Denosumab prevented periprosthetic bone resorption better than risedronate after total hip arthroplasty.

INTRODUCTION: Periprosthetic fracture caused by periprosthetic bone loss is an important concern in total hip arthroplasty (THA). Denosumab has been approved for postmenopausal women with osteoporosis who are at high risk of fracture. In this randomized controlled trial, we compared the effects of denosumab and risedronate on periprosthetic bone mineral density (BMD) after THA. MATERIALS AND METHODS: The current study analyzed 108 patients who were scheduled to have THA. For 2 years, the patients were randomly assigned to the following two treatment groups: denosumab (60 mg subcutaneously every 6 months) or risedronate (17.5 mg oral weekly). The BMD changes in all Gruen zones and bone turnover markers were measured at the 5th postoperative day (baseline) and 6, 12, 18, and 24 months postoperatively. RESULTS: The mean BMD in zones 1, 2, 6, and 7 was significantly higher with denosumab all administration at all postoperative time points compared to the risedronate group. The mean percentage changes in the BMD in these zones from baseline to 24 months postoperatively were + 11.9, + 2.9, + 8.1, and + 5.9% with denosumab group and - 9.6% -3.6, - 2.3, and - 19.2% with risedronate, respectively. The osteoclastic marker, tartrate-resistant acid phosphatase-5b (TRACP-5b), was significantly lower in the denosumab group compared to the risedronate group by 2 months. CONCLUSION: Denosumab is more effective in preventing periprosthetic bone resorption than risedronate in the proximal femur. It also increased BMD around the stem implant following THA.

Effects of perioperative exercise therapy combined with nutritional supplementation on functional recovery after fast-track total hip arthroplasty.

BACKGROUND: The combination of exercise therapy combined with nutritional supplementation (Nutr) is widely used for frail or sarcopenic older persons. However, the effects of Nutr in elderly patients after fast-track total hip arthroplasty (THA) are unknown. This study examined the effects of perioperative Nutr on muscle strength, functional performance, and quality of life (QOL) in frail elderly women after fast-track THA. METHODS: A total of 58 frail elderly women aged 65-80 years scheduled for unilateral primary THA were randomly allocated to two groups: the physical exercise (Ex) combined with Nutr (Ex + Nutr; n = 29) group, and the Ex alone (Ex; n = 29) group. Protein and vitamin D supplements were provided daily from 4 weeks preoperatively to 8 weeks postoperatively (12 weeks) to the patients in the Ex + Nutr group, whereas the Ex group did not receive any supplements. Surgery and postoperative rehabilitation programmes during intervention were identical in both groups. Hip abductor and knee extensor muscle strength, functional performance (Timed Up & Go test, Harris Hip Score), and QOL (Japanese Orthopaedic Association Hip Disease Evaluation Questionnaire) were assessed at baseline and at 12 weeks (8 weeks postoperatively). RESULTS: After the intervention, hip abductor muscle strength on the contralateral leg and knee extensor muscle strength on both sides significantly improved in the Ex + Nutr group compared to the Ex group (p = 0.03, 0.01, and 0.01, respectively). However, hip abductor muscle strength on the operated side did not differ significantly between the groups (p = 0.23). There were no significant differences in functional performance and QOL. CONCLUSION: Ex + Nutr does not have an additional effect on the improvement of hip abductor strength, functional performance, and QOL compared to Ex alone after fast-track THA. However, significant improvements were observed in the strength of some muscles after fast-track THA. TRIAL REGISTRATION: UMIN 000042964. THE IRB APPROVAL: This study was approved by the Mirai Iryo Reesearch Center (approval number TGE1602-115).

Clinical efficacy of risk-stratified prophylaxis with low-dose aspirin for the management of symptomatic venous thromboembolism after total hip arthroplasty.

BACKGROUND: Pulmonary thromboembolism (PTE) and deep vein thrombosis (DVT) are serious complications after total hip arthroplasty (THA). Aspirin has been considered a safe and cost-effective prophylaxis for venous thromboembolism (VTE), and there have been some reports about the incidence of PTE (0%-0.57%) and DVT (0.1%-0.35%) with low-dose aspirin for prophylaxis after THA. The aim of this study was to investigate the incidence of postoperative symptomatic VTE in our hospital and to evaluate the clinical efficacy of our prophylactic regimen. PATIENT AND METHODS: We retrospectively reviewed the medical records of consecutive patients who underwent THA in our hospital between 2011 and 2016. A total of 3295 hips (male: 337 patients, 365 hips; female: 2527 patients, 2930 hips) were enrolled in this study. Patients were divided into low-risk and high-risk groups. Low-risk patients were administered aspirin (100 mg/day) for 28 days postoperatively. High-risk patients, such as those diagnosed with obesity and/or with a history of VTE, received anticoagulants (enoxaparin or edoxaban) for 5 days postoperatively, followed by a dose of aspirin for 28 days. Based on our criteria, 218 of 3295 hips were considered high risk. RESULTS: No VTE-related mortality was observed. One patient developed symptomatic PTE, and one patient developed symptomatic DVT. Both were successfully treated. Postoperative fatal bleeding or bleeding from any organ such as gastrointestinal and cerebral hemorrhage were not observed. A low incidence (0.03%) was observed for symptomatic DVT and PTE. CONCLUSIONS: This study demonstrated that the hospital's risk-stratified protocol using low-dose aspirin or anticoagulants was clinically effective in preventing symptomatic VTE. These results were considerably better than those reported from Western countries. However, all patients in this study were the Japanese. It was unclear whether similar results were given to non-Japanese patients. Therefore, this protocol needs severe carefulness to be applied to non-Japanese populations.

Additional intraarticular tranexamic acid further reduced postoperative blood loss compared to intravenous and topical bathed tranexamic acid in total hip arthroplasty: a retrospective sequential series study.

BACKGROUND: Topical tranexamic acid (TXA) administration has been described to be effective in decreasing blood loss in total hip arthroplasty (THA). The aim of this retrospective study was to evaluate whether topical intraarticular TXA administration in addition to intravenous (IV) and topical bathed TXA further reduces blood loss in THA patients. STUDY DESIGN AND METHODS: Four-hundred patients were enrolled in this sequential series study with two different phases during four different time periods. Patients were divided based on TXA usage and route of administration: those with and without IV TXA (IVTA-I and no-IVTA groups, respectively) and those with and without intraarticular TXA (TITA and IVTA-II groups, respectively). Both IVTA-II and TITA groups had IV TXA, and all four groups used topical bathed TXA. These four groups had 100 cases each. The primary outcomes were evaluated with total blood loss and postoperative hemoglobin level. RESULTS: The total blood loss was 1106 and 875 mL in the no-IVTA and IVTA-I groups, respectively (p < 0.05). Postoperative Hb was 10.9 and 11.51 g/dL in the no-IVTA and IVTA-I groups, respectively (p < 0.05). Total blood loss was 813 and 646 mL in the IVTA-II and TITA groups, respectively (p < 0.05). Intraarticular with IV and bathed TXA administration was more effective than IV and bathed TXA in reducing blood loss. CONCLUSION: This study suggests that the combined administration of topical intraarticular, bathed, and IV TXA was effective in reducing blood loss in THA patients.

Anti-interleukin-6 receptor antibody prevents systemic bone mass loss via reducing the number of osteoclast precursors in bone marrow in a collagen-induced arthritis model.

Systemic bone loss is a hallmark of rheumatoid arthritis (RA). Inflammatory cytokines such as interleukin (IL)-6 promote bone resorption by osteoclasts. Sphingosine-1-phosphate (S1P) controls the migration of osteoclast precursor cells (OCPs) between the blood and bone marrow, in part via S1P receptors (S1PR1 and S1PR2) expressed on the surface of OCPs. OCPs (CD11b(+) Gr-1(low+med) ) isolated from bone marrow of DBA/1J mice were stimulated with IL-6. S1P-directed chemotaxis of OCPs was evaluated using a transwell plate. mRNA expression of S1PR1 and S1PR2 was measured. DBA/1J mice were immunized with bovine type II collagen (days 0 and 21) and anti-mouse IL-6 receptor antibody (MR16-1) was administered on days 0 and/or 21. Trabecular bone volume was analysed using micro-computed tomography. The percentage of OCPs in tibial bone marrow and S1PR1 and S1PR2 mRNA expression in OCPs were measured. IL-6 stimulation significantly decreased S1P-directed chemotaxis of OCPs. IL-6 induced S1PR2 mRNA expression, but not S1PR1 mRNA expression, in OCPs. Bone volume was significantly lower in arthritic mice than in non-arthritic control mice on day 35. Treatment of immunized mice with MR16-1 significantly inhibited bone loss. In MR16-1-treated mice, the percentage of OCPs and expression of S1PR2 mRNA was each decreased compared with arthritic mice on day 14, but not on day 35. IL-6 increased the number of OCPs in tibial bone marrow via up-regulating S1PR2, thus playing a crucial role in systemic bone loss induced by inflammation.

Clinical Efficacy of Nasal Screening and Methicillin-Resistant Staphylococcusaureus Decolonization in Total Hip Arthroplasty without Chlorhexidine Soap or Vancomycin.

Purpose: Nasal colonization with methicillin-resistant Staphylococcus aureus (MRSA) is a known risk factor for periprosthetic joint infection (PJI). In our facility, preoperative prophylaxis with mupirocin without the chlorhexidine soap scrub or vancomycin was consistently implemented for more than 15 years. This study aimed to evaluate the current screening and treatment of intranasal MRSA colonization in our elective primary THA patient population. Methods: All patients who underwent primary THA between April 2011, and March 2021 were included in this analysis. All patients were screened preoperatively for nasal MRSA approximately 1 month before surgery. Patients with nasal MRSA contamination are treated with topical mupirocin to eradicate the bacteria before surgery. The patients were examined again approximately two weeks before surgery. We evaluated the current screening and treatment of intranasal colonization with MRSA in our elective primary total hip arthroplasty (THA) patient population. Results: Out of 6251 patients, 106 (1.7%) had nasal MRSA contamination. The bacteria were not eradicated in three (3.6%) patients at the second screening. Twenty-two joints (0.35%) out of the 6251 had deep infections. Only 1 patient out of the 106 MRSA nasal carriers suffered from PJI. Twenty-one of the 6145 non-carriers had PJI. The difference between the prevalence of nasal MRSA contamination and the incidence of deep infections was not statistically significant. Conclusion: Our findings suggest that screening of all patients for nasal MRSA before THA followed by mupirocin calcium treatment if needed is sufficient PJI prophylaxis.

Murine tumor necrosis factor α-induced adipose-related protein (tumor necrosis factor α-induced protein 9) deficiency leads to arthritis via interleukin-6 overproduction with enhanced NF-κB, STAT-3 signaling, and dysregulated apoptosis of macrophages.

OBJECTIVE: To elucidate the role of tumor necrosis factor α-induced adipose-related protein (TIARP; or tumor necrosis factor α-induced protein 9 [TNFAIP-9]) in the development and pathogenesis of arthritis. METHODS: We generated TIARP-deficient (TIARP(-/-) ) mice and investigated several organs in aged mice. Peritoneal macrophages were collected and cultured with lipopolysaccharide (LPS) and TNFα, and then the production of cytokines and subsequent NF-κB signal transduction were analyzed. We also examined the susceptibility of young TIARP(-/-) mice to collagen-induced arthritis (CIA). Draining lymph nodes and splenocytes were isolated and cultured, and serum levels of anti-type II collagen (anti-CII) antibodies, interleukin-6 (IL-6), and TNFα on day 60 were measured. We further investigated the effects of anti-IL-6 receptor monoclonal antibody (mAb) on the development of arthritis in TIARP(-/-) mice. IL-6/STAT-3 signaling was also analyzed using TIARP(-/-) macrophages. RESULTS: TIARP(-/-) mice developed spontaneous enthesitis and synovitis, had high serum levels of IL-6, had increased CD11b+ cell counts in the spleen, and showed enhanced LPS- and TNFα-induced IL-6 expression in macrophages. Sustained degradation of IκBα with dysregulated apoptosis was also noted in TIARP(-/-) macrophages. CIA was clearly exacerbated in TIARP(-/-) mice, accompanied by marked neutrophil and macrophage infiltration in joints. The levels of anti-CII antibodies in serum were unchanged, whereas autoreactive Th1 cell and Th17 cell responses were higher in TIARP(-/-) mice. Treatment with anti-IL-6 receptor mAb prevented the development of CIA in TIARP(-/-) mice, and TIARP(-/-) macrophages showed increased IL-6-induced STAT-3 phosphorylation. CONCLUSION: These findings suggest that TIARP acts as a negative regulator of arthritis by suppressing IL-6 production, its signaling and TNFα-induced NF-κB signaling, resulting in enhanced apoptosis in macrophages.

Adiponectin induces CCL20 expression synergistically with IL-6 and TNF-α in THP-1 macrophages.

Adiponectin (Ad) is an adipokine secreted from adipocytes. It is reported that Ad has many biological activities. However, its influence on inflammation is controversial. In the present study, we examined the influence of Ad on production of CCL20 from THP-1 macrophages. THP-1 macrophages were prepared from THP-1 monocytes by PMA treatment. THP-1 macrophages were cultured for 24h with Ad, IL-6, or TNF-α alone or with combinations of Ad and cytokines. CCL20 mRNA expression was then determined by real-time PCR. Full-length Ad (fAd) slightly but significantly induced CCL20 mRNA expression, and interestingly, co-stimulation with fAd and IL-6 or with fAd and TNF-α synergistically increased the expression of CCL20 mRNA. We explored the mechanism behind the synergistic effect of fAd and these cytokines. fAd did not affect the expression of receptors for IL-6 and TNF, and IL-6 and TNF-α did not increase the expression of the receptor for Ad in THP-1 macrophages. The increased expression of CCL20 by fAd is much higher in THP-1 macrophages compared with THP-1 monocytes. Furthermore, MMP-12 production was increased by IL-6 and TNF-α in THP-1 macrophages but it was not detectable in THP-1 monocytes. Treatment of fAd with MMP-12 induced globular Ad (gAd), and the expression of CCL20 in THP-1 macrophages was increased more potently by gAd than by fAd. MMP inhibitor (UK370106) inhibited the expression of CCL20 induced by co-stimulation with fAd and IL-6 or TNF-α. In conclusion, gAd played an important role in CCL20 expression, and MMP-12 induced by IL-6 or TNF-α was involved in the synergistic effect of fAd and cytokines.

Atherogenic effects of TNF-α and IL-6 via up-regulation of scavenger receptors.

Patients with chronic inflammatory disorders such as rheumatoid arthritis (RA) have a high risk of developing cardiovascular disease. We evaluated the effects of TNF-α and IL-6 on foam cell formation, a pivotal process in atherogenesis. Accumulation of intracellular oxidized LDL (oxLDL) was induced when THP-1/macrophages were stimulated with TNF-α or IL-6. TNF-α induced the expressions of scavenger receptors SR-A and LOX-1, and IL-6 induced SR-A expression. Inhibition of the NF-κB signaling markedly decreased TNF-α-induced foam cell formation and SR-A expression. Serum from RA patients, but not healthy subjects, induced foam cell formation, which was partially reversed by either IL-6 or TNF-α blockade in conjunction with inhibiting the induction of scavenger receptors. The present study clearly showed that in patients with chronic inflammation mediated by TNF-α and IL-6, these cytokines are directly implicated in atherosclerotic plaque formation.

IL-6/IL-6 receptor system and its role in physiological and pathological conditions.

IL (interleukin)-6, which was originally identified as a B-cell differentiation factor, is a multifunctional cytokine that regulates the immune response, haemopoiesis, the acute phase response and inflammation. IL-6 is produced by various types of cell and influences various cell types, and has multiple biological activities through its unique receptor system. IL-6 exerts its biological activities through two molecules: IL-6R (IL-6 receptor) and gp130. When IL-6 binds to mIL-6R (membrane-bound form of IL-6R), homodimerization of gp130 is induced and a high-affinity functional receptor complex of IL-6, IL-6R and gp130 is formed. Interestingly, sIL-6R (soluble form of IL-6R) also binds with IL-6, and the IL-6-sIL-6R complex can then form a complex with gp130. The homodimerization of receptor complex activates JAKs (Janus kinases) that then phosphorylate tyrosine residues in the cytoplasmic domain of gp130. The gp130-mediated JAK activation by IL-6 triggers two main signalling pathways: the gp130 Tyr759-derived SHP-2 (Src homology 2 domain-containing protein tyrosine phosphatase-2)/ERK (extracellular-signal-regulated kinase) MAPK (mitogen-activated protein kinase) pathway and the gp130 YXXQ-mediated JAK/STAT (signal transducer and activator of transcription) pathway. Increased IL-6 levels are observed in several human inflammatory diseases, such as rheumatoid arthritis, Castleman's disease and systemic juvenile idiopathic arthritis. IL-6 is also critically involved in experimentally induced autoimmune diseases. All clinical findings and animal models suggest that IL-6 plays a number of critical roles in the pathogenesis of autoimmune diseases. In the present review, we first summarize the IL-6/IL-6R system and IL-6 signal transduction, and then go on to discuss the physiological and pathological roles of IL-6.

Single and local blockade of interleukin-6 signaling promotes neuronal differentiation from transplanted embryonic stem cell-derived neural precursor cells.

Safe and efficient transplantation of embryonic stem (ES) cells to the brain requires that local inflammatory and immune responses to allogeneic grafts are inhibited. To investigate cytokines that affect graft cell survival and differentiation, we used stromal cell-derived inducing activity to induce the differentiation of neural progenitor cells (NPCs) from mouse ES cells and transplanted the NPCs into mouse brain. Examination of surrounding brain tissue revealed elevated expression levels of interleukin (IL)-1ß, IL-4, and IL-6 in response to NPC transplantation. Among these, only IL-6 reduced neuronal differentiation and promoted glial differentiation in vitro. When we added anti-IL-6 receptor antibodies to NPCs during transplantation, this single and local blockade of IL-6 signaling reduced the accumulation of host-derived leukocytes, including microglia. Furthermore, it also promoted neuronal differentiation and reduced glial differentiation from the grafted NPCs to an extent similar to that with systemic and continuous administration of cyclosporine A. These results suggest that local administration of anti-IL-6 receptor antibodies with NPCs may promote neuronal differentiation during the treatment of neurological diseases with cell replacement therapy.

Blockade of interleukin-6 signaling augments regulatory T-cell reconstitution and attenuates the severity of graft-versus-host disease.

Graft-versus-host disease (GVHD) is the major complication after allogeneic bone marrow transplantation and is characterized by the overproduction of proinflammatory cytokines. In this study, we have identified interleukin-6 (IL-6) as a critical inflammatory cytokine that alters the balance between the effector and regulatory arms of the immune system and drives a proinflammatory phenotype that is a defining characteristic of GVHD. Our results demonstrate that inhibition of the IL-6 signaling pathway by way of antibody-mediated blockade of the IL-6 receptor (IL-6R) markedly reduces pathologic damage attributable to GVHD. This is accompanied by a significant increase in the absolute number of regulatory T cells (Tregs) that is due to augmentation of thymic-dependent and thymic-independent Treg production. Correspondingly, there is a significant reduction in the number of T helper 1 and T helper 17 cells in GVHD target organs, demonstrating that blockade of IL-6 signaling decreases the ratio of proinflammatory T cells to Tregs. These studies demonstrate that antibody blockade of the IL-6R serves to recalibrate the effector and regulatory arms of the immune system and represents a novel, potentially clinically translatable, strategy for the attenuation of GVHD.

IL-6 plays an essential role in neutrophilia under inflammation.

In the present study, we explored the involvement of interleukin-6 (IL-6) in neutrophilia under inflammatory conditions. The neutrophil count in the peripheral blood was high in arthritic monkeys, and anti-IL-6 receptor antibody reduced neutrophil counts to normal levels. IL-6 injection into normal monkeys significantly increased neutrophil counts in the blood 3h after injection. The expression of cluster of differentiation (CD) 162 on circulating neutrophils was reduced by IL-6 injection. IL-6 treatment in vitro did not affect CD162 expression on neutrophils from human blood. In IL-6-treated monkeys, IL-8 and granulocyte-macrophage colony-stimulating factor (GM-CSF) levels in plasma were clearly elevated. IL-8 and GM-CSF treatment in vitro reduced cell-surface CD162 expression on human neutrophils, and moreover, increased soluble CD162 expression in the cell supernatant. The addition of IL-6 into human whole peripheral blood induced IL-8 production and reduced CD162 expression on neutrophils. Furthermore, IL-8 and GM-CSF augmented mRNA expression of a disintegrin and metalloprotease like domain 10 (ADAM10) in neutrophils. Knock-down of ADAM10 by siRNA in neutrophil-like HL-60 cells partially reversed the expression of CD162 reduced by GM-CSF and IL-8 on HL-60 cells. In conclusion, IL-6 induced neutrophilia and reduced CD162 expression on neutrophils in inflammation.

Effects of alfacalcidol on mechanical properties and collagen cross-links of the femoral diaphysis in glucocorticoid-treated rats.

Bone fragility is increased in glucocorticoid (GC)-induced osteopenia even though GC-treated patients have higher bone mineral density (BMD), suggesting that the impaired bone quality may affect bone strength. This study was conducted to clarify the effects of GC on bone strength and collagen cross-links of adult rats and the effect of coadministration of alfacalcidol (ALF), a prodrug of active vitamin D(3). Six-month-old male Wistar-Imamichi rats (n = 32) were divided into the following four groups with equal average body weight: (1) 4-week age-matched controls, (2) 4-week GC (prednisolone, 10 mg/kg daily, i.m.) with concomitant administration of vehicle, (3) 4-week GC with concomitant administration of ALF (0.05 µg/kg daily, p.o.), and (4) 4-week GC with concomitant administration of ALF (0.1 µg/kg daily, p.o.). At the end of treatment, BMD, collagen cross-links, mechanical properties of the femoral midshaft, bone metabolic markers, and biochemical parameters were analyzed. In the GC group, femoral bone strength decreased without any change of BMD. This was accompanied by a decrease in the content of enzymatic cross-links. ALF (0.1 µg/kg) inhibited the GC-induced reduction in bone strength. The content of mature cross-links in the 0.1-µg/kg ALF group was significantly higher than that in the GC group. GC treatment caused a decrease in bone metabolic markers and serum calcium levels, which was counteracted by ALF coadministration. Preventive treatment with ALF inhibited the deterioration of bone mechanical properties primarily in association with the restoration of enzymatic cross-link formation and amelioration of the adverse effects of GC treatment on calcium metabolism.

Anti-IL-6 receptor antibody causes less promotion of tuberculosis infection than anti-TNF-α antibody in mice.

Objective. Our aim was to investigate the effects of IL-6 blockade on the progression of Mycobacterium tuberculosis (TB) and compare them with those of TNF-α blockade in mice. Methods. Mice were intravenously infected with TB and injected with antibodies. Survival was monitored and histological and immunological studies were carried out. Results. All anti-IL-6R Ab-treated mice and 8 of 10 control mice survived until sacrificed 224 days after TB challenge, whereas anti-TNF-α Ab-treated mice all died between 120 and 181 days. Anti-IL-6R Ab-treated mice exhibited no significant differences in TB CFU in organs, including the lungs, and no deterioration in histopathology compared to control mice at 4 weeks. In contrast, anti-TNF-α Ab-treated mice exhibited increased TB CFU and greater progression of histopathological findings in organs than control mice. Spleen cells from anti-TNF-α Ab-treated mice had decreased antigen-specific response in IFN-γ release and proliferation assays. The results in anti-IL-6R Ab-treated mice suggest that spleen cell responses were decreased to a lesser degree. Similar results were obtained in IL-6 knockout (KO) mice, compared with TNF receptor 1 (TNFR1) KO and TNFR1/IL-6 double KO (DKO) mice. Conclusion. IL-6R blockade promotes the progression of TB infection in mice far less than TNF-α blockade.

Induction of high-dose tolerance to the rat anti-mouse IL-6 receptor antibody in NZB/NZW F1 mice.

MR16-1 is a monoclonal antibody to mouse IL-6 receptor (IL-6R) and a good tool to investigate the involvement of IL-6 in mouse disease models. However, long-term administration of MR16-1 induced anti-MR16-1 antibody that inhibited IL-6 blocking activity of MR16-1. In this study, we treated NZB/NZW F1 (BWF1) mice with MR16-1 (0.5 mg, weekly) and tested for proteinuria (an indicator of autoimmune disease) after inducing tolerance by intraperitoneal injection of anti-CD4 mAb, or in an exploratory experiment, by prior intravenous injection of 2 mg MR16-1. Anti-CD4 mAb treatment inhibited anti-MR16-1 antibody production. And the appearance of proteinuria was significantly delayed. However, anti-CD4 mAb injection alone also significantly delayed the onset of nephritis compared with saline treatment. Intravenous MR16-1 (2 mg) followed by weekly MR16-1 injections inhibited the production of anti-MR16-1 antibody and consequently decreased the prevalence of proteinuria and the level of anti-DNA antibodies. These results established the viability of intravenous MR16-1 injection as a means of inducing tolerance. It is superior to the anti-CD4 mAb method because it enabled the effects of MR16-1 monotherapy to be evaluated without the confounding effects of anti-CD4 mAb.

IL-6 blockade preferentially inhibits Th17 differentiation in collagen-induced arthritis.

We examined the time course of cytokine production by CD4 T cells from mice with collagen-induced arthritis (CIA), and we determined the influence of interleukin-6 (IL-6) blockade on cytokine production. CD4 T cells purified from spleen were cultured with both collagen and anti-CD28 antibody for 48 h and the production of interferon-γ (IFN-γ), IL-4, and IL-17 by the cells, secreted into the supernatants, was measured at various time intervals. The production of all these cytokines started 7 days after the first immunization. A marked increase in IFN-γ production was observed after the second immunization, but IL-4 and IL-17 production was not affected by a second immunization. A single injection of anti-mouse IL-6 receptor antibody (MR16-1) on the day of the first immunization suppressed the onset of arthritis. IL-17 production by CD4 T cells from MR16-1-treated mice was significantly lower than that from the control mice. On the other hand, treatment with MR16-1 showed only a tendency to suppress the production of IL-4 and IFN-γ. Injection of MR16-1 on day 21 did not suppress the onset of arthritis. We examined the direct influence of MR16-1 on cytokine production by differentiated CD4 T cells from arthritic mice. Production of IL-4, IFN-γ, and IL-17 was not affected by MR16-1. In conclusion, IL-6 inhibition preferentially suppresses the induction of Th17 cells and does not seem to impact on cytokine production of already differentiated Th17 cells.

IL-6 blockade inhibits the induction of myelin antigen-specific Th17 cells and Th1 cells in experimental autoimmune encephalomyelitis.

The development of Th17 cells is a key event in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine model of human multiple sclerosis (MS). Previous studies have demonstrated that an IL-6-dependent pathway is involved in the differentiation of Th17 cells from naïve CD4-positive T cells in vitro. However, the role of IL-6 in vivo in the development of Th17 cells in EAE has remained unclear. In the present study, we found that IL-6 blockade by treatment with an anti-IL-6 receptor monoclonal antibody (anti-IL-6R mAb) inhibited the development of EAE and inhibited the induction of myelin oligodendrocyte glycoprotein (MOG) peptide-specific CD4-positive, CD8-positive, and Th17 T cells, in inguinal lymph nodes. Thus, the protective effect of IL-6 blockade in EAE is likely to be mediated via the inhibition of the development of MOG-peptide-specific Th17 cells and Th1 cells, which in turn leads to reduced infiltration of T cells into the CNS. These findings indicate that anti-IL-6R mAb treatment might represent a novel therapy for human MS.

Adverse Local Tissue Reaction and Late-Onset Eosinophilic Gastroenteritis After Primary Total Hip Arthroplasty: A Case Report.

CASE: A 67-year-old woman suffered from chronic diarrhea at 10 years after right total hip arthroplasty. She also had a pseudotumor caused by an adverse local tissue reaction (ALTR) in her right pelvis. We performed revision arthroplasty, in part because we suspected the diarrhea may have been associated with the intrapelvic pseudotumor. She was later diagnosed with eosinophilic gastroenteritis (EGE). CONCLUSION: Although these two diseases were thought be be related through a similar immune reaction, our patient's clinical course suggests that the ALTR and EGE were independent events.