Michihito Kono

The efficacy of tacrolimus in patients with interstitial lung diseases complicated with polymyositis or dermatomyositis

OBJECTIVE Interstitial lung diseases (ILDs) complicated with PM or DM are frequently aggressive and refractory to treatment. Recently some reports have suggested the potential benefit of tacrolimus for severe ILD complicated with PM/DM. However, little evidence has yet shown the efficacy of tacrolimus in these settings. The aim of this study was to evaluate the efficacy of tacrolimus as a treatment for PM-/DM-related ILD. METHODS This retrospective study comprised 49 previously untreated patients diagnosed as PM-/DM-related ILD admitted to Hokkaido University Hospital from January 2000 to July 2013. These patients were treated with tacrolimus plus conventional therapy or only with conventional therapy (prednisolone, i.v. CYC and/or ciclosporin). The primary endpoint was defined as the time to relapse or death of respiratory cause or a serious adverse event. The secondary endpoint was defined as the time from the initiation of immunosuppressive treatment to relapse or death of respiratory cause. Endpoints were compared by adjusted Cox regression model by using inverse probability of treatment weighting in order to reduce the impact of these selection biases and potential confounding factors. RESULTS After adjustment, the tacrolimus group (n = 25) had significantly longer event-free survival as compared with the conventional therapy group (n = 24). The weighted hazard ratio (HR) was 0.32 (95% CI 0.14, 0.75, P = 0.008). In addition, the tacrolimus group had significantly longer disease-free survival as compared with the conventional therapy group. The weighted HR was 0.25 (95% CI 0.10, 0.66, P = 0.005). CONCLUSION The addition of tacrolimus to conventional therapy significantly improved the prognosis of patients with PM-/DM-related ILD.

Engagement of SLAMF3 enhances CD4+ T-cell sensitivity to IL-2 and favors regulatory T-cell polarization in systemic lupus erythematosus

Significance Systemic lupus erythematosus (SLE) is characterized by compromised IL-2 production and regulatory T-cell function. Studies in human SLE and in murine lupus models report that IL-2 replenishment ameliorates clinical lupus manifestations. Here we show that engagement of signaling lymphocytic activation molecule family 3 (SLAMF3), a coregulatory receptor of T cells, restores the sensitivity of SLE CD4+ T cells to IL-2, increasing their response to exogenous IL-2 via up-regulation of the IL-2Rα subunit. Moreover, activation of naïve CD4+ T cells with a monoclonal antibody directed against SLAMF3 promotes T helper cell differentiation toward a suppressive phenotype. These data suggest that the SLAMF3 receptor may be a promising therapeutic target in SLE. Signaling lymphocytic activation molecule family 3 (SLAMF3/Ly9) is a coregulatory molecule implicated in T-cell activation and differentiation. Systemic lupus erythematosus (SLE) is characterized by aberrant T-cell activation and compromised IL-2 production, leading to abnormal regulatory T-cell (Treg) development/function. Here we show that SLAMF3 functions as a costimulator on CD4+ T cells and influences IL-2 response and T helper cell differentiation. SLAMF3 ligation promotes T-cell responses to IL-2 via up-regulation of CD25 in a small mothers against decapentaplegic homolog 3 (Smad3)-dependent mechanism. This augments the activation of the IL-2/IL-2R/STAT5 pathway and enhances cell proliferation in response to exogenous IL-2. SLAMF3 costimulation promotes Treg differentiation from naïve CD4+ T cells. Ligation of SLAMF3 receptors on SLE CD4+ T cells restores IL-2 responses to levels comparable to those seen in healthy controls and promotes functional Treg generation. Taken together, our results suggest that SLAMF3 acts as potential therapeutic target in SLE patients by augmenting sensitivity to IL-2.

ICER is requisite for Th17 differentiation

Inducible cAMP early repressor (ICER) has been described as a transcriptional repressor isoform of the cAMP response element modulator (CREM). Here we report that ICER is predominantly expressed in Th17 cells through the IL-6–STAT3 pathway and binds to the Il17a promoter, where it facilitates the accumulation of the canonical enhancer RORγt. In vitro differentiation from naive ICER/CREM-deficient CD4+ T cells to Th17 cells is impaired but can be rescued by forced overexpression of ICER. Consistent with a role of Th17 cells in autoimmune and inflammatory diseases, ICER/CREM-deficient B6.lpr mice are protected from developing autoimmunity. Similarly, both anti-glomerular basement membrane-induced glomerulonephritis and experimental encephalomyelitis are attenuated in ICER/CREM-deficient mice compared with their ICER/CREM-sufficient littermates. Importantly, we find ICER overexpressed in CD4+ T cells from patients with systemic lupus erythematosus. Collectively, our findings identify a unique role for ICER, which affects both organ-specific and systemic autoimmunity in a Th17-dependent manner.

Ras guanine nucleotide-releasing protein 4 is aberrantly expressed in the fibroblast-like synoviocytes of patients with rheumatoid arthritis and controls their proliferation.

Ras guanine nucleotide–releasing protein 4 (RasGRP‐4) is a calcium‐regulated guanine nucleotide exchange factor and diacylglycerol/phorbol ester receptor not normally expressed in fibroblasts. While RasGRP‐4–null mice are resistant to arthritis induced by anti–glucose‐6‐phosphate isomerase autoantibodies, the relevance of these findings to humans is unknown. We undertook this study to evaluate the importance of RasGRP‐4 in the pathogenesis of human and rat arthritis.

Transcriptional factor ICER promotes glutaminolysis and the generation of Th17 cells

Significance Th17 cells unlike other CD4+ T helper subsets use glutaminolysis as a source of energy and upregulate Gls1. Inhibition of Gls1 ameliorates Th17 differentiation in vitro and experimental autoimmune encephalomyelitis in mice. Mechanistically this is accomplished through the upregulation of Gls1 by the Th17-promoting transcription factor, inducible cAMP early repressor (ICER). These findings claim an essential role of glutaminolysis in the generation of Th17 cells and offer an approach to control diseases linked to their generation. Glutaminolysis is a well-known source of energy for effector T cells but its contribution to each T cell subset and the mechanisms which are responsible for the control of involved metabolic enzymes are not fully understood. We report that Th17 but not Th1, Th2, or Treg cell induction in vitro depends on glutaminolysis and the up-regulation of glutaminase 1 (Gls1), the first enzyme in the glutaminolysis pathway. Both pharmacological and siRNA-based selective inhibition of Gls1 reduced in vitro Th17 differentiation and reduced the CD3/TCR-mediated increase of the mammalian target of rapamycin complex 1 activity. Treatment of mice with a Gls1 inhibitor ameliorated experimental autoimmune encephalomyelitis. Furthermore, RAG1-deficient mice that received Gls1-shRNA–transfected 2D2 T cells had reduced experimental autoimmune encephalomyelitis scores compared with those that received control-shRNA–treated cells. Next we found that T cells deficient in inducible cAMP early repressor (ICER), a transcriptional factor known to promote Th17 differentiation, display reduced activity of oxidative phosphorylation rates in the presence of glutamine and reduced Gls1 expression, both of which could be restored by ICER overexpression. Finally, we demonstrate that ICER binds to the gls1 promoter directly and increases its activity. These findings demonstrate the importance of glutaminolysis in the generation of Th17 and the direct control of Gls1 activity by the IL-17–promoting transcription factor ICER. Pharmaceutical modulation of the glutaminolysis pathway should be considered to control Th17-mediated pathology.

CaMK4 compromises podocyte function in autoimmune and nonautoimmune kidney disease

Podocyte malfunction occurs in autoimmune and nonautoimmune kidney disease. Calcium signaling is essential for podocyte injury, but the role of Ca2+/calmodulin–dependent kinase (CaMK) signaling in podocytes has not been fully explored. We report that podocytes from patients with lupus nephritis and focal segmental glomerulosclerosis and lupus-prone and lipopolysaccharide- or adriamycin-treated mice display increased expression of CaMK IV (CaMK4), but not CaMK2. Mechanistically, CaMK4 modulated podocyte motility by altering the expression of the GTPases Rac1 and RhoA and suppressed the expression of nephrin, synaptopodin, and actin fibers in podocytes. In addition, it phosphorylated the scaffold protein 14-3-3&bgr;, which resulted in the release and degradation of synaptopodin. Targeted delivery of a CaMK4 inhibitor to podocytes preserved their ultrastructure, averted immune complex deposition and crescent formation, and suppressed proteinuria in lupus-prone mice and proteinuria in mice exposed to lipopolysaccharide-induced podocyte injury by preserving nephrin/synaptopodin expression. In animals exposed to adriamycin, podocyte-specific delivery of a CaMK4 inhibitor prevented and reversed podocyte injury and renal disease. We conclude that CaMK4 is pivotal in immune and nonimmune podocyte injury and that its targeted cell-specific inhibition preserves podocyte structure and function and should have therapeutic value in lupus nephritis and podocytopathies, including focal segmental glomerulosclerosis.

Effectiveness of whole-body magnetic resonance imaging for the efficacy of biologic anti-rheumatic drugs in patients with rheumatoid arthritis: A retrospective pilot study

Abstract Objectives: To evaluate the scoring of whole-body magnetic resonance imaging (WBMRI) for efficacy assessment in rheumatoid arthritis (RA) patients receiving biological disease-modifying anti-rheumatic drugs (bDMARDs). Methods: Thirty consecutive RA patients receiving bDMARDs were included in this retrospective study. Contrast WBMRI was performed before and 1 year after bDMARDs initiation. Results: At baseline, mean age was 57.1 years and mean disease duration was 3.0 years. Median disease activity score in 28 joints improved from 5.1 to 2.1. Treatment with bDMARDs improved mean whole-body synovitis score from 31.2 to 23.2 and median whole-body bone-edema score from 11 to 3. Whole-body bone-erosion score improved in seven patients and deteriorated in 17 patients. Logistic regression analysis identified whole-body synovitis score as a poor prognostic factor for whole-body bone-erosion progression. Bone-edema score in individual bones was identified as a poor prognostic factor for the progression of bone-erosion. Changes in hand synovitis score correlated with those of other joints, but neither changes in bone-edema nor erosion score of hands correlated with those of other joints in WBMRI. Conclusions: WBMRI scoring may be a novel useful tool to evaluate the efficacy of anti-rheumatic drugs, as well as a potential predictor of joint prognosis, in patients with RA.

Bi-ventricular interplay in patients with systemic sclerosis-associated pulmonary arterial hypertension: Detection by cardiac magnetic resonance

Abstract Objectives: Pulmonary arterial hypertension (PAH) associated with systemic sclerosis (SSc) has a poor prognosis compared to PAH associated with other connective tissue diseases (CTD). The objective of this study was to examine the difference in hemodynamic state between SSc-PAH and other CTD-PAH by performing cardiac magnetic resonance (CMR) imaging. Methods: A single center retrospective analysis was conducted comprising 40 consecutive CTD patients who underwent right heart catheterization and CMR at the same period from January 2010 to October 2015. Results: Thirty-two patients had pre-capillary pulmonary hypertension. Of these, 15 had SSc and 17 had other CTD. CMR measurements, particularly the ratio of right to left end-diastolic volume (RVEDV/LVEDV), correlated well with mean pulmonary arterial pressure (mPAP). Conversely, RVEDV/LVEDV and mPAP correlated differently in SSc and non-SSc patients. In SSc patients, the ratio of RVEDV/LVEDV to mPAP was significantly higher compared to non-SSc patients. In the follow-up study, 2 SSc patients exhibited increased RVEDV/LVEDV in spite of decreased mPAP following treatment. Kaplan–Meier analysis revealed poor prognosis of patients with increased RVEDV/LVEDV following treatment. Conclusions: Our data indicated that altered bi-ventricular interplay detected at CMR may represent SSc-related cardiac involvement and reflect poor prognosis of SSc-PAH.

Prognosis and progress in immunotherapies for organ involvements in systemic autoimmune diseases.

Treatment of organ involvements accompanied by systemic autoimmune diseases is still challenging for clinicians, reminding the existence of unmet needs. Among them, lupus nephritis (LN), neuropsychiatric lupus, interstitial lung diseases (ILD) complicated with polymyositis/dermatomyositis (PM/DM) or systemic sclerosis (SSc) are the most severe conditions with poor prognosis. Because of the rarity and severity of the disease status, and of variety in evaluation methods, randomized clinical trials tend to be difficult in recruiting patients, in designing protocols, and in meeting primary endpoints. In such tough conditions, superiority of IVCY over corticosteroids alone for LN has been established, which is now going to be replaced by mycophenolate mofetil (MMF). Moreover, non-inferiority of tacrolimus to MMF is reported and efficacy of biologics such as Rituximab and Abatacept for LN is under investigation. In contrast, PM/DM-ILD is not suitable for randomized controlled trial because of the severity/acute progression in some patients. Intensive immunosuppressive regimen is recommended for those with poor prognostic factor(s). Cyclophosphamide has limited efficacy in SSc-ILD. Hematopoietic stem cell transplantation elongated patient survival and improved ILD, but with high treatment-related mortality rate. Efficacy of rituximab and MMF has been reported in small-sized trials. In this review, previously established treatment as well as emerging immunotherapies for organ involvements will be discussed. Our experiences in autoimmune settings also will be introduced.

Diversity of borderline pulmonary arterial pressure associated with systemic sclerosis: 3 case series

Abstract Mean pulmonary arterial pressure of 21 to 24 mmHg, called borderline pulmonary arterial pressure (BoPAP), may represent a pre-pulmonary arterial hypertension (PAH) condition but has not so far been indicated for specific PAH therapy. Despite the recent progress in PAH-targeted therapy, the prognosis of patients with systemic sclerosis (SSc)-associated PAH still remains poor. One of the possible strategies to improve the prognosis of those patients is the early detection and therapeutic intervention of pre-PAH conditions. We present three different clinical courses of BoPAP associated with SSc, which include successful treatment with bosentan and tocilizumab, an improvement following the treatment of interstitial lung disease, and spontaneous progression to fatal PAH, and suggest the efficacy of frequent follow-up examinations and therapeutic intervention for BoPAP in SSc patients.