Bronchiectasis is as crucial as interstitial lung disease in the severe pneumonia that occurs during treatment with biologic DMARDs in rheumatoid arthritis: a retrospective cohort study in a single facility.

Interstitial lung disease (ILD) carries a risk for severe pneumonia in patients with rheumatoid arthritis (RA). Bronchiectasis, another risk of severe pneumonia, has not been well elucidated in RA. We investigated the types of respiratory diseases in RA and correlated them to severe pneumonia during the course of treatment using biologic DMARDs (bDMARDs), with special attention to bronchiectasis and ILD. RA patients were examined by computed tomography before starting bDMARDs and divided into three groups: normal, bronchiectasis and ILD. The log-rank test and Dunnett's multiple comparisons test were employed for the statistical analysis. Among 424 patients, 350 were categorized as normal, 32 as having bronchiectasis, and 42 as having ILD. Two in the normal group, three in the bronchiectasis group and four in the ILD group developed severe pneumonia. The log-rank test showed a significant difference among the three groups (p < 0.0001). The pneumonia-free rates in the bronchiectasis and ILD groups were significantly lower than the normal group, respectively, with Dunnett's multiple comparison test (p < 0.0001). This study suggests that the bronchiectasis that occurs in RA carries a risk of severe pneumonia during treatment with bDMARDs that is comparable to ILD.

Liver dysfunction in anti-melanoma differentiation-associated gene 5 antibody-positive patients with dermatomyositis.

The objective was to investigate the clinical and histological features of liver dysfunction in patients with polymyositis (PM) or dermatomyositis (DM).A total of 115 patients (38 with PM and 77 with DM), who were admitted to our hospital between 2001 and 2012, were retrospectively reviewed. Liver dysfunction was defined as an alanine transaminase (ALT) level ≥ 60 U/l and a disproportionate ALT elevation relative to the creatine kinase level. The histological findings from liver biopsies were also assessed.The frequencies of liver dysfunction were 3% and 17% in the patients with PM and DM, respectively. Liver dysfunction was not observed in the patients who had malignancies. Among the patients with DM with no malignancies (n = 50), 20% had liver dysfunction, and all of the patients with liver dysfunction were positive for the anti-melanoma differentiation-associated gene 5 (MDA5) antibody. Compared with those in the patients who did not have liver dysfunction, the ALT, alkaline phosphatase, γ-glutamyl transferase, and KL-6 levels were significantly elevated in the patients who had liver dysfunction. Six patients, comprising four with DM and two with PM, underwent liver biopsies, and the common histological findings associated with DM were steatosis, hepatocyte ballooning, increases in the pigmented macrophage numbers, and glycogenated nuclei. Hemophagocytosis was detected in two of three patients with DM who underwent liver biopsies and bone marrow aspirations. In conclusion, Liver dysfunction might be an extramuscular manifestation in patients with DM who are anti-MDA5 antibody-positive. Steatosis and hepatocyte ballooning could be common histological features.

Wide difference in biologics usage and expenditure for the treatment of patients with rheumatoid arthritis in each prefecture in Japan analyzed using "National Database of Health Insurance Claims and Specific Health Checkups of Japan".

To analyze the biologics usage and expenditure for the treatment of patients with rheumatoid arthritis (RA) in each prefecture throughout Japan using the national open database, the Ministry of Health, Labour and Welfare of Japan disclosed; in Oct 2016, the data of the top 30 most-frequently prescribed drugs during a 1-year period from April 2014 to March 2015 in each prefecture in Japan, along with the patients' age and sex. Seldom-used drugs were excluded. We picked up only biologics for the present study. The total expenditure on biologics used in each prefecture was correlated with the population thereof. However, there was a big difference, up to ~ twofold, in the average expenditure used for an RA patient: highest in Toyama and lowest in Wakayama. There was also a big difference, ~ 4.5-fold, in the number of rheumatologists/1000 RA patients, highest in Kyoto and lowest in Aomori. The average expenditure used for an RA patient was correlated with the number of rheumatologists in the western part of Japan. Etanercept seemed to be used most frequently to Japanese RA patients followed closely by infliximab. Abatacept was used more frequently to the elderly than other biologics. There was a big difference in the number of rheumatologists and expenditure on biologics for the treatment of an RA patient among prefectures in fiscal 2014. Factors that brought this unevenness need to be scrutinized for universal implementation of good RA care throughout Japan, where there are uniform health insurance system and free access to rheumatologists.

Beneficial use of serum ferritin and heme oxygenase-1 as biomarkers in adult-onset Still's disease: A multicenter retrospective study.

BACKGROUND: Heme oxygenase (HO)-1 is a heme-degrading enzyme highly expressed in monocyte/macrophage, serum levels of which may be promising biomarker for adult-onset Still's disease (AOSD). We here report data on the use of serum ferritin and HO-1 levels in AOSD. METHODS: Under the Hypercytokinemia Study Group collaboration, we collected sera from a total of 145 AOSD patients. Three independent experts judged whether the patients were definite AOSD depending on the clinical information. These 91 'definite AOSD' patients were further divided into active, remission, and relapse groups. Forty-six cases of systemic vasculitis, sepsis, etc. were included as disease controls. Serum ferritin and HO-1 levels were measured using ELISA. Associations between clinical symptoms, serum ferritin, and HO-1 were explored. Multivariate regression analysis was performed to identify independent variables associated with definite AOSD diagnosis. RESULTS: Serum ferritin and HO-1 levels were significantly higher in active and relapsed AOSD cases compared to disease controls, and were reduced by the treatment. Although a significant correlation was found between serum ferritin and HO-1 levels, a discrepancy was found in some cases such as iron-deficiency anemia. Receiver operating characteristic analysis identified optimal levels of serum ferritin (>819 ng/ml; sensitivity 76.1% and specificity 73.8%), and serum HO-1 (>30.2 ng/ml; sensitivity 84.8% and specificity 83.3%) that differentiated AOSD from controls. Interestingly, 88.9% of patients with AOSD who relapsed exceeded the cut-off value of serum HO-1 > 30.2 ng/ml, but only 50.0% exceeded serum ferritin >819 ng/ml (p = .013), suggesting that serum HO-1 levels may be a convenient indicator of AOSD disease status. Multivariate analysis identified neutrophilia, RF/ANA negativity, sore throat, and elevated serum HO-1 as independent variables associated with AOSD diagnosis. CONCLUSION: We confirmed that serum ferritin and HO-1 serve as highly specific and sensitive biomarkers for AOSD. A future prospective study with large sample size is necessary to determine whether these biomarkers could be included in Yamaguchi's Criteria.

Difference in relapse-rate and clinical phenotype by autoantibody-subtype in Japanese patients with anti-neutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVE: To correlate the serotype specificity to myeloperoxidase (MPO) and proteinase-3 (PR3) with clinical characteristics in anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Clinical characteristics and outcomes of patients with AAV in our division from 2005 to 2014 were retrospectively compared on the basis of ANCA subtype. RESULTS: We collected the data from 88 patients with MPO-ANCA vasculitis, and 17 with PR3-ANCA vasculitis. Patients with PR3-ANCA vasculitis were younger, and had higher involvement-rates in the eye, nose, and ear. In both MPO- and PR3-ANCA vasculitis, the most frequently involved organ was the respiratory system. Interstitial pneumonia was more frequent in MPO-ANCA vasculitis (52.3% versus 5.9%, p < 0.01), whereas nodular shadow was more frequent in PR3-ANCA vasculitis (9.1% versus 58.8%, p < 0.01). Multivariable Cox proportional hazard regression analysis showed that the hazard ratio of PR3-ANCA for relapse was 2.48 (95% confidence interval 1.14-5.42, p = 0.02). There was no difference in the survival and the progression to end-stage kidney disease and respiratory failure between the two vasculitides. CONCLUSION: MPO-ANCA vasculitis was a predominant form of AAV in Japan. Classification based on ANCA subtype would be clinically relevant in the prediction of organ involvement and relapse.

Prediction of the therapeutic response to methotrexate at 24 weeks by methotrexate-polyglutamates concentration in erythrocytes at 8 weeks in patients with rheumatoid arthritis.

OBJECTIVES: The objective of this study is to evaluate the pharmacokinetics and pharmacodynamics of methotrexate-polyglutamates (MTX-PGs) in erythrocytes in patients with rheumatoid arthritis and correlate them with the efficacy. METHODS: MTX-PG concentrations in erythrocytes were measured in 42 MTX-naïve patients repeatedly for 24 weeks by high-performance liquid chromatography. In 56 patients receiving stable MTX doses for at least 12 weeks, the correlation between MTX doses and MTX-PG concentrations was examined. The efficacy was measured by the change of DAS28CRP (ΔDAS28CRP). RESULTS: There were moderate correlations between MTX dose and MTX-PG 3, 4, and 5. At 24 weeks, MTX-PG2, 3, 4, and 1-5 were higher in patients with ΔDAS28CRP >1.2 than in those with ≤1.2. The cutoff value of MTX-PG1-5 to discriminate ΔDAS28CRP >1.2 from ≤1.2 at 24 weeks was 68.7 nM. Among 20 patients with MTX-PG1-5 > 50.6 nM at 8 weeks, seven already improved at 8 weeks and additional 11 improved at 24 weeks (p < 0.001). On the contrary, among the nine patients with MTX-PG1-5 ≤ 50.6 nM at 8 weeks, none improved at 8 weeks and only one improved at 24 weeks (p = 0.500). CONCLUSIONS: Erythrocyte MTX-PGs might be a potential indicator and predictor of MTX efficacy.

Tocilizumab in systemic juvenile idiopathic arthritis in a real-world clinical setting: results from 1 year of postmarketing surveillance follow-up of 417 patients in Japan.

OBJECTIVES: To evaluate the safety and effectiveness of tocilizumab (TCZ) in patients with systemic juvenile idiopathic arthritis (sJIA) in real-world clinical settings in Japan. METHODS: Paediatric patients with sJIA initiating TCZ between April 2008 and February 2012 and those previously enrolled in clinical trials who initiated TCZ before April 2008 were enrolled in a Japanese registry surveillance programme. Safety and effectiveness parameters were collected for 52 weeks. RESULTS: Of 417 patients enrolled, mean age was 11.2 years and 48.0% were female. TCZ exposure was 407.0 patient-years (PYs). Baseline corticosteroid use was higher than in clinical trials. Rates of total adverse events (AEs) and serious AEs (SAEs) were 224.3/100 PYs and 54.5/100 PYs, respectively, with SAEs higher than previously reported. The most frequent AEs and SAEs were infections and infestations (69.8/100 PYs and 18.2/100 PYs, respectively). 74 serious infections occurred in 55 patients (18.2/100 PYs); higher than previously reported. 26 macrophage activation syndrome events were reported in 24 patients (6.4/100 PYs). Fever and rash symptoms improved from baseline to week 52 (54.6% to 5.6% and 43.0% to 5.6%, respectively). At 4 weeks, 8 weeks and 52 weeks, 90.5%, 96.2% and 99.0% of patients achieved normal C reactive protein levels (<0.3 mg/dL), respectively. CONCLUSIONS: These first real-world data demonstrated that TCZ was well tolerated, with acceptable safety and effectiveness in patients with sJIA. Higher incidences of SAEs and serious infections may be due to differences, such as corticosteroid use and concomitant diseases, between patient populations enrolled in previously reported clinical trials and this study.

A novel method predicting clinical response using only background clinical data in RA patients before treatment with infliximab.

OBJECTIVES: The aim of the present study was to generate a novel method for predicting the clinical response to infliximab (IFX), using a machine-learning algorithm with only clinical data obtained before the treatment in rheumatoid arthritis (RA) patients. METHODS: We obtained 32 variables out of the clinical data on the patients from two independent hospitals. Next, we selected both clinical parameters and machine-learning algorithms and decided the candidates of prediction method. These candidates were verified by clinical variables on different patients from two other hospitals. Finally, we decided the prediction method to achieve the highest score. RESULTS: The combination of multilayer perceptron algorithm (neural network) and nine clinical parameters shows the best accuracy performance. This method could predict the good or moderate response to IFX with 92% accuracy. The sensitivity of this method was 96.7%, while the specificity was 75%. CONCLUSIONS: We have developed a novel method for predicting the clinical response using only background clinical data in RA patients before treatment with IFX. Our method for predicting the response to IFX in RA patients may have advantages over the other previous methods in several points including easy usability, cost-effectiveness and accuracy.

[DRUG-INDUCED LUPUS CAUSED BY LONG TERM MINOCYCLINE TREATMENT FOR ACNE VULGARIS].

An 18-year-old Japanese girl had received oral minocycline 200mg daily for treatment of acne vulgaris since 16 years old. She had a fever three months before admission, followed by joint pains in her knees, elbows and several proximal interphalangeal joints one month before admission. She was referred to our hospital because of a high serum level of anti-DNA antibody. She had already discontinued oral minocycline five weeks before admission, because she missed her medication refilled. On admission, the arthralgia and fever spontaneously resolved, and there were no laboratory evidence of hypocomplementemia and cytopenia. She had neither erythema nor internal organ involvements. Because her symptoms subsided spontaneously after the cessation of minocycline, she was considered to have drug-induced lupus. Both the arthralgia and fever did not relapse, and anti-ds DNA antibody returned to normal during a follow-up period without treatment. There are few reports of drug-induced lupus caused by minocycline in Japan. This case highlights the importance of considering minocycline-induced lupus.

IgG anti-NR2 glutamate receptor autoantibodies from patients with systemic lupus erythematosus activate endothelial cells.

OBJECTIVE: To investigate the possibility that IgG anti-NR2 glutamate receptor antibodies (anti-NR2) derived from patients with systemic lupus erythematosus (SLE) cause an immunologic interaction with endothelial cells (ECs) in the blood-brain barrier, resulting in inflammation of the blood-brain barrier, allowing the entrance of these autoantibodies into the cerebrospinal fluid. METHODS: Purified IgG anti-NR2 antibodies from 14 patients with SLE were tested for their ability to bind to double-stranded DNA (dsDNA) and ECs, to modulate endothelial adhesion molecule expression and cytokine production by ECs, and to activate the NF-κB pathways in the ECs. Purified IgG from 5 normal subjects was used as a negative control. RESULTS: Purified IgG anti-NR2 antibodies bound to dsDNA in an IgG-dose-dependent manner. This interaction up-regulated the expression of endothelial leukocyte adhesion molecule 1, vascular cell adhesion molecule 1, and intercellular adhesion molecule 1 on the EC surface and increased the production of interleukin-6 (IL-6) and IL-8, but not tumor necrosis factor α or IL-1ß, by ECs. Purified IgG anti-NR2 also activated the degradation of cytoplasmic IκB, indicating the activation of NF-κB in the ECs. CONCLUSION: EC activation through the NF-κB signaling pathway induced by IgG anti-NR2 antibodies in the central nervous system of SLE patients may lead to inflammation of the blood-brain barrier, initiating the pathogenesis of neuropsychiatric SLE.

Effects of phosphodiesterase type 5 inhibitors on Raynaud's phenomenon.

Raynaud's phenomenon (RP) is commonly observed in fingers and toes of patients with connective tissue diseases (CTDs). However, existing vasodilators have very limited efficacy. In this study, phosphodiesterase type 5 inhibitors (PDE-5Is) were administered to evaluate efficacy on RP. Three patients with mixed connective tissue disease and three patients with systemic sclerosis having RP were enrolled. Oral sildenafil, vardenafil, or tadalafil was administered. The fingertip temperature was measured by thermography before and 120 min after administration. To evaluate longer effects, vardenafil was administered daily for 12 weeks; the fingertip temperature was measured by thermography before and 12 weeks after administration. As compared with the pre-administration of sildenafil, vardenafil, and tadalafil, the mean fingertip temperature increased by 2.17, 3.47, and 3.59 °C, respectively, in 120 min. In the 12-week trial with vardenafil in 3 patients, the mean fingertip temperature increased by 3.04, 7.96, and 3.32 °C from baseline in each patient. PDE-5Is significantly increased fingertip temperature within 120 min, and the effect of vardenafil lasted for 12 weeks under daily use. PDE-5Is were safe and would be an effective treatment for RP with CTDs.

Diminished antibody response to SARS-CoV-2 in rheumatoid arthritis compared to metabolic disorders following the primary series of vaccinations and its recovery with a booster: A single-center prospective observational study.

AIM: To compare antibody responses after vaccinations between patients with rheumatoid arthritis (RA) and patients with metabolic disorders (MD). The study places special emphasis on understanding how common diseases affect antibody responses in individuals with RA within real-world settings. METHODS: The participants were 117 patients with RA (66 with RA only and 51 with RA and MD) and 37 patients with MD who received both the primary series of vaccinations and a booster. Antibody titers were compared after the primary series of vaccinations and a booster, and factors influencing the antibody response were assessed. RESULTS: Following the primary series of vaccinations, a significant reduction in antibody titers was observed in patients with longer days between vaccination and antibody measurement, the use of IL-6 inhibitors, selective T cell co-stimulation modulators, and methotrexate. Comorbid MD did not exhibit significant influences on antibody response in RA. Notably, the presence of RA itself was not significant in multivariate linear regression analysis. After the administration of the booster, however, day between vaccination and antibody measurement, the use of IL-6 inhibitor, and methotrexate no longer remained significant. Only the use of selective T cell co-stimulation modulators retained its significance. CONCLUSIONS: MD did not exhibit a significant impact on antibody responses in RA patients. The reduced antibody response following the primary series in RA patients appeared to be attributed more to specific RA medications rather than to the disease itself. Booster vaccines are vital in restoring the antibody response in RA.

Biomarker combination predicting imminent relapse after discontinuation of biological drugs in patients with rheumatoid arthritis in remission.

OBJECTIVES: Compared to conventional disease-modifying antirheumatic drugs (DMARDs), biological DMARDs demonstrate superior efficacy but come with higher costs and increased infection risks. The ability to stop and resume biological DMARD treatment while maintaining remission would significantly alleviate these barriers and anxieties. The objective of this study was to identify biomarkers that can predict an imminent relapse, hopefully enabling the timely resumption of biological DMARDs before relapse occurs. METHODS: Forty patients with rheumatoid arthritis who had been in remission for more than 12 months were included in the study. The patients discontinued their biological DMARD treatment and were monitored monthly for the next 24 months. Out of the 40 patients, 14 (35%) remained in remission at the end of the 24-month period, while 26 (65%) experienced relapses at different time points. Among the relapse cases, 13 patients experienced early relapse within 6 months, and another 13 patients had late relapse between 6 months and 24 months. Seventy-three cytokines in the sera collected longitudinally from the 13 patients with late relapse were measured by multiplex immunoassay. Using cytokines at two time points, immediately after withdrawal and just before relapse, volcano plot and area under the receiver operating characteristic curves (AUC) were drawn to select cytokines that distinguished imminent relapse. Univariate and multivariate logistic regression analyses were used for the imminent relapse prediction model. RESULTS: IL-6, IL-29, MMP-3, and thymic stromal lymphopoietin (TSLP) were selected as potential biomarkers for imminent relapse prediction. All four cytokines were upregulated at imminent relapse time point. Univariate and multivariate logistic regression showed that a combination model with IL-6, MMP-3, and TSLP yielded an AUC of 0.828 as top predictors of imminent relapse. CONCLUSIONS: This methodology allows for the prediction of imminent relapse while patients are in remission, potentially enabling the implementation of on- and off-treatments while maintaining remission. It also helps alleviate patient anxiety regarding the high cost and infection risks associated with biological DMARDs, which are the main obstacles to benefiting from their superb efficacy.

No increased mortality in patients with rheumatoid arthritis treated with biologics: results from the biologics register of six rheumatology institutes in Japan.

OBJECTIVE: To investigate the influence of biologics on mortality and risk factors for death in rheumatoid arthritis (RA) patients. METHODS: RA patients treated with at least one dose of biologics in daily practice in six large rheumatology institutes ("biologics cohort") were observed until 15 May 2010 or death, whichever occurred first. Mortality of the biologics cohort and the "comparator cohort" (comprising patients among the IORRA cohort who had never been treated with biologics) was compared to that of the Japanese general population. Factors associated with mortality were assessed by a Cox model. RESULTS: Among 2683 patients with 6913.0 patient-years of observation, 38 deaths were identified in the biologics cohort. The probability of death in patients lost to follow-up, calculated using the weighted standardized mortality ratio (SMR), was 1.08 [95 % confidence interval (CI) 0.77-1.47] in the biologics cohort and 1.28 (95 % CI 1.17-1.41) in the comparator cohort. Pulmonary involvement was the main cause of death (47.4 %), and the disease-specific SMR of pneumonia was 4.19 (95 % CI 1.81-8.25). Risk factors for death included male gender [hazard ratio (HR) 2.78 (95 % CI 1.24-6.22)], advanced age (HR 1.07, 95 % CI 1.03-1.11), and corticosteroid dose (HR 1.08, 95 % CI 1.01-1.17). CONCLUSION: Mortality in RA patients exposed to biologics did not exceed that in patients not exposed to biologics, but death from pulmonary manifestations was proportionally increased in RA patients exposed to biologics.

Low level of seroconversion after a novel influenza A/H1N1/2009 vaccination in Japanese patients with rheumatoid arthritis in the 2009 season.

We examined change in the antibody titre against pandemic influenza A/H1N1/2009 before and after vaccination in Japanese patients with rheumatoid arthritis. This observational study was conducted with the participation of five hospitals in Japan. A total of 89 patients with rheumatoid arthritis were included in this study. The seroprotection and seroresponse rates to vaccination with the pandemic influenza A/H1N1/2009 vaccine were analysed. The seroprotection rates prior to the vaccination were 5.6% in the Japanese patients with rheumatoid arthritis. The seroprotection rates after subcutaneous vaccination were 55.1%. The seroresponse rate after subcutaneous vaccination was 50.6% in the patients with rheumatoid arthritis. Both the seroprotection and seroresponse rates obtained after the vaccination with the pandemic influenza A/H1N1/2009 vaccine were low in Japanese patients with rheumatoid arthritis. We should realise that a vaccination against this newly emerged influenza virus may protect only half of the Japanese patients with rheumatoid arthritis in a real world.

Healthcare-associated infections in rheumatology in Japan.

Prospective observational study was performed to elucidate the incidence and characteristics of healthcare-associated infections in a university hospital for rheumatology care. In this study, a total of 1,226 patients were prospectively enrolled between March 2004 and February 2006 and between April 2008 and December 2008. Healthcare-associated infection was defined as an infection developing after the third day of admission to the rheumatology ward. We detected the following 54 healthcare-associated infections in 49 patients: respiratory tract infection, 14 cases; Clostridium difficile infection, 2 cases; urinary tract infection, 4 cases; bloodstream infection, 9 cases; skin infection, 2 cases; reactivation of latent cytomegalovirus infection, 6 cases; herpes zoster infection, 5 cases; Candida infection, 7 cases; others, 4 cases. The incidence rate of respiratory tract infection was the highest. Methicillin-resistant Staphylococcus aureus was the causative bacterium in 21% of respiratory tract infections cases. Bloodstream infection due to the insertion of a catheter and opportunistic infection by a latent virus were also occurred commonly. Respiratory tract infection, bloodstream infection and opportunistic infection by a latent virus were the most common causes of healthcare-associated infection in rheumatology. It is important to pay more attention to healthcare-associated infection.

Sustained elevation of interleukin-33 in sera and synovial fluids from patients with rheumatoid arthritis non-responsive to anti-tumor necrosis factor: possible association with persistent IL-1ß signaling and a poor clinical response.

Although TNF inhibitors have dramatically improved the outcome of patients with rheumatoid arthritis, 30-40% of patients do not respond well to them and treatment needs to be changed. In an effort to discriminate good and poor responders, we focused on the change in serum and synovial fluid levels of interleukin (IL-) 33 before and after treatment with TNF inhibitors. They were also measured in synovial fluids from 17 TNF inhibitor-naïve patients, and fibroblast-like synoviocytes (FLS) in-culture from 6 patients and correlated with various pro-inflammatory cytokines. Serum levels of IL-33 at 6 months after treatment decreased significantly in responders, while they did not change in non-responders. Synovial fluid levels of IL-33 in 6 patients under treatment with TNF inhibitors stayed high in 3 who were refractory and slightly elevated in 2 moderate responders, while they were undetectable in one patient under remission. Among inflammatory cytokines measured in 17 synovial fluids from TNF inhibitor-naïve patients, levels of IL-33 showed a significant positive correlation only to those of IL-1ß. IL-1ß increased IL-33 expression markedly in FLS in vitro, compared to TNF-α. IL-1ß might be inducing RA inflammation through producing pro-inflammatory IL-33 in TNF inhibitor-hypo-responders. Sustained elevation of serum and/or synovial levels of IL-33 may account for a poor response to TNF inhibitors, although how TNF inhibitors affect the level of IL-33 remains to be elucidated.

Influence of antibodies against infliximab and etanercept on the treatment effectiveness of these agents in Japanese patients with rheumatoid arthritis.

We investigated the influence of antibodies against infliximab and etanercept on the serum trough levels of these agents and the influence of these antibodies on the effectiveness of treatment in patients with rheumatoid arthritis treated with these agents. Forty patients treated with infliximab for 54 weeks and 40 patients treated with etanercept for 32 weeks were enrolled. They were divided into responder and non-responder groups. Serum trough levels of and antibodies against these agents were measured by enzyme-linked immunosorbent assay or radioimmunoassay. Of the 40 patients treated with infliximab, 14 (35%) had anti-infliximab antibodies. Serum trough levels were significantly lower in the non-responder group (14 patients) than in the responder group (26 patients) 6 weeks after initiation of infliximab (p < 0.05). Conversely, titers of anti-infliximab antibody were significantly higher in the non-responder group than in the responder group between 6 and 38 weeks after initiation of infliximab (p < 0.05). Anti-etanercept antibodies were not detected in any patients on etanercept. Serum trough levels of etanercept were not significantly different between the responder (31 patients) and non-responder groups (9 patients). It seems that the appearance of anti-infliximab antibodies might decrease infliximab serum concentrations and, thereby, reduce the agent's effectiveness. The clinical efficacy of etanercept does not appear to be affected by the serum concentrations if it is administered at standard doses.

Therapeutic response of patients with adult Still's disease to biologic agents: multicenter results in Japan.

OBJECTIVE: The efficacy of biologics in treating adult Still's disease (ASD) is suggested, but the information is still lacking and the validation is insufficient. To determine the efficacy of several biologic agents in refractory ASD in Japan, a multicenter survey was performed. METHOD: Clinical data on 16 ASD patients who had been treated with at least 1 of the biological agents (total 24 occasions) were collected retrospectively. RESULTS: Infliximab was used in 9 cases, etanercept in 4, and tocilizumab in 11. Half of the patients that had been treated initially with infliximab or etanercept were changed to another biologics. Tocilizumab was effective in cases switched from another 2 drugs. Tocilizumab showed efficacy in treating both systemic and arthritic symptoms and showed apparent steroid-sparing effect and the highest continuation rate. CONCLUSION: Tocilizumab may be a promising biologic agent in refractory ASD.