Good response to methotrexate is associated with a decrease in the gene expression of ABCG2, a drug transporter, in patients with rheumatoid arthritis.

OBJECTIVES: Methotrexate (MTX) is used as an anchor drug in the treatment of rheumatoid arthritis (RA), although more than a half of the patients with RA require additional treatments. We designed a prospective study involving two medical centers in Japan to examine the association between the expression of MTX-related genes including a drug transporter ATP-binding cassette sub-family G member 2 (ABCG2) gene and the clinical response to MTX in MTX-naive patients with RA. METHODS: The primary endpoint of this study was good response based on the European League Against Rheumatism (EULAR) response criteria by Disease Activity Score using 28-joint count (DAS28). We evaluated the association between the baseline expression of six genes involved in the intracellular pharmacokinetics of MTX, including ABCG2, as well as their temporal changes, and the clinical response at week 12 from the initiation of MTX. RESULTS: Based on the clinical response at 12 weeks after the initiation of MTX, 24 patients were classified into good responders (n = 9) and non-good responders (n = 15; 10 moderate responders and 5 non-responders) groups. A univariate logistic regression analysis of the baseline gene expression levels to predict the EULAR good response at week 12 showed a significant association with ABCG2 expression alone. Furthermore, the rate of baseline expression of ABCG2 mRNA above the cut-off value determined using a receiver operating characteristic curve was higher in good responders than in non-good responders (p = .012). Moreover, ABCG2 expression decreased in almost all good responders, but not in non-good responders, after MTX treatment for 12 weeks (median -76% vs. +41% from baseline, respectively; p = .011). The ABCG2 expression level did not correlate with DAS28 at baseline or week 12. CONCLUSIONS: Our study revealed that good response to MTX is associated with a decrease in the expression of ABCG2 in patients with RA.

2019 Diagnostic criteria for mixed connective tissue disease (MCTD): From the Japan research committee of the ministry of health, labor, and welfare for systemic autoimmune diseases.

OBJECTIVE: To update and revise the diagnostic criteria for mixed connective tissue disease (MCTD) issued by the Japan Research Committee of the Ministry of Health, Labor, and Welfare (MHLW), a round table discussion by experts from rheumatology, dermatology, and pediatric medicine was conducted in multiple occasions. METHODS: The definition of MCTD, and items included in the diagnostic criteria were generated by consensus method and evaluation using clinical data of typical and borderline cases of MCTD, by applying to the diagnostic criteria for MCTD proposed in 1996 and 2004 by the Research Committee of MHLW. RESULTS: To the end, all committee members reached consensus. Then, the criteria were assessed in an independent validation cohort and tested against preexisting criteria. The revised criteria facilitate an understanding of the overall picture of this disease by describing the concept of MCTD, common manifestations, immunological manifestation and characteristic organ involvement. Conditions with characteristic organ involvement include pulmonary arterial hypertension, aseptic meningitis and trigeminal neuropathy. Even if the overlapping manifestations are absent, MCTD can be diagnosed based on the presence of the characteristic organ involvement. Furthermore, the criteria were validated for applicability in actual clinical cases, and public comments were solicited from the Japan College of Rheumatology and other associated societies. CONCLUSION: After being reviewed through public comments, the revised diagnostic criteria have been finalized.

Development and exacerbation of pulmonary nontuberculous mycobacterial infection in patients with systemic autoimmune rheumatic diseases.

Objectives: To examine the development and exacerbation of pulmonary nontuberculous mycobacterial (NTM) infection in patients with systemic autoimmune rheumatic diseases (SARD).Methods: We conducted a case-control study. Seventeen of 7013 patients with SARD fulfilling the criteria for pulmonary NTM infection were enrolled in the NTM group. The control group was matched for age, sex, and SARD at a ratio of 2:1.Results: Eight patients with rheumatoid arthritis, four with systemic vasculitis, three with Sjögren's syndrome, and one each with dermatomyositis and systemic lupus erythematosus were included in the NTM group. Mycobacterium avium was detected in 12 (71%) patients, M. chelonae in 2, and M. intracellulare, M. abscessus, and M. kansasii in 1 patient each. Preexisting lung disease was more common in the NTM group than in the control group (88% versus 38%, p = .0009), particularly bronchiectasis (65% versus 29%, p = .033). The body mass index and serum albumin level were significantly lower in the NTM group than in the control group. Six patients (35%) experienced NTM exacerbation during observation. Clinical immune status at the time of NTM diagnosis, as indicated by the peripheral blood leukocyte/lymphocyte count and serum immunoglobulin G level, was unremarkable and comparable between patients with and without exacerbation, as were the treatments for SARD.Conclusions: In patients with SARD, pulmonary NTM infection may develop and exacerbate without clinically apparent immunosuppression.

Consensus-based identification of factors related to false-positives in ultrasound scanning of synovitis and tenosynovitis.

INTRODUCTION: We aimed to identify causes of false-positives in ultrasound scanning of synovial/tenosynovial/bursal inflammation and provide corresponding imaging examples. METHODS: We first performed systematic literature review to identify previously reported causes of false-positives. We next determined causes of false-positives and corresponding example images for educational material through Delphi exercises and discussion by 15 experts who were an instructor and/or a lecturer in the 2013 advanced course for musculoskeletal ultrasound organized by Japan College of Rheumatology Committee for the Standardization of Musculoskeletal Ultrasonography. RESULTS: Systematic literature review identified 11 articles relevant to sonographic false-positives of synovial/tenosynovial inflammation. Based on these studies, 21 candidate causes of false-positives were identified in the consensus meeting. Of these items, 11 achieved a predefined consensus (≥ 80%) in Delphi exercise and were classified as follows: (I) Gray-scale assessment [(A) non-specific synovial findings and (B) normal anatomical structures which can mimic synovial lesions due to either their low echogenicity or anisotropy]; (II) Doppler assessment [(A) Intra-articular normal vessels and (B) reverberation)]. Twenty-four corresponding examples with 49 still and 23 video images also achieved consensus. CONCLUSIONS: Our study provides a set of representative images that can help sonographers to understand false-positives in ultrasound scanning of synovitis and tenosynovitis.

Cartilage evaluation by ultrasonography in patients with rheumatoid arthritis: a scoping review.

BACKGROUND: This study aimed to provide an overview of ultrasonographic cartilage evaluation in patients with rheumatoid arthritis (RA) and identify research gaps in the utilization of cartilage evaluation. METHODS: The study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews guidelines. A systematic literature search of the PubMed, Embase, and Cochrane Library databases was conducted for articles published up to July 2022 using the search term variations of "cartilage," "ultrasonography," and "rheumatoid arthritis." Studies that included patients with RA who underwent cartilage evaluation by ultrasonography were selected. Articles published in languages other than English and about juvenile idiopathic arthritis were excluded. RESULTS: Twenty-nine articles were identified. Most were cross-sectional studies (86%), mainly involving the metacarpophalangeal (55%) and knee (34%) joints. Assessments were performed using quantitative, binary, and semi-quantitative methods in 15, 10, and 15 studies, respectively. Reliability assessments were conducted in 10 studies, which showed feasible reliability but were limited to the finger joints. The validity assessment was validated in one study each that compared cartilage thickness measurements with cadaveric specimens and histological and semi-quantitative methods with surgical specimens, respectively. Comparisons with conventional radiography were also performed in six studies, which showed significant correlations. However, there was heterogeneity in the examination and assessment methods, and no adequate longitudinal evaluation was conducted. CONCLUSION: This review highlights the need for further research and validation of ultrasonographic cartilage assessment in patients with RA.

Sustained remission following the discontinuation of tofacitinib in patients with rheumatoid arthritis (XANADU study): an open-label randomised study.

OBJECTIVE: To investigate sustained remission following the discontinuation of tofacitinib in patients with rheumatoid arthritis. METHODS: Patients who had an inadequate response to methotrexate (MTX) with or without biological disease-modifying antirheumatic drugs were randomly divided into two groups at baseline, and tofacitinib treatment in combination with MTX was administered to both groups. Either MTX or tofacitinib was then withdrawn if patients achieved Clinical Disease Activity Index remission at week 52. The primary outcome was the proportion of patients who sustained clinical remission at week 104. RESULTS: A total of 113 patients participated in this study. Among them, a total of 48 patients achieved remission at week 52. After discontinuation of tofacitinib, only 29.2% (7/24) of patients remained remission, while 50.0% (10/20) of patients, which was numerically higher but not statistically significant, sustained remission after MTX discontinuation. A greater proportion of bio-naïve patients achieved remission at week 52 and sustained low disease activity with tofacitinib discontinuation at week 104. Additionally, the patients who were able to discontinue tofacitinib without flares had lower rheumatoid factor (p=0.04) and lower anti-cyclic citrullinated peptide antibody (p=0.051) before discontinuation of tofacitinib. No severe adverse events were recorded after discontinuation of tofacitinib or MTX. In patients who relapsed after tofacitinib discontinuation, 71.4% achieved remission with resumption of tofacitinib. CONCLUSIONS: This study implies that a blanket cessation of tofacitinib may not be suitable for all patients, given that 58% of the participants experienced relapse. However, the withdrawal of tofacitinib is unlikely to result in the acquisition of treatment-resistance.

Reduced Rate of Disease Flares in Japanese Patients with Systemic Lupus Erythematosus: An Altered Balance between the Use of Glucocorticoids and Immunosuppressants in Recent Decades.

Objective This study examined whether or not the disease control in Japanese patients with systemic lupus erythematosus (SLE) had improved in recent years and its possible association with altered balance between the use of glucocorticoids and immunosuppressants. Methods We enrolled Japanese patients with SLE who visited our medical center during 2013-2017 (Group A, 75 patients) and compared them with patients encountered during 1999-2003 (Group B, 69 patients; not overlapping with Group A). Patient background characteristics, doses of glucocorticoids, and the use of immunosuppressants at the times of SLE onset and disease flares were reviewed from the medical records. Disease flare was defined as new British Isles Lupus Assessment Group 2004 A or B scores in at least one system. Results Lupus nephritis and neuropsychiatric manifestations were less frequently observed in Group A than in Group B (p=0.042 and p=0.045, respectively). Although the initial glucocorticoid dosage was similar between the groups, the inclusion rate of immunosuppressants in the initial SLE treatment was significantly higher in Group A than in Group B (56% vs. 6% in Group B, p<0.001). The median number of SLE flares per person-year was significantly lower in Group A than in Group B (0 vs. 0.3, respectively, p<0.001), and a propensity score-matched analysis indicated the association of SLE flare with the non-use of immunosuppressants in the initial treatment (p=0.012). The rates of infectious diseases and other complications were similar between the groups. Conclusion The recent aggressive use of immunosuppressants in Japan resulted in a reduction in the rate of SLE flare.

Performance of the Revised Classification Criteria for Systemic Autoimmune Rheumatic Diseases and Their Overlap Syndromes.

Objective We evaluated the performance of the revised classification criteria for assessing different systemic autoimmune rheumatic diseases and their overlap syndromes. Methods A total of 652 patients with or highly suspected of having systemic lupus erythematosus (SLE), systemic sclerosis (SSc), polymyositis (PM)/dermatomyositis (DM) or rheumatoid arthritis (RA) were included in this study. The 1997 revised American College of Rheumatology (ACR) and the 2019 European League Against Rheumatism (EULAR)/ACR criteria for SLE, the 1980 ACR and the 2013 ACR/EULAR criteria for SSc, the criteria by Bohan and Peter and the 2017 EULAR/ACR criteria for PM/DM, and the 1987 revised ACR and 2011 ACR/EULAR criteria for RA were used for disease classification. Results The old and new criteria and a clinical diagnosis were used to respectively classify 103, 106 and 105 SLE patients; 35, 47 and 58 SSc patients; 18, 23 and 33 PM/DM patients; and 297, 389 and 468 RA patients. Sensitivity increased from 82.9% to 92.4% in SLE, from 56.9% to 79.3% in SSc, from 54.5% to 66.7% in PM/DM, and from 62.6% to 80.8% in RA. SLE-SSc was the predominant type of clinical overlap syndrome, while SLE-RA was the most classifiable. Conclusion The revised classification criteria for all the diseases showed an improved sensitivity, and SLE-overlap syndrome was predominant, regardless of the criteria sets.

Prediction of disease flare by biomarkers after discontinuing biologics in patients with rheumatoid arthritis achieving stringent remission.

To elucidate the disease-flare process in rheumatoid arthritis (RA) after discontinuing biological disease-modifying antirheumatic drugs (bDMARDs), we first focused on RA-flare prediction after achieving stringent remission criteria. Patients with RA who maintained a simplified disease activity index ≤ 3.3 for ≥ 3 months during November 2014-January 2018 in our medical centre in Tokyo, Japan, were eligible. The primary endpoint was flare (disease activity score 28-erythrocyte sedimentation rate ≥ 3.2 with increase from baseline > 0.6) within 2 years after bDMARD discontinuation. Comprehensive clinical assessments, ultrasonographic evaluation of 40 joints, and blood sampling for 12 biomarkers were performed every 2-3 months for 2 years unless patients experienced flare. Flare-positive and flare-negative patients were compared using univariate and Kaplan-Meier analyses. Thirty-six patients (80.6% female, median disease duration, 5.2 years; median treatment period with discontinued bDMARD, 2 years; median remission duration, 18 months) were enrolled. Twenty patients (55.6%) experienced RA flare 43-651 (median, 115) days after the first skipped date of bDMARDs. Two patients who withdrew without disease flare were excluded from the comparison. Clinical and ultrasonographic evaluations did not show significant between-group differences; Kaplan-Meier analysis showed that higher baseline soluble tumour necrosis factor receptor 1 (sTNFR1) concentration impacted subsequent disease flare (p = 0.0041); higher baseline interleukin (IL)-2 concentration was exclusively beneficial to patients with lower sTNFR1 (p = 0.0058), resulting in remission maintenance in 83.3% of patients with lower sTNFR1 and higher IL-2. We demonstrated the usefulness of combined biomarker evaluation for predicting sustained remission after bDMARD discontinuation in RA.

Finger Joint Cartilage Evaluated by Semiquantitative Ultrasound Score in Patients With Rheumatoid Arthritis.

OBJECTIVE: Joint destruction in rheumatoid arthritis (RA) includes both bone and cartilage lesions. Since joint space narrowing (JSN) is not a direct evaluation of cartilage using radiography, we aimed to examine the validity of ultrasound (US) cartilage evaluation using a semiquantitative method in patients with RA. METHODS: We enrolled 103 patients with RA who were in remission or showing low disease activity and 42 healthy subjects. The cartilage thickness of the bilateral metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of the second to fifth fingers was measured by US, and the recorded images were scored semiquantitatively using a scale of 0-2. In addition, the JSN of the corresponding joints was scored using a hand radiograph. The relationships between total cartilage thickness, its semiquantitative score, and JSN score were assessed using Spearman's rank correlation coefficients. RESULTS: Total cartilage thickness was significantly thinner in patients with RA compared to healthy subjects for both the MCP and PIP joints (both P < 0.001). The semiquantitative sum of 16 joints ranged from 2 to 26 (median 8) in patients with RA, which was significantly greater than the 0-11 (median 4) in healthy subjects (P < 0.001). In patients with RA, the semiquantitative score showed a significant negative correlation with cartilage thickness (ρ = -0.64, P < 0.001) and a significant positive correlation with JSN score (ρ = 0.66, P < 0.001). Furthermore, these scores showed a significant correlation with RA disease duration. CONCLUSION: A simplified and direct evaluation of finger joint cartilage damage by semiquantitative US score is valid and useful for patients with RA.

Association of age with the non-achievement of clinical and functional remission in rheumatoid arthritis.

Patient-reported outcome (PRO) is included in the remission criteria of rheumatoid arthritis (RA). We aimed to determine the effect of age on PRO and the subsequent achievement of clinical and functional RA remission criteria. Three hundred and one patients with non-rheumatic diseases were evaluated using the 0-10 cm visual analog scale (VAS) assessment for musculoskeletal symptoms and a functional health assessment questionnaire-disability index (HAQ-DI). These assessments were compared with those obtained from 149 patients with RA with negative tender/swollen joint counts and normal serum C-reactive levels (objective clinical remission). Of the 301 patients, 32.2%, 26.6%, and 41.2% were classified as non-elderly (< 65 years), early elderly (65-74 years), and late-elderly (≥ 75 years) patients, respectively. VAS > 1 cm and HAQ-DI ≥ 0.5 were observed in 7.3% and 14.5%, respectively, in late-elderly patients, whereas ≤ 1.0% of non-elderly and early elderly patients for the both. Among 149 RA patients in objective remission, however, > 20% and > 10% of early elderly patients (and even non-elderly patients) had VAS > 1 cm and HAQ-DI ≥ 0.5, respectively, and 34.0% and 35.8% of late-elderly patients with RA had VAS > 1 cm and HAQ-DI ≥ 0.5, respectively. Multivariate logistic analysis revealed that age and RA were associated with the non-achievement of VAS ≤ 1 cm and HAQ-DI < 0.5. Therefore, the effect of age, which was independent of the presence of RA even without any objective disease activity, on PRO and the non-achievement of clinical and functional remission criteria was demonstrated.

Global assessments of disease activity are age-dependent determinant factors of clinical remission in rheumatoid arthritis.

OBJECTIVE: The aim of the study is to assess the factors associated with clinical remission of patients with rheumatoid arthritis (RA) in daily clinical practice. METHODS: This analysis was based on the data of 304 RA patients in our center between May 2014 and March 2015. The following information was included: tender, swollen, and symptomatic joint counts, patient's and physician's global assessments, functional disability, laboratory and radiographic data, and RA treatments received. RESULTS: The patients were predominantly female (77.6%), with a median age of 71 years and a median disease duration of 5.8 years. Clinical remission rate, determined using the simplified disease activity index (SDAI), was 49.7%. Patient's and physician's global assessments (/10cm) showed a higher score among patients who did not achieve SDAI remission than among those who did (median: 3.2 versus 0.3, p < 0.0001; and median: 1.8 versus 0.3, p < 0.0001, respectively). The contribution of serum C-reactive protein values (mg/dL) to SDAI was limited (median: 0.19 versus 0.06; p < 0.0001), as well as tender or swollen joint counts (median = 0 or 1). On multivariate analysis of factors not directly related to the disease activity, age was an independent risk factor for non-remission, and global assessment scores by patients and physicians showed an age-dependent increase, while counts of tender, swollen and symptomatic joints were comparable among elderly and non-elderly patients. CONCLUSION: Global assessment of disease activity was age-dependent and independent of joint counts, and it provides a critical determinant of clinical non-remission.

Concordance of Patient-Reported Joint Symptoms, Physician-Examined Arthritic Signs, and Ultrasound-Detected Synovitis in Rheumatoid Arthritis.

OBJECTIVE: Ultrasonography has been prevalently used as a valid and objective modality for joint examination in patients with rheumatoid arthritis (RA). This study aimed to examine and compare the concordance between ultrasound, clinical assessment, and patient-reported assessment of joint synovitis in RA. METHODS: Fifty patients with RA (84% female, median age 69 years, median disease duration 31 months, and median Disease Activity Score in 28 joints 3.8) completed the self-evaluation of joint symptoms, including pain and considerable stiffness in the (proximal) interphalangeal, metacarpophalangeal, wrist, elbow, shoulder, knee, and ankle joints. These joints were also examined by a physician in order to assess the presence of tenderness or swelling; the presence of imaging synovitis was assessed by ultrasonography. RESULTS: In a total of 1,492 evaluated joints, symptoms (pain and stiffness), tenderness, and swelling were noted in 288 (19.3%), 182 (12.2%), and 220 (14.7%) joints, respectively, while ultrasound indicated synovitis in 317 (21.2%) joints. Overall concordance with ultrasound findings was lowest for joint tenderness (κ = 0.30), followed by symptoms (κ = 0.39), and by swelling (κ = 0.43), irrespective of the evaluated joint, except for the elbow. Moreover, the percentages of inflamed joints detected only on the basis of symptoms, tenderness, or swelling were 18.6%, 2.2%, and 8.5%, respectively, of all joints with signs of synovitis on ultrasonography. CONCLUSION: Joint swelling showed the best concordance with ultrasonography, followed by patient-reported joint symptoms, and joint tenderness. Joint symptoms, rather than tenderness evaluation, may be a better clinical indicator of synovitis in RA patients.

[Autoimmune diseases and seasonal variations].

It has been reported that the exacerbation or development of autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis may have seasonality, although the seasonal characteristic depends on each disease. For example, the sunlight (ultraviolet) and infectious pathogens are involved in important environmental factors contributing the seasonality of the diseases. Furthermore, recent advances include the association between vitamin D and autoimmune diseases, and the different pathogenesis among the same clinical category according to the autoantibodies.