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It was recently pointed out that rituximab (RTX) is effective against IgG4-related disease (IgG4-RD).1 We found that RTX is effective as an induction therapy for IgG4-RD in the short term, but that it is necessary to repeat the prescription of RTX. Furthermore, we had a patient who presented with resistance to RTX.2 After obtaining informed consent, we started the patient on abatacept (ABT) treatment. We have followed the patient for 8 months, and the patient presented with good response to ABT. This is the first report of the efficacy of ABT against IgG4-RD.
The patient was a 65-year-old Japanese woman who presented with IgG4-related dacryoadenitis and sialadenitis, and autoimmune pancreatitis. A submandibular gland biopsy specimen showed prominent infiltration of IgG4-bearing plasma cells (the ratio of IgG4/IgG-positive cells: 40%) with fibrosis and germinal centres (figure 1A, B). We diagnosed this case as IgG4-RD.3 She was initially treated with 40 mg/day of prednisolone, but several relapses occurred with tapering the dose to 10 mg/day. We administered ciclosporin A and mizoribine with steroid, but we could not get enough efficacy. RTX treatment was started, and the glucocorticoid dose could be decreased to 4 mg/day. RTX initially led to immediate clinical remission, but the effective period of RTX gradually became shorter than that of the initial treatment. After the sixth administration of RTX, the patient presented with no effect.2 We performed re-biopsy of the lacrimal glands, which again showed abundant infiltration of IgG4-positive plasmacytes (the ratio of IgG4/IgG-positive cells: 70%) with fibrosis and a lot of germinal centres (figure 1G, H), but the translocation to malignant lymphoma was not observed. There was no anti-RTX antibody in the serum. We re-obtained her informed consent and switched her from RTX to 500 mg of ABT intravenously every 4 weeks with 10 mg/day of prednisolone. Bilateral enlargement of the lacrimal and submandibular glands gradually improved. 18F-fludeoxyglucose-positron emission tomography imaging at 3 months after the initial ABT revealed the disappearance of abnormal accumulation in the pancreas (figure 2). The level of serum IgG4 gradually continued to decrease to half that of the baseline value. Complement levels and the titre of rheumatoid factor normalised over 8 months. No adverse events occurred. The reason of RTX resistance for this patient was unclear, but it became clear that the efficacy and safety in such a RTX-resistant IgG4-RD case.
Histological examination of submandibular and lacrimal gland specimens. (A–F) Submandibular gland specimen at the diagnosis (×200). (A) H&E staining, (B) IgG4, (C) CD80, (D) CD86, (E) CD28, and (F) cytotoxic T-lymphocyte antigen 4 (CTLA-4) immunohistochemical staining. (G–L) Lacrimal gland specimen before abatacept treatment (×200). (G) H&E staining, (H) IgG4, (I) CD80, (J) CD86, (K) CD28, and (L) CTLA-4 immunohistochemical staining. Both submandibular and lacrimal gland specimens showed abundant infiltration of IgG4 and fibrosis. High level expression of CD86 and moderate expression of CD80 and CTLA-4 was detected, but CD28 expression was not observed.
Effect of abatacept on pancreas assessed by 18F-fludeoxyglucose-positron emission tomography (FDG-PET) and CT. (A and B) FDG-PET images of the pancreas pre- (A) and post- (B) abatacept treatment. (C and D) CT images of the pancreas pre- (C) and post- (D) abatacept treatment. The abnormal accumulation at, and enlargement of the pancreas (arrows in A and C) were improved by abatacept treatment (arrows in B and D). Abatacept is effective for autoimmune pancreatitis.
We analysed cell surface markers of blood cells (CD3, CD4, CD8, and CD19) at every visit, but no significant changes were observed. The expressions of CD80, CD86, cytotoxic T-lymphocyte antigen 4 (CTLA-4) were observed in the both lacrimal and submandibular gland specimens (figure 1C, D, F, L), but CD28 expression was not detected (figure 1E, K). A recent study reported a reduction in focus score following RTX,4 and ABT also reduced the absolute number of foci in Sjogren's syndrome.5 It is also suggested that both RTX and ABT present similar efficacy for IgG4-RD. ABT inhibits co-stimulation of CD28 cells, but there was no CD28-positive cell in the specimens from this case. Recently, Iwata reported a decrease in follicular helper T (Tfh)-cells in peripheral blood after ABT treatment for rheumatoid arthritis.6 There are prominent enlarged germinal centres in the lesions of IgG4-RD.7 ABT might affect Tfh cells in the germinal centres because Tfh cells are needed for maintenance of the germinal centres.
In conclusion, we have treated an RTX-resistant IgG4-RD patient with ABT for 8 months, and the patient presents with good response and safety. We have to accumulate the cases treated with ABT for a long term and consider carrying out the clinical trial of ABT for IgG4-RD.
Footnotes
Contributors All members were involved in the discussion of her treatment.
Funding This work was supported by the Research on Measures for Intractable Diseases Project matching fund subsidy from the Ministry of Health, Labour, and Welfare, Japan and the Japan Agency for Medical Research and Development.
Competing interests None declared.
Patient consent Obtained.
Ethics approval The protocol was approved by Sapporo Medical University Hospital Institutional Review Board subject to applicable laws and regulations and ethical principles consistent with the Declaration of Helsinki.
Provenance and peer review Not commissioned; externally peer reviewed.