Anti-tumor Necrosis Factor Monoclonal Antibody Research Articles

Covering the Cover

Covering the Cover

Reverse Signaling Contributes to Control of Chronic Inflammation by Anti-TNF Therapeutics

Anti-tumor necrosis factor (TNF) monoclonal antibodies and TNF receptor ectodomain fusion protein are in clinical use to neutralize circulating TNF and ameliorate symptoms of many autoimmune diseases and pathological conditions with chronic inflammation. In this paper we present data to prove that reverse signaling, elicited by agonist molecules interacting with the membrane-bound TNF of myeloid cells, significantly contributes to the therapeutic effect of these anti-TNF medicines. Interaction of agonist monoclonals with cell surface TNF significantly attenuates the expression of pro-inflammatory cytokines and induces changes in the production of extracellular and intracellular signaling molecules. This phenomenon is not dependent on the Fc portion of antibodies as Fab constructs are as efficient as full antibody molecules.

Treatment of Sarcoidosis.

In general, sarcoidosis treatment should be offered to palliate symptoms and improve quality of life or to prevent end-organ disease. Symptoms include pulmonary as well as extra-pulmonary manifestations of the disease. The assessment of response to disease includes functional studies such as the forced vital capacity. Radiologic imaging such as chest x-ray has also been used to assess response, although standardized measures have rarely been tested. There are sufficient clinical trials to make specific recommendations regarding treatment of symptomatic pulmonary disease. Initial therapy is usually prednisone or a similar glucocorticoid. However, there are several features of this treatment which are unknown. This includes the initial dose, timing of reduction of dose, and when to discontinue treatment. Since many patients are intolerant of prednisone, steroid-sparing alternatives have been studied. Methotrexate is the most widely used anti-metabolite, but azathioprine, leflunomide, and mycophenolate have also been reported as helpful. The biologic agents, especially monoclonal anti-tumor necrosis factor (anti-TNF) antibodies, have proved effective in patients who have failed other treatments. Infliximab, the most widely studied anti-TNF antibody, has proved effective for a range of refractory sarcoidosis. However, there remain questions regarding dose and duration of therapy. For the clinician, the many treatment options allow for a specific treatment regimen for each patient which minimizes risk while enhancing benefit.

Efficacy of anti-tumor necrosis factor therapy for extra-articular manifestations in patients with ankylosing spondylitis: a meta-analysis.

BackgroundWe performed a meta-analysis to evaluate the effect of anti–tumor necrosis factor (TNF) therapy on the frequency of extra–articular manifestations (EAMs) in patients with ankylosing spondylitis (AS).MethodsWe searched with the terms ‘ankylosing spondylitis’, ‘infliximab’, ‘etanercept’, ‘adalimumab’, ‘golimumab’, ‘certolizumab’, ‘TNF inhibitor/blocker/antagonists’ or ‘anti-TNF’ on MEDLINE, EMBASE and Cochrane Library for randomized controlled trials (RCTs) of ≥12 weeks with parallel or crossover design of TNF inhibitor versus placebo to treat uveitis, inflammatory bowel disease (IBD) and/or psoriasis of AS, published before February 2014.ResultsWe found 8 RCTs that fit our criteria. Anti–TNF therapy was associated with less uveitis than placebo in patients with AS (OR: 0.35, 95% CI: 0.15–0.81, P = 0.01). Subgroup analysis showed receptor fusion proteins were more efficacious for uveitis than placebo (OR: 0.30, 95% CI: 0.09–0.94, P = 0.04), but monoclonal antibodies were not (OR: 0.43, 95% CI: 0.12–1.49, P = 0.18). Anti–TNF therapy and placebo group did not significantly differ in treating IBD in AS patients (OR: 0.75, 95% CI: 0.25–2.29, P = 0.61). In subgroup analysis, neither monoclonal antibodies (OR: 0.45, 95% CI: 0.10–1.92, P = 0.28) nor receptor fusion proteins (OR: 1.52, 95% CI: 0.25–9.25, P = 0.65) significantly differed from placebo in treating IBD. We found no suitable reports on psoriasis.ConclusionsAnti–TNF therapy was preventive for flares or new onset of uveitis in AS patients, and might be an alternative for these patients. However, monoclonal anti–TNF antibodies and TNF receptor fusion proteins were not efficacious for IBD in AS patients.

Development of Vitiligo during Treatment with Adalimumab: A Plausible or Paradoxical Response?

Dear Editor: Adalimumab is a complete human monoclonal anti-tumor necrosis factor α (anti-TNFα) that is generally well tolerated. With increasing use of adalimumab and other anti-TNFα therapies, several cutaneous adverse events have been reported during the therapy, including immune-mediated skin lesions1. A 39-year-old woman who had an 11-year history of Crohn's disease and was treated with adalimumab (40 mg administered subcutaneously every other week) presented at our clinic with multiple achromic macules and patches on the extremities (Fig. 1). The lesions developed abruptly about 12 months after the initiation of adalimumab therapy. The diagnosis of vitiligo was made after the patient's skin turned blue under a Wood's lamp. Laboratory tests were also performed to check for other autoimmune conditions, including thyroid disorders, and no abnormality was diagnosed. The patient denied any family history of vitiligo. She has been treated with a combination therapy of excimer laser and topical tacrolimus without stopping the adalimumab therapy for about 1 year, and has shown minimal response thus far. Fig. 1 Multiple well-demarcated irregularly shaped depigmented macules and patches (A) on the left proximal thigh, (B) dorsum of the right foot, (C) dorsum of the right hand, and (D) right forearm. The role of anti-TNFα inhibitors in the development of vitiligo is complicated and contradictory. There have been several case reports that showed improvement in vitiligo in patients receiving anti-TNFα therapy for other diseases2. The therapeutic effect of anti-TNFα inhibitors on vitiligo might result from stopping the physiological effect of TNFα on melanogenesis. Concretely, it has been reported that TNFα decreases the level of tyrosinase, a rate-limiting enzyme in melanin biosynthesis in vitro3. The melanocytotoxic effect of TNFα in vitiligo has also been demonstrated2. On the contrary, anti-TNFα inhibitors have been associated with the development of a considerable number of autoimmune diseases such as vitiligo, as well as leukocytoclastic vasculitis, systemic lupus erythematosus, psoriasis-like lesions, and alopecia areata1. Several theories were proposed to explain the mechanisms underlying the development of autoimmunity during treatment with anti-TNFα inhibitors. In vivo, nucleosome numbers (major autoantigens released during apoptosis) increase in patients receiving anti-TNFα therapies. This could lead to the subsequent induction of autoantibodies4. To our knowledge, only two cases of vitiligo have been attributed to adalimumab use. The first case was that of newly developed vitiligo after 8 months of adalimumab therapy for Crohn's disease; this was similar to our case5. In the second case, there was rapid deterioration of vitiligo within 3 months of adalimumab therapy for managing ankylosing spondylitis4. In our case, it could not be determined whether vitiligo was caused by adalimumab therapy or if it developed in association with Crohn's disease because the concomitant occurrence of vitiligo with inflammatory bowel disease has been rarely reported. The long duration of Crohn's disease, and the sudden onset and rapid spreading of cutaneous lesions support the former possibility. Previous reports and our case suggest that anti-TNFα agents, including adalimumab, can induce vitiligo development. Dermatologists should be aware of this possibility for an earlier detection and treatment of vitiligo in patients receiving anti-TNFα therapy.

Serum bacterial toxins are related to the progression of inflammatory bowel disease

Objectives. Inflammatory bowel disease (IBD), including Crohn’s disease (CD) and ulcerative colitis (UC), is an autoimmune disease. Disorder of intestinal microbes is thought to play a critical role in the pathogenesis of IBD. Detection of bacterial toxins could become a new approach to judge the situation of this disease. Materials and methods. Serum samples were collected from 142 IBD patients and 40 healthy donors as well as 15 CD patients with anti-tumor necrosis factor (TNF) monoclonal antibody (infliximab [IFX]). Enzyme-linked immunosorbent assay kits for Clostridium difficile, Escherichia coli O157, salmonella, and Staphylococcus aureus were used to analyze these bacterial toxins in sera. Results. The positive rates of bacterial toxins from C. difficile, E. coli O157, salmonella, and S. aureus in the IBD patients were found in low incidences and associated with disease duration, colonic involvement, and treatment with prednisone and immunomodulators. The active CD and UC patients had significant higher positive rates of these bacterial toxins than those in remission or healthy controls. Blockage of TNF with IFX in CD patients resulted in significant decreases of the levels of toxins of C. difficile, E. coli O157, salmonella, and S. aureus in sera. Conclusions. Some bacterial toxins are present in the sera of active IBD patients, and patients with long disease duration, colonic involvement, or treatment with prednisone and immunomodulators are more susceptible to bacterial infection. Inhibition of inflammation with IFX would reduce the bacterial toxins via improvement of intestinal inflammation. Detecting bacteria-derived toxins in sera can be used to predict the progression of IBD.

Inflammatory Bowel Disease: Etiology, Pathogenesis and Current Therapy

Ulcerative colitis (UC) and Crohn's disease (CD) constitute the two major groups of idiopathic disorders in inflammatory bowel disease (IBD). Environmental factors, genetic factors and immune responses have been considered as the major etiology of IBD. Despite the diversified pathogenesis of the disease, no guaranteed curative therapeutic regimen has been developed so far. This review summarizes the knowledge on the pathophysiology and current treatment approaches of IBD. Since IBD is caused by excessive and tissue- disruptive inflammatory reactions of the gut wall, down-regulation of the immune responses may allow the damaged mucosa to heal and reset the physiological functions of the gut back to normal. Current pharmacotherapy through modulation of neutrophil-derived factors, cytokines, adhesion molecules and reactive oxygen/nitrogen metabolites has been utterly described. Categories of treatment modalities include corticosteroids, aminosalicylates, immunomodulators, antibiotics, probiotics, and a series of unique novel agents. The use of anti-tumor necrosis factor monoclonal antibody (Infliximab), recombinant anti-inflammatory cytokines and related gene therapy has been covered. In addition, discussions on dietary supplementation and heparin treatment are also included. The anti-inflammatory and immunoregulatory potential of investigational agents such as nicotine and the filtered protective compounds from tobacco smoke, as well as active herbal medicinal compounds were tested in our previous experimental works, whereas promising findings have been presented here. With the discovery of novel target-oriented agents, more effective and relatively harmless approaches of IBD therapy could be established to achieve a curative outcome. Indeed, more experimental and clinical studies are needed to confirm the relevance of these therapies.

The safety and efficacy of adalimumab in patients with Crohn's disease: the experience of a single Canadian tertiary care centre

Background.Adalimumab (ADA), an antitumor necrosis factor (anti-TNF) monoclonal antibody, is effective in treating moderate-to-severely active Crohn's disease (CD). ADA has been associated with a variety of adverse events (AE). The purpose of this study is to determine the safety and efficacy of ADA in CD patients in clinical practice. Methods.A retrospective analysis was performed on CD patients treated with ADA. Data extracted and analyzed included patient and CD demographics, remission and response rates with ADA, and safety and tolerability of ADA. Results. A total of 149 ADA-treated CD patients were included. The mean duration of therapy with ADA was 20 months with 32% of patients discontinuing treatment. Anti-TNF-naïve and anti-TNF-exposed patients on ADA achieved clinical remission in 45% and 32%, had a clinical response in 23% and 23%, and had no clinical response in 32% and 45%, respectively. Anti-TNF-naïve and anti-TNF-exposed patients maintained remission in 82% and 67%, respectively. Fistulas healed in 19% and improved in 19%. AE occurred in 38% of patients with infection being the most common (20%). Serious infections lead to death in one (<1%). Logistic regression of AE did not identify statistically significant predictors except for colonic disease location (odds ratio [OR] = 0.31, 95% CI = 0.12–0.82, p = 0.018) and the rate of ADA discontinuation (OR = 3.24, 95% CI = 1.58–6.64, p = 0.0013). Conclusion.ADA is an effective treatment for CD. AE can occur commonly leading to discontinuation of medication and may be influenced by disease location. Although serious complications are rare, close monitoring of all patients on ADA is needed.

Golimumab, a Human Anti–Tumor Necrosis Factor Monoclonal Antibody, Injected Subcutaneously Every 4 Weeks in Patients With Active Rheumatoid Arthritis Who Had Never Taken Methotrexate: 1‐Year and 2‐Year Clinical, Radiologic, and Physical Function Findings of a Phase III, Multicenter, Randomized, Double‐Blind, Placebo‐Controlled Study

ObjectiveTo assess 2‐year golimumab efficacy/safety in patients with active rheumatoid arthritis (RA) who had never taken methotrexate (MTX).MethodsRA patients who had never taken MTX (n = 637) were randomized (1:1:1:1) to placebo + MTX (group 1), golimumab 100 mg + placebo (group 2), golimumab 50 mg + MTX (group 3), or golimumab 100 mg + MTX (group 4) every 4 weeks. Nonresponders based on week 28 swollen/tender joint counts changed treatment as follows: group 1 added golimumab 50 mg, group 2 added MTX, group 3 increased golimumab to 100 mg, and group 4 had no change. Most group 1 patients (85%) initiated golimumab 50 mg + MTX at week 28 or subsequently at week 52. After the last patient completed week 52 and blinding was broken, the investigator could escalate golimumab to 100 mg and/or adjust MTX. The co–primary end points (week 24 American College of Rheumatology criteria for 50% improvement [ACR50] response and week 52 change in Sharp/van der Heijde score [SHS]) have been published previously. We now detail week 52 major secondary end points (Health Assessment Questionnaire [HAQ] disability index [DI] scores and SHS among patients with a baseline C‐reactive protein [CRP] level &gt;1.0 mg/dl) and week 104 findings.ResultsAt week 52 for combined groups 3 and 4 versus group 1, the respective proportions of patients achieving ACR20 and ACR50 responses were 63.2% versus 51.9% (P = 0.017) and 45.3% versus 35.6% (P = 0.044). Respective week 52 mean HAQ DI improvements were 0.70 versus 0.58 (P = 0.053); mean SHS changes were 0.41 versus 1.37 (P = 0.006) among all patients and 0.74 versus 2.16 (P = 0.003) in patients with a CRP level &gt;1.0 mg/dl. Improvements were maintained through week 104. Golimumab + MTX for 2 years yielded statistically less radiographic progression than initial MTX or golimumab 100 mg monotherapy. Golimumab safety profiles through weeks 24, 52, and 104 were generally consistent with those observed in other golimumab studies.ConclusionIn RA patients who had never taken MTX, up to 2 years of golimumab + MTX yielded sustained improvements in clinical signs/symptoms, physical function, and radiographic progression.

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Immunogenicity of Monoclonal Antibodies Against Tumor Necrosis Factor Used in Chronic Immune-Mediated Inflammatory Conditions

Knowledge of the immunogenicity of biologic agents may be helpful for the development of strategies for treatment of chronic immune-mediated inflammatory diseases. To summarize the influence of antibodies against biologic agents (AABs [seropositivity]) on efficacy and safety in immune-mediated inflammatory diseases. DATA SOURCES MEDLINE, EMBASE, Cochrane Library, and the Web of Knowledge were searched for articles published in English, Spanish, French, Italian, or Portuguese between 2000 and March 2012. The search strategy focused on synonyms of diseases, immunogenicity, and biologic agents. Abstracts from 2001 to 2011 of the European League Against Rheumatism and American College of Rheumatology congresses were also included. The selection criteria were (1) observational or interventional studies in rheumatoid arthritis, juvenile idiopathic arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis; (2) studies including patients who received biologic agents; and (3) studies collecting data on AABs. Data collected included publication details, study design, characteristics of patients and treatments, presence of antibodies, and definition of response. The primary end point was the association of AABs with response to treatment. Secondary end points were the association of AABs with safety, the association of AABs with concentration of the drug, and the influence of use of concomitant immunosuppressive therapy in the formation of AABs. The search captured 10 728 articles and abstracts. By hand and reverse search, 31 articles were additionally included. After evaluation of the full reports, 60 references were selected. They included 59 studies of anti-tumor necrosis factor monoclonal antibodies: 1 with etanercept, 2 with rituximab, and 2 with abatacept. In rheumatoid arthritis but not in inflammatory bowel disease or spondyloarthritis, seropositive patients presented worse clinical response at 6 months or less (odds ratio [OR], 0.03; 95% CI, 0.01-0.21), and at 6 months or more (0.03; 0.00-0.30) by meta-analysis. In rheumatoid arthritis, discontinuation of the biologic agent for all reasons was more common in seropositive patients (OR, 3.53; 95% CI, 1.60-7.82). In all conditions, seropositive patients had a higher risk of hypersensitivity reactions (OR, 3.97; 95% CI, 2.36-6.67). Overall, concomitant treatment with disease-modifying antirheumatic drugs, including azathioprine, decreased the risk of seropositivity (OR, 0.32; 95% CI, 0.25-0.42). Presence of antibodies against anti-tumor necrosis factor monoclonal antibodies confers a risk of discontinuation of treatment in rheumatoid arthritis and a risk of development of hypersensitivity reactions in all immune-mediated inflammatory diseases. The combined use of anti-tumor necrosis factor monoclonal antibodies and disease-modifying antirheumatic drugs reduces the development of antibodies and subsequent risks. Information on other biologic agents is fragmentary.

SAT0123 Reactivation of latent tuberculosis infection and new infection of tuberculosis in patients with anti-tumor necrosis factor therapy for tuberculosis-endemic area

BackgroundProphylaxis of tuberculosis in patients treated with anti-tumor necrosis factor (Anti-TNF) prevents the latent tuberculosis infections (LTBI). But incidence rate of tuberculosis with anti-TNF therapy in tuberculosis-endemic area is higher...

FRI0332 Etanercept therapy in patients with refractory behcet’s disease: uveitis and beyond.

BackgroundBehcet’s disease (BD) is a chronic relapsing multisystem inflammatory where Tumor necrosis factor alpha is believed to play a pivotal role.[1-3]ObjectivesInvestigate the benefit of one year treatment with etanercept, a...

Effects of adalimumab therapy on musculoskeletal manifestations and health-related quality of life in patients with active psoriatic arthritis

Objectives Adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, was retrospectively evaluated for its effect on musculoskeletal manifestations and health-related quality of life in patients with psoriatic arthritis (PsA) during daily clinical practice.Methods Patients who initiated adalimumab therapy after March 2010 were followed for at least 24 weeks with the clinical outcome measures. Eleven patients, all men with a mean age of 45.4 years, had mean psoriasis durations of 16.2 and 8.4 years at baseline.Results After 24 weeks, 72.7, 63.6, and 45.5 % of the patients met the ACR 20, 50, and 70 response criteria, respectively, while 81.8 % achieved the PsA response criteria. Disease Activity Score using the 28-joint count and CRP declined from 3.2 ± 1.2 at baseline to 1.3 ± 0.4 at week 24 (P < 0.01). The Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores also decreased significantly (both P values were <0.01). After 24 weeks, three out of eight dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey and Physical Component Summary were significantly improved (all P values were <0.05).Conclusions Adalimumab exerted its effect as early as week 4, and it was sustained until the end of the 24-week observation period in the PsA patients.

Diarrhoea in a patient with metastatic melanoma: Ipilimumab ileocolitis treated with infliximab

Administration of ipilimumab, a cytotoxic T-lymphocyte associated antigen-4-blocking monoclonal antibody, leads to enhancement of the anti-tumor T-cell respons and as a result shows a significant survival benefit in metastatic melanoma patients. Therefore patients are currently receiving this promising therapy as a second-line strategy. Unfortunately, by activation of the T-cell immune response, ipilimumab therapy may lead to an unwanted induction of different autoimmune phenomena. Diarrhoea and colitis occur in up to one third of patients. Here we present a case of ipilimumab induced ileocolitis which was successfully treated with infliximab, an anti-tumor necrosis factor monoclonal antibody, after corticosteroid therapy failure. Although formal trials are lacking, recently publicated series suggest that infusional therapy of infliximab is effective in ipilimumab induced ileocolitis.

Poster 114 Multifocal Acquired Demyelinating Sensory and Motor (MADSAM) Neuropathy Secondary to Infliximab Infusion: A Case Report

Disclosures: A. Sinha, No Disclosures. Case Description: A 69-year-old man with a history of ulcerative colitis, status post C4-C7 fusion (secondary to myelopathy over 10 years ago), presented with a 1-year history of right upper extremity pain and paresthesia. Recent MRI of the cervical spine showed evidence of a well-healed fusion from C4-C7 with findings of degenerative changes at C3-4 and C7-T1. The patient did have an MRI of the brachial plexus, which was unremarkable. The patient denied any lower extremity symptoms; however, he did have some paresthesias in the sole of his feet. The patient noted that most of his symptoms began after infliximab infusion therapy for ulcerative colitis. His last infliximab infusion was 8 weeks prior to this appointment. He denied any bowel or bladder dysfunction. On physical examination, the patient was neurologically intact, except for except for 4/5 strength in the right hand intrinsics. There were no upper motor neuron signs. Setting: Outpatient spine practice. Results or Clinical Course: Electrodiagnostic studies of the upper and lower extremities showed prolonged latencies, diminished amplitudes and conduction velocities, in multiple nerves in a non-focal distribution. Diminished recruitment and polyphasic potentials were found in the majority of muscles in the upper and lower extremities. The patient was diagnosed with multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy. He was referred to neurology where he was advised to begin intravenous immunoglobulin (IVIg) therapy. Discussion: Multifocal acquired demyelinating sensory and motor (MADSAM) neuropathy is defined clinically by a multifocal pattern of motor and sensory loss, with nerve conduction studies showing conduction block and features of demyelination. Also known as Lewis-Sumner syndrome, this neuropathy is a rarely reported complication in patients undergoing treatment with the antitumor necrosis factor (TNF) monoclonal antibody infliximab. Symptoms may resolve after cessation of the antibody treatment; however IV Ig infusion therapy is the treatment of choice if symptoms persist. Conclusions: We present a rarely reported case of MADSAM, or Lewis-Sumner syndrome, following infliximab treatment. Clinicians should be aware that electrodiagnostic studies are essential in the diagnosis of this complex neuropathy.

Effects of adalimumab therapy on musculoskeletal manifestations and health-related quality of life in patients with active psoriatic arthritis

Adalimumab, a fully human anti-tumor necrosis factor monoclonal antibody, was retrospectively evaluated for its effect on musculoskeletal manifestations and health-related quality of life in patients with psoriatic arthritis (PsA) during daily clinical practice. Patients who initiated adalimumab therapy after March 2010 were followed for at least 24 weeks with the clinical outcome measures. Eleven patients, all men with a mean age of 45.4 years, had mean psoriasis durations of 16.2 and 8.4 years at baseline. After 24 weeks, 72.7, 63.6, and 45.5 % of the patients met the ACR 20, 50, and 70 response criteria, respectively, while 81.8 % achieved the PsA response criteria. Disease Activity Score using the 28-joint count and CRP declined from 3.2 ± 1.2 at baseline to 1.3 ± 0.4 at week 24 (P < 0.01). The Bath Ankylosing Spondylitis Disease Activity Index and Bath Ankylosing Spondylitis Functional Index scores also decreased significantly (both P values were <0.01). After 24 weeks, three out of eight dimensions of the Medical Outcomes Study 36-Item Short Form Health Survey and Physical Component Summary were significantly improved (all P values were <0.05). Adalimumab exerted its effect as early as week 4, and it was sustained until the end of the 24-week observation period in the PsA patients.

Bone and cartilage destruction in RA and its intervention. Biological agents

The combination therapy of biological agents such as anti-tumor necrosis factor monoclonal antibody and methotrexate resulted in the arrest of joint destruction in most of the patients with rheumatoid arthritis, and even repair of damaged joints in some patients. The fact that the combination therapy leads to less joint destruction than methotrexate monotherapy in patients with comparable disease activity indicates the beneficial effects of biological agents for patients without remission state. Furthermore, the RISING study revealed the importance of sufficient dosing of biological agents such as infliximab because of the different requirement for the dosage of biological agents among patients with rheumatoid arthritis.

Genes Associated with Intestinal Permeability in Ulcerative Colitis: Changes in Expression Following Infliximab Therapy

Alterations in intestinal permeability have been implicated in ulcerative colitis (UC). Infliximab, a monoclonal anti-tumor necrosis factor alpha (TNFα) antibody, can induce clinical response in UC. Gene expression in colonic biopsies taken from responders and nonresponders to infliximab can provide insight into the mechanisms of the altered intestinal permeability at a molecular level. Colonic biopsies (n = 18 anti-TNFα naïve UC patients; n = 8 normal controls; n = 80 Active Ulcerative Colitis Trial [ACT] 1 patients) were analyzed for mRNA expression using gene expression microarrays. Computational reverse causal reasoning was applied to build causal network models of UC and response and nonresponse of UC to treatment. Quantitative reverse-transcription polymerase chain reaction (qPCR) was used to confirm differentially expressed genes. Reverse causal reasoning on mRNA expression data from anti-TNFα-naïve UC and normal samples provided a mechanistic disease model of the biology of gene expression observed in UC. mRNA expression data from the ACT 1 study enabled construction of a mechanistic model describing the biology of nonresponders to infliximab, including evidence for increased intestinal permeability compared with normal and responder samples. Gene expression changes identified as central to intestinal permeability dysregulation were confirmed in normal, UC, and infliximab-treated patients by qPCR analysis. Gene expression returned toward normal levels in infliximab responders, but not in nonresponders. Gene expression analysis and causal network modeling in combination showed that aberrant mRNA expression of genes involved in intestinal epithelial permeability for infliximab responders was restored toward levels observed in normal samples. Infliximab nonresponders showed no equivalent restoration in the expression of these genes.

Familial Mediterranean fever and related periodic fever syndromes/autoinflammatory diseases

The spectrum of periodic fever syndromes (PFS)/autoinflammation diseases is continuously expanding. This review provides an overview of the primary research and an update on the main clinical developments in these disorders published in the past 12-18 months. IL-1β is pivotal to the pathogenesis of most of the PFS. In familial Mediterranean fever (FMF) MEFV mutations lead to gain of pyrin function, resulting in inappropriate IL-1β release that is dependent on ASC but not the NLRP3 inflammasome. Anti-IL-1 therapy is effective in tumour necrosis factor receptor-associated periodic syndrome (TRAPS), whilst both spontaneous and pathogen-associated molecular patterns (PAMPs) induced IL-1β release have been demonstrated in NLRP12-associated periodic syndrome (NAPS12). Somatic NLRP3/CIAS1 mosaicism is a significant cause of cryopyrin-associated periodic syndromes (CAPS). Close connections have also been established between metabolic and inflammatory pathways. In TRAPS increased reactive oxygen species (ROS) of mitochondrial origin leads to production of pro-inflammatory cytokines, whilst NLRP3 inflammasome activation in type 2 diabetes (T2D) is induced by oligomers of islet amyloid polypeptides (IAPP). Caspase 1 activation and IL-1β release is central to the pathogenesis of many autoinflammatory syndromes. This is supported by the effectiveness of anti-IL-1 biologics in treatment of these disorders.