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.

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.

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.

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.

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.

Relationship between quadriceps femoris muscle volume and muscle torque after anterior cruciate ligament repair.

This study was performed to obtain evidence regarding bilateral hindrance of motor unit (MU) recruitment in the quadriceps femoris (QF) of patients with anterior cruciate ligament (ACL) reconstruction. The subjects included 70 patients who underwent ACL reconstruction and 35 healthy subjects. To identify the muscle torque per unit volume (MTPUV), the peak torque of each velocity of isokinetic performance was divided by muscle volume of the QF measured by a series of cross-sectional images obtained by magnetic resonance imaging scans. Tests revealed that the mean MTPUV of the uninjured (0.113+/-0.03 N m/cm3 at 60 degrees /s, 0.081+/-0.02 N m/cm3 at 180 degrees /s) and injured sides (0.109+/-0.03 N m/cm3 at 60 degrees /s, 0.079+/-0.023 N m/cm3 at 180 degrees /s) were significantly lower than those of the control group (0.144+/-0.05 N m/cm3 at 60 degrees /s, 0.096+/-0.04 N m/cm3 at 180 degrees /s). Previous studies suggested that MU recruitment in the QF of patients with ACL injury was hindered bilaterally. However, the design of their studies could not provide evidence of bilateral hindrance of MU recruitment in the QF. The results of the present study demonstrated that the MTPUV of both injured and uninjured sides of patients were significantly lower than those of the control group.

Endovascular GDC Treatment of an Idiopathic Carotid-Cavernous Fistula Caused by Aneurysmal Rupture of the Intra-Cavernous Carotid Artery. Case Report.

SUMMARY: Aneurysmal rupture of the intra-cavernous carotid artery may cause idiopathic carotid-cavernous fistula (CCF), and the treatment choice for occluding shunting fistula in this type of CCF is an endovascular approach using detachable balloons. However, little has been reported on treating such lesions with the intra-aneurysmal embolization using Guglielmi detachable coils (GDCs).To our knowledge, ours is the first reported case of successful treatment by selective intra-fistula and intra-aneurysmal embolization with GDCs. A 74-year-old woman exhibited proptosis and chemosis of her left eye over a period of one month. Symptoms of double vision in conversion and pulsatile murmur in her left eye were also noted. Angiography revealed an intra-cavernous aneurysm of the left internal carotid artery (ICA) with a shunting fistula, which drained into the dilated cavernous sinus, superior orbital vein (SOV), superior petrosal sinus, inferior petrosal sinus, and pterygoid plexus.We thought the fistula would occlude by intra-aneurysmal embolization, but we had no confidence of tight packing of the aneurysm since the aneurismal neck was relatively wide. So, we embolized the venous side of the shunting fistula and then the dome of the aneurysm with GDCs. Immediately after the operation, her symptoms and signs were ameliorated, and complete occlusion of the CCF was observed on long-term follow-up. We suggest selective intrafistula and intra-aneurysmal embolization with GDCs as an alternative method of treatment of idiopathic CCF originating from aneurysmal rupture of the intra-cavernous carotid artery.

GABAergic synaptic transmission modulates swimming in the ascidian larva.

To examine the role of the amino acid GABA in the locomotion of basal chordates, we investigated the pharmacology of swimming and the morphology of GABA-immunopositive neurones in tadpole larvae of the ascidians Ciona intestinalis and Ciona savignyi. We verified that electrical recording from the tail reflects alternating muscle activity during swimming by correlating electrical signals with tail beats using high-speed video recording. GABA reversibly reduced swimming periods to single tail twitches, while picrotoxin increased the frequency and duration of electrical activity associated with spontaneous swimming periods. Immunocytochemistry for GABA revealed extensive labelling throughout the larval central nervous system. Two strongly labelled regions on either side of the sensory vesicle were connected by an arc of labelled fibres, from which fibre tracts extended caudally into the visceral ganglion. Fibre tracts extended ventrally from a third, more medial region in the posterior sensory vesicle. Two rows of immunoreactive cell bodies in the visceral ganglion extended neurites into the nerve cord, where varicosities were seen. Thus, presumed GABAergic neurones form a network that could release GABA during swimming that is involved in modulating the time course and frequency of periods of spontaneous swimming. GABAergic and motor neurones in the visceral ganglion could interact at the level of their cell bodies and/or through the presumed GABAergic fibres that enter the nerve cord. The larval swimming network appears to possess some of the properties of spinal networks in vertebrates, while at the same time possibly showing a type of peripheral innervation resembling that in some protostomes.

[Multi-vessel dissection; report of a case].

We report an extremely rare case of multi-vessel dissection including left carotid artery, ascending aorta and thoracoabdominal aorta independently. A 65-year-old man suffered from cerebral infarction due to left carotid artery dissection. Five days later, he complained of severe back pain and was diagnosed as acute DeBakey type IIIb aortic dissection. He had been treated medically. One month later, computed tomography (CT) scan demonstrated DeBakey type II as well as type IIIb aortic dissections. The ascending aorta was replaced on August 8, 2001. Then replacement of the descending thoracic aorta with reconstruction of the eighth and tenth intercostal arteries was performed on September 26, 2001. The left carotid artery dissection has been treated medically.

Clinical manifestations, character of aneurysms, and surgical results for unruptured cerebral aneurysms presenting with ophthalmic symptoms.

OBJECTS: Cases with unruptured cerebral aneurysms presenting with visual symptoms were investigated about their site, size, symptom, operative methods and results. MATERIAL: Between 1984 and 1999, 8 cases were treated in Sendai National Hospital. One man and 7 women, mean age 66.4 years. Ophthalmic symptoms were as follows: diplopia in 6, visual acuity deterioration in 2, impaired visual field in 2 and ptosis in 3. Aneurysm location was IC cavernous in 3, IC ophthalmic in 3, ICPC in 1 and Acom in 1. Aneurysms of more than 25 mm numbered 6 cases. RESULTS: Operative methods and results were as follows: Direct clipping 3 cases, parent artery occlusion + EC/IC bypass 4 cases, Aneurysm trapping + EC/IC bypass 1 case. One patient who underwent direct clipping died following intraoperative complication. Of the remaining 7 cases, visual symptoms were improved in 4, remained unchanged in 2 cases, worsened in 1 case. CONCLUSIONS: These results suggest that in cases with unruptured large or giant aneurysms presenting with ophthalmic symptoms, especially in IC cavernous or IC ophthalmic aneurysms, parent artery occlusion + EC/IC bypass is the safest operative procedure.

[A case of anaplastic astrocytoma arising 8 years after initial treatment by partial resection and irradiation for central neurocytoma].

A 31-year-old female developed the anaplastic astrocytoma in the right basal ganglia and temporal lobe 8 years after partial resection and irradiation of the central neurocytoma. Probably the malignant astrocytoma was an irradiation-induced tumor. Postoperative radiation therapy for the central neurocytoma appears to have a good effect on tumor local control. But it should be carefully decided whether to use radiation therapy for residual tumor because of the risk of delayed complications of irradiation, such as the present case.

Gene expression profiles in Ciona intestinalis tailbud embryos.

A set of 3423 expressed sequence tags derived from the Ciona intestinalis tailbud embryos was categorized into 1213 independent clusters. When compared with DNA Data Bank of Japan database, 502 clusters of them showed significant matches to reported proteins with distinct function, whereas 184 lacked sufficient information to be categorized (including reported proteins with undefined function) and 527 had no significant similarities to known proteins. Sequence similarity analyses of the 502 clusters in relation to the biosynthetic function, as well as the structure of the message population at this stage, demonstrated that 390 of them were associated with functions that many kinds of cells use, 85 with cell-cell communication and 27 with transcription factors and other gene regulatory proteins. All of the 1213 clusters were subjected to whole-mount in situ hybridization to analyze the gene expression profiles at this stage. A total of 387 clusters showed expression specific to a certain tissue or organ; 149 showed epidermis-specific expression; 34 were specific to the nervous system; 29 to endoderm; 112 to mesenchyme; 32 to notochord; and 31 to muscle. Many genes were also specifically expressed in multiple tissues. The study also highlighted characteristic gene expression profiles dependent on the tissues. In addition, several genes showed intriguing expression patterns that have not been reported previously; for example, four genes were expressed specifically in the nerve cord cells and one gene was expressed only in the posterior part of muscle cells. This study provides molecular markers for each of the tissues and/or organs that constitutes the Ciona tailbud embryo. The sequence information will also be used for further genome scientific approach to explore molecular mechanisms involved in the formation of one of the most primitive chordate body plans.

Brachyury (T) gene expression and notochord development in Oikopleura longicauda (Appendicularia, Urochordata).

Appendicularia (Larvacea) is a subgroup of Urochordata (Tunicata) comprised of holoplanktonic organisms that retain their tailed architecture throughout their life history, while other tunicates, including ascidians and doliolids, resorb the tail after metamorphosis. In order to investigate the characteristics of the appendicularian unresorbed notochord, we isolated a partial genomic clone and a full-length cDNA sequence homologous to the mouse Brachyury (T) gene from the appendicularian Oikopleura longicauda. Brachyury is known to be predominantly expressed in the notochord cells and plays an important role in their differentiation in other chordates. While phylogenetic analysis robustly supports the orthology of the isolated Brachyury gene, the exon-intron organization found in the genomic clone was distinct from that well-conserved among other T-box genes. In addition to a detailed observation of notochord development in living specimens, whole-mount double in situ hybridization was carried out using a Brachyury probe along with a muscle actin probe. The Brachyury transcripts were found in the notochord of the tailbud embryos and persisted into later stages. The present study highlights characteristics of notochord development in the appendicularian. Furthermore, these results provide basic knowledge for comprehensive understanding of the cellular- and molecular-based mechanisms needed to build the characteristic cytoarchitecture of notochord that varies among tunicate species.

The simple tail of chordates: phylogenetic significance of appendicularians.

Appendicularia comprises a group of pelagic tunicates that retain the tail throughout their life without exhibiting the drastic metamorphosis seen in ascidians or doliolids. They are known to possess a simple body architecture that is comparable with that of other chordates. Recent phylogenetic studies suggest that appendicularians represent a sister group of the clade of other tunicates. Very recently, two independent research groups reported molecular-based approaches to the appendicularian development. We review here some general descriptions and results of recent analyses on the anatomy and developmental biology of appendicularians, focusing upon their simple tail architecture. We emphasize future possibilities for a comprehensive understanding of the divergent patterns in lifestyle of tunicates as well as for investigating the phylogenetic novelty and innovation of chordates such as the tail.