Mitsuhiro Akiyama

Number of Circulating Follicular Helper 2 T Cells Correlates With IgG4 and Interleukin-4 Levels and Plasmablast Numbers in IgG4-Related Disease.

To elucidate the pathologic role of follicular helper T (Tfh) cells and their subsets in active, untreated IgG4‐related disease.

Enhanced IgG4 production by follicular helper 2 T cells and the involvement of follicular helper 1 T cells in the pathogenesis of IgG4-related disease

BackgroundThe aim of this study was to elucidate the function of circulating follicular helper T (Tfh) cell subsets in helping B cells in patients with active, untreated IgG4-related disease (IgG4-RD) and determine their relationship with disease activity.MethodsSeventeen consecutive patients with active, untreated IgG4-RD, 20 with primary Sjögren syndrome (pSS), 5 with multicentric Castleman’s disease (MCD), and 12 healthy controls (HC) were enrolled. Tfh cell subset function was evaluated by co-culture with naïve B cells in vitro. Activated Tfh cell subsets were defined as a CCR7lowPD-1high subset among Tfh cell subsets. Disease activity was evaluated by IgG4-RD responder index (IgG4-RD RI) score.ResultsThe number of Tfh2 cells was significantly higher in IgG4-RD compared to pSS, MCD, or HC, and correlated with serum IgG4 level or the number of plasmablasts. In vitro, Tfh2 cells more efficiently induced the differentiation of naïve B cells into plasmablasts compared to Tfh1 or Tfh17 cells. Of note, while IgG production in culture supernatants of Tfh2 cells was comparable between IgG4-RD and HC, IgG4 production was significantly higher with Tfh2 cells from patients with IgG4-RD than in those from HC. Accordingly, the IgG4:IgG ratio in culture supernatants was also significantly higher with Tfh2 cells from IgG4-RD compared to HC. Moreover, the number of activated Tfh2 cells was higher in IgG4-RD compared to pSS, MCD, or HC, and strongly correlated with IgG4-RD RI score in the baseline active phase. Particularly, the number of activated Tfh2 cells was associated with the number of affected organs and serum IgG4 level. Importantly, the number of activated Tfh2 cells was decreased after glucocorticoid treatment and paralleled disease improvement. Moreover, the number of activated Tfh1 cells was also increased in IgG4-RD compared to pSS, MCD, or HC, correlating with IgG4-RD RI score, but not with serum IgG4 level.ConclusionsTfh2 cells, but not Tfh1 or Tfh17 cells, induce the differentiation of naïve B cells into plasmablasts and enhanced production of IgG4 in patients with active, untreated IgG4-RD. Furthermore, activated Tfh2 cells reflect disease activity, suggesting the involvement of this T cell subset in the pathogenesis of IgG4-RD. Interestingly, the number of activated Tfh1 cells was also increased in IgG4-RD, correlating with disease activity but not with serum IgG4 level, suggesting the involvement of Tfh1 cells but not in the process of IgG4 production in patients with IgG4-RD.

Follicular helper T cells in the pathogenesis of IgG4-related disease

IgG4-related disease (IgG4-RD) is a recently recognized disease entity characterized by high serum IgG4 concentrations and infiltration of IgG4+ plasma cells with hyperplastic ectopic germinal centres at affected sites. Although the underlying immune mechanism of this disease remains unclear, T cells are abundantly present at affected sites and key players in IgG4-RD pathogenesis. The role of T cell subsets has been investigated thoroughly in this disease. Recent advances in this field have clarified the importance of T follicular helper cells. In this review, we describe the role of T follicular helper cells in the disease process of IgG4-RD, in particular, for IgG4 class-switching, plasmablast and plasma cell differentiation, and germinal centre formation.

Resolution of elevated circulating regulatory T cells by corticosteroids in patients with IgG4-related dacryoadenitis and sialoadenitis

Dear Editor, Immunoglobulin G4-related disease (IgG4-RD) is characterized by elevated serum IgG4 concentrations and tissue infiltration by IgG4-positive plasmacytes. Patients with autoimmune pancreatitis (AIP) are reported to have increased numbers of circulating CD4+CD25 regulatory T cells (Tregs). In addition, large numbers of Tregs have been found in affected tissues in patients with IgG4-related dacryoadenitis and sialoadenitis (IgG4-DS) and autoimmune pancreatocholangitis. Regarding treatment for IgG4-DS, corticosteroids were considered effective and are first-line therapy. However, the impact of corticosteroids on the frequency of Tregs in IgG4-DS patients remains unclear. Here, we report two cases of IgG4-DS in which the percentage of circulating Tregs in CD4+ T cells was analyzed by flow cytometry during treatment with corticosteroids. This study was approved by the ethics committee of our institution and informed consent had been obtained from all individual patients.

Acute Kidney Injury due to Renal Sarcoidosis during Etanercept Therapy: A Case Report and Literature Review

We herein report a case of renal sarcoidosis presenting as acute kidney injury (AKI) during treatment with etanercept for rheumatoid arthritis. Blood tests showed a high level of angiotensin-converting enzyme and a renal biopsy demonstrated non-caseating granulomatous tubulointerstitial nephritis. The administration of high-dose steroid therapy (1 mg/kg) and discontinuation of etanercept resulted in an improvement in the patients renal function. Although renal sarcoidosis induced by anti-tumor necrosis factor (TNF) therapy is an extremely rare manifestation, this case suggests that renal sarcoidosis should be considered in the differential diagnosis of AKI in patients receiving anti-TNF therapy, as providing an early diagnosis and treatment is important for preventing irreversible renal impairment.

Distinct features distinguishing IgG4-related disease from multicentric Castleman's disease

Objectives Differentiating IgG4-related disease (IgG4-RD) from multicentric Castleman’s disease (MCD) is challenging because both diseases present high serum IgG4. The objective of this study is to clarify the differences in characteristics and identify a clinically useful approach to differentiate these two diseases. Methods Forty-five consecutive patients with untreated active IgG4-RD and 33 patients with MCD were included in this study, who visited our institution from January 2000 to August 2016. The clinical and laboratory findings for the patients of the two diseases were compared. Various combinations of the distinctive findings were evaluated to identify the most efficient differentiating features between IgG4-RD and MCD. Results The levels of serum IgG4 were not different between the two diseases. Orbits, lacrimal glands, salivary glands or pancreas were involved in 88.9% of IgG4-RD cases and only in 3.0% of MCD cases. All MCD cases involved lymph nodes. Atopic history was characteristic for IgG4-RD. The levels of C reactive protein (CRP) with a cut-off of 0.80 mg/dL and IgA with a cut-off of 330 mg/dL were the most distinctive. The combination of ‘Orbits, lacrimal glands, salivary glands or pancreas involvement, atopic history, or non-involvement of lymph node’ and ‘CRP ≤ 0.8 mg/dL or IgA ≤ 330 mg/dL’ yielded the probability of 97.8% in IgG4-RD, while that of 3.0 % in patients with MCD. Conclusions Our study revealed distinct features between IgG4-RD and MCD. Differentiating between the diseases based on those distinct features, including distribution of organ involvement, atopic history, levels of IgA and CRP, was a useful approach.

IgG4-related disease involving vital organs diagnosed with lip biopsy: A case report and literature review.

AbstractImmunoglobulin G4-related disease (IgG4-RD) is a recently recognized new disease entity characterized by elevated serum IgG4 and infiltration of IgG4+ plasma cells in affected tissues. Histological examination is essential for definitive diagnosis, as other pathological conditions can also present with serum IgG4 elevation. However, IgG4-RD frequently involves vital or internal organs that are difficult to perform biopsies. We herein report a unique case of IgG4-RD involving vital organs that could be successfully diagnosed by alternative lip biopsy, an accessible, little invasive procedure, despite no apparent manifestation demonstrating the involvement in labial salivary gland.A 60-year-old man with swelling of both submandibular glands and elevated serum creatinine level visited our hospital. His labial salivary glands appeared normal. His blood test showed high serum IgG4, and positron-emission computed tomography revealed abnormal uptake in submandibular glands, periaorta, and left kidney with hydronephrosis. We suspected him of IgG4-RD; however, the involved organs were difficult to approach for histological examination. Alternatively, we performed lip biopsy and proved massive infiltration of IgG4+ plasma cells leading to the diagnosis with IgG4-RD. Treatment with prednisolone resulted in the remarkable improvement of organ involvements and the normalization of serum IgG4 level after 3 months. Prednisolone was gradually tapered without the relapse of disease.The early recognition and diagnosis of IgG4-RD is clinically important because delay in the treatment initiation leads to fibrosis with irreversible organ damage. Our case highlights the possibility that lip biopsy is a promising option for histological examination in patients with IgG4-RD in whom affected organs are difficult to access, leading to early diagnosis with appropriate treatment.

Polymyositis with elevated serum IgG4 levels and abundant IgG4 + plasma cell infiltration

Introduction: Polymyositis (PM) is a type of autoimmune, inflammatory myopathy. IgG4-related disease (IgG4-RD) is a recently recognized disease entity characterized by elevated serum IgG4 levels and IgG4+ plasma-cell infiltration of various organs. However, several reports have described cases of other diseases that present with those features, suggesting the importance of careful differential diagnosis. Herein, we report the first case of PM with elevated serum IgG4 levels and IgG4+ plasma cells in the muscles, mimicking IgG4-RD. A 73-year-old woman visited our hospital because of proximal muscle weakness of both thighs. Her blood test showed high levels of serum creatinine kinase, aldolase, and IgG4. Magnetic resonance imaging of the thighs showed muscle edema. Needle electromyography showed findings typical of myositis. Histological analysis of her left quadriceps revealed infiltration of IgG4+ plasma cells as well as CD8+ T cells. Scattered necrotic and regenerating muscle fibers with no specific findings for IgG4-RD (storiform fibrosis and obliterative phlebitis) were typical for PM. We diagnosed her condition as PM and treated her with 40 mg/day of prednisolone that decreased levels of muscle enzymes and improved muscle weakness. Conclusion: Our case indicated that PM could present with high serum IgG4 levels and IgG4+ plasma-cell infiltration, mimicking IgG4-RD. Although the mechanism of IgG4 elevation in such PM is unclear, our case highlights the necessity to recognize that high serum IgG4 levels and IgG4+ plasma-cell infiltration in organs are not specific for IgG4-RD.

Interleukin-6 in idiopathic multicentric Castleman’s disease after long-term tocilizumab

Dear Editor, Idiopathic multicentric Castleman’s disease (iMCD) is a poorly understood lymphoproliferative disorder driven by the overrepresentation of interleukin (IL)-6 [1–5]. Since IL-6 plays a central role in the pathogenesis of iMCD, the normalization of serum IL-6 level is indispensable for the complete cure of the disease. To date, it remains unclear whether long-term treatment with tocilizumab can normalize levels of serum IL-6 in patients with iMCD. We herein report 6 cases with iMCD which showed negative HIV serology and no replicating HHV-8 virus by polymerase chain reaction in the peripheral blood. Median age at diagnosis was 48 years (range 45–55 years) and 4 of 6 (66.7%) were female. All patients were treated with long-term intravenous tocilizumab (8 mg/kg, every 2 weeks) with the median duration of 74 months (range 8–175 months). Ageand sex-matched patients with untreated active IgG4-related disease and six healthy donors were included as controls. The levels of serum IL-6 were strikingly higher in untreated active patients with iMCD (median level, 19.5 pg/ mL: range 8.6–41.8 pg/mL) compared to IgG4-related disease (median level, 1.5 pg/mL: range 0.8–3.5 pg/mL, P = 0.0022) and healthy donors (median level, 1.7 pg/ mL: range 0.9–2.4 pg/mL, P = 0.0022) (Fig. 1a). Significant improvement of hyperimmunoglobulinemia (median level, 5375 mg/dL: range 2896–10,800 mg/dL vs. median level, 2063 mg/dL: range 830–2434 mg/dL, P = 0.0313; Fig. 1b), levels of serum CRP (median level, 8.13 mg/dL: range 5.11–11.88 mg/dL vs. median level, 0.14 mg/dL: range 0.02–0.79 mg/dL, P = 0.0313; Fig. 1c), and anemia (median level, 8.6 g/dL: range 7.6– 12.1 g/dL vs. median level, 13.0 g/dL: range 11.2–14.1 g/ dL, P = 0.0313; Fig. 1d) was demonstrated after long-term treatment with tocilizumab, but elevation of serum IL-6 were not normalized in all patients (median level, 19.45 pg/mL: range 8.6–41.8 pg/mL vs. median level, 307.0 pg/mL: range 105–752 pg/mL, P = 0.0313; Fig. 1e). Furthermore, the case which was followed by the accidental cessation of tocilizumab due to the orthopedic surgery resulted in immediate relapse of the disease and the status was re-stabilized by re-introduction of tocilizumab after the surgery (Fig. 1f). To our knowledge, our study is the first report clearly showing the effect of long-term treatment with tocilizumab on levels of serum IL-6 in patients with iMCD. Our results emphasize that underlying disease process inducing hyper IL-6 is not corrected despite long-term treatment with tocilizumab as shown by the continued high levels of serum IL-6. In line with this observation, lifelong administration of tocilizumab is required to control disease activity because we observed the recurrent case after the accidental cessation of long-term tocilizumab. Interestingly, in contrast, recent reports demonstrated the normalization of serum IL-6 levels in parallel with disease improvement after treatment with tocilizumab in patients with thrombocytopenia, anasarca, fever, reticulin fibrosis, and organomegaly (TAFRO) syndrome, a unique clinicopathologic variant of MCD [6–8]. Thus, iMCD is a distinct disease entity from TAFRO syndrome even though some of the characteristics including hyper IL-6 and histopathology of lymph node are similar between the two diseases. Further research around * Tsutomu Takeuchi tsutake@z5.keio.jp

Polychondritis presenting with oculomotor and abducens nerve palsies as the initial manifestation

We treated a patient with relapsing polychondritis (RP) who presented with intermittent oculomotor and abducens nerve palsies as the first manifestation. Ear swelling and laryngeal edema emerged 7 months later, which led us to diagnose him with RP. Moderate doses of glucocorticoid resolved all symptoms. Our experience with RP accompanied by oculomotor nerve palsy suggests that RP should be considered in patients with cranial nerve palsies so that they may be promptly diagnosed and treated.