Maria Laura Sorgi

Mixed cryoglobulinemia secondary to visceral Leishmaniasis.

We describe a case of type II mixed cryoglobulinemia, with monoclonal IgMkappa rheumatoid factor, associated with visceral leishmaniasis caused by Leishmania infantum. Involvement of Leishmania antigen(s) in the formation of cryoprecipitable immune complexes was suggested by the fact that cryoglobulinemic vasculitis subsided after antiparasite therapy and that anti-Leishmania antibodies, as well as rheumatoid factor, were enriched in the cryoprecipitate. We observed 2 additional patients with visceral leishmaniasis and cryoglobulinemic vasculitis. All 3 patients had seemingly contracted leishmaniasis in Italy, were hepatitis C virus negative, and were initially diagnosed as having autoimmune disorders. These findings indicate that Leishmania can be an etiologic agent of type II mixed cryoglobulinemia. This parasitosis should be taken into consideration in the differential diagnosis of vasculitides in endemic areas.

TCD4 pos lymphocytosis in rheumatoid and psoriatic arthritis patients following TNFα blocking agents

BackgroundLymphocyte expansion and true lymphocytosis are commonly observed in the everyday clinical practice. The meaning of such phenomenon is often poorly understood so that discrimination between benign and malignant lymphocytosis remains difficult to establish. This is mainly true when lymphocytosis rises in patients affected by immune-mediated chronic inflammatory diseases under immunosuppressive treatment, conditions potentially associated with lymphomagenesis. In this brief report the development of mild T CD4pos lymphocytosis in a group of patients with chronic arthritis under anti-TNF-α treatment is described.MethodsTwo hundred eight rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients have been evaluated longitudinally for at least 1-year before and 2-years after anti-TNF-α therapy introduction for the possible appearance of a lymphocyte expansion. In patients who developed lymphocyte expansion, T, B and NK cells were analysed.ResultsTwenty-five out of 208 (12%) subjects developed a mild T CD4pos lymphocytosis, during anti-TNF-α therapy, which reverted after its interruption. Higher lymphocyte count, more frequent use of steroids and shorter disease duration, before biological therapy start, have emerged as risk factors for lymphocytosis development.ConclusionsThis is the first longitudinal cohort study evaluating the onset of lymphocytosis in RA and PsA patients under anti-TNF-α treatment and its possible clinical relevance. A mild T CD4pos lymphocytosis has been observed in 12% of RA and PsA patients probably related to anti-TNF-α treatment as previously reported by anecdotal cases. Patients with higher baseline lymphocyte count, use of steroids and shorter disease duration before the introduction of biologic therapy, seem to be prone to develop this laboratory reversible abnormality.

An incomplete form of childhood Behçet's disease treated with infliximab.

Behçets disease (BD) is a multi-systemic vasculitis characterized by the possible presence of cutaneous, ocular, articular and neurological manifestations. In this report, we examine the case of a fifteen-year-old boy with an incomplete form of juvenile Behcets disease which began with joint involvement and developed into a complete form only after several years. The patient showed a rapid response to anti-TNF-alpha (infliximab) with an improvement of mucocutaneous lesions (oral and genital ulcers, pseudofolliculitis) and arthritis.

Analysis of Gut Microbiota in Rheumatoid Arthritis Patients: Disease-Related Dysbiosis and Modifications Induced by Etanercept

A certain number of studies were carried out to address the question of how dysbiosis could affect the onset and development of rheumatoid arthritis (RA), but little is known about the reciprocal influence between microbiota composition and immunosuppressive drugs, and how this interaction may have an impact on the clinical outcome. The aim of this study was to characterize the intestinal microbiota in a groups of RA patients treatment-naïve, under methotrexate, and/or etanercept (ETN). Correlations between the gut microbiota composition and validated immunological and clinical parameters of disease activity were also evaluated. In the current study, a 16S analysis was employed to explore the gut microbiota of 42 patients affected by RA and 10 healthy controls. Disease activity score on 28 joints (DAS-28), erythrocyte sedimentation rate, C-reactive protein, rheumatoid factor, anti-cyclic citrullinated peptides, and dietary and smoking habits were assessed. The composition of the gut microbiota in RA patients free of therapy is characterized by several abnormalities compared to healthy controls. Gut dysbiosis in RA patients is associated with different serological and clinical parameters; in particular, the phylum of Euryarchaeota was directly correlated to DAS and emerged as an independent risk factor. Patients under treatment with ETN present a partial restoration of a beneficial microbiota. The results of our study confirm that gut dysbiosis is a hallmark of the disease, and shows, for the first time, that the anti-tumor necrosis factor alpha (TNF-α) ETN is able to modify microbial communities, at least partially restoring a beneficial microbiota.

Anti-polysaccharide and anti-diphtheria protective antibodies after 13-valent pneumococcal conjugate vaccination in rheumatoid arthritis patients under immunosuppressive therapy

Immunogenicity of 13-valent pneumococcal polysaccharide (PnPS) conjugate vaccine (PCV13) was evaluated in 38 rheumatoid arthritis patients under immunosuppressive treatment and 20 healthy controls (HC). Antibodies to all PnPS and diphtheria-toxin analogue conjugate protein were measured pre- (T0), 1 (T1), 6 (T2), 12 (T3) months post-immunization. Patients and HC had similar response to individual PnPS. Mean antibody levels to all PnPS but one doubled at T1 compared with T0, with T3 persistence for only 8-7/13 PnPS. Baseline antibody levels was inversely associated with the rate of responders at T1 (T1/T0≥2) to 11/13 PnPS. Few subjects reached protective IgG levels against some serotypes frequently isolated in Italian patients with invasive pneumococcal disease. Antibody response was not influenced by therapy, except the one to PS7F, which was reduced by tumor necrosis factor-α-inhibitors. Vaccination increased also anti-diphtheria IgG. Despite this study substantially confirmed the PCV13 immunogenicity in immunocompromised patients, it also revealed some limitations.

AB0391 Immunogenicity of 13-Valent Conjugate Pneumococcal Vaccine in Patients with Rheumatoid Arthritis

Background Vaccine administration is an effective tool to prevent infectious diseases. Patients with autoimmune diseases have a higher risk of infections -mainly at respiratory level- as a consequence of immune system dysregulation as well as of immunosuppressive treatment. Therefore, prevention by specific available vaccinations is crucial, as suggested by different studies and by EULAR and ACR recommendations. To date, literature data support the effectiveness of vaccinations with pneumococcal polysaccharide vaccine in patients with Rheumatoid Arthritis (RA); on the contrary, the 13-valent conjugate pneumococcal vaccine has not yet been studied in RA patients receiving immunosuppressive treatment. Objectives The aim of this study was to evaluate the immunogenicity of the 13-valent conjugate pneumococcal vaccine in patients with RA receiving Methotrexate (MTX)+TNF blockers, MTX alone or TNF blockers monotherapy compared to healthy controls (HC). The secondary objective was to determine vaccine safety. Methods Consecutive RA patients with low-moderate disease activity treated with stable dose of glucocorticoids, MTX and/or anti-TNF drugs were enrolled. The pneumococcal vaccine was administered intramuscularly at baseline visit; patients underwent clinical and laboratory evaluation at the time of vaccination (T0) and after 1 (T1) and 6 (T2) months. Blood samples for the evaluation of specific anti-pneumococcal antibodies were collected at the same time-points. The immunogenicity was evaluated with the enzyme-linked immunosorbent assay (ELISA). Data were expressed as mean ± standard deviation; t-test was used to evaluate the difference in serum levels of antibodies to pneumococcal antigens at 1 and 6 months compared to baseline values. A p value <0.05 was considered statistically significant. Results 38 patients [36F/2M, age 62.1±11 yrs] and 6 healthy controls [2F/4M age 63.7±2 yrs] were enrolled; 11 patients were treated with MTX alone, 12 with TNF blocking monotherapy (Etanercept n=7, Adalimumab n=3 and Certolizumab n=2) and 15 with MTX in combination with TNF blockers (Infliximab n=1, Etanercept n=6, Adalimumab n=6 and Golimumab n=2). Actually, 24 patients and 3 HC have completed 6 months of follow-up. More than half of patients (61%) developed a positive antibody response to the thirteen polysaccharides (twofold increase of antibody titer). The most immunogenic pneumococcal antigens were polysaccharides 1, 4 and 9V (Image 1). At 1 month a threefold increase in antibody titre with a protective level maintained throughout 6 months was observed. After 1 and 6 months of treatment, no significant change in DAS28 was observed in vaccinated patients. During the follow-up we did not observe any severe adverse reactions in RA patients nor in healthy controls. Mild systemic and local adverse events (redness and/or swelling of injection site) were reported by 44% of vaccinated RA patients and by 16% of healthy subjects. Conclusions This is the first preliminary study to demonstrate safety and immunogenicity of the 13-valent conjugate pneumococcal vaccine in RA patients on immunosuppressive treatment. Disclosure of Interest None declared

FRI0195 Treatment with anti-tnf biologics in patient with rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis does not increase the risk of malignancy

Background Systemic inflammatory rheumatic diseases, may increase the risk of malignancy, and in particular of lymphoproliferative disorders1. If anti-TNFα therapy is associated with this risk is still controversial2,3. Objectives The aim of this study was to compare the risk of malignancy in 399 patients with Rheumatoid Arthritis (RA), Psoriatic Arthritis (PA) and Ankylosing Spondilylitis (AS), treated with either TNFα inhibitors plus DMARDs or DMARDs alone. Methods An observational retrospective case-control study in 202 RA, 147 PA and 50 AS patients, 279 (69.9%) of whom under anti-TNFα therapy (etanercept, adalimumab, infliximab) plus DMARDs and 119 (30.1%) under DMARDs alone, has been performed in the period 2004-2011. Two hundred-fiftysix (64.2%) patients, balanced between the two treatment groups, also received low-dose (<7,5 mg/day) corticosteroids (CCS). Fourteen (3.5%) malignancies, four of which lymphomas, have been observed. In order to analyze possible association between different variables and cancer/lymphoma development, univariate and multivariate analysis taking into account age, sex, smoking habits, disease duration, autoantibody (rheumatoid factor and anti-cyclic citrullinated peptide) positivity, erythrocyte sedimentation rate and C-reactive protein levels as well as different therapies and comorbidities (diabetes, COPD/asthma, hypertension) have been performed. Results No increased risk of cancer was found in the study group (OR 0.56, 95% CI: 0.23-1.16 for female sex; OR 1.08, 95% CI: 0.47-2.12 for males). Otherwise, the risk of lymphoma seems significantly higher among females (7.69, 95% CI: 1.59-22.48), but not among males (OR 4.76, 95% CI: 0.12-26.53). No association between cancer (multivariate analysis: OR 3.11, 95% CI 0.67-14.41) or lymphoma (univariate analysis: OR 1.29, 95% CI 0.13-12.56) and anti-TNFα inhibitor therapy has been observed among patients treated with TNFα inhibitors, compared with patients treated with DMARDs alone. Conclusions Overall, the risk of lymphoma seems higher among female patients, but anti-TNFα therapy in RA, PA, AS patients seems not to be associated with an increased risk of solid or haematological malignancies. References Turesson C, Matteson EL. Malignancy as a comorbidity in rheumatic diseases. Rheumatology (Oxford). 2013 Jan;52(1):5-14 Bongartz T, Sutton AJ, Sweeting MJ, Buchan I, Matteson EL, Montori V. Anti-TNFantibody therapy in rheumatoid arthritis and the risk of serious infections and malignancies: systematic review and meta-analysis of rare harmful effects in randomized controlled trials. JAMA 2006;295:2275-85 Lopez-Olivo MA, Tayar JH, Martinez-Lopez JA, Pollono EN, Cueto JP, Gonzales-Crespo MR, Fulton S, Suarez-Almazor ME. Risk of malignancies in patients with rheumatoid arthritis treated with biologic therapy: a meta-analysis. JAMA 2012;308:898-908 Disclosure of Interest None Declared

AB0286 Biological drugs in chronic inflammatory arthropathies: discontinuation rate of first anti-tnf treatment.

Background Anti-TNF drugs revolutioned inflammatory arthropathies treatment, cutting down their clinical evolution and giving rise to remarkable benefits in patients life quality. Objectives It has been carried out a retrospective study to evaluate the correlations with demographic data and clinical parameters in patients suffering of arthritis rheumatoid (RA) or psoriatic arthritis (PsA) in case of interruption of the first anti-TNF drug treatment. Methods From November 2004 to October 2011, 239 patients affected by RA (n=165), PsA (n=74) have been recruited for first anti-TNF drug treatment For every patient have been weighed: age, sex, pre-therapy illness activity, evaluated by DAS44, selected anti-TNF drug (infliximab, etanercept, adalimumab), interruptions of the treatment and their causes, divided in adverse events, inefficacy, and other ones (pregnancy, poor compliance, surgical operations etc.). The patients that did not interrupt the treatment have been defined as Responder and those who stop it or who make a switch as Non Responder. A statistical assessment about the possible correlation between Responder/Non Responder condition, different drugs used and demographic and clinical parameters was made by Chi-Quadro and T-Student tests. Results 110 of the 239 patients (46%) stopped the treatment with the first anti-TNF drug: 45% (n=74) patients with RA, 49% (n=36) with PsA. Statistically significant differences are not recorded among global rate of patients who interrupt etanercept (56% n=63), infliximab 50% (n=17) and adalimumab 50% (n=30). A more detailed analysis among the stopping reasons found adverse events in the 22% of the cases (n=52), ineffectiveness in 13% (n=32), and other causes in 9.2% (n=26). Infliximab showed the onset of adverse events in 38% of cases (13 pts) in comparison to 19% (28 pts) for etanercept and to 18% (11 pts) for adalimumab. Etanercept appears to be associated with a statistically significant lower occurrence of discontinuation for adverse events, compared to infliximab (p<0.03). Comparing to same factor adalimumab vs infliximab we obtain a correlation near to statistical significance (p<0.054). Among the analyzed demographic and clinical parameters, pre-treatment disease activity showed a statistical correlation with first anti-TNF interruption: Non Responder patients with RA e PsA presented a higher value of DAS respect to the Responder ones (p<0.005); the group of the Non Responder patients showed a longer duration of illness respect the group of Responder patients (p<0.052). Conclusions Infliximab is associated to higher discontinuation rate for adverse events, in comparison with etanercept and adalimumab. Among evaluated demographic and clinical data, duration of illness and high disease activity to recruitment seem to negatively affects the answer to the first anti-TNF, suggesting that such parameters may have predictive value for the interruption of the drug. Disclosure of Interest None Declared

Role for familiarity and genetic features in the therapeutic response of psoriatic arthritis

AIM OF THE STUDY To analyze PsA patients with and without a familiar distribution for Ps and PsA, in order to better evaluate the genetic data, to verify the existence of different expression of the disease and finally to define the susceptibility to treatment in these patients. MATERIALS AND METHODS 230 PsA patients were selected for familiar or sporadic distribution of the disease and were evaluated for the main clinical, demographic, radiological and laboratory features, as well as for the ongoing treatments. In each patient HLA class I (A,B,C) and II (DRB1, DQB1) antigens were typed with PCR-SSP method while MICA-A exon 5 microsatellite typing was performed by heteroduplex analysis in 122 subjects. RESULTS A familiar distribution for Ps and PsA was found in 68 patients (29.6%) although only two patients had familiarity for PsA. In the familiar PsA group the male prevalence was significantly higher respect to the sporadic one (p<0.001) and the more frequently involved relative was the father (28%). Mean age (p<0.006) and age at onset of Ps (p<0.004) and PsA (p<0.014) were significantly lower in familiar respect to sporadic PsA. Between the two groups no difference was found concerning the articular involvement, the radiological findings, the disease activity (including number of painful/swollen joints), the inflammatory laboratory parameters (including ESR and CRP) and genetic aspects, including the frequencies of MICA-A alleles that were analysed in 30 patients with the familiar form and in 92 with the sporadic one. In the follow-up the therapeutic response to any evaluated treatment adopted for PsA did not show any significant difference in the two groups. All these results were confirmed even when the patients in the two groups were matchable for sex, age and disease duration. CONCLUSION Our results confirm that familiar PsA is characterized by an early onset of the disease and by a male and fatherly predominance respect to the sporadic form, although the clinical-radiologic findings, the genetic typing and the therapeutic response do not permit us to identify any particular subset.