Ultrasound detects joint damage and bleeding in haemophilic arthropathy: a proposal of a score.

Haemarthrosis triggers haemophilic arthropathy (HA) because bleeding starts synovitis immediately, damages cartilage and leads to loss of function and disability. The aim of our study was to investigate the capacity of ultrasonography (US) in detecting bleeding and joint damage in HA. The joints of 62 patients (pts) with haemophilia A or haemophilia B were consecutively evaluated and scored (score ranging from 0 to 21) for effusion (E), bone remodelling (BR), cartilage damage (CD), synovial hypertrophy (SH), haemosiderin (H), osteophytes (O), haemarthrosis (Hae), erosion (Er) and fibrotic septa (FS) with US. X-rays [Pettersson Score (PXS)] were performed in 61 patients and clinical evaluation [World Federation Haemophiliac orthopaedic score (WFHO)] was performed in all patients. A total of 20 healthy subjects and 20 patients affected by Rheumatoid Arthritis (RA) were used as controls. Power Doppler US (PDUS) was performed in all patients on the knee, ankle and elbow joints. A total of 83 joints were studied (50 knees; 12 elbows and 21 ankles). US showed effusion in 57 joint, bone remodelling in 62, cartilage damage in 64, synovial hypertrophy in 45, haemosiderin in 39, osteophytes in 30, haemarthrosis in 24, erosion in 5 and fibrotic septa in 3. The X-rays score showed remodelling in 47 joints, narrowing joint space in 44, displacement/angulation in 39, osteoporosis in 42, subchondral irregularity in 44, subchondral cyst formation in 37, osteophytes in 36 and erosions in 25. The US score in healthy subjects was always ≤ 5 (range 0 to 4). In haemophiliacs, 34 of 83 joints showed US score ≤ 5, and 49 US score > 5. Joints with US score ≤ 5 had a low PXS (SRCC = 0.375, P < 0.01) and joints with US score > 5 showed a high PXS (SRCC = 0.440, P < 0.01). A significant correlation between US score and PXS for bone remodelling [Spearman's rho Correlation Coefficient (SRCC) = 0.429, P < 0.01] and for osteophytes (SRCC = 0.308, P < 0.05) was found. The correlation between the US score and number of bleedings in 83 joints was very significant (SRCC = 0.375, P < 0.01). A total of 24 bleeding joints were identified and verified with aspiration of haematic fluid. US may detect bone and cartilage alterations and synovitis. Indeed, PDUS identified bleeding also in asymptomatic joints and was able to show different entity of haemarthrosis. US may be a feasible and reliable tool to evaluate joint modifications in HA.

Mycophenolate mofetil for the treatment of juvenile onset SLE: a multicenter study.

Mycophenolate mofetil (MMF) has proved to be an efficacious and safe therapy in adult lupus nephritis. Recently, this drug has been suggested as a possible new alternative treatment also for juvenile-onset SLE (juvenile-SLE). A multicenter study has been performed to evaluate the efficacy and safety of MMF in controlling the disease activity in children and adolescents with juvenile-SLE. Our results show that MMF was effective in reducing the disease activity or as a steroid-sparing agent in 14 of 26 patients (54%), stabilised the disease in 8 (31%) and was ineffective in 4 (15%). In particular, in patients without renal involvement, a good response was registered in 9 of 13 patients (69%). Among those patients with renal involvement, MMF was effective in 5 of 13 patients (38%), partially effective in 4 (31%) and ineffective in 4 (31%). No severe side effects have been observed; only two patients stopped the drug because of severe diarrhoea and abdominal pain. With the limits of a retrospective study, MMF seems to be effective and safe for the treatment of juvenile-SLE, especially in patients with no renal involvement.

QuantiFERON-TB Gold and the TST are both useful for latent tuberculosis infection screening in autoimmune diseases.

Screening for active tuberculosis (TB) and latent TB infection (LTBI) is mandatory prior to the initiation of tumour necrosis factor-alpha inhibitor therapy. However, no agreement exists on the best strategy for detecting LTBI in this population. The aim of the present study was to analyse the performance of the tuberculin skin test (TST) and QuantiFERON-TB Gold in-tube (QFT-GIT) on LTBI detection in subjects with immunomediated inflammatory diseases (IMID). The TST and QFT-GIT were prospectively performed in 398 consecutive IMID subjects, 310 (78%) on immunosuppressive therapy and only 16 (4%) had been bacillus Calmette-Guérin (BCG) vaccinated. Indeterminate results to QFT-GIT were found in five (1.2%) subjects. Overall, 74 (19%) out of 393 subjects were TST-positive and 52 (13%) were QFT-GIT-positive. Concordance between TST and QFT-GIT results was good (87.7%): 13 were QFT-GIT-positive/TST-negative and 35 QFT-GIT-negative/TST-positive. By multivariate analysis both tests were significantly associated with older age. Only the TST was associated with BCG vaccination and radiological lesions of past TB. Use of immunosuppressive drugs differently modulated QFT-GIT or TST scoring. Use of the QuantiFERON-TB Gold in-tube, as a screening tool for latent tuberculosis among immunomediated inflammatory disease subjects, is feasible. Until further data will elucidate discordant tuberculin skin test/QuantiFERON-TB Gold in-tube results, a strategy of simultaneous tuberculin skin and QuantiFERON-TB Gold in-tube testing in a low prevalence bacillus Calmette-Guérin vaccinated population, should maximise potentials of latent tuberculosis diagnosis.

Genetic markers of osteoarticular disorders: facts and hopes.

Osteoarthritis and osteoporosis are the two most common age-related chronic disorders of articular joints and skeleton, representing a major public health problem in most developed countries. Apart from being influenced by environmental factors, both disorders have a strong genetic component, and there is now considerable evidence from large population studies that these two disorders are inversely related. Thus, an accurate analysis of the genetic component of one of these two multifactorial diseases may provide data of interest for the other. However, the existence of confounding factors must always be borne in mind in interpreting the genetic analysis. In addition, each patient must be given an accurate clinical evaluation, including family history, history of drug treatments, lifestyle, and environment, in order to reduce the background bias. Here, we review the impact of recent work in molecular genetics suggesting that powerful molecular biology techniques will soon make possible both a rapid accumulation of data on the genetics of both disorders and the development of novel diagnostic, prognostic, and therapeutic approaches.

European multicentre study to define disease activity criteria for systemic sclerosis. I. Clinical and epidemiological features of 290 patients from 19 centres.

OBJECTIVE: To investigate the existence of differences among European referral centres for systemic sclerosis (SSc) in the pattern of attendance and referral and in the clinical and therapeutical approaches. METHODS: In 1995 the European Scleroderma Study Group initiated a multicentre prospective one year study whose aim was to define the disease activity criteria in SSc. During the study period each participating European centre was asked to enroll consecutive patients satisfying American College of Rheumatology criteria for SSc and to fill out for each of them a standardised clinical chart. Patients from various centres were compared and differences in epidemiological, clinical, and therapeutical aspects were analysed. RESULTS: Nineteen different medical research centres consecutively recruited 290 patients. The patients could be divided into two subgroups: 173 with the limited (lSSc) and 117 with the diffuse (dSSc) form of the disease. The clinical and serological findings for the series of 290 patients seemed to be similar to data previously reported. However, when the data were analysed to elicit any differences between the participating centres, a high degree of variability emerged, in both epidemiological and clinical features and in the diagnostic and therapeutic approaches to the disease. CONCLUSIONS: The clinical approach to SSc, not only in different countries but also in different centres within the same country, is not yet standardised. To overcome this problem, it will be necessary for the scientific community to draw up a standardised procedure for the management of patients with SSc. This would provide a common research tool for different centres engaged in research on this complex disease.

European multicentre study to define disease activity criteria for systemic sclerosis. II. Identification of disease activity variables and development of preliminary activity indexes.

OBJECTIVE: To develop criteria for disease activity in systemic sclerosis (SSc) that are valid, reliable, and easy to use. METHODS: Investigators from 19 European centres completed a standardised clinical chart for a consecutive number of patients with SSc. Three protocol management members blindly evaluated each chart and assigned a disease activity score on a semiquantitative scale of 0-10. Two of them, in addition, gave a blinded, qualitative evaluation of disease activity ("inactive to moderately active" or "active to very active" disease). Both these evaluations were found to be reliable. A final disease activity score and qualitative evaluation of disease activity were arrived at by consensus for each patient; the former represented the gold standard for subsequent analyses. The correlations between individual items in the chart and this gold standard were then analysed. RESULTS: A total of 290 patients with SSc (117 with diffuse SSc (dSSc) and 173 with limited SSc (lSSc)) were enrolled in the study. The items (including Delta-factors-that is, worsening according to the patient report) that were found to correlate with the gold standard on multiple regression were used to construct three separate 10-point indices of disease activity: (a) Delta-cardiopulmonary (4.0), Delta-skin (3.0), Delta-vascular (2.0), and Delta-articular/muscular (1.0) for patients with dSSc; (b) Delta-skin (2.5), erythrocyte sedimentation rate (ESR) >30 mm/1st h (2.5), Delta-cardiopulmonary (1.5), Delta-vascular (1.0), arthritis (1.0), hypocomplementaemia (1.0), and scleredema (0.5) for lSSc; (c) Delta-cardiopulmonary (2.0), Delta-skin (2.0), ESR >30 mm/1st h (1.5), total skin score >20 (1.0), hypocomplementaemia (1.0), scleredema (0.5), digital necrosis (0.5), Delta-vascular (0.5), arthritis (0.5), TLCO <80% (0.5) for all patients with SSc. The three indexes were validated by the jackknife technique. Finally, receiver operating characteristic curves were constructed in order to define the value of the index with the best discriminant capacity for "active to very active" patients. CONCLUSIONS: Three feasible, reliable, and valid preliminary indices to define disease activity in SSc were constructed.

Emerging potentials for an antioxidant therapy as a new approach to the treatment of systemic sclerosis.

Oxidative stress, favoring disease progression by a rapid degeneration of endothelial cell function is deeply involved in Systemic Sclerosis (SSc) pathogenesis. Raynaud's phenomenon (RP), present in 90% of patients with SSc, provoking frequent daily episodes of hypoxia-reperfusion injury, produces several episodes of free radicals-mediated endothelial derangement. These events results in a positive feedback effect of luminal narrowing and ischemia and therefore to the birth of a vicious cycle of oxygen free radicals (OFR) generation, leading to endothelial damage, intimal thickening and fibrosis. Thus ischemia and reperfusion are two criticals events that may induce oxidative stress and inactivation of antioxidant enzymes. In RP and SSc, a reduced concentration of ascorbic acid, alpha-tocopherol and beta-carotene as well as low values of Selenium have been reported. This antioxidative potential deficiency increases the propensity to oxidative stress. favoring the development of injury mediated by OFR. We reviewed several antioxidant compounds, aiming at their capacity of reverting endothelial dysfunction and damage, scavenging lipid peroxidation and reducing multiple episodes of hypoxia-reperfusion injury. In order to interrupt SSc vicious cycle, we propose a main strategy for SSc treatment by a supplementation of antioxidants and different kind of drugs with antioxidant property, such as Lazaroids, Resveratrol, Melatonin and Probucol.

Polyneuropathy as initial manifestation of systemic sclerosis (scleroderma).

We report the first case of a young female patient who developed a sensory-motor polyneuropathy, without any skin or internal involvement characteristic of SSc, but with a serological positivity of antitopoisomerase I antibodies. After 4 years she developed a rapid skin tightening with lung involvement, in a full blown picture of the diffuse subset of SSc. The case suggests that the peripheral nervous system deserves more attention, in particular in the earliest phase of SSc.

Oxidative stress in Systemic Sclerosis.

In 63 patients affected by Systemic Sclerosis (SSc) (limited subset: 40; diffuse subset: 23; early: 30; advanced: 33) the peroxidation product diene-conjugates (DC) and antibodies against oxidised low density lipoproteins (Ab oxLDL) were tested in serum by a spectrophotometer (absorbance 234 mn) and by a standard ELISA respectively. The data were compared with those obtained by 21 healthy subjects. DC was significantly higher in patients (73.3 +/- 37.2 microM/l; p < 0.0001) than in controls (48.4 +/- 16.7) as well as in the limited (80 +/- 48.8; p < 0.05) than in the diffuse subset (64.5 +/- 36.4); and in early (84.1 +/- 31.4; p < 0.05) than in advanced stage of the disease (67.9 +/- 42.5). The levels of Ab oxLDL were significantly higher in SSc patients (309.5 +/- 367.2 mU/ml; p < 0.0001) in all its subsets (limited: 351.9 +/- 351.1, p < 0.0001; diffuse: 207.7 +/- 316.1, p < 0.05; early: 428.9 +/- 417.1, p < 0.001; advanced: 302.7 +/- 89.9, p < 0.0001) than in controls (89.3 +/- 29.1). These antibodies levels were higher in limited subset than in diffuse (p < 0.05) and in early SSc than in advanced SSc (p < 0.05). The highest values of parameters of oxidative stress are found in the early stages, when the episodes of reperfusion after ischemic episodes (Raynaud's phenomenon) are very frequent. Moreover, the damage is higher in the early stages of SSc, with intact microvessels, than in late stages, when microvessels are very reduced in number, destroyed by the worsening of the disease. These data show that the respiratory burst deduced by the lipoperoxidation is higher in SSc than in controls, and may be an important pathogenetic factors involved in tissue changes in SSc.

Congenital conduction defects in children born to asymptomatic mothers with anti-SSA/SSB antibodies: report of two cases.

It is very difficult to identify pregnant asymptomatic mothers carrying anti-SSA/SSB antibodies. We report two cases of neonatal lupus erythematosus, born to asymptomatic mothers with anti-SSA/Ro antibody, who developed isolated complete congenital cardiac heart block and transient second degree conduction defect associated with cardiac abnormalities, respectively. The first died suddenly of acute myocarditis at the age of 20 months, while the second underwent surgery at the age of 10 years for a ventricular septal defect, after two episodes of second degree atrioventricular block in infancy. We believe that in both cases the diagnosis could have been made in utero after correct heart beat analysis. We propose careful monitoring of fetal heart beat in all pregnant mothers. The occurrence of heart beat modification should prompt clinicians to test the mother for antibody positivity. This approach may permit early diagnosis and in utero treatment in order to spare the child from cardiac conduction defects. We provide the evidence of these cases and propose a flow chart for all physicians dealing with pregnancy.

Antisense targeting of the urokinase receptor blocks urokinase-dependent proliferation, chemoinvasion, and chemotaxis of human synovial cells and chondrocytes in vitro.

Proliferation and invasion of synovial pannus in rheumatoid arthritis and cartilage remodeling in osteoarthritis are key events in development of disability of arthritic joints. The mechanisms that trigger these events are still poorly understood. The production of urokinase-type plasminogen activator (u-PA) by synovial cells and chondrocytes and the subsequent interaction of u-PA with its membrane receptor (u-PAR) is under the control of a variety of growth factors and cytokines released within the inflamed joints. Here we show that u-PA, on interaction with the specific receptor, regulates movement and invasion as well as proliferation of human synovial cells and chondrocytes. Targeting the urokinase receptor with an antisense oligonucleotide blocks the u-PA-dependent synoviocyte and chondrocyte proliferation and chemoinvasion, suggesting a possible use for this new class of drugs in the progression of the disease in rheumatoid arthritis and osteoarthritis.

Synoviocytes from osteoarthritis and rheumatoid arthritis produce plasminogen activators and plasminogen activator inhibitor-1 and display u-PA receptors on their surface.

The production of plasminogen activators and their inhibitors was studied in vitro in osteoarthritic (OA) and rheumatoid arthritic (RA) synovial fibroblasts (SF), obtained from RA and OA patients undergoing joint surgery. Subcultured SF were cultivated for 2, 4, 6, 8, 10 and 13 days and the medium assayed for the presence of both plasminogen activators (PAs) and plasminogen activator inhibitor-1 (PAI-1). The presence of urokinase-Plasminogen Activator (u-PA) receptors (u-PAR) on the surface of synovial cells was investigated by radio-ligand binding assay and cross-linking and by transmission electron microscopy (TEM) of a gold-u-PA complex. Our results showed a low production of tissue-type-Plasminogen Activator (t-PA) in both OA and RA SF, but relatively high levels of u-PA, until confluence, both in OA and in RA. SF were also able to produce plasminogen activator inhibitor in large amounts, in particular in RA since the very beginning of the culture. Receptors for u-PA were evident on both RA and OA SF. Our data show that SF in vitro produce mainly u-PA, the most important plasminogen activator involved in tissue modifications. The demonstration of u-PA receptors on the surface of OA and RA SF represents a step forward in the understanding of the possible role of fibrinolytic and tissue destructive proteinase cascade in joint inflammation.

Neuropeptides and steroid hormones in arthritis.

Primary afferent nociceptive and peptidergic efferent nerves are sensitized in arthritis and thus easily stimulated by mechanical and chemical stimuli. This leads to increased or disturbed release of neuropeptides from nerve terminals. This local (at the site of stimulation), expanded (expanded and additional receptive fields), and remote (cross-spinal reflexes) neuropeptide release leads to disturbed tissue homeostasis and neurogenic inflammation. In arthritis, raised levels of neuropeptides were detected in the synovial fluid, whereas nerve fibers were lacking in the synovial tissue. It has been hypothesized that cycles of nerve fiber destruction and degeneration follow the cycles of joint inflammation. This evidence suggests that the peripheral nervous system, through its neuropeptides, may contribute to the generation of inflammation, i.e., "neurogenic inflammation." Altered hypothalamic-pituitary-adrenocortical axis function and sex hormone status have been suggested to contribute to the development and persistence of arthritis. In particular, current evidence indicates that glucocorticoid secretion is closely and reciprocally interrelated with inflammation, and that an adrenal insufficiency is present in many forms of immune-mediated arthritis. Conversely, gonadal steroids seem to play a central role as predisposing factors in many forms of arthritis, with estrogens involved as immuno-enhancing hormones and androgens as natural immunosuppressors. Functional receptors for sex hormones have been described in cells involved in the immune response and, after activation, the hormone-receptor complex might modulate the expression of selected cytokines. The possibility of targeting the efferent nerves with specific peptides and replacement therapies with selected steroid hormones may represent a new and potentially efficient and natural system of modulation of the arthritis.

Methotrexate-associated appearance and rapid progression of rheumatoid nodules in systemic-onset juvenile rheumatoid arthritis.

Rheumatoid nodules are a rare extraarticular manifestation of juvenile rheumatoid arthritis (JRA), usually detected in patients with polyarticular-onset disease and positive rheumatoid factor (RF). To date, there has not been a published report of rheumatoid nodules in systemic-onset JRA. Low-dose methotrexate (MTX) is generally considered to be the most useful second-line drug in the treatment of polyarticular JRA. In adult RA, MTX has been shown to be associated with appearance and progression of rheumatoid nodules. This report describes a 3-year-old girl with RF-negative, antinuclear antibody-negative systemic JRA who developed multiple rheumatoid nodules on the scalp and trunk during MTX therapy. The first nodule developed on the scalp 6 months after MTX treatment was initiated. Previous treatment with azathioprine was not associated with nodulosis. This represents an atypical case of MTX-associated accelerated nodulosis in systemic JRA, and raises the problem of treatment plan modification in the presence of this side effect.

New approaches to Raynaud's phenomenon [corrected].

Dysfunction of vascular tone control is mainly caused by the derangement of endothelium and of the peripheral nervous system. Studies have suggested changes in the nervous system at either the peripheral level (loss of sensory motor nerves, increased alpha 2-receptor activity, and so on) or the central level (impaired thermoregulation), always linked to the profound abnormality of endothelial function. This dual involvement consistently affects the blood flow, which can be measured with several tools (laser Doppler velocimetry, digital blood pressure response, and so on). Studies have analyzed serologic and instrumental predictors of a possible development of a connective tissue disease in Raynaud's phenomenon. A new wave of studies addressed the role of reperfusion injury and oxygen radicals in provoking chromosomal breakage and generating an immune response through fragmentation of autoantigens in the presence of metals. Antioxidants have been proposed as efficacious treatment of Raynaud's phenomenon. The continued study of regeneration of vessels (therapeutic angiogenesis) may open a new avenue for the treatment of Raynaud's phenomenon and the loss of angiogenesis as in diffuse scleroderma.

Clinical and laboratory features and disease outcome of kawasaki disease: the analysis of our experience and literature review.

Clinical, laboratory features and the outcome of 73 children affected with Kawasaki Disease (KD) (62 with typical KD and 11 in which one or more of the Japanese Committee criteria were lacking) were analyzed and compared with those of the literature. All patients, except 14 admitted before 1982, received the current specific treatment with aspirin and intravenous immunoglobulin (WIG) (400 mg/kg/for 5 days or a single infusion of 2 g/kg). Three children underwent a second cycle of IVIG because fever and coronary alterations persisted after the first infusion. The frequency of cardiac involvement in our complete KD (29|X%) was comparable with that reported in the literature (coronary dilatation 20|X% and coronary aneurysm 4|X%), while in the incomplete cases no coronary abnormalities were detected. The outcome of the KD was good in all children. Remodeling of coronary vessels was noted in all patients with coronary artery damage, 2 to 24 months from the disease onset.We believe that the frequency of atypical or incomplete KD needs emphasis. Since others have reported coronary abnormalities in such cases, close 2D echocardiographic monitoring should be done in all children with otherwise unexplained prolonged fever, red lips, leukocytosis, and high erythrocyte sedimentation rate. We believe that when KD is strongly suspected, even in absence of all criteria for the diagnosis, prompt treatment with both aspirin and IVIG is appropriate to avoid even a low risk of coronary damage.

The nervous system in systemic sclerosis (scleroderma). Clinical features and pathogenetic mechanisms.

The involvement of the nervous system in SSc is well recognized today. Different pathogenetic mechanisms are suggested that may alternatively explain the multiform appearance of the clinical spectrum (mononeuritis, mononeuritis multiplex, carpal tunnel syndrome, and so forth). It is now clear that the ANS is the earliest structure targeted by the disease in the gastrointestinal tract. The importance of this observation has not yet been adequately interpreted but may, together with the increasing evidence of the nervous system involvement in SSc, become a leading factor in understanding of the importance of the nervous system in the onset, development, and maintenance of the disease.