Analysis and evaluation of factors contributing to the occurrence of immune-related adverse events with immune checkpoint inhibitors.

In recent years, there has been a growing trend in the use of immune checkpoint inhibitors (ICIs) for treating a larger patient population. However, it is important to note that immune-related adverse events (irAEs) frequently arise as a result. Therefore, precise patient monitoring becomes essential. We present the findings of a retrospective study conducted at the International University of Health and Welfare Narita Hospital (referred to as "our hospital") that aimed to identify risk factors linked to the occurrence of irAEs. The study focused on analyzing various factors, including therapeutic and lifestyle backgrounds, as well as laboratory values of patients who received ICI treatment and were subsequently diagnosed with irAE. The study included patients who met the eligibility criteria for ICIs (both single agent and combination therapy) as well as ICI in combination with anticancer drugs. The inclusion period for the study encompassed April 2020 to May 2022 at our hospital. The fifty patients were divided into two groups based on the severity of irAEs: the first group consisted of patients with irAE Grade 2 or lower (referred to as irAE Grade under 2), while the second group included patients with irAE Grade 3 or higher (referred to as irAE Grade over 3). Statistical analysis revealed significant differences in age (p=0.027) and CRP (C-reactive protein) levels (p=0.008) among the background factors when comparing the two groups. Additionally, statistically significant differences were observed among different ICI treatment groups in the occurrence of irAEs (p=0.035). however, it was indicated to be a relatively weak correlation. Moving forward, we shifted our focus to examine the frequency of irAEs in relation to exposure. However, we did not observe any significant correlation between exposure and irAE grade. Additionally, even when exposure was doubled through the use of ipilimumab in combination with ICIs (referred to as "Mod exposure"), no correlation was found. Exposure was further categorized into three groups: the PD-1 group, PD-L1 group, and PD-1 + CTLA-4 group. However, no significant correlation was observed between exposure in any of these groups and the grade of irAEs. Similarly, no significant correlation was observed between the dosage of ICI in the fixed-dose group and the weight-based dosage group with exposure and irAE Grade. Based on our study findings, there is a suggestive relationship between age and CRP levels and the occurrence of irAEs of Grade 3 or higher. These factors may play a role in contributing to the development of more severe irAEs.

Campylobacter and Salmonella are prevalent in broiler farms in Kyushu, Japan: results of a 2-year distribution and circulation dynamics audit.

AIM: To elucidate the distribution and circulation dynamics of Campylobacter and Salmonella in Japanese chicken broiler flocks. METHODS AND RESULTS: A 2-year investigation of the distribution of Campylobacter and Salmonella was conducted in 25 broiler flocks at nine farms in Japan from 2013 to 2014. Campylobacter and Salmonella tested positive in 11 (44·0%) and 24 (96·0%) broiler flocks respectively. One hundred and ninety-five Campylobacter and 184 Salmonella isolates were characterized into 12 Campylobacter (including two novel genotypes) and three Salmonella MLST genotypes. Only Salmonella isolation between caecal and environmental samples were significantly correlated. Further, one litter sample tested positive for Salmonella before new chicks were introduced. The Campylobacter strains rapidly lost culturability within 2-18 days; in contrast, the Salmonella strains survived from 64-211 days in artificially inoculated water samples. CONCLUSION: No persistent circulation-mediated Campylobacter contamination was observed. In contrast, circulation of Salmonella in broiler houses was seen, apparently due to the litter excreted from broiler flocks, as well as Salmonella-contaminated water and feed. SIGNIFICANCE AND IMPACT OF THE STUDY: This paper provides the distribution, genotypic data and circulation dynamics of Campylobacter and Salmonella as recently observed in Japanese chicken broiler farms.

Dynamical Fano-Like Interference between Rabi Oscillations and Coherent Phonons in a Semiconductor Microcavity System.

We report on dynamical interference between short-lived Rabi oscillations and long-lived coherent phonons in CuCl semiconductor microcavities resulting from the coupling between the two oscillations. The Fourier-transformed spectra of the time-domain signals obtained from semiconductor microcavities by using a pump-probe technique show that the intensity of the coherent longitudinal optical phonon of CuCl is enhanced by increasing that of the Rabi oscillation, which indicates that the coherent phonon is driven by the Rabi oscillation through the Fröhlich interaction. Moreover, as the Rabi oscillation frequency decreases upon crossing the phonon frequency, the spectral profile of the coherent phonon changes from a peak to a dip with an asymmetric structure. The continuous wavelet transformation reveals that these peak and dip structures originate from constructive and destructive interference between Rabi oscillations and coherent phonons, respectively. We demonstrate that the asymmetric spectral structures in relation to the frequency detuning are well reproduced by using a classical coupled oscillator model on the basis of dynamical Fano-like interference.

Expression of B7-H3, a potential factor of tumor immune evasion in combination with the number of regulatory T cells, affects against recurrence-free survival in breast cancer patients.

BACKGROUND: In the tumor microenvironment, factors inhibiting the targeting of cancer cells by activated T cells have recently been noted. B7-H3 belongs to the B7 superfamily of immune regulatory ligands and plays an important role in the adaptive immune response of co-inhibitory/stimulatory factors in regulating T cells. However, the degree to which B7-H3 directly affects tumor immune evasion mechanisms remains unclear, particularly in patients with breast cancer. Regulatory T cells (Tregs) are known as a key player in the inhibition of immune mechanisms. The present study demonstrated that expression of B7-H3 on tumor cells and the number of Tregs in the tumor microenvironment independently affected prognosis in breast cancer patients. METHODS: We immunohistochemically investigated the presence of B7-H3 and forkhead box P3 (Foxp3)-positive Tregs in pathological specimens from 90 patients with breast cancer. RESULTS: Positive B7-H3 expression was associated with shorter recurrence-free survival (RFS) (p = 0.014). A higher percentage of Foxp3-positive cells also correlated with shorter RFS (p = 0.039). Multivariate analysis showed B7-H3 as an independent factor on RFS. Foxp3 expression in tumor-infiltrating lymphocytes (TILs) correlated significantly with larger tumor size (>2 cm), expression of human epidermal growth factor receptor 2 (HER2), and higher nuclear grade (p = 0.003, p < 0.001, p = 0.001, respectively). No correlation was identified between expression of B7-H3 and the percentage of Foxp3-positive TILs. CONCLUSIONS: B7-H3 and Foxp3 can be regarded as markers of poor prognosis in breast cancer. These expressions were not correlated, suggesting that B7-H3 expression plays an independent role in tumor immune evasion, regardless of Tregs.

Preventive and therapeutic effects of rapamycin, a mammalian target of rapamycin inhibitor, on food allergy in mice.

BACKGROUND: Because few curative treatments are available for food allergy, we investigated the therapeutic potential of rapamycin, a mammalian target of rapamycin (mTOR) inhibitor, on mouse food allergy. METHODS: The preventive and therapeutic effects of oral rapamycin on anaphylactic symptoms induced by oral ovalbumin (OVA) challenge in food allergy mice were investigated. Mast cell functions in response to rapamycin were also measured in the passive systemic anaphylaxis model and bone marrow-derived mast cells (BMMCs). RESULTS: Daily rapamycin from the first challenge (preventive protocol) attenuated food allergy symptoms including diarrhea, anaphylactic reactions, and hypothermia in mice. The treatment decreased the challenge-induced increases in mouse mast cell protease-1 in serum and mast cell numbers in the intestine. Notably, the mice that already showed food allergy symptoms by previous challenges recovered from the disease with daily administration of rapamycin (therapeutic protocol). Anti-OVA IgG1 and IgE levels in serum, as well as IFN-γ, IL-4, IL-13, IL-9, IL-10, and IL-17 secretion from splenocytes, were decreased by the treatments. In contrast, a single dose of rapamycin failed to affect passive systemic anaphylaxis. Spontaneous and IL-9-dependent survival and IgE-induced IL-13 secretion, but not degranulation, of BMMCs were reduced by rapamycin. CONCLUSION: Our data show that mouse food allergy was attenuated by rapamycin through an immunosuppressive effect and inhibition of intestinal mast cell hyperplasia. Inhibition of the IL-9 production-mast cell survival axis is one of the mechanisms of the therapeutic effect of rapamycin. Rapamycin and other mTOR inhibitors might be good candidates for therapeutic drugs for food allergy.

Tyrosine kinase inhibitor sunitinib relieves systemic and oral antigen-induced anaphylaxes in mice.

BACKGROUND: Systemic and oral antigen-induced anaphylaxes are mediated by immunoglobulin (Ig) E and mast cells, but there is no satisfactory treatment for the life-threatening allergic reaction. We investigated the potential of the multitargeted receptor tyrosine kinase inhibitor sunitinib to relieve anaphylactic reactions in food allergy and systemic anaphylaxis. METHODS: Efficacy of oral sunitinib on oral and parenteral antigen-induced anaphylaxes in Balb/c mice was evaluated. IgE-dependent degranulation and growth of rat basophilic leukemia RBL2H3 and bone marrow-derived mast cells (BMMCs) in response to sunitinib were investigated. RESULTS: Daily administration of sunitinib throughout antigen challenges prevented oral antigen-induced anaphylaxis including diarrhea, anaphylactic symptoms, and hypothermia. The mouse mast cell protease (MMCP)-1 concentration in serum and mast cell number in intestinal tissue after challenge were also decreased by the treatment. Spleen cells from sunitinib-treated mice contained smaller numbers of antigen-specific IgG-producing cells and secreted lower amounts of both Th1 and Th2 cytokines than those of the control mice, whereas the levels of antigen-specific antibodies in serum were not decreased. The reactions and MMCP-1 release in oral antigen-induced anaphylaxis and passive systemic anaphylaxis were attenuated even by a single predose of sunitinib. Degranulation and growth of RBL2H3 cells and BMMCs were greatly reduced by sunitinib. CONCLUSION: These results suggested that sunitinib relieves systemic and oral antigen-induced anaphylaxes by the prevention of mast cell activation and hyperplasia in intestinal tissue directly and indirectly through an immunosuppressive effect. Sunitinib and its related kinase inhibitors might be potential drugs for the treatment of food allergy and systemic anaphylaxis.

Aspergillus oryzae lectin induces anaphylactoid oedema and mast cell activation through its interaction with fucose of mast cell-bound non-specific IgE.

We investigated whether Aspergillus oryzae lectin (AOL), a fucose-specific lectin, induces anaphylactoid reactions and mast cell activation. The injection of AOL into footpads of mice produced a dose-related acute paw oedema. The AOL-induced oedema was attenuated by predose of histamine H1 receptor blocker or pretreatment of the lectin with fucose before injection and was not observed in SCID and mast cell-deficient WBB6F1-W/Wv mice. These results suggested that the AOL-induced anaphylactoid reaction was mediated by histamine released from mast cells. In addition, the activation of mast cells was seemed to be induced by the crosslinking of IgE on the cell surface following the binding of AOL to fucose residues in IgE. Consistent with the in vivo results, AOL induced the degranulation of the rat mast cell line RBL2H3 sensitized with monoclonal IgE. As AOL induced the increase in intracellular Ca(2+) concentration of IgE-sensitized RBL2H3 cells as well as antigen stimulation, AOL could input signals from FcεRI. The degranulation of IgE-sensitized RBL2H3 cells by AOL was diminished by pretreatment of AOL with fucose. Defucosylated IgE did not induce degranulation of RBL2H3 cells in response to AOL stimulation, in spite of its ability to induce degranulation by antigen stimulation as intact IgE. These results indicated that AOL bound to fucose residue of IgE causing antigen-independent IgE-mediated mast cell activation and anaphylactoid reactions in vitro and in vivo, respectively. AOL bound to human IgE as well as to mouse IgE, suggesting the possible implication of AOL in the allergic response to Aspergillus oryzae in humans.

Depletion of alpha/beta T cells by a monoclonal antibody against the alpha/beta T cell receptor suppresses established adjuvant arthritis, but not established collagen-induced arthritis in rats.

The effects of treatment with a monoclonal antibody (R73 mAb) against T cell receptor alpha/beta (TCR-alpha/beta) on both established adjuvant arthritis (EAA) and established collagen-induced arthritis (ECIA) in rats have been investigated. Rats were treated with R73 mAb when arthritis reached a peak. Treatment with the anti-TCR-alpha/beta mAb markedly suppressed EAA, whereas ECIA was not affected by the mAb treatment. Histologically, R73 mAb-treated rats with EAA showed mild hyperplasia of synovial tissues, sparse infiltration of inflammatory cells, and minimal erosion of cartilage, whereas arthritic rats treated with PBS and an irrelevant control mAb against Giardia had marked hyperplasia of synovium with pannus, massive inflammatory cell infiltrate, and severe destruction of cartilage and subchondral bone. R73 mAb-treated rats with ECIA exhibited pronounced formation of pannus containing many inflammatory cells and marked cartilage and subchondral damage similar to those in arthritic rats that received the control treatments. Treatment with R73 mAb depleted markedly alpha/beta+ T cells in both peripheral blood and synovial tissues of rats with EAA and ECIA. R73 mAb treatment was associated with marked reduction in arthritogen-specific delayed-type hypersensitivity responses in both EAA and ECIA. The titers of antibodies against type II collagen produced in rats with ECIA were not affected by the mAb. Thus, alpha/beta+ T cells appear to have a central role in EAA, but not in chronic ECIA.

Antioxidative role of interleukin-6 in septic lung injury in mice.

We have previously demonstrated the protective role of interleukin (IL)-6 against septic lung injury induced by lipopolysaccharide (LPS) using IL-6 knock-out (-/-) mice. This protection is mediated, at least partly, through the inhibition of the enhanced local expression of proinflammatory cytokines. In the present study, we addressed whether IL-6 regulates oxidative stress in the lung generated by LPS exposure using IL-6 (-/-) and corresponding wild type (WT) mice. Intraperitoneal LPS (1 mg/kg) challenge induced transcriptional expressions of inducible nitric oxide synthase and heme oxygenase -1 in the lung of mice with both genotypes. In the presence of LPS, these expressions were significantly greater in IL-6 (-/-) than in WT mice. Immunohistochemistry also showed that LPS induced a significant increase in 8-hydroxy-2'-deoxyguanosine formation in the lung as compared to vehicle. Furthermore, the formation was more intense in IL-6 (-/-) than in WT mice in the presence of LPS challenge. In the presence of LPS, lipid peroxidation in the lung was significantly greater in IL-6 (-/-) than in WT mice. These data suggest that the possible mechanisms in which endogenous IL-6 protects against septic lung injury induced by LPS involve, at least in part, its antioxidative properties.

Routine Referral by Urologists Increase Opportunities for Corneal Donation.

BACKGROUND: The levels of corneal donation are insufficient to meet the demand for corneal transplantation in Japan. To overcome this problem, we started to routinely mention the possibility of corneal donation to the families of patients who died in our hospital's Urology Department in February 2008. In this study, we evaluated the effectiveness of this approach. METHODS: We retrospectively reviewed the medical records of the patients who died in the Department of Urology, St. Marianna University School of Medicine Hospital, and analyzed the patients' characteristics and information about corneal donation. RESULTS: In total, 211 patients died in our department between February 2008 and March 2017, and 155 patients were medically suitable corneal donors. We mentioned the possibility of corneal donation to 129 (83.2%) families, and 29 (18.7%) families agreed. Three families subsequently withdrew their consent. Finally, 26 (16.8%) of the families that were approached about corneal donation by urologists agreed to donate their relatives' corneas. Another 2 families voluntarily offered to donate their relatives' corneas. Thus, 28 (18.1%) of 155 medically suitable donors donated their corneas for transplantation. Twenty-six (92.8%) donors were 60 years or older and all donors were affected with malignant genitourinary tumors. Fifty-four (96.4%) corneas were successfully transplanted into recipients. CONCLUSIONS: Even elderly patients who die of solid carcinoma can be an important source of corneal donors. In this study, we showed that routine referral by urologists increased corneal donation. If this approach were adopted by other departments, it might further increase the number of corneal donations.

Effects of nanoparticles on lung physiology in the presence or absence of antigen.

Ambient particulate matter (PM) exacerbates allergic airway diseases. Our previous study showed that diesel exhaust particles, the main constituents in urban PM, enhance airway hyperresponsivness in mice. In addition, health effects of PM with a diameter of less than 100 nm, called nanoparticles, have been reported, and we have also demonstrated that carbon nanoparticles exacerbate antigen-related airway inflammation. The present study investigates the effects of pulmonary exposure to two sizes of carbon nanoparticles on lung physiology and lung expression of Muc5ac in the presence or absence of antigen in mice. Nanoparticles alone or ovalbumin (OVA) alone moderately enhanced cholinergic airway reactivity, as assessed by total respiratory system resistance (R) and Newtonian resistance (Rn). In the nanoparticle + OVA groups, all the parameters for lung responsiveness, such as R, compliance, elastance, Rn, tissue damping, and tissue elastance, were worse than those in the vehicle group, the corresponding nanoparticle groups or the OVA group. The lung mRNA level for Muc5ac was significantly higher in the OVA group than in the vehicle group, and further increased in the nanoparticle + OVA groups than in the OVA or the nanoparticle groups. These data suggest that carbon nanoparticles can enhance lung hyperresponsiveness, especially in the presence of antigen. The effects may be mediated, at least partly, through the enhanced lung expression of Muc5ac.

Pulmonary exposure to diesel exhaust particle components enhances circulatory chemokines during lung inflammation.

This study examines the effects of DEP components on circulatory CC and CXC chemokines, potent activators and chemoattractants for macrophage and leukocyte subpopulations, in a murine model of lung inflammation. ICR mice were divided into six experimental groups which received intratracheal inoculation of vehicle, LPS alone (2.5 mg/kg), organic chemicals in DEP (DEP-OC: 4 mg/kg) extracted with dichloromethane, residual carbonaceous nuclei after the extraction (washed DEP: 4 mg/kg), DEP-OC + LPS, or washed DEP + LPS. Intratracheal instillation of each DEP component alone did not significantly change the circulatory level of macrophage inflammatory protein (MIP)-1alpha, MIP-2, and macrophage chemoattractant protein-1 (MCP-1) 24 h after the exposure as compared with vehicle instilled alone. In the LPS group, MCP-1, but not MIP-1alpha or MIP-2, was significantly greater than in the vehicle group. The combined administration of LPS and washed DEP caused a further three to five-fold increase in MIP-1alpha, MIP-2, and MCP-1 proteins in the serum as compared with LPS administered alone. No significant difference between the LPS + DEP-OC group and the LPS group was observed. These results indicate that pulmonary exposure to washed DEP enhances circulatory level of chemokines during lung inflammation. The enhancement may be important in the aggravations of systemic inflammatory responses and ischemic cardiovascular conditions associated with air pollution.

DNA fingerprinting of isolates of Streptococcus mutans by pulsed-field gel electrophoresis.

Forty isolates and five standard laboratory strains, representing serotypes c, e and f of Streptococcus mutans were analyzed by pulsed-field gel electrophoresis (PFGE) after digestion of the genomic DNA with BssH II. The digestion patterns of standard laboratory strains were characteristic of serotypes c, e and f. Serotypes c and f generated diagnostic DNA fragments of approximately 145 kbp and of approximately 130-175 kbp in length, respectively. Serotype e generated a ladder of at least 14 fragments of 15-155 kbp in length. The digestion patterns of isolates were essentially similar to those of the standard laboratory strains. The patterns of almost all isolates obtained from a single individual were identical, but patterns of a few different types were also observed among isolates obtained from two individuals. Digestion with BssH II revealed differences among isolates obtained from different individuals. We used differences in banding patterns among isolates to construct a dendrogram. The dendrogram included two major clusters, one that consisted of isolates of serotypes c and f, and an other that consisted of isolates of serotype e. Our results indicate that BssH II is a useful enzyme for distinguishing among isolates of S. mutans and that digestion patterns obtained by PFGE can be used for chromosomal DNA fingerprinting.

Treatment continuation rate in relation to efficacy and toxicity in long-term therapy with low-dose methotrexate, sulfasalazine, and bucillamine in 1,358 Japanese patients with rheumatoid arthritis.

OBJECTIVE: To evaluate the effectiveness of disease-modifying antirheumatic drugs, namely, methotrexate (MTX), sulfasalazine (SSZ) and bucillamine (BUC) at low-doses (4, 6 or 8 mg MTX, 500 or 1,000 mg SSZ, and 100 or 200 mg BUC) in 1,358 patients with a follow-up of at least 12 months and more than 120 months. METHODS: Clinical assessments were based on the number of painful joints (NPJ) and that of swollen joints (NSJ), CRP level, erythrocyte sedimentation rate, rheumatoid factor level and morning stiffness before and after treatment. Results were evaluated on the basis of the duration of treatment for each drug with inefficacy or inadequate efficacy as one endpoint for discontinuation and adverse drug reactions (ADRs) as the other in single agent and combination therapy. The incidence and nature of ADRs in single and combination treatment are described. RESULTS: The effects of MTX, SSZ and BUC on clinical parameters were monitored over the first three months, and in particular, NPJs and NSJs were found to decrease significantly during single agent MTX or BUC treatment over 108 months. CRP levels remained significantly improved for more than 120 months with MTX. In the single and combination long-term treatments, continuation rate with inefficacy or inadequate efficacy as the end point achieved for each of the treatments were 83.1% for MTX, 76.0% for BUC, 68.5% for SSZ, and in the case of the combination treatments, these rates were 83.3% for MTX + BUC and 71.0% for MTX+SSZ. Continuation rates using ADRs as the end point were 88% for SSZ, 79.6% for BUC and 79.4% for MTX. The incidences of ADRs for the various treatments were: MTX 22.2%, SSZ 11.0%, BUC 20.6%, MTX + BUC 30.0% and MTX + SSZ 31.2%. CONCLUSION: MTX showed the highest efficacy even though it was administrated at a low dose (6-8 mg), as a single agent or in combination with other treatment. However, in combination treatments, the continuous duration of treatment ending in ADRs as the end point were lower than those in single treatments with MTX, SSZ and BUC.

Intranasal exposure to monoclonal antibody Fab fragments to Japanese cedar pollen Cry j1 suppresses Japanese cedar pollen-induced allergic rhinitis.

BACKGROUND AND PURPOSE: Fab fragments (Fabs) of antibodies have the ability to bind to specific allergens but lack the Fc portion that exerts effector functions via binding to receptors including FcεR1 on mast cells. In the present study, we investigated whether intranasal administration of the effector function-lacking Fabs of a monoclonal antibody IgG1 (mAb, P1-8) to the major allergen Cry j1 of Japanese cedar pollen (JCP) suppressed JCP-induced allergic rhinitis in mice. EXPERIMENTAL APPROACH: Balb/c mice sensitized with JCP on days 0 and 14 were challenged intranasally with the pollen on days 28, 29, 30 and 35. Fabs prepared by the digestion of P1-8 with papain were also administered intranasally 15 min before each JCP challenge. KEY RESULTS: Intranasal administration of P1-8 Fabs was followed by marked suppression of sneezing and nasal rubbing in mice with JCP-induced allergic rhinitis. The suppression of these allergic symptoms by P1-8 Fabs was associated with decreases in mast cells and eosinophils and decreased hyperplasia of goblet cells in the nasal mucosa. CONCLUSIONS AND IMPLICATIONS: These results demonstrated that intranasal exposure to P1-8 Fabs was effective in suppressing JCP-induced allergic rhinitis in mice, suggesting that allergen-specific mAb Fabs might be used as a tool to regulate allergic pollinosis.

Preventive therapy for non-steroidal anti-inflammatory drug-induced ulcers in Japanese patients with rheumatoid arthritis: the current situation and a prospective controlled-study of the preventive effects of lansoprazole or famotidine.

BACKGROUND: There is a lack of evidence for the efficacy of preventive medications for peptic ulcers (PUs) among long-term users of non-steroidal anti-inflammatory drugs (NSAIDs) in Japan. AIM: To estimate the preventive effect by normal dose, not high-dose histamine-H2 receptor antagonists (H2RA) for NSAID-induced ulcers. METHODS: We designed two different studies to assess the efficacy of anti-ulcer agents in rheumatoid arthritis (RA) in patients treated over a long term with NSAIDs. An investigative survey divided patients into those not taking anti-ulcer agents (non-medication group); those taking mucosal protective agents (mucosal protectant group), H2RA (H2RA group), proton pump inhibitors (PPI group), or a prostaglandin E1 analog (PG) (PG group). The second study compared prospectively the preventive effects of either famotidine 20 mg bd (famotidine group) or lansoprazole 15 mg daily (lansoprazole group) in patients with PU scars. RESULTS: The prevalence of PU in the H2RA group was significantly lower compared to the mucosal protectant group (P < 0.05), and the mucosal protectant group was not significantly different to the non-medication group. The prospective study revealed that the PU onset rate of the famotidine group was 8% (1/13), and lansoprazole group was 15% (2/13), indicating no significant differences between the two. CONCLUSIONS: In Japan, normal-dose H2RA is expected to be a new PU preventive treatment strategy in patients requiring long-term NSAID therapy.

The ability of disease modifying antirheumatic drugs to induce and maintain improvement in patients with rheumatoid arthritis. epidemiology of DMARDs treatment in Japan.

OBJECTIVE: The effectiveness of the disease-modifying antirheumatic drugs (DMARDs) methotrexate (MTX), bucillamine (BUC), salazosulphapyridine (SASP) and gold sodium thiomalate (GST) over two courses of treatment with a follow-up period of at least 12 months was evaluated in 425 patients with rheumatoid arthritis. METHODS: Clinical efficacy was evaluated on the basis of the numbers of painful and swollen joints, morning stiffness, grip strength, erythrocyte sedimentation rate, C-reactive protein and rheumatoid factor levels before and after treatment. Results were evaluated on the basis of the survival rate (Kaplan-Meier method) and the incidence and types of adverse drug reactions (ADR) following single and combined therapies. RESULTS: In the first course of treatment, the survival rates for MTX, GST, BUC and SASP were 52.3%, 40.4%, 33.0% and 24.8%, respectively. The rates of development of ADR were 22.9%, 23.5%, 26.3% and 30.0% for BUC, SASP, GST and MTX, respectively. In the second course, the survival rates for MTX, BUC and SASP were 36.6%, 14.1% and 10%, respectively. CONCLUSION: DMARDs used in the first course of treatment improved the clinical parameters until the 6th month after initiation of treatment. Combination treatments showed some effectiveness, but because of the high incidence of ADR the survival rate was low. DMARDs used in the second course of treatment were not efficacious and there was no improvement in the survival rate compared to the first course of treatment.

Adeno-associated virus vector-mediated anti-angiogenic gene therapy for collagen-induced arthritis in mice.

OBJECTIVE: The goal of this study was to determine the utility of adeno-associated virus (AAV) vectors for anti-angiogenic gene therapy in a mouse model of collagen-induced arthritis (CIA). METHODS: CIA mice were generated by immunization with bovine type-II collagen and Freund's complete adjuvant. AAV vectors containing angiostatin and enhanced green fluorescent protein (eGFP) expression units (AAV-Ang/GFP) or the GFP and neomycin phosphotransferase (NeoR) expression units (AAV-GFP/NeoR) were injected into mouse knee joints before development of arthritis. The expression of transgenes was confirmed by reverse transcriptase polymerase chain reaction (RT-PCR) and immunostaining, and the incidence and severity of arthritis was determined histologically via assessment of synovial hyperplasia, cartilage erosion and bone erosion. Vascularity in the knee joint was evaluated by immunohistochemical staining with anti-von Willebrand factor antibody. RESULTS: AAV vectors were capable of efficient gene transfer into chondrocytes and synovial cells, and the extent of synovial hyperplasia and other parameters of arthritis were significantly reduced in the knee joints injected with AAV-Ang/GFP compared with the joints treated with either AAV-GFP/NeoR or phosphate-buffered solution (PBS). Reduction in the number of vessels was confirmed in AAV-Ang/GFP-treated joints. CONCLUSION: AAV-vector-mediated local expression of angiostatin efficiently inhibited the development of collagen-induced arthritis in the treated joint. Anti-angiogenic gene therapy using AAV vector may provide a new approach for the effective treatment of rheumatoid arthritis.

Effects of mirthful laughter on growth hormone, IGF-1 and substance P in patients with rheumatoid arthritis.

OBJECTIVE: Growth hormone (GH) plays an ancillary role in the regulation of immune function. GH has been shown to be associated with joint symptoms such as pain and swelling. On the other hand, mirthful laughter has favorable effects on the neuroendocrine-immune system. We evaluated the levels of serum GH, insulin-like growth factor-1 (IGF-1) in RA patients and evaluated the effect of mirthful laughter on GH and IGF-1. METHODS: We compared with the levels of serum GH, IGF-1 and substance P (SP) in patients with RA and healthy subjects (control group) before and after exposure to "Rakugo", a traditional Japanese comical story that induces mirthful laughter. RESULTS: The basal level of serum GH in the RA group was significantly higher than in the control group. After experiencing mirthful laughter, the level of serum GH in the RA group significantly decreased, approaching that in the control group. The serum IGF-1 level was lower in the RA group than in the control group. There was no significant difference in the level of serum SP between the RA group and the control group. CONCLUSION: The basal level of serum GH in the RA group was significantly higher than in the control group, and the level of serum GH significantly decreased after experiencing mirthful laughter These results suggest that the homeostasis of GH in patients with RA is disturbed, and the increased serum GH levels in RA patients may be associated with their stress condition.

Effect of varying types of anti-arthritic drugs on Th1 and Th2 immune responses in mice.

The present study was undertaken to study the effect of varying types of anti-arthritic drugs on Th1 and Th2 immune responses in mice. To immunize mice, ovalbumin (OVA) emulsified with complete Freund's adjuvant was injected s.c. at the base of the tail (day 0). Indomethacin (IND) as a non-steroidal antiinflammatory drug (NSAID), dexamethasone (DEX) as a steroidal antiinflammatory drug, methotrexate (MTX), auranofin (AUR), and D-penicillamine (D-PA) as an anti-rheumatic drugs were orally administrated daily from days 0 to 20. On day 21, anti-OVA IgG2a and interferon (IFN)-gamma as indicators of Th1 responses and anti-OVA IgG1 and interleukin (IL)-10 as those of Th2 responses were measured. Treatments with IND, DEX, MTX and AUR were followed by decreases in OVA-specific IgG and proliferation of spleen cells to the antigen. Treatments with IND, DEX, MTX and AUR inhibited both Th1 and Th2 immune responses, although the inhibitory effects of these drugs on the antigen-specific IgG2a and IFN-gamma production appeared to be greater than those on IgG1 and IL-10 production. D-PA failed to influence anti-OVA IgG, IgG2a and IgG1 production as well as IFN-gamma and IL-10 secretion. Administrations of all the drugs used resulted in suppression of antigen (OVA)-induced arthritis in mice which was associated with inhibition of anti-OVA IgG2a but not IgG1 production. These results suggest that anti-arthritic drugs including IND, DEX, MTX and AUR appear to suppress Th1 and, to a lesser extent, Th2 immune responses, and their anti-inflammatory effects on human rheumatoid arthritis might be at least in part explained by downregulation by these drugs of Th1 responses involved in the disease.