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Introduction: The development of certain immune-mediated diseases (IMD) in patients with inflammatory bowel diseases [IBD; Crohn's disease (CD), ulcerative colitis (UC)] has been linked to treatment of IBD. Hair loss in some patients may be due to immune-mediated alopecia areata (AA). Risk factors and outcomes of AA in patients with IBD have not been previously explored. Methods: This was a retrospective, multi-center case–control study. Cases were identified as individuals who developed IBD before AA diagnosis. Controls comprised of those who were never diagnosed with AA and treated contemporaneously, selected using random number generator. We extracted demographic and IBD treatment history. Severity of Alopecia Tool (SALT) was used to stratify AA severity. AA outcomes and interventions were compared within controls. Results: We identified 58 cases and 90 controls. Cases had significantly higher rate of tumor necrosis factor α antagonist (anti-TNF) use compared to controls (40.7% vs. 20.0%, p = 0.006). Both groups had similar IBD disease location, behavior, and related surgery. Majority of cases had endoscopic remission or mild disease activity at AA diagnosis. There was no difference in partial or complete improvement of AA between those who stopped or continued IBD therapy (p = 0.57). Those with severe AA were significantly less likely to have complete (0% vs 33.3%, p = 0.01) or any improvement (50% vs 84.9%, p = 0.02) of AA compared to those with non-severe AA. Discussion: Individuals with IBD who later develop AA were more likely to have been on anti-TNF at time of AA onset. Severity of AA was a significant predictor of AA resolution. Fortunately many patients had improvement in their AA despite continuation of IBD therapy. [ABSTRACT FROM AUTHOR]

Tumor necrosis factor (TNF) inhibitors have been used as an excellent therapeutic option in a variety of chronic inflammatory conditions. However, a recognized significant adverse effect of TNF inhibitor therapy is the increased risk of infections. The influence of TNF inhibitors on the course of coexisting or newly developed viral infections has not been extensively investigated. Therefore, we reviewed the recent publications to highlight the incidence, clinical features, management, and prevention of herpes zoster in patients who are receiving TNF inhibitors.

Anti-TNFα are recommended for preventing Crohn's disease (CD) postoperative recurrence (POR) in patients with risk factors. However, few data exploring anti-TNFα efficacy in patients with preoperative anti-TNFα failure are available so far. The aim of the present study was to compare the efficacy of anti-TNFα with other biologics and immunosuppressants to prevent POR in this setting. Consecutive CD patients who underwent bowel resection between January 2010 and December 2019 after failure of at least one anti-TNFα were retrospectively included among three tertiary centers if they started a postoperative medical prophylaxis within the three months after index surgery. The main outcome was to compare rates of objective recurrence (endoscopic or radiological recurrence in absence of colonoscopy) between patients treated with an anti-TNFα agent or another treatment as prevention of POR. Among the 119 patients included, 71 patients received an anti-TNFα (26 infliximab, 45 adalimumab) and 48 another treatment (18 ustekinumab, 7 vedolizumab, 20 azathioprine and 3 methotrexate) to prevent POR. Rates of objective recurrence at two years were 23.9% in patients treated with anti-TNFα and 44.9% in the others (p = 0.011). Anti-TNFα remained an effective option to prevent POR for patients operated upon with previous anti-TNFα failure. [ABSTRACT FROM AUTHOR]

Although dementia is a heterogenous group of diseases, inflammation has been shown to play a central role in all of them and provides a common link in their pathology. This review aims to highlight the importance of immune response in the most common types of dementia. We describe molecular aspects of pro-inflammatory signaling and sources of inflammatory activation in the human organism, including a novel infectious agent, SARS-CoV-2. The role of glial cells in neuroinflammation, as well as potential therapeutic approaches, are then discussed. Peripheral immune response and increased cytokine production, including an early surge in TNF and IL-1β concentrations activate glia, leading to aggravation of neuroinflammation and dysfunction of neurons during COVID-19. Lifestyle factors, such as diet, have a large impact on future cognitive outcomes and should be included as a crucial intervention in dementia prevention. While the use of NSAIDs is not recommended due to inconclusive results on their efficacy and risk of side effects, the studies focused on the use of TNF antagonists as the more specific target in neuroinflammation are still very limited. It is still unknown, to what degree neuroinflammation resulting from COVID-19 may affect neurodegenerative process and cognitive functioning in the long term with ongoing reports of chronic post-COVID complications. [ABSTRACT FROM AUTHOR]

Although dementia is a heterogenous group of diseases, inflammation has been shown to play a central role in all of them and provides a common link in their pathology. This review aims to highlight the importance of immune response in the most common types of dementia. We describe molecular aspects of pro-inflammatory signaling and sources of inflammatory activation in the human organism, including a novel infectious agent, SARS-CoV-2. The role of glial cells in neuroinflammation, as well as potential therapeutic approaches, are then discussed. Peripheral immune response and increased cytokine production, including an early surge in TNF and IL-1β concentrations activate glia, leading to aggravation of neuroinflammation and dysfunction of neurons during COVID-19. Lifestyle factors, such as diet, have a large impact on future cognitive outcomes and should be included as a crucial intervention in dementia prevention. While the use of NSAIDs is not recommended due to inconclusive results on their efficacy and risk of side effects, the studies focused on the use of TNF antagonists as the more specific target in neuroinflammation are still very limited. It is still unknown, to what degree neuroinflammation resulting from COVID-19 may affect neurodegenerative process and cognitive functioning in the long term with ongoing reports of chronic post-COVID complications.

We report the clinical case of an emergent Crohn’s disease (CD) as a paradoxical effect after 24 months of successfully treatment with etanercept for active ankylosing spondylitis in a young women. Despite rapid and sustained response of articular disease (remission achieved as soon as three months and maintained through the entire period of administration), new onset intestinal manifestations developed during biological therapy. A complex assessment comprising clinical, endoscopic and histopathologic evaluation, associated with high levels of fecal calprotectin confirmed drug-induced inflammatory bowel disease (IBD) compatible with CD. Although optimal treatment strategy is not yet validated, discontinuation of putative etanercept and cycling to a monoclonal anti-TNF antibody (adalimumab) demonstrated positive outcomes for both articular and IBD. New onset CD may be considered as an immune-mediated injury induced etanercept and should be considered in any patient with spondylarthritis in whom IBD develops with a clear temporal relationship with TNF inhibitors, especially etanercept.

TNF antagonists such as infliximab are effective for the treatment of several inflammatory and autoimmune diseases. Recent clinical studies have advocated the importance of measuring trough infliximab levels to guide treatment decisions. We have developed a novel assay for measuring serum free infliximab levels using inductively coupled plasma-mass spectrometry (ICP-MS). The method involves the incubation of patient serum in wells coated with recombinant TNF, followed by detection with lanthanide-labeled monoclonal anti-human IgG1 and ICP-MS analysis. Full method validation was performed and results for clinical samples tested with the new method were compared with those obtained from a capture ELISA and a cell-based assay. Validation of the ICP-MS assay revealed a lower limit of detection of 0.4 μg/mL in serum. The linear range of quantitation was 1–50 μg/mL. The within-run and between-run precision had a coefficient of variation (CV) of <10%, and the accuracy of the assay had a CV of <15%. In serum samples, the ICP-MS method was devoid of analytical interferences by high levels of hemoglobin, bilirubin and triglycerides. Serum sample results from 123 drug-naïve donors revealed a test cutoff at 0.5 μg/mL. Test results from clinical samples obtained by the ICP-MS method showed strong correlation with both the ELISA and cell-based assay. The ICP-MS methodology presented in this study is a robust method for measuring TNF antagonist serum levels, which makes it well suited for therapeutic drug monitoring in the clinical laboratory. [ABSTRACT FROM AUTHOR]

Aim: To evaluate outcomes of early dose optimization of golimumab in ulcerative colitis (UC) patients with inadequate response to golimumab induction treatment. Methods: This observational, multicenter, cohort study included patients with moderate-to-severe active UC and with inadequate response to subcutaneous golimumab induction doses, in whom weight-based golimumab maintenance dose (European labeling) of 50 mg every 4 weeks (q4wk) was optimized before week 14 to 100 mg q4wk. At week 14, we assessed clinical response and remission using the partial Mayo score. In the long term we evaluate the cumulative probabilities of golimumab failure-free survival and colectomy-free survival. Results: A total of 209 patients who received golimumab induction doses were eligible. Of these, 151 patients (72.2%) weighing less than 80 kg were assigned to a golimumab maintenance dose of 50 mg q4wk. Twenty-four patients (15.9% [12.5% overall]), in whom scheduled doses of 50 mg q4wk were optimized to 100 mg q4wk before week 14, compose the study population. At week 14, 16 patients (66.7%, 95% CI 45.7-87.6) had clinical response, of these 12 were corticosteroid free. Four patients (16.7%) achieved corticosteroid-free remission. After a median follow-up of 12 months (IQR 10-22), 13 patients (54.2%) maintained clinical benefit. Thirteen of 16 patients (81.2%) with clinical response at week 14 maintained clinical benefit at last follow-up. All patients avoided colectomy. In none of the patients was golimumab dose de-escalated. There were no adverse events leading to golimumab withdrawal. Conclusion: Early optimization of golimumab dose induces clinical response at week 14 in two thirds of UC patients and leads to long-term clinical benefit in over half of patients. [ABSTRACT FROM AUTHOR]

Lara el Hayderi, Fany Colson, Bita Dezfoulian, Arjen F Nikkels Department of Dermatology, CHU du Sart Tilman, University Hospital of Liège, Liège, Belgium Abstract: As TNF-α is a major factor in the immune defense against herpes zoster (HZ); an increased incidence and severity of HZ cases were suspected in patients undergoing treatment with TNF antagonists. Several studies and clinical experience provided evidence that the incidence of HZ increases by twofold to threefold in this patient category. The number of severe cases of HZ, with multisegmental, disseminated cutaneous, and/or systemic involvement, is also increased. Concerning psoriasis patients under biologicals, the clinician should be more alert for an eventual HZ event, in particular during the first year of biological treatment, and be aware of the possibility of more severe HZ cases. HZ may also undergo an age-shift toward younger patients. Rapid identification of risk factors for severe HZ, such as severe prodromal pains and/or the presence of satellite lesions, is recommended. The treatment recommendations of HZ in this patient group are identical to the recently published guidelines for the management of HZ. The live attenuated viral vaccine OKA/Merck strain anti-HZ vaccination is recommended before initiating biological treatment in psoriasis patients. The new adjuvanted anti-HZ vaccine will probably also benefit patients while on biological treatment. Keywords: herpes zoster, TNF antagonists, anti-IL17, anti-IL12/23, psoriasis, aciclovir

The objective of this position statement from the Saudi Gastroenterology Association is to guide gastroenterologists on the use of tumor necrosis factor-alfa (TNF-α) antagonists for the treatment of the idiopathic inflammatory bowel diseases, Crohn’s disease, and ulcerative colitis. In this article, we summarize the relevant literature regarding the safety and efficacy of TNF-α antagonists, highlight relevant safety concerns specific to the environment in Saudi Arabia, and provide specific recommendations for the use of these agents.

Background: There is conflicting evidence on the impact of biologic treatment on the rate of complications and surgeries in Crohn's disease (CD). We aimed to assess realworld consequences of biologic treatment of CD. Methods: All adult patients with CD treated with infliximab and adalimumab in the years 2012-2014 were identified from the database of the National Health Fund in Poland. Mixed models were used to assess the impact of biologics on medical resource utilization by comparing the periods before and after the first use of biologics (pre-index vs. post-index). The additional analyses including quintile of total exposure to biologic treatment were performed. Results: Data on 1393 patients (age, 31.9 years; males, 52.6%) were analyzed over a median of 1064 days (range: 71, 1148). During the post-index period, patients received from one to four treatments with biologic agents (maximum allowed period of 12 months per treatment). We observed a reduction in the rates of surgeries (by 27%, p = 0.001), hospitalizations for CD excluding surgical procedures (by 45%, p < 0.001), as well as consumption of antibiotics (by 31%, p < 0.001) and steroids (by 35%, p < 0.001) in the post-index compared with the pre-index period. The reduction in the rate of surgeries, hospitalizations for CD, and steroid intake increased with the increase of exposure to biologic agents. Conclusion: Biologic treatment changed the management patterns by lowering the rate of surgeries and other healthcare resources related to complications or worsening of CD. The reduction in the resource utilization was dependent on the level of exposure to treatment, suggesting that limitation of the treatment period itself may be inadequate. [ABSTRACT FROM AUTHOR]

The therapeutic landscape for inflammatory bowel disease [IBD] is rapidly evolving. Two new biologic drugs, vedolizumab and ustekinumab, have recently entered the marketplace, the first biosimilars have been introduced, and several other agents are at an advanced stage of clinical development. In parallel, therapeutic goals have shifted from symptom control towards mucosal healing and prevention of bowel damage. In the coming years, gastroenterologists will be faced with unprecedented choices when selecting the best treatment for their patients with IBD. In this article, we review existing data on the mechanisms of action, efficacy, and safety of recently approved and late-stage pipeline therapies, and use this information to speculate on the positioning of these drugs, alone or in combination, in therapeutic algorithms for Crohn's disease and ulcerative colitis. [ABSTRACT FROM AUTHOR]

Psoriasis vulgaris, affecting the skin, is one of the most common organ-specific autoimmune diseases in humans. Until recently, psoriasis was treated by agents or approaches discovered largely through serendipity. Many of the available drugs were inherently quite toxic when used as continuous treatment for many years in this chronic disease. However, an increasing understanding of disease-specific immune pathways has spurred development of pathway-targeted therapeutics during the past decade. Psoriasis is now the most effectively treated human autoimmune disease, with high-level clinical improvements possible in ∼90% of patients using a new generation of drugs that selectively target the IL-23/Type 17 T cell axis. Thus, psoriasis is a model for the success of a translational-medicine approach based on cellular and molecular dissection of disease pathogenesis in humans. [ABSTRACT FROM AUTHOR]

Background Employing the secondary action or adaptative reaction of the organism as therapeutic response, homeopathy uses the treatment by similitude ( similia similibus curentur ) administering to sick individuals the medicines that caused similar symptoms in healthy individuals. Such homeostatic or paradoxical reaction of the organism is scientifically explained through the rebound effect of drugs, which cause worsening of symptoms after withdrawal of several palliative treatments. Despite promoting an improvement in psoriasis at the beginning of the treatment, modern biological therapies provoke worsening of the psoriasis (rebound psoriasis) after discontinuation of drugs. Method Exploratory qualitative review of the literature on the occurrence of the rebound effect with the use of immunomodulatory drugs [T-cell modulating agents and tumor necrosis factor (TNF) inhibitors drugs] in the treatment of psoriasis. Results Several researches indicate the rebound effect as the mechanism of worsening of psoriasis with the use of efalizumab causing the suspension of its marketing authorization in 2009, in view of some severe cases. Other studies also have demonstrated the occurrence of rebound psoriasis with the use of alefacept, etanercept and infliximab. Conclusion As well as studied in other classes of drugs, the rebound effect of biologic agents supports the principle of similitude (primary action of the drugs followed by secondary action and opposite of the organism). [ABSTRACT FROM AUTHOR]

Treatment with tumour necrosis factor (TNF) antagonists may lead to enhanced susceptibility to certain malignancies. In particular, an association is seen emerging between TNF antagonists and development of squamous cell carcinomas (SCCs) of the skin (in association with psoriasis), the oral cavity, and in the anogenital areas (possibly related to prior human papilloma virus infection). We present here a case of a 53-year old woman with a history of severe rheumatoid arthritis (RA), most recently treated with the TNF antagonist etanercept plus methotrexate, presented to our service after several months of increasing left pelvis and buttock pain. Evaluation with a computerised tomography (CT)-directed biopsy of a pelvic side wall mass revealed a metastatic SCC. On a fluorodeoxyglucose (FDG) positron-emission tomography (PET) an additional area of uptake was identified in the left posterior rectum corresponding to a 1 cm nodule palpable on digital exam. Colonoscopic biopsy revealed a basaloid SCC of the rectum as the likely primary site. Immunosuppression following TNF antagonist therapy may have given arise to this unrestrained neoplastic growth. It thereby underscores the need for an initial baseline study of risk factors and identification of patients who are at higher risk for development of a malignancy, in order to achieve a diagnosis at an early stage. [ABSTRACT FROM AUTHOR]

Conversions and reversions of interferon-gamma (IFN-γ) release assays (IGRAs) were observed when these tests were repeated over time in the same individuals, including those treated with biological agents. In most studies, the variability of IFN-γ plasma levels was not paralleled by clinical change, but a few exceptions exist, in which IGRA conversion predicted the emergence of active tuberculosis (TB). We report the case of a Peruvian patient with rheumatoid arthritis (RA) and Crohn's disease scheduled for treatment with adalimumab. TB screening demonstrated latent TB infection (LTBI), and the patient was started on isoniazid (INH) for 9 months. Adalimumab was initiated after 1 month since INH. QuantiFERON-TB Gold In-Tube, one of the IGRAs currently available, was serially repeated to monitor the status of TB infection during treatment with the biological agent. The patient developed active TB preceded by progressively rising levels of released IFN-γ. We came to know that she had withdrawn INH after 2 months on her own initiative. Considering the low rate of INH completion, serial IGRAs may help in the clinical vigilance during prophylaxis as well as anti-TNF treatment, at least in patients presenting other risk factors aside from the state of immunosuppression. [ABSTRACT FROM AUTHOR]

The objective of this position statement from the Saudi Gastroenterology Association is to guide gastroenterologists on the use of tumor necrosis factor‑alfa (TNF‑α) antagonists for the treatment of the idiopathic inflammatory bowel diseases, Crohn's disease, and ulcerative colitis. In this article, we summarize the relevant literature regarding the safety and efficacy of TNF‑α antagonists, highlight relevant safety concerns specific to the environment in Saudi Arabia, and provide specific recommendations for the use of these agents. [ABSTRACT FROM AUTHOR]

Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality attributed to traditional cardiovascular risk factors and/or the chronic systemic inflammation. We investigated the effect of a TNF antagonist (adalimumab-ADA) on aortic stiffness in RA patients. We studied 18 RA patients with active disease despite therapy with disease modifying antirheumatic drugs (DMARDs), treated with ADA (alone or in combination with DMARDs) for 12 weeks. Disease activity markers as well as aortic stiffness indices (carotid-femoral pulse wave velocity-PWV, augmentation index-AIx), were measured at baseline and at the end of treatment. Eighteen RA patients treated with methotrexate (MTX) were included as controls. Patients were categorized as responders (decrease of Disease Activity Score-DAS28 > 1.2) or nonresponders. There was a statistically significant decrease in PWV (from 8.18 ± 2.03 to 7.01 ± 1.78 m/s, p = 0.00006) and DAS28 (from 6.65 ± 1.22 to 4.69 ± 1.46, p = 0.00007) in RA patients treated with ADA. The decrease in PWV was observed both in responders ( n = 12) and nonresponders ( n = 6). Multivariate analysis showed that the decrease of PWV was independent of changes in disease activity or other parameters. There was no significant change in PWV in patients treated with MTX (from 8.87 ± 1.91 to 8.41 ± 2.17, p = 0.29). No significant change in AIx or traditional cardiovascular risk factors was observed. Treatment with ADA significantly reduced aortic stiffness in RA patients regardless of their response to therapy. These findings imply a direct protective effect of ADA in vascular wall in RA patients. [ABSTRACT FROM AUTHOR]

To analyse the effectiveness of optimization of biologics in rheumatoid arthritis (RA). It was a single-centre retrospective observational study from January 2009 to September 2012. The effectiveness of the optimization of TNF antagonists, tocilizumab and abatacept in RA was studied. Optimization included predefined dose down-titration and/or expansion of dose interval in early arthritis with sustained DAS28-ESR <2.6 and established arthritis with a sustained DAS28-ESR <3.2. Primary outcome was time to relapse defined as increase in DAS28-ESR greater than 20 % over baseline. Cox's regression analysis was performed to identify predictors of relapse. Sixty-four patients were included in the study. In the survival analysis, rates of relapse were 9.8 % at 6 months, 31.4 % at 12 months and 44.6 % at 18 months. Rates of patients with an increase in DAS28-ESR > 20 % and ≥1 inflamed joint at 6, 9 and 18 months were 1.6, 17.2 and 27.1 %, respectively. In relapsing patients, mean DAS28-ESR at relapse was 3.44 (2.94-4.79) and mean DAS28-ESR following the return to the prior dose of the biologic was 2.52 (1.42-3.21). No predictors of relapse were found in multivariate analysis. Optimization of the treatment with biologics in RA is an efficacious and safe treatment option. [ABSTRACT FROM AUTHOR]

Biologic therapies, predominantly TNF-α inhibitors, have revolutionized the treatment of rheumatoid arthritis (RA). However, their clinical utility can be limited by the development of antidrug antibodies (ADAs). Immunogenicity is a complex phenomenon related to various drug, disease, and patient characteristics, and may be more common with the monoclonal antibodies than with etanercept, a soluble TNF receptor-Fc immunoglobulin fusion protein. Neutralizing antibodies - those that hinder bioactivity by preventing drug molecules from binding to TNF - are correlated with reduced serum drug concentrations, loss of therapeutic response, adverse events, and treatment discontinuation. Cost-effective use of these agents will depend on further research into drug and ADA assays, and how they should guide dose reduction or switching strategies. [ABSTRACT FROM AUTHOR]

Although monitoring tuberculosis ( TB) infection during long-term treatment with tumour necrosis factor ( TNF) antagonists is of great importance, no monitoring strategy has yet proved successful. Indeed, even the newly proposed interferon-gamma release assays ( IGRAs) are known to produce dynamic changes in IFN-γ plasma levels, making them unreliable indicators of patients' pathological/clinical status. We used intracellular cytokine flow cytometry ( ICCFC) to investigate the performance of multi-functional CD4+ T cells producing IFN-γ, interleukin ( IL)-2 and/or TNF in response to Mycobacterium tuberculosis-specific antigens in subjects treated with TNF antagonists. Patients were classified into three groups based on their TB status before commencement of treatment and on IFN-γ level fluctuations evaluated by IGRA during a 36-month follow-up period. The cytokine profile of M. tuberculosis-specific CD4+ T cells showed that latent tuberculosis infection ( LTBI) subjects had a higher frequency of double-positive IFN-γ+ IL-2+ CD4+ T cells and triple-positive IFN-γ+ IL-2+ TNF+ CD4+ T cells compared to those without LTBI, who showed IFN-γ-level fluctuations over time. In contrast, this latter group of patients showed similar proportions of cells producing IFN-γ alone, IL-2 alone and IL-2 in combination with TNF in response to M. tuberculosis-specific antigens. It therefore appears that patients with and without LTBI infection are characterized by different intracellular cytokine profiles. This is the first study evaluating ICCFC in patients treated with TNF antagonists, and suggests that multi-functional analysis of CD4+ T cells could be useful for ruling out TB infection in patients classified at screening as LTBI-negative but who show IGRA fluctuations under long-term TNF antagonist treatment. [ABSTRACT FROM AUTHOR]

Background: Until late in the 20th century, the therapy of rheumatic diseases relied on the use of drugs that had been developed through empirical approaches without detailed understanding of the molecular mechanisms involved. That approach changed with the introduction of biologic therapeutics at the end of the 20th century and by the recent development of small-molecule inhibitors of intracellular signal transduction pathways. Here we compare and discuss the advantages and disadvantages of those two groups of targeted anti-inflammatory therapeutics. Discussion: TNF-blocking biologic agents were introduced into the therapy of rheumatoid arthritis and other autoimmune and inflammatory diseases in the late 1990s. Further biologic agents targeting cytokine networks or specific lymphocyte subsets have since been added to the armamentarium of anti-rheumatic therapy. During the last few years, another wave of novel discoveries led to the development of a new class of small molecule anti-inflammatory compounds targeting intracellular signal transduction molecules, such as tyrosine kinases. In all those cases, the specific targets of the drugs are well defined and significant knowledge about their role in the disease pathomechanism is available, qualifying them for being targeted therapeutics for inflammatory rheumatic diseases. While both groups of targeted therapeutics offer significant clinical benefit, they clearly differ in several aspects, such as the localization of their targets, their route of administration and target specificity, as well as technical details such as manufacturing procedures and cost basis. In this debate paper, we compare the advantages and disadvantages of the two different approaches, aiming to shed light on the possible future of targeted therapies. Summary: Biologic therapeutics and small-molecule inhibitors both have significant advantages and disadvantages in the therapy of rheumatic diseases. The future of targeted therapies is one of the most exciting questions of current rheumatology research and therapy. [ABSTRACT FROM AUTHOR]

Patients with established rheumatoid arthritis (RA) have a higher cardiovascular morbidity and mortality in comparison with the general population. It is considered to be an independent risk factor for cardiovascular disease. The purpose of this article is to describe the mechanisms responsible for accelerated atherogenesis in RA patients and to give an overview of the effects of different RA therapies (methotrexate, TNF antagonists and other biologicals). [ABSTRACT FROM AUTHOR]

Abstract: Objective: To systematically analyze literature with the aim of examining whether rheumatoid factor (RF) is a predictor of response to tumor necrosis factor (TNF) antagonists in rheumatoid arthritis (RA). Methods: A systematic review and meta-analysis of observational studies were conducted. All studies on the association of baseline RF (titer and/or status) and response to any TNF antagonists, or with enough information to estimate this association were included. Qualitative analysis and meta-analysis using random-effects approach by type of outcome response and RF test was performed. Risk of publication bias was also evaluated. Results: The systematic review included 18 studies of 4163 identified articles, involving 5703 patients with homogeneous baseline characteristics. The most common outcome to assess response was European League Against Rheumatism (EULAR) response criteria, normally merging good and moderate categories as response. The weighted mean difference (WMD) of baseline IgM RF titer in meta-analysis was higher in the non-responders group [−101.58 (95% CI −156.58,−46.59) I2 =0.0]. Combined odds ratios (ORs) of positive IgM RF, positive IgA RF, and positive IgG RF to achieve good/moderate response were 1.08 (0.80, 1.47), I2 =40.9%; 0.83 (0.39, 1.73), I2 =39.8%, and 1.30 (0.48, 3.51), I2 =62.9%, respectively. We did not find an association between a positive IgM RF and EULAR good response or remission. Conclusions: This meta-analysis does not support baseline IgM RF titer as a predictor of response to TNF antagonists in RA. However, this conclusion is hampered by high heterogeneity in the studies included in this meta-analysis. [Copyright &y& Elsevier]

Abstract: Current data on therapeutic immunomodulation used to treat systemic vasculitides are reviewed in this paper, which also discusses ongoing and future developments in the field. In vasculitides associated with anti-neutrophil cytoplasmic antibodies, rituximab is a validated induction treatment that can serve as an alternative to cyclophosphamide and must be followed by maintenance treatment. In addition, the usefulness of rituximab as maintenance treatment was established recently. Immunoglobulins can be helpful adjuncts, most notably in patients with severe immunodepression. Plasmapheresis is indicated in patients with severe renal failure and may have a role in the treatment of alveolar hemorrhage syndromes. Mepolizumab has produced encouraging preliminary results in eosinophilic granulomatosis with polyangiitis (Churg-Strauss). Rituximab can be used in cryoglobulinemic vasculitis associated with hepatitis C virus infection when antiviral therapy fails or the disease is severe. Very low doses of interleukin-2 may be helpful in refractory forms. Rituximab is also an option in essential mixed cryoglobulinemia with uncontrolled vasculitis despite glucocorticoid and/or immunosuppressive treatment. In polyarteritis nodosa associated with the hepatitis B virus, a combination of short-course glucocorticoids, plasmapheresis, and antiviral therapy produces excellent outcomes. Intravenous immunoglobulins are used to treat Kawasaki disease, in which they diminish the incidence of coronary artery aneurysms. Several prospective controlled trials are currently assessing tocilizumab in giant-cell arteritis. Rituximab has useful effects in systemic vasculitis associated with rheumatoid arthritis. In Goodpasture's syndrome, plasmapheresis is indicated to clear the antibodies to glomerular membrane antigen, which can induce glomerulonephritis. [Copyright &y& Elsevier]

In England and Wales, the National Institute for Health and Clinical Excellence (NICE) has provided guidance [technology appraisals (TAs) 130, 186, 195, 198 and 225] on the use of biologic drugs for the treatment of RA. This is based on an analysis of efficacy, safety and cost-effectiveness, and has resulted in a complex management pathway that restricts freedom to prescribe biologics according to their licensed indications. Specifically, TNF antagonists are the only class of biologics that can be used first line in DMARD-inadequate responders, and only in patients with a persistent 28-joint DAS score of &geq;5.1. Alternative biologic agents are denied to those with contraindications to anti-TNF drugs and are also not supported following intolerance to TNF antagonists. Rituximab is the only class of biologic permitted after TNF antagonist inefficacy, in the absence of a contraindication to its use, whereas abatacept and tocilizumab are licensed and may be a more efficacious choice at this stage in some patient groups. Furthermore, for patients who demonstrate sequential inadequate responses, treatment is restricted to one TNF antagonist, rituximab and tocilizumab, whereas abatacept is only a permitted choice when rituximab is contraindicated or has been withdrawn because of an adverse event. In this review, we discuss the treatment algorithm published by NICE, and suggest alternatives where perceived deficiencies exist. [ABSTRACT FROM PUBLISHER]

Objectives: To estimate the rate of demyelinating diseases in patients with rheumatic diseases treated with tumor necrosis factor (TNF) antagonists and to describe the cases reported to 3 different pharmacovigilance sources. Methods: All confirmed cases of demyelinating disease, optic neuritis, and multiple sclerosis (MS) in patients with rheumatic diseases treated with TNF-antagonists were reviewed from 3 different sources: (1) the Spanish Registry of biological therapies in rheumatic diseases (BIOBADASER); (2) the Spanish Pharmacovigilance Database of Adverse Drug Reactions (FEDRA); and (3) a systematic review (PubMed, EMBASE, and the Cochrane Library). In BIOBADASER, the incidence rate per 1000 patients was estimated with a 95% confidence interval (95% CI). Results: In 21,425 patient-years in BIOBADASER, there were 9 patients with confirmed demyelinating disease, 4 with optic neuritis, and 1 with MS. In addition, 22 patients presented polyneuropathies, paresthesias, dysesthesias, facial palsy, or vocal cord paralysis without confirmed demyelination. The incidence rate of demyelinating disease in patients with rheumatic diseases exposed to TNF-antagonists in BIOBADASER was 0.65 per 1000 patient-years (95% CI: 0.39-1.1). The incidence of MS in BIOBADASER was 0.05 (95% CI: 0.01-0.33), while the incidence in the general Spanish population was 0.02 to 0.04 cases per 1000. Compared with BIOBADASER, cases in FEDRA (n = 19) and in the literature (n = 48) tend to be younger, have shorter exposure to TNF-antagonists, and recover after discontinuation of the drug. Conclusions: It is not clear whether TNF antagonists increase the incidence of demyelinating diseases in patients with rheumatic diseases. Differences between cases depending on the pharmacovigilance source could be explained by selective reporting bias outside registries. [Copyright &y& Elsevier]

Life-threatening disseminated tuberculosis developed in a 17-year-old girl who was treated with the TNF-α blocker adalimumab for refractory SAPHO syndrome. The patient presented to the emergency department with dyspnea and somnolence and within 2 h developed the clinical picture of a septic shock. In addition to this unusual presentation, she showed a complicated course with increasing cerebral granuloma formation in spite of adequate antimycobacterial treatment. Immune reconstitution after discontinuation of TNF blockade may contribute to this "paradoxical reaction." Possible implications for screening, diagnosis, and treatment of tuberculosis in children and adolescents receiving anti-TNF treatment are discussed. [ABSTRACT FROM AUTHOR]

Objective: To describe the risk of cancer in patients exposed to tumor necrosis factor (TNF) antagonists. Methods: The following 2 clinical cohorts were studied: (1) BIOBADASER 2.0: a registry of patients suffering from rheumatic diseases exposed to TNF antagonists (2531 rheumatoid arthritis (RA), 1488 spondyloarthropathies, and 675 other rheumatic conditions); and (2) EMECAR: a cohort of 789 RA patients not exposed to TNF antagonists. Cancer incidence rates (IR) per 1000 patient-years and incidence rate ratios (IRR) were calculated for BIOBADASER 2.0 and EMECAR patients. The IR over time in BIOBADASER 2.0 patients was analyzed by joinpoint regression. The IRR was estimated to compare cancer rates in exposed versus nonexposed RA patients. Standardized incidence and mortality ratios (SIR, SMR) were also estimated. Risk factors for cancer in patients exposed to TNF antagonists were investigated by generalized linear models. Results: The SMR for cancer in BIODASER 2.0 was 0.67 (95% CI: 0.51-0.86), and the SIR was 0.1 (95% CI 0.03-0.23). The IR in RA patients exposed to TNF antagonists was 5.8 (95% CI: 4.4-7.6), and the adjusted IRR was 0.48 (95% CI: 0.09-2.45). The IR in patients with previous cancer was 26.4 (95% CI: 4.1-171.5). Age, chronic obstructive pulmonary disease, and steroids were associated with a higher risk of developing cancer. The IR decreased after the first 4 months of exposure, without statistical significance. Conclusion: Overall cancer and mortality rates in patients with rheumatic diseases exposed to TNF antagonists are no higher than in the background Spanish population. However special attention should be paid to elderly patients, those with previous cancers, and patients treated with steroids. [Copyright &y& Elsevier]

Background: Conventional therapy of extensive psoriasis is effective but has complications. Biologics are safer but expensive. Objective: To assess the efficacy of sulfasalazine and pentoxifylline, which have TNF antagonizing and anti-proliferative action in the treatment of psoriasis. Methods: In this randomized controlled trial, 32 patients with extensive psoriasis were divided into four groups: group A received sulfasalazine; group B received pentoxifylline; group C received both drugs; and group D received methotrexate. The Psoriasis Area and Severity Index (PASI) score was done at weeks 0, 2, 4, 6 and 8. Results: A significant reduction in PASI score occurred in groups C and D ( p = 0.043 and 0.018, respectively). A significantly higher percentage of PASI score reduction occurred in group D compared with groups A, B and C ( p = 0.006, 0.003 and 0.030, respectively). An excellent response occurred in one patient (14.3%) in group D. A very good response occurred in two patients (22.2%) in group C, and in five patients (71.4%) in group D. A moderate response occurred in three patients (37.5%) in group A, one patient (12.5%) in group B, and one patient (14.3%) in group D. Conclusion: Although incomparable to methotrexate, combined sulfasalazine and pentoxifylline produced a good response in cases of extensive psoriasis. Multicentre studies are needed to validate these results. [ABSTRACT FROM AUTHOR]

Objectives: To estimate the rate of demyelinating diseases in patients with rheumatic diseases treated with tumor necrosis factor (TNF) antagonists and to describe the cases reported to 3 different pharmacovigilance sources. Methods: All confirmed cases of demyelinating disease, optic neuritis, and multiple sclerosis (MS) in patients with rheumatic diseases treated with TNF-antagonists were reviewed from 3 different sources: (1) the Spanish Registry of biological therapies in rheumatic diseases (BIOBADASER); (2) the Spanish Pharmacovigilance Database of Adverse Drug Reactions (FEDRA); and (3) a systematic review (PubMed, EMBASE, and the Cochrane Library). In BIOBADASER, the incidence rate per 1000 patients was estimated with a 95% confidence interval (95%CI). Results: In 21,425 patient-years in BIOBADASER, there were 9 patients with confirmed demyelinating disease, 4 with optic neuritis, and 1 with MS. In addition, 22 patients presented polyneuropathies, paresthesias, dysesthesias, facial palsy, or vocal cord paralysis without confirmed demyelination. The incidence rate of demyelinating disease in patients with rheumatic diseases exposed to TNF antagonists in BIOBADASER was 0.65 per 1000 patient-years (95%CI: 0.39-1.1). The incidence of MS in BIOBADASER was 0.05 (95%CI: 0.01-0.33), while the incidence in the general Spanish population was 0.02 to 0.04 cases per 1000. Compared with BIOBADASER, cases in FEDRA (n = 19) and in the literature (n = 48) tend to be younger, have shorter exposure to TNF-antagonists, and recover after discontinuation of the drug. Conclusions: It is not clear whether TNF antagonists increase the incidence of demyelinating diseases in patients with rheumatic diseases. Differences between cases depending on the pharmacovigilance source could be explained by selective reporting bias outside registries. [Copyright &y& Elsevier]

Osteoporosis (OP) is a frequent complication of ankylosing spondylitis (AS), even in early stages of the disease, and is associated with elevated levels of biochemical markers of bone turnover, proinflammatory cytokines, and acute-phase reactants. This suggests that systemic inflammatory mediators, such as interleukin-6 and tumor necrosis factor-α, may be involved. Various factors that conceivably work in conjunction with one another also cause bone loss in AS (eg, genetic polymorphisms of vitamin D, low levels of osteoprotegerin and sex steroid hormones, and impaired calcium and vitamin D absorption). Dual x-ray absorptiometry for assessing bone mineral density (BMD) has limitations in patients with AS because of unreliability of spinal measurements, particularly in advanced disease with new bone formation. Femoral neck BMD is reduced and correlates with increased risk of vertebral fractures. Hence, measurement of BMD at the femoral neck may provide the most accurate means of detecting osteopenia and OP and could assess fracture risk in AS patients. No guidelines are available for detection and treatment of OP in AS, and most patients are young men, who are less likely to be screened. The only evidence-based recommendation is that optimal control of disease activity in AS prevents bone loss. A recent study showed a beneficial effect of infliximab therapy on bone turnover markers and BMD in AS. Also, bisphosphonates may be useful in managing OP in AS. [ABSTRACT FROM AUTHOR]

Abstract: Bipolar disorder (BD) is associated with high rates of morbidity, comorbidity, disability, economic and human capital costs as well as premature mortality. Although, the past decade has witnessed substantial progress in the treatment of BD, high rates of non-recovery, inter-episodic symptomatology, and episode recurrence remain an ongoing deficiency. Conventional treatments for BD are capable of alleviating ‘surface-based’ symptomatology yet no agent is disease-modifying. Translational research initiatives provide evidence that mood disorder symptomatology is subserved by disturbances in interacting immuno-inflammatory, metabolic, and neuroendocrine networks. Numerous studies document elevated pro-inflammatory circulating cytokines [e.g. interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-α)], in individuals with BD as compared to healthy volunteers. Elevated peripheral levels of TNF-α and its receptors (i.e. TNF-R1 and TNF-R2) are a frequent findings across depressive and manic states and may persist into euthymia. As such, TNF-α may constitute a trait marker of BD. Other markers of inflammation including acute phase reactants (e.g. C-reactive protein) and vascular adhesion molecules (e.g. intercellular adhesion molecule-1) are also altered in BD. Herein, we review supporting evidence for the hypothesis that disturbances in inflammatory homeostasis, as marked by elevated TNF-α levels, are salient to the pathophysiology of BD and provide a platform for novel drug discovery. In this review, we propose that TNF-α modulation is a target for disease-modifying treatment of BD. To support this hypothesis, we review evidence from clinical trials evaluating the efficacy of TNF-α antagonists (i.e. adalimumab, etanercept, and infliximab) on depressive symptoms and mental health-associated quality of life measures. [Copyright &y& Elsevier]

Abstract: Several cases of TNF antagonist-related reactivation of hepatitis B have been reported. Here, we describe 4 cases in patients with spondyloarthropathies. Long-term monitoring of the hepatitis B virus (HBV) load is in order in HBV-positive patients treated with TNF antagonists. Case reports: There were 3 men and 1 woman, aged 30–40 years. Follow-up ranged from 1 to 5 years. In 2 patients, the HBV infection was not discovered until the pre-TNF antagonist therapy workup. A viral load increase was noted after a TNF antagonist was added to methotrexate in 2 patients, whose viral load values returned to baseline after the introduction of the antiviral agent lamivudine. Lamivudine was started at the same time as the TNF antagonist in the other 2 patients, whose viral loads remained undetectable. Escape phenomenon requiring a switch to another antiviral agent was required in 1 patient after more than 4 years of treatment with 3 TNF antagonists. Conclusion: These 4 case reports illustrate the challenges raised by latent HBV infection in patients who require TNF antagonist therapy. They support routine HBV testing before treatment initiation, followed in HBV-positive patients by viral load monitoring. Antiviral therapy can be used preventively and should be given if the viral load increases under TNF antagonist therapy. In patients on antiviral therapy, viral load monitoring should be continued, given the risk of escape phenomenon after several years. [Copyright &y& Elsevier]

Objective: to analyze the effect of the TNF blocking agents (aTNF) on the serum levels of interleukin 15 (IL-15). To determine whether baseline IL15 serum levels or their response to aTNF therapy can predict the clinical response to this treatment. Patients and method: We studied 75 patients suffering from rheumatoid arthritis that were selected to start aTNF therapy. Serum samples were obtained at baseline visit and after three months of aTNF treatment. Measurement of IL-15 serum concentration was performed through immune-enzyme assay. We collected the clinical and analytical parameters needed to calculate DAS28 both at baseline and final visit, as well as sociodemographic variables and other such as rheumatoid factor, previous disease modifying anti-rheumatic drugs (DMARD), etc. We defined remission as a DAS28 < 2.6 and clinical response when the decrease in DAS28 value was higher than 1.2. Results: there was a significant correlation between IL-15 serum level and the number of previous DMARD. We also detected a significant decrease in the concentration of serum IL-15 after three months of treatment with aTNF. However, neither the baseline IL-15 serum level nor the decrease in the concentration of IL-15 were associated with a specific pattern of response to aTNF. Conclusions: our data seem to support previous in vitro findings suggesting that TNF is involved in the regulation of IL-15 expression. Nevertheless, the measurement of IL-15 serum levels does not seem to be a useful tool to select those patients that should be treated with aTNF therapy. [ABSTRACT FROM AUTHOR]

Abstract: The advent of TNF antagonists has had a revolutionary impact on the treatment of ankylosing spondylitis (AS). However, whether the benefits recorded in controlled trials are replicated in everyday practice has not been extensively evaluated. Objectives: To evaluate the effectiveness of infliximab in patients with axial spondyloarthropathies, to identify factors associated with the treatment response, and to assess fulfillment of modified New York criteria and compliance with guidelines about using TNF antagonists. Methods: Retrospective review of patients given infliximab for axial spondyloarthropathy between 2001 and 2003. Disease activity, motion limitation, laboratory tests, and the 6-week response rate were recorded. Results: Of the 86 included patients (48 women and 38 men, mean age, 44±11years), 37% responded to infliximab therapy. Uveitis and C-reactive protein elevation at baseline predicted a response. Only 53% of patients met modified New York criteria and only 23% met ASAS criteria for starting TNF antagonist therapy. Conclusion: Infliximab was less effective in our patients with axial spondyloarthropathy than expected based on the results of controlled trials. However, many patients did not meet New York criteria for AS and/or ASAS criteria for TNF antagonist therapy. Therefore, our results do not challenge the usefulness of TNF antagonists in axial AS. Our patients were treated before the development of guidelines for TNF antagonist therapy and before the introduction of magnetic resonance imaging as an evaluation tool in AS. Strict criteria should be used to decide when TNF antagonist therapy is appropriate in patients with spondyloarthropathies. [Copyright &y& Elsevier]