Pediatric cutaneous Crohn disease: A case series of 89 patients and review.

BACKGROUND: Cutaneous (or "Metastatic") Crohn disease (CCD) is a rare and underrecognized disease characterized by cutaneous granulomatous inflammation. We describe patient demographics, clinical characteristics, histology, and treatment of 89 pediatric cases of CCD, including 78 previously reported and 11 new cases seen at four academic institutions. We emphasize the efficacy of biologic mono- and dual therapy. METHODS: PubMed identified cases using keywords including "metastatic Crohn disease" and "cutaneous Crohn disease". Patients were identified by retrospective review of the electronic health record including histopathologic diagnosis consistent with CCD. Chart review collected demographic, clinical, and histologic data. RESULTS: Most pediatric patients with CCD are male 55% (49/89), present with edema (73/89, 82%) and erythema (47/89, 53%) of the genitals (33/49, 67%), and have intestinal Crohn disease (69/89, 78%). Oral corticosteroids (53/75, 71%) and metronidazole (29/75, 39%) are the most frequently prescribed medications. Of the 17 patients treated with tumor necrosis factor (TNF)-blockade, 94% (16/17) had partial or total clearance. Ustekinumab resulted in clearance of cutaneous disease in two patients (2/3, 67%) and partial clearance in one patient (1/3, 33%). Two cases achieved total clearance with the use of dual biologic therapy defined as the use of two biologic therapies with differing mechanisms of action or the use of a biologic therapy and small molecule inhibitor. CONCLUSIONS: TNF blockade is an effective treatment for pediatric CCD, and interleukin-12/23 inhibitors may be similarly effective. Consideration of dual biologic therapy may be useful in pediatric patients requiring discordant therapies for their intestinal and cutaneous CD.

Combination biologic therapy in pediatric inflammatory bowel disease: Safety and efficacy over a minimum 12-month follow-up period.

OBJECTIVES: The severe course of inflammatory bowel diseases (IBDs) refractory to advanced therapies in children results in the search for new therapeutic methods. The aim of this study was to evaluate the efficacy and safety of dual therapy with biologics in a cohort of children with IBD. METHODS: Retrospective analysis of data from 29 children with a diagnosis of IBD, 19 with ulcerative colitis (66%), 10 with Crohn's disease (CD) (34%) qualified for dual biological therapy (DBT). The median age of patients was five (interquartile range [IQR], 1-15) years at diagnosis of IBD and 14 (IQR, 3-17) years at eligibility for dual therapy. Thirteen (45%) patients were treated with vedolizumab/adalimumab (VDZ + ADA), 13 (45%) with ustekinumab/adalimumab (UST + ADA), three (10%) with infliximab/vedolizumab (IFX + VDZ). RESULTS: Clinical remission was achieved in 13 (45%; seven UC and six CD) and 12 (41%; seven UC and five CD) Pediatric Weighted Crohn's Disease Activity Index (wPCDAI)/Pediatric Ulcerative Colitis Activity Index (PUCAI) patients after 4 and 12 months at the initiation of dual therapy. Clinical response based on wPCDAI/PUCAI was reported in 16 (55%; nine UC and seven CD) and 12 (41% seven UC and five CD) children after 4 and 12 months of follow-up, respectively. The median fecal calprotectin decreased significantly from 1240 µg/g (53-10,100) to 160 µg/g (5-2500; p = 0.004) between baseline and Month 4 and from 749 at baseline (57-10,100) to 17 (5-3110; p = 0.12) over 12 months. Moreover, 34% (six UC and four CD) of patients achieved endoscopic remission. CONCLUSIONS: DBT seems to be an effective alternative therapeutic option for patients with moderate and severe IBD.

Combination of Biological Therapy in Severe Asthma: Where We Are?

Biological drugs have revolutionized the management of severe asthma. However, a variable number of patients remain uncontrolled or only partially controlled even after the appropriate administration of a biologic agent. The combination of two biologics may target different inflammatory pathways, and it has been used in patients suffering from uncontrolled severe asthma with evidence of both allergic and eosinophilic phenotypes or severe asthma and type2 comorbidities. Combination therapy has also been used to handle anti-IL4/13R induced hypereosinophilia. There is insufficient data on combining biologics for the treatment of severe uncontrolled asthma and type 2 comorbidities, also because of the high cost, and currently no guideline recommends dual biologic therapy. A systematic search was performed using the Medline and Scopus databases. Published data on concurrent administration of two biological drugs in severe, uncontrolled asthma patients has been reported in 28 real-world studies and 1 clinical trial. Data extraction was followed by a descriptive and narrative synthesis of the findings. Future studies should be conducted to further assess the safety, efficacy, and cost-effectiveness of this therapeutic strategy.

Advanced Combination Treatment With Biologic Agents and Novel Small Molecule Drugs for Inflammatory Bowel Disease.

The use of combination therapy with a biologic agent and immunosuppressant has well-established efficacy and safety and is common practice in the management of inflammatory bowel disease (IBD). Current research has shifted focus toward the use of advanced combination treatment (ACT). This term was coined to describe combination therapy using 2 or more advanced treatments (biologic agents and/or oral small molecule drugs) with the aim of achieving optimal disease control in selected patients. An ACT approach may be particularly beneficial in patients with documented medically refractory IBD and in patients with a poor prognosis, extraintestinal manifestations, or concomitant immune-mediated inflammatory diseases. To date, the body of evidence for ACT strategies in IBD is largely comprised of uncontrolled retrospective case series and cohort studies in highly refractory patients. Recently, results from the VEGA trial have suggested that combination induction therapy with guselkumab and golimumab was more effective in ulcerative colitis than either agent alone. However, questions remain about issues such as related costs, ACT duration, and optimal combinations to adopt. Future randomized controlled trials are likely to evaluate rationally selected combinations of agents. This article summarizes the available literature on ACT, including comparisons with traditional combination therapy and the rheumatology field, and discusses practical recommendations, profiles of IBD patients who should be considered for combination approaches in clinical practice, and remaining knowledge gaps.

Emerging role of dual biologic therapy for the treatment of inflammatory bowel disease.

Biologic agents have now been used in the management of inflammatory bowel disease (IBD) for many years where experience, expertise and confidence in their use has developed over time. In the United Kingdom, there are well established guidelines and recommendations for both single agent biologic treatments, and with combination therapy of a biologic agent with a small molecule agent in maintenance therapy. In recent times, there has been increasing interest and experience using dual biologic therapy (DBT) in IBD, primarily in difficult to treat and refractory cases with high disease burden. However, published data on use, experience and safety profiles is limited and large-scale studies remain low in number in this developing area. We therefore aim to present a summary and review of the available published data in this area to help us better understand the emerging role of DBT in IBD.

New progress on the use of Dual Biologic Therapy for patients with Inflammatory Bowel Disease / 中国综合临床

At present, the incidence of inflammatory bowel disease in China is increasing. Although new biological agents continue to emerge, which induce a higher clinical remission rate in moderate and severe patients than traditional drugs and have much advantages in reducing the risk of surgery and changing the natural history, the remission rate of biological agents monotherapy is still not enough. In this context, dual biologic therapy is a viable strategy. Dual biologic therapy is mainly indicated for patients with inflammatory bowel disease that is refractory or complicated with extraintestinal manifestations.It is often used in combination with clinical practice according to the characteristics of drugs, showing relatively great efficacy and safety, but a series of key questions still need a high level of research evidence to explore.

Dual Advanced Therapies and Novel Pharmacotherapies for Moderately to Severely Active Crohn's Disease.

Over the past 2 decades, there have been incredible advances in the pharmacotherapeutic options for the treatment of patients with moderately to severely active Crohn's disease. Despite the leaps and strides in safety, efficacy, and mechanistic specificity of treatment targets, a significant portion (up to ∼20-50%) of patients have refractory Crohn's disease ± concomitant rheumatologic disease/extraintestinal manifestations for which existing biologic and small molecule therapies are ineffective. In this review, we will explore the available evidence for the use of dual advanced therapies (combination of biologic and/or small molecule therapies) and novel pharmacotherapies in phase 2 to 3 clinical trials.

Dual biologic therapy with ocrelizumab for multiple sclerosis and vedolizumab for Crohn's disease: A case report and review of literature.

BACKGROUND: Little is known about the safety and efficacy of using two or more biologics for the treatment of immune-mediated diseases, including Crohn's disease (CD). CASE SUMMARY: This case report and narrative review demonstrate the potential safety of dual biologic therapy (DBT) in a 45-year-old female with two separate immune-mediated diseases. She had a history of multiple sclerosis for which she was receiving treatment with ocrelizumab, and she had been recently diagnosed with CD after presenting with diarrhoea. The CD diagnosis was confirmed radiologically, endoscopically, histologically, and biochemically. The patient received treatment with vedolizumab, a gut-specific inhibitor of the α4ß7 integrin on leukocytes. No adverse reactions were observed for the duration of treatment. The safety of ocrelizumab and vedolizumab for the treatment of different immune-mediated diseases was demonstrated. CONCLUSION: DBT may be a safe and effective option for the treatment of refractory disease or multiple immune-mediated diseases. Newer biologics, which have improved safety profiles and gut specificity, may provide promising avenues for treatment. However, caution must be exercised in the appropriate selection of biologics given their inherent immunosuppressive properties, side effects, and efficacy profiles. Current evidence suggests that biologic therapy is not associated with a worse prognosis in patients with coronavirus disease 2019, but treatment decisions should be made in a multidisciplinary setting. Further research from controlled trials is needed to better understand the safety profile of DBT in CD. The immunopathological mechanisms underlying DBT also remain to be clarified.

Coesisting inflammatory skin diseases: Tildrakizumab to control psoriasis and omalizumab for urticaria.

In Western countries, the number of individuals suffering from an autoimmune condition is constantly growing and often patients suffering from autoimmune disease are susceptible to developing a second autoimmune disorder. We report a case of an adult female patient affected by psoriasis vulgaris and treated with tildrakizumab, a humanized monoclonal antibody targeting interleukin-23, who later developed chronic spontaneous urticaria and started omalizumab, a humanized antibody to IgE, showing a favorable outcome. We speculate that the two combined therapies have restored the cytokine balance bringing it toward tolerance and remission of the two pathologies. It is conceivable that tildrakizumab may have a synergic action with omalizumab in the treatment of urticaria in patients affected by both psoriasis and urticaria. Our case and the study of the mechanisms of action of the two drugs suggest how the two therapies can act with an interlocking mechanism in achieving the final therapeutic effect.

Dual Biologic Therapy in a Patient With Niemann-Pick Type C and Crohn Disease: A Case Report and Literature Review.

Dual biologic therapy has become a new area of interest in inflammatory bowel disease (IBD). Monogenic/polygenic IBD and the role of genetics in IBD is an evolving field, with many of these patients having difficult treatment courses. We present a case of a teenage patient with Niemann-Pick disease type C and Crohn colitis, who sustained clinical remission only after escalating to dual biologic therapy (anti-tumor necrosis factor alpha [infliximab] and anti-interleukin-12/anti-interleukin-23 [ustekinumab]). A literature review of dual biologic therapy in pediatric IBD revealed 8 case series and 1 cohort study. In pediatric patients with genetic disorders and IBD who are not responding adequately to biologic therapy, adding a second biologic medication with a different mechanism of action may be efficacious. Targeting both anti-tumor necrosis factor alpha (which induces pro-inflammatory cytokines) and the pro-inflammatory cytokines themselves (interleukin-12/interleukin-23) may be important in impaired macrophage function and increased cytokine response. Our case adds to the sparse literature on the utility of combining ustekinumab and infliximab in pediatric IBD and is the first to describe its use for treating ongoing active luminal disease.

Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis.

BACKGROUND AND AIMS: We conducted a systematic review and meta-analysis to summarize emerging data on the safety and effectiveness of dual biologic therapy in combination or with tofacitinib in patients with refractory inflammatory bowel disease (IBD). METHODS: Through a systematic search of multiple electronic databases through November 9, 2020, we identified cohort studies or case series (>10 patients) reporting the safety and effectiveness of simultaneous use of biologic agents in combination or with tofacitinib in patients with IBD. Rates of adverse events, clinical remission, and endoscopic remission were synthesized using pooled data, and we identified factors associated with successful dual therapy. RESULTS: We identified 30 studies reporting 288 trials of dual biologic or small molecule therapy in 279 patients (76% Crohn's disease; median duration of treatment 24 weeks (IQR25-IQR75 1332)). The main indications for dual therapy included medically refractory IBD (81%) and concurrent extra-intestinal manifestations or rheumatologic disease (12%). The most common combinations of dual therapy included tumor necrosis factor-α antagonists & anti-integrins (48%), ustekinumab & anti-integrins (19%); 61% of patients had previously failed at least one of the two therapies used in combination. Over a median follow-up of 32 weeks (IQR25-IQR75 24-52), pooled rates of adverse and serious adverse events were 31% (95% CI, 13%-54%) and 6.5% (95% CI, 2.1%-13.1%); pooled rates of clinical and endoscopic remission were 59% (95% CI, 42%-74%), and 34% (95% CI, 23%-46%), respectively. 12% (95% CI, 4%-24%) of patients required surgery. Rates of success were higher in patients on dual therapy due to EIM. Heterogeneity was not significant for endoscopic response (P = .88, I2 = 0%), endoscopic remission (P = .44, I2 = 0%), and malignancy (P = .87, I2 = 0%). However, significant heterogeneity existed for other outcomes. CONCLUSIONS: Dual biologic or small molecule therapy may be a possible option in highly selected, refractory IBD patients at specialized centers. Higher quality combination of therapies with a significant improvement in the quality of data is required prior to more widespread use.

Dual Biologic Therapy in Moderate to Severe Pediatric Inflammatory Bowel Disease: A Retrospective Study.

BACKGROUND: Inflammatory bowel diseases in children are characterized by a wide variety of symptoms and often a severe clinical course. In the treatment, we aimed to induce and maintain remission. We focused on assessing the efficacy and safety of the concomitant use of two biologic therapies including: anti-TNF (infliximab, adalimumab) vedolizumab and ustekinumab in a refractory pediatric IBD cohort. METHODS: Fourteen children (nine ulcerative colitis, one ulcerative colitis/IBD-unspecified, four Crohn's disease) with a disease duration of 5.2 (8 months-14 years) years, initiated dual therapy at an age of 11.7 (3-17) years after failure of monotherapy with a biological drug. Five patients (36%) were treated with vedolizumab/adalimumab (VDZ + ADA), five (36%) with ustekinumab/adalimumab (UST + ADA), and three (21%) with infliximab/vedolizumab (IFX + VDZ). One patient (7%) was switched from a combination of vedolizumab and adalimumab to ustekinumab and adalimumab during follow-up. RESULTS: A clinical improvement was obtained in ten children (73%; 5 UC, 1 UC/IBD-unspecified, 4 CD) on the PCDAI/PUCAI scale after 4 months of a second biological drug being added. The median fecal calprotectin decreased from 1610 µg/g (140-10,100) to 586 µg/g (5-3410; p = 0.028) between baseline and 4 months. CONCLUSIONS: Our clinical experience suggests that dual therapy may be an option for pediatric patients with moderate and severe courses of IBD with limited therapeutic options.