Association between glucocorticoid discontinuation and incidence of infection in older adults with rheumatoid arthritis: A retrospective cohort study.

AIM: Old age and glucocorticoid (GC) use increase the susceptibility to infection in patients with rheumatoid arthritis (RA). Accordingly, we investigated whether GC discontinuation reduces the incidence of infection in older adults with RA and analyzed factors associated with GC discontinuation. METHODS: Medical records of patients with RA aged ≥60 years were retrieved, and the association between GC use and the incidence of infection was investigated. The participants were divided into three groups: GC-continued, GC-discontinued, and non-GC; the incidence of infection was statistically analyzed. Furthermore, patient treatments and comorbidities were examined. RESULTS: Among 389 patients with RA included in the study (n = 122, n = 126, and n = 141 in the GC-discontinued, GC-continued, and non-GC groups, respectively), 65 (16.7%) patients developed infection, and the incidence of infection was significantly higher in the GC-continued group than in the GC-discontinued (p = .021) and non-GC (p = .0003) groups; there was no significant difference between the non-GC and GC-discontinued groups (p = .659). The GC-discontinued group was more likely to require biologic use throughout the disease course than the other two groups. Comorbidities, especially malignancies (p = .004), were more common in the GC-continued group than in the GC-discontinued group (p = .007). CONCLUSION: In patients with RA aged ≥60 years receiving GCs, GC discontinuation reduced the incidence of infection. Therefore, a further analysis of factors that help reduce GC use is necessary.

COVID-19 and adult-onset Still's disease as part of hyperferritinemic syndromes.

The coronavirus disease (COVID-19) is known to cause hyperferritinemia and haemophagocytic lymphohistiocytosis. Including this laboratory parameter, symptoms similar to COVID-19 have been observed in adult-onset Still's disease (AOSD), catastrophic antiphospholipid syndrome, macrophage activation syndrome, and septic shock, which has led to the proposal of a concept called 'hyperferritinemic syndromes'. High levels of some clinical markers in both COVID-19 and AOSD make them difficult to differentiate. While the efficacy of ciclesonide had been expected for mild pneumonia with COVID-19, the efficacy of tocilizumab (TCZ), which is a known treatment for AOSD, was not established. We report the first known occurrence of COVID-19 diagnosed in March 2020, preceded by the diagnosis of AOSD in April 2019. The patient was given prednisolone and TCZ, which led to remission. With the dyspnea and ground-glass appearance on chest computed tomography, PCR test revealed COVID-19 infection. Ciclesonide was started on Day 7 of the disease onset, which led to improved inflammatory markers. We infer that while TCZ is theoretically useful for COVID-19 due to its inhibition of interleukin 6. AOSD and COVID-19 may be differentiated by levels of ferritin, and appropriate treatment must be allocated.

Pregnancy outcomes in patients with rheumatoid arthritis who discontinue methotrexate treatment to conceive.

INTRODUCTION/OBJECTIVES: Rheumatoid arthritis (RA) develops at reproductive age. Methotrexate (MTX), the anchor drug for RA treatment, is contraindicated during pregnancy. We investigated pregnancy outcomes in RA patients in whom MTX was withdrawn. METHOD: Pregnancy outcomes, RA treatment, and infertility factors were examined in patients with RA who discontinued MTX prior to attempting conception. The Mann-Whitney U test and Fisher's exact test were used to evaluate differences between the groups. RESULTS: Of the 52 patients enrolled in this study, 33 gave birth after discontinuing MTX and 19 did not. The age at MTX discontinuation was significantly different between the childbirth and non-childbirth groups (p = 0.0258). The use of non-steroidal anti-inflammatory drugs (NSAIDs) and salazosulfapyridine was significantly different between the groups (p = 0.0079 and p = 0.0438, respectively). Patients whose time from MTX discontinuation to pregnancy was longer than 12 months had a longer previous MTX administration period (p = 0.0182) and were older at the time of pregnancy (p = 0.0128) than those whose was shorter. CONCLUSIONS: The results suggest that to ensure successful childbirth in women with RA, the decision to conceive should be made at the youngest possible age, NSAIDs should not be used, and a shorter duration of MTX treatment should be considered before pregnancy. Nevertheless, additional studies with larger sample sizes are warranted to analyse the effects of other factors on pregnancies in patients with RA. KEY POINTS: • Patients with RA who plan to conceive must discontinue MTX therapy. • To achieve successful pregnancy outcomes, female patients with RA should become pregnant when they are young, discontinue NSAIDs prior to conception, and shorten their durations of MTX therapy before attempting pregnancy.

Rheumatoid arthritis relapse in patients with other iatrogenic immunodeficiency-associated lymphoproliferative disorders and its treatment.

OBJECTIVES: Rheumatoid arthritis (RA) in patients undergoing immunosuppressive therapy (IS) is sometimes involved with other iatrogenic immunodeficiency-associated lymphoproliferative disorders (LPD). We aimed to clarify the effects of LPD treatment on RA and the current status of RA treatment options after LPD onset and subsequent IS withdrawal. METHODS: We retrospectively analyzed data of patients who had RA with LPD and examined the relationship between LPD course and RA treatment as well as that between RA relapse and LPD treatment. RESULTS: LPD patients were categorized into two groups: patients who regressed spontaneously (n = 19) and those who needed chemotherapy (n = 12). The chemotherapy group had significantly less RA relapse than the spontaneous regression group (p = .041). RA almost relapsed early in the spontaneous regression group and needed treatment for RA. Chemotherapy with rituximab prevented long-term RA relapse, and RA did not relapse for long even after rituximab monotherapy. The total dose of rituximab in monotherapy correlated with the time to RA relapse. Six patients with RA relapse received biologics and had no LPD relapse for more than 1 year. CONCLUSIONS: Rituximab in chemotherapy for LPD may help prevent RA relapse with LPD. Large-scale studies are required in the future for verification.

Anti-IL-10 antibody in systemic lupus erythematosus.

PURPOSE: IL-10 is a cytokine known to inhibit inflammatory cytokines. To determine its role in the pathogenesis of systemic lupus erythematosus (SLE), the presence of anti-IL-10 antibody is required to be examined. Although antibodies against cytokines are known to be present in SLE, no studies have determined the role of IL-10, particularly in Japanese patients. We assayed anti-IL-10 antibody in SLE and examined the clinical significance. PATIENTS AND METHODS: We performed a retrospective study of 80 Japanese patients with SLE. Sixteen scleroderma patients, 19 rheumatoid arthritis (RA) patients, 23 Behcet's disease patients, and 23 healthy subjects were selected as control groups. Clinical information was abstracted from medical records. Anti-IL-10 antibody level was determined with an ELISA. RESULTS: With the cutoff established as serum absorbance +2 SDs (OD 0.729) in healthy subjects, we defined any sample above this cutoff as anti-IL-10 antibody-positive. Fourteen patients with SLE (17.5%) were found to be anti-IL-10 antibody positive. Absorbance was significantly higher in serum from patients with SLE and RA than in healthy individuals. In SLE, patients with low complement values were significantly more common in the antibody-positive group. Serum IgG levels were significantly higher in the antibody-positive group. In multivariable analysis, high level of serum IgG is associated with anti-IL-10 antibody positive. CONCLUSION: The present study found that anti-IL-10 antibody is present in SLE and related to clinical parameters. These results suggest that the presence of anti-IL-10 antibody was associated with high level of serum IgG, but is not associated with disease activity in patients with SLE.

Activin type IB receptor signaling in prostate cancer cells promotes lymph node metastasis in a xenograft model.

Activin, a member of the transforming growth factor-ß family, has been known to be a growth and differentiating factor. Despite its pluripotent effects, the roles of activin signaling in prostate cancer pathogenesis are still unclear. In this study, we established several cell lines that express a constitutive active form of activin type IB receptor (ActRIBCA) in human prostate cancer cells, ALVA41 (ALVA-ActRIBCA). There was no apparent change in the proliferation of ALVA-ActRIBCA cells in vitro; however, their migratory ability was significantly enhanced. In a xenograft model, histological analysis revealed that the expression of Snail, a cell-adhesion-suppressing transcription factor, was dramatically increased in ALVA-ActRIBCA tumors, indicating epithelial mesenchymal transition (EMT). Finally, mice bearing ALVA-ActRIBCA cells developed multiple lymph node metastases. In this study, we demonstrated that ActRIBCA signaling can promote cell migration in prostate cancer cells via a network of signaling molecules that work together to trigger the process of EMT, and thereby aid in the aggressiveness and progression of prostate cancers.

Smad2 protein disruption in the central nervous system leads to aberrant cerebellar development and early postnatal ataxia in mice.

Smad2 is a critical mediator of TGF-ß signals that are known to play an important role in a wide range of biological processes in various cell types. Its role in the development of the CNS, however, is largely unknown. Mice lacking Smad2 in the CNS (Smad2-CNS-KO) were generated by a Cre-loxP approach. These mice exhibited behavioral abnormalities in motor coordination from an early postnatal stage and mortality at approximately 3 weeks of age, suggestive of severe cerebellar dysfunction. Gross observation of Smad2-CNS-KO cerebella demonstrated aberrant foliations in lobule IX and X. Further analyses revealed increased apoptotic cell death, delayed migration and maturation of granule cells, and retardation of dendritic arborization of Purkinje cells. These findings indicate that Smad2 plays a key role in cerebellar development and motor function control.

GLI1, a crucial mediator of sonic hedgehog signaling in prostate cancer, functions as a negative modulator for androgen receptor.

Sonic hedgehog (SHH) signaling, acting in a combinatorial manner with androgen signaling, is essential for prostate patterning and development. Recently, elevated activation of SHH signaling has been shown to play important roles in proliferation, progression and metastasis of prostate cancer. In this report, we demonstrate for the first time, that GLI1, which has been shown to play a central role in SHH signaling in prostate cancer, can act as a co-repressor to substantially block androgen receptor (AR)-mediated transactivation, at least in part, by directly interacting with AR. Our observations suggest that the SHH-GLI pathway might be one of determinants governing the transition of prostate cancer from anandrogen-dependent to an androgen-independent state by compensating, or even superseding androgen signaling.

Genetic interactions between activin type IIB receptor and Smad2 genes in asymmetrical patterning of the thoracic organs and the development of pancreas islets.

Signaling through activin type IIB receptor (ActRIIB) has been shown to regulate the axial formation and the development of foregut-derived organs such as the pancreas in mice. Here, we provide genetic evidence that ActRIIB and Smad2 genes cooperatively regulated asymmetrical patterning of the thoracic organs and pancreas development in mice. The loss of one allele of Smad2 on ActRIIB-/- background resulted in the increased severity of ActRIIB-/- phenotypes, including right pulmonary isomerism and complex cardiac malformations, and resulted in 100% frequency of death soon after birth. Of interest, 14% of compound heterozygous ActRIIB+/- Smad2+/- mice exhibited the ActRIIB-/- phenotypes and died soon after birth. In the pancreas, hypoplastic islets were found not only in ActRIIB-/- but also in Smad2+/- mice. A more severe phenotype was also found in ActRIIB+/- Smad2+/- mice. As well, these mutant mice exhibited impaired glucose tolerance in a gene dosage-sensitive manner. This genetic evidence strongly suggested that ActRIIB and Smad2 function in the same signaling pathway to regulate axial patterning and pancreas islet formation by means of a threshold mechanism.