Michihiro Ogasawara

Investigation of the clinical effect of large volume leukocytapheresis on methotrexate-resistant rheumatoid arthritis.

Abstract:  Leukocytapheresis (LCAP) is already being used in a clinical setting for the treatment of autoimmune diseases such as inflammatory bowel disease and rheumatoid arthritis, and it has been reported to be effective. However, it is totally or partially ineffective in some patients, which has forced clinicians to rethink therapeutic strategies and concurrent treatment. With the aim of enhancing the therapeutic effect, we carried out large volume leukocytapheresis, with a throughput of 5000 mL instead of the 3000‐mL throughput of conventional leukocytapheresis in nine patients with rheumatoid arthritis resistant to methotrexate treatment. Using Cellsorba, the column filled with the unwoven fabric made of the polyethylene phthalate, a leukocyte removal filter, large volume leukocytapheresis was carried out once a week for a total of five sessions. The observation period was the 12‐week period following completion of treatment. The American College of Rheumatology (ACR) core set was used for assessment of efficacy. Eight weeks after completion of treatment, a 20% improvement in ACR was observed in 77.8% (7/9) of subjects, a 50% improvement in ACR was seen in 55.6% (5/9) of subjects, and a 70% improvement in ACR was observed in 22.2% (2/9) of subjects. C‐reactive protein decreased gradually as treatment progressed, and a significant decrease was observed 4 weeks after completion of treatment. The fact that some subjects had an ACR70 response, few reports of which are observed in the case of conventional leukocytapheresis, and the fact that the effect continued up to 12 weeks after completion of treatment suggests that the degree and duration of the effect of large volume leukocytapheresis might be longer than those of conventional leukocytapheresis.

Involvement of Mucosal-associated Invariant T cells in Ankylosing Spondylitis

Objective. Ankylosing spondylitis (AS) is characterized by chronic inflammation of the axial and peripheral joints and ligamentous attachments. Gut immunity is thought to be involved in AS, because a prominent coexistence of gut and joint inflammation has been observed in patients with AS. Mucosal-associated invariant T (MAIT) cells are preferentially located in the gut lamina propria and produce inflammatory cytokines such as interleukin 17 (IL-17) and tumor necrosis factor-α (TNF-α), which are therapeutic targets for AS. This study aimed to investigate the involvement of MAIT cells in AS. Methods. The frequency of MAIT cells and their cytokine production were determined in patients with AS and healthy controls (HC). The expression of a MAIT cell activation marker (CD69) was analyzed in patients with AS by using flow cytometry. Results. The frequency of MAIT cells in the peripheral blood was lower in patients with AS compared with HC. The levels of IL-17 produced by MAIT cells after activation were higher in patients with AS than in the HC. CD69 expression on MAIT cells correlated with the Ankylosing Spondylitis Disease Activity Score in patients with AS. Conclusion. These results suggest the involvement of MAIT cells in the pathogenesis of AS.

Anti-Ro/SSA Antibodies Are an Independent Factor Associated with an Insufficient Response to Tumor Necrosis Factor Inhibitors in Patients with Rheumatoid Arthritis

Objective. To study the significance of anti-Ro/SSA antibodies (anti-Ro) in the clinical response to tumor necrosis factor (TNF) inhibitors in patients with rheumatoid arthritis (RA). Methods. The clinical responses of a cohort of 190 patients with RA who were treated with infliximab, etanercept, or adalimumab (n = 112, 64, and 14, respectively) as the first biologics were examined using the Disease Activity Score in 28 joints (DAS28) at 24 weeks and the discontinuation rate at 56 weeks. The baseline characteristics of responders and the nonresponders were compared. The clinical response was compared between anti-Ro-negative and -positive patients. The factors associated with the inefficiency of TNF inhibitors were estimated with a multivariable logistic regression analysis. Results. The positive rate of anti-Ro was significantly higher in patients with no European League Against Rheumatism (EULAR) response at 24 weeks (OR 3.64, 95% CI 1.45–9.01, p = 0.003). In anti-Ro-positive patients, a moderate or good EULAR response rate was significantly lower with a sustaining higher median DAS28 (p = 0.006), and this difference was greater among infliximab-treated patients. The discontinuation rate for TNF inhibitors due to inefficacy at 56 weeks was also higher in anti-Ro-positive patients (OR 4.68, 95% CI 1.82–11.99, p = 0.0005), and 75% of these patients received infliximab. The presence of anti-Ro was strongly associated with no EULAR response at 24 weeks and a higher discontinuation rate of TNF inhibitors by 56 weeks (OR 5.22, 95% CI 1.75–15.57, p = 0.003 and OR 10.18, 95% CI 2.18–49.56, p = 0.003). Conclusion. The presence of anti-Ro might be related to the lesser clinical response to infliximab compared to other TNF inhibitors, suggesting that the presence of anti-Ro should be considered when choosing the appropriate biologics for patients with RA.

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.

Observational cross-sectional study revealing less aggressive treatment in Japanese elderly than nonelderly patients with rheumatoid arthritis.

Background:Elderly patients with rheumatoid arthritis (RA) have more aging-related complications than nonelderly patients with RA. Objectives:The objective of the study was to investigate the treatment status of elderly patients with RA. Methods:Between January and March 2008, 969 patients with RA were enrolled in this observational cross-sectional study. Prescription of disease-modifying antirheumatic drugs (DMARDs) and corticosteroids and laboratory data related to RA, including matrix metalloproteinase 3, rheumatoid factor, and anti-cyclic citrullinated peptide antibody levels, were compared between the elderly and the nonelderly patients. Results:Fewer DMARDs were prescribed to the elderly patients (1.40 [SD, 0.57] vs. 1.51 [SD, 0.61]; P = 0.029). Furthermore, a lower percentage of patients received methotrexate (MTX) (47.2% vs. 56.9%; P = 0.0001), a lower average dosage of MTX was administered (5.46 [SD, 1.66] mg/wk vs. 5.96 [SD, 1.77] mg/wk; P = 0.0001), and fewer biologic DMARDs were used (1.46% vs. 5.59% for infliximab, P = 0.0008; 0.58% vs. 3.19% for etanercept, P = 0.0038) in the elderly group. The laboratory data suggested that the disease status was uncontrolled to a greater extent, and complications were more common in the elderly group. Conclusion:Elderly patients with RA receive less aggressive treatment than nonelderly patients with RA, despite laboratory evidence for poorly controlled disease status among the elderly. The use of a less aggressive regimen could be attributed to the higher prevalence of complications and problems. Therefore, the elderly with RA should be considered a different patient population from the viewpoint of treatment and be administered specialized medical care.

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.

Ultrasound Assessment of Synovial Pathologic Features in Rheumatoid Arthritis Using Comprehensive Multiplane Images of the Second Metacarpophalangeal Joint: Identification of the Components That Are Reliable and Influential on the Global Assessment of the Whole Joint

The aim of this pilot study was to provide groundwork that could be utilized to optimize the global ultrasound (US) assessment of the whole joint for synovial pathologic features in patients with rheumatoid arthritis (RA).

Polyarticular septic arthritis with bilateral psoas abscesses following acupuncture

We report a case of polyarticular septic arthritis with bilateral psoas abscesses. A 50-year-old woman was admitted with fever, multiple joint swelling and pain. She had a clinical history of acupuncture therapy for treatment of her chronic lower back pain two days before the appearance of her symptoms. Methicillin-sensitive Staphylococcus aureus was isolated from blood culture, knee joint fluids and psoas abscess. After a long course of antibiotics for 70 days together with drainage of the abscess, the condition completely resolved. The acupuncture is the probable cause of the infection, and this case report reveals the importance of asking about a clinical history of acupuncture treatment and of making repeated bacterial examinations in undiagnosed polyarthritis patients.

Investigation of pathological and clinical features of lupus nephritis in 73 autopsied cases with systemic lupus erythematosus

The aims of this study were to analyze the clinical and pathological features of lupus nephritis (LN) and examine the association between these features and pathological condition, treatment, and prognosis. Of the 177 systemic lupus erythematosus patients who died while receiving inpatient care at Juntendo University Hospital between 1960 and 2001, we investigated the clinical features, treatment, and pathological features of 73 of these who underwent pathological autopsy and had a clear medical history. We divided these cases into two groups, i.e., those up to 1979 (Group A) and those during and after 1980 (Group B) in order to investigate changes in tendencies by age. We also divided the cases into three groups by time interval between diagnosis and death to investigate long-term prognosis. Uremia was the direct cause of death in 38.9% of cases in Group A and only 10.8% of cases in Group B. Pathological features showed a tendency to change to a sclerotic lesion as the duration of the disorder became longer. Uremia attributable to LN was the direct cause of death in relatively fewer cases, although it is still found in the majority of LN cases and remains a problem requiring stringent management. The treatment of sclerotic lesions may be an issue that needs further attention.

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

Abstract 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.