TNF Blockade Therapy Research Articles

Association of MICA-129Met/Val polymorphism with clinical outcome of anti-TNF therapy and MICA serum levels in patients with rheumatoid arthritis

MHC class I polypeptide-related sequence A (MICA) is a stress-induced protein involved in activation of NK and T cells through interaction with NKG2D receptor. These molecules are atypically expressed in synovium of patients diagnosed with rheumatoid arthritis (RA). A total of 279 patients with RA, qualified to TNF-blockade therapy, were genotyped for MICA rs1051792 SNP. The effectiveness of anti-TNF agents was assessed with European League Against Rheumatism criteria. Significant relationship between MICA rs1051792 and outcome of TNF-blockade therapy has been found. The MICA rs1051792 GG genotype was overrepresented in patients non-responsive to anti-TNF drugs in comparison with other genotypes (p = 0.010). On the other hand, beneficial therapeutic response was more frequently detected among RA subjects possessing heterozygous genotype than those with homozygous genotypes (p = 0.003). Furthermore, increased MICA concentrations in serum were observed in patients possessing MICA rs1051792 GG genotype as compared with those with GA or AA genotypes (p = 1.8 × 10−5). The results from this study indicate the potential influence of MICA rs1051792 polymorphism on modulation of therapeutic response to TNF-blockade treatment in RA.

Impact of prophylactic TNF blockade in the dual PD-1 and CTLA-4 immunotherapy efficacy and toxicity

The TNF blockade therapy is currently a well-established treatment option for a variety of autoimmune diseases such as rheumatoid arthritis (RA), psoriasis or Crohn's disease, given the proinflammatory role of TNF in the course of these diseases. Importantly, TNF neutralization is also used for the treatment of corticosteroid-refractory immune-related adverse events (irAEs) induced by the combined anti-PD-1 and anti-CTLA-4 immunotherapy. The manifestation of these toxicities is an important limiting factor for the successful implementation of the inhibitory checkpoint blockade therapy (ICB), restraining its anti-tumor efficacy. In our recent study (Perez-Ruiz et al., Nature 569(7756): 428-432.), we analyzed the potential impact of prophylactic TNF neutralization therapy in the anti-PD1/CTLA-4 efficacy. Through several mouse models, we demonstrated that TNF neutralization ameliorated ICB-exacerbated colitis in addition to improving ICB-dependent anti-tumor efficacy. Similar results were obtained after prophylactic TNF blockade in graft vs host xenografted mouse models with human immune cells, which showed a reduction in colitis and hepatitis. Importantly, there was a preservation of the immunotherapeutic control of xenografted tumors after ICB treatment. Moreover, TNF and TNF-dependent gene expression is upregulated in the colon mucosa from patients affected by colitis as a side effect of ipilimumab and nivolumab. Our results, thus, provide evidence of the successful combination of prophylactic TNF neutralization with ICB therapy strategy to ameliorate toxicities, while keeping or even ameliorating anti-tumor efficacy. The prophylactic TNF blockade strategy is clinically feasible since excellent TNF inhibitors have been approved for the treatment of autoimmunity and are used for the immune-related serious adverse events in immunotherapy.

TNF and Bone Remodeling.

The mechanisms involved in the TNF-mediated deregulated bone remodeling are little appreciated. This review will discuss and summarize the impact of TNF, Notch, and RBP-J signaling on bone remodeling. The integrity of the adult skeleton undergoes constant and dynamic remodeling throughout life to maintain a proper bone homeostasis, which is achieved by the essential tight control of coupling between osteoclast-mediated bone resorption and osteoblast-mediated bone formation. The studies in this field include not only the differentiation and function of osteoblasts and osteoclasts, but also the mechanisms that simultaneously control both cell types during bone remodeling. Chronic inflammation is one of the most evident and common pathological settings that often leads to deregulated bone remodeling. The resounding success of TNF blockade therapy has demonstrated a key role for TNF in inflammation and the pathogenesis of inflammatory bone resorption associated with diseases such as rheumatoid arthritis and periodontitis. Recent studies have highlighted the function of Notch and RBP-J signaling in both physiological and TNF-mediated inflammatory bone remodeling.

Use of a 12-week observational period for predicting low disease activity at 52 weeks in RA patients treated with abatacept: a retrospective observational study based on data from a Japanese multicentre registry study.

Only a few studies have assessed predictive factors for the long-term efficacy of abatacept. This study aimed to provide clinical evidence of an adequate observational period for predicting low disease activity (LDA) achievement at 52 weeks in RA patients treated with abatacept. Participants were all patients registered in a Japanese multicentre registry who were treated with abatacept and had at least 52 weeks of follow-up (n = 254). Areas under the receiver operating characteristic curves for the 28-joint count with CRP (DAS28-CRP) at each time point for LDA achievement at 52 weeks were: 0.686 (cut-off score: 4.6) at baseline, 0.780 (3.8) at 4 weeks, 0.875 (3.3) at 12 weeks, and 0.900 (3.0) at 24 weeks. Although patients with a DAS28-CRP score < 3.0 at 24 weeks had the highest proportion of LDA achievement at 52 weeks (79.3%), the proportion for those with a score < 3.3 at 12 weeks was comparable (77.2%, P = 0.697). Proportions were significantly lower in patients with a score < 3.8 at 4 weeks or < 4.6 at baseline. Multivariate logistic regression demonstrated that a DAS28 score of < 3.3 at 12 weeks was an independent strong predictor for LDA at 52 weeks (adjusted odds ratio: 15.2, P < 0.001). Twelve weeks is an adequate observational period to judge the long-term clinical efficacy of abatacept, and is about as early as the period for assessing TNF blockade therapy.

OP0051 Differential Methylation Related to Response to Etanercept in Patients with Rheumatoid Arthritis

BackgroundThe introduction of biologic drug therapies targeting specific components of the inflammatory response represents a huge advance in the treatment of rheumatoid arthritis (RA). Despite this, up to 40% of...

α-MSH-Stimulated Tolerogenic Dendritic Cells Induce Functional Regulatory T Cells and Ameliorate Ongoing Skin Inflammation

The neuropeptide α-melanocyte-stimulating hormone (α-MSH) is a well-known mediator of skin pigmentation. More recently, it has been shown that α-MSH also exerts a strong anti-inflammatory and immunosuppressive activity. To elucidate the mechanisms underlying α-MSH-induced immunosuppression, we investigated whether α-MSH affects dendritic cell/T cell communication, as especially this interaction has an important role in the regulation of immune responses. Here, we show that α-MSH, by binding to MC-1R, induced tolerogenic dendritic cells, which were capable of expanding CD4(+)CD25(+)Foxp3(+) regulatory T cells (Tregs) in vitro, as well as in vivo. Notably, those α-MSH-induced Tregs were functional as they efficiently inhibited cutaneous contact allergy and ongoing psoriasis-like skin inflammation in mice. Furthermore, α-MSH induced tolerogenic dendritic cells capable of generating functional Tregs in human blood. Interestingly, human Tregs expanded via α-MSH-stimulated dendritic cells suppressed the proliferation and cytokine secretion of pathogenic T-helper-17 (Th17) cells from individuals with psoriasis. Taken together, these data indicate that α-MSH induced immunosuppressive Tregs in vitro and in vivo, which inhibited disease progression in a mouse model of psoriasis-like skin inflammation and suppressed the activation and proliferation of effector T cells from subjects with psoriasis.

Spondyloarthritides: evolving therapies

TNF blockade therapy has substantially advanced the treatment of peripheral spondyloarthritides but revolutionised the treatment of severe ankylosing spondylitis. The capacity of biologic treatment to improve dramatically symptoms and quality of life in patients with spinal disease is undoubted, although important questions remain. Notable amongst these are concerns about skeletal disease modification and the true balance between costs and effectiveness. Guidelines for the biologic treatment of ankylosing spondylitis and psoriatic arthritis have been introduced in North America and Europe with considerable consensus. However, the absence of clear criteria for the diagnosis of early disease leaves the issue of biologic treatment of ankylosing spondylitis at the pre-radiographic stage unresolved. Newer biologic agents are entering the field, although superiority over TNF blockers will be difficult to demonstrate.

S1105 Psoriasis and Eczema Skin Lesions Associated with TNF-Blockade Therapy in IBD: Natural History and Clinical Characteristics

S1105 Psoriasis and Eczema Skin Lesions Associated with TNF-Blockade Therapy in IBD: Natural History and Clinical Characteristics

Induction and exacerbation of psoriasis with TNF-blockade therapy: A review and analysis of 127 cases

Background: There are reports of rare adverse effects of tumor necrosis factor (TNF) inhibitors, including infections, malignancies, and induction of autoimmune conditions. Intriguing, are cases of induction or exacerbation of psoriasis in conjunction with TNF inhibitor therapy, given that they are approved for treatment of the same condition. Objective: Published cases of psoriasis occurring during anti-TNF therapy were analyzed, including overviews of proposed etiologies and treatment recommendations. Methods: A literature search using Ovid MEDLINE and PubMed was performed for articles published between January 1990 and September 2007 to collect reported cases of psoriasis in patients receiving therapy with TNF blocking agents. Results: A total of 127 cases were identified: 70 in patients on infliximab (55.1%), 35 with etanercept (27.6%), and 22 with adalimumab (17.3%). Females comprised 58% of cases; mean age of reported patients was 45.8 years, and the time from initiation of treatment to onset of lesions averaged 10.5 months. These patients suffered from a number of primary conditions, with rheumatoid arthritis, ankylosing spondylitis, and Crohn's disease accounting for the vast majority. Palmoplantar pustular psoriasis was observed in 40.5% of the cases, with plaque-type psoriasis in 33.1%, and other types comprising the remainder. Topical corticosteroids were the most commonly employed treatment modality but led to resolution in only 26.8% of cases in which they were employed solely. Switching to a different anti-TNF agent led to resolution in 15.4% of cases. Cessation of anti-TNF therapy with systemic therapy led to resolution in 64.3% of cases. Conclusion: More information and cases are needed. Biopsies of TNF-blockade-induced lesions may reveal what cytokines and cell types drive the development of these lesions. Additionally, there is a need to develop an algorithm to treat this paradoxical side effect of therapy with TNF-blockers.

A case of rheumatoid arthritis complicated by demyelination in both cerebral cortex and spinal cord during etanercept therapy

Tumor necrosis factor (TNF) antagonists, including etanercept, have been approved for the treatment of rheumatoid arthritis (RA). These agents are not free of adverse events like other antirheumatic agents. Several important adverse events in CNS lesions have been reported. In this paper, we report on one patient with RA that had complications from a demyelinating disorder during TNF-blockade therapy using etanercept at 24 months after initial administration. A 66-year-old Japanese woman was diagnosed with RA in 1959. She received various disease-modifying antirheumatic drugs (DMARDs), but all of these agents were ineffective. She was administered etanercept in June 2005, and stayed well. Twenty-four months after the initial administration of etanercept, she developed palsy of bilateral upper extremities and gait disturbance subacutely, and was then admitted to our institute in August 2007. MRI of her spinal cord revealed a high-intensity lesion from the third through to the seventh cervical (C3-C7) levels. Additionally, T2-weighted MRI images showed disseminated high-intensity lesions in the white matter of brain. She was suspected of having a demyelinating disorder based on these MRI findings. There was no significant finding that pointed to another neurological disorder. High-dose corticosteroid therapy was conducted and was effective for her.

Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs

Tumor necrosis factor (TNF) is a prototypic proinflammatory cytokine that contributes significantly to the development of immunopathology in various disease states. A complication of TNF blockade therapy, which is used increasingly for the treatment of chronic inflammatory diseases, is the reactivation of latent tuberculosis. This study used a low-dose aerogenic model of murine tuberculosis to analyze the effect of TNF neutralization on disease progression in mice with chronic tuberculous infections. Histological, immunohistochemical, and flow cytometric analyses of Mycobacterium tuberculosis-infected lung tissues revealed that the neutralization of TNF results in marked disorganization of the tuberculous granuloma, as demonstrated by the dissolution of the previously described B-cell-macrophage unit in granulomatous tissues as well as by increased inflammatory cell infiltration. Quantitative gene expression studies using laser capture microdissected granulomatous lung tissues revealed that TNF blockade in mice chronically infected with M. tuberculosis leads to the enhanced expression of specific proinflammatory molecules. Collectively, these studies have provided evidence suggesting that in the chronic phase of M. tuberculosis infection, TNF is essential for maintaining the structure of the tuberculous granuloma and may regulate the granulomatous response by exerting an anti-inflammatory effect through modulation of the expression of proinflammatory mediators.

Influence of biologic therapy on return to work in people with work disability due to ankylosing spondylitis

To answer the question 'does TNF blockade therapy enable people with severe AS to return to work or work more productively?'. All patients with AS currently receiving anti-TNF therapy at two UK Hospitals were asked to complete a questionnaire. This asked about occupational history, type of work, degree of job-related physical activity, working hours and sickness absence from work both currently (on anti-TNF treatment) and pre-treatment. Sixty-five patients (72.3% male), aged 29-64 (mean 46.1) yrs, whose duration of anti-TNF treatment ranged from 3 to 56 (mean 19.1) months were studied. Twenty-four (36.9%) patients were receiving infliximab, 21 (32.3%) etanercept and 20 (30.8%) adalimumab. Pre-treatment, 46 (70.8%) were in employment (1 was a student); 38 (58.5%) were working full-time and 8 (12.3%) part-time; 19 (29.2%) were not working. On treatment, 50 (76.9%) patients were working, 44 (67.7%) full-time and 6 (9.2%) part-time. Two individuals who worked part-time pre-treatment had returned to work full-time. Thus, on treatment, 4 of the 19 patients who were previously unable to work returned to employment, and 2 others increased their work from part-time to full-time. Patients rated the effect of AS on work capacity as 7.05/10 pre-treatment and 2.92/10 post-treatment. Those who were working lost, on average, 15 days from work due to sick leave in the 12 months pre-treatment and 0.91 days in the first 12 months on treatment. Treatment of active AS with TNF blockade appears to be associated with improved capacity for work.