Clinical and ultrasound features of difficult-to-treat rheumatoid arthritis: A multicenter RA ultrasound cohort study.

OBJECTIVE: The optimal strategy for difficult-to-treat (D2T) rheumatoid arthritis (RA) has not been identified, and the ultrasound characteristics of D2T RA have not been reported. We investigated the clinical characteristics and factors contributing to the outcome in D2T RA in a multicentre RA ultrasound observational cohort. METHOD: We reviewed 307 Japanese patients diagnosed with RA who underwent treatment with biological and targeted synthetic disease-modifying anti-rheumatic drugs (b/tsDMARDs). We compared the differences in patient characteristics between the D2T RA and non-D2T RA groups. We examined the factors contributing to a good response [defined as b/tsDMARD continuation and Clinical Disease Activity Index (CDAI) ≤ 10 at 12 months] in the D2T RA patient group. RESULTS: Forty-three patients (14%) were categorized as D2T RA and the remaining 264 (86%) as non-D2T RA at baseline. The grey-scale (GS) score, disease duration, and CDAI at the initiation of treatment were significantly higher in the D2T RA group than in the non-D2T RA group. In contrast, the power Doppler (PD) score was not significantly different between the two groups. Of the 43 D2T RA patients, 20 achieved a good response. The introduction of CTLA4-Ig (n = 5) was significantly associated with a good response in analysis based on inverse probability weighting with propensity score. GS and PD scores at baseline were not significantly associated with therapeutic response at 12 months in D2T RA patients. CONCLUSIONS: Patients with D2T RA had high clinical and ultrasound activity and poor responses to treatment with b/tsDMARDs. CTLA4-Ig was associated with a good response at 12 months in D2T RA patients.

Ultrasound efficacy of targeted-synthetic disease-modifying anti-rheumatic drug treatment in rheumatoid arthritis: a multicenter prospective cohort study in Japan.

OBJECTIVE: This study investigated the effectiveness of treatment with Janus kinase (JAK) inhibitors in rheumatoid arthritis (RA) assessed by ultrasonography (US) activity, and the influence of patient characteristics and previous treatments. METHOD: This prospective study assessed 60 treatment initiations among 53 Japanese patients diagnosed with RA who underwent treatment with JAK inhibitors during June 2013 to February 2020. Of the 53 patients, seven patients were enrolled in duplicate because they were treated with two different JAK inhibitors at different periods. For each case, the improvement rate on the power Doppler (PD) score was assessed at 6 month follow-up. Median improvement rate of PD score was used to classify cases as either US responders or non-responders, and patient characteristics were compared between the two groups. RESULTS: All indicators of clinical disease activity and US activity showed a significant improvement at 3 months compared with baseline. Although the JAK inhibitor-cycler group and the interleukin-6 (IL-6) inhibitor inadequate response (IR) group tended to show a later improvement for US activity, all indicators of clinical disease activity and US activity showed a significant improvement at 6 months compared with baseline for both groups. Multivariate analysis showed that concomitant methotrexate use and an IR to the previous biologic or targeted-synthetic disease-modifying anti-rheumatic drug (b/tsDMARD) treatment were independently and significantly associated with US responders. CONCLUSION: Use of a JAK inhibitor in combination with methotrexate and an absence of IR to any previous b/tsDMARDs demonstrated superior effectiveness for patients with RA.

Fluorescence optical imaging in patients with active rheumatoid arthritis: a comparison with ultrasound and an association with biomarkers.

Objectives: This study compared indocyanine green (ICG)-enhanced fluorescence optical imaging (FOI) and musculoskeletal ultrasound (MSUS), and explored the significance of the FOI findings based on the association between the FOI and MSUS findings and serum biomarkers in patients with rheumatoid arthritis (RA). The study also explored the association between the FOI findings and patients' joint destruction at the joint-area level.Method: We enrolled 50 consecutive patients with active RA from among the patients hospitalized from May 2014 to March 2016 at Nagasaki University Hospital, Japan. FOI images were acquired with the Xiralite® fluorescence imaging system and compared with the patients' clinical examination results and MSUS findings. On the same day, the patients' clinical disease activity and levels of serum biomarkers (including vascular endothelial growth factor) were obtained.Results: Although the FOI detected synovitis with high sensitivity, the frequency of positive findings and the diagnostic performance with MSUS as the reference standard for FOI differed considerably among the phases of FOI as well as among the affected joint regions. The FOI scores were positively correlated with clinical disease activity, MSUS scores, and serum biomarkers. The severity of FOI-proven synovitis was associated with the presence of MSUS-proven bone erosion.Conclusion: FOI is effective for detecting joint inflammation in RA patients, with high accuracy. The severity of the FOI score was closely associated with the joint destruction at the joint-area level. However, the significance of positive FOI findings differed depending on not only the phase of FOI but also the affected joint regions.

Significance of anti-Ro/SSA antibodies in the response and retention of abatacept in patients with rheumatoid arthritis: a multicentre cohort study.

Objective: To determine whether the positivity of baseline anti-Ro/Sjögren's syndrome antigen A (SSA) antibodies influences the response to abatacept, we compared therapeutic responses between anti-Ro/SSA antibody-negative and -positive patients with rheumatoid arthritis (RA) using a multicentre RA ultrasonography prospective cohort. Method: We reviewed Japanese patients with RA who started abatacept as the first biological disease-modifying anti-rheumatic drug between June 2013 and April 2018. We assessed 28-joint Disease Activity Score-erythrocyte sedimentation rate (DAS28-ESR) change between baseline and 6 or 12 months after treatment in RA patients treated with abatacept, and European League Against Rheumatism (EULAR) response at 6 and 12 months. The Global OMERACT-EULAR Synovitis Score (GLOESS) was calculated at baseline and at 6 and 12 months. Results: Overall, 51 patients were enrolled and divided into anti-Ro/SSA antibody-negative and -positive groups of 35 and 16, respectively. Median age at baseline was significantly higher in the anti-Ro/SSA antibody-negative group (p = 0.04). The retention rate and percentage of EULAR good responders at 12 months were significantly higher in the anti-Ro/SSA antibody-negative group (both p = 0.02). Anti-Ro/SSA antibody-negative patients exhibited larger decreases in both DAS28-ESR and DAS28-C-reactive protein at 12 months than anti-Ro/SSA antibody-positive patients (p = 0.02 and 0.04, respectively). GLOESS decreased significantly at 6 months in anti-Ro/SSA antibody-negative patients (p = 0.03). Multivariate analyses showed that anti-Ro/SSA antibody positivity was an independent factor associated with change in the DAS28-ESR at 6 months (p < 0.05). Conclusion: Anti-Ro/SSA antibody positivity predicts a poor response to abatacept and low retention rate.

Discrepancy between clinical and ultrasound remissions in rheumatoid arthritis: a multicentre ultrasound cohort study in Japan.

Objectives: Using multicentre ultrasound (US) cohort data among patients with rheumatoid arthritis (RA), we aimed to identify baseline factors that permit differentiation between two patient cohorts achieving US remission and clinical remission, and to determine the factors contributing to the discrepancy.Method: We reviewed 248 Japanese patients diagnosed with RA who underwent treatment with biological disease-modifying anti-rheumatic drugs at 13 centres. We performed US assessments of the synovia of 22 joints. We assessed the percentages of patients with clinical remission and US remission, defined as total power Doppler scores of 0 at 12 months.Results: The 87 patients who achieved US remission were divided into a group that achieved both clinical and US remission (n = 53) and a group that achieved US remission only (n = 34). Baseline factors that were significantly and independently associated with clinical remission at 12 months among patients who also achieved US remission included short disease duration, the presence of concomitant methotrexate use, and low patient global assessment score (p < 0.05, p < 0.05, and p < 0.005, respectively).Conclusions: RA patients with baseline high patient global assessment scores and long disease duration at baseline were unlikely to achieve clinical remission even after achieving US remission. Objective joint assessments using US provide additional information of potential importance for the management of RA.

Anti-citrullinated protein antibody titre as a predictor of abatacept treatment persistence in patients with rheumatoid arthritis: a prospective cohort study in Japan.

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.

Usefulness of soluble CD163 as a biomarker for macrophage activation syndrome associated with systemic lupus erythematosus.

OBJECTIVE: We aimed to study the usefulness of serum soluble CD163 (sCD163) as a biomarker for macrophage activation syndrome (MAS) associated with systemic lupus erythematosus (SLE). METHODS: Serum sCD163 levels were retrospectively measured by enzyme-linked immunosorbent assay for SLE patients associated with MAS (SLE-MAS), lupus nephritis (LN), or autoimmune hemolytic anemia (AIHA) and/or immune thrombocytopenia (ITP) and healthy controls (HCs). Posttreatment samples were also evaluated in the available SLE-MAS patients. The associations between serum sCD163 levels and clinical information were statistically analyzed. RESULTS: The serum sCD163 levels in SLE-MAS, LN and SLE-AIHA/ITP groups were significantly higher than those in HCs (n = 17, 29, 13, and 68, respectively; p < 0.01 for all comparisons). In addition, the serum sCD163 levels in the SLE-MAS group were even higher than those in the LN and SLE-AIHA/ITP groups (p < 0.01 for both comparisons). Serum sCD163 levels were correlated with the SLE Disease Activity Index 2000 scores (r = 0.53), whereas they were not correlated with the serum ferritin levels. With the determined cut-off value, the sensitivity and specificity of serum sCD163 for the diagnosis of SLE-MAS were 59% and 86%, respectively. Retesting showed that the serum sCD163 levels decreased significantly following treatment in parallel with disease amelioration in the SLE-MAS group (p < 0.01). CONCLUSIONS: The present study suggests the usefulness of serum sCD163 as a diagnostic and disease-activity biomarker for SLE-associated MAS. Serum sCD163 might also have a different role as a biomarker for SLE-associated MAS than serum ferritin does.

The efficacy of adjunct tacrolimus treatment in pregnancy outcomes in patients with systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) involves multiple organ systems and primarily affects women during their reproductive years. Pregnancy in a woman with SLE may lead to higher rates of disease flares. Little is known regarding which medications are safe to maintain remission and/or treat flares throughout such pregnancies. Here we retrospectively analyzed the efficacy of tacrolimus (TAC) in the pregnancy outcomes of SLE patients. We studied the 54 deliveries of 40 SLE patients over an eight-year period from 2008 to 2016. We used analyses of covariance with adjustments for the propensity score and inverse probability of treatment weights to compare the patient backgrounds between the TAC users and non-TAC users. TAC was administered to the patient in 15 of the 54 (27.8%) pregnancies, and these patients had a significantly higher dose of prednisolone, hypocomplementemia, lower estimated glomerular filtration rate, past history of lupus nephritis, and complication with antiphospholipid syndrome. In the adjusted background of the TAC deliveries, the risks of decreased fetal body weight, low birth weight infant, non-reassuring fetal status (NRFS), and preterm birth were not increased compared to the non-TAC deliveries. Thrombocytopenia and hypertension during the pregnancy were extracted as independent predictive risk factors for decreased fetal body weight and NRFS, respectively. We had anticipated that the maternal and fetal outcomes in the TAC-use deliveries would be poor before the analysis; however, the TAC-use group showed no significant difference in risks contributing to outcomes compared to the non-TAC group, suggesting that adjunct TAC treatment corrected various risk factors during the lupus pregnancies.

Clinical manifestation and treatment strategy for non hemorrhagic cerebral arterial dissection.

Spontaneous dissections of cerebral and cervical artery are relatively uncommon lesions in Japan. Although reported cases of cerebral and cervical arterial dissection are gradually increasing, natural history and optimal treatment remain unclear. The purpose of this study was to clarify the clinical features, natural history, and optimal treatment for patients suffering from non-hemorrhagic cerebral arterial dissection. Fifty-four males and 14 females with cerebral or cervical arterial dissection were treated between January 1998 and December 2003 at the Stroke Center, Sendal Medical Center in Japan. Although most patients suffering from non-hemorrhagic cerebral arterial dissection recover well by conservative treatments, some cases require surgical treatment if they are complicated by enlargement of aneurysms, cerebral ischemia due to bilateral vertebral arterial dissection.

Inhibition of the tumor-promoting action of 12-O-tetradecanoylphorbol-13-acetate by some oleanane-type triterpenoid compounds.

Since glycyrrhetinic acid was proved to suppress tumor promoter effects, several oleanane-type triterpenes which were chemically derived from oleanolic acid and hederagenin were tested in vitro and in vivo against the action of tumor promoter, 12-O-tetradecanoylphorbol 13-acetate. By in vitro experiment monitoring with 12-O-tetradecanoylphorbol-13-acetate-induced stimulation of 32Pi incorporation into phospholipids and an in vivo test on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene and promoted with 12-O-tetradecanoylphorbol-13-acetate, 18 beta-olean-12-ene-3 beta,28-diol (= erythrodiol), 18 beta-olean-12-ene-3 beta,23,28-triol, 18 alpha-olean-12-ene-3 beta,28-diol, and 18 alpha-olean-12-ene-3 beta,23,28-triol showed remarkable suppressive effects. Especially 18 alpha-oleanane derivatives having a CH2OH grouping converted from the COOH group initially allocated at C-17 were 100 times more effective than glycyrrhetinic acid both in vitro and in vivo.

cDNA cloning of a mouse pituitary adenylate cyclase-activating polypeptide receptor.

A cDNA clone for mouse pituitary adenylate cyclase-activating polypeptide (PACAP) receptor (PACAP-R) was obtained from the brain using reverse transcription-polymerase chain reaction (RT-PCR). The recombinant PACAP receptor expressed in COS cells bound PACAP with about 1000-times higher affinity than vasoactive intestinal polypeptide (VIP), and PACAP stimulated adenylate cyclase through the cloned PACAP receptor. The mouse PACAP receptor consists of 496 amino acids, contains seven transmembrane segments and has 98.4%, 93.0%, and 92.5% identity with the rat, bovine, and human PACAP-R, respectively.

Structure of the gene encoding the mouse pituitary adenylate cyclase-activating polypeptide receptor.

The PACAP-R gene, encoding the mouse pituitary adenylate cyclase-activating polypeptide receptor (PACAP-R), has been isolated and its structural organization has been determined. PACAP-R spans more than 50 kb and is divided into 18 exons. PACAP-R contains two alternative exons encoding the putative third intracellular loop, as found in the rat PACAP-R. The proximal promoter region is highly G+C rich and lacks an apparent TATA box, but contains a CCAAT box and two potential Sp1-binding sites.

Cloning and characterization of the mouse pituitary adenylate cyclase-activating polypeptide (PACAP) gene.

The gene encoding the mouse precursor of pituitary adenylate cyclase-activating polypeptide (PACAP) has been cloned, and its structural organization was determined. Using the 5'-rapid amplification of cDNA ends (RACE) procedure, three types of transcription initiation produced by alternative exon usage of two untranslated alternative exons (exons 1A and 1B) were defined. The PACAP gene spans 6.6kb of genomic DNA and is composed of six exons including the alternative exons. The signal peptide, PACAP-related peptide and mature 38-amino acid PACAP (PACAP-38) are encoded within exons 2, 4 and 5, respectively. The 5'-flanking region of the PACAP gene contains several sequence motifs homologous to cAMP response element, TPA response element, and growth hormone factor-1 binding site. A dinucleotide repeat sequence is present in an intron. In addition, there are di- and tetranucleotide repeat sequences 2.4kb and 3.2kb upstream to the translation start point, respectively. The overall intron-exon organization and the production of the alternate mRNAs of the PACAP gene are markedly similar to those of the growth hormone-releasing hormone (GHRH), supporting the hypothesis that the two genes encoding GHRH or PACAP were originated from a gene duplication. Promoter analysis of the 5'-flanking region of the PACAP gene using a luciferase gene reporter system revealed that the isolated 5'-flanking region has functional promoter activity and is responsible for inducible expression.

Anti-tumor-promoting activity of derivatives of abieslactone, a natural triterpenoid isolated from several Abies genus.

Abiesenonic acid methyl ester (AVB-I acid methyl ester), a triterpenoid compound prepared from abieslactone, suppressed tumor promoter-induced phenomena in vitro and in vivo; i.e., AVB-I acid methyl ester inhibited 12-o-tetradecanoylphorbol-13-acetate (TPA)-stimulated 32Pi-incorporation into phospholipids of cultured cells and the promoting action of TPA on skin tumor formation in mice initiated with 7,12-dimethylbenz[a]anthracene.

Thrombin may contribute to the pathophysiology of central nervous system injury.

Thrombin has multiple functions, including its function as a key enzyme during blood coagulation and other physiologic activities. We studied brain tissue reactions to thrombin that might be present in the central nervous system (CNS) following injury. Thrombin and three different types of controls--buffer, albumin, and plasmin--were individually infused into the rat caudate nucleus by a continuous osmotic mini-pump. Brains were examined by conventional histologic and immunohistologic techniques. Antibodies for bromodeoxyuridine (BrdU), glial fibrillary acidic protein (GFAP), vimentin, and laminin were employed to assess the infiltration of inflammatory cells, proliferation activity of cells, and reaction of astrocytes and mesenchymal cells, respectively. The number of inflammatory cells, number of BrdU-positive cells, area and number of vimentin-positive astrocytes, and the area of GFAP-positive astrocytes were quantitatively analyzed. Thrombin caused infiltration of inflammatory cells, proliferation of mesenchymal cells, induction of angiogenesis, and an increase in vimentin-positive reactive astrocytes. These histologic changes caused by thrombin infusion resembled the inflammation, scar formation, and reactive gliosis in the CNS following injury. These results suggest that thrombin may play an important role in inflammatory responses to CNS injury since thrombin is one of the blood borne factors that may interact with brain tissue after CNS injury. The data further suggest that the therapeutic application of antithrombin agents for CNS injury suppresses inflammation and the excessive gliosis and scar formation, which are barriers to neuronal regeneration.

Methotrexate, vinblastine, doxorubicin, and cisplatin for advanced urothelial cancer.

A series of 31 patients with advanced urothelial cancer were treated with combination chemotherapy consisting of 1-4 cycles of methotrexate, vinblastine, doxorubicin, and cisplatin (M-VAC). Of the 31 patients, 29 had measurable and evaluable lesions. A complete remission was achieved by 4 of these 29 patients (14%) for 1-46 months. A partial remission was observed in 14 of the 29 patients (48%) for 1-9 months. Whereas bony and hepatic metastatic lesions did not respond, some nodal (7/12), pulmonary (4/8), and pelvic lesions (2/3) as well as primary bladder tumors (4/6) and a tumor marker (1/2) responded. Complete tumor remission was observed in nodal (2/12) and pulmonary (1/8) metastatic lesions, in invasive lesions to the prostate and seminal vesicle (1/1), and in primary lesions in the bladder (2/6), ureter (1/1), and urethra (1/1). Two of three patients with non-transitional cell tumors attained a partial remission for 1-7 months. Complete remission of the pulmonary lesions was obtained in a case of squamous cell cancer of the bladder with pulmonary metastases. The toxicity of this regimen was generally tolerable and included moderate to severe myelosuppression, mild to moderate nausea and vomiting, renal toxicity, and mucositis. These results suggest that the M-VAC regimen holds promise for the treatment of advanced metastatic transitional cell cancer as well as non-transitional cell cancer of the urothelium.

Retrograde transport of horseradish peroxidase in sciatic nerve of rats and dystrophy mice.

The relationship between nerve or muscle activity and retrograde HRP transport was studied in rat Sciatic nerve and in dystrophy mice. sciatic nerve stimulation facilitated transport to 250% of control level, while colchicine decrease transport depending on dosage. Tendonectomy as well as colchicine treatment ultimately decreased HRP transport, but before the decrease, there was a transient facilitatory phase in both colchicine treated and tendonectomized rats. In dystrophy mice, almost twice as much nerve trunk injected HRP was transported as in control mice. This suggests that retrograde transport level increases in some stage of dystrophy.

Steroidal saponins from the bulbs of Lilium longiflorum and their antitumour-promoter activity.

Two new spirostanol saponins and two new furostanol saponins were isolated from the fresh bulbs of Lilium longiflorum together with several known saponins. The structures of new compounds were determined to be (25S)-spirost-5-ene-3 beta, 27-diol 3-O-(O-alpha-L-rhamnopyranosyl-(1-->2)-O- [alpha-L-arabinopyranosyl-(1-->3)]-beta-D-glucopyranoside), (25R)-27-O-[(S)-3-hydroxy-3-methylglutaryl]-spirost-5-ene-3 beta,27 diol 3-O-(O-alpha-L-rhamnopyranosyl-(1-->2)-O-[alpha-L-arabinopyranosyl -(1-->3)] - beta-D-glucopyranoside), 22-O-methyl-26-O-beta-D-glucopyranosyl-(25R)-furost-5-ene-3 beta,22 xi, 26-triol 3-O-(O-alpha-L-rhamnopyranosyl-(1-->2)-O-[alpha-L- arabinopyranosyl-(1-->3)]-beta-D-glucopyranoside) and 22-O-methyl-26-O-beta-D-glucopyranosyl-(25R)-furost-5-ene-3 beta, zeta, 26-triol 3-O-(O-alpha-L-rhamnopyranosyl-(1 --> 2)- O-[beta-D-xylopyranosyl-(1 --> 3)]-beta-D-glucopyranoside). The isolated saponins and their derivatives were examined for inhibitory activity on 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated 32P-incorporation into phospholipids of HeLa cells as the primary screening test to find new antitumour-promoter compounds.

Steroidal glycosides from Allium macleanii and A. senescens, and their inhibitory activity on tumour promoter-induced phospholipid metabolism of HeLa cells.

A new polyhydroxylated cholestane trisdesmoside and a new spirostanol pentasaccharide, together with five known spirostanol saponins, were isolated from the bulbs of Allium macleanii, and two known spirostanol saponins were isolated from the bulbs of A. senescens. The identification and structural assignments of the steroidal glycosides were performed by spectroscopic analysis and hydrolysis. Furthermore, the isolated compounds were evaluated for inhibitory activity on 12-O-tetradecanoylphorbol-13-acetate (TPA)-stimulated 32P-incorporation into phospholipids of HeLa cells, which is recognized as an excellent primary screening test to identify new antitumour-promoter compounds.