Combination Biologic Therapy Research Articles

Comparative effectiveness of combined biologic agents versus standard therapies in the treatment of plaque psoriasis: a retrospective analysis.

Plaque psoriasis is a persistent skin disorder that necessitates efficient management. This study investigates the therapeutic effectiveness and timeline for skin lesion resolution in plaque psoriasis patients treated with combined biologic agents compared to standard therapies. Conducted retrospectively between March 2020 and March 2023, the study included 162 patients with moderate to severe plaque psoriasis. Participants were divided into two groups: the Control Group, which received standard treatments, and the Combined Biologic Agent Group, which received additional biologic therapy with secukinumab. Participants in the Control Group received standard treatments, while those in the Combined Biologic Agent Group received standard treatments plus secukinumab. The results showed that the Combined Biologic Agent Group experienced a significantly faster onset of therapeutic effects, with an average time of 3.04 ± 2.25 days compared to 6.12 ± 2.06 days in the Control Group. Additionally, skin lesion resolution occurred more rapidly in the biologic agent group (7.04 ± 2.13 days) than in the control group (14.56 ± 4.73 days). By week 24, the Psoriasis Area and Severity Index (PASI) scores demonstrated a more substantial reduction in the biologic agent group, decreasing from 26.98 ± 11.28 to 2.48 ± 3.01, whereas the control group showed a reduction from 25.82 ± 10.47 to 10.40 ± 7.63. The overall effectiveness rate was higher in the biologic agent group, with no cases of ineffectiveness, compared to a 20.99% ineffectiveness rate in the control group. Furthermore, there was no recurrence of the disease in the biologic agent group, while the control group experienced an 11.11% recurrence rate. Both groups had a similar incidence of adverse reactions, indicating that the addition of biologic agents does not significantly increase the risk of adverse events. These findings suggest that combined biologic agent therapy offers a more effective and faster treatment option for plaque psoriasis without compromising safety. However, larger-scale clinical trials are necessary to validate these results and establish the long-term benefits and safety of this treatment approach in diverse patient populations.

Guidelines How to Integrate Surgery and Targeted Therapy with Biologics for the Treatment of Hidradenitis Suppurativa: Delphi Consensus Statements from an Italian Expert Panel.

Hidradenitis suppurativa (HS) is a chronic inflammatory skin disease characterized by recurrent and painful nodules and abscesses in intertriginous skin areas, which can progress to sinus tract formation, tissue destruction, and scarring. HS is highly debilitating and severely impairs the psychological well-being and quality of life of patients. The therapeutic approach to HS is based on medical therapy and surgery. First-line medical therapy includes topical antibiotics, systemic antibiotics, and biologics. Main surgical procedures include deroofing, local excision, and wide local excision. Despite the availability of multiple therapeutic options, the rates of disease recurrence and progression continue to be high. In recent years, the possibility of combining biologic therapy and surgery has raised considerable interest. In a clinical trial, the perioperative use of adalimumab has been associated with greater response rates and improved inflammatory load and pain, with no increased risk of postoperative infectious complications. However, several practical aspects of combined biologic therapy and surgery are poorly defined. In June 2022, nine Italian HS experts convened to address issues related to the integration of biologic therapy and surgery in clinical practice. To this purpose, the experts identified 10 areas of interest based on published evidence and personal experience: (1) patient profiling (diagnostic criteria, disease severity classification, assessment of response to treatment, patient-reported outcomes, comorbidities); (2) tailoring surgery to HS characteristics; (3) wide local excision; (4) presurgery biologic treatment; (5) concomitant biologic and surgical treatments; (6) pre- and postsurgery management; (7) antibiotic systemic therapy; (8) biologic therapy after radical surgery; (9) management of adverse events to biologics; and (10) management of postoperative infectious complications. Consensus between experts was reached using the Estimate-Talk-Estimate method (Delphi Method). The statements were subsequently presented to a panel of 27 HS experts from across Italy, and their agreement was assessed using the UCLA Appropriateness Method. This article presents and discusses the consensus statements.

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

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. 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). Clinical remission was achieved in 13 (45%; sevenUCand sixCD) and 12 (41%; sevenUCand fiveCD) 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%; nineUCand sevenCD) and 12 (41% sevenUC andfiveCD) 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 UCand fourCD) of patients achieved endoscopic remission. DBT seems to be an effective alternative therapeutic option for patients with moderate and severe IBD.

Combination biologic therapy for ulcerative colitis

In The Lancet Gastroenterology & Hepatology, Brian Feagan and colleagues report the results of VEGA, the first randomised, controlled trial investigating the efficacy and safety of short-term combination therapy with biologics in patients with moderate-to-severe ulcerative colitis. 1 Feagan BG Sands BE Sandborn WJ et al. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trial. Lancet Gastroenterol Hepatol. 2023; (published online Feb 1.)https://doi.org/10.1016/S2468-1253(22)00427-7 Google Scholar Patients were randomly assigned (1:1:1) to receive anti-tumour necrosis factor (TNF) inhibitor golimumab, interleukin (IL)-23p19 inhibitor guselkumab, or combined therapy with both golimumab and guselkumab, referred to as combined therapy hereafter. The primary endpoint of the trial was clinical response at week 12. At week 12, 59 (83%) of 71 patients in the combination therapy group had achieved clinical response compared with 44 (61%) of 72 patients in the golimumab monotherapy group (adjusted treatment difference 22·1% [80% CI 12·9 to 31·3]; nominal p=0·0032) and 53 (75%) of 71 patients in the guselkumab monotherapy group (adjusted treatment difference 8·5% [–0·2 to 17·1; nominal p=0·2155). However, the prespecified criterion for significance (the superiority of combination therapy to both monotherapy groups for the primary endpoint at the two-sided significance level of 0·2) was not met. The fact that the primary endpoint of the trial was not met does not detract from the importance of the study findings: twice as many patients in the combination therapy group achieved the more stringent endpoint of clinical remission when compared with either monotherapy group. At weeks 12 and 38, the proportion of patients who met other objective endpoints, including endoscopic, histological, and composite histological-endoscopic endpoints was numerically higher in the combination therapy group than either monotherapy. Guselkumab plus golimumab combination therapy versus guselkumab or golimumab monotherapy in patients with ulcerative colitis (VEGA): a randomised, double-blind, controlled, phase 2, proof-of-concept trialData from this proof-of-concept study suggest that combination therapy with guselkumab and golimumab might be more effective for ulcerative colitis than therapy with either drug alone. These findings require confirmation in larger trials. Full-Text PDF

P617 Dual biologic therapy in pediatric Inflammatory Bowel Disease

Abstract Background There is paucity of data on the effectiveness of combination biologic agents as an option for children with refractory inflammatory bowel disease (IBD) that is inadequately controlled by biologic monotherapy. The aims of this study were to determine the effectiveness and safety of combination biologic use in pediatrics IBD. Methods A retrospective cohort study of children with IBD seen at Sidra Medicine and who received combination biologic therapy from October 2018 to April 2022. The diagnosis of IBD was established according to the revised Porto criteria. Children with IBD on two or more biologics were identified from our IBD database and their electronic medical records were reviewed. Patients included in the study must have been on combination biologic therapy for at least two months. Relevant clinical and demographic data were collected. Results Out of the 211 patients in our IBD database, we identified a total of 14 patients who had received dual biologic therapy within the study period. 3 patients were excluded because they had received dual biologic therapy for less than 2 months. 11 patients with IBD met our inclusion criteria and were included in this study. All 11 patients had Crohn’s disease. Overall, 7 patients (63%) were male, the median age at the start of starting combination therapy was 15.1 years (IQR 13.9 to 17.4), and the median disease duration was 2.3 years (IQR 1.4 to 3.2). Patients had been on the first biologic for a median of 20.3 months (IQR 13.0 to 32.3) before the addition of the second biologic. The reasons for dual biologic therapy included active disease, failure of single biological therapy, and development of complications. The patients had failed therapy with a median of two (range 1-3) prior biological medications. Concomitant dermatological disease (psoriasis) was present in one patient (9.1%). After a median follow-up of 5.2 months (IQR 2.9-5.5), median PCDAI significantly reduced from 22.5(IQR 16.75-30) to 5(1.25-13.75) {P<0.001}…Figure 1. Median fecal calprotectin reduced from 1534 (1361-1612) to 489 (379-658) {P<0.001}. No adverse events were noted. Conclusion Dual biologic therapy was associated with clinical and biomarker improvements in patients with Crohn’s disease who previously failed at least one single biologic. Dual biologic treatment was not associated with adverse events during the study period. Dual biologic therapy may be an attractive strategy but the lack of randomized controlled trials as well as long-term safety concerns means that there is a need for further trials on this subject. Future studies should assess risk: benefit ratios, safety, and efficacy of specific combinations of biologic use in IBD.

P811 Combination biological or small molecule therapy in patients with refractory inflammatory bowel disease: a multicenter Brazilian experience

Abstract Background This preliminary study describes the Brazilian experience on dual biologic therapy or small molecule combined with a biologic therapy in patients with inflammatory bowel disease (IBD) refractory to multiple biologics. Methods We identified patients from 6 IBD centers in Brazil between April 2020 and November 2022 who received treatment with a combination of two biologics or a biologic and a small molecule drug due to refractory disease or concomitant immunomediated condition. The primary endpoint was clinical remission at week 16, defined as a total Mayo score of ≤2 for UC and Harvey-Bradshaw Index (HBI) <4 for CD. Secondary endpoints were improvement in disease activity scores and biomarkers. Adverse events were monitored and summarized descriptively. Results Twenty-nine patients were identified (69% CD, n=20), 51.8% female, mean age 38.8 years old [SD= ± 14.8 years]). Seventy per cent (n=14) had penetrating behavior among CD patients. Twenty-seven had failed to, at least, one anti-TNF; 79.9% had failed to ustekinumab (UST), and 34.5% to vedolizumab (VEDO). Twenty-six patients were treated with combination advanced therapy due to loss of response to biologics and three patients had concomitant ankylosing spondylitis. The most common combination used was UST+ADA (n=12, 41.4%), followed by UST+VEDO (n=6, 21.7%). Mean treatment time was 53.8 weeks (SD= 40.4 weeks, CI 95% [37.5 – 70]). At week 16, clinical remission rates were 80% and 66% for CD and UC, respectively. All patients under VEDO + UST combination achieved clinical remission at 16w, in both diseases. Baseline HBI mean was 10.8 (SD= ± 3.6 points; CI 95% [9.1- 12.5]), decreasing to a mean of 5.5 at week 16 (SD= ± 3.5 points; CI 95% [3.8 - 7.2]) and plateauing at 7 by week 24 (SD= ±5.4 CI 95% [3.4- 10.6]). There was a notable decrease in HBI at week 16 (p< 0.001) and a significant decrease at week 24 (p= 0.02) compared to baseline. Mean CRP at week 16 was significantly lower than baseline in CD (17.4mg/dL vs 5.5 mg/dL, p=0.001) and numerically lower in UC (from 14.3mg/dL to 9.9mg/dL, p= 0.5). Fecal calprotectin decreased from 2509mcg/g to 1472mcg/g in both groups (p=0,2). In addition, all patients with ankylosing spondylitis showed symptomatic remission. No new safety signals were identified during follow-up Conclusion Despite combination of advanced therapies in IBD is not yet recommended by treatment guidelines, this strategy seems to be a promising option for patients with refractory IBD or concomitant autoimmune disease. Our data indicate that further investigation in this direction is worthwhile.

P695 Effectiveness and Safety of Combination Biologic or Small Molecule Therapy in Inflammatory Bowel Disease

Abstract Background Biologic and small molecule therapies have revolutionised the treatment of inflammatory bowel disease (IBD). Despite these advances, there appears to be a therapeutic ceiling with single agent therapy with up to 50% of patients failing to achieve long term remission. Combination of two biologic therapies or a biologic therapy and small molecule agent, with differing mechanisms of action, has the potential to improve IBD therapy outcomes. Information on the effectiveness and safety of this treatment strategy in IBD remains limited. Methods A retrospective, multicentre study was carried out at five Irish Academic Centres within the Initiative Network. Combination biologic or small molecule use was defined as concomitant use of two biologics or one biologic and small molecule therapy licenced or undergoing clinical trial assessment for treatment of IBD. Patients who had received combination therapy were identified from institutional databases. Review of clinical records was performed and demographic data collected. Combination therapy persistence was considered a proxy for successful therapy outcome. Adverse events were documented. P values < 0.05 were considered significant in analyses. Results The study cohort included 85 patients; 70% Crohn’s disease (CD), 30% ulcerative colitis (UC); median (IQR) number of prior biologic therapies 3 (2 – 3); median (IQR) study follow up 40.71 weeks (13.68 – 82.86). Further baseline characteristics are described in Figure 1. 97 combination therapy trials were undertaken in 85 patients. 13 different combination therapy regimes were utilised with ustekinumab & vedolizumab being the most common regimen. 76.5% (n=65 patients) remained on combination therapy at last follow up. Higher rates of combination therapy discontinuation (p=0.04) and shorter time to combination therapy discontinuation were observed in UC compared with with CD (HR 0.48 [95% CI 0.21-1.11], p<0.05). 3.1% of the study cohort developed a serious or opportunistic infection. No deaths or intensive care unit admissions occurred during study follow up. Conclusion Combination therapy is an effective therapeutic strategy with an acceptable safety profile in refractory IBD patients. Randomised controlled trials are required to clearly define the role of combination therapy in the management of IBD.

Dual biologic therapy for the treatment of rheumatic diseases and asthma: a case series.

Combination biological therapies are being considered increasingly for patients with multiple co-morbidities requiring biologics. There are limited data available on this approach, and concerns remain about the possible risk of adverse events, particularly infection. We present three patients on dual biologics for rheumatic disease and asthma. The biologic combinations used were etanercept and mepolizumab, infliximab and omalizumab, and etanercept and omalizumab. The time on combination biologic therapies ranged from 24 to 36 months. Patients were monitored for any serious adverse events. All three patients were able to tolerate combined biologic therapies, with no serious adverse events. All three patients gained improvement in their rheumatic and asthma disease control, with reduction in disease activity scores and reduction in steroid usage. The decision to start dual biologic therapy should be considered carefully, on a case-by-case basis. The number of patients who are on combination biological therapy is small, and data are sparse. Real-world data are needed to examine the long-term benefits and risks of different forms of combination biologic therapies.

S47 Combined Therapy With Ustekinumab and Vedolizumb in Severe Colitis in HIV Patients

Background: Combined therapy as well as drug sequencing, using induction and maintenance with different therapeutic classes, are possibilities of treatment in inflammatory bowel diseases. Among the different combined biological therapy options, the combination of ustekinumab and vedolizumab is among the most cited since they use different mechanisms of action with a good safety profile. Combined biological therapy has been suggested as an option to achieve better results in cases that are refractory to previous biological treatments or with a high risk of developing complications, and in the concomitance of uncontrolled extra-intestinal manifestation. There is a scarcity in the literature regarding the treatment of IBD and HIV, however, in individuals with controlled disease, there seems to be no restriction on any of the available options. In the presence of severe UC and a history of infections, the ideal therapeutic agent should have a rapid onset of action and a good safety profile in the maintenance treatment. Methods: The present study is a clinical case followed at the Oswaldo Cruz University Hospital, Recife-PE, during the period from February to August 2022, with data collected from the medical records. Results: A 53-year-old male patient with HIV for 14 years, on antiretroviral treatment for 10 years, currently with CD4 308 and an undetectable viral load. He was diagnosed with ulcerative colitis (UC), Montreal E2, in march 2021, with irregular follow-up, frequent hospitalizations until readmission in december 2021 with severe UC activity. He remained dependent on high doses of corticosteroids for about 5 months and presented several infectious complications, such as neurotoxoplasmosis and CMV colitis. He was discharged with disease under clinical control but readmitted for urinary infection and severe UC activity after 4 days of undue corticosteroid suspension. Given the severity and availability of intravenos ustekinumab per donation, it was decided to administer the dose of induction (260 mg). After 2 weeks, there was little clinical improvement, at which time he had access to vedolizumab by the public health system. UC became mildly active at week 2 of induction and the patient was discharged. He is currently in clinical and biomarker remission, on regular maintenance infusions of vedolizumab and steroid-free since week 6 of induction. Conclusion: In the present report, we considered that prolonged and recurrent hospitalizations, prolonged use of corticosteroids and previous infectious complications in patients with severe UC and HIV justified the combination of biological agents. A rapid induction strategy with ustekinumab followed by reinduction and maintenance with vedolizumab was chosen, given its best safety profile. Such association proved to be safe and effective. Although the results are attractive, there is still no formal indication in clinical practice for its use. Thus, combined biological therapy should be prescribed with caution, under consent, with close monitoring and individually indicated.

OA09 Challenging case of psoriatic arthritis: what should we do next?

Introduction/BackgroundPsoriatic arthritis (PsA) is a chronic inflammatory enthesoarthro-osteopathy associated with extra-articular manifestations and several co-morbidities occurring in up to 42% of patients with psoriasis. The heterogeneity of PsA is the reason why the term ‘Psoriatic Disease’ (PsoD) has been proposed to reveal more precisely how the PsA patients suffer.Description/MethodWe report a case of refractory PsA presenting with a flare raising therapeutic challenges.In 2019, a 27-year-old man who was diagnosed since 2014 with PsA and psoriasis presented with flare up of psoriasis affecting almost all of his body and peripheral joints mainly MCPs. There was no uveitis or IBD history.PsArc score: Tender joint count (TJC)=5, swollen joint count (SJC)=4 and VAS= 4/5He was on methotrexate 10 mg orally once weekly that was increased to 15 mg with folic acid once weekly. Unremarkable other medical history.Drug history included: Phototherapy without response (2007), then cyclosporine 100mg BD for six weeks which stopped due to severe mood changes.Unsuccessful trials of 20 mg oral methotrexate once weekly because of elevated liver enzymes, subcutaneous form causing significant neurapraxia, adalimumab (2010-2013) stopped due to secondary failure, ustekinumab (2013-2014) stopped after three injections (primary failure), Infliximab (2014-2015) stopped due to throat swelling during transfusion, apremilast 30mg BD stopped due to complete inefficacy. Secukinumab was started by another trust for one year that helped his condition but he lost follow up, we arranged secukinumab continuation that was very effective for only six months and the patient presented severe flare of his skin in the form of widespread different sized erythematous indurated scaly plaques affecting all his body with PsArc score TJC=10 SJC=6, VAS was 5/5. PASI score 14.In 2020 ixecuzimaub was started by the dermatologists that show dramatic improvement in his skin, PASI score became 1.6 but unfortunately not working for joints with 12 tender joints and evidence of tenosynovitis in almost all small joints of hands. He tried leflunomide 20 mg orally daily but stopped due to deranged liver functions.Investigations showed fluctuating CRP levels (3-87 mg/l), normal blood counts and negative RF.Discussion/ResultsWe present a case of PsA that was treated by almost all synthetic and biologic DMARDS that show high efficacy in most of cases of PsA patients. Certolizumab or golimumab were suggested by Guys and St Thomas hospital to start on. Dual biologic therapy is recently reported in the psoriatic literature including ustekinumab plus etanercept, secukinumab plus etanercept, and apremilast with all biologic agents in patients with plaque psoriasis or psoriatic arthritis not responding adequately to single biologics alone. But there was an increased incidence of urinary tract and upper respiratory infections, including a hospitalization for H2N1 flu in the ustekinumab plus etanercept case.Key learning points/ConclusionMost physicians are often reluctant to prescribe dual biologic therapy because of safety concerns. Very little data exist regarding the safety of dual biologic medications for concomitant psoriasis and psoriatic arthritis. Additionally, the possibility of a major adverse cardiovascular event related to combined biologic therapy has been reported. More research is warranted to explore dual therapy in refractory patients.

COMBINATION BIOLOGIC AND SMALL MOLECULE THERAPY FOR REFRACTORY ULCERATIVE COLITIS

Abstract INTRODUCTION Some inflammatory bowel disease (IBD) patients do not achieve remission with maximal medical therapy. We present a case of refractory UC who achieved clinical, endoscopic, and histologic remission after combining biologic and small molecule therapy. CASE DESCRIPTION A 25-year-old Caucasian male was referred to our clinic for refractory UC. Since diagnosis four years prior, he failed mesalamine, azathioprine (intolerant), adalimumab (secondary nonresponse), vedolizumab (secondary nonresponse) with inability to taper prednisone. Upon presentation to our clinic he was at week 14 of infliximab therapy without clinical improvement. Therapeutic drug monitoring revealed adequate infliximab levels without antibodies. Colonoscopy revealed mayo 2-3 disease with discrete ulcerations (Figure 1). Due to primary non-response, he was initiated on ustekinumab (UST). He remained clinically active despite dose escalation up to evey four weeks and prednisone use. Tofacitinib was initiated with initial clinical improvement, then worsening after 3 months. The Tofacitinib dosing was increased from twice daily to three times daily and repeat colonoscopy revealed pan-colitis with Mayo 2 disease. Due to refractory disease the patient was started on combined therapy of tofacitinib twice daily with UST. On dual therapy the patient experienced progressive clinical improvement. After a year of dual treatment colonoscopy showed no disease activity, and biopsies showed no evidence of cryptitis, or crypt abscesses or active inflammatory infiltrate (Figure 2). DISCUSSION This case highlights the benefit of combination biologic therapy with small molecule therapy in medically refractory IBD. There are limited prospective data to endorse the widespread implementation of combination therapy. A meta-analysis of thirty studies, involving 279 patients, reported 59% were able to achieve clinical remission and 34% achieved endoscopic remission with treatment of dual biologic or small molecule therapy1. Concerns involving safety of combination biologic and small molecule therapy continue to be evaluated. In our case, the patient achieved clinical, endoscopic, and histologic remission with tofacitinib and UST without adverse effects. We present this case to support the safety and efficacy of combination therapy in medically refractory patients. REFERENCES Ahmed W, Galati J, Kumar A et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021. https://doi.org/10.1016/j.cgh.2021.03.034.

COMBINATION BIOLOGIC AND SMALL MOLECULE THERAPY FOR REFRACTORY ULCERATIVE COLITIS

Some inflammatory bowel disease (IBD) patients do not achieve remission with maximal medical therapy. We present a case of refractory UC who achieved clinical, endoscopic, and histologic remission after combining biologic and small molecule therapy. A 25-year-old Caucasian male was referred to our clinic for refractory UC. Since diagnosis four years prior, he failed mesalamine, azathioprine (intolerant), adalimumab (secondary nonresponse), vedolizumab (secondary nonresponse) with inability to taper prednisone. Upon presentation to our clinic he was at week 14 of infliximab therapy without clinical improvement. Therapeutic drug monitoring revealed adequate infliximab levels without antibodies. Colonoscopy revealed mayo 2-3 disease with discrete ulcerations (Figure 1). Due to primary non-response, he was initiated on ustekinumab (UST). He remained clinically active despite dose escalation up to evey four weeks and prednisone use. Tofacitinib was initiated with initial clinical improvement, then worsening after 3 months. The Tofacitinib dosing was increased from twice daily to three times daily and repeat colonoscopy revealed pan-colitis with Mayo 2 disease. Due to refractory disease the patient was started on combined therapy of tofacitinib twice daily with UST. On dual therapy the patient experienced progressive clinical improvement. After a year of dual treatment colonoscopy showed no disease activity, and biopsies showed no evidence of cryptitis, or crypt abscesses or active inflammatory infiltrate (Figure 2). This case highlights the benefit of combination biologic therapy with small molecule therapy in medically refractory IBD. There are limited prospective data to endorse the widespread implementation of combination therapy. A meta-analysis of thirty studies, involving 279 patients, reported 59% were able to achieve clinical remission and 34% achieved endoscopic remission with treatment of dual biologic or small molecule therapy1. Concerns involving safety of combination biologic and small molecule therapy continue to be evaluated. In our case, the patient achieved clinical, endoscopic, and histologic remission with tofacitinib and UST without adverse effects. We present this case to support the safety and efficacy of combination therapy in medically refractory patients. Ahmed W, Galati J, Kumar A et al. Dual Biologic or Small Molecule Therapy for Treatment of Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 2021. https://doi.org/10.1016/j.cgh.2021.03.034.Figure 2Colonoscopy after 1 year of dual therapyView Large Image Figure ViewerDownload Hi-res image Download (PPT)

P9‐82: Combination biologic therapy for refractory asthma: A report of two cases

P9‐82: Combination biologic therapy for refractory asthma: A report of two cases

A control‐based mathematical study on psoriasis dynamics with special emphasis on IL−21 and IFN−γ interaction network

Psoriasis is characterized by the excessive growth of keratinocytes (skin cells), which is initiated by chaotic signaling within the immune system and irregular release of cytokines. Pro‐inflammatory cytokines: Interleukin 21 ( ) and Interferon gamma ( ), released by cell and activated natural killer cells (NK cells) respectively, play central role in the disease pathogenesis. In this work, we have constructed two sets of nonlinear differential equations. One is representing the growth of three vital immune cells (T helper cells (type I and II) and activated NK cells) along with keratinocyte and the other set is for cytokines' ( and ) dynamics. The hazardous effects of these cytokines, preconditions for disease persistence and validation of the stability criteria of endemic equilibrium have been studied analytically. We have also observed the effect of the combined biologic therapy (anti and inhibitor) by considering an optimal control problem. Analytical and numerical results reveal that the impact of activated NK cells on excessive formation of keratinocytes is mostly regulated by the effects of and .

P401 Risk of severe COVID-19 outcomes associated with inflammatory bowel disease medications: Reassuring insights from the United Kingdom PREPARE-IBD multicentre cohort study

BackgroundDuring the early COVID-19 pandemic, the British Society of Gastroenterology (BSG) developed a risk stratification grid to inform the United Kingdom (UK) government regarding strict social isolation, termed “shielding”. This advised inflammatory bowel disease (IBD) patients thought to be most clinically vulnerable to SARS-CoV-2 infection or severe COVID-19 outcomes, to stay at home and minimize face to face contact, even with household members. Those considered at highest risk included recent commencement of combination biologic and immunomodulator therapy, prednisolone ≥20mg/day, presence of comorbidities, age ≥70 years or clinically active disease in those receiving immunosuppression. Mesalazine was not considered to increase risk. An acknowledged limitation was an absence of COVID-19 risk data. This study sought to identify patient or IBD medication-related factors associated with severe outcomes from COVID-19.MethodsPREPARE-IBD was a multi-centre observational United Kingdom (UK) cohort study including adult IBD patients (≥18 years) diagnosed with COVID-19 by PCR between 1st March 2020 and 31st August 2020. The primary outcome was severe COVID-19 defined as requirement for intensive care admission, invasive ventilation or death. We tested associations of severe outcomes with medications and other covariates using multiple logistic regression.Results211 patients were included from 60 UK centres. 56 of 211 patients (26.5%) met the primary outcome. Severe COVID-19 was more common in ulcerative colitis relative to Crohn’s disease patients (33.9% [37/109] vs. 18.6% [16/86], p=0.018). Shortness of breath, nausea and vomiting were more common with severe COVID-19 (p<0.001 and p=0.023 respectively). Multivariable analysis identified co-morbidities and age as associated with severe COVID-19 outcomes; odds ratio (OR [95% CI]) 1.68 (1.23-2.35) for each co-morbidity, and an OR 1.03 (1.00-1.05) with each successive year of age. Neither clinically active IBD (OR 0.58 [0.26-1.26]), non-white ethnicity (OR 1.98 [0.92-4.28]), nor prednisolone use (OR 2.42 [0.47-11.26]) were associated with increased risk. On multivariable analysis, mesalazine was associated with severe COVID-19 outcomes (OR 2.03 [1.01-4.12]). Univariable analysis identified biologics and thiopurines as protective (OR 0.38 [0.15-0.87] and 0.32 [0.092-0.86] respectively). On multivariable analysis no association of severe COVID-19 outcomes with thiopurine or biologic exposure was seen.ConclusionOur data provide reassurance for the continued evidence-based use of corticosteroids, immunomodulators and biologic therapies in IBD during the ongoing COVID-19 pandemic, and is consistent with an as yet unexplained association between mesalazine use and severe COVID-19 outcomes.

Sequential therapy with rituximab and belimumab in patients with systemic lupus erythematosus

Objective: to determine the efficiency of sequential (combined) therapy with rituximab (RTM) and belimumab (BLM) in patients with active systemic lupus erythematosus (SLE).Patients and methods. Twelve patients with true SLE having moderate-to-high activity were followed up. Six of them were noted to have skin and articular manifestations and 6 had kidney damage, vasculitis. The patients took RTM at 500–2000-mg doses, with 6-methylprednisolone as premedication, whereupon they were prescribed BLM according to the standard regimen of 10 mg/kg once monthly. The follow-up period was 1 year. At baseline and every three months after RTM administration, the efficiency and tolerability of therapy were evaluated, the concentrations of autoantibodies and complement components was estimated, and the dose of oral glucocorticoids (GCs) was recorded.Results and discussion. During combined therapy with the biological agents (BAs), there was a considerable clinical and laboratory improvement: reductions in disease activity (median (Me) SLEDAI-2K scores were 12 [9.5; 17] at baseline and 2 [2; 6] at Visit 4), the Me concentrations of anti-double-stranded DNA (anti-ds-DNA) antibodies, 101 [39; 250] and 28 [6; 112] U/ml, respectively; those of complement component 3 (C3), 0.44 [0.39; 0.59] and 0.83 [0.81; 0.87] g/L, respectively; and those of complement C4, 0.06 [0.031; 0.1] and 0.16 [0.15; 0.18] g/l, respectively). Most patients received the medium and low doses of oral GCs as initiating therapy. During the year, the dose of GCs was reduced by more than a quarter and they could be completely discontinued.evaluated, the concentrations of autoantibodies and complement components was estimated, and the dose of oral glucocorticoids (GCs) was recorded. Results and discussion. During combined therapy with the biological agents (BAs), there was a considerable clinical and laboratory improvement: reductions in disease activity (median (Me) SLEDAI-2K scores were 12 [9.5; 17] at baseline and 2 [2; 6] at Visit 4), the Me concentrations of anti-double-stranded DNA (anti-ds-DNA) antibodies, 101 [39; 250] and 28 [6; 112] U/ml, respectively; those of complement component 3 (C3), 0.44 [0.39; 0.59] and 0.83 [0.81; 0.87] g/L, respectively; and those of complement C4, 0.06 [0.031; 0.1] and 0.16 [0.15; 0.18] g/l, respectively). Most patients received the medium and low doses of oral GCs as initiating therapy. During the year, the dose of GCs was reduced by more than a quarter and they could be completely discontinued. Conclusion. Combined biological therapy with RTM and BLM is a promising treatment for active SLE. The use of this regimen promotes a rapid and effective reduction in disease activity, normalization of laboratory markers of SLE (anti-ds-DNA antibody and complement C3 and C4 levels), and decreases in the dose of oral GCs and, as a consequence, in the risk of irreversible organ damages.. Combined biological therapy with RTM and BLM is a promising treatment for active SLE. The use of this regimen promotes a rapid and effective reduction in disease activity, normalization of laboratory markers of SLE (anti-ds-DNA antibody and complement C3 and C4 levels), and decreases in the dose of oral GCs and, as a consequence, in the risk of irreversible organ damages.

S0707 The Use of Combination Vedolizumab and Ustekinumab in Crohn's Disease: A Retrospective Cohort Study

INTRODUCTION: There is limited data on the use of more than one biologic in the treatment of patients with inflammatory bowel disease (IBD). The aim of our study was to determine the effectiveness and safety of combining vedolizumab (VDZ) and ustekinumab (UST) in patients with Crohn's disease (CD). METHODS: We collected data on 30 patients with CD who received treatment with a combination of VDZ and UST from 2015 to 2019 for persistent disease activity or concomitant rheumatologic or dermatologic disease. Clinical scoring and laboratory markers (ESR, CRP, albumin, and vitamin D) were collected at baseline (prior to starting combination therapy) and at follow up (after at least two months on combination therapy). Endoscopic data was collected within 6 months prior to initiation of combination therapy and at follow up (after at least two months on combination therapy). Adverse events were documented. The primary outcome was effectiveness defined by improvement in laboratory parameters, clinical, and endoscopic scoring; the secondary outcome was safety. RESULTS: The mean age was 37 (+/-12.2) years, 63% were female, 73% Caucasian, with a disease duration of 14 (+/-10.6) years. Patients had failed therapy with a median of 2 (2–3) previous biologic medications. The mean ESR decreased, 42.8 vs 27.3, P = 0.04, and mean albumin improved, 3.4 vs 4.0, P = 0.0005. The median HBI score improved from 7 to 5, P = 0.004 at follow up. There was no significant improvement in endoscopic score at follow up, however 50% of the group did not yet have follow up available. There were 5 serious adverse events (SAE), and no deaths. On multivariate analysis, immunomodulator use, longer disease duration, increasing age, and albumin were found to be risk factors for serious infection. CONCLUSION: Combination biologic therapy with VDZ and UST may be an effective option for CD patients with refractory disease or concomitant autoimmune disease inadequately controlled by biologic monotherapy. There appears to be an increased risk of serious infection compared to biologic monotherapy, however this risk might be minimized by discontinuing immunomodulators prior to the initiation of combination therapy. Larger prospective studies are needed to confirm these findings.Table 1Table 2

S2307 COVID-19 in a Patient on Dual Biologic Therapy for Inflammatory Bowel Disease

INTRODUCTION: Preliminary data suggest that dual biologic therapy might be effective and safe in a subgroup of inflammatory bowel disease (IBD) patients. However, the safety and outcomes of dual biologic therapy in IBD with Coronavirus Disease 19 (COVID-19) is unknown. Here, we present a case of a Crohn’s disease (CD) patient on adalimumab (ADA) and ustekinumab (UST) combination therapy who developed COVID-19. CASE DESCRIPTION/METHODS: This is a 24-year-old man with fibrostenotic Crohn’s ileocolitis diagnosed at age 9. He had a secondary loss of response to infliximab despite dose escalation to 10 mg/kg in combination with methotrexate (MTX). He was then transitioned to ADA and dose was escalated to 40 mg weekly with MTX (subsequently self-discontinued MTX). He achieved clinical response but not remission with ADA. Magnetic resonance enterography showed active inflammation in the terminal ileum, distal sigmoid colon, and rectum (Image 1). A colonoscopy showed ulcerated and polypoid mucosa in the terminal ileum and at the ileocecal valve with narrowing and patchy, mild pan-colonic inflammation (Image 2A/B). ADA level was 17 mcg/mL without antibodies. Switching to a different biologic was recommended. The patient was hesitant about discontinuing ADA due to symptomatic improvement. After discussion of risks and benefits, it was decided to bridge with UST and continue ADA with a plan to eventually discontinue ADA if remission was achieved. He received standard intravenous UST loading followed by 90 mg subcutaneously every 8 weeks. Five months later, he tested positive for COVID-19 due to exposure to an infected individual. He was asymptomatic from a respiratory standpoint and his gastrointestinal (GI) symptoms were at baseline. He received a dose of UST 1 day prior to COVID-19 testing and last ADA was 1 week prior to testing. ADA was held and resumed 2 weeks after as he remained without fever, respiratory symptoms or new onset GI symptoms at 2 and 6 weeks after testing positive for COVID-19. DISCUSSION: This case describes a favorable outcome of a CD patient who tested positive for COVID-19 while on ADA and UST. Multiple series have demonstrated that biologic monotherapy is not associated with poor outcomes in COVID-19 infected IBD patients. Instead, corticosteroids, advanced age and co-morbidities are predictors of adverse outcomes. However, more data is needed on the safety of combination biologic therapy in the COVID-19 era.Image 1.: Magnetic resonance enterography (coronal T1 weighted image) showing wall thickening, edema and hyperenhancement involving the terminal ileum over a length of approximately 20 cm with associated vascular engorgement is present.Image 2.: Colonoscopy images showing polypoid stenotic ileoceal valve (A) and the terminal ileum showing ulcerations (B).

Treatment of Juvenile Spondyloarthritis: Where We Stand

Juvenile spondyloarthritis is a subset of juvenile idiopathic arthritis (JIA) with onset in late childhood and adolescence and a strong association with human leukocyte antigen (HLA) B-27 positivity and familial aggregation that has the potential for axial involvement, potentially leading to ankylosing spondylitis. Current therapy for severe disease relies heavily on tumor necrosis factor inhibitors (TNFi). Treatment paradigms in children largely consist of extrapolation from studies on adults with spondyloarthritis. Additional therapies studied in adults include non-steroidal anti-inflammatory drugs (NSAIDs), blockade of the interleukin-17 (IL-17) and IL-23 axes, blockade of T-cell stimulation, phosphodiesterase (PDE)-4 inhibition, and Janus-activated kinase (JAK) pathway alteration. IL-17 blockade and IL-23 blockade are guideline approved after TNFi failure (and even as an alternative to TNFi) in adults, depending on concomitant inflammatory bowel and skin disease, with JAK and PDE-4 inhibition options following biologic failure. Neither pediatric nor adult guidelines address IL-6 blockade, T-cell co-stimulation blockade, or combination biologic therapy.

Sequence of biologic therapies and surgery affects survival in non–small cell lung cancer

Biologic therapy is changing the landscape of lung cancer treatment. The objectives of this study were to compare overall survival (OS) between patients with non-small cell lung cancer (NSCLC) undergoing neoadjuvant and adjuvant biologic therapy in combination with surgery and to evaluate the impact of chemotherapy on survival after combination biologic therapy and surgery. The National Cancer Database was queried for cases of NSCLC from 2004 to 2016. Patient treatment was categorized into neoadjuvant and adjuvant biologic therapy in combination with surgery. Kaplan-Meier curves were generated to compare OS between treatment groups and between those who did and did not also undergo chemotherapy. Cox regression was used to identify factors predictive of OS. Six hundred seventy-three patients underwent both biologic therapy and surgery. The unadjusted overall 5-year OS was longer for patients undergoing neoadjuvant biologic therapy than for those undergoing adjuvant biologic therapy (P = .006), with OS being 56.2% and 33.0%, respectively. When comparing OS between those who did and did not undergo additional chemotherapy, no difference was observed. Neoadjuvant biologic therapy was associated with longer OS than adjuvant biologic therapy. Chemotherapy did not have an effect on OS when combined with biologic therapy and surgery.