Relationship between lymphocyte count and risk of infection in Japanese rheumatoid arthritis patients treated with tofacitinib.

OBJECTIVES: We characterised changes in absolute lymphocyte counts (ALCs) and lymphocyte subset counts (LSCs), and their relationship to incidence of serious infection events (SIEs) and herpes zoster (HZ) events in Japanese patients with moderate to severe rheumatoid arthritis enrolled in the tofacitinib clinical programme. METHODS: Data included 765 patients receiving tofacitinib in Phase 2, Phase 3, and long-term extension studies. ALCs/LSCs and incidence rates (patients with events/100 patient-years) of SIEs and HZ were analysed over 75 months. RESULTS: Median ALCs were generally stable over 75 months of treatment. Transient numerical increases from baseline in median LSCs were observed at Month 3; LSCs were generally lower than baseline for Months 36-75. SIE/HZ incidence rates were higher in patients with ALC <0.5 × 103 cells/mm3 versus those with ALC ≥0.5 × 103 cells/mm3 during tofacitinib treatment. Baseline LSCs were similar in patients with/without SIEs or HZ events. CONCLUSIONS: SIE/HZ risk was highest in patients with ALC <0.5 × 103 cells/mm3, supporting this threshold as clinically relevant for defining increased SIE/HZ risk in Japanese patients with rheumatoid arthritis receiving tofacitinib. However, SIEs and HZ events did not necessarily occur simultaneously with confirmed lymphopenia, preventing conclusions on possible causal relationships being drawn.

Six-month safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in Japan: Interim analysis of post-marketing surveillance.

OBJECTIVES: We evaluated the real-world safety/effectiveness of tofacitinib, an oral Janus kinase inhibitor for the treatment of rheumatoid arthritis (RA), in patients with RA in Japan registered in a post-marketing surveillance study. METHODS: This interim analysis included data from July 2013 to December 2018. Adverse events (AEs), serious AEs (SAEs), Simplified Disease Activity Index (SDAI)/Clinical Disease Activity Index (CDAI)/Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4(ESR)] scores, and rates of SDAI/CDAI/DAS28-4(ESR)-defined remission and low disease activity were analysed using 6 months of data. Risk factors for serious infections were assessed by multivariable analyses. RESULTS: Safety and disease activity were evaluated in 6866 and 6649 patients, respectively. Overall, 32.73%/7.37% of patients reported AEs/SAEs. Clinically important AEs with tofacitinib included serious infections/infestations [3.13% of patients; incidence rate (IR; patients with events) 6.91/100 patient-years (PY)], herpes zoster (3.63%; IR 8.02/100 PY), and malignancies (0.68%; IR 1.45/100 PY). SDAI/CDAI/DAS28-4(ESR) scores and remission/low disease activity rates improved over 6 months. Male sex, older age, Steinbrocker's stage IV, history of infection, and diabetes mellitus at baseline were independent risk factors for serious infection. CONCLUSIONS: In patients with RA receiving tofacitinib in Japan, safety was consistent with the reported profile, and disease activity improved over 6 months. STUDY IDENTIFIER: NCT01932372.

Post-marketing surveillance of high-dose methotrexate (>8 mg/week) in Japanese patients with rheumatoid arthritis: A post hoc sub-analysis of patients according to duration of prior methotrexate use.

OBJECTIVES: To explore whether the duration of prior low-dose methotrexate treatment (MTX; ≤8 mg/week) influences the safety and effectiveness of high-dose MTX (>8 mg/week) in Japanese patients with rheumatoid arthritis (RA). METHODS: This post hoc sub-analysis of a Japanese post-marketing surveillance study evaluated patients initiating high-dose MTX with ≥1 year or <1 year prior low-dose MTX use. Over 24 or 52 weeks, adverse drug reactions (ADRs) were monitored, and effectiveness was assessed using the Disease Activity Score in 28 joints, erythrocyte sedimentation rate [DAS28-4 (ESR)]. RESULTS: One thousand two hundred and ninety-two MTX ≥1 year and 1001 MTX <1 year patients were included. The incidence of ADRs during the 24- and 52-week follow-up period was significantly more frequent in MTX <1 year than ≥1 year patients and serious ADRs were significantly higher in MTX <1 year than ≥1 year patients during the 52-week follow-up period (all p < .05). Over both follow-up periods, the mean DAS28-4 (ESR) significantly decreased from baseline for all groups. Remission and low disease activity rates (DAS28-4 (ESR) <2.6 and <3.2, respectively) increased from baseline for all groups. CONCLUSION: High-dose MTX reduced disease activity regardless of prior treatment duration, but ADRs occurred more frequently among MTX <1 year patients compared to MTX ≥1 year patients.

Radiographic and clinical effects of 10 mg and 25 mg twice-weekly etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis.

OBJECTIVES: To compare the radiographic and clinical effects of 25 versus 10 mg twice-weekly (BIW) etanercept over 52 weeks in Japanese patients with active rheumatoid arthritis (RA). METHODS: This was a post-hoc analysis of a Phase 3 study where Japanese patients with active RA were randomized to receive BIW etanercept 25 mg (n = 182), etanercept 10 mg (n = 192), or methotrexate (n = 176) for 52 weeks (NCT00445770). This analysis included assessments of week-24 and week-52 disease activity, week-52 radiographic progression, and the relationship between baseline characteristics and week 52 clinical outcomes with clinically relevant radiographic progression (CRRP) at week 52. RESULTS: At week 52, there were no significant differences between 25 and 10 mg etanercept in terms of achieving low disease activity or remission. CRRP was observed in 36% and 32% of patients in the 10 and 25 mg groups, respectively. Predictor analysis suggested that worse background disease status, treatment with methotrexate rather than etanercept, and poorer clinical outcomes at week 52 were associated with CRRP. CONCLUSIONS: The 25 mg BIW etanercept dosage does not appear to be significantly more efficacious than 10 mg in Japanese patients with RA. Further studies evaluating the optimal etanercept dosing regimen in this patient population may be merited. NCT: NCT00445770.

Radiographic and clinical outcomes following etanercept monotherapy in Japanese methotrexate-naïve patients with active rheumatoid arthritis.

Objectives: Compare outcomes with methotrexate (MTX) or etanercept (ETN) monotherapy in Japanese patients with active rheumatoid arthritis (RA) who were MTX-naïve or with intolerance or inadequate response to prior MTX (MTX-IR).Methods: Post hoc analysis of a phase 3 study comparing MTX, ETN 10 mg twice weekly, and ETN 25 mg twice weekly in Japanese patients with RA. Disease activity was evaluated using American College of Rheumatology (ACR) scores and 28-joint Disease Activity Score (DAS28), radiographic progression evaluated using van der Heijde's modified Total Sharp Score (mTSS), and functional status evaluated using Health Assessment Questionnaire Disability Index (HAQ-DI).Results: Among MTX-naïve and MTX-IR patients, greater proportions of those randomized to either ETN group achieved ACR20, ACR50, ACR70, DAS28 ≤3.2 or <2.6, clinically relevant inhibition of mTSS changes, and reductions in HAQ-DI compared with MTX at the majority of time points. There were very few clinically meaningful differences between ETN groups for any of the variables evaluated.Conclusion: ETN monotherapy was more effective than MTX in both MTX-naïve and MTX-IR patients, with very few clinically meaningful differences between ETN 10 mg and ETN 25 mg when given twice weekly. The relative benefits of ETN were greater in MTX-naïve patients than MTX-IR patients.ClinicalTrials.gov identifierNCT00445770.

Three-year safety and two-year effectiveness of etanercept in patients with rheumatoid arthritis in Japan: Results of long-term postmarketing surveillance.

Objectives: To evaluate the real-world safety and effectiveness of etanercept (ETN) in Japanese patients with rheumatoid arthritis. Methods: This postmarketing surveillance study (NCT00503139) assessed the safety and effectiveness of ETN treatment over 3 and 2 years (from June 2007 to September 2011), respectively. Safety was evaluated by occurrence and seriousness of adverse drug reactions (ADRs), and of adverse events (AEs) for malignancies. Effectiveness was assessed using the Disease Activity Score in 28 joints based on the erythrocyte sedimentation rate (ESR) with four variables (swollen and tender joint counts, ESR, and patient global assessment; DAS28-4/ESR). Treatment was considered effective if patients had a good/moderate response by the European League Against Rheumatism response criteria. Results: ADRs occurred in 256/675 (37.9%) patients, the most common being injection site reactions (4.4%) and nasopharyngitis (3.3%). Serious ADRs occurred in 60/675 (8.9%) patients, the most frequent being pneumonia (1.2%). The incident rate of malignancies (AEs) was 1.06 per 100 patient-years. Mean baseline DAS28-4/ESR for the 581 patients included in effectiveness analysis was 5.42, which decreased to 3.32 at 2 years. Eighty-two percent of patients achieved a moderate/good response at 2 years. Conclusion: Long-term ETN treatment safety and effectiveness were sustained over 3 and 2 years, respectively.

Efficacy and safety of tofacitinib in Japanese patients with rheumatoid arthritis by background methotrexate dose: A post hoc analysis of clinical trial data.

Objectives: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). We investigated concomitant methotrexate (MTX) dose on tofacitinib efficacy/safety in Japanese RA patients. Methods: This post hoc analysis pooled data from a 3-month phase 2 study (NCT00603512) and a 24-month phase 3 study (NCT00847613). Patients (N= 254) received tofacitinib (low-dose (1 or 3 mg), 5 mg, 10 mg) twice daily (BID) or placebo, with low-dose (>0 to 8 mg/week) or high-dose (>8 mg/week) MTX. Efficacy (ACR20/50/70 and DAS28-4 (ESR)<2.6 response rates; changes from baseline (CFB) in DAS28-4 (ESR) and HAQ-DI) and safety (adverse events (AEs), discontinuations due to AEs, serious AEs, and deaths) were assessed through month 3. Results: At month 3, ACR20/50/70 response rates, mean DAS28-4 (ESR) CFB and HAQ-DI CFB were similar across MTX doses and generally greater for all tofacitinib doses versus placebo. AE rates with low-dose/high-dose MTX were: placebo, 28.6%/52.9%; tofacitinib low-dose, 50.0%/66.7%; 5 mg BID, 56.5%/64.3%; 10 mg BID, 73.8%/67.7%. Conclusion: Tofacitinib efficacy in Japanese RA patients may be unaffected by background MTX dose. AE rates with low-dose versus high-dose MTX were lower with placebo, tofacitinib low-dose or 5 mg BID, but not 10 mg BID, with no apparent differences across system organ class/laboratory parameters.

The role of lymphotoxin-α in rheumatoid arthritis.

BACKGROUND: The role of tumor necrosis factor (TNF) in the inflammatory response in rheumatoid arthritis (RA) is well established, whereas less is known about the role of TNF's close homolog, lymphotoxin alpha (LTα). FINDINGS: Increased levels of LTα are found in the serum and synovial tissue of patients with RA, and in vitro studies found that LTα-induced proliferation of RA fibroblast-like synoviocytes was at a similar level to TNF. These findings support the idea that anti-LTα treatment could be beneficial in patients with RA, but pateclizumab, an anti-LTα antibody, was not as efficacious as the anti-TNF agent adalimumab in reducing symptoms of RA in a head-to-head study, suggesting that anti-LTα therapies might not represent a valid alternative treatment option in patients with RA. However, suppression of LTα activity might be relevant in the context of RA-related comorbidities, as patients with RA have an increased risk of myocardial infarction (MI) compared with the general population, and specific polymorphisms of the LTα gene have been linked to increased MI risk. CONCLUSIONS: In this review, we summarize the key characteristics of LTα and the most recent findings on the role of LTα in RA.

Acute Mesenteric Ischemia: Multidetector CT Findings and Endovascular Management.

Acute mesenteric ischemia is a rare life-threatening condition that accounts for approximately one in 1000 hospital admissions. The mortality rate is 50%-69% owing to the absence of specific symptoms and laboratory data, which makes early detection of this condition difficult. If the use of contrast material is possible, biphasic contrast material-enhanced multidetector computed tomography (CT) is the first-line imaging test for early diagnosis of the disease and for differentiation from other causes of acute abdomen. Multidetector CT can depict mesenteric ischemia, its underlying causes, and its severity. Mesenteric ischemia is classified as either acute or chronic. The causes of AMI include arterial embolism, arterial thrombosis, venous thrombosis, and nonocclusive mesenteric ischemia, among which arterial causes are far more common than venous causes. Recently, endovascular procedures such as thrombolysis, thrombectomy, thrombus fragmentation, and stent placement have been successfully and safely performed when the ischemia is reversible. Online DICOM image stacks are available for this article. ©RSNA, 2018.

Prevalence, comorbidities, and treatment patterns of Japanese patients with alopecia areata: A descriptive study using Japan medical data center claims database.

Real-world data on alopecia areata (AA) demographics, comorbidities, and treatment patterns are sparse, not only in Japan but worldwide. This cross-sectional study assessed the current prevalence of AA in Japan, including analysis of severe subsets, frequency of comorbidities, and unmet medical needs surrounding treatment. Patients registered in the Japan Medical Data Center claims database (January 2012 to December 2019) and diagnosed with AA were included. Prevalence was calculated yearly, with the most common comorbidities evaluated, and treatments described in the Japanese Dermatological Association AA management guidelines and approved in Japan were included in the analysis. In total, 61 899 patients were diagnosed with AA. Among them, 1497 were diagnosed with severe subtypes. AA prevalence in Japan has been gradually increasing (from 0.16% in 2012 to 0.27% in 2019). The most common comorbidities are allergic rhinitis, atopic dermatitis, and asthma. Depression and anxiety are frequent in these patients, as are autoimmune diseases, e.g., vitiligo, thyroid diseases, and rheumatoid arthritis. Intriguingly, the analysis found Down syndrome to be a comorbidity associated with severe AA in children. The principal treatments were topical corticosteroids, followed by carpronium chloride and cepharanthine. The use of systemic corticosteroids and antihistamines is increased in severe disease. The Japanese Dermatological Association guidelines do not support the use of oral corticosteroids in children; however, in the database, this has been prescribed in up to 2.5% and 9.8% of all pediatric and severe pediatric AA cases, respectively. Despite the limitations of using a claims database, the current study demonstrates that AA prevalence in Japan has gradually increased in recent years, with allergic diseases being the most common comorbidities. The data also imply that there is a need for effective and safe therapies, especially for severe and pediatric cases.

Cost-Effectiveness Analysis of Etanercept 25 mg Maintenance Therapy After Treatment With Etanercept 50 mg for Moderate Rheumatoid Arthritis in the PRESERVE Trial in Japan.

OBJECTIVES: To use Markov modeling to estimate the cost-effectiveness of treatment with etanercept 25 mg once weekly plus methotrexate (MTX) in Japanese patients with rheumatoid arthritis who had achieved remission or low disease activity with etanercept 50 mg once weekly plus MTX. METHODS: Effectiveness data were estimated based on results from a clinical trial (PRESERVE) in patients with rheumatoid arthritis who had achieved remission or low disease activity and who were then randomized to receive etanercept 25 mg plus MTX or placebo plus MTX. A Markov model was established and included flare rates of 21% and 62% in the etanercept 25 mg and placebo groups, respectively. EQ-5D was calculated using an ordinary least-squares model that included the health assessment questionnaire disability index and pain visual analog scale. Worsening of the health assessment questionnaire score over 1 year was estimated to be 0.047 for patients with flare, and when associated with radiographic progression it was estimated to increase by 0.006 and 0.025 in the etanercept 25 mg and placebo groups, respectively. A cycle length of 1 year was applied to calculate the cumulative cost and effectiveness for a 10-year time span. RESULTS: Compared with the placebo group, the quality-adjusted life-years for the etanercept 25 mg group was increased by 0.841. The incremental cost-effectiveness ratio was ¥6 173 772. CONCLUSION: These results suggest that maintenance treatment with etanercept 25 mg is cost-effective.

Clinical Management of Herpes Zoster in Patients With Rheumatoid Arthritis or Psoriatic Arthritis Receiving Tofacitinib Treatment.

INTRODUCTION: Risk of herpes zoster (HZ) is increased with Janus kinase inhibitor use. We evaluated clinical study data relating to HZ management in patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) receiving tofacitinib. METHODS: This post hoc analysis included data from 21 RA and 3 PsA clinical studies; data were pooled for tofacitinib doses. Outcomes of HZ events (serious and non-serious) and tofacitinib treatment changes were evaluated in response to first and second HZ events. Median time to resolution was stratified by dermatomal involvement, history of HZ prior to tofacitinib, changes to tofacitinib treatment, anti-viral and corticosteroid use, and tofacitinib dose. RESULTS: Seven hundred eighty-three (11.1%, N = 7061) patients with RA experienced ≥ 1 HZ event, 63 (8.0%) of whom had ≥ 2 HZ events. In patients with PsA, 36 (4.6%, N = 783) experienced ≥ 1 HZ event, 1 (2.8%) of whom had ≥ 2 HZ events. For most HZ events, tofacitinib treatment was unchanged or temporarily discontinued. The majority of patients received anti-viral treatment, most within 3 days of onset. Post-herpetic neuralgia developed in 6.9% and 3.2% of patients with RA with first and second events, respectively, and in 2.8% of patients with PsA with a first event. Most first and second events resolved (RA: 97.6% and 96.8%, respectively; PsA: 94.4% and 100%, respectively). Median time to resolution was 22.0 days for first and 15.0 days for second events for RA and 20.5 days for first and 11.0 days for second events (n = 1) for PsA. Time to resolution of first events for RA and PsA was generally numerically shorter for patients with single dermatomal HZ, history of HZ, or anti-viral use versus those without. CONCLUSION: Among patients receiving tofacitinib, recurrent events were more common in patients with RA versus PsA; HZ duration was shorter for repeat events. TRIAL REGISTRATION: NCT01262118, NCT01484561, NCT00147498, NCT00413660, NCT00550446, NCT00603512, NCT00687193, NCT01164579, NCT00976599, NCT01059864, NCT01359150, NCT02147587, NCT00960440, NCT00847613, NCT00814307, NCT00856544, NCT00853385, NCT01039688, NCT02187055, NCT00413699, NCT00661661, NCT01877668, NCT01882439, NCT01976364.

Patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA) have weakened immune responses and are more likely to get herpes zoster (HZ; also known as shingles) infections compared with the general population. Patients who receive treatments for RA or PsA that have an effect on their immune system are more likely to get HZ. Here, we assessed how common HZ was in patients with RA or PsA who were given tofacitinib during clinical trials, the management of these infections, and how this affected the course of the infection. Approximately 1 in 10 patients with RA and 1 in 20 patients with PsA had HZ. Of those patients who had HZ, 1 in 12 with RA and 1 in 36 with PsA were infected again at a later point. A small number of patients also had long-lasting pain after HZ infection. When patients had a HZ infection, most either continued treatment with tofacitinib or paused treatment for a period of time. Pausing or continuing treatment did not appear to affect how long the infection lasted or whether patients had another infection. Most patients received treatment for HZ infection, and patients who were treated had shorter infections. In most patients, infections cleared up and were more likely to clear up more quickly when patients had HZ previously.

Automatic liver segmentation method featuring a novel filter for multiphase multidetector-row helical computed tomography.

PURPOSE: To introduce an automatic liver segmentation method that includes a novel filter for multiphase multidetector-row helical computed tomography. MATERIALS AND METHODS: We acquired 3-phase multidetector-row computed tomographic scans that included unenhanced, arterial, and portal phases. The liver was segmented using our novel adaptive linear prediction filter designed to reduce the difference between filter input and output values in the liver region and to increase these values outside the liver region. RESULTS: The segmentation algorithm produced a mean dice similarity coefficient (DSC) value of 91.4%. CONCLUSION: The application of our adaptive linear prediction filter was effective in automatically extracting liver regions.

Burden of illness, medication adherence, and unmet medical needs in Japanese patients with atopic dermatitis: A retrospective analysis of a cross-sectional questionnaire survey.

Atopic dermatitis (AD) negatively affects patients' daily lives. Poor medication adherence is a major barrier to treatment success. However, factors causing patients' poor adherence are unclear. This study aimed to identify factors associated with improvement of medication adherence in Japanese patients with AD and to evaluate illness burden and unmet medical needs for AD. We retrospectively analyzed Web-based questionnaire surveys conducted in 2018 in patients with AD aged 15 years and above who had been in- or outpatients within the past year from the survey. Quality of life using the EuroQol 5-Dimension (EQ-5D), and work productivity and activity impairment using Work Productivity and Activity Impairment Questionnaire (WPAI) were compared between patients and matched controls who had not visited a hospital for any disease within the past year. Subpopulation analysis was performed to explore factors affecting medication adherence. Unmet medical needs in AD treatment were identified by the percentage of patients who rated issues on the questionnaire as important but who were unsatisfied with them. In this study, we identified 1739 patients with AD. The scores of EQ-5D and WPAI showed that patients had statistically lower quality of life and higher impairment of work and activities than controls. High medication adherence scores were seen in patients with high health literacy levels and those who were well satisfied with communication with health-care providers, information received from them, or explanations of AD. Current unmet medical needs for AD were medical treatment costs, ease of hospital visits and explanations about disease prognosis. Patients tended to put a higher priority on communication with physicians than on that with nurses and pharmacists. In conclusion, we have identified patients' higher health literacy levels and satisfaction with the communication with their health-care provider as potential factors to improve medication adherence.

Differences and similarities in clinical and functional responses among patients receiving tofacitinib monotherapy, tofacitinib plus methotrexate, and adalimumab plus methotrexate: a post hoc analysis of data from ORAL Strategy.

BACKGROUND: This post hoc analysis assessed clinical and functional responses to tofacitinib monotherapy, tofacitinib + methotrexate (MTX), and adalimumab + MTX, in patients with rheumatoid arthritis enrolled in the ORAL Strategy study, including evaluation of patient-level data using cumulative probability plots. METHODS: In the 12-month, phase IIIb/IV ORAL Strategy study, patients with rheumatoid arthritis and an inadequate response to MTX were randomized to receive tofacitinib 5 mg twice daily (BID), tofacitinib 5 mg BID + MTX, or adalimumab 40 mg every other week + MTX. In this post hoc analysis, cumulative probability plots were generated for mean percent change from baseline (%∆) in the Clinical Disease Activity Index (CDAI; clinical response) and mean change from baseline (∆) in the Health Assessment Questionnaire-Disability Index (HAQ-DI; functional response) at month 12. Median C-reactive protein (CRP) levels by time period were summarized by CDAI remission (≤ 2.8) status at months 6 and 12. RESULTS: Data for 1146 patients were analyzed. At month 12, cumulative probability plots for %∆CDAI and ∆HAQ-DI were similar across treatments in patients with greater response. At lower levels of response, patients receiving tofacitinib monotherapy did not respond as well as those receiving combination therapies. With tofacitinib + MTX, numerically higher baseline CRP levels and numerically larger post-baseline CRP reductions were seen in patients achieving CDAI remission at months 6 and 12 vs those who did not. CONCLUSIONS: These results suggest that patients with a greater response did well, irrespective of which therapy they received. Patients with lesser response had better outcomes with combination therapies vs tofacitinib monotherapy, suggesting they benefitted from MTX. High pre-treatment CRP levels may be associated with better response to tofacitinib + MTX. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02187055. Registered on 08 July 2014.

Contribution of a European-Prevalent Variant near CD83 and an East Asian-Prevalent Variant near IL17RB to Herpes Zoster Risk in Tofacitinib Treatment: Results of Genome-Wide Association Study Meta-Analyses.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA), psoriatic arthritis, and ulcerative colitis, and has been previously investigated for psoriasis (PsO). This meta-analysis of genome-wide association studies (GWAS) was performed to identify genetic factors associated with increased risk/faster onset of herpes zoster (HZ) in subjects with RA or PsO receiving tofacitinib treatment, and to determine potential mechanisms that could be attributed to the varying rates of HZ across ethnicities. METHODS: In an ethnicity/indication-specific, trans-ethnic, trans-population meta-analysis of GWAS in subjects with RA or PsO from phase II, phase III, and long-term extension studies of tofacitinib, 8 million genetic variants were evaluated for their potential association with time to an HZ event and incidence of an HZ event (case versus control) with tofacitinib treatment, using Cox proportional hazard and logistic regression analyses, respectively. RESULTS: In total, 5,246 subjects were included (3,168 with RA and 2,078 with PsO). After adjustment for age, baseline absolute lymphocyte count, genetically defined ethnicity, and concomitant methotrexate use (in RA subjects only), 4 loci were significantly associated with faster onset of HZ in European subjects (P < 5 × 10-8 ), including a single-nucleotide polymorphism (SNP) near CD83 (frequency of risk allele ~2% in European subjects versus ~0.1% in East Asian subjects). In the trans-ethnic, trans-population meta-analysis, the CD83 SNP remained significant. Four additional significant loci were identified in the meta-analysis, among which a SNP near IL17RB was associated with faster onset of HZ (meta-analysis hazard ratio 3.6 [95% confidence interval 2.40-5.44], P = 7.6 × 10-10 ; frequency of risk allele ~12% in East Asian subjects versus <0.2% in European subjects). CONCLUSION: Genetic analysis of tofacitinib-treated subjects with RA or PsO identified multiple loci associated with increased HZ risk. Prevalent variants near the immune-relevant genes CD83 and IL17RB in European and East Asian populations, respectively, may contribute to risk of HZ in tofacitinib-treated subjects.

Maclaurin-series method for calculating dispersion in arrayed-waveguide grating multiplexers.

We present a Maclaurin-series method for calculating the dispersion from phase error and amplitude distributions in arrayed waveguide grating (AWG) multiplexers. By using this method, we can easily derive the intercept, the gradient, and the curvature of the dispersion in the center frequency region of a passband. A third-order Maclaurin series was calculated by using the measured phase error and amplitude distributions of AWGs having a channel frequency spacing of 12.5 GHz. The calculated results are in good agreement with the dispersions measured with an optical network analyzer. We also discuss the physical effect of the phase error on dispersion by assuming certain limited cases.

Foreign-body granulomas and abscesses caused by dropped gallstones after cholecystectomy: Four cases diagnosed with multimodality imaging.

Four cases (age range, 60-78 years, male:female = 1:3) who had undergone cholecystectomy presented with fever (n = 1), right abdominal pain with fever (n = 1), appetite loss with fever (n = 1), and absence of symptoms (n = 1). Computed tomography (CT) showed an irregular-shaped invasive mass or fluid collection in the right Morrison's pouch, right paracolic gutter, gallbladder fossa, subphrenic space, or abdominal wall. CT and ultrasound revealed gallstones in the granuloma in 3 cases and an abscess in one case. The inflammatory process induced by dropped gallstones may mimic peritoneal malignancies. Awareness of cholecystectomy and the detection of gallstones in the lesion are essential for the diagnosis of dropped gallstones.

Phase-modulation method for AWG phase-error measurement in the frequency domain.

We report a phase-modulation method for measuring arrayed waveguide grating (AWG) phase error in the frequency domain. By combining the method with a digital sampling technique that we have already reported, we can measure the phase error within an accuracy of +/-0.055 rad for the center 90% waveguides in the array even when no carrier frequencies are generated in the beat signal from the interferometer.

Herpes Zoster and Tofacitinib: Clinical Outcomes and the Risk of Concomitant Therapy.

OBJECTIVE: Patients with rheumatoid arthritis (RA) are at increased risk of herpes zoster (HZ), and the risk appears to be increased in patients treated with tofacitinib. The aim of this study was to evaluate whether concomitant treatment with conventional synthetic disease-modifying antirheumatic drugs (csDMARDs) or glucocorticoids (GCs) contributes to the increased risk of HZ in RA patients treated with tofacitinib. METHODS: HZ cases were identified from the databases of 2 phase I, 9 phase II, 6 phase III, and 2 long-term extension studies of tofacitinib in RA patients. Crude incidence rates (IRs) of all HZ events (serious and nonserious) per 100 patient-years (with 95% confidence intervals [95% CIs]) were calculated for unique patients. Within phase III studies, we described HZ rates according to concomitant csDMARD treatment and baseline GC use. A multivariable Cox proportional hazards regression model was used to evaluate HZ risk factors across studies. RESULTS: Across all studies (6,192 patients; 16,839 patient-years), HZ was reported in 636 tofacitinib-treated patients (IR 4.0, 95% CI 3.7-4.4). In most cases (93%), HZ was classified as nonserious, and the majority of patients (94%) had involvement of only 1 dermatome. HZ IRs varied across regions, from 2.4 (95% CI 2.0-2.9) in Eastern Europe to 8.0 (95% CI 6.6-9.6) in Japan and 8.4 (95% CI 6.4-10.9) in Korea. Within phase III studies, HZ IRs varied according to tofacitinib dose, background csDMARD treatment, and baseline use of GCs. The IRs were numerically lowest for monotherapy with tofacitinib 5 mg twice daily without GCs (IR 0.56 [95% CI 0.07-2.01]) and highest for tofacitinib 10 mg twice daily with csDMARDs and GCs (IR 5.44 [95% CI 3.72-7.68]). Age, GC use, tofacitinib dose, and enrollment within Asia were independent risk factors for HZ. CONCLUSION: Patients receiving treatment with tofacitinib and GCs appear to have a greater risk of developing HZ compared with patients receiving tofacitinib monotherapy without GCs.