Transitions in vascular ultrasonography findings of temporal arteritis in a GCA case with progressive temporal headache and visual impairment.

The European League Against Rheumatism and the American College of Rheumatology have stated that the halo sign on vascular ultrasonography (v-US) is relevant in diagnosing giant cell arteritis (GCA) and is equivalent to temporal artery biopsy. However, there are only a few reports about transitions in v-US findings after glucocorticoid (GC) therapy. We report the transitions in the v-US findings in a case of GCA after GC therapy. The patient had rapidly progressive symptoms, and there were concerns about blindness. After GC therapy, we first observed improvement in headache and visual impairment symptoms within 1 week, followed by rapid improvement in laboratory findings within 2 weeks. Subsequently, there were improvements in v-US findings after more than 2 months. In conclusion, these findings showed a dissociation between improvements in clinical symptoms and v-US findings of the temporal artery. Additionally, this case suggests that regular examination of v-US findings is useful in evaluating GCA with evident vascular wall thickness before GC therapy.

Reimbursement for therapeutic apheresis devices and procedures for using the healthcare insurance system in Japan.

The aim of this paper was to explain the insurance coverage status of therapeutic apheresis (excluding CHDF) in Japan, alongside the social system of medical reimbursement and concerns regarding the future sustainability of the healthcare system. Insurance schemes and premiums differed for individuals at different levels in the society (eg, municipal residents, employees, and public servants). Insurance premiums and their rates varied depending on the total household income, the number of people living together, age, and the place of residence. In addition, the medical expense subsidies for children through public expenditure were also described. Japan's generous insurance system and multiple medical expense subsidies provide financial support for patients. With Japan's history of medical expense subsidies based on the policy of supporting intractable diseases, we have established an environment where all citizens can receive therapeutic apheresis when needed if they are affected by a disease for which insurance coverage is indicated.

Changes in the Expression of Circulating microRNAs in Systemic Lupus Erythematosus Patient Blood Plasma After Passing Through a Plasma Adsorption Membrane.

MicroRNAs (miRNAs, miRs) are small non-coding RNAs that mainly function in the post-transcriptional regulation of genes. miRNA that is secreted outside of cells, and which circulates in the peripheral blood, is called circulating microRNA. Systemic lupus erythematosus (SLE) is a typical autoimmune connective tissue disease and is mainly treated with immunosuppressive drugs. Therapeutic apheresis is often used to eliminate autoantibodies and cytokines. We have previously shown that circulating miRNAs in the blood of patients with SLE can be separated and removed from the blood using a plasma separation membrane. In the present study, we further separated circulating miRNA from three SLE patient's blood plasma by passing it through a plasma adsorption membrane, and then measured changes in miRNA levels using miRNAs microarray chip. Although the levels of many miRNAs were unaffected after passage through the plasma adsorption membrane, expression of some miRNAs, including miR-1246, miR-4732-5p, and miR-6088 are declined.

Safety and efficacy of the leukocytapheresis procedure in eighty-five patients with rheumatoid arthritis.

Rheumatoid arthritis (RA) is a systemic inflammatory disease in which the predominant symptom is polyarthritis that follows a chronic and progressive clinical course characterized by destructive synovitis and various immune disorders. Striking progress in RA treatment was achieved with the emergence of monoclonal antibodies to target cytokines. However, drug choices are limited for many patients due to resistance to multidrug antirheumatic therapy, concomitant disease, and infection. We evaluated the efficacy of treatment in 85 patients with RA for whom leukocytapheresis (LCAP) was initiated at our hospital between 2006 and 2015. All patients continued drug therapy and were treated with LCAP once a week for up to 5 weeks. The clinical response was evaluated at the completion of LCAP series and 4 weeks later using the American College of Rheumatology (ACR) criteria and the 28-joint disease activity score (DAS28) of European League Against Rheumatism (EULAR). The tender joint counts, swollen joint counts, and C-reactive protein (CRP) levels decreased remarkably. DAS28-CRP was significantly improved by LCAP. And furthermore, the efficacy lasted at least 4 weeks after the completion of LCAP. These results suggest that LCAP is a beneficial and are consistent with several trials' reported effect of LCAP. This treatment can contribute to improvements in activities of daily living (ADLs) and long-term outcome by improving swollen and tender joint counts and CRP levels even in refractory patients for whom the use of conventional disease-modifying antirheumatic drugs (DMARDs) and biopharmaceuticals is problematic. LCAP might be a promise therapy to refractory RA.

Separation of Circulating MicroRNAs Using Apheresis in Patients With Systemic Lupus Erythematosus.

MicroRNAs (miRNAs), which are important inhibitors of mRNA translation, participate in differentiation, migration, cell proliferation, and cell death. The pathology of miRNAs results in alterations in protein expression. Recently, miRNAs circulating in peripheral blood have been shown to control the synthesis and translation of proteins at distal sites after intake into local cells. A number of studies are currently being conducted to investigate how to use miRNAs in disease treatment, but no studies have attempted to alleviate disease by directly eliminating miRNAs from blood. Therefore, we examined whether the removal or reduction of circulating miRNAs with apheresis improved pathologies caused by miRNAs. After approval of the study by our medical school's ethics committee, we collected blood and separated plasma samples from three patients with systemic lupus erythematosus who were undergoing plasmapheresis at our hospital. Peripheral blood was collected before and after it was passed through a primary membrane, centrifuged, and used to extract circulating miRNAs. A comprehensive expression analysis was then performed with a miRNA array chip. The levels of expression of a large number of circulating miRNAs were measured in the plasma samples separated by the primary membranes from all 3 patients with systemic lupus erythematosus. We present the first report that circulating miRNAs in peripheral blood can be separated and possibly directly removed using membrane separation apheresis.

The synovial grade corresponding to clinically involved joints and a feasible ultrasound-adjusted simple disease activity index for monitoring rheumatoid arthritis.

OBJECTIVES: To determine which grade of ultrasound (US) synovitis corresponds to clinically involved joints in rheumatoid arthritis (RA) and develops a new US-adjusted composite measure. METHODS: Clinical and US examinations were performed on 137 patients with RA (28 joints). Synovial effusion, hypertrophy, and blood flow were semiquantitatively graded from 0 to 3 using gray scale (GS) and power Doppler (PD) modes. We calculated US-adjusted simple disease activity index (SDAI) and assessed feasibility, and external validity by comparing with erythrocyte sedimentation rate (ESR), and modified health assessment questionnaires (MHAQ). RESULTS: GS ≥2 and PD ≥0 corresponds to clinically swollen joints, and GS ≥2 and PD ≥1 corresponds to tender joints. The US-adjusted SDAI showed the highest correlation when US-determined swollen joints were defined as PD ≥2 with ESR, and GS ≥3 and PD ≥2 with MHAQ. A feasible US-adjusted SDAI examining only clinically involved joints still showed a higher correlation with ESR and MHAQ than SDAI. CONCLUSION: Our composite measure complemented by US only for clinically involved joints is feasible and reliable for monitoring disease activity.

Predictive grade of ultrasound synovitis for diagnosing rheumatoid arthritis in clinical practice and the possible difference between patients with and without seropositivity.

OBJECTIVE: To determine the degree of contribution and the contributing factors of ultrasound in the diagnosis of rheumatoid arthritis (RA) in daily clinical practice and the predictive differences depending on seropositivity. METHODS: We included 122 patients who presented with the main complaint of finger and/or wrist joint pain but for whom no definite diagnosis was reached or treatment strategy was provided. Ultrasound was performed on at least 22 joints (both wrist joints, proximal interphalangeal joint, and metacarpophalangeal joints), and patients were followed for ≥6 months. Factors contributing to RA diagnosis were determined and compared between seropositive and seronegative RA patients. RESULTS: RA was diagnosed in 52 of 122 patients, in whom the American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) classification criteria (odds ratio [OR] = 4.74, P = 0.01) and gray scale (GS) grade of 3 (OR = 3.64, P = 0.04) for ≥ 1 joint were the contributing factors. In seropositive RA, the ACR/EULAR criteria (OR = 15.53, P < 0.001) and power Doppler (PD) ≥ 2 for ≥ 1 joint (OR = 10.48, P = 0.0048) were the contributing factors. In seronegative RA, PD ≥ 1 for ≥ 1 joint contributed the most (OR = 20.00, P = 0.0044), but the ACR/EULAR criteria did not contribute to RA diagnosis (P = 0.57). CONCLUSION: Ultrasound findings contributed to RA diagnosis in clinical practice. The contributing factors are different in the presence or absence of seropositivity, and ultrasound complementation was particularly useful in seronegative RA patients.

Predictive value of bone destruction and duration of clinical remission for subclinical synovitis in rheumatoid arthritis patients.

OBJECTIVES: Treatment for rheumatoid arthritis (RA) should aim to achieve full remission. The aim of this study was to investigate predictors of persistent subclinical synovitis and whether longer clinical remission is effective in reducing subclinical synovitis. METHODS: Forty-four RA patients who achieved DAS28ESR clinical remission for at least 3 months were enrolled in this study and underwent ultrasound examination of 22 joints (bilateral proximal interphalangeal joints, metacarpophalangeal joints, and wrists); bilateral hand X-ray; and blood examination. The severity of synovial effusion, synovial hypertrophy, and blood flow were semi-quantitatively graded from 0 to 3 using gray-scale (GS) and power Doppler (PD) modes. RESULTS: Among patients with DAS28ESR-defined clinical remission, 59.1% (26/44) demonstrated residual synovitis (≥ PD1) in at least one joint. Genant-modified total Sharp score (TSS) demonstrated the highest statistical difference between patients with and without residual subclinical synovitis (p = 0.0057), and full remission was only observed in patients with low TSS. A nonsignificant trend for decreased residual synovitis with longer sustained clinical remission was also observed (p = 0.724). CONCLUSION: Residual synovitis can persist during clinical remission, particularly in patients with progressive bone destruction. Early treatment and longer sustained clinical remission prior to bone destruction are critical for full remission.

Weighting with the Lansbury articular index improves the correlation of ultrasound score with serum matrix metalloproteinase-3 level in rheumatoid arthritis patients.

OBJECTIVE: To determine whether weighting improves the correlation of ultrasound (US) score with serum matrix metalloproteinase-3 (MMP-3) level in rheumatoid arthritis (RA). METHODS: As ultrasound examination was performed on 100 RA patients, and the severity of synovial effusion and synovial hypertrophy and the blood flow were semi-quantitatively graded from 0 to 3 by using the gray-scale (GS) and power Doppler (PD) modes. We then calculated the sums of the scores of the 28 joints of each patient in the 2 modes, that is, the GS28 and PD28 scores, as well as the respective scores weighted using the Lansbury articular index (LAI, shoulder and elbow, × 12; wrist, × 8; and knee, × 24)-Lans GS28 and Lans PD28 scores. RESULT: The Lans PD28 score showed a higher correlation with MMP-3 (r = 0.591; 95% confidence interval, 0.446-0.705, p < 0.0001) than the existing measures. The scores of the large joints-the knee, shoulder, and elbow-correlated well with the serum MMP-3 level. CONCLUSION: Weighting with the LAI can improve the correlation of US findings with serum MMP-3 level. Bidirectional approach based on both serum MMP-3 level and US scores can further improve the assessment of disease activity in RA patients.

Reduction in bradykinin generation during leukocytapheresis using novel cellsorba(TM) CS-180S: Effects of changing the filling solution.

We evaluated the bradykinin generation level during leukocytapheresis (LCAP) using novel Cellsorba(TM) CS-180S, which has sodium pyrosulfite and sodium carbonate as a filling solution. Subjects of this study were 14 rheumatoid arthritis patients. Regardless of the type of anticoagulant used, bradykinin levels were lower with the novel CS-180S than with the conventional CS-180S (28.7 ± 53.3 vs. 8.0 ± 2.7 as the mean ± standard deviation). When anticoagulants other than nafamostat mesilate were used with the conventional CS-180S, bradykinin levels increased at the column outlet compared with the column inlet, and adverse effects of bradykinin were seen in several cases. In contrast, bradykinin levels remained low and no bradykinin-associated adverse events were observed with the novel CS-180S. We recommend using the novel column instead of the conventional column in the treatment of LCAP.

Can routine clinical measures predict ultrasound-determined synovitis and remission in rheumatoid arthritis patients?

OBJECTIVES: The purpose of this study was to determine if routine clinical measures can predict the presence and severity of ultrasound synovitis in rheumatoid arthritis (RA) patients. METHODS: Bilateral 1-5 MCP (metacarpopharangeal) and wrist joints were examined using power Doppler (PD) ultrasound (US). Correlations between PD scores and routine clinical measures of RA - swollen joint count (SJC), tender joint count, patient's global assessment (GA), physician's GA, CRP, ESR, MMP-3, RF and anti-CCP antibody - were determined and used to identify significant predictors of PD score. Clinical measures were then compared between two groups (patients with and without PD) and analysed using multiple logistic regression, to derive a model that predicted the absence of PD signals. RESULTS: SJC was the most significant predictor of PD score (R2 = 0.4566, p value <0.0001), but was an inadequate predictor of PD signal remission. However, the combination of Steinbrocker's stage I or II (odds ratio [OR] 9.23, p=0.0049), SJC=0 in 1-5 MCP and wrist joints on both sides (OR 6.60, p=0.0039), and SDAI (or CDAI) remission (OR 5.06, p=0.0450) had a positive predictive value of 100%, predicting the absence of PD signals in all study patients meeting the 3 criteria. CONCLUSIONS: PD score and absence of PD signals can be predicted using routine clinical measures. When used in combination, Steinbrocker's stage, SJC and SDAI (or CDAI) can estimate disease activity and identify patients likely to have synovitis and requiring US.

Clinical miscount of involved joints denotes the need for ultrasound complementation in usual practice for patients with rheumatoid arthritis.

OBJECTIVES: Ultrasound (US) examination can visualise and clarify involved joints anatomically in patients with rheumatoid arthritis (RA), and it enables physicians to verify the accuracy of clinical assessments of involved joints. Here, we studied the practical 'miscount'- calculated by subtracting US-determined involved joint count from clinically determined involved joint count - and analysed possible contributing factors for increased miscount. METHODS: The study population consisted of 137 patients with RA. Physical joint examination was performed by 3 assessors with different levels of experience in rheumatology, followed by US joint examination. Clinical and US examinations were performed on 28 joints (proximal interphalangeal, metacarpophalangeal, wrist, elbow, shoulder, and knee on both sides). Miscount was calculated for all patients, and multivariate analysis was conducted on possible contributing factors for miscount, including age, sex, body mass index, disease duration, Steinbrocker stage, erythrocyte sedimentation rate (ESR), C-reactive protein level, patient global assessment (GA), evaluator GA, matrix metalloproteinase-3 level, and power Doppler (PD) score. RESULTS: A high variability in concordance rate among the joint sites was observed among the 3 assessors. The average miscount was 1.07 (SD, 5.19; range, 18 to -11). ESR and patient GA were determined as significant contributing factors for false-positive miscount, whereas PD score and age were significant factors for false-negative miscount. CONCLUSIONS: In addition to the condition of the involved joint distribution and the assessor's clinical examination skills, the patients' background can also lead to increased miscount. Assessors should be blinded to patients' background information, and US complementation should be included in usual clinical joint examinations.

Predicting bacteremia based on nurse-assessed food consumption at the time of blood culture.

BACKGROUND: Bacteremia and its complications are important causes of morbidity and mortality in hospitalized patients. However, the yield of blood cultures is relatively low, with many false-positive results from bacterial contamination. METHODS: We investigated the relationship between patient food consumption and the presence of bacteremia. This was an observational analysis of a cohort of 1179 patients who underwent blood culture analysis between January 2005 and December 2009. Patients with anorexia-inducing conditions, such as gastrointestinal illness and malignant disease treated with chemotherapy, were excluded. Food consumption was rated by nurses as the percentage of food consumed during the meal preceding the blood culture. Groupings were as follows: low consumption (<50%), moderate (>50% to <80%), and high (>80%). RESULTS: Low consumption was observed in 39.8% of patients, moderate in 17.8%, and high in 41.6%. The average body temperature was 38.1 ± 1.1°C. Bacteremia was present in 18.5%, 3.9%, and 1.4% of patients in the low, moderate, and high food consumption groups, respectively. The negative predictive value was 98.3%, suggesting that bacteremia is very unlikely in the setting of good food intake. CONCLUSION: Bacteremia is an unlikely occurrence in hospitalized patients who maintain adequate food consumption at the time of blood culture.

Gene expression analysis using a high-resolution DNA microarray of peripheral whole blood immediately before and after leukocytapheresis for rheumatoid arthritis.

Leukocytapheresis (LCAP) is a safe, unique therapy pertaining to intractable rheumatoid arthritis (RA) even in cases of drug allergy or infectious states. To investigate how to represent LCAP efficacy, we have conducted gene expression analyses from the peripheral blood of RA patients treated with non-woven polyethylene terephthalate filters. Peripheral blood samples were collected immediately before and after treatment from eight RA patients who received LCAP. Among these patients, all of them achieved 20% improvement in the core set of the American College of Rheumatology (ACR20), and thus, they were confirmed as LCAP responders. Gene expression analysis was done with a high-resolution DNA microarray. The results of each of the two groups' gene expression values (immediately before and after LCAP) were calculated using Welch's t-test. Calculations were performed with a statistical software R.basic package: if the P-value was less than 0.05, this was seen as a significant change. In a comparison of 25,370 gene expressions, the number of genes showing a P-value < 0.05 in the upregulating group was 2110, and in the downregulating group it was 1864. The results of pathway analysis using the MetaCore program indicate that gene groups work for cytoskeletal remodeling are upregulated, and genes related to immune responses, such as antigens presenting via major histocompatibility complex class I and II, are downregulated just after LCAP. These findings may relate to LCAP efficacy for RA patients, but this needs further investigation.

Autofeedback from ultrasound images provides rapid improvement in palpation skills for identifying joint swelling in rheumatoid arthritis.

OBJECTIVE: Joint swelling, an important factor in the classification criteria and disease activity assessment in rheumatoid arthritis (RA), renders joint palpation a necessary skill for physicians. Ultrasound (US) examination that visualizes soft tissue abnormalities is now used to assess musculoskeletal disease. We assessed the usefulness of US assessments in enhancing physical joint examination skills. METHODS: We examined 1944 joints (bilateral shoulder, elbow, wrist, metacarpophalangeal joints 1-5, and knee joints) in 108 patients with RA during April-July 2011. We first physically examined and confirmed joint swelling; subsequently, the same rheumatologist conducted US examinations and multiple assessors graded the joint swelling. When the 2 results differed, we received autofeedback from the US results to improve the physical examination skills. RESULTS: The sensitivities and specificities of physical examination for US-detected swollen joint, the correlation coefficient (CC) of the swollen joint counts, and the concordance rate in each patient for joint swelling sites and power Doppler (PD)-positive sites with the κ coefficients between the physical and US examinations were compared over time. We found that the sensitivity of physical examination increased by 42 percentage points (pp), while the specificity decreased by 18 pp. The average CC in June-July was greater than that in April-May. The percentage of κ coefficients > 0.8 increased from 8.8% to 17% for joint swelling and from 8.3% to 14% for PD-positive sites. CONCLUSION: Our results suggest that autofeedback from US assessment provides quick improvement in palpation skills for identifying joint swelling in patients with RA.