bluuebunny/crossref_metadata_2025 huggingface dataset:
Maintenance of infliximab treatment in ankylosing spondylitis: Results of a one‐year randomized controlled trial comparing systematic versus on‐demand treatment
Authors: Breban Maxime , Ravaud Philippe , Claudepierre Pascal , Baron Gabriel , Henry Yves‐Dominique , Hudry Christophe , Euller‐Ziegler Liana , Pham Thao , Solau‐Gervais Elisabeth , Chary‐Valckenaere Isabelle , Marcelli Christian , Perdriger Aleth , Le Loët Xavier , Wendling Daniel , Fautrel Bruno , Fournié Bernard , Combe Bernard , Gaudin Philippe , Jousse Sandrine , Mariette Xavier , Baleydier Alain , Trape Gérard , Dougados Maxime ,   French Ankylosing Spondylitis Infliximab Network
Published: December 2007

Objective

Continuous treatment with the anti–tumor necrosis factor α (anti‐TNFα) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested.

Methods

Patients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on‐demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on‐demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58.

Results

Of 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on‐demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on‐demand treatment (75% versus 46%; P < 0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on‐demand group (mean ± SD 5.8 ± 2.2 versus 3.5 ± 2; P < 0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered.

Conclusion

These findings indicate that continuous treatment of AS with infliximab is more efficacious than on‐demand treatment, and that the addition of MTX to infliximab provides no significant benefit.
Investigation of sensory neurogenic components in a bleomycin‐induced scleroderma model using transient receptor potential vanilloid 1 receptor– and calcitonin gene‐related peptide–knockout mice
Authors: Szabó Árpád , Czirják László , Sándor Zoltán , Helyes Zsuzsanna , László Terézia , Elekes Krisztián , Czömpöly Tamás , Starr Anna , Brain Susan , Szolcsányi János , Pintér Erika
Published: December 2007

Objective

Along with their classic afferent function (nociception), capsaicin‐sensitive transient receptor potential vanilloid 1 (TRPV1) receptor–expressing sensory nerve terminals exert local and systemic efferent activities. Activation of TRPV1 causes sensory neuropeptide release, which modulates the inflammation process. The aim of the present study was to examine the role of this modulatory role of TRPV1 receptor and that of calcitonin gene‐related peptide (CGRP) in bleomycin‐induced scleroderma, using transgenic mice.

Methods

Cutaneous sclerosis was induced with daily subcutaneous injections of bleomycin for 30 days. Control groups were treated with phosphate buffered saline (PBS). TRPV1 receptor gene–deficient (TRPV1−/−) mice and CGRP‐knockout (CGRP−/−) mice and their wild‐type (WT) counterparts were investigated. A composite sclerosis score was calculated on the basis of thickening, leukocyte infiltration, and the amount/orientation of collagen bundles. Dermal thickness and the number of α‐smooth muscle actin (α‐SMA)–positive cells were also determined. The quantity of the collagen‐specific amino acid hydroxyproline was measured by spectrophotometry.

Results

Bleomycin treatment induced marked cutaneous thickening and fibrosis compared with that observed in control mice treated with PBS. The composite sclerosis score was 18% higher, dermal thickness was 19% higher, the number of α‐SMA–positive cells was 47% higher, and the amount of hydroxyproline was 57% higher in TRPV1−/− mice than in their WT counterparts. Similarly, the composite sclerosis score was 47% higher, dermal thickness was 29% higher, the number of α‐SMA–positive cells was 76% higher, and the amount of hydroxyproline was 30% higher in CGRP−/− mice than in the respective WT groups.

Conclusion

These results suggest that activation of the TRPV1 receptor by mediators of inflammation induces sensory neuropeptide release, which might exert protective action against fibrosis. We confirmed the protective role of CGRP in the development of cutaneous sclerosis.
Sphingomyelinase decreases type II collagen expression in bovine articular cartilage chondrocytes via the ERK signaling pathway
Authors: Gilbert S. J. , Blain E. J. , Duance V. C. , Mason D. J.
Published: December 2007

Objective

Ceramide, a mediator of proinflammatory cytokine signaling, induces cartilage degradation and reduces type II collagen synthesis in articular cartilage. The accumulation of ceramide is associated with arthritis in Farber's disease. The aim of this study was to investigate the mechanism of ceramide‐induced down‐regulation of type II collagen.

Methods

Bovine articular chondrocytes were stimulated with sphingomyelinase (SMase) to increase levels of endogenous ceramide. Components of the ERK pathway were inhibited by Raf‐1 kinase inhibitor and the MEK inhibitor, PD98059. Cell extracts were analyzed by Western blotting for ERK‐1/2, SOX9, c‐Fos, and type II collagen, and the level of c‐fos messenger RNA (mRNA) was analyzed by quantitative polymerase chain reaction. Localization of ERK‐1/2, SOX9, and c‐Fos was assessed by immunocytochemistry and confocal microscopy.

Results

SMase treatment of chondrocytes caused sustained phosphorylation of ERK‐1/2 throughout the cytoplasm and nucleus that was reduced by inhibitors of Raf‐1 kinase and MEK‐1/2. SMase treatment of chondrocytes also induced translocation of c‐Fos to the nucleus and phospho‐SOX9 to the cytoplasm and increased expression of c‐fos mRNA. Type II collagen expression, which was down‐regulated by SMase treatment, was restored by the MEK‐1/2 inhibitor, PD98059.

Conclusion

SMase down‐regulates type II collagen in articular chondrocytes via activation of the ERK signaling cascade, redistribution of SOX9, and recruitment of c‐Fos. This new mechanism for cartilage degradation provides potential targets for future treatment of arthritic disease.
Central bone marrow lesions in symptomatic knee osteoarthritis and their relationship to anterior cruciate ligament tears and cartilage loss
Authors: Hernández‐Molina Gabriela , Guermazi Ali , Niu Jingbo , Gale Daniel , Goggins Joyce , Amin Shreyasee , Felson David T.
Published: December 2007

Objective

Medial and lateral compartment bone marrow lesions (BMLs) have been tied to cartilage loss. We undertook this study to assess 2 types of BMLs in the central region of the knee (type 1 BMLs, which are related anatomically to anterior cruciate ligament [ACL]/posterior cruciate ligament [PCL] insertions, and type 2 BMLs, which encompass both the central region and either the medial or the lateral compartment) and determine their relationship to cartilage loss and ACL tears.

Methods

Magnetic resonance imaging (MRI) of the knee was performed at baseline and at followup (15 and/or 30 months) in 258 subjects with symptomatic osteoarthritis (OA). At baseline, we assessed ACL tears and central BMLs located at or between the tibial spines or adjacent to the femoral notch. Cartilage loss was present if the score in any region of the tibiofemoral joint increased by ≥1 units at the last available followup, using a modified Whole‐Organ MRI Score. We used logistic regression adjusted for alignment, body mass index, Kellgren/Lawrence score, sex, and age.

Results

One hundred thirty‐nine knees (53.8%) had central BMLs, of which 129 had type 1 BMLs (96 abutted the ACL and had no coexistent type 2 features) and 25 had type 2 BMLs (often overlapped with type 1). Type 1 lesions were associated with ACL tears (odds ratio [OR] 5.9, 95% confidence interval [95% CI] 2.2–16.2) but not with cartilage loss (OR 1.6, 95% CI 0.8–3.1), while medial type 2 BMLs were related to medial cartilage loss (OR 6.1, 95% CI 1.0–35.2).

Conclusion

Central BMLs that abutted the ACL were highly prevalent and strongly related to ACL pathology, suggesting a role of enthesopathy in OA. Only BMLs with medial extension were related to ipsilateral cartilage loss.
Expression of mucin 3 and mucin 5AC in arthritic synovial tissue
Authors: Volin Michael V. , Shahrara Shiva , Haines G. Kenneth , Woods James M. , Koch Alisa E.
Published: December 2007

Objective

Rheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by hypertrophy of the synovial tissue, leukocyte infiltration, angiogenesis, and ultimately joint destruction. Mucins (MUCs) are a family of heavily glycosylated proteins that protect epithelial membranes and are used as ligands for cell adhesion. MUC gene expression has been found to be altered in many cancers and inflammatory states. This study was undertaken to examine its expression in synovial tissue (ST) and role in arthritis.

Methods

We performed immunohistochemistry, Western blotting, and reverse transcriptase–polymerase chain reaction to determine expression patterns of MUC1, MUC2, MUC3, and MUC5AC in RA, osteoarthritic (OA), and normal human ST.

Results

MUC3 was expressed in synovial lining cells, macrophages, and fibroblasts. Significantly more RA (n = 12) and OA (n = 13) synovial lining cells expressed MUC3 than did normal synovial lining cells (n = 7) (22% and 24% versus 0.4%, respectively; P < 0.05). Additionally, macrophages in RA and OA ST expressed significantly more MUC3 than did macrophages in normal ST (50% and 51% versus 10%, respectively; P < 0.05). MUC5AC was expressed at low levels in synovial lining cells, macrophages, and endothelial cells in RA and OA ST, and was barely expressed in normal ST. MUC1 and MUC2 proteins were not detected in ST. Messenger RNA (mRNA) for MUC3 and MUC5AC was detected in ST, and mRNA for MUC3 was detected in cultured ST fibroblasts.

Conclusion

These data demonstrate up‐regulated MUC expression by ST cells and suggest a novel role of MUC3 and MUC5AC in the pathogenesis of arthritis.
Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II
Authors: Lawrence Reva C. , Felson David T. , Helmick Charles G. , Arnold Lesley M. , Choi Hyon , Deyo Richard A. , Gabriel Sherine , Hirsch Rosemarie , Hochberg Marc C. , Hunder Gene G. , Jordan Joanne M. , Katz Jeffrey N. , Kremers Hilal Maradit , Wolfe Frederick ,   National Arthritis Data Workgroup
Published: December 2007

Objective

To provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions.

Methods

The National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition.

Results

We estimated that among US adults, nearly 27 million have clinical osteoarthritis (up from the estimate of 21 million for 1995), 711,000 have polymyalgia rheumatica, 228,000 have giant cell arteritis, up to 3.0 million have had self‐reported gout in the past year (up from the estimate of 2.1 million for 1995), 5.0 million have fibromyalgia, 4–10 million have carpal tunnel syndrome, 59 million have had low back pain in the past 3 months, and 30.1 million have had neck pain in the past 3 months.

Conclusion

Estimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions more studies generalizable to the US or addressing understudied populations are needed.
Atacicept in patients with rheumatoid arthritis: Results of a multicenter, phase ib, double‐blind, placebo‐controlled, dose‐escalating, single‐ and repeated‐dose study
Authors: Tak P. P. , Thurlings R. M. , Rossier C. , Nestorov I. , Dimic A. , Mircetic V. , Rischmueller M. , Nasonov E. , Shmidt E. , Emery P. , Munafo A.
Published: December 2007

Objective

Atacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.

Methods

In this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.

Results

Atacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.

Conclusion

Atacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.
Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: Role of interleukin‐18
Authors: Tucci Marco , Quatraro Cosima , Lombardi Lucia , Pellegrino Cecilia , Dammacco Franco , Silvestris Franco
Published: December 2007

Objective

Defective circulating dendritic cells (DCs) have been described in systemic lupus erythematosus (SLE) and correlated with high levels of interferon‐α (IFNα). DCs are differentiated as being either myeloid or plasmacytoid, according to chemokine expression and the tendency to migrate toward inflamed tissue. We investigated the potential role of interleukin‐18 (IL‐18) in driving the glomerular migration of DCs in lupus nephritis (LN) and in affecting the ability of DCs to induce an imbalance in the Th1:Th2 ratio.

Methods

DC subsets were characterized by flow cytometry and defined as either myeloid or plasmacytoid according to the expression of CD11c/blood dendritic cell antigen 1 (BDCA‐1) and CD123/BDCA‐2, respectively. The serum Th1:Th2 profile was studied by enzyme‐linked immunosorbent assay. IL‐18 receptor (IL‐18R) and other chemokine receptors were analyzed by flow cytometry. Glomerular levels of IL‐18/IL‐18R and the presence of plasmacytoid DCs and myeloid DCs were investigated by immunohistochemical analysis.

Results

The number of peripheral plasmacytoid DCs was decreased in patients with SLE compared with control subjects, and this defect in the number of DCs was correlated with LN. Patients with LN showed a prevalent Th1 response, with high production of IL‐18, IL‐12 and IFNγ. Only plasmacytoid DCs expressed IL‐18R. Patients with severe LN showed a high accumulation of IL‐18 within glomeruli in association with the presence of plasmacytoid DCs, whereas myeloid DCs were almost absent.

Conclusion

A deficient number of peripheral plasmacytoid DCs correlated with high levels of Th1 cytokines and was associated with LN. Both serum and glomerular IL‐18 were increased in LN. It is suggested that the high level of expression of IL‐18R by peripheral plasmacytoid DCs allows the DCs to relocate within glomeruli under IL‐18 stimulation and triggers the resident T cells, thus promoting renal damage.
High N‐terminal pro–brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis
Authors: Allanore Y. , Borderie D. , Avouac J. , Zerkak D. , Meune C. , Hachulla E. , Mouthon L. , Guillevin L. , Meyer O. , Ekindjian O. G. , Weber S. , Kahan A.
Published: December 2007

Objective

To evaluate predictors of pulmonary arterial hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc).

Methods

Routine clinical assessments as well as measurements of the diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA) ratio and N‐terminal pro–brain natriuretic peptide (NT‐proBNP) level were performed in a prospective cohort of 101 SSc patients who did not have PAH or severe comorbidities. After a planned 36‐month followup, we evaluated the predictive value of these parameters for the development of precapillary PAH, as demonstrated by cardiac catheterization, disease progression, and death. Criteria for cardiac catheterization were a systolic pulmonary artery pressure (PAP) of >40 mm Hg on echocardiography, a DLCO value of <50% without pulmonary fibrosis, and unexplained dyspnea.

Results

Eight patients developed PAH, 29 had disease progression, and 10 died during a median followup of 29 months. Kaplan‐Meier analysis identified the following baseline parameters as being predictors of PAH: DLCO/VA ratio <70% or <60% (P < 0.01 for each comparison), elevated plasma NT‐proBNP level (>97th percentile of normal; P = 0.005), echocardiographically estimated systolic PAP >40 mm Hg (P = 0.08), and erythrocyte sedimentation rate >28 mm/hour (P = 0.015). In multivariate analyses, an elevated baseline NT‐proBNP level (hazard ratio [HR] 9.97 [95% confidence interval (95% CI) 1.69–62.42]) and a DLCO/VA ratio <60% (HR 36.66 [95% CI 3.45–387.6]) were predictors of the occurrence of PAH during followup. An increased NT‐proBNP level together with a decreased DLCO/VA ratio of <70% was highly predictive of the occurrence of PAH during followup (HR 47.20 [95% CI 4.90–450.33]).

Conclusion

This prospective study identified a decreased DLCO/VA ratio and an increased NT‐proBNP as predictors of PAH in SSc. Use of these markers should result in improved PAH risk stratification and allow earlier initiation of therapy.
Antibodies against citrullinated vimentin in rheumatoid arthritis: Higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides
Authors: Mathsson Linda , Mullazehi Mohammed , Wick Marius C. , Sjöberg Olof , van Vollenhoven Ronald , Klareskog Lars , Rönnelid Johan
Published: December 2007

Objective

The Sa autoantigen can be found in inflamed synovium of patients with rheumatoid arthritis (RA), and at least part of the humoral RA‐specific anti‐Sa response is directed against citrullinated vimentin. This study was undertaken to evaluate the sensitivity, specificity, and prognostic value of determination of levels of antibodies against modified citrullinated vimentin (anti‐MCV) as compared with antibodies against cyclic citrullinated peptides (anti‐CCP) in an inception cohort of patients with early RA.

Methods

Clinical data, radiographs, and measurements of levels of anti‐MCV and anti‐CCP antibodies were obtained in 273 patients with early RA at baseline, after 3 months, and after 1, 2, 3, and 5 years. Autoantibodies were also analyzed in 100 healthy controls.

Results

Of the 273 patients, 193 (70.7%) were anti‐MCV positive and 158 (57.9%) were anti‐CCP positive at the time of diagnosis, with nearly equal specificities (95% and 96%, respectively). Forty (14.7%) were anti‐MCV positive only, and 5 (1.8%) were anti‐CCP positive only. Anti‐MCV–positive and anti‐MCV–negative patients had similar disease activity at baseline, but presence of anti‐MCV was predictive of subsequent high disease activity and continued radiographic progression. Changes in anti‐MCV level showed stronger correlation with changes in clinical parameters than did changes in anti‐CCP level. The subgroup of patients who were anti‐MCV positive and anti‐CCP negative showed a higher rate of radiographic destruction than did patients who were negative for both anti‐MCV and anti‐CCP.

Conclusion

These findings show that when patients with early RA are compared with healthy controls, analysis of anti‐MCV yields greater sensitivity and unchanged specificity as compared with analysis of anti‐CCP. Anti‐MCV also appears to perform better than anti‐CCP in identifying poor radiographic prognosis in patients with early RA.
Amphipathic weak acid glucocorticoid prodrugs remote‐loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a Beagle dog: A novel approach to treating autoimmune arthritis
Authors: Avnir Yuval , Ulmansky Rina , Wasserman Veronica , Even‐Chen Simcha , Broyer Maya , Barenholz Yechezkel , Naparstek Yaakov
Published: December 2007

Objective

The use of glucocorticoids (GCs) in rheumatoid arthritis is limited by side effects related to unfavorable pharmacokinetics and biodistribution. Liposomal GC formulations have been studied since the 1970s in an attempt to overcome this obstacle, but none has entered clinical use. We undertook this study to determine whether a novel approach could overcome the limitations that have thus far prevented the clinical use of these formulations: low drug:lipid ratio, low encapsulation efficiency, and lack of controlled release.

Methods

We used ∼80‐nm sterically stabilized (pegylated) nanoliposomes (NSSLs), which were remote‐loaded with an amphipathic weak acid GC (such as methyl prednisolone hemisuccinate) utilizing an intraliposome (aqueous compartment)–high/extraliposome (bulk medium)–low transmembrane calcium acetate gradient. This unique method actually “traps” the GC in the liposomal aqueous phase as a calcium–GC precipitate.

Results

Our liposome formulation exhibited high encapsulation efficiency (94%) and a high drug:lipid mole ratio (0.41) and demonstrated controlled release of the encapsulated GC during systemic circulation and in inflamed paws in rats with adjuvant‐induced arthritis. In addition, both in arthritic rats and in a Beagle dog, we showed the pharmacokinetic advantage of using liposomes as GC carriers. Finally, we demonstrated the superior therapeutic efficacy of our liposome formulation over that of free GCs in arthritic rats, both in early and in peak disease stages.

Conclusion

Amphipathic weak acid GCs remote‐loaded into ∼80‐nm NSSLs overcome past limitations of liposomal GC formulations. The unique loading method, which also leads to controlled release, improves the therapeutic effect both systemically and locally. Such a development has great potential for improving GC therapy.
Early‐onset degeneration of the intervertebral disc and vertebral end plate in mice deficient in type IX collagen
Authors: Boyd Lawrence M. , Richardson William J. , Allen Kyle D. , Flahiff Charlene , Jing Liufang , Li Yefu , Chen Jun , Setton Lori A.
Published: December 2007

Objective

Type IX collagen is an important component of the intervertebral disc extracellular matrix. Mutations in type IX collagen are associated with premature disc degeneration in mice and a predisposition to disc disorders in humans. The aim of this study was to assess the prevalence and timeline of intervertebral disc degeneration in mice homozygous for an inactivated Col9a1 gene.

Methods

Intact spine segments were harvested from wild‐type (WT) and type IX collagen–knockout (Col9a1−/−) mice at 3, 6, and 12 months of age. Sagittal spine sections were evaluated for evidence of histologic changes, by 2 blinded graders, using a semiquantitative grading method.

Results

There was evidence of more degeneration of the disc and end plate in the spines of Col9a1−/− mice compared with those of WT controls, at most time points. These findings were significant for the disc region at 3 and 6 months (P < 0.01) and at 12 months (P < 0.10) and for the end plate region only at 6 months (P < 0.10). Degenerative changes in the disc consisted of cellular changes and mucous degeneration. Degeneration in the end plates was associated with more cell proliferation, cartilage disorganization, and new bone formation.

Conclusion

A deletion mutation for type IX collagen is associated with connective tissue changes characteristic of musculoskeletal degeneration in bony and cartilaginous tissue regions. Some of the observed changes were similar to cartilage changes in osteoarthritis, while others were more similar to disc degenerative changes in humans. The finding of premature onset of intervertebral disc degeneration in this mouse model may be useful in studies of the pathology and treatment of human disc degeneration.
Uridine supplementation antagonizes zidovudine‐induced mitochondrial myopathy and hyperlactatemia in mice
Authors: Lebrecht Dirk , Deveaud Catherine , Beauvoit Bertrand , Bonnet Jacques , Kirschner Janbernd , Walker Ulrich A.
Published: December 2007

Objective

Zidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of mitochondrial DNA (mtDNA). Because zidovudine inhibits thymidine kinases, the mechanism of mtDNA depletion may be related to an impairment of the de novo synthesis of pyrimidine nucleotides, which are required building blocks of mtDNA. This study was undertaken to determine whether mitochondrial myopathy is a class effect of antiretroviral nucleoside analogs, and whether the muscle disease can be prevented by treatment with uridine as a pyrimidine nucleotide precursor.

Methods

BALB/c mice were treated with zidovudine or zalcitabine. Some of the mice were cotreated with mitocnol, a dietary supplement with high uridine bioavailability. Mice hind limb muscles were examined after 10 weeks.

Results

Zidovudine induced muscle fiber thinning, myocellular fat deposition, and abnormalities of mitochondrial ultrastructure. In mice treated with zidovudine, organelles contained low mtDNA copy numbers and reduced cytochrome c oxidase activity. The expression of the mtDNA‐encoded cytochrome c oxidase I subunit, but not of nucleus‐encoded mitochondrial proteins, was impaired. Zidovudine also increased the levels of myocellular reactive oxygen species and blood lactate. Uridine supplementation attenuated or normalized all pathologic abnormalities and had no intrinsic effects. Zalcitabine did not elicit muscle toxicity.

Conclusion

Our findings indicate that zidovudine, but not zalcitabine, induces mitochondrial myopathy, which is substantially antagonized by uridine supplementation. These results provide proof of the importance of pyrimidine pools in the pathogenesis of zidovudine myopathy. Since uridine supplementation is tolerated well by humans, this treatment strategy should be investigated in clinical trials.
Index to ring finger length ratio and the risk of osteoarthritis
Authors: Zhang W. , Robertson J. , Doherty S. , Liu J. J. , Maciewicz R. A. , Muir K. R. , Doherty M.
Published: December 2007

Objective

To determine the relationship between the index to ring finger (2D:4D) length ratio and the risk of knee and hip osteoarthritis (OA).

Methods

We conducted a case–control study, in which cases with persistent symptoms and radiographic evidence of knee or hip OA were compared with controls with no symptoms and no radiographic evidence of knee or hip OA. Hand radiographs were visually classified as type 1 (index finger longer than the ring finger), type 2 (index finger equal to the ring finger), or type 3 (index finger shorter than the ring finger). The 2D:4D phalangeal and metacarpal length ratios were measured separately. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated and adjusted for possible confounding factors using a logistic regression model.

Results

Of 2,049 cases, 1,013 had radiographic evidence of knee OA and 995 had hip OA. Of 1,123 controls, 836 had no knee OA and 1,050 had no hip OA. The type 3 finger pattern was associated with knee OA (OR 1.94, 95% CI 1.54–2.44), and the risk was greater in women (OR 3.05, 95% CI 2.08–4.47) than in men (OR 1.45, 95% CI 1.08–1.95). There was a dose‐response relationship between both 2D:4D phalangeal and metacarpal length ratios and the risk of knee OA. The risk of hip OA was inconsistent.

Conclusion

Compared with types 1 and 2, the type 3 “male” pattern 2D:4D length ratio is associated with OA, especially knee OA. The risk is independent of other major OA risk factors.
A randomized controlled trial of the people with arthritis can exercise program: Symptoms, function, physical activity, and psychosocial outcomes
Authors: Callahan Leigh F. , Mielenz Thelma , Freburger Janet , Shreffler Jack , Hootman Jennifer , Brady Teresa , Buysse Katherine , Schwartz Todd
Published: December 2007

Objective

To evaluate the basic 8‐week People with Arthritis Can Exercise (PACE) program for improvements in primary (symptoms, functioning, level of physical activity) and secondary (psychosocial) outcomes.

Methods

A total of 346 individuals with self‐reported arthritis from 18 sites participated in a randomized controlled trial of PACE. Outcomes were measured at baseline and 8 weeks. The intervention group completed self‐reported assessments at 3 and 6 months. Two‐level multiple linear regression models were estimated to calculate adjusted outcome means in the intervention and control groups. A mixed‐effects repeated‐measures model was used to calculate adjusted means in the intervention group at 3 and 6 months. Both intent‐to‐treat (ITT) and as‐treated (AT) analyses were conducted.

Results

At 8 weeks, the intervention group had improvements in the following outcomes: 2 symptom outcomes (pain, fatigue) and 1 psychosocial outcome (self‐efficacy for managing arthritis) in the ITT analyses; 1 symptom outcome (pain), 1 function outcome (chair stands), and 1 psychosocial outcome (self‐efficacy for arthritis management) in the AT analyses. In addition, completers who attended ≥9 classes had improvements in 3 symptom outcomes (pain, fatigue, stiffness), 2 function outcomes (10‐pound lifts, chair stands), and 1 psychosocial outcome (self‐efficacy for arthritis management) at 8 weeks. Relative to baseline, PACE participants maintained significant improvements in symptoms at 6 months, but declined in function and self‐efficacy for exercise.

Conclusion

If adults with arthritis attend a majority of PACE classes, they may expect improvements in symptoms, self‐efficacy for arthritis management, and upper and lower extremity function. Achieving sustained improvement in outcomes may require continued participation in PACE.
Reduced lower extremity vibratory perception in osteoarthritis of the knee
Authors: Shakoor Najia , Agrawal Alan , Block Joel A.
Published: December 2007

Objective

Vibratory perception threshold (VPT) assesses a distinct yet related sensory pathway that has been associated with neuropathic arthropathy but has not been assessed in knee osteoarthritis (OA). The purpose of this study was to evaluate VPT in subjects with knee OA to determine whether the lower extremity afferent deficits observed in knee OA involve more than just proprioception.

Methods

Twenty‐seven individuals with symptomatic and radiographic knee OA were compared with 14 age‐matched normal subjects. VPT was assessed using a biothesiometer. Five sites of the lower extremity were evaluated. VPT of OA subjects was compared with VPT of normal subjects.

Results

VPT of the OA subjects was significantly reduced at all 5 testing sites compared with normal subjects (P < 0.05 at all sites). VPT scores (mean ± SEM volts) for OA subjects and normal subjects were as follows: first metatarsophalangeal joint (15.0 ± 1.9 versus 6.4 ± 0.9), medial malleolus (22.0 ± 2.2 versus 12.3 ± 1.4), lateral malleolus (22.3 ± 2.0 versus 10.4 ± 0.8), medial femoral condyle (25.8 ± 1.8 versus 15.9 ± 1.9), and lateral femoral condyle (27 ± 1.9 versus 18.9 ± 2.4).

Conclusion

This was the first study to evaluate VPT in OA and demonstrate that VPT is reduced at the lower extremity of subjects with knee OA. The noted deficits in VPT may have significant implications in the neuromechanical pathophysiology of OA. VPT is a simple and reliable technique to measure sensory deficits in subjects with OA of the knee.
Patellar taping and bracing for the treatment of chronic knee pain: A systematic review and meta‐analysis
Authors: Warden Stuart J. , Hinman Rana S. , Watson Mark A. , Avin Keith G. , Bialocerkowski Andrea E. , Crossley Kay M.
Published: December 2007

Objective

To evaluate the evidence for patellar taping and bracing in the management of chronic knee pain.

Methods

Randomized or quasi‐randomized studies assessing patellar taping or bracing effects on chronic knee pain were sourced from 7 electronic databases (to November 2006), and assessed using the Physiotherapy Evidence Database scale. Weighted mean differences were determined, and pooled estimates of taping and bracing effects were obtained using random‐effects models.

Results

Of 16 eligible trials, 13 investigated patellar taping or bracing effects in individuals with anterior knee pain, and 3 investigated taping effects in individuals with knee osteoarthritis (OA). The methodologic quality of the taping studies was significantly higher than the bracing studies (mean ± SD 4.8 ± 2.1 versus 2.8 ± 0.8; P < 0.05). On a 100‐mm scale, tape applied to exert a medially‐directed force on the patella decreased chronic knee pain compared with no tape by 16.1 mm (95% confidence interval [95% CI] −22.2, −10.0; P < 0.001) and sham tape by 10.9 mm (95% CI −18.4, −3.4; P < 0.001). For anterior knee pain and OA, medially‐directed tape decreased pain compared with no tape by 14.7 mm (95% CI −22.8, −6.9; P < 0.001) and 20.1 mm (95% CI −26.0, −14.3; P < 0.001), respectively. There was disputable evidence from low‐quality studies for patellar bracing benefits.

Conclusion

There was evidence that tape applied to exert a medially‐directed force on the patella produces a clinically meaningful change in chronic knee pain. There was limited evidence to demonstrate the efficacy of patellar bracing. These outcomes were limited by the presence of high heterogeneity between study outcomes and significant publication bias.
Understanding ethnic disparities in the use of total joint arthroplasty: Application of the health belief model
Authors: Ang Dennis C. , Monahan Patrick O. , Cronan Terry A.
Published: December 2007

Objective

The Health Belief Model holds promise in understanding patient‐related factors that may explain disparities in the use of total joint arthroplasty (TJA). We examined whether patients' health beliefs differ between African Americans and whites.

Methods

In a primary care clinic setting, 691 African Americans and whites with at least a moderately severe degree of osteoarthritis (OA) completed the Arthritis‐related Health Belief Instrument. The instrument has 4 scales: perceived benefits of TJA, perceived barriers to obtaining TJA, perceived severity of arthritis, and perceived susceptibility of arthritis to worsen.

Results

The sample (40% women) consisted of 263 (38%) African Americans and 428 (62%) whites who were similar with respect to education, amount of insurance coverage, number of comorbidities, and self‐report OA severity score. The African American group was younger, had less men, had more participants who reported an annual income <$15,000, and had a higher body mass index than whites. After controlling for confounders, African Americans were almost 50% (odds ratio [OR] 0.60, 95% confidence interval [95% CI] 0.42–0.86, P = 0.005) as likely as whites to perceive that TJA is beneficial or helpful for their arthritis. Furthermore, African Americans were 70% (OR 1.7, 95% CI 1.18–2.44, P = 0.004) more likely than whites to recognize barriers (e.g., risky, etc.) to TJA. Race was not associated with either the perceived severity or the perceived susceptibility of arthritis to worsen.

Conclusion

Among patients with at least moderately severe OA, African Americans were significantly less likely than whites to perceive the benefits of TJA and more likely to recognize barriers to TJA.
Asking the experts: Exploring the self‐management needs of adolescents with arthritis
Authors: Stinson Jennifer N. , Toomey Patricia C. , Stevens Bonnie J. , Kagan Susan , Duffy Ciarán M. , Huber Adam , Malleson Peter , McGrath Patrick J. , Yeung Rae S. M. , Feldman Brian M.
Published: December 2007

Objective

To explore the self‐management needs of adolescents with juvenile idiopathic arthritis and the acceptability of a Web‐based program of self‐management aimed at improving quality of life.

Methods

A descriptive qualitative design was used. A convenience sample of 36 adolescents (male and female) who varied in age, disease onset subtype, and disease severity were recruited from 4 Canadian tertiary care pediatric centers. Individual (n = 25) and 3 focus‐group (n = 11) interviews were conducted with adolescents using semistructured interview guides. After each interview session, the audiotaped interview data were transcribed verbatim. NUD*IST 6.0 was used to assist with the sorting, organizing, and coding of the data. Data were organized into categories that reflected emerging themes.

Results

Adolescents articulated how they developed effective self‐management strategies through the process of “letting go” from others who had managed their illness (health care professionals, parents) and “gaining control” over managing their illness on their own. The 2 strategies that assisted in this process were gaining knowledge and skills to manage the disease and experiencing understanding through social support. Five further subthemes emerged around skills to manage the disease, including knowledge and awareness about the disease, listening to and challenging care providers, communicating with the doctor, managing pain, and managing emotions.

Conclusion

Adolescents were united in their call for more information, self‐management strategies, and meaningful social support to better manage their arthritis. They believed that Web‐based interventions were a promising avenue to improve accessibility and availability of these interventions.
Sugar‐sweetened soft drinks, diet soft drinks, and serum uric acid level: The third national health and nutrition examination survey
Authors: Choi Jee Woong J. , Ford Earl S. , Gao Xiang , Choi Hyon K.
Published: December 2007

Objective

Sugar‐sweetened soft drinks contain large amounts of fructose, which may significantly increase serum uric acid levels and the risk of gout. Our objective was to evaluate the relationship between sugar‐sweetened soft drink intake, diet soft drink intake, and serum uric acid levels in a nationally representative sample of men and women.

Methods

Using data from 14,761 participants age ≥20 years from the Third National Health and Nutrition Examination Survey (1988–1994), we examined the relationship between soft drink consumption and serum uric acid levels using linear regression. Additionally, we examined the relationship between soft drink consumption and hyperuricemia (serum uric acid level >7.0 mg/dl for men and >5.7 mg/dl for women) using logistic regression. Intake was assessed by a food‐frequency questionnaire.

Results

Serum uric acid levels increased with increasing sugar‐sweetened soft drink intake. After adjusting for covariates, serum uric acid levels associated with sugar‐sweetened soft drink consumption categories (<0.5, 0.5–0.9, 1–3.9, and ≥4 servings/day) were greater than those associated with no intake by 0.08, 0.15, 0.33, and 0.42 mg/dl, respectively (95% confidence interval 0.11, 0.73; P < 0.001 for trend). The multivariate odds ratios for hyperuricemia according to the corresponding sweetened soft drink consumption levels were 1.01, 1.34, 1.51, and 1.82, respectively (P = 0.003 for trend). Diet soft drink consumption was not associated with serum uric acid levels or hyperuricemia (multivariate P > 0.13 for trend).

Conclusion

These findings from a nationally representative sample of US adults suggest that sugar‐sweetened soft drink consumption is associated with serum uric acid levels and frequency of hyperuricemia, but diet soft drink consumption is not.
Daily spiritual experiences of older adults with and without arthritis and the relationship to health outcomes
Authors: McCauley Jeanne , Tarpley Margaret J. , Haaz Steffany , Bartlett Susan J.
Published: December 2007

Objective

Strategies to improve coping with chronic disease are increasingly important, especially with the aging US population. For many, spirituality serves as a source of strength and comfort. However, little is known about the prevalence of daily spiritual experiences (DSE) and how they may relate to physical and mental health.

Methods

We surveyed older adults age >50 years with chronic health conditions seen in a primary care setting about their DSE, health perceptions, pain, energy, and depression.

Results

Of 99 patients, 80% reported DSE most days and many times per day. Women had significantly lower DSE scores than men (reflecting more frequent DSE, mean ± SD 37.3 ± 15.0 versus 45.8 ± 17.5; P = 0.012). African American women reported the most frequent DSE and white men reported the least frequent DSE (mean ± SD 35.9 ± 13.6 versus 52.2 ± 19.1). Frequent DSE were significantly associated with a higher number of comorbid conditions (P = 0.003), although not with age, education, or employment status. Persons with arthritis reported significantly more DSE than those without arthritis (mean ± SD 35.2 ± 12.1 versus 47.1 ± 18.6; P < 0.001). After adjustment for age, race, sex, pain, and comorbid conditions, more frequent DSE were associated with increased energy (P < 0.009) and less depression (P < 0.007) in patients with arthritis.

Conclusion

DSE are common among older adults, especially those with arthritis. Increased DSE may be associated with more energy and less depression. DSE may represent one pathway through which spirituality influences mental health in older adults.
Clinical remission and/or minimal disease activity in patients receiving adalimumab treatment in a multinational, open‐label, twelve‐week study
Authors: Burmester Gerd R. , Ferraccioli Gianfranco , Flipo René‐Marc , Monteagudo‐Sáez Indalecio , Unnebrink Kristina , Kary Sonja , Kupper Hartmut
Published: December 2007

Objective

To evaluate the effect of adalimumab treatment on clinical remission and/or minimal disease activity (MDA) in 6,610 patients with active rheumatoid arthritis (RA) who were enrolled in the Research in Active RA trial, a multinational, open‐label, 12‐week study with an optional extension period.

Methods

Clinical remission was defined as a Disease Activity Score in 28 joints (DAS28) <2.6, Simplified Disease Activity Index (SDAI) score ≤3.3, or Clinical Disease Activity Index (CDAI) score ≤2.8. MDA required absence of tender and swollen joints plus erythrocyte sedimentation rate (ESR) ≤10 mm/hour; DAS28 score ≤2.85; or achievement of 5 of 7 core criteria for pain, swollen/tender joints, physical function, physician/patient global assessment, and ESR. Time to and time in remission/MDA and response predictors were analyzed using Kaplan‐Meier estimates and Cox proportional hazards regression analysis, respectively.

Results

A total of 38%, 24%, and 27% of patients achieved remission defined as DAS28 <2.6, SDAI ≤3.3, and CDAI ≤2.8, respectively. MDA was observed in 45% of patients by DAS28 ≤2.85, in 43% by the core set of criteria, and in 13% by absence of tender/swollen joints plus ESR ≤10 mm/hour. Median times in continuous remission and MDA were 3.4 and 4.4 months, respectively. Predictors for remission (DAS28 <2.6) and MDA (DAS28 ≤2.85) were male sex; younger age; concomitant disease‐modifying antirheumatic drug use; lower baseline DAS28, CRP concentration, and Health Assessment Questionnaire disease index score; ≤1 comorbidity; and tumor necrosis factor antagonist naivety.

Conclusion

During adalimumab treatment, 25% of patients experienced clinical remission and nearly half achieved MDA. To our knowledge, this analysis represents the largest prospective clinical trial data set to be assessed using Outcome Measures in Rheumatology Clinical Trials MDA criteria.
Responsiveness of exercise parameters in children with inflammatory myositis
Authors: Takken Tim , van der Net Janjaap , Engelbert Raoul H. H. , Pater Suzanne , Helders Paul J. M.
Published: December 2007

Objective

Juvenile dermatomyositis (DM) is an inflammatory myopathy in which the immune system targets the microvasculature of the skeletal muscle and skin, leading to significant muscle weakness and exercise intolerance, although the precise etiology is unknown. The goal of this study was to investigate the changes in exercise capacity in children with myositis during active and inactive disease periods and to study the responsiveness of exercise parameters.

Methods

Thirteen children with juvenile DM (mean ± SD age 11.2 ± 2.6 years) participated in this study. Patients performed a maximal exercise test using an electronically braked cycle ergometer and respiratory gas analysis system. Exercise parameters were analyzed, including peak oxygen uptake (VO2peak), peak work rate (Wpeak), and ventilatory anaerobic threshold (VAT). All children were tested during an active period of the disease and during a remission period. From these data, 4 different response statistics were calculated.

Results

The children performed significantly better during a remission period compared with a period of active disease. Most exercise parameters showed a very large response. The 5 most responsive parameters were Wpeak, Wpeak (percent predicted), oxygen pulse, VO2peak, and power at the VAT.

Conclusion

We found in our longitudinal study that children with active juvenile DM had significantly reduced exercise parameters compared with a remission period. Moreover, we found that several parameters had very good responsiveness. With previously established validity and reliability, exercise testing has been demonstrated to be an excellent noninvasive instrument for the longitudinal followup of children with myositis.