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. 2015 Dec;74(12):2236-43.
doi: 10.1136/annrheumdis-2014-205799. Epub 2014 Aug 20.

B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease

Emanuel Della-Torre  1 , Eoin Feeney  2 , Vikram Deshpande  3 , Hamid Mattoo  4 , Vinay Mahajan  4 , Maria Kulikova  4 , Zachary S Wallace  5 , Mollie Carruthers  5 , Raymond T Chung  2 , Shiv Pillai  4 , John H Stone  5
Affiliations

B-cell depletion attenuates serological biomarkers of fibrosis and myofibroblast activation in IgG4-related disease

Emanuel Della-Torre et al. Ann Rheum Dis. 2015 Dec.

Abstract

Objectives: Fibrosis is a predominant feature of IgG4-related disease (IgG4-RD). B-cell depletion induces a prompt clinical and immunological response in patients with IgG4-RD, but the effects of this intervention on fibrosis in IgG4-RD are unknown. We used the enhanced liver fibrosis (ELF) score to address the impact of rituximab on fibroblast activation. The ELF score is an algorithm based on serum concentrations of procollagen-III aminoterminal propeptide, tissue inhibitor of matrix metalloproteinase-1 and hyaluronic acid.

Methods: Ten patients with active, untreated IgG4-RD were enrolled. ELF scores were measured and correlated with the IgG4-RD Responder Index, serum IgG4, circulating plasmablasts and imaging studies. Through immunohistochemical stains for CD3, CD20, IgG4 and α-smooth muscle actin, we assessed the extent of the lymphoplasmacytic infiltration and the degree of fibroblast activation in one patient with tissue biopsies before and after rituximab.

Results: The ELF score was increased in patients with IgG4-RD compared with healthy controls (8.3±1.4 vs 6.2±0.9; p=0.002) and correlated with the number of organs involved (R(2)=0.41; p=0.04). Rituximab induced significant reductions in the ELF score, the number of circulating plasmablasts and the IgG4-RD Responder Index (p<0.05 for all three parameters). Rituximab reduced both the lymphoplasmacytic infiltrate and myofibroblast activation. IgG4-RD relapse coincided with recurrent increases in the ELF score, indicating reactivation of collagen deposition.

Conclusions: The ELF score may be a clinically useful indicator of active fibrosis and the extent of disease in IgG4-RD. B-cell depletion has the potential to halt continued collagen deposition by attenuating the secretory phenotype of myofibroblasts in IgG4-RD lesions.

Keywords: B cells; Fibroblasts; Inflammation.

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Figures

Figure 1
Figure 1
Enhanced liver fibrosis (ELF) score is increased in IgG4-related disease (IgG4-RD) and correlates with the number of organs involved. (A) The ELF score is significantly increased in patients with IgG4-RD, compared with controls (p=0.002). (B) The ELF score correlates positively with the numbers of organs involved by IgG4-RD (R2=0.41; p=0.04).
Figure 2
Figure 2
Rituximab improves the overall degree of systemic fibrosis in IgG4-related disease. (A) Treatment with rituximab induces a significant reduction in the enhanced liver fibrosis (ELF) score and total circulating plasmablasts (paired t test analyses: p=0.004 and p=0.04, respectively). (B) CT scan (stars) and positron emission tomography scan (arrowheads) of the head and neck of Patient #362 showing a decrease in dimension and 18-fluorodeoxyglucose uptake of the parotid glands after rituximab. Abdominal CT scan of Patient #355 showing persistence of the retroperitoneal fibrotic mass after rituximab.
Figure 3
Figure 3
Rituximab decreases dermal myofibroblast activation in IgG4-related disease (IgG4-RD) affected tissue. Immunohistochemistry for α-smooth muscle actin stain on skin biopsies from a patient with cutaneous IgG4-RD involvement, before (A and B) and after (C and D) treatment with rituximab. The number of moderately to strongly positive brown pixels per square micrometer decreases after rituximab in the regions containing predominantly dermal fibroblasts (outlined in blue) (original magnification: A and C 10×, inserts 20×). The morphology of individual fibroblasts before and after treatment is depicted at a higher magnification (40×) in B and D.
Figure 4
Figure 4
Rituximab reduces myofibroblast volume in IgG4-related disease (IgG4-RD) lesions. H&E stain of consecutive skin biopsies from a patient with cutaneous IgG4-RD involvement from the same site, before (A and B) and after (C and D) treatment with rituximab. The dermal fibroblasts (arrows) exhibit abundant cytoplasm and large nuclei in active disease, and shrink after rituximab-mediated remission (original magnification: A and C 20×, B and D 40×).
Figure 5
Figure 5
Clinical response corresponds to decreased B and T lymphoplasmacytic infiltrate in IgG4-related disease (IgG4-RD) affected tissue. Clinical pictures from a patient with cutaneous IgG4-RD involvement before (A) and after (D) rituximab. H&E, and CD3 stain of skin biopsies before (B and C, respectively) and after (E and F, respectively) treatment with rituximab (original magnification 10×). Immunohistochemistry for IgG4 before (B) and after (E) rituximab is shown in inserts (original magnification 20×).
Figure 6
Figure 6
IgG4-related disease (IgG4-RD) relapse corresponds to a new increase in the enhanced liver fibrosis (ELF) score. (A) Time course of ELF scores, IgG4-Responder Index and circulating plasmablasts after rituximab therapy in two patients who relapsed (#361 and #365) after initial treatment. (B) CT scan of Patient 365 showing the course of IgG4-RD lesions in the lung (arrowheads) and retroperitoneum (circle) at disease onset, remission and relapse.
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References

    1. Stone JH, Zen Y, Deshpande V. IgG4-related disease. N Engl J Med. 2012;366:539–551. - PubMed
    1. Deshpande V, Zen Y, Chan JK, et al. Consensus statement on the pathology of IgG4-related disease. Mod Pathol. 2012;25:1181–1192. - PubMed
    1. Stone JH, Khosroshahi A, Deshpande V, et al. Recommendations for the nomenclature of IgG4-related disease and its individual organ system manifestations. Arthritis Rheum. 2012;64:3061–3067. - PMC - PubMed
    1. Yamamoto M, Takahashi H, Ohara M, et al. A new conceptualization for Mikulicz’s disease as an IgG4-related plasmacytic disease. Mod Rheumatol. 2006;16:335–340. - PMC - PubMed
    1. Geyer JT, Ferry JA, Harris NL, et al. Chronic sclerosing sialadenitis (Küttner tumor) is an IgG4-associated disease. Am J Surg Pathol. 2010;34:202–210. - PubMed

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