Systemic lupus erythematosus (SLE) is an autoimmune disease that causes multiple organ damage in women of childbearing age and has a relapsing-remitting course. SLE is caused by the interaction ...between genetic and environmental factors, however, its underlying triggers remain unknown. Among the environmental factors, the involvement of infections as a trigger for SLE, especially those of viral etiology, has been widely reported. Human endogenous retroviruses (HERVs) may put patients at a genetic predisposition to SLE, while the Epstein-Barr virus (EBV) may play a role as an environmental factor that triggers the development of SLE. It has been suggested that EBV-infected B-cells may become resistant to apoptosis, resulting in the activation, proliferation, and antibody production of autoreactive B-cells, which cause tissue damage in SLE. However, the interaction between the virus and immune cells, as well as the impact of the virus on the differentiation and dysfunction of immune cells, remain unclear. In this review, we focus on the relationship between the development and pathogenesis of SLE and viral infections, as well as the mechanism of SLE exacerbation via activation of immune cells, such as B-cells, based on the latest findings.
Abstract
Through treatment with biological DMARDs (bDMARDs) or targeted synthetic (tsDMARDs) such as Janus kinase (JAK) inhibitors in addition to MTX, clinical remission has become a realistic ...therapeutic goal for the majority of patients with RA, and sustained remission facilitates prevention of joint damage and physical dysfunction. Long-term safety and sustained inhibition of structural changes and physical dysfunction by bDMARDs have been reported. The development of next-generation bDMARDs and expansion of their indications to various autoimmune diseases are expected. Five JAK inhibitors show comparable efficacy to bDMARDs, and the latest ones are effective for overcoming difficult-to-treat RA regardless of prior medications. Patients treated with JAK inhibitors should be adequately screened and monitored for infection, cardiovascular disorders, thrombosis, malignancies and so on. Advances in therapeutic strategies, including the differential use of therapeutic drugs and de-escalation of treatment after remission induction, are prioritized.
Rheumatoid arthritis (RA) is a chronic inflammatory disorder characterized by progressive joint destruction. Recent studies have indicated the critical involvement of osteoclasts in bone destruction ...in RA. The osteoclast differentiation factor receptor activator of NF-κB ligand (RANKL), which belongs to the tumor necrosis factor superfamily, plays a critical role in osteoclast differentiation and bone destruction in RA. Denosumab, an antibody against human RANKL, efficiently suppressed the progression of bone erosion in RA patients in randomized controlled studies, and is considered as a putative therapeutic option for preventing bone destruction in RA.
In the original publication of the article, the title of Table was published incorrectly. The correct title should read as “Baseline patient demographics and characteristics in DESIRABLE trial. ...Adopted from Reference with permission”.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to ...evaluate whether concomitant treatment with conventional synthetic disease‐modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib.
Methods
HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long‐term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient‐years (with 95% confidence intervals 95% CIs) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies.
Results
Across all studies (6,192 patients; 16,839 patient‐years), HZ was reported in 636 tofacitinib‐treated patients (IR 4.0, 95% CI 3.7–4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0–2.9) in Eastern Europe to 8.0 (95% CI 6.6–9.6) in Japan and 8.4 (95% CI 6.4–10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 95% CI 0.07–2.01) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 95% CI 3.72–7.68). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ.
Conclusion
Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The effectiveness and safety of biological disease-modifying antirheumatic drugs (bDMARDs) by age group (< 65, 65-74, and ≥ 75 years) are uncertain. We examined retention rates reflecting the ...effectiveness and safety of bDMARDs in actual clinical practice for clarifying optimal therapeutic strategies for rheumatoid arthritis (RA) by age groups.
Data of patients who were treated with tumor necrosis factor inhibitors (TNFi), abatacept (ABA), and tocilizumab (TCZ) between February 2011 and April 2017 were collected from a prospective observational registry of RA patients. A total of 1362 patients were enrolled, of which 695 were aged < 65 years, 402 were aged 65-74 years, and 265 were aged ≥ 75 years. Primary outcome was the drug retention rate in adjusted data using inverse probability of treatment weighting based on generalized propensity scores.
In patients aged < 65 years, 3-year retention rates of TNFi, ABA, and TCZ were 43%, 47%, and 69%, respectively (ABA versus TCZ, p = 0.017; TNFi versus TCZ, p = 0.002). In patients aged 65-74 years, 3-year retention rates of TNFi, ABA, and TCZ were 44%, 53%, and 60%, respectively (TCZ versus TNFi, p = 0.034). In patients aged ≥ 75 years, 3-year retention rates for TNFi, ABA, and TCZ were 38%, 63%, and 58%, respectively (ABA versus TNFi, p = 0.017).
We found that the effectiveness and safety of TCZ were maximal in patients aged < 75 years and that patients aged ≥ 75 years might be suitable candidates for TCZ and ABA therapy. The use of therapeutic strategies appropriate to each age group might improve the outcomes of bDMARD therapy for RA.
The treatment of rheumatoid arthritis was revolutionized with the use of molecular-targeted drugs that target immunoregulatory molecules. The success of treatment with these drugs prompted the ...development of molecular-targeted drugs for systemic lupus erythematosus. However, systemic lupus erythematosus is a disease with high heterogeneous immune abnormalities, and diverse cells or molecules can be treatment targets. Thus, the identification of subpopulations based on immune abnormalities is essential for the development of effective treatment. One analytical method used to identify subpopulations is the immunophenotyping of peripheral blood samples of patients. This analysis evaluates the validity of target molecules for peripheral blood immune cell subsets, which are expected to be developed as biomarkers for precision medicine in which appropriate treatment targets are set for each subpopulation.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
IgG4-related disease (IgG4RD) is a novel clinical disease entity characterized by elevated serum IgG4 concentration and tumefaction or tissue infiltration by IgG4-positive plasma cells. IgG4RD may be ...present in a certain proportion of patients with a wide variety of diseases, including Mikulicz’s disease, autoimmune pancreatitis, hypophysitis, Riedel thyroiditis, interstitial pneumonitis, interstitial nephritis, prostatitis, lymphadenopathy, retroperitoneal fibrosis, inflammatory aortic aneurysm, and inflammatory pseudotumor. Although IgG4RD forms a distinct, clinically independent disease category and is attracting strong attention as a new clinical entity, many questions and problems still remain to be elucidated, including its pathogenesis, the establishment of diagnostic criteria, and the role of IgG4. Here we describe the concept of IgG4RD and up-to-date information on this emerging disease entity.
Biosimilars remain a hot topic in rheumatology, and some physicians are cautious about their application in the real world. With many products coming to market and a wealth of guidelines and ...recommendations concerning their use, there is a need to understand the changing landscape and the real clinical and health-economic potential offered by these agents. Notably, rheumatologists will be at the forefront of the use of biosimilar monoclonal antibodies/soluble receptors. Biosimilars offer cost savings and health gains for our patients and will play an important role in treating rheumatic diseases. We hope that these lower costs will compensate for inequities in access to therapy based on economic differences across countries. Since approved biosimilars have already demonstrated highly similar efficacy, it will be most important to establish pharmacovigilance databases across countries that are adequate to monitor long-term safety after marketing approval.
Human mesenchymal stem cells (MSCs) are multipotent and exert anti-inflammatory effects, but the underlying mechanism remains to be elucidated. In the current study, we investigated the regulatory ...mechanism of regulatory T cell (Treg) induction through the growth factors released by human MSCs. Human naive CD4
T cells were stimulated with anti-CD3/28 Abs and cocultured with human MSC culture supernatant for 48 h. The proliferation and cytokine production of CD4
T cells and surface molecule expression on CD4
T cells were evaluated. The proliferation of anti-CD3/28 Abs-stimulated CD4
T cells was suppressed by the addition of human MSC culture supernatant; in addition, the production of IL-10 and IL-4 increased. The human MSC culture supernatant induced CD4
FOXP3
Tregs that expressed CD25, CTLA-4, glucocorticoid-induced TNFR-related protein, insulin-like growth factor (IGF)-1R, and IGF-2R, showing antiproliferative activity against CD4
T cells. In addition, the induction of Tregs by human MSC culture supernatant was enhanced by the addition of IGF and suppressed by the inhibition of IGF-1R. In contrast, a significant amount of IGF binding protein (IGFBP)-4, an inhibitor of IGF action, was detected in the human MSC culture supernatant. After neutralization of IGFBP-4 in the human MSC culture supernatant by anti-IGFBP-4 Ab, Treg numbers increased significantly. Thus, our results raise the possibility that human MSC actions also involve a negative-regulatory mechanism that suppresses Treg proliferation by releasing IGFBP-4. The results of this study suggest that regulation of IGF may be important for treatments using human MSCs.
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