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The differential diagnosis of psoriatic arthritis (PsA) and rheumatoid arthritis (RA) is difficult because of the lack of diagnostic clinical signs and reliable biomarkers. This study investigated microRNAs (miRNA) and adipokines as potential additional markers to discriminate PsA from RA. The expression profile of miRNA (miR-21, miR-140, miR-146a, miR-155, miR-181b, miR-223, miR-let-7e) and inflammatory cytokines (IL-1β, IL-6, IL-17a, IL-23a, TNF-α) from peripheral blood mononuclear cells of PsA and RA patients compared to healthy controls (HC) were evaluated by real-time PCR, and serum adipokines (adiponectin, chemerin, leptin, resistin, visfatin) and cytokines by ELISA assay. Univariable binary logistic regression was used to find the association between PsA and potential predictors. The gene expression of miRNA and cytokines and the serum levels of adipokines were found significantly different in PsA and RA patients compared to HC, as well as in PsA versus RA. MiR-140 gene expression resulted up-regulated in PsA patients and reduced in RA in comparison to HC, and, for the first time, significantly higher in PsA compared with RA. Serum levels of IL-23a and leptin were significantly increased in PsA and RA populations than in HC, as well as in PsA versus RA. Furthermore, circulating TNF-α was up-regulated in PsA and RA in comparison to controls, while resulted higher in RA than in PsA. Univariable binary logistic regression analysis found the above-mentioned markers associated to PsA versus RA. Our results first demonstrated an increased expression of circulating miR-140 and serum leptin in PsA patients compared to RA, which were identified as potential additional biomarkers to discriminate PsA from RA. Since the differential diagnosis of PsA and RA poses challenges in clinical practice, our data may help to enhance the diagnostic performance of PsA in daily practice.

Crenobalneotherapy is a treatment commonly used in Europe and Middle East. It uses mineral water sometimes combined with different hydrotherapy techniques. Most patients treated in spa centers suffer from low back pain. The purpose of this work is to identify clinical trials on crenobalneotherapy for low back pain. Publication research was performed on Medline, Cochrane, and PEDRO databases. Clinical trials were analyzed for internal validity, external validity, quality of statistical analysis, and quality of collection of adverse events. We present the best level of evidence. Bibliographic research identified 21 clinical trials and the coauthors added 5 references. The 26 trials represent 2695 patients. Some have good methodological quality and allow considering crenobalneotherapy as a potential treatment for low back pain, even if the role of mineral water remains uncertain. The methodological quality of therapeutic trials should be improved. These trials should be analyzed in the future guidelines on low back pain.

Lysosomal storage diseases (LSDs) are rare to extremely rare monogenic disorders. Their incidence, however, has probably been underestimated owing to their complex clinical manifestations. Sialidosis is a prototypical LSD inherited as an autosomal recessive trait and caused by mutations in the NEU1 gene that result in a deficiency of alpha-N-acetyl neuraminidase 1 (NEU1). Two basic forms of this disease, type I and type II, are known. The dysmorphic type II form features LSD symptoms including congenital hydrops, dysmorphogenetic traits, hepato-splenomegaly and severe intellectual disability. The diagnosis is more challenging in the normosomatic type I forms, whose clinical findings at onset include ocular defects, ataxia and generalized myoclonus. Here we report the clinical, biochemical and molecular analysis of five patients with sialidosis type I. Two patients presented novel NEU1 mutations. One of these patients was compound heterozygous for two novel NEU1 missense mutations: c.530A>T (p.Asp177Val) and c.1010A>G (p.His337Arg), whereas a second patient was compound heterozygous for a known mutation and a novel c.839G>A (p.Arg280Gln) mutation. We discuss the impact of these new mutations on the structural properties of NEU1. We also review available clinical reports of patients with sialidosis type I, with the aim of identifying the most frequent initial clinical manifestations and achieving more focused diagnoses.

Balneotherapy (BT) is one of the most commonly used non-pharmacologic complementary therapies for different rheumatic diseases. Its beneficial properties probably derived from a combination of mechanical, thermal, and chemical effects, but the exact mechanism of action is not elucidated. This review aimed at summarizing the current knowledge about the effects of BT, and identifying its possible mechanism of action in different rheumatic diseases. Pubmed and Scopus were used to perform a search of the literature to extract articles including terms related to BT and rheumatic diseases published in the period from 2010 to 2021. We selected pre-clinical studies, randomized controlled trials, and clinical trials. The results of clinical studies confirmed the beneficial properties on different mediators and factors of inflammation, oxidative stress, cartilage metabolism, and humoral and cellular immune responses in patients affected by chronic degenerative musculoskeletal disorders. The data derived from OA and RA-induced murine models revealed the efficacy of different BT treatments in decreasing pain, inflammation, and improving mobility, as well as in reducing the expression of matrix-degrading enzymes and markers of oxidative stress damage. Different in vitro studies analyzed the potential effect of a mineral water, as a whole, or of a mineral element, demonstrating their anti-inflammatory, antioxidant, and chondroprotective properties in OA cartilage, synoviocytes and chondrocytes, and osteoblast and osteoclast cultures. The presented data are promising and confirm BT as an effective complementary approach in the management of several low-grade inflammation, degenerative, and stress-related pathologies, as rheumatic diseases.

The optimal management of hand osteoarthritis (HOA) is still challenging. To evaluate the effects of glucosamine sulfate (GS) in addition to conventional therapy compared to conventional therapy alone in HOA. This 6-month retrospective study included 108 patients with concomitant knee and hand OA. Fifty-five patients (GS Group) were treated for six consecutive months with crystalline GS (1500 mg once/day) in addition to conventional therapy for HOA [exercise combined with acetaminophen and/or non-steroidal anti-inflammatory drugs (NSAIDs)] and 53 patients (Control Group) with the conventional therapy alone. Primary outcomes were the difference between groups in the change of hand pain on a Visual Analogue Scale (VAS) and in the Functional Index for Hand Osteoarthritis (FIHOA) from baseline to 6 months. Secondary outcomes were Health Assessment Questionnaire (HAQ), medical outcomes study 36-item short form (SF-36) and symptomatic drug consumption. The patients who received GS presented a significant decrease (p

Background The importance of systemic sclerosis (SSc) autoantibodies for diagnosis has become recognized by their incorporation into the 2013 ACR/EULAR classification criteria. Clear prognostic and phenotypic associations with cutaneous subtype and internal organ involvement have been also described. However, little is known about the potential of autoantibodies to exert a direct pathogenic role in SSc. The aim of the study is to assess the pathogenic capacity of anti-DNA-topoisomerase I (anti-Topo-I) and anti-centromeric protein B (anti-Cenp-B) autoantibodies to induce pro-fibrotic markers in dermal fibroblasts. Methods Dermal fibroblasts were isolated from unaffected and affected skin samples of (n = 10) limited cutaneous SSc (LcSSc) patients, from affected skin samples of diffuse cutaneous (DcSSc) patients (n = 10) and from healthy subjects (n = 20). Fibroblasts were stimulated with anti-Topo-I, anti-Cenp-B IgGs, and control IgGs in ratios 1:100 and 1:200 for 24 h. Cells were also incubated with 10% SSc anti-Topo-I+ and anti-Cenp-B+ whole serum and with 10% control serum for 24 h. Viability was assessed by MTT test, while apoptosis was assessed by flow cytometry. Activation of pro-fibrotic genes ACTA2, COL1A1, and TAGLN was evaluated by quantitative real-time PCR (qPCR), while the respective protein levels alpha-smooth-muscle actin (α-SMA), type-I-collagen (Col-I), and transgelin (SM22) were assessed by immunocytochemistry (ICC). Results MTT showed that anti-Cenp-B/anti-Topo-I IgGs and anti-Cenp-B+/anti-Topo-I+ sera reduced viability (in a dilution-dependent manner for IgGs) for all the fibroblast populations. Apoptosis is induced in unaffected LcSSc and control fibroblasts, while affected LcSSc/DcSSc fibroblasts showed apoptosis resistance. Basal mRNA (ACTA2, COL1A1, and TAGLN) and protein (α-SMA, Col-1, and SM22) levels were higher in affected LcSSc/DcSSc fibroblasts compared to LcSSc unaffected and to control ones. Stimulation with anti-Cenp-B/anti-Topo-I IgGs and with anti-Cenp-B+/anti-Topo-I+ sera showed a better induction in unaffected LcSSc and control fibroblasts. However, a statistically significant increase of all pro-fibrotic markers is reported also in affected LcSSc/DcSSc fibroblasts upon stimulation with both IgGs and sera. Conclusions This study suggests a pathogenic role of SSc-specific autoantibodies to directly induce pro-fibrotic activation in human dermal fibroblasts. Therefore, besides the diagnostic and prognostic use of those autoantibodies, these data might further justify the importance of immunosuppressive drugs in the early stages of the autoimmune disease, including SSc. Electronic supplementary material The online version of this article (10.1186/s13075-019-1931-x) contains supplementary material, which is available to authorized users.

Thumb-base osteoarthritis (TBOA) is a common condition, mostly affecting post-menopausal women, often inducing a significant impact on quality of life and hand functionality. Despite its high prevalence and disability, the therapeutic options in TBOA are still limited and few have been investigated. Among the pharmacological strategies for TBOA management, it would be worthwhile to mention the injection-based therapy. Unfortunately, its efficacy is still the subject of debate. Indeed, the 2018 update of the European League Against Rheumatism (EULAR) recommendations for the management of hand osteoarthritis (OA) stated that intra-articular (IA) injections of glucocorticoids should not generally be used, but may be considered in patients with painful interphalangeal joints, without any specific mention to the TBOA localization and to other widely used injections agents, such as hyaluronic acid (HA) and platelet-rich plasma (PRP). Even American College of Rheumatology (ACR) experts conditionally recommended against IA HA injections in patients with TBOA, while they conditionally encouraged IA glucocorticoids. However, the recommendations from international scientific societies don’t often reflect the clinical practice of physicians who routinely take care of TBOA patients; indeed, corticosteroid injections are a mainstay of therapy in OA, especially for patients with pain refractory to oral treatments and HA is considered as a safe and effective treatment. The discrepancy with the literature data is due to the great heterogeneity of the clinical trials published in this field: indeed, the studies differ for methodology and protocol design, outcome measures, treatment (different formulations of HA, steroids, PRP, and schedules) and times of follow-up. For these reasons, the current review will provide deep insight into the injection-based therapy for TBOA, with particular attention to the different employed agents, the variety of the schedule treatments, the most common injection techniques, and the obtained results in terms of efficacy and safety. In depth, we will discuss the available literature on corticosteroids and HA injections for TBOA and the emerging role of PRP and other injection agents for this condition. We will consider in our analysis not only randomized controlled trials (RCTs) but also recent pilot or retrospective studies trying to step forward to identify satisfactory management strategies for TBOA.

Balneotherapy (BT) is a complementary therapy widely used in several rheumatic conditions, however, the evidence in hand osteoarthritis (HOA) is still scarce. The aim of this preliminary study is to retrospectively evaluate the symptomatic effects of a cycle of mud-bath therapy in HOA patients. Two hundred twelve outpatients with primary bilateral HOA treated with 12 daily local mud packs and generalized thermal baths with a sulfurous-arsenical-ferruginous mineral water added to usual treatment were included in the study. Each patient was examined at baseline and at the end of thermal therapy (2 weeks). Primary outcome measures were global spontaneous hand pain on a Visual Analogue Scale (VAS) and the Functional Index for Hand Osteoarthritis (FIHOA) score; secondary outcomes were handgrip strength, duration of morning stiffness, Health Assessment Questionnaire (HAQ), Short Form Health Survey (SF-12), tolerability and patients’ and physicians’ global impression of treatment efficacy and tolerability. Our results demonstrated that the efficacy of mud-bath therapy was significant in all the assessed parameters at the end of therapy, except for the physical component score of SF-12. The thermal treatment was well tolerated. The patient’s and the physician’s global assessments showed a high level of satisfaction in terms of efficacy and safety. In conclusion, our results may suggest a short-term effectiveness of mud-bath therapy in controlling pain and improving functionality in HOA patients, supporting the role of this treatment as a complementary strategy in the management of HOA; however, further randomized controlled trials with a long-term follow-up are needed.

The study was aimed to compare the impact of thumb base osteoarthritis (TBOA) on pain, function, and quality of life in patients with erosive or non-erosive hand osteoarthritis (HOA).This observational retrospective study included 232 patients: 64 with erosive HOA (EHOA) and concomitant TBOA, 36 with isolated EHOA, 97 with non-erosive HOA (non-EHOA) and TBOA, and 35 with isolated non-EHOA. Hand pain by a visual analogue scale (VAS), Functional Index for Hand Osteoarthritis (FIHOA) score, Health Assessment Questionnaire (HAQ), the Medical Outcomes Study 36-Item Short Form (SF-36), and the possible correlations between VAS and FIHOA with radiological score were assessed.No differences were found between EHOA with TBOA and isolated EHOA in VAS and FIHOA scores; opposite, there was a significant difference in VAS (p 0.01) and FIHOA (p 0.001) between subjects with non-EHOA and TBOA and patients with only non-EHOA. VAS and FIHOA values resulted slightly higher in patients with EHOA and TBOA vs non-EHOA and TBOA; they were significantly more elevated in EHOA and TBOA group compared to isolated non-EHOA (p ≤ 0.001) and in isolated EHOA vs isolated non-EHOA (p 0.01 and p 0.001, respectively). HAQ, SF-36 resulted significantly better in isolated non-EHOA patients compared to the other groups. Finally, we observed a significant correlation between FIHOA and all the Kallman scales in EHOA patients with TBOA and between FIHOA and Kallman's thumb score in non-EHOA-TBOA group.EHOA has a more severe clinical burden than non-EHOA; the presence of TBOA appeared an important determinant of pain and disability in non-EHOA.Key Points• Each subset of HOA can have a different impact on pain and functionality, with EHOA determining more severe effects on hand symptoms and disability than non-EHOA.• The presence of TBOA appeared an important determinant of pain and disability in non-EHOA, but not in EHOA.• Our findings support the need for an individualized therapy for each phenotype of hand osteoarthritis.

Scleroderma (systemic sclerosis) is an autoimmune connective tissue disease which presents endothelial dysfunction and fibroblast dysregulation, resulting in vascular and fibrotic disorders. Pulmonary hypertension is frequent in patients with systemic sclerosis: the natural evolution of the disease can induce the development of different forms of pulmonary hypertension, representing one of the main causes of death. Among the different forms of pulmonary hypertension in systemic sclerosis, pulmonary arterial hypertension is the most frequent one (rate of occurrence is estimated between 7% and 12%). This pulmonary vascular complication should be treated with a combination of drugs that is able to counteract endothelial dysfunction, antagonizing the endothelin-1 system and replacing prostaglandin I2 and nitric oxide activity. A correct diagnosis is mandatory, because it is possible only for pulmonary arterial hypertension to use specific drugs that are able to control the symptomatic condition and the evolution of the disease. According to the most recent guidelines, for the patients with systemic sclerosis, also without pulmonary hypertension symptoms, echocardiography screening for the detection of pulmonary hypertension is recommended. Pulmonary arterial hypertension screening programs in systemic sclerosis patients is able to identify milder forms of the disease, allowing earlier management and better long-term outcome.

Discoid lupus erythematosus (DLE) is a chronic dermatological disease that can lead to scarring, alopecia and dyspigmentation, if not properly treated. Actually, no drugs are specifically approved for the treatment of CLE, although the first-line therapy usually consists of photoprotection associated to topical or oral steroids, topical calcineurin inhibitors and hydroxychloroquine (HCQ). In cases of DLE refractory to these medications, many other agents have been employed, such as dapsone, methotrexate, azathioprine, cyclophosphamide, biologic drugs and Intravenous Immunoglobulin (IVIG). We described the case of a DLE patient resistant to combination therapy with steroid and HCQ who was successfully treated with cyclical IVIG therapy. The treatment with IVIG resulted rapidly effective with persistent efficacy and low rates of relapses, although more cycles of IVIG are needed to achieve a stable clinical remission. We also discussed the beneficial and promising effects of IVIG in patients with Cutaneous Lupus reporting the previously published data.

Knee osteoarthritis (OA) is a degenerative disease which is expected to become one of the leading causes of disability by the next years. This work aims to assess if balneotherapy and spa therapy can significantly improve Quality of Life (QoL) of patients with knee OA. Medline via PubMed, Scopus, Web of Science, Cochrane Library, and PEDro were systematically searched for articles about trials involving patients with knee OA and measuring the effects of balneotherapy and spa therapy on study participants' QoL with validated scales. A qualitative and quantitative syntheses were performed. Seventeen studies were considered eligible and included in the systematic review. Fourteen trials reported significant improvements in at least one QoL item after treatment. Ten studies were included in quantitative synthesis. When comparing balneological interventions with standard treatment, results favored the former in terms of long-term overall QoL [ES = - 1.03 (95% CI - 1.66 to - 0.40)]. When comparing balneological interventions with sham interventions, results favored the former in terms of long-term pain improvement [ES = - 0.38 (95% CI - 0.74 to - 0.02)], while no significant difference was found when considering social function [ES = - 0.16 (95% CI - 0.52 to 0.19)]. In conclusion, even though limitations must be considered, evidence shows that BT and spa therapy can significantly improve QoL of patients with knee OA. Moreover, reduction of drug consumption and improvement of algofunctional indexes may be other beneficial effects. Further investigation is needed because of limited available data.

The aim of this study was to assess the efficacy and tolerability of balneotherapy (BT) in patients with primary fibromyalgia syndrome (FS). In a prospective, randomized, controlled, double-blind trial with a 6-month follow-up, 100 FS patients were randomized to receive a cycle of BT with highly mineralized sulfate water (BT group) or with tap water (control group). Clinical assessments were performed at screening visit, at basal time, and after treatment (2 weeks, 3 and 6 months). The primary outcome measures were the change of global pain on the Visual Analogue Scale (VAS) and Fibromyalgia Impact Questionnaire total score (FIQ-Total) from baseline to 15 days. Secondary outcomes included Widespread Pain Index, Symptom Severity Scale Score, Short Form Health Survey, State-Trait Anxiety Inventory (STAI), and Center for Epidemiologic Studies Depression Scale. We performed an intent-to-treat analysis. The Kolmogorov-Smirnov test was applied to verify the normality distribution of all quantitative variables and the Student’s t test to compare sample data. In the BT group, we observed a significant improvement of VAS and FIQ-Total at the end of the treatment that persisted until 6 months, while no significant differences were found in the control group. The differences between groups were significant for primary parameters at each time point. Similar results were obtained for the other secondary outcomes except for the STAI outcome. Adverse events were reported by 10 patients in the BT group and by 22 patients in the control group. Our results support the short- and long-term therapeutic efficacy of BT in FS. Trial registration: NCT02548065

To evaluate, by means of a longitudinal study, radiographic involvement of metacarpophalangeal and radio-carpal joints in hand osteoarthritis, its relationship with erosive disease and its progression, 368 patients with hand osteoarthritis were enrolled. All patients underwent hand X-rays. On the basis of the presence of central erosions in interphalangeal joints, patients were divided into three groups: 0-no central erosions, 1-one joint with central erosion, and 2-two or more joints with central erosions. A longitudinal study on 44 patients and nine normal controls, whose X-rays were available after 3.9 years, was performed. The radiological involvement of metacarpophalangeal and radio-carpal joints was evaluated using Kellgren-Lawrence and OARSI scores. Low number of joints showed Kellgren-Lawrence values ≥2 group 0, 42/1290 (3.3%); group 1, 10/410 (2.4%); and group 2, 36/1980 (1.8%). Low score values were obtained for all radiographic items. Only metacarpophalangeal joint space narrowing score showed significant increase from groups 0 to 2. Subsequent adjustment for age, gender, and BMI did not confirm the statistical significance. Marginal erosions were rarely found (6.7% of joints). Metacarpophalangeal and radio-carpal radiographic per patient scores significantly worsened at follow-up, but no significant increase in joints with Kellgren-Lawrence score ≥2 was found. In normal controls, no significant radiographic worsening was found. Only a minority of metacarpophalangeal joints shows a Kellgren-Lawrence value ≥2. Metacarpophalangeal and to lesser extent radiocarpal joints had significant worsening at follow-up. Metacarpophalangeal joint involvement in hand osteoarthritis is mild but progressive. Radiocarpal involvement is negligible.

Background Osteoarthritis (OA) is a theme currently representing an emerging topic for its increasing incidence. It is well known that it is a chronic disease that could lead to important long-lasting disability; this generates increasing costs for the health care system. OA treatment options vary: localization, etiology, grading and symptomatology should be considered before choosing the most adequate therapy. Currently, a modern approach to managing OA involves SYmptomatic Slow-Acting Drug for OsteoArthritis (SYSADOAs). However, while all preparations may claim to deliver a therapeutic level of glucosamine or chondroitin, not all of them are supported by clinical evidence. Recently the European Society for Clinical and Economic aspects of Osteoporosis, Osteoarthritis and musculoskeletal diseases (ESCEO), produced an evidenced based document providing practitioners with the latest clinical and economic information, thereby allowing them to optimize the management of knee OA. According to this report, only crystalline glucosamine sulphate and the pharmaceutical-grade chondroitin sulphate are considered as effective in the first line approach to treating knee OA as an alternative drug to acetaminophen. However, some OA guidelines do not agree are not concordant in recommending the use of SYSADOA, perhaps because they are generally considered as a class and distinctions among formulations are not made. Aim Aim of this study was to identify the main aspects involved in patient selection, the choice of therapeutic agents and the safety profile in using SYSADOA. Design Delphi method Consenus Statement. Population Italian Physicians having expertise in Osteoarthritis management. Methods A committee of 11 experts from Italian universities, public hospitals, territorial services, research institutes and patient associations was set up. Sixty-three clinicians from a large number of Italian medical centers specialized in osteoarthritis management took part in a Delphi process which was aimed at obtaining consensus statements among the participants. Results Large consensus was obtained for statements grouped under the following main themes: treatment indications; drug/medical devices choice; treatment efficacy. Conclusions Results from the Italian consensus on appropriateness of OA therapies in osteoarthritis seems to be in line with the stepwise approach proposed by the ESCEO algorithm, where crystalline glucosamine sulphate shows greater clinical efficacy than other glucosamine-based formulations, according to several independent meta-analyses. Clinical rehabilitation impact This study may be used as a practical reference tool to help Italian physicians treat osteoarthritis patients using SYSADOA.

We evaluated the presence of sarcopenia in a population of systemic sclerosis (SSc) patients, with respect to nutritional, clinical, and laboratory features. A total of 62 patients who met the ACR/EULAR 2013 classification criteria were enrolled. Sarcopenia was defined according to the Relative Skeletal Mass Index (RSMI) and hand grip strength (HGS). Body composition was assessed with the calculation of the Body Mass Index (BMI), lean body mass (LBM) and fat mass (FM). Malnutrition was evaluated according to the ESPEN criteria. Clinical evaluation included nailfold capillaroscopy and skin evaluation by modified Rodnan Skin Score (mRSS), pulmonary function tests (PFT) with diffusing capacity for carbon monoxide adjusted for hemoglobin (DLCO), high-resolution computed tomography (HR-CT) of the lungs, echocardiography and high-resolution manometry (HRM) for esophageal involvement. Laboratory evaluation included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), hemoglobin, creatinine, creatine kinase (CK), transaminases, lipid profile, glycemia, albumin, and vitamin-D. Antinuclear antibodies (ANA) and extractable nuclear antigens (ENA) were also assessed. Considering RSMI, the prevalence of sarcopenia is 42%. In this case, age, malnutrition, disease duration, mRSS, capillaroscopy score, esophageal involvement, ESR, and ANA titer are higher in the sarcopenic group, while DLCO and LBM are lower. Considering HGS, the prevalence of sarcopenia is 55%. Age, disease duration, malnutrition, FM, mRSS, capillaroscopy score, esophageal involvement, ESR, and ENA positivity are higher in the sarcopenic group, while DLCO is lower. By using both RSMI and HGS to assess sarcopenia in SSc, the results of this study demonstrated that this condition correlates with different nutritional, clinical, and biochemical parameters associated with the worsening of the disease.

Background The importance of systemic sclerosis (SSc) autoantibodies for diagnosis has become increasingly recognized, as evidence by incorporation into the 2013 ACR/EULAR clinical classification criteria (1). Clear prognostic and phenotypic associations with cutaneous subtype and internal organ involvement have been extensively described (2). However, little is known about the potential of those autoantibodies to exert a direct pathogenetic role in the disease (3). Objectives The aim of the study is to assess the potential pathogenetic role of anti-topo isomerase I (Topo-I) and anti-centromeric protein B (Cenp B) autoantibodies to induce pro-fibrotic markers in dermal fibroblasts. Methods Dermal fibroblasts were isolated from unaffected and affected skin samples of (n=10) limited cutaneous SSc (LcSSc) patients, from affected skin samples of (n=10) diffuse cutaneous (DcSSc) patients and from (n=20) healthy subjects. Fibroblasts were stimulated with serum-isolated fractions of Topo-I, Cenp B and control IgGs in ratios 1:100 and 1:200 for 24 and 48 hours. Cells were also incubated with 10% SSc Topo-I+, Cenp B+ whole serum and with 10% control serum for 24 and 48 hours. Viability was assessed by MTT test, while apoptosis was assessed by flow cytometry. Activation of pro-fibrotic genes ACTA2, COL1A1 and TAGLN was evaluated by quantitative-real-time-PCR (qPCR), while protein levels alpha-smooth-muscle actin (α-SMA), type-I-collagen (Col-I) and SM22 were assessed by immunocitochemistry (ICC). Results MTT test showed that Cenp B (p Conclusion This study demonstrates the pathogenetic role of antibodies targeting Topo-I and Cenp B to directly induce pro-fibrotic activation of fibroblasts. Therefore, besides the diagnostic and prognostic use of those autoantibodies in SSc, these data justify the importance of therapeutic use of immunosuppressive drugs in the early stages of the disease. References [1] Denton CP. Advances in pathogenesis and treatment of systemic sclerosis. Clin Med (Lond) 2016;16:55-60. [2] Asano Y. Systemic Sclerosis. J Dermatol 2017; doi: 10.1111/1346-8138.14153. [3] Yayla ME, Ilgen U, Duzgun N. An analysis of the relationship between autoantibodies and clinical findings in patients with systemic sclerosis. Turk J Med Sci 2018;48(1):10-15. Disclosure of Interests None declared

Hand osteoarthritis (HOA) includes different subsets; a particular and uncommon form is erosive HOA (EHOA). Interleukin- (IL-) 1βplays a crucial role in the pathogenesis of osteoarthritis (OA); it is synthesized as an inactive precursor which requires the intervention of a cytosolic multiprotein complex, named inflammasome, for its activation. The aim of this study was to investigate the involvement of IL-1βand the NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome in patients with EHOA and nonerosive HOA (NEHOA) compared to healthy controls. In particular, we evaluated the gene expression of IL-1βand NLRP3, the serum levels of IL-1β, IL-6, IL-17, and tumor necrosis factor- (TNF-)α, and the protein levels of IL-1βand NLRP3. We also assessed the relationships between IL-1βand NLRP3 and clinical, laboratory, and radiological findings. Fifty-four patients with HOA (25 EHOA and 29 NEHOA) and 20 healthy subjects were included in the study. Peripheral blood mononuclear cell (PBMC) gene and protein expressions of IL-1βand NLRP3 were quantified by quantitative real-time PCR and western blot. IL-1β, IL-6, IL-17, and TNF-αserum levels were determined by ELISA. IL-1βgene expression was significantly reduced (p=0.0208) in EHOA compared to healthy controls. NLRP3 protein levels were significantly increased in the NEHOA group versus the control (p=0.0063) and EHOA groups (p=0.0038). IL-1βserum levels were not significantly different across the groups; IL-6, IL-17, and TNF-αwere not detectable in any sample. IL-1βconcentrations were negatively correlated with the Kellgren-Lawrence score in the whole population (r=−0.446;p=0.0008) and in NEHOA (r=−0.608;p=0.004), while IL-1βgene expression was positively correlated with the number of joint swellings in the EHOA group (r=0.512;p=0.011). Taken together, our results, showing poorly detectable IL-1βconcentrations and minimal inflammasome activity in the PBMCs of HOA patients, suggest a low grade of systemic inflammation in HOA. This evidence does not preclude a possible involvement of these factors at the local level.

Rationale:Aromatase inhibitors (AIs) are a class of drugs widely used in the treatment of estrogen sensitive breast and ovarian cancer which convert testosterone to estradiol and androstenedione to estrogen. The AIs of third generation, including anastrazole, letrozole and exemestane, have a

Background:In Italy Osteoarthritis (OA) is a widespread and disabling disease that affects an increasingly large number of patients in the population, representing one of the main causes of morbidity and disability with high socio-economic costs. The etiology of OA is multifactorial, even if the significant association with some modifiable risk factors like mechanical overload and obesity is now well demonstrated. Early diagnosis and treatment strategies in OA could reduce both patient morbidity and associated costs.Objectives:Promoted by the Italian Society of Rheumatology (SIR), The Early Symptomatic OsteoaRThritis (ESORT) registry has the aim to study the natural history of OA from the earliest stages (pre- radiographic) considering risk factors in the progression of the disease, and the influence of therapeutic factors on long-term disease outcomes. The ESORT register aims to describe the socio-demographic and clinical characteristics of patients affected by OA in Italy; evaluates the extent of symptoms, functional damage, comorbidities, the frequency of use of drugs currently indicated in our country, and differences related to clinical subsets according with comorbidities and geographical localization of the patient.Methods:Actually 8 Italian Rheumatology centers are involved in the online data entry data of the SIR registry (developed and validated by SIR Study Center), considering patients affected by OA. In particular, the electronic database collects information about main demographic variables, significant anamnestic elements (risk factors and comorbidities), localization of OA, laboratory data, clinimetric indices with WOMAC / FIHOA / VAS scales, radiographic instrumental data and therapy in act. These data are reported in specific forms in the register with annual reassessment.Results:Currently, 318 patients with OA are included in the “ESORT” registry with an extension of observation up to 48 months, 214 women and 104 men with an average age of 71 years and an average weight of 72 kg. About 14% of patients affected by knee OA show Kellgren and Lawrence radiological stage 0 in presence of painful symptoms at the knees. The most frequent localization of OA is the knee (63%), followed by the hip (41%), hand (36%), spine (34%), and other sites (16%). The Table 1 shows details of some parameters (average age, average weight, intake of NSAIDs, intake of opioids and intake of chondroprotectors) according to the localization of the disease. From the registry data, patients with OA results treated mainly with NSAIDs and chondroprotectors, and patients with knee OA are the most frequently treated with opioid analgesics (44%), less used in other OA locations.Conclusion:The “ESORT” register is a useful tool for epidemiological and clinical information relating to patients with OA and for monitoring the evolution of the disease and the response to therapy.Average age (years)Average weight (kg)Intake of NSAIDs (% of patients)Intake of opioids (% of patients)Intake of chondroprotectors (% of patients)OA hand706774%10%25-31%OA knee747585%44%53-59%OA hip697075%25%24-28%OA spine757576%14%19-28%OA other localization747369%13%15-35%Disclosure of Interests:Gianfranco Gigliucci: None declared., Orazio De Lucia: None declared., Antonella Fioravanti: None declared., Felice Galluccio: None declared., Serena Guiducci: None declared., Antimo Moretti: None declared., Marco Matucci-Cerinic Speakers bureau: Consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Grant/research support from: Consulting fees or honorarium from Actelion, Janssen, Inventiva, Bayer, Biogen, Boehringer, CSL Behring, Corbus, Galapagos, Mitsubishi, Samsung, Regeneron, Acceleron, MSD, Chemomab, Lilly, Pfizer, Roche, Antonella Murgo: None declared., Simone Parisi Speakers bureau: Personal fees (as speaker and/or consultant) from NOVARTIS, BMS, LILLY, UCB, MSD, PFIZER, ABBVIE, BIOGEN, AMGEN, JANSENN CILAG, CHIESI and GRUNENTHAL outside the submitted work;, Consultant of: Personal fees (as speaker and/or consultant) from NOVARTIS, BMS, LILLY, UCB, MSD, PFIZER, ABBVIE, BIOGEN, AMGEN, JANSENN CILAG, CHIESI and GRUNENTHAL outside the submitted work;, Roberta Ramonda: None declared., Sara Tenti: None declared., Enrico Tirri: None declared., Alberto Migliore Speakers bureau: Grants from Abiogen,Lilly,Fidia,Jansen (outside the submitted work), Consultant of: Grants from Abiogen,Lilly,Fidia,Jansen (outside the submitted work), Grant/research support from: Grants from Abiogen,Lilly,Fidia,Jansen (outside the submitted work).

Balneotherapy (BT) is widely used in daily clinical practice for the management of osteoarthritis (OA) in many European countries, as well as in Turkey, Israel and Japan (OA). However, despite its long history and tradition, the scientific value of BT is still the subject of discussion. The aim of this overview was to discuss the current evidence and critical points about the mechanisms of action, clinical efficacy and cost-effectiveness of BT in OA as well as the definition of the used term of “Balneotherapy”. BT traditionally involves either immersion in mineral and/or thermal waters from natural springs and/or balneological interventions with natural gases or peloids (mud). The mechanisms of action of BT are not fully elucidated; the net benefit is probably the result of a combination of mechanical, thermal and chemical effects. Various randomized controlled clinical trials (RCTs) in patients with OA support a beneficial effect of BT on pain, function and quality of life that lasts over time after the treatment. Economic evaluations in this field are rare, however preliminary cost-effectiveness analysis have shown a favourable economic profile for BT in OA. Some aspects have to be clarified regarding the absorption of the mineral elements dissolved in waters, their concentration in the joints and the ideal concentration of each element to obtain a therapeutic response. Further well-designed RCTs are needed in order to support the beneficial effects of BT in OA. Additional preclinical and clinical studies are necessary to clarify the mechanisms of action of BT to improve the scientific value of BT.

Aromatase inhibitors (AIs) have radically changed the prognosis of hormone receptor positive breast cancer (BC) in post-menopausal women, and are a mainstay of the adjuvant therapy for BC after surgery in place of, or following, Tamoxifen. However, AIs aren’t side effect-free; frequent adverse events involve the musculoskeletal system, in the form of bone loss, AI-associated arthralgia (AIA) syndrome and autoimmune rheumatic diseases. In this narrative review, we reported the main clinical features of these three detrimental conditions, their influence on therapy adherence, the possible underlying molecular mechanisms and the available pharmacological and non-pharmacological treatments. The best-known form is the AIs-induced osteoporosis, whose molecular pathway and therapeutic possibilities were extensively investigated in the last decade. AIA syndrome is a high prevalent joint pain disorder which often determines a premature discontinuation of the therapy. Several points still need to be clarified, as a universally accepted diagnostic definition, the pathogenetic mechanisms and satisfactory management strategies. The association of AIs therapy with autoimmune diseases is of the utmost interest. The related literature has been recently expanded, but many issues remain to be explored, the first being the molecular mechanisms.

Osteoarthritis (OA) is the most common musculoskeletal disease leading to functional decline and loss in quality of life. Knees, hands and hips are frequently affected joints with a relevant clinical and socio-economic burden. An evidence-based approach to OA management is essential in order to improve patients’ health and to decrease social burdens. Since new international clinical practice guidelines (CPGs) focused on diagnosis or pharmacological/non-pharmacological treatment have become available in the last ten years, the Italian Society for Rheumatology (SIR) was prompted to revise and customize them for a multidisciplinary audience of specialists involved in the management of OA. The framework of the Guidelines International Network Adaptation Working Group was adopted to identify, appraise (AGREE II), synthesize, and customize the existing CPGs on OA to the needs of the Italian healthcare context. The task force, consisting of rheumatologists from the SIR epidemiology research unit and a committee with experience of OA, identified key health questions to guide a systematic review of published guidelines. The target audience included physicians and health professionals who manage OA. An external panel of stakeholders rated the guidelines. From a systematic search in databases (Pubmed/Medline, Embase) and grey literature, 11 CPGs were selected and appraised by two independent raters. Combining evidence and statements from these CPGs and clinical expertise, 16 guidelines were developed and graded according to the level of evidence. Agreement and potential impact on clinical practice were assessed. These revised guidelines are intended to provide guidance for diagnosis and treatment of OA and to disseminate best evidence-based strategies management of the disease.

Background Systemic Sclerosis (SSc) is an autoimmune disease characterised by progressive fibrosis of the skin and internal organs, coupled to widespread vascular pathology.1 The pathogenesis is still poorly understood and there is no effective treatment for the fibrotic process.1 Relaxin is a potent anti-fibrotic hormone that has been tested in the past to ameliorate skin, lung and kidney fibrosis in SSc, but the results remain controversial.2 Objectives The aim of the study is to evaluate the presence of mutations in RXFP1 gene (encoding the relaxin receptor RXFP1/LGR7), and to assess mRNA and protein levels of the receptor in dermal fibroblasts of SSc patients, in order to understand the clinical inefficacy of relaxin-based anti-fibrotic treatments in the disease. Methods Fibroblasts were isolated from unaffected and affected skin samples of (n=20) of limited cutaneous SSc (LcSSc) and from (n=20) affected skin of diffuse cutaneous SSc (DcSSc) patients. Fibroblasts derived from healthy subjects were used as controls. Sequencing of exonic target regions of interest for gene RXFP1 was performed coupled with mRNA transcript variant analysis. RXFP1/LGR7 mRNA and protein levels were assessed by quantitative-real-time-PCR (qPCR) and by immunocitochemistry (ICC) in cultured SSc and healthy fibroblasts. Finally, synthesis of collagen and alpha-smooth-muscle actin (a-SMA) of transforming-growth-factor-beta-1 (TGF-β1) induced fibroblasts were assessed after 24 hours pre-treatment with serelaxin (a recombinant form of human relaxin-2 targeting the relaxin receptor RXFP1/LGR7). Results Sequencing of RXFP1 gene showed no relevant (single nucleotide polymorphisms) SNPs or small insertions and deletions (InDels) in affected LcSSc/DcSSc fibroblasts. No relevant mutations were found in unaffected LcSSc and healthy fibroblasts as well. However, alternatively spliced transcript variants encoding multiple isoforms were observed for this gene in all the fibroblast populations. The total RXFP1 mRNA levels resulted upregulated (p Conclusions The absence/altered expression of relaxin receptor RXFP1/LGR7 in the affected fibroblasts of SSc patients could explain the inefficacy of relaxin-based anti-fibrotic treatments in the disease. The exclusion of RXFP1 gene mutations could lead to the hypothesis that the presence of receptor splice variants could exert a dominant negative effect on the wild type isoform in terms of maturation, and subsequent trafficking to the cell surface, resulting in loss of function. References [1] Denton CP. Advances in pathogenesis and treatment of systemic sclerosis. Clin Med (Lond)2016;16:55–60. [2] McVicker BL, Bennet RG. Novel Anti-fibrotic therapies. Front Pharmacol2017;8:318. Disclosure of Interest None declared

Purpose: To evaluate serum levels of visfatin, resistin and adiponectin in patients with erosive (E) and non-erosive (NE) osteoarthritis (OA) of the hand (HOA) compared to normal controls (NC). Methods: 94 outpatients with E HOA and NE HOA and 21 NC were enrolled. The radiological assessment of both hands was performed according to the Kellgren–Lawrence and Kallman score. Patients were divided into two subsets (lone HOA or generalized OA) based on clinically OA involvement of knee and hip. Serum visfatin, resistin and adiponectin levels were determined by ELISA assay. Results: Visfatin was significantly higher in E HOA patients in comparison to NC and NE HOA group. Resistin showed a significant increase in both E HOA and NE HOA groups versus NC, in particular in generalized OA. No significant differences among groups were found in adiponectin. The Kallman score was more severe in the two subsets of E HOA patients compared to NE HOA. Conclusions: This study showed increased levels of resistin in erosive and non-erosive HOA, and higher visfatin levels in E HOA in comparison to NE HOA. These data suggest the adipokines possible role in the pathogenesis of HOA and their potential usefulness as biomarkers of the disease.

// Pierpaolo Correale 1 , Cirino Botta 2 , Nicoletta Staropoli 3 , Valerio Nardone 4 , Pierpaolo Pastina 4 , Cristina Ulivieri 5 , Claudia Gandolfo 6 , Tatiana Cosima Baldari 5 , Stefano Lazzi 7 , Domenico Ciliberto 3 , Rocco Giannicola 1 , Antonella Fioravanti 8 , Antonio Giordano 9 , Silvia Zappavigna 10 , Michele Caraglia 9, 10 , Pierfrancesco Tassone 2, 3, 10 , Luigi Pirtoli 4 , Maria Grazia Cusi 6 and Pierosandro Tagliaferri 3 1 Unit of Medical Oncology, Grand Metropolitan Hospital Bianchi Melacrino Morelli, Reggio-Calabria, Italy 2 Medical Oncology Unit, AUO Mater Domini, Magna Graecia University, Catanzaro, Italy 3 Department of Experimental and Clinical Medicine, Magna Graecia University , Catanzaro, Italy 4 Unit of Radiotherapy, Department of Surgery, Medicine and Neurological Science, Siena University Hospital, Siena, Italy 5 Department of Science of Life, Siena University, Siena, Italy 6 Microbiology and Virology Unit, Department of Medical Biotechnology, Siena University, Siena, Italy 7 Unit of Pathology, Department of Surgery, Medicine and Neurological Science, Siena University Hospital, Siena, Italy 8 Unit of Rheumatology, Department of Clinical Medicine and Immunologic Sciences, University of Siena, Siena, Italy 9 Department of Biotechnology, Temple University, Sbarro Foundation, Philadelphia, Pennsylvania, USA 10 Department of Precision Medicine, University of Campania L. Vanvitelli, Naples, Italy Correspondence to: Pierosandro Tagliaferri, email: tagliaferri@unicz.it Pierpaolo Correale, email: correalep@yahoo.it Keywords: bio-markers; cancer vaccine; colorectal cancer; K-ras; thymidylate synthase Received: August 24, 2017 Accepted: February 21, 2018 Published: April 17, 2018 ABSTRACT TSPP is an anticancer poly-epitope peptide vaccine to thymidylate synthase, recently investigated in the multi-arm phase Ib TSPP/VAC1 trial. TSPP vaccination induced immune-biological effects and showed antitumor activity in metastatic colorectal cancer (mCRC) patients and other malignancies. Progression-free and overall survival of 41 mCRC patients enrolled in the study correlated with baseline levels of CEA, immune-inflammatory markers (neutrophil/lymphocyte ratio, CRP, ESR, LDH, ENA), IL-4 and with post-treatment change in p-ANCA and CD56 dim CD16 bright NKs ( p < 0.04). A subset of 19 patients with activating k-ras mutations showed a different immune-inflammatory response to TSPP as compared to patients with k-ras/wt and a worse outcome in term of PFS ( p = 0.048). In patients with k-ras/mut, inflammatory markers lost their predictive value and their survival directly correlated with the baseline levels of IL17/A over the median value ( p = 0.01). These results provide strong hints for the design of further clinical trials aimed to test TSPP vaccination in mCRC patients.

N-acetylglutamate synthase deficiency (NAGSD) is an extremely rare urea cycle disorder (UCD) with few adult cases so far described. Diagnosis of late-onset presentations is difficult and delayed treatment may increase the risk of severe hyperammonemia. We describe a 52-year-old woman with recurrent headaches who experienced an acute onset of NAGSD. As very few papers focus on headaches in UCDs, we also report a literature review of types and pathophysiologic mechanisms of UCD-related headaches. In our case, headaches had been present since puberty (3–4 days a week) and were often accompanied by nausea, vomiting, or behavioural changes. Despite three previous episodes of altered consciousness, ammonia was measured for the first time at 52 years and levels were increased. Identification of the new homozygous c.344C>T (p.Ala115Val) NAGS variant allowed the definite diagnosis of NAGSD. Bioinformatic analysis suggested that an order/disorder alteration of the mutated form could affect the arginine-binding site, resulting in poor enzyme activation and late-onset presentation. After optimized treatment for NAGSD, ammonia and amino acid levels were constantly normal and prevented other headache bouts. The manuscript underlies that headache may be the presenting symptom of UCDs and provides clues for the rapid diagnosis and treatment of late-onset NAGSD.

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Osteoarthritis (OA) is the most common form of arthritis and its current treatment includes non-pharmacological and pharmacological modalities. Spa therapy represents a popular treatment for many rheumatic diseases. The aim of this review was to summarize the currently available information on clinical effects and mechanisms of action of spa therapy in OA of the hand. We conducted a search of the literature to extract articles describing randomized clinical trials (RCTs) in hand OA published in the period 1952-2015. We identified three assessable articles reporting RCTs on spa therapy in hand OA. Data from these clinical trials support a beneficial effect of spa therapy on pain, function and quality of life in hand OA. Spa therapy seems to have a role in the treatment of hand OA. However, additional RCTs are necessary to clarify the mechanisms of action and the effects of the application of thermal treatments.

Adipocytokines, including adiponectin, resistin, and visfatin may play an important role in the pathophysiology of osteoarthritis (OA). Spa therapy is one of the most commonly used non-pharmacological approaches for OA, but its mechanisms of action are not completely known. The aim of the present study was to assess whether a cycle of mud-bath therapy (MBT) influences the serum levels of adiponectin, resistin, and visfatin in patients with knee OA. As part of a prospective randomized, single blind-controlled trial evaluating the efficacy of MBT in knee OA, we included in this study 95 outpatients. One group (n = 49) received a cycle of MBT at the spa center of Chianciano Terme (Italy) in addition to the usual treatment, and one group (control group; n = 46) continued their regular care routine alone. Patients were assessed at basal time and at the end of the study (15 days) for clinical and biochemical parameters. Clinical assessments included spontaneous pain on a visual analog scale (VAS) score and the Western Ontario and McMaster Universities index (WOMAC) subscores for knee OA evaluated as total pain score (W-TPS), total stiffness score (W-TSS), and total physical function score (W-TPFS). Adiponectin, resistin and visfatin serum levels were assessed by enzyme immunoassay methods. At the end of the mud-bath therapy, serum adiponectin levels showed a significant decrease (p

Background Osteoarthritis (OA) of the trapeziometacarpal joint (TMJ) is a disabling condition with a significant impact on quality of life. The optimal management of hand OA requires a combination of non-pharmacological and pharmacological treatments that include intra-articular (i.a.) therapy. EULAR experts recommend corticosteroid injections in TMJ OA and underline the usefulness of hyaluronic acid (HA). The aim of this study was the assessment of the efficacy and tolerability of i.a. injections of a hybrid formulation of HA (Sinovial H-L®) in comparison to triamcinolone in patients with TMJ OA. Methods This 6-months observational comparative study, retrospective analyzed the medical records of 100 patients with monolateral or bilateral TMJ OA, treated with two injections of Sinovial H-L® (Sinovial H-L Group) or of triamcinolone acetonide (Triamcinolone Group). Clinical assessments were recorded at the time of the first and second injection and after one, 3 and 6 months. The primary outcomes were the change in global pain on a Visual Analogue Scale (VAS) and in hand function evaluated by the Functional Index for Hand OA (FIHOA) from baseline to month 6. Secondary outcomes were the improvement of the duration of morning stiffness, Health Assessment Questionnaire (HAQ) and the Medical Outcomes Study 36-Item Short Form (SF-36). The comparison between the two groups of treatment were performed with the Wilcoxon rank-sum test for continuous variables and with chi-square or Fisher exact test for categorical variables. Statistical significance was set at p

Background Selective cyclooxigenase (COX)-2 inhibitors were developed to prevent NSAIDs gastro-intestinal adverse effects. VA692, a new hydroxyetyl selective COX-2 inhibitor, showed anti-inflammatory, anti-nociceptive and chondroprotective properties. Proteomics is being applied for the study of drug mode of action, toxicity and to identify new drugs targets. Objectives The aim of this study was to analyze the anti-inflammatory effect of VA692, in comparison with celecoxib. By iTRAQ methodology, we quantitatively analyzed the different expressed profiles in T/C-28a2 cell line treated with the studied drugs in presence of IL-1β. Methods Human T/C-28a2 chondrocytes cell line were generated by Goldring group. Human articular cartilage was obtained from femoral heads of five OA patients. Cells were incubated with VA692 and celecoxib (1, 0.5 and 0.2μM) in presence of Interleukin (IL)-1β (5ng/ml) for 48h. The expression of inflammatory cytokines and anti-oxidant enzymes was evaluated by quantitative qRT-PCR, PGE2 release by ELISA, and apoptosis and ROS production by flow cytometry. T/C-28a2 cell line was also processed to carry out western blot tests and finally employed for the iTRAQ analysis. Statistical analysis was performed by ANOVA and Bonferroni multiple comparison tests. Results IL-1β-stimulated chondrocytes showed a significant increase (p Conclusions Our data demonstrated the anti-inflammatory effect of VA692, suggesting also its anti-apoptotic and anti-oxidant role. The proteomic profile showed that VA692 induced not only an anti-inflammatory effect in chondrocytes but, interestingly, this compound also seemed to regulate their anabolic response. References Hochberg MC et al.Arthritis Care Res 2012. McAlindon TE et al. Osteoarthritis Cartilage 2014. Bingham CO III. Cleve Clin J Med 2002. Anzini M et al. J Med Chem 2013. Calamia V et al.Arthritis Res Ther 2010. Disclosure of Interest None declared

Background MicroRNAs (miRNAs) are a class of 19–23 nucleotides long non-coding RNAs that post-transcriptionally regulate the activity of target mRNAs. MicroRNAs are involved in cartilage homeostasis and play an important role in the pathogenesis of osteoarthritis (OA). They have been detected in human plasma and in synovial fluid and are considered as potential diagnostic biomarkers and therapeutic targets of OA. Balneotherapy is a common non-pharmacological treatment for OA patients. In a previous published prospective single-blind randomized clinical trial in patients with knee OA, we showed that a cycle of mud-bath therapy (MBT) in addition to conventional treatments induced an improvement on pain, functional capacity and quality of life in comparison to standard treatment alone. Objectives as part of this study we evaluated the whole blood levels of miR-155, 223, 181a, 146a and miR-let-7e, which are involved in the pathogenesis of OA. Methods Thirty-two patients aged between 50 and 75 years with knee OA defined by the ACR criteria were included for the current analysis, based on the availability of blood sample at basal time and after 2 weeks. Twenty-one patients (MBT group) were daily treated with a combination of daily local mud-packs at 42°C and baths in mineral water, at 37°C for 15 min, for a total of 12 applications over a period of 2 weeks, in addition to standard therapy; the other eleven patients (control group) continued their conventional treatment alone. Clinical parameters [global pain score by a 0–100 mm Visual Analog Scale (VAS); physical function, total pain score and total stiffness score (WOMAC)] and microRNAs expression were performed at basal time and after 2 weeks. Peripheral whole blood was collected into PAXgeneTM Blood RNA tubes and then stored a -80°C. Total RNA was extracted using the PAXgeneTM Blood miRNA kit and the relative expression of miR-146a, miR-155, miR-223, miR-181a and miR-let-7e were determined by qRT-PCR. Results At the end of MBT we observed a statistically significant improvement of clinical paramethers. Furthermore, we observed a significant decrease of miR-155, 181a and miR-146a (p Conclusions Our data showed that MBT can modify the expression levels of miR-155, 181a, 146a and 223 expression levels, that are up-regulated in OA. This MBT effect could be explained considering the role of the heat stress and of the hydrostatic pressure, since some miRNAs were found to be temperature and mechano-responsive. Further studies are needed to better explain the mechanism of action of MBT and the role of miRNAs in OA. References Cheleschi S et al. Int J Mol Sci. 2017. De Palma A et al. Clin Exp Rheumatol. 2017. Fioravanti A et al. Int J Biometeorol. 2015. Potla R. et al. RNA. 2015. Disclosure of Interest None declared

The aim of this study was to evaluate the whole-blood levels of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e in patients with bilateral knee osteoarthritis (OA) after a cycle of mud-bath therapy (MBT). Thirty-two patients with knee OA defined by the ACR criteria were included. Twenty-one patients (MBT group) were daily treated with a combination of local mud-packs at 42 °C and baths in mineral water, at 37 °C for 15 min, for 12 applications over a period of 2 weeks, in addition to standard therapy; 11 patients (control group) continued their conventional treatment alone. Global pain score evaluated by visual analog scale (VAS), WOMAC subscores, and microRNA expression were evaluated at baseline and after 2 weeks. Peripheral whole blood was collected into PAXgene™ Blood RNA tubes, stored at − 80 °C, and total RNA was extracted. The expression of miR-155, miR-223, miR-181a, miR-146a, and miR-let-7e was determined by qRT-PCR. After MBT, we observed a statistically significant improvement of clinical parameters and a significant decrease of miR-155, miR-181a, miR-146a (p

Osteoarthritis (OA) continues to be one of the leading causes of 'years lived with disability' worldwide. Symptomatic knee OA is highly prevalent among people aged 50 years and over and is destined to become an ever more important healthcare problem. Current management of knee OA includes non-pharmacological and pharmacological treatments. Spa therapy is one of the most commonly used non-pharmacological approaches for OA in many European countries, as well as in Japan and Israel. Despite its long history and popularity, spa treatment is still the subject of debate and its role in modern medicine continues to be unclear. The objective of this review is to summarize the currently available information on clinical effects and mechanisms of action of spa therapy in knee OA. Various randomized controlled clinical trials (RCTs) were conducted to assess the efficacy and tolerability of balneotherapy and mud-pack therapy in patients with knee OA. Data from these clinical trials support a beneficial effect of spa therapy on pain, function and quality of life in knee OA that lasts over time, until 6-9 months after the treatment. The mechanisms by which immersion in mineral or thermal water or the application of mud alleviate suffering in OA are not fully understood. The net benefit is probably the result of a combination of factors, among which the mechanical, thermal and chemical effects are most prominent. In conclusion, spa therapy seems to have a role in the treatment of knee OA. Additional RCTs and further studies of mechanisms of action with high methodological quality are necessary to prove the effects of spa therapy.

Introduction Phytothermotherapy (PTT) is a singular treatment consisting in immersing oneself in pools of fermenting alpine grass, to exploit its heat and rich aromatic components. The efficacy of PTT in rheumatic diseases (RD) is bolstered by ancient tradition. However, there is a marked lack of clinical validation of its efficacy and tolerability in current literature. The objective of this review was to summarize the actually available knowledges on possible effects of PTT in RD. Methodology We conducted a search of the literature in May 2012. Medline was searched using the term “phytothermotherapy” and “hay baths” in combination with “rheumatic diseases”, “fibromyalgia syndrome”, “osteoarthritis”. Results We identified one article reporting the clinical effects of PTT in 56 patients with fibromyalgia syndrome (FMS) and 3 trials describing the results of PTT in osteoarthritis (OA). The available data demonstrate that PTT is efficacy in decreasing pain and disability and improving function in patients with FMS and OA. Furthermore, the tolerability of PTT is excellent. The actual mechanism of action of PTT is yet not completely known, although it's probably due to different combined mechanical, physical and chemical effects. Discussion PTT could represent a useful aid in the treatment of FMS and OA. However, further studies on a larger number of patients are needed to provide more precise therapeutic guidelines on the modalities of use of PTT. Additionally, there is a need for further botanical investigations and researches on the mechanisms of actions of PTT.

Diffuse idiopathic skeletal hyperostosis (DISH) is a disease characterized by calcification and ossification of ligaments and entheseal sites (1). Although the exact cause of DISH remains unknown, ...

Thymidylate synthase (TS) is a tumor-associated enzyme critical for DNA replication and main 5′-fluorouracil (5′-FU) target. TSPP/VAC1 is a multi-arm trial phase-Ib trial program aimed to investigate the toxicity and biomodulatory activity of a poly-epitope-peptide vaccine to TS (TSPP) in cancer patients (pts). Here, we present the results of the TSPP/VAC1/arm C trial aimed to evaluate TSPP in combination with chemo-immunotherapy in pretreated metastatic colo-rectal cancer (mCRC) pts. Twenty-nine pts, 14 males and 15 females, received poly-chemotherapy with gemcitabine [GEM; 1,000mg/sqm, day-1], oxaliplatin [OX; 80mg/sqm, day-2], levofolinate [100mg/sqm, days 1–2], bolus/infusional 5′-FU [400mg/800mg/sqm, days 1–2], sargramostim [50μg, days 3–7/q30], and interleukin-2 [sc. 0.5 MIU twice a day, days 8–14/18–30] [GOLFIG-regimen]. Seventeen pts received sc. TSPP injections at escalating dosage [3 pts, 100µg (DL-1); 3 pts, 200µg (DL-2) and 11pts, 300µg (DL-3)] one week after each chemotherapy cycle (concomitant module), while 10 out 12 pts received TSPP (300µg) after 12 GOLFIG courses [dose level (DL)-0] (sequential module). TSPP MTD was not achieved. Adverse events consisted in swelling/erythema at injection sites (17 cases), G1–2 haematological (16 cases) and gastro-enteric events (12), fever, rhinitis, conjunctivitis, and poly-arthralgia and rise in auto-antibodies [ANA, ENA, c-ANCA, p-ANCA in the DL1–3 pts]. Both treatment-modules showed immunomodulating and antitumor activity (disease-control-rate, DL1–3 and DL0 were 70.6% and 83.3%, respectively) with a better survival recorded in the second group [median OS DL1–3vs. DL0 = 8vs. 16mo, p = 0.049]. The promising long-term survival produced by the sequential treatment module deserves further phase II evaluation.

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.

In addition to erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP), there are other known inflammatory markers, such as serum amyloid A protein (SAA).1 SAA is an acute-phase reactant transported mainly as an apolipoprotein in high-density lipoprotein, and is primarily synthesized in the liver by activated monocytes and macrophages in response to proinflammatory cytokines. Several cytokines, principally interleukin-6 (IL-6), IL-1 and tumor necrosis factor (TNF), are involved in the induction of SAA synthesis in hepatocytes.2 SAA has been shown to correlate with disease activity in ankylosing spondylitis, and the superiority of SAA to ESR and CRP in this regard has recently been suggested.3,4 The aim of our study was to evaluate the association between circulating levels of SAA and disease activity in patients with juvenile idiopathic arthritis (JIA). Our study group included 41 children (9 males, 32 females) with JIA, classified according to the International League of Associations for Rheumatology (ILAR) criteria.5 Sixteen had polyarticular onset disease and 25 had oligoarticular onset disease. Among 25 patients with oligoarticular disease, three had extended oligoarthritis. No patient had systemic onset disease. Eleven patients with polyarticular and seven with the oligoarticular disease were treated with oral methotrexate; 2 patients with oligoarticular disease were receiving oral sulphasalazine. The remaining patients were treated with nonsteroidal anti-inflammatory drugs only. Twenty-six healthy children (14 male, 12 female) attending our outpatient clinic (Department of Paediatrics, Rheumatology Unit, Anna Meyer Children's Hospital, University of Florence, Florence, Italy) for musculoskeletal pain and without signs of inflammation were enrolled as controls. Table 1 summarizes the baseline demographic characteristics and acute phase reactant circulating levels in the JIA patients and healthy controls. We excluded subjects who had a medical or surgical condition such as recent infection, trauma, and/or a neoplastic disease, in order to remove confounding factors affecting SAA levels. Table 1 Clinical and Demographic Characteristics of Patients SAA serum concentration was determined by a commercial solid phase sandwich Enzyme linked-immuno-sorbent assay (Human SAA; BioSource Europe S.A., Nivelles, Belgium). The assay sensitivity was

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.

Pharmacologic treatment of osteoarthritis has been confined mostly to analgesic or nonsteroidal antiinflammatory drugs that only modify the symptoms. We asked whether anthraquinone-2,6-disulfonic acid might act as a disease-modifying osteoarthritis drug. We evaluated the in vitro inhibitory effect of anthraquinone-2,6-disulfonic acid on cathepsin B activity and proteoglycan release from cultured rabbit cartilage challenged with interleukin-1beta in comparison with diacerhein, the prodrug of rhein. We studied the in vivo activity in an experimental osteoarthritis model induced by medial monolateral meniscectomy in rabbits. After 3 months of treatment with oral anthraquinone-2,6-disulfonic acid or diacerhein at 25 mg/kg/day, the animals were sacrificed and the knees were retrieved; cluster chondrocytes, fibrillations, fissures, and osteophytes were studied on cartilage biopsies. The evidence for disease-modifying activity of anthraquinone-2,6-disulfonic acid was (1) the in vitro dose-dependent inhibition of cathepsin B activity, (2) the in vitro time- and dose-dependent inhibition of interleukin-1beta-stimulated proteoglycan release from the cartilage matrix, and (3) the in vivo reduction of all cartilage degeneration parameters. Our data suggest anthraquinone-2,6-disulfonic acid is worth exploring for treating osteoarthritis.

The efficacy of balneotherapy in fibromyalgia syndrome (FS) has been well demonstrated, while controlled studies using mud packs are lacking. We performed a randomized clinical trial to evaluate the effects and the tolerability of mud-bath treatment in FS patients, who are poor responders to pharmacological therapy. Eighty patients with primary FS, according to ACR criteria, were randomly allocated to two groups: 40 were submitted to a cycle of 12 mud packs and thermal baths, and 40 were considered as controls. At baseline, after thermal treatment and after 16 weeks, patients were evaluated by FIQ, tender points count, VAS for "minor" symptoms, AIMS1 and HAQ. Control patients were assessed at the same time periods. A significant improvement of all evaluation parameters after mud-bath therapy and after 16 weeks was observed. Mud packs were well tolerated and no drop-outs were recorded. Our results suggest the efficacy and the tolerability of mud-bath treatment in primary FS.

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.

Canakinumab is a human IgGκ monoclonal antibody that neutralizes the activity of interleukin (IL)-1β blocking interaction with IL-1β receptors. Our study aimed to evaluate the in vitro effect of canakinumab on human osteoarthritic (OA) chondrocytes cultivated in the presence or absence of tumor necrosis factor (TNF)-α. Articular cartilage was obtained from the femoral heads of patients with osteoarthritis (OA). Chondrocytes were incubated with two concentrations (1μg/ml and 10μg/ml) of canakinumab alone or with TNF-α (10ng/ml) for 48h. We evaluated cell viability, release of proteoglycans (PG) and nitric oxide (NO) in culture medium, inducible nitric oxide synthase (iNOS) and metalloproteinanes (MMP)-1,3,13 gene expression, apoptosis, necrosis and morphological feature by transmission electron microscopy (TEM). Canakinumab alone did not have cytotoxic effect. Cell viability was reduced significantly (p

Spa therapy and short wave therapy are two of the most commonly used non-pharmacological approaches for osteoarthritis. The aim of this study was to assess their efficacy in comparison to conventional therapy in patients with osteoarthritis of the knee in a single blind, randomized, controlled trial. Seventy-four outpatients were enrolled; 30 patients were treated with a combination of daily local mud packs and arsenical ferruginous mineral bath water from the thermal resort of Levico Terme (Trento, Italy) for 3 weeks; 24 patients were treated with short wave therapy for the same period and 20 patients continued regular, routine ambulatory care. Patients were assessed at baseline, upon completion of the 3-week treatment period, and 12 weeks later. Spa therapy and short wave therapy both demonstrated effective symptomatic treatment in osteoarthritis of the knee at the end of the treatment, but only the spa therapy was shown to have efficacy persistent over time. Our study demonstrated the superiority of arsenical ferruginous spa therapy compared to short wave therapy in the treatment of osteoarthritis of the knee, probably in relationship to the specific effects of the minerals in this water.