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Nailfold capillaroscopy (NVC) is a simple and non-invasive method used for the assessment of patients with Raynaud's phenomenon (RP) and in the differential diagnosis of various connective tissue diseases. The scleroderma pattern abnormalities (giant capillaries, haemorrages and/or avascular areas) have a positive predictive value for the development of scleroderma spectrum disorders. Thus, an analytical approach to nailfold capillaroscopy can be useful in quantitatively and reproducibly recording various parameters. We developed a new method to assess patients with RP that is capable of predicting the 5-year transition from isolated RP to RP secondary to scleroderma spectrum disorders. This model is a weighted combination of different capillaroscopic parameters (giant capillaries, microhaemorrages, number of capillaries) that allows physicians to stratify RP patients easily using a relatively simple diagram to deduce prognosis.

Background: Puberty is an essential step in bone mass accrual. Growth failure and impairment of sexual maturation are frequent manifestations of chronic illnesses in the paediatric population, and chronic rheumatologic disorders such as juvenile idiopathic arthritis (JIA) are no exception to this., Methods: The aim of our study was to prospectively evaluate bone density in adolescent females with JIA, and to correlate the results with clinical variables, in particular with age at menarche. Lumbar spine (L2-L4) area bone mineral density (aBMD) (assessed by Dual X-ray Absorbiometry, DXA) was monitored every 6-12 months in a group of 38 girls with JIA. The evaluated bone density accrual during the peripubertal time as well as absolute and relative (Z-score) aBMD in relationship with age at menarche, JIA subset, disease activity (as evaluated by ESR and Hgb), corticosteroid and methotrexate treatment (mean pro kg daily dose, cumulative dose) was assessed. Height, body mass index (BMI), bone mass content (BMC) values were also collected. Volumetric BMD (vBMD) evaluated with a geometric correction formula has been calculated and compared to aBMD., Results: Patients were divided into two groups: - group I included girls with menarche age within normal limits for Italian standards; - group II included girls with delayed menarche. The BMD values and Z scores in group I were not significantly different to normal population. The BMD values and Z scores in group II were significantly decreased when compared to the normal population (p<0.001). With a multivariate analysis only age at menarche seemed independently related to peripubertal mineralization (p=0.025, r between -0.65 and -0.75). With a binary logistic analysis only disease activity (ESR and Hgb values) seems independently related to a menarche delay (1.24+/-0.4 for each mm/h)., Conclusion: Our data show a critical role for disease activity in determination of a regular pubertal onset and an optimal bone density achievement.

The therapeutic approach to JIA is sometimes very troublesome and progression to erosive polyarthritis may occur in all JIA categories. Only Methotrexate has shown efficacy and safety in a large controlled trial. Nevertheless, in many cases, drug resistance or intolerance has led to try other therapeutic options, with still debatable results. Therefore, there has been space, in the last few years, for new therapies as the TNF-inhibitors. This therapeutic approach has shown a dramatic clinical benefit in active polyarticular refractory JIA: the rate and rapidity of response have exceeded those of all other studied DMARDs. Preliminary data show that they are efficacious also for other pediatric rheumatic disease (spondyloarthropathies, autoimmune uveitis, dermatomyositis, Kawasaki syndrome and some autoinflammatory diseases). TNF-inhibitors in JIA have demonstrated a favourable benefit-to-risk profile. However, as their use has increased worldwide, some unusual, usually not serious, adverse events have emerged. Severe infections, including TB, and deaths have been reported. Long-lasting active disease, systemic disease, concurrent and previous immunosuppressive therapies, all contribute to risk of infection and other serious AEs. Given the evidence that TNF has a primary role in the pathogenesis of JIA, particularly in joint destruction, neutralizing this cytokine early, within the window of opportunity, could halt or delay progression of joint damage and debilitating consequences of the disease. Thus, for JIA patients whose disease is not quickly controlled with MTX, TNF blockers may be considered as first-line treatment, although long-term safety data still need to be established.

Arthroscopy is a mini-invasive technique that allows the direct observation of the joint cavity and the execution of diagnostic and therapeutic procedures; arthroscopy needs a very long learning-time curve as well as dedicated spaces and instruments. Ultrasonography is an imaging technique that enables to perform an immediate extension of the standard physical examination. The opportunity to visualize soft tissues, to obtain multiplanar and dynamic images in real time makes this practice easy repeatable at low costs. Ultrasonography allows to detect a variety of changes during inflammatory processes. The wide experience in arthroscopy of rheumatic patients acquired through the years by our team at the G. Pini Institute led us to study in vivo, during arthroscopy, the correspondence between arthroscopic and ultrasonographic images. Up to now three knee arthroscopies have been conducted with the double equipment (ultrasonographic and arthroscopic devices) in operating room. In our experience, the combination of the two methods in operating room may improve the validation of ultrasonography with arthroscopy as gold standard, helps to train the ultrasonographer to give immediate answers in order to clear the doubts aroused by ultrasonographic images; it also allows the arthroscopist to visualize the deeper layers of the synovial membrane making double guided targeted biopsies possible. Limits are the complexity of the procedure (instruments, operators, spaces, training of the doctors), the loose of power-doppler signal with the blood tourniquet and the always difficult evaluation of cartilage.

Objectives: To evaluate, in long-term open label prospective study, infliximab as therapeutic choice for Juvenile Idiopathic Arthritis (JIA) non responsive to conventional therapy., Methods: We enrolled to treat with infliximab 78 JIA patients (66 females, 12 males): the mean age was 20.7+/-7.1 years (median 20.9, range 5.4-34.9); mean JIA duration was 13.6+/-7.6 years (median 13.5, range 0.4-31.4). Infliximab, at dose of 3-10 mg/kg/infusion added to weekly subcutaneous Methotrexate or other previous DMARDs, was administered by intravenous infusions at weeks 0, 2, 6 and every 8 weeks thereafter. Chest X-ray, Mantoux's test, electrocardiogram were performed at baseline; laboratory tests and clinical evaluation were performed at each infusion. Response was evaluated according to ACR improvement criteria., Results: Mean treatment period was 21.6 months+/-18.8 (median 14.7, range 1.4-72.4). Just after first infusion most of patients reported significant improvement in pain, fatigue, morning stiffness. Infliximab is still successfully administered to 23 patients (29.5%); 55 (70.5%) patients suspended because of: inefficacy (7), infusion reactions (17), adverse events (9), disease flare-up after a period of effectiveness on synovitis, pain, and morning stiffness (19), remission (2), lack of compliance to treatment (1). Infusion reactions, like dyspnea, flushing, chills, headache, hypotension, anxiety, throat oedema, were observed in 29 patients (34.5%). Anti-DNA antibodies were present in 7 patients (none developed Systemic Lupus Erythematous)., Conclusions: Infliximab showed impressive effectiveness treating refractory JIA, although most of patients had to discontinue treatment because of disease flare-up or adverse events. Infliximab may represent a good therapeutic choice in patients non-responders to Methotrexate.

Objectives: To report adverse events registered in our population affected by JIA and treated with anti-TNFalpha blockers., Methods: Ninety-five patients were enrolled to be treated with Etanercept, median age 14 years (range 4-34); median duration of therapy 12 months (range 1-40). 19 patients were also treated with MTX (median dose 12.5 mg/week). Fifty-six patients were enrolled to be treated with Infliximab associated with MTX (median dose of MTX 8.8 mg/week), median age 23.2 years (range 7.8-34.9); median duration of therapy 20.1 months (range 1.4-60.4). All adverse events were divided in definitely, probably and possibly related to the biologic agent., Results: Side effects definitely related to Infliximab were the reactions to infusions and the Anti-dsDNA positivity. Side effects definitely related to Etanercept were severe headache and thrombocytopenia. Side effects probably correlated to both the biological agents were behavioural modifications and pain amplification syndrome. Probably correlated to the treatment with Etanercept was the onset of Crohn's disease in 3 patients. Possibly correlated to the biological agents were the new onset or flare-up of Chronic Iridocyclitis and single cases of thyroideal cancer, hypoglossal nerve paralysis and a severe Cytomegalovirus pulmonary infection. No case of tuberculosis infection was registered during this study., Conclusions: Treatment with a TNFalpha antagonist seems to be associated with various adverse events. Some of them, like onset of Crohn's disease, behavioural modifications are unusual and others, like pain amplification syndrome were never described before. Children and young adults affected by JIA should be monitored very carefully so as to limit as much as possible the risk of serious side effects on anti-TNFalpha therapy.

Background: Recently, several studies have demonstrated the presence of circulating endothelial progenitors (CEPs) responsible for angiogenesis. Notably, these cells are able to migrate to ischemic tissues and differentiate in situ in mature endothelial cells. Aim of this study was to assess the presence of CEPs in the peripheral blood of patients with Sistemic Sclerosis (SSc) and evaluate their significance as an attempt of re-vascularization, Material and Methods: Samples of peripheral blood from 40 healthy subjects and 56 patients with SSc were studied. Five-parameter, 3-color flow cytometry was performed with a FACScan. CEPs were defined as CD45 negative, CD34 and CD133 positive. In addition, plasma levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) were detected by commercial ELISA (R&D Systems)., Results: Levels of CEPs (CD133+/CD34+/CD45-) were significantly higher in patients with SSc in comparison to HC (P = 0.01). No correlation was found between CEPs and any clinical parameter of disease neither activity score. CEPs were significantly higher in the group of patients with early disease, while their number decreased in the late phases of disease. Plasma levels of VEGF, but not bFGF, were significantly higher in SSc in comparison to HC (P<0.001) but no correlation was found between VEGF concentrations and CEP number., Conclusions: The presence of CEPs in patients with SSc suggest that sclerodermic hypoxic tissues could induce the mobilization of bone-marrow derived cells in an attempt to provided new vessels, in the early phase of the disease, at least.

Objective: About 65% of children suffering from juvenile idiopathic arthritis (JIA) shows a more or less marked involvement of temporo-mandibular joint (TMJ) with altered mandibular growth, resorption of the condyles, occlusary instability, reduced chewing ability and facial dysmorphia. The purpose of our study is to prevent and to treat the progressive evolution of JIA on craniofacial growth and morphology with a functional appliance; surgery should be considered only in so far as the adequacy of TMJ movement is concerned., Methods: From 1992 until now 72 children with proved JIA and TMJ involvement have been treated (50 females, 22 males, aged 6 to 16 years old). TMJ involvement was bilateral in 61% and unilateral in 39% of patients. A diagnostic workup was carried out involving tomograms of TMJ and cephalometric radiograph and analysis. The authors used a bimaxillary activator in the attempt to modify the unfavourable growth pattern and provide a gradual ante-rotation of the jaw., Results: Almost all JIA patients showed satisfactory long term results, easing of pain, reduced skeletal discrepancy, increased function and good facial profile., Conclusions: The long term results of this study indicate that orthopaedic therapy might control the vicious circle of the malocclusion in children with JIA, preventing exacerbation of mandibular clockwise rotation. Surgical intervention for the improvement of TMJ function should be considered only if a severe restricted state is imminent.

Objective: Circulating endothelial cells (CECs) have been described in different conditions with vascular injury. Vascular abnormalities play a key role in the pathogenesis of Systemic Sclerosis (SSc). The aim of our study was to look for the presence of CECs in SSc patients and to evaluate their clinical significance., Methods: We studied 52 SSc patients and 40 healthy controls (HC). Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD31 and P1H12 positive, and activated CECs as CD45 negative and P1H12, CD62, or CD106 positive., Results: Total and activated CEC counts were significantly higher in SSc patients when compared with HC and positively correlated with disease activity score. We found a significant association between CECs and disease activity; as regard with organ involvement, CEC number correlate with the severity of pulmonary hypertension., Conclusions: Raised counts of CECs may represent direct evidence of active vascular disease in SSc as regard as visceral involvement, the association between CECs and pulmonary hypertension suggest a relevant role for CECs as a marker of prominent endothelial involvement.

The author commemorates, in the 20th year since his death, Camillo Benso Ballabio, unforgettable figure of rheumatologist, renowned clinician, man of great culture. The most important stages of his life are described, by adding to the biographical sketches some quotations that confirm the intellectual depth of such a protagonist of the history of the Italian rheumatology.

Aims: It is increasingly important to determine the economic consequences of diseases considering the policy of limited health-care budgets. In this study we evaluated the annual direct and indirect costs of Systemic Sclerosis (SSc) and we tried also to identify any cost predictors., Methods: We studied 106 patients (103 female, 3 male), 57 affected by Limited Systemic Sclerosis (LSSc) and 49 affected by Diffuse Systemic Sclerosis (DSSc). Mean age was 57 years (SD +/- 13.8) and mean disease duration was 8,9 years (SD +/- 7.2). Direct Costs: data were calculated referring to DRG (Disease Related Group) expenses for the in-patients. We referred to national pharmacopoeia to calculate the pharmaceutical cost for the out-patients. Indirect costs: we estimated the expense comparing our cases to literature data. Intangible costs: these are attributable to pain and psychological suffering. It is very difficult to express the intangible costs in monetary terms and they are often conveyed as disability and poorer quality-of-life. We used the Health Assessment Questionnaire "HAQ" and the Short Form-36 "SF-36" to evaluate this issues., Results: Our study confirms, the extremely high costs caused by Systemic Sclerosis (total cost's 2001 year is 1,173,842.93 Euro, and average yearly patient cost is 11,073.99 Euro). Considering an estimated prevalence of 375 cases/106, the total yearly economic impact of SSc in Italy should be 249 million euro. Intangible costs were calculated as modifications of the health status. Average value of the HAQ was significantly higher than the control population (0.94 +/- 0.72), average values in the SF-36 were significantly lower than the control population (49.99 +/- 19.16 for physical dimension and 58.42 +/- 27.71 for mental dimension). The diffuse form of SSc, anti-Scl 70 antibodies, high skin score and a poor health status (HAQ and SF-36) were found to be cost predictors., Conclusions: As reported in the literature, our study confirms, the extremely high costs for total and single patients caused by Systemic Sclerosis. The DSSc are more expensive than the LSSc approximately 11% (p=0.0067). The direct costs are 30% higher in the DSSc than the LSSc (p < 0.001). The indirect and intangible costs are not significantly different. Moreover, our study shows also the possibility of identifying different cost predictors.

Objective: to evaluate the prevalence and clinical significance of anti-chromatin antibodies (Abs) in juvenile rheumatoid arthritis (JRA)., Methods: IgG anti-chromatin Abs were detected by an enzyme-linked immunosorbent assay (ELISA), in sera of 94 children with JRA (10 children with systemic, 38 with polyarticular and 46 with oligoarticular disease onset). As control group, 33 age- and-sex-matched healthy children (HC) were also examined., Results: Abs to chromatin were detected in 24/94 (25.5%) of children suffering from JRA. Particularly, the higher prevalence of anti-chromatin Abs has been found in children with oligoarticular (30,4%) and polyarticular (23.7%) onset JRA. In these groups Abs titers were significantly higher compared to systemic JRA and HC (p=0.003). Anti-chromatin Abs were observed more frequently in patients with oligoarticular disease and chronic uveitis (21.7%). Furthermore, higher levels of anti-chromatin Abs has been found in all the patients treated with anti-TNF-alpha therapy (p< 0.0001)., Conclusions: our results confirm previous data about the prevalence of anti-chromatin Abs in JRA. These Abs were significantly higher in the group of patients with oligoarticular onset with past or present history of ocular involvement and in the group with polyarticular JRA treated with biologic therapy. A long-term follow-up study could be useful to evaluate the potential utility of these autoantibodies.

By now many authors regard arthroscopic synovectomy an integral part of therapeutic treatment of many rheumatic diseases with favourable results on post operating course and clinical picture in the long term. The pathologic synovial tissue during articular inflammatory rheumatism is well known to have a damaging effect responsible of early cartilage injury, as well as symptomatic action (e.g. articular stiffness, effusion, pain, functional limitation). Therefore to value the removal of such a tissue you should think of the secondary prevention of cartilage injury, besides the symptomatic point of view. Since 1996 we performed 190 arthroscopic synovectomy, the adopted criteria of judgement were: pain (spontaneous, during active and passive movements), effusion or swelling presence, articular range and cartilage state (evaluated during arthroscopy according to Outerbridg's classification). 70% of the cases showed good results and six years later the beginning of this activity we retain arthroscopic synovectomy as a valid help in articular inflammatory rheumatism treatment.

Aims: To evaluate the quality of life of patients affected by systemic sclerosis (SSc) through the application of the Medical Outcome Survey Short-Form 36 (SF-36) questionnaire and to correlate the results with the disability index of the health assessment questionnaire (HAQ-DI) and the systemic involvement., Methods: We studied 95 (3 M, 91 F) patients affected by SSc (mean age 60 years, range 39-83, mean duration of disease 6 years, range 1-34). The organ system involvement was evaluated by skin score, chest High Resolution Computed Tomography (HRCT), electrocardiography according to Holter, Doppler-echocardiography and esophagogram., Results: Considering the values of the 8 question groups of the SF-36 the most different between the patients and the control population are the values relevant to the physical dimension. The general health values estimating the physical and social dimension are significantly lower in the patients than in the control population (t=9,324; p<0,0001). A very good correlation was found between the DI (r = -0,7903; p <0.0001) and all the scores of SF-36. The skin involvement showed a statistically significant correlation with the DI (r=0.3709; p=0.0002) and the PA score of the SF- 36 (r =0.2853; p=0.0051). No other statistically significant correlation was found between any of the SF-36 dimensions and involvement of a specific organ., Conclusion: SF-36 showed to be a valid instrument to evaluate the quality of life and the disability of patients with SSc and it seems to correlate with extent of skin involvement.

Chemokines play a central role in the pathogenesis of rheumatoid arthritis (RA) synovitis which is characterised by new blood vessel formation, thickening of the lining layer and infiltration of immune cells. The inflammatory infiltrate is generated by a series of events which include the recruitment of leukocytes from the blood stream into the tissue, their local retention and activation to effector cells. All these processes are finely regulated by the interplay of different cell adhesion molecules (CAMs) and chemoattractant factors called chemokines (CK). CK are a superfamily of small proteins that play a crucial role in immune and inflammatory reactions. These chemoattractant cytokines share structural similarities including four conserved cysteine residues which form disulphide bonds in the tertiary structure of the proteins. CK mediate their effects by binding specific receptors (CK-R) characterised by a domain structure which spans the cell membrane seven times and signal through heterotrimeric GPT-binding proteins. Activation of the CK network results in an amplification of the inflammatory cascade and consequently in the progressive destruction of RA joints. The recognition of the central role of CK in inflammation has paved the way to the development of new agents capable of interfering with CK and CK-R. This review will focus in particular on the role of CK in regulating leukocyte trafficking in RA joints.

OBJECTIVE: The aim of the study was to investigate the relationship between Systemic Sclerosis (SSc) and HLA antigens, and to correlate these antigens with the clinical manifestations of the disease. MATERIALS AND METHODS: 55 patients were stratified according a) to the cutaneous involvement b) to the positivity of Scl-70 and anticentromere antibody and c) to the internal organ involvement, in particular we used HRCT to demonstrate lung fibrosis, echocardiography for the diagnosis of pulmonary hypertension, blood creatinine, urinalysis and arterial hypertension to demonstrate renal failure, and esophagus double-contrast barium swallow for the diagnosis of esophagopathy. The control group consisting of 2000 healthy Caucasian subjects was recruited from the same population. RESULTS: The frequency of the antigens A23 (p=0.003, RR=3.69), B18 (p<0.0001, RR=3.57), and DR11 (p<0.0001, RR=6.18) was statistically increased in the patients population compared with the healthy controls. Although there is no any significant correlation between HLA antigens and different clinical subsets of scleroderma, antigens B18 and DR11 could be associated with more severe clinical features. CONCLUSIONS: The presence of a significant association between SSc and specific HLA antigens (A23, B18, and DR11) could link the HLA system with SSc.