CD20(+)CD27(+)CD43(+) B (CD43(+) B) cells have been newly defined among PBMCs and proposed to be human B1 cells. However, it is controversial as to whether they are orthologs of murine B1 cells and how they are related to other B-cell populations, particularly CD20(+)CD27(+)CD43(-) memory B cells and CD20(low)CD27(high)CD43(high) plasmablasts. Our objective is to identify phenotypically the position of CD43(+) B cells among peripheral B-lineage cell compartments in healthy donors, with reference to B-cell subsets from patients with systemic lupus erythematosus (SLE). We found that CD43(+) B cells among PBMCs from healthy subjects were indistinguishable phenotypically from memory B cells in terms of surface markers, and spontaneous in vitro Ig and IL-10 secretion capability, but quite different from plasmablasts. However, a moderate correlation was found in the frequency of CD43(+) B cells with that of plasmablasts in healthy donors but not in SLE patients. An in vitro differentiation experiment indicated that CD43(+) B cells give rise to plasmablasts more efficiently than do memory B cells, suggesting that they are more closely related to plasmablasts developmentally than are memory B cells, which is also supported by quantitative PCR analysis of mRNA expression of B-cell and plasma cell signature genes. Thus, we conclude that, in healthy individuals, CD43(+) B cells are closely related not only to memory B cells phenotypically but also to plasmablasts developmentally, although the developmental origin of CD43(+) B cells is not necessarily the same as that of plasmablasts.

Autophagy is an intracellular degradation system that plays an important role in T-cell survival. However, the precise mechanism linking autophagy and cell death in primary human T cells is unclear because methods for monitoring autophagy in small numbers of primary human cells remain controversial. We established a novel method for assessing autophagy in activated human T cells using a retroviral GFP-LC3 expression system. We found that autophagy was induced after TCR stimulation and that autophagy-defective naive CD4(+)T cells were susceptible to apoptosis through the intrinsic apoptotic pathway. Enhanced apoptosis of autophagy-defective T cells resulted from accumulation of ROS due to impaired mitophagy. We also demonstrated that effector memory CD4(+) T cells had lower autophagic activity than naive CD4(+) T cells, which contributed to their enhanced apoptosis due to increased ROS. Moreover, blocking autophagy increased intracellular mitochondrial volume and ROS levels in activated T cells. These results suggest a protective role of autophagy as an anti-oxidant system in activated human T cells. The combination of an autophagy blocker and a mitochondrial electron transport chain inhibitor has a synergistic effect on T-cell death, which could be a novel strategy for induction of T-cell apoptosis.

Acute necrotizing encephalopathy (ANE) is characterized by symmetrical brain necrosis, suggested to be due to breakdown of the blood-brain barrier (BBB). We experienced a rare case of ANE complicated with systemic lupus erythematosus (SLE), and found that the patient's serum (V10-5) had binding activity to human umbilical vein endothelial cells (HUVECs). By SARF (Serological identification system for Autoantigens using a Retroviral vector and Flow cytometry) method using V10-5 IgG, a clone bound to V10-5 IgG was isolated. This cell clone was integrated with cDNA identical to EphB2, which plays critical roles in neuronal cells and endothelial cells. HUVECs and human brain microvascular endothelial cells expressed EphB2 and the V10-5 IgG bound specifically to EphB2-transfected cells. Anti-EphB2 antibody was not detected in other SLE patients without ANE. In this report, we identified EphB2 as a novel autoantigen, and anti-EphB2 antibody may define a novel group of brain disorders. Anti-EphB2 antibody can interfere not only with endothelial cells including those of the BBB (acting as an anti-endothelial cell antibody), but also neuronal cells (acting as an anti-neuronal antibody) if the BBB has been breached. Future studies should determine the clinical prevalence and specificity of anti-EphB2 antibody, and the molecular mechanisms by which anti-EphB2 antibody mediates neuronal and vascular pathological lesions.

In the HLA class II-associated autoimmune syndrome rheumatoid arthritis (RA), CD4 T cells are critical drivers of pathogenic immunity. We have explored the metabolic activity of RA T cells and its impact on cellular function and fate. Naive CD4 T cells from RA patients failed to metabolize equal amounts of glucose as age-matched control cells, generated less intracellular ATP, and were apoptosis-susceptible. The defect was attributed to insufficient induction of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a regulatory and rate-limiting glycolytic enzyme known to cause the Warburg effect. Forced overexpression of PFKFB3 in RA T cells restored glycolytic flux and protected cells from excessive apoptosis. Hypoglycolytic RA T cells diverted glucose toward the pentose phosphate pathway, generated more NADPH, and consumed intracellular reactive oxygen species (ROS). PFKFB3 deficiency also constrained the ability of RA T cells to resort to autophagy as an alternative means to provide energy and biosynthetic precursor molecules. PFKFB3 silencing and overexpression identified a novel extraglycolytic role of the enzyme in autophagy regulation. In essence, T cells in RA patients, even those in a naive state, are metabolically reprogrammed with insufficient up-regulation of the glycolytic activator PFKFB3, rendering them energy-deprived, ROS- and autophagy-deficient, apoptosis-sensitive, and prone to undergo senescence.

Autoantibodies against integral membrane proteins are usually pathogenic. Although anti-endothelial cell antibodies (AECAs) are considered to be critical, especially for vascular lesions in collagen diseases, most molecules identified as autoantigens for AECAs are localized within the cell and not expressed on the cell surface. For identification of autoantigens, proteomics and expression library analyses have been performed for many years with some success. To specifically target cell-surface molecules in identification of autoantigens, we constructed a serological identification system for autoantigens using a retroviral vector and flow cytometry (SARF). Here, we present an overview of recent research in AECAs and their target molecules and discuss the principle and the application of SARF. Using SARF, we successfully identified three different membrane proteins: fibronectin leucine-rich transmembrane protein 2 (FLRT2) from patients with systemic lupus erythematosus (SLE), intercellular adhesion molecule 1 (ICAM-1) from a patient with rheumatoid arthritis, and Pk (Gb3/CD77) from an SLE patient with hemolytic anemia, as targets for AECAs. SARF is useful for specific identification of autoantigens expressed on the cell surface, and identification of such interactions of the cell-surface autoantigens and pathogenic autoantibodies may enable the development of more specific intervention strategies in autoimmune diseases.

INTRODUCTION: Anti-endothelial cell antibodies (AECAs) are thought to be critical for vasculitides in collagen diseases, but most were directed against molecules localized within the cell and not expressed on the cell surface. To clarify the pathogenic roles of AECAs, we constructed a retroviral vector system for identification of autoantigens expressed on the endothelial cell surface. METHODS: AECA activity in sera from patients with collagen diseases was measured with flow cytometry by using human umbilical vein endothelial cells (HUVECs). A cDNA library of HUVECs was retrovirally transfected into a rat myeloma cell line, from which AECA-positive clones were sorted with flow cytometry. cDNA of the cells was analyzed to identify an autoantigen, and then the clinical characteristics and the functional significance of the autoantibody were evaluated. RESULTS: Two distinct AECA-positive clones were isolated by using serum immunoglobulin G (IgG) from a patient with systemic lupus erythematosus (SLE). Both clones were identical to cDNA of fibronectin leucine-rich transmembrane protein 2 (FLRT2). HUVECs expressed FLRT2 and the prototype AECA IgG bound specifically to FLRT2-transfected cells. Anti-FLRT2 antibody activity accounted for 21.4% of AECAs in SLE. Furthermore, anti-FLRT2 antibody induced complement-dependent cytotoxicity against FLRT2-expressing cells. CONCLUSIONS: We identified the membrane protein FLRT2 as a novel autoantigen of AECAs in SLE patients by using the retroviral vector system. Anti-FLRT2 antibody has the potential to induce direct endothelial cell cytotoxicity in about 10% of SLE patients and could be a novel molecular target for intervention. Identification of such a cell-surface target for AECAs may reveal a comprehensive mechanism of vascular injury in collagen diseases.

In rheumatoid arthritis (RA), the aging process of the immune system is accelerated. Formerly, this phenomenon was suspected to be a consequence of chronic inflammatory activity. However, newer data strongly suggest that deficiencies in maintaining telomeres and overall DNA stability cause excessive apoptosis of RA T cells, imposing proliferative pressure and premature aging on the system. Already during the early stages of their life cycle, and long before they participate in the inflammatory process, RA T cells are lost owing to increased apoptotic susceptibility. A search for underlying mechanisms has led to the discovery of defective pathways of repairing broken DNA and elongating and protecting telomeric sequences at the chromosomal ends. Two enzymatic machineries devoted to DNA repair and maintenance have been implicated. RA T cells fail to induce sufficient amounts of the telomeric repair enzyme telomerase, leaving telomeric ends uncapped and thus susceptible to damage. Of equal importance, RA T cells produce low levels of the DNA repair enzyme ataxia telangiectasia mutated and the complex of nucleoproteins that sense and fix DNA double-strand breaks. The inability to repair damaged DNA renders naive T cells vulnerable to apoptosis, exhausts T-cell regeneration and reshapes the T cell repertoire. Therapeutic attempts to reset the immune systems of patients with RA and prevent premature immunosenescence should include restoration of DNA repair capability.

In rheumatoid arthritis (RA), dysfunctional T cells sustain chronic inflammatory immune responses in the synovium. Even unprimed T cells are under excessive replication pressure, suggesting an intrinsic defect in T cell regeneration. In naive CD4 CD45RA(+) T cells from RA patients, DNA damage load and apoptosis rates were markedly higher than in controls; repair of radiation-induced DNA breaks was blunted and delayed. DNA damage was highest in newly diagnosed untreated patients. RA T cells failed to produce sufficient transcripts and protein of the DNA repair kinase ataxia telangiectasia (AT) mutated (ATM). NBS1, RAD50, MRE11, and p53 were also repressed. ATM knockdown mimicked the biological effects characteristic for RA T cells. Conversely, ATM overexpression reconstituted DNA repair capabilities, response patterns to genotoxic stress, and production of MRE11 complex components and rescued RA T cells from apoptotic death. In conclusion, ATM deficiency in RA disrupts DNA repair and renders T cells sensitive to apoptosis. Apoptotic attrition of naive T cells imposes lymphopenia-induced proliferation, leading to premature immunose-nescence and an autoimmune-biased T cell repertoire. Restoration of DNA repair mechanisms emerges as an important therapeutic target in RA.

In rheumatoid arthritis (RA), chronically stimulated T lymphocytes sustain tissue-destructive joint inflammation. Both naive and memory T cells in RA are prematurely aged with accelerated loss of telomeres suggesting excessive proliferative pressure or inadequate telomeric maintenance. Upon stimulation, RA naive CD4 T cells are defective in up-regulating telomerase activity (P < 0.0001) due to insufficient induction of the telomerase component human telomerase reverse transcriptase (hTERT); T cell activation and cell cycle progression are intact. Telomerase insufficiency does not affect memory T cells or CD34 hematopoietic stem cells and is present in untreated patients and independent from disease activity. Knockdown of hTERT in primary human T cells increases apoptotic propensity (P = 0.00005) and limits clonal burst (P = 0.0001) revealing a direct involvement of telomerase in T cell fate decisions. Naive RA CD4 T cells stimulated through the T cell receptor are highly susceptible to apoptosis, expanding to smaller clonal size. Overexpression of ectopic hTERT in naive RA T cells conveys apoptotic resistance (P = 0.008) and restores proliferative expansion (P < 0.0001). Telomerase insufficiency in RA results in excessive T cell loss, undermining homeostatic control of the naive T cell compartment and setting the stage for lymphopenia-induced T cell repertoire remodeling. Restoring defective telomerase activity emerges as a therapeutic target in resetting immune abnormalities in RA.

Human parvovirus B19 (B19) often causes acute polyarthritis in adults. in this papers we analyzed nucleotide sequences of the B19 genome of patients with rheumatoid arthritis (RA), and then introduced the nonstructual protein 1 (NS1) gene of B19 into C57BL/6 mice that had a genetic origin not susceptible to arthritis. The transgenic mice developed no lesions spontaneously, but were susceptible to type H collagen (CH)-induced arthritis. B19 NS1 was expressed in synovial cells on the articular lesions that were histologically characteristic of granulomatous synovitis and pannus formation in cartilage and bone. Serum levels of anti-CII Abs and TNF-alpha increased in NS1 transgenic mice to the same levels as those of DBA/1 mice, which were susceptible to polyarthritis. Stimulation with CH increased secretion of Th1-type- and Th2-type cytokines in NS1 transgenic mice, indicating that a nonpermissive H-2(b) haplotype in the wild type of C57BL/6 mice can be made susceptible to polyarthritis through the expression of NS1. This study is the first to show that a viral agent from the joints in humans can cause CH-induced arthritis resembling RA.

Background. To clarify whether vascular endothelial adhesion molecules in glomeruli might contribute to the severity and diversity of glomerular lesions in lupus nephritis, their expression in lupus models was analyzed. Methods. The expression levels of E- and P-selectin and vascular cell adhesion molecule-1 (VCAM-1) in glomeruli of different histopathologic grades of MRL/MpJ-lpr/lpr (MRL/lpr) lupus mice was studied using laser-capture microdissection of the glomeruli, followed by reverse transcription-polymerase chain reaction (RT-PCR) analysis. The glomerular lesions in SCID mice injected with the 2B11.3 and 7B6. 8 clones, which are derived from an MRL/lpr mouse and induce endocapillary proliferative and wire loop type of glomerular lesions, respectively, were analyzed. To investigate the effect of a soluble form of E-selectin (sE-selectin) on the development of glomerular lesions, sE-selectin-producing L cells were prepared by transfection of the cDNA encoding sE-selectin and injected into SCID mice. Results. The glomeruli in MRL/lpr mice showed increased expression of these adhesion molecules, corresponding to the severity of the glomerular lesions. The endocapillary proliferative type lesions in SCID mice induced by the 2B11.3 clone showed significantly increased expression of the adhesion molecules, especially E-selectin and P-selectin, but the wire loop type lesion induced by the 7B6.8 clone expressed only VCAM-1. Formation of the endocapillary proliferative type lesions induced by the 2B11.3 clone was markedly prevented in association with elevation of the serum level of sE-selectin produced by the tansfected L cells. Conclusion. The severity and diversity of the histopathology of lupus nephritis are partially associated with the expression of vascular endothelial adhesion molecules in glomeruli.

Background. One of the crucial events in lupus nephritis is the glomerular deposition of immunoglobulins (Igs), of which pathogenic properties have been proposed mostly to be either type II or type III allergic reactions. Some of IgG3-producing hybridoma clones established from an MRL/MpTn-gld/gld (MRL/gld) lupus mouse generate wire loop-like lesions in glomeruli resembling lupus nephritis when injected into SCID mice. These clones are useful for analyzing the mechanisms of glomerular deposition of antibodies in lupus nephritis at the monoclonal level. Methods. Glomerular lesions of SCID mice injected with the hybridoma clones, 17H8a or 1G3 as control were analyzed by light and electron microscopy. Interaction of the antibodies with human glomerular endothelial cells (HGECs) and human umbilical vein endothelial cells (HUVECs) in vitro was studied by fluorescence microscopy, electron microscopy, and flow cytometry. Results. Both antibodies did not show any antigen specificity for mouse glomeruli. The glomerular lesions generated by 17H8a, but not by 1G3, contained electron-dense deposits not only in subendothelial regions but also in the cytoplasm of endothelial cells, suggesting internalization of the 17H8a antibodies by endothelial cells. In cell culture studies, internalization of only 17H8a antibodies by HGECs and HUVECs was observed, but the antibodies did not have antigen specificity for both types of endothelial cells. The internalization by HUVECs was mediated by actin polymerization, and it was inhibited by RGDS (Arg-Gly-Asp-Ser) tetrapeptide, antihuman fibronectin and antihuman integrin β1 monoclonal antibodies. Conclusion. The interaction between particular antibodies and endothelial cell surface integrins via fibronectin may be involved in their subsequent internalization by endothelial cells leading to antibody deposition in glomeruli. This may be one of the mechanisms of glomerular injury in lupus nephritis.

BACKGROUND: In systemic lupus erythematosus (SLE), autoreactive B cells are thought to develop by-passing immune checkpoints and contribute to its pathogenesis. Toll-like receptor (TLR) 7 and 9 signaling have been implicated in their development and differentiation. Although some B cell subpopulations such as T-bet + double negative 2 (DN2) cells have been identified as autoreactive in the past few years, because the upregulated surface markers of those cells are not exclusive to them, it is still challenging to specifically target autoreactive B cells in SLE patients. METHODS: Our preliminary expression analysis revealed that phospholipase D4 (PLD4) is exclusively expressed in plasmacytoid dendritic cells (pDCs) and B cells in peripheral blood mononuclear cells (PBMCs) samples. Monoclonal antibodies against human PLD4 were generated, and flow cytometry analyses were conducted for PBMCs from 23 healthy donors (HDs) and 40 patients with SLE. In vitro cell culture was also performed to study the conditions that induce PLD4 in B cells from HDs. Finally, recombinant antibodies were synthesized from subpopulations of PLD4 + B cells from a patient with SLE, and their antinuclear activity was measured through enzyme-linked immunosorbent assay. RESULTS: pDCs from both groups showed comparable frequency of surface PLD4 expression. PLD4 + B cells accounted for only a few percent of HD B cells, whereas they were significantly expanded in patients with SLE (2.1% ± 0.4% vs. 10.8% ± 1.2%, P < 0.005). A subpopulation within PLD4 + B cells whose cell size was comparable to CD38 + CD43 + plasmablasts was defined as "PLD4 + blasts," and their frequencies were significantly correlated with those of plasmablasts (P < 0.005). PLD4 + blasts phenotypically overlapped with double negative 2 (DN2) cells, and, in line with this, their frequencies were significantly correlated with several clinical markers of SLE. In vitro assay using healthy PBMCs demonstrated that TLR7 or TLR9 stimulation was sufficient to induce PLD4 on the surface of the B cells. Finally, two out of three recombinant antibodies synthesized from PLD4 + blasts showed antinuclear activity. CONCLUSION: PLD4 + B cells, especially "blastic" ones, are likely autoreactive B cells undergoing TLR stimulation. Therefore, PLD4 is a promising target marker in SLE treatment.

Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases, characterized by activated macrophages with hemophagocytosis and multiple organ damage. We report a case of MAS associated with systemic lupus erythematosus that initially presented with severe liver dysfunction. Although it was improved with steroids and plasmapheresis, severe pancytopenia was subsequently experienced, and the bone marrow showed severe aplasia similar to aplastic anemia. Nevertheless, the administration of immunosuppressants resulted in the recovery of blood counts within two weeks. When severe MAS results in cytokine overproduction, bone marrow aplasia may occur, for which immunosuppressive therapy may be highly effective.

OBJECTIVES: Methotrexate (MTX) is associated with extensive side effects, including myelosuppression, interstitial pneumonia, and infection. It is, therefore, critical to establish whether its administration is required after achieving remission with tocilizumab (TCZ) and MTX combination therapy in patients with rheumatoid arthritis (RA). Therefore, the aim of this multicenter, observational, cohort study was to evaluate the feasibility of MTX discontinuation for the safety of these patients. METHODS: Patients with RA were administered TCZ, with or without MTX, for 3 years; those who received TCZ+MTX combination therapy were selected. After remission was achieved, MTX was discontinued without flare development in one group (discontinued [DISC] group, n = 33) and continued without flare development in another group (maintain [MAIN] group, n = 37). The clinical efficacy of TCZ+MTX therapy, patient background characteristics, and adverse events were compared between groups. RESULTS: The disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 3, 6, and 9 months was significantly lower in the DISC group (P < .05, P < .01, and P < .01, respectively). Further, the DAS28-ESR remission rate at 6 and 9 months and Boolean remission rate at 6 months were significantly higher in the DISC group (P < .01 for all). Disease duration was significantly longer in the DISC group (P < .05). Furthermore, the number of patients with stage 4 RA was significantly higher in the DISC group (P < .01). CONCLUSIONS: Once remission was achieved, MTX was discontinued in patients who responded favorably to TCZ+MTX therapy, despite the prolonged disease duration and stage progression.

OBJECTIVES: Anti-melanoma differentiation-associated protein-5 (MDA5) autoantibodies (Abs) are associated with rapidly progressive interstitial lung disease (RP-ILD) in dermatomyositis (DM). Because the addition of plasma exchange (PE) and rituximab (RTX) to triple therapy is inadequate in severe cases, we treat such cases with intensive induction therapy (IIT) combining all these options with tofacitinib (TOF). In this study, we investigated the poor prognostic factors and the efficacy and safety of IIT. METHODS: Thirty-three patients diagnosed with anti-MDA5 Ab-positive DM in our institution between 2014 and 2021 were included. The clinical characteristics of poor prognosis were retrospectively analysed using principal component analysis (PCA), and the outcomes of IIT were analysed in terms of survival, assessed using the Kaplan-Meier test, and adverse events. RESULTS: Although triple therapy with RTX, PE, or intravenous immunoglobulin was administered before the introduction of IIT, eight of 12 RP-ILD cases with a ferritin level >400 ng/mL (mean, 2,342) died within a median of 2.5 months. PCA revealed distinct clusters for prognosis, and age and serum ferritin were leading predictors of the prognosis. IIT, consisting of combinations of triple therapy with higher doses of methylprednisolone, PE, RTX, and TOF, was applied to eight patients (mean ferritin, 3,558). Although two patients died even with these regimens, a significant improvement in survival was documented. Several IIT-related adverse events were observed, including viral and fungal infections and cytopenia. CONCLUSIONS: IIT significantly improved the survival of patients with severe anti-MDA5 Ab-positive RP-ILD. Although infections are noted, their benefits outweigh the risks in younger patients with high serum ferritin levels.

There have been many reports on serologic autoantibodies in inflammatory bowel diseases (IBD),1 consisting of ulcerative colitis (UC) and Crohn's disease (CD), and recently Kuwada et al2 reported a new autoantibody against integrin αvβ6 with high sensitivity and specificity for UC. Concurrently, we had discovered autoantibodies against endothelial protein C receptor (EPCR) in Takayasu arteritis (TAK), which is sometimes complicated by UC.3 Interestingly, this autoantibody was found in most patients with TAK associated with UC, and we found that the positivity rate in patients with UC without TAK was also high, suggesting that anti-EPCR antibody is a candidate autoantibody useful for the diagnosis of UC.4 To clarify the diagnostic usefulness of anti-EPCR antibodies in patients with IBD and their relationship to several disease subphenotypes and their disease activities, we analyzed the serum samples from patients with IBD and non-IBD control subjects in Japan and the United States.

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the production of various autoantibodies and deposition of immune complexes on tissues. Acquired thrombotic thrombocytopenic purpura (TTP) is a life-threatening hematological disorder that rarely develops in SLE, mainly caused by inhibitory or clearing autoantibody against ADAMTS13. Although B cells play critical roles in the pathogenesis of two diseases, the role of B-cell depletion therapy using rituximab (RTX), a chimeric monoclonal antibody targeting CD20, in the management of TTP associated with SLE remains unclear. We present a 27-year-old woman who manifested TTP and nephritis simultaneously at diagnosis of SLE. This patient successfully responded to high-dose glucocorticoids combined with plasma exchange, and early administration of RTX-induced sustained remission of TTP without relapse over 16 months. This literature review in light of our case demonstrates relationship between early intervention with RTX and better treatment response despite the degree of ADAMTS13 activity. Moreover, we discuss the clinical features in TTP associated with SLE, risk factors for the development of TTP in SLE, and possible outcomes based on RTX dose. It is important to consider upfront RTX as a promising treatment strategy for SLE-associated secondary TTP to improve short-term response and long-term prognosis.

Although Takayasu arteritis (TAK) is a form of large vessel vasculitis, complications of glomerulonephritis have occasionally been observed, with mesangial proliferative glomerulonephritis as the most common. The aim of this work was to present a case-based review regarding the association of glomerulonephritis and IgA nephropathy (IgAN) with TAK. A literature search was carried out using the PubMed and Scopus databases for articles published in English, and the Ichu-shi Web for Japanese. A 34-year-old Japanese man was evaluated for proteinuria, and IgAN was diagnosed by renal biopsy. Simultaneously, aortic wall thickening and right renal artery stenosis confirmed a coexisting TAK. Prednisolone and methotrexate improved both diseases, and percutaneous transluminal renal angioplasty resulted in right renal artery reopening. Our case and literature review revealed that membranous proliferative glomerulonephritis and IgAN are common in eastern Asia, while focal segmental glomerulosclerosis and mesangial proliferative glomerulonephritis are common in other regions. The incidence of IgAN is higher in TAK cases and is mostly reported in Asia. Abdominal aortic involvement and renal artery stenosis are common in cases with preceding TAK. IgAN could be related to the cytokine network involving interleukin-6, suggesting the usefulness of tocilizumab in patients with TAK accompanied by IgAN. The type of glomerulonephritis complicated with TAK differs among regions, and patients with TAK are more likely to experience IgAN than the healthy population.

We report the first case of proteinase 3 (PR3)- antineutrophil cytoplasmic antibody (ANCA)-positive granulomatosis with polyangiitis (GPA) with predominant ears, nose, and throat (ENT) manifestations following COVID-19 vaccination. A 63-year-old woman presented with aural fullness three days after vaccination. She presented with progressive rhinosinusitis and otitis media leading to profound hearing loss within three weeks. Clinical imaging revealed soft-tissue shadows in the paranasal sinuses with multiple pulmonary nodules, and histopathology was consistent with a diagnosis of GPA. It is crucial to be wary of the possibility of GPA in patients who received COVID-19 vaccines due to its rapid disease progression.

Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic autoimmune disorder classified under anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, predominantly affecting small- to medium-sized vessels, characterized by asthma, eosinophilia, and necrotizing granulomatous inflammation. Most patients with EGPA experience peripheral neuropathy, whereas intracerebral hemorrhage is rare as EGPA-related presentation in central nervous system involvement, causing severe morbidity and mortality. Here, we present a 45-year-old man with refractory EGPA who developed intracerebral hemorrhage as the first manifestation, followed by cardiac involvement. This patient with a history of bronchial asthma developed a right putaminal hemorrhage caused by EGPA. Although intravenous cyclophosphamide (IVCY) and mepolizumab (MPZ) induced remission, relapse was frequently observed. Subsequently, he developed cardiomyopathy despite administration of rituximab (RTX) substituted from IVCY and MPZ. Combined immunosuppressive therapy, including IVCY, MPZ, and RTX was required to inhibit vascular inflammation, leading to sustained remission. We review previously published literature while focusing on the clinical features of patients with intracerebral hemorrhage caused by EGPA and describe clinical characteristics for detecting EGPA in patients with intracerebral hemorrhage, emphasizing rapid evaluation and recognition of EGPA and adequate intervention in the early vasculitic phase of this disease. We also refer to the immunological aspects of this case. It is important to consider "multi-targeted therapy" through interleukin-5 suppression and B cell depletion in the management of refractory EGPA.

Sjögren's syndrome manifests with a wide variety of neurologic symptoms. This case report presents a 53-year-old woman with Sjögren's syndrome associated with temporal hemiplegia, which was suspected to be a transient ischemic attack. After induction of immunosuppressive therapies [high-dose prednisolone (1 mg/kg/day) and intravenous cyclophosphamide (total 5 g)], the hemiplegia did not reappear and the blood flow abnormalities remarkably improved as depicted on electroencephalography and single photon emission computed tomography. This case suggests that temporal hemiplegia presenting with transient ischemia-like attack symptoms may be a neurologic manifestation of Sjögren's syndrome and responsive to immunosuppressive therapy.

LILRB4 (B4, also known as ILT3/CD85k) is an immune checkpoint of myeloid-lineage cells, albeit its mode of function remains obscure. Our recent identification of a common ligand for both human B4 and its murine ortholog gp49B as the fibronectin (FN) N-terminal 30-kDa domain poses the question of how B4/gp49B regulate cellular activity upon recognition of FN in the plasma and/or the extracellular matrix. Since FN in the extracellular matrix is tethered by FN-binding integrins, we hypothesized that B4/gp49B would tether FN in cooperation with integrins on the cell surface, thus they should be in close vicinity to integrins spatially. This scenario suggests a mode of function of B4/gp49B by which the FN-induced signal is regulated. FN pull-down complex was found to contain gp49B and integrin β1 in bone marrow-derived macrophages. The confocal fluorescent signals of the three molecules on the intrinsically FN-tethering macrophages were correlated to each other. When FN-poor macrophages adhered to culture plate, the gp49-integrin β1 signal correlation increased at the focal adhesion, supporting the notion that gp49B and integrin β1 become spatially closer to each other there. While adherence of RAW264.7 and THP-1 cells to immobilized FN induced phosphorylation of spleen tyrosine kinase, whose level was augmented under B4/gp49B deficiency. Thus, we concluded that B4/gp49B can co-tether fibronectin in cooperation with integrin in the cis configuration on the same cell, forming a B4/gp49B-FN-integrin triplet as a regulatory unit of focal adhesion-dependent proinflammatory signal in macrophages.

Although pregnancy is an important risk factor for autoimmune rheumatic diseases, little is known regarding the association between pregnancy and dermatomyositis (DM) or polymyositis (PM). Herein, we present two patients with DM that developed during the perinatal period. The first patient was positive for anti-aminoacyl synthetase (ARS) antibody and developed DM in the 14th week of pregnancy. Despite treatment, her foetus died of intrauterine growth restriction in the 27th week. The second patient was positive for anti-melanoma differentiation-associated gene 5 (MDA-5) antibody and developed DM 1 week after miscarriage at 9 weeks of gestation. The patient developed severe interstitial pneumonia, and intensive therapy including tofacitinib and rituximab administration was required. Our cases and a literature review revealed that various myositis-specific autoantibodies, including anti-ARS, anti-Mi-2, anti-TIF-1γ, and anti-MDA-5, are associated with DM and PM triggered by pregnancy. We also found that delay in commencing treatment in case of active disease including myositis and interstitial pneumonia, and poor response to corticosteroids were related to poor foetal outcomes in DM and PM. Although rare in pregnant women, it is critical to consider the possibility of DM and PM in patients presenting with rash, fever, weakness, and cough, and testing for myositis-specific autoantibodies is recommended.

Relapse of Takayasu arteritis (TAK) is frequent, and the use of biologics is required in refractory cases. Tocilizumab (TCZ), a biological agent used in TAK, is known to increase the incidence of diverticulitis in patients with rheumatoid arthritis. Adverse events of TCZ in TAK have been poorly recognised. This study aimed to investigate the occurrence of severe colitis among patients with TAK receiving TCZ. We enrolled 116 patients with TAK who met the criteria of the American College of Rheumatology and visited our department between 2018 and 2020. The occurrence of severe colitis and its clinical characteristics were retrospectively evaluated. TCZ was introduced in 34 of 116 patients (29.3%). Severe colitis that required hospitalisation was observed in three of the 34 patients receiving TCZ (8.8%). All patients were female and had Numano type V artery lesions, and the ascending colon was commonly affected. Wide lesions that reached the sigmoid colon, colonic perforation, bacteraemia, or positive stool cultures were observed in some patients. All patients received antibiotics and intestinal rest, and TCZ was resumed in one patient. IL-6 plays a physiological role in the intestine, including recovery from ischaemic damage. In addition to infectious aetiology, blocking the physiological roles of IL-6 by TCZ is considered important for the development of colitis in TAK. Severe colitis is an important adverse event in patients with TAK who receive TCZ. The risk of bloodstream infection associated with colitis should be recognised, especially in patients who have undergone vascular surgery. Key Points • Severe colitis was observed in 8.8% of patients with TAK receiving tocilizumab • Patients had type V artery lesions and ascending colon involvement and were under long-term use of corticosteroids • Inhibition of the physiological roles of IL-6 in the intestinal tract might also be involved.

OBJECTIVES: To investigate 6-year drug survival (median: 48.5 months) of golimumab and predictors for lack of efficacy leading to golimumab discontinuation in Japanese patients with rheumatoid arthritis (RA) in routine practice. METHODS: This retrospective single-center study included 60 patients with RA treated with golimumab from November 2011 to August 2020. Patients were divided into 2 groups (retention, n = 28; withdrawal due to lack of efficacy, n = 24). The retention rate was assessed using the Kaplan-Meier method, and variables associated with golimumab discontinuation were identified using the Cox proportional hazard model. RESULTS: The prevalence of concomitant methotrexate and no biologics use was significantly higher in the retention than in the withdrawal group. Overall drug survival of golimumab was 66.3%, 48.3%, and 24.5% at 12, 36, and 72 months, respectively. There were statistical differences in retention rates among groups stratified by initiation dose, methotrexate, and biologics use. Multivariate analysis revealed the factor associated with golimumab discontinuation as history of 1 (hazards ratio: 4.42, 95% CI: 1.35-19.93, P = .012) and ≥2 biologics use (7.49, 1.97-36.27, P = .003). CONCLUSIONS: Prior exposure of increasing number of biologics was identified as the most important factor negatively affecting long-term golimumab retention in Japanese patients with RA.

Hypertrophic pachymeningitis (HP) presents with thickening of the dura mater in the cerebrum and spine, and its symptoms vary depending on the affected location. The association of HP with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis has been recognized, and most cases are complicated by granulomatosis with polyangiitis. We report the case of a 47-year-old man who presented with HP upon relapse of eosinophilic granulomatosis with polyangiitis (EGPA), with literature review. He presented with disturbance of consciousness, and magnetic resonance imaging (MRI) revealed thickening of the dura mater around the left parietal lobe. Although myeloperoxidase (MPO)-ANCA was positive on EGPA diagnosis, the elevation of MPO-ANCA was not documented at the onset of HP. Brain perfusion scintigraphy showed an increase in blood flow in the left parietal lobe and temporal lobe, and electroencephalogram (EEG) revealed slow waves in the left parietal lobe. He was treated with a high dose of corticosteroid and rituximab, and the slow waves on EEG and brain perfusion were normalized. Although the most frequent symptom of HP is headache, disturbance of consciousness can be the manifestation of HP, and inflammation of HP could affect the cerebral parenchyma, which can be documented as abnormal EEG and perfusion scintigraphy. Literature review revealed that most of the HP in EGPA developed when EGPA relapsed, and was observed in patients with MPO-ANCA positivity. HP develops without evidence of other clinical features of EGPA; therefore, adequate imaging, including contrast-enhanced MRI, is necessary. Rituximab may be effective for treating HP complicated with EGPA.

BACKGROUND: Although cyclophosphamide (CPA) is the key drug for the treatment of autoimmune diseases including vasculitides, it has some well-known adverse effects, such as myelosuppression, hemorrhagic cystitis, infertility, and infection. However, CPA-associated severe enteritis is a rare adverse effect, and only one case with a lethal clinical course has been reported. Therefore, the appropriate management of patients with CPA-associated severe enteritis is unclear. CASE SUMMARY: We present the case of a 61-year-old woman diagnosed with granulomatosis with polyangiitis based on the presence of symptoms in ear, lung, and, kidney with positive myeloperoxidase-antineutrophil cytoplasmic antibody. She received pulsed methylprednisolone followed by prednisolone 55 mg/d and intravenous CPA at a dose of 500 mg/mo. Ten days after the second course of intravenous CPA, she developed nausea, vomiting, and diarrhea, and was admitted to the hospital. Laboratory testing revealed hypoalbuminemia, suggesting protein-losing enteropathy. Computed tomography revealed wall thickening of the stomach, small intestine, and colon with contrast enhancement on the lumen side. Antibiotics and immunosuppressive therapy were not effective, and the patient's enteritis did not improve for > 4 mo. Because her condition became seriously exhausted, corticosteroids were tapered and supportive therapies including intravenous hyperalimentation, replenishment of albumin and gamma globulin, plasma exchange, and infection control were continued. These supportive therapies improved her condition, and her enteritis gradually regressed. She was finally discharged 7 mo later. CONCLUSION: Immediate discontinuation of CPA and intensive supportive therapy are crucial for the survival of patients with CPA-associated severe enteritis.

OBJECTIVES: To collect clinical information and NOD2 mutation data on patients with Blau syndrome and to evaluate their prognosis. METHODS: Fifty patients with NOD2 mutations were analysed. The activity of each NOD2 mutant was evaluated in HEK293 cells by reporter assay. Clinical information was collected from medical records through the attending physicians. RESULTS: The study population comprised 26 males and 24 females aged 0-61 years. Thirty-two cases were sporadic, and 18 were familial from 9 unrelated families. Fifteen different mutations in NOD2 were identified, including 2 novel mutations (p.W490S and D512V); all showed spontaneous nuclear factor kappa B activation, and the most common mutation was p.R334W. Twenty-six patients had fever at relatively early timepoints in the disease course. Forty-three of 47 patients had a skin rash. The onset of disease in 9 patients was recognised after BCG vaccination. Forty-five of 49 patients had joint lesions. Thirty-eight of 50 patients had ocular symptoms, 7 of which resulted in blindness. After the diagnosis of Blau syndrome, 26 patients were treated with biologics; all were antitumour necrosis factor agents. Only 3 patients were treated with biologics alone; the others received a biologic in combination with methotrexate and/or prednisolone. None of the patients who became blind received biologic treatment. CONCLUSIONS: In patients with Blau syndrome, severe joint contractures and blindness may occur if diagnosis and appropriate treatment are delayed. Early treatment with a biologic agent may improve the prognosis.

Staphylococcus aureus uses IsdG and IsdI to convert heme into a mixture of staphylobilin isomers, 15-oxo-β-bilirubin and 5-oxo-δ-bilirubin, formaldehyde, and iron. The highly ruffled heme found in the heme-IsdI and IsdG complexes has been proposed to be responsible for the unique heme degradation products. We employed resonance Raman (RR) and electron paramagnetic resonance (EPR) spectroscopies to examine the coordination and electronic structures of heme bound to IsdG and IsdI. Heme complexed to IsdG and IsdI is coordinated by a neutral histidine. The trans ligand is hydroxide in the ferric alkaline form of both proteins. In the ferric neutral form at pH 6.0, heme is six-coordinated with water as the sixth ligand for IsdG and is in the mixture of the five-coordinated and six-coordinated species for IsdI. In the ferrous CO-bound form, CO is strongly hydrogen bonded with a distal residue. The marker lines, ν2 and ν3, appear at frequencies that are distinct from other proteins having planar hemes. The EPR spectra for the ferric hydroxide and cyanide states might be explained by assuming the thermal mixing of the d-electron configurations, (dxy)2(dxz,dyz)3 and (dxz,dyz)4(dxy)1. The fraction for the latter becomes larger for the ferric cyanide form. In the ferric neutral state at pH 6.0, the quantum mechanical mixing of the high and intermediate spin configurations might explain the peculiar frequencies of ν2 and ν3 in the RR spectra. The heme ruffling imposed by IsdG and IsdI gives rise to unique electronic structures of heme, which are expected to modulate the first and subsequent steps of the heme oxygenation.

© 2020 The Author(s). Background: Glucocorticoid-induced osteoporosis and vertebral fracture are common complications in patients on glucocorticoid treatment for rheumatological diseases. The present study aimed to identify the risk factors of vertebral fracture in Japanese female patients with glucocorticoid-induced osteoporosis. Methods: This study included 225 Japanese women with glucocorticoid-induced osteoporosis and 72 patients with postmenopausal osteoporosis. All participants were treated with bisphosphonate or denosumab for osteoporosis with active form of vitamin D for at least 3 years. The differences of clinical parameters, including age, disease duration, body mass index (BMI), bone mineral density (BMD), and the dose and treatment duration of glucocorticoid were assessed between patients with and without vertebral fracture. Multivariate logistic regression analysis was also performed to evaluate the association of vertebral fracture with clinical parameters. Results: The significant differences related to age, BMD of the hip, disease duration, glucocorticoid treatment duration between patients with and without vertebral fractures were demonstrated. The present study indicated that disease duration, BMI, and the total hip BMD were independent risk factors for vertebral fractures in patients with glucocorticoid-induced osteoporosis. Conclusions: Prolonged disease duration, low BMI, and low total hip BMD could be risk factors of vertebral fracture in patients on glucocorticoid treatment for rheumatological diseases.

BACKGROUND: Glucocorticoid-induced osteoporosis and vertebral fracture are common complications in patients on glucocorticoid treatment for rheumatological diseases. The present study aimed to identify the risk factors of vertebral fracture in Japanese female patients with glucocorticoid-induced osteoporosis. METHODS: This study included 225 Japanese women with glucocorticoid-induced osteoporosis and 72 patients with postmenopausal osteoporosis. All participants were treated with bisphosphonate or denosumab for osteoporosis with active form of vitamin D for at least 3 years. The differences of clinical parameters, including age, disease duration, body mass index (BMI), bone mineral density (BMD), and the dose and treatment duration of glucocorticoid were assessed between patients with and without vertebral fracture. Multivariate logistic regression analysis was also performed to evaluate the association of vertebral fracture with clinical parameters. RESULTS: The significant differences related to age, BMD of the hip, disease duration, glucocorticoid treatment duration between patients with and without vertebral fractures were demonstrated. The present study indicated that disease duration, BMI, and the total hip BMD were independent risk factors for vertebral fractures in patients with glucocorticoid-induced osteoporosis. CONCLUSIONS: Prolonged disease duration, low BMI, and low total hip BMD could be risk factors of vertebral fracture in patients on glucocorticoid treatment for rheumatological diseases.

BackgroundGlucocorticoid-induced osteoporosis and vertebral fracture are common complications in patients on glucocorticoid treatment for rheumatological diseases. The present study aimed to identify the risk factors of vertebral fracture in Japanese female patients with glucocorticoid-induced osteoporosis.MethodsThis study included 225 Japanese women with glucocorticoid-induced osteoporosis and 72 patients with postmenopausal osteoporosis. All participants were treated with bisphosphonate or denosumab for osteoporosis with active form of vitamin D for at least 3years. The differences of clinical parameters, including age, disease duration, body mass index (BMI), bone mineral density (BMD), and the dose and treatment duration of glucocorticoid were assessed between patients with and without vertebral fracture. Multivariate logistic regression analysis was also performed to evaluate the association of vertebral fracture with clinical parameters.ResultsThe significant differences related to age, BMD of the hip, disease duration, glucocorticoid treatment duration between patients with and without vertebral fractures were demonstrated. The present study indicated that disease duration, BMI, and the total hip BMD were independent risk factors for vertebral fractures in patients with glucocorticoid-induced osteoporosis.ConclusionsProlonged disease duration, low BMI, and low total hip BMD could be risk factors of vertebral fracture in patients on glucocorticoid treatment for rheumatological diseases.

We report a case of polycythaemia vera (PV) associated with IgA vasculitis. A 45-year-old man was admitted for evaluation of abdominal pain and palpable purpura. IgA vasculitis was diagnosed, and oral prednisolone therapy (30 mg/day) was initiated. On day 6, the patient developed left hemiparesis, and magnetic resonance imaging revealed acute cerebral infarction. Bone marrow biopsy results and the identification of a Janus kinase 2 (JAK2) mutation led to the diagnosis of PV. Despite steroid therapy, urine protein levels increased to 15 g/g・Cre. Renal biopsy demonstrated mild mesangial proliferation with IgA deposits, but immunosuppressive therapy was partially effective. This case suggests that PV can be a complication of IgA vasculitis and that preventive measures for thrombosis should be taken in such cases.

We herein report a case of migratory aortitis after the administration of granulocyte-colony-stimulating factor (G-CSF) to a 65-year-old woman with a history of pancreatic cancer. She was being administered pegfilgrastim and developed aortitis around the aortic arch. Although it resolved within two weeks, she again developed aortitis around the descending aorta, presenting as migratory aortitis, after pegfilgrastim was resumed. We further experienced three additional cases of G-CSF-induced aortitis that also showed spontaneous resolution, suggesting no or short-term use of immunosuppression. Aortitis due to G-CSF can present as migratory aortitis, since aortitis can quickly resolve and inflammation can recur at a different location.

Polymyalgia rheumatica (PMR) is an inflammatory disorder in the elderly and is characterized by pain in the shoulders and lower back. Previous studies from western countries have shown that relapse is frequent; however, there are only a few reports on the relapse rate in Japan. Here we examined the relapse rate, and sought to identify factors that predict recurrence in patients with PMR. Of 110 patients who fulfilled the Bird's criteria for PMR between May 2011 and June 2019, 21 patients were excluded, and the remaining 89 patients were followed up until July 2019. Relapse was defined when clinical symptoms were exacerbated and serum C-reactive protein level increased. The relapse-free survival curves were plotted using the Kaplan-Meier method, and log-rank test was used for statistical analysis. The mean age of the 89 patients (50 males and 39 females) was 71.8 years. The mean dose of initial prednisolone (PSL) was 11.8 mg/day. The 1-, 3-, and 5-year relapse-free survival rates were 81.6%, 58.0%, and 52.3% (N = 59, 21, and 7), respectively. In patients who experienced recurrence, the 1- and 3-year second relapse-free survival rates were 58.3% and 27.3% (N = 18 and 3), respectively. Immunosuppressants, such as methotrexate and tacrolimus, were added to PSL in 19 of 30 patients who experienced relapse at the discretion of the attending physicians; however, none of the immunosuppressants worked for preventing second relapses and had steroid-sparing effects. These results indicate that effective immunosuppressants are required to suppress relapse in the treatment of PMR.

Recently, biological disease-modifying antirheumatic drugs (bDMARDs) have revolutionized the treatment of rheumatoid arthritis (RA) and provided patients with a higher chance of achieving clinical remission. Among them, abatacept (ABT), which selectively inhibits T cell activation through blocking costimulation signal, has been reported efficacious in controlling disease activity. Previous studies have shown that ABT has a high retention rate of up to three years with tolerable adverse events; however, it remains unclear whether this is maintained in the longer term. Here we conducted a retrospective five-year follow-up study to explore prognostic factors concerning better retention. In total, 98 patients who were treated with ABT from May 2011 to July 2019 in Osaki Citizen Hospital were enrolled, including 73 female patients (74.5%). The Kaplan-Meier method was used to estimate the retention rate of ABT. The mean age of ABT initiation was 72.1 years. Concomitant methotrexate was prescribed for 39 patients, and ABT was used as the first-line bDMARD for 65 patients. Rheumatoid factor (RF) was positive in 79 patients. One-, three-, and five-year retention rates of ABT were 83.3%, 66.2%, and 62.7%, respectively. Approximately two-thirds of discontinuation resulted from an inadequate response. Multivariate logistic regression analysis revealed that positive RF was associated with better drug retention. Receiver operating characteristics analysis showed that patients with high RF (≥ 45 IU/mL) had better retention rate of ABT. In conclusion, ABT shows high retention rate among patients with positive RF. The present study may provide better insights when selecting bDMARDs.

Systemic sclerosis (SSc) is characterized by skin sclerosis and multiple organ damages which may cause mortality and is usually accompanied with several specific autoantibodies, each of which is associated with characteristic complications. Among them, anticentriole antibody is recently reported to be highly associated with SSc-associated pulmonary arterial hypertension (SSc-PAH). In general, several vasodilators are used as therapeutic drugs for SSc-PAH, whereas immunosuppressive therapies are not. Here, we report the case of a 62-year-old female with anticentriole antibody-positive SSc-PAH treated with immunosuppressants and vasodilators. She presented with two-year exertional dyspnea and was diagnosed with PAH and SSc owing to the centriole staining pattern and other symptoms without digital sclerosis. Oral vasodilators were initially administered but were not sufficiently effective on dyspnea. Immunosuppressants such as prednisolone and cyclophosphamide were started. Both of them improved mean pulmonary arterial pressure and 6-minute walk distance, and the anticentriole antibody also disappeared. In this case, SSc-PAH with anticentriole antibody was properly diagnosed and immunosuppressants and vasodilators improved the hemodynamics of PAH with anticentriole antibody and stably maintained it and, in addition, reduced the titer of anticentriole antibody. This indicates that anticentriole antibody might represent a good responsive group to therapies among subgroups of patients with SSc-PAH.

Methotrexate (MTX)-associated classical Hodgkin lymphoma (CHL) is unlikely to regress following discontinuation of MTX, and its treatment usually requires chemotherapy. Standard chemotherapy for CHL is the ABVD regimen, which contains pneumotoxic bleomycin. This can be problematic in MTX-CHL patients suffering from an autoimmune disease (AID), such as rheumatoid arthritis (RA), as they frequently have pulmonary complications. However, brentuximab vedotin (BV)-containing chemotherapy without bleomycin (A + AVD regimen) was recently reported to show favorable efficacy for CHL, and could therefore be beneficial in MTX-CHL. We treated three cases of MTX-CHL using the A + AVD regimen. All were female and had received MTX for more than 15 years. Underlying AIDs in these patients were RA in two patients, and overlap syndrome with systemic lupus erythematosus and dermatomyositis in one patient. The A + AVD regimen resulted in a complete response in all patients. Peripheral neuropathy developed in two patients, necessitating reduction of the BV dose. All three patients experienced hematological toxicity necessitating dose reduction; however, no severe adverse effects, including infection or pulmonary complication, were documented. RA was well-controlled without additional immunosuppressants. The A + AVD regimen is a promising chemotherapy for MTX-CHL with favorable efficacy and tolerable toxicity profiles.

Systemic lupus erythematosus (SLE) is an autoimmune disease. It is characterized by the production of various pathogenic autoantibodies and is suggested to be triggered by increased type I interferon (IFN) signature. Previous studies have identified increased plasmablasts in the peripheral blood of SLE patients. The biological characteristics of SLE plasmablasts remain unknown, and few treatments that target SLE plasmablasts have been applied despite the unique cellular properties of plasmablasts compared with other B cell subsets and plasma cells. We conducted microarray analysis of naïve and memory B cells and plasmablasts (CD38+CD43+ B cells) that were freshly isolated from healthy controls and active SLE (n = 4, each) to clarify the unique biological properties of SLE plasmablasts. The results revealed that all B cell subsets of SLE expressed more type I IFN-stimulated genes. In addition, SLE plasmablasts upregulated the expression of cell cycle-related genes associated with higher FOXM1 and FOXM1-regulated gene expression levels than that in healthy controls. This suggests that a causative relationship exists between type I IFN priming and enhanced proliferative capacity through FOXM1. The effects of pretreatment of IFNα on B cell activation and FOXM1 inhibitor FDI-6 on B cell proliferation and survival were investigated. Pretreatment with IFNα promoted B cell activation after stimulation with anti-IgG/IgM antibody. Flow cytometry revealed that pretreatment with IFNα preferentially enhanced the Atk and p38 pathways after triggering B cell receptors. FDI-6 inhibited cell division and induced apoptosis in activated B cells. These effects were pronounced in activated B cells pretreated with interferon α. This study can provide better understanding of the pathogenic mechanism of interferon-stimulated genes on SLE B cells and an insight into the development of novel therapeutic strategies.

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.

OBJECTIVE:Within the spectrum of polyarteritis nodosa (PAN), cutaneous PAN (cPAN) is further classified into mild cPAN and severe cPAN which presents with ulcers, necrosis, or neuritis. As distinguishing between severe cPAN and systemic PAN can be difficult, this study evaluated the clinical characteristics of patients with necrotizing arteritis of medium-sized arteries. METHODS:Forty-one patients diagnosed with necrotizing arteritis of medium-sized arteries between 2008 and 2017 at our institution were enrolled in this study. Clinical background, laboratory findings, treatments, and rates of relapse and death were evaluated. RESULTS:Thirty-six patients were classified as having cPAN (mild, 15; ulcer, nine; neuritis, eight; both, four), and five cases manifested systemic vasculitis. Clinical characteristics of mild cPAN included female predominance (84.6%) and younger age (median 31 years); those of systemic PAN included older age (median 71 years) and higher levels of inflammatory markers. Severe cPAN manifested with intermediate phenotypes. The median doses of prednisolone used to treat mild cPAN, severe cPAN, and systemic PAN were 20.0, 40.0, and 40.0 mg/day, respectively. Immunosuppressants were used in 20.0% of mild cPAN, 90.5% of severe cPAN, and 80.0% of systemic PAN patients. Although the mortality rates were indistinguishable, the relapse rates of severe cPAN (ulcer type) were significantly higher than those of other types (88.9%). CONCLUSION:The clinical characteristics of mild cPAN, severe cPAN (ulcer type), severe cPAN (neuritis type), and systemic PAN were distinct from each other. In particular, patients with severe cPAN (ulcer type) had higher relapse rates, indicating the importance of combination therapy.

A 16-year-old boy, who had been initially examined for bilateral blepharedema and slight eruption, presented with rapidly deteriorating symptoms in associating with headache and consciousness disturbance. He was diagnosed to have primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAE-CTL) by a biopsy of the skin and brain. After whole-brain radiation and some courses of chemotherapy, cord blood transplantation was performed with myeloablative conditioning. After transplantation, the cerebral dysfunction gradually improved. Disease remission was confirmed by the disappearance of any abnormal findings on electroencephalogram and magnetic resonance imaging. PCAE-CTL is reported to be an extremely aggressive disease with a poor prognosis, but the timely performance of cord blood transplantation is considered to be a promising treatment strategy.

© 2018 The Japanese Society of Internal Medicine. We report a rare case of a 27-year-old woman with Takayasu arteritis (TAK) complicated by diffuse sclerosing osteomyelitis. She first presented with sclerosing osteomyelitis of the right mandible without evidence of arteritis in the carotid arteries. Eight months later, she complained of left neck pain, and imaging studies revealed the presence of arteritis in the left carotid artery. She was diagnosed with TAK, and immunosuppressive treatment was initiated, which was effective for both the arteritis and the osteomyelitis. Osteomyelitis is an important complication of TAK and bone scintigraphy is useful for its detection.

A previously healthy 58-year-old man was admitted for muscle pain and weakness [manual muscle testing (MMT) of 4/4 for upper and lower limbs]. We detected elevated levels of inflammatory makers and PR3-anti-neutrophil cytoplasmic antibody (ANCA). Subsequently, the muscle weakness rapidly progressed to an MMT of 2 for all limbs. Magnetic resonance imaging indicated muscle edema, and the creatine kinase (CK) level increased to 29,998 U/L. Methylprednisolone (mPSL) and cyclophosphamide pulse therapy improved the patient symptoms. MMT recovered to 4 for all limbs. A muscle biopsy showed degenerated muscle fibers surrounded by neutrophil-predominant infiltration. In addition, lamina elastic breakdown and fibrinoid necrosis of arterioles were observed. A final diagnosis of microscopic polyangiitis (MPA) limited to the muscles was made.

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 Sjogren'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.

© 2016 Japan College of Rheumatology. Objective: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). Methods: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. Results: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. Conclusions: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by extensive fibrosis and autoantibodies. Its clinical manifestations are diverse and include Raynaud's phenomenon, gastrointestinal dysmotility, interstitial lung disease (ILD), pulmonary hypertension, and renal crisis. Among these, ILD is the primary cause of SSc-related death. It has been considered that acute exacerbation of ILD (AE-ILD) is not common in patients with SSc; however, little is known about the prevalence of AE-ILD in Japanese patients with SSc. In this study, we aimed to clarify the prevalence, clinical characteristics, and prognosis of patients with SSc who developed AE-ILD and to identify predictive factors for AE-ILD in our Japanese cohorts. Clinical data of patients who visited our department from 1990 to 2014 and fulfilled the 2013 classification criteria for SSc were retrospectively reviewed. A total of 139 patients were enrolled. The mean age of onset was 49.1 years, and 113 (81.3%) patients were female; 116 (83.5%) had limited cutaneous involvement, and the overall 10-year survival rate was 92.0%. Among 66 (47.5%) patients with ILD, 13 (9.4%) developed AE-ILD. Patients with AE-ILD had a significantly higher incidence of overlap with polymyositis (PM) or dermatomyositis (DM) and lower prevalence of anticentromere antibodies with higher mortality rate compared with those without AE-ILD. Multivariate Cox regression analysis identified that an overlap with PM or DM was the most significant predictive factor for AE-ILD. Our study results suggest that Japanese patients with SSc, particularly patients overlapped with PM or DM, have a high risk of AE-ILD.

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.

AimAlthough 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 (&gt; 40 years) TAK. MethodsWe 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. ResultsMean 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. ConclusionsThese results suggested that TAK and GCA differed substantially, and that the age restriction ( 40 years) may not be necessary for the diagnosis of TAK.

Systemic lupus erythematosus (SLE) is an autoimmune disease and can cause multi-organ damage. Peritoneal involvement, also called lupus peritonitis, is a rare but sometimes fatal manifestation. Deposition of immune complexes consisting of immunoglobulin G and complement is considered to be involved in the pathogenesis of lupus peritonitis; however, it remains unknown whether inflammatory cytokines contribute to the pathology of this manifestation. Here we present two patients with treatment-resistant lupus peritonitis: a 37-year-old woman with a 26-year history of SLE who had been treated with prednisolone and cyclophosphamide followed by azathioprine and a 65-year-old woman with a 33-year history of SLE who had been treated with prednisolone alone. Both patients were admitted to our department because of abdominal distention. Computed tomography scans showed massive ascites. Ascitic fluid examinations of both patients showed leukocytosis with no evidence of malignancy or infection. After eliminating other causes for ascites, they were diagnosed with lupus peritonitis. Despite the intensified immunosuppressive therapy, they died of uncontrolled peritonitis several months after admission. Examinations of the ascites at admission also revealed a large content of interleukin (IL)-6, compared with other inflammatory cytokines, IL-1 beta and tumor necrosis factor-a. In fact, the ascitic IL-6 levels of these two patients were 12,389 pg/mL and 5,486 pg/mL, much higher than their serum IL-6 levels of 36 pg/mL and 140 pg/mL, respectively. We therefore suggest that IL-6 may contribute to the pathogenesis of lupus peritonitis and that the inhibition of IL-6 signaling may provide a novel therapeutic strategy for lupus peritonitis.

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.

A 59-year-old woman who had been diagnosed with systemic lupus erythematosus (SLE) was admitted to our hospital due to paralysis in all of her limbs. The patient presented with dysarthria, cerebellar ataxia and hypoxia. Magnetic resonance imaging (MRI) revealed vasogenic edema in the brain stem and the cerebellum. She was diagnosed with neuropsychiatric lupus syndrome (NPSLE) and pulmonary arterial hypertension (PAH), and was successfully treated using immunosuppressive therapy. To our knowledge, this is the first reported case of simultaneously developing NPSLE and PAH.

Objective To clarify the prevalence and time course of hepatitis B virus (HBV) infection in patients with systemic lupus erythematosus under immunosuppressive therapy. Methods We performed serological examination of 248 lupus patients to determine the presence of HBV, including hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc). Serum HBV DNA levels were measured in HBsAg-positive patients or resolved HBV carriers (HBsAg-negative, anti-HBs-positive, and/or anti-HBc-positive). If possible, we repeatedly performed examination of markers of HBV infection in resolved carriers. Results Two (0.8 %) patients were positive for HBsAg. Among 41 (16.5 %) patients who were considered as resolved HBV carriers, 1 (2.4 %) showed serum HBV DNA, which indicated occult HBV infection. The mean age and positive rate of anti-double stranded DNA antibody were significantly higher in resolved carriers than in anti-HBs- and anti-HBc-negative patients. Repeated examination showed that the anti-HBs and anti-HBc titer decreased below the threshold in 4 resolved carriers. Conclusions The prevalence of resolved HBV carriers in Japanese lupus patients was 16.5 %. Among them, occult HBV infection and decrease in anti-HBs and anti-HBc titer were observed. These findings indicated that all lupus patients should undergo serological examination for HBV before treatment. If patients have already been treated, we must carefully monitor their liver function, even when all HBV markers are negative.

Here, we present the case of a 74-year-old Japanese man with segmental intestinal necrosis, which developed after treatment with pulsed methylprednisolone for mononeuritis multiplex. The patient was weakly positive for myeloperoxidase (MPO)-anti-neutrophil cytoplasmic antibody (ANCA). Computed tomography and surgical findings were compatible with nonocclusive mesenteric ischemia (NOMI). He underwent small intestinal resection by emergency surgery and an intestinal fistula was made. Pathologically, necrotizing vasculitis with fibrinoid necrosis was present in medium to small-sized arteries, which was equivalent to Arkin's classification II-IV. Most of the arteries had fibrous intimal thickening, which was considered to obstruct the arteries and thus cause segmental intestinal necrosis. A diagnosis of polyarteritis nodosa (PAN) was made, and intravenous cyclophosphamide pulse therapy was added to the therapeutic regimen. This patient was successfully treated with these multidisciplinary therapies and his stoma was finally closed. This is a very rare and indicative case of PAN weakly positive for MPO-ANCA and clinically mimicking NOMI, which occurred even after treatment with pulsed methylprednisolone. (c) 2013 Baishideng. All rights reserved.

Objective. To evaluate the safety and efficacy of ocrelizumab (OCR) in Japanese patients with rheumatoid arthritis (RA) with an inadequate response to methotrexate (MTX). Methods. RA patients with an inadequate response to MTX 6-8 mg/week received an infusion of 50, 200, or 500 mg OCR or placebo on Days 1 and 15 and were observed for 24 weeks. The double-blind period was prematurely terminated because of a possible risk for serious infection from OCR. Results. A total of 152 patients were randomized into the study. The incidence of infection was 37.7% (43/114) in the OCR groups combined, compared to 18.9% (7/37) in the placebo group. Serious infections occurred in 7 patients in the OCR groups combined there were no serious infections in the placebo group. Among the serious infections, Pneumocystis jirovecii pneumonia occurred in 2 patients in the OCR 200 mg group. The American College of Rheumatology 20% response rates at Week 24 (the primary endpoint) of the OCR 50, 200, and 500 mg groups were 54.1% (p = 0.0080), 55.6% (p = 0.0056), and 47.2% (p = 0.044), respectively, all significantly higher than that of the placebo group (25.0%). Conclusion. These results suggest inappropriate benefit-risk balance of OCR in this patient population. Because rituximab is not approved for treatment of RA in Japan, it will be necessary to investigate safety and efficacy of other anti-B cell therapies in Japanese patients with RA. The Journal of Rheumatology Copyright © 2012. All rights reserved.

頭痛・発熱を伴う髄膜炎，口腔潰瘍，陰部潰瘍を初発症状としてBehçet病を発症した一例を経験した．初発時，症状がそろわずBehçet病の確定診断ができなかった．髄膜炎は細菌性を否定できなかったが，神経Behçet病を疑いメチルプレドニゾロンパルス療法にメロペネムを併用し治療したところ翌日には症状はほぼ消失した．神経Behçet病が強く疑われた際は速やかな治療の開始が重要と考えられた．また本例は血清プロカルシトニンが陰性で，細菌性髄膜炎との鑑別に有用と思われた．<br>

A 46-year-old man presented with fever, thrombocytopenia, and a considerable accumulation of ascites. Although prednisolone and intravenous cyclophosphamide pulse (IVCY) were effective, he experienced recurrence. Renal insufficiency and hemolytic anemia developed subsequently. Schistocytes, negative Coombs&apos; test, and elevated lactate dehydrogenase levels indicated thrombotic microangiopathy (TMA). He recovered well after receiving plasma infusion, IVCY, and prednisolone. Renal biopsy revealed subendothelial widening, thereby confirming TMA. This is a very rare case of TMA that presented with a considerable volume of ascites.

Here, we present a 54-year-old man with proptosis and swelling below the left eyelid. Laboratory findings showed high levels of PR3-ANCA and histological examination of the first biopsy revealed acute inflammation. Together with the findings of MRI, a diagnosis of WG was made. However, the disease progressed rapidly and histological examination of the second biopsy revealed infiltration of neoplastic T lymphocytes with aberrant loss of CD7. A final diagnosis of peripheral T cell lymphoma, not otherwise specified (WHO) was made, and complete remission was achieved by chemotherapy. This is a very rare case of T cell lymphoma with a high titer of PR3-ANCA.<br>

Objective. To clarify the direct effect of Tacrolimus (FK506) on T cell function in relation to CD29. Methods. Human T cell line H9 and phytohemagglutinin (PHA)-activated T cells were incubated with or without Tacrolimus. The cells underwent cell migration assay by using fibronectin-coated trans-wells, and at the same time the degree of adherence by cultured cells to fibronectin-coated plastic wells was measured. For H9 cells, intracellular filamentous actin formation and the cell surface expression of CD3, CD11a, CD25, CD26, CD44, CD29 were measured by usingflow cytometry. Intracellular tyrosin-phosphorylation induced by fibronectin by CD29 stimulation in H9 cells was analyzed by immunoblotting. Results. The ability of H9 cells and PHA-activated T cells incubated with Tacrolimus for 2 hours (hrs) to migrate and to adhere to fibronectin was significantly suppressed. However, the inhibiton was transient, because the ability of cells incubated with Tacrolimus for 24 hrs to migrate was not affected despite the suppression of cell replication. Tacrolimus showed slight but significant reduction of cell surface expression of CD29 within 4 hrs, but CD3, CD11a, CD25, CD26 and CD44 were not affected. Tacrolimus rapidly inhibited intracellular filamentous actin formation the maximum inhibition was within 2 hrs and the effect was not observed at 6 hrs. Intracellular tyrosin-phosphorylation induced by CD29 stimulation was also inhibited by Tacrolimus in H9 cells. Conclusion. Tacrolimus appeared to have transient early phase inhibitory effects on CD29-relatedfunction that may be associated with T cell migration.

Carotid intimal-medial thickening was observed in a 23-year-old woman with acute cytomegalovirus (CMV) infection. The thickening disappeared after her recovery from the infection. As endothelial cells are common targets of CMV, this thickening suggests that CMV infection causes vascular lesions, even in otherwise healthy individuals.

A 42-year-old woman with systemic lupus erythematosus (SLE) had an episode of fever, arthralgia and anemia. In order to treat the suspected activation of SLE, the daily dose of steroid was increased, however, the anemia progressed and pancytopenia developed. Both IgM anti-B19 antibodies to human parvovirus B19 (B19) and B19 DNA were positive, and bone marrow analysis revealed pure red cell aplasia with giant proerythroblasts. High dose gamma globulin was administered and the daily dose of steroid was tapered, resulting in the improvement of her condition. B19 infection should be ruled out in cases with reactivation of autoimmune diseases.

Human parvovirus B19 (1319) infects cells of erythroid lineage. Production of neutralizing antibodies (Abs) is indispensable for recovery from B19-related disease state. In this study, we used a convenient method to measure neutralizing activities in human sera by using a real-time quantitative PCR based assay. Erythroid cell line KU812Ep6 was incubated with test sera before infection with B19 virus. The copy number of B19-DNA in cultures was decreased in the presence of the sera from patients who recovered from acute B19 infection, whereas no decrease in B19-DNA was in cultures incubated with sera from healthy volunteers who had no B19 infection. The decrease in B19-DNA copy number was calculated and the inhibition percentage was expressed as neutralizing activity to B19. A clinical study showed that the levels of neutralizing ability were high in patients who recovered soon after acute B19 infection, but were low in some patients with a prolonged clinical course for recovery from B19 infection. This method is simple and convenient compared with methods described previously, showing its usefulness to evaluate the neutralizing activity to B19. (C) 2002 Elsevier Science B.V. All rights reserved.

A 43-year-old woman with systemic lupus erythematosus (SLE) had an episode of mononeuritis multiplex prior to developing protein-losing gastroenteropathy. Four years later, she had another episode of mononeuritis multiplex, followed by choroidopathy. These manifestations are uncommon in SLE, but may be attributed to vasculitis. The laboratory findings indicated that the elevation of D-dimer and thrombin-antithrombin complex levels seen in this case might be useful in evaluating vascular lesions in SLE.

Rheumatoid arthritis (RA) is chronic polyarthritis in which a variety of inflammatory cytokines play a role. Since tumor necrosis factor-alpha (TNF-alpha) is one of the most important cytokines in the pathogenesis of RA, we evaluated the feasibility of ribozymes as a therapeutic agent to control the inflammatory process of RA synovium. A hammerhead ribozyme against TNF-alpha was chemically modified to increase nuclease resistance and added to RA fibroblastlike cell cultures without using a delivery system. The cellular uptake of fluorescent-labeled ribozyme into synovial cells was found to last at least 48 hr by confocal laser scanning microscopy. The ribozyme targeting TNF-alpha gene inhibited both the expression of TNF-alpha mRNA and the secretion of TNF-alpha and IL-6. The cytotoxic effect by the ribozyme on synovial cells was negligible when determined by an alamar blue assay. Chemically modified ribozymes designed to suppress the TNF-alpha gene may be potential as a therapeutic agent for rheumatoid arthritis.