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Avacopan, an orally administered C5a receptor antagonist, is effective in microscopic polyangiitis via the inhibition of neutrophil priming induced by C5a. However, the exact effect of avacopan on the production of myeloperoxidase antineutrophil cytoplasmic antibody (MPO-ANCA) is yet to be clearly established. This report presents a microscopic polyangiitis patient without major organ damage where high levels of MPO-ANCA persisted with high-dose steroid therapy and azathioprine, but the addition of avacopan led to a reduction in MPO-ANCA titres. The present case implies that avacopan-mediated inhibition of C5a may lead to a reduction in MPO-ANCA levels, thereby potentially ameliorating the pathophysiology of ANCA-associated vasculitis. Nevertheless, the impact of avacopan on MPO-ANCA production cannot be asserted solely based on this report; therefore, further examination is necessary through subgroup analysis using data from larger-scale studies.

Objective: Antimelanoma differentiation-associated gene 5 (anti-MDA5)-positive dermatomyositis with interstitial lung disease (DM-ILD) progresses rapidly and has a poor prognosis. Previously, we reported the efficacy of a combination therapy comprising high-dose glucocorticoids (GCs), calcineurin inhibitors (CNIs), and intravenous cyclophosphamide (IV CYC) in a multicenter clinical trial (UMIN000014344). In the present study, we evaluated the long-term outcomes and effects of induction therapy on the maintenance of remission. Methods: All participants from our previous trial were followed up for > 5 years. Seventy-three other patients with anti-MDA5–positive DM-ILD from our institute were retrospectively integrated into the previous trial for further analysis. Sixty-eight patients achieved remission and survived for > 6 months. Based on the induction treatment, we classified the patients into 2 groups: (1) group T (n = 56), with triple combination therapy (GCs, CNIs, and IV CYC), and (2) group C (n = 12), with monotherapy/dual therapy. The recurrence-free and drug-withdrawal rates of immunosuppressive agents were compared. Results: The overall survival and recurrence-free survival rates at 5 years were 100% for the participants in the previous trial. The 5-year cumulative withdrawal rates for CNIs and GCs were 70% and 53%, respectively. In a comprehensive analysis, the recurrence-free rates in group T were higher than those in group C(90% vs 56%; P < 0.05). The drug-withdrawal rates of CNIs and GCs at 10 years in group T were also higher than those in group C(79% vs 0% and 43% vs 0%, respectively; P < 0.05). Conclusion: Triple combination therapy in the induction phase can reduce the risk of recurrence and facilitate drug withdrawal in anti-MDA5-positive DM-ILD.

Immunoglobulin (Ig) G4 is an IgG subclass that can exhibit inhibitory functions under certain conditions because of its capacity to carry out Fab-arm exchange, inability to form immune complexes, and lack of antibody-dependent and complement-dependent cytotoxicity. Although several diseases have been associated with IgG4, its role in the disease pathogeneses remains unclear. Since mice do not express an IgG subclass that is identical to the human IgG4 (hIgG4), we generated hIGHG4 knock-in (KI) mice and analyzed their phenotypes. To preserve the rearrangement of the variable, diversity, and joining regions in the IGH gene, we transfected a constant region of the hIGHG4 gene into C57BL/6NCrSlc mice by using a gene targeting method. Although the mRNA expression of hIGHG4 was detected in the murine spleen, the serum level of the hIgG4 protein was low in C57BL/6-IgG4KI mice. To enhance the production of IgG4, we established an MRL/lpr-IgG4KI mice model by backcrossing. These mice showed a high IgG4 concentration in the sera and increased populations of IgG4-positive plasma cells and CD3+B220+CD138+ T cells in the spleen. Moreover, these mice showed aggravated inflammation in organs, such as the salivary glands and stomach. The MRL/lpr-IgG4KI mouse model established in the present study might be useful for studying IgG4-related disease, IgG4-type antibody-related diseases, and allergic diseases.

[Background] Although the survival rates of patients with relapsing polychondritis (RP) have increased remarkably, the high recurrence rate remains a significant concern for physicians and patients. This retrospective study aimed to investigate the risk factors for RP recurrence. [Methods] Patients with RP who presented to Kyoto University Hospital from January 2000 to March 2020 and fulfilled Damiani’s classification criteria were included. Patients were classified into recurrence and non-recurrence groups. Risk factors for RP recurrence were analysed using a Cox proportional hazards model, and Kaplan–Meier survival curves were drawn. [Results] Thirty-four patients were included. Twenty-five patients (74%) experienced 64 recurrences (mean: 2.56 recurrences per patient). The median duration before the first recurrence was 202 [55−382] days. The median prednisolone dose at the initial recurrence was 10 [5−12.75] mg/day. Tracheal involvement was significantly more frequent in the recurrence group at the initial presentation (44.0% vs. 0.0%, p=0.0172) than in the non-recurrence group, and pre-treatment C-reactive protein levels were significantly higher in the recurrence group than in the non-recurrence group (4.7 vs 1.15 mg/dL, p=0.0024). The Cox proportional hazards model analysis revealed that tracheal involvement (hazard ratio [HR] 4.266 [1.535−13.838], p=0.0048), pre-treatment C-reactive protein level (HR 1.166 [1.040−1.308], p=0.0085), and initial prednisolone monotherapy (HR 4.443 [1.515−16.267], p=0.0056) may be associated with recurrence. The median time before the initial recurrence was significantly longer in patients who received combination therapy with prednisolone and immunosuppressants or biologics (400 vs. 70 days, p=0.0015). [Conclusions] Tracheal involvement, pre-treatment C-reactive protein level, and initial prednisolone monotherapy were risk factors for recurrence in patients with RP. Initial combination therapy with prednisolone and immunosuppres

OBJECTIVES: Numerous case reports have referred to new onset or flare of SLE after SARS-CoV-2 messenger RNA (mRNA) vaccines. Several observational studies showed that the short-term flare rate of SLE after SARS-CoV-2 vaccination is low. However, well-controlled clinical surveys are unavailable and the medium-term impact of the SARS-CoV-2 mRNA vaccines against the flare of SLE is uncertain. Therefore, we aimed to analyse the association between vaccination and medium-term subjective and objective disease activities of SLE and flares using matched pair methods. METHODS: Altogether, 150 patients with SLE from the Kyoto Lupus Cohort were included. Patients who received two doses of the SARS-CoV-2 mRNA vaccines were 1:1 matched with unvaccinated patients based on the first vaccination date. The outcome measures were the SLE Disease Activity Index-2000 (SLEDAI-2K), the Japanese version of the SLE Symptom Checklist Questionnaire (SSC-J) and the Safety of Estrogens in Lupus Erythematosus National Assessment-SLEDAI flare index at 30, 60 and 90 days after vaccination. RESULTS: SLEDAI-2K levels were not significantly different in vaccinated and unvaccinated patients with SLE at 30, 60 and 90 days after the second vaccination (adjusted estimate (95% CI): 30 days: -0.46 (-1.48 to 0.56), p=0.39; 60 days: 0.38 (-0.64 to 1.40), p=0.47; 90 days: 0.40 (-0.54 to 1.34), p=0.41). Similar results were observed in the SSC-J score (adjusted estimate (95% CI), 30 days: 0.05 (-1.46 to 1.56), p=0.95; 60 days: -0.63 (-2.08 to 0.82), p=0.40; 90 days: 0.27 (-1.04 to 1.58), p=0.69) and flare index (adjusted OR (95% CI), 30 days: 0.81 (0.36 to 1.85), p=0.62; 60 days: 1.13 (0.50 to 2.54), p=0.77; 90 days: 0.85 (0.32 to 2.26), p=0.74). CONCLUSION: SARS-CoV-2 vaccination did not significantly influence the medium-term subjective and objective disease activities or flares of SLE until 90 days after the second vaccination.

The mature form of sterol regulatory element-binding protein (SREBP)1 is a transcription factor involved in lipid synthesis, which participates in toll like receptor 4-triggered inflammatory pathways during the resolution phase of inflammation in macrophages. SREBP1 has thus attracted interest as a candidate target molecule for ameliorating inflammation. Fatostatin is a small molecule that inhibits the maturation and function of SREBP, and its role in regulating inflammation is poorly understood. To evaluate the anti-inflammatory effect of fatostatin, we compared body weight, footpad and hock dimensions, and arthritis scores between K/BxN serum-induced arthritis mice treated with fatostatin and those treated with dimethyl sulfoxide as the vehicle control. We performed hematoxylin and eosin staining of joints of distal paws to assess tissue inflammation. Moreover, inflammatory cytokine production levels and cell viability were measured in lipopolysaccharide-responsive human embryonic kidney 293 cells (293/hTLR4A-MD2-CD14 cells) after fatostatin administration. In K/BxN serum-induced arthritis mice, fatostatin treatment significantly reduced the arthritis scores and hyperplasia. In vitro analysis revealed that fatostatin significantly inhibited the secretion of inflammatory cytokines from cells activated with lipopolysaccharide, without affecting cell viability. This is the first study to demonstrate that fatostatin is an anti-inflammatory agent that modulates the processing of lipid transcription factors without affecting cell viability. Accordingly, the study reveals the potential of anti-inflammatory therapeutics that link lipid regulation and inflammation.

[Background] Relapsing polychondritis (RP) is a rare inflammatory disease characterized by recurrent inflammation and destruction of cartilaginous tissues. RP has characteristics of autoimmune disease and some reports have noted co-occurrence with autoimmune thyroid disease (AITD), consisting of Graves’ disease (GD) and Hashimoto thyroiditis (HT). However, there have been no detailed studies on the co-occurrence of RP and AITD. In this study, we aimed to determine whether patients with RP tend to be complicated with AITD. We also analyzed the clinical and genetic profiles of patients in whom these diseases co-occur. [Methods] We recruited 117 patients with RP and reviewed their medical records. Furthermore, we genotyped Human Leucocyte Antigen (HLA)-A, B Cw, DRB1, DQB1, and DPB1 alleles for 93 of the 117 patients. The prevalence of AITD among the patients with RP was compared with that among the general Japanese population. We also analyzed the clinical and genetic features of the patients with both RP and AITD. [Results] The prevalence of GD among the patients with RP was 4.3% (5 among 117 patients), significantly higher than that among Japanese (0.11%) (p = 2.44 × 10–7, binomial test). RP patients with GD tended to have nasal involvement (p = 0.023) (odds ratio (OR) 2.58) and HLA-DPB1*02:02 (p = 0.035, OR 10.41). We did not find significant enrichment of HT in patients with RP. [Conclusions] Patients with RP appear to be at elevated risk of GD. Nasal involvement and HLA-DPB1*02:02 characterize the subset of RP patients with GD, which may guide attempts to characterize a distinct subtype of RP for precision medicine.

BACKGROUND: Pulmonary artery involvement (PAI) in Takayasu arteritis (TAK) can lead to severe complications, but the relationship between the two has not been fully clarified. METHODS: We retrospectively investigated 166 consecutive patients with TAK who attended Kyoto University Hospital from 1997 to 2018. The demographic data, clinical symptoms and signs, comorbidities, treatments, and imaging findings were compared between patients with and without PAI. TAK was diagnosed based on the American College of Rheumatology Classification Criteria (1990) or the Japanese Clinical Diagnostic Criteria (2008). PAI was identified using enhanced computed tomography, magnetic resonance imaging, or lung scintigraphy. RESULTS: PAI was detected in 14.6% (n = 24) of total TAK patients. Dyspnea (25.0% vs. 8.6%; p = 0.043), pulmonary arterial hypertension (PAH) (16.7% vs. 0.0%; p < 0.001), ischemic heart disease (IHD) (29% vs. 9.3%; p = 0.018), respiratory infection (25.0% vs. 6.0%; p = 0.009), and nontuberculous mycobacteria (NTM) infection (20.8% vs. 0.8%; p < 0.001) were significantly more frequent, and renal artery stenosis (0% vs. 17%; p = 0.007) was significantly less frequent in TAK patients with PAI than in those without PAI. PAI and biologics were risk factors for NTM. CONCLUSIONS: TAK patients with PAI more frequently have dyspnea, PAH, IHD, and respiratory infection, including NTM, than TAK patients without PAI.

Pulmonary arterial hypertension (PAH) is a rare complication of ANCA-associated vasculitis (AAV). We report a 37-year-old man with PAH complicated by both AAV and SSc who presented with dyspnea, cardiac enlargement, positive myeloperoxidase (MPO)-ANCA, anti-centromere antibodies, proteinuria, and urinary casts. Elevated pulmonary arterial pressure (58/22/34 mmHg) and low PAWP (2 mmHg) were confirmed by right heart catheterization. Treatment with glucocorticoids (GC) decreased urinary protein and serum MPO-ANCA; however, PAH did not respond to GC. Therefore, a combination of beraprost, bosentan, and tadalafil was needed. The differences in responses to GC suggest that the pathophysiology of nephropathy is different from that of PAH. We considered that nephropathy was associated with AAV but that PAH was associated with SSc in the present case. We discuss the pathophysiology and treatment response of PAH complicated by AAV, referring to nine past cases.

The pathomechanisms and treatment strategy for rare presentations of reversible cerebral vasoconstriction syndrome (RCVS) with anti-phospholipid syndrome (APS) remain to be determined. We report a 67-year-old woman with APS who presented with ischemic stroke due to RCVS. She was treated with low-dose cilostazol and lomerizine hydrochloride, which resulted in functional improvement and recovery of vasoconstriction within 12 weeks. Her plasma endothelin-1 level was decreased after relief of vasoconstriction, compared with the pre-treatment condition. Increased plasma endothelin-1 may be related to the underlying pathomechanism of RCVS with APS, against which cilostazol and lomerizine hydrochloride could be effective.

Glucocorticoids (GC) are effective for treating IgG4-related disease (IgG4-RD); however, relapse is often observed. We conducted a retrospective multicentre study to investigate risk factors in GC regimens associated with relapses of IgG4-RD. Data on 166 patients with definitive IgG4-RD diagnosis were collected from 12 institutions. Comprehensive surveillance of clinical backgrounds and GC regimens as well as multivariate analysis of factors associated with treatment responses and relapses was performed. To determine the initial maximal GC dose, the patients were stratified into three groups depending on the initial prednisolone (PSL) dosage: <0.39, 0.4–0.69 and >0.7 mg/kg/day. The multivariate analysis extracted the disease duration and reduction speed of initial GC dose. Patients treated with initial GC <0.39 or >0.7 mg/kg/day of PSL showed higher relapse rates than those treated with 0.4–0.69 mg/kg/day. The relapse rates were significantly higher in patients with fast reduction of the initial dose (>0.4 mg/day) than in patients with slow reduction (<0.4 mg/day). To avoid relapse, 0.4–0.69 mg/kg/day of initial PSL with slow reduction speed (<0.4 mg/day) is needed in the early treatment of IgG4-RD.

Anti-centromere antibody (ACA) is one of the classical anti-nuclear antibody (ANA) staining patterns. However, characteristics of ACA in comparison with the other ANA patterns and clinical features of ACA-positive subjects have not been elucidated. Here, we examined all ANA patterns by indirect immunofluorescence for 859 rheumatoid arthritis (RA) patients. Together with the ANA data of 9, 575 healthy volunteers, we compared distributions of the ANA levels. ACA was the only ANA that demonstrated a definite bimodal distribution of levels. ACA showed significantly higher levels than the other ANA staining patterns in both RA and healthy population (p < 0.0001). ACA-positivity was associated with old age and was observed more in females. We further recruited another cohort of 3, 353 RA patients and confirmed the findings. ACA was also associated with Raynaud’s phenomenon (p = 6.8 × 10−11) in RA. As a conclusion, ACA displays a specific ANA staining pattern with a bimodal distribution, and ACA-positive RA may constitute a distinct subset with specific clinical features.

We assessed the utility of two forms of osteopontin (OPN), OPN full and its cleaved form (OPN N-half), in plasma and urine as markers of disease activity in lupus nephritis (LN). Samples were collected from patients with systemic lupus erythematosus (SLE) (LN: N = 29, non- LN: N = 27), IgA nephropathy (IgAN) (N = 14), minimal change nephrotic syndrome (MCNS) (N = 5), diabetic nephropathy (DN) (N = 14) and healthy volunteers (HC) (N = 17). While there was no significant difference in urine OPN full concentration between groups, urine OPN N-half concentration was significantly higher in patients with LN than HC (p < 0.05). Moreover, urine OPN N-half was higher in LN patients with overt proteinuria (urine protein/ creatinine ratio: P/C > 0.5) than LN patients with minimal proteinuria (P/C < 0.5, p < 0.0001), and also higher than in DN patients with overt proteinuria (P/C > 0.5, p < 0.01). Urine thrombin activity correlated with urine OPN N-half concentration (p < 0.0001), but not with urine OPN full concentration. These results suggest that urine OPN N-half concentration reflects renal inflammation. Thus, urine OPN N-half may be a novel disease activity marker for LN.

Hereditary hemochromatosis (HH) is an inherited disorder usually seen in Northern Europeans, which results in iron overload syndrome. A few cases have also been reported in Japan. We herein report a Japanese man presenting with fever, arthritis, liver dysfunction, and hyperferritinemia who was diagnosed with type 4 HH. He was heterozygous for the 1520A>G (His507Arg) mutation in the ferroportin-1 gene (SLC40A1). He had a familial cataract as an infant, but hereditary hyperferritinemia cataract syndrome was excluded. This is the first report of type 4 HH with juvenile cataracts and suggests that there is an association between hyperferritinemia and early cataract formation.

Objective It is well known that grapefruit juice (GFJ) elevates the blood tacrolimus (TAC) concentration. We investigated the efficacy and safety of GFJ intake with TAC in cases of connective tissue diseases in which the TAC blood concentration was insufficiently high for clinical improvement, even when 3 mg/day or more of TAC was administered. Methods Seven patients took 200 mL of GFJ every day. The trough levels of the TAC blood concentration were measured before and after GFJ intake and the clinical courses were monitored thereafter. Results First, we surveyed the blood TAC trough levels of 30 recent patients who took 3 mg/day of TAC, and found that 21 patients (70%) did not achieve the minimum target TAC concentration (>5 ng/mL). Seven patients took GFJ due to a lack of efficacy and a relatively low TAC blood concentration. GFJ increased the TAC level from 4.3±2.4 ng/mL to 13.8±6.9 ng/mL (average increase: 3.3-fold). GFJ was also effective in achieving a clinical improvement in most cases without causing any severe adverse events, and it helped to decrease the dosages of glucocorticoid and TAC. In some cases, the blood TAC concentration fluctuated for no apparent reason. Conclusion GFJ intake was effective for the elevation of TAC concentration by approximately three fold and clinical improvement, but special care is required for monitoring its influence on concomitantly used drugs as well as TAC concentration. The addition of GFJ to TAC treatment could be an efficacious treatment option, when the plasma TAC concentration does not reach the minimal target concentration.

Objective: To examine how connective tissue diseases affect finger-vein pattern authentication. Methods: The finger-vein patterns of 68 patients with connective tissue diseases and 24 healthy volunteers were acquired. Captured as CCD (charge-coupled device) images by transmitting near-infrared light through fingers, they were followed up in once in each season for one year. The similarity of the follow-up patterns and the initial one was evaluated in terms of their normalized cross-correlation C. Results: The mean C values calculated for patients tended to be lower than those calculated for healthy volunteers. In midwinter (February in Japan) they showed statistically significant reduction both as compared with patients in other seasons and as compared with season-matched healthy controls, whereas the values calculated for healthy controls showed no significant seasonal changes. Values calculated for patients with systemic sclerosis (SSc) or mixed connective tissue disease (MCTD) showed major reductions in November and, especially, February. Patients with rheumatoid arthritis (RA) and patients with dermatomyositis or polymyositis (DM/PM) did not show statistically significant seasonal changes in C values. Conclusions: Finger-vein patterns can be used throughout the year to identify patients with connective tissue diseases, but some attention is needed for patients with advanced disease such as SSc.

[Background]Immunoglobulin (Ig) G4-related disease (IgG4-RD) is characterized by elevated serum IgG4 and infiltration of IgG4+ plasma cells into multiple organs. It is not known whether serum IgG4 is autoreactive in IgG4-RD. [Methods]We measured anti-nuclear antibody (ANA) in 19 IgG4-RD cases, determined IgG subclasses of the ANA, and compared them with those of other systemic autoimmune diseases (systemic lupus erythematosus, Sjögren’s syndrome, systemic sclerosis, and polymyositis), using subclass-based ANA test (indirect immunofluorescence). [Results]58 % of IgG4-RD cases were ANA-positive (cut-off: 1:40). Whereas their subclass of ANA was predominantly IgG2, we observed no IgG4-type ANA. In systemic autoimmune diseases, subclasses of ANA were mostly IgG1, 2, or 3, but IgG4-type ANA was very rarely detected. We also found several patients in whose serum ANA patterns differed among IgG subclasses, probably due to the difference of corresponding autoantigens. [Conclusions]Although IgG4 is highly elevated in sera of IgG4-RD patients, their ANA do not include IgG4 subclass. These results offer new insight into the role of IgG4 and the pathogenesis of IgG4-RD, implying that each IgG subclass tends to cover its own spectrum of antigens, and IgG4 is not preferentially used to make ANA.

Although the association between CYP3A5 polymorphism and blood concentration of tacrolimus (TAC) in patients with solid organ transplantation was established, whether the association is also true in patients with connective tissue disease (CTD) who usually receive small amount of TAC is uncertain. Here, we performed a quantitative linear regression analysis to address the association between CYP3A5 and blood TAC concentration in patients with CTD. A total of 72 patients with CTD were recruited in the current study and genotyped for rs776746 in CYP3A5, which showed strong association with TAC concentration in patients with solid organ transplantation. The blood trough concentration of TAC after taking 3 mg per day was retrospectively obtained for each patient. As a result, allele A of rs776746 showed a significant association with a decreasing blood concentration of TAC (P=0.0038). Those who are carrying at least one copy of the A allele displayed decreased mean concentration of TAC by 31.0% compared with subjects with GG genotype. Rs776746 is associated with concentrations of TAC in patients with CTD.

Rheumatoid arthritis (RA) is a joint-destructive autoimmune disease. Three composite indices evaluating the same 28 joints are commonly used for the evaluation of RA activity. However, the relationship between, and the frequency of, the joint involvements are still not fully understood. Here, we obtained and analyzed 17,311 assessments for 28 joints in 1,314 patients with RA from 2005 to 2011 from electronic clinical chart templates stored in the KURAMA (Kyoto University Rheumatoid Arthritis Management Alliance) database. Affected rates for swelling and tenderness were assessed for each of the 28 joints and compared between two different sets of RA patients. Correlations of joint symptoms were analyzed for swellings and tenderness using kappa coefficient and eigen vectors by principal component analysis. As a result, we found that joint affected rates greatly varied from joint to joint both for tenderness and swelling for the two sets. Right wrist joint is the most affected joint of the 28 joints. Tenderness and swellings are well correlated in the same joints except for the shoulder joints. Patients with RA tended to demonstrate right-dominant joint involvement and joint destruction. We also found that RA synovitis could be classified into three categories of joints in the correlation analyses: large joints with wrist joints, PIP joints, and MCP joints. Clustering analysis based on distribution of synovitis revealed that patients with RA could be classified into six subgroups. We confirmed the symmetric joint involvement in RA. Our results suggested that RA synovitis can be classified into subgroups and that several different mechanisms may underlie the pathophysiology in RA synovitis.

[Objectives]: The anti-Wa antibody found in systemic sclerosis patients reacts with a transfer RNA (tRNA)-associated 48-kDa protein and immunoprecipitates several tRNAs. We investigated the Wa antigen and its binding to tRNA species. [Methods]: We performed molecular cloning of the Wa antigen and made its recombinant protein. To investigate Wa antigen distribution in the cell, we performed an indirect immunofluorescence study. To determine the Wa-bound tRNA species, we performed a reverse transcription (RT)-polymerase chain reaction (PCR) using the RNAs immunoprecipitated by anti-Wa antibody as templates, and synthetic primers of mammalian tRNA sequences. To clarify the tissue expression of Wa antigen, we performed quantitative and semi-quantitative PCR of the cDNA. [Results]: We demonstrated that the Wa antigen was identical to NEFA (DNA binding/EF-hand/acidic amino acid rich region), otherwise known as nucleobindin-2. A full-length and an alternative splice variant cDNA lacking exon 11 were isolated by cloning NEFA cDNA. Anti-Wa-positive sera stained both the nucleus and cytoplasm of HEp-2 cells. RT-PCR suggested that Wa binds at least six tRNA species. In human tissues, NEFA is expressed predominantly in exocrine glands. [Conclusions]: We have demonstrated that the Wa antigen is NEFA or nucleobindin-2, which binds specific tRNA species, and is distributed in specific human tissues.

[Introduction]B cell-activating factor of the tumor necrosis factor family (BAFF) and a proliferation-inducing ligand (APRIL) play a crucial role in B cell development, survival, and antibody production. Here we analyzed the serum levels of BAFF and APRIL and their respective clinical associations in patients with an immunoglobulin (Ig) G4-related disease (IgG4-RD). [Methods]We measured serum levels of BAFF and APRIL in patients with IgG4-RD, primary Sjögren's syndrome (pSS), and healthy individuals. Serum BAFF and APRIL levels in IgG4-RD were assessed for correlations with serological parameters, including Ig, particularly IgG4, and the number of affected organs. Serum BAFF and APRIL levels in IgG4-RD were monitored during glucocorticoid (GC) therapy. [Results]Serum BAFF and APRIL levels in patients with IgG4-RD were significantly higher (P < 0.01) than in healthy individuals. The BAFF levels of patients with IgG4-RD were comparable to those of patients with pSS. Although clinical parameters, such as serum IgG4 and the number of affected organs, were not correlated with the levels of BAFF, serum APRIL levels were inversely correlated with serum IgG4 levels (r = -0.626, P < 0.05). While serum BAFF levels decreased following GC therapy, serum APRIL levels increased during follow-up. [Conclusion]These results indicate that BAFF and APRIL might be useful markers for predicting disease activity in IgG4-RD. Further studies are needed to elucidate the role of BAFF and APRIL in the pathogenesis of IgG4-RD.

[Introduction]The induction of antinuclear antibodies (ANAs) or anti-double-stranded (ds) -DNA antibodies (Abs) after infliximab (IFX) therapy in rheumatoid arthritis (RA) is a well-known phenomenon, but the correlation of such Abs with the clinical response to IFX has not yet been determined. The aims of this retrospective observational study were to examine the prevalence of positive ANA and anti-ds-DNA Abs before and after IFX therapy in patients with RA and to investigate whether an increased titer of such Abs is associated with the clinical efficacy of IFX. [Methods]One hundred eleven RA patients who had received IFX were studied. ANA (indirect immunofluorescence with HEp-2 cells) and anti-ds-DNA Abs (Farr assay) results were examined before and after IFX therapy. [Results]The overall clinical response assessed by EULAR response criteria was as follows: good response in 55%, including remission in 38%; moderate response in 18%; and no response (NOR) in 27%. The positivity of ANA (≥ 1:160) and anti-ds-DNA Abs significantly increased from 25% to 40% (P = 0.03) and from 3% to 26% (P < 0.001) after IFX, respectively. EULAR response differed significantly according to the ANA titer before IFX (P = 0.001), and the efficacy of IFX became worse as the ANA titer before starting IFX increased. Furthermore, the differences in the clinical response of the ANA titer before IFX ≤ 1:80 and ≥ 1:160 were significant (good, moderate, and no response were 66%, 9%, and 25% in ≤ 1:80 group versus 26%, 33%, 41% in ≥ 1:160 group, respectively; P < 0.001). In 13 patients whose ANA had increased after IFX, 10 showed NOR, only one showed a good response, and none reached remission. These clinical responses were significantly different from ANA no-change patients. In 21 patients with positive anti-ds-DNA Abs after IFX, 16 showed NOR, only two showed a good response, and none reached remission. [Conclusions]The present study suggests that the ANA titer before starting IFX predicts the cli