TNF-alpha Antagonists Research Articles

Clinical applicability of Quantiferon‐TB‐Gold testing in psoriasis patients during long‐term anti‐TNF‐alpha treatment: a prospective, observational study

Psoriasis patients who are treated with tumour necrosis factor (TNF)-alpha antagonists are at increased risk of reactivation of latent tuberculosis infection (LTBI) and should be adequately screened and monitored during active treatment. To evaluate in a prospective study, the performance of Quantiferon-TB-Gold in tube (QFT) in vitro assay compared to the conventional tuberculin skin test (TST) in detecting LTBI among a cohort of non-BCG-vaccinated patients with moderate-to-severe psoriasis during long-term treatment (12 months) with TNF-alpha antagonists. A total of 50 patients underwent QFT and TST testing at baseline and after 6 and 12 months of continuous anti-TNF-alpha treatment. Diagnosis of LTBI was made on the basis of a positive QFT result and negative chest-radiographic and microbiological assays. Patients with LTBI were subjected to standard isoniazid chemoprophylaxis and after 1 month, they resumed anti-TNF-alpha treatment with subsequent QFT and TST testing after 6 months. In all the cases, a follow-up period of 12 months was observed. During the 12-month-study period, 14% of patients presented a QFT conversion. During active anti-TNF-alpha treatment, a QFT conversion was observed in 10% of patients (five cases). Agreement between QFT and TST was moderate (κ=0.408) at screening, good (κ=0.734) after 6 months and fair (κ=0.328) after 12 months of treatment. A total of 18% of patients presented a positive, discordant TST during the study period. A single-test QFT-based screening strategy for LTBI in psoriasis patients receiving long-term anti-TNF-alpha treatment could reduce the incidence of false-positive LTBI cases, preventing unnecessary TB chemoprophylaxis.

TNF-alpha antagonists for treatment of juvenile ankylosing spondylitis

Background Juvenile onset sondylarthropathy is a term that refers to a group of human leucocyte antigen (HLA) -B27 associated inflammatory disorders affecting children under the age of 16 years. The increased expression of tumor necrosis factor alpha (TNF-alpha) in synovial tissue of patients with juvenile onset and adults with active ankylosing spondylitis suggests a significant pathogenic role of TNF-alpha.

Switching between TNFα antagonists in rheumatoid arthritis: personal experience and review of the literature

To evaluate the clinical response after switching to another TNFalpha antagonist in patients with rheumatoid arthritis (RA) and provide a review of the literature on this topic. In this ongoing, longitudinal, observational study we have prospectively collected data of patients starting biological treatments since 2000. The present analysis is restricted to RA patients who switched to another anti-TNFalpha due to lack of efficacy (LaE), loss of efficacy (LoE), or adverse events (AEs) by the end of December 2007. Disease activity score (ESR-based DAS28) was calculated and the clinical response (none, moderate, good) was evaluated according to the European League Against Rheumatism (EULAR) criteria. Clinical remission (DAS28 <2.6) and low disease activity (DAS28 </=3.2) were also evaluated. A total of 692 anti-TNFalpha-naïve patients has been registered, of whom 395 with a diagnosis of RA. Thirtyseven RA patients switched to another TNFalpha antagonist. Three months after switching, the proportion of patients with remission, low disease activity, good and moderate/good EULAR responses grew from 0%, 2.7%, 0%, and 5.4% (baseline before switching) to 16.2%, 35.1%, 27%, and 62.2% (p<0.05, p<0.001, p<0.001, p<0.000001, respectively). Of the patients who switched because of LaE, LoE, and AEs a moderate/good EULAR response was achieved in 38.4%, 66.6%, and 88.8% of patients, respectively. Mean treatment duration with the second anti-TNFalpha was significantly longer in patients switching for LoE and AEs than in those switching for LaE (p<0.05). The findings of this study suggest that RA patients may be successfully treated with another TNFalpha antagonist, especially those withdrawing for LoE or AEs.

Using TNF-alpha antagonist Adalimumab for treatment for multisystem sarcoidosis: a case study

We report the usage of the TNF-alpha antagonist adalimumab in patients with progressive multisystem sarcoidosis. Three patients with multisystem sarcoidosis (MSS) were treated with adalimumab for 12 months. All three patients were quickly responded to adalimumab and experienced a nearly complete regression of the symptoms that lead to an intensive immunosuppression. However, some accompanying symptoms of sarcoidosis, such as splenomegalia, did not respond. One patient suffered 18 months later a new unspecified abdominal lymphadenopathy. TNF-alpha antagonists can be helpful agents in the treatment for MSS. However, the experience with TNF-alpha antagonists in patients with sarcoidosis is still limited. Multicenter trials and a comparison of the different agents are needed to validate the safety and efficacy in these patients. Optimal dosage, duration of therapy and long-term toxicity of anti-TNF therapy in patients with refractory sarcoidosis are yet to be determined in prospective trials.

TNF alpha antagonist therapy and safety monitoring

Objectives To develop and/or update fact sheets about TNFα antagonists treatments, in order to assist physicians in the management of patients with inflammatory joint disease. Methods 1. selection by a committee of rheumatology experts of the main topics of interest for which fact sheets were desirable; 2. identification and review of publications relevant to each topic; 3. development and/or update of fact sheets based on three levels of evidence: evidence-based medicine, official recommendations, and expert opinion. The experts were rheumatologists and invited specialists in other fields, and they had extensive experience with the management of chronic inflammatory diseases, such as rheumatoid. They were members of the CRI (Club Rhumatismes et Inflammation), a section of the Société Francaise de Rhumatologie. Each fact sheet was revised by several experts and the overall process was coordinated by three experts. Results Several topics of major interest were selected: contraindications of TNFα antagonists treatments, the management of adverse effects and concomitant diseases that may develop during these therapies, and the management of everyday situations such as pregnancy, surgery, and immunizations. After a review of the literature and discussions among experts, a consensus was developed about the content of the fact sheets presented here. These fact sheets focus on several points: 1. in RA and SpA, initiation and monitoring of TNFα antagonists treatments, management of patients with specific past histories, and specific clinical situations such as pregnancy; 2. diseases other than RA, such as juvenile idiopathic arthritis; 3. models of letters for informing the rheumatologist and general practitioner; 4. and patient information. Conclusion These TNFα antagonists treatments fact sheets built on evidence-based medicine and expert opinion will serve as a practical tool for assisting physicians who manage patients on these therapies. They will be available continuously at www.cri-net.com and updated at appropriate intervals.

Identification of Inflammatory Bowel Disease (IBD)-Specific Diagnostic Biomarkers Using Transcriptional Profiling of Peripheral Blood Mononuclear Cells (PBMC) From Treatment NaïVE Children With Either IBD or Non-IBD Gastrointestinal Inflammatory Disorders

2010, we identified pediatric patients who had pelvic MRI for perianal fistula prior to starting anti-TNF alpha therapy. RESULTS: We identified 15 patients (11 male; mean age 14 years; range 8-19 years) who had an MRI identifying a perianal fistula and subsequently received infliximab (5-10mg/kg). Subjects who failed treatment with infliximab or developed an adverse reaction changed to adalimumab or certolizumab. Nine patients had perianal fistulas, 3 had combined perianal/peritoneal fistulas, 1 had a recto-vaginal and 2 had recto-scrotal fistulas. 10 of the 15 patients had multiple fistulas on presentation and 11 had associated fluid collections seen on MRI. Based on the Parks criteria, there were 9 intersphincteric fistulas, 12 transphincteric, and 3 suprasphincteric. Six of 15 patients (40 percent) with perianal fistulas had a complete clinical response (mean duration to resolution 29.3 months); 1 of these 6 patients relapsed after infliximab was discontinued and did not respond to retreatment (6 months). Two patients (13 percent) had a partial clinical response to antiTNF therapy and 7 patients (47 percent) had minimal response with continued drainage. Seton drainage and/or fistulectomy were used prior to medical treatment in a total of 6 patients, 2 of whom had a complete response. Of the 6 patients with complete clinical response, 1 had a recto-vaginal fistula, and 1 had a recto-scrotal fistula. Repeat MRI evaluation was performed on 4 of the 6 patients with complete clinical response, showing complete radiologic healing in 3 patients and persistence of fistula with active inflammation in 1 patient. Both of the patients with partial response had MRI:one showed worsening of the fistula tract and the other was improved. Three of the 7 patients with minimal response to anti-TNF therapy had repeat imaging and all demonstrated persistence of active fistulous tracts. Two of these patients eventually required diversion procedures. CONCLUSIONS: TNF alpha antagonist therapy resulted in complete healing in 40 percent of pediatric and adolescent Crohn's patients with perianal fistulas and partial healing in 13 percent. Mean time to complete clinical response was longer than expected almost 30 months. Clinical response to treatment correlated with radiologic evaluation in 7 of 9 patients who underwent repeat imaging. Based on Parks criteria, the complexity of the fistula did not appear to influence the response to treatment. Supported in part by a grant from The Pediatric IBD Foundation

Clinical Correlates of Infliximab (IFX) Failure in Pediatric Patients With Inflammatory Bowel Disease (IBD): A Single Center Experience of Patient Characteristics, Concomitant Medical Therapy and Outcomes

2010, we identified pediatric patients who had pelvic MRI for perianal fistula prior to starting anti-TNF alpha therapy. RESULTS: We identified 15 patients (11 male; mean age 14 years; range 8-19 years) who had an MRI identifying a perianal fistula and subsequently received infliximab (5-10mg/kg). Subjects who failed treatment with infliximab or developed an adverse reaction changed to adalimumab or certolizumab. Nine patients had perianal fistulas, 3 had combined perianal/peritoneal fistulas, 1 had a recto-vaginal and 2 had recto-scrotal fistulas. 10 of the 15 patients had multiple fistulas on presentation and 11 had associated fluid collections seen on MRI. Based on the Parks criteria, there were 9 intersphincteric fistulas, 12 transphincteric, and 3 suprasphincteric. Six of 15 patients (40 percent) with perianal fistulas had a complete clinical response (mean duration to resolution 29.3 months); 1 of these 6 patients relapsed after infliximab was discontinued and did not respond to retreatment (6 months). Two patients (13 percent) had a partial clinical response to antiTNF therapy and 7 patients (47 percent) had minimal response with continued drainage. Seton drainage and/or fistulectomy were used prior to medical treatment in a total of 6 patients, 2 of whom had a complete response. Of the 6 patients with complete clinical response, 1 had a recto-vaginal fistula, and 1 had a recto-scrotal fistula. Repeat MRI evaluation was performed on 4 of the 6 patients with complete clinical response, showing complete radiologic healing in 3 patients and persistence of fistula with active inflammation in 1 patient. Both of the patients with partial response had MRI:one showed worsening of the fistula tract and the other was improved. Three of the 7 patients with minimal response to anti-TNF therapy had repeat imaging and all demonstrated persistence of active fistulous tracts. Two of these patients eventually required diversion procedures. CONCLUSIONS: TNF alpha antagonist therapy resulted in complete healing in 40 percent of pediatric and adolescent Crohn's patients with perianal fistulas and partial healing in 13 percent. Mean time to complete clinical response was longer than expected almost 30 months. Clinical response to treatment correlated with radiologic evaluation in 7 of 9 patients who underwent repeat imaging. Based on Parks criteria, the complexity of the fistula did not appear to influence the response to treatment. Supported in part by a grant from The Pediatric IBD Foundation

TNF-alpha Down-Regulates Filaggrin and Loricrin Through c-Jun N-Terminal Kinase: Role for TNF Antagonists to Improve Skin Barrier

RATIONALE: Psoriasis is characterized by over-expression of TNF-alpha and impaired skin barrier. Therefore we investigated whether skin barrier proteins are modulated by TNF-alpha, and determined the effect of clinical treatment with a TNF-alpha antagonist on barrier protein expression.

Tumor necrosis factor‐alpha antagonist administration recovers skeletal muscle dysfunction in ovariectomized rats

Skeletal muscles deteriorate after ovariectomy. Molecular pathway of this deterioration has not been defined. Tumor necrosis factor (TNF)-alpha activation is assumed to trigger muscle atrophy and administration of its antagonist is hypothesized to recover this atrophy in rats. Slow-twitch soleus and fast-twitch extensor digitorum longus muscle functions were investigated in intact, ovariectomized (OVX), and OVX plus 10 µg/g/week TNF-alpha antagonist administered female rats. Maximum isometric twitch and tetanic contraction responses were lower in the OVX groups. Maximum isometric twitch amplitudes recovered in the extensor digitorum longus but not in the soleus muscles after TNF-alpha antagonist administration. The decrease in responses to tetanic stimulations recovered in the OVX-TNF group at frequencies higher than 20 Hz in both muscle types. OVX animals body weight was 21% higher than intact animals. Muscle weight to body weight ratios of the OVX groups were higher than the control group which recovered after TNF-alpha antagonist administration. Findings suggest that the functional loss in OVX rat muscles is TNF-alpha pathway dependent. Skeletal muscle atrophy and function after OVX recovered by TNF-alpha antagonist administration.

Endometrium cancer in a female with psoriatic arthritis treated with TNF alpha antagonist adalimumab

Endometrium cancer in a female with psoriatic arthritis treated with TNF alpha antagonist adalimumab

Systemic and spinal administration of etanercept, a tumor necrosis factor alpha inhibitor, blocks tactile allodynia in diabetic mice

Painful diabetic neuropathy is one of the most common forms of neuropathic pain syndromes. Tumor necrosis factor alpha (TNF-alpha) is a proinflammatory cytokine that has been implicated as a key pain mediator in the development and maintenance of neuropathic pain conditions. Recent studies showed that endogenous TNF-alpha production was also accelerated in neural tissues and spinal cord under chronic hyperglycemia. Thus, in this study, we investigated whether pharmacological inhibition of TNF-alpha by etanercept, a TNF-alpha antagonist, could block behavioral sign of diabetic neuropathic pain. Diabetes was induced by streptozotocin (STZ) (200 mg/kg, i.p.) in Balb-c mice and behavioral tests were performed between 45 and 60 days after STZ administration. Mechanical and thermal sensitivities were measured by a series of calibrated Von Frey filaments and hot plate test, respectively. Etanercept was given by either intravenous (i.v.), intrathecal (i.th.) or intraplantar (i.pl.) routes to the diabetic mice. Tactile allodynia, but not thermal hyperalgesia, developed in diabetic mice. Both i.v. (1, 10 and 20 mg/kg) or i.th. (1, 5 and 10 μg/mouse) treatments with etanercept produced dose dependent reversal of tactile allodynia in diabetic mice. However, etanercept was found to be inactive against allodynia when given i.pl. (1, 5 and 10 μg/mouse). Our results suggest that etanercept has promising effects on diabetic neuropathic pain with antiallodynic effects when given systemically or intrathecally.

Infliximab, a TNF-alpha antagonist treatment in patients with ankylosing spondylitis: the impact on depression, anxiety and quality of life level

The objective of this study was to assess the effect of infliximab on depression, anxiety and quality of life in patients with active ankylosing spondylitis (AS). In this 6-week longitudinal study, 16 patients with AS were assessed. Active disease as defined by BASDAI ≥4.0 was sought for inclusion. Infliximab was administered 5mg/kg at 0, 2weeks and 6weeks. Collected data included age, sex and date of onset of rheumatologic disease. Activity of disease was measured using Bath Ankylosing Spondylitis Disease Activity Index (BASDAI). Biological activity was evaluated with erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP). ESR and CRP were assessed at baseline and day 42. The Hospital Anxiety and Depression scale (HADS), Beck Depression Inventory (BDI) and 36-item Short Form Health Survey (SF-36) were used to evaluate anxiety, depression and quality of life. BASDAI, SF-36, HADS and BDE were assessed prior to the initial infliximab dose and at 2nd, 14th and 42nd day. Seven (43.8%) AS patients had depression scores above the cut off value for both the HADS depression (HADS-D) and BDI and 4 (25 %) had high HADS anxiety scores at baseline. Significant time effect for BDI and HADS-D scores were observed. Although significantly lower BDI scores were found after first, second and third infusions of infliximab, compared to initial score, the significant decrease in HADS-D appeared after second and third infusions. A significant time effect for HADS-anxiety scores were found as well. All of the subscales of SF-36 improved significantly during the course, with an exception of role emotional, for which the difference approached to the significance. The change in BASDAI scores and CRP and ESR, in the treatment process, were not correlated with the change in depression and anxiety scores. Infliximab which is an anti-TNF-α drug, may be effective in the treatment of depression accompanying AS. Possible implications for the treatment of major depressive disorder were discussed, as well.

Tumor Necrosis Factor-Alpha Antagonist-Induced Sarcoidosis

Sarcoidosis is a multisystem granulomatous disease of unknown etiology. Tumor necrosis factor (TNF)-alpha is an important player in granuloma formation, and recent clinical trials have investigated the efficacy of TNF-alpha inhibitors in sarcoidosis. Paradoxically, there are several case reports in the medical literature describing the development of sarcoidosis in patients treated with TNF-alpha inhibitors. We describe 3 cases of TNF-alpha antagonist-induced sarcoidosis: 1 case of pulmonary, ocular and cutaneous sarcoidosis developing in a patient receiving infliximab for erosive rheumatoid arthritis, 1 case of etanercept-induced sarcoidosis in a patient with seronegative rheumatoid arthritis, and 1 case of sarcoidosis developing in a patient receiving etanercept for erosive rheumatoid arthritis. We also provide a brief discussion on the role of TNF alpha in granuloma formation and implications in the use of TNF-alpha antagonists in autoimmune disease.

Cutaneous Sarcoidosis

Sarcoidosis is a systemic disease with skin manifestations. Skin manifestations are classified as nonspecific if they are not characterized by granulomatous inflammation and specific if the lesions have granulomas histologically. Erythema nodosum is the most common nonspecific skin manifestation, and it portends a good prognosis. Specific skin lesions have a varied clinical appearance, although often they can be distinguished by their yellow translucent character. Despite the potential variable appearance, there are common clinical presentations. Lupus pernio lesions are nodular violaceous specific skin lesions found predominantly on the face associated with scarring and a poor prognosis. Treatment of cutaneous sarcoidosis is primarily done to avoid scarring and cosmetic disfigurement. Local and systemic corticosteroids are the mainstay of treatment for the disease. Corticosteroid-sparing agents used to manage the disease include antimalarials, methotrexate, and tetracycline antibiotics. Tumor necrosis factor-alpha (TNF-alpha) antagonists such as infliximab may have a role in cutaneous sarcoidosis, especially in refractory cases that are resistant to the standard regimens.

Treatment of refractory adult‐onset pityriasis rubra pilaris with TNF‐alpha antagonists: a case series

Pityriasis rubra pilaris (PRP) is a rare inflammatory dermatosis with frequent clinical presentation as erythroderma. Conventional systemic treatment is often unsatisfactory and limited by long-term toxicity. The use of tumour necrosis factor (TNF) antagonists has been reported previously in single cases, but lacking long-term follow-up or comparison between different biological agents. To assess the long-term efficacy and safety of TNF-alpha antagonist, infliximab and etanercept, either in monotherapy or in combination therapy of severe, refractory adult-onset PRP. Seven patients of adult-onset PRP, six newly diagnosed type-I and 1 type-II, which were resistant or ineligible to conventional systemic treatment, received a single course of infliximab or etanercept therapy, alone or in combination with low-dose acitretin (>0.25 mg/kg/daily). After complete remission and treatment discontinuation, a follow-up period of 12 months was evaluated for relapses. Six patients obtained complete remission after a single course of anti-TNF-alpha therapy: mean therapy duration was 19.3 weeks (range 6-48 weeks). All patients obtained significant clearing (>75% of body surface area) of skin lesions at week 12. Two patients with marked keratoderma developed localized disease recurrence during treatment. During follow-up, only a single patient, affected by type II PRP, had disease relapse. Both TNF-alpha antagonists proved successful for the treatment of refractory, adult-onset PRP, yielding complete and persistent clinical responses in type-I PRP. Infliximab was associated with a more rapid onset of action, while treatment duration was comparable with etanercept. PRP type II warranted long-term therapy and showed relapse after drug discontinuation.

Motor neuropathy with multiple conduction blocks associated with TNF-alpha antagonist

Infliximab, eternecept and adalimumab are tumour necrosis alpha factor (TNF-alpha) antagonists which recently became part of several auto-immune diseases therapeutic arsenal, mainly in rheumatoid arthritis, ankylosing spondilitis, psoriatic arthritis, as well as inflammatory bowel diseases1,2 […] Motor neuropathy with multiple conduction blocks associated with TNF-alpha antagonist

APOPTOSIS SIGNALING MOLECULES IN PATIENTS WITH ARTERIAL HYPERTENSION: PP.1.02

Objective: Direct and indirect evidence from a number of studies demonstrates that cardiomyocytes apoptosis may be one of the causes that lead to transition from compensatory hypertrophy to heart failure (HF) in hypertension. Apoptotic cell death induced by stress-activated cytokines plays an important role in the pathogenesis of various cardiovascular diseases including essential hypertension. Soluble tumor necrosis factor receptor 1 (sTNF-R1) is natural TNF-alpha antagonist that can inhibit TNF-mediated apoptosis. Soluble Fas ligand (sFasL) promotes binding between Fas and FasL and induces apoptosis. The aim of our study was to investigate plasma sTNF-R1 and sFasL levels in hypertensive patients depend on HF severity. Design and Methods: Cytokines plasma levels were measured by ELISA in 78 patients with arterial hypertension (AH). Patients were divided into 2 groups: group1 (n = 34) – NYHA I-II, group 2 (n = 44) – NYHA III-IV. Results: The study showed increased sTNF-R1 levels (2.16+/-0.12 ng/ml) at the early stages of HF (NYHA I-II) that could represent adaptive mechanism, which prevent cells damage. At the terminal stage (NYHA III-IV) plasma sTNF-R1 levels were decreased (2.09+/-0.12 ng/ml) reflecting loss of protective effect. Circulating sFasL levels elevated from 0.34+/-0.05 ng/ml in the patients of group 1 to 0.45+/-0.04 ng/ml in the patients of group 2 (p < 0.05). Conclusion: Our findings indicate changes of soluble apoptosis signaling molecules levels in relation to the severity of heart failure in hypertensive patients. Therefore, circulating sTNF-R1 and sFasL could play an important role as indirect markers of heart dysfunction associated with cardiomyocytes apoptosis in patients with arterial hypertension.

Etanercept: An Evolving Role in Psoriasis and Psoriatic Arthritis

Tumor necrosis factor alpha (TNFalpha) plays a key pathophysiological role in psoriasis and psoriatic arthritis (PsA). Recent interest has thus focused on the clinical potential of TNFalpha antagonists (e.g. etanercept) in these settings. In psoriasis, several large pooled analyses and well-designed clinical trials documented the significant clinical efficacy and generally favorable tolerability of etanercept for up to 96 weeks. Similarly, in PsA, a large phase III trial showed that, etanercept significantly reduced arthritic symptoms and inhibited radiographic disease progression; sustained clinical benefit was again evident for up to 2 years. Etanercept is at the forefront of psoriatic disease management, and continued evolution and evaluation of the compound - for example, in detailed comparative studies and economic analyses - is likely to confirm a key role for etanercept in the treatment of psoriasis and PsA.

Treatment of relapsing polychondritis with the TNF-alpha antagonist adalimumab

Relapsing polychondritis (RP) is a rare immune-mediated disease which is associated with inflammation in cartilaginous tissue throughout the body. Especially, the cartilaginous structures of ear, respiratory tract, nose, and joints are affected. Around 30% of the cases are associated with other diseases especially systemic vasculitis. Onset of RP is most likely between the ages of 40-60years. This case reports the often disguised and similar symptoms of RP to Wegner's granulomatosis and the challenge of diagnosis. The relative rarity of RP has not permitted clinical trials to determine the efficacy and safety of different therapies. Current treatment is largely empiric and based on case reports. In this case, we successfully used a treatment with the TNF-alpha antagonist adalimumab.

Infliximab-Induced Psoriaform Rash

Infliximab-Induced Psoriaform Rash