B cell depletion therapy in systemic lupus erythematosus

Anolik, Jennifer H.; Sanz, Iñaki; Looney, R. John

doi:10.1007/s11926-003-0020-x

Cited by 67 publications

(49 citation statements)

References 45 publications

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“…Persistence of small germinal centers was in fact shown in thyroid surgical specimens from thyroidectomy of one of our patients carried out at the time of initial B-cell return (15). Discrepancies between a positive clinical response and an effect on circulating autoantibodies after RTX have been observed in systemic autoimmune diseases such as lupus (28) and rheumatoid arthritis (29). In our study, the findings argue against a pathogenic role of TRAb in TAO (30).…”

Section: Discussionsupporting

confidence: 57%

Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

Salvi¹,

Vannucchi²,

Campi³

et al. 2007

eur j endocrinol

239

187

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Introduction: Hyperthyroid Graves' disease (GD) is a B-cell-mediated condition caused by TSH receptor antibodies (TRAb), which decline when GD remits. Anti-CD20 monoclonal antibody rituximab (RTX) induces transient B-cell depletion that may potentially modify the active inflammatory phase of thyroid-associated ophthalmopathy (TAO). Methods: Nine patients with GD, (seven with active TAO, two with mild lid signs) were studied. The trial was only approved as an open pilot study; thus we compared the effect of RTX therapy to that of i.v. glucocorticoids (IVGC) in 20 consecutive patients. Patients were treated with RTX (1000 mg i.v. twice at 2-week interval) or with IVGC (500 mg i.v. for 16 weeks). TAO was assessed by the clinical activity score (CAS) and severity was classified using NOSPECS (No signs or symptoms; Only signs (lid); Soft tissue involvement; Proptosis, Extraocular muscle involvement; Corneal involvement; Sight loss). Thyroid function and lymphocyte count were measured by standardized methods. Results: All patients attained peripheral B-cell depletion with the first RTX infusion. Minor side effects were reported in three patients. Thyroid function was not affected by RTX therapy and hyperthyroid patients required therapy with methimazole. After RTX, the changes in the levels of thyroglobulin antibodies, thyroperoxidase antibodies and TRAb were neither significant nor correlated with CD20C depletion (PZNS). CAS values before RTX were 4.7G0.5 and decreased to 1.8G0.8 at the end of follow-up (P!0.0001) and more significantly compared with IVGC (P!0.05). Proptosis decreased significantly after RTX both in patients with active TAO (ANOVA; P!0.0001) and those with lid signs (ANOVA; P!0.003). The degree of inflammation (class 2) decreased significantly in response to RTX (ANOVA; P!0.001). Relapse of active TAO was not observed in patients treated with RTX, but occurred in 10% of those treated with IVGC, who also experienced adverse effects more frequently (45 vs 33% of patients). Conclusions: RTX positively affects the clinical course of TAO, independently of either thyroid function or circulating antithyroid antibodies, including TRAb. If our findings are confirmed in large controlled studies, RTX may represent a useful therapeutic tool in patients with active TAO.

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Section: Discussionsupporting

confidence: 57%

Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

Salvi¹,

Vannucchi²,

Campi³

et al. 2007

eur j endocrinol

239

187

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“…27,46 Thus, it is likely that there are additional mechanisms by which B-cell-lineage depletion modulates autoimmune diseases. 20,47,48 This is supported by reports showing that in patients with RA with lymphoid aggregates within the synovium, B cells function as antigen-presenting cells and provide costimulatory signals that promote expansion of effector T cells. 49 B cells within the synovium may also secrete proinflammatory cytokines and contribute to inflammation.…”

mentioning

confidence: 76%

B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model

Dunussi-Joannopoulos¹,

Hancock²,

Kunz³

et al. 2005

Blood

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IntroductionThe pathogenesis of autoimmune diseases involves a complicated network of tissue-damaging mechanisms that are governed primarily by recognition of self-antigens and an imbalance in cytokine production. 1,2 In rheumatoid arthritis (RA), major cell types responsible for chronic inflammation and subsequent cartilage destruction and bone erosion in the joints are macrophages, synovial fibroblasts, neutrophils, and lymphocytes. Recent studies demonstrated that T and B lymphocytes that infiltrate inflamed synovial tissues are often organized into structures that resemble lymphoid follicles. [3][4][5][6][7] Normally, in T-dependent immune responses antigen-activated B cells migrate into lymphoid follicles of lymphoid organs and form germinal centers. Within the unique milieu of the germinal center, hypermutation leads to diversification and selection of the B-cell repertoire for high affinity and differentiation into antibody-secreting plasma cells or memory B cells. [8][9][10] Molecular analysis of B cells isolated from synovial follicular structures during rheumatoid arthritis demonstrated the importance of B cells in local antigen-driven specific immune responses and increased production of rheumatoid factor (RF), the high-affinity antibodies with self-reactivity. 5 Positivity for RF is associated with more aggressive articular disease and higher frequency of extraarticular manifestations. 11 Studies using RA synovium-severe combined immunodeficiency (SCID) mouse chimeras showed that activation of synovial germinal center CD4 ϩ T cells required the presence of B cells, but not macrophages and dendritic cells, raising the possibility that B cells provided critical function in T-cell activation or harbored the relevant antigens. 12 The significance of extranodal lymphoid follicle formation in inflamed RA joints is unknown, and it remains to be defined whether the reaction is a bystander effect induced by the local chronic inflammation or results from an autoimmune reaction directly related to the pathogenesis of the disease.Intriguing evidence on the pathogenic contribution of B cells in the development of arthritis was recently provided using K/BxN T-cell receptor (TCR) transgenic mice, which spontaneously develop joint disorders with many of the clinical, histologic, and immunologic characteristics of human RA. 13 The articular manifestations are caused by arthritogenic antibodies directed against glucose-6-phosphate isomerase, which develop at high titers in K/BxN transgenic mice. [14][15][16] More convincing evidence regarding the pathogenicity of B cells in RA was recently obtained from clinical trials in patients with refractory disease by using B-cell ablation with rituximab (Rituxan), a human chimeric anti-CD20 monoclonal antibody (mAb). 17,18 Expression of CD20, a B-cellspecific transmembrane glycoprotein with similar patterns of expression and function in humans and in mice, emerges on late pre-B cells and is extinguished on plasma cells. 19,20 Anti-CD20 therapy has also been tested in several ot...

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“…Circulating TRAb could therefore be measured for as long as 4-6 weeks, if one considers that the half life of human IgG is of approximately 3 weeks (21). In systemic lupus erythematosus, significant peripheral B-cell depletion after RTX has been reported to correlate with clinical disease improvement, but significant changes in anti-dsDNA titers and complement levels were not observed (22). On the other hand, association between the clinical relapse and a rise in autoantibodies, rather than only return of B-cell, has been observed in rheumatoid arthritis (23).…”

Section: Discussionmentioning

confidence: 99%

Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression

et al. 2006

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One patient with Graves' hyperthyroidism and ophthalmopathy in its active phase and unresponsive to steroid, was treated with the anti-CD20 monoclonal antibody, rituximab (RTX), as part of an open study. The effect of RTX in the thyroid and the orbital tissues was studied. The ophthalmopathy responded to RTX therapy by ameliorating the eye signs with a decrease in the clinical activity score from 5 to 2 in 3 months, while the patient had peripheral B-cell depletion. Hyperthyroidism did not improve during the 6 months of B-cell depletion and serum TSH-receptor antibodies (TRAb) levels did not significantly change after RTX therapy. Therefore, the patient underwent total thyroidectomy and few B-cells were found in the thyroid tissue specimens. While the patient eye disease remained stable (clinical activity score ¼ 2), we performed corrective orbital decompression and we found absence of lymphocytes in the orbital tissue specimens. We believe that RTX treatment in Graves' disease may cause amelioration of ophthalmopathy by depleting total lymphocytes population in the orbit. The persistence of Graves' hyperthyroidism suggests that a single cycle of RTX does not result in complete lymphocyte depletion in thyroid tissue and thus no decline in serum TRAb was observed.European Journal of Endocrinology 154 511-517

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B cell depletion therapy in systemic lupus erythematosus

Cited by 67 publications

References 45 publications

Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

Treatment of Graves’ disease and associated ophthalmopathy with the anti-CD20 monoclonal antibody rituximab: an open study

B-cell depletion inhibits arthritis in a collagen-induced arthritis (CIA) model, but does not adversely affect humoral responses in a respiratory syncytial virus (RSV) vaccination model

Efficacy of rituximab treatment for thyroid-associated ophthalmopathy as a result of intraorbital B-cell depletion in one patient unresponsive to steroid immunosuppression

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