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ID PMID Title PublicationDate abstract
16545585 Osteoarthritis of the first carpometacarpal joint: a study of radiology and clinical epide 2006 May BACKGROUND: The radiological and epidemiological data from the Copenhagen Osteoarthritis Study (COS) were analysed in order to assess the prevalence of osteoarthritis (OA) of the first carpometacarpal joint (CMCJ). Another aim of the study was to analyse relationships between radiologic CMCJ OA and self-reported pain. The third aim was to analyse if additional information could be obtained applying a new method of correlating individual radiological features to self-reported pain, compared to Kellgren and Lawrence's (K-L's) radiologic OA classification. METHODS: Between 1992 and 1994 standardised radiographs of both hands were recorded in 3,355 participants of the COS cohort. Subjects with known rheumatoid arthritis, other inflammatory arthritis or earlier fractures of the hand were excluded. OA of the CMCJ was assessed according to K-L's radiologic classification by two senior radiologists at our institution. The radiologists further evaluated individual radiologic features of CMCJ OA as recommended by K-L according to the text attached to each picture in their radiologic atlas of OA. To estimate inter- and intraobserver reproducibility a subset of 100 radiographs was reread. RESULTS: Our analyses demonstrated that the K-L method was not able to classify all X-rays. In 608 (18.1%) cases, combinations of joint space width (JSW) measurements, the graduation of osteofytes, sclerosis and cysts fell outside the classification. The radiological evaluation of individual features of OA demonstrated an acceptable reproducibility, intrapersonal (kappa=0.79) as well as interpersonal (kappa=0.65). The prevalence of each radiological feature increased after the fifth decade, progressively more so among women (P<0.001), with the highest prevalence (36.0%) of grades 3 and 4 JSW reduction among women>80 years. A significant correlation was found between signs of radiologic degeneration and self-reported pain (P<0.001); however, different combinations of OA features had different relations to symptoms. Logistic regression analyses revealed sclerosis to have an independent influence on pain in the thumb compared with the presence of osteofytes, cysts and diminished JSW. Body mass index (BMI) was positively related to radiological changes. In logistic regression analyses BMI did not demonstrate an independent positive relation to OA. CONCLUSION: Radiological degenerative changes in the CMCJ by age especially among women are quite common. However, it is demonstrated that global radiologic classifications of OA of the CMCJ have serious limitations in epidemiological studies. Not all cases fit into classification based on the K-L-atlas. Among the radiological features, subchondral sclerosis is significantly related to self-reported pain. Specific radiologic data should be incorporated in epidemiological studies on hand OA.
16737433 [Pneumonia by Corynebacterium pseudodiphteriticum: an infection to consider]. 2006 Mar Corynebacterium pseudodiphteriticum has been considered a very infrequent respiratory pathogen. We report three cases of pneumonia due to C. pseudodiphteriticum, describing their clinical and microbiological features. There were two patients with pre-existing chronic respiratory disease, one of their with steroidal therapy, and other associated with endotracheal intubation. The diagnostic was made by Gram stain and quantitative cultures from respiratory tract specimens. All patients were cured after treatment with amoxicillin-clavulanate, ceftriaxone and vancomycin respectively. C. pseudodiphteriticum must be consider as a possible causal agent of pneumonia in patients with underlying respiratory disease or endotracheal intubation. Antimicrobial susceptibility testing of C. pseudodiphteriticum may be useful for correct treatment of infected patients, but beta-lactam antibiotics are an appropriate therapeutic option against this bacteria.
16300639 c-Jun NH2-terminal kinase mediates interleukin-1beta-induced inhibition of lacrimal gland 2006 Jan Sjögren's syndrome, an inflammatory disease affecting the lacrimal and salivary glands, is the leading cause of aqueous tear-deficient type of dry eye. We previously showed that interleukin-1beta (IL-1beta) protein is up regulated in the lacrimal gland of a murine model of Sjögren's syndrome and that exogenous addition of this cytokine inhibits neurotransmitter release and lacrimal gland protein secretion. In the present study we investigated the role of c-Jun NH2-terminal kinase (JNK) in IL-1beta-mediated inhibition of lacrimal gland secretion and tear production. In vitro, IL-1beta induced a time-dependent activation of JNK with a maximum 7.5-fold at 30 min. SP600125, a JNK inhibitor, inhibited, in a concentration-dependent manner, IL-1beta-induced activation of JNK with a maximum of 87% at 10(-4) m. In vivo, IL-1beta stimulated JNK and the expression of the inducible isoform of nitric oxide synthase (iNOS). IL-1beta inhibited high KCl and adrenergic agonist induced protein secretion by 85% and 66%, respectively. SP600125 alleviated the inhibitory effect of IL-1beta on KCl- and agonist-induced protein secretion by 79% and 47%, respectively, and completely blocked the expression of iNOS. Treatment for 7 days with SP600125 increased tear production in a murine model of Sjögren's syndrome dry eye. We conclude that JNK plays a pivotal role in IL-1beta-mediated inhibition of lacrimal gland secretion and subsequent dry eye.
16095013 Exacerbation of Whipple's disease associated with infliximab treatment. 2005 Mar A 34-year-old man with chronic inflammatory joint disease and recurrent fever over 6 years was diagnosed as having Still's disease. Treatment with corticosteroids and azathioprine was ineffective. Therefore, infliximab/ methotrexate was started. The patient subsequently developed a wasting disease with rapid weight loss, erythema nodosum, diarrhoea, progressive lymph node enlargement, and a sigmoido-vesical fistula. Histological analysis of several enlarged lymph nodes, the margins of the fistula, and the small bowel established the diagnosis of Whipple's disease (WD). The presence of Tropheryma whipplei (Tw) DNA in the tissues was confirmed by polymerase chain reaction (PCR). Careful re-evaluation of biopsies taken from the ileum and the liver 2 years earlier, which at that time was not judged to be diagnostic for WD, retrospectively showed subtle histological signs of WD and were positive for Tw DNA. In summary, infliximab treatment seems to increase the risk of exacerbation of WD. WD should be carefully ruled out prior to application of tumour necrosis factor-alpha (TNF-alpha) blockade.
15700116 Anti-CENP-H antibodies in patients with Sjogren's syndrome. 2006 Feb Anti-centromere antibody (ACA) has been reported to be associated with Sjogren's syndrome (SS) and the clinical significance of anti-CENP-H antibody remains unknown. To determine the clinical significance of anti-CENP-H and anti-centromere antibodies in primary SS, sera from 62 patients with primary SS and 40 normal controls were examined for anti-SS-A/SS-B antibodies, ACA and anti-CENP-H antibodies, by enzyme-linked immunosorbent assay and indirect immunofluorescence (IIF), respectively. Of the 62 serum samples with primary SS, 17 were positive with ACA and anti-CENP-H antibodies. Sera from SS patients with anti-CENP-H and ACA antibodies do not contain anti-SS-A/Ro and/or anti-SS-B/La antibodies. No anti-CENP-H antibody was found in sera of normal controls. An increased frequency of ACA and anti-CENP-H antibodies was found for the first time in patients with SS. Anti-CENP-H antibodies and anti-SS-A/Ro or anti-SS-B/La antibodies are present mutually exclusive. Patients with anti-CENP-H antibodies had a lower frequency of rheumatoid factor (RF). SS can be subdivided serologically into two groups; group one with anti-SS-A/Ro and/or anti-SS-B/La antibody, group two with ACA and/or anti-CENP-H antibodies. We recommend that ACA or anti-CENP-H antibodies should be considered as one of the serological markers for SS.
17164992 A new conceptualization for Mikulicz's disease as an IgG4-related plasmacytic disease. 2006 Mikulicz's disease (MD) has been included within the diagnosis of primary Sjögren's syndrome (SS), but it represents a unique condition involving persistent enlargement of the lacrimal and salivary glands characterized by few autoimmune reactions and good responsiveness to glucocorticoids, leading to the recovery of gland function. Mikulicz's disease was recently reported to be associated with elevated immunoglobulin G4 (IgG4) concentrations in the serum and prominent infiltration of plasmacytes expressing IgG4 into the lacrimal and salivary glands. The following features were used for diagnosis: (1) visual confirmation of symmetrical and persistent swelling in more than two lacrimal and major salivary glands; (2) prominent mononuclear cell infiltration of lacrimal and salivary glands; and (3) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. These features are not observed in most SS cases. The complications of MD include autoimmune pancreatitis, retroperitoneal fibrosis, tubulointerstitial nephritis, autoimmune hypophysitis, and Riedel's thyroiditis, all of which show IgG4 involvement in their pathogenesis. Mikulicz's disease thus differs from SS and may be a systemic IgG4-related plasmacytic disease.
16729722 Interferon alpha and its contribution to autoimmunity. 2006 May It is now well accepted that interferon (IFN)alpha plays a critical role in the pathogenesis and perpetuation of specific autoimmune diseases, including systemic lupus erythematosus (SLE), autoimmune thyroid disease and type 1 diabetes. IFNalpha-based treatments are widely used for the treatment of chronic viral infections, particularly chronic hepatitis C virus infection; however, several case reports have emerged describing autoimmune conditions that have developed during IFNalpha therapy. The data support the pathogenic potential of IFNalpha in autoimmunity, although it is clear that genetic and environmental factors are also key to the development of autoimmune conditions. Several points of interaction between IFNalpha and immune effector cells have been experimentally defined, the functional consequences of many of which remain poorly understood. This review describes the most recent data in support of an important role for IFNalpha in autoimmunity, particularly SLE, and the potential mechanisms by which IFNalpha contributes to immune dysfunction. Future approaches to IFNalpha modulation as a therapeutic strategy for use in the treatment of autoimmune diseases are also discussed.
16178870 Mechanisms dependent on tryptophan catabolism regulate immune responses in primary Sjögre 2005 Oct To investigate the possible role of tryptophan metabolism in immune regulation of primary Sjögren's syndrome (pSS) the serum concentrations of tryptophan and its metabolite kynurenine were measured by reverse-phase high-performance liquid chromatography (HPLC) in 103 patients with pSS, 56 patients with sicca symptoms and 309 healthy blood donors. The kynurenine per tryptophan ratio (kyn/trp), which reflects the activity of the indoleamine-pyrrole 2,3-dioxygenase (IDO) enzyme involved in tryptophan catabolism, was calculated. Both female and male patients with pSS had significantly higher serum kynurenine concentrations and kyn/trp than subjects with sicca symptoms or healthy blood donors. The median (quartile range) concentration of kynurenine in female patients with pSS was 2.41 micromol/l (1.86-3.26) compared with 1.85 micromol/l (1.58-2.38, P < 0.0001) in subjects with sicca symptoms and 1.96 micromol/l (1.65-2.27, P < 0.0001) in healthy blood donors. Their kyn/trp x 1000 was 34.0 (25.1-44.3) compared with 25.3 (21.1-31.5, P < 0.0001) in subjects with sicca symptoms and 24.3 (21.0-28.9, P < 0.0001) in healthy blood donors. Female pSS patients with high IDO activity (kyn/trp x 1000 > or = 34.0) had significantly higher ESR, serum C-reactive protein, serum IgA and serum beta-2 microglobulin concentrations as well as higher serum creatinine levels, and they had positive antinuclear antibodies more frequently and presented with more American-European consensus group criteria than those with low IDO activity (kyn/trp x 1000 < 34.0). These data suggest that mechanisms dependent on tryptophan catabolism regulate immune responses in pSS. Tryptophan degradation is enhanced in patients with pSS, and high IDO activity is associated with severity of pSS.
16276048 [Three cases of childhood-onset male systemic lupus erythematosus (SLE) successfully treat 2005 Oct We reported three cases of childhood-onset male systemic lupus erythematosus (SLE), all of whom successfully treated with a combination of pulse methylprednisolone (mPSL) and pulse cyclophosphamide (IVCY). All of them had severe lupus nephritis and were complicated with other collagen diseases. Two cases were complicated with Sjögren syndrome (SS) and the other was complicated with both SS and anti-phospholipid syndrome (APS). After a combination of pulse mPSL and IVCY for a year, followed by oral predonisolone (PSL) and azathioprine (AZA), following up renal biopsy were performed in all cases, which showed histological improvement in glomerulonephritis. One case had flares a year later, but no flares were observed either in clinical symptoms or in laboratory examinations in the others. Their autoantibodies except anti-nuclear antibody (ANA) were eliminated. We suggest a combination of pulse mPSL and IVCY is effective for the patients who are suffering with severe lupus nephritis complicated with the other collagen diseases.
17071741 Sjögren's syndrome-like disease in mice with T cells lacking class 1A phosphoinositide-3- 2006 Nov 7 Sjögren's syndrome (SS) is an autoimmune disease that is characterized by infiltration of exocrine tissues, resulting in xerostomia (dry mouth) and keratoconjunctivitis sicca (dry eyes). Here, we show that mice with T cell-specific loss of class IA phosphoinositide 3-kinase function develop organ-specific autoimmunity that resembles the human disease SS. Most mutant mice aged 3-8 months develop corneal opacity and eye lesions due to irritation and constant scratching. These mice display cardinal signs of primary SS such as marked lymphocytic infiltration of the lacrimal glands, antinuclear antibodies in the serum, and elevated titer of anti-SS-A antibody, in the absence of kidney pathology. Immunofluorescence studies show the presence of numerous CD4+ T cells with a smaller number of CD8+ T cells and B cells in the lacrimal glands. CD4+ T cells from these mice exhibit aberrant differentiation in vitro. These results indicate that aberrant T cells with impaired class IA phosphoinositide 3-kinase signaling can lead to organ-specific autoimmunity. In addition, the mouse model described here represents a tool to study the pathogenesis and treatment of SS.
16802367 Identification of transitional type II B cells in the salivary glands of patients with Sjà 2006 Jul OBJECTIVE: To identify B cell subpopulations participating in the lymphocyte infiltrate of salivary glands from patients with primary Sjögren's syndrome. A special emphasis was placed on those B lymphocytes included in the ectopic germinal centers (GCs). METHODS: The presence of B cells in salivary glands and their polyclonality were ascertained by phenotyping and reverse transcription-polymerase chain reaction in salivary gland samples from 18 patients. Their phenotype was thoroughly analyzed using a number of double-staining combinations. The results obtained in tissue sections were confirmed by fluorescence-activated cell sorting analysis of B cells eluted from salivary glands, and these findings were compared with those in tonsils. RESULTS: Memory-type B cells were defined as CD20+, CD27+ and were seen in all specimens, whereas GCs were found in only 7 specimens. Furthermore, B cells found in these GCs lacked certain characteristics of centroblasts and centrocytes. Instead, they fulfilled the criteria for transitional type II (TII) B cells and resembled marginal-zone B cells. BAFF (the assistance of which is required for proper transformation of transitional TI B cells into transitional TII B cells) accumulated adjacent to transitional and marginal-zone-like B lymphocytes. Further evidence for the involvement of BAFF came from the expression of its receptors on infiltrating B cells. CONCLUSION: These transitional TII and marginal-zone-like B cells are probably instrumental in the local production of autoantibodies and possibly influential in the ensuing destruction of epithelial cells.
16385503 BAFF-induced changes in B cell antigen receptor-containing lipid rafts in Sjögren's syndr 2006 Jan OBJECTIVE: To determine the effect of excessive production of BAFF on the distribution and function of B cell subsets in patients with primary Sjögren's syndrome (SS). METHODS: The phenotype of B lymphocytes was analyzed by flow cytometry. Differences in the expression level of membrane IgD and CD38 were used to identify B lymphocyte subsets evolving from naive Bm1 through memory Bm5 cells. Based on our finding of a low expression of CD45RA, we sorted Bm2/Bm2' cells to determine the time course of translocation of the CD19 molecule and the B cell receptor into lipid rafts, by confocal microscopy. Serum levels of BAFF were measured by an enzyme-linked immunosorbent assay developed in-house. RESULTS: "Circulating" Bm2/Bm2' cells were expanded in patients with primary SS compared with rheumatic disease controls and with normal controls. In addition, these B cell subsets were functionally abnormal. Prolonged residency of the B cell receptor in lipid rafts in these cells was associated with elevated CD19 expression in B cells, most notably, Bm2 and Bm2' cells, obtained from the patients with primary SS. BAFF levels were higher in the patients than in the normal controls and correlated with the percentage of Bm2/Bm2' cells and their expression of CD19 in primary SS patients. These correlations were confirmed by placing sorted Bm1 or Bm2 cells from normal controls in culture in the presence or absence of BAFF. CONCLUSION: Bm2/Bm2' cells express more CD19 molecules in primary SS patients than in normal controls. BAFF might participate in this elevated expression of CD19. These patients might be suitable candidates for treatment with BAFF antagonists.
15903026 The serological pattern of autoantibodies to the Ro52, Ro60, and La48 autoantigens in prim 2005 OBJECTIVE: Sjögren's syndrome (SS) is characterized by exocrine secretion dysfunction. Hallmarks of the chronic autoimmune disease are cellular infiltration of the exocrine glands and the presence of serum autoantibodies against Ro and La. The purpose of this study was to perform a detailed characterisation of the serological pattern against the Ro and La autoantigens in terms of antigen specificity and antibody isotype. METHODS: Serum samples from 100 patients with primary SS and 100 matched healthy controls were tested by enzyme-linked immunosorbent assay (ELISA) with recombinant human Ro and La proteins as antigens. RESULTS: There were higher frequencies of Ro and La positive serum in the SS patients than in the control sera, and the titres were higher in the positive sera from SS patients than the controls. The SS patients often had antibodies against two or three of the antigens tested, while the positive control sera often reacted against only one of the autoantigens. The SS patients had a broader immunoglobulin isotype repertoire in their autoantibodies while the controls when positive usually had one antigen specific isotype. CONCLUSION: We found a distinct and significant difference in the serum antibody specificity and immunoglobulin isotype pattern between SS patients and matched controls. This variance may point to different mechanisms by which these autoantibodies are generated.
15762888 Alpha-fodrin as a putative autoantigen in Graves' ophthalmopathy. 2005 Apr Alpha-fodrin, an intracellular organ-specific cytoskeleton protein is a recently identified autoantigen associated with Sicca- and Sjogren's syndrome (SS). SS frequently affects patients with Graves' ophthalmopathy (GO). We have therefore cloned and expressed the human recombinant 120-kDa fodrin-fragment. A sequential purification procedure was applied to isolate the recombinant protein. Using sera from patients with SS, the antigenicity of the purified fodrin fragment was demonstrated by immunoblotting. Sera from 144 patients with GO and 1200 blood donors were screened for the presence of anti-alpha-fodrin IgA and IgG antibodies by a newly developed ELISA using the human alpha-fodrin fragment as an autoantigen. In contrast to controls (<1% IgA only, P < 0.001) and to subjects with various autoimmune diseases (P < 0.001), alpha-fodrin antibodies were detected in 22% of patients with GO (n = 32). IgA and IgG antibodies were present in 21 (15%) and 14 (10%) GO subjects, respectively. A total of 45 patients with GO (31%) had at least one fodrin- or SS-antibody. GO patients with SS showed SS- and high titres of alpha-fodrin-antibodies. In GO patients, fodrin antibodies correlated with TPO- (P < 0.05) and SS-A (P = 0.002) antibodies. Thus, for the first time, antibodies reactive with fodrin are reported in patients with GO.
17157576 Functional visual acuity in Stevens-Johnson syndrome. 2006 Dec PURPOSE: To evaluate the correlation of functional visual acuity (FVA) measurement with ocular surface findings in patients with Stevens-Johnson syndrome (SJS). DESIGN: Prospective comparative study. METHODS: Sixty-nine eyes of 38 patients with chronic SJS assessed at the Tokyo Dental College, Tokyo Medical Center, and the Kyoto Prefectural University of Medicine, Department of Ophthalmology, Kyoto, Japan, were studied. Twenty eyes of 10 normal subjects and 40 eyes of 20 patients with Sjögren syndrome (SS) were also studied. Conventional Landolt visual acuity (VA) and FVA examinations and slit-lamp examinations were performed. FVA was measured continuously by the FVA measurement system during a 30-second blink-free period in one eye. The visual maintenance ratio (VMR) was calculated as follows: VMR = [(2.7 - FVA)/(2.7 - baseline VA)], where logarithm of minimal angle of resolution values of FVA were entered into the formula and 2.7 represented the lowest visual acuity in this series. Slit-lamp examinations, Schirmer test, and fluorescein vital stainings were also performed in all subjects. RESULTS: VMR was markedly lower in patients with SJS compared with patients with SS and controls. FVA values showed a relation with the presence of corneal opacity and vascularization. CONCLUSIONS: The FVA measurement system is not only a useful tool in the evaluation of dynamic VA changes, but also reflects the ocular surface clinical findings in SJS.
15725576 A peptide of human muscarinic acetylcholine receptor 3 is antigenic in primary Sjogren's s 2005 Feb To evaluate the antigenicity of a peptide representing a part of the second extracellular loop of the human muscarinic acetylcholine receptor 3 (m3AChR) with autoimmune sera from primary Sjogren's syndrome (pSS), enzyme-linked immunosorbent assays (ELISAs) were developed. On the basis of the computer-predicted data, a 16-mer synthetic peptide KRTVPPGECFIQFLSE (KRSE213-228) was produced by solid-phase peptide synthesis. cDNA coding for the KRSE peptide was chemically synthetized and utilized to express the recombinant glutathione S-transferase (GST)-KRSE fusion protein. The immunoreactivities of the two antigens were tested in ELISAs with the sera of 40 pSS patients and 40 healthy controls. The specificity of the reaction was confirmed by inhibition assays and immunoblottings. The pSS sera resulted in significantly higher mean optical densities than those of the healthy controls (KRSE: 0.4149 vs 0.1494, p<0.0001; GST-KRSE 0.4765 vs 0.1764, p<0.0001). The immunological recognition with the recombinant fusion antigen was significantly better than that for the free peptide (p=0.0068). The sensitivities of the assays were 77.5% (KRSE) and 97% (GST-KRSE). The results of the concentration-dependent inhibition assays by the two systems of peptide presentation indicated that the KRSE sequence is specific for pSS sera. This is the first demonstration of the antigenicity of a novel peptide fragment of the human m3AChR in pSS. The analysed peptide could be of diagnostic relevance.
15184937 Effects of the topical treatment with NSAIDs on corneal sensitivity and ocular surface of 2005 May AIM AND PURPOSE: To evaluate the effects of two NSAIDs on corneal sensitivity and ocular surface in Sjögren's syndrome (SS) patients. METHODS: In all, 20 SS patients with epithelial corneal defects, were randomly divided into two groups: group 1 (10 females, age 35-63 years), treated with 0.1% indomethacin, one drop three times a day; group 2 (nine females, one male, age 38-65 years) treated with 0.1% diclofenac, at the same regimen. No systemic NSAIDs were allowed. Use of tear substitute was allowed. Corneal sensitivity, corneal staining, BUT, and ocular discomfort, were evaluated before and after 15, 30 days of treatment and 7 days after NSAID discontinuation. For statistical analysis, the Student's t-test and Mann-Whitney U test were used. RESULTS: Both groups showed at day 30 a statistically significant reduction of corneal sensitivity (P<0.05), although the diclofenac-treated group showed a statistically significant lower sensitivity if compared to the indomethacin-treated group (P<0.05). Corneal fluorescein score showed a statistically significantly worst alteration in group 2, 7 days after the discontinuation of the therapy (P=0.02). The ocular discomfort score was statistically significantly reduced in both groups starting from day 15 (P<0.05). DISCUSSION: The results indicate that NSAIDs can be useful in resolving symptoms of ocular discomfort in SS patients. However, they should be used with caution and under close monitoring, and the treatment should be promptly discontinued if corneal epithelial defects develop or worsen during treatment.
16385526 Production of a novel class of polyreactive pathogenic autoantibodies in BXD2 mice causes 2006 Jan OBJECTIVE: The BXD2 mouse strain spontaneously develops glomerulonephritis and erosive arthritis. The goal of this study was to identify the antigenic target proteins and epitopes and to unravel the mechanisms by which the related conditions arise in BXD2 mice. METHODS: Individual hybridomas isolated from the spleen of a 10-month-old BXD2 mouse were injected intraperitoneally into nonautoimmune mice for evaluation of pathogenicity of each autoantibody. Autoantigens were immunoprecipitated with the pathogenic autoantibody L3A4. Autoantigens were identified using enzyme-linked immunosorbent assay, Western blotting, 2-dimensional gel electrophoresis, and matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MS) and tandem MS. Antigenic epitopes were determined using a high-throughput epitope mapping method. RESULTS: The production of autoantibodies in BXD2 mice occurred in an orderly progression, with peak levels of autoantibodies to nitrotyrosine (NT)-modified enolase, Ro, alpha-actin, and heat-shock proteins (HSPs) preceding peak levels of antihistone, anti-DNA, and rheumatoid factor. Two monoclonal autoantibodies, L3A4 and T56G10, were identified that could induce immune complexes, renal disease, and/or arthritis. Both L3A4 and T56G10 were polyreactive, and each reacted with separate sets of autoantigens. The antigenic targets of L3A4 consisted of NT-modified enolase, ATP5b, alpha-actin, and Hsp70 family proteins including Hspa5 and Hsp74. The antigenic epitopes of NT-modified enolase and Hspa5 exhibited sequence homology and cross-reactivity, suggesting that epitope spreading may occur through a molecular mimicry mechanism. CONCLUSION: The polyreactivity of autoantibodies that target a novel class of autoantigens may enable these autoantibodies to induce erosive arthritis or glomerulonephritis either by direct pathogenic mechanisms or indirectly via Fc or immune complex deposition.
17023256 Open-label study of clarithromycin in patients with undifferentiated connective tissue dis 2006 Oct OBJECTIVE: The macrolide family of antibiotics (erythromycin, clarithromycin, and others), have both antimicrobial and immunomodulatory effects. This study explored the effect of clarithromycin on the clinical course of patients with undifferentiated connective tissue disease (UCTD) in a 12-week open-label study. METHODS: The diagnosis of UCTD was based on symptoms/signs of connective tissue disease, and the presence of 1 or more positive autoimmune disease tests, but with insufficient criteria to make a definitive diagnosis. Screening and monthly follow-up visits over 12 weeks included the following: history and physical examination; concurrent medications; the 68/66 tender/swollen joint count; visual analog scores 0 to 100 mm for patient and physician global assessment of disease activity, and patient pain; antinuclear antibody panel, rheumatoid factor, erythrocyte sedimentation rate, C-reactive protein, and blood chemistry. RESULTS: Seven patients with rheumatic disease were treated with clarithromycin; 6 of 7 had symptomatic relief. Two subjects treated empirically before the decision to perform an open-label study responded favorably. Four of 5 patients who completed the prospective open-label study had mean maximal improvements from baseline of 78, 75, and 79% in patient pain, patient global, and investigator global assessments, respectively. Pain relief occurred as early as 1 week. Drug withdrawal with rechallenge in 2 patients resulted in flare followed by recapture of symptomatic relief. CONCLUSIONS: Clarithromycin, a macrolide antibiotic, led to clinical improvement in patients with UCTD. Efficacy and safety data support further investigation of macrolide antibiotic use as a primary or adjunctive treatment in various connective tissue diseases.
17064780 Copper chelating anti-inflammatory agents; N1-(2-aminoethyl)-N2-(pyridin-2-ylmethyl)-ethan 2007 Jan An in vitro and in vivo study of some copper chelating anti-inflammatory agents for alleviation of inflammation associated with rheumatoid arthritis (RA) has been conducted. Two copper chelating agents, N(1)-(2-aminoethyl)-N(2)-(pyridin-2-ylmethyl)ethane-1,2-diamine ([555-N]) and N-(2-(2-aminoethylamino)ethyl)picolinamide ([H(555)-N]) have been synthesized as their hydrochloride salt; their protonation constants and formation constants with Cu(II), Zn(II) and Ca(II) determined by glass electrode potentiometry at 298K and an ionic strength of 0.15M. Cu(II) formed stable complexes at physiological pH while the in vivo competitors, Zn(II) and Ca(II) formed weak complexes with both chelating agents. Both [555-N] and [H(555)-N] showed better selectivity for Cu(II) than for Zn(II) and Ca(II). Electronic spectra for species formed at physiological pH suggest a square planar geometry. Speciation calculations using a blood plasma model predicted that these copper chelating agents are able to mobilize Cu(II) in vivo, while bio-distribution studies of their (64)Cu(II)-labelled complexes at physiological pH showed tissue accumulation and retention indicating an encouraging biological half life.