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1.
BJOG ; 129(4): 664-670, 2022 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-34524725

RESUMO

OBJECTIVE: To compare the incidence of systemic conditions between women who had surgical treatment for stress incontinence with mesh and without mesh. DESIGN: National cohort study. SETTING: English National Health Service. POPULATION: Women with no previous record of systemic disease who had first-time urinary incontinence surgery between 1 January 2006 and 31 December 2013, followed up to the earliest of 10 years or 31 March 2019. METHODS: Competing-risks regression was used to estimate hazard ratios (HR), adjusted for patient characteristics, with HR > 1 indicating increased incidence following mesh surgery. MAIN OUTCOME MEASURES: First postoperative admission with a record of autoimmune disease, fibromyalgia or myalgic encephalomyelitis up to 10 years following the first incontinence procedure. RESULTS: The cohort included 88 947 women who had mesh surgery and 3389 women who had non-mesh surgery. Both treatment groups were similar with respect to age, socio-economic deprivation, comorbidity and ethnicity. The 10-year cumulative incidence of autoimmune disease, fibromyalgia or myalgic encephalomyelitis was 8.1% (95% CI 7.9-8.3%) in the mesh group and 9.0% (95% CI 8.0-10.1%) in the non-mesh group (adjusted HR 0.89, 95% CI 0.79-1.01; P = 0.07). A sensitivity analysis including only autoimmune diseases as an outcome returned a similar result. CONCLUSIONS: These findings do not support claims that synthetic mesh slings cause systemic disease. TWEETABLE ABSTRACT: No evidence of increased risk of systemic conditions after stress incontinence treatment with a mesh sling.


Assuntos
Slings Suburetrais/estatística & dados numéricos , Telas Cirúrgicas/efeitos adversos , Incontinência Urinária por Estresse/cirurgia , Adulto , Idoso , Doenças Autoimunes/etiologia , Estudos de Coortes , Síndrome de Fadiga Crônica/etiologia , Feminino , Fibromialgia/etiologia , Humanos , Pessoa de Meia-Idade , Modelos de Riscos Proporcionais , Medição de Risco , Slings Suburetrais/efeitos adversos , Incontinência Urinária por Estresse/epidemiologia
2.
Lupus ; 20(14): 1547-50, 2011 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-21993386

RESUMO

Pure red cell aplasia (PRCA) is a recognized but rare complication of systemic lupus erythematosus (SLE) and is characterized by the near absence of red blood cell precursors in the bone marrow but with normal megakaryocyte and granulocytes. We report a novel case of acquired PRCA occurring simultaneously with immune thrombocytopenia in the context of active SLE. Both syndromes were refractory to conventional treatment but responded to rituximab and cyclophosphamide.


Assuntos
Lúpus Eritematoso Sistêmico/complicações , Aplasia Pura de Série Vermelha/etiologia , Trombocitopenia/imunologia , Anticorpos Monoclonais Murinos/uso terapêutico , Antirreumáticos/uso terapêutico , Ciclofosfamida/uso terapêutico , Feminino , Glucocorticoides/uso terapêutico , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Aplasia Pura de Série Vermelha/tratamento farmacológico , Rituximab , Trombocitopenia/tratamento farmacológico , Adulto Jovem
4.
Rheumatology (Oxford) ; 46(7): 1052-6, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17500073

RESUMO

The year 2007 marks the 50th anniversary of the identification of antibodies to double-stranded (ds) DNA. Whilst widely regarded as synonymous with patients who have systemic lupus erythematosus (SLE), doubts have been raised about their significance and the extent to which they are genuinely part of the pathogenesis of the disease rather than being mere bystanders. Problems with assays used to detect them are still evident but they remain widely utilized both to help establish the diagnosis of SLE and to monitor the progress of the disease. This review explores each of these aspects and concludes that whilst some way short of ideal, their measurement remains a useful criterion for the disease and some of these antibodies do appear to be genuinely pathogenic. However, further research is needed to establish beyond 'reasonable doubt' whether they are merely part of the spectrum of anti-nucleosome antibodies, the precise mechanisms by which they 'exert' their pathogenic effects and to what extent blocking them would be a useful therapeutic goal.


Assuntos
Anticorpos Antinucleares/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Animais , Anticorpos Antinucleares/sangue , Ativação do Complemento , DNA/imunologia , Imunofluorescência , Humanos , Imunoglobulinas/imunologia , Rim/imunologia , Nefrite Lúpica/imunologia , Camundongos , Modelos Animais
5.
Rheumatology (Oxford) ; 46(1): 29-36, 2007 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-16735454

RESUMO

OBJECTIVE: To assess the presence and phenotype of B-lineage cells in the bone marrow (BM) of rheumatoid arthritis (RA) patients after rituximab therapy. METHODS: Six patients were studied. BM aspirates were collected 3 months after the treatment and analysed using the four-colour flow cytometry. RESULTS: CD19+ (B-lineage) cells in BM samples varied from 0.1 to 3.25% in the lymphoid gate. CD34+ cells varied from 1.23 to 4.86%. The proportion of CD34+ cells committed to the B-lineage varied between 0 and 42.19%. Pro-B-cells were undetectable in one case. The majority of B-cell precursors were pro-B-cells in Patients 5 and 6 (50 and 62% of CD19+ cells, respectively), pre-B-cells in Patients 3 and 4 (64 and 70%) and immature B-cells in Patient 1 (44%). Detectable CD20 expression on CD19+ cells was either low or absent. Plasma cells varied from 0.01 to 0.36% of the total nucleated cells. There was a trend towards longer duration of clinical response in patients with evidence of more complete depletion in BM. CONCLUSION: In this small cohort of RA patients treated with rituximab, differences in proportion and phenotype of CD19+ BM cells were detected. These differences suggest variation in the degree of depletion achieved and correlate with time to relapse. Although pro-B-cells are not targeted directly by rituximab as they do not express CD20, the levels were unexpectedly low.


Assuntos
Anticorpos Monoclonais/farmacologia , Artrite Reumatoide/imunologia , Subpopulações de Linfócitos B/efeitos dos fármacos , Células da Medula Óssea/efeitos dos fármacos , Depleção Linfocítica/métodos , Adulto , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Murinos , Antígenos CD20/metabolismo , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Células da Medula Óssea/imunologia , Feminino , Citometria de Fluxo/métodos , Seguimentos , Humanos , Imunofenotipagem , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Plasmócitos/efeitos dos fármacos , Rituximab
6.
Ann Rheum Dis ; 65(7): 942-5, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16269424

RESUMO

OBJECTIVES: To report the clinical outcome and safety profile of repeated B cell depletion in seven patients with refractory systemic lupus erythematosus (SLE). METHODS: Since June 2000, seven patients with refractory SLE had repeated cycles of B cell depletion (18 cycles in total, up to three cycles per patient) because of disease relapse. The clinical response (assessed by the British Isles Lupus Activity Guide (BILAG) activity index), duration of B cell depletion, and adverse events in these patients was reviewed. RESULTS: Four patients (Nos 1, 2, 3, 6) had three cycles of treatment and three (Nos 4, 5, 7) had two cycles. Four of the seven patients (Nos 1, 3, 5, 6) improved. The mean global BILAG scores dropped from 15 to 6 at 5-7 months. The median duration of clinical response and B cell depletion was 13 months and 6 months, respectively. After the third cycle, 2/4 patients (Nos 1 and 2) improved. The median duration of clinical benefit was 12 months. Most patients tolerate re-treatment very well. CONCLUSION: Re-treatment with B cell depletion of patients with severe SLE is safe and may be effective for 6-12 months on average.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Linfócitos B/imunologia , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/imunologia , Depleção Linfocítica , Adulto , Autoanticorpos/sangue , Complemento C3/análise , Seguimentos , Humanos , Imunoglobulinas/sangue , Infliximab , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Recidiva
7.
Rheumatology (Oxford) ; 44(12): 1542-5, 2005 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-16188950

RESUMO

OBJECTIVES: To assess the clinical and basic serological consequences of B-cell depletion with rituximab in the treatment of patients with systemic lupus erythematosus (SLE) who have failed conventional immunosuppression. METHODS: An open study of 24 patients with severe SLE followed for a minimum of 3 months is reported. In the majority of patients (19 out of 24), 6 months follow-up data are described. Disease activity in these patients was assessed every 1-2 months using the British Isles Lupus Assessment Group (BILAG) system and estimates of anti-double-stranded DNA antibodies and serum C3 levels. During the follow-up period, significant side-effects were sought and the reduction in oral prednisolone was recorded. It was our general practice to stop concomitant immunosuppression (e.g. azathioprine, mycophenolate) when B-cell depletion was given (in most cases in the form of two 1 g intravenous infusions of rituximab 2 weeks apart accompanied by two 750 mg intravenous cyclophosphamide infusions and two methylprednisolone infusions of 250 mg each). RESULTS: Twenty-two patients were female and two male. At the time of B-cell depletion, the mean age was 28.9 yr (range 17-49) and the mean disease duration was 7.9 yr (range 1-18). The global BILAG score (P < 0.00001), serum C3 (P < 0.0005) and double-stranded DNA binding (P < 0.002) all improved from the time of B-cell depletion to 6 months after this treatment. Only one patient failed to achieve B-lymphocyte depletion in the peripheral blood. The period of B-lymphocyte depletion ranged from 3 to 8 months except for one patient who remains depleted at more than 4 yr. Analysis of the regular BILAG assessments showed that improvements occurred in each of the eight organs or systems. The mean daily prednisolone dose fell from 13.8 mg (s.d. 11.3) to 10 mg (s.d. 3.1). CONCLUSION: In this open study of patients who had failed conventional immunosuppressive therapy, considerable utility in the use of B-cell depletion has been demonstrated. Our data provide strong support for the performance of a full double-blind control trial.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Subpopulações de Linfócitos B/imunologia , Imunossupressores/uso terapêutico , Lúpus Eritematoso Sistêmico/terapia , Depleção Linfocítica/métodos , Adolescente , Adulto , Anticorpos Antinucleares/sangue , Anticorpos Monoclonais Murinos , Antígenos CD20/imunologia , Complemento C3/análise , Feminino , Seguimentos , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Rituximab , Índice de Gravidade de Doença , Resultado do Tratamento
8.
Lupus ; 14(3): 192-6, 2005.
Artigo em Inglês | MEDLINE | ID: mdl-15807195

RESUMO

Inhibitors of 3-hydroxy-3-methylgluttaryl coenzyme A (HMG-CoA) reductase, or statins, are used extensively to reduced elevated lipid levels and reduce cardiovascular risk. However, accumulated evidence suggests that stains not only act by lowering cholesterol levels, but also exert pleiotropic effects on many essential cellular functions including cell proliferation, differentiation, and survival and participate in the regulation of cell shape and motility. Thus cardiovascular benefit is provided by lowering raised cholesterol levels and by modulation of the inflammatory component of this disease. Such an anti-inflammatory effect may also benefit patients with autoimmune rheumatic disease. This overview assesses the evidence for using statins in patients with rheumatoid arthritis and systemic lupus erythematosus (SLE).


Assuntos
Inibidores de Hidroximetilglutaril-CoA Redutases/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Doenças Reumáticas/tratamento farmacológico , Animais , Humanos , Fatores Imunológicos/imunologia , Fatores Imunológicos/uso terapêutico , Lúpus Eritematoso Sistêmico/imunologia , Doenças Reumáticas/imunologia
9.
Rheumatology (Oxford) ; 43(1): 49-54, 2004 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-12867580

RESUMO

OBJECTIVE: To devise new tools to assess activity and damage in patients with idiopathic myopathies (IIM). METHODS: An international multidisciplinary consensus effort to standardize the conduct and reporting of the myositis clinical trials has been established. Two tools, known as the myositis intention to treat index (MITAX) and the myositis disease activity assessment visual analogue scale (MYOACT), have been developed to capture activity in patients with IIM. In addition, the myositis damage index (MDI) has been devised to assess the extent and severity of damage developing in different organs and systems. These measures have been reviewed by the myositis experts participating in the International Myositis Assessment and Clinical Studies (IMACS) group and have been found to have good face validity and to be comprehensive. The instruments were assessed in two real patient exercises involving patients with adult dermatomyositis and inclusion body myositis. RESULTS: The reliability of MITAX, MYOACT and MDI, measured by the intraclass correlation coefficient among the physicians, and the inter-rater reliability, as assessed by variation in the physicians' rating of patients, was fair to good for most aspects of the tools. Reliability and inter-rater agreement improved at the second exercise after the participants had completed additional training. CONCLUSIONS: The MITAX, MYOACT and MDI tools, which are now undergoing validity testing, should enhance the consistency, comprehensiveness and reliability of disease activity and damage assessment in patients with myositis.


Assuntos
Músculo Esquelético/fisiopatologia , Miosite/diagnóstico , Miosite/imunologia , Doença Aguda , Análise de Variância , Teste de Esforço , Humanos , Reprodutibilidade dos Testes
10.
Lupus ; 11(12): 790-2, 2002.
Artigo em Inglês | MEDLINE | ID: mdl-12529042

RESUMO

This session had as its central theme the analysis of peptide epitopes and their relationship with lupus pathogenesis. New information on the role of peptides opens up the possibility of treatments based on inducing immunological tolerance although care needs to be taken since it is difficult to predict flare or remission of disease after exposure to critical antigenic peptides. The provenance of these peptides may be self or foreign antigens, or autoantibody idiotypes.


Assuntos
Linfócitos B/citologia , Comunicação Celular/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/citologia , Animais , Linfócitos B/imunologia , Humanos , Linfócitos T/imunologia
12.
Proc Natl Acad Sci U S A ; 98(25): 14553-8, 2001 Dec 04.
Artigo em Inglês | MEDLINE | ID: mdl-11717399

RESUMO

Isotype switching involves a region-specific, nonhomologous recombinational deletion that has been suggested to occur by nonhomologous joining of broken DNA ends. Here, we find increased donor/acceptor homology at switch junctions from PMS2-deficient mice and propose that class switching can occur by microhomology-mediated end-joining. Interestingly, although isotype switching and somatic hypermutation show many parallels, we confirm that PMS2 deficiency has no major effect on the pattern of nucleotide substitutions generated during somatic hypermutation. This finding is in contrast to MSH2 deficiency. With MSH2, the altered pattern of switch recombination and hypermutation suggests parallels in the mechanics of the two processes, whereas the fact that PMS2 deficiency affects only switch recombination may reflect differences in the pathways of break resolution.


Assuntos
Adenosina Trifosfatases/deficiência , Adenosina Trifosfatases/genética , Enzimas Reparadoras do DNA , Proteínas de Ligação a DNA/deficiência , Proteínas de Ligação a DNA/genética , Switching de Imunoglobulina , Animais , Pareamento Incorreto de Bases , Sequência de Bases , DNA/genética , Reparo do DNA/genética , Camundongos , Camundongos Knockout , Endonuclease PMS2 de Reparo de Erro de Pareamento , Dados de Sequência Molecular , Proteína 2 Homóloga a MutS , Mutação , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Homologia de Sequência do Ácido Nucleico
13.
Philos Trans R Soc Lond B Biol Sci ; 356(1405): 21-8, 2001 Jan 29.
Artigo em Inglês | MEDLINE | ID: mdl-11205326

RESUMO

Following antigen encounter, two distinct processes modify immunoglobulin genes. The variable region is diversified by somatic hypermutation while the constant region may be changed by class-switch recombination. Although both genetic events can occur concurrently within germinal centre B cells, there are examples of each occurring independently of the other. Here we compare the contributions of class-switch recombination and somatic hypermutation to the diversification of the serum immunoglobulin repertoire and review evidence that suggests that, despite clear differences, the two processes may share some aspects of their mechanism in common.


Assuntos
Switching de Imunoglobulina , Imunoglobulinas/genética , Mutação , Recombinação Genética , Animais , Pareamento de Bases , Transporte Biológico , Dano ao DNA/genética , Sequência Rica em GC , Genes myc , Humanos , Isotipos de Imunoglobulinas , Imunoglobulinas/metabolismo
14.
Philos Trans R Soc Lond B Biol Sci ; 355(1395): 357-60, 2000 Mar 29.
Artigo em Inglês | MEDLINE | ID: mdl-10794054

RESUMO

In the humoral arm of the immune system, the memory response is not only more quickly elicited and of greater magnitude than the primary response, but it is also different in quality. In the recall response to antigen, the antibodies produced are of higher affinity and of different isotype (typically immunoglobulin G rather than immunoglobulin M). This maturation rests on the antigen dependence of B-cell maturation and is effected by programmed genetic modifications of the immunoglobulin gene loci. Here we consider how the B-cell response to antigen depends on the affinity of the antigen receptor interaction. We also compare and draw parallels between the two processes, which underpin the generation of secondary-response antibodies: V gene somatic hypermutation and immunoglobulin heavy-chain class switching.


Assuntos
Afinidade de Anticorpos/imunologia , Linfócitos B/imunologia , Memória Imunológica/imunologia , Animais , Switching de Imunoglobulina
15.
Appl Biochem Biotechnol ; 83(1-3): 53-60; discussion 60-2, 145-53, 2000.
Artigo em Inglês | MEDLINE | ID: mdl-10826948

RESUMO

The physiological mechanism for producing antigen-specific antibodies is based on a two-phase neo-Darwinian process: the first phase consists of diversity generation (formation of the repertoire), and the second phase is antigen-mediated selection. In this article, we consider how the natural immunoglobulin gene-diversification processes can be exploited both in vivo and in vitro in order to allow the generation of novel antibody (and heterologous protein) repertoires.


Assuntos
Diversidade de Anticorpos/genética , Rearranjo Gênico do Linfócito B , Seleção Genética , Animais , Anticorpos Monoclonais/biossíntese , Anticorpos Monoclonais/genética , Afinidade de Anticorpos/genética , Especificidade de Anticorpos/genética , Linhagem Celular , Genes de Imunoglobulinas , Humanos , Camundongos , Camundongos Transgênicos , Mutação
16.
J Exp Med ; 191(7): 1253-8, 2000 Apr 03.
Artigo em Inglês | MEDLINE | ID: mdl-10748243

RESUMO

Serum immunoglobulin (Ig)M provides the initial response to foreign antigen and plays a regulatory role in subsequent immune response development, accelerating the production of high-affinity IgG. Here we show that mice deficient in serum IgM have an increased propensity to spontaneous autoimmunity as judged by the development with age of serum IgG anti-DNA antibodies and the renal deposition of IgG and complement. They also exhibit augmented anti-DNA IgG production on exposure to lipopolysaccharide. Thus, deficiency in serum IgM leads to diminished responsiveness to foreign antigens but increased responsiveness to self-a paradoxical association reminiscent of that described in humans deficient in complement or IgA. We wondered whether serum IgM might play an analogous role with regard to the response to self-antigens. However, here-in contrast to the sluggish response to foreign antigens-we find that deficiency in serum IgM actually predisposes to the development of IgG antibodies to autoantigens.


Assuntos
Autoanticorpos/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Cadeias mu de Imunoglobulina/imunologia , Animais , Linhagem Celular , Imunoglobulina M/sangue , Camundongos , Camundongos Endogâmicos C57BL
18.
EMBO J ; 18(12): 3484-90, 1999 Jun 15.
Artigo em Inglês | MEDLINE | ID: mdl-10369687

RESUMO

During maturation of the immune response, IgM+ B cells switch to expression of one of the downstream isotypes (IgG, A or E). This class switching occurs by region-specific recombination within the IgH locus through an unknown mechanism. A lack of switch recombination in mice deficient in components of the DNA-dependent protein kinase (DNA-PK)-Ku complex has pointed to a role for non-homologous end joining. Here we characterize a switching defect in mice lacking a protein involved in DNA mismatch recognition. Mice deficient in Msh2 give diminished IgG (but not IgM) responses following challenge with both T cell-dependent and T cell-independent antigens. This appears to reflect a B cell-intrinsic defect since B cells from Msh2-deficient mice also exhibit impaired switching (but not blasting or proliferation) on in vitro culture with lipopolysaccharide. Furthermore, those switches that do occur in Msh2-deficient B cells reveal a shift in the distribution of recombination sites used: the breakpoints are more likely to occur in consensus motifs. These results, which intriguingly parallel the effects of Msh2 deficiency on hypermutation, suggest a role for Msh2 in the mechanics of class-switch recombination.


Assuntos
Proteínas de Ligação a DNA , Switching de Imunoglobulina/genética , Mutagênese , Proteínas Proto-Oncogênicas/metabolismo , Animais , Antígenos T-Independentes/imunologia , Antígenos T-Independentes/farmacologia , Linfócitos B/citologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/imunologia , Linfócitos B/metabolismo , Pareamento Incorreto de Bases/genética , Sequência de Bases , Células Cultivadas , Reparo do DNA/genética , Ficoll/análogos & derivados , Ficoll/farmacologia , Imunoglobulina A/genética , Switching de Imunoglobulina/efeitos dos fármacos , Switching de Imunoglobulina/imunologia , Imunoglobulina G/sangue , Imunoglobulina G/genética , Imunoglobulina M/sangue , Imunoglobulina M/genética , Lipopolissacarídeos/farmacologia , Ativação Linfocitária/efeitos dos fármacos , Camundongos , Camundongos Knockout , Dados de Sequência Molecular , Proteína 2 Homóloga a MutS , Mutagênese/efeitos dos fármacos , Mutação/genética , Nódulos Linfáticos Agregados/citologia , Nódulos Linfáticos Agregados/imunologia , Nódulos Linfáticos Agregados/metabolismo , Proteínas Proto-Oncogênicas/deficiência , Proteínas Proto-Oncogênicas/genética , Recombinação Genética/efeitos dos fármacos , Recombinação Genética/genética
20.
Immunity ; 9(1): 135-41, 1998 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-9697843

RESUMO

Likely creation of mismatches during somatic hypermutation has stimulated interest in the effect of mismatch repair deficiency on the process. Analysis of unselected mutations in the 3' flank of VH rearrangements in germinal center B cells revealed that MSH2 deficiency caused a 5-fold reduced mutation accumulation. This might reflect ectopic effects of the Msh2 disruption; indeed, the mice exhibit other perturbations within the B cell compartment. However, that MSH2 (or factors dependent upon it) plays a role in the mechanism of mutation fixation is indicated by a strikingly increased focusing of the mutations on intrinsic hot spots. We propose two phases to hypermutation targeting. The first is hot spot focused and MSH2 independent; the second, MSH2-dependent phase yields a more even spread of mutation fixation.


Assuntos
Linfócitos B/imunologia , Proteínas de Ligação a DNA , Genes de Imunoglobulinas , Cadeias Pesadas de Imunoglobulinas/genética , Mutação , Proteínas Proto-Oncogênicas/fisiologia , Animais , Sítios de Ligação , Linhagem Celular , Feminino , Masculino , Camundongos , Camundongos Knockout , Proteína 2 Homóloga a MutS , Proteínas Proto-Oncogênicas/genética
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