Antinuclear factor.
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Antibodies, Antinuclear↗
Biomedical subjects
P J Charles
Publications and source records attributed to P J Charles.
Assessment of antibodies to double-stranded DNA induced in rheumatoid arthritis patients following treatment with infliximab, a monoclonal antibody to tumor necrosis factor alpha: findings in open-label and randomized placebo-controlled trials.
OBJECTIVE: To compare the incidence of anti-double-stranded DNA (anti-dsDNA) antibodies in rheumatoid arthritis (RA) patients receiving either single or multiple doses of a chimeric anti-tumor necrosis factor alpha (anti-TNFalpha) antibody or placebo infusions, with or without methotrexate, in open-label, randomized, placebo-controlled trials. METHODS: Multiple sera obtained from 156 patients before and after treatment with infliximab and from 37 patients treated with placebo infusions were tested for anti-dsDNA antibodies by 3 methods: Crithidia luciliae indirect immunofluorescence test (CLIFT), a commercial Farr assay (Ortho Diagnostics radioimmunoassay [RIA]) in which the antigen source is mammalian DNA, and a Farr assay employing 125I-labeled circular plasmid DNA (Central Laboratory of The Netherlands Red Cross Blood Transfusion Service [CLB] RIA). Patients with positive findings on the CLIFT were also tested for antibodies to histones (H1-H5) and chromatin and for IgM rheumatoid factors (IgM-RFs). RESULTS: None of the RA patients had a serum sample that was positive for anti-dsDNA antibodies by the CLIFT prior to infliximab therapy. Of the 22 patients who developed a positive CLIFT result, 11 (7% of 156 exposed to infliximab) also had positive findings on the Ortho RIA at a concentration of >10 units/ml and another 8 (5%) were positive at a concentration of >25 units/ml. In all but 1 patient, the anti-dsDNA antibodies were solely of the IgM isotype. Only 1 patient had detectable anti-dsDNA antibodies by the CLB RIA. All sera containing anti-dsDNA by the CLIFT contained antibodies to chromatin, and sera from 2 patients also contained antibodies to histones. IgM-RF titers showed a significant reduction following infliximab therapy in these 22 patients. One patient developed anti-dsDNA antibodies of IgG, IgA, and IgM isotype and had positive results on both Farr assays (peaking at 22 weeks and resolving by 54 weeks); this was associated with a reversible lupus syndrome. CONCLUSION: Anti-dsDNA antibodies of IgM class are induced by infliximab therapy; the frequency is dependent on the assay method used. Only 1 of the 156 patients who were treated with infliximab developed a self-limiting clinical lupus syndrome; that patient developed high titers of anti-dsDNA antibodies of IgG, IgM, and IgA class, as detected by the CLIFT and by 2 different Farr assays.
Adult↗
Anaemia of chronic disease in rheumatoid arthritis: in vivo effects of tumour necrosis factor alpha blockade.
Anaemia of chronic disease (ACD) is a common feature of active rheumatoid arthritis (RA). Inflammatory cytokines, particularly tumour necrosis factor alpha (TNF-alpha), interleukin-1 (IL-1) and interleukin-6 (IL-6), are thought to contribute to the pathogenesis of ACD, possibly by inhibiting erythropoietin (EPO) production. In this study, we examined the in vivo effects of TNF-alpha blockade with a chimeric monoclonal antibody, cA2, on erythropoiesis in RA patients with ACD. Administration of cA2 led to a dose-dependent increase in haemoglobin levels compared to placebo and these changes were accompanied by a reduction in both EPO and IL-6 levels. The data support the notion that TNF-alpha is important in the causation of ACD, but suggest a mechanism independent of EPO suppression. Instead, TNF-alpha may act directly on bone marrow red cell precursors.
Anemia↗
Sulphasalazine-induced autoimmune abnormalities in patients with rheumatic disease.
Sulphasalazine is a commonly used second line agent in rheumatoid arthritis (RA) and other inflammatory joint diseases and is reported to be one of the least toxic of this group of drugs. Recently a severe allergic reaction and cases of lupus-like disease have been described in patients with RA after treatment with sulphasalazine. We describe five patients, all with inflammatory arthropathy who developed cutaneous vasculitis, lupus-like disease or atypical serology after exposure to sulphasalazine. Three of four cases investigated were found to have the slow acetylator phenotype. These reactions can complicate the diagnosis and delay discontinuation of the drug. Moreover, present guidelines for the diagnosis of drug-induced lupus do not apply to the majority of patients with sulphasalazine-induced lupus.
Adult↗
Monoclonal anti-TNF alpha antibody as a probe of pathogenesis and therapy of rheumatoid disease.
Rheumatoid arthritis is a common cause of chronic disability for which current therapies are of limited value in controlling the disease process and outcome. Our initial approach to understanding the pathogenesis of RA and defining a novel therapeutic target was to investigate the role of cytokines by blocking their action with antibodies on cultured synovial-derived mononuclear cells in vitro. These investigations suggested that neutralization of TNF alpha with antibodies significantly inhibited the generation of other pro-inflammatory cytokines also over-produced, such as, IL-1, GM-CSF, IL-6 and IL-8. The implication that blockade of a single cytokine, TNF alpha might have far-reaching effects on multiple cytokines and thereby exert significant anti-inflammatory and protective effects on cartilage and bone of joints, was tested in arthritic DBA/1 mice immunized with collagen II. Impressive amelioration of joint swelling and joint erosions in this model encouraged clinical trials with a monoclonal anti-TNF alpha antibody. The cA2 chimeric anti-TNF alpha high-affinity antibody was initially tested in an open-label study at a dose of 20 mg/kg on 20 patients, with substantial and universal benefit. Subsequently, a randomized placebo-controlled double-blind trial was performed on 73 patients comparing a single intravenous injection of placebo (0.1% human serum albumin) with two doses of cA2. Using a composite disease activity index, at 4 weeks post infusion, 8% of patients receiving placebo improved compared with 44% receiving 1 mg/kg cA/2 and 79% receiving 10 mg/kg. Between 2 to 4 repeated cycles of cA2 were administered to 7 patients and all patients showed improvement of a similar magnitude with each cycle. These data support our proposition that TNF alpha is implicated in the pathogenesis of RA, and is thus a key therapeutic target. Monoclonal anti-TNF alpha antibodies control disease flares and are candidate agents for longer-term control of RA, although repeated therapy with cA2 is associated with anti-idiotypic responses in 50% of patients and a trend toward shortening of the duration of response. In the DBA/1 arthritic mice, synergy of action of anti-TNF and anti-CD4 is observed together with suppression of an anti-globulin response, indicating one way in which benefit might be augmented in the future.
Animals↗
Immunological intervention reveals reciprocal roles for tumor necrosis factor-alpha and interleukin-10 in rheumatoid arthritis and systemic lupus erythematosus.
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Animals↗
Antibodies to neutrophil cytoplasmic antigens in rheumatoid arthritis.
In this study we examined the sera from 42 randomly selected patients with RA. ANCA was demonstrated by indirect immunofluorescence on human granulocytes in 10 patients with active disease and in none of the patients with inactive disease. ELISA's for the detection of specific antigens showed the presence of anti-myeloperoxidase in 3 patients, and anti-lactoferrin in 1 patient. The specificity of the remaining antibodies was unidentified. All 3 patients with antibodies to myeloperoxidase had vasculitis.
Antibodies, Antineutrophil Cytoplasmic↗
Serological profile of rheumatoid arthritis in west Africa.
Rheumatoid arthritis (RA) in West Africa is atypical in a number of respects. In order to investigate this we evaluated the serological profile of a series of West African patients diagnosed as having RA. We found the presence of a wide range of autoantibodies including antinuclear antibodies (ANA), anticardiolipin antibodies and antineutrophil cytoplasmic antibodies but the pattern of these autoantibodies was similar to that reported in other studies. Our serological studies support the hypothesis that these patients do have RA and the presence of these autoantibodies is of interest with regards to implications for diagnosis.
Adult↗
Antineutrophil cytoplasmic antibody titres in patients with recent infection.
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Antibodies, Antineutrophil Cytoplasmic↗
Serological and immunogenetic markers of extraglandular primary Sjögren's syndrome.
The clinical course of 48 patients with primary Sjögren's syndrome (primary SS) was reviewed. Forty-three north European patients were typed for HLA class I and class II alloantigens. In this population with primary SS HLA B8, DR3 and DRw52 all occurred more frequently than in the control population (P < 0.009, P < 0.0035, P < 0.02 respectively). The subgroup of primary SS patients with antibodies to Ro and/or La antigen had the greatest prevalence of DR3 (relative risk 33.4). The primary SS patients fall into two distinct groups: those with extraglandular disease in whom lymphopaenia, hypergammaglobulinaemia, antibodies to Ro and/or La and HLA DR3 were all more frequent and those patients with either glandular disease alone or only one extraglandular feature. There was no difference in disease duration between the two groups, although on average the latter group were 10 years older.
Adolescent↗
Antiribosomal P protein antibodies in different populations of patients with systemic lupus erythematosus.
We report a significantly increased prevalence of antiribosomal P protein antibodies in Malaysian Chinese patients (38%) with SLE compared to white Caucasian (13%) and Afro-Caribbean (20%) patients. The increased prevalence was not due to a generalized increase in autoantibody production because anti-dsDNA and anti-SSA antibodies were present in comparable frequencies in the three ethnic groups while anti-Sm and anti-SSB antibodies were rarely found in the Malaysian Chinese patients.
Antibodies, Anti-Idiotypic↗
The clinical implications of autoantibody detection in rheumatology.
The laboratory plays an increasing role in the diagnosis and clinical management of patients with rheumatic diseases. It is therefore essential that the results of laboratory tests are both accurate and reliable, and give clinicians correct information. It is also important to keep clinicians informed of the changes occurring in the rapidly evolving field of investigation of autoantibodies.
Autoantibodies↗
Antibodies to protein P in systemic lupus erythematosus.
A synthetic peptide was used to develop an enzyme linked immunosorbent assay (ELISA) to detect antibodies to the ribosomal proteins P0, P1, and P2. Significantly increased levels of IgG antibodies to protein P were found in 16% (18/116) of patients with systemic lupus erythematosus but slightly increased levels were detected in 2% (2/98) of patients with rheumatoid arthritis and one normal control subject. No association was observed between the presence of IgG antibodies to protein P and either lupus psychosis or depression. Sequential studies in individual patients failed to show an association between antibody levels and the development of psychosis.
Antibodies↗
Antinuclear antibody determination methods.
Screening rheumatology patients for anti-nuclear and anti-cytoplasmic antibodies is easily done in a qualitative manner using the IF, CIE and ID assays. The immunoblot is of use for anti-La and anti-RNP assays but gives anomalous results for Sm binding by anti-RNP sera and is not easily quantitated. These deficiencies of the immunoblot do not apply to the ELISA. Advances in cloning of autoantigens will enable standardisation of antigen preparations used for these ELISAs. The quantitation of autoantibody appears significant since disease flares occur together with elevations in specific autoantibody. IgM anti-Sm autoantibody was detected with a different disease distribution to IgG anti-Sm but the prognostic implications for this remain to be determined.
Antibodies, Antinuclear↗
Antinuclear antibodies and the diagnosis of systemic lupus erythematosus in patients with acute intermittent porphyria.
To investigate the previously postulated association of systemic lupus erythematosus (SLE) and porphyria 38 patients with various types of porphyria were investigated for clinical and laboratory evidence of a connective tissue disease. Antinuclear antibodies (ANAs) were found in 8/15 (53%) patients with acute intermittent porphyria. These patients were more likely to have had a recent acute attack of porphyria, but only one patient had clinical evidence of SLE. Antinuclear antibodies were not found in any patients with latent acute intermittent porphyria or appreciably in any of the other types of porphyria studied. This finding of ANAs in patients with acute intermittent porphyria may explain the previously described association with SLE. Strict diagnostic criteria need to be used in any one patient as these two disorders have many similar clinical manifestations.
Adult↗
Preparative isolation of p67, A, B, B' and D from nRNP/Sm and Sm antigens by reverse-phase chromatography. Use in a polypeptide-specific ELISA for independent quantitation of anti-nRNP and anti-Sm antibodies.
The p67 (67 kDa) and A (33 kDa) polypeptides of nRNP/Sm antigen and the B, B' (28 and 29 kda) and D (16 kDa) polypeptides of 'free' Sm antigen were isolated and used in enzyme-linked immunoadsorbent assays (ELISA) for human autoantibodies. ELISA specificity was demonstrated using monoclonal antibodies. The ELISA using HPLC-purified polypeptides was found to be more sensitive than immunoblotting for detecting antibody. 86% of sera with precipitating anti-nRNP antibodies were positive in the ELISA, as were all sera with precipitating anti-Sm antibodies. Patients with rheumatoid arthritis (RA), Sjögrens syndrome (SS) and undifferentiated connective tissue disease (UCTD) had low levels of anti-p67 with a prevalence 11.6% and 18%, respectively, whilst patients with systemic lupus erythematosus (SLE) and mixed connective tissue disease (MCTD) had high levels and prevalence rates of 55.2% and 80%, respectively. Anti-B or anti-D antibodies were detected at high levels in SLE (prevalence 30%) but were found rarely in UCTD and MCTD (prevalence 7% and 10%) and not at all in RA or SS sera.
Animals↗
Antibodies to La, Jo-1, nRNP and Sm detected by multi-track immunoblotting using a novel filter holder: a comparative study with counterimmunoelectrophoresis and immunodiffusion using sera from patients with systemic lupus erythematosus and Sjögren's syndrome.
The use of Western blotting or immunoblotting to detect autoantibodies in the serum of patients with autoimmune connective tissue diseases was investigated. An apparatus suitable for simultaneously screening 16 sera on immunoblots was used to show that a complex pattern of antibody binding polypeptides was present in whole HeLa cells. A simpler and readily interpreted pattern of binding was achieved using affinity-purified rabbit thymus antigens. Seventy-seven patients with systemic lupus erythematosus, 44 with primary Sjögren's syndrome and 50 normals were screened for anti-Sm, anti-La, anti-nRNP and anti-Jo-1 by immunoblotting and the results compared with those obtained by counterimmunoelectrophoresis and immunodiffusion. It was shown that both IgG and IgM antibodies must be analysed on immunoblots to detect the maximum number of positive sera, and that the immunoblot detects many anti-La sera which do not form precipitins.
Antibody Specificity↗
Antibody class differences are detected in anti-nRNP and anti-Sm antibodies directed against distinct antigen subunits.
Antibodies to nRNP, Sm and La were detected and characterised by immunoblot analysis. A comparison was made between IgG and IgM autoantibodies in 77 patients with systemic lupus erythematosus (SLE) and 50 normal subjects. No antibodies were detected in the normal subjects. In all 3 antigen specificity groups, a heterogeneity of antibody class was observed between patients. Antibodies to the 2 nRNP-specific polypeptides (33 and 67 kD) were approximately equally frequent. Although IgG antibodies to the 67 kD polypeptide were detected in 88% of patients with antibodies to this polypeptide, IgG antibodies to the 33 kD polypeptide were only detected in 43% of patients with antibodies to this polypeptide. This suggested either that anti-33 kD antibody is produced by a B cell which cannot mature to an IgG-secretor, or that anti-33 kD antibody production succeeds an initial immune response producing anti-67 kD. Reactivity with the 29 kD, Sm-specific polypeptide appeared to be the most frequent in anti-Sm sera compared with the 16 kD polypeptide suggesting that this polypeptide may be the primary immunogenic component of Sm.
Antibodies, Antinuclear↗