Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves’ orbitopathy: A five-year follow-up study

Erdei, Annamária; Paragh, György; Kovács, P.; Karányi, Zsolt; Berényi, Ervin; Galuska, László; Lenkey, Ágota; Szabados, Lajos; Győry, Ferenc; Ujhelyi, Bernadett; Berta, András; Boda, Judit; Berta, Eszter; Bodor, Miklós; Gazdag, Annamaria; Nagy, Endre

doi:10.3109/08916934.2014.939266

Cited by 19 publications

(17 citation statements)

References 30 publications

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“…However, several case report studies demonstrated the relationship between rituximab administration and a decrease of inflammatory orbital infiltration, particularly complete depletion of CD20+ lymphocytes [11,14,17]. Significant changes of 99m Tclabelled diethylenetriaminepentaacetic acid orbital uptake and of T2 relaxation times of extraocular muscles on magnetic resonance imaging showing the effect of rituximab treatment for GO were also reported [18]. Positive correlations between CAS improvement and decrease of CD20+ and CD19+ lymphocytes and lack of a correlation between CAS improvement and TRAbs decrease in our study group favour the therapeutic effect of rituximab over the natural course of disease on GO clinical activity.…”

Section: Discussionmentioning

confidence: 97%

Clinical and immunological changes in patients with active moderate-to-severe Graves̕ orbitopathy treated with very low-dose rituximab

Karásek

Cibičková

Karhanová

et al. 2015

Endokrynologia Polska

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Introduction: Glucocorticoids represent the therapy of choice for active and moderate-to-severe Graves' orbitopathy (GO). In some patients, rituximab, a monoclonal antibody against the cluster of differentiation (CD) 20 receptor of B-lymphocytes, can serve as a second-line or an alternative treatment. The effect of very low-dose of rituximab on the clinical activity of GO and corresponding clinical or laboratory changes is reported. Material and methods: Changes of Clinical Activity Score (CAS) for GO, proptosis, levels of thyroid-stimulating hormone receptor antibodies, and depletion of CD19+ and CD20+ B-lymphocytes were determined in ten patients (two men and eight women) with active moderate-to-severe GO treated with a single 100-mg dose of rituximab. Correlations between differences of clinical and laboratory parameters were performed. Results: A significant decrease of CAS was found during subsequent examinations compared to the baseline values. A significant depletion of CD19+ and CD20+ B-lymphocytes was detected after rituximab administration. Differences between follow-up and baseline levels of CD20+ positively correlated with differences in CAS after six (p < 0.05) and 12 months (p < 0.01). Differences in CD19+ levels correlated with differences in CAS after 12 months (p < 0.05) of the treatment. Two patients developed dysthyroid optic neuropathy (DON) requiring orbital decompression. No other rituximab side effects were reported during the whole study duration. Conclusions: A single very low-dose of rituximab appears to be very well tolerated and effective enough to reduce clinical activity in active moderate-to-severe GO patients without impending DON. (Endokrynol Pol 2017; 68 (5): 498-504)

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Section: Discussionmentioning

confidence: 97%

Clinical and immunological changes in patients with active moderate-to-severe Graves̕ orbitopathy treated with very low-dose rituximab

Karásek

Cibičková

Karhanová

et al. 2015

Endokrynologia Polska

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“…The implications of this data is that RTX may be indirectly responsible also for the depletion of autoreactive T cells, as a consequence of the decrease of T cell promoting cytokines and chemokines released by B cells, depleted by RTX. Preliminary studies have suggested that RTX can be effective either as first line treatment for moderate to severe GO or as additional therapy in patients resistant to ivMP [87][88][89][90][91][92][93].…”

Section: Targeting Cytokines/chemokines With Monoclonal Antibodiesmentioning

confidence: 99%

Medical Treatment of Graves’ Orbitopathy

Salvi

Campi

2015

Horm Metab Res

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The medical treatment of Graves? orbitopathy (GO) is usually reserved to moderate to severe disease. Steroids have been widely employed and possess anti-inflammatory activity, but about 20?30% of patients are not responsive and about 20% present with disease recurrence. Immunosuppressive therapy alternative to corticosteroids may target the different antigens involved in pathogenic mechanisms of GO. Some have already been employed in clinical studies and showed interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the TSH receptor and the IGF-1 receptor on the fibroblasts, inflammatory cytokines, B and T cells. Most promising results are obtained by interacting with the PIK3/mTORC1 signaling cascades for adipogenesis and the anti-IGF-1R with the monoclonal antibody teprotumumab. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials. Clinical practice will greatly benefit from the use of disease modifying agents in GO, as compared to steroids, currently standard treatment for GO. Among these, rituximab may be useful, especially in patients resistant to steroid or with contraindications to steroids. However, larger randomized controlled trials are needed for definitive data on the potential disease-modifying role of rituximab in GO. Direct targeting of the orbital fibroblast via immunosuppression or nonimmunosuppressive drugs is emerging as a promising alternative.

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“…Other authors have described a decline of serum TSH receptor binding antibodies (TRAb) in patients with active GO after RTX therapy, whether the patients were on antithyroid drugs or euthyroid on L-T4 replacement therapy [12], suggesting again a direct effect of RTX on antibodies. Others have found that the beneficial effect of RTX on GO was not correlated to the decrease of serum TRAb [13]. A more precise picture of the effect of RTX on TRAb has been provided by the study of Vannucchi et al [14], who were not able to show a distinct decrease of circulating TSH receptor stimulating antibodies in patients with GD and GO after RTX, if compared to the decline of serum TSH receptor binding antibodies (TRAb) observed during the patients' follow-up when they reached the euthyroid state.…”

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confidence: 93%

B cells in Graves’ Orbitopathy: more than just a source of antibodies?

Salvi

Covelli

2018

Eye

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B cells have multiple actions on different phases of an immune reaction, mainly resulting in B and T cell-interaction (help), production of cytokines, regulation of dendritic cells and downregulation of regulatory B cells. The effectiveness of B cell depletion therapy is probably due to blockade of the antigen-presenting function of B cells, occurring very early in the setting of autoimmune reactions. B cells undergo a maturation process from stem cells during which the CD 20 antigen, which is the target of rituximab (RTX), is expressed from the stage of pre-B cells to mature and memory B cells, but not on plasma cells. During the maturation process, the cytokine B cell stimulating factor (BAFF) induces maturation of B cells and expansion of clones to produce plasma cells and eventually antibodies. The effect of RTX in GO is rather rapid, with significant improvement of the disease already 4-6 weeks after the first RTX infusion. Based on the evidence of significant lymphocytic infiltration in the orbits of patients with active GO, it is reasonable to postulate that RTX may cause depletion of B cells and block their antigen-presenting cell mechanism. Since it has been reported that serum BAFF concentrations are elevated in hyperthyroid GD patients and that BAFF is expressed on the thyrocytes of patients with either autoimmune disease or nodular goiter, the hypothesis that belimumab, an anti-BAFF monoclonal antibody, may be effective in patients with active GO his currently being tested in a randomized controlled trial.

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Rapid response to and long-term effectiveness of anti-CD20 antibody in conventional therapy resistant Graves’ orbitopathy: A five-year follow-up study

Cited by 19 publications

References 30 publications

Clinical and immunological changes in patients with active moderate-to-severe Graves̕ orbitopathy treated with very low-dose rituximab

Clinical and immunological changes in patients with active moderate-to-severe Graves̕ orbitopathy treated with very low-dose rituximab

Medical Treatment of Graves’ Orbitopathy

B cells in Graves’ Orbitopathy: more than just a source of antibodies?

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