Intravenous Golimumab in Patients with Polyarticular Juvenile Idiopathic Arthritis and Juvenile Psoriatic Arthritis and Subcutaneous Ustekinumab in Patients with Juvenile Psoriatic Arthritis: Extrapolation of Data from Studies in Adults and Adjacent Pediatric Populations.

OBJECTIVES: To describe the extrapolation approaches used to support intravenous (IV) golimumab for polyarticular juvenile idiopathic arthritis (pJIA) and juvenile psoriatic arthritis (jPsA) and subcutaneous (SC) ustekinumab for jPsA. METHODS: Pharmacokinetic, clinical response, and safety data from trials of IV golimumab and SC ustekinumab in polyarticular-course JIA (pc-JIA) (GO-VIVA) or pediatric psoriasis (PsO) (CADMUS and CADMUS Jr) and data from pivotal, phase 3 trials of these agents in adults with similar diseases were used to support extrapolation in pJIA and jPsA. In the phase 3 GO-VIVA trial, patients with pc-JIA aged 2 to < 18 years received IV golimumab 80 mg/m2 at weeks 0, 4, then every 8 weeks (Q8W). In the phase 3, randomized, placebo-controlled CADMUS trial, patients with PsO aged ≥ 12 to < 18 years received ustekinumab at weeks 0, 4, then Q12W. In the phase 3 CADMUS Jr trial, patients with PsO aged ≥ 6 to < 12 years received ustekinumab at weeks 0, 4, then Q12W. The ustekinumab analyses used data only from patients who received the standard ustekinumab dosing regimen (≤ 60 kg: 0.75 mg/kg; > 60 to ≤ 100 kg: 45 mg; > 100 kg: 90 mg). RESULTS: In the 127 patients with pc-JIA treated with IV golimumab (GO-VIVA), pharmacokinetic and exposure-response results were similar to those in adults with rheumatoid arthritis treated with IV golimumab. Additionally, pharmacokinetic and clinical response data from five patients with jPsA in GO-VIVA were comparable to those in adults with PsA treated with IV golimumab. No new safety signals were observed in GO-VIVA. Pharmacokinetic and clinical response data observed in the four pediatric patients with PsO and jPsA treated with ustekinumab in CADMUS and CADMUS Jr were similar to those in the 91 pediatric patients with PsO without jPsA in these trials and to those in adults with PsA treated with ustekinumab. Safety was extrapolated from CADMUS or CADMUS Jr; no new signals were observed. CONCLUSIONS: These three sets of analyses corroborate similar exposure and efficacy of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in patients with jPsA to support extrapolation of established adult efficacy. The overall safety profiles of IV golimumab in pediatric patients with pc-JIA or jPsA and SC ustekinumab in pediatric patients with PsO with or without jPsA were consistent with the safety profiles of these agents in the context of their clinical programs and cumulative use. Based on these analyses, the US Food and Drug Administration approved IV golimumab for polyarticular JIA and active PsA in patients 2 years and older and SC ustekinumab for pediatric PsA in patients 6 years and older, highlighting how use of an extrapolation approach can help streamline drug development for pediatric patient populations in whom larger clinical trials are not feasible. CLINICAL TRIAL REGISTRATION: GO-VIVA (NCT02277444) was registered at clinicaltrials.gov on 29 October 2014; CADMUS (NCT01090427) was registered on 22 March 2010; and CADMUS Jr (NCT02698475) was registered on 3 March 2016.

Reasons for Initiating Canakinumab among Patients with Systemic Juvenile Idiopathic Arthritis and Adult-Onset Still's Disease in the U.S. Real-World Settings.

INTRODUCTION: The aim of this study was to understand the reasons for canakinumab initiation among patients with Still's disease, including systemic juvenile idiopathic arthritis (SJIA) and adult-onset Still's disease (AOSD), in US clinical practice. METHODS: Physicians retrospectively reviewed the medical charts of patients with Still's disease (regardless of age at symptom onset) who were prescribed canakinumab from 2016 to 2018. Patients aged < 16 years at symptom onset were classified as having SJIA and those aged ≥ 16 years at symptom onset (calculated from case-record forms) were classified as having AOSD. Patient treatment history and physician reasons for canakinumab initiation were analyzed. Overall results were presented as SJIA/AOSD. Sensitivity analyses were performed for the robustness of the results. RESULTS: Forty-three physicians in the USA (rheumatologists/dermatologists/immunologists/allergists: 51.2/27.9/11.6/9.3%; subspecialty in adults/pediatrics: 67.4/32.6%) abstracted information for 72 patients with SJIA/AOSD (SJIA/AOSD/age unknown at symptom onset: 75.0/18.1/6.9%; mean age 19.4 years; children 61.1%; females 56.9%). Most patients (90.3%) received treatment directly preceding canakinumab initiation (etanercept 27.7%; anakinra 18.5%; adalimumab 16.9%); the respective treatment was discontinued due to lack of efficacy/effectiveness (43.1%) and availability of a new treatment (27.8%). Most common reasons for canakinumab initiation were physician perceived/experienced efficacy/effectiveness of canakinumab (77.8%; children/adults: 81.8/71.4%), lack-of-response to previous treatment (45.8%; children/adults: 36.4/60.7%), convenient administration/dosing (26.4%; children/adults: 29.5/21.4%) and ability to discontinue/spare steroids (25.0%; children/adults: 20.5/32.1%). The sensitivity analysis provided similar results. CONCLUSIONS: In US clinical practice, physician perceived/experienced efficacy/effectiveness of canakinumab and lack-of-response to previous treatment were the primary reasons for canakinumab initiation among patients with SJIA/AOSD. Physician perceived/experienced efficacy/effectiveness and convenient administration/dosing of canakinumab were the most common reasons for canakinumab initiation among children, whereas lack-of-response to previous treatment and ability to discontinue/spare steroids being the most frequent reasons among adults.

Reasons for canakinumab initiation among patients with periodic fever syndromes: a retrospective medical chart review from the United States.

BACKGROUND: Although canakinumab has demonstrated efficacy in multiple trials in patients with periodic fever syndromes (PFS), the evidence on initiation of canakinumab among PFS patients in real world setting is not well understood. We aimed to characterize the reasons for canakinumab initiation among patients with PFS, specifically, cryopyrin-associated periodic syndrome (CAPS), hyperimmunoglobulin D syndrome/mevalonate kinase deficiency (HIDS/MKD), TNF receptor-associated periodic syndrome (TRAPS) and familial Mediterranean fever (FMF). METHODS: Physicians retrospectively reviewed the medical charts of PFS patients prescribed canakinumab between 2016 and 2018. Information collected included patient clinical characteristics, reasons for previous treatment discontinuation and canakinumab initiation. The results were summarized for overall patients, and by children (< 18 years) and adults and by subtype of PFS. RESULTS: Fifty-eight physicians in the US (rheumatologists, 44.8 %; allergists/immunologists, 29.3 %; dermatologists, 25.9 %) abstracted information for 147 patients (children, 46.3 %; males, 57.1 %; CAPS, 36.7 %; TRAPS, 26.5 %; FMF, 26.5 %; HIDS/MKD, 6.8 %; Mixed, 3.4 %). Overall, most patients (90.5 %) received treatment directly preceding canakinumab (NSAIDs, 27.8 % [40.0 % in HIDS/MKD]; anakinra, 24.1 % [32.7 % in CAPS]; colchicine, 21.8 % [35.9 % in FMF]), which were discontinued due to lack of efficacy/effectiveness (39.5 %) and availability of a new treatment (36.1 %). The common reasons for canakinumab initiation were physician perceived efficacy/effectiveness (81.0 %; children, 75.0 %; adults, 86.1 %), lack of response to previous treatment (40.8 %; children, 38.2 %; adults, 43.0 %) and favorable safety profile/tolerability (40.1 %; children, 42.6 %; adults, 38.0 %). Within subtypes, efficacy/effectiveness was the most stated reason for canakinumab initiation in HIDS/MKD (90.9 %), lack of response to previous treatment in FMF (52.4 %) and convenience of administration/dosing in CAPS (27.1 %). CONCLUSIONS: This study provided insights into how canakinumab is initiated in US clinical practice among PFS patients, with physician perceived efficacy/effectiveness of canakinumab, lack of response to previous treatment and favorable safety profile/tolerability of canakinumab being the dominant reasons for canakinumab initiation in all patients and in children and adults and PFS subtypes. Notably, the favorable safety profile/tolerability of canakinumab was more often the reason for initiation among children versus adults.

Burden of illness in hereditary periodic fevers: a multinational observational patient diary study.

OBJECTIVES: This study aimed to characterise the burden of illness of patients with inadequately controlled hereditary periodic fevers (HPFs), during and outside of flares. It was focused on the burden to the patients and also considered the wider impact on their caregivers and families. METHODS: The target population was patients or caregivers of patients with clinically/genetically confirmed colchicine resistant FMF (crFMF), mevalonate kinase deficiency/hyperimmunoglobinaemia D with periodic fever syndrome (MKD/HIDS) or TRAPS, who were expected to flare at least once in a 6-month period based on patient history. Disease burden was captured during and between flares using an electronic diary (e-diary) with questions on patient functioning, emotional/social well-being and pain, using validated instruments. RESULTS: HPF-related symptoms such as fever, joint, muscle or bone pain and tiredness and fatigue were reported by patients both during and outside of a flare. The SF-10 Health Survey (SF-10v2) (paediatric patients) and SF-12 Health Survey (SF-12v2) (adult patients) showed that flares negatively impacted patients' psychosocial and physical health. Negative effect of on-flare status on health utility index score assessed by the Short-Form Six-Dimension (SF-6D) was significant only for crFMF patients. Furthermore, the Sheehan Disability Score (SDSv3) showing the on-flare status resulted in significant functional impairment in all 3 disease cohorts through assessment of impact on work/school, social and family life. CONCLUSIONS: crFMF, MKD/HIDS and TRAPS negatively affected the quality of life (QoL) of adult and paediatric patients, including their physical, mental, psychosocial health, and social functioning. There remains, however, a high number of unmet needs for these patients to reduce their disease burden.

A systematic literature review of efficacy, effectiveness and safety of biologic therapies for treatment of familial Mediterranean fever.

OBJECTIVES: To identify and summarize the existing evidence on the efficacy, effectiveness and safety of biologic therapies used, either as indicated or off-label, in the treatment of FMF. METHODS: A systematic literature review was conducted using Embase®, MEDLINE®, MEDLINE®-In Process, and Cochrane databases to identify randomized/non-randomized controlled trials (RCTs/non-RCTs) and real-world observational studies of FMF published as full-text articles (2000-September 2017) or conference abstracts (2014-September 2017). Studies with data for ≥1 biologic were included. Studies with <5 patients were excluded. RESULTS: Of the 3342 retrieved records, 67 publications, yielding 38 unique studies, were included. All studies were published after the year 2010, and the majority (21) were full-text articles. Most studies (33/38) were prospective/retrospective observational; three were double-blind, placebo-controlled RCTs (one each of anakinra, canakinumab and rilonacept); and two were non-RCTs (both canakinumab). Anakinra (26), canakinumab (21) and etanercept (6) were the most frequently used biologics across studies, whereas use of adalimumab, tocilizumab, rilonacept and infliximab was limited (1-2 studies). The available evidence suggested benefits of anakinra and canakinumab in FMF. CONCLUSION: Anti-IL-1 therapies (i.e. anakinra and canakinumab) appear to be effective and safe options in the treatment of overall FMF, including patients with colchicine resistance and FMF-related amyloidosis. There is a need for properly designed prospective or controlled studies to conclude the superiority of one anti-IL-1 therapy over another. Evidence on the use of TNF-α and IL-6 inhibitors is limited, and further research is suggested.

The patient journey to diagnosis and treatment of autoinflammatory diseases.

BACKGROUND: Limited data are available on the experiences of patients with autoinflammatory diseases (AIDs) and their families along the path to diagnosis and treatment. We sought to describe these experiences in patients with AIDs including tumor necrosis factor receptor-associated periodic syndrome (TRAPS), mevalonate kinase deficiency/hyperimmunoglobulin D syndrome (MKD/HIDS), and familial Mediterranean fever (FMF). METHODS: Ninety-minute, semi-structured qualitative interviews and 5-day written/video diaries were used to gather information on the experiences of patients with AIDs and their families. RESULTS: Twelve families of patients from the US (TRAPS [n = 4], MKD/HIDS [n = 5], FMF [n = 5]) participated in this study from August to November 2015. The study included two families with multiple afflicted siblings. Patients' ages ranged from 1 to 28 years. Most parents reported realizing that something was seriously wrong with their child after medical emergencies and/or hospitalizations, which initiated the difficult path to diagnosis. For most, the process included multiple specialist visits, extensive and repeated testing, and many misdiagnoses. Over time, 92% of parents reported losing confidence in the healthcare system's ability to find an answer to their child's symptoms, while they also struggled with unsupportive school personnel and dismissive friends and relatives. Patients and their parents reported holding on to memories of "what life was like" before the onset of symptoms and mourning their subsequent loss of "normalcy." Even after diagnosis, patients and parents continued to feel uncertain about what to expect in the future. CONCLUSIONS: All families emphasized the need for efficient early diagnosis of AIDs. Initiatives that improve the speed and accuracy of diagnosis, provide more comprehensive patient education, and support patients and families through the illness have the potential to significantly improve the quality of life of patients with AIDs and their families. Healthcare providers should be aware of the impact of the long diagnostic journey on families and work to create an environment of trust and collaboration in the face of a difficult and prolonged diagnostic process.

Impact of systemic juvenile idiopathic arthritis/Still's disease on adolescents as evidenced through social media posts.

PURPOSE: To understand the experience of adolescent systemic juvenile idiopathic arthritis (SJIA) patients and those of their parents based on their social media posts. METHODS: English language posts related to SJIA, Still's disease, or juvenile arthritis were collected and analyzed. RESULTS: In total, 71 posts created between 2009 and 2015 on 15 websites were identified in November 2015. Of the 32 unique authors, 17 were SJIA patients aged 13-20 years (40 posts), 7 were mothers of SJIA patients (12 posts), and 8 patients had unspecified forms of juvenile arthritis (19 posts). Many patients posted about similar diagnostic experiences marked by 5 phases: 1) early prediagnosis: pain and fatigue overlooked until crisis occurred, 2) first misdiagnosis: doctors talked about "growing pains" and psychosocial problems ("fake pains" to avoid school), 3) second misdiagnosis: severity acknowledged, but diagnosed as leukemia or another cancer, 4) tests: tests leading to diagnosis and treatment conducted, and 5) cognitive identity: patient accepted the diagnosis and its implications. Many adolescent patients, looking back at disease onset in their childhood, described themselves as a "sleeping child" rather than the typical active child. Several patients tried to hide their illness from friends, but expressed concerns openly online. Many patients described SJIA as a powerful external enemy, using terms like "bulldozer," "dragon," and "monster." Many posts from patients and their mothers used superhero language/imagery to help "fight" SJIA. Some patients also posted about the risk of death. CONCLUSION: Although most adolescent SJIA patients openly posted about the difficulties of their disease online, they made efforts to hide their disease in the real world. They frequently used superhero words and images in describing their fight for better health. Physicians can use these insights when counseling SJIA patients to provide a narrative that meshes with the patients' worldview and perhaps to improve physician-patient communication to increase treatment adherence.

The burden of systemic juvenile idiopathic arthritis for patients and caregivers: an international survey and retrospective chart review.

OBJECTIVES: To investigate the burden of systemic juvenile idiopathic arthritis (SJIA) on health-related quality of life (HRQOL) and resource use of patients and caregivers (families) on biologic therapy. METHODS: This international study assessed SJIA burden in patients on biologics, using a caregiver questionnaire and retrospective chart review. Validated measures included: Child Health Questionnaire Parent-Form 50 (CHQ-PF50), 36-Item Short-Form Health Survey (SF-36v2) and Work Productivity and Activity Impairment questionnaire: Specific Health Problem (WPAI:SHP). Caregivers completed function, treatment satisfaction and resource utilisation questions. RESULTS: Sixty-one biologic treated patients participated (12 anakinra, 25 canakinumab, 24 tocilizumab). Mean age at diagnosis and survey completion was 6.4 and 11.3 years, respectively. Mean (±SD: standard deviation) CHQ-PF50 physical (PhS) and psychosocial (PsS) summary scores were significantly lower in SJIA patients than a normative population (PhS: 40.0±18.2 vs. 53.0±8.8; PsS: 46.6±11.3 vs. 51.2±9.1) as was caregivers' mean SF-36v2 mental component score (MCS; 46.2±10.7 vs. 50.0±10). Assistive devices were required by 54%; 20% required home/car alterations. According to caregivers, biologic treatment completely improved SJIA symptoms in 48% on canakinumab or tocilizumab and 32% on anakinra. Over 2 months, patients missed 2.9 school days due to SJIA (10% yearly loss). Caregivers lost 25 work days annually and 27.5 days of productivity (WPAI-SHP: mean absenteeism 10%; presenteeism 11%). Yearly SJIA travel/treatment costs averaged $1,130. CONCLUSIONS: SJIA patients on biologic therapy experience HRQOL impairment, caregivers' mental well-being suffers and productivity losses and expenses are incurred. Therapeutic interventions that reduce the burden of SJIA are required.

International Retrospective Chart Review of Treatment Patterns in Severe Familial Mediterranean Fever, Tumor Necrosis Factor Receptor-Associated Periodic Syndrome, and Mevalonate Kinase Deficiency/Hyperimmunoglobulinemia D Syndrome.

OBJECTIVE: Periodic fever syndrome (PFS) conditions are characterized by recurrent attacks of fever and localized inflammation. This study examined the diagnostic pathway and treatments at tertiary centers for familial Mediterranean fever (FMF), tumor necrosis factor receptor-associated periodic syndrome (TRAPS), and mevalonate kinase deficiency (MKD)/hyperimmunoglobulinemia D syndrome (HIDS). METHODS: PFS specialists at medical centers in the US, the European Union, and the eastern Mediterranean participated in a retrospective chart review, providing de-identified data in an electronic case report form. Patients were treated between 2008 and 2012, with at least 1 year of followup; all had clinical and/or genetically proven disease and were on/eligible for biologic treatment. RESULTS: A total of 134 patients were analyzed: FMF (n = 49), TRAPS (n = 47), and MKD/HIDS (n = 38). Fever was commonly reported as severe across all indications. Other frequently reported severe symptoms were serositis for FMF patients and elevated acute-phase reactants and gastrointestinal upset for TRAPS and MKD/HIDS. A long delay from disease onset to diagnosis was seen within TRAPS and MKD/HIDS (5.8 and 7.1 years, respectively) compared to a 1.8-year delay in FMF patients. An equal proportion of TRAPS patients first received anti-interleukin-1 (anti-IL-1) and anti-tumor necrosis factor (anti-TNF) biologic agents, whereas IL-1 blockade was the main choice for FMF patients resistant to colchicine and MKD/HIDS patients. For TRAPS patients, treatment with anakinra versus anti-TNF treatments as first biologic agent resulted in significantly higher clinical and biochemical responses (P = 0.03 and P < 0.01, respectively). No significant differences in responses were observed between biologic agents among other cohorts. CONCLUSION: Referral patterns and diagnostic delays highlight the need for greater awareness and improved diagnostics for PFS. This real-world treatment assessment supports the need for further refinement of treatment practices.

Managing the child with severe primary insulin-like growth factor-1 deficiency (IGFD): IGFD diagnosis and management.

Growth failure associated with severe primary insulin-like growth factor 1 (IGF-1) deficiency (SPIGFD), a condition defined as basal IGF-1 standard deviation score (SDS) less than or equal to -3 and height SDS less than or equal to -3 in a child with normal or elevated levels of growth hormone, can be successfully treated with the recombinant human IGF-1 mecasermin. In this review, we describe the most safe and effective way to use mecasermin in the treatment of patients with SPIGFD, including how to initiate dosing, key side effects, and how to monitor treatment. Finally, mention of how to reinitiate therapy is made, given the recent drug shortage with mecasermin.

Patient perspectives on the impact of acromegaly: results from individual and group interviews.

PURPOSE: Acromegaly is a chronic condition resulting from a growth hormone-secreting pituitary tumor that can substantially impact patients' physical and emotional well-being. We sought to understand the impact of acromegaly on disease-related concerns and treatment choices from the patient perspective. The path to diagnosis, current disease management, interactions with the treating health care providers (HCPs), and support networks were also assessed. METHODS: Acromegaly patients were recruited primarily from a patient support group (Acromegaly Community). In Phase I, ten patients participated over the course of 5 days in a moderated online discussion board and they answered questions about their disease. In Phase II, a separate nine-patient cohort participated in face-to-face interviews conducted during an acromegaly patient conference. Data were summarized qualitatively by grouping similar answers and quotations. RESULTS: Nineteen acromegaly patients were recruited across the two cohorts, and both groups shared similar concerns. They demonstrated a notable interest in understanding their disease and its treatment. Patients were focused on the impact of the disease on their life, and they expressed a desire to get beyond reminders of their disease. The patients described long journeys to a correct diagnosis and relief at having a name for their condition. Many shared a sense of shock at needing pituitary surgery and felt unsatisfied by the treatment decision process, motivating them to discuss it with other patients. Patients not connected to a patient support group reported feeling helpless and lonely. Most patients shared a desire to improve their general knowledge about acromegaly to spare others their protracted diagnostic period. Patients also reported hesitancy in asking questions or sharing details about the disease's impact on their lives with their HCPs. CONCLUSION: Acromegaly can be a life-changing diagnosis with profound, ongoing effects on patients' lives. Patients struggle with many issues they fail to openly share with their HCPs, but may discuss these issues more easily with other acromegaly patients. Better collaboration between patients and care providers could lead to increased patient satisfaction.

Lanreotide extended-release aqueous-gel formulation, injected by patient, partner or healthcare provider in patients with acromegaly in the United States: 1-year data from the SODA registry.

Lanreotide depot (LD; commercial name Somatuline(®) Depot) is an injectable, extended-release formulation of the synthetic somatostatin analog (SSA) lanreotide. In recent clinical trials, LD was found to be suitable for self or partner administration, avoiding the need to travel to a medical facility. The Somatuline(®) Depot for Acromegaly (SODA) study is an ongoing, multicenter, observational study in the US investigating the efficacy, safety, convenience and symptom relief provided by LD in patients with acromegaly. Sub-analyses explore outcomes according to who administered the injection: patient, partner, healthcare provider (HCP) or a combination. Data reported here reflect one year of patient experience. Patients are eligible for inclusion if they have a diagnosis of acromegaly, are treated with LD and can give signed informed consent. Baseline data include patient demographics, previous acromegaly treatment and investigations, GH and IGF-I levels, LD dose and dose adjustment frequency. Symptom frequency, injection pain and treatment convenience are assessed using patient-reported questionnaires. As of 18 April 2012, 166 patients had enrolled in SODA. Most (72 %) achieved normal IGF-I levels after 12 months of LD treatment. Disease control was similar in self or partner injectors and in patients who received injections from their HCP, although self or partner injecting was deemed more convenient. LD was well-tolerated irrespective of who performed the injection. Self injection led to more injection-site reactions, but this did not increase the rate of treatment interruption. Acromegaly symptoms remained stable. Biochemical, safety and convenience data support the clinical validity of injecting LD at home.

Serum adalimumab concentration and clinical remission in patients with Crohn's disease.

BACKGROUND: Drug concentration monitoring may be useful to guide therapeutic adjustments for anti-tumor necrosis factor agents in Crohn's disease. The relationship between serum adalimumab concentrations and clinical outcomes was assessed using data from CLinical Assessment of Adalimumab Safety and Efficacy Studied as Induction Therapy in Crohn's Disease (CLASSIC) I/II. METHODS: Serum adalimumab concentrations at week 4 of CLASSIC I and weeks 4, 24, and 56 of CLASSIC II were compared by clinical remission status (yes/no). Logistic regression and Classification and Regression Tree analyses explored factors associated with remission at weeks 4, 24, and 56. Threshold analyses and receiver operating characteristic curves evaluated the relationship between serum concentrations and clinical remission/response. RESULTS: Serum adalimumab concentrations for 275 patients were available. Median adalimumab concentrations were significantly higher in patients who achieved clinical remission than those who did not at week 4 of CLASSIC I (8.10 versus 5.05 µg/mL, P < 0.05). At all time points, adalimumab concentrations demonstrated considerable variability and overlap between patients with and without remission. With Classification and Regression Tree analyses, baseline Crohn's Disease Activity Index, baseline C-reactive protein, and adalimumab concentrations were associated with early remission at week 4 of CLASSIC I and week 4 of CLASSIC II, but not at weeks 24 and 56. Receiver operating characteristic curves demonstrated low utility of cutoff thresholds to discriminate by clinical response/remission status. CONCLUSIONS: A positive association between serum adalimumab concentration and remission was identified at several time points. A threshold concentration reliably associated with remission was not identified. Further prospective evaluations are needed before recommendations for adalimumab concentration monitoring can be made.

Patient perspectives on the impact of Crohn's disease: results from group interviews.

AIM: To understand the impact of Crohn's disease (CD) on various aspects of daily life from the perspective of patients living with CD. Awareness of the disease and biologic therapies, patient satisfaction and adherence, and physician (provider) relationships were also assessed. BACKGROUND: CD is a chronic, inflammatory, autoimmune disorder of the gastrointestinal tract that substantially impacts patients' physical and emotional well-being. For patients eligible for biologic therapy, anti-tumor necrosis factor agents represent an important addition to the available therapies for CD. METHODS: The study sample included biologic-naïve and biologic-experienced patients who had self-reported moderate to severe CD, were under the care of a specialist, and agreed to film a video diary and participate in a focus group. Data from the videos and group interviews were collected from May to June of 2009 and summarized qualitatively by grouping similar answers and quotations. RESULTS: Of the 44 participants who submitted video diaries, 23 were biologic-experienced and 21 were biologic-naïve. Participants stated that CD caused fear and embarrassment, that they were reluctant to share the full impact of CD with family and providers, and that they relied on their provider for treatment decisions. Many participants accepted a new state of normalcy if their current medication helped their most bothersome symptoms without providing sustained remission. Participants receiving biologic therapy generally were more informed, more satisfied, and more likely to adhere to treatment regimens. CONCLUSION: Participants' responses suggest a need for more patient education and more collaborative relationships between patients and providers (physicians) regarding treatment decisions.

Adalimumab induces and maintains mucosal healing in patients with Crohn's disease: data from the EXTEND trial.

BACKGROUND & AIMS: We investigated the efficacy of adalimumab for inducing and maintaining mucosal healing in patients with Crohn's disease (CD). METHODS: A randomized, double-blind, placebo-controlled trial (extend the safety and efficacy of adalimumab through endoscopic healing [EXTEND]) evaluated adalimumab for induction and maintenance of mucosal healing in 135 adults with moderate to severe ileocolonic CD. The baseline degree of mucosal ulceration was documented by ileocolonoscopy. All patients received induction therapy (subcutaneous adalimumab 160/80 mg at weeks 0/2). At week 4, patients were randomly assigned to groups given 40 mg adalimumab or placebo every other week through week 52. Open-label adalimumab was given to patients with flares or no response, starting at week 8. Mucosal healing was reassessed by ileocolonoscopy at weeks 12 and 52. RESULTS: Twenty-seven percent of patients receiving adalimumab had mucosal healing at week 12 (the primary end point) versus 13% given placebo (P = .056). At week 52, rates of mucosal healing were 24% and 0, respectively (P < .001). Remission rates, based on the Crohn's Disease Endoscopic Index of Severity, were 52% for adalimumab and 28% for placebo at week 12 (P = .006) and 28% and 3%, respectively, at week 52 (P < .001). Rates of clinical remission based on the Crohn's Disease Activity Index were greater among patients given continuous adalimumab therapy versus placebo at weeks 12 (47% vs 28%; P = .021) and 52 (33% vs 9%; P = .001). Five serious (1 during induction and 4 during open-label therapy) and 3 opportunistic infections (1 in each group during double-blind therapy and 1 during open-label therapy) were reported (n = 135). CONCLUSIONS: Following induction therapy with adalimumab, patients with moderately to severely active CD who continue to receive adalimumab are more likely to achieve mucosal healing than those given placebo.

Adalimumab for the induction and maintenance of clinical remission in Japanese patients with Crohn's disease.

BACKGROUND AND AIMS: Adalimumab has been shown to be efficacious and well-tolerated in Western patients with Crohn's disease. These 2 randomized, double-blind clinical trials evaluated adalimumab efficacy and safety in Japanese patients with moderate to severe Crohn's disease. METHODS: 90 patients enrolled in the induction trial and were randomized to receive adalimumab 160/80 mg, adalimumab 80/40 mg or placebo at Weeks 0/2. At Week 4, patients who achieved a decrease in CDAI ≥ 70 points versus Baseline entered the maintenance trial and were randomized to adalimumab 40 mg every other week or placebo for 52 weeks. All other patients received 4 more weeks of blinded adalimumab before entering the open-label portion of the maintenance trial. At/after Week 4 of the maintenance trial, blinded patients who flared/failed to respond entered the open-label portion. Open-label maintenance patients received adalimumab 40 mg every other week with the option of 80 mg every other week for flare/non-response. RESULTS: Clinical remission rates at Week 4 in the induction trial were 33.3%, 17.6% and 13.0% in the adalimumab 160/80 mg, adalimumab 80/40 mg and placebo groups, respectively. Maintenance remission rates were 38.1% for adalimumab and 9.1% for placebo at Week 52. Anti-TNF naïve patients achieved greater efficacy than anti-TNF exposed patients. Patients randomized to adalimumab achieved greater quality of life improvement versus placebo. There were no clinically relevant differences in safety between adalimumab and placebo. CONCLUSIONS: Adalimumab is effective and well-tolerated for inducing and maintaining clinical remission in Japanese patients with moderate to severe Crohn's disease.

Comparison of two adalimumab treatment schedule strategies for moderate-to-severe Crohn's disease: results from the CHARM trial.

OBJECTIVES: To compare outcomes of induction dosing followed by continuous adalimumab treatment with those of induction dosing with reinitiation of adalimumab (in the event of clinical deterioration) for patients with moderate-to-severe Crohn's disease (CD) who participated in the Crohn's Trial of the Fully Human Antibody Adalimumab for Remission Maintenance (CHARM). METHODS: In the CHARM trial, all patients received open-label induction therapy with adalimumab 80 mg and 40 mg at weeks 0 and 2, respectively. In total, 778 patients were randomized at week 4 to one of three groups: (1) placebo after initial induction doses (followed by reinitiation of adalimumab therapy); (2) continuous maintenance treatment with adalimumab 40 mg every other week (e.o.w.); and (3) continuous maintenance treatment with adalimumab 40 mg every week. At/after week 12, patients receiving placebo with flare or non-response could reinitiate open-label adalimumab 40 mg e.o.w., and patients receiving continuous blinded adalimumab therapy could switch to open-label 40 mg e.o.w. Patients in all groups could switch to weekly therapy with continued flare/non-response. In the previously published primary analysis, results for only those patients who had responded at week 4 (decrease in Crohn's Disease Activity Index (CDAI) of > or = 70 points, referred to as "randomized responders") and remained on blinded therapy were analyzed. In this analysis, data from all randomized patients were analyzed based on original randomized treatment using an intention-to-treat analysis, regardless of whether they subsequently switched to open-label therapy. Disease activity, clinical remission, number of flares, Inflammatory Bowel Disease Questionnaire (IBDQ) score, number of CD-related surgeries, and hospitalization incidence were compared between the continuous and induction only/reinitiation adalimumab groups. RESULTS: Results for all outcome measures were superior for both continuous groups compared with the induction only/reinitiation group. On the basis of median CDAI and IBDQ results, patients in both continuous treatment groups achieved statistically significantly greater improvements vs. the induction only/reinitiation group (P < 0.05). At week 56, a significantly greater percentage of patients who had received continuous adalimumab (51% for e.o.w. and 49% for weekly) were in clinical remission vs. the induction only/reinitiation group (38%, P < 0.05). Continuous adalimumab therapy was also associated with fewer flares and fewer CD-related surgeries (P < 0.05). Patients in both continuous adalimumab groups had significantly lower risks of CD-related and all-cause hospitalizations than did patients in the induction only/reinitiation group (P < 0.05). CONCLUSIONS: For patients with active CD, continuous treatment with adalimumab was more effective than a strategy of induction dosing followed by reinitiation of adalimumab with clinical deterioration for maintenance of clinical remission, improved quality-of life outcomes, reduced flares, and a decrease in number of surgeries and risk of hospitalization.

Effects of adalimumab therapy on incidence of hospitalization and surgery in Crohn's disease: results from the CHARM study.

BACKGROUND & AIMS: We determined the effects of adalimumab maintenance treatment on the risks of hospitalization and surgery in Crohn's disease (CD). METHODS: A total of 778 patients with CD were randomized to placebo, adalimumab 40 mg every other week or adalimumab 40 mg weekly, all after an 80-mg/40-mg adalimumab induction regimen. All-cause and CD-related hospitalizations and major CD-related surgeries were compared between the placebo and adalimumab groups (every other week, weekly, and both combined) using Kaplan-Meier analysis and Cox proportional hazard models. RESULTS: Both 3- and 12-month hospitalization risks were significantly lower for patients who received adalimumab. Hazard ratios for all-cause hospitalization were 0.45, 0.36, and 0.40 for the adalimumab every other week, weekly, and combined groups, respectively (all P < .01 vs placebo). Hazard ratios for CD-related hospitalization were 0.50, 0.34, and 0.42, respectively (all P < .05). Cox model estimates demonstrated adalimumab every other week and weekly maintenance therapies were associated with 52% and 60% relative reductions in 12-month, all-cause hospitalization risk, and 48% and 64% reductions in 12-month risk of CD-related hospitalization. The combined adalimumab group was associated with 56% reductions in both all-cause and CD-related hospitalization risks. Fewer CD-related surgeries occurred in the adalimumab every other week, weekly, and combined groups compared with placebo (0.4, 0.8, and 0.6 vs 3.8 per 100 patients; all P < .05). CONCLUSIONS: Patients with moderate-to-severe CD treated with adalimumab had lower 1-year risks of hospitalization and surgery than placebo patients.