Anti-tumour Necrosis Factor-α Agents Research Articles

Ankylosing spondylitis: what all should anaesthesiologist know?

Ankylosing Spondylitis (AS) may present significant issues to the anaesthesiologist as potential difficult airway, respiratory and cardiovascular complications, and the concomitant medication therapy to modify symptoms and disease. Awake fibreoptic intubation (AFOI) is a safe option in anticipated difficult airway, as it permits neurological monitoring throughout the attempt at achieving definitive airway. Central neuraxial blockade and peripheral nerve blocks may have good application for these cases. This morbidity renders the patients to greater risk of neurological complications in the peri-surgical period. Neurophysiological monitoring assists the clinician in timely diagnosis and intervention during surgery for cervical spine deformity correction. Addition of anti-tumour necrosis factor-α agents to the medical management has resulted in improved outcomes, however, with concomitant increased potential for wound infections in treated patients. Understanding of potential issues can pave the way for appropriate perioperative management.

Paternal use of medications for inflammatory bowel disease and the risk of hospital-diagnosed infections in the offspring: a nationwide cohort study.

SummaryBackgroundInformation regarding the impact of paternal inflammatory bowel disease (IBD) medications on child outcomes is scarce.AimTo examine the risk of childhood infections associated with fathers' use of anti‐inflammatory/immunosuppressive medications taken before conception.MethodsThis is a nationwide cohort study based on Danish health registries, comprising all live‐born singleton children born between January 1997 and February 2019 who were fathered by men with IBD. Exposed cohorts included children fathered by men treated with 5‐aminosalicylates (5‐ASAs), thiopurines, corticosteroids or anti‐tumour necrosis factor‐α (anti‐TNF‐α) agents within 3 months before conception. The unexposed cohort included children not exposed to paternal IBD medications. Outcomes were the first infection, diagnosed in the hospital setting in the first year of life, and from the age of 1 to 3 years.ResultsIn all, 2178 children were fathered by men exposed to 5‐ASAs, 843 to thiopurines, 417 to systemic corticosteroids and 436 to anti‐TNF‐α agents; 6799 children were unexposed. The adjusted hazard ratio (aHR) for infections within the first year of life for 5‐ASAs was 0.78 (95% CI, 0.66–0.91), thiopurines 0.89 (95% CI, 0.73–1.09), systemic corticosteroids 0.95 (95% CI, 0.70–1.29), and anti‐TNF‐α agents 1.17 (95% CI, 0.94–1.46). The aHR for infections from 1 to 3 years for 5‐ASAs was 0.97 (95% CI, 0.83–1.13), thiopurines 0.87 (95% CI, 0.71–1.07), systemic corticosteroids 1.25 (95% CI, 0.94–1.65), and anti‐TNF‐α agents 0.79 (95% CI, 0.60–1.03).ConclusionFathers' use of anti‐inflammatory/immunosuppressive medications before conception was not significantly associated with childhood infections. These results fill an important research gap regarding paternal medication safety.

P415 Paradoxical onset of Takayasu’s arteritis in patients with inflammatory bowel disease treated with anti-tumour necrosis factor-α agents

Abstract Background Takayasu’s arteritis (TA) is a rare complication associated with inflammatory bowel disease (IBD). TA is a granulomatous systemic vasculitis of uncertain aetiology affecting large arteries, predominantly the aorta and its main branches, leading to stenotic and expansible lesions. The estimated prevalence of coexisting of TA in patients with ulcerative colitis (UC) is 0.3%, and that in patients with Crohn’s disease (CD) is 0.1%. Anti-tumour necrosis factor-α (TNF-α) agents are used to treat both TA and IBD, although some patients with IBD paradoxically develop TA during treatment with anti-TNF-α agents. However, data regarding the incidence and clinical features of TA in such cases are lacking. This study was performed to clarify the prevalence, risk factors, and clinical features of TA that develops paradoxically during treatment with anti-TNF-α agents in patients with IBD. Methods Consecutive patients with IBD who were regularly seen at our centre, a tertiary IBD centre in Japan, from 2000 to 2019 were included in this retrospective single-centre study. We evaluated the prevalence of TA according to the presence or absence of treatment with anti-TNF-α agents and the patients’ clinical manifestations. Results Of 1846 patients with UC and 1249 patients with CD, 7 (0.23%) patients with UC developed TA. The prevalence of TA in patients treated with anti-TNF-α agents was significantly higher (4/254, 1.6%) than that in patients without anti-TNF-α agent treatment (3/1592, 0.19%) (p=0.0087, Fisher’s exact test). Among four patients with UC who paradoxically developed TA during treatment with anti-TNF-α agents, three (75%) received infliximab, one (25%) received adalimumab, and one (25%) received golimumab. One was male and three (75%) were female. The median interval from starting treatment with anti-TNF-α agents to diagnosis of TA was 49.0 (34–63) months. All patients had pancolitis as well as persistent active colitis resistant to anti-TNF-α antibody treatment. The treatments for TA administered after anti-TNF-α therapy were as follows: Two (50%) patients discontinued anti-TNF-α agent therapy, three (75%) were treated with prednisolone, and one (25%) received tocilizumab. No patient required an operation for TA. Conclusion To our knowledge, this is the first study to show the prevalence and clinical features of TA in patients with IBD following administration of anti-TNF-α agent therapy. Although TA is a rare complication, our results suggest that it can develop as paradoxical reaction following administration of anti-TNF-α agents.

A growing family of outcome measurement proposals for hidradenitis suppurativa.

Linked Article: Goldfarb et al. Br J Dermatol 2021; 184:905–912.

EP19 Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis: a case report

EP19 Renal sarcoidosis associated with certolizumab pegol treatment for psoriatic arthritis: a case report

Long-term effectiveness and safety of secukinumab for treatment of refractory mucosal and articular Behçet’s phenotype: a multicentre study

ObjectiveTo evaluate the effectiveness and safety of secukinumab in patients with a mucosal and articular Behçet’s phenotype resistant to conventional and biologic treatment.MethodsA multicentre retrospective study was performed on 15...

Antitumour necrosis factor-α agents and development of new-onset cirrhosis or non-alcoholic fatty liver disease: a retrospective cohort

ObjectiveElevated tumour necrosis factor (TNF)-α has been implicated in the progression of liver fibrosis and pathogenesis of non-alcoholic fatty liver disease (NAFLD). We aim to investigate the impact of anti-TNF-α...

P623 Cumulative incidence of infliximab use after a first flare of acute severe colitis

Abstract Background Since 2005, infliximab (IFX), an anti-tumour necrosis factor-α agent, has proven to be efficient as salvage and maintenance therapy for ulcerative colitis. In 2011, a randomised controlled comparative trial has demonstrated the short-term efficacy as a second-line treatment for acute severe colitis (ASC). Since then, few studies had evaluated the probability of first IFX use after a first flare of ASC. The aim of this study was to assess the cumulative incidence of IFX use after a first flare of ASC occurring after 2011. Methods Between June 2018 and January 2011, all inpatients with a first non-complicated flare of ASC were retrospectively randomised. Steroid resistance was concluded in patients undergoing colectomy or put into second-line medical therapy. Cumulative incidence of IFX use was evaluated by Fine and Gray model, considering colectomy and death as competing events. Results Twenty-five patients were reviewed (median age: 35y. (14-58y.); 11 females and 14 males). Thirty per cent of patients were active smokers. Only one patient had severe comorbidities. Half of the patients were admitted for an inaugural flare. A family history of an inflammatory bowel disease was noted in 12% of cases. sixteen per cent of patients had extraintestinal manifestations. At the moment of presentation, three-quarters of patients were not receiving any immunosuppressive therapy. Truelove and Witts criteria were present in 70% of cases. The average rates of CRP, plasmatic albumin and haemoglobin were respectively 131 mg/dl(43–260), 28 g/l (19–40), and 11g/dl (6,5-14). Sixty-four per cent of the patients responded to first-line medical therapy. Among patients with steroid-refractory colitis (9 patients), timely colectomy was performed in 1 case, 1 patient received cyclosporin (2mg/Kg per day) and 7 patients received infliximab (5mg/Kg on days 0, 14 and 42). Clinical response to second-line medical therapy was observed in 87% of patients. After a median follow- up period of 26 mo. (0,26-81 mo), 4 patients underwent colectomy: 2 urgent colectomies at the same hospitalisation and 2 subsequent colectomies for chronic active disease. Colectomy free survival rate at 5 years was 82%. Cumulative incidence of first infliximab use at 1 and 5 years was, respectively, 40% and 70%. In multivariate analysis, resistance to steroids (p = 0.0005) and history of thiopurines intake (p = 0.002) were significantly associated with subsequent use of IFX. No death was observed during the analysis period. Conclusion During follow-up, the vast majority of patients needed subsequent IFX use after their first flare of ASC.

P572 Clinical outcomes after discontinuation of anti-tumour necrosis factor-α agents in inflammatory bowel disease patients with clinical remission: KASID multicenter study

Abstract Background Despite proven efficacy of anti-tumour necrosis factor-α agents (ant-TNF) for inflammatory bowel disease (IBD), some patients have to be discontinuation of anti-TNF for various reasons in a real-world clinical setting. The aim of this study was to evaluate the long-term outcomes and risk factors of relapse after discontinuation of anti-TNF in IBD patients with clinical remission. Methods A retrospective multicenter cohort study was conducted at 10 referral hospitals, affiliated in IBD Study Group of the Korean Association for the Study of Intestinal Diseases. The study population comprised patients diagnosed with Crohn’s disease (CD) or Ulcerative colitis (UC) who had been treated with anti-TNF (infliximab (IFX) or adalimumab (ADA)) to induce remission and in whom ant-TNF had been discontinued after clinical remission was achieved. The patients were excluded for follow-up of <12 months after discontinuation of anti-TNF. Results A total of 125 IBD patients were eligible. Among them, 109 IBD patients including 71 CD and 38 UC were analyzed and median follow-up period was 56 months (interquartile range, 35–90 months). The reasons of discontinuation of anti-TNF was physician’s decision (n = 32, 29.4%), patient’s own preference (n = 30, 27.5%), anti-TNF-related adverse events/opportunistic infection (n = 18, 16.5%), and other reasons (n = 29, 26.6%). After discontinuation of anti-TNF, relapse occurred in 49 CD patients (69%) and 19 UC patients (50%). Relapse-free survival rate at 1, 2, 3, and 5 years in patients with CD were 11.3%, 31.4%, 46.7%, and 62.5%, respectively, and that in patients with UC was 28.9%, 34.8%, 45.3%, and 60.9%, respectively. Multivariate Cox regression analysis identified the risk of relapse was associated with adalimumab use (vs. infliximab: hazard ratio [HR], 4.41; 95% confidence interval [CI], 1.18–16.41; p = .027) and discontinuation due to physician’s decision (vs. patient’s preference: HR, 0.13, 95% CI, 0.04–0.49, p = .002) in patients with CD, whereas that was decreased in UC patients with mucosal healing (vs. non-mucosal healing: HR=0.07, 95% CI, 0.01–0.58, p = .014). Retreatment with anti-TNF was done in 54 patients (49.5%) and effective in 45 patients(83.3%). Conclusion The discontinuation of anti-TNF was associated with increased risk of relapse. Although retreatment of anti-TNF seems to be effective and safe, the discontinuation of anti-TNF should be carefully considered based on the type of anti-TNF, the reason for discontinuation, and the mucosal healing status.

Early vedolizumab trough levels at induction in inflammatory bowel disease patients with treatment failure during maintenance

Vedolizumab (VDZ) is effective as an induction and maintenance treatment for Crohn's disease and ulcerative colitis, but, as observed with antitumour necrosis factor-α (anti-TNFα) agents, some patients are nonetheless experiencing loss of response. The aim of this study was to investigate the impact of the pharmacokinetics of VDZ during induction on long-term treatment response. This study focused on a single cohort of 103 inflammatory bowel disease patients treated with VDZ. VDZ trough levels (TLs) were measured by enzyme-linked immunosorbent assay (n=536 samples), and thereafter correlated to clinical, biological, endoscopic and serological data. For patients exposed previously to infliximab, antibodies to infliximab were measured at baseline. On the basis of the outcome at the end of follow-up, patients were then categorized into long-term response, optimized and treatment failure groups. During VDZ induction, at week 6, inflammatory bowel disease patients with long-term response had higher TLs compared with patients in the treatment failure group (33 vs. 24 µg/ml, P=0.02). A cut-off TL of 28 µg/ml predicted a sustained response in the follow-up with an area under curve of 0.723 (95% confidence interval=0.567-0.878, P=0.02). Patients with mucosal healing in maintenance had higher TLs at week 6 (41.65 µg/ml) compared with patients with mild (26 µg/ml) or severe endoscopic activity (20.8 µg/ml), P=0.009. Positive perinuclear antineutrophil cytoplasmic antibody serology was associated with lower TLs. Patients previously exposed to anti-TNFα had lower TLs than naive patients (22.5 vs. 36 µg/ml, P=0.03) without any impact of detectable antibodies to infliximab. Finally, the presence of an immunomodulator at induction did not impact on VDZ TLs at induction. We confirmed that a drug exposure-efficacy association was found early on at induction. This study emphasizes that previous exposure to anti-TNFα and positive perinuclear antineutrophil cytoplasmic antibody serology are important factors influencing VDZ TLs at induction.

Burden and outcomes for complex perianal fistulas in Crohn's disease: Systematic review.

AIMTo systematically review the literature on epidemiology, disease burden, and treatment outcomes for Crohn’s disease (CD) patients with complex perianal fistulas.METHODSPubMed, Embase, and Cochrane were searched for relevant articles (published 2000-November 2016) and congress abstracts (published 2011-November 2016).RESULTSOf 535 records reviewed, 62 relevant sources were identified (mostly small observational studies). The cumulative incidence of complex perianal fistulas in CD from two referral-centre studies was 12%-14% (follow-up time, 12 years in one study; not reported in the second study). Complex perianal fistulas result in greatly diminished quality of life; up to 59% of patients are at risk of faecal incontinence. Treatments include combinations of medical and surgical interventions and expanded allogeneic adipose-derived stem cells. High proportions of patients experience lack of or inadequate response to treatment (failure and relapse rates, respectively: medical, 12%-73% and 0%-41%; surgical: 0%-100% and 11%-20%; combined medical/surgical: 0%-80% and 0%-50%; stem cells: 29%-47% and not reported). Few studies (1 of infliximab; 3 of surgical interventions) have been conducted in treatment-refractory patients, a population with high unmet needs. Limited data exist on the clinical value of anti-tumour necrosis factor-α dose escalation in patients with complex perianal fistulas in CD.CONCLUSIONComplex perianal fistulas in CD pose substantial clinical and humanistic burden. There is a need for effective treatments, especially for patients refractory to anti-tumour necrosis factor-α agents, as evidenced by high failure and relapse rates.

TNF-α level affects etanercept clearance: TNF-α concentration as a new correction factor of allometric scaling to predict individual etanercept clearances in patients with ankylosing spondylitis.

Etanercept (ETN) is a widely used anti-tumour necrosis factor-α (TNF-α) agent, which relieves the symptoms of ankylosing spondylitis (AS) by binding to TNF-α to inhibit its inflammation effects. In this study, the effect of TNF-α level on ETN clearance (CL) was investigated, and the TNF-α concentration was initially set as a correction factor for allometric scaling to improve the predictions of individual ETN CLs. Individual ETN CLs and TNF-α concentrations in healthy volunteers and patients with AS were determined by performing ETN pharmacokinetic studies in the two cohorts. Accordingly, individual ETN CLs in both healthy volunteers and patients with AS were predicted from data of two animal species using different methods, including simple allometric scaling, scaling with a correction factor of maximum life span potential or brain weight, and scaling with a correction factor of the TNF-α concentration. The accuracies of such predictions were evaluated by the percentage errors. Consequently, increased TNF-α concentration was shown to improve ETN CL, by comparing both ETN CLs and TNF-α concentrations between healthy volunteers and patients with AS. More importantly, better predictions of individual ETN CLs were achieved in patients with AS using allometric scaling with TNF-α concentration as the correction factor. In conclusion, in vivo levels of TNF-α can affect ETN CL, and allometric scaling corrected with the TNF-α concentration can be used to estimate the individual CLs of anti-TNF-α monoclonal antibodies based on preclinical data.

Preventing Collateral Damage in the Inflammatory Bowel Disease Patient: Using Disease Assessment and Prognostic Factors to Optimise Clinical Outcomes

Inflammatory bowel diseases (IBDs) are chronic disabling conditions. Despite the benefits of anti-tumour necrosis factor-α agents in improving quality of life and reducing the need for surgery in many patients, only one-third achieve clinical remission after 1 year of treatment. It is important that treatments go beyond just the alleviation of symptoms, and help to achieve mucosal healing and deep remission.1 The symposium reviewed the natural course of IBD and discussed how focussing management strategies away from simple symptomatic control towards maintaining mucosal healing can significantly improve the quality of life and wider clinical outcomes of patients with IBD. However, this shift in approach requires the redefining of disease severity to highlight the importance of inflammation control and mucosal healing in preventing long-term damage and disability. Dr Peyrin-Biroulet opened the sessions by reviewing how the Randomised Evaluation of an Algorithm for Crohn’s Treatment (REACT) study has enhanced the understanding of the natural history of IBD, and how complete mucosal healing provides the best outcomes in IBD.2 Dr Colombel highlighted that uncontrolled inflammation in IBD can lead to poor outcomes, and how simple demographic and clinical features can guide the clinician in identifying patients at higher risk for disease complications both at diagnosis and throughout the disease course. Dr Ghosh discussed the importance of defining disease severity in IBD and reinforced that while symptoms related to disease activity are a component of overall disease severity, many factors need to be considered to understand the total impact on a patient’s quality of life.

Next generation of small molecules in inflammatory bowel disease

Inflammatory bowel disease (IBD) encompasses two major entities: ulcerative colitis (UC) and Crohn's disease (CD).1 Both are chronic, progressive, disabling conditions that require lifelong medical treatment in most cases. IBD...

Body mass index and response to abatacept in rheumatoid arthritis.

Previous studies suggested that obesity could negatively affect the response to antitumour necrosis factor-α (TNFα) agents in rheumatoid arthritis (RA). However, data are lacking on whether obesity affects the response to abatacept (ABA). We aimed to determine whether body mass index (BMI) affects the response to ABA in RA. In this multicenter retrospective study, we included RA patients who received ABA. BMI was calculated at the initiation of treatment. After 6 months of treatment, change from baseline in DAS28, pain on a visual analog scale, erythrocyte sedimentation rate and C-reactive protein level, tender and swollen joint count were analysed. The primary endpoint was decrease in DAS28 ≥ 1·2. Secondary outcomes were good response and remission by EULAR criteria. At baseline, among 141 RA patients included, the median [interquartile range] BMI was 26·0 [22·9-30·8] kg/m². The number of patients with normal weight, overweight and obesity was 64 (45·4%), 38 (27%) and 39 (27·6%), respectively. Baseline characteristics did not differ among the three BMI subgroups. Univariate analysis revealed no difference in BMI between responders and nonresponders: DAS28 decrease ≥ 1·2 (25·0 [23·4-31·3] vs. 26·3 [22·9-30·2], P = 0·95), EULAR good response (26·4 [23·5-30·9] vs. 26·0 [22·9-30·6], P = 0·96) and remission (26·7 [21·7-30·3] vs. 26·0 [23·0-30·1], P = 0·83). In our real-life study, BMI did not affect the response to ABA in RA. If confirmed, these results suggest that obesity is not a limitation of ABA use in RA.

Usefulness of sulfasalazine for patients with refractory-ulcerative colits

BackgroundPatients with refractory-ulcerative colitis (UC) require therapy escalation. Sulfasalazine (SASP) could deliver a high concentration of 5-aminosalicylic acid to the colon. The usefulness of SASP for refractory-UC patients, however, is...

Anti-TNFα agents curb platelet activation in patients with rheumatoid arthritis

BackgroundCardiovascular disease is important in rheumatoid arthritis (RA). Tissue factor (TF) is expressed upon platelet activation and initiates coagulation. Anti-tumour necrosis factor-α (TNFα) agents seem to decrease RA-associated cardiovascular events....

Psoriatic alopecia.

Alopecia and other hair abnormalities occurring in patients with psoriasis were first recognized over four decades ago, yet psoriatic alopecia is not a well-known concept among clinicians. Alopecia may be directly related to the psoriasis itself, and can affect both the scalp and other parts of the body. On the scalp, psoriatic alopecia most commonly affects lesional skin, but may present as a generalized telogen effluvium. In most cases, there is regrowth of hair, but in rare cases it can cause scarring alopecia. Histological findings include features of psoriasis in the interfollicular epithelium, along with perifollicular inflammation and atrophy or loss of the sebaceous glands. Late changes include destruction of the hair follicle, with perifollicular fibrosis and 'naked' hair shafts lying free in the dermis. In addition to the hair loss caused by the psoriasis itself, data from population and genetic studies reveal that patients with psoriasis are at greater risk of developing alopecia areata. Psoriasis treatments may also contribute to hair loss. Application of topical preparations may cause hair loss through friction, and many of the systemic treatments used for psoriasis can also cause hair problems. Treatment with anti-tumour necrosis factor-α agents can precipitate de novo psoriasis and subsequent psoriatic alopecia.

Abatacept (cytotoxic T lymphocyte antigen 4-immunoglobulin) improves B cell function and regulatory T cell inhibitory capacity in rheumatoid arthritis patients non-responding to anti-tumour necrosis factor-α agents.

The use of biological agents combined with methotrexate (MTX) in rheumatoid arthritis (RA) patients has strongly improved disease outcome. In this study, the effects of abatacept on the size and function of circulating B and T cells in RA patients not responding to anti-tumour necrosis factor (TNF)-α have been analysed, with the aim of identifying immunological parameters helpful to choosing suitable tailored therapies. We analysed the frequency of peripheral B and T cell subsets, B cell function and T regulatory cell (Treg ) inhibitory function in 20 moderate/severe RA patients, according to the European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) criteria, primary non-responders to one TNF-α blocking agent, who received abatacept + MTX. Patients were studied before and 6 months after therapy. We found that abatacept therapy significantly reduced disease activity score on 44 joints (DAS)/erythrocyte sedimentation rate (ESR) values without causing severe side effects. The size of the circulating B and T cell compartments in RA patients was not significantly different from healthy donors, but B cell proliferation and plasma cell differentiation was impaired before therapy and restored by abatacept. While Treg cell frequency was normal, its inhibitory function was absent before therapy and was partially recovered 6 months after abatacept. B and Treg cell function is impaired in RA patients not responding to the first anti-TNF-α agent. Abatacept therapy was able to rescue immune function and led to an effective and safe clinical outcome, suggesting that RA patients, in whom anti-TNF-α failed, are immunologically prone to benefit from an agent targeting a different pathway.

Humoral immune response to vaccines in patients with rheumatoid arthritis treated with tocilizumab: results of a randomised controlled trial (VISARA)

ObjectiveTo evaluate the effect of tocilizumab (TCZ), an interleukin 6 receptor inhibitor, on humoral immune responses to immunisations in patients with rheumatoid arthritis (RA).MethodsPatients with RA with inadequate response/intolerance to...