bluuebunny/crossref_metadata_2025 huggingface dataset:
Evidence for increased bone resorption in patients with progressive knee osteoarthritis: Longitudinal results from the Chingford study
Authors: Bettica Paolo , Cline Gary , Hart Deborah J. , Meyer Joan , Spector Tim D.
Published: December 2002

Objective

Several studies have suggested that increased subchondral bone turnover is a determinant of progression of osteoarthritis (OA). To test this hypothesis, the level of urinary N‐terminal type I collagen telopeptides (NTx) and C‐terminal type I collagen telopeptides (CTx), which are validated markers of bone resorption, was measured at 3 different time points in a subset of patients from the Chingford study.

Methods

The original Chingford study population comprised 1,003 women. From this group, postmenopausal women not receiving any bone‐modifying medication who had a baseline knee radiograph and a repeat radiograph 4 years later, and for whom a baseline lumbar spine bone mineral density (BMD) measurement was available, were identified and separated into 4 groups as follows: controls (n = 50), progressive OA (n = 71), nonprogressive OA (n = 36), and osteoporosis (n = 59). NTx and CTx were measured in urine samples collected at baseline, year 1, and year 2.

Results

Patient age and years since menopause were similar among groups at baseline. As expected, both body mass index (BMI) and BMD were lowest in patients with osteoporosis. Median resorption marker levels over the 3 time points were 31–87% higher in patients with either progressive OA or osteoporosis than in controls and patients with nonprogressive OA (P < 0.01, except for levels of CTx in patients with progressive OA versus nonprogressive OA). Levels of NTx and CTx did not differ significantly between women with progressive OA (defined either by the presence of osteophytes or by joint space narrowing) and those with osteoporosis or between controls and women with nonprogressive OA. Results were essentially unchanged after adjustment for age, BMI, BMD, and past use of hormone replacement therapy, or when NTx and CTx values at each time point were analyzed separately.

Conclusion

Our data demonstrate that bone resorption is increased in patients with progressive knee OA and is not increased in those with nonprogressive knee OA. The increase in bone resorption seen in patients with progressive knee OA is similar to that observed in patients with osteoporosis. Altered bone turnover may be a diagnostic or therapeutic target in patients with progressive OA.
Timing of total joint replacement affects clinical outcomes among patients with osteoarthritis of the hip or knee
Authors: Fortin Paul R. , Penrod John R. , Clarke Ann E. , St‐Pierre Yvan , Joseph Lawrence , Bélisle Patrick , Liang Matthew H. , Ferland Diane , Phillips Charlotte B. , Mahomed Nizar , Tanzer Michael , Sledge Clement , Fossel Anne H. , Katz Jeffrey N.
Published: December 2002

Objective

To determine the predictors of outcome in patients with osteoarthritis 2 years after receiving total hip or knee replacement.

Methods

A prospective cohort study of 222 osteoarthritis patients undergoing total hip or knee replacement in Boston and Montreal was done. Their postoperative outcomes at 6 months were previously reported. This followup reports on the outcomes after 2 years among the 165 patients (74%) who remained. The subjects were divided into 2 groups according to the median value of their preoperative Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) function score. The Short Form 36‐item physical function subscale and the WOMAC pain and function subscale scores were collected at baseline and at 3, 6, and 24 months postoperatively. Clinical outcomes were analyzed at 2 years, using descriptive and multiple regression analyses.

Results

Improvements in pain and function at 2 years were similar to those observed at 6 months. Those subjects with the worst function and pain at the time of surgery (baseline) had comparatively worse function 2 years after surgery.

Conclusion

In this comparison, the poor outcomes observed at 6 months following total joint replacement in patients with worse baseline functional status persisted after 2 years. Although there are no validated indications for when a patient should optimally have total joint replacement, these data suggest that timing of surgery may be more important than previously realized and, specifically, that performing surgery earlier in the course of functional decline may be associated with better outcome.
Up‐regulated expression of cartilage intermediate‐layer protein and ANK in articular hyaline cartilage from patients with calcium pyrophosphate dihydrate crystal deposition disease
Authors: Hirose Jun , Ryan Lawrence M. , Masuda Ikuko
Published: December 2002

Objective

Excess accumulation of extracellular inorganic pyrophosphate (ePPi) in aged human cartilage is crucial in calcium pyrophosphate dihydrate (CPPD) crystal formation in cartilage matrix. Two sources of ePPi are ePPi‐generating ectoenzymes (NTPPPH) and extracellular transport of intracellular PPi by ANK. This study was undertaken to evaluate the role of NTPPPH and ANK in ePPi elaboration, by investigating expression of NTPPPH enzymes (cartilage intermediate‐layer protein [CILP] and plasma cell membrane glycoprotein 1 [PC‐1]) and ANK in human chondrocytes from osteoarthritic (OA) articular cartilage containing CPPD crystals and without crystals.

Methods

Chondrocytes were harvested from knee cartilage at the time of arthroplasty (OA with CPPD crystals [CPPD], n = 8; OA without crystals [OA], n = 10). Normal adult human chondrocytes (n = 1) were used as a control. Chondrocytes were cultured with transforming growth factor β1 (TGFβ1), which stimulates ePPi elaboration, and/or insulin‐like growth factor 1 (IGF‐1), which inhibits ePPi elaboration. NTPPPH and ePPi were measured in the media at 48 hours. Media CILP, PC‐1, and ANK were determined by dot‐immunoblot analysis. Chondrocyte messenger RNA (mRNA) was extracted for reverse transcriptase–polymerase chain reaction to study expression of mRNA for CILP, PC‐1, and ANK. NTPPPH and ANK mRNA and protein were also studied in fresh frozen cartilage.

Results

Basal ePPi elaboration and NTPPPH activity in conditioned media from CPPD chondrocytes were elevated compared with normal chondrocytes, and tended to be higher compared with OA chondrocytes. Basal expression of mRNA for CILP (chondrocytes) and ANK (cartilage) was higher in both CPPD chondrocytes and CPPD cartilage extract than in OA or normal samples. PC‐1 mRNA was less abundant in CPPD chondrocytes and cartilage extract than in OA chondrocytes and extract, although the difference was not significant. CILP, PC‐1, and ANK protein levels were similar in CPPD, OA, and normal chondrocytes or cartilage extracts. Both CILP and ANK mRNA expression and ePPi elaboration were stimulated by TGFβ1 and inhibited by IGF‐1 in chondrocytes from all sources.

Conclusion

CILP and ANK mRNA expression correlates with chondrocyte ePPi accumulation around CPPD and OA chondrocytes, and all respond similarly to growth factor stimulation. These findings suggest that up‐regulated CILP and ANK expression contributes to higher ePPi accumulation from CPPD crystal–forming cartilage.
Effects of β2‐glycoprotein I and monoclonal anticardiolipin antibodies in platelet interaction with subendothelium under flow conditions
Authors: Font Josep , Espinosa Gerard , Tàssies Dolors , Pino Marc , Khamashta Munther A. , Gallart Teresa , Cervera Ricard , Escolar Ginés , Hughes Graham R. V. , Ingelmo Miguel , Ordinas Antoni , Reverter Joan‐Carles
Published: December 2002

Objective

To evaluate whether the effect of human monoclonal anticardiolipin antibodies (aCL) on platelet interaction with the subendothelium under flow conditions is dependent on β2‐glycoprotein I (β2GPI).

Methods

Three monoclonal IgM aCL with anti‐β2GPI activity (TM1B3, GR1D5, and EY2C9) obtained from patients with antiphospholipid syndrome, a monoclonal aCL with lupus anticoagulant activity but without anti‐β2GPI activity (FRO) obtained from a patient with a splenic lymphoma, and a control monoclonal IgM without aCL activity were used. TM1B3, GR1D5, EY2C9, FRO, and control IgM (30 μg/ml) were added to reconstituted blood containing gel‐filtered platelets (200 × 109/liter), factor VIII (100 units/dl), and fibrinogen (1.5 gm/liter). Samples were perfused (wall‐shear rate 800 seconds−1), with and without the addition of purified β2GPI (20 μg/ml), through annular chambers containing collagen‐rich denuded vascular segments, and the percentages of surface covered by platelets and by thrombi were evaluated.

Results

No differences in the percentages of surface covered by platelets and by thrombi were observed among samples with TM1B3, GR1D5, EY2C9, FRO, and control IgM added when reconstituted blood samples without β2GPI were used. However, a significant increase in the percentage of surface covered by platelets was observed in the presence of TM1B3, GR1D5, and EY2C9 but not in the presence of FRO when samples containing β2GPI were used. Increased thrombi formation was induced by TM1B3 and GR1D5 but not by EY2C9 or FRO in samples with added β2GPI.

Conclusion

Monoclonal aCL require anti‐β2GPI activity to promote platelet interaction with the subendothelium under flow conditions.
Inhibition of adjuvant‐induced arthritis by systemic tissue inhibitor of metalloproteinases 4 gene delivery
Authors: Çeliker Mahmut Y. , Ramamurthy Nungavaram , Xu Jin‐Wen , Wang Mingsheng , Jiang Yangfu , Greenwald Robert , Shi Y. Eric
Published: December 2002

Objective

An imbalance in the matrix metalloproteinase:tissue inhibitor of metalloproteinases (MMP:TIMP) ratio in favor of MMP appears to be an important determinant of tissue damage in arthritis. We undertook this study to explore whether reversal of this imbalance in favor of TIMP would alter this process and to examine the mechanism of this alteration.

Methods

We administered human TIMP‐4 by electroporation‐mediated intramuscular injection of naked DNA using the rat adjuvant‐induced arthritis (AIA) model.

Results

Intramuscular naked TIMP‐4 gene administration resulted in high circulating TIMP‐4 levels and completely abolished arthritis development in the rat AIA model. This inhibition was associated with significantly decreased MMP activity in the joint tissue as well as with significantly decreased serum and tissue tumor necrosis factor α levels and serum interleukin‐1α levels compared with animals with arthritis. The mutation of cysteine at position 1 of TIMP‐4 failed to block the development of AIA.

Conclusion

Our data indicate that TIMP‐4 is a potent antiinflammatory agent, and that its antiarthritis function may be mediated by MMPs. Arthritis‐inhibiting effects of TIMP‐4 may suggest a unique application of this gene therapy method for arthritis.
Nonrandom evolution of end‐stage osteoarthritis of the lower limbs
Authors: Shakoor Najia , Block Joel A. , Shott Susan , Case John P.
Published: December 2002

Objective

Patients with unilateral hip or knee replacements for end‐stage osteoarthritis (OA) are at high risk for future progression of OA in other joints of the lower extremities, often requiring additional joint replacements. Although the risks of future surgery in the contralateral cognate joints (i.e., contralateral hip replacement after an initial hip replacement) have been evaluated, the evolution of end‐stage hip OA to OA involving the knee joints, and vice versa (i.e., noncognate progression) has not been investigated. Because characterization of OA progression in noncognate joints may shed light on the pathogenesis of multijoint OA, we investigated the pattern of evolution of end‐stage lower extremity OA in a large, clinical cohort.

Methods

Total joint replacement (TJR) was selected as a marker of end‐stage OA, and a database comprising all lower extremity TJRs performed at a large referral center between 1981 and 2001 was accessed. Of the 5,894 patients identified, 486 patients with idiopathic OA who underwent hip replacement and 414 who underwent initial knee replacement were analyzed to determine the relative likelihood of subsequent TJRs. Patients with the systemic inflammatory arthropathy, rheumatoid arthritis (RA), were evaluated as a control population because RA progression is not considered to be a primarily mechanically mediated process.

Results

The contralateral cognate joint was the most common second joint to undergo replacement in both the OA and the RA groups. However, in OA patients for whom the second TJR was in a noncognate joint, that joint was >2‐fold more likely to be on the contralateral limb than on the ipsilateral limb (hip to knee P < 0.001; knee to hip P = 0.013). In contrast, among the RA cohort, the evolution was random and no laterality for noncognate TJR was observed at either the hip or the knee (P = 0.782).

Conclusion

This characterization of end‐stage lower extremity OA demonstrates that the disease evolves nonrandomly; after 1 joint is replaced, the contralateral limb is significantly more likely to show progression of OA than is the ipsilateral limb. Thus, OA in 1 weight‐bearing joint appears to influence the evolution of OA in other joints. The absence of such laterality in RA suggests that OA progression may be mediated by extrinsic factors such as altered joint loading.
Growth‐related oncogene α induction of apoptosis in osteoarthritis chondrocytes
Authors: Borzi Rosa Maria , Mazzetti Ilaria , Magagnoli Giorgia , Paoletti Samantha , Uguccioni Mariagrazia , Gatti Rita , Orlandini Guido , Cattini Luca , Facchini Andrea
Published: December 2002

Objective

To evaluate the apoptotic effect of the chemokine growth‐related oncogene α (GROα), which we recently reported to be up‐regulated in osteoarthritis (OA) chondrocytes. Chondrocyte apoptosis is considered to be a major determinant of cartilage damage in OA, a disease resulting from the aberrant production of inflammatory mediators (cytokines and chemokines) and effectors (matrix metalloproteinases and reactive oxygen and nitrogen species) by chondrocytes.

Methods

We investigated the apoptotic effect of GROα on isolated human cells and on in vitro–cultured cartilage explants by conventional methods (morphology, detection of DNA fragmentation in situ and in solution, exposure of phosphatidylserine) and by analysis of “early” biochemical events (plasma membrane depolarization, activation of caspase 3, and phosphorylation of c‐Jun N‐terminal kinase/stress‐activated protein kinase).

Results

We clearly demonstrated that GROα was able to initiate a series of morphologic, biochemical, and molecular changes that led to chondrocyte apoptosis. Moreover, we found that additional signals delivered from the extracellular matrix (ECM) were essential in the control of chondrocyte susceptibility to GROα‐induced apoptosis, since cell death was detected only when cells were stimulated after reestablishment of their proper interactions with the ECM, or in cartilage explant samples with reduced ECM, as indicated by decreased Safranin O staining.

Conclusion

GROα can induce apoptosis in articular chondrocytes, and the induction is dependent upon additional signals from the ECM. These findings are relevant to understanding the pathogenesis of OA, in view of the availability of the GROα chemokine in the joint space in the course of this rheumatic disease.
RP105‐lacking B cells from lupus patients are responsible for the production of immunoglobulins and autoantibodies
Authors: Kikuchi Yuji , Koarada Syuichi , Tada Yoshifumi , Ushiyama Osamu , Morito Fumitaka , Suzuki Noriaki , Ohta Akihide , Miyake Kensuke , Kimoto Masao , Horiuchi Takahiko , Nagasawa Kohei
Published: December 2002

Objective

We previously reported that B cells lacking the RP105 molecule, which proved to be highly activated B cells, are increased in the peripheral blood of patients with systemic lupus erythematosus (SLE). In the present study, we attempted to determine whether RP105‐negative B cells obtained from SLE patients would be capable of producing autoantibodies as well as immunoglobulins.

Methods

RP105‐positive and RP105‐negative B cells, sorted by cell sorter, were cultured for 5 days without stimulation, or were stimulated with Staphylococcus aureus Cowan 1 strain (SAC) or recombinant interleukin‐6 (IL‐6). For the assay of autoantibodies, RP105‐positive and RP105‐negative B cells were cultured separately for 10 days with anti‐CD3 antibody–stimulated T cells. The production of immunoglobulins and autoantibodies was determined by enzyme‐linked immunosorbent assay.

Results

We demonstrated that RP105‐negative B cells, but not RP105‐positive B cells, obtained from SLE patients could spontaneously produce IgG and IgM in vitro until day 5. SAC and IL‐6 enhanced production of IgG and IgM by RP105‐negative B cells but failed to induce such production by RP105‐positive B cells. The latter cells, however, when cocultured with activated T cells in the presence of IL‐10, produced IgG, although the amount was very small compared with that produced by RP105‐negative B cells. Most important, under these conditions, anti–double‐stranded DNA antibodies were produced only by the RP105‐negative B cells obtained from SLE patients.

Conclusion

These data indicate that RP105‐negative B cells, constituting a subset of B cells in SLE patients, are highly activated and may be responsible for the production of autoantibodies as well as polyclonal immunoglobulins.
Identity of the RNase MRP– and RNase P–associated Th/To autoantigen
Authors: Van Eenennaam Hans , Vogelzangs Judith H. P. , Lugtenberg Dorien , Van Den Hoogen Frank H. J. , Van Venrooij Walther J. , Pruijn Ger J. M.
Published: December 2002

Objective

To characterize the molecular identity of the Th/To autoantigen, which is targeted by autoantibodies in scleroderma and which is associated with the human RNase MRP and RNase P ribonucleoprotein complexes.

Methods

Proteins immunoprecipitated by anti‐Th/To+ patient antisera from biotinylated total HeLa cell extracts were analyzed by immunoblotting. The association of autoantigenic proteins with the RNase MRP complex was analyzed by reconstitution experiments and ultraviolet crosslinking. The reactivity of patient sera with all known RNase MRP/RNase P proteins was analyzed by immunoprecipitation of the individual recombinant proteins.

Results

The previously defined Th40 autoantigen appeared to be identical to the Rpp38 protein. Paradoxically, Rpp38 did not bind to the P3 domain of the RNase MRP RNA, as suggested by previously published data for Th40, and only half of the anti‐Th/To+ sera contained anti‐Rpp38 reactivity. Two other RNase MRP/RNase P subunits, Rpp20 and Rpp25, were found to interact with the P3 domain. The previously reported 40‐kd species associated with this domain appeared to consist of Rpp20 and/or Rpp25 associated with a nuclease‐resistant RNA fragment. Finally, we demonstrated that almost all tested anti‐Th/To+ patient sera contained autoantibodies to Rpp25 and hPop1, indicating that these proteins harbor the most frequently targeted Th/To determinants.

Conclusion

Our data unequivocally define the identity of the Th/To autoantigen and demonstrate that Th/To autoepitopes are found on several protein subunits of RNase MRP/RNase P.
Infliximab in primary Sjögren's syndrome: One‐year followup
Authors: Steinfeld Serge D. , Demols Paul , Appelboom Thierry
Published: December 2002

Objective

To evaluate the safety and efficacy of a maintenance regimen of infliximab in patients with active primary Sjögren's syndrome (SS) over a 1‐year period.

Methods

This followup study included 10 of the 16 patients with primary SS who participated in a pilot study. Patients who continued to have symptoms received additional infusions of infliximab for 1 year.

Results

All patients completed the 1‐year followup for evaluation of efficacy. After 1 year, a statistically significant decrease in global and local disease manifestations was observed in all 10 patients. Treatment was generally well tolerated, with the main side effect being a mild, self‐limited infusion reaction.

Conclusion

Sustained improvement of active primary SS may be possible with infliximab treatment.
Bcl‐3 is an interleukin‐1–responsive gene in chondrocytes and synovial fibroblasts that activates transcription of the matrix metalloproteinase 1 gene
Authors: Elliott Sarah F. , Coon Charles I. , Hays Ezra , Stadheim Terrance A. , Vincenti Matthew P.
Published: December 2002

Objective

To define the role of Bcl‐3, a member of the inhibitor of nuclear factor κB (NF‐κB) family and a known regulator of NF‐κB, in interleukin‐1 (IL‐1)–induced matrix metalloproteinase 1 (MMP‐1) transcription in chondrocytes and synovial fibroblasts.

Methods

SW‐1353 cells, a human chondrosarcoma cell line, were stimulated with IL‐1β, and the harvested RNA was subjected to microarray analysis and quantitative real‐time reverse transcription–polymerase chain reaction (RT‐PCR). The SW‐1353 cells were stimulated with IL‐1 or transfected with a plasmid that constitutively expressed Bcl‐3, and then MMP‐1 messenger RNA (mRNA) expression was assayed by quantitative real‐time RT‐PCR. SW‐1353 cells were transfected with antisense oligonucleotides to Bcl‐3, and IL‐1–induced MMP‐1 mRNA expression was assayed by quantitative RT‐PCR. SW‐1353 cells and rabbit synovial fibroblasts were transfected with a 4.3‐kb human MMP‐1 promoter construct along with Bcl‐3 and NF‐κB1 expression constructs, and MMP‐1 transcription was assayed.

Results

Microarray analysis and real‐time RT‐PCR showed Bcl‐3 to be an IL‐1β–responsive gene in SW‐1353 cells. Exogenous expression of Bcl‐3 in SW‐1353 cells activated MMP‐1 transcription. Endogenous Bcl‐3 expression was required for IL‐1β induction of MMP‐1 gene expression. Bcl‐3 also activated MMP‐1 transcription in primary synovial fibroblasts. We showed previously that NF‐κB1 contributes to IL‐1β induction of MMP‐1 transcription in stromal cells. We showed here that Bcl‐3 can cooperate with NF‐κB1 to activate MMP‐1 transcription in SW‐1353 cells.

Conclusion

These data define a new role for Bcl‐3 in joint cells as an IL‐1β–responsive early gene involved in cell‐mediated cartilage remodeling. Our findings implicate Bcl‐3 as an important contributor to chronic inflammatory disease states, such as osteoarthritis and rheumatoid arthritis.
The geometric architecture of the subtalar and midtarsal joints in rheumatoid arthritis based on magnetic resonance imaging
Authors: Woodburn James , Udupa Jayaram K. , Hirsch Bruce E. , Wakefield Richard J. , Helliwell Philip S. , Reay Naomi , O'Connor Philip , Budgen Adam , Emery Paul
Published: December 2002

Objective

To compare in vivo the 3‐dimensional (3‐D) geometric architecture of the subtalar and midtarsal joints in normal and rheumatoid arthritic (RA) feet, using magnetic resonance imaging (MRI) analysis.

Methods

MRI was performed on 23 patients with RA, all of whom had disease activity in the subtalar and/or midtarsal joints. Image processing techniques were used to create 3‐D reconstructions of the calcaneus (C), cuboid (c), navicular (N), and talus (T) bones. Twenty‐four standard architectural parameters were measured from the reconstructions and were compared with data from 10 normal subjects. These parameters defined both 3‐D distance and angular relationships among the 4 bones studied. Pattern classification techniques were used to establish a geometric architecture foot profile for the RA patients. The degree of individual patient fit to the new RA foot profile and to profiles for normal, pes planus, and pes cavus foot types was derived. Logistic regression was used to examine the relationship of foot architecture to inflammatory disease characteristics and physical examination variables.

Results

Subtalar or midtarsal pain was reported by all 23 patients, and 22 of the 23 patients presented with ≥1 clinical feature of pes planovalgus deformity. In 21 patients, ultrasonography revealed synovitis at ≥1 tarsal joint or surrounding tendon. In the RA group, the normalized distances between the geometric centroids were significantly closer for bone pairs Cc and cT and significantly distracted for bone pair CN compared with the distances in normal subjects. In RA patients (versus normal subjects), the angles subtended at the bone centroids were significantly decreased in 3 bone groups (CNc, TCN, and TNc) and significantly increased in 3 bone groups (CcN, CcT, NTc). The angles formed between the major principal axes of bone pairs CT and cT were significantly increased in RA patients compared with those in normal subjects. Pattern classification defined 11 RA feet as having normal structure and 12 as having abnormal structure. However, the abnormal feet did not fit consistently with structures defined for RA, pes planus, or pes cavus foot types. Logistic regression demonstrated that subtalar joint synovitis was the only predictive factor for abnormal subtalar and midtarsal architecture (odds ratio 19.2, 95% confidence interval 1.77–200.0).

Conclusion

This unique 3‐D MRI‐based technique successfully quantified the effects of RA on the geometric architecture of the foot and the patient‐specific nature of these changes. This technique can be used to provide logical therapy for correction.
A new conformational epitope generated by the binding of recombinant 70‐kd protein and U1 RNA to anti–U1 RNP autoantibodies in sera from patients with mixed connective tissue disease
Authors: Murakami Akihiro , Kojima Kazuo , Ohya Kazuhiko , Imamura Koji , Takasaki Yoshinari
Published: December 2002

Objective

To establish an enzyme‐linked immunosorbent assay (ELISA) using a complex of in vitro–transcribed U1 RNA and recombinant 70‐kd, A, and C proteins (C‐ELISA) to detect anti–U1 RNP antibodies reactive in double immunodiffusion (DID), but not in ELISA using the proteins alone (P‐ELISA).

Methods

Sera from 196 patients with mixed connective tissue disease were used to test reactivity in P‐ and C‐ELISAs, and the specificity of the sera was also tested by DID and immunoprecipitation (IP).

Results

In P‐ELISA, 15 of 196 sera positive for anti–U1 RNP in DID did not react, while all sera reacted in C‐ELISA. The reactivity of 15 sera to the U1 RNA was tested by IP and ELISA, and only 3 sera reacted with the U1 RNA. These results indicated that the increased reactivity in C‐ELISA was not due to the U1 RNA itself. We confirmed that the 70‐kd and A proteins were bound directly to the U1 RNA by IP using antibodies to His‐tag, and we tested the reactivity of the sera to the U1 RNA–70‐kd protein complex and the U1 RNA–A protein complex by IP. All sera reacted with the U1 RNA–70‐kd protein complex, and 1 sample reacted with the U1 RNA–A protein complex.

Conclusion

These results suggest that some anti–U1 RNP–positive sera specifically recognize the conformational structure altered by the binding of U1 RNA to the proteins, and the ELISA using U1 RNA and recombinant proteins is as useful as the DID method for detecting anti–U1 RNP antibodies.
Relief of inflammatory pain in rats by local use of the selective P2X7 ATP receptor inhibitor, oxidized ATP
Authors: Dell'Antonio Giacomo , Quattrini Angelo , Cin Elena Dal , Fulgenzi Alessandro , Ferrero Maria Elena
Published: December 2002

Objective

Oxidized ATP (oATP) is a selective inhibitor of the P2Z/P2X7 ATP receptor for extracellular ATP, which contributes to the antinociceptive effect. This study sought to determine the mechanism by which local administration of oATP is able to relieve inflammatory pain in arthritic rat paws.

Methods

Arthritis was induced in Wistar rats by injections of Freund's complete adjuvant into one hind paw. Nociceptive thresholds were measured before and after local injection of oATP into the inflamed paws. The influence on pain transmission due to the presence of recruited inflammatory cells at the site of inflammation was determined by inhibiting the initial phase of their migration (by intravenous treatment with fucoidin, which blocks the adhesion molecules of the selectin family). ATP intraplantar content was determined in the different experimental conditions. Histologic features of the hind paws were evaluated by using the anti–P2X7 receptor polyclonal antibody.

Results

Intraplantar administration of oATP into inflamed paws significantly relieved inflammatory pain. The antinociceptive effect of oATP was independent of the immune‐cell recruitment. ATP levels in inflamed tissues were significantly reduced by oATP treatment. A variable presence of P2X7 receptors on cutaneous sensory nerves with respect to the different treatments was observed. Following oATP treatment, there was a reduction in P2X7 expression in the endings of peripheral nerves, as well as in endothelial cells.

Conclusion

Oxidized ATP inhibits inflammatory pain in arthritic rats by inhibition of the P2X7 receptor for ATP, which is localized on nerve terminals.
Tumor necrosis factor antagonist therapy and lymphoma development: Twenty‐six cases reported to the Food and Drug Administration
Authors: Brown S. Lori , Greene Mark H. , Gershon Sharon K. , Edwards Evelyne T. , Braun M. Miles
Published: December 2002

Objective

Etanercept and infliximab are tumor necrosis factor (TNF) antagonists that have been recently approved for the treatment of rheumatoid arthritis (RA) and Crohn's disease (CD). This study was undertaken to investigate the occurrence of lymphoproliferative disorders in patients treated with these agents.

Methods

Relevant data in the MedWatch postmarket adverse event surveillance system run by the US Food and Drug Administration were reviewed.

Results

We identified 26 cases of lymphoproliferative disorders following treatment with etanercept (18 cases) or infliximab (8 cases). The majority of cases (81%) were non‐Hodgkin's lymphomas. The interval between initiation of therapy with etanercept or infliximab and the development of lymphoma was very short (median 8 weeks). In 2 instances (1 infliximab, 1 etanercept), lymphoma regression was observed following discontinuation of anti‐TNF treatment, in the absence of specific cytotoxic therapy directed toward the lymphoma.

Conclusion

Although data from a case series such as this cannot establish a clear causal relationship between exposure to these medications and the risk of lymphoproliferative disease, the known predisposition of patients with RA and CD to lymphoma, the known excess of lymphoma in other immunosuppressed populations, and the known immunosuppressive effects of the anti‐TNF drugs provide a biologic basis for concern and justification for the initiation of additional epidemiologic studies to formally evaluate this possible association.
Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti‐CD154: A randomized, double‐blind, placebo‐controlled trial
Authors: Kalunian Kenneth C. , Davis John C. , Merrill Joan T. , Totoritis Mark C. , Wofsy David ,   for the IDEC‐131 Lupus Study Group
Published: December 2002

Objective

To evaluate the safety and efficacy of a humanized monoclonal antibody against CD154 (IDEC‐131) in patients with active systemic lupus erythematosus (SLE).

Methods

In this phase II, double‐blind, placebo‐controlled, multiple‐center, multiple‐dose study, 85 patients with mild‐to‐moderately active SLE were randomized to receive 6 infusions of IDEC‐131, ranging from 2.5 mg/kg to 10.0 mg/kg, or placebo over 16 weeks. Efficacy was assessed at week 20, primarily by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and secondarily, by multiple measures of disease activity. Safety was assessed through week 28 by clinical and laboratory evaluation. Immunogenicity studies were also performed.

Results

SLEDAI scores improved from the baseline levels of disease activity in all groups, including the placebo group. However, these scores were not statistically different among the IDEC‐131 treatment and placebo groups at week 20. Evaluations of secondary variables did not indicate significant differences between the IDEC‐131 treatment and placebo groups. The type and frequency of adverse events were similar between the IDEC‐131 and placebo groups.

Conclusion

IDEC‐131 administered at doses ranging 2.5–10.0 mg/kg over 16 weeks was safe and well tolerated in patients with SLE. Efficacy of the drug compared with placebo was not demonstrated. There were statistically significant improvements from baseline in all groups, including the placebo group.
The effect of education and income on need and willingness to undergo total joint arthroplasty
Authors: Hawker Gillian A. , Wright James G. , Glazier Richard H. , Coyte Peter C. , Harvey Bart , Williams J. Ivan , Badley Elizabeth M.
Published: December 2002

Objective

Individuals with lower socioeconomic status (SES) receive less arthritis care, including joint arthroplasty. However, no studies have considered the expectations or needs of the patients. Our objective was to assess the effect of education and income on the potential need for, and the willingness to consider hip and knee arthroplasty.

Methods

Through a mail/telephone survey of 48,218 persons ages 55 years or older residing in 2 areas of Ontario, Canada, 3,307 individuals with moderate‐to‐severe hip/knee problems were identified. These individuals received a questionnaire to assess education, income, arthritis severity, and comorbidity. In a subset of these subjects, we conducted interviews to evaluate the willingness to consider arthroplasty, and we also performed clinical and radiographic examinations of the joints to validate self‐reports of arthritis. The potential need for arthroplasty was defined as the presence of severe arthritis (as scored by the Western Ontario and McMaster Universities Osteoarthritis Index), with no absolute contraindications to surgery. Separate logistic regression models examined the independent effects of education and income on the potential need for, and definite willingness to consider arthroplasty, after controlling for age, sex, and region of residence. Potential unmet need was estimated as the proportion of subjects with the need for arthroplasty who were not already on a surgery waiting list, who were definitely willing to consider arthroplasty, and who had evidence of arthritis by examination and radiography.

Results

Response rates were at least 72% for all questionnaires and interviews. Less education (adjusted odds ratio [OR] 1.57 for less than high school versus postsecondary education, 95% confidence interval [95% CI] 1.17–2.11) and lower income (adjusted OR 1.83 for ≤$20,000 versus >$40,000, 95% CI 1.24–2.70) were independently associated with a greater likelihood of having the potential need for arthroplasty. Among the subjects with potential need, neither education nor income was independently associated with a definite willingness to consider arthroplasty. Thus, taking willingness into consideration, individuals with less education and/or lower income were more likely to have potential unmet need for arthroplasty.

Conclusion

Persons with lower SES had a greater need for, and were equally willing to consider arthroplasty, compared with those with higher SES. Thus, observed SES disparities in the rates of performed arthroplasties cannot be explained by a lower need or less willingness to undergo arthroplasty in those with lower SES.
Induction of cell death by sera from patients with acute brain injury as a mechanism of production of autoantibodies
Authors: López‐Escribano Herminio , Miñambres Eduardo , Labrador Moisés , Bartolomé María José , López‐Hoyos Marcos
Published: December 2002

Objective

To investigate the capacity of blood draining from the central nervous system of patients with acute brain injury to induce cell death, and to determine whether this phenomenon could be a way to induce the production of autoantibodies.

Methods

The induction of cell death of several human leukemia cell lines cultured in vitro in the presence of serum collected from the brain or the systemic circulation of patients with acute brain injury was analyzed by flow cytometry after staining with annexin V and propidium iodide. The percentages of apoptotic lymphocytes derived directly from the patients were also quantified. To investigate the mechanisms responsible for the induction of cell death, the expression of apoptosis‐related molecules, as well as the effect of addition of several molecules known to interfere with apoptosis, was evaluated in the cell cultures. The presence of serum autoantibodies at the time of injury and 6 months later was studied.

Results

Systemic serum and, especially, serum draining from the brain lesions induced the in vitro death of the leukemia cell lines used. Moreover, there were higher percentages of ex vivo dead lymphocytes in regional blood than in systemic blood 48 hours after injury. These effects seemed to be induced by an exogenous and/or endogenous opioid, since they were blocked by the opioid antagonist, naloxone. Furthermore, such effects were mediated by an increased expression of Bax. Importantly, apoptotic Jurkat cells were bound to autoantibodies, and patients with acute brain injury produced serum autoantibodies some months after the injury. However, they did not develop a full autoimmune disease at that time.

Conclusion

Serum factors from acute brain injuries induce cell death, both in vivo and in vitro. Apoptotic cells and, even more so, necrotic cells in acute brain injury are potential sources for autoantigen presentation that may stimulate autoimmune responses.
Cigarette smoking as a significant risk factor for digital vascular disease in patients with systemic sclerosis
Authors: Harrison Beverley J. , Silman Alan J. , Hider Samantha L. , Herrick Ariane L.
Published: December 2002

Objective

Patients with systemic sclerosis (SSc) are at high risk for digital vascular complications, including amputation and gangrene. Cigarette smoking is an important risk factor for vascular disease in the general population. We investigated the influence of cigarette smoking on digital ischemia in patients with SSc.

Methods

We studied 101 patients with SSc (87 women and 14 men, median age 53 years, median disease duration 13 years). Smoking history was defined in terms of current smoking status and total number of pack‐years. Digital ischemic events were classified as debridement, hospital admission for intravenous (IV) administration of vasodilators, and digital amputation. The influence of smoking on digital ischemic events was examined using logistic regression, adjusting for age, sex, and disease duration. Results are expressed as the odds ratio (OR) and 95% confidence interval (95% CI).

Results

Of the 101 patients, 21 (21%) were current smokers, 37 (37%) were ex‐smokers, and 43 (43%) had never smoked. After adjusting for age, sex, and disease duration, current smokers were significantly more likely than never‐smokers to have had debridement (OR 4.5, 95% CI 1.1–18.3) or admission for IV vasodilators (OR 3.8, 95% CI 1.1–12.9). Patients smoking at higher intensity were more likely to require admission for IV vasodilators.

Conclusion

Among patients with SSc, current smokers are 3–4 times more likely than never‐smokers to incur digital vascular complications. Resources should be directed to supporting smoking cessation in patients with SSc.
Functional replacement of oxygen by other oxidants in articular cartilage
Authors: Lee Robert B. , Urban Jill P. G.
Published: December 2002

Objective

Articular cartilage chondrocytes consume remarkably little O2 in comparison with most other animal cells; glycolysis forms the principal source of ATP in this cartilage. Although not lethal for many days, imposition of anoxia immediately lowers intracellular ATP, inhibits rates of glycolysis, and prevents articular chondrocytes from producing extracellular matrix macromolecules. This study was undertaken to investigate the role of O2 in articular chondrocyte metabolism.

Methods

We examined the effects of oxygen and of several other classes of exogenous oxidants, i.e., 1) the dyes methylene blue and 2,6‐dichlorophenol‐indophenol, 2) the iron (III) complex ferricyanide, and 3) the keto‐acids oxaloacetate and pyruvate (and phosphoenolpyruvate, a metabolic precursor of pyruvate), on rates of glycolysis and of sulfate incorporation by bovine articular cartilage in vitro.

Results

Lactate production was lowest under conditions of anoxia and was stimulated severalfold by addition of O2 (air‐saturated medium). Under strict anoxia, other oxidants restored lactate production to rates at least comparable with those seen in aerobic controls; under aerobic conditions, they had little effect. Oxygen and all of the other oxidants examined stimulated sulfate incorporation more strongly than lactate production. The compounds that promoted glycolysis and hence sulfate incorporation in cartilage under anoxia were themselves reduced; that is, they functioned as oxidants in lieu of O2.

Conclusion

For normal function, articular cartilage appears to require exogenous oxidants to stimulate glycolysis and produce ATP and extracellular matrix. Under physiologic conditions, oxygen acts as this oxidant, but its role can be adequately assumed by other agents.
Peptide‐induced suppression of collagen‐induced arthritis in HLA–DR1 transgenic mice
Authors: Myers Linda K. , Sakurai Yoshihiko , Tang B. , He Xiaowen , Rosloniec Edward F. , Stuart John M. , Kang Andrew H.
Published: December 2002

Objective

To identify peptides capable of altering the immune response to type II collagen (CII) in the context of HLA–DR.

Methods

Immunizing mice transgenic for the human HLA–DRB1*0101 immune response gene with CII elicits an arthritis (collagen‐induced arthritis [CIA]) that resembles rheumatoid arthritis. We have previously identified an immunodominant determinant of CII, CII (263–270), recognized by T cells in the context of DR1. To produce synthetic peptides with the potential of disrupting the DR1‐restricted immune response, synthetic analog peptides were developed that contain site‐directed substitutions in critical positions. These peptides were used to treat CIA in DR1 transgenic mice.

Results

An analog peptide, CII (256–276, N263, D266), that inhibited T cell responses in vitro, was identified. When DR1 mice were coimmunized with CII and CII (256–276, N263, D266), the incidence and severity of arthritis were greatly reduced, as was the antibody response to CII. Moreover, CII (256–276, N263, D266) was effective in down‐regulating the immune responses to CII and arthritis, even when administered 2 weeks following immunization with CII. Spleen and lymph node cells from CII‐immunized mice cultured with CII (256–276, N263, D266) in vitro produced increased amounts of interleukin‐4 (IL‐4) compared with cells cultured with the wild‐type peptide, CII (256–276). Furthermore, CII (256–276, N263, D266) was incapable of preventing arthritis in DR1 IL‐4−/− mice (genetically deficient in IL‐4).

Conclusion

These data establish that CII (256–276, N263, D266) is a potent suppressor of the DR‐mediated immune response to CII. Its effect is mediated, at least in part, by IL‐4. These experiments represent the first description of an analog peptide of CII recognized by T cells in the context of a human major histocompatibility complex molecule that can suppress autoimmune arthritis.
De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal‐onset multisystem inflammatory disease (NOMID): A new member of the expanding family of pyrin‐associated autoinflammatory diseases
Authors: Aksentijevich Ivona , Nowak Miroslawa , Mallah Mustapha , Chae Jae Jin , Watford Wendy T. , Hofmann Sigrun R. , Stein Leonard , Russo Ricardo , Goldsmith Donald , Dent Peter , Rosenberg Helene F. , Austin Frances , Remmers Elaine F. , Balow James E. , Rosenzweig Sergio , Komarow Hirsh , Shoham Nitza G. , Wood Geryl , Jones Janet , Mangra Nadira , Carrero Hector , Adams Barbara S. , Moore Terry L. , Schikler Kenneth , Hoffman Hal , Lovell Daniel J. , Lipnick Robert , Barron Karyl , O'Shea John J. , Kastner Daniel L. , Goldbach‐Mansky Raphaela
Published: December 2002

Objective

Neonatal‐onset multisystem inflammatory disease (NOMID; also known as chronic infantile neurologic, cutaneous, articular [CINCA] syndrome) is characterized by fever, chronic meningitis, uveitis, sensorineural hearing loss, urticarial skin rash, and a characteristic deforming arthropathy. We investigated whether patients with this disorder have mutations in CIAS1, the gene which causes Muckle‐Wells syndrome and familial cold autoinflammatory syndrome, two dominantly inherited disorders with some similarities to NOMID/CINCA syndrome.

Methods

Genomic DNA from 13 patients with classic manifestations of NOMID/CINCA syndrome and their available parents was screened for CIAS1 mutations by automated DNA sequencing. Cytokine messenger RNA (mRNA) levels were assessed by real‐time polymerase chain reaction on peripheral blood leukocyte mRNA, and serum cytokine levels were assayed by enzyme‐linked immunosorbent assay. Protein expression was assessed by Western blotting of lysates from plastic‐adherent peripheral blood mononuclear cells.

Results

In 6 of the 13 patients, we found 6 heterozygous missense substitutions in CIAS1. Five of the 6 mutations are novel. None of these sequence changes was observed in a panel of >900 chromosomes from healthy controls. Two distinct nucleotide changes in a single codon in unrelated patients resulted in the same amino acid change. In 4 mutation‐positive children whose parental DNA was available, no mutation was found in the parental DNA, supporting the conclusion that the mutations arose de novo. Consistent with the recently discovered role of CIAS1 in the regulation of interleukin‐1 (IL‐1), we found evidence of increased IL‐1β, as well as tumor necrosis factor, IL‐3, IL‐5, and IL‐6, but not transforming growth factor β, in a mutation‐positive patient compared with normal controls.

Conclusion

Our data increase the total number of known germline mutations in CIAS1 to 20, causing a spectrum of diseases ranging from familial cold autoinflammatory syndrome to Muckle‐Wells syndrome to NOMID/CINCA syndrome. Mutations in CIAS1 were only found in ∼50% of the cases identified clinically as NOMID/CINCA syndrome, which raises the possibility of genetic heterogeneity. IL‐1 regulation by CIAS1 suggests that IL‐1 receptor blockade may constitute a rational approach to the treatment of NOMID/CINCA syndrome.
Expression of matrix metalloproteinases in articular cartilage of temporomandibular and knee joints of mice during growth, maturation, and aging
Authors: Gepstein Amira , Shapiro Sarah , Arbel Gil , Lahat Nitza , Livne Erella
Published: December 2002

Objective

This study examined the involvement of different matrix metalloproteinases (MMPs) in articular cartilage in the process of growth, maturation, and aging of mice, and compared the temporal changes in the expression of MMPs between temporomandibular joints (TMJ) and knee joints.

Methods

Homogenates of intact tibial plateau, femoral condyle, and TMJ condyle cartilages from animals of different ages were assessed for gelatinase (MMP‐2 and MMP‐9) activity by zymography. The messenger RNA (mRNA) expression of MMPs 1, 2, 3, 9, and 13 in tibial plateau cartilage was determined by semiquantitative reverse transcription–polymerase chain reaction, and immunohistochemistry was used to localize MMPs 2, 3, 9, and 13 in the knee joints and TMJ from mice of different ages.

Results

The pattern of gelatinase (MMP‐2 and MMP‐9) activity and their protein expression as well as that of MMPs 3 and 13 varied with the age of the mouse, and differences in expression were observed between the knee and TMJ cartilage. The expression of mRNA for the MMPs in the tibial plateau was also age related.

Conclusion

This study demonstrated changes in the protein and mRNA expression of MMPs 2, 9, 3, and 13 during growth, maturation, and aging in mice. The temporal changes were characteristic of the joint, and distinct differences were observed between the TMJ and knee cartilage. The differences in temporospatial expression of MMPs between the knee joint and TMJ may be the result of differences in load and function of these joints. The information provided in this study contributes to a better understanding of the role of these MMPs in the maintenance and integrity of cartilage tissue.