Case Report: A case of TAFRO syndrome with severe and prolonged thrombocytopenia: diagnostic pitfalls.

Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction, and organomegaly (TAFRO) syndrome is a rare condition with diverse clinical and pathological characteristics related to multi-organ damage. We report a case of TAFRO syndrome complicated by immune thrombocytopenia with prolonged fever and thrombocytopenia for several weeks. A 61-year-old man was transferred with sepsis caused by Enterococcus faecalis, and developed disseminated intravascular coagulation. Antibiotics treatment was initiated: however, low-grade fever and thrombocytopenia persisted despite the adequate antimicrobial treatment. Systemic edema, pleural effusion, and ascites had developed before hospitalization, and renal and liver function had deteriorated, resulting in progressive multi-organ damage. Prednisolone 40 mg/day was initiated based on the assumption of a condition in which excessive production of inflammatory cytokines would lead to systemic deterioration and fatal organ damage. Subsequently, the fever resolved, and renal function began to normalize. However, thrombocytopenia did not show much recovery trend after Helicobacter pylori eradication therapy and initiation of thrombopoietin receptor agonists. Bone marrow biopsy results showed normal bone marrow with no malignant findings. Alternatively, significant clinical signs met the diagnostic criteria for TAFRO syndrome, and a renal biopsy revealed thrombotic microangiopathy, which is also reasonable for renal involvement in TAFRO syndrome. The use of cyclosporine remarkably corrected the thrombocytopenia. We considered this a case of TAFRO syndrome that developed after sepsis with disseminated intravascular coagulation and performed the differential diagnosis of prolonged thrombocytopenia and excluded it. Although TAFRO syndrome is a unique disease concept, diagnostic criteria may consist of nonspecific elements such as generalized edema, thrombocytopenia, persistent fever, and elevated inflammatory response, and there are many differential conditions to exclude, requiring caution in diagnosing TAFRO syndrome.

Suspected Immune Thrombocytopenic Purpura Induced by Lenalidomide for the Treatment of Myelodysplastic Syndrome with Deletion of Chromosome 5q: A Case Report.

Lenalidomide (LEN), one of the key drugs in the treatment of myelodysplastic syndromes (MDS) with 5q deletion, as well as multiple myeloma (MM), has various immunomodulatory effects and has been associated with autoimmune diseases, including immune thrombocytopenic purpura (ITP). A 78-year-old man presented with pancytopenia and was diagnosed with MDS with 5q deletion and other chromosomal abnormalities. Two cycles of LEN therapy (one cycle: 10 mg/day for 21 days) resulted in a transient improvement in anemia, followed by MDS progression with severe thrombocytopenia (4 × 109/L) refractory to platelet transfusions. As other non-immune and alloimmune causes of transfusion-refractory thrombocytopenia were excluded, and the level of platelet-associated immunoglobulin G was extremely high compared with the level before treatment with LEN, the diagnosis of ITP was highly suspected. Despite treatment with prednisolone (PSL), eltrombopag, and repeated platelet transfusions, his platelet count did not increase, and he died of a gastrointestinal hemorrhage. Several cases of ITP induced by LEN used to treat MM had been reported, but the platelet count recovered after administration of PSL in these previous cases. However, we should be mindful of using LEN for patients with MDS because its treatment may become extremely difficult if ITP develops.

A rare case of sporadic inclusion body myositis and rheumatoid arthritis exhibiting ectopic lymphoid follicle-like structures: a case report and literature review.

Sporadic inclusion body myositis (sIBM) is a degenerative, intractable, inflammatory myopathy with an immune pathomechanism. We report on a case of a 44-year-old Japanese man who began developing progressive muscle weakness at age 40. Rheumatoid arthritis symptoms manifested at 43 with strongly positive anti-cyclic citrullinated peptide antibodies. Along with typical sIBM pathology, a muscle biopsy revealed dramatic inflammation with prominent perivascular B-cell infiltration forming ectopic lymphoid follicle-like structures (ELFLSs). Exome sequencing identified no causative variants of hereditary myopathy or immune disorders. A combination of immunotherapy slowed the progression of the muscular symptoms. This unusual form of sIBM, including earlier age at onset, a partial response to immunotherapy, and a histopathology presenting B-cell infiltrate with ectopic lymphoid follicle-like structures, indicates a possible association of rheumatoid arthritis and heterogeneity with the autoimmune involvement of sIBM. We review the clinical and pathological features of patients with rheumatoid arthritis associated sIBM in the literature.

Spontaneous Regression of Blastic Plasmacytoid Dendritic Cell Neoplasm Following Sepsis by Serratia marcescens: A Case Report and Literature Review.

Spontaneous regression is rare in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). An 85-year-old man presented with pancytopenia and skin lesions, and the bone marrow exhibited 79.6% CD4+, CD56+, CD123+, and TCL-1+ abnormal cells, with a normal karyotype; he was thus diagnosed with BPDCN. While being followed without chemotherapy, he was admitted due to sepsis induced by Serratia marcescens, which was successfully treated with antibiotics. Notably, his blood cell counts improved, and the skin lesions disappeared. To our knowledge, this is the first reported case of spontaneous regression of BPDCN with a decrease in tumor cells in the bone marrow following sepsis.

Identification of two major autoantigens negatively regulating endothelial activation in Takayasu arteritis.

The presence of antiendothelial cell antibodies (AECAs) has been documented in Takayasu arteritis (TAK), a chronic granulomatous vasculitis. Here, we identify cell-surface autoantigens using an expression cloning system. A cDNA library of endothelial cells is retrovirally transfected into a rat myeloma cell line from which AECA-positive clones are sorted with flow cytometry. Four distinct AECA-positive clones are isolated, and endothelial protein C receptor (EPCR) and scavenger receptor class B type 1 (SR-BI) are identified as endothelial autoantigens. Autoantibodies against EPCR and SR-BI are detected in 34.6% and 36.5% of cases, respectively, with minimal overlap (3.8%). Autoantibodies against EPCR are also detected in ulcerative colitis, the frequent comorbidity of TAK. In mechanistic studies, EPCR and SR-BI function as negative regulators of endothelial activation. EPCR has also an effect on human T cells and impair Th17 differentiation. Autoantibodies against EPCR and SR-BI block the functions of their targets, thereby promoting pro-inflammatory phenotype.

Refractory Takayasu arteritis successfully treated with rituximab: case-based review.

Takayasu arteritis (TAK) is a subtype of the large-vessel vasculitis, affecting the aorta and its major branches. Although T cell-mediated autoimmunity is mainly involved in vascular inflammation, in recent years, accumulating evidence suggests the important role of B cells in the pathogenesis and effectiveness of B-cell-targeted therapy with rituximab (RTX), a chimeric anti-CD20 monoclonal antibody in refractory TAK. Herein, we report for the first time a case involving a 34-year-old man with TAK who was refractory to four different biologic agents, such as one selective T-cell co-stimulation modulator (abatacept), one anti-interleukin-6 receptor monoclonal antibody (tocilizumab), and two tumor necrosis factor-α inhibitors (infliximab and etanercept), but eventually achieved remission with RTX. He received a total of six courses of RTX, and doses of prednisolone and methotrexate were tapered without relapse. The current case provided further evidence to the potential role of RTX therapy in patients with refractory TAK, and its efficacy needs to be validated in a controlled trial.

Nasal Septal Perforation in Propylthiouracil-Induced Anti-Neutrophil Cytoplasmic Antibody-Associated Vasculitis.

Here, we present the case of a 29-year-old woman with nasal septal perforation and positive myeloperoxidase- (MPO-) anti-neutrophil cytoplasmic antibody (ANCA). She had been diagnosed with Graves' disease and had been treated with propylthiouracil (PTU) for 14 months. A biopsy of the nasal septum revealed an infiltration of inflammatory cells, with no evidence of malignancy or granulomatous change. Because of the use of PTU, destructive nasal lesion, and positive MPO-ANCA, she was diagnosed with drug-induced ANCA-associated vasculitis (AAV) and was treated with prednisolone and methotrexate after the cessation of PTU. Although PTU is known to be the medicine that induces drug-induced AAV, the manifestation of nasal septal perforation in drug-induced AAV is poorly identified. This is the rare case of drug-induced AAV which manifested only nasal septal perforation.

Bortezomib treatment induces a higher mortality rate in lupus model mice with a higher disease activity.

BACKGROUND: Bortezomib (Bz) is a proteasome inhibitor that directly targets antibody-producing plasma cells. We recently reported the first randomized control trial that evaluated the effects of Bz in patients with systemic lupus erythematosus (SLE). In that study, we demonstrated that Bz treatment is associated with many adverse reactions in patients with refractory disease. In the present study, we examine the therapeutic and toxic effects of Bz on MRL/MpJ-lpr/lpr (MRL/lpr) mice with severe disease activity. METHODS: Female MRL/lpr mice at 10 and 14 weeks of age were treated with phosphate buffered saline (PBS) (n = 19), Bz (750 µg/kg twice weekly) (n = 27), or cyclophosphamide (Cyc) (1 mg/body, once in 2 weeks) (n = 20). Cellular subsets, serum immunoglobulin, anti-double-stranded DNA (anti-dsDNA) antibody titer, and a pathological index of glomerulonephritis were then analyzed at 22 weeks of age. Survival curves of the 10-week-old and 14-week-old Bz-treated groups were compared. Blood counts, creatinine, liver enzymes, and serum cytokine levels were measured 1 week after Bz treatment. Gene expression profiling of spleens from Bz and Cyc treatment mice were compared with those from control mice. RESULTS: The anti-dsDNA antibody levels were significantly higher in 14-week-old than in 10-week-old mice, indicating a higher disease activity at 14 weeks. A significant decrease in the number of splenic cells and glomerulonephritis index was observed in Bz-treated and Cyc-treated mice. Bz, but not Cyc, significantly decreased serum immunoglobulin and anti-dsDNA antibody titer levels. Survival curve analysis revealed a significantly higher mortality rate in 14-week-old than in 10-week-old Bz-treated and control groups. Following two injections of Bz, serum IL-6 and TNF-α levels were significantly more elevated in 14-week-old than in 10-week-old mice. Potentially immunogenic molecules, such as heat shock proteins, were characteristically upregulated in spleens of Bz-treated but not Cyc-treated mice. CONCLUSIONS: In spite of its therapeutic effect, Bz treatment had more toxic effects associated with increased proinflammatory cytokine levels in mice with a higher disease activity. Understanding the mechanism of the toxicity and developing preventive strategies against it is important for the safe clinical application of Bz in human SLE.

Ulcerative keratitis in patients with rheumatoid arthritis in the modern biologic era: a series of eight cases and literature review.

AIM: To assess the prevalence, clinical characteristics, treatment, and outcomes of patients who developed ulcerative keratitis (UK) during the course of rheumatoid arthritis (RA) in the modern biologic era. METHOD: We retrospectively reviewed the medical records of 589 patients with RA who visited our department between April 2003 and October 2014, and identified patients who developed UK. We also obtained data about clinical characteristics of RA and UK, complications, treatment, and both visual and life prognoses of these patients. RESULTS: Among 589 patients with RA, eight patients (1.4%) were diagnosed with UK. The mean age at the onset of RA was 61.0 years, while the mean age at the onset of UK was 73.0 years. Most of the patients were seropositive and had established RA with a relatively low disease activity. Secondary Sjögren's syndrome was observed in two patients. Peripheral UK occurred as a complication of scleritis, while central UK was not associated with scleritis. Although the mean duration of follow-up was only 3.7 years, visual and life prognoses were both tolerable with therapy, including the use of topical and systemic corticosteroids and calcineurin inhibitors, sometimes combined with biologic disease-modifying antirheumatic drugs (DMARDs) and corneal transplantation. CONCLUSION: This retrospective study demonstrated that the prevalence of UK in patients with RA was 1.4%. Immediate combination therapy, including topical and systemic corticosteroids and calcineurin inhibitors, together with biologic DMARDs and corneal transplantation, was effective for treating RA patients who developed UK in the modern biologic era.

Retrospective analysis of 95 patients with large vessel vasculitis: a single center experience.

AIM: Although Takayasu arteritis (TAK) and giant cell arteritis (GCA) have been considered as distinct disease entities, similarities of these diseases have been recently reported. However, little data is available regarding this issue in Japanese patients with TAK and GCA. In addition, the classification criteria for TAK established in 1990 by the American College of Rheumatology (ACR) have been criticized due to the age restriction for disease onset (≤ 40 years). Thus, we aimed to compare the clinical characteristics of Japanese patients with TAK and those with GCA and to clarify whether clinical differences existed between patients with early-onset (≤ 40 years) and late-onset (> 40 years) TAK. METHODS: We enrolled 86 patients with TAK and nine with GCA who visited our department from 1990 to 2014. The diagnoses of TAK and GCA were based on the criteria of the Japanese Circulation Society and the ACR, respectively. RESULTS: Mean ages at onset for TAK and GCA were 36.4 and 71.0 years, respectively. Patients with TAK had significantly higher incidences of aortic regurgitation and carotid and subclavian arterial involvement, lower frequencies of polymyalgia rheumatica, and better prognoses than those with GCA. In contrast, the clinical characteristics, distribution of arterial lesions, treatments administered, and prognoses of patients with early- and late-onset TAK were comparable. CONCLUSIONS: These results suggested that TAK and GCA differed substantially, and that the age restriction (≤ 40 years) may not be necessary for the diagnosis of TAK.

Long-term follow-up of 124 patients with polymyositis and dermatomyositis: Statistical analysis of prognostic factors.

OBJECTIVES: The aims of this study were to clarify the long-term outcome of patients with polymyositis and dermatomyositis (PM/DM) and to elucidate prognostic factors using statistical analysis. METHODS: We enrolled patients with PM/DM who visited our department between 1990 and 2014. Diagnoses of PM/DM and clinically amyopathic DM were based on the definitions of Bohan and Peter, and Sontheimer, respectively. We also obtained clinical data, such as age of onset, sex, medications, and presence of interstitial lung disease and malignancies, as well as laboratory tests, including the values of creatine kinase, KL-6, and ferritin. The follow-up was conducted until June 2014. RESULTS: A total of 124 patients (PM: 46, DM: 78) were enrolled. The mean age of onset was 53.5 years, and females were predominant (64.5%). Overall survival rates were 93%, 86%, and 78% for 1, 5, and 10 years, respectively. The survival rates were significantly lower in patients with higher age of onset, with malignancies, and with hyperferritinemia in univariate analysis; however, multivariate analysis identified age of onset and serum ferritin as the most significant prognostic factors. CONCLUSIONS: Our study indicates that when age of onset and serum ferritin are used in combination, we can predict prognosis of patients with PM/DM.

Synovitis in a Patient with IgG4-related Disease.

A 71-year-old man was admitted to our department due to arthralgia and renal dysfunction. A physical examination disclosed swelling of the right shoulder and left wrist joints. Laboratory tests showed elevated serum IgG4 and creatinine levels, and magnetic resonance imaging of the wrist revealed bone erosion and synovitis. In addition, fluorodeoxyglucose positron emission tomography showed uptake in the submandibular glands, pancreas, kidneys, and affected joints and a renal biopsy revealed tubulointerstitial nephritis with the infiltration of IgG4+ plasma cells. The patient was subsequently diagnosed with IgG4-related disease (IgG4-RD) and successfully treated with corticosteroid therapy. This case suggests that erosive arthritis may occur in patients with IgG4-RD.

Effect of TLR agonists on the differentiation and function of human monocytic myeloid-derived suppressor cells.

Tumors persist by occupying immunosuppressive microenvironments that inhibit the activity of tumoricidal T and NK cells. Monocytic myeloid-derived suppressor cells (mMDSC) are an important component of this immunosuppressive milieu. We find that the suppressive activity of mMDSC isolated from cancer patients can be reversed by treatment with TLR7/8 agonists, which induce human mMDSC to differentiate into tumoricidal M1-like macrophages. In contrast, agonists targeting TLR1/2 cause mMDSC to mature into immunosuppressive M2-like macrophages. These two populations of macrophage are phenotypically and functionally discrete and differ in gene expression profile. The ability of TLR7/8 agonists to reverse mMDSC-mediated immune suppression suggests that they might be useful adjuncts for tumor immunotherapy.

Impact of anti-interleukin-6 receptor blockade on circulating T and B cell subsets in patients with systemic lupus erythematosus.

BACKGROUND: Circulating plasmablasts/plasma cells and activated B and T cells are increased in systemic lupus erythematosus (SLE). Interleukin (IL)-6 induces differentiation of B cells into antibody-forming cells and of T cells into effector cells. OBJECTIVE: To examine the hypothesis that blocking IL-6 would reverse some of the immune abnormalities present in SLE. METHODS: Fifteen patients with SLE with mild-to moderate disease activity were treated with biweekly infusions of tocilizumab, a humanised anti-IL-6 receptor monoclonal antibody for 12 weeks. Lymphocyte subsets (analysed by flow cytometry) and serum immunoglobulin levels were compared at baseline and at weeks 6 and 12. RESULTS: Tocilizumab decreased activated T and B cells, the frequency of CD27(high)CD38(high)IgD- plasmablasts/plasma cells and IgD-CD27+ post-switched memory B cells as well as IgG+ memory B cell, whereas it increased the frequency of IgD+CD27- antigen-inexperienced B cells. Among antigen-inexperienced IgD+CD27- B cells, CD38(low) mature naïve B cells increased significantly and CD38(Intermediate)CD5+ pre-naïve B cells showed a decreasing trend, whereas CD38(high)CD5+ transitional type 1 B cells did not change. Most of the changes occurred in patients who had abnormal values at baseline. IgG, IgA, IgG1 and IgG3 serum levels decreased albeit within the normal range. The frequency of CD4+CD45RA+CCR7+ naïve T cells increased. CONCLUSIONS: In vivo blockade of the IL-6 receptor decreases lymphocyte activation and restores B and T cell homoeostasis by either blocking differentiation and/or trafficking in patients with SLE and leads to normalisation of the abnormal B and T cell subsets seen at baseline.

Intratumoral injection of CpG oligonucleotides induces the differentiation and reduces the immunosuppressive activity of myeloid-derived suppressor cells.

Immunostimulatory CpG oligonucleotides (ODN) activate cells that express TLR9 and have been shown to improve the host's response to tumor Ags. Unfortunately, the immunosuppressive microenvironment that surrounds many cancers inhibits Ag-specific cellular responses and thus interferes with CpG-mediated immunotherapy. Myeloid-derived suppressor cells (MDSC) represent an important constituent of this immunosuppressive milieu. Large numbers of MDSC are present in and near tumor sites where they inhibit the activity of Ag-specific T and NK cells. Current studies indicate that the delivery of CpG ODN directly into the tumor bed reduces the immunosuppressive activity of monocytic (CD11b(+), Ly6G(-), Ly6C(high)) MDSC. Monocytic MDSC express TLR9 and respond to CpG stimulation by 1) losing their ability to suppress T cell function, 2) producing Th1 cytokines, and 3) differentiating into macrophages with tumoricidal capability. These findings provide insight into a novel mechanism by which CpG ODN contribute to tumor regression, and they support intratumoral injection as the optimal route for their delivery.

Severe hypogammaglobulinemia persisting for 6 years after treatment with rituximab combined chemotherapy due to arrest of B lymphocyte differentiation together with alteration of T lymphocyte homeostasis.

We report a case of prolonged severe hypogammaglobulinemia after rituximab combined chemotherapy for follicular lymphoma. Although the patient's globulin level was within the normal limits before treatment, the level of IgG dropped below 100 mg/dL, and both IgA and IgM became undetectable after treatment, and the levels have shown no changes for 6 years despite recovery of peripheral B cell counts. Phenotypic analysis of B cells revealed a reduction of class-switched CD27+IgM-IgD- memory B cells below 0.5% and overexpression of CD95. On the other hand, we observed the predominance of memory T cell subsets in both of CD4+ and CD8+ T cells as the result of reduction of naïve T cells. These increased memory T cells overexpressed activation markers such as CD69, CD95, and HLA-DR. Furthermore, the patient's B cells failed to differentiate into memory B or plasma cells in the presence of IL-6, IL-10, IL-15, and BAFF in vitro in comparison with those from healthy controls and showed significant impairment of IgG production. These findings suggest that rituximab combined chemotherapy may induce persistent differentiation arrest and apoptosis of B cell lineage with alteration of T lymphocyte homeostasis resulting in pan-hypogammaglobulinemia.

Identification and characterization of circulating human transitional B cells.

Murine B-cell development begins in bone marrow and results in the generation of immature transitional B cells that transit to the spleen to complete their maturation. It remains unclear whether the same developmental pathway takes place in humans. Using markers characteristic of human bone marrow immature B cells, we have identified a population of circulating human B cells with a phenotype most similar to mouse transitional type I (T1) B cells, although these human counterparts express CD5. These cells die rapidly in culture, and B-cell activation factor member of the tumor necrosis factor (TNF) family (BAFF) does not effect their survival regardless of B-cell receptor (BCR) stimulation. In contrast, bone marrow stromal cells or interleukin-4 (IL-4) significantly enhanced their survival. In the presence of T-cell signals provided by IL-4 or CD40 ligation, BCR stimulation can induce progression into cell cycle. Interestingly, circulating B cells that phenotypically and functionally resemble murine T2 B cells are found in cord blood and adult peripheral blood, suggesting that B-cell maturation may not be restricted to the spleen. Notably, increased proportions of T1 B cells were found in blood of patients with systemic lupus erythematosus (SLE), although bone marrow production and selection appeared to be normal.