CX3CL1/fractalkine regulates the differentiation of human peripheral blood monocytes and monocyte-derived dendritic cells into osteoclasts.

Osteoclast differentiation is promoted under inflammatory conditions and osteoclasts play a major role in bone destruction in rheumatoid arthritis (RA). Chemokine (C-X3-C motif) ligand 1 (CX3CL1), also known as fractalkine, functions as a chemoattractant and adhesion molecule, and is involved in the pathogenesis of RA. The blockade of CX3CL1 inhibits the migration of macrophages and osteoclast precursor cells into the inflamed synovium. In the present study, we investigated the direct stimulatory effects of CX3CL1 on osteoclast differentiation from human peripheral blood monocytes and monocyte-derived dendritic cells. A stimulation with CX3CL1 significantly promoted osteoclast differentiation from CD16- monocytes and also monocyte-derived dendritic cells induced by macrophage colony-stimulating factor (M-CSF) and receptor activator of NF-κB ligand (RANKL). On the other hand, CD16+ monocytes treated with M-CSF and RANKL did not differentiate into osteoclasts, even with CX3CL1. Calcium resorption was significantly increased by monocyte-derived osteoclasts, but not by dendritic cell-derived osteoclasts, following the addition of CX3CL1. The present results suggest that CX3CL1 directly regulates osteoclast differentiation. CX3CL1 may play important roles in the pathogenesis of RA, not only through the accumulation of inflammatory cells, but also through osteoclastogenesis.

The growth factor midkine may play a pathophysiological role in rheumatoid arthritis.

OBJECTIVES: Midkine (MK) is involved in cell proliferation, differentiation, migration, and survival. In this study, we measured serum MK levels in rheumatoid arthritis (RA) and investigated the correlation of serum MK with RA disease activity. Expression and effect of MK in RA synovial tissue were also examined. METHODS: Serum MK and production of inflammatory mediators by rheumatoid synovial fibroblasts (RSFs) were measured by enzyme-linked immunosorbent assay. MK expression in synovial tissue was examined by immunohistochemistry. MK receptor expression was analyzed by RT-PCR and Western blotting. RESULTS: RA patients had a significantly higher serum MK level than healthy controls. In RA patients, the MK level was correlated with DAS28-ESR, disability index of the Health Assessment Questionnaire, and rheumatoid factor level. The serum MK level tended to be decreased by anti-TNF therapy. MK was expressed by synovial lining cells in RA synovial tissues and it enhanced the production of IL-6, IL-8, and CCL2 by RSFs. RSFs expressed LDL receptor-related protein 1, candidate receptor for MK. CONCLUSIONS: The serum MK level could be a marker of disease activity in RA and an indicator of a poor prognosis. MK may have a role in the pathogenesis of RA via induction of inflammatory mediators.

[Glucocorticoid and Bone. Significance of serum soluble RANKL measurement in patients under glucocorticoid therapy].

Receptor activator of nuclear factor-κB ligand (RANKL) stimulates osteoclast differentiation and activation via binding to its receptor RANK on the pre-osteoclast cells. RANKL is a transmembrane protein, but soluble form (soluble RANKL ; sRANKL) is also circulating in the blood. The origins of the sRANKL have been thought to be produced by cleavage of membrane RANKL or secreted by T-lymphocytes, however, it is recently reported that osteocytes were one of the major sources of sRANKL. However, the pathophysiological roles of serum sRANKL has not been clarified yet. We prospectively measured serum sRANKL and OPG levels before and after the initiation of glucocorticoid therapy in patients with systemic autoimmune diseases. It was suggested that serum sRANKL might be a useful marker of bone remodeling in these patients under glucocorticoid therapy. This paper reviewed significance of sRANKL measurement in various bone metabolic diseases including glucocorticoid-induced osteoporosis.

A Case of Anti-Synthetase Syndrome With Anti-Glycyl tRNA Synthetases Antibody Developed After COVID-19.

Coronavirus disease 2019 (COVID-19) is a life-threatening respiratory disease characterized by severe acute infection. In some cases, COVID-19 symptoms may persist for a long term, posing a significant social problem. Long-term COVID-19 symptoms resemble those observed in various autoimmune diseases, such as dermatomyositis and polymyositis. In this report, we present the case of a 55-year-old woman who had been experiencing persistent dyspnea on exertion since contracting COVID-19 a month ago and was subsequently diagnosed with anti-synthetase syndrome (ASS). The patient presented with fever, dyspnea, rash, mechanic's hands, and arthritis. Computed tomography imaging revealed findings indicative of interstitial pneumonia. Immunological test results were positive for anti-EJ antibody, leading to a diagnosis of ASS based on Solomon's established criteria. The patient's condition improved following treatment with prednisolone, tacrolimus, and intravenous cyclophosphamide. Pathological findings of transbronchial biopsy revealed nonspecific interstitial pneumonia with organizing pneumonia, leading to speculation that ASS had developed after COVID-19. Given the scarcity of reports on ASS development post COVID-19, we conducted a literature review and compared our present case to previous ones. This report highlights the importance of considering ASS in the differential diagnosis of patients with long-term COVID-19 symptoms.

Relationship Between the Lipidome Profile and Disease Activity in Patients with Rheumatoid Arthritis.

Lipid mediators have been suggested to play important roles in the pathogenesis of rheumatoid arthritis (RA). Lipidomics has recently allowed for the comprehensive analysis of lipids and has revealed the potential of lipids as biomarkers for the early diagnosis of RA and prediction of therapeutic responses. However, the relationship between disease activity and the lipid profile in RA remains unclear. In the present study, we performed a plasma lipidomic analysis of 278 patients with RA during treatment and examined relationships with disease activity using the Disease Activity Score in 28 joints (DAS28)-erythrocyte sedimentation rate (ESR). In all patients, five lipids positively correlated and seven lipids negatively correlated with DAS28-ESR. Stearic acid [FA(18:0)] (r = -0.45) and palmitic acid [FA(16:0)] (r = -0.38) showed strong negative correlations. After adjustments for age, body mass index (BMI), and medications, stearic acid, palmitic acid, bilirubin, and lysophosphatidylcholines negatively correlated with disease activity. Stearic acid inhibited osteoclast differentiation from peripheral blood monocytes in in vitro experiments, suggesting its contribution to RA disease activity by affecting bone metabolism. These results indicate that the lipid profile correlates with the disease activity of RA and also that some lipids may be involved in the pathogenesis of RA.

Changes in Arterial Stiffness Monitored Using the Cardio-Ankle Vascular Index in Patients with Rheumatic Disease Receiving Initial Glucocorticoid Therapy: A Clinical Pilot Study.

Systemic inflammatory rheumatic diseases predispose to premature birth, accelerated atherosclerosis, and increased cardiovascular disease (CVD). While glucocorticoids (GCs) are used in various rheumatic diseases, and the associations between GC excess and increased prevalence of CVD complications are well established, the mechanisms underlying GCs' role in atheroma development are unclear. We conducted an observational study to address GC therapy's effect on arterial stiffness using the cardio-ankle vascular index (CAVI) in patients with rheumatic diseases. Twenty-eight patients with rheumatic disease received initial GC therapy with prednisolone at doses ranging from 20 to 60 mg/d. CAVI was examined at baseline and 3 and 6 months after GC therapy. Changes in CAVI and inflammatory parameters were evaluated. GC therapy increased the mean CAVI after 3 months but decreased it to pretreatment levels after 6 months. The mean CAVI substantially decreased with GC treatment in patients <65 years but increased in patients ≥65 years. Alterations in CAVI during the 6-month GC treatment negatively correlated with the lymphocyte-to-monocyte ratio (LMR) at baseline. Conversely, no correlation was observed between alterations in CAVI values and conventional inflammatory markers (C-reactive protein and erythrocyte sedimentation rate). Multivariate analysis of factors related to changes in CAVI highlighted young age, high prednisolone dosage, and LMR at baseline. GC temporarily exacerbates but eventually improves arterial stiffness in rheumatic diseases. Particularly in young patients, GC may improve arterial stiffness by reducing inflammation. Therefore, the LMR before GC therapy in rheumatic diseases may be a potential predictor of arterial stiffness.

Serum IgG4-negative IgG4-related disease with a cardiac mass: A case report.

RATIONALE: Although IgG4-related disease (IgG4-RD) can affect various organs, its association with a cardiac mass is exceptionally rare. Here, we report a case of a woman with IgG4-RD and a cardiac mass and discuss 10 similar cases reported previously. PATIENT CONCERNS: A 65-year-old woman was referred to our hospital for chest discomfort and back pain. DIAGNOSES: In accordance with the 2019 ACR/EULAR diagnostic criteria for IgG4-RD, she was diagnosed with IgG4-RD based on dense lymphocytic infiltration on histopathology, IgG/IgG4-positive cell ratio <40%, >10/hpf IgG4-positive cells on immunostaining, and paraspinal zone soft tissue lesions in the chest. INTERVENTIONS: An external pacemaker was implanted for the complete atrioventricular block on the electrocardiogram. After the diagnosis of IgG4-RD, she was treated with glucocorticoids and rituximab. OUTCOMES: She remains under observation without disease recurrence. LESSONS: IgG4-RD are usually treated with glucocorticoids; however, in cases of a cardiac mass, life-threatening complications may occur and surgery is often needed. Combination therapy with glucocorticoids and rituximab may be effective even in patients with IgG4-RD and cardiac mass, which may avoid the need of invasive treatments, such as surgery.

Origin of Osteoclasts: Osteoclast Precursor Cells.

Osteoclasts are multinucleated bone-resorbing cells and a key player in bone remodeling for health and disease. Since the discovery of osteoclasts in 1873, the structure and function of osteoclasts and the molecular and cellular mechanisms of osteoclastogenesis have been extensively studied. Moreover, it has been well established that osteoclasts are differentiated in vitro from myeloid cells such as bone marrow macrophages or monocytes. The concept showing that osteoclasts are derived from a specific population (named osteoclast precursor cells [OCPs]) among myeloid cells has been long hypothesized. However, the specific precursor population of osteoclasts is not clearly defined yet. A growing body of work provides evidence of the developmental origin and lifespan of murine osteoclasts, particularly in vivo. Here, we review the emerging evidence that supports the existence of OCPs and discuss current insights into their identity.

Development of giant cell arteritis after vaccination against SARS-CoV2: A case report and literature review.

RATIONALE: Giant cell arteritis (GCA) is an autoimmune vasculitis that affects large and medium-sized blood vessels. The mRNA vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has been associated with the development of immune-mediated diseases. In this article, we present a case of GCA that developed after vaccination against SARS-CoV2. PATIENT CONCERNS: A 77-year-old man developed fever, general fatigue, and headache 1 day after the third dose of vaccination against SARS-CoV2. Nodular swelling and tenderness of the bilateral temporal arteries were observed. DIAGNOSES: Although right temporal artery biopsies were negative, the patient was diagnosed with GCA based on criteria established by the American College of Rheumatology for the classification of GCA. INTERVENTIONS: The patient received methylprednisolone 1000 mg for 3 days. This was followed by prednisolone 1 mg/kg/d, which was decreased by 10 mg every week to 30 mg. From day 16 of hospitalization, the patient received tocilizumab 162 mg/wk every other week. OUTCOMES: There was no occurrence of acute side effects. After 38 days of treatment, the condition improved and the patient was discharged from the hospital; as stated above, the dose of prednisolone was tapered to 30 mg/d. LESSONS: We experienced a case of GCA that occurred immediately after vaccination against SARS-CoV2 with an mRNA vaccine. Early signs of GCA include fever, fatigue, and headache, and often resemble those noted after vaccination against SARS-CoV2. The potential presence of GCA should be determined in individuals with persistent fever and headache after vaccination against SARS-CoV2.

RANKL-responsive epigenetic mechanism reprograms macrophages into bone-resorbing osteoclasts.

Monocyte/macrophage lineage cells are highly plastic and can differentiate into various cells under different environmental stimuli. Bone-resorbing osteoclasts are derived from the monocyte/macrophage lineage in response to receptor activator of NF-κB ligand (RANKL). However, the epigenetic signature contributing to the fate commitment of monocyte/macrophage lineage differentiation into human osteoclasts is largely unknown. In this study, we identified RANKL-responsive human osteoclast-specific superenhancers (SEs) and SE-associated enhancer RNAs (SE-eRNAs) by integrating data obtained from ChIP-seq, ATAC-seq, nuclear RNA-seq and PRO-seq analyses. RANKL induced the formation of 200 SEs, which are large clusters of enhancers, while suppressing 148 SEs in macrophages. RANKL-responsive SEs were strongly correlated with genes in the osteoclastogenic program and were selectively increased in human osteoclasts but marginally presented in osteoblasts, CD4+ T cells, and CD34+ cells. In addition to the major transcription factors identified in osteoclasts, we found that BATF binding motifs were highly enriched in RANKL-responsive SEs. The depletion of BATF1/3 inhibited RANKL-induced osteoclast differentiation. Furthermore, we found increased chromatin accessibility in SE regions, where RNA polymerase II was significantly recruited to induce the extragenic transcription of SE-eRNAs, in human osteoclasts. Knocking down SE-eRNAs in the vicinity of the NFATc1 gene diminished the expression of NFATc1, a major regulator of osteoclasts, and osteoclast differentiation. Inhibiting BET proteins suppressed the formation of some RANKL-responsive SEs and NFATc1-associated SEs, and the expression of SE-eRNA:NFATc1. Moreover, SE-eRNA:NFATc1 was highly expressed in the synovial macrophages of rheumatoid arthritis patients exhibiting high-osteoclastogenic potential. Our genome-wide analysis revealed RANKL-inducible SEs and SE-eRNAs as osteoclast-specific signatures, which may contribute to the development of osteoclast-specific therapeutic interventions.

Efficacy of Denosumab for Osteoporosis in Patients with Rheumatic Diseases.

Objective Denosumab, an anti-RANKL monoclonal antibody, was reported to improve bone mineral density (BMD) and reduce fracture risk, offering favorable efficacy against postmenopausal osteoporosis. However, some patients have experienced a reduced BMD despite denosumab therapy. Methods We performed an observational study to clarify the clinical efficacy of denosumab for osteoporosis in rheumatic disease patients. Serum levels of bone turnover markers and lumber BMD in 100 rheumatic disease patients were examined at baseline and 6 and 12 months after denosumab therapy. The independent influence of changes in the BMD was examined by multiple regression analyses adjusted for patient characteristics and bone turnover markers. Results As bone resorption markers, serum levels of N-telopeptide crosslinked of type I collagen (NTx) and tartrate-resistant acid phosphatase isoform 5b were statistically decreased after 12 months. As bone formation markers, serum levels of osteocalcin, procollagen type I N-terminal peptide, and bone alkaline phosphatase were significantly decreased after 12 months. The mean BMD was significantly increased after 12 months. However, in 10 patients, the BMD decreased. A multivariate analysis of factors related to BMD changes highlighted a young age, low prednisolone dosage, and reduction in NTx. Conclusions Denosumab increases the BMD to combat osteoporosis in rheumatic disease patients, and potential predictors of a better response to denosumab include a young age, reduction in bone turnover markers, and low-dose glucocorticoid use.

Adiponectin stimulates prostaglandin E(2) production in rheumatoid arthritis synovial fibroblasts.

OBJECTIVE: Adipokines may influence inflammatory and/or immune responses. This study was undertaken to examine whether adiponectin affects the production of prostaglandin E(2) (PGE(2)) by rheumatoid arthritis synovial fibroblasts (RASFs). METHODS: Synovial tissue was obtained from patients with RA who were undergoing joint replacement surgery. Fibroblast-like cells from the third or fourth passage were used as RASFs. Expression of adiponectin receptor messenger RNA (mRNA) and protein was detected. PGE(2) (converted from arachidonic acid) was measured by enzyme-linked immunosorbent assay (ELISA). Expression of mRNA and protein for cyclooxygenase 2 (COX-2) and membrane-associated PGE synthase 1 (mPGES-1), key enzymes involved in PGE(2) synthesis, was detected in RASFs. The effects of RNA interference (RNAi) targeting the adiponectin receptor genes and the receptor signal inhibitors were examined. The influence of adiponectin on NF-kappaB activation in RASFs was measured with an ELISA kit. RESULTS: Adiponectin receptors were detected in RASFs. Adiponectin increased both COX-2 and mPGES-1 mRNA and protein expression by RASFs in a time- and concentration-dependent manner. PGE(2) production by RASFs was also increased by the addition of adiponectin, and this increase was inhibited by RNAi for the adiponectin receptor gene, or coincubation with the receptor signal inhibitors. Enhancement of NF-kappaB activation by adiponectin as well as by interleukin-1beta was observed in RASFs. CONCLUSION: Our findings indicate that adiponectin induces COX-2 and mPGES-1 expression, resulting in the enhancement of PGE(2) production by RASFs. Thus, adiponectin may play a role in the pathogenesis of synovitis in RA patients.

Glucocorticoid therapy suppresses Wnt signaling by reducing the ratio of serum Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1.

OBJECTIVE: Our previous study suggested that suppression of Wnt/ß-catenin signaling by increasing serum Wnt co-receptor inhibitors, sclerostin and Dickkopf-1, impairs bone formation in the first week after starting glucocorticoid therapy. The objective of this study was to investigate the involvement of the Wnt/ß-catenin signaling pathway and its clinical significance in the subsequent suppression of bone formation. METHODS: A total of 53 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg daily) were prospectively enrolled. We measured serum levels of Wnt3a and Wnt inhibitors, secreted Frizzled-related protein 1 (sFRP-1) and Wnt inhibitory factor 1 (Wif-1), before starting glucocorticoid therapy and every week for 4 weeks after its initiation. RESULTS: Serum levels of sFRP-1 and Wif-1 slightly decreased compared with before glucocorticoid therapy from the second week. The serum Wnt3a level decreased from the first week. The ratios of Wnt3a to sFRP-1 and that of Wnt3a to Wif-1 both decreased from the first week onward. CONCLUSION: The reduction of the ratio of Wnt3a to Wnt inhibitors, sFRP-1 and Wif-1, suppresses Wnt signaling, which may result in impaired bone formation. Taken together with our previous studies, glucocorticoids may suppress Wnt signaling by inhibiting co-receptors of the Wnt/ß-catenin signaling pathway in the early phase of glucocorticoid therapy and inhibiting its ligand in the subsequent weeks, which together impair bone formation. Key Points • The decrease in Wnt pathway-related molecules by glucocorticoids impairs bone formation. • Glucocorticoids inhibit co-receptors of Wnt signaling in the early phase of therapy. • Glucocorticoids inhibit ligands of Wnt signaling in the subsequent phase of therapy.

Glucocorticoid-induced osteonecrosis in systemic lupus erythematosus patients.

Osteonecrosis (ON) is a complex and multifactorial complication of systemic lupus erythematosus (SLE). ON is a devastating condition that causes severe pain and compromises the quality of life. The prevalence of ON in SLE patients is variable, ranging from 1.7% to 52%. However, the pathophysiology and risk factors for ON in patients with SLE have not yet been fully determined. Several mechanisms for SLE patients' propensity to develop ON have been proposed. Glucocorticoid is a widely used therapeutic option for SLE patients and high-dose glucocorticoid therapy in SLE patients is strongly associated with the development of ON. Although the hips and knees are the most commonly affected areas, it may be present at multiple anatomical locations. Clinically, ON often remains undetected until patients feel discomfort and pain at specific sites at which point the process of bone death is already advanced. However, strategies for prevention and options for treatment are limited. Here, we review the epidemiology, risk factors, diagnosis, and treatment options for glucocorticoid-induced ON, with a specific focus on patients with SLE.

Methotrexate-associated lymphoproliferative disorders in the central nervous system and stomach: A case report.

RATIONALE: Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a serious complication in patients treated using methotrexate. It occasionally develops in extra-nodal sites, but rarely in the central nervous system (CNS) or in 2 different sites at the same time. We present the rare case of a patient with rheumatoid arthritis who developed lymphoma in the CNS and stomach during MTX therapy. PATIENT CONCERNS: A 75-year-old Japanese man with rheumatoid arthritis who received methotrexate was admitted to our hospital because of gait ataxia and anorexia. DIAGNOSES: Imaging findings and biopsy led to a diagnosis of 2 different types of MTX-LPD in the central nervous system and stomach. INTERVENTIONS: The lesion in his stomach improved after methotrexate withdrawal, whereas the cerebellar mass required high-dose methotrexate and rituximab therapy. OUTCOMES: Complete remission has been maintained for the 2 years following the initiation of chemotherapy. LESSONS: In patients with RA who receive MTX and develop new neurological symptoms, CNS lymphoma as an MTX-LPD may be considered as a differential diagnosis.

A Case of Dermatomyositis Along with Esophageal Cancer and Screening of Serum Transcriptional Intermediary Factor 1 Gamma Antibodies in Various Cancer Patients.

BACKGROUND Dermatomyositis (DM) is occasionally associated with malignancy, which is so-called cancer-associated myositis. The cancer screening in patients with dermatomyositis is an important clinical issue. That is because malignant disease underlying dermatomyositis is potentially life-threatening. Transcriptional intermediary factor 1γ (TIF1γ) antibodies (anti-TIF1γ Abs) are one of the myositis-specific autoantibodies, which are investigated as potential predictors of malignancy in patients with dermatomyositis. However, the etiology of anti-TIF1γ Abs generations in various cancer patients is not known. CASE REPORT A 70-year-old male patient was admitted for muscle pain and weakness in both legs. Erythematous on the face, eruption, and a V sign were also observed. Laboratory tests showed the elevation of creatine kinase, myoglobin, and aldolase. He was diagnosed as dermatomyositis. Cancer screening was performed, and esophageal cancer was detected in the lower esophagus. Despite the symptoms of dermatomyositis were improved with steroid, methotrexate, and radical esophagectomy, he died with esophageal cancer 3 years after the onset of dermatomyositis. TIF1γ is frequently overexpressed in cancer tissues. Therefore, some cancer patients without dermatomyositis could be positive for anti-TIF1γ Abs. We retrospectively analyzed anti-TIF1γ Abs in cancer patients (n=131). However, the screening of anti-TIF1γ Abs in cancer patients without dermatomyositis (n=130) showed there were no seropositive patients. Only this cancer-associated myositis patient was positive for anti-TIF1γ Abs. CONCLUSIONS Our result suggested the generation of anti-TIF1γ Abs is specific for cancer associated myositis, not for tumorigenesis.

Tacrolimus therapy for systemic lupus erythematosus without renal involvement: a preliminary retrospective study.

We conducted a pilot study to investigate whether tacrolimus was effective for treating patients with systemic lupus erythematosus (SLE) without renal involvement. Ten SLE patients with symptoms such as arthritis and erythema, but no active nephritis, were treated with tacrolimus. They included 8 women and 2 men aged from 24 to 62 years [mean +/- standard deviation (SD): 42.1 +/- 11.3 years]. Tacrolimus was administered at doses of 1-3 mg daily, and efficacy was assessed from the SLE Disease Activity Index (SLEDAI) after 1 year. Two patients ceased treatment due to adverse reactions (after 4 days for chest pain and 7 months for recurrent infections). The other 8 patients completed 1 year of treatment, and significant improvement of disease activity was observed in 6 of them. The mean (+/-SD) SLEDAI showed a significant decrease after 1 year of tacrolimus therapy, from 6.8 +/- 3.1 to 3.4 +/- 0.9; p < 0.05 by Student's paired t test. The mean (+/-SD) dose of prednisolone also decreased significantly, from 16.8 +/- 8.6 to 9.3 +/- 4.6 mg/day; p < 0.05. Although a prospective controlled study will be necessary to confirm, tacrolimus might be a treatment option for active SLE without renal involvement.

Efficacy of mycophenolate mofetil in Japanese patients with systemic lupus erythematosus.

OBJECTIVES: To assess the renal and non-renal efficacy of mycophenolate mofetil (MMF) in Japanese patients with systemic lupus erythematosus (SLE). METHODS: We conducted a retrospective study to assess the renal and non-renal efficacies of MMF in Japanese patients with systemic lupus erythematosus (SLE). We analyzed 14 patients with lupus nephritis (LN) who were given MMF, and 13 patients who received monthly intravenous cyclophosphamide (IVCY) as induction therapy, and a further 19 patients without LN who were treated with MMF, and 13 patients who took tacrolimus (TAC) to reduce glucocorticoid dosages. We assessed the therapeutic effects of each therapeutic regime on renal and non-renal disease manifestations over a six-month period after treatment initiation. RESULTS: Median urine protein to creatinine ratios in the MMF and IVCY groups significantly decreased from 2.2 to 0.7 g/gCr and from 3.3 to 0.5 g/gCr, respectively. Significant improvements in serum immunological variables (serum complements C3 and C4 and the anti-double stranded DNA antibody) and reductions in the SLE disease activity index (SLEDAI) and daily prednisolone dosages were observed in each group with LN. MMF and TAC significantly improved SLEDAI and serum immunological variables and reduced daily prednisolone dosages in patients without LN. CONCLUSION: The present results demonstrated that MMF might be an effective treatment for renal and non-renal manifestations in Japanese patients with SLE and has potential as a good therapeutic alternative and steroid-sparing agent.

Glucocorticoid therapy causes contradictory changes of serum Wnt signaling-related molecules in systemic autoimmune diseases.

The objective of this study was to investigate the clinical significance of the Wnt/ß-catenin signaling pathway in glucocorticoid-induced osteoporosis. A total of 91 patients with systemic autoimmune diseases who received initial glucocorticoid therapy with prednisolone (30-60 mg daily) were prospectively enrolled. We measured serum levels of N-terminal peptide of type I procollagen (P1NP), bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase isoform 5b (TRACP-5b), N-telopeptide cross-linked type I collagen (NTX), sclerostin, Dickkopf-1 (Dkk-1), and Wnt3a before starting glucocorticoid therapy and every week for 4 weeks after its initiation. The effects of dexamethasone on expression of mRNA and protein of sclerostin and Dkk-1 by cultured normal human osteoblasts (NHOst) were evaluated by RT-PCR and ELISA, respectively. Serum levels of sclerostin and Dkk-1 increased significantly by 1 week of glucocorticoid therapy and then decreased from the second week onward. Serum Wnt3a tended to decrease and serum P1NP showed a significant decrease. However, TRACP-5b was significantly elevated from the first week of treatment onwards. In vitro study, dexamethasone increased Dkk-1 mRNA expression in cultured NHOst, but sclerostin mRNA was not detected. Dexamethasone also increased Dkk-1 protein production by osteoblasts, whereas sclerostin protein was not detected. Bone formation might be impaired at least in the first week of the initiation of glucocorticoid therapy by increase of the serum Wnt signaling inhibitors; however, their reductions in the subsequent weeks were contradictory to the maintained suppression of the bone formation markers after glucocorticoid therapy for patients with systemic autoimmune diseases.