Facial Hyperpigmentation: A Rare Side Effect of Adalimumab.

This report describes a case of facial hyperpigmentation in a patient with Crohn's disease receiving adalimumab, a tumor necrosis factor (TNF)-alpha inhibitor. The onset of hyperpigmentation coincided with adalimumab administration, and its discontinuation resulted in significant improvement. Histopathological findings suggest a postinflammatory process at the dermo-epidermal junction. However, the precise mechanism remains unclear.

Predictors of Therapy Success in Weekly Adalimumab for Refractory Uveitis: A Retrospective Cohort Study.

PURPOSE: To determine predictors of treatment success after dose escalation of adalimumab, including measurement of anti-adalimumab antibodies as a predictor of success DESIGN: Retrospective clinical cohort study SETTING: Single-center academic institution STUDY POPULATION: Patients with noninfectious uveitis who were inadequately controlled or developed recurrent disease on biweekly adalimumab and required dose escalation or therapy modification OBSERVATION PROCEDURES: Patients who had anti-adalimumab antibodies checked with resultant low to intermediate levels were compared to patients who had no testing performed prior to adalimumab dose escalation. Of note, patients with testing and resultant high levels of anti-adalimumab antibodies were not escalated. Predictors of escalation success and utility of antibody testing prior to escalation were analyzed using Kaplan Meier survival analysis and Cox proportional hazard models. MAIN OUTCOME MEASURES: Treatment success defined as anterior chamber grade ≤0.5+ cell, topical corticosteroids ≤1 drop/day, oral prednisone ≤5 mg/day, resolution of macular edema, and resolution of angiographic signs of inflammation without any addition or escalation of therapy. RESULTS: 24 patients had antibodies tested with low to intermediate levels (average: 32.3 ng/mL, range: 0 - 154), while 41 did not have antibody testing. A greater treatment success rate post escalation was observed among the "low antibody" group compared to the "no testing" group (HR: 2.63, standard error: 1.19, p=0.031, 95% CI 1.09 - 6.37). Among the entire cohort, patients with panuveitis (n = 14) had a lower treatment success rate compared to the reference of anterior uveitis (n = 26) (HR: 0.09, standard error: 0.11, p = 0.05, 95% CI 0.01 - 0.99). CONCLUSIONS: Patients with low anti-adalimumab antibodies had a greater treatment success compared to patients in whom antibodies were not checked. This suggests a utility to checking antibodies prior to dose escalation and that low levels of antibodies may confer a success advantage. Overall, patients with panuveitis had a lower rate of success after escalation while patients with anterior uveitis patients had a very high rate of success suggesting that certain disease characteristics may guide clinicians when determining who to escalate versus changing therapy.

Adopting adalimumab combined surgery in the management of moderate to severe hidradenitis suppurativa: Experience from a single medical center in southern Taiwan.

Hidradenitis suppurativa (HS) is a chronic inflammatory disorder primarily affecting the intertriginous and anogenital regions. Guidelines recommend various treatments for HS, including biologic agents like adalimumab for moderate to severe cases. Adalimumab is a type of human monoclonal IgG1 antibody designed to target tumor necrosis factor α. Recent studies have shown the effectiveness of adalimumab, either alone or combined with surgery, in managing HS. We retrospectively analyzed the medical chart of HS patients in a southern Taiwan medical center from 2019 to 2022 and investigated clinical features and treatment response. The institutional review board at Chang Gung Medical Foundation granted approval for the study. We primarily focused on moderate to severely affected patients. One hundred and two clinically diagnosed HS patients participated, with a male-to-female ratio of 2:1 and an average age of 31.8 at diagnosis. Among them, 41.2% were in Hurley stage III and 32.4% in stage II. Nineteen patients received excision with pre-surgical adalimumab; their average age at diagnosis was 31.1, with a gender ratio of 5.3:1. Surgery was most common on the buttocks (68%), axillae (21%), and groin (10%). Excision patients were primarily in advanced stages (Hurley III 94.7%, II 5.3%) with high body mass index. Adalimumab and surgery combined yielded a 68.4% improvement rate, while 15.8% remained stable and 15.8% did not respond as expected. In addition, smoking and obesity were prevalent among patients. Adalimumab showed promising results in moderate to severe HS, with significant improvement observed in our cases. The combination of adalimumab and surgery appeared effective in advanced HS patients with larger involved areas and more tunnels. No severe adverse events were reported. However, our study was limited by its retrospective nature and the lack of a control group. Despite these limitations, our study revealed the benefits of integrating adalimumab with suitable surgical procedures in managing patients experiencing moderate to severe HS in real-world scenarios.

Efficacy and safety of infliximab and adalimumab in inflammatory bowel disease patients.

INTRODUCTION: Inflammatory bowel disease (IBD), consists of two primary types: Ulcerative Colitis (UC) and Crohn's Disease (CD). Infliximab (IFX) and Adalimumab (ADA) are frequently utilized in the management of moderate to severe cases of IBD. AIM: This study aimed to assess the efficacy and safety of IFX and ADA in individuals diagnosed with moderate to severe IBD. METHOD: This study is a prospective open-labeled randomized parallel study that included moderate to severe IBD patients treated with either IFX or ADA. A total of 56 patients participated, with 34 patients received IFX and 22 patients received ADA. Various measures, including Crohn's Disease Activity Index (CDAI), Mayo Score/ Disease Activity Index (DAI), and C-reactive protein (CRP) levels, were taken at baseline and week 14 to assess the efficacy of the treatments. In addition, the levels of drugs and sTREM-1 were measured at 14 weeks. Patient safety was monitored throughout the study period. RESULTS: In the group received IFX, there was a notable decrease in CDAI (P = 0.045), DAI (P = 0.026), and CRP (P = 0.023 for CD, and P = 0.021 for UC) levels. In addition, the group received ADA experienced a significant reduction in CDAI (P = 0.001), DAI (P = 0.032), and CRP (P < 0.018 for CD and P = 0.003 for UC) levels. Responders had higher drug concentrations than non-responders, notably IFX concentration was higher in responders with CD (P = 0.001) and UC (P < 0.001). ADA concentration was higher in UC (P <= 0.001) and all CD patients responded to the treatment. The same trend was observed for sTREM-1 levels in CD and UC patients (P = 0.042, and P = 0.015, respectively) in the IFX group. In UC patients treated with ADA, the level of sTREM-1 was significantly low (P = 0.002). CONCLUSION: Both IFX and ADA have a good safety profile and deliver a beneficial clinical and laboratory response in moderate-severe IBD patients. CLINICAL TRIAL REGISTRATION: This study is registered on ClinicalTrials.gov under the identifier NCT05291039. (You can access the study at https://clinicaltrials.gov/study/NCT05291039 (First Posted: March 22, 2022).

To switch or to swap? Evidence from a meta-analysis for the best treatment approach in childhood chronic uveitis resistant to the I anti-TNF.

Objective: Since adalimumab approval in childhood chronic non-infectious uveitis (cNIU), the prognosis has been dramatically changed, but the 25 % failed to achieve inactivity. There is not accordance if it is better to switch to another anti-TNF or to swap to another category of biologic. Thus, we aim to summarize evidence regarding the best treatment of cNIU refractory to the first anti-TNF. Methods: A systematic literature review and meta-analysis, according to PRISMA Guidelines, was performed(Jan2000-Aug2023). Studies investigating the efficacy of treatment in cNIU refractory to the first anti-TNF were considered for inclusion. The primary outcome was the improvement of intraocular inflammation according to SUN. A combined estimation of the proportion of children responding to switch or swap and for each drug was performed. Results: 23 articles were eligible, reporting 150 children of whom 109 switched anti-TNF (45 adalimumab, 49 infliximab, 9 golimumab) and 41 swapped to another biologics (31 abatacept, 8 tocilizumab and 1 rituximab). The proportion of responding children was 46 %(95 % CI 23-70) for switch and 38 %(95 % CI 8-73) for swap (χ20.02, p = 0.86). Instead analysing for each drug, the proportion of responding children was the 24 %(95 % CI 2-55) for adalimumab, 43 %(95 % CI 2-80) for abatacept, 79 %(95 % CI 61-93) for infliximab, 56 %(95 % CI 14-95) for golimumab and 96 %(95 % CI 58-100) for tocilizumab. We evaluated a superiority of tocilizumab and infliximab compared to the other drugs(χ2 27.5 p < 0.0001). Conclusion: Although non-conclusive, this meta-analysis suggests that, after the first anti-TNF failure, tocilizumab and infliximab are the best available treatment for the management of cNIU.

Liver enzyme profiles after initiating biological treatment in children with inflammatory bowel diseases.

OBJECTIVES: Biological treatments (BTs) are essential in managing pediatric inflammatory bowel diseases (PIBDs). Elevated liver enzymes sometimes succeed BT, yet elucidating studies are scarce. We addressed liver biochemistry after introducing BT and searched for their determinants. METHODS: We identified PIBD patients receiving infliximab, adalimumab, vedolizumab, or ustekinumab at the Children's Hospital, University of Helsinki, Finland, in 2000-2023, and followed their alanine transaminase (ALT) and γ-glutamyl transpeptidase (GT) levels for 24 months. ALT was categorized based on the age- and sex-specific upper limit of normal. We disregarded 46 patients with underlying primary sclerosing cholangitis with/without autoimmune hepatitis (AIH), pretreatment AIH diagnosis, and elevated liver enzymes at the beginning of BT from the analyses. RESULTS: Of 618 BT episodes in 403 patients, 22.2% exhibited increased ALT or GT (ALT in 117, GT in 4, and both ALT/GT in 16 episodes). Of all ALT elevations (n = 133), 41.4% occurred within the first 3 months. ALT elevation was more common after infliximab (representing 59.5% of BTs) than other BTs (25.9% vs. 14.2%, adjusted odds ratio [OR]: 2.41, 95% confidence interval [CI]: 1.23-4.72). AIH followed 1.5% (n = 9) of BT episodes. Ninety-five percent of ALT elevations resolved within 6 months. Antibiotic exposure (particularly to metronidazole) was associated with ALT elevation in general (adjusted OR: 5.76, 95% CI: 2.40-13.9) and short disease duration before starting BT with notable ALT elevation (adjusted OR: 1.10, 95% CI: 1.01-1.22). CONCLUSIONS: Benign ALT elevation is common within 3 months after starting BT (especially infliximab) and scarcely led to cessation of the treatment. AIH is a rare finding during the first year of BT.

Plasma Cytokines for the Prediction of the Effectiveness of TNFα Inhibitors Etanercept, Infliximab, and Adalimumab in the Treatment of Psoriasis.

Background/Objectives: Psoriasis is a chronic, inflammatory, immuno-mediated cutaneous disease characterized by a prominent TNFα-IL23/IL17 immune axis. In recent years, targeted therapies have become standard practice for managing moderate-to-severe psoriasis and have demonstrated efficacy. At the same time, identifying factors associated with the success or failure of TNFα inhibitor therapy remains one of the most difficult aspects in psoriasis treatment. Methods: A clinical, non-randomized study was conducted to evaluate the impact of TNFα inhibitors on the plasma cytokine profiles in patients with moderate-to-severe psoriasis vulgaris (ICD-10 code L40.0). The patients were treated with either etanercept, adalimumab, or infliximab for 16 weeks. Plasma cytokine profiles were assessed using a BioPlex200 System. Results: By the 16th week of therapy, a positive treatment response (PASI ≥ 75) was observed in 51 patients (63%), while 30 patients (37%) showed no response (PASI ≤ 50). When using etanercept, a positive effect was observed in 11 patients (41%), in 14 patients (52%) using adalimumab, and in 26 patients (96%) using infliximab. Analysis of the baseline cytokine levels revealed no differences between the "positive effect" and "no effect" groups, except for IL20, which was 2.61 times higher in the "positive effect" group compared to the "no effect" group, suggesting its potential predictive role in the effectiveness of therapy with TNFα inhibitors. Treatment led to a decrease in IL17F, IL31, sCD40L, and VEGF for all patients, and in IL20 for the "positive effect" group. The increase in ICAM1 in the "no effect" group suggests the possible retention of active migration and the fixation of T cells in the affected skin in these patients. No significant difference in cytokine levels was observed when categorizing patients into subgroups based on the effectiveness of therapy with etanercept, infliximab, and adalimumab; only a pre- and post-treatment difference in the whole cohort was noted. A random forest model showed the importance of VEGF, sCD40L, and ICAM1. Conclusions: The baseline levels of VEGF, sCD40L, and ICAM1, as well as IL20, could serve as potential predictors of treatment effectiveness using TNFa inhibitors. However, this hypothesis requires confirmation with a larger patient population.

Adalimumab induced psoriasis in a Crohn's disease patient: A case report.

Adalimumab is a human monoclonal antibody that selectively targets tumour necrosis factor-alpha (TNF- α), a cytokine involved in the pathogenesis of various inflammatory and autoimmune disorders. Adalimumab has been approved worldwide for the treatment of several chronic immune-mediated diseases, including rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, and juvenile idiopathic arthritis. One of the adverse reactions caused by Adalimumab is psoriasis. This study reports the case of a 37-year-old male with palmoplantar psoriasis triggered by adalimumab for treatment of Crohn's disease. This eruption resisted complete clearance with various potent corticosteroids. The patient was referred back to the treating rheumatologist to possibly change adalimumab to another type of therapy.

A prediction method for the individual serum concentration and therapeutic effect for optimizing adalimumab therapy in inflammatory bowel disease.

OBJECTIVES: Adalimumab (ADM) therapy is effective for inflammatory bowel disease (IBD), but a significant number of IBD patients lose response to ADM. Thus, it is crucial to devise methods to enhance ADM's effectiveness. This study introduces a strategy to predict individual serum concentrations and therapeutic effects to optimize ADM therapy for IBD during the induction phase. METHODS: We predicted the individual serum concentration and therapeutic effect of ADM during the induction phase based on pharmacokinetic and pharmacodynamic (PK/PD) parameters calculated using the empirical Bayesian method. We then examined whether the predicted therapeutic effect, defined as clinical remission or treatment failure, matched the observed effect. RESULTS: Data were obtained from 11 IBD patients. The therapeutic effect during maintenance therapy was successfully predicted at 40 of 47 time points. Moreover, the predicted effects at each patient's final time point matched the observed effects in 9 of the 11 patients. CONCLUSION: This is the inaugural report predicting the individual serum concentration and therapeutic effect of ADM using the Bayesian method and PK/PD modelling during the induction phase. This strategy may aid in optimizing ADM therapy for IBD.

Modelling the opportunity for cost-savings or patient access with biosimilar adalimumab and tocilizumab: a European perspective.

OBJECTIVES: Biosimilars improve patient access by providing cost-effective treatment options. This study assessed the potential for savings and expanded patient access with increased use of two biosimilar disease modifying anti-rheumatic drugs (DMARDs): (a) approved adalimumab biosimilars and (b) the first tocilizumab biosimilar, representing an established biosimilar field and a recent biosimilar entrant in France, Germany, Italy, Spain, and the United Kingdom (UK). METHODS: Separate ex-ante analyses were conducted for each country, parameterized using country-specific list prices, unit volumes annually, and market shares for each therapy. Discounting scenarios of 10%, 20%, and 30% were tested for tocilizumab. Outputs included direct cost-savings associated with drug acquisition or the incremental number of patients that could be treated if savings were redirected. Two biosimilar conversion scenarios were tested. RESULTS: Savings associated with a 100% conversion to adalimumab biosimilar ranged from €10.5 to €187 million (UK and Germany, respectively), or an additional 1,096 to 19,454 patients that could be treated using the cost-savings. Introduction of a tocilizumab biosimilar provided savings up to €29.3 million in the most conservative scenario. Exclusive use of tocilizumab biosimilars (at a 30% discount) could increase savings to €28.8 to €113 million or expand access to an additional 43% of existing tocilizumab users across countries. CONCLUSION: This study demonstrates the benefits that can be realized through increased biosimilar adoption, not only in an untapped tocilizumab market, but also through incremental increases in well-established markets such as adalimumab. As healthcare budgets continue to face downwards pressure globally, strategies to increase biosimilar market share could prove useful to help manage financial constraints.

Effectiveness of adalimumab in severe ulcerative colitis: A systematic review and a meta-analysis.

Background and Aim: Ulcerative colitis (UC) causes chronic inflammation in the digestive tract, leading to abdominal pain and diarrhea. Adalimumab, a monoclonal antibody, is used to treat moderate to severe cases. This review and meta-analysis evaluated adalimumab's effectiveness for severe UC, considering patient age, disease duration, and gender. Methods: This study was designed as a systematic review and a meta-analysis. Articles were searched in PubMed, Scopus, and Web of Science databases based on the keywords of adalimumab and UC. The titles, the abstracts, and, if necessary, the full texts of the articles were read. Then for further review, the full texts of the related articles were carefully examined, and the final articles were selected. Seventy-eight articles were searched based on the keywords, and after reading the articles, 50 articles were related to the topic of the dissertation. The 50 articles were evaluated critically based on a checklist prepared by a statistical consultant and four articles with a score above 70% were selected. In the four articles, the main indicators of the effectiveness of adalimumab, including mucosal healing, clinical remission, and clinical response, were evaluated. Results: The effectiveness of adalimumab on the mucosal healing index was 75.40%, the clinical remission index was 70.79%, and the clinical response index was 83.02%, based on different doses and treatment durations in the study. In the four meta-analysis studies on adalimumab's effectiveness, 1613 UC patients were treated with varying doses over 8 and 52 weeks. Based on a meta-analysis over 8 and 52 weeks for treating moderate to severe UC, adalimumab's effectiveness was 70%-83%. The highest effectiveness, based on three main indices, was with a 40 mg dose over 52 weeks. Conclusion: According to the meta-analysis, the effectiveness of adalimumab for treating moderate to severe UC over 8 and 52 weeks was 70%-83%. The highest effectiveness, based on three main indices, was with a 40 mg dose over 52 weeks.

The potential for medical therapies to address fistulizing Crohn's disease: a state-of-the-art review.

INTRODUCTION: Crohn's disease (CD) is a chronic, relapsing immune mediated disease, which is one of the two major types of inflammatory bowel disease (IBD). Fistulizing CD poses a significant clinical challenge for physicians. Effective management of CD requires a multidisciplinary approach, involving a gastroenterologist and a GI surgeon while tailoring treatment to each patient's unique risk factors, clinical representations, and preferences. AREAS COVERED: This comprehensive review explores the intricacies of fistulizing CD including its manifestations, types, impact on quality of life, management strategies, and novel therapies under investigation. EXPERT OPINION: Antibiotics are often used as first-line therapy to treat symptoms. Biologics that selectively target TNF-α, such infliximab (IFX), have shown high efficacy in randomized controlled trials. However, more than 50% of patients lose response to IFX, prompting them to explore alternative strategies. Current options include adalimumab and certolizumab pegol combination therapies, as well as small-molecule drugs targeting Janus kinases such as Upadacitinib. Furthermore, a promising treatment for complex fistulas is mesenchymal stem cells such as Darvadstrocel (Alofisel), an allogeneic stem cell-based therapy. However, surgical interventions are necessary for complex cases or intra-abdominal complications. Setons and LIFT procedures are the most common surgical options.

The Use of TNF-α Inhibitors in Active Ankylosing Spondylitis Treatment.

Ankylosing spondylitis (AS) is a challenging disease, characterized by chronic inflammation and structural damage primarily affecting the axial skeleton, while extra-articular manifestations may also appear. This results in the deterioration of patients' quality of life. Over the past few decades, tumor necrosis factor-α (TNF-α) inhibitors have revolutionized the management of AS, offering substantial relief from symptoms and improving patient outcomes. The aim of this review is to assess the efficacy of TNF-α inhibitors in patients with active AS. A search was performed in the PubMed database using the following keywords: ("TNF alpha inhibitors" OR "anti TNF-a" OR "TNF-a inhibitors" OR "anti TNF-alpha" OR "Etanercept " OR "Golimumab" OR "Infliximab" OR "Certolizumab pegol" OR "Adalimumab") AND "ankylosing spondylitis". The search was completed in February 2024, and 35 studies were included in this review following PRISMA guidelines. The findings reveal evidence supporting the efficacy of TNF-α inhibitors in reducing inflammation, preventing structural damage, and enhancing overall well-being in AS patients. Overall, TNF-α inhibitors have emerged as a cornerstone in the therapeutic algorithm against AS with a very satisfactory safety profile.

Progressive Dyspnea in a Woman With Tracheal Stenosis and Rheumatoid Arthritis.

CASE PRESENTATION: An 82-year-old woman with a remote tracheostomy due to vocal cord paralysis and long-standing erosive, seropositive rheumatoid arthritis (RA) well controlled with methotrexate sought treatment at the ED with 1 month of dyspnea, chest tightness, and cough productive of blood-tinged sputum. She had been treated unsuccessfully as an outpatient with multiple courses of antibiotics. She did not smoke or drink alcohol and had no recent travel outside the country. Given concern for airway compromise, she was admitted to the hospital.

Pregnancy Recommendations Solely Based on Preclinical Evidence Should Be Integrated with Real-World Evidence: A Disproportionality Analysis of Certolizumab and Other TNF-Alpha Inhibitors Used in Pregnant Patients with Psoriasis.

Treatment for pregnant women with psoriasis is limited by the lack of information typically related to clinical trials. While anti-tumor necrosis factor (TNF) drugs offer therapeutic benefits, their safety during pregnancy is a concern. Notably, certolizumab is comparatively safer than adalimumab, etanercept, infliximab, and golimumab according to the current recommendations. Thus, this study aimed to conduct a pharmacovigilance comparative analysis of maternal and neonatal outcomes associated with certolizumab versus other anti-TNF drugs by using data from EudraVigilance. A descriptive analysis was performed of Individual Case Safety Reports (ICSRs) associated with an anti-TNF drug and related to the pregnant patients with psoriasis from 2009 and 2023, focusing our analysis on the specific pregnancy outcomes and fetal/neonatal disorders. The most common pregnancy-related adverse event was spontaneous abortion, predominantly related to adalimumab and certolizumab. Certolizumab was also reported in cases of caesarean section, gestational diabetes, abortion, fetal death, fetal distress syndrome, pre-eclampsia, and premature separation of placenta. Generally, the findings from our study depicted a safety profile that overlapped for each anti-TNF drug, both in maternal/neonatal outcomes and other adverse events, suggesting no substantial differences between treatments. We advocate for further investigations before making concrete recommendations.

What are the benefits of therapeutic drug monitoring in the optimization of adalimumab therapy? a systematic review and meta-analysis up to 2022.

Aims: Persistent uncertainties exist surrounding the therapeutic drug monitoring (TDM) of adalimumab in clinical settings. To address these issues, we conducted a systematic review to assess the current evidence regarding the benefits of TDM for adalimumab. Methods: PubMed, EMBASE, and Cochrane Databases were searched from inception to October 2022. The trials regarding to the list three key questions were considered: 1) Could routine proactive TDM assist in improving outcomes in patients receiving adalimumab? 2) Could reactive TDM assist in guiding subsequent treatment strategies for patients with treatment failure to adalimumab? 3) Could TDM assist in informing dose reduction or discontinuation in patients with low disease activity or in remission treated with adalimumab? Two reviewers independently selected the studies and extracted the data. Meta-analysis was performed to calculate the relative risk (RR) and 95% confidence interval (CI). Results: A total of 9 studies was included in this review. For proactive TDM, meta-analysis indicated that proactive TDM (n = 163/257, 63.42%) showed no significant superiority over reactive TDM and/or conventional management (n = 336/606, 55.44%) in achieving and/or maintaining clinical remission by random effects model (RR: 1.24, 95% CI 0.98-1.58, I 2 = 73%). There were three studies that supporting the reactive TDM, low drug levels in the absence of anti-drug antibodies (ADA) strongly indicate the need for dose intensification, and infliximab is a feasible choice for patients with low drug levels and ADA positivity. While swapping to another class should be considered in patients with adequate drug levels. In addition, TDM can help clinicians optimize dosing schedules and prevent overtreatment in patients who have achieved low disease activity and sufficient drug concentrations, with no predictive value for successful adalimumab discontinuation. Conclusion: Current evidence suggests that proactive TDM is numerically but not statistically significant superiority over reactive TDM and/or conventional management. Reactive TDM can aid in understanding treatment failure and developing subsequent therapy. For patients reaching low disease activity and remission, TDM can help successful dose reduction, while it cannot inform the successful drug discontinuation. However, existing trials are limited, and more well-designed trials are necessary to clarify the role of TDM in adalimumab treatment.

Management of JIA associated uveitis.

Juvenile Idiopathic Arthritis (JIA) is the most common chronic rheumatic disease in childhood, and is associated with uveitis in up to 20-25% of cases. Typically, the uveitis is chronic, asymptomatic, non-granulomatous and anterior. For this reason, screening for uveitis is recommended to identify uveitis early and allow treatment to prevent sight-threatening complications. The management of JIA associated uveitis requires a multidisciplinary approach and a close collaboration between paediatric rheumatologist and ophthalmologist. Starting the appropriate treatment to control uveitis activity and prevent ocular complications is crucial. Current international recommendations advise a step-wise approach, starting with methotrexate and moving on to adalimumab if methotrexate alone is not sufficient to control the disease. If the uveitis remains active despite standard treatment other therapeutic options may be considered including anti-IL6 or other anti-TNF agents such as infliximab, although the evidence for these agents is limited.

TNF-alpha blockade in Primary Chronic Non-Bacterial Osteomyelitis of the Mandible.

OBJECTIVES: Primary chronic Non-Bacterial Osteomyelitis of the jaw is a rare auto-inflammatory disease of unknown aetiology that bears pathophysiological resemblance to both the synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome in adults and chronic recurrent multifocal osteomyelitis (CRMO) in children. Both SAPHO and CRMO respond to TNF-alpha blockade. Previously reported treatment regimens in CNOM including non-steroidal anti-inflammatory drugs, corticosteroids, antibiotics, anti-resorptive therapy, and surgery all bear disappointing results. TNF- α blockade is suggested as a treatment option by some experts but this is not backed by any clinical data.We sought to retrospectively and exhaustively report our experience of anti-TNF alpha therapy in refractory CNOM. METHODS: Fifteen patients with refractory CNOM and high disease burden were referred to our centre. TNF- α blockade was attempted in 10 cases, given its efficacy in neighbouring diseases, its good tolerance profile and failure of previous treatment strategiesWe herein retrospectively report detailed outcomes for all patients having received anti-TNF alpha therapy for this indication in our centre. RESULTS: TNF-α-targeting therapy resulted in a rapid and sustained remission in a majority of patients with CNOM, without serious adverse events. Treatment was tapered and stopped without relapse in some patients despite a refractory course of several years. Male sex seems to be associated with a poorer outcome. CONCLUSION: Our results suggest that blocking TNF-α is efficient and safe in CNOM.

Prediction of human serum concentration-time profiles of therapeutic monoclonal antibodies using common marmosets (Callithrix jacchus): initial assessment with canakinumab, adalimumab, and bevacizumab.

Cynomolgus monkeys and human FcRn transgenic mice are generally used for pharmacokinetic predictions of therapeutic monoclonal antibodies (mAbs). In the present study, the application of the common marmoset, a small nonhuman primate, as a potential animal model for prediction was evaluated for the first time.Canakinumab, adalimumab, and bevacizumab, which exhibited linear pharmacokinetics in humans, were selected as the model compounds. Marmoset pharmacokinetic data were reportedly available only for canakinumab, and those for adalimumab and bevacizumab were acquired in-house.Four pharmacokinetic parameters for a two-compartment model (i.e. clearance and volume of distribution in the central and peripheral compartments) in marmosets were extrapolated to the values in humans with allometric scaling using the average exponents of the three mAbs. As a result, the observed human serum concentration-time curves of the three mAbs following intravenous administration and those of canakinumab and adalimumab following subcutaneous injections (with an assumed absorption rate constant and bioavailability) were reasonably predicted.Although further prediction studies using a sufficient number of other mAbs are necessary to evaluate the versatility of this model, the findings indicate that marmosets can be an alternative to preceding animals for human pharmacokinetic predictions of therapeutic mAbs.

SERENE ER Analysis Part 1-SERENE CD: Exposure-Response Analysis of Higher Versus Standard Adalimumab Dosing Regimens for Patients With Moderately to Severely Active Crohn Disease.

SERENE CD (NCT02065570) evaluated whether a higher adalimumab induction dose would improve patients with Crohn disease response and suggested a flat dose-response relationship for efficacy in the induction study. We investigated exposure-response relationships in induction and maintenance studies considering patients' baseline characteristics. Adalimumab exposures were simulated using the established population pharmacokinetic model. Efficacy end points (clinical remission/endoscopic response) at Weeks 4, 12, and 56 were evaluated in exposure-response analyses using multivariable logistic regression. Analyses showed an increasing trend with heterogeneity between induction regimens, which suggested that average concentration has an impact on coprimary efficacy end points within each group, but data did not fit a single-response curve. Although higher concentrations within arms were associated with improved outcomes, increasing the concentration through a higher induction dose was not associated with increasing clinical remission/endoscopic response at Week 4/12. A model including inverse effective clearance eliminated heterogeneity and described trends across induction regimens with a single curve. In the maintenance study, the response rates at Week 56 showed no heterogeneity. In the induction study, patients with lower effective adalimumab clearance responded better, whereas in the maintenance study average concentration drove primary efficacy end points at Week 56. Research extending these findings to other indications is needed.