Ulrich A Walker

Publications of Ulrich A Walker

• Evolution of radiographic joint damage in rituximab-treated versus TNF-treated rheumatoid arthritis cases with inadequate response to TNF antagonists.

  Authors: Axel Finckh, Burkhard Möller, Jean Dudler, Ulrich A Walker, Diego Kyburz, Cem Gabay

  Annals of the rheumatic diseases. 03/2012;

  BACKGROUND: Observational studies have suggested that patients with rheumatoid arthritis (RA) who experience inadequate response to anti-tumour necrosis factor (anti-TNF) agents respond moreBACKGROUND: Observational studies have suggested that patients with rheumatoid arthritis (RA) who experience inadequate response to anti-tumour necrosis factor (anti-TNF) agents respond more favourably to rituximab (RTX) than to an alternative anti-TNF agent. However, the relative effectiveness of these agents on long-term outcomes, particularly in radiographic damage, remains unclear.OBJECTIVE: To compare the effectiveness of RTX against anti-TNF agents in preventing joint damage in patients with RA who have experienced inadequate response to at least one prior anti-TNF agent.METHODS: This is a prospective cohort study within the Swiss registry of patients with RA who discontinued at least one anti-TNF agent and subsequently received either RTX or an alternative anti-TNF agent. The primary outcome, progression of radiographic joint erosions (Ratingen erosion score)over time, and the secondary outcome, functional disability (Health Assessment Questionnaire Disability Index), were analysed using regression models for longitudinal data and adjusted for potential confounders.RESULTS: Of the 371 patients included, 104 received RTX and 267 received an alternative anti-TNF agent. During the 2.6-year median follow-up period, the rates of Ratingen erosion score progression were similar between patients taking RTX and patients taking an alternative anti-TNF agent (p=0.67). The evolution of the Health Assessment Questionnaire score was statistically significantly better in the RTX group (p=0.016), but the magnitude of the effect was probably not clinically relevant.CONCLUSION: This observational study suggests that RTX is as effective as an alternative anti-TNF agent in preventing erosions in patients with RA who have previously experienced inadequate response to anti-TNF agents.

• Antiretroviral nucleoside analogues suppress antibody synthesis in human B-lymphocytes.

  Authors: Bernhard Setzer, Ulrich A Walker

  Antiviral therapy. 03/2012;

  BACKGROUND: Some antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) impair mitochondrial polymerase-γ and T-cell proliferation, possibly by pyrimidine depletion. We aimed to analyseBACKGROUND: Some antiretroviral nucleoside reverse transcriptase inhibitors (NRTI) impair mitochondrial polymerase-γ and T-cell proliferation, possibly by pyrimidine depletion. We aimed to analyse NRTI effects on the content of mitochondrial DNA (mtDNA) and B-cells, and on their proliferation and antibody synthesis. METHODS: Peripheral blood B-lymphocytes from six healthy individuals were stimulated in vitro with interleukin-4 and Staphylococcus aureus superantigen in the presence or absence of NRTI in concentrations equivalent to, or fivefold exceeding, human peak plasma levels. We also tested the effects of uridine, a pyrimidine precursor, which has antagonized NRTI toxicities in other models. RESULTS: During 9 days of culture, B-lymphocyte proliferation and vitality were not affected by NRTI. Didanosine and stavudine, but not zidovudine, dose-dependently induced mtDNA depletion. All three NRTI significantly and dose-dependently impaired the synthesis of all immunoglobulin classes. The lymphocytotoxic effects of the thymidine analogues zidovudine and stavudine on B-lymphocytes were antagonized by the addition of uridine. CONCLUSIONS: Didanosine, stavudine and zidovudine induce mitochondrial toxicity in human B-lymphocytes and impair the immunoglobulin synthesis in vitro, warranting further studies on their in vivo effects.

• Erectile dysfunction is frequent in systemic sclerosis and associated with severe disease: a study of the EULAR Scleroderma Trial and Research group.

  Authors: Chingching Foocharoen, Alan Tyndall, Eric Hachulla, Edoardo Rosato, Yannick Allanore, Dominique Farge-Bancel, Paola Caramaschi, Paolo Airó, Starovojtova M Nikolaevna, José António Pereira da Silva [......] Ingo Tarner, Vanessa Smith, Anna T Onken, Walid Ahmed Abdel Atty Mohamed, Oliver Distler, Jadranka Morović-Vergles, Andrea Himsel, Paloma Garcia de la Peña Lefebvre, Thomas Hügle, Ulrich A Walker

  Arthritis research & therapy. 02/2012; 14(1):R37.

  ABSTRACT: INTRODUCTION: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. METHOD: ThisABSTRACT: INTRODUCTION: Erectile dysfunction (ED) is common in men with systemic sclerosis (SSc) but the demographics, risk factors and treatment coverage for ED are not well known. METHOD: This study was carried out prospectively in the multinational EULAR Scleroderma Trial and Research database by amending the electronic data-entry system with the International Index of Erectile Function-5 and items related to ED risk factors and treatment. Centres participating in this EULAR Scleroderma Trial and Research substudy were asked to recruit patients consecutively. RESULTS: Of the 130 men studied, only 23 (17.7%) had a normal International Index of Erectile Function-5 score. Thirty-eight per cent of all participants had severe ED (International Index of Erectile Function-5 score ≤ 7). Men with ED were significantly older than subjects without ED (54.8 years vs. 43.3 years, P < 0.001) and more frequently had simultaneous non-SSc-related risk factors such as alcohol consumption. In 82% of SSc patients, the onset of ED was after the manifestation of the first non-Raynaud's symptom (median delay 4.1 years). ED was associated with severe cutaneous, muscular or renal involvement of SSc, elevated pulmonary pressures and restrictive lung disease. ED was treated in only 27.8% of men. The most common treatment was sildenafil, whose efficacy is not established in ED of SSc patients. CONCLUSIONS: Severe ED is a common and early problem in men with SSc. Physicians should address modifiable risk factors actively. More research into the pathophysiology, longitudinal development, treatment and psychosocial impact of ED is needed.

• Streptococcal hypersensitivity reloaded: severe inflammatory syndrome in Behcet's disease following 23-valent polysaccharide Streptococcus pneumoniae vaccine.

  Authors: Thomas Hügle, Andreas Bircher, Ulrich A Walker

  Rheumatology (Oxford, England). 12/2011;

• The impact of ¹⁸F-FDG PET on the management of patients with suspected large vessel vasculitis.

  Authors: Martin Fuchs, Matthias Briel, Thomas Daikeler, Ulrich A Walker, Helmut Rasch, Scott Berg, Quinn K T Ng, Heike Raatz, David Jayne, Ina Kötter [......] Maria C Cid, Sergio Prieto-González, Peter Lamprecht, Carlo Salvarani, Zaharenia Karageorgaki, Richard Watts, Raashid Luqmani, Jan Müller-Brand, Alan Tyndall, Martin A Walter

  European journal of nuclear medicine and molecular imaging. 11/2011; 39(2):344-53.

  We aimed to assess the impact of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis. An international expert panelWe aimed to assess the impact of (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis. An international expert panel determined diagnoses and clinical management in patients with suspected large vessel vasculitis, with and without the results of (18)F-FDG PET, respectively. The accuracy of the clinical diagnosis and the resulting clinical management with and without the (18)F-FDG PET results were compared using logistic regression models. The analysis included 30 patients referred to a tertiary care centre with large vessel vasculitis and 31 controls. (18)F-FDG PET had an overall sensitivity of 73.3% [95% confidence interval (CI) 54.1-87.7%], a specificity of 83.9% (95% CI 66.3-94.5%), a positive predictive value of 81.5% (95% CI 61.9-93.7%) and a negative predictive value of 76.5% (95% CI 58.8-89.3%). The diagnostic accuracy of (18)F-FDG PET was higher in patients not receiving immunosuppressive drugs (93.3 vs 64.5%, p = 0.006). Taken in context with other available diagnostic modalities, the addition of (18)F-FDG PET increased the clinical diagnostic accuracy from 54.1 to 70.5% (p = 0.04). The addition of (18)F-FDG PET increased the number of indicated biopsies from 22 of 61 patients (36.1%) to 25 of 61 patients (41.0%) and changed the treatment recommendation in 8 of 30 patients (26.7%) not receiving immunosuppressive medication and in 7 of 31 patients (22.6%) receiving immunosuppressive medication. (18)F-FDG PET is a sensitive and specific imaging tool for large vessel vasculitis, especially when performed in patients not receiving immunosuppressive drugs. It increases the overall diagnostic accuracy and has an impact on the clinical management in a significant proportion of patients.

• FDG-PET in Large Vessel Vasculitis

  Authors: Quinn K.T. Ng, Bernd Klaeser, Ulrich A. Walker, Martin A. Walter

  11/2011;

  ISBN: 978-953-307-786-4

• Comparison of dorsocervical with abdominal subcutaneous adipose tissue in patients with and without antiretroviral therapy-associated lipodystrophy.

  Authors: Ksenia Sevastianova, Jussi Sutinen, Dario Greco, Meline Sievers, Kaisa Salmenkivi, Julia Perttilä, Vesa M Olkkonen, Dick Wågsäter, Martin E Lidell, Sven Enerbäck, Per Eriksson, Ulrich A Walker, Petri Auvinen, Matti Ristola, Hannele Yki-Järvinen

  Diabetes. 05/2011; 60(7):1894-900.

  Combination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat isCombination antiretroviral therapy (cART) is associated with lipodystrophy, i.e., loss of subcutaneous adipose tissue in the abdomen, limbs, and face and its accumulation intra-abdominally. No fat is lost dorsocervically and it can even accumulate in this region (buffalo hump). It is unknown how preserved dorsocervical fat differs from abdominal subcutaneous fat in HIV-1-infected cART-treated patients with (cART+LD+) and without (cART+LD-) lipodystrophy. We used histology, microarray, PCR, and magnetic resonance imaging to compare dorsocervical and abdominal subcutaneous adipose tissue in cART+LD+ (n=21) and cART+LD- (n=11). Albeit dorsocervical adipose tissue in cART+LD+ seems spared from lipoatrophy, its mitochondrial DNA (mtDNA; copies/cell) content was significantly lower (by 62%) than that of the corresponding tissue in cART+LD-. Expression of CD68 mRNA, a marker of macrophages, and numerous inflammatory genes in microarray were significantly lower in dorsocervical versus abdominal subcutaneous adipose tissue. Genes with the greatest difference in expression between the two depots were those involved in regulation of transcription and regionalization (homeobox genes), irrespective of lipodystrophy status. There was negligible mRNA expression of uncoupling protein 1, a gene characteristic of brown adipose tissue, in either depot. Because mtDNA is depleted even in the nonatrophic dorsocervical adipose tissue, it is unlikely that the cause of lipoatrophy is loss of mtDNA. Dorsocervical adipose tissue is less inflamed than lipoatrophic adipose tissue. It does not resemble brown adipose tissue. The greatest difference in gene expression between dorsocervical and abdominal subcutaneous adipose tissue is in expression of homeobox genes.

• Nail fold capillaroscopy differs widely between systemic sclerosis and chronic graft vs host disease of the skin.

  Authors: Markus Aschwanden, Jörg P Halter, Ulrich A Walker, Daniel Staub, André Tichelli, Thomas Daikeler, Kurt A Jaeger, Alan Tyndall

  Rheumatology (Oxford, England). 03/2011; 50(6):1168-9.

• Th17 cells, not IL-17+ γδ T cells, drive arthritic bone destruction in mice and humans.

  Authors: Bernadette Pöllinger, Tobias Junt, Barbara Metzler, Ulrich A Walker, Alan Tyndall, Cyril Allard, Serkan Bay, Roland Keller, Friedrich Raulf, Franco Di Padova, Terrence O'Reilly, Nicole J Horwood, Dhavalkumar D Patel, Amanda Littlewood-Evans

  Journal of immunology (Baltimore, Md. : 1950). 02/2011; 186(4):2602-12.

  The mechanism whereby IL-17 drives rheumatoid arthritis remains incompletely understood. We demonstrate that anti-IL-17 therapy in collagen-induced arthritis ameliorates bone damage by reducing theThe mechanism whereby IL-17 drives rheumatoid arthritis remains incompletely understood. We demonstrate that anti-IL-17 therapy in collagen-induced arthritis ameliorates bone damage by reducing the number of osteoclasts in joints. We found equal numbers of CD4(+) Th17 and IL-17 producing γδ T cells in the joints of arthritic mice, and in vitro, both populations similarly induced osteoclastogenesis. However, individual depletion and adoptive transfer studies revealed that in vivo, Th17 cells dominated with regard to bone destruction. Unlike γδ T cells, Th17 cells were found in apposition to tartrate-resistant acid phosphatase positive osteoclasts in subchondral areas of inflamed joints, a pattern reproduced in patient biopsies. This localization was caused by Ag-specific retention, because OVA-primed Th17 cells showed a γδ T cell-like diffuse distribution. Because IL-23, as produced by osteoclasts, enhanced T cell-mediated osteoclastogenesis, we propose that Ag-specific juxtaposition is key to foster the molecular cross talk of Th17 cells and osteoclasts, thus driving arthritic bone destruction.

• EUSTAR biobanking: recommendations for the collection, storage and distribution of biospecimens in scleroderma research.

  Authors: Christian Beyer, Jörg H W Distler, Yannick Allanore, Martin Aringer, Jérôme Avouac, László Czirják, Maurizio Cutolo, Nemanja Damjanov, Francesco Del Galdo, Kim Fligelstone [......] Ulf Müller-Ladner, Gabriela Riemekasten, Ingo H Tarner, Alan Tyndall, Ann Tyrrell Kennedy, Gabriele Valentini, Serena Vettori, Ulrich A Walker, Christopher Denton, Oliver Distler

  Annals of the rheumatic diseases. 02/2011; 70(7):1178-82.

  The European League Against Rheumatism Scleroderma Trials and Research Group (EUSTAR) has established an online database with clinical data of currently more than 8200 patients with systemicThe European League Against Rheumatism Scleroderma Trials and Research Group (EUSTAR) has established an online database with clinical data of currently more than 8200 patients with systemic sclerosis (SSc). In addition to clinical research, EUSTAR fosters biomolecular studies to develop novel biomarkers and therapies for SSc. High-quality biospecimens are the basis for successful biomolecular studies. The EUSTAR biobanking group has therefore developed recommendations to standardise the collection, storage and distribution of SSc biospecimens at EUSTAR centres. These recommendations consider the scientific challenges associated with biomolecular research in SSc and the organisational requirements of EUSTAR. They were approved by the EUSTAR executive committee as well as the EUSTAR board. Once they become effective, these recommendations will be the basis for international EUSTAR studies with large numbers of SSc biospecimens. These recommendations might also be followed by other SSc consortia to enable exchange of biosamples between different SSc initiatives and might serve as a template for biobanking initiatives in other rheumatic diseases.

• Do new biologics meet the unmet medical need in rheumatoid arthritis? Safety and efficacy of abatacept following B-cell depletion.

  Authors: Ulrich A Walker, Delphine S Courvoisier, Jean Dudler, Daniel Aeberli, Johannes von Kempis, Almut Scherer, Axel Finckh

  Rheumatology (Oxford, England). 01/2011; 50(1):243-4.

• Clinical images: Calcinosis and capillaries.

  Authors: Markus Aschwanden, Kurt Jaeger, Daniela Benz, Alan Tyndall, Ulrich A Walker

  Arthritis and rheumatism. 01/2011; 63(1):179.

• Registries in systemic sclerosis: a worldwide experience.

  Authors: Felice Galluccio, Ulrich A Walker, Svetlana Nihtyanova, Pia Moinzadeh, Nicholas Hunzelmann, Thomas Krieg, Virginia Steen, Murray Baron, Percival Sampaio-Barros, Cristiane Kayser, Peter Nash, Chris P Denton, Alan Tyndall, Ulf Müller-Ladner, Marco Matucci-Cerinic

  Rheumatology (Oxford, England). 01/2011; 50(1):60-8.

  SSc is a multisystem disease characterized by an unpredictable course, high mortality and resistance to therapy. The complexity and severity of SSc is a growing burden on the health-care systems. AsSSc is a multisystem disease characterized by an unpredictable course, high mortality and resistance to therapy. The complexity and severity of SSc is a growing burden on the health-care systems. As a result, researchers are seeking new therapeutic strategies for effectively managing these patients. Disease registries are used to support care management efforts for groups of patients with chronic diseases and are meaningful to capture and track key patient information to assist the physicians in managing patients. For these reasons, SSc surveys, research associations and consortiums are pivotal to conduct ongoing research and data collection to enhance disease knowledge and support research projects. Currently, there are several national SSc registries in the UK, Germany, USA, Canada, Brazil and Australia. There is also an international registry established by the European League Against Rheumatism scleroderma trial and research (EUSTAR) called minimal essential data set (MEDS) Online, which collects data from over 8000 patients from 92 centres worldwide, including 21 European centres and 9 centres outside Europe. By collecting, analysing and disseminating data on disease progression and patient responses to long-term disease management strategies, registries help to improve understanding of the disease and keep medical professionals up to date on the latest advances.

• Role of pyrimidine depletion in the mitochondrial cardiotoxicity of nucleoside analogue reverse transcriptase inhibitors.

  Authors: Kerstin Balcarek, Nils Venhoff, Catherine Deveaud, Bertrand Beauvoit, Jacques Bonnet, Janbernd Kirschner, Ana C Venhoff, Dirk Lebrecht, Ulrich A Walker

  Journal of acquired immune deficiency syndromes (1999). 12/2010; 55(5):550-7.

  Long-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrialLong-term antiretroviral treatment with nucleoside analogue reverse transcriptase inhibitors (NRTI) may result in a cardiomyopathy due to mitochondrial DNA (mtDNA) depletion. An intact mitochondrial function is required for the synthesis of intramyocardial pyrimidine nucleotides, which in turn are building blocks of mtDNA. We investigated if NRTI-related cardiomyopathy can be prevented with pyrimidine precursors. Mice were fed with zidovudine or zalcitabine with or without simultaneous Mitocnol, a dietary supplement with high uridine bioavailability. Myocardia were examined after 9 weeks. Both NRTI induced a cardiomyopathy with mitochondrial enlargement, a disrupted cristal architecture on electron microscopy and diminished myocardial mtDNA copy numbers. The myocardial mtDNA-encoded cytochrome c-oxidase I subunit was impaired more profoundly than the nucleus-encoded cytochrome c-oxidase IV subunit. The myocardial formation of reactive oxygen species and mtDNA mutations was enhanced in zidovudine and zalcitabine treated animals. Mitocnol attenuated or normalized all myocardial pathology when given with both NRTI, but by itself had no intrinsic effects and no apparent adverse effects. Zidovudine and zalcitabine induce a mitochondrial cardiomyopathy, which is antagonized with uridine supplementation, implicating pyrimidine pool depletion in its pathogenesis. Pyrimidine pool replenishment may be exploited clinically because uridine is well tolerated.

• Uridine supplementation in the treatment of HIV lipoatrophy: results of ACTG 5229.

  Authors: Grace A McComsey, Ulrich A Walker, Chakra B Budhathoki, Zhaohui Su, Judith S Currier, Lisa Kosmiski, Linda G Naini, Stéphannie Charles, Kathy Medvik, Judith A Aberg

  AIDS (London, England). 10/2010; 24(16):2507-15.

  Lipoatrophy is prevalent on thymidine nucleoside reverse transcriptase inhibitors (tNRTIs). A pilot trial showed that uridine (NucleomaxX) increased limb fat. A5229 was a multicenter trial in whichLipoatrophy is prevalent on thymidine nucleoside reverse transcriptase inhibitors (tNRTIs). A pilot trial showed that uridine (NucleomaxX) increased limb fat. A5229 was a multicenter trial in which HIV-infected individuals with lipoatrophy on tNRTI regimens were randomized to NucleomaxX or placebo. Primary endpoint was change in limb fat from baseline to week 48. The study was powered to detect 400-g difference between arms at week 48. A stratified Wilcoxon rank-sum test was used to assess between-arm differences. The 165 participants were 91% men, 62% white; median age 49 years, CD4 cell count 506 cells/μl, and limb fat 3037 g; 81% had HIV-1 RNA 50 copies/ml or less; 76% were on zidovudine (ZDV). Baseline characteristics were similar between groups. Only 59% completed 48 weeks of treatment; however, only three participants (one on uridine) discontinued due to toxicity (diarrhea). In intent to treat, there was no difference for changes in limb fat between treatments at week 24 or week 48. On as-treated analysis, uridine resulted in an increase in %limb fat vs. placebo (3.4 vs. -0.8%, P = 0.01) at week 24 but not at week 48 (1.8 vs. 3.8%, P = 0.93). Similar results were seen when limiting the analysis to patients with at least 80% adherence. The results were not related to severity of lipoatrophy or type of tNRTI. No changes were found in facial anthropometrics, fasting lipids, trunk fat, CD4 cell count, or HIV RNA. We found a modest transient improvement in limb fat after 24 weeks of uridine. The lack of sustained efficacy at week 48 was not due to changes in adherence or reduction in sample size. Uridine was well tolerated and did not impair virologic control.

• Causes and risk factors for death in systemic sclerosis: a study from the EULAR Scleroderma Trials and Research (EUSTAR) database.

  Authors: Anthony J Tyndall, Bettina Bannert, Madelon Vonk, Paolo Airò, Franco Cozzi, Patricia E Carreira, Dominique Farge Bancel, Yannick Allanore, Ulf Müller-Ladner, Oliver Distler [......] Paulo C Coelho, Ina Kötter, Ismail Simsek, Paloma García de la Pena Lefebvre, Eric Hachulla, James R Seibold, Simona Rednic, Jirí Stork, Jadranka Morovic-Vergles, Ulrich A Walker

  Annals of the rheumatic diseases. 10/2010; 69(10):1809-15.

  To determine the causes and predictors of mortality in systemic sclerosis (SSc). Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in theTo determine the causes and predictors of mortality in systemic sclerosis (SSc). Patients with SSc (n=5860) fulfilling the American College of Rheumatology criteria and prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) cohort were analysed. EUSTAR centres completed a structured questionnaire on cause of death and comorbidities. Kaplan-Meier and Cox proportional hazards models were used to analyse survival in SSc subgroups and to identify predictors of mortality. Questionnaires were obtained on 234 of 284 fatalities. 55% of deaths were attributed directly to SSc and 41% to non-SSc causes; in 4% the cause of death was not assigned. Of the SSc-related deaths, 35% were attributed to pulmonary fibrosis, 26% to pulmonary arterial hypertension (PAH) and 26% to cardiac causes (mainly heart failure and arrhythmias). Among the non-SSc-related causes, infections (33%) and malignancies (31%) were followed by cardiovascular causes (29%). Of the non-SSc-related fatalities, 25% died of causes in which SSc-related complications may have participated (pneumonia, sepsis and gastrointestinal haemorrhage). Independent risk factors for mortality and their HR were: proteinuria (HR 3.34), the presence of PAH based on echocardiography (HR 2.02), pulmonary restriction (forced vital capacity below 80% of normal, HR 1.64), dyspnoea above New York Heart Association class II (HR 1.61), diffusing capacity of the lung (HR 1.20 per 10% decrease), patient age at onset of Raynaud's phenomenon (HR 1.30 per 10 years) and the modified Rodnan skin score (HR 1.20 per 10 score points). Disease-related causes, in particular pulmonary fibrosis, PAH and cardiac causes, accounted for the majority of deaths in SSc.

• Late-onset systemic sclerosis--a systematic survey of the EULAR scleroderma trials and research group database.

  Authors: Thomas Hügle, Philipp Schuetz, Thomas Daikeler, Alan Tyndall, Marco Matucci-Cerinic, Ulrich A Walker, Jacob M van Laar

  Rheumatology (Oxford, England). 09/2010; 50(1):161-5.

  The clinical course of SSc depends on subtype, organ involvement and age. Few data are reported on patients suffering from late-onset SSc. We analysed data from 8554 patients prospectively followedThe clinical course of SSc depends on subtype, organ involvement and age. Few data are reported on patients suffering from late-onset SSc. We analysed data from 8554 patients prospectively followed in the EULAR Scleroderma Trials and Research (EUSTAR) group database. Late-onset SSc was defined as onset of non-RP disease features at or beyond 75 years of age. Disease characteristics, clinical features, disease course and mortality were evaluated. A total of 123 patients with SSc onset at or beyond 75 years of age were identified. Compared with patients<75 years they had more frequently limited than diffuse SSc and a higher prevalence of anti-centromere autoantibodies. Fewer old patients had digital ulcers. The modified Rodnan's skin score, the prevalence of lung fibrosis and renal crisis did not differ significantly between groups. Pulmonary hypertension (PH) measured by echocardiography was more prevalent in the late-onset group, as well as arterial hypertension and diastolic dysfunction. Late-onset SSc remained a positive predictor for PH in multivariate analyses. No significant difference of the two groups in skin score or diffusion capacity was observed during follow-up. Mortality due to SSc was higher in the late-onset group, but the survival time from diagnosis was longer compared with the younger patients. Late-onset SSc shows a distinct clinical presentation and outcome. Patients with late-onset SSc suffer more frequently from the limited subtype and PH, but fewer patients have digital ulcers. PH may in part be determined by underlying cardiovascular disease.

• Skeletal muscle mitochondrial DNA content and aerobic metabolism in patients with antiretroviral therapy-associated lipoatrophy.

  Authors: Jussi Sutinen, Marko S Laaksonen, Ulrich A Walker, Bernhard Setzer, Jukka Kemppainen, Pirjo Nuutila, Hannele Yki-Järvinen

  The Journal of antimicrobial chemotherapy. 07/2010; 65(7):1497-504.

  To assess whether mitochondrial dysfunction in skeletal muscle characterizes antiretroviral therapy (ART)-associated lipoatrophy (LA). A cross-sectional study comparing HIV-infected,To assess whether mitochondrial dysfunction in skeletal muscle characterizes antiretroviral therapy (ART)-associated lipoatrophy (LA). A cross-sectional study comparing HIV-infected, antiretroviral-treated patients with LA (n = 5; LA+) and without LA (n = 5; non-LA) was conducted. Positron emission tomography was used to measure blood flow, oxygen extraction and oxygen consumption in quadriceps femoris muscle during rest and aerobic exercise. Mitochondrial DNA (mtDNA) was quantified by PCR. Body composition was measured by dual-energy X-ray absorptiometry and magnetic resonance imaging. All data are given as means +/- SEM. Compared with the non-LA group, the LA+ group had significantly less limb fat and more intra-abdominal fat, but similar leg muscle mass. The LA+ group versus the non-LA group had reduced mtDNA content per nucleus in adipose tissue (173 +/- 38 versus 328 +/- 62; P = 0.067), but not in skeletal muscle (2606 +/- 375 versus 2842 +/- 309; P = 0.64). Perfusion in resting muscle (34 +/- 7 versus 28 +/- 6 mL/kg/min in the LA+ group versus the non-LA group; P = 0.5), and the mean absolute (277 +/- 30 versus 274 +/- 43 mL/kg/min, respectively; P = 0.95) and relative (10.6 +/- 2.5- versus 11.9 +/- 1.5-fold change, respectively; P = 0.67) increases in perfusion during exercise were similar between the groups. Oxygen consumption at rest (2.2 +/- 0.7 versus 2.1 +/- 0.3 mL/kg/min in the LA+ group versus the non-LA group; P = 0.9), and the mean absolute (14.6 +/- 1.7 versus 24.3 +/- 8.8 mL/kg/min, respectively; P = 0.3) and relative (10.3 +/- 2.8- versus 11.7 +/- 2.4-fold change, respectively; P = 0.73) exercise-induced increases in oxygen consumption were similar between the groups. The oxygen extraction fraction was comparable between the groups, both at rest and during exercise. Plasma lactate concentrations remained unchanged in both groups during exercise. HIV-infected patients with ART-associated LA have similar mtDNA content in skeletal muscle and comparable skeletal muscle aerobic exercise metabolism to antiretroviral-treated non-lipoatrophic patients.

• Vascular involvement in patients with giant cell arteritis determined by duplex sonography of 2x11 arterial regions.

  Authors: Markus Aschwanden, Friederike Kesten, Martin Stern, Christoph Thalhammer, Ulrich A Walker, Alan Tyndall, Kurt A Jaeger, Christoph Hess, Thomas Daikeler

  Annals of the rheumatic diseases. 07/2010; 69(7):1356-9.

  To define the specificity and extent of duplex sonography (DS) findings suggestive of vessel wall inflammation in patients with giant cell arteritis (GCA). Patients admitted between December 2006 andTo define the specificity and extent of duplex sonography (DS) findings suggestive of vessel wall inflammation in patients with giant cell arteritis (GCA). Patients admitted between December 2006 and April 2009 to the University Hospital Basel with a suspicion of GCA were eligible for the study. DS of 2x11 arterial regions was performed in all study participants, and American College of Rheumatology criteria were applied to classify patients into GCA or non-GCA groups. GCA was diagnosed in 38 of the 72 participants (53%). A DS pattern suggestive of vessel wall inflammation was not observed in any of the patients in the non-GCA group but, in 21 of the 38 patients with GCA (55%), DS signs suggestive of vessel wall inflammation of > or =1 vessel region were detected. In 12 of the 38 patients with GCA (32%), DS signs of large vessel vasculitis (LVV) were found in > or =1 vessel region(s) of both upper and lower limb vessels. Follow-up DS was performed 6 months after the baseline examination in 9 of the 12 patients with LVV and showed the persistence of most findings despite normalised signs of systemic inflammation. DS detects changes in the vessel wall that appear to be specific for GCA; they can be present in upper and lower limb arteries of patients with GCA. Surprisingly, DS-detectable LVV and signs of systemic inflammation are largely dissociated.

• Oral uridine supplementation antagonizes the peripheral neuropathy and encephalopathy induced by antiretroviral nucleoside analogues.

  Authors: Nils Venhoff, Dirk Lebrecht, Catherine Deveaud, Bertrand Beauvoit, Jacques Bonnet, Klaus Müller, Janbernd Kirschner, Ana C Venhoff, Ulrich A Walker

  AIDS (London, England). 01/2010; 24(3):345-52.

  Peripheral neuropathy and central nervous system neurodegeneration may result from the mitochondrial toxicity of some antiretroviral nucleoside analogues. We investigated whether this neuropathologyPeripheral neuropathy and central nervous system neurodegeneration may result from the mitochondrial toxicity of some antiretroviral nucleoside analogues. We investigated whether this neuropathology may be antagonized by uridine supplementation in vivo. Because of the obvious difficulties in obtaining human neural tissues, the mitochondrial neurotoxicity of the nucleoside analogues was studied in mice. BALB/C mice (7 weeks of age) were fed for 9 weeks with zalcitabine (13 mg/kg per day) or zidovudine (100 mg/kg per day) with or without mitocnol (340 mg/kg per day), a dietary supplement with high uridine bioavailability. Hippocampal and sciatic nerve mitochondria were analyzed. Zalcitabine and to a lesser extent zidovudine induced a significant peripheral neuropathy and encephalopathy with disrupted mitochondrial ultrastructure, depleted mitochondrial DNA, reduced levels of cytochrome c oxidase activity and diminished expression of mitochondrial DNA-encoded cytochrome c oxidase subunit I. Mitocnol had no intrinsic effects but attenuated or fully normalized all measured disorder of the peripheral and central nervous system. Zidovudine and zalcitabine induce a mitochondrial disorder in the peripheral and central nervous system, both of which are antagonized by uridine supplementation.