Mirikizumab as Induction and Maintenance Therapy for Ulcerative Colitis.

BACKGROUND: Mirikizumab, a p19-directed antibody against interleukin-23, showed efficacy in the treatment of ulcerative colitis in a phase 2 trial. METHODS: We conducted two phase 3, randomized, double-blind, placebo-controlled trials of mirikizumab in adults with moderately to severely active ulcerative colitis. In the induction trial, patients were randomly assigned in a 3:1 ratio to receive mirikizumab (300 mg) or placebo, administered intravenously, every 4 weeks for 12 weeks. In the maintenance trial, patients with a response to mirikizumab induction therapy were randomly assigned in a 2:1 ratio to receive mirikizumab (200 mg) or placebo, administered subcutaneously, every 4 weeks for 40 weeks. The primary end points were clinical remission at week 12 in the induction trial and at week 40 (at 52 weeks overall) in the maintenance trial. Major secondary end points included clinical response, endoscopic remission, and improvement in bowel-movement urgency. Patients who did not have a response in the induction trial were allowed to receive open-label mirikizumab during the first 12 weeks of the maintenance trial as extended induction. Safety was also assessed. RESULTS: A total of 1281 patients underwent randomization in the induction trial, and 544 patients with a response to mirikizumab underwent randomization again in the maintenance trial. Significantly higher percentages of patients in the mirikizumab group than in the placebo group had clinical remission at week 12 of the induction trial (24.2% vs. 13.3%, P<0.001) and at week 40 of the maintenance trial (49.9% vs. 25.1%, P<0.001). The criteria for all the major secondary end points were met in both trials. Adverse events of nasopharyngitis and arthralgia were reported more frequently with mirikizumab than with placebo. Among the 1217 patients treated with mirikizumab during the controlled and uncontrolled periods (including the open-label extension and maintenance periods) in the two trials, 15 had an opportunistic infection (including 6 with herpes zoster infection) and 8 had cancer (including 3 with colorectal cancer). Among the patients who received placebo in the induction trial, 1 had herpes zoster infection and none had cancer. CONCLUSIONS: Mirikizumab was more effective than placebo in inducing and maintaining clinical remission in patients with moderately to severely active ulcerative colitis. Opportunistic infection or cancer occurred in a small number of patients treated with mirikizumab. (Funded by Eli Lilly; LUCENT-1 and LUCENT-2 ClinicalTrials.gov numbers, NCT03518086 and NCT03524092, respectively.).

Multidetector Computed Tomography Perfusion in Head and Neck Squamous Cell Carcinomas: Evaluation of a Dose Reduction Strategy.

Background Computed tomography perfusion (CTp), a useful technique in oncology, is not widely utilized due to the high radiation dose delivered from it. It involves scanning the region of interest every second for 50 seconds following intravenous contrast administration. Doubling sampling interval (SI) to 2 seconds will half the radiation dose, but may impact its effectiveness, which needs to be evaluated. Objectives To evaluate a dose reduction strategy in CTp by determining agreement between standard dose (SD) CTp (acquisition with SI 1 second) and low-dose CTp techniques with SI of 2 seconds (achieved either by reconstruction only or true low-dose acquisition). Materials and methods This cross-sectional study was conducted on histopathology-proven head and neck squamous cell carcinoma (HNSCC) patients who underwent CTp on 64 slice multidetector CT. A total of 56 patients had SD and 24 patients underwent true low dose (LD) acquisition. SD data were also reconstructed at SI 2 seconds to obtain a dataset simulating low dose (low-dose reconstruction [LDr]). Paired t -test was applied to compare CTp in SD and LDr groups and the Bland-Altman plot drawn to calculate 95% confidence limit of agreement. The Kolmogorov-Smirnov test compared CTp parameters for LDr and LD groups. Results There was no statistical difference in CTp parameters (except blood flow in malignant) in SD and LDr groups for both malignant and normal tissues. CTp of malignant tissue was not statistically different in LDr and LD groups but the radiation dose was half in the LD group. Conclusion Reduction of radiation dose to half achieved by doubling the SI does not affect the CTp parameters significantly. So LD acquisitions will increase the use of CTp in HNSCC.

Risk Benefit Analysis of Routine Thymectomy for Differentiated Thyroid Cancers: A Systematic Review.

Background Central compartment lymph node dissection (CLND) is a part of the surgical management of differentiated thyroid cancer (DTC). Therapeutic CLND is done to address clinically significant central compartment nodes in patients with DTC, while prophylactic CLND is performed in the presence of high-risk features in the absence of clinically significant neck nodes. Removal of thymus-unilateral or bilateral-during CLND to achieve complete clearance of level VI and VII lymph node stations and address thymic metastasis is debatable. Objective The present systematic review was conducted to summarize the evidence, delineating the role of thymectomy during CLND in patients with DTC. Methods Electronic databases of PubMed, Embase, and Cochrane were searched from their inception to July 2020 using keywords-thyroid neoplasms or tumors, thyroidectomy, and thymectomy-to identify the articles describing the role of thymectomy during CLND in DTC. A pooled analysis of surgicopathological outcomes was performed using metaprop command in STATA software version 16. Result A total of three studies and 347 patients-total thyroidectomy (TT) with bilateral thymectomy in 154, TT with unilateral thymectomy in 166, and TT alone in 27 patients with DTC-were included in the systematic review. The pooled frequency of thymic metastasis was a mere 2% in patients undergoing either unilateral or bilateral thymectomy. The routine addition of thymectomy does not result in better lymph node clearance. Unilateral and bilateral thymectomy were associated with high chances of transient hypocalcemia (12.0% and 56.1%, respectively). Conclusion Routine thymectomy is not warranted during CLND, considering minimal oncological benefit and high risk of postoperative hypocalcemia.

Systemic administration of a ß2-adrenergic receptor agonist reduces mechanical allodynia and suppresses the immune response to surgery in a rat model of persistent post-incisional hypersensitivity.

Beta 2 adrenergic receptor (ß2 AR) activation in the central and peripheral nervous system has been implicated in nociceptive processing in acute and chronic pain settings with anti-inflammatory and anti-allodynic effects of ß2-AR mimetics reported in several pain states. In the current study, we examined the therapeutic efficacy of the ß2-AR agonist clenbuterol in a rat model of persistent postsurgical hypersensitivity induced by disruption of descending noradrenergic signaling in rats with plantar incision. We used growth curve modeling of ipsilateral mechanical paw withdrawal thresholds following incision to examine effects of treatment on postoperative trajectories. Depletion of spinal noradrenergic neurons delayed recovery of hypersensitivity following incision evident as a flattened slope compared to non-depleted rats (-1.8 g/day with 95% CI -2.4 to -1.085, p < 0.0001). Chronic administration of clenbuterol reduced mechanical hypersensitivity evident as a greater initial intercept in noradrenergic depleted (6.2 g with 95% CI 1.6 to 10.8, p = 0.013) and non-depleted rats (5.4 g with 95% CI 1.2 to 9.6, p = 0.018) with plantar incision compared to vehicle treated rats. Despite a persistent reduction in mechanical hypersensitivity, clenbuterol did not alter the slope of recovery when modeled over several days (p = 0.053) or five weeks in depleted rats (p = 0.64). Systemic clenbuterol suppressed the enhanced microglial activation in depleted rats and reduced the density of macrophage at the site of incision. Direct spinal infusion of clenbuterol failed to reduce mechanical hypersensitivity in depleted rats with incision suggesting that beneficial effects of ß2-AR stimulation in this model are largely peripherally mediated. Lastly, we examined ß2-AR distribution in the spinal cord and skin using in-situ hybridization and IHC. These data add to our understanding of the role of ß2-ARs in the nervous system on hypersensitivity after surgical incision and extend previously observed anti-inflammatory actions of ß2-AR agonists to models of surgical injury.

Central Reading of Ulcerative Colitis Clinical Trial Videos Using Neural Networks.

BACKGROUND AND AIMS: Endoscopic disease activity scoring in ulcerative colitis (UC) is useful in clinical practice but done infrequently. It is required in clinical trials, where it is expensive and slow because human central readers are needed. A machine learning algorithm automating the process could elevate clinical care and facilitate clinical research. Prior work using single-institution databases and endoscopic still images has been promising. METHODS: Seven hundred and ninety-five full-length endoscopy videos were prospectively collected from a phase 2 trial of mirikizumab with 249 patients from 14 countries, totaling 19.5 million image frames. Expert central readers assigned each full-length endoscopy videos 1 endoscopic Mayo score (eMS) and 1 Ulcerative Colitis Endoscopic Index of Severity (UCEIS) score. Initially, video data were cleaned and abnormality features extracted using convolutional neural networks. Subsequently, a recurrent neural network was trained on the features to predict eMS and UCEIS from individual full-length endoscopy videos. RESULTS: The primary metric to assess the performance of the recurrent neural network model was quadratic weighted kappa (QWK) comparing the agreement of the machine-read endoscopy score with the human central reader score. QWK progressively penalizes disagreements that exceed 1 level. The model's agreement metric was excellent, with a QWK of 0.844 (95% confidence interval, 0.787-0.901) for eMS and 0.855 (95% confidence interval, 0.80-0.91) for UCEIS. CONCLUSIONS: We found that a deep learning algorithm can be trained to predict levels of UC severity from full-length endoscopy videos. Our data set was prospectively collected in a multinational clinical trial, videos rather than still images were used, UCEIS and eMS were reported, and machine learning algorithm performance metrics met or exceeded those previously published for UC severity scores.

Discordance of COVID-19 guidelines for patients with cancer: A systematic review.

This review was aimed to systematically evaluate the available literature on the impact of COVID-19 on cancer care and to critically analyze the diagnostic and therapeutic strategies suggested by various healthcare providers, societies, and institutions. Majority guidelines for various types of cancers favored a delay in treatment or a nonsurgical approach wherever feasible. These guidelines are based on a low level of evidence and have significant discordance for the role and timing of surgery, especially in early tumors.

Are Histomorphological Features Predictive of p16 Immunopositivity Different for Oral and Oropharyngeal Squamous Cell Carcinoma?

Evidence from current studies show that squamous cell carcinomas at oral and oropharyngeal sites are distinct and unique, with their own separate etiopathogenesis, treatment, and prognosis. The aim of this work is to correlate p16 immunohistochemical expression with histomorphological features suggestive of HPV infection in oral and oropharyngeal squamous cell carcinoma. A total of 50 consecutive biopsy cases of oral squamous cell carcinoma (OSCC) and 50 consecutive biopsy cases of oropharyngeal squamous cell carcinoma (OPSCC) were evaluated for features suggestive of HPV infection like focal basaloid appearance, nests, and lobules of tumor cells with pushing borders, absence of stromal reaction, central necrosis, focal lymphoepithelial morphology, presence of koilocytes, and non-keratinizing or hybrid morphology. Immunostaining was performed using p16 monoclonal antibody (clone mouse 16P04). Only cases showing a moderate (2+) to high intensity (3+) staining in more than 75% cells were taken as p16 immunopositive. The histological features were correlated with p16 immunopositivity. A total of 18/50 (36%) cases of oral squamous cell carcinoma and 27/50 (54%) cases of oropharyngeal squamous cell carcinoma were p16 immunopositive. On statistical analysis, only nests/lobules with pushing borders were found to have a significant correlation with p16 immunopositivity (P value = 0.0012) for OSCC cases. For OPSCC cases, four histological features namely nests and lobules with pushing borders (P value = 0.0001), focal basaloid appearance (P value = 0.0041), lymphoepithelial morphology (P value = 0.0029), and non-keratinizing/hybrid morphology (P value = 0.0141) had a significant correlation with p16 immunopositivity. Histomorphological features are more helpful in predicting p16 immunopositivity in OPSCC than OSCC.

Status and strategies for the management of head and neck cancer during COVID-19 pandemic: Indian scenario.

In India, oral cancer is the most common head and neck cancer (HNC) in men, mainly caused by the consumption of smoked and smokeless tobacco. During the current pandemic, delaying surgery for even 1 or 2 months may lead to more extensive surgery or inoperability, where only supportive care can be provided. Being semi-emergent in nature, treatment for these patients is currently on hold or delayed in most centers across the country. This study was conducted to assess the impact of COVID-19 pandemic and inability of the health system to treat HNC in a timely fashion and how surgeons are coping to this emergent situation. This article highlights the situation in India, a country burdened with one of the highest incidence rates of HNC.

Absence of VEGFR-1/Flt-1 signaling pathway in mice results in insensitivity to discogenic low back pain in an established disc injury mouse model.

Although degenerative disc disease (DDD) and related low back pain (LBP) are growing public health problems, the underlying disease mechanisms remain unclear. An increase in the vascular endothelial growth factor (VEGF) levels in DDD has been reported. This study aimed to examine the role of VEGF receptors (VEGFRs) in DDD, using a mouse model of DDD. Progressive DDD was induced by anterior stabbing of lumbar intervertebral discs in wild type (WT) and VEGFR-1 tyrosine-kinase deficient mice (vegfr-1TK-/- ). Pain assessments were performed weekly for 12 weeks. Histological and immunohistochemical assessments were made for discs, dorsal root ganglions, and spinal cord. Both vegfr-1TK-/- and WT mice presented with similar pathological changes in discs with an increased expression of inflammatory cytokines and matrix-degrading enzymes. Despite the similar pathological patterns, vegfr-1TK-/- mice showed insensitivity to pain compared with WT mice. This insensitivity to discogenic pain was related to lower levels of pain factors in the discs and peripheral sensory neurons and lower spinal glial activation in the vegfr-1TK- /- mice than in the WT mice. Exogenous stimulation of bovine disc cells with VEGF increased inflammatory and cartilage degrading enzyme. Silencing vegfr-1 by small-interfering-RNA decreased VEGF-induced expression of pain markers, while silencing vegfr-2 decreased VEGF-induced expression of inflammatory and metabolic markers without changing pain markers. This suggests the involvement of VEGFR-1 signaling specifically in pain transmission. Collectively, our results indicate that the VEGF signaling is involved in DDD. Particularly, VEGFR-1 is critical for discogenic LBP transmission independent of the degree of disc pathology.

Genetic markers associated with clinical and radiographic response in adalimumab plus methotrexate- or methotrexate-treated rheumatoid arthritis patients in OPTIMA.

OBJECTIVES: Biologics, including tumour necrosis factor inhibitors such as adalimumab (ADA), have significantly improved outcomes in rheumatoid arthritis (RA). Because the clinical course of RA and response to therapy may be influenced by the genetic background of the patient, the objective of this retrospective parallel-assigned case-control analysis was to evaluate the associations between candidate genetic markers for RA with clinical and radiographic responses to ADA + methotrexate (MTX) or MTX monotherapy in the Optimal Protocol for Treatment Initiation with MTX and ADA (OPTIMA) study. METHODS: Three candidate genetic markers were tested: HLA-DRB1 shared epitope (SE), interleukin 4 receptor (IL4R) single nucleotide polymorphism (SNP) rs1805010, and Fc gamma receptor IIb (FcgRIIb) SNP rs1050501. Genetic associations with week 26 clinical and radiographic responses during treatment with ADA + MTX or MTX monotherapy were assessed using summary statistics, chi-square or Fisher's exact test, correlation, regression models, and corrected for multiple-comparisons. RESULTS: Low disease activity (p=0.008) and improvement in American College of Rheumatology 20%, 50% and 70% response criteria (p=0.02, 0.01, and 0.02, respectively) were associated with HLA-DRB1 SE copy numbers in the ADA + MTX treatment arm, and the FcgRIIb SNP was a predictor of remission. The IL4R SNP correlated with radiographic progression in patients receiving MTX monotherapy, supporting previous findings. CONCLUSIONS: This pharmacogenetic analysis identified genetic components that contribute to clinical responses to anti-rheumatic therapy.

Surgical Experience in Pediatric Patients with Chiari-I Malformations Aged ≤18 Years.

OBJECTIVE: The objective of this study was to retrospectively study Chiari I malformation patients (<18 years) treated surgically. MATERIALS AND METHODS: Chiari I malformation patients (<18 years) treated surgically at our institute were retrospectively studied. RESULTS: During the study period between January 1999 and June 2011, fifty patients, aged ≤18 years with Chiari malformation, were treated surgically and formed the basis for this series. There were 21 female children (42%) and 29 male children (58%), with a female-to-male ratio of 1:1. At the last follow-up, oropharyngeal symptoms were improved in 33% (n = 3/9). Headache/neck/back pain improved in 69.56% of children (n = 16/23). Upper-extremity pain/weakness/numbness improved in 73.91% of children (n = 17/23). Ataxia improved in 66.66% of children (n = 4/6). Lower-limb weakness/hyperreflexia improved in 83.33% of children (n = 5/6). At follow-up, magnetic resonance imaging for patients with syrinx was available for 75% of patients (n = 30/50) and not available for 25% of patients (n = 10/40). Syrinx was diminished in size or resolved in 66.33% of patients (n = 19/30) and the remaining was same for 36.66% of patients (n = 11/30). CONCLUSIONS: The main goal of surgery is to arrest the progression of neurological deficits. Foramen magnum decompression with a lax duroplasty is the surgical procedure of choice.

Psychosocial Stress Delays Recovery of Postoperative Pain Following Incisional Surgery in the Rat.

Psychosocial factors such as anxiety, depression and catastrophizing, commonly associated with established chronic pain, also may be associated with an increased risk of chronic postsurgical pain (CPSP) when present preoperatively. We used a repeat social defeat (RSD) paradigm to induce psychosocial stress in rodents prior to incisional surgery of the paw. Mixed effects growth curve models were utilized to examine resolution of mechanical hypersensitivity in rats for four weeks following surgery. Eight days following surgery, immunohistochemistry was conducted to examine glial activation as well as evoked neuronal activation in the spinal cord. Here we document that RSD resulted in reduced weight gain and increased depressive symptoms prior to surgery. Rats exposed to RSD displayed delayed resolution of mechanical hypersensitivity in the ipsilateral paw following surgery compared to non-defeated rats. Prior exposure to RSD significantly increased microglial activation and neuronal sensitization (pERK-IR) within the ipsilateral spinal cord. In conclusion, we found that chronic social stress alters the neurobiological response to surgical injury, resulting in slowed recovery. This model maybe useful for future interventional studies examining the mechanistic interactions between depression and risk of CPSP.

Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS: More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol. CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).

Disruption of Spinal Noradrenergic Activation Delays Recovery of Acute Incision-Induced Hypersensitivity and Increases Spinal Glial Activation in the Rat.

UNLABELLED: Results of clinical studies suggest that descending inhibitory controls from the brainstem are important for speeding recovery from pain after surgery. We examined the effects of destroying spinally projecting noradrenergic neurons via intrathecally administered antibody to dopamine ß-hydroxylase conjugated to saporin (DßH-saporin) on recovery in an acute incisional pain model. Mechanical and thermal paw withdrawal thresholds and nonevoked spontaneous guarding scores were tested for several weeks postoperatively and analyzed using mixed effects growth curve modeling. DßH-saporin treatment resulted in a significant prolongation in the duration of mechanical and to a lesser degree thermal hypersensitivity in the ipsilateral paw of incised rats but did not increase the duration of spontaneous guarding. DßH-saporin treatment was also associated with increased microglial and astrocyte activation in the ipsilateral spinal cord 21 days after incision compared with immunoglobulin G-saporin treated controls. Chronic intrathecal administration of the α2 adrenergic receptor antagonist atipamezole (50-200 µg/d) produced similar effects. These data suggest that spinally projecting noradrenergic pathways and spinal α2 adrenergic receptor activation are important for speeding recovery from hypersensitivity after surgical incision possibly by reducing spinal glial activation. Interventions that augment the noradrenergic system might be important to speed recovery from pain after surgery. PERSPECTIVE: Endogenous descending spinal noradrenergic activation promotes resolution of incision-induced hypersensitivity and inhibits spinal microglial and astrocyte activation in part through α2 adrenergic receptors.

Juvenile ossifying fibroma diagnosed on fine needle aspiration cytology: a diagnostic challenge.

Preoperative diagnosis of jaw lesions is not always possible on the basis of clinico-radiological findings alone and needs to be confirmed before attempting any surgical intervention. Fibro-osseous lesions of the jaw comprise a spectrum of diseases which include cement-osseous dysplasia, fibrous dysplasia, and ossifying fibroma. The cytomorphological distinction between these individual entities is difficult. We present a case of maxillary fibro-osseous lesion in an adolescent girl diagnosed and categorized as juvenile ossifying fibroma preoperatively on cytology and confirmed on histopathology. Although aspirates are usually paucicellular in fibro-osseous lesions, certain cytological features if present in cellular cytosmears can offer further categorization and a definitive diagnosis may be possible in light of clinico-radiological correlation.

Adalimumab for the treatment of Japanese patients with intestinal Behçet's disease.

BACKGROUND & AIMS: Behçet's disease is a chronic, relapsing inflammatory disease that can involve the mouth, skin, eyes, genitals, and intestines. Active intestinal Behçet's disease can be complicated by gastrointestinal (GI) bleeding and perforation. We performed a multicenter, open-label, uncontrolled study to evaluate the efficacy and safety of adalimumab, a fully human monoclonal antibody against tumor necrosis factor α, in patients with intestinal Behçet's disease who were refractory to corticosteroid and/or immunomodulator therapies. METHODS: The study was conducted at 12 sites in Japan, from November 2010 through October 2012. Twenty patients were given 160 mg adalimumab at the start of the study and 80 mg 2 weeks later, followed by 40 mg every other week for 52 weeks; for some patients, the dose was increased to 80 mg every other week. A composite efficacy index, combining GI symptom and endoscopic assessments, was used to evaluate efficacy. The primary efficacy end point was the percentage of patients with scores of 1 or lower for GI symptom and endoscopic assessments at week 24. Secondary end points included complete remission and resolution of non-GI Behçet's-related symptoms. RESULTS: Nine patients (45%) had GI symptom and endoscopic assessment scores of 1 or lower at week 24 of treatment, and 12 patients (60%) had these scores by week 52. Four patients (20%) achieved complete remission at weeks 24 and 52. Individual global GI symptom and endoscopic scores improved for most patients at weeks 24 and 52. Two thirds of patients with oral aphthous ulcers, skin symptoms, and genital ulcers, and 88% of patients with erythema nodosum had complete resolution of these conditions at week 52. A total of 9 of 13 patients (69%) taking steroids at baseline were able to taper (n = 1) or completely discontinue steroids (n = 8) during the study. No new safety signals were observed. CONCLUSIONS: Adalimumab is a potentially effective treatment for intestinal Behçet's disease in Japanese patients who are refractory to conventional treatments. ClinicalTrials.gov number: NCT01243671.

Long-term safety and efficacy of adalimumab in Japanese patients with moderate to severe Crohn's disease.

BACKGROUND AND AIMS: Adalimumab has been shown to be effective and well tolerated in patients with Crohn's disease. This analysis reports the results of a cohort of Japanese patients with moderate to severe Crohn's disease who were evaluated for up to 3years to assess the long-term use of adalimumab. METHODS: The study consisted of a double-blind part and an open-label part. Patients were included either in the 52-week double-blind, placebo-controlled part of the study followed by a 96-week open-label extension or in the open-label part from the beginning or in the event of a flare. Patients were treated with adalimumab and evaluated for up to 148weeks as 3 data cohorts: the all-adalimumab cohort (patients receiving ≥1 injection of adalimumab), the 148-week follow-up subcohort (patients who completed 148weeks of follow-up after the first adalimumab dose), and the dose-escalation subcohort (patients receiving adalimumab doses that increased to 80mg every other week). RESULTS: In the all-adalimumab cohort (n=79), clinical remission rates were approximately 30% after 36weeks of exposure to adalimumab and for the remainder of the study (35%, 33%, and 28% for weeks 48, 108, and 144, respectively). An improvement in quality of life was also maintained over the same period. In the dose-escalation subcohort (n=40), the clinical remission rate was 75% (6/8) 48weeks after dose escalation. Adalimumab was tolerated, and no deaths were reported. CONCLUSIONS: Adalimumab is effective for maintaining long-term clinical remission in Japanese patients with moderate to severe Crohn's disease (NCT00445432).

Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years.

The objective of this study was to assess the safety of adalimumab in patients aged 2 to <4 years old or ≥4 years old weighing <15 kg with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). Clinical effectiveness and pharmacokinetics (PK) of adalimumab were also evaluated. This was an international, multicenter, open-label, phase 3b study in 32 patients with active JIA that were treated with adalimumab 24 mg/m(2) (maximum = 20 mg/dose) every other week up to 120 weeks, with or without concomitant methotrexate. Adverse events (AEs) were summarized for completed visits. Efficacy endpoints included American College of Rheumatology pediatric (PedACR) 30/50/70/90 responses and JIA core components. Adalimumab serum trough concentrations were measured in a subset of patients. Among the patients, 88 % were female. Baseline mean age, weight, and JIA duration were 3 years, 13 kg, and 12 months, respectively; 39 % had elevated C-reactive protein. AE incidence rates included any AEs (29/32, 91 %), serious AEs (5/32, 16 %), infectious AEs (25/32, 78 %), and serious infections (3/32, 9 %). No deaths, malignancies, or opportunistic infections were reported. Growth was not adversely impacted. At week 96, 92 % of patients achieved PedACR30, and 77 % achieved PedACR70. Improvements in JIA core components were observed. Mean steady-state serum adalimumab trough concentrations were 7-8 µg/mL at weeks 12 and 24. Adalimumab was well tolerated in JIA patients aged 2 to <4 years old or ≥4 years old weighing <15 kg. The efficacy and PK of adalimumab were comparable to those seen in older JIA patients.

Adalimumab, a human anti-TNF monoclonal antibody, outcome study for the prevention of joint damage in Japanese patients with early rheumatoid arthritis: the HOPEFUL 1 study.

OBJECTIVES: To evaluate the efficacy and safety of adalimumab+methotrexate (MTX) in Japanese patients with early rheumatoid arthritis (RA) who had not previously received MTX or biologics. METHODS: This randomised, double-blind, placebo-controlled, multicentre study evaluated adalimumab 40 mg every other week+MTX 6-8 mg every week versus MTX 6-8 mg every week alone for 26 weeks in patients with RA (≤2-year duration). The primary endpoint was inhibition of radiographic progression (change (Δ) from baseline in modified total Sharp score (mTSS)) at week 26. RESULTS: A total of 171 patients received adalimumab+MTX (mean dose, 6.2±0.8 mg/week) and 163 patients received MTX alone (mean dose, 6.6±0.6 mg/week, p<0.001). The mean RA duration was 0.3 years and 315 (94.3%) had high disease activity (DAS28>5.1). Adalimumab+MTX significantly inhibited radiographic progression at week 26 versus MTX alone (ΔmTSS, 1.5±6.1 vs 2.4±3.2, respectively; p<0.001). Significantly more patients in the adalimumab+MTX group (62.0%) did not show radiographic progression (ΔmTSS≤0.5) versus the MTX alone group (35.4%; p<0.001). Patients treated with adalimumab+MTX were significantly more likely to achieve American College of Rheumatology responses and achieve clinical remission, using various definitions, at 26 weeks versus MTX alone. Combination therapy was well tolerated, and no new safety signals were observed. CONCLUSIONS: Adalimumab in combination with low-dose MTX was well tolerated and efficacious in suppressing radiographic progression and improving clinical outcomes in Japanese patients with early RA and high disease activity.