Comparative efficacy and safety of biologic therapies for moderate-to-severe Crohn's disease: a systematic review and network meta-analysis.

BACKGROUND: Data are needed to inform the positioning of biologic therapy in the treatment of moderate-to-severe Crohn's disease, both first line and after previous biologic exposure. We aimed to assess the comparative efficacy and safety of biologics in patients with Crohn's disease. METHODS: We did a systematic review and network meta-analysis of phase 2 and phase 3 randomised controlled trials done in adults (≥18 years) with moderate-to-severe Crohn's disease (Crohn's Disease Activity Index [CDAI] 220-450) treated with tumour necrosis factor (TNF) antagonists, anti-integrin, anti-interleukin (IL)-12 and IL-23p40, or anti-IL23p19 agents, either alone or in combination with immunosuppressants, as their first-line biologic or after previous biologic exposure, compared with placebo or an active comparator. The minimum duration of therapy was 14 days for trials reporting induction of remission in active disease and 22 weeks in trials reporting maintenance of remission. We searched Medline, EMBASE, the Cochrane CENTRAL Register of Controlled Trials, conference proceedings, trial registries, and unpublished data from inception to June 3, 2021, without any language restrictions. Summary estimates of the primary and secondary outcomes were extracted from the published reports; individual patient-level data were not sought. The primary endpoint was induction of clinical remission in patients with active disease (CDAI <150) and maintenance of remission in patients with response to induction therapy, with data extracted from published reports. A network meta-analysis with multivariate consistency model random-effects meta-regression was done, with rankings based on surface under the cumulative ranking curve (SUCRA) values. FINDINGS: The search strategy yielded 18 382 citations, of which 31 trials were eligible for inclusion. On the basis of 15 randomised controlled trials including 2931 biologic-naive patients, infliximab monotherapy (odds ratio [OR] 4·53 [95% CI 1·49-13·79]), infliximab combined with azathioprine (7·49 [2·04-27·49]), adalimumab (3·01 [1·25-7·27]), and ustekinumab (2·63 [1·10-6·28]) were associated with significantly higher odds of inducing remission compared to certolizumab pegol (all moderate confidence); infliximab and azathioprine combination therapy was also associated with significantly higher odds of inducing remission than vedolizumab (3·76 [1·01-14·03]; low confidence). On the basis of ten randomised controlled trials including 2479 patients with previous biologic exposure, adalimumab after loss of response to infliximab (OR 2·82 [95% CI 1·20-6·62]; low confidence), and risankizumab (2·10 [1·12-3·92]; moderate confidence), were associated with higher odds of inducing remission than vedolizumab. No differences between active interventions were observed in maintenance trials. Most trials were at low or uncertain risk of bias. INTERPRETATION: Although biologic treatment choices in patients with moderate-to-severe Crohn's disease must be individualised for each patient, this analysis suggests that either infliximab with azathioprine or adalimumab might be preferred as a first-line therapy, and adalimumab (after infliximab loss of response) or risankizumab might be preferred as a second-line therapy, for induction of clinical remission. FUNDING: None.

Seven Weeks of High-Dose Vitamin D Treatment Reduces the Need for Infliximab Dose-Escalation and Decreases Inflammatory Markers in Crohn's Disease during One-Year Follow-Up.

BACKGROUND: Seven weeks of high-dose vitamin D treatment decreases intestinal IL17A and IFN-γ mRNA expression in active Crohn's disease (CD). In this follow-up study, we investigated whether seven-week vitamin D treatment affected the infliximab response in the following 45 weeks compared to placebo. METHODS: CD patients (n = 40) were initially randomised into four groups: infliximab + vitamin-D; infliximab + placebo-vitamin-D; placebo-infliximab + vitamin-D; and placebo-infliximab + placebo-vitamin-D. Infliximab (5 mg/kg) or placebo-infliximab was administered at weeks 0, 2 and 6. Vitamin D (5 mg bolus followed by 0.5 mg/day for 7 weeks) or placebo-vitamin D was handed out. After the 7-week vitamin D period, all patients received infliximab during follow-up. Results are reported for Group D+ (infliximab + vitamin-D and placebo-infliximab + vitamin-D) and Group D- (infliximab + placebo-vitamin-D and placebo-infliximab + placebo-vitamin-D). RESULTS: Group D- patients had greater needs for infliximab dose escalation during follow-up compared to group D+ (p = 0.05). Group D+ had lower median calprotectin levels week 15 (p = 0.02) and week 23 (p = 0.04) compared to group D-. Throughout follow-up, group D+ had 2.2 times (95% CI: 1.1-4.3) (p = 0.02) lower median CRP levels compared with group D-. CONCLUSIONS: Seven weeks high-dose vitamin D treatment reduces the need for later infliximab dose-escalation and reduces inflammatory markers. EudraCT no. 2013-000971-34.

Adherence to intravenous biological treatment in inflammatory bowel disease patients during the COVID-19 pandemic.

The objective of this study was to determine the adherence to biological treatment in inflammatory bowel disease (IBD) patients during the COVID-19 pandemic at Hospital Universitario La Paz, in Madrid. All patients from our IBD Unit were informed via e-mail, social networks and websites about the convenience of continuing with treatment. In addition, patients were contacted by telephone a few days before to remind them of their appointment and the importance of adherence.

Tumor Necrosis Factor Inhibitor-Induced Psoriasis in a Pediatric Crohn's Disease Patient Successfully Treated with Ustekinumab.

BACKGROUND: Tumor necrosis factor (TNF) inhibitors are widely used in pediatric patients with inflammatory bowel disease, as well as psoriasis. However, there is growing evidence that these medications can also paradoxically induce a psoriasiform skin reaction in a subset of patients. GOALS: We seek to share our experience in treating severe TNF inhibitor-induced psoriasis in a pediatric patient with Crohn’s disease. STUDY: We report a case of a 10-year-old female with Crohn’s disease, who developed psoriasis after twelve months of infliximab therapy. Her skin disease was recalcitrant to topical therapies, methotrexate, and phototherapy. RESULTS: The patient was transitioned to ustekinumab with significant improvement in her symptoms and maintenance of remission of her bowel disease. CONCLUSION: This is the first reported case of a school-age pediatric patient with TNF inhibitor-induced psoriasis treated with ustekinumab. Controlled trials are warranted to fully assess the safety and efficacy of ustekinumab for treating TNF inhibitor-induced psoriasis in the pediatric population.J Drugs Dermatol. 2020;19(3): doi:10.36849/JDD.2020.2106.

A 55-Year-Old Man With Cough and Hematochezia.

CASE PRESENTATION: A 55-year-old man presented to the ED with a 3-week history of worsening cough and shortness of breath. He had blood-tinged sputum, fever, night sweats, and a 2.7 kg weight loss within the same period. For the past few days, he had taken amoxicillin-clavulanate for presumed sinusitis. Despite this, his symptoms persisted, prompting him to seek further evaluation. His medical history was significant for ulcerative colitis and he had some bloody diarrhea for the past few weeks. Medications included aspirin, mesalamine, multivitamins, folic acid, and herbal supplements including gingko biloba, ginseng, and turmeric-ginger. He never smoked and drank alcohol occasionally. Family history was notable for stroke and myocardial infarction.

Total remission of Tolosa-Hunt Syndrome with single-dose of infliximab / Remissão total da Síndrome de Tolosa-Hunt com dose única de infliximabe

Abstract Tolosa-Hunt syndrome is a painful ophthalmoplegia caused by non-specific granulomatous inflammation, corticoid-sensitive, of the cavernous sinus. The etiology is unknown. Recurrences are common. The diagnosis is made by exclusion, and a variety of other diseases involving the orbital apex, superior orbital fissure and cavernous sinus should be ruled out. This study reports a case of a 29-year-old woman, diagnosed with Tolosa-Hunt Syndrome, who presented ophthalmoparesis and orbital pain. She had poor response to corticotherapy and developed colateral effects, so she was treated with single infliximab dose immunosuppression, evolving total remission of the disease.

Resumo A Síndrome de Tolosa-Hunt é uma oftalmoplegia dolorosa causada por uma inflamação granulomatosa não específica, sensível a corticoides, do seio cavernoso. A etiologia é desconhecida. Recorrências são comuns. O diagnóstico é feito por exclusão, devendo ser descartada uma variedade de outras doenças que envolvem o ápice orbitário, fissura orbitária superior e seio cavernoso. O presente estudo trata-se de um relato de caso de uma paciente de 29 anos, diagnosticada com Síndrome de Tolosa-Hunt, que apresentou paresia e dor em região orbital. Obteve resposta pouco efetiva a corticoterapia e desenvolveu efeitos colaterais, por isso foi tratada com dose única de infliximabe, evoluindo com remissão total da doença.

Longitudinal Trajectory of Fatigue With Initiation of Biologic Therapy in Inflammatory Bowel Diseases: A Prospective Cohort Study.

BACKGROUNDS AND AIMS: Fatigue is prevalent in patients with inflammatory bowel diseases [IBD]. Biologic therapy is effective in achieving symptomatic and endoscopic remission, but its impact on fatigue is less well established. Our aim is to define the longitudinal trajectory of fatigue over 1 year in patients initiating biologic therapy. METHODS: This prospective cohort enrolled patients diagnosed with Crohn's disease [CD] or ulcerative colitis [UC] initiating biologic therapy with infliximab, adalimumab, ustekinumab, or vedolizumab. Fatigue was quantified using the seven-point fatigue question in the Short Inflammatory Bowel Disease Questionnaire [SIBDQ]. A score of ≤4 for this question was used to define fatigue. Multivariable regression models adjusting for relevant confounders examined the independent association between attaining clinical remission and resolution of fatigue. RESULTS: Our study included 326 patients [206 CD, 120 UC] initiating biologic therapy [144 anti-tumour necrosis factor, 129 vedolizumab, 63 ustekinumab]. A total of 61% of the included patients reported significant fatigue at baseline. This was associated with female gender, depressive symptoms, active disease, and disturbed sleep [p < 0.001]. Among the 198 patients who were fatigued at therapy initiation, 86 [70%], 55 [63%], and 44 [61%] remained fatigued at Week 14, 30, and 54, respectively. At each of these time points, achieving clinical remission was associated with lower likelihood of persistent fatigue. However, despite achieving remission, 35%, 30%, and 28% of patients experienced persistent fatigue at Week 14, 30, and 54, respectively. CONCLUSIONS: Fatigue is common in IBD. Though biologic therapy improves fatigue parallel symptomatic improvement, a significant proportion continue to experience persistent fatigue up to 1 year.

The Cost-effectiveness of Biological Therapy Cycles in the Management of Crohn's Disease.

OBJECTIVES: To examine the cost-effectiveness of continued treatment for patients with moderate-severe Crohn's disease in clinical remission, with a combination of anti-tumour necrosis factor alpha [anti-TNFα] [infliximab] and immunomodulator therapy compared with two different withdrawal strategies: [1] withdrawal of the anti-TNFα therapy; and [2] withdrawal of the immunomodulator therapy, respectively. METHODS: A decision-tree model was constructed mimicking three treatment arms: [1] continued combination therapy with infliximab and immunomodulator; [2] withdrawal of infliximab; or [3] withdrawal of the immunomodulator. Relapses in each arm are managed with treatment intensification and re-institution of the de-escalated drug according to a prespecified algorithm. State-dependent relapse risks, remission probabilities, and quality of life weights were collected from previous published studies. RESULTS: Combination therapy was less costly and more efficient than the withdrawal of the immunomodulator, and more costly and more efficient than withdrawal of infliximab. Whether or not combination therapy is cost-effective, compared with the alternatives, depends primarily on current pharmaceutical prices and the willingness-to-pay per additional quality-adjusted life-year [QALY]. CONCLUSIONS: Combination therapy using a combination of anti-TNFα [infliximab] and an immunomodulator is cost-effective in the treatment of Crohn's disease compared with treatment cycles in which the immunomodulator is withdrawn. Combination treatment is cost-effective compared with treatment cycles in which infliximab is withdrawn, at prices of infliximab below€192/100 mg, given a willingness-to-pay threshold at€49 020 [Sweden] per additional QALY.

Infliximab as an alternative therapy for refractory adult onset Kawasaki disease: A case report.

RATIONALE: Kawasaki disease (KD) is an acute febrile illness predominantly affecting children less than 5 years of age and characterized by systemic inflammation in all medium-sized arteries. Adult-onset KD (AKD) is rare with only 105 case reports published. Recently, the efficacy of infliximab (IFX) for patients with refractory KD has been demonstrated. PATIENT CONCERNS: A previously healthy 24-year-old man was admitted because of a persistent fever, and elevated serum level of AST, ALT, LDH, and CRP. DIAGNOSIS: The patients met the diagnostic criteria for KD based on the findings of persistent fever, polymorphous exanthema, unilateral cervical lymphadenopathy, non-purulent palpebral conjunctivitis and membranous desquamation. Echocardiogram revealed the dilatation at the proximal sites of the right coronary artery (7.9 mm) and left anterior descending artery (5 mm). The patient was treated with high-dose intravenous immunoglobulin (1 g/kg/day for 2 days) and ASA (100 mg daily). However, his fever and arthralgia persisted. INTERVENTIONS: He was administered single 5 mg/kg doses of IFX. OUTCOMES: He became afebrile the next day and his arthralgia improved. LESSONS: We report the first case of administration of IFX in a patient with AKD refractory to intravenous immunoglobulin (IVIG), and successful reduction of systemic inflammation. However, the effectiveness of IFX in the regression of coronary artery aneurysm remains to be determined.

No Benefit of Concomitant 5-Aminosalicylates in Patients With Ulcerative Colitis Escalated to Biologic Therapy: Pooled Analysis of Individual Participant Data From Clinical Trials.

OBJECTIVES: 5-aminosalicylates (5-ASA) are frequently continued in patients with moderate-severe ulcerative colitis (UC), even after escalation to biologic agents, without evaluation of the benefit of this approach. We conducted an individual participant data (IPD) pooled analysis of trials of infliximab and golimumab in UC, to evaluate whether concomitant use of 5-ASA modifies clinical outcomes among anti-tumor necrosis factor (TNF)-α-treated patients. METHODS: We included IPD from five trials of infliximab and golimumab in patients with moderate-severe UC (ACT-1 and -2, PURSUIT-SC, PURSUIT-M, NCT00336492). Patients treated with infliximab or golimumab were categorized as receiving concomitant 5-ASA or not at time of trial entry. Primary outcome was clinical remission (Mayo Clinic Score < 3) at last follow-up for each trial; secondary outcomes were clinical response and mucosal healing. Using multivariable logistic regression analysis, we evaluated association between concomitant 5-ASA and clinical remission, after adjusting for sex, smoking, baseline disease activity, disease extent, biochemical variables (C-reactive protein, albumin, hemoglobin), and concomitant prednisone and immunomodulators. RESULTS: We included 2183 infliximab-treated or golimumab-treated patients (1715 [78.6%] on 5-ASA). Concomitant use of 5-ASA was not associated with odds of achieving clinical remission (adjusted OR, 0.67 [95% CI, 0.45-1.01], p = 0.06), clinical response (aOR, 0.89 [0.60-1.33], p = 0.58) or mucosal healing (aOR, 1.12 [0.82-1.51], p = 0.48). These results were consistent in trials of induction and maintenance therapy, and in trials of infliximab and golimumab. CONCLUSIONS: Based on IPD pooled analysis, in patients with moderate-severe UC who are escalated to anti-TNF therapy, continuing 5-ASA does not improve clinical outcomes.

Monoterapia con fármacos biológicos en la artritis reumatoide: efecto del bloqueo de la IL-6 / Monotherapy with biological agents in rheumatoid arthritis: effect of interleukin-6 blockade

Actualmente, las diferentes guías de tratamiento de la artritis reumatoide recomiendan el uso de los fármacos biológicos en combinación con metotrexato (u otros fármacos antirreumáticos modificadores de la enfermedad de naturaleza sintética) siempre que sea posible. Pero la realidad de prescripción, según diferentes registros, muestra que los tratamientos biológicos se utilizan en muchas ocasiones en monoterapia. En la actualidad existen 2 fármacos biológicos inhibidores del receptor de la IL-6 aprobados por la European Medicines Agency para el tratamiento de la artritis reumatoide, uno con amplia experiencia clínica, tocilizumab, y otro a punto de su comercialización en nuestro país, sarilumab. Estos fármacos biológicos inhibidores de la IL-6 en monoterapia serían más efectivos que otros biológicos en monoterapia en el tratamiento de la artritis reumatoide, según demuestran diversos estudios. El objetivo de esta revisión es proporcionar los datos disponibles sobre el uso de los distintos fármacos biológicos inhibidores de IL-6 en monoterapia en la artritis reumatoide, y analizar de forma comparativa el papel de los otros agentes biológicos en monoterapia en esta enfermedad

The current recommendations and guidelines for the treatment of RA include the use of biological DMARDs (bDMARDs) in combination with methotrexate or other conventional synthetic DMARDs whenever possible. However, bDMARDS are frequently used in monotherapy according to data from several registries. Nowadays, two bDMARDS aimed at the IL-6 receptor have been approved by the European Medicines Agency (EMA) for treating RA: tocilizumab, with extensive clinical experience, and sarilumab, which will soon be commercialised in Spain. Several studies have confirmed that both IL-6 inhibitors are more effective than other bDMARDs when used in monotherapy. The aim of this review is to update the available information on the use of IL-6 inhibitors in monotherapy and to analyse the comparative role of the remaining bDMARDS when used in monotherapy in RA

Twenty years of biological therapy in an patient with IBD.

This interesting case is the first to our knowledge to report outcomes of a patient with Crohn's disease (CD) treated with the biological drug, infliximab, for around 20 years. The case highlights the positive effect of long-term use of infliximab in achieving and maintaining remission in a patient with CD.In this case, loss of response to infliximab was not dependent on length of exposure to the drug. It also appeared that infliximab was still efficacious after drug holidays, which can be especially important around times of pregnancy. Of interest, 'loss of response' to infliximab occurred at one particular time point. The drug was then reintroduced at a later date, which gave the patient clinical benefit. This case suggests that in some situations infliximab can be reintroduced in patients with previous 'loss of response'.Importantly, in this case, Infliximab had no major adverse effects during the 20 years follow-up.

Biologic Therapies in Ulcerative Colitis: Primi Inter Pares?

BACKGROUND: In the last decade, the introduction of the first anti-tumor necrosis factor (TNF)-α agent infliximab has revolutionized the treatment of ulcerative colitis (UC). However, this drug is not a magic bullet since up to 50% of UC patients do not respond (primary failure) or lose response to infliximab (secondary failure). Hence the demand for novel drugs to fill the unmet medical need. OBJECTIVE: The aim of this review is to discuss the data from randomized controlled trials (RCTs) of available biological agents for the treatment of moderate-to-severe UC in adults, in order to support clinical decision making. RESULTS AND CONCLUSION: New biological agents are now available for the treatment of moderate-tosevere UC. Adalimumab and golimumab are anti-TNF-α monoclonal antibodies, as is infliximab, whereas vedolizumab blocks the integrin α4ß7/mucosal addressin cell adhesion molucule-1 (MAd- CAM). Additions to the therapeutic arsenal boost the chances of successful treatment of UC, but lead to difficulty choosing the most appropriate biological drug: which biologic to use first and when and how to switch. In the absence of head-to-head trials to answer these questions, a network metaanalysis of the available RCTs can provide estimates of relative efficacy between interventions. Other factors, including convenience and satisfaction for the patient, route of administration, the cost of treatment, and the safety and efficacy profile, should all be considered.

Examining maintenance care following infliximab salvage therapy for acute severe ulcerative colitis.

BACKGROUND AND AIM: Data supporting the optimal maintenance drug therapy and strategy to monitor ongoing response following successful infliximab (IFX) induction, for acute severe ulcerative colitis (ASUC), are limited. We aimed to evaluate maintenance and monitoring strategies employed in patients post-IFX induction therapy. METHODS: Patients in six Australian tertiary centers treated with IFX for steroid-refractory ASUC between April 2014 and May 2015 were identified via hospital IBD and pharmacy databases. Patients were followed up for 1 year with clinical data over 12 months recorded. Analysis was limited to patient outcomes beyond 3 months. RESULTS: Forty one patients were identified. Five of the 41 (12%) patients underwent colectomy within 3 months, and one patient was lost to follow-up. Six of 35 (17%) of the remaining patients progressed to colectomy by 12 months. Maintenance therapy: Patients maintained on thiopurine monotherapy (14/35) versus IFX/thiopurine therapy (15/35) were followed up. Two of 15 (13%) patients who received combination maintenance therapy underwent a colectomy at 12 months, compared with 1/14 (7%) patients receiving thiopurine monotherapy (P = 0.610). Monitoring during maintenance: Post-discharge, thiopurine metabolites were monitored in 15/27 (56%); fecal calprotectin in 11/32 (34%); and serum IFX levels in 4/20 (20%). Twenty of 32 (63%) patients had an endoscopic evaluation after IFX salvage with median time to first endoscopy of 109 days (interquartile range 113-230). CONCLUSION: Following IFX induction therapy for ASUC, the uptake of maintenance therapy in this cohort and strategies to monitor ongoing response were variable. These data suggest that the optimal maintenance and monitoring strategy post-IFX salvage therapy remains to be defined.

Persistency of Biologic Therapies for Plaque Psoriasis in 2 Large Community Practices.

BACKGROUND: Biologics have transformed the management of moderate to severe psoriasis. The persistency of biologics lacks real-world data. OBJECTIVES: To quantify drug survival of infliximab (IFX), adalimumab (ADA), etanercept (ETA), and ustekinumab (UST) and to identify potential factors affecting drug survival. METHODS: An observational, retrospective 2-centre study consisting of 906 patients from private practices in Ontario between July 2003 and June 13, 2016, was conducted, including patients with plaque psoriasis receiving commercial treatment with ADA, ETA, IFX, and UST. Paper and electronic records of each patient were reviewed. RESULTS: Median survival times for UST, IFX, ADA, and ETA were respectively, in months, 68, 23, 33, and 28. Female sex was determined to be a statistically significant positive predictor of drug survival. Our study was consistent with the literature in that UST had the highest survival rate compared to the other biologics, and the shape of our drug survival curve suggested that loss of drug efficacy is a stochastic occurrence. Compared to other studies, our data exhibited lower survival rates at various time points for all the biologics studied, and female sex did not predict drug survival in other studies. We also investigated potential reasons for differences in biologic survival times between different practices; the main differentiator was drug dosage, as higher dosages were associated with greater survival. CONCLUSION: UST has a higher drug survival rate than ADA, ETA, and IFX, as observed in other studies. When practice patterns are compared, dosage difference is the main factor that may cause differing survival rates.

Hemophagocytic Syndrome Complicated with Dermatomyositis Controlled Successfully with Infliximab and Conventional Therapies.

A 57-year-old woman was admitted to our hospital because of a high fever, anemia, and hyperferritinemia. Since a bone marrow examination revealed hemophagocytosis, she was diagnosed with hemophagocytic syndrome (HPS). During treatment of HPS, a heliotrope rash and Gottron's sign appeared with elevated levels of serum aldolase. She also developed heart failure. She was diagnosed with dermatomyositis (DM) and associated myocarditis. Although the administration of glucocorticoids, calcineurin inhibitors, intravenous immunoglobulins, and etoposide ameliorated the clinical findings of DM and cytopenia, the fever and hyperferritinemia remained. The addition of infliximab to glucocorticoids and tacrolimus improved the fever and hyperferritinemia and enabled a reduction in the dose of prednisolone without relapse of the diseases.

A Review of the Active Treatments for Toxic Epidermal Necrolysis.

Toxic epidermal necrolysis (TEN) is a severe adverse drug reaction associated with the separation of skin and mucous membranes at the dermal-epidermal junction. Although it is rare, many treatments have been trialed because of its high mortality rate. Active interventions performed to date include the use of systemic corticosteroids, intravenous immunoglobulins (IVIg), cyclosporine, plasmapheresis, anti-tumor necrosis factor drugs and N-acetylcysteine, but none has been established as the most effective therapy. IVIg and short-term high-dose corticosteroids were regarded as the most promising treatments for TEN in a comprehensive review of all reported TEN cases from 1975-2003. When used with an appropriate dose and timing, the beneficial effects of IVIg can be maximized. Although no randomized controlled trials have been conducted, cyclosporine and plasmapheresis are considered to be beneficial. As no gold standard for active intervention for TEN has been established, the choice of treatment relies partly on the available guidelines and the experience of the dermatologist. There is still much to be investigated regarding the pathogenesis of TEN, and new findings may contribute to the identification of an effective active intervention strategy.

Patterns of Care for Biologic-Dosing Outliers and Nonoutliers in Biologic-Naive Patients with Rheumatoid Arthritis.

BACKGROUND: Although most biologic medications for patients with rheumatoid arthritis (RA) have recommended fixed dosing, actual biologic dosing may vary among real-world patients, since some patients can receive higher (high-dose outliers) or lower (low-dose outliers) doses than what is recommended in medication package inserts. OBJECTIVE: To describe the patterns of care for biologic-dosing outliers and nonoutliers in biologic-naive patients with RA. METHODS: This was a retrospective, longitudinal cohort study of patients with RA who were not pregnant and were aged ≥ 18 and < 90 years from an integrated health care delivery system. Patients were newly initiated on adalimumab (ADA), etanercept (ETN), or infliximab (IFX) as index biologic therapy between July 1, 2006, and February 28, 2014. Outlier status was defined as a patient having received at least 1 dose < 90% or > 110% of the approved dose in the package insert at any time during the study period. Baseline patient profiles, treatment exposures, and outcomes were collected during the 180 days before and up to 2 years after biologic initiation and compared across index biologic outlier groups. Patients were followed for at least 1 year, with a subanalysis of those patients who remained as members for 2 years. RESULTS: This study included 434 RA patients with 1 year of follow-up and 372 RA patients with 2 years of follow-up. Overall, the vast majority of patients were female (≈75%) and had similar baseline characteristics. Approximately 10% of patients were outliers in both follow-up cohorts. ETN patients were least likely to become outliers, and ADA patients were most likely to become outliers. Of all outliers during the 1-year follow-up, patients were more likely to be a high-dose outlier (55%) than a low-dose outlier (45%). Median 1- and 2-year adjusted total biologic costs (based on wholesale acquisition costs) were higher for ADA and ETA nonoutliers than for IFX nonoutliers. Biologic persistence was highest for IFX patients. Charlson Comorbidity Index score, ETN and IFX index biologic, and treatment with a nonbiologic disease-modifying antirheumatic drug (DMARD) before biologic initiation were associated with becoming high- or low-dose outliers (c-statistic = 0.79). CONCLUSIONS: Approximately 1 in 10 study patients with RA was identified as a biologic-dosing outlier. Dosing outliers did not appear to have better clinical outcomes compared with nonoutliers. Before initiating outlier biologic dosing, health care providers may better serve their RA patients by prescribing alternate DMARD therapy. DISCLOSURES: This study was sponsored by Janssen Scientific Affairs. It is the policy of Janssen Scientific Affairs to publish all sponsored studies unless they are exploratory studies or are determined a priori for internal use only (e.g., to inform business decisions). Meyer is an employee of Janssen Scientific Affairs and a stockholder in Johnson and Johnson, its parent company. Delate and Jenkins have nothing to disclose. Study concept and design were contributed by Delate and Meyer. Delate took the lead in data collection, along with Jenkins. All authors participated in data analysis. The manuscript was written primarily by Delate, along with Meyers and Jenkins, and was revised by Meyer, along with Delate and Jenkins.

Biosimilars in inflammatory bowel disease: A review of post-marketing experience.

Biologic compounds are obtained from living organisms or cell cultures by means of biotechnology methods. A similar biologic drug, commonly called biosimilar, is a product copied by a native approved biologic drug whose license has expired. Biosimilar drugs usually are marketed at a lower price and provide important financial savings for public healthcare systems. Some differences between biosimilars and original biologic drugs might exist but they are acceptable if they fall within defined "boundaries of tolerance": differences in some features between the two molecules are considered important only if clinical relevant. Considering that the efficacy of the innovator biologic drug has already been established, the clinical studies required for approval of a biosimilar could be reduced compared with those required for the approval of the originator. In this review, real life data available in inflammatory bowel disease patients treated with biosimilars are reported, documenting in general satisfactory outcomes, sustained efficacy and no sign of increased immunogenicity, although, further controlled data are awaited.

Repeated intensified infliximab induction - results from an 11-year prospective study of ulcerative colitis using a novel treatment algorithm.

BACKGROUND: Anti-tumour necrosis factor (TNF) agents play a pivotal role in the treatment of moderate to severe ulcerative colitis (UC), and yet, no international consensus on when to discontinue therapy exists. OBJECTIVE: The aim of this study is to study the long-term performance of a treatment algorithm of repeated intensified induction therapy with infliximab (IFX) to remission, followed by discontinuation in patients with UC. PATIENTS AND METHODS: Patients with moderate to severe UC were enroled in an open prospective study design. The following algorithm was implemented: (a) intensified induction treatment to remission (Ulcerative Colitis Disease Activity Index score 0-2); (b) discontinuation of IFX; and (c) reinduction treatment if relapse. Mucosal gene expression for TNF was measured with qPCR. RESULTS: A total of 116 patients were included. The median observation time was 47 and 51 months in intention to treat and per protocol. Remission rates of the first three inductions were 95, 93 and 91% per protocol and 83, 56 and 59% by intention to treat. The median time in remission was 40 months per protocol and 34 months by intention to treat. Long-term remission without further anti-TNF treatment during the observation period was obtained for 41%, with a median observation time of 48 months (range: 18-129 months). The median time to relapse was 33 and 11 months with/without normalization of mucosal TNF, respectively. The 5-year success rate for maintaining the effect of IFX in the algorithm was 66%. CONCLUSION: The treatment algorithm is highly effective for achieving long-term clinical remission in UC. Normalization of mucosal TNF gene expression predicts long-term remission upon discontinuation of IFX.