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ID PMID Title PublicationDate abstract
15559322 [Clinical significance of cevimeline hydrochloride in the treatment of dry mouth in patien 2004 Oct To evaluate the efficacy and safety of cevimeline hydrochloride for the treatment of dry mouth in patients with Sjögren's syndrome (SS), eight SS patients received 30 mg of cevimeline twice or three times daily for 24 weeks. Six out of the eight patients had improvement in dry mouth. Five patients had more than 20% increase in saliva secretion. In the assessment of salivary gland scintigraphy, three patients showed improvement. There was a significant negative correlation between the improvement of saliva secretion and the severity of tissue damage assessed by MR sialography (r= - 0.754, p<0.05). One patient stopped cevimeline at 4 weeks because of headache and nausea. There was no significant change in laboratory data. Cevimeline is safe and effective medicine for dry mouth in patients with SS, in particular, with less severe salivary gland destruction.
15245543 Improvement of adult Still's disease with granulocyte and monocyte adsorption apheresis. 2004 Jul Adult Still's disease is characterized by a high spiking fever, transient skin rash, and polyarthralgia. Joint pain is one of the major complaints and is often intractable. We assessed the efficacy of granulocyte and monocyte adsorption apheresis (GCAP) therapy for treating arthralgia in adult Still's disease. A 33-year-old woman with adult Still's disease who suffered from recalcitrant arthralgia resistant to systemic corticosteroids was treated with GCAP therapy. She underwent five GCAP treatments at 5-day intervals. Her joint pain responded dramatically to the GCAP therapy, suggesting that GCAP may be useful for treating adult Still's disease. We present a detailed description of the patient and this novel therapy.
12061088 HLA system and autoantibodies in primary Sjögren's syndrome. 2002 The primary Sjögren's syndrome is an autoimmune exocrinopathy in which is established a correlation between the production of antibodies and certain HLA determinants. A significant number of antigens from A, B, C, DR and DQ loci was investigated in 50 patients with primary Sjögren's syndrome with positive autoantibodies against dsDNA, ssDNA, Ro (SS-A), La (SS-B), RNP antigens, as well as with higher titer of anticardiolipin antibodies from IgM and IgG classes. The HLA antigens were investigated by a microlimphocytotoxic test and a prolonged test, while the autoantibodies by an indirect immunofluorescency, counter electrophoresis and ELISA. A significant correlation was established between HLA-A1 and HLA-DR3 and the anti-Ro, anti-La, anti-DNA and anti-RNP antibodies, as well as between the higher titer of JgM and JgG anticardiolipins and the HLA-A1, B8 and DR3 antigens. No association was found between the specific for the disease anti-Ro and anti-La autoantibodies and certain genetic markers. The achieved results confirm the hypothesis that the autoantibodies' production in primary Sjören's syndrome is to a certain extent genetically determined. (Tab. 1, Ref. 5.)
12788129 Arthritis and uveitis in children. A pediatric rheumatology perspective. 2003 Jun PURPOSE: We describe important characteristics of the chronic arthritides of childhood associated with anterior uveitis. DESIGN: Literature review and commentary based on the investigators' experiences. METHOD: A review of pertinent publications provides a background of current understanding of those forms of childhood arthritis that are of interest to ophthalmologists caring for children. Recommendations regarding screening for asymptomatic anterior uveitis in this patient group are reviewed, and current advances in therapy are noted. A new classification of childhood arthritis is compared with existing classifications. RESULTS: Uveitis complicates several forms of juvenile idiopathic arthritis (oligoarthritis, rheumatoid factor-negative polyarthritis, psoriatic arthritis, and enthesitis-related arthritis). Uveitis is a complication in up to 30% of children with chronic arthritis, particularly in those with oligoarticular disease. CONCLUSIONS: Visual prognosis is guarded for children with chronic arthritis and uveitis. Surveillance and early therapy are important factors for ensuring a good outcome.
12180715 Modifications in adenoviral coat fiber proteins and transcriptional regulatory sequences e 2002 Aug OBJECTIVE: To characterize the adenoviral properties required to enhance intracellular transgene expression for gene therapy. METHODS: Primary human fibroblasts and macrophages were infected with standard replication-defective adenoviruses, adenoviral vectors containing modified fiber coat proteins expressing Arg-Gly-Asp (RGD) or heparin sulfate binding moieties, or a tetracycline-regulatable transgene transcription system. Each of these vectors expressed the beta-galactosidase gene (beta-Gal), which was quantified by flow cytometry. Ankle joints from rats with adjuvant induced arthritis were transduced intraarticularly with each of the vectors and B-Gal expression was quantified by flow cytometry. RESULTS: Primary human fibroblasts and macrophages displayed marked increases in transgene expression from both modified fiber protein vectors and from the tetracycline-regulatable vector, compared to an unmodified vector expressing the transgene from the cytomegalovirus promoter/enhancer. In the rat model, the modified fiber protein vectors and the tetracycline-regulatable vector system also displayed increased transgene expression in inflamed rat joints. CONCLUSION: Adenovirus attachment and uptake by cells and promoter strength limit transgene expression from conventional adenoviral vectors in models of rheumatoid arthritis.
15593180 Assessment of the efficacy of different statins in murine collagen-induced arthritis. 2004 Dec OBJECTIVE: Hydroxymethylglutaryl-coenzyme A reductase inhibitors (statins) are widely used lipid-lowering agents. In addition to their well-known effect on cholesterol levels, statins have been reported to display antiinflammatory activities both in vitro and in vivo. In this context, in vivo prophylactic and therapeutic effects of simvastatin were recently demonstrated in mouse collagen-induced arthritis, a well-described experimental model for human rheumatoid arthritis (RA). The aim of this study was to further investigate in vivo effects of 3 different statins, atorvastatin, rosuvastatin, and simvastatin, using the same experimental model. METHODS: Different doses and routes of administration were used for the various statins in an attempt to elicit antiarthritic activity in preventive and curative treatment protocols. RESULTS: Atorvastatin and rosuvastatin had no in vivo efficacy, as indicated by clinical, histologic (synovial hyperplasia, exudate, and cartilage damage), immunologic (anti-type II collagen IgG production), and biochemical (interleukin-6, serum amyloid A, and glucocorticoid production) parameters of inflammation and autoimmunity. The previously described beneficial effects of administration of intraperitoneal simvastatin were reproduced in our experiments, but could be accounted for by very severe side effects of the treatment, leading to increased glucocorticoid levels. CONCLUSION: This work shows that different statins have no effect in a murine model of arthritis, an unexpected observation given the previously described therapeutic effect of statins in immune-mediated inflammatory diseases. It is still unclear whether statins will have benefit in the treatment of RA.
15132930 Clinical outcome of tibiotalar arthrodesis utilizing the chevron technique. 2004 Apr Tibiotalar arthrodesis remains the gold standard reconstructive procedure for the treatment of disabling ankle arthritis. The purpose of this study was to review the clinical results of tibiotalar arthrodesis utilizing the chevron fusion technique. The results of 46 consecutive patients who underwent ankle arthrodesis utilizing the chevron technique were reviewed. The etiology of the tibiotalar arthritis was posttraumatic in 29 of 46 patients. Of the remaining 17 patients, seven had osteoarthritis, five had talar osteonecrosis, two had rheumatoid arthritis, one had hemophilic arthropathy, one had gouty arthropathy, and one had unrecognized chronic osteomyelitis. Three patients had prior hindfoot arthrodeses, and two patients had bilateral ankle fusions at last follow-up. All patients were followed for a minimum of 2 years. Of the 46 patients, 41 were available for review, with an average follow-up of 7.3 years (range, 2-20 years). Twelve patients had greater than 10-year follow-up. The Mazur ankle score was calculated for all 41 patients. The average Mazur ankle score for the 41 patients available for review was 72.8, out of a maximum possible score of 90. Eighteen patients had excellent results, 11 patients had good results, five patients had fair results, and seven patients had poor results. The most common reasons for fair or poor results were symptomatic subtalar arthritis and multiple medical comorbidities. All patients with postoperative symptomatic subtalar arthritis had preoperative radiographic evidence of subtalar arthrosis. Of the 12 patients with greater than 10-year follow-up, nine had excellent or good results, and an average Mazur ankle score of 76.6. All patients with either prior hindfoot arthrodeses or bilateral ankle fusions had excellent or good results. Of the 41 arthrodeses included in the study, 38 (38/41, 93%) went on to clinical and radiographic union. The chevron technique provides a predictable method to obtain fusion of the tibiotalar joint. Most patients can expect excellent or good results. In the current study, 90% (37/41) of patients were satisfied with the outcome of their surgery and would undergo the same operation again under similar circumstances.
12452734 Monitoring and assessing the safety of disease-modifying antirheumatic drugs: a West Midla 2002 BACKGROUND: Serious adverse events may occur from the use of disease modifying antirheumatic drugs (DMARDs) used to treat rheumatoid arthritis. We describe preliminary data from a regional surveillance scheme. Our aims were to identify a broad range of potential adverse events, to identify deficiencies in care and examine the management of common events in order to improve care. METHODS: Adverse events were sought by regular postcards to clinicians in the West Midlands region of the UK. Each reported case was carefully described and the opinions of at least three peer-reviewers were sought on cause-effect relationships, the potential for prevention and the appropriateness of management. RESULTS: Forty-four serious adverse events associated with DMARD use were reported between December 1999 and October 2001. Events included eight patients with malignancies, two with pancytopenia taking methotrexate, three with septic arthritis, and two with septicaemias. Fifteen cases have been peer-reviewed in detail, so far. At least two reviewers thought that eight events were related to DMARD use and that two were preventable. Agreement between pairs of reviewers was fair or moderate (weighted kappa 0.23-0.5). DISCUSSION: We have successfully implemented a regional system for identifying potential drug-related serious adverse events. A diverse range of potential drug-related events has been seen. Early analyses have highlighted the difficulties of determining cause-effect relationships between a drug and an event.
15067089 Matrix metalloproteinases as targets for the immune system during experimental arthritis. 2004 Apr 15 Novel therapies for rheumatoid arthritis aiming at intervention in the inflammatory process by manipulation of autoreactive T and B lymphocytes receive major interest. However, the development of such therapies is largely hampered by the lack of knowledge of self-Ags recognized during the disease process. Recently, we predicted putative T cell self-epitopes based on a computer search profile. In the present study, the predicted self-epitopes were tested for T cell recognition in two experimental arthritis models, and their arthritogenic capacity was analyzed. Fourteen of n = 51 predicted self-epitopes were recognized during experimental arthritis of which six were able to actively induce arthritis. Interestingly, three of these six peptides were derived from matrix metalloproteinases (MMP), and only T cells responsive to MMP-derived epitopes were able to passively transfer arthritis to naive rats. Moreover, we demonstrate the presence of Abs to MMP-3 during the course of adjuvant arthritis. Together these data indicate that MMPs play a pivotal role as target for T and B cells during the development of inflammatory arthritis. This finding sheds new light on the pathophysiological role of MMPs during arthritis and opens novel possibilities for Ag-specific immunotherapy.
12784391 Relationships between autoantibody responses to deletion mutants of Ki antigen and clinica 2003 Jun OBJECTIVE: To determine the relationships between subtypes of anti-Ki antibodies and clinical manifestations of systemic lupus erythematosus. METHODS: The cDNA encoding full-length bovine Ki antigens or N- or C-terminal fragments were produced by polymerase chain reaction, and the fragments of Ki antigen were expressed as GST fusion proteins. Immunoreactivities of anti-Ki antibodies were tested by Western blotting. RESULTS: Of 60 sera reactive with full-length Ki antigen (KiF), 21 sera recognized only KiF. KiC5, a fragment containing the last 69 C-terminal amino acids, was recognized by 23 sera. Since no significant difference was observed in prevalence of reactivities between fragments from KiC2 to KiC5, a domain within the last 69 C-terminal amino acids was suggested to be the most common antigenic domain expressed among the GST fusion proteins. All 11 sera reacting with a fragment containing the initial 81 N-terminal amino acids also recognized all other fragments. A domain homologous to SV40 nuclear localization signal was required for N-terminal recognition by 8 sera. Reactivity to the last 69 C-terminal amino acids and the initial 81 N-terminal amino acids showed specificities to systemic lupus erythematosus without and with Sjögren's syndrome, respectively. Sicca was significantly more prevalent in patients whose sera reacted with both N- and C-terminal fragments, while prevalence of anti-SSA/Ro antibody was low. CONCLUSION: Ki antigen contains multiple epitopes recognized by autoimmune sera. Autoantibody profiles revealed distinctive immune responses, associated with certain clinical subtypes.
11887252 [Intrauterine therapy and outcome in four pregnancies of one mother with anti ro-autoantib 2002 Jan Autoantibodies against 52/60kD-Ro proteins, frequently present in patients with Sjoegren's Syndrome or systemic lupus erythematosus, are transmitted to the fetus during pregnancy. These autoantibodies can damage the cardiac conductive system of the fetus and cause a complete atrioventricular block, with a mortality of 30 %. We report the intrauterine therapy during four pregnancies of the same mother with high 52/60kD-Ro autoantibodies and the outcome of her infants. Our patient with primary Sjoegren's Syndrome suffered an early miscarriage during her first pregnancy. During the second pregnancy, a fetal atrioventricular block was observed at 23 weeks of gestation. Although subsequently dexamethasone therapy and daily plasmaphereses were started, a cesarean section was necessary at 26 weeks due to hydrops fetalis. The girl died from the atrioventricular block after two days. During the third and fourth pregnancies, dexamethasone therapy was begun already at 7 weeks, and regular plasmaphereses at 15 weeks. The children were delivered by cesarean section at 32 and 36 weeks because of growth retardation. Both had normal electrocardiograms after birth and after 2 and 4 years. In pregnant women with connective tissue diseases, monitoring of anti Ro-autoantibodies and fetal heart function is important. Intrauterine therapeutic options are dexamethasone therapy to suppress maternal and fetal inflammatory reactions and repeated plasmaphereses to reduce autoantibody levels. Postnatal follow up of the infants for atrioventricular block and rheumatic manifestations is necessary.
11817594 Characterization of the cysteine-rich secretory protein 3 gene as an early-transcribed gen 2002 Jan OBJECTIVE: To identify genes that may participate in the pathophysiology of Sjögren's syndrome (SS), the technique of differential display was applied to labial minor salivary gland (MSG) biopsy samples. METHODS: Total RNA was isolated from MSG biopsy samples from a woman with primary SS and a control subject, and the differential display protocol with 8 different random oligonucleotide primers was performed. One particular differentially expressed fragment showed 98% homology with the cysteine-rich secretory protein 3 (CRISP-3) gene. The result was verified by reverse transcription-polymerase chain reaction (RT-PCR) with messenger RNA (mRNA) samples from MSG biopsy tissues obtained from 4 women with primary SS. A CRISP-3 RNA probe was synthesized for in situ hybridization of 7 MSG biopsy samples from patients with primary SS. In an attempt to interpret the expression of CRISP-3, normal peripheral blood lymphocytes (PBLs) were activated in vitro at different time points and assayed for CRISP-3 expression. Finally, B cells were transfected with the coding region of CRISP-3 and monitored for the up-regulation of different B cell activation markers. RESULTS: The CRISP-3 gene was detected by RT-PCR in all SS patients tested. Mainly the mononuclear cells infiltrating the MSGs of patients expressed CRISP-3 mRNA. In addition, CRISP-3 was detected by RT-PCR between 30 minutes and 6 hours in phorbol myristate acetate-activated normal PBLs, while staurosporine inhibited this expression. CRISP-3-transfected B cells exhibited an up-regulation in CD25 surface expression. CONCLUSION: The CRISP-3 gene is identified as a novel early response gene that may participate in the pathophysiology of the autoimmune lesions of SS.
15509627 Clinical and pathological differences between Mikulicz's disease and Sjögren's syndrome. 2005 Feb OBJECTIVE: Mikulicz's disease (MD) has been included within the diagnosis of primary Sjögren's syndrome (SS), but represents a unique condition involving enlargement of the lachrymal and salivary glands and characterized by few autoimmune reactions and good responsiveness to glucocorticoids. We have previously described elevated immunoglobulin (Ig) G4 in the serum of four patients with MD. In this paper, we accumulated more MD cases and undertook clinical and histopathological analysis of these patients to clarify differences between MD and SS. METHODS: We diagnosed seven patients with MD according to the following criteria: (i) visual confirmation of symmetrical and persistent swelling in more than two lachrymal and major salivary glands; (ii) prominent mononuclear infiltration of lachrymal and salivary glands; and (iii) exclusion of other diseases that present with glandular swelling, such as sarcoidosis and lymphoproliferative disease. We summarized the clinical and serological characteristics (IgG subclasses and IFN-gamma/IL-4 ratio) of seven patients with MD, compared with SS with glandular swelling (SSw) and without glandular swelling (SSo). After steroid administration, we analysed changes in IgG subclasses in MD. Labial salivary gland specimens in MD, SSw and SSo were stained with anti-IgG4 antibodies. RESULTS: The concentration (+/-s.d.) of IgG4 was 1169.7 +/- 892.2 mg/dl in MD, 24.4 +/- 7.0 mg/dl in SSw (P<0.005) and 82.6 +/- 189.7 mg/dl in SSo (P<0.005). The IFN-gamma/IL-4 ratio was 0.392 +/- 0.083 (0.78 +/- 0.23/2.14 +/- 0.31 IU/pg) in MD, 0.004 +/- 0.002 (0.20 +/- 0.07/57.02 +/- 14.05 IU/pg) in SSw (P<0.05) and 0.012 +/- 0.009 (0.58 +/- 0.86/116.24 +/- 207.65 IU/pg) in SSo (P<0.05). The concentration (+/-s.d.) of IgG4 in MD decreased to 254.0 +/- 50.3 mg/dl (P<0.05) after glucocorticoid treatment. Histopathologically, only MD was associated with prominent infiltration of IgG4-positive plasmacytes into lachrymal and salivary glands. CONCLUSION: Mikulicz's disease is quite different from SS clinically and histopathologically. MD is suggested to be an IgG4-related systemic disease.
14613281 Extrasalivary lymphoma development in Sjögren's syndrome: clonal evolution from parotid g 2003 Nov OBJECTIVE: To characterize Sjögren's syndrome (SS)-related B cell lymphoproliferation at the premalignant stage and during the evolution to B cell lymphoma, and to better understand the pathobiologic mechanisms associated with clonal expansion and the possible influence of different microenvironments on neoplastic transformation. METHODS: We analyzed sequential parotid and lung biopsy specimens that were obtained from a single patient with SS at multiple time points over a 7-year period. Polymerase chain reaction DNA amplification, cloning, and sequencing of the immunoglobulin heavy chain variable region showed clonality, somatic mutations, intraclonal heterogeneity, and genealogic relationships of the B cell clones in the different biopsy specimens. RESULTS: The evolution of a nonmalignant B cell clone that was present in the parotid gland and evolved into a B cell lymphoma was documented. During such a process, one subclone was selected that accumulated somatic mutations in a pattern consistent with the preservation of antigen receptor functionality, possibly attributable to continued hypermutation and selection. Intraclonal diversity indicated the presence of local triggers in both the parotid and lung microenvironments. CONCLUSION: Molecular followup of B cell lymphoproliferation in SS, from nonmalignant stage to overt B cell lymphoma, indicated a role for B cell receptor engagement in clonal survival. The outgrowth of one subclone, with malignant transformation in the lung, a target organ different from the initial site of the lymphoproliferative process (the parotid gland), indicates that resident stimuli in different microenvironments may locally sustain ongoing lymphoproliferation and B cell transformation.
12415596 Presence of hepatitis C virus RNA in the salivary glands of patients with Sjögren's syndr 2002 Nov OBJECTIVE: To determine whether hepatitis C virus (HCV) RNA could be detected in the salivary glands of patients with both a diagnosis of Sjögren's syndrome (SS) and HCV infection. METHODS: Five patients with primary SS (European criteria) and chronically infected by HCV and 3 controls (one with primary SS without HCV infection, another with HCV infection without sicca syndrome, and a third without SS and HCV infection) were tested for the presence of HCV-RNA (using reverse transcriptase-polymerase chain reaction) in their saliva, serum, and salivary glands. RESULTS: In the patient group, HCV-RNA was detected in the serum and saliva of all cases and RNA extracted from salivary gland specimens tested positive in 3 cases. In the control group, HCV-RNA was not detected in the serum, saliva, or salivary glands from subjects without HCV infection. Only the control subject with HCV but without sicca syndrome tested positive for the presence of HCV-RNA in the serum, saliva, and salivary gland tissue. CONCLUSION: Our results showed that HCV may propagate and reside within salivary gland tissue, leading to HCV associated sialadenitis or Sjögren's-like syndrome in some cases, a phenomenon that does not seem specific. However, a direct role for HCV in the physiopathology of certain cases of primary SS is suggested.
12151695 Yoghurt biotherapy: contraindicated in immunosuppressed patients? 2002 Jun A fatal case of Lactobacillus rhamnosus septicaemia after prolonged oral vancomycin for recalcitrant Clostridium difficile infection is reported. The patient was immunosuppressed with cyclophosphamide and steroids for Sjögren's syndrome. The administration of Lactobacillus spp as "biotherapy" may be hazardous in such circumstances.
11950013 Raynaud's phenomenon in primary Sjögren's syndrome. Prevalence and clinical characteristi 2002 Apr OBJECTIVE: To determine the prevalence of Raynaud's phenomenon (RP) in a large series of patients with primary Sjögren's syndrome (SS) and to identify the clinical and immunological features related to its presence. METHODS: In a cross sectional study, we investigated 320 consecutive patients with primary SS (294 women, 26 men; mean age at onset 60 yrs, range 16-87 yrs). All patients fulfilled 4 or more of the diagnostic criteria for SS proposed by the European Community Study Group in 1993. Diagnosis of RP in patients with SS was defined as intermittent attacks of digital pallor and/or cyanosis in the absence of any other associated disease or anatomical abnormalities. RESULTS: RP was present in 40 (13%) patients. All were women, with a mean age of 57 yrs (range 18-78). RP preceded onset of sicca symptomatology in 18 (45%) patients. The main triggering factor was exposure to cold, which induced RP in all patients, while emotional stress was a factor in 12 patients, as was job related predisposition in 2. Fifteen (38%) patients required pharmacological treatment with calcium channel blockers (12 patients) or angiotensin converting enzyme inhibitors (2 patients) during colder months, and one patient required treatment with intravenous prostacyclin for ischemic complications. Compared with SS patients without RP, those with RP showed a higher prevalence of articular involvement (50 vs 31%; p = 0.031), cutaneous vasculitis (30 vs 11%; p = 0.003), antinuclear antibodies (95 vs 65%; p < 0.001), anti-Ro/SSA (59 vs 31%; p < 0.001) and anti-La/SSB antibodies (44 vs 20%, p = 0.003). CONCLUSION: We found RP in 13% of patients with primary SS, in almost half of whom RP was the first autoimmune symptomatology. These patients constituted a subset of SS with a higher frequency of some extraglandular features and positive immunological markers. The clinical course of RP seems to be milder in patients with primary SS than in those with other systemic autoimmune diseases such as systemic sclerosis, with no vascular complications and pharmacological treatment needed in only 40% of patients.
15584966 A dual role for interferon-gamma in the pathogenesis of Sjogren's syndrome-like autoimmune 2004 Dec Sjogren's syndrome-like autoimmune exocrinopathy (AEC) in the nonobese diabetic (NOD) mouse progresses from a preimmune phase to an immune phase, resulting in dry mouth and/or dry eyes. In the present study, the impact of the prototypical T-helper type 1 cytokine, interferon-gamma (IFN-gamma), on the onset of AEC was investigated using both the IFN-gamma and the IFN-gamma receptor gene knockout mice, NOD.IFN-gamma(-/-) and NOD.IFN-gammaR(-/-), respectively. Neither the NOD.IFN-gamma(-/-) nor the NOD.IFN-gammaR(-/-) mice exhibited increased acinar cell apoptosis and abnormal salivary protein expression, typically observed in parental NOD mice prior to disease. Without these preimmune phase abnormalities, NOD.IFN-gamma(-/-) and NOD.IFN-gammaR(-/-) mice showed no subsequent autoimmune responses against the salivary glands at 20 weeks. Interestingly, real-time polymerase chain reaction and electrophoretic gel mobility shift assays suggested that IFN-gamma and STAT1, as well as the transcriptional activity of STAT1 in NOD glands, were increased at birth. Unlike the neonatal submandibular glands of NOD or NOD-scid mice that show abnormal glandular morphogenesis at birth, the submandibular glands of the newly constructed congenic strain, NOD-scid.IFN-gamma(-/-), were found to be normal. Taken together, IFN-gamma appears to play a critical role not only during the later immune phase of AEC, but also the early preimmune phase, independent of effector functions of immune cells. How exactly IFN-gamma functions during this period remains speculative.
15188376 Induction of arthritis in HLA-DR4-humanized and HLA-DQ8-humanized mice by human cartilage 2004 Jun OBJECTIVE: To determine whether the rheumatoid arthritis (RA)-predisposing class II molecules of the major histocompatibility complex (MHC) can present cartilage proteoglycan (PG) aggrecan, and if so, to determine the epitope repertoire of the human cartilage PG in HLA-transgenic mice and determine whether HLA-transgenic mice develop arthritis in response to immunization with human cartilage PG. METHODS: Mice transgenic for HLA-DR2.Ab(0), DR3.Ab(0), DR4.Ab(0), and DQ8.Ab(0), lacking their own (mouse) class II antigens (Ab(0)), on the original (arthritis-resistant) and the arthritis-susceptible BALB/c backgrounds, were immunized with human cartilage PG. The T cell epitope repertoire presented by these class II MHC alleles was determined using a synthetic peptide library (143 peptides of the core protein of human cartilage PG), and arthritis development was monitored and compared in wild-type and HLA-transgenic/congenic BALB/c mice. RESULTS: Mice of the 4 HLA-transgenic lines, either on the original mixed, arthritis-resistant background or DR4.Ab(0)- and DQ8.Ab(0)-transgenic/congenic mice on the arthritis-susceptible BALB/c genetic background, responded well to PG immunization (as assessed by T cell responses and antibody and cytokine production), and a number of T cell epitopes along the core protein of human cartilage PG were identified. DR4.Ab(0)- and DQ8.Ab(0)-transgenic mice immunized with human cartilage PG developed arthritis, but only when these class II MHC molecules were present on the arthritis-susceptible (BALB/c) genetic background. CONCLUSION: A number of human cartilage PG epitopes can be presented by HLA alleles that predispose to the development of RA, but the epitopes of the cartilage PG presented by HLA-DR4 or HLA-DQ8 can induce arthritis only in the presence of an appropriate genetic (non-MHC) background.
11914895 Imaging of low-grade bone infection with a technetium-99m labelled monoclonal anti-NCA-90 2002 Apr Low-grade bone infection represents a serious clinical problem. Diagnostic options are often insufficient, yet the therapeutic implications of proven disease are important, especially in patients with prosthetic joint replacement. Technetium-99m labelled monoclonal anti-NCA-90 granulocyte antibody Fab' fragment (MN3 Fab') has been shown to be useful in bone and joint infection, but there are no data specifically referring to low-grade bone infection. We therefore analysed 38 scans in 30 consecutive patients (age range, 30-85 years; median age, 62 years) referred for suspected low-grade bone infection. There were 17 patients (21 scans) with total hip arthroplasty (THA), six with total knee arthroplasty (TKA), three who had undergone hip or knee surgery for trauma and five (seven scans) with resected hips and no endoprostheses (Girdlestone situations); one of these five patients had been investigated before with THA in situ and another prior to surgery for low-grade coxitis. There were no patients with rheumatoid arthritis as the underlying disease. Results were verified by means of bacteriological cultures, histopathological findings and/or follow-up and compared with the respective Zimmerli scores, which were used for clinical assessment of inflammatory activity. In one patient, the final diagnosis could not be established. One, 5 and 24 h after intravenous injection of up to 1.1 GBq of MN3 Fab', whole-body and planar scans were performed using a dual-head gamma camera. Scans were analysed visually and semiquantitatively adopting an arbitrary score ranging from 0 to 3. There were 13 true positive, 14 true negative and 10 false positive outcomes, yielding an overall sensitivity of 100%, an overall specificity of 58%, an accuracy of 73% and positive and negative predictive values of 57% and 100%, respectively. In patients with THA or TKA, accuracy was 81% and 80%, respectively, while it dropped to 43% in patients with Girdlestone situations owing to a high proportion of false positive findings (4/7) in this subgroup. Scintigraphic score was 1 in all of the false positive and in 11/13 true positive findings. The two remaining true positive findings displayed scintigraphic scores of 2 and 3, respectively. Scintigraphic and Zimmerli scores were loosely correlated (Spearman rho=0.38, P<0.05). Infection was excluded in 22/24 investigations with Zimmerli scores of <6. In this group, there were 13 scintigraphically true negative, nine false positive outcomes, and just two true positive outcomes. In 11/12 investigations with Zimmerli scores of 6 or 7, infection was verified and scintigraphic outcome was accordingly true positive, while the remaining patient was true negative. In conclusion, MN3 Fab' scintigraphy proved to be highly sensitive but not specific in diagnosing low-grade infections of the hip and knee regions in patients with previous joint surgery. The method seems reliable in excluding but not in proving the presence of infection. MN3 Fab' scintigraphy should not be applied in patients with Girdlestone situations. Assessment of infection using the Zimmerli score was more reliable than MN3 Fab' scintigraphy in this group of patients without rheumatoid arthritis as the underlying disease. Considering results from the literature concerning leucocyte scintigraphy, MN3 Fab' scintigraphy may be clinically useful in evaluating low-grade bone infection in THA and TKA patients with Zimmerli scores above 5 and concomitant rheumatoid arthritis or other inflammatory diseases.