Different Tendencies in Muscle Ultrasound Characteristic in Amyotrophic Lateral Sclerosis and Chronic Inflammatory Demyelinating Polyradiculoneuropathy.

INTRODUCTION: The difference in muscle ultrasound (MUS) characteristics in primary axonal degeneration and demyelination has not been well established. The authors aimed to investigate the subject based on the correlation between MUS findings (echo intensity and muscle thickness) and compound muscle action potential (CMAP) amplitude in amyotrophic lateral sclerosis (ALS) and chronic inflammatory demyelinating polyradiculoneuropathy. METHODS: Fifteen patients with ALS and 16 patients with chronic inflammatory demyelinating polyradiculoneuropathy were examined. For each patient, echo intensity and muscle thickness of the abductor pollicis brevis, abductor digiti minimi, and first dorsal interosseous muscles were investigated. Compound muscle action potential amplitudes were measured by median and ulnar nerve conduction studies. RESULTS: In total, 45 muscles were evaluated in each group. The ALS group showed a linear correlation between the MUS finding and CMAP amplitude (rs = -0.70 and 0.59 for echo intensity and muscle thickness, respectively), whereas the chronic inflammatory demyelinating polyradiculoneuropathy group showed a weaker correlation than the ALS group (rs = -0.32 for echo intensity and rs = 0.34 for muscle thickness). CONCLUSIONS: The relationship between MUS abnormalities and CMAP amplitude showed different tendencies in ALS and chronic inflammatory demyelinating polyradiculoneuropathy. The results suggested that MUS abnormalities substantially reflect the muscle function in primary axonal degeneration, whereas a discrepancy between MUS findings and muscle function can be frequently seen in demyelination; specifically, MUS findings tend to be normal even though CMAP showed a reduction. These tendencies originating from underlying pathophysiology should be considered when MUS findings are used as biomarkers of disease severity.

Utility of nerve ultrasound in the management of primary neurolymphomatosis: Case report and review of the literature.

Introduction: Primary neurolymphomatosis (NL) is a critical differential diagnosis of asymmetric multiple mononeuropathy and radiculoplexopathy. Its diagnosis is often challenging due to the lack of typical clinical signs of systemic lymphoma. We report a case of primary NL where nerve ultrasound (NUS) played an important role in the diagnosis and follow-up of the disease. Case presentation: A 52-year-old man developed asymmetric painful multiple mononeuropathy in the right upper limb with cranial nerve involvement. After being referred to our department, the patient underwent NUS, which revealed marked enlargement and increased vascularity in the right upper limb nerves, brachial plexus, and cervical nerve roots. Furthermore, an epineural hypoechoic mass, a characteristic finding of NL, was seen in the right median nerve. These NUS findings prompted us to perform 18F-fluorodeoxyglucose positron emission tomography/computed tomography and a subsequent biopsy on the right axillary lymph node, confirming NL. Notably, the NUS abnormalities dramatically subsided, demonstrating the effectiveness of chemotherapy. Discussion: The diagnostic utility of NUS for NL has been documented by many recent reports. Additionally, NUS can work as a quick follow-up tool for NL, as seen in our case.

Hereditary angio-oedema with normal C1-INH, developing recurrent acute abdomen after taking low-dose oestrogen-progestin: A case report.

Hereditary angio-oedema (HAE) is a rare genetic disease characterised by repeated episodes of temporary organ swelling. Three types of HAE are known, of which HAE with normal C1 inactivator is difficult to be diagnosed due to its lack of laboratory abnormalities. Here, we describe a case of HAE with normal C1 inactivator and recurrent acute abdomen following low-dose oestrogen-progestin therapy. Notably, genetic analysis by Sanger sequencing led to the identification of a recurrent heterozygous missense mutation c.988A > G (p.K330E) in the plasminogen (PLG) gene of the patient. Prophylactic tranexamic acid and on-demand selective bradykinin B2 receptor blockers are used to treat her symptoms.

[A patient with rheumatoid arthritis who developed liver cirrhosis after increased soft drinks intake].

A Japanese woman in her 80s with rheumatoid arthritis (RA) was admitted for weakness, edema, and ascites. She was obese (148 cm in height, 60 kg in weight) and had a high gamma-glutamyltransferase level according to her laboratory findings before treatment. She had received methotrexate (MTX) at a dose of 6 mg/week for 1 year and 9 months. She had consumed large amounts of soft drinks (about 110 g of sugar/day) for a long time, but during the course of treatment for RA, she began drinking even more (170 g/day). Her condition improved with the discontinuation of MTX, adequate nutrition, and administration of diuretics. We diagnosed her with liver cirrhosis caused by both drug-induced hepatic injury due to MTX and by exacerbation of non-alcoholic steatohepatitis due to excessive sugar intake.

Stability of enveloped and nonenveloped viruses in hydrolyzed gelatin liquid formulation.

BACKGROUND: The thermal stability of viruses in gelatin liquid formulations for medical research and application is poorly understood and this study aimed to examine the thermal stability of 4 enveloped and nonenveloped DNA and RNA viruses in hydrolyzed gelatin liquid formulations. METHODS: Bovine herpesvirus (BHV) was used as a model virus to examine the molecular weight (MW), concentration and gelatin type and to optimize virus stability in liquid formulations at 25 °C and 4 °C. Using the model virus liquid formulation, the stability of multiple enveloped and nonenveloped RNA and DNA viruses, including parainfluenza virus, reovirus (RV), BHV, and adenovirus (AdV), was monitored over up to a 30-week storage period. RESULTS: The BHV model virus was considered stable after 3 weeks in hydrolyzed gelatin (MW: 4000) with a 0.8 LRV (log10 reduction value) at 25 °C or a 0.2 LRV at 4 °C, compared to the stabilities observed in higher MW gelatin (60,000 and 160,000) with an LRV above 1. Based on the gelatin type, BHV in alkaline-treated hydrolyzed gelatin samples were unexpectantly more stable than in acid-treated hydrolyzed gelatin sample. All four viruses exhibited stability at 4 °C for at least 8 weeks, BHV or AdV remained stable for over 30 weeks of storage, and at 25 °C, AdV and RV remained stable for 8 weeks. CONCLUSION: The results demonstrated that 5% of 4000 MW hydrolyzed gelatin formulation can act as a relevant stabilizer for the thermal stability of viruses in medical research and application.

Ultrasonographic evaluation reveals thinning of cervical nerve roots and peripheral nerves in spinal and bulbar muscular atrophy.

BACKGROUND: Ultrasonography (US) is a noninvasive and patient-friendly tool for the evaluation of peripheral nerves. In motor neuron diseases, amyotrophic lateral sclerosis (ALS) has been reported to show the atrophy of peripheral nerves on US. However, the US findings are still unclear in spinal and bulbar muscular atrophy (SBMA), an adult-onset lower motor neuron disease caused by an abnormal CAG repeat expansion in the androgen receptor gene. METHODS: We prospectively recruited and evaluated 11 patients with genetically confirmed SBMA and 9 patients with ALS diagnosed according to the revised El Escorial ALS criteria or the Awaji electrodiagnostic criteria. The C5-C7 cervical nerve roots and the median and ulnar nerves were evaluated ultrasonographically. RESULTS: The cross-sectional areas (CSAs) of the C6 and C7 nerve roots, the median nerve in the upper arm and forearm, and the ulnar nerve in the upper arm were smaller in patients with SBMA than those in patients with ALS (p < 0.05), whereas the CSAs of the C5 nerve root and the ulnar nerve in the forearm were not smaller. CONCLUSIONS: US showed that the peripheral nerves in patients with SBMA were thinner than those in patients with ALS despite similar degrees of weakness and motor neuron loss. Possible causes include additional sensory nerve involvement and longer disease duration in patients with SBMA than those in patients with ALS.

Successful rituximab treatment in a patient with ANCA-negative granulomatosis with polyangitis: A case report.

A 68-year-old woman was referred to our hospital for further evaluation of fever, nasal congestion, deafness, and multiple pulmonary nodules refractory to antibiotic use. Despite negative findings of antineutrophil cytoplasmic antibodies, she was diagnosed with granulomatosis with polyangiitis based on the analysis of biopsy specimens of pulmonary nodules. The administrations of oral prednisolone and six intravenous cyclophosphamide (IVCY) resulted in the prompt relief of symptoms and disappearance of pulmonary nodules. However, 3 months after the completion of IVCY therapy, nasal congestion and deafness flared up with an increase in the C-reactive protein level; a repeat computed tomography revealed a left lung nodule. Consequently, she underwent remission induction and maintenance therapy with rituximab (RTX), which resulted in the symptomatic improvement and disappearance of pulmonary nodules after 6 months. The patient remained in remission thereafter. Therefore, RTX may be an effective therapeutic option even in the absence of detectable autoantibodies.

Acute respiratory distress syndrome relapsing in 10 months with an initial manifestation of polymyositis.

Autoimmune disorders are an important cause of acute respiratory distress syndrome (ARDS). We report a case of a patient with steroid-responsive ARDS that relapsed in 10 months with an initial manifestation of seronegative polymyositis. ARDS associated with polymyositis may develop earlier than myopathy and may relapse later.

Application of bioluminescence resonance energy transfer-based cell tracking approach in bone tissue engineering.

Bioluminescent imaging (BLI) has emerged as a popular in vivo tracking modality in bone regeneration studies stemming from its clear advantages: non-invasive, real-time, and inexpensive. We recently adopted bioluminescence resonance energy transfer (BRET) principle to improve BLI cell tracking and generated the brightest bioluminescent signal known to date, which thus enables more sensitive real-time cell tracking at deep tissue level. In the present study, we brought BRET-based cell tracking strategy into the field of bone tissue engineering for the first time. We labeled rat mesenchymal stem cells (rMSCs) with our in-house BRET-based GpNLuc reporter and evaluated the cell tracking efficacy both in vitro and in vivo. In scaffold-free spheroid 3D culture system, using BRET-based GpNLuc labeling resulted in significantly better correlation to cell numbers than a fluorescence based approach. In scaffold-based 3D culture system, GpNLuc-rMSCs displayed robust bioluminescence signals with minimal background noise. Furthermore, a tight correlation between BLI signal and cell number highlighted the robust reliability of using BRET-based BLI. In calvarial critical sized defect model, robust signal and the consistency in cell survival evaluation collectively supported BRET-based GpNLuc labeling as a reliable approach for non-invasively tracking MSC. In summary, BRET-based GpNLuc labeling is a robust, reliable, and inexpensive real-time cell tracking method, which offers a promising direction for the technological innovation of BLI and even non-invasive tracking systems, in the field of bone tissue engineering.

Homeostatic Milieu Induces Production of Deoxyribonuclease 1-like 3 from Myeloid Cells.

DNase 1-like 3 (DNase1L3), which belongs to DNase1 family, was originally identified as one of apoptosis- and necrosis-related endonucleases that fragmentate intranucleosomal DNA. A loss-of-function mutation has been reported in murine models of systemic lupus erythematosus (SLE) and in familial SLE patients. These reports suggest DNase1L3 plays an important role in the prevention of developing SLE; however, expression and function of DNase1L3 in human immune systems have been largely unclarified. As previous reports showed DNase1L3 is expressed in hematopoietic organs, we first analyzed expression levels of DNase1L3 in each subset of human peripheral blood cells by quantitative real-time PCR. Plasmacytoid dendritic cells showed the highest expression levels of DNase1L3 mRNA among peripheral blood cells. IL-4 enhanced DNase1L3 expression in monocytes, monocyte-derived dendritic cells, and monocyte-derived macrophages (MDMs), but not in T cells, B cells, or plasmacytoid dendritic cells. Together with IL-4, all-trans retinoic acid and apoptotic cells efficiently upregulated expression of DNalse1L3 in MDMs. As a result of intracellular signaling analysis, Jak1-IRS2-ERK/PI3K pathway was essential for IL-4-induced DNase1L3 expression. IL-4-treated monocyte-derived dendritic cells and MDMs secreted active DNase1L3 protein that could degrade liposome-DNA complexes, which were resistant to DNase1. Our results indicate DNase1L3 is secreted by innate immune cells and may play a critical role in the tissue homeostasis and on prevention of developing autoimmunity by degrading self-DNA.

Shoulder ultrasound and serum lactate dehydrogenase predict inadequate response to glucocorticoid treatment in patients with polymyalgia rheumatica.

We aimed to identify predictors of inadequate response to glucocorticoid (GC) treatment in patients with polymyalgia rheumatica (PMR). We retrospectively studied 32 patients as a derivation cohort and 24 patients as a validation cohort. The patients were divided into two groups according to the response to GC treatment: GC-responders and GC-inadequate responders (GC-IRs). We compared laboratory data and bilateral shoulder ultrasound findings between the groups. Receiver operating characteristic (ROC) analysis was performed to determine the optimal cutoff value of candidate predictors of treatment response; the predictors were examined using multivariate logistic analysis. Gray-scale ultrasound findings of long head of the biceps (LHB) tenosynovitis and subacromial/subdeltoid (SAD) bursitis were scored semiquantitatively (0-3). A total gray-scale score (TGSS) was calculated as the sum of the gray-scale scores. In the derivation cohort, serum lactate dehydrogenase (LDH) levels and TGSS were significantly higher in GC-IRs than in GC-responders. On ROC analysis, the cutoff values of serum LDH levels ≥ 175 IU/ml and TGSS ≥ 5 were found to be the candidate predictors. Multivariate logistic analysis revealed an independent association of both the predictors with inadequate response to GC treatment. In the validation cohort, patients with one or both predictors exhibited a higher incidence of inadequate response to GC treatment. These findings indicate that the severities of LHB tenosynovitis and SAD bursitis evaluated using ultrasound and serum LDH levels are independent predictors of inadequate response to GC treatment in patients with PMR. Treatment adjustment based on prediction model may allow precise treatment of patients with PMR.

Long-term efficacy and safety of tocilizumab in refractory Takayasu arteritis: final results of the randomized controlled phase 3 TAKT study.

OBJECTIVE: To investigate the long-term efficacy and safety of the IL-6 receptor antibody tocilizumab in patients with Takayasu arteritis (TAK). METHODS: Patients completing the randomized, double-blind, placebo-controlled period of the TAKT (Takayasu arteritis Treated with Tocilizumab) trial were followed up during open-label extended treatment with weekly s.c. tocilizumab 162 mg for up to 96 weeks or longer, with oral glucocorticoid tapering performed at the investigators' discretion. Endpoints of the extension analysis included steroid-sparing effects of tocilizumab, imaging data, patient-reported outcomes (36-Item Short Form Health Survey) and safety. RESULTS: All 36 patients enrolled in the double-blind period entered the open-label extension; 28 patients received tocilizumab for 96 weeks. The median glucocorticoid dose was 0.223 mg/kg/day at the time of relapse before study entry, 0.131 mg/kg/day (interquartile range 0.099, 0.207) after 48 weeks and 0.105 mg/kg/day (interquartile range 0.039, 0.153) after 96 weeks. Overall, 46.4% of patients reduced their dose to <0.1 mg/kg/day, which was less than half the dose administered at relapse before study entry (mean difference -0.120 mg/kg/day; 95% CI -0.154, -0.087). Imaging evaluations indicated that most patients' disease was improved (17.9%) or stable (67.9%) after 96 weeks compared with baseline. Mean 36-Item Short Form Health Survey physical and mental component summary scores and 7 of 8 domain scores were clinically improved from baseline and maintained over 96 weeks of tocilizumab treatment. No unexpected safety issues were reported. CONCLUSION: These results in patients with Takayasu arteritis provide evidence of a steroid-sparing effect and improvements in well-being during long-term treatment with once-weekly tocilizumab 162 mg, with no new safety concerns. TRIAL REGISTRATION: JAPIC Clinical Trials Information, http://www.clinicaltrials.jp/user/cteSearch_e.jsp, JapicCTI-142616.

Abatacept reduces disease activity of rheumatoid arthritis independently of modulating anti-citrullinated peptide antibody production.

Abatacept may exert its clinical effect on rheumatoid arthritis (RA) by suppressing anti-cyclic citrullinated peptide (CCP) antibody production. This study was undertaken to test this hypothesis by examining the changes of disease activity of RA and anti-CCP antibody levels over time after starting abatacept. Sixty Japanese RA patients who started abatacept were included in this multicenter, prospective observational study. Simple Disease Activity Index (SDAI) and anti-CCP antibody levels were evaluated at 12, 24, and 52 weeks. The mean SDAI score significantly decreased within 12 weeks after starting abatacept and was maintained thereafter. On the contrary, the mean anti-CCP antibody levels did not change until 52 weeks. At the individual level, there were substantial changes of anti-CCP antibody levels, but these were not correlated with the changes of disease activity at any time points. Thus, abatacept reduces the disease activity of RA independently of modulating anti-CCP antibody production.

Suppression of joint destruction with subcutaneous tocilizumab for Japanese patients with rheumatoid arthritis in clinical practice.

Objectives: To investigate the efficacy of suppressing joint destruction with subcutaneous tocilizumab (TCZ-SC) for Japanese rheumatoid arthritis (RA) patients in the real-world clinical setting.Methods: This 1-year prospective, multicenter study included 110 RA patients in whom TCZ-SC was newly initiated. Primary endpoint was the change from baseline in vdH-modified total Sharp score (mTSS) at week 52. Structural remission was defined as yearly mTSS of 0.5 or less. Disease activity was evaluated using the disease activity score (DAS28-ESR) and clinical disease activity index (CDAI).Results: At baseline, the patients' mean age was 58.6 years, and the mean disease duration was 10.6 years. The proportion of patients who were naïve for biologics was 44.5%, and 64.5% concomitantly received methotrexate. The yearly mTSS showed significant improvement from 9.41 before TCZ-SC initiation to -0.15 after 52 weeks. The structural remission rate was 76.1%. After 52 weeks, the DAS28-ESR and CDAI remission rates were 52% and 21%, respectively. Although the previous usage of biologics and baseline disease activity significantly affected the clinical remission, no factors with significant effects on structural remission were identified.Conclusion: These findings support the efficacy of TCZ-SC in suppressing disease activity as well as joint destruction over a 1-year period.

CCR6+ group 3 innate lymphoid cells accumulate in inflamed joints in rheumatoid arthritis and produce Th17 cytokines.

BACKGROUND: Recent studies show that innate lymphoid cells (ILCs) contribute to the development of chronic inflammation and autoimmune disease. In this study, we assessed the ILC function in the development of rheumatoid arthritis (RA). METHODS: In a mouse model of collagen-induced arthritis (CIA), we identified and purified the ILC subsets in peripheral blood (PB), local lymph nodes (LNs), and joints by fluorescence-activated cell sorting and used quantitative PCR to assess the expression levels of representative cytokines. We also correlated the frequencies of each ILC subset in synovial fluid (SF) with clinical parameters in RA patients. RESULTS: In the CIA model, the proportion of CCR6+ ILC3s to total ILCs in joints with active inflammation significantly increased relative to non-arthritic joints (median 29.6% vs 16.7%, p = 0.035). CCR6+ ILC3s from mice with arthritis expressed significantly higher levels of IL-17A and IL-22 mRNA than did comparable cells from control mice (p < 0.0001 and p = 0.015). In RA patients, the proportion of CCR6+ ILCs in SF was positively correlated with tender joint counts (TJC) and swollen joint counts (SJC) (ρ=0.689, p = 0.0032 and ρ=0.644, p = 0.0071, respectively). Levels of CC chemokine ligand 20 (CCL20) increased in SF of patients with RA and were significantly correlated with CCR6+ ILC number (ρ=0.697, p = 0.0001). CONCLUSION: CCR6+ ILC3s may play some roles in the development of RA through the production of IL-17 and IL-22.

CD34-selected versus unmanipulated autologous haematopoietic stem cell transplantation in the treatment of severe systemic sclerosis: a post hoc analysis of a phase I/II clinical trial conducted in Japan.

BACKGROUND: The effectiveness of autologous haematopoietic stem cell transplantation (auto-HSCT) in treating severe systemic sclerosis (SSc) is established; however, the necessity of purified CD34+ cell grafts and the appropriate conditioning regimen remain unclear. This study aimed to compare the efficacy and safety of CD34-selected auto-HSCT with unmanipulated auto-HSCT to treat severe SSc. METHODS: This study was a post hoc analysis of a phase I/II clinical trial conducted in Japan. Nineteen patients with severe SSc were enrolled. Peripheral blood stem cells (PBSCs) were mobilised with cyclophosphamide (4 g/m2) and filgrastim (10 µg/kg/day). Following PBSC collection by apheresis, CD34+ cells were immunologically selected in 11 patients. All patients were treated with high-dose cyclophosphamide (200 mg/kg) monotherapy as a conditioning regimen and received CD34-selected (n = 11) or unmanipulated auto-HSCT (n = 8). Changes in skin sclerosis and pulmonary function were assessed over an 8-year follow-up period. Differences in the changes, toxicity, progression-free survival (PFS) and overall survival were compared between patients who had received CD34-selected auto-HSCT and those who had received unmanipulated auto-HSCT. RESULTS: Skin sclerosis progressively improved after transplantation over an 8-year follow-up period in both groups, and the improvement was significantly greater in the CD34-selected group than in the unmanipulated group. Forced vital capacity in the CD34-selected group continuously increased over 8 years, whereas in the unmanipulated group it returned to baseline 3 years after transplantation. Toxicity and viral infections, such as cytomegalovirus infection and herpes zoster, were more frequently found in the CD34-selected group than in the unmanipulated group. The frequency of severe adverse events, such as bacterial infections or organ toxicity, was similar between the two groups. No treatment-related deaths occurred in either treatment group. PFS of the CD34-selected group was greater than that of the unmanipulated group, and the 5-year PFS rates of the CD34-selected and unmanipulated group were 81.8% and 50% respectively. CONCLUSIONS: CD34-selected auto-HSCT may produce favourable effects on improvement of skin sclerosis and pulmonary function compared with unmanipulated auto-HSCT. Use of CD34-selected auto-HSCT with high-dose cyclophosphamide monotherapy as a conditioning regimen may offer an excellent benefit-to-risk balance.

Long-term efficacy of infliximab treatment and the predictors of treatment outcomes in patients with refractory uveitis associated with Behçet's disease.

OBJECTIVE: To assess the long-term efficacy and safety of infliximab (IFX) treatment for refractory uveitis associated with Behçet's disease (BD) and to identify predictors of long-term IFX therapy outcomes. METHODS: We retrospectively studied 44 consecutive BD patients with uveitis who were started on IFX therapy and analyzed the efficacy and safety of IFX and the treatment continuation rate. To determine predictors of IFX responsiveness, we analyzed the clinical characteristics of the patients who received regular maintenance therapy and those who required treatment intensification. The serum cytokine levels prior to IFX were measured through the Bio-Plex human cytokine assays. RESULTS: IFX significantly reduced the frequency of ocular attacks and improved the visual acuity of patients with BD-related uveitis. However, approximately half of the patients required dose escalations, necessitating a shortening of the intervals between IFX infusions due to loss of efficacy during the 5-year treatment. The frequency of ocular attacks was significantly higher in patients with complete BD than in patients with incomplete BD. A multiplex cytokine analysis revealed that patients with BD-related uveitis exhibited increased serum IL-2, IL-6, IL-8, and MCP-1 levels. Moreover, among BD patients, the serum IL-2 and IL-6 levels were particularly high in those who maintained remission and received regular IFX treatments. CONCLUSION: We confirmed the long-term efficacy and tolerability of IFX in patients with BD-related uveitis. Our results indicate that complete BD may be less responsive to IFX and that the pretreatment serum cytokine profiles may be useful for predicting the long-term IFX therapy outcomes.

Molecular mechanisms of action of anti-TNF-α agents - Comparison among therapeutic TNF-α antagonists.

Tumor necrosis factor (TNF)-α is a potent pro-inflammatory and pathological cytokines in inflammatory diseases such as rheumatoid arthritis and inflammatory bowel diseases. Anti-TNF-α therapy has been established as an efficacious therapeutic strategy in these diseases. In clinical settings, three monoclonal anti-TNF-α full IgG1 antibodies infliximab, adalimumab, and golimumab, PEGylated Fab' fragment of anti-TNF-α antibody certolizumab pegol, extracellular domain of TNF receptor 2/IgG1-Fc fusion protein etanercept, are almost equally effective for rheumatoid arthritis. Although monoclonal full IgG1 antibodies are able to induce clinical and endoscopic remission in inflammatory bowel diseases, certolizumab pegol without Fc portion has been shown to be less effective for inflammatory bowel diseases compared to full IgG1 antibodies. In addition, there are no evidences that etanercept leads clinical remission in inflammatory bowel diseases. Besides the common effect of anti-TNF-α agents on neutralization of soluble TNF-α, each anti-TNF-α agent has its own distinctive pharmacological properties which cause the difference in clinical efficacies. Here we focus on the distinctions of action of anti-TNF-α agents especially in following points; (1) blocking ability against ligands, transmembrane TNF-α and lymphotoxin, (2) effects toward transmembrane TNF-α-expressing cells, (3) effects toward Fcγ receptor-expressing cells, (4) degradation and distribution in inflamed tissue. Accumulating evidence will give us the idea how to modify anti-TNF-α agents to enhance the clinical efficacy in inflammatory diseases.