LAUSR

IgG4-related disease (IgG4-RD) is an immune-mediated systemic disease characterized by the development of mass lesions in or the enlargement of multiple organs. Whereas the optimum treatment has not been established yet, moderate to high dose of glucocorticoids is recommended as an initial treatment, and the response of the disease to glucocorticoids is generally good [1]. After remission induction, glucocorticoids can be tapered gradually, even stopped in some cases, however, 15–33% of patients have been reported to relapse along with glucocorticoids dose reduction [2–4]. Various immunosuppressive agents have been tried in such refractory cases; azathioprine has been the most frequently reported drug, followed by mycofenolate mofetil, methotrexate, calcineurin inhibitors, and cyclophosphamide [5]. Even the use of biological agents such as rituximab and abatacept has been reported [6,7]. However, the selection of a steroidsparing agent is still challenging because of the lack of evidence on the efficacy of those drugs. Here, we report the effectiveness of tacrolimus, a calcineurin inhibitor, in patients with IgG4-RD. We reviewed all 93 patients with IgG4-RD in our institution and identified five patients who were treated with tacrolimus for the relapse of IgG4-RD without increasing glucocorticoids (Table 1). Diagnosis of IgG4-RD was made based on the 2011 comprehensive diagnostic criteria [8]. All patients had been initially treated with moderate dose of prednisolone and achieved remission. At a median dose of prednisolone of 5mg/day with one patient free of glucocorticoids (case 1), re-enlargement of organs such as lacrimal or submandibular glands with an elevation of IgG4 levels were observed. In cases 3 and 4, imaging evaluations were conducted or systemic survey at the time of relapse. Case 3 underwent abdominal ultrasonography, which showed no abnormal findings as was at the time of diagnosis. Case 4 underwent Gallium scintigraphy, which revealed uptake of Gallium in lacrimal glands, submandibular glands, mediastinal lymph nodes, and hilar lymph nodes. They started tacrolimus of 1.0–2.5mg/day with a stable dose of prednisolone. Tough levels of tacrolimus were 5.0–10.0 ng/mL in four patients, and that of the other one patient was 2.0–3.0 ng/mL. In 4 of 5 patients (case 1, 3–5), the swelling of those organs disappeared in 4 patients approximately two months later, and the other patient showed reduction of lacrimal glands swelling six months later (case 2). In case 3, Gallium scintigraphy 18 months after starting tacrolimus showed no significant uptake in any organs including lacrimal glands. In case 4, ten months after starting tacrolimus, CT and MRI revealed disappearance of lacrimal glands swelling, and mediastinal lymph nodes and hilar lymph nodes enlargement. Eleven months later, Gallium scintigraphy revealed no uptake in lacrimal glands, submandibular glands, and lymph nodes. Serum IgG4 levels, a biomarker to reflect disease activity [4], also decreased in all patients whose serum levels were elevated at the time of relapse (case 1, 2, 4, 5). During the observation period of a median of 17 months, all patients were in stable disease activity except for one patient (case 3) in whom lacrimal glands enlarged again. Our cases demonstrated the effectiveness of tacrolimus for disease control of IgG4-RD. In particular, one patient achieved remission again without the use of glucocorticoids, suggesting tacrolimus could work independently for IgG4RD. A systematic review reported that many immunosuppressive agents were used in patients with IgG4-RD [2]. However, the effectiveness of those drugs has not been clearly shown because they are usually started simultaneously with an increase in prednisolone dose, making the interpretation of how much the improvement was due to the immunosuppressive agent difficult. Our cases received tacrolimus without changing prednisolone dose, which made it certain that the disappearance of organ swelling and the decrease in IgG4-levels could be ascribed to tacrolimus. Recent studies have shown that T follicular helper (Tfh) cell is a key player in the pathogenesis of IgG4-RD in that Tfh cells are critical in germinal center formation, plasmablast and plasma cell differentiation, and IgG4 class-switching [9–11]. Tacrolimus can prevent calcineurin activation and block dephosphorylation of nuclear factor of activated T cells [12], which prevents activating the transcription of IL-2 gene, an important activator and growth factor for T cells. Moreover, tacrolimus specifically suppresses both lymph nodes and circulating Tfh cells [13]. Thus, tacrolimus can be a reasonable choice, and our cases have corroborated the strategy of controlling IgG4-RD by tacrolimus. Our study had several limitations. First, the number of patients in this study is small. We need to conduct a large-