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Objective: Fibromyalgia (FM) is characterized by the presence of chronic widespread pain throughout the musculoskeletal system and diffuse tenderness. Unfortunately, no laboratory tests have been appropriately validated for FM and correlated with the subsets and activity. The aim of this study was to apply a proteomic technique in saliva of FM patients: the Surface Enhance Laser Desorption/Ionization Time-of-Flight (SELDI-TOF)., Methods: For this study, 57 FM patients and 35 HC patients were enrolled. The proteomic analysis of saliva was carried out using SELDI-TOF. The analysis was performed using different chip arrays with different characteristics of binding. The statistical analysis was performed using cluster analysis and the difference between two groups was underlined using Student’s t-test., Results: Spectra analysis highlighted the presence of several peaks differently expressed in FM patients compared with controls. The preliminary results obtained by SELDI-TOF analysis were compared with those obtained in our previous study performed on whole saliva of FM patients by using electrophoresis. The m/z of two peaks, increased in FM patients, seem to overlap well with the molecular weight of calgranulin A and C and Rho GDP-dissociation inhibitor 2, which we had found up-regulated in our previous study., Conclusion: These preliminary results showed the possibility of identifying potential salivary biomarker through salivary proteomic analysis with MALDI-TOF and SELDI-TOF in FM patients. The peaks observed allow us to focus on some of the particular pathogenic aspects of FM, the oxidative stress which contradistinguishes this condition, the involvement of proteins related to the cytoskeletal arrangements, and central sensibilization.

Objective: Papanicolau (Pap) smear abnormalities are more frequently observed in systemic lupus erythematosus (SLE) respect to the general population. The primary objective of the present study was to evaluate the adherence to cervical cancer (CC) screening in an Italian cohort of SLE patients and, secondly, to evaluate the disease-related factors possibly influencing the patients' behavior., Methods: Consecutive 25 to 64 year old SLE patients and aged- matched healthy women were enrolled for the study. All patients were interviewed during ambulatory visits, at admission to the clinic or by a telephone contact; disease related variables were also collected from the clinical charts., Results: 140 SLE patients (mean age 48.3±12 years) and 70 controls matched for demographic and sociocultural characteristics were enrolled. Ninety-three SLE patients (66.4%) declared to perform the Pap test at least every three years (23.6% yearly and 42.8% when asked by the screening programs) while 47 (33.6%) did not perform regular CC screening (16.4% never did the test and 17.1% only occasionally). No significant differences were observed between patients and controls in cancer screening adherence. No significant associations were observed between the screening program behaviors and disease-related variables., Conclusions: Despite the growing evidence of an increased risk of CC in SLE, and regardless of the broad availability of screening programs and official recommendations, our results show insufficient CC surveillance among SLE patients and emphasize to rheumatologists and/or general practitioners the importance to discuss with patients this aspect during routine evaluations in order to encourage compliance to the recommended preventive measures.

Objectives: To evaluate the long- term outcome of a group of systemic lupus erythematosus (SLE) patients with diffuse proliferative glomerulonephritis (DPGN) treated with pulse steroids and a short course of pulse cyclophosphamide (Cyc) in order to find out baseline predictor variables of disease outcome at the end of the follow-up., Methods: Female SLE patients fulfilling ACR criteria with active DPGN treated with pulse steroids and pulse Cyc were enrolled in the study and retrospectively analyzed with particular interest to renal flares and poor renal outcome at the end of follow- up as outcome measures., Results: 30 female patients with DPGN were included, of these 20 (66,7%) patients are actually in follow-up at our unit, 4 (13.3%) died and 6 (20%) were lost during the follow-up. Fourteen patients (46.6%) presented at least one renal flare (RF) during the follow up for a total of 21 flares. At our last observation, 18 (60%) presented a good renal outcome while 12 (40%) had a poor outcome. Lower age at kidney biopsy resulted an important prognostic factor for the occurrence of both RF and poor long- term renal outcome; additionally, a poor renal outcome resulted significantly correlated with an inadequate response at the end of the protocol and with the number of renal flares after remission., Conclusions: These data suggest that, in general, a short course therapy with Cyc might be effective in controlling disease activity but demonstrated high rate of RF and poor renal outcome over time; however, this protocol might represent an effective therapeutic strategy in a subgroup of patients with specific epidemiological and clinical characteristics and suggest the possibility of tailoring immunosuppressive therapy on the basis of prognostic factor at baseline.

Objective: To develop a set of national evidence-based recommendations for the use of Methotrexate (MTX) in daily clinical practice., Methods: A panel of 37 Italian Rheumatologists reviewed 10 international recommendations formulated during the "3E (Evidence, Expertise, Exchange) initiative" for the year 2007-8, following a systematic literature search in Medline, Embase, Cochrane Library, and 2005-7 American College of Rheumatology/European League Against Rheumatism meeting abstracts and the revision of selected papers and the appraisal of Oxford levels of evidence. Moreover, the same panel by the same methodology formulated further 5 recommendations on topics previously selected by Italian representatives to 3E initiative. The agreement about the set of proposed recommendations was stated by a consensus process and the potential impact on clinical practice was assessed., Results: International Recommendations were analysed and changed when appropriate. In addition, 5 national recommendations were developed by identifying 6371 references, selecting and evaluating the 29 ones satisfying Evidence Based Medicine principles., Conclusions: A set of 15 national recommendations for the use of MTX in daily clinical practice was developed. These recommendations are evidence-based and integrate the expertise of a large panel of Italian rheumatologists.

TNFalpha has a key role in cell recruitment, proliferation and death, expression of adhesion molecules and immune responses. In RA, TNFalpha is involved in matrix degradation and osteoclastogenesis. TNFalpha inhibitors are either soluble receptors (etanercept) or monoclonal antibodies (infliximab and adalimumab; golimumab and certolizumab are in development). TNFalpha antagonists, alone or in combination with methotrexate, reduce bone erosions and thinning of cartilage, but they differ as regards ligand binding, pharmacokinetics, pharmacodynamics, and clinical indications. Etanercept is the only TNFalpha antagonist that also neutralises LFT-alpha. Infliximab and adalimumab are more immunogenic. Cytotoxicity and cellular lysis are also higher with infliximab and adalimumab. Etanercept slows progression of joint damage in recently diagnosed RA when given alone, but much more when given with methotrexate; anti-TNF monoclonal antibodies also were shown to slow progression alone and in combination with methotrexate. Patients with early and long-standing RA treated with etanercept have now shown improvement in ACR scores, inflammation and disability for up to 9 years. Outcomes with infliximab and adalimumab are similar to those with etanercept, but only in combination with methotrexate. As a result of neutralizing antibodies, increasing doses of anti-TNFalpha antibodies may be required to maintain clinical response. As regards side effects, opportunistic infections seem more frequent with monoclonal antibodies. TNFalpha antagonists produce more QALYs than traditional DMARDs, counteracting higher costs. The efficacy, safety, and quality of life benefits of TNFalpha antagonists suggest using them possibly earlier than today, even in clinically moderate RA. Thanks to its overall profile, etanercept might be considered as one of the first-choices in TNFalpha antagonism in RA management.

Objective: This study was aimed at verifying any potential correlation between anti-myeloperoxidase antineutrophil cytoplasmic antibodies (ANCA-MPO) and clinical features and outcome indices in Churg-Strauss Syndrome (CSS)., Methods: Thirty-eight Churg-Strauss syndrome patients were selected from the medical records of all vasculitis patients attending the Rheumatology and Immunology Unit at the Department of Internal Medicine of the University of Pisa in the decades between 1989 and 2008. Data were analysed retrospectively. Statistical analyses of the results were carried out using the Mann-Whitney test to determine the correlations between the clinical and serological parameters. Qualitative variables were compared using contingency table analysis and Fisher's exact test., Results: ANCA-MPO were detected in15/38 (39%) patients. Positive ANCA status was associated with peripheral neuropathy (p=0.0006), whereas negative ANCA status was associated with lung involvement (p=0.002). Relapses were strongly associated with positive ANCA status (p=0.01) and with an increase in- or a reappearance of ANCA-MPO levels (p=0.006). Finally, ANCA-MPO were significantly associated with neurological damage (p=0.003)., Conclusions: The presence or absence of ANCA-MPO identify different clinical subsets in CSS. Overall, ANCA-MPO appears as a useful tool in the monitoring of CSS and in particular a good predictor of CSS relapses.

Objective: Interstitial lung disease (ILD) and pulmonary arterial hypertension (PAH) are common complications of systemic sclerosis (SSc). Echocardiography evaluates PAH, and chest sonography detects even mild ILC as ultrasound lung comets (ULC), i.e. multiple comet-tails fanning out from the lung surface and originating from subpleural interlobular septa thickened by fibrosis., Aim: to assess ILaD and PAH by integrated cardiac and chest ultrasound in SSc., Methods: We enrolled 30 consecutive SSc patients (age= 54+/-13 years, 23 females) in the Rheumatology Clinic of Pisa University. In all, we assessed systolic pulmonary arterial pressure (SPAP), from maximal velocity of tricuspid regurgitation flow, and ULC score with chest sonography (summing the number of ULC from each scanning space of anterior and posterior right and left chest, from second to fifth intercostal space). All patients underwent plasma assay for anti-topoisomerase antibodies (anti-Scl70), and antiicentromere associated with development of pulmonary involvement. Twenty-eight patients also underwent high resolution computed tomography, HRCT (from 0= no fibrosis to 3= honey combing)., Results: ULC number - but not SPAP - was correlated to HRCT fibrosis and presence Scl-70 antibodies. ULC number was similar in localized or diffuse forms (16+/-20 vs 21+/-19, p=ns) and was unrelated to SPAP (r=0.216, p=ns)., Conclusions: Chest sonography assessment and ULC allow a complete, simple, radiation-free characterization of interstitial lung involvement in SSc - all in one setting and with the same instrument, same transducer and the same sonographer. In particular, ULC number is associated with HRCT evidence of lung fibrosis and presence of Scl-70 antibodies.

Objective: Hypereosinophilic syndromes are a heterogeneous group of uncommon disorders characterized by the presence of marked peripheral blood eosinophilia, tissue eosinophilia, or both, resulting in a wide variety of clinical manifestations, often without an identifiable cause. Churg-Strauss syndrome is a systemic vasculitis characterized by prominent peripheral eosinophilia, asthma and systemic involvement. The presence of mild to severe eosinophilia and systemic involvement raise the search of many trigger factor that need to be ruled out. Distinguishing CSS from idiopathic hypereosinophilic syndrome may be particularly challenging, especially in ANCA negative patients., Methods: The aim of the present study was to present a small case series of patients referred to a Rheumatology Unit for mild to severe eosinophilia and signs and symptoms of systemic involvement and to outline the clinical significance of molecular biology in the work-up of hypereosinophilia., Results: Eleven patients with moderate to severe peripheral eosinophylia, were referred to our Unit from 1996 to 2007. Female to male ratio was 7/4, mean age 40.54 (range 22-75). Three out of eleven patients resulted positive for molecular biology. The diagnosis of idiopathic hypereosinophylia was confirmed in one out of three on the basis of the clinical picture and bone marrow biopsy., Conclusions: Molecular biology may be useful in the screening and in the follow-up of a new hypereosinophylic patient.

Objective: To analyse FN gene polymorphisms in type II mixed cryoglobulinemic syndrome (MCsn), an immune-complex mediated systemic vasculitis linked to hepatitis C virus (HCV) infection and characterized by rheumatoid factor (RF) positive B-cell proliferation at high risk for the progression into non Hogkin's lymphoma (NHL)., Methods: Samples from eighty-one patients, with MCsn (type II serum cryoglobulins and clinical signs of vasculitis were studied. Sixty-five (65/81, 80.3%) patients were HCV-positive. Twenty-one (25.9%) patients had developed a B-cell NHL during the course of MCsn. Seventy-two patients with HCV-negative and MC-unrelated NHL and 110 healthy blood donors (HBDs) were taken as controls. HaeIIIb and MspI FN gene polymorphisms were analysed by ELISA, whenever possible., Results: HaeIIIb and MspI allele and genotypic frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI allele and genotype frequencies did not differ between MCsn patients and HBDs. Of note, the DD-MspI (OR = 5.56; DI = 1.67-18.51, p = 0.0046) and the AA-HaeIIIb (OR = 5.54, CI = 1.64- 18.76, p = 0.0066) homozygosis appeared significantly and independently associated with the development of B-cell NHL in MCsn patients, with the HaeIIIbA allele possibly conferring an increased risk of NHL in the general population (OR = 1.72, CI = 1.128-2.635, p = 0.0133). In contrast, the major vasculitic manifestations, such as peripheral neuropathy, skin ulcers and glomerulonephritis tended to be associated with the counterpart MspI C allele. No association between FN plasma levels and FN genotypes was found., Conclusion: Genotyping for MspI and HaeIIIb FN gene polymorphisms may be clinically relevant to define the predisposition to the major clinical manifestations in MCsn.

The term undifferentiated connective tissue diseases (UCTD) is used to identify systemic autoimmune diseases not fulfilling classificative criteria for defined connective tissue diseases (CTD). Aim of the present study was to evaluate the evolution to defined CTD of an historical cohort of 91 UCTD patients followed at our Unit and to describe clinical and serological characteristics of stable UCTD patients with a disease duration of more than 5 years. Patients, previously described, were selected for having an undifferentiated profile after 1 year of follow up. These patients have been regularly followed at our Unit and their diagnosis has been reassessed annually based on the existing classificative criteria. Seven UCTD patients with a follow up of less than 5 years have been excluded from the study, therefore 84 patients (F: 81, M: 3) have been analysed. During the follow up 28 patients (33%) developed a defined CTD. In particular 22 patients developed systemic lupus erythematosus (SLE), while the remaining 6 patients developed other CTDs (2 primary Sjögren's syndrome, 2 overlap syndromes, 1 Systemic Sclerosis, 1 rheumatoid arthritis). The evolution to a defined CTD occurred after a mean disease duration of 80.6+/- 66.8 months (min 14, max 336, median 72); the evolution to SLE occurred after a mean disease duration of 66.8+/-43.3 months (min 17, max 216, median 57). Anti-cardiolipin antibodies were the only variable correlated with the evolution to SLE (p<0.05). Stable UCTD were characterized by a simplified clinical picture with no major organ involvement and by a simplified autoantibody profile (anti-Ro/SSA antibodies and anti-RNP antibodies were the single antibody specificities observed in 22% and 13% of patients respectively). These results confirm previous data showing that about 30% of UCTD patients will develop a defined CTD, the predictive role of anti-cardiolipin antibodies for the evolution to SLE, and the existence of stable UCTD, distinct clinical entities with a simplified clinico-serological profile. The early identification of stable UCTD is very important both from a clinical and a research point of view. Future research is needed to define a new set of classification criteria.

The recommendations for the management of osteoarthritis (OA) of the hip were proposed by EULAR in 2005. Among the most important objectives of the expert charged to provide these recommendations were their wide dissemination and implementation. Thus, the information generated can be used by each individual country to produce their own set of management guidelines and algorithms for treatment in primary care. According with that previously executed for the EU-LAR recommendation 2003 for the knee, the Italian Society of Rheumatology (SIR) has organised a Consensus on the EULAR recommendations 2005 for the management of hip OA. To obtain an acceptability as large as possible, the group of experts was composed by many physicians interested in the management of hip OA, including Orthopaedics, Rheumatologists, Physiatrists, and General Practitioners. Main aim of the Consensus was to analyse the acceptability and applicability of the recommendations according to own experience and local situations in the Italy. The results of this Consensus have demonstrated that a large majority of the EULAR recommendations are endorsed by the Italian experts. Furthermore, the final document of the Italian Consensus clearly indicated the need that the specialists involved in the management of hip OA strongly encourage the dissemination of the EULAR 2005 recommendations also in Italy.

Objective: Cardiovascular complications, mainly caused by an accelerated atherosclerosis, are one of the leading causes of death and disability in patients with systemic autoimmune diseases. Endothelial dysfunction is considered the earliest and reversible step of atherogenesis. Aim of the present study is to investigate endothelial function (EF) in patients with systemic lupus erythematosus (SLE), undifferentiated connective tissue diseases (UCTD) and correlate the results with clinical and laboratory variables., Methods: EF was assessed on the peripheral microcirculation by the perfused forearm technique that can estimate both endothelium- dependent and endothelium- independent vasodilatation. The same evaluation has been repeated in two patients after the administration of 20 mg of 6-metilprednisolone., Results: Twenty-three female patients with SLE or UCTD, with a follow up of at least 1 year have been studied and compared with 8 healthy controls matched for epidemiological variables and traditional risk factors for cardiovascular disease. A significant reduction both in endothelium dependent than endothelium independent vasodilatation was observed in both patients groups compared with controls. In addition, UCTD patients demonstrated a significant reduction in the nitric oxide pathway compared with controls and SLE patients. Finally, steroid administration induced an improvement of vascular reactivity., Conclusions: Despite the well documented side effects of chronic corticosteroid therapy, our data might suggest a role for antinflammatory and immunosuppressive therapy in the prevention of premature atherosclerosis in patients with systemic autoimmune diseases.

Objective: To describe clinical and serological features of a large series of patients affected by primary Sjogren's syndrome (pSS), assessing the evolution of the disease in a long-term follow-up study., Methods: Clinical and laboratory data of 250 patients with pSS attending our Unit for a mean follow-up period of 140 months were retrospectively collected and analysed. In all the cases the diagnosis was made according with the recent international criteria., Results: Glandular involvement was almost universally present, typically as the first manifestation of the disease and a slow progression of the salivary and lachrymal dysfunction was seen during the observation period. Extraglandular involvement was mild, quite rare and delayed. The respective percentages for muscle-skeletal disease, urogenital, haematological, skin, pulmonary, gastrointestinal, neurological and renal involvement were 60%, 40%, 24%, 20%, 11%, 7%, 8% and 3%. Only 6 patients developed a lymphoma. The serological pattern of the majority of patients remained constant throughout the follow-up period., Conclusions: pSS is often a benign condition. Since some patients may develop lymphoid malignancies, clinical follow-up is recommended.

The commercially available inhibitors of TNF are constituted by two classes of molecules: the soluble receptors (Etanercept: Amgen Inc. Wyeth) and the monoclonal antibodies (Adalimumab: Abbott Laboratories and Infliximab: Centocor, Inc.). The differences in their molecular structure, mechanism of action, pharmacokinetics (PK) and pharmacodynamics (PD) are discussed, along with the differences concerning dose, administration regimens, drug concentrations and pharmacological interactions. In order to explain the clinical differences observed when these agents are used in the "real world", which can arise from the respective PK characteristics (kinetics, route and frequency of administration, type of TNF binding, effects on cytokines) and PD responses and peculiar mechanisms of action, with distinctive immune function (LFTα inactivation; apoptosis induction, TNF immunoprecipitation, C1q binding and CDC induction; Fcγ cross-linking and ADCC induction), the dynamics of interaction of the two classes of neutralizing molecules with TNF, and the ability in restoring TNF homeostasis, are outlined.

Aim: Many theories have been proposed as to the relationship between fibromyalgia (FM) and temporomandibular disorders (TMD). The aim of this study was to investigate the clinical features of the involvement of the stomatognathic system in patients with fibromyalgia, and to compare signs and symptoms of masticatory dysfunction between TMD and FM patients., Methods: The study sample consisted of 30 subjects with fibromyalgia recruited at the Rheumatology Disease Department, University of Pisa, Italy, and of 30 with temporomandibular disorders at the Section of Prosthetic Dentistry, Department of Neurosciences, University of Pisa, Italy. Masticatory dysfunction has been compared between the 2 groups by means of a clinical assessment conducted according to the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD). Patients of the TMD group underwent a rheumatologic examination to investigate for the presence of previously undiagnosed fibromyalgia., Results: As regards specific clinical variables and RDC/TMD diagnoses, differences between the 2 groups appear to be not relevant, with the exception of the values of mouth opening, both voluntary and passive, and the presence of trigger points. FM patients showed a decrease in both maximum voluntary and passive mouth opening which was about 2 mm worse than that recorded in TMD patients. FM patients also showed a significantly higher number of trigger points, even though muscle palpation evoked tenderness in the same number of sites in the 2 groups., Conclusions: This study showed that most patients with fibromyalgia (86.7%) report signs and symptoms localized at the stomatognathic system; by contrast, only a minority of patients with temporomandibular disorders (10%) are actually affected by fibromyalgia.

Objectives: To evaluate the characteristics of pain in a cohort of Italian patients with osteoarthritis (OA) of the hip and knee., Methods: The 657 general practitioners participating in the study were asked to enroll 10 consecutive patients with OA diagnosed according to the American College of Rheumatology (ACR) clinical criteria. A questionnaire evaluating demographic data, clinical characteristics of OA, including the "Questionario Semantico Reumatologico" (QSR) pain questionnaire, the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the Lequesne indices, and information on previous diagnostic and therapeutic interventions was administered., Results: A total of 4,109 patients were enrolled. Of them, 2356 were affected by knee OA and 1817 by hip OA. There were 2863 (69.7%) women and 1246 (30.3%) men. Median age was 68.2 years (range 50-103 years). Of the 4109 enrolled subjects, 3128 (76.1%) reported one or more medical comorbidities, mostly cardiovascular (52.7%), endocrinological (14.7%), gastrointestinal (13.4%), and respiratory (11.2%) disorders. The median pain visual analogue scale (VAS) score was 58.1+/-22.6 mm, higher in women (60.2+/-22.3 mm) than in men (53.3+/-22.6mm) (p<0.00001). OA pain was also higher in patients from Southern Italy (p<0.00001). NSAIDs were administered to nearly 70% of patients, COX-2 inhibitors to 55%, disease-modifying anti OA drugs to 19% and analgesics to 28.2%. Differences in drugs utilization were associated with OA localization and patient's geographical origin. Results of the WOMAC index were similar throughout groups. Responses to the QSR pain questionnaire showed differences, which are related to OA localization and geographical origin of the patients., Conclusions: The MI.D.A. study can help to better understand the patterns of pain in osteoarthritis and the associated treatment.

The idiopathic inflammatory myopathies (IIM) comprise a group of diseases characterized by chronic inflammation of the skeletal muscles. The definition of the long-term outcome of IIM, has been limited by the difficulty in objectively evaluating the rate of muscle function impairment. Aim of our study, was to define the long term outcome in a group of 37 IIM patients, followed at our centres between 1979 and 1999. A protocol, evaluating CK levels, muscle function, and disability in daily life activity was prospectively designed. The disease outcome was defined on the basis the patient's functional evaluation. Disease activity was defined as the presence of an increase in serum CK levels associated with an increase of therapy. At the end of follow up, 27% of the patients had an active disease and 35% had a poor functional outcome. On the basis of our results we could distinguish three different outcomes of IIM: (i) good functional outcome (65%); (ii) poor functional outcome with inactive disease (13.5%); (iii) poor functional outcome and active disease (21,5%). In conclusion, although IIM seem to have a good evolution in terms of disease activity, in about 46% of patients they are associated with an elevated incidence of functional impairment, probably attributable both to the disease's damage and to the side effects of therapy.

In the last decade the possible role of dietary therapy in the treatment of different rheumatic diseases has undergone serious reconsideration. Elimination diets may be useful in a subgroup of patients with rheumatoid arthritis, in whom food antigens probably play an important role in the onset and perpetuation of the inflammatory process. In mixed cryoglobulinemia a low-antigen-diet might reduce the amount of macromolecular food antigens which cross the mucosal barrier of the gut and cause either an immune response and/or compete with the immune complexes in the mononuclear phagocytic system. Supplementing the diet with essential fatty acids (omega-3 and/or omega-6) may inhibit the production of some of the mediators of inflammation, such as leukotriene-B4 and interleukin-1. However, currently employed doses often result in only modest or moderate clinical improvement. Controlled studies in a larger number of patients and with differentiated treatment protocols are needed to establish to what extent dietary therapy may improve the course of different rheumatic diseases, and to determine whether this therapy might be used in association with or even substitute for other well recognized treatments.

The Authors report their favourable experience concerning the treatment of five cases of connective tissue diseases with high-dose intravenous immunoglobulins: three cases of systemic lupus erythematosus with nephritis, hematological involvement and fever; one case of antiphospholipid antibody-associated pregnancy; and one case of juvenile dermatomyositis. Disease manifestations had proved refractory to previous conventional and sometimes aggressive therapies in all the patients. The results obtained are discussed on the basis of more recent data from the literature. Further investigation in the treatment of connective tissue diseases with intravenous immunoglobulins is suggested. However, this therapy should be employed only in carefully selected patients.