of a 69-year-old patient, affected by rheumatoid arthritis, who developed psoriatic lesions on her trunk and arms, three months after the second course of rituximab. Similar cases appearing in the literature will also be briefly mentioned.

Thromboangiitis obliterans (TAO, or Buerger’s disease) is a rare inflammatory vasculitis that commonly involves small and medium-sized arteries of the extremities of tobacco smokers between the ages of 25 and 50 years. Although the diagnosis is based on the clinical picture and angiographic findings, we studied the microvascular involvement by nailfold capillaroscopy. We evaluated by nailfold capillaroscopy 2 patients with Buerger’s disease, at baseline and after 6 months of tobacco discontinuation and therapy with prostanoids. Both patients presented similar capillaroscopic abnormalities, resembling a scleroderma-like pattern. The microvascular rearrangement was significantly reduced after 6 months of evaluation. The capillaroscopic abnormalities shown in the two patients could be related to thromboangiitis obliterans, and nailfold capillaroscopy could be a useful tool to evaluate disease progression and the response to treatment.

Rheumatoid arthritis (RA) is a chronic autoimmune inflammatory disease primarily affecting synovial joints and is characterized by persistent high-grade systemic inflammation. Proinflammatory cytokines, particularly interleukin-6 (IL-6), are of crucial importance in the pathogenesis of the disease, driving both joint inflammation and extra-articular comorbidities. Tocilizumab, a humanized IL-6 receptor-inhibiting monoclonal antibody, has been the first, and, to date, the only, IL-6 inhibitor approved for the treatment of RA. Many studies have demonstrated the potency and effectiveness of tocilizumab in controlling disease activity and radiological progression of RA. These successful results have encouraged the development of novel IL-6 inhibitors, among which a promising agent is sirukumab (SRK), a human anti-IL-6 monoclonal antibody currently under evaluation in Phase II/III studies in patients with RA, systemic lupus erythematosus, giant-cell arteritis, and major depressive disorder. The evidence to date indicates SRK as an effective and well-tolerated new therapeutic tool for patients with active RA, with some preliminary data suggesting a specific beneficial impact on relevant systemic complications associated with the disease, such as depression and cardiovascular disease. Conversely, although pathophysiological considerations make plausible the hypothesis that IL-6 blockade with SRK may also be beneficial in the treatment of many diseases other than RA (either autoimmune or not), available clinical data in patients with systemic lupus erythematosus do not seem to support this view, also giving rise to potentially relevant concerns about drug safety. If large Phase III clinical trials currently in progress in patients with RA confirm the efficacy and tolerability of SRK, then in the long term, this drug could, in the near future, occupy a place in the treatment of the disease, potentially also opening the doors to a more extended use of SRK in a wide range of disorders in which IL-6 plays a key pathogenic role.

The antiphospholipid syndrome (APS) is defined by the occurrence of venous and arterial thromboses and recurrent fetal losses, frequently accompanied by a moderate thrombocytopenia, in the presence of antiphospholipid antibodies (aPL), namely lupus anticoagulant (LA), anticardiolipin antibodies (aCL), or anti-β2 glycoprotein-I (β2GPI) antibodies. The current mainstay of treatment for thrombotic APS is heparin followed by long-term anticoagulation, while in obstetric APS, the accepted first-line treatment consists in low-dose aspirin (LDA) plus prophylactic unfractionated or low-molecular-weight heparin (LMWH). Recently, new emerging treatment modalities, including intravenous immunoglobulins (IVIG), have been implemented to manage APS refractory to conventional therapy. The objective of this review is to summarize the currently available information on the IVIG therapy in APS, focusing on the use of IVIG in the obstetric form, CAPS and on primary or secondary thromboprophylaxis. We analyzed 35 studies, reporting the effects of IVIG in APS patients, and we discussed their results. IVIG in obstetric APS seem to be very useful in selected situations (patients not responsive to the conventional treatment, concomitant autoimmune manifestations or infections or patients in whom anticoagulation is contraindicated). IVIG treatment represents an important component of the combination therapy of CAPS and they could be useful, in addition to the standard therapy, to prevent recurrent thrombosis in APS patients refractory to conventional anticoagulant treatment. Anyway, in some cases we also found controversial results that claim the need of further well-designed studies to definitely state the efficacy and tolerability of IVIG in CAPS, obstetric and non-APS.

Osteoarthritis (OA) is a multifaceted disorder defined by the alteration of homeostasis and degradation in articular cartilage. Recently mounting evidence suggests that OA should be conceived as an inflammatory disease rather than a simple wear-and-tear problem. Bradykinin (BK) and B2 receptors play a role in the pathogenesis of OA. The aim of this paper is to analyze preclinical and clinical studies examining the potential role of BK and of B2 receptor blockade in OA pathogenesis. We analyzed the data about the effects of BK in synoviocytes, endothelial cells and chondrocytes cultures and described the action of B2 receptor antagonists (Icatibant and Fasitibant). In conclusion, the BK is an endogenous proinflammatory molecule that is involved in the pathophysiology of OA, and B2 receptor antagonists are believed to be considered as a potential symptomatic therapy for this disease. There is a need for further preclinical and clinical trials to better explain the mechanisms of action and the efficacy and tolerability of the B2 receptor antagonists in OA.

A 53-year-old male developed left knee and left ankle arthritis associated with marked induration of the skin and soft tissues distal to the knees. The left knee was swollen, tender, and with a non-reducible contracture and similarly the left ankle and the subtalar joint were stiff and moderately swollen. In addition, diffuse, bluish, small vascular ectasia, hypertrichosis and skin pigmentation of the affected sites were evident (fig1). These symptoms began 20 years before and the patient had been diagnosed with eosinophilic fasciitis and treated with daily prednisone leading to partial improvement of the symptoms, but not of the knee deformity and soft tissue induration. This article is protected by copyright. All rights reserved.

Thymidylate synthase (TS) poly-epitope peptide (TSPP) is a 27-mer peptide vaccine containing the amino acidic sequences of three epitopes with HLA-A2.1-binding motifs of TS, an enzyme overexpressed in cancer cells, which plays a crucial role in DNA repair and replication. Based on the results of preclinical studies, we designed a phase Ib trial (TSPP/VAC1) to investigate, in a dose escalation setting, the safety and the biological activity of TSPP vaccination alone (arm A) or in combination with GM-CSF and IL-2 (arm B) in cancer patients. Twenty-one pretreated metastatic cancer patients, with a good performance status (ECOG≤1) and no severe organ failure or immunological disease, were enrolled in the study (12 in arm A, nine in arm B) between April 2011 and January 2012, with a median follow-up of 28months. TSPP resulted safe, and its maximal tolerated dose was not achieved. No grade 4 toxicity was observed. The most common adverse events were grade 2 dermatological reactions to the vaccine injection, cough, rhinitis, fever, poly-arthralgia, gastro-enteric symptoms and, to a lesser extent, moderate hypertension and hypothyroidism. We detected a significant rise in auto-antibodies and TS-epitope-specific CTL precursors. Furthermore, TSPP showed antitumor activity in this group of pretreated patients; indeed, we recorded one partial response and seven disease stabilizations (SD) in arm A, and three SD in arm B. Taken together, our findings provide the framework for the evaluation of the TSPP anti-tumor activity in further disease-oriented clinical trials.

Osteoarthritis (OA) is the most common disabling joint disease worldwide and its treatment is based on a combination of non-pharmacological and pharmacological modalities. Commonly prescribed OA medications include symptomatic drugs (non-steroidal anti-inflammatory drugs, analgesics, locally administered corticosteroids, viscosupplementation) and new compounds that are potentially able to reduce or stop the disease progression, called "Disease Modifying Osteoarthritis Drugs (DMOADs)". Strontium ranelate (SR) is an anti-osteoporotic treatment that increases bone formation, while decreasing bone resorption and it potentially acts as a new DMOAD. The objective of this review is to summarize the currently available information on clinical effects and mechanism of action of SR in OA. We have examined two post hoc analysis conducted on the large, randomized Treatment of Peripheral Osteoporosis study and the double-blind, randomized, controlled trial about SR in knee OA. Furthermore, we analyzed three studies in animal models and two in vitro experiments to better understand the mechanism of action of SR in OA. The available data demonstrate that SR could be considered a new promising symptomatic and disease-modifying agent in the treatment of OA and was safe and well tolerated. Additionally, there is a need for further investigations to establish the optimal dosage and to better clarify the mechanism of action of SR in OA.

Thymidylate synthase (TS) is a tumor-associated enzyme critical for DNA replication. TSPP is a poly-epitope-peptide vaccine to TS, which elicits a multi-epitopic CTL response with antitumor activity in preclinical models. TSPP has been tested in 50 advanced cancer patients enrolled in a multi-arm dose-finding TSPP/VAC1 phase Ib trial program (Eudract:# 2009-016897-33)(Table1) between May 2011 and January 2013. The trial results revealed that TSPP is safe and immune-biologically active, and provided preliminary evidence of a antitumor activity in pretreated mCRC patients (Cusi MG et al 2015 and Correale P et al 2015). This population of 41 patients presented a progression-free-survival and an overall-survival (OS) of 6.9 and 11.3 months, respectively, with a one-year survival rate of 32% (13 patients). We focused on mCRC patients as they represented the most relevant and homogeneous population in the trial. We performed Kaplan-Meier curves, log-rank tests and regression curves to correlate immunobiological findings and patients’ outcome. We found that their OS correlated with lower (under the median) ECOG scores (p:0.039), CEA levels (p:0.021), and serum levels of inflammatory markers (NLR, CRP, ESR, and LDH/LDHNR and ENA; p inferior 0.04) at baseline. Patients’ OS also correlated with greater (over the median) baseline levels of IL4 (p:0.028) and 17 (P:0.049), and with a post-treatment increase in anti-neutrophil-cytoplasm-antibodies/anti-proteinase-3 (Fold change to baseline values grater than 1; p:0.039). Activating K-ras mutations did not correlate with survival, however, inflammatory markers, cytokines, and autoantibodies lost their correlation with the survival in patients bearing these mutations. These results suggest that TSPP-antitumor activity in mCRC patients is affected by their baseline inflammatory/immunological status at baseline. TSPPVAC1 Phase Ib program; patients’ distributionARM A1. ADJ + TSPP 100 μg (n = 3)2. ADJ + TSPP 200 μg (n = 3)3. ADJ + TSPP 300 μg (n = 6)ARM B1. ADJ + TSPP 100 μg + IG-1 (n = 3)2. ADJ + TSPP 200 μg + IG-1 (n = 3)3. ADJ + TSPP 300 μg + IG-1 (n = 3)ARM C (DL1-3)1. GOLFIG + ADJ+TSPP 100 μg + IG-1 (n = 3)2. GOLFIG + ADJ+TSPP 200 μg + IG-1 (n = 3)3. GOLFIG + ADJ+TSPP 300 μg + IG-1 (n = 11)ARM C(DL0) 1. GOLFIG (12 courses) -> ADJ + TSPP 300 μg + IG-1 (n = 10)Figure legend: ADJ = montanide; n = number of patients; IG1 = sc. GM-CSF and sc. Aldesleukine; GOLFIG = gemcitabine + FOLFOX4 polychemotherapy + IG1 regimen Citation Format: Pierpaolo Correale, Cirino Botta, Elodia Claudia Martino, Valerio Nardone, Cristina Ulivieri, Claudia Gandolfo, Tatiana Cosima Baldari, Stefano Lazzi, Alessandro Ginori, Antonella Fioravanti, Giacomo Maria Guidelli, Luigi Pirtoli, Antonio Giordano, Pierfrancesco Tassone, Pierosandro Tagliaferri, Maria Grazia Cusi. Immune-inflammatory markers predict the outcome of metastatic colorectal cancer patients treated with the thymidylate synthase poly-epitope peptide (TSPP) vaccine: results from a multi-arm TSPP/VAC phase Ib program. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2232.

e13098 Background: TSPP is a poly-epitope peptide anticancer vaccine able to generate a thymidylate syntase (TS) specific T cell response with antitumor activity in preclinical models, expecially when used in sequential combination with 5-FU. TS is in fact involved in DNA replication and is the major pharmacological target of fluoropyrimidines whose activity leads in turn to TS upregulation. On these basis we designed a phase Ib trial where we investigated the safety and the immunobiological activity of TSPP + GOLFIG (Gemcitabine + FOLFOX-4 + GM-CSF + IL-2) regimen. Methods: TSPP/VAC-1 (Eudract 2009-016897-33) is a monocentric dose finding Phase Ib trial. 12 pretreated metastatic colon cancer patients were enrolled between April and November 2011. All of them received biochemotherapy according to the GOLFIG regimen biweekly and TSPP (on day 7) diluted in motanide ISA720 (1:1) at the dosage of 100 (3 patients), 200 (3 patients) and 300 ug (6 patients). Results: No life-threatening adverse events were observed. Grade 3 leucopenia (2 cases), thrombocitopenia (3 cases), anemia (3 cases), nausea/vomiting (2 cases), and dyarrhea (4 cases) along with 3 cases of oxaliplatin reaction were recorded. Fever and flu-like symptoms were common along cytokine administration. An IFN-gamma ELISPOT assay recorded an increase in TS specific CTL precursors in 3/6 evaluable patients; it was also observed an increase in lymphocytes, eosinophils, terminal effector memory and central memory T cells and in both c-ANCA and p-ANCA (P= 0.02) in the peripheral blood and a significant reduction in inflammatory markers (LDH, CRP and ESR). Quality of life analysis revealed a general improvement in patients’health state along the treatment. 1 partial response, 6 disease stabilizations and 2 progessions of disease were recorded. TSPP Maximal Tolerated Dose was not reached, while the Optimal Biological Dose was identified at 300 ug. Conclusions: Our results suggest that the GOLFIG + TSPP vaccine combination is safe and immunologically active and deserves to be evaluated in a further phase II trial.

Background TSPP is a poly-epitope peptide vaccine to the thymidylate syntase (TS) an enzyme commonly over-expressed in replicating cancer cells and recognized as a major target of fluoropyrimidines. TSPP showed immunological and anticancer activity in preclinical models, thus in the present study we investigated its safety and immunobiological activity in advanced cancer patients. This study was designed to identify TSPP Maximum Tolerated Dose (MTD) and Optimal Biological Dose (OBD) when used alone (arm A) or in combination with GM-CSF and IL-2 according to the IG-1 regimen (arm B). Patients and methods TSPP/VAC-1 (Eudract 2009-016897-33) is a monocentric phase Ib trial including 21 pretreated advanced cancer patients (12 in arm A and 9 in arm B) enrolled between April and October 2011 (12 with colorectal, 1 with breast, 1 with gastric, 1 with biliary tract and 6 with non small cell lung cancer). All patients presented a good performance status (ECOG ≤ 1). Each patient received every 3 weeks a sc administration of TSPP diluted in motanide ISA720 (1:1) at the dosage of 100 µg (6 patients), 200 µg (6 patients), and 300 µg (9 patients). Patients enrolled in arm B also received daily sc GM-CSF (100 µg) from day 1 to 5 and sc IL-2 (0.5 MIU) bid from day 6 to 15. Results No life-threatening adverse events were recorded; 1 case of grade 3 hypothyroidism (arm B), 4 cases of poly-articular arthropaty (arm A), and 4 cases of conjuntivitis (arm A) were observed. In arm B, cytokine-related flu-like syndrome, nausea, vomiting, and dyarrhea were commonly reported. An IFN-gamma ELISPOT assay revealed an increase in TS specific CTL precursors in 5 patients in arm A and 2 in arm B. It was also observed an increase in terminal effector memory and central memory T cells in the peripheral blood in both arms. Patients enrolled in arm A showed a significant decline in peripheral immune-regulatory (CD4+CD25hi+FoxP3+) T cells (baseline vs 3 vaccinations (B vs III): 3.8 vs 1.7 %; p= 0.041) and inhibitory myeloid cells (CD11c+CD15+) [Baseline (Bs) vs III vaccinations (Vc): 5.09 vs 1.02%; p= 0.05] associated to an increase in anti-proteinase III (Bs vs III Vs:0.48 vs 1.38; p= 0.04) and anti-myeloperoxidase auto-antibodies (Bs vs III Vc: 0.76 vs 1.50; p= 0.02) and reduced level of inflammatory markers (CRP, ESR, and LDH). A quality of life analysis did not reveal significant treatment-related changes in arm A, while a detrimental effect was observed in arm B. It was recorded 1 partial response (arm A);11 disease stabilitazions (8/12 patients arm A, and 3/9 arm B) and 8 disease progressions (3/12 patients arm A and 5/9 arm B). MTD was not reached, while OBD was defined as a TSPP dosage of 300 µg. Conclusion Our results suggest that the TSPP vaccine is safe and immunologically active. On these bases we believe that TSPP deserves to be evaluated in further phase II trials in cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-229. doi:1538-7445.AM2012-LB-229

Fibromyalgia syndrome (FS) is a common musculoskeletal disorder characterized by otherwise unexplained chronic widespread pain, a lowered pain threshold, high tender point counts, sleep disturbances, fatigue, headache, irritable bowel syndrome, morning stiffness, paraesthesias in the extremities, often psychological distress and depressed mood. Consequently, FS has a negative impact on working capacity, family life, social functioning and quality of life. Because of unknown etiology and not clearly understood pathogenesis, there is no standard therapy regime for FS. A variety of medical treatments, including antidepressants, opioids, analgesic or non-steroidal anti-inflammatory drugs, sedatives, muscle relaxants and antiepileptics, have been used to treat FS. Currently, no pharmacological treatment for FS is consistently successful. According to recent guidelines, the optimal treatment of FS requires a multidisciplinary approach with a combination of non-pharmacological and pharmacological treatment modalities. Spa therapy is a popular treatment for FS in many European countries, as well as in Japan and Israel. However, despite their long history and popularity spa treatments are still the subject of debate and their role in modern medicine is still not clear. The objective of this review is to summarize the currently available information on clinical effects and mechanism of action of spa therapy in FS. We also provide some suggestions for further development in this area.