Management and treatment outcomes of rheumatoid arthritis in the era of biologic and targeted synthetic therapies: evaluation of 10-year data from the KURAMA cohort.

BACKGROUND: Advances in rheumatoid arthritis (RA) treatment, highlighted by biological disease-modifying antirheumatic drugs (bDMARDs) and targeted synthetic DMARDs (tsDMARDs), have altered the paradigm of RA treatment in the last decade. Therefore, real-world clinical evidence is needed to understand how treatment strategies and outcomes have changed. METHODS: Using an observational cohort of RA from 2012 to 2021, we collected cross-sectional data of RA patients annually to analyze a trend in RA management. For patients who initiated b/tsDMRDs, we evaluated treatment outcomes between b/tsDMARDs. Mixed-effect models were applied to examine the statistical implications of changes over time in treatment outcomes with a background adjustment. RESULTS: We analyzed annual cross-sectional data from 5070 patients and longitudinal data from 1816 patients in whom b/tsDMARDs were initiated between 2012 and 2021. b/tsDMARD use increased, whereas glucocorticoid use decreased from 2012 to 2021. Disease activity and functional disability measures improved over time. The percentage of tsDMARD prescriptions considerably increased. All b/tsDMARDs showed clinical improvements in disease activity and functional disability. Statistically, TNFi showed better short-term improvements in b/tsDMARD-naïve patients, while IL6Ri demonstrated significant long-term benefits. IL6Ri had better retention rates in switched patients. After adjustment for patient characteristics, the annual change of RA disease activity and functional disability fared significantly better from 2012 to 2021. CONCLUSIONS: With the development of new RA therapeutics, overall treatment outcomes advanced in the past decade.

Genetic architecture underlying IgG-RF production is distinct from that of IgM-RF.

OBJECTIVE: HLA-DRB1 alleles, particularly the shared epitope (SE) alleles, are strongly associated with RA. Different genetic structures underlie the production of the various autoantibodies in RA. While extensive genetic analyses have been conducted to generate a detailed profile of ACPA, a representative autoantibody in RA, the genetic architecture underlying subfractions of RF other than IgM-RF, namely IgG-RF, known to be associated with rheumatoid vasculitis, is not well understood. METHODS: We enrolled a total of 743 RA subjects whose detailed autoantibody (IgG-RF, IgM-RF, and ACPA) data were available. We evaluated co-presence and correlations of the levels of these autoantibodies. We analysed associations between the presence or levels of the autoantibodies and HLA-DRB1 alleles for the 743 RA patients and 2008 healthy controls. RESULTS: We found both IgG-RF(+) and IgG-RF(-) RA subjects showed comparable associations with SE alleles, which was not observed for the other autoantibodies. Furthermore, there was a clear difference in SE allele associations between IgG-RF(+) and (-) subsets: the association with the IgG-RF(+) subsets was solely driven by HLA-DRB1*04:05, the most frequent SE allele in the Japanese population, while not only HLA-DRB1*04:05 but also HLA-DRB1*04:01, less frequent in the Japanese population but the most frequent SE allele in Europeans, were main drivers of the association in the IgG-RF(-) subset. We confirmed that these associations were irrespective of ACPA presence. CONCLUSION: We found a unique genetic architecture for IgG-RF(-) RA, which showed a strong association with a SE allele not frequent in the Japanese population but the most frequent SE allele in Europeans. The findings could shed light on uncovered RA pathology.

Ultrasonographic Changes of the Knee Joint Reflect Symptoms of Early Knee Osteoarthritis in General Population; The Nagahama Study.

OBJECTIVE: Radiographic changes in knee osteoarthritis (OA) are not always associated with symptoms, especially in its early stages. Ultrasonography (US) can detect early changes in the knee joint, but the changes that reflect symptoms have not been fully elucidated. This study aimed to identify US-detectable changes in the knee that are often associated with knee symptoms and demonstrate the feasibility of early diagnosis in symptomatic knee OA using US. DESIGN: In this cross-sectional community-based study, 1,667 participants aged ≥60 years (1,103 women [66%]) were included. All participants concurrently underwent US and radiography of the knee and completed the Knee Society Knee Scoring System (KSS) questionnaire. Simple and multiple regression analyses were used to examine the associations between US findings and KSS symptom subscales. RESULTS: Among all participants, medial meniscus protrusion and medial osteophytes, age, and body mass index showed significant associations with KSS symptom scores. Among 894 participants with Kellgren-Lawrence (KL) grade ≤1, medial osteophytes and age were significantly associated with KSS symptom score. US measures were more related to KSS symptoms than KL grades. CONCLUSIONS: Among the knee US-detectable changes, medial osteophytes were strongly associated with knee symptoms. Osteophytes are reliable predictors of symptomatic early knee OA, even in participants with few radiographic OA changes.

Region specificity of rheumatoid foot symptoms associated with ultrasound-detected synovitis and joint destruction.

OBJECTIVES: We aimed to clarify the clinical implication of ultrasound (US)-detected foot joint inflammation in tightly controlled patients with rheumatoid arthritis (RA). METHODS: We evaluated bilateral foot joints (second to fifth metatarsophalangeal joints of forefoot; tarsometatarsal, cuneonavicular and midtarsal joints of midfoot) of 430 RA patients for synovitis using Power Doppler (PD) imaging by US. We made a cross-sectional and a 3-year longitudinal analysis about the associations of US-detected synovitis with clinical, laboratory and radiographic data as well as foot-specific outcomes using a self-administered foot evaluation questionnaire (SAFE-Q). RESULTS: The US-detected foot synovitis was seen in 28% of patients. The US-detected synovitis was closely related to 28 joint-disease activity score (DAS28) more in the forefoot than in the midfoot, while related to joint destruction in both. Multiple regression analyses showed significant associations between midfoot PD positivity and SAFE-Q in the remission group. SAFE-Q was worsened after the 3-year interval, but PD positivity at baseline did not contribute to the changes. On the other hand, destruction of the joints with US-detected synovitis significantly progressed in 3 years than with not. CONCLUSIONS: US-detected synovitis on foot joints were related to systemic inflammation, clinical symptoms, and future joint destruction with region specificity.

Tenderness of the knee is associated with thinning of the articular cartilage evaluated with ultrasonography in a community-based cohort: The Nagahama study.

OBJECTIVES: This study aimed to elucidate the association between joint line tenderness (JLT) of the knee and knee joint structural changes evaluated with ultrasonography (US) for the early diagnosis of knee osteoarthritis (KOA). METHODS: This cross-sectional study included 121 participants (age 71.7 ± 5.8 years, 75 women) from a community-based population. Bilateral structural changes in the knee joint were evaluated with US, and the presence or absence of JLT was evaluated using a pressure algometer. Logistic regression analysis was performed to evaluate the odds ratios (ORs) of US findings for the presence of JLT. Moreover, when the analysis was limited to knees with pre-/early radiographic KOA, the ORs were also calculated using logistic regression analysis. RESULTS: Among the 242 knees, 38 had medial JLT, which was significantly associated with female sex (OR 11.87) and loss of cartilage thickness of the distal medial femoral condyle (CTh-MFC) (OR 0.12). Among 96 knees with Kellgren-Lawrence grade ≤ 2, 18 knees had medial JLT, which was also significantly associated with loss of CTh-MFC (OR 0.07) and medial osteophytes (OR 2.01). CONCLUSIONS: JLT is significantly associated with thinning of the femoral cartilage and larger osteophytes in elderly patients, even in those with pre-/early radiographic KOA.

Factors associated with anxiety and depression in rheumatoid arthritis patients: a cross-sectional study.

BACKGROUND: The management of anxiety and depression symptoms in rheumatoid arthritis (RA) patients is vital. Previous study findings on this topic are conflicting, and the topic remains to be thoroughly investigated. This study aimed to clarify the association of RA disease activity with anxiety and depression symptoms after controlling for physical disability, pain, and medication. METHODS: We conducted a cross-sectional study of RA patients from the XXX Rheumatoid Arthritis Management Alliance cohort. We assessed patients using the Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and Hospital Anxiety and Depression Scale (HADS). Anxiety and depression symptoms were defined by a HADS score ≥ 8. We analyzed the data using multivariable logistic regression analyses. RESULTS: Of 517 participants, 17.6% had anxiety symptoms and 27.7% had depression symptoms. The multivariable logistic regression analysis demonstrated that DAS28 was not independently associated with anxiety symptoms (odds ratio [OR] [95% confidence interval; CI] 0.93 [0.48-1.78]; p = 0.82) and depression symptoms (OR [95% CI] 1.45 [0.81-2.61]; p = 0.22). However, DAS28 patient global assessment (PtGA) severity was associated with anxiety symptoms (OR [95% CI] 1.15 [1.02-1.29]; p = 0.03) and depression symptoms (OR [95% CI] 1.21 [1.09-1.35]; p < 0.01). Additionally, HAQ-DI scores ≤ 0.5 were associated with anxiety symptoms (OR [95% CI] 3.51 [1.85-6.64]; p < 0.01) and depression symptoms (OR [95% CI] 2.65 [1.56-4.50]; p < 0.01). Patients using steroids were more likely to have depression than those not using steroids (OR [95% CI] 1.66 [1.03-2.67]; p = 0.04). CONCLUSIONS: No association was found between RA disease activity and anxiety and depression symptoms in the multivariable logistic regression analysis. Patients with high PtGA scores or HAQ-DI scores ≤ 0.5 were more likely to experience anxiety and depression symptoms, irrespective of disease activity remission status. Rather than focusing solely on controlling disease activity, treatment should focus on improving or preserving physical function and the patient's overall sense of well-being.

Severe joint deformity and patient global assessment of disease are associated with discrepancies between sonographic and clinical remission: A cross-sectional study of rheumatoid arthritis patients.

OBJECTIVE: Although recent clinical trials showed that ultrasound (US) remission is not required to achieve good outcomes at the group level, it currently remains unclear whether the prognosis of individual patients in clinical remission, but not US remission, i.e. those with subclinical sonographic synovitis (SSS), is favorable. However, it is no longer acceptable to perform US on all patients in order to identify those with SSS. Therefore, the present study was initiated to elucidate the conditions under which SSS is frequently detected. METHODS: In total, 563 consecutive RA patients were recruited. Bilateral 2-5 MCP, wrist, ankle, and 2-5 MTP joints were scanned by US, and Gray scale and Power Doppler (PD) images were scored semi-quantitatively. Clinical data were obtained by physicians who were blind to US results. Changes in the modified Total Sharp Score (mTSS) of tocilizumab (TCZ) users were calculated. RESULTS: A total of 402 patients were included. SSS was more frequently detected in patients with more severe joint deformity, even if they were in remission. In contrast, a high Patient Global Assessment of Disease (PtGA) did not reflect SSS. Furthermore, the relationship between PtGA and PD scores was weak. Although the frequency of SSS was high in TCZ user, the presence of SSS in TCZ users not always results in the progression of mTSS. CONCLUSIONS: While remission is overestimated in patients with severe joint deformity, underestimations may occur in those who do not fulfill remission criteria because of a high PtGA.

Factors associated with anxiety and depression in rheumatoid arthritis patients: a cross-sectional study

Abstract Background: The management of anxiety and depression symptoms in rheumatoid arthritis (RA) patients is vital. Previous study findings on this topic are conflicting, and the topic remains to be thoroughly investigated. This study aimed to clarify the association of RA disease activity with anxiety and depression symptoms after controlling for physical disability, pain, and medication. Methods: We conducted a cross-sectional study of RA patients from the XXX Rheumatoid Arthritis Management Alliance cohort. We assessed patients using the Disease Activity Score (DAS28), Health Assessment Questionnaire Disability Index (HAQ-DI), and Hospital Anxiety and Depression Scale (HADS). Anxiety and depression symptoms were defined by a HADS score ≥ 8. We analyzed the data using multivariable logistic regression analyses. Results: Of 517 participants, 17.6% had anxiety symptoms and 27.7% had depression symptoms. The multivariable logistic regression analysis demonstrated that DAS28 was not independently associated with anxiety symptoms (odds ratio [OR] [95% confidence interval; CI] 0.93 [0.48-1.78]; p = 0.82) and depression symptoms (OR [95% CI] 1.45 [0.81-2.61]; p = 0.22). However, DAS28 patient global assessment (PtGA) severity was associated with anxiety symptoms (OR [95% CI] 1.15 [1.02-1.29]; p = 0.03) and depression symptoms (OR [95% CI] 1.21 [1.09-1.35]; p < 0.01). Additionally, HAQ-DI scores ≤ 0.5 were associated with anxiety symptoms (OR [95% CI] 3.51 [1.85-6.64]; p < 0.01) and depression symptoms (OR [95% CI] 2.65 [1.56-4.50]; p < 0.01). Patients using steroids were more likely to have depression than those not using steroids (OR [95% CI] 1.66 [1.03-2.67]; p = 0.04). Conclusions: No association was found between RA disease activity and anxiety and depression symptoms in the multivariable logistic regression analysis. Patients with high PtGA scores or HAQ-DI scores ≤ 0.5 were more likely to experience anxiety and depression symptoms, irrespective of disease activity remission status. Rather than focusing solely on controlling disease activity, treatment should focus on improving or preserving physical function and the patient's overall sense of well-being.

Destructive arthritis with cutaneous polyarteritis nodosa requiring surgical intervention: a case report and review of the literature.

Arthralgia is a well-known complication of cutaneous polyarteritis nodosa (CPN). However, few cases of destructive arthritis with CPN resulting in chronic pain and disability have been documented. Here we report a case of CPN associated with destructive arthritis of the right foot, accompanied by seronegative arthritis in the right ankle, for which orthopaedic surgery was necessary. X-ray and computed tomography revealed progressive joint destruction in the right talonavicular joint, and magnetic resonance imaging demonstrated severe synovitis of the right talocrural joint. When the talonavicular joint was opened, we observed marked synovitis and a defect in the cartilage that had expanded within the joint. Although mild cartilage degeneration was observed in the talocrural joint, arthroscopic observation revealed no massive defect on the articulated surface. Arthrodesis and arthroscopic synovectomy yielded a good midterm clinical outcome, indicating that surgical intervention was useful for the treatment for destructive arthritis with CPN. Rheumatologists and orthopaedic surgeons should be aware of potential complications such as destructive arthritis when treating patients with CPN.

Soluble Lectin-like Oxidized Low-Density Lipoprotein Receptor 1 Predicts the Changes of Rheumatoid Factor Titers in Rheumatoid Arthritis.

OBJECTIVE: The aim of this longitudinal study was to examine the clinical significance of soluble lectin-like oxidized low-density lipoprotein receptor 1 (sLOX-1) in patients with rheumatoid arthritis. METHODS: We gathered demographic and clinical data for a large rheumatoid arthritis cohort at 3 time points. Blood samples were collected at each time point; the number of samples was 282 cases in 2012, 431 cases in 2013, and 500 cases in 2014. Plasma sLOX-1 was measured by enzyme-linked immunosorbent assay. Correlations between sLOX-1 and clinical data were analyzed. Predictive factors associated with changes in sLOX-1 and rheumatoid factor (RF) were analyzed by multivariate linear regression. RESULTS: Plasma sLOX-1 level was significantly correlated with RF titer and other clinical parameters. The longitudinal analyses showed that changes in sLOX-1 were significantly correlated with changes in RF titers and with those at baseline. Multivariate linear regression analysis revealed that changes in RF and baseline RF were predictive factors for changes in sLOX-1. Conversely, the changes in RF were significantly correlated with the changes in sLOX-1 in all years. A stepwise regression analysis showed that the change in sLOX-1 was a predictive factor for the change in RF. CONCLUSIONS: The change in sLOX-1 has predictive value for assessing the change in RF, indicating the usefulness of sLOX-1 in clinical practice.

The minimum clinically important difference for the Japanese version of the new Knee Society Score (2011KSS) after total knee arthroplasty.

BACKGROUND: The new Knee Society Score (2011KSS) has been used to evaluate post-operative outcomes after total knee arthroplasty (TKA). However, there is no minimum clinically important difference (MCID) for 2011KSS. The purpose of this study is to define MCID of 2011KSS after TKA. METHODS: Patients who underwent primary TKA for primary knee osteoarthritis between April 2012 and December 2016 were included in the study. The Japanese version of 2011KSS and original Knee Society Score (OKSS) were recorded preoperatively and at one-year postoperatively. With improvement in pain score of OKSS as an anchor, an anchor-based approach was used to identify the MCID of 2011KSS. The improvement in pain of OKSS was classified into 5 categories. The MCID was determined using a linear regression analysis of delta 2011KSS against improvement in the category of pain in OKSS. The MCID for 2011KSS expectation was not calculated because the items of pre- and post-operative questionnaires were different. RESULTS: Five hundred and twenty-two cases were enrolled (age: 74.8 ± 7.3 years, female: 80.0%). After 1-year follow-up, 344 TKAs were finally included (age: 74.6 ± 7.1 years, female: 77.9%). Linear regression analyses showed that MCID for 2011KSS was 1.9 (95% confidential interval (CI): 1.3-2.5) in symptom, 2.2 (95%CI: 1.4-2.9) in satisfaction, and 4.1 (95%CI: 2.5-5.7) in functional activities. CONCLUSIONS: MCID for 2011KSS was successfully calculated. These MCID values make the 2011KSS a more efficient tool for evaluating the physical activities of the populations of patients undergoing TKA. These MCID values can also be used to calculate sample size to evaluate the power of a study in designing clinical studies.

Low back pain precedes the development of new knee pain in the elderly population; a novel predictive score from a longitudinal cohort study.

BACKGROUND: To investigate the association between knee pain and risk factors including low back pain and to develop a score to predict new knee pain in an older population, using population-based longitudinal cohort data. METHODS: We collected a questionnaire on self-reported knee pain and demographic data in a systematic manner from community residents aged ≥ 50 years twice, at baseline, and after 5 years. Multivariate logistic regression analyses were performed to investigate the association between knee pain and risk factors and to build a predictive model that would enable calculation of the risk of the development of knee pain within 5 years. The model is presented in the form of score charts. RESULTS: A total of 5932 residents aged ≥ 50 years from the cohort of 9764 that completed the first questionnaire were enrolled in the second survey. After exclusions, paired data for the two time points an average of 5.4 years apart were analyzed for 4638 participants. Multivariate analyses showed older age, female sex, higher BMI, weight increase, lower mental health score, and higher back pain/disability score were independent risk factors for knee pain. The predictive score comprised six factors: age, sex, BMI, weight increase, mental health, and low back pain/disability. The risk of developing knee pain ranged from 11.0 to 63.2% depending on the total score. CONCLUSION: This study demonstrated a significant association between knee and low back pain/disability along with other risk factors. The score we developed can be used to identify a population without any imaging modality who are at high risk of developing knee pain.

The Effects of Well-Rounded Exercise Program on Systemic Biomarkers Related to Cartilage Metabolism.

Nonsurgical treatment such as exercise is the preferred method for management of knee osteoarthritis (OA). A combination of aerobic, muscle strengthening, and flexibility exercises is recommended for older adults. However, effects of the exercise intervention on cartilage metabolism remain unclear. This study used biomarkers to investigate the effects of well-rounded exercise program on cartilage metabolism in 42 women (mean age: 59 years). Participants started a weekly supervised exercise program and continued for 12 weeks. Before and after the program, we measured physical performance on the Timed Up-and-Go Test, 3-Minute Walk Test, and 30-Second Chair Stand Test. We collected serum and urine samples at the start of the program until 24 weeks and measured the concentrations of 4 biomarkers related to type II collagen metabolism: serum cartilage type II procollagen carboxy propeptide (sPIICP), urine C-terminal telopeptide of collagen type II (uCTX-II), urine cleavage of type II collagen by collagenases (uC2C), and serum cartilage oligomeric matrix protein (sCOMP). Participants were divided into pre-OA and OA groups based on X-ray findings. The pre-OA group showed significant increases and decreases in sPIICP and uCTX-II concentrations with improved physical performance, respectively. sCOMP concentrations significantly increased in both groups. The exercise also improved physical performance with no detrimental effect on type II collagen metabolism in the OA group. Thus, well-rounded exercise may not only improve physical capacity but also have beneficial effects on type II collagen metabolism, especially in people without radiological OA.

Effect of Physical State on Pain Mediated Through Emotional Health in Rheumatoid Arthritis.

OBJECTIVE: Pain is one of the main symptoms of patients with rheumatoid arthritis (RA). Pain in RA is caused by specific physical changes, such as joint destruction, and is therefore used as a disease activity marker. Although pain can also be influenced by emotional factors, neither the effect of emotional health nor the indirect effect of the physical state mediated by emotional health on pain has been quantified. METHODS: A total of 548 patients with RA participated. Emotional health was assessed using the Hospital Anxiety and Depression Scale (HADS). Measures routinely used in practice were used to evaluate the physical state and pain. To quantify the effects of the physical state on emotional health, and the effects of both physical and emotional health on pain, we used structural equation modeling, with emotional health, physical state, and pain as latent variables. RESULTS: The prevalence of anxiety and depression (HADS score ≥8 for each) among patients with RA was 18.7% and 29.4%, respectively. Emotional health was significantly influenced by the physical state (ß = 0.21). Pain was affected by physical (ß = 0.54) and emotional health (ß = 0.29). The effect of the physical state on pain was mediated by emotional health, with this mediation effect (ß = 0.06) accounting for 10.2% of the total effect. CONCLUSION: The magnitude of pain in RA is determined by the mediation effect of emotional health as well as the direct physical state. Our findings suggest that emotional factors should be taken into account when assessing RA disease activity.

Prevalence and factors associated with sarcopenia in patients with rheumatoid arthritis.

Objectives: Sarcopenia is characterized by loss of muscle strength and mass, leading to falls and adverse health outcomes. Our aim was to determine the prevalence of sarcopenia in patients with rheumatoid arthritis (RA) and to identify factors associated with sarcopenia in these patients. Methods: A cross-sectional study of 388 consecutive women with RA was conducted, assessing muscle mass and strength, and walking speed. Falls and bone fractures sustained over the prior year were evaluated. The association between sarcopenia and RA characteristics, falls, and bone fractures was evaluated using logistic regression analyses. Results: The prevalence of sarcopenia was 37.1% (14.7%, severe sarcopenia; 22.4%, sarcopenia), with 49.0% classified as having low muscle mass. The incidence of falls, fractures, and lower bone mineral density was higher in patients with than without sarcopenia. Age, RA duration, Steinbrocker's stage, the high Mini-Nutritional Assessment-Short Form score and the use of biological disease-modifying anti-rheumatic drugs (bDMARDs) were independent factors associated with sarcopenia. Conclusion: We confirmed that sarcopenia develops in a significant proportion of patients with RA. Age, longer disease duration, joint destruction and malnutrition were positively associated with sarcopenia, with the use of bDMARDs being negatively associated.

No differences in patient-reported outcomes between medial pivot insert and symmetrical insert in total knee arthroplasty: A randomized analysis.

BACKGROUND: Although total knee arthroplasty (TKA) using a medial pivot insert reportedly improves kinematics compared with a symmetrical insert, improvements in patient-reported outcomes have not yet been reported. The aim of this study was to determine whether insert designs influenced patient-reported outcomes. METHODS: Seventy TKAs for osteoarthritis were randomly allocated to a symmetrical dish insert (SD group: 35 knees) or medial pivot insert (MP group: 35 knees). Thirty-two of the SD group (74.4 ±â€¯6.6 years old) and 33 of the MP group (73.8 ±â€¯6.0 years old) completed the two-year follow-up. The knee range of motion (ROM) and 2011 Knee Society score (2011KSS) were analyzed pre-operatively and postoperatively. RESULTS: There was no difference in pre-operative ROM or 2011KSS (Symptom: 7.3 ±â€¯5.9 in SD group, 8.4 ±â€¯5.4 in MP group, P = 0.432; Satisfaction: 12.6 ±â€¯6.9 in SD group, 11.8 ±â€¯5.9 in MP group, P = 0.581; Activity: 35.8 ±â€¯18.1 in SD group, 35.2 ±â€¯18.6 in MP group, P = 0.883). At two years, although both group showed good improvement, there were no differences in ROM or 2011KSS (Symptom: 19.3 ±â€¯5.0 in SD group, 18.3 ±â€¯4.1 in MP group, P = 0.351; Satisfaction: 24.0 ±â€¯7.6 in SD group, 22.9 ±â€¯7.9 in MP group, P = 0.548; Activity: 60.3 ±â€¯14.8 in SD group, 54.3 ±â€¯17.3 in MP group, P = 0.137). CONCLUSIONS: The medial pivot insert was not superior to the symmetrical insert in patient-reported outcomes at two years after TKA.