Clinical features and human T-cell leukemia virus type-1 (HTLV-1) proviral load in HTLV-1-positive patients with rheumatoid arthritis: Baseline data in a single center cohort study.

Objective: Recently, Human T-cell leukemia virus type-1 proviral load (HTLV-1 PVL) has been evaluated as an important predictor of adult T-cell leukemia/lymphoma (ATL) in HTLV-1 carriers. We aimed to evaluate whether HTLV-1 PVL is also important for the development of ATL among HTLV-1-positive patients with rheumatoid arthritis (RA).Methods: We established a cohort of 82 HTLV-1-positive RA patients between 2017 and 2018. Of those, 27 (32.9%) were treated with biological disease-modifying anti-rheumatic drugs (bDMARDs) with/without methotrexate. We measured HTLV-1 PVL in peripheral blood mononuclear cells (PBMCs) at study entry and compared the value by clinical status and treatment options.Results: The median PVL for all was 9.6 copies per 1000 PBMCs without sex difference (male 17.2 and female 8.6; p = .24). The median PVL was significantly higher for patient's comorbid bronchiectasis, malignancies, and opportunistic infectious diseases, compared with patients without comorbidity. There were no significant differences in PVL levels among types of bDMARDs, although the level was tended to be higher for patients treated with JAK inhibitor.Conclusions: HTLV-1 seropositive RA patients comorbid for any diseases having higher HTLV-1 PVLs will be a higher risk for developing ATL. Careful follow-up of these patients is necessary to detect ATL development.

Clinical predictors of inadequate response to conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis patients: A single-center observational study.

Objectives: To investigate predictors of inadequate response to first conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) including methotrexate (MTX) in untreated rheumatoid arthritis (RA) patients in daily clinical practice.Methods: Inadequate response to MTX or other csDMARDs was defined as being not low disease activity at 12 months in more than 3 of 4 composite measures, and discontinuation or start of biologic DMARDs. The association between baseline factors and csDMARDs-IR was assessed by univariate and multivariate logistic regression analyses.Results: Four hundred and eleven and 146 patients were started on MTX and other csDMARDs, respectively; 218 patients were responsive to MTX, with a response rate of 47.0%. Tender joint count (TJC, ≥6 in 28joints, odds ratio [OR] = 1.67, 95% confidence interval [CI] 1.06-2.64) and CRP (≥1.0 mg/dL, OR = 1.72, 95%CI: 1.10-2.70) at baseline were identified as predictors on multivariate logistic regression analysis. TJC (OR = 3.60, 95%CI: 1.29-10.00) was the factor identified as a predictor of the development of other csDMARDs-IR.Conclusion: In this observational study, patients with untreated RA at risk of inadequate response to MTX included those with a higher TJC and higher CRP, while a higher TJC was the only independent predictor of an inadequate response to csDMARDs other than MTX.

Hepatitis B virus reactivation in patients with rheumatoid arthritis: A single-center study.

OBJECTIVES: This study aimed to investigate the frequency of hepatitis B virus (HBV) reactivation in patients with rheumatoid arthritis (RA) and to verify the guidelines relating to HBV reactivation in Japan. METHODS: We retrospectively investigated 1351 RA patients who were treated with antirheumatic drugs at our hospital. RESULTS: Fifty patients (3.7%; 50/1351) were determined to be HBV carriers and 360 patients (26.7%; 360/1351) had resolved infections. HBV reactivation occurred in six cases (1.7%: 6/360) with resolved infections, of whom, two cases (0.6%; 2/360) developed de novo HBV infections. Eleven of the patients who were HBV carriers received a nucleoside analogue (NA) prophylactically. In all of the cases, the HBV-DNA levels became undetectable and the patients' liver function normalized. Sixteen patients, who had lower titers of the HBV surface antigen and undetectable HBV-DNA levels, did not show HBV reactivation in the absence of NA therapy. CONCLUSIONS: The results from this study suggest that HBV reactivation might not be so frequent among RA patients, and that reliable indicators for prescribing a NA should be clarified for RA patients.

Evaluation of switching from intravenous to subcutaneous formulation of tocilizumab in patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the efficacy of switching the route from intravenous tocilizumab (TCZ) infusion (TCZ-IV) to subcutaneous TCZ injection (TCZ-SC) in a real-world setting through a comparison of the clinical response. METHODS: Fifty-eight rheumatoid arthritis (RA) patients, for whom TCZ-SC was initiated following TCZ-IV between June 2013 and August 2014, were consecutively enrolled. Disease activity score (DAS)28-ESR, simplified disease activity index (SDAI), and clinical disease activity index (CDAI) were examined at baseline and after switching from TCZ-IV to TCZ-SC for 3 months. We investigated whether body weight and body mass index (BMI) affected the efficacy of TCZ-SC. RESULTS: Most of the patients had achieved remission or low disease activity at baseline (77.6% examined by DAS28). Fifty-seven patients (98%) continued the TCZ-SC treatment, and the disease activity was well controlled after 3 months. ΔDAS28 tended to be worsened after switching to TCZ-SC in the high-body-weight groups (≥60 kg) as compared with the groups with body weight <60 kg, although no statistical significance was found. BMI did not affect the efficacy of TCZ-SC. CONCLUSIONS: Caution should be exercised in the high-body-weight subjects, but these data indicate that TCZ-SC maintains the favorable RA disease activity established using TCZ-IV.

Improvement of plasma endothelin-1 and nitric oxide in patients with systemic sclerosis by bosentan therapy.

The aim of this study was to evaluate the effects of bosentan on plasma endothelin-1 (ET-1) and nitric oxide (NO) as pulmonary hypertension (PH)-associated biochemical markers in patients with systemic sclerosis (SSc). Twenty-four SSc patients receiving bosentan for 24 weeks were registered in this prospective observational study. Ten patients were complicated with clinically suspected PH. Plasma levels of ET-1 and NO were assessed at baseline and after 24 weeks of treatment in SSc patients and in 15 healthy controls. Plasma levels of ET-1 and NO at baseline were significantly higher in SSc patients than in healthy controls (p < 0.000), and they were also significantly higher in SSc patients with PH than in those without PH (p < 0.01). Plasma ET-1 levels were significantly decreased after 24 weeks of bosentan therapy (p < 0.0001), and ET-1 levels of SSc patients with PH decreased to a level comparable to that in patients without PH. In the 10 SSc patients with PH, changes in plasma ET-1 levels during the 24 weeks of the study were significantly larger in the 5 patients whose functional class (FC) improved than in the 5 patients whose FC was unchanged (p < 0.05). Plasma NO levels were also slightly decreased in SSc patients after 24 weeks of bosentan therapy. Plasma ET-1 levels could reflect the presence and severity of PH in SSc patients. Additionally, changes in plasma ET-1 levels may indicate the response to bosentan therapy in SSc patients with PH.

A Case Series of Rheumatoid Arthritis Flare Including Extra-articular Manifestations Following SARS-CoV-2 mRNA Vaccination: A Comprehensive Cytokine Assay.

INTRODUCTION: The administration of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccines has played a pivotal role in managing the COVID-19 pandemic. Nonetheless, there have been instances of atypical immune reactions to the vaccine, notably among patients with autoimmune inflammatory rheumatic diseases such as rheumatoid arthritis (RA). AIM: This study was designed to analyze the cytokine profiles of RA patients who suffered from severe or fatal disease flares after receiving the SARS-CoV-2 mRNA vaccine, to unravel the immunological bases for such responses. METHODS: We conducted a retrospective observational study involving three RA patients. These individuals had their disease under control prior to experiencing severe disease flares post-mRNA vaccination. A detailed serum cytokine analysis was carried out and compared with that of a healthy control group. RESULTS: Post-vaccination, each patient displayed a marked cytokine storm, with notably increased levels of IL-1ß (342, 109, and 27.5 pg/mL, respectively), IL-6 (67.8, 82.7, and 201 pg/mL, respectively), IL-17A (172, 51.6, and 30.3 pg/mL, respectively), and TNF-α (279, 97.5, and 59.4 pg/mL, respectively). Two patients responded well to treatment with biological and synthetic DMARDs, including baricitinib and abatacept. Unfortunately, one patient passed away even after receiving tocilizumab. CONCLUSION: The findings from the comprehensive cytokine assays indicate severe cytokine abnormalities, pointing to cytokine storm syndrome. This suggests that SARS-CoV-2 mRNA vaccination may trigger a disruption in immune homeostasis, potentially leading to the acute worsening of pulmonary complications in RA patients, even those with previously low disease activity. It's necessary to weigh the risks of severe outcomes from COVID-19 against the potential for flares or other adverse reactions following vaccination. Such risk assessments should take into account the individual patient's health status, existing conditions, and other risk factors. Close follow-up after vaccination is crucial, especially for patients with RA.

Comparative analysis of renal decline rates in microscopic polyangiitis: unveiling the slowly progressive phenotype.

Although rapidly progressive glomerulonephritis (RPGN) is the main renal phenotype of microscopic polyangiitis (MPA), we aim to clarify the clinical features of slowly progressive MPA. This retrospective observational study included 12 patients diagnosed with MPA in our hospital between January 2012 and February 2022. We investigated the differences in surrogate markers, rate of decline of estimated glomerular filtration rate (eGFR) between the slowly progressive and rapidly progressive MPA groups. Of the 12 patients with MPA, 3 (25.0%) had slowly progressive MPA: MPA within 30% decrease in eGFR 3 months pretreatment, all of whom developed RPGN during the course. Patients with slowly progressive MPA had lower levels of C-reactive protein, myeloperoxidase anti-neutrophil cytoplasmic antibodies, and interleukin-6; higher levels of sialylated carbohydrate antigen KL-6. Slowly progressive MPA is not uncommon in our hospital. A linear relationship was found between slower rate of eGFR decline and lower surrogate markers of disease activity. Some MPA cases have slowly progressive glomerulonephritis leading to RPGN, which may be clinically characterized by low disease activity. It may be useful to measure myeloperoxidase anti-neutrophil cytoplasmic antibody in chronic kidney disease with concomitant urinary abnormalities to diagnose MPA with slowly progressive glomerulonephritis.

Rapidly progressive glomerulonephritis is the main renal phenotype of microscopic polyangiitis (MPA), and slowly progressive MPA is rarely observed.Slowly progressive MPA was not rare in our hospital and was characterized clinically by low disease activity and complicated by interstitial pneumonia.When encountering patients with undiagnosed chronic kidney disease complicated by interstitial pneumonia, measuring myeloperoxidase anti-nuetrophil cytoplasmic antibody regardless of the rate of renal function decline, potentially leads to the diagnosis of slowly progressive MPA.

Impact of SARS-CoV-2 mRNA vaccine on arthritis condition in rheumatoid arthritis.

Background: The SARS-CoV-2 mRNA vaccine has been reported to cause various adverse reactions, including the development or exacerbation of autoimmune diseases, but the adverse reactions and the effects of the vaccines on disease activity in patients with rheumatoid arthritis (RA) remain unknown. We therefore investigated the arthritis condition in RA patients after SARS-CoV-2 vaccination. Methods: RA patients who visited our hospital from January to April 2022 completed a questionnaire regarding adverse reactions to the SARS-CoV-2 vaccine. We compared the frequency and duration of post-vaccination arthralgia between RA patients and health care workers in our hospital. For the RA patients who reported post-vaccination arthralgia, we collected medical records for the 6 months after vaccination. Results: Of the 1198 vaccinated RA patients, 256 (21.4%) had systemic inflammatory symptoms, 18 (1.5%) had allergies including urticaria and asthma, and 37 (3.1%) had arthralgia. A few patients had extra-articular manifestations such as acute exacerbation of interstitial lung disease. Compared with health care workers, RA patients more frequently developed arthralgia, and the arthralgia was longer lasting than that in controls: only 9 (0.8%) of the 1117 health care workers reported arthralgia, and all cases resolved within 3 days. Data from 31 of the 37 RA patients with post-vaccination arthralgia were further analyzed; in these patients, disease activity was highest after 2 months, and 10 patients required additional DMARDs within 6 months. The proportion of concomitant use of PSL at vaccination was higher in these patients. No patients on biological DMARDs or targeted synthetic DMARDs prior to vaccination needed additional DMARDs or a change of regimen. Conclusion: RA patients had more frequent and longer-lasting arthralgia after vaccination than healthy subjects, and one-third of patients with post-vaccination arthralgia required additional DMARDs. Although the SARS-CoV-2 mRNA vaccine was administered safely in most RA patients, in some patients RA symptoms may worsen after vaccination.

Hypocomplementemic urticarial vasculitis case with hemophagocytic lymphohistiocytosis following SARS-CoV-2 mRNA vaccination.

A 61-year-old man with no previous record of autoimmune disease developed fever, polyarthralgia, purpura, and urticaria-like rash 2 weeks after the first dose of the Moderna mRNA-1273 vaccine, and symptoms deteriorated following the second dose. He presented reduced erythrocyte and platelet counts, hyperferritinemia, high sIL-2R levels, and severe hypocomplementemia. We diagnosed hypocomplementemic urticarial vasculitis (HUVS), and his symptoms as well as laboratory findings improved following treatment with mPSL 1000 mg/day for 3 days and PSL 40 mg/day. Twelve weeks following treatment initiation, the patient relapsed with fever, sore throat, pancytopenia, and hyperferritinemia when the PSL dose was reduced to 12.5 mg/day. Bone marrow biopsy and MRI presented fatty marrow and hemophagocytosis. The patient's blood cells started recovering using ATG + CsA + EPAG therapy for hemophagocytic lymphohistiocytosis (HLH). This is the first case report of HUVS and HLH following SARS-CoV-2 mRNA vaccination. It is presumed that SARS-CoV-2 mRNA vaccine can induce the excessive production of certain types of cytokines, such as TNF-α, IL-1, IL-4, IL-5, IL-6, and IL-17 as a consequence of IL-6 Amplification (IL-6 Amp). SARS-CoV-2 mRNA-vaccines can cause disruption of immune homeostasis in healthy individuals. An extremely rare disease of HUVS complicated by HLH can be developed as a consequence.

The Evaluation of Lipoma Arborescens with Intermittent Knee Joint Effusion Based on an Analysis of Serum Cytokine Levels and an Immunohistological Examination: A Case Report.

We herein report a 27-year-old woman who presented with recurrent knee pain. Laboratory findings revealed minimal inflammation. Arthrography revealed structures resembling adipose tissues. Magnetic resonance imaging showed a high signal intensity of these structures, leading to the diagnosis of lipoma arborescens (LA). Synovectomy was performed. Pathology revealed adipocyte proliferation and B-cell clusters but no T-cell infiltration. A serum cytokine analysis revealed low levels of interleukin-6 and tumor necrosis factor-α compared with patients with rheumatoid arthritis. The pathogenesis of LA remains unclear, but immunostaining and serum cytokine levels may provide valuable data for future investigations.

Tocilizumab-induced hyperbilirubinemia in Japanese patients with rheumatoid arthritis: its association with UDP glucuronosyltransferase 1A1 gene polymorphisms.

This study was performed to explore the possibility of an association between polymorphisms within the uridine diphosphate glucuronosyltransferase 1A1 gene (UGT1A1) and hyperbilirubinemia arising during tocilizumab therapy. We examined the distributions of 3 variant alleles, UGT1A1*6, *28, and *27, in 46 Japanese patients with rheumatoid arthritis (RA) who had received tocilizumab therapy for at least 24 weeks, grouped the patients according to their carriage status of these UGT1A1 variants, and determined the frequency of hyperbilirubinemia in each of the groups. Of the 46 patients treated with tocilizumab, 34 maintained normal bilirubin levels after 24 weeks, whereas the remaining 12 developed mild or moderate hyperbilirubinemia. Patients carrying 2 copies of UGT1A1*28 (*28/*28) were more likely to develop hyperbilirubinemia than those without UGT1A1*28. In addition, patients carrying 2 copies of variant alleles, either as homozygotes (UGT1A1*6/*6 or *28/*28) or as compound heterozygotes (UGT1A1*6/*28), were at higher risk of hyperbilirubinemia as compared with those without either UGT1A1*6 or UGT1A1*28 (odds ratio [OR] 28.33; 95% confidence interval [CI] 2.39-336.00; p = 0.005). Multivariate logistic regression analysis confirmed the strong association of tocilizumab-induced hyperbilirubinemia with the presence of 2 copies of variant alleles (OR 25.51; 95% CI 2.35-276.53; p = 0.008), yielding an area under the receiver operating characteristics curve of 0.78 (95% CI 0.60-0.95, p = 0.005). Tocilizumab can induce hyperbilirubinemia in RA patients, especially those carrying UGT1A1*6/*6, *6/*28, and *28/*28 genotypes. Considering this genetic association, it may be unnecessary to withdraw this drug from RA patients in the absence of other signs of hepatic injury. Given that tocilizumab has the potential to inhibit UGT1A1-mediated glucuronidation, however, it may inhibit not only bilirubin metabolism but also UGT1A1-dependent detoxification of drugs, thereby increasing the risk of unwanted adverse events during RA therapy.

High serum matrix metalloproteinase 3 is characteristic of patients with paraneoplastic remitting seronegative symmetrical synovitis with pitting edema syndrome.

Recently, it was reported that remitting seronegative symmetrical synovitis with pitting edema (RS3PE) syndrome could be complicated with solid tumors. In a retrospective, multicenter study between October, 2003 and September, 2010, we investigated the characteristics of patients with paraneoplastic RS3PE syndrome who fulfilled following criteria: (1) bilateral pitting edema of hands or feet or both, (2) sudden onset of polyarthritis, and (3) age >50 years, (4) seronegativity for rheumatoid factor (RF). A total of 33 cases fulfilled the above criteria. Eight patients (seven men and one woman) developed cancer within 2 years of RS3PE syndrome onset. There was no significant difference between the neoplastic and nonneoplastic groups in the proportions of patients with fever, symmetrical polyarthritis, pitting edema, and good response to corticosteroids. Serum matrix metalloproteinase 3 (MMP-3) level (median 437.3 ng/ml) in the paraneoplastic RS3PE patients was significantly higher than that in patients without neoplasia (median 114.7 ng/ml) (p < 0.05). We found that high serum MMP-3 is characteristic of patients with paraneoplastic RS3PE syndrome.

The Association of Increase of Human T-Cell Leukemia Virus Type-1 (HTLV-1) Proviral Load (PVL) With Infection in HTLV-1-Positive Patients With Rheumatoid Arthritis: A Longitudinal Analysis of Changes in HTLV-1 PVLs in a Single Center Cohort Study.

Objective: We evaluated changes of HTLV-1 proviral loads (PVLs) during treatment for rheumatoid arthritis (RA) and investigated whether these changes affect the clinical course in HTLV-1-positive RA patients. Methods: A total of 41 HTLV-1-positive RA patients were analyzed. Their clinical picture including disease activity [Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR), DAS28-CRP, simplified disease activity index (SDAI), and clinical disease activity index (CDAI)] and comorbidity were evaluated over a 2-year period. PVLs from peripheral blood mononuclear cells were investigated by real-time polymerase chain reaction (PCR). We investigated whether HTLV-1 PVLs is altered, or which clinical characteristics affect changes of HTLV1-PVLs during 2-year treatment. Results: Clinical disease activity was not changed during the 2-year observational period. The mean HTLV-1 PVL value change from baseline to 2 years was -1.2 copies/1000 PBMCs, which was not statistically significant. No baseline clinical characteristics influenced changes in HTLV-1 PVL. However, a numerical change of HTLV-1 PVLs was increased in 4 patients initiating the new biological/targeted synthetic disease-modifying antirheumatic drugs (b/tsDMARDs) at 2-10 months after starting the new b/ts DMARDs (numerical increase was 24.87 copies/1000 PBMCs). Infection occurred in 4 patients, and 3 of those patients showed an increased HTLV-1 PVL. Univariate analysis revealed an association between increase of HTLV-1 PVL and incidence of infection. Conclusions: Over 2 years, HTLV-1 PVL did not significantly change in our HTLV-1-positive RA patients. Individual changes in HTLV-1 PVL were correlated with incidence of infection but not disease activity which indicate that we may take precaution toward infection at the uptick of HTLV-1 PVL in HTLV-1-positive RA patients.

Risk factors of adverse events during treatment in elderly patients with rheumatoid arthritis: an observational study.

OBJECTIVES: The risk factors of adverse events during a number of currently used treatments for rheumatoid arthritis (RA) in elderly patients were examined. METHODS: A retrospective observational study was conducted for 300 elderly RA patients registered in December 2009 at Sasebo Chuo Hospital, Japan, and the adverse events during the treatments for RA were assessed. RESULTS: The average age of the patients was 74.3 ± 5.8 years. The Steinbrocker stage was IV in almost one-half of the patients. Methotrexate (MTX) was used in 54.0% of patients and biologics in 23.0% of patients. Adverse events occurred in 103 patients (34.3%). The most common adverse events were infections (46.6%), including pneumonia (21.4%). Multiple logistic analyses revealed that the factors significantly related to infection were advanced Steinbrocker stage and the existence of respiratory diseases, and that of pneumonia was the existence of diabetes mellitus (DM). CONCLUSIONS: The elderly RA patients with advanced stage, respiratory diseases or DM should be monitored for infections, including pneumonia, carefully during treatment.

Efficacy and safety at 24 weeks of daily clinical use of tofacitinib in patients with rheumatoid arthritis.

OBJECTIVE: We evaluated the efficacy and safety of tofacitinib in patients with rheumatoid arthritis (RA) in a real-world setting. METHODS: Seventy consecutive patients, for whom tofacitinib was initiated between November 2013 and May 2016, were enrolled. All patients fulfilled the 2010 ACR/EULAR classification criteria for RA. All patients received 5 mg of tofacitinib twice daily and were followed for 24 weeks. Clinical disease activity indicated by disease activity score (DAS)28-ESR, the simplified disease activity index, and the clinical disease activity index as well as adverse events (AEs) were evaluated. Statistical analysis was performed to determine which baseline variables influenced the efficacy of tofacitinib at 24 weeks. RESULTS: Fifty-eight patients (82.9%) continued tofacitinib at 24 weeks. Clinical disease activity rapidly and significantly decreased, and this efficacy continued throughout the 24 weeks: i.e., DAS28-ESR decreased from 5.04 ± 1.33 at baseline to 3.83 ± 1.11 at 4 weeks and 3.53 ± 1.17 at 24 weeks (P<0.0001, vs. baseline). 15 AEs including 5 herpes zoster infection occurred during tofacitinib treatment. The efficacy of tofacitinib was not changed in patients without concomitant use of methotrexate (MTX) or patients whose treatment with tocilizumab (TCZ) failed. Multivariable logistic analysis showed that the number of biologic DMARDs (bDMARDs) previously used was independently associated with achievement of DAS-low disease activity. CONCLUSIONS: Our present study suggests that tofacitinib is effective in real-world settings even without concomitant MTX use or after switching from TCZ. Our results also suggest that its efficacy diminishes if started after use of multiple bDMARDs.