Akio Mimori

A functional variant in FCRL3, encoding Fc receptor-like 3, is associated with rheumatoid arthritis and several autoimmunities

Rheumatoid arthritis is a common autoimmune disease with a complex genetic etiology. Here we identify a SNP in the promoter region of FCRL3, a member of the Fc receptor-like family, that is associated with susceptibility to rheumatoid arthritis (odds ratio = 2.15, P = 0.00000085). This polymorphism alters the binding affinity of nuclear factor-κB and regulates FCRL3 expression. We observed high FCRL3 expression on B cells and augmented autoantibody production in individuals with the disease-susceptible genotype. We also found associations between the SNP and susceptibility to autoimmune thyroid disease and systemic lupus erythematosus. FCRL3 may therefore have a pivotal role in autoimmunity.

A Genome-Wide Association Study Identified AFF1 as a Susceptibility Locus for Systemic Lupus Eyrthematosus in Japanese

Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage. Although recent genome-wide association studies (GWAS) have contributed to discovery of SLE susceptibility genes, few studies has been performed in Asian populations. Here, we report a GWAS for SLE examining 891 SLE cases and 3,384 controls and multi-stage replication studies examining 1,387 SLE cases and 28,564 controls in Japanese subjects. Considering that expression quantitative trait loci (eQTLs) have been implicated in genetic risks for autoimmune diseases, we integrated an eQTL study into the results of the GWAS. We observed enrichments of cis-eQTL positive loci among the known SLE susceptibility loci (30.8%) compared to the genome-wide SNPs (6.9%). In addition, we identified a novel association of a variant in the AF4/FMR2 family, member 1 (AFF1) gene at 4q21 with SLE susceptibility (rs340630; P = 8.3×10−9, odds ratio = 1.21). The risk A allele of rs340630 demonstrated a cis-eQTL effect on the AFF1 transcript with enhanced expression levels (P<0.05). As AFF1 transcripts were prominently expressed in CD4+ and CD19+ peripheral blood lymphocytes, up-regulation of AFF1 may cause the abnormality in these lymphocytes, leading to disease onset.

Endothelin-1 release from cultured endothelial cells induced by sera from patients with systemic lupus erythematosus.

OBJECTIVES--To clarify the pathophysiological role of endothelin-1 (ET-1) in the vascular injury associated with systemic lupus erythematosus (SLE) by investigating the effect of sera from patients with SLE on ET-1 release from cultured human umbilical vein endothelial cells. METHODS--Confluent monolayers of cultured human umbilical vein endothelial cells were incubated with serum samples (diluted 1:10) from 25 patients with SLE and 16 normal controls for two hours at 37 degrees C and ET-1 concentration in the culture supernatant was measured by enzyme immunoassay. RESULTS--The mean release of ET-1 from endothelial cells in the presence of serum from SLE patients was greater than in the presence of serum from normal controls (p < 0.005). ET-1 release from endothelial cells significantly correlated with the titre of IgM anti-endothelial cell antibodies (IgM-AECA) and immune complex concentration in sera from SLE patients (p < 0.05 and p < 0.01, respectively). After gel chromatography of the serum from an SLE patient, those fractions containing IgM-AECA or immune complex were shown to stimulate ET-1 release from endothelial cells. Heat aggregated IgG also stimulated ET-1 release from endothelial cells in a concentration dependent manner. CONCLUSIONS--IgM-AECA and immune complexes may stimulate ET-1 release from endothelial cells and ET-1 may play an important role in the initiation and development of vascular injury, such as pulmonary hypertension and lupus nephritis, in SLE.

Benefit and a possible risk of tocilizumab therapy for adult-onset Still’s disease accompanied by macrophage-activation syndrome

We report a 57-year-old female case of intractable adult-onset Still’s disease (AOSD). Initial high-dose prednisolone therapy was ineffective, and macrophage-activation syndrome (MAS) manifested after one session of additional tocilizumab therapy. After successful treatment for MAS with lipo-dexamethasone and cyclosporin, tocilizumab therapy aided in the rapid reduction of the therapeutic steroid dose. Tocilizumab may be useful for maintenance therapy for AOSD, although its efficacy is unclear for the highly active phase of the disease.

FDG PET for rheumatoid arthritis: basic considerations and whole-body PET/CT

[18F]Fluorodeoxyglucose (FDG) is a tracer for glucose metabolism. Its distribution is not specific to cancer cells but is also observed in inflammatory tissue, including macrophages, capillaries, and fibroblasts. Rheumatoid arthritis (RA) is a systemic, chronic inflammation of the joints resulting in synovitis. The disease is characterized by fibrovascular proliferation leading to the formation of a pannus and causing high FDG uptake. Several clinical studies of RA have demonstrated that FDG uptake in affected joints reflects the disease activity of RA, with strong correlations between uptake and various clinical parameters having been noted. Furthermore, the use of FDG PET for the sensitive detection and monitoring of the response to RA therapy has been reported. FDG PET/computed tomography (CT) enables the detailed evaluation of disease in large joints throughout the whole body, which is a unique advantage of PET/CT. FDG PET/CT can also be used to detect high‐risk disease complications, such as atlanto‐axial joint involvement, at an early stage. The possible contribution of FDG PET to the management of patients with RA remains to be studied in detail.

Expression of BAFF and BAFF-R in the synovial tissue of patients with rheumatoid arthritis.

Objective: The elevated expression of B‐cell‐activating factor belonging to the TNF family (BAFF) is associated with systemic autoimmune disease, including rheumatoid arthritis (RA). The present study was undertaken to determine the distribution of BAFF and its receptor BAFF‐R in the cells residing in the rheumatoid synovium. Methods: The expression of BAFF and BAFF‐R in synovial tissues obtained from 12 RA patients was examined by immunohistochemistry and flow cytometry. The mRNA expression of these molecules was determined by reverse transcriptase polymerase chain reaction (RT‐PCR). Soluble BAFF levels were measured with an enzyme‐linked immunosorbent assay (ELISA). Fibroblast‐like synoviocytes (FLS) purified from the RA (RA‐FLS) were co‐cultured with peripheral B cells. The degree of apoptosis in the B cells was measured to assess the effects on the viability of the B cells. Results: The RA synovium showed focal or diffuse infiltration of mononuclear cells (MNCs), and one specimen showed germinal centre (GC)‐like structures. Synovial sublining cells, but not lining cells, expressed BAFF. These sublining cells were negative for BAFF‐R. BAFF and BAFF‐R were expressed in B and T cells extracted from the RA synovium. Notably, RA‐FLS spontaneously expressed cytoplasmic BAFF after 4–6 passages; however, they did not express BAFF or BAFF‐R on their cell surface. RA‐FLS could support the survival of B cells by preventing their apoptosis, but its effect on B cells might not be BAFF dependent. Conclusions: BAFF and BAFF‐R are widely expressed in the RA synovium. The cells residing in the RA synovium might affect each other through BAFF.

Similarities and differences in fluorodeoxyglucose positron emission tomography/computed tomography findings in spondyloarthropathy, polymyalgia rheumatica and rheumatoid arthritis

OBJECTIVES We assessed fluorine-18 ((18)F)-labelled fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) findings in patients with seronegative spondyloarthritis (SpA), polymyalgia rheumatica (PMR), and rheumatoid arthritis (RA). METHODS We studied 53 patients with SpA (n=21), PMR (n=16), or RA (n=16) admitted to our hospital between 2006 and 2011. Disease activity in the ischial tuberosities, greater trochanters, spinous processes, vertebral bodies, and sacroiliac joints (SIJ) were evaluated by determining FDG accumulation using maximum standardized uptake values (SUV(max)) and FDG scores. RESULTS SUV(max) for ischial tuberosities was significantly higher in PMR than SpA or RA. SUV(max) for greater trochanters and spinous processes was significantly higher in PMR than RA (P<0.001) and significantly higher in SpA than in PMR or RA for SIJ (P=0.01). No significant difference in vertebral scores was observed among groups (P=0.488). FDG scores yielded similar results. X-ray findings were consistent with PET/CT findings in 3/15 (20%) patients with sacroiliitis, whereas magnetic resonance imaging findings were consistent with PET/CT findings in 4/7 (57.1%) patients. CONCLUSIONS PET/CT detection of inflammation in the ischial tuberosities, greater trochanters, and spinous processes discriminated between PMR and RA, but not between SpA and PMR. PET/CT findings can distinguish SpA from RA and PMR and are useful for the early diagnosis of sacroiliitis.

Subarachnoid hemorrhage and systemic lupus erythematosus

The frequency, clinical profile, treatment and outcome of subarachnoid hemorrhage (SAH) in patients with systemic lupus erythematosus (SLE) were assessed retrospectively, based on the case records of SLE of the Jichi Medical School Hospital over a 20 year period. Clinically defined SAH was found in 10 (3.9%) out of 258 SLE patients, which represented a frequency higher than previously assumed. Five patients had active SLE and lacked an apparent cause of SAH, other than SLE. A high mortality rate (5=5), no visible aneurysm on angiogram (3=4), and an onset during intractable SLE or after discontinued or no steroid therapy because of medical noncompliance (4=5) were characteristic of patients with active SLE, and thus an earlier successful suppression of SLE, if possible, might have prevented their SAH. In contrast, in the 5 patients with inactive SLE, 2 out of 3 saccular aneurysms were succcessfuly clipped and small bleeding of one patient without aneurysms remitted spontaneously without the need for additional steroid therapy. When one death, which occurred outside of medical care, was excluded, the survival ratio of the hospitalized SAH patients with inactive SLE was significantly better than that with active SLE (3=4 versus 0=5, P ‘ 0.0476). In conclusion, the relatively common occurence of SAH in SLE patients, and a significantly different clinical impact of SAH in respect to active and inactive SLE, were suggested from the results.

Induction of long interspersed nucleotide element-1 (L1) retrotransposition by 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct

Long interspersed nucleotide element-1 (L1) is a retroelement comprising about 17% of the human genome, of which 80–100 copies are competent as mobile elements (retrotransposition: L1-RTP). Although the genetic structures modified during L1-RTP have been clarified, little is known about the cellular signaling cascades involved. Herein we found that 6-formylindolo[3,2-b]carbazole (FICZ), a tryptophan photoproduct postulated as a candidate physiological ligand of the aryl hydrocarbon receptor (AhR), induces L1-RTP. Notably, RNA-interference experiments combined with back-transfection of siRNA-resistant cDNAs revealed that the induction of L1-RTP by FICZ is dependent on AhR nuclear translocator-1 (ARNT1), a binding partner of AhR, and the activation of cAMP-responsive element-binding protein. However, our extensive analyses suggested that AhR is not required for L1-RTP. FICZ stimulated the interaction of the L1-encoded open reading frame-1 (ORF1) and ARNT1, and recruited ORF1 to chromatin in a manner dependent on the activation of mitogen-activated protein kinase. Along with our additional observations that the cellular cascades for FICZ-induced L1-RTP were different from those of L1-RTP triggered by DNA damage, we propose that the presence of the cellular machinery of ARNT1 mediates L1-RTP. A possible role of ARNT1-mediated L1-RTP in the adaptation of living organisms to environmental changes is discussed.

Clinical value of whole-body PET/CT in patients with active rheumatic diseases

Advanced imaging techniques may enable early diagnosis and monitoring of therapy in various rheumatic diseases. To prevent irreversible tissue damage, inflammatory rheumatic disease must be diagnosed and treated in pre-clinical stages, requiring highly sensitive detection techniques. Positron emission tomography (PET) provides highly sensitive, quantitative imaging at a molecular level, revealing the important pathophysiological processes underlying inflammation. This review provides an overview of the current utility of 18 F-fluorodeoxyglucose (FDG)-PET/computed tomography (CT) in patients with active rheumatic diseases such as rheumatoid arthritis, spondyloarthritis, polymyalgia rheumatica, adult-onset Stills disease, relapsing polychondritis, immunoglobulin G4-related disease, large-vessel vasculitis, Wegeners granulomatosis, polymyositis, and dermatomyositis. We also discuss the role of FDG-PET/CT in the diagnosis and monitoring of these diseases.