Feasibility of methotrexate discontinuation following tocilizumab and methotrexate combination therapy in patients with long-standing and advanced rheumatoid arthritis: a 3-year observational cohort study.

OBJECTIVES: Methotrexate (MTX) is associated with extensive side effects, including myelosuppression, interstitial pneumonia, and infection. It is, therefore, critical to establish whether its administration is required after achieving remission with tocilizumab (TCZ) and MTX combination therapy in patients with rheumatoid arthritis (RA). Therefore, the aim of this multicenter, observational, cohort study was to evaluate the feasibility of MTX discontinuation for the safety of these patients. METHODS: Patients with RA were administered TCZ, with or without MTX, for 3 years; those who received TCZ+MTX combination therapy were selected. After remission was achieved, MTX was discontinued without flare development in one group (discontinued [DISC] group, n = 33) and continued without flare development in another group (maintain [MAIN] group, n = 37). The clinical efficacy of TCZ+MTX therapy, patient background characteristics, and adverse events were compared between groups. RESULTS: The disease activity score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) at 3, 6, and 9 months was significantly lower in the DISC group (P < .05, P < .01, and P < .01, respectively). Further, the DAS28-ESR remission rate at 6 and 9 months and Boolean remission rate at 6 months were significantly higher in the DISC group (P < .01 for all). Disease duration was significantly longer in the DISC group (P < .05). Furthermore, the number of patients with stage 4 RA was significantly higher in the DISC group (P < .01). CONCLUSIONS: Once remission was achieved, MTX was discontinued in patients who responded favorably to TCZ+MTX therapy, despite the prolonged disease duration and stage progression.

Suspected Immune Thrombocytopenic Purpura Induced by Lenalidomide for the Treatment of Myelodysplastic Syndrome with Deletion of Chromosome 5q: A Case Report.

Lenalidomide (LEN), one of the key drugs in the treatment of myelodysplastic syndromes (MDS) with 5q deletion, as well as multiple myeloma (MM), has various immunomodulatory effects and has been associated with autoimmune diseases, including immune thrombocytopenic purpura (ITP). A 78-year-old man presented with pancytopenia and was diagnosed with MDS with 5q deletion and other chromosomal abnormalities. Two cycles of LEN therapy (one cycle: 10 mg/day for 21 days) resulted in a transient improvement in anemia, followed by MDS progression with severe thrombocytopenia (4 × 109/L) refractory to platelet transfusions. As other non-immune and alloimmune causes of transfusion-refractory thrombocytopenia were excluded, and the level of platelet-associated immunoglobulin G was extremely high compared with the level before treatment with LEN, the diagnosis of ITP was highly suspected. Despite treatment with prednisolone (PSL), eltrombopag, and repeated platelet transfusions, his platelet count did not increase, and he died of a gastrointestinal hemorrhage. Several cases of ITP induced by LEN used to treat MM had been reported, but the platelet count recovered after administration of PSL in these previous cases. However, we should be mindful of using LEN for patients with MDS because its treatment may become extremely difficult if ITP develops.

Clinical efficacy of belimumab in patients with systemic lupus erythematosus and headache. A report of two cases.

Intractable headache, one of the manifestations of neuropsychiatric systemic lupus erythematosus (SLE), is difficult to diagnose and decide on an appropriate treatment. In addition to conventional therapy based on the type of headache, the treatment should be conducted considering the disease activity of SLE rather than the headache. We report two patients with intractable headache who were successfully treated using belimumab therapy. The headaches in both patients were relieved after 2 weeks of belimumab administration. The neutralisation of B lymphocyte stimulator and reduced production of cytokines from B lymphocytes might contribute to the early effects. The potential benefits of using belimumab as an additional immunosuppressant for treating intractable headache complicated with SLE have been discussed.

Decrease of infectious complications in outpatients with autoimmune diseases from 2019 to 2020 under the COVID-19 pandemic: A single-centre, retrospective cohort study in Japan.

OBJECTIVES: To examine how the novel coronavirus disease (COVID-19) has changed infectious complications in outpatients with autoimmune diseases. METHODS: We performed a retrospective, record-linked cohort study and questionnaire about lifestyle changes in patients who visited our department in 2019 and 2020. RESULTS: We surveyed 1316 outpatients in 2019 and 1284 in 2020. The most common underlying diseases were rheumatoid arthritis (842 vs. 814) and systemic lupus erythematosus (SLE) (126 vs. 127). No significant difference in median age (66 vs. 67 years), respiratory comorbidities (30.4% vs. 32.0%), or corticosteroid use (42.2% vs. 44.3%) was found between the years. Immunomodulating agents were used more in 2020 (33.1% vs. 39.7%, p < .001). Total number of infections (28.0/100 vs. 19.4/100 person-years), pneumonia (3.6 vs. 1.6), influenza (2.1 vs. 0.1), and nonviral dermatological infections (3.8 vs. 2.1) were significantly lower in 2020. No significant difference was found for herpes zoster (2.2 vs. 1.8), urinary tract infections (3.3 vs. 3.8), or gastrointestinal infections (2.9 vs. 3.0). According to the questionnaire, 75% of the respondents became more conscious about wearing masks and 81% began to use hand sanitizer during the pandemic. CONCLUSION: Under the COVID-19 pandemic, some infectious complications have decreased in outpatients with autoimmune diseases.

Spontaneous Regression of Blastic Plasmacytoid Dendritic Cell Neoplasm Following Sepsis by Serratia marcescens: A Case Report and Literature Review.

Spontaneous regression is rare in patients with blastic plasmacytoid dendritic cell neoplasm (BPDCN). An 85-year-old man presented with pancytopenia and skin lesions, and the bone marrow exhibited 79.6% CD4+, CD56+, CD123+, and TCL-1+ abnormal cells, with a normal karyotype; he was thus diagnosed with BPDCN. While being followed without chemotherapy, he was admitted due to sepsis induced by Serratia marcescens, which was successfully treated with antibiotics. Notably, his blood cell counts improved, and the skin lesions disappeared. To our knowledge, this is the first reported case of spontaneous regression of BPDCN with a decrease in tumor cells in the bone marrow following sepsis.

Two cases of rheumatoid arthritis complicated by organising pneumonia successfully treated with tofacitinib therapy.

Organising pneumonia (OP) complicated by rheumatoid arthritis (RA), a rare type of interstitial lung disease, is sometimes refractory and resistant to immunosuppressive therapy. We report for the first time two cases of refractory OP with RA for which tofacitinib, an inhibitor of Janus kinase, was highly effective. Two women, aged 84 and 65 years, developed refractory OP during treatment for RA with biologics, certolizumab pegol, and etanercept. A moderate amount of prednisolone was effective in both cases; however, recurrences were observed with reduced glucocorticoid dosage. When tofacitinib was administered, OP and RA were well controlled. Thus, the glucocorticoid dosage was successfully tapered low enough until no side effects were observed. Tofacitinib therapy may be a treatment option for refractory OP.

Rheumatoid arthritis patients with low baseline Health Assessment Questionnaire scores have a risk of functional disability progression: a post hoc analysis of a nationwide longitudinal cohort in Japan.

OBJECTIVES: To determine prognostic factors for the Health Assessment Questionnaire-Disability Index (HAQ-DI) progression in patients with rheumatoid arthritis (RA) in clinical practice. METHODS: We evaluated 388 biological disease-modifying anti-rheumatic drug (bDMARD)-naïve Japanese patients with RA with moderate to high disease activity at study entry after being treated with conventional synthetic DMARDs. These patients were treated according to a treat-to-target (T2T) strategy for one year. The Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) and the HAQ-DI were assessed every three months. We also evaluated joint destruction using a modified total Sharp score at baseline and at one year. HAQ-DI progression was defined as the yearly progression of HAQ-DI >0.1. We performed a multiple logistic regression analysis to explore the factors predicting HAQ-DI progression at one year. RESULTS: HAQ-DI progression was observed in 18% of the patients. The multiple logistic regression analysis revealed the independent variables associated with HAQ-DI progression were: DAS28-ESR >5.1 at baseline (odds ratio [OR] 0.31, 95% con dence interval [CI] 0.13-0.74, p=0.0083); HAQ-DI score at baseline <0.5 (OR 2.27, 95% CI 1.22-4.26, p=0.0102); and achievement of low disease activity at 12 weeks (OR 0.42, 95% CI 0.21-0.82, p=0.0112). CONCLUSIONS: Our data suggest that maintaining clinical improvement according to T2T and initiating the treatment at an early stage are important for functional improvement after one year and that patients with low baseline HAQ scores have a higher risk of HAQ disability progression.

Anti-citrullinated peptide antibodies are the strongest predictor of clinically relevant radiographic progression in rheumatoid arthritis patients achieving remission or low disease activity: A post hoc analysis of a nationwide cohort in Japan.

OBJECTIVES: To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) achieving remission or low disease activity (LDA) in clinical practice. METHODS: Using data from a nationwide, multicenter, prospective study in Japan, we evaluated 198 biological disease-modifying antirheumatic drug (bDMARD)-naïve RA patients who were in remission or had LDA at study entry after being treated with conventional synthetic DMARDs (csDMARDs). CRRP was defined as the yearly progression of modified total Sharp score (mTSS) >3.0 U. We performed a multiple logistic regression analysis to explore the factors to predict CRRP at 1 year. We used receiver operating characteristic (ROC) curve to estimate the performance of relevant variables for predicting CRRP. RESULTS: The mean Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) was 2.32 ± 0.58 at study entry. During the 1-year observation, remission or LDA persisted in 72% of the patients. CRRP was observed in 7.6% of the patients. The multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: anti-citrullinated peptide antibodies (ACPA) positivity at baseline (OR = 15.2, 95%CI 2.64-299), time-integrated DAS28-ESR during the 1 year post-baseline (7.85-unit increase, OR = 1.83, 95%CI 1.03-3.45), and the mTSS at baseline (13-unit increase, OR = 1.22, 95%CI 1.06-1.42). CONCLUSIONS: ACPA positivity was the strongest independent predictor of CRRP in patients with RA in remission or LDA. Physicians should recognize ACPA as a poor-prognosis factor regarding the radiographic outcome of RA, even among patients showing a clinically favorable response to DMARDs.

Prognostic Factors Toward Clinically Relevant Radiographic Progression in Patients With Rheumatoid Arthritis in Clinical Practice: A Japanese Multicenter, Prospective Longitudinal Cohort Study for Achieving a Treat-to-Target Strategy.

To determine prognostic factors of clinically relevant radiographic progression (CRRP) in patients with rheumatoid arthritis (RA) in clinical practice.We performed a multicenter prospective study in Japan of biological disease-modifying antirheumatic drug (bDMARD)-naive RA patients with moderate to high disease activity treated with conventional synthetic DMARDs (csDMARDs) at study entry. We longitudinally observed 408 patients for 1 year and assessed disease activity every 3 months. CRRP was defined as yearly progression of modified total Sharp score (mTSS) > 3.0 U. We also divided the cohort into 2 groups based on disease duration (<3 vs ≥3 years) and performed a subgroup analysis.CRRP was found in 10.3% of the patients. A multiple logistic regression analysis revealed that the independent variables to predict the development of CRRP were: CRP at baseline (0.30 mg/dL increase, 95% confidence interval [CI] 1.01-1.11), time-integrated Disease Activity Score in 28 joints-erythrocyte sedimentation rate (DAS28-ESR) during the 1 year postbaseline (12.4-unit increase, 95%CI 1.17-2.59), RA typical erosion at baseline (95%CI 1.56-21.1), and the introduction of bDMARDs (95%CI 0.06-0.38). The subgroup analysis revealed that time-integrated DAS28-ESR is not a predictor whereas the introduction of bDMARDs is a significant protective factor for CRRP in RA patients with disease duration <3 years.We identified factors that could be used to predict the development of CRRP in RA patients treated with DMARDs. These variables appear to be different based on the RA patients' disease durations.

Clinical and structural remission rates increased annually and radiographic progression was continuously inhibited during a 3-year administration of tocilizumab in patients with rheumatoid arthritis: A multi-center, prospective cohort study by the Michinoku Tocilizumab Study Group.

OBJECTIVE: To evaluate the clinical and structural efficacy of tocilizumab (TCZ) during its long-term administration in patients with rheumatoid arthritis (RA). METHODS: In total, 693 patients with RA who started TCZ therapy were followed for 3 years. Clinical efficacy was evaluated by DAS28-ESR and Boolean remission rates in 544 patients. Joint damage was assessed by calculating the modified total Sharp score (mTSS) in 50 patients. RESULTS: When the reason for discontinuation was limited to inadequate response or adverse events, the 1-, 2-, and 3-year continuation rates were 84.0%, 76.8%, and 72.2%, respectively. The mean DAS28-ESR was initially 5.1 and decreased to 2.5 at 6 months and to 2.2 at 36 months. The Boolean remission rate was initially 0.9% and increased to 21.7% at 6 months and to 32.2% at 36 months. The structural remission rates (ΔmTSS/year ≤ 0.5) were 68.8%, 78.6%, and 88.9% within the first, second, and third years, respectively. The structural remission rate at 3 years (ΔmTSS ≤ 1.5) was 66.0%, and earlier achievement of swollen joint count (SJC) of 1 or less resulted in better outcomes. CONCLUSIONS: TCZ was highly efficacious, and bone destruction was strongly prevented. SJC was an easy-to-use indicator of joint destruction.

[Case of cerebral venous thrombosis caused by MPO-ANCA associated hypertrophic pachymeningitis].

This report describes a 72-year-old woman presenting MPO-ANCA-associated hypertrophic pachymeningitis and venous thrombosis. Five years prior, positive MPO-ANCA and renal dysfunction had been indicated. At that time, oral steroids and tacrolimus were given to treat systemic vasculitis. During the course of the disease, she repeated otitis media. Saddle nose appeared. She was suspected of having localized type granulomatosis with polyangiitis (GPA). She was hospitalized because of consciousness disturbance and was diagnosed as having MPO-ANCA-associated hypertrophic pachymenigitis and venous thrombosis. Brain MRI detected thick dura mater with abnormal enhancement, predominantly on the right cerebral hemisphere, and tentorium cerebella partially along with the cerebral sulci. MRI revealed vasogenic brain edema lesions in the right occipital, parietal, and temporal lobes and cytotoxic edema lesions in the right parietal lobe and centrum semiovale. MR venography revealed stenosis of the venous sinus including confluence of sinuses, straight sinus, and right transverse sinus. Subsequent treatment with corticosteroids, an immunosuppressant, and an anticoagulant led to recovery. No patient with MPO-ANCA-associated hypertrophic pachymenigitis and venous thrombosis that developed alternation of consciousness has ever been reported. This is therefore regarded as a rare case.

Q fever with clinical features resembling systemic lupus erythematosus.

A 23-year-old woman with prolonged fever, rash, and pericarditis associated with high titers of antinuclear, anti-Sm, and anti-RNP antibodies was suspected of having systemic lupus erythematosus (SLE). However, we also considered infectious diseases, particularly Q fever, as the C-reactive protein level was elevated and the patient reported contact with zoo animals around two weeks before the onset. The condition responded rapidly to administration of minocycline; symptoms resolved without using steroids. Thereafter, no recurrence of the illness was observed. Titer of Coxiella burnetii antibody was high and the illness was accordingly diagnosed as acute Q fever rather than SLE.

Human parvovirus B19 infection of monocytic cell line U937 and antibody-dependent enhancement.

Human parvovirus B19 (B19) infects human erythroid lineage cells. Accumulating evidence also shows that B19 is detectable in nonerythroid lineage cells in vivo, but the mechanism of infection is still not clear. In this study, we explored the mode of B19 infection of human monocytic cell line U937. An in vitro infection study demonstrated B19 binding of U937 and slow replication of B19-DNA with B19-NS1 mRNA transcription. B19-DNA replication in U937 was accompanied by undetectable level of B19-VP1 mRNA transcription, indicating that B19 infection of U937 cells may be abortive. Levels of B19-DNA and B19-NS1 mRNA transcription increased in the presence of anti-B19 IgG antibodies, but this effect decreased in the presence of anti-Fc receptor antibodies, showing antibody-dependent enhancement by B19 infection. Antibody-dependent enhancement also caused the increased production of TNFalpha in U937. This study is the first to suggest B19 infection of nonerythroid lineage cells with antibody-dependent enhancement.

Ku80 autoantigen as a cellular coreceptor for human parvovirus B19 infection.

Human parvovirus B19 (B19) infects human erythroid cells expressing P antigen. However, some cell lines that were positive for P antigen failed to bind B19, whereas some cell lines had an ability to bind B19 despite undetectable expression of P antigen. We here demonstrate that B19 specifically binds with Ku80 autoantigen on the cell surface. Furthermore, transfection of HeLa cells with the gene of Ku80 enabled the binding of B19 and allowed its entry into cells. Moreover, reduction of cell-surface expression of Ku80 in KU812Ep6 cells, which was a high-sensitive cell line for B19 infection, by short interfering RNA for Ku80 resulted in the marked inhibition of B19 binding in KU812Ep6 cells. Although Ku80 originally has been described as a nuclear protein, human bone marrow erythroid cells with glycophorin A or CD36, B cells with CD20, or T cells with CD3 were all positive for cell-surface expression of Ku80. B19 infection of KU812Ep6 cells and bone marrow cells was inhibited in the presence of anti-Ku80 antibody. Our data suggest that Ku80 functions as a novel coreceptor for B19 infection, and this finding may provide an explanation for the pathologic immunity associated with B19 infection.

Cellular and molecular studies of B cells exhibiting reverse somatic mutation throughout life.

Somatic mutation of immunoglobulin (Ig) genes plays an important role in generating antibody diversity. The frequency of somatic mutation appears to vary throughout life. However, this process has been difficult to study in vivo because the DNA in and around rearranged V genes undergoes random mutation, causing silent or replacement mutations. Therefore, we have developed a transgenic mouse model for studying the frequency of B cells exhibiting mutation in young and old mice. The system is based on a reporter transgene (HuG-X) that encodes a chimeric Ig heavy chain composed of a murine VDJ segment and a human IgG1 constant region. The VDJ has been mutated to contain a TAG stop codon in the D segment. Therefore, the transgene is transcribed but not translated. Point mutation of the stop codon results in expression of the chimeric H chain, which is readily detected as human IgG1 expression. In vivo, we found that the transgene undergoes spontaneous reverse somatic mutation at a low frequency. Treatment of HuG-X mice with anti-IgD greatly increases the frequency of somatic mutation. The observed mutation frequency in anti-IgD-treated mice increases with age until adulthood, then plateaux and finally declines in aged mice. The mutations in the stop codon were associated with increased double-stranded DNA breaks (DSB) within and around the TAG site. Our results demonstrate that the rate of frequency of spontaneous reverse mutation is very low in vivo, yet it is significantly increased after stimulation with anti-IgD antibodies. The frequency of point mutation is age dependent and correlates with increased DSB.

Molecular studies on the diversification of hemagglutinin-specific human neonatal repertoire subsequent to immunization with naked DNA.

It is well known that newborns and infants respond poorly to immunization with influenza virus vaccines. The poor response of neonates may be related to restricted B cell repertoire and high susceptibility of neonates to high dose tolerance. Protective antibody response against hemagglutinin (HA) of influenza virus is a T-dependent response. While the immunization of neonates with live virus caused a long lasting unresponsiveness, the immunization with a plasmid containing influenza virus HA circumvents the neonatal unresponsiveness. Genetic immunization primes efficiently neonatal HA-specific B cells, and induces memory cell enabling the animals to develop a strong secondary response and to survive to challenge with a lethal dose. The most striking effect of neonatal immunization consists of a shift of neonatal HA-specific B cell repertoire to adult-type as assessed by analysis of reactivity pattern of HA-specific clonotypes. The diversification is associated with the induction of germinal centers, increased number of B220(+)GL-7(+) cells and with the re-expression of RAG genes. This suggests that the receptor revision may contribute to the diversification of HA-specific neonatal B repertoire.

Acute cytomegalovirus infection and transient carotid intimal-medial thickening in a young, otherwise healthy woman.

Carotid intimal-medial thickening was observed in a 23-year-old woman with acute cytomegalovirus (CMV) infection. The thickening disappeared after her recovery from the infection. As endothelial cells are common targets of CMV, this thickening suggests that CMV infection causes vascular lesions, even in otherwise healthy individuals.

Molecular mechanisms of interleukin-4-induced up-regulation of type I collagen gene expression in murine fibroblasts.

OBJECTIVE: There is evidence that interleukin-4 (IL-4) plays a major role in the induction of extracellular matrix protein synthesis in fibrotic disease. We therefore examined the effect of IL-4 on collagen synthesis in primary fibroblasts isolated from normal and TSK/+ mice, which spontaneously develop a scleroderma-like syndrome characterized by diffuse cutaneous hyperplasia. METHODS: Expression of the IL-4 receptor was determined by flow cytometry and Western blotting. The IL-4 signal transduction cascade was analyzed by Western blotting. We assessed the role of signal transducer and activator of transcription 6 (STAT-6) in IL-4 induction of alpha2(I) collagen promoter activity and message levels via luciferase reporter assay and real-time polymerase chain reaction. The activation status of the transcription factors activator protein 1 (AP-1) and Sp-1 upon stimulation with IL-4 in normal and TSK/+ fibroblasts was examined by electrophoretic mobility shift assay. RESULTS: Flow cytometry and Western blotting showed that IL-4 receptor alpha expression was elevated in TSK/+ fibroblasts compared with normal fibroblasts. After IL-4 stimulation, janus-activated kinase 1 (JAK-1) and JAK-2 were phosphorylated to a greater degree in TSK/+ fibroblasts than in C57BL/6 fibroblasts. TSK/+ fibroblasts appeared to be hyperresponsive to IL-4, displaying increased synthesis of alpha1(I) collagen messenger RNA (mRNA), collagen protein, and activity of a luciferase reporter construct containing the -300 to +54 murine alpha2(I) collagen promoter. Overexpression of STAT-6 enhanced this effect, whereas expression of a dominant-negative STAT-6 abrogated the ability of IL-4 to induce alpha1(I) collagen mRNA in TSK/+ fibroblasts. Moreover, IL-4 induced increased DNA binding activity of transcription factors that are important for collagen synthesis. CONCLUSION: Our observations indicate that IL-4 has a profound effect on several factors that have been identified as playing major roles in the regulation of collagen synthesis and suggest that IL-4 increases the expression of type I collagen through a mechanism involving the activation of transcription factors that bind to and activate collagen promoter.