Does polymorphysm of genes coding for pro-inflammatory mediators predict the clinical response to tnf alpha blocking agents? A review analysis of the literature

Tumor necrosis factor-\u3b1 (TNF-\u3b1) has a key role in the pathogenesis of rheumatoid arthritis (RA) and the introduction of anti-TNF\u3b1 biological therapies has dramatically altered the treatment of RA. Anti-TNF\u3b1 agents display good clinical efficacy in patients resistant to traditional disease-modifying antirheumatic drugs and superior efficacy in the suppression of erosive joint damage, even if a significant non-response rate has been reported (30-40%). Because anti-TNF\u3b1 therapy is associated with expensive treatment costs, leading to restrictions in the numbers of patients who may be treated, the identification of predictors of treatment outcome may improve the cost-effectiveness of anti-TNF\u3b1 therapies. Several candidate gene studies have addressed this topic, but they have had limited success in identifying predictors. It is not clear whether the response to anti-TNF\u3b1 treatment will be conferred through a number of genes, each with a small effect size, or whether genes may predict the outcome of the treatmen

Cutaneous Manifestations of ANCA-Associated Small Vessels Vasculitis

Skin lesions are frequent manifestations of underlying systemic conditions, including systemic autoimmune vasculitis. In particular, anti-neutrophil cytoplasmic antibodies (ANCA) are associated with distinct forms of vasculitis characterized by inflammatory cell infiltration of the walls of small and medium-sized vessels leading to vascular destruction and tissue necrosis. ANCA-associated vasculitis is rare and systemic diseases, which can be classified based on different distribution of vascular inflammation and presence or absence of granulomatosis and asthma. Despite their diversities, ANCA-associated vasculitis, namely microscopic polyangiitis, granulomatosis with polyangiitis and eosinophilic granulomatosis with polyangiitis, can all display a broad variety of cutaneous manifestations, which can appear during the course of the disease or even as first sign at the time of onset. Different skin manifestations might coexist in the same patient and occur in different occasions during the course of the vasculitis. Thus, a deep knowledge of the spectrum of skin lesions as part of ANCA-associated vasculitis is mandatory for a correct diagnostic process, whenever cutaneous vasculitis is suspected. Due to this broad variety of manifestations, the diagnosis of skin involvement in ANCA-associated vasculitis is very challenging and it must be supported by a detailed medical history, accurate physical examination, specific histopathological analysis of skin biopsy and the presence of ANCA serology. In this review, we focus on the cutaneous manifestations that can develop in the context of ANCA-associated vasculitis, detailing the clinical features, the histopathological aspects as well as the direct immunofluorescence studies for each of the three conditions. Moreover, we acknowledged the differential diagnoses that must be ruled out in the diagnostic process and the main therapeutic approaches available for treatment of ANCA-associated vasculitis

Choroidal impairment and macular thinning in patients with systemic sclerosis : the acute study

Raynaud's phenomenon (RP) is a reversible vasospastic response of the extremities to cold or emotion, and can be the first manifestation or may be present before the development of an overt systemic sclerosis (SSc). The disturbance of the balance between vasodilation and vasoconstriction is not limited to the peripheral microcirculation of the skin, but it is also observed in other organs, such as the choroidal plexus of the eye. We aimed to examine the choroidal thickness (CT), the macular thickness and ganglion cell complex (GCC) average in thirty consecutive patients, without visual symptoms, classified as primary RP (pRP), RP secondary to suspected SSc, and overt SSc. All the patients underwent rheumatologic and ophthalmologic examination, capillaroscopy, test for anti-nuclear antibodies, anti-dsDNA, and anti-extractable nuclear antigens. Ophthalmologic examination included: best corrected visual acuity; slit lamp biomicroscopy; intraocular pressure measurements, fundus examination, and Spectral Domain-Optical Coherence Tomography (SD-OCT) with enhanced depth imaging scan system. Twenty-seven healthy subjects similar for gender and age were analyzed. In pRP, CT was significantly thinner than controls in the outer nasal and temporal regions. In secondary RP, the inner and outer nasal areas were significantly thinner than controls. In SSc, the central, inner inferior, inner nasal, inner superior, outer temporal, outer inferior, and outer nasal regions were significantly thinner than controls. A decreasing trend of central foveal thickness was noted. All the patients had GCC average significantly lower than controls. A thinning of choroidal and macular thickness, as well as of GCC was observed in patients with pRP and becomes more severe and extensive in RP secondary to suspected SSc and overt SSc. To our knowledge, this is the first study to analyze the choroidal features using SD-OCT in RP. These data may be clinically useful in suggesting an early involvement of ocular microcirculation with significant reduction of choroidal perfusion

Activation of inflammation, coagulation and fibrinolysis in patients with Rheumatoid Arthritis : inhibition by Tumor Necrosis Factor alpha blockade

Objective: Rheumatoid arthritis (RA) is associated with increased cardiovascular risk and activation of inflammation and coagulation pathways. Its treatment with infliximab, a chimeric monoclonal antibody to tumour necrosis factor-a (TNF-a), reduces inflammation, but its effects on coagulation and fibrinolysis are unknown. We therefore investigated plasma biomarkers of inflammation, coagulation and fibrinolysis before and after infliximab treatment in RA patients. Methods: We studied 18 patients with active RA and 36 healthy controls. RA patients, receiving a stable dose of methotrexate (10 mg/week), were treated with infliximab (3 mg/kg) at week 0, 2, 6 and 14. At baseline and at week 14, we determined: disease activity score (DAS28), visual analogue scale (VAS) pain, erythrocyte sedimentation rate (ESR), and plasma levels of C-reactive protein (CRP), TNF-a, IL-6, prothrombin fragment 1+2 (F1+2) and D-dimer. In six patients, we also evaluated inflammation and coagulation parameters one hour after infliximab infusion. Results: At baseline, ESR, CRP, TNF-a and IL-6 levels were significantly higher in the RA patients (p=0.001\u2013p=0.0001), as were F1+2 and D-dimer levels (p=0.0001). After 14 weeks of infliximab treatment, there was a significant clinical improvement (decrease in DAS28, VAS pain, number of swollen and tender joints) and a significant decrease in ESR and CRP, IL-6, F1+2 and Ddimer levels (p=0.03\u2013p=0.003). The levels of TNF-a, IL-6, F1+2 and D-dimer significantly decreased one hour after infliximab infusion (p=0.05\u2013p=0.008). Conclusions: In RA patients, infliximab leads to a rapid clinical improvement and a decrease in inflammation and coagulation biomarkers. The reduction in the latter suggests that it may reduce thrombotic risk

Enhanced liver fibrosis test : a further step toward depiction of fibrotic process in very early diagnosis of systemic sclerosis

Background/Purpose: Enhanced Liver Fibrosis (ELF) test is derived from an algorithm of 3 serum biomarkers of fibrosis (i.e. tissue inhibitors of matrix metalloproteinases, hyaluronic acid and aminoterminal propeptide of type III procollagen); it has been suggested as a sensitive/predictive tool for liver fibrosis. Aim of the study was to evaluate whether ELF may help in differentiating primary Raynaud\u2019s phenomenon (Rp) from very early Systemic Sclerosis (SSc) in a cross-sectional multi-center study. Methods: 110 consecutive adult subjects with \u201cisolated\u201d Rp (i.e. without any symptoms/signs suggesting a connective tissue disease) referring to 3 Italian Rheumatology Centers in approximately 6 months time were enrolled. Patients underwent as first screening nailfold capillaroscopy (NC) and were tested for anti-nuclear antibodies (ANA) by IFF and blotting and classified as primary Rp (pRp) (i.e. NC and ANA negative), very early SSc (i.e. ANA and NC positive), or Rp with NC or ANA positive. Patients with any other fibrosing disorder and treated with interferon were excluded. 15 limited cutaneous (lc)-SSc and 15 diffuse cutaneous (dc)-SSc with disease duration 5 years were also studied. ELF score was determined blindly by an independent commercial service (iQur, UK). Statistical analysis was performed by regression modelling this score as a function of the diagnosis and age. The discriminant performance was evaluate by ROC curve analysis adjusting for age. Results: 60 subjects had pRp (mean age 43.1 yrs), 35 had Rp with positive ANA only (mean age 43.6 yrs), 4 had Rp with NC scleroderma pattern only (mean age 38.2 yrs) and 10 had a diagnosis of very early SSc (mean age 59.7 yrs). There were significantly differences between ELF scores in subjects with pRp (mean 7.84) vs patients with very early SSc (mean 8.44), lc-SSc (mean 8.68) and dc-SSc (mean 9.00) (p 0.03, 0.001 and 0.0001 respectively). ELF score in pRp and Rp with positive ANA or NC scleroderma pattern only was not statistically different, although a progressive increase was observed (mean 7.84, 7.90 and 7.95 respectively). Considering patients with and without SSc, the area under the ROC curve was 0.7465 (CI 95%: 0.6578\u20130.8351). When adjusting for age the AUC for youngest patients was 0.77 and it significantly decreased for the older patients. A correlation was observed between ELF score and age. Conclusion: ELF score shows unbalanced fibrosis biomarkers in very early SSc; it may represent useful potential tool in identifying Rp associated with a scleroderma signature