Anti-tumour Necrosis Factor Alpha Treatment Research Articles

Discontinuation of anti-tumour necrosis factor alphatreatment owing to blood test abnormalities, and cost-effectiveness of alternate blood monitoring strategies.

There is no evidence base to support the use of 6-monthly monitoring blood tests for the early detection of liver, blood and renal toxicity during established anti-tumour necrosis factor alpha (TNFα) treatment. To evaluate the incidence and risk factors of anti-TNFα treatment cessation owing to liver, blood and renal side-effects, and to estimate the cost-effectiveness of alternate intervals between monitoring blood tests. A secondary care-based retrospective cohort study was performed. Data from the British Association of Dermatologists Biologic and Immunomodulators Register (BADBIR) were used. Patients with at least moderate psoriasis prescribed their first anti-TNFα treatment were included. Treatment discontinuation due to a monitoring blood test abnormality was the primary outcome. Patients were followed-up from start of treatment to the outcome of interest, drug discontinuation, death, 31 July 2021 or up to 5 years, whichever came first. The incidence rate (IR) and 95% confidence intervals (CIs) of anti-TNFα discontinuation with monitoring blood test abnormality was calculated. Multivariate Cox regression was used to examine the association between risk factors and outcome. A mathematical model evaluated costs and quality-adjusted life years (QALYs) associated with increasing the length of time between monitoring blood tests during anti-TNFα treatment. The cohort included 8819 participants [3710 (42.1%) female, mean (SD) age 44.76 (13.20) years] that contributed 25 058 person-years (PY) of follow-up and experienced 125 treatment discontinuations owing to a monitoring blood test abnormality at an IR of 5.85 (95% CI 4.91-6.97)/1000 PY. Of these, 64 and 61 discontinuations occurred within the first year and after the first year of treatment start, at IRs of 8.62 (95% CI 6.74-11.01) and 3.44 (95% CI 2.67-4.42)/1000 PY, respectively. Increasing age (in years), diabetes and liver disease were associated with anti-TNFα discontinuation after a monitoring blood test abnormality [adjusted hazard ratios of 1.02 (95% CI 1.01-1.04), 1.68 (95% CI 1.00-2.81) and 2.27 (95% CI 1.26-4.07), respectively]. Assuming a threshold of £20 000 per QALY gained, no monitoring was most cost-effective, but all extended periods were cost-effective vs. 3- or 6-monthly monitoring. Anti-TNFα drugs were uncommonly discontinued owing to abnormal monitoring blood tests after the first year of treatment. Extending the duration between monitoring blood tests was cost-effective. Our results produce evidence for specialist society guidance to reduce patient monitoring burden and healthcare costs.

Antitumour necrosis factor alpha treatment in Crohn’s disease: long-term efficacy, side effects and need for surgery

Objectives To examine the long-term efficacy and side effects of antitumour necrosis factor alpha (anti-TNF) therapy in patients with Crohn’s disease (CD), the need for surgery and the clinical outcome after discontinuing anti-TNF therapy. Material and methods Data were collected from the inflammatory bowel disease (IBD)-TNF register at Østfold Hospital Trust. Clinical and sociodemographic data were recorded for patients initiating anti-TNF therapy from January 2000 until December 2011. Follow-up was conducted until December 2017. Results Complete remission (CR) was achieved in 40/154 (26%) patients at the last follow-up (median follow-up time 10 years). A total of 40 (26%) patients had to discontinue treatment due to serious side effects, and malignancy was recorded in 10 (6.5%) patients. Surgical resection was performed in 55 (36%) patients during follow-up. Patients with Montreal phenotype B2 before anti-TNF therapy were estimated to have a 2.54-fold greater risk of surgery than patients with phenotype B1 (p = .001). Of those with phenotype B1 before anti-TNF therapy, 19 (24%) of them developed stenosis in need of surgical resection (‘phenotype migration’). In patients followed up after discontinuing anti-TNF therapy (n = 89, median observational time six years), CR was achieved in most patients. Conclusions Long-term complete remission was achieved in only one in four patients receiving anti-TNF therapy, and one in four patients had to discontinue therapy due to side effects. Despite anti-TNF therapy, one in four patients with a baseline luminal disease phenotype needed subsequent surgical resection.

Paradoxical Skin Reaction to Certolizumab, an Overlap of Pyoderma Gangrenosum and Psoriasis in a Young Woman Treated for Ankylosing Spondylitis: Case Report with Literature Review.

IntroductionBiologic agents form an indispensable part of modern therapeutic regimens for the treatment of severe inflammatory diseases, especially in the fields of rheumatology, dermatology and gastroenterology. They are favoured by both physicians and patients due to their high effectiveness, good patient tolerance and safety. However, interference in the regulation and dynamics of inflammatory cytokines can on occasion lead to an onset of a dermatological condition also known as paradoxical skin reaction. Here, we present a case of paradoxical skin reaction induced by certolizumab.Case ReportA young woman with ankylosing spondylitis developed a severe and complex cutaneous reaction after 6 months of otherwise successful treatment with certolizumab. The diagnosis of a rare paradoxical cutaneous reaction post anti-tumour necrosis factor alpha treatment was based on overlapping features of pyoderma gangrenosum and palmoplantar pustular psoriasis. Alopecia developed and there was also nail involvement. Treatment proved to be challenging as the disease did not remit after the patient ceased treatment with certolizumab. The patient was started on a combination of secukinumab and methotrexate to control the symptoms, with a promising outcome.ConclusionParadoxical skin reactions are an emerging clinical entity that require further research in order to establish risk factors and best personalized treatment.

Long-term efficacy and safety of antitumour necrosis factor alpha treatment in rhupus: an open-label study of 15 patients

BackgroundThe efficacy of antitumour necrosis factor alpha (anti-TNF-α) treatment is well recognised in rheumatoid arthritis (RA) but remains controversial in systemic lupus erythematosus (SLE). Therefore, the role of anti-TNF-α treatment...

Primary nasal tuberculosis during anti-tumour necrosis factor alpha treatment of a patient with rheumatoid arthritis

Anti-tumour necrosis factor alpha (anti-TNFα) therapy is increasingly used in several inflammatory disease processes, including rheumatoid arthritis. However it has a significant potential for adverse events, such as reactivation of latent tuberculosis, which is frequently found in disseminated or extrapulmonary forms. We present a rare case of primary nasal tuberculosis within the context of anti-TNFα therapy for rheumatoid arthritis. To our knowledge, this is the first reported case of primary nasal tuberculosis in a patient with rheumatoid arthritis receiving anti-TNFα therapy.

AB0439 Clinical remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis

BackgroundRheumatoid arthritis is characterised by impaired endothelial function which contributes to increased cardiovascular morbidity and mortality. Modern therapies such as tumour necrosis factor alpha antagonists appear to reduce cardiovascular risk...

Su1284 Role of Anti-Tumour Necrosis Factor Alpha Treatment in Patients With Autoimmune Liver Disease

Su1284 Role of Anti-Tumour Necrosis Factor Alpha Treatment in Patients With Autoimmune Liver Disease

Clinical remission following treatment with tumour necrosis factor-alpha antagonists is not accompanied by changes in asymmetric dimethylarginine in patients with rheumatoid arthritis

ObjectivesRheumatoid arthritis (RA) is characterised by impaired endothelial function which contributes to increased cardiovascular morbidity and mortality. Asymmetric dimethylarginine (ADMA) is an endogenous competitive inhibitor of nitric oxide synthase and contributes to endothelial dysfunction. The aim of the present longitudinal study was to investigate the effects of tumour necrosis factor alpha (TNFα) antagonists on serum concentrations of ADMA in RA patients. Design and methodsThirty-five patients (age (mean±SD) 55±15years, 21 women) who qualified for anti-TNFα therapy were included in the study. ADMA was measured by ELISA in all patients prior to starting anti-tumour necrosis factor alpha treatment, and 2weeks and 3months after initiation of treatment. Generalised estimating equations were used to analyse the change in a range of factors after the treatment commenced, and to test the relationship between ADMA and various inflammatory parameters. ResultsAnti-tumour necrosis factor alpha therapy significantly reduced ESR, CRP, fibrinogen and disease activity score 28 (all p<0.001). ADMA levels did not change significantly following 2weeks or 3months treatment using three different tumour necrosis factor alpha inhibitors, despite the fact that CRP (p=0.016), and DAS28 (p=0.025) were found to be significantly associated with ADMA levels after treatment with TNFα antagonists. ConclusionADMA levels do not change significantly during anti-TNF therapy, despite the fact that they associate with CRP and DAS28, which are significantly reduced during such treatment in patients with rheumatoid arthritis. Levels of inflammation after treatment with TNFα antagonists are significantly associated with ADMA levels in patients with rheumatoid arthritis.

Effect of COX-2 inhibitor lumiracoxib and the TNF-α antagonist etanercept on TNBS-induced colitis in Wistar rats

Crohn's disease (CD) is associated with gut barrier dysfunction. Besides the baseline barrier defect, a subgroup of patients also expresses an intestinal barrier hyperresponsiveness to nonsteroidal anti-inflammatory drugs. On the other hand, the anti-tumour necrosis factor alpha (TNF-α) treatment has brought benefits to these patients. Thus, this study aimed to evaluate the effect of lumiracoxib, a selective-cyclooxygenase-2 (COX-2) inhibitor, and Etanercept (ETC), a TNF-α antagonist on the 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced experimental colitis. A total of 47 Wistar rats were randomized into seven groups, as follows: (1) Sham: sham induced-colitis; (2) TNBS: nontreated induced-colitis; (3) Lumiracoxib control; (4) Lumiracoxib-treated induced-colitis; (5) ETC control; (6) ETC-treated induced-colitis; (7) Lumiracoxib-ETC-treated induced-colitis. Rats from groups 6 and 7 presented significant improvement of macroscopic and histopathological damages in the distal colon. The gene expression of COX-2 mRNA, as well of TNF-α mRNA, decreased significantly in groups 6 and 7 compared to the TNBS nontreated and lumiracoxib-treated groups. The treatment only with lumiracoxib did not reduce the inflammation on TNBS-induced experimental colitis. ETC attenuated the damage seen in the colon and reduced the inflammation caused by TNBS. Our results suggest that down-regulation of TNF-α and COX-2 resulted in a decrease in inflammation caused by TNBS and thus provided some protection from the colonic damage caused by TNBS.

Aseptic meningitis in a patient receiving treatment with anti-tumour necrosis factor alpha

We read with interest the review by Antonio Tristano [1] regarding neurological adverse events associated with antitumour necrosis factor alpha (anti-TNF-a) treatment. We believe that aseptic meningitis is also a potential complication of anti-TNF-a treatment and we report the following case. A 53-year-old plumber presented with 3 weeks of night sweats, fevers and generalised headache. There was no weight loss, recent foreign travel, occupational exposure to sewage or chemicals. He had a single female sexual partner and a recent negative human immunodeficiency virus (HIV) test. He had a pet dog and no further contact with animals or insect bites. His past history included IgA nephropathy (currently quiescent), hypothyroidism and an undifferentiated seronegative inflammatory arthritis. This had involved generalised joint pains but had particularly involved his right ankle and a biopsy had shown synovitis. He was HLA B27 negative. He had been treated with sulphasalazine, which was not tolerated. Despite methotrexate and oral steroids he had continuing right subtalar joint inflammation and adalimumab was added. At presentation his disease was inactive. His medications were levothyroxine, Humira (adalimumab) 40 mg/week since 2008 and oral methotrexate 20 mg/week since 2007 and his arthritis symptoms were well controlled. He was not taking non-steroidal antiinflammatory medication, and took paracetamol (acetaminophen) only for his headache. On admission, examination revealed a pyrexia, \5 splinter haemorrhages, normal heart sounds, chest, abdomen, neurological examination and no meningism, lymphadenopathy or oro-genital ulceration. Investigations showed white cell count 12.7 9 10/L (reference range 3.8–10.6 9 10/L), neutrophil count 9.16 9 10/L (reference range 1.8–6.5 9 10/L), monocyte count 1.12 9 10/L (reference range 0.2–0.8 9 10/L) with C-reactive protein, lactate dehydrogenase and blood film normal. IgA was mildly elevated at 4.11 g/L (reference range 0.8–4.0 g/L). Liver, renal, and thyroid function, plasma viscosity, creatinine kinase, chest X-ray and unenhanced MRI brain/ enhanced MRI spine were normal. Three sets of blood cultures were negative. Urinalysis including Bence-Jones protein and a myeloma screen were negative. Two urine specimens and a sputum specimen were also negative for auramine-phenol stain and tuberculosis (TB) culture after 6 weeks. Complement, extractible nuclear antigens, lupus anticoagulant, anticardiolipin antibody, double stranded DNA and antinuclear antibody were negative. Classical anti neutrophil cytoplasmic antibody (cANCA) was positive (titre 1:320), MPO and PR-3 negative. Cerebrospinal fluid (CSF) was measured serially (see Table 1). Oligoclonal bands were negative. A cytospin with immunophenotyping showed evidence of lymphocyte infiltration, the lymphocyte population consisting of both B and T cells. Cytology revealed reactive lymphocytes. Auramine-phenol stain for TB and TB culture was negative. Cryptococcal antigen and fungal cultures were negative after extended incubation. Herpes simplex virus DNA, enterovirus RNA and CMV (via PCR) were not detected. A CT scan of the thorax/abdomen/pelvis and trans-thoracic echocardiography were normal. HIV and hepatitis A. J. Hamilton (&) N. J. Gutowski Department of Neurology, Royal Devon and Exeter Hospital, Barrack Road, Exeter, Devon EX2 5DW, UK e-mail: alexander.hamilton@nhs.net

A Case of Severe Psoriasis with an Apparent Incomplete Response to Anti-Tumour Necrosis Factor Alpha Treatment

This report covers a case of severe psoriasis that appeared to respond well to treatment with subcutaneous etanercept, with good recovery of the arthropathic component. However, there were distinct areas at the patient's hands and wrists that failed to respond to such treatment. A standard series of patch tests yielded strong positive responses to the vaseline ointment and mercaptobenzothiazole mix, substances that the patient had constantly applied, twice daily, before and during the anti-tumour necrosis factor alpha therapy course, as an emollient, rubber-gloved topical treatment. This case is reported to provide further evidence of the efficacy of etanercept treatment, and to confirm that the immunopathological pathway leading to psoriasis and allergic contact dermatitis (ACD) sometimes goes into 'overdrive' in ACD, giving a mixed pattern, involving each of the branches of the immune system.

Anti‐tumour necrosis factor‐α treatment for perianal Crohn's disease in Australia

To examine the prevalence of perianal Crohn's disease (PCD) and the eligibility of PCD patients to access anti-tumour necrosis factor-alpha (anti-TNFalpha) treatment under current Australian Pharmaceutical Benefits Scheme (PBS) guidelines. A retrospective study of patients with Crohn's disease (CD) and PCD attending four large adult inflammatory bowel disease (IBD) centres in Australia between January 2004 and May 2008. Patients for whom anti-TNFalpha therapy was clinically indicated were assessed to determine whether they satisfied PBS criteria for subsidised medication. Prevalence of CD and PCD in patients attending different IBD centres; eligibility of PCD patients for PBS-subsidised anti-TNFalpha medication. Data were available on 3589 patients, representing about 6% of all patients with IBD in Australia. Of the 1815 patients with CD, 310 (17%) had PCD. Anti-TNFalpha therapy was deemed clinically indicated for 166 patients with PCD (54%), of whom 49 (30%) did not qualify for PBS-funded therapy. Thirty per cent of patients with clinically significant PCD currently do not have access to PBS-subsidised optimal medical treatment. We believe that PBS criteria should be extended to include this subgroup of IBD patients.

Potential Effect of Anti-Tumour Necrosis Factor-Alpha Treatment on Reducing the Cardiovascular Risk Related to Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a chronic systemic inflammatory disease that affects about 1% of the adult population. RA sufferers not only have a high chronic disease burden, but may also experience increased cardiovascular disease (CVD) and mortality as the prevalence of myocardial infarction (MI) is 4 times higher in RA patients than in general population, and there is ample evidence showing that coagulation processes are active in RA. Fibrin accumulation in the synovium is one of the most striking pathological features of rheumatoid synovitis and characteristic RA antibodies such as anti-citrullinated protein antibodies (ACPA) can cross-react with epitopes exposed on fibrin and fibrinogen molecules, and thus impair fibrinolysis. The inflammation, coagulation and fibrinolytic systems are modulated by a common mechanism that includes the involvement of proinflammatory cytokines, such as tumour necrosis factor-alpha (TNF-alpha) and interleukin 6 (IL-6). It has long been recognised that extensive cross-talk takes place between the coagulation pathway and the inflammatory process at various levels, and there is growing evidence that this interaction may be relevant to arthritis. Large-scale, long-term studies have shown that anti-TNF-alpha treatment improves the clinical and laboratory measures of disease activity, and reduces local and systemic inflammation. TNF-alpha blockade may therefore also reduce the impaired coagulation and cardiovascular risk associated with RA. This review provides an overview of the pathophysiological role of TNF-alpha in thrombotic mechanisms and the evidence so far available indicating that anti-TNF-alpha treatment can modify cardiovascular risk in RA.

‘It's magic stuff’: The experiences of patients with ankylosing spondylitis taking anti‐TNF‐α medication

Several studies have identified the efficacy of anti-tumour necrosis factor-alpha (anti-TNF-alpha) treatment in ankylosing spondylitis (AS). However, few studies have explored the perceptions of patients taking this new medication. The aim of this study was to explore the impact of anti-TNF-alpha on the quality of life of people with AS. A qualitative approach was adopted to provide a holistic understanding of participants' views and experiences in the context of their overall lives. Semi-structured interviews were undertaken and transcribed verbatim. Data were analysed using thematic analysis. Ethical approval and informed consent were obtained. Eight people participated and described a significant improvement in their physical and psychological status, leading to a more positive outlook on their life. Specific areas highlighted were employment, activities of daily living, hobbies and relationships with partners and family, some of which are not captured by current AS-specific outcome measures. Negative aspects of anti-TNF-alpha use were described as the inconvenience of monitoring and issues relating to travelling abroad. All participants expressed concern about the possibility of being withdrawn from treatment and the perceived impact this would have on their lives. Anti-TNF-alpha treatment has a positive impact on the lives of people with AS, such that a major concern is being withdrawn from treatment, highlighting the need to provide tailored support to people being withdrawn from treatment. To capture the full impact of anti-TNF-alpha treatment, further consideration needs to be given to the choice of appropriate outcome measures.

Evaluating guidelines on continuation of anti-tumour necrosis factor treatment after 3 months: clinical effectiveness and costs of observed care and different alternative strategies

Objective:To study the adherence of rheumatologists to the Dutch guidelines for anti-tumour necrosis factor alpha (TNF-α) treatment. The secondary objective was to evaluate alternatives to the present guidelines with regard...

The effect of infliximab on circulating levels of leptin, adiponectin and resistin in patients with inflammatory bowel disease

Tumour necrosis factor alpha is a critical mediator of inflammation-related altered metabolism in inflammatory bowel disease (IBD), possibly through its interaction with adipokines, which play an important role in IBD. Infliximab is a well established antitumour necrosis factor alpha treatment in IBD. We studied serum levels of leptin, adiponectin and resistin in 20 IBD patients before and after infliximab treatment using commercially available enzyme-linked immunosorbent assays. The results were correlated with alterations of disease activity, BMI and C-reactive protein. Infliximab induced clinical response or remission in 18 out of 20 treated IBD patients. Mean serum-leptin levels were 4.6+/-0.5 and 5.1+/-0.5 ng/ml (P=0.41), mean serum-adiponectin levels were 10513.9+/-1216.9 and 9653.5+/-1031.5 ng/ml (P=0.36) and mean serum-resistin levels were 26.3+/-4.1 and 13.9+/-1.4 ng/ml (P=0.004), before and after infliximab treatment, respectively. No significant correlation between the changes of BMI, C-reactive protein or the clinical indices of activity and alterations of the examined adipokines was found. Serum levels of leptin and adiponectin had no significant alterations, whereas serum-resistin levels are significantly decreased after infliximab therapy in IBD patients, suggesting a possible proinflammatory status for resistin in IBD and a role as a marker of successful therapy.

Etanercept treatment for three months is safe in patients with rheumatological manifestations associated with hepatitis C virus

The treatment of the rheumatological manifestations associated with hepatitis C virus (HCV) remains difficult. To examine the safety of anti-tumour necrosis factor-alpha treatment, nine patients having rheumatological manifestations associated with HCV were treated with etanercept 25 mg twice a week for 3 months. Five patients had a positive viral load at study entry (Group I), four were negative (Group II). Clinical data recorded were: disease duration, painful and swollen joint count, patient global and physician global assessment, the number of 18 specified fibromyalgia tender points and the Health Assessment Questionnaire score. Laboratory studies included checking for the presence of cryoglobulinaemia and transaminase levels. Quantitative HCV viral RNA was performed by real-time polymerase chain reaction (PCR). At 3 months, no patient was found to have evidence of increased hepatic inflammation based on serial serum transaminase levels. In the five patients from Group I with detectable HCV RNA, no significant viral load increase was observed. No reactivation was observed in the four patients from Group II with undetectable HCV RNA. The effect on the clinical rheumatological manifestations was more heterogeneous but appears to be lower than that observed in rheumatoid arthritis. In this phase II open short-term study, etanercept appeared to be safe in patients with articular manifestations associated with HCV.

Anti-tumour Necrosis Factor-Alpha Treatment of Juvenile Idiopathic Arthritis in a Patient with Common Variable Immunodeficiency

Anti-tumour Necrosis Factor-Alpha Treatment of Juvenile Idiopathic Arthritis in a Patient with Common Variable Immunodeficiency

Anti-tumour necrosis factor alpha treatment in patients affected by rheumatoid arthritis with anti-Ro/SSA antibodies

Anti-tumour necrosis factor alpha treatment in patients affected by rheumatoid arthritis with anti-Ro/SSA antibodies

Tumour necrosis factor-alpha receptor 1 and 2 polymorphisms in inflammatory bowel disease and their association with response to infliximab.

The role of tumour necrosis factor-alpha in the pathogenesis of inflammatory bowel disorders is well-known and is underscored by the effectiveness of antitumour necrosis factor-alpha treatment. Tumour necrosis factor-alpha exerts its effect by binding TNFR1 and TNFR2, which genes map to inflammatory bowel disorders susceptibility loci. Since TNFR1 and TNFR2 are good candidate genes for inflammatory bowel disorders, we studied the functional TNFR2T587G and the TNFR1A36G mutation in 344 Crohn's disease and 152 ulcerative colitis patients and investigated the relation with disease phenotypes. An association with response to infliximab was evaluated in 166 Crohn's disease patients. The TNFR2 587G allele was more frequent in ulcerative colitis compared with controls (P = 0.03). Both single nucleotide polymorphisms were negatively associated with smoking at diagnosis in Crohn's disease (TNFR1A36G odds ratio: 0.614, 95% confidence interval: 0.452, 0.99 and TNFR2T587G odds ratio: 0.572, 95% confidence interval: 0.820, 0.875). There was a positive association between pancolitis and the TNFR1A36G polymorphism in ulcerative colitis (odds ratio: 5.341, 95% confidence interval: 1.484, 19.39). The biological response to infliximab was lower in patients carrying TNFR1 36G (odds ratio: 0.47, 95% confidence interval: 0.234, 0.946). The TNFR2 587G allele was more frequent in ulcerative colitis. Both single nucleotide polymorphisms were negatively associated with smoking in Crohn's disease. A relation between TNFR1A36G and pancolitis was found in ulcerative colitis. There was no clear effect of the polymorphisms on infliximab response although, the TNFR1 minor was associated with a lower response to infliximab.