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Lia Millucci,
Adriano Spreafico,
Laura Tinti,
Daniela Braconi,
Lorenzo Ghezzi,
Eugenio Paccagnini,
Giulia Bernardini,
Loredana Amato,
Marcella Laschi, Enrico Selvi,
Mauro Galeazzi,
Alessandro Mannoni,
Maurizio Benucci,
Pietro Lupetti,
Federico Chellini,
Maurizio Orlandini,
Annalisa Santucci
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ABSTRACT: Alkaptonuria (AKU) is an ultra-rare disease developed from the lack of homogentisic acid oxidase activity, causing homogentisic acid (HGA) accumulation that produces a HGA-melanin ochronotic pigment, of unknown composition. There is no therapy for AKU. Our aim was to verify if AKU implied a secondary amyloidosis. Congo Red, Thioflavin-T staining and TEM were performed to assess amyloid presence in AKU specimens (cartilage, synovia, periumbelical fat, salivary gland) and in HGA-treated human chondrocytes and cartilage. SAA and SAP deposition was examined using immunofluorescence and their levels were evaluated in the patients' plasma by ELISA. 2D electrophoresis was undertaken in AKU cells to evaluate the levels of proteins involved in amyloidogenesis. AKU osteoarticular tissues contained SAA-amyloid in 7/7 patients. Ochronotic pigment and amyloid co-localized in AKU osteoarticular tissues. SAA and SAP composition of the deposits assessed secondary type of amyloidosis. High levels of SAA and SAP were found in AKU patients' plasma. Systemic amyloidosis was assessed by Congo Red staining of patients' abdominal fat and salivary gland. AKU is the second pathology after Parkinson's disease where amyloid is associated with a form of melanin. Aberrant expression of proteins involved in amyloidogenesis has been found in AKU cells. Our findings on alkaptonuria as a novel type II AA amyloidosis open new important perspectives for its therapy, since methotrexate treatment proved to significantly reduce in vitro HGA-induced A-amyloid aggregates.
Biochimica et Biophysica Acta 07/2012; 1822(11):1682-91. · 4.66 Impact Factor
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Estrella Garcia Gonzalez, Enrico Selvi,
Epifania Balistreri,
Alfiya Akhmetshina,
Katrin Palumbo,
Sauro Lorenzini,
Pietro Enea Lazzerini,
Cinzia Montilli,
Pier Leopoldo Capecchi,
Monica Lucattelli,
Caterina Baldi,
Elena Gianchecchi,
Mauro Galeazzi,
Franco Laghi Pasini,
Jörg H W Distler
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ABSTRACT: Cannabinoids modulate fibrogenesis in scleroderma. Ajulemic acid (AjA) is a non-psychoactive synthetic analogue of tetrahydrocannabinol that can bind the peroxisome proliferator-activated receptor-γ (PPAR-γ). Recent evidence suggests a key role for PPAR-γ in fibrogenesis.
To determine whether AjA can modulate fibrogenesis in murine models of scleroderma.
Bleomycin-induced experimental fibrosis was used to assess the antifibrotic effects of AjA in vivo. In addition, the efficacy of AjA in pre-established fibrosis was analysed in a modified model of bleomycin-induced dermal fibrosis and in mice overexpressing a constitutively active transforming growth factor β (TGFβ) receptor I. Skin fibrosis was evaluated by quantification of skin thickness and hydroxyproline content. As a marker of fibroblast activation, α-smooth muscle actin was examined. To study the direct effect of AjA in collagen neosynthesis, skin fibroblasts from patients with scleroderma were treated with increasing concentrations of AjA. Protein expression of PPAR-γ, and its endogenous ligand 15d-PGJ2, and TGFβ were assessed before and after AjA treatment.
AjA significantly prevented experimental bleomycin-induced dermal fibrosis and modestly reduced its progression when started 3 weeks into the disease. AjA strongly reduced collagen neosynthesis by scleroderma fibroblasts in vitro, an action which was reversed completely by co-treatment with a selective PPAR-γ antagonist.
AjA prevents progression of fibrosis in vivo and inhibits fibrogenesis in vitro by stimulating PPAR-γ signalling. Since therapeutic doses of AjA are well tolerated in humans, it is suggested that AjA as an interesting molecule targeting fibrosis in patients with scleroderma.
Annals of the rheumatic diseases 04/2012; 71(9):1545-51. · 8.11 Impact Factor
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Pietro Enea Lazzerini,
Mariarita Natale,
Elena Gianchecchi,
Pier Leopoldo Capecchi,
Cinzia Montilli,
Stefania Zimbone,
Monica Castrichini,
Epifania Balistreri,
Gianluca Ricci, Enrico Selvi,
Estrella Garcia-Gonzalez,
Mauro Galeazzi,
Franco Laghi-Pasini
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ABSTRACT: Systemic sclerosis (SSc) is a connective tissue disease characterised by exaggerated collagen deposition in the skin and visceral organs. Adenosine A2A receptor stimulation (A2Ar) promotes dermal fibrosis, while the cannabinoid system modulates fibrogenesis in vitro and in animal models of SSc. Moreover, evidence in central nervous system suggests that A2A and cannabinoid (CB1) receptors may physically and functionally interact. On this basis, we investigated A2Ar expression and function in modulating collagen biosynthesis from SSc dermal fibroblasts and analysed the cross-talk with cannabinoid receptors. In sclerodermic cells, A2Ar expression (RT-PCR, Western blotting) was evaluated together with the effects of A2A agonists and/or antagonists on collagen biosynthesis (EIA, Western blotting). Putative physical and functional interactions between the A2A and cannabinoid receptors were respectively assessed by co-immuno-precipitation and co-incubating the cells with the unselective cannabinoid agonist WIN55,212-2, and the selective A2A antagonist ZM-241385. In SSc fibroblasts, (1) the A2Ar is overexpressed and its occupancy with the selective agonist CGS-21680 increases collagen production, myofibroblast trans-differentiation, and ERK-1/2 phosphorylation; (2) the A2Ar forms an heteromer with the cannabinoid CB1 receptor; and (3) unselective cannabinoid receptor stimulation with a per se ineffective dose of WIN55,212-2, results in a marked anti-fibrotic effect after A2Ar blockage. In conclusion, A2Ar stimulation induces a pro-fibrotic phenotype in SSc dermal fibroblasts, either directly, and indirectly, by activating the CB1 cannabinoid receptor. These findings increase our knowledge of the pathophysiology of sclerodermic fibrosis also further suggesting a new therapeutic approach to the disease.
Journal of Molecular Medicine 03/2012; 90(3):331-42. · 4.67 Impact Factor
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ABSTRACT: Alkaptonuria (AKU) results from defective homogentisate1,2-dioxygenase (HGD), causing degenerative arthropathy. The deposition of ochronotic pigment in joints is so far attributed to homogentisic acid produced by the liver, circulating in the blood and accumulating locally. Human normal and AKU osteoarticular cells were tested for HGD gene expression by RT-PCR, mono- and 2D-Western blotting. HGD gene expression was revealed in chondrocytes, synoviocytes, osteoblasts. Furthermore, HGD expression was confirmed by Western blotting, that also revealed the presence of five enzymatic molecular species. Our findings indicate that AKU osteoarticular cells produce the ochronotic pigment in loco and this may strongly contribute to induction of ochronotic arthropathy.
Journal of Cellular Physiology 11/2011; 227(9):3254-7. · 3.87 Impact Factor
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ABSTRACT: There is increasing evidence that the endocannabinoid system may be involved in pathological fibrosis, and that its modulation might limit fibrotic responses. The aim of this study was to examine the capacity of a synthetic cannabinoid receptor agonist to modify skin fibrosis in the bleomycin mouse model of scleroderma.
Skin fibrosis was induced by local injections of bleomycin in two groups of DBA/2J mice. One group was cotreated with the synthetic cannabinoid WIN55,212-2 at 1 mg/kg/day. Skin fibrosis was evaluated by histology and skin thickness and hydroxyproline content were quantified. Markers of fibroblast activation, including α smooth muscle actin and the profibrotic cytokines transforming growth factor (TGF)β, connective tissue growth factor (CTGF) and platelet-derived growth factor (PDGF)-BB, were examined. Levels of PSMAD2/3, which are crucial in extracellular matrix overproduction, were analysed.
Bleomycin treatment induced typical skin fibrosis. Upon WIN55,212-2 treatment dermal fibrosis was completely prevented. Subcutaneous inflammatory cell infiltration, dermal thickness and collagen content resulted similar to those of the control group. The synthetic cannabinoid prevented fibroblasts activation induced by bleomycin, paralleled by a strong inhibition of TGFβ, CTGF and PDGF-BB expression. Phosphorylation of SMAD2/3 was significantly downregulated after WIN55,212-2 exposure.
Taken together, the results indicate that the synthetic cannabinoid WIN55,212-2 is capable of preventing skin fibrosis in a mouse model of scleroderma.
Annals of the rheumatic diseases 01/2011; 70(4):695-9. · 8.11 Impact Factor
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Laura Tinti,
Adriano Spreafico,
Daniela Braconi,
Lia Millucci,
Giulia Bernardini,
Federico Chellini,
Giovanni Cavallo, Enrico Selvi,
Mauro Galeazzi,
Roberto Marcolongo,
James A Gallagher,
Annalisa Santucci
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ABSTRACT: Alkaptonuria (AKU) is a rare autosomal recessive disease, associated with deficiency of homogentisate 1,2-dioxygenase activity in the liver. This leads to an accumulation of homogentisic acid (HGA) and its oxidized derivatives in polymerized form in connective tissues especially in joints. Currently, AKU lacks an appropriate therapy. Hence, we propose a new treatment for AKU using the antioxidant N-acetylcysteine (NAC) administered in combinations with ascorbic acid (ASC) since it has been proven that NAC counteracts the side-effects of ASC. We established an in vitro cell model using human articular primary chondrocytes challenged with an excess of HGA (0.33 mM). We used this experimental model to undertake pre-clinical testing of potential antioxidative therapies for AKU, evaluating apoptosis, viability, proliferation, and metabolism of chondrocytes exposed to HGA and treated with NAC and ASC administered alone or in combination addition of both. NAC decreased apoptosis induced in chondrocytes by HGA, increased chondrocyte growth reduced by HGA, and partially restored proteoglycan release inhibited by HGA. A significantly improvement in efficacy was found with combined addition of the two antioxidants in comparison with NAC and ASC alone. Our novel in vitro AKU model allowed us to demonstrate the efficacy of the co-administration of NAC and ASC to counteract the negative effects of HGA for the treatment of ochronotic arthropathy.
Journal of Cellular Physiology 10/2010; 225(1):84-91. · 3.87 Impact Factor
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ABSTRACT: Evidence exists that the pleiotropic properties of the hydroxy-methyl-glutaryl Coenzyme A reductase inhibitors (statins) are not restricted to the cardiovascular system, as they can also favorably affect the joints, with intriguing implications for the treatment of many rheumatic diseases. In the view of the increasing interest on this topic, we here review the current state of the art.
The PubMed database was searched for articles published between 1966 and 2010 for key words referring to statins and joint diseases. All relevant English-written articles were reviewed.
Many pivotal studies clearly demonstrated that HMG-CoA reductase inhibitors exert a wide spectrum of beneficial effects on the 3 main compartments of the joint, ie, the synovium, the cartilage, and the subchondral bone. Such (1) anti-inflammatory, (2) immunomodulating, and (3) anabolic effects strongly support a potential role of these drugs in the treatment and/or the prevention of the most important chronic joint diseases. However, although the majority of the in vivo studies with statins on animal models of inflammatory and degenerative joint diseases showed a marked protective activity substantially confirming the in vitro experiments, data arising from clinical trials are less probative and more conflicting.
Statins display multiple joint-protective effects. Since oral administration of statins could result in a relatively low drug bioavailability to the joints, alternative routes of administration of the drug (transdermal, intra-articular) and/or specific delivery systems should be developed to establish the entire therapeutic potential of statins in this clinical setting.
Seminars in arthritis and rheumatism 09/2010; 40(5):430-46. · 4.72 Impact Factor
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BMJ (Clinical research ed.). 01/2010; 341:c4441.
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Estrella Garcia-Gonzalez, Enrico Selvi,
Epifania Balistreri,
Sauro Lorenzini,
Roberta Maggio,
Maria-Rita Natale,
Pier-Leopoldo Capecchi,
Pietro-Enea Lazzerini,
Marco Bardelli,
Franco Laghi-Pasini,
Mauro Galeazzi
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ABSTRACT: It has been demonstrated that the endocannabinoid system is up-regulated in pathologic fibrosis and that modulation of the cannabinoid receptors might limit the progression of uncontrolled fibrogenesis. The aim of this study was to investigate whether the synthetic cannabinoid receptor agonist WIN55,212-2 could modulate fibrogenesis in an in vitro model of dcSSc.
The expression of cannabinoid receptors CB1 and CB2 was assessed in dcSSc fibroblasts and healthy control fibroblasts. To investigate the effect of WIN55,212-2 on dcSSc fibrogenesis, we studied type I collagen, profibrotic cytokines, fibroblast transdifferentiation into myofibroblasts, apoptotic processes and activation of the extracellular signal-related kinase 1/2 pathway prior to and after the treatment with the synthetic cannabinoid at increasing concentrations.
Both CB1 and CB2 receptors were over-expressed in dcSSc fibroblasts compared with healthy controls. WIN55,212-2 caused a reduction in extracellular matrix deposition and counteracted several behavioural abnormalities of scleroderma fibroblasts including transdifferentiation into myofibroblasts and resistance to apoptosis. The anti-fibrogenic effect of WIN55,212-2 was not reverted by selective cannabinoid antagonists.
Our preliminary findings suggest that cannabinoids are provided with an anti-fibrotic activity, thereby possibly representing a new class of agents targeting fibrosis diseases.
Rheumatology (Oxford, England) 08/2009; 48(9):1050-6. · 4.24 Impact Factor
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ABSTRACT: The arrhythmogenicity of anti-Ro/SSA antibodies for the foetal heart and their crucial role in the development of congenital heart block is now well established, representing a paradigmatic model of passively acquired autoimmunity. Recently, intriguing data suggest that also the adult heart may represent a possible target of anti-Ro/SSA antibody-mediated autoimmune injury. The prolongation of the QTc interval, possibly resulting from a direct inhibitory interaction between the anti-Ro/SSA antibodies and the potassium current I(Kr) in the heart seems the abnormality more frequently observed in adults with anti-Ro/SSA-positive CTD. Although the possibility that anti-Ro/SSA positivity may be considered a risk factor for arrhythmic sudden death in adults has not been demonstrated as yet, preliminary data suggest a relationship among anti-Ro/SSA antibodies, QTc prolongation, and the prevalence of ventricular arrhythmias, also life threatening, in adult patients.
Autoimmunity reviews 04/2009; 9(1):40-4. · 6.37 Impact Factor
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Case Reports 01/2009; 2009.
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ABSTRACT: Reports suggest that infliximab (IFX) may be associated with life-threatening tachyarrhythmias and bradyarrhythmias. We evaluated the prevalence of cardiac rhythm disorders during acute infusion of IFX in a prospective, single-blind, placebo-controlled crossover study of patients with chronic arthritis. Effects of the drug on measures of arrhythmia risk such as QT interval and heart rate variability (HRV) were evaluated.
Seventy-five patients with spondyloarthritis (SpA; n=55) or rheumatoid arthritis (RA) underwent an ambulatory 12-channel electrocardiogram (ECG) recording to monitor cardiac arrhythmias, QT interval, and HRV during the infusion of IFX and saline (placebo).
The occurrence of both tachyarrhythmias and bradyarrhythmias was not statistically different during IFX or placebo infusion. During IFX infusion, new-onset ventricular tachyarrhythmias had an 8% incidence (2.7% with placebo; OR 3.17, 95% CI 0.61-16.26) and were more severe. In these patients, mainly with RA, baseline-corrected QT interval and HRV values were significantly prolonged and depressed, respectively, in comparison with subjects without such arrhythmias. IFX acutely produced a significant shift toward a relative vagal prevalence without affecting QT interval measurements.
New-onset cardiac arrhythmias, particularly ventricular tachyarrhythmias, developed during IFX infusion, but their incidence did not achieve statistical significance. We identified some specific risk factors possibly characteristic of the small subset of patients with a higher risk for ventricular arrhythmias. The acute effects of IFX on autonomic balance may substantiate the role of the complex interaction between autonomic nervous system and inflammation during chronic arthritis.
The Journal of Rheumatology 09/2008; 35(10):1958-65. · 3.69 Impact Factor
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ABSTRACT: Human type B synoviocytes are involved in joint injury during rheumatic diseases by producing inflammatory mediators such as interleukin-6 (IL-6). The increased level of purine and pirimidine nucleotides in the synovial fluid of rheumatoid arthritis (RA) patients could activate the large family of P2 receptors. Thus, we investigated the presence of P2 receptors in human type B synoviocytes from rheumatoid joints, also evaluating whether the P2X7 receptor is involved in IL-6 release. Reverse transcriptase polymerase chain reaction analysis revealed messenger ribonucleic acid (mRNA) expression for the P2X1, P2X2, P2X4, P2X5, P2X6, P2X7, P2Y1, P2Y4, P2Y11, P2Y12, P2Y13, and P2Y14 but not the P2X3, P2Y2, and P2Y6 receptors. The expression of the P2X7 receptor was confirmed by Western blot analysis. Adenosine triphosphate (ATP) and the P2X7 receptor agonist 2'-3'-O-(4-benzoylbenzoyl)ATP (BzATP) triggered an increase in intracellular calcium, thereby suggesting the expression of functional P2 receptors, including the P2X7 receptor. Moreover, BzATP treatment upregulated both IL-6 mRNA and protein expression. Synoviocytes spontaneously released low quantities of IL-6; the incubation with BzATP induced the release of larger amounts of the cytokine, and such a release was blunted by the P2X7 antagonist oxidized ATP. The selective P2X1 and P2X3 receptor agonist alpha,beta-methylene ATP did not affect IL-6 release. Finally, BzATP failed to induce a significant uptake of the large-molecule YO-PRO, thus suggesting the lack of pore formation after P2X7 receptor stimulation. In conclusion, among the different P2 receptors expressed on human RA type B synoviocytes, the P2X7 receptor may modulate IL-6 release but not inducing changes in cell membrane permeability.
Journal of Molecular Medicine 07/2008; 86(8):937-49. · 4.67 Impact Factor
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ABSTRACT: Cardiac arrhythmias, including conduction defects and tach- yarrhythmias, represent an important source of morbidity and mortality in industrialized countries. Among the different pathophysiological mechanisms involved in the arrhythmogenesis, an inappropriate activation of the immune system represents a field of recent increasing interest. In fact, a large amount of studies suggest that specific autoantibody may be significantly involved in the pathogenesis of cardiac arrhythmias not only in the course of systemic autoimmune disease, but also in a number of rhythm disorders currently classified as "idiopathic." Although the strongest evidence concerns the relationship between anti-Ro/SSA antibodies and the development of congenital heart block in foetus and newborn, other specific autoantibodies demonstrated the aptitude to affect directly the myocardial tissue, thus producing interference in its bioelectric activity thereby leading to rhythm disorders, also life-threatening. The identification of an immunological autoantibody-mediated mechanism opens new perspectives in the treatment and prevention of cardiac arrhythmias in such patients, including the use of immunosuppressive agents and/or the removal of autoantibodies by immuno-adsorption technique.
Archiv für Kreislaufforschung 02/2008; 103(1):1-11. · 7.35 Impact Factor
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Pietro Enea Lazzerini,
Pier Leopoldo Capecchi,
Francesca Guideri,
Francesca Bellisai, Enrico Selvi,
Maurizio Acampa,
Agnese Costa,
Roberta Maggio,
Estrella Garcia-Gonzalez,
Stefania Bisogno,
Gabriella Morozzi,
Mauro Galeazzi,
Franco Laghi-Pasini
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ABSTRACT: A previous study of electrocardiography at rest showed that anti-Ro/SSA-positive patients with connective tissue disease (CTD) frequently had corrected QT (QTc) interval prolongation. Because QTc interval prolongation is a definite risk factor for arrhythmic sudden death in the general population, a 24-hour electrocardiographic monitoring study was performed to investigate the possible relation between QTc interval prolongation and incidence of ventricular arrhythmias as a possible expression of immunomediated electric instability of the myocardium in anti-Ro/SSA-positive patients with CTD. The study population consisted of 46 patients with CTD; 26 anti-Ro/SSA-positive and 20 anti-Ro/SSA-negative (control group) patients (Sjögren's syndrome, 9 and 3 patients; systemic lupus erythematosus, 4 and 9 patients; systemic sclerosis, 2 and 4 patients; undifferentiated CTD, 8 and 1 patients; mixed CTD, 2 and 2 patients, and polymyositis/dermatomyositis, 1 and 1 patient, respectively). All patients underwent ambulatory Holter electrocardiography to obtain 24-hour monitoring of the QTc interval and ventricular arrhythmias. With respect to the control group, anti-Ro/SSA-positive patients with CTD (1) commonly showed QTc interval prolongation (46% vs 5%), and this abnormality, when present, persisted for the 24 hours (global mean 24-hour QTc interval 440.5+/-23.4 vs 418.2+/-13.2 ms); (2) had a higher incidence of complex ventricular arrhythmias (i.e., Lown classes 2 to 5, 50% vs 10%) also in the absence of detectable cardiac abnormalities; and (3) in patients with CTD, there is a direct relation between global mean 24-hour QTc interval and ventricular arrhythmic load independently of age and disease duration. In conclusion, anti-Ro/SSA-positive patients with CTD seemed to have a particularly high risk of developing ventricular arrhythmias. The risk appeared related mainly to abnormalities in ventricular electrophysiologic characteristics emerging in the clinical setting as QTc interval prolongation.
The American Journal of Cardiology 10/2007; 100(6):1029-34. · 3.37 Impact Factor
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ABSTRACT: Hyperhomocysteinemia is independently associated with the development of coronary, cerebral and peripheral vascular disease and deep-vein thrombosis in the general population. The evidence that cardiovascular involvement is particularly frequent and advanced in patients affected with several autoimmune diseases (AD), in which hyperhomocysteinemia represent a common finding, led to an intensive investigation on homocysteine (Hcy) as a putative risk factor for the development of cardiovascular disease in such subjects. Indeed, recent data intriguingly expanded the spectrum of the possible pathogenetic implications for hyperhomocysteinemia in the course of AD. In fact, a bi-directional link seems to connect Hcy and the immuno-inflammatory activation characterizing AD, in which immuno-inflammatory activation may contribute to Hcy increase, and Hcy, in its turn, may act as a pro-inflammatory and immuno-stimulating molecule putatively cooperating to the injury of the disease-specific target organs, at least in rheumatoid arthritis and inflammatory bowel disease. Moreover, Hcy may be also a trigger of autoimmune reactions through its capability to bind and structurally modify specific proteins, then resulting in neoantigens formation potentially relevant either in the onset of specific AD and in the progression of the associated cardiovascular damage. More investigation is necessary to fully define the clinical relevance of such phenomena.
Autoimmunity Reviews 09/2007; 6(7):503-9. · 6.62 Impact Factor
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ABSTRACT: We report a case of subcutaneous panniculitis-like T-cell lymphoma (SPTCL), associated with macrophage activation syndrome, mimicking a lupus erythematosus panniculitis (LEP). A 29-year-old woman presented with high fever, general malaise, nausea, vomiting, and subcutaneous nodules and ulcerating lesions located on the lower extremities. The histopathology showed an infiltration of the panniculus, mostly involving fat, and periadnexial and perivascular structures consistent with lymphocytic lobular panniculitis (LLP). LLP is a shared feature of LEP and SPTCL. The immunophenotyping of the cell infiltrate was crucial for a correct diagnosis.
Clinical Rheumatology 03/2007; 26(2):244-6. · 2.00 Impact Factor
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ABSTRACT: Idiopathic hypereosinophilic syndrome (IHES) is a rare condition of uncertain etiology characterized by marked peripheral blood eosinophilia and organ system dysfunction that cannot be explained by any factor other than the presence of eosinophils or their potentially toxic products. Diagnostic criteria include 1) a sustained eosinophilia greater than 1500/mm for longer than 6 months, 2) absence of other causes of eosinophilia, including parasitic infections and allergic diseases, and 3) multiorgan involvement (ie, lungs, heart, central nervous system, skin, liver, joints). Steroids represent the initial therapeutic approach, although for those patients unresponsive to steroids, cytotoxic chemotherapy should be considered. We describe a case of IHES characterized by polyarticular inflammatory joint involvement, hypereosinophilia, and urticarioid skin manifestations without visceral involvement. Synovial fluid smears as well as pathology of skin lesions and knee synovial membrane confirmed the presence of numerous eosinophils. The patient was successfully treated with a combination therapy of a cysteinyl leukotriene receptor antagonist (montelukast) and ketotifen. Hypereosinophilic syndrome like in this patient is a rare cause of polyarthritis.
JCR Journal of Clinical Rheumatology 01/2005; 10(6):344-6. · 1.36 Impact Factor
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Clinical Rheumatology 11/2004; 23(5):475-7. · 2.00 Impact Factor
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The Journal of Rheumatology 04/2004; 31(3):622. · 3.69 Impact Factor
