Andrea Picchianti Diamanti

Higher risk of tuberculosis reactivation when anti-TNF is combined with immunosuppressive agents: a systematic review of randomized controlled trials

Abstract Objective. Treatment with tumour necrosis factor antagonists (anti-TNF) has been recognized as a risk factor for tuberculosis (TB) reactivation. Our aim was to evaluate risk of TB reactivation in rheumatologic and non-rheumatologic diseases treated with the same anti-TNF agents with and without concomitant therapies. Methods. We searched for randomized controlled trials (RCTs) evaluating infliximab, adalimumab, and certolizumab in both rheumatologic and non-rheumatologic diseases until 2012. Results were calculated as pooled rates and/or pooled odd ratios (OR). Results. Overall, 40 RCTs with a total of 14,683 patients (anti-TNF: 10,010; placebo: 4673) were included. TB reactivation was 0.26% (26/10,010) in the anti-TNF group and 0% (0/4673) in the control group, corresponding to an OR of 24.8 (95% CI 2.4–133). TB risk was higher when anti-TNF agents were combined with methotrexate or azathioprine as compared with either controls (24/4241 versus 0/4673; OR 54; 95% CI 5.3–88) or anti-TNF monotherapy (24/4241 versus 2/5769; OR 13.3; 95% CI 3.7–100). When anti-TNF was used as monotherapy, TB risk tended to be higher than placebo (2/5769 versus 0/4673; OR 4; 95% CI 0.2–15.7). Conclusions. TB risk with anti-TNF agents appeared to be increased when these agents were used in combination with methotrexate or azathioprine as compared with monotherapy regimen. TB risk seemed to be higher than placebo, even when monotherapy is prescribed.

Biological Therapies for Rheumatoid Arthritis: Progress to Date

Biologic drugs for the management of rheumatoid arthritis (RA) have revolutionized the therapeutic armamentarium with the development of several novel monoclonal antibodies, which include murine, chimeric, humanized, fully human antibodies and fusion proteins. These biologics bind to their targets with high affinity and specificity. Since 1998, nine different biologics have been approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for the treatment of RA, and several others are in different stages of clinical trials. This field is in continuous evolution and new biologics are tested every year. Therefore a precise analysis is required in order to have a detailed and updated state of the art of this field. In this review, our main aim is to analyse all available biological therapies that are FDA and EMA approved for the treatment of RA and also those that are in clinical trials for the management of RA patients.

Could early rheumatoid arthritis resolve after periodontitis treatment only?: case report and review of the literature.

AbstractRheumatoid arthritis (RA) is an immune-mediated polyarthritis; currently no pathogenic agent has been identified as a disease trigger. A patient with RA, presumably caused by periodontal infection, whose remission has been observed after periodontitis treatment in absence of specific RA therapy, is reported here for the first time, to our knowledge.A 61-year-old male patient presented migrant arthritis associated with antibodies against citrullinated protein antigens positivity. The clinical features allowed to make RA diagnosis according to the 2010 European League against Rheumatism/American College of Rheumatology RA classification criteria. X-ray of the second upper molar showed chronic apical periodontitis. After its treatment, arthritis remission has been observed in the absence of specific RA therapy.It has been suggested that periodontitis may have a trigger role in RA pathogenesis. This could be explained by the enzymatic action of Porphyromonas gingivalis, probably leading to break tolerance to collagen. The identification and subsequent treatment of periodontitis should therefore be considered pivotal in RA prophylaxis and management.

Microbiota and chronic inflammatory arthritis: an interwoven link

BackgroundOnly recently, the scientific community gained insights on the importance of the intestinal resident flora for the host’s health and disease. Gut microbiota in fact plays a crucial role in modulating innate and acquired immune responses and thus interferes with the fragile balance inflammation versus tolerance.Main bodyCorrelations between gut bacteria composition and the severity of inflammation have been studied in inflammatory bowel diseases. More recently similar alterations in the gut microbiota have been reported in patients with spondyloarthritis, whereas in rheumatoid arthritis an accumulating body of evidence evokes a pathogenic role for the altered oral microbiota in disease development and course. In the context of dysbiosis it is also important to remember that different environmental factors like stress, smoke and dietary components can induce strong bacterial changes and consequent exposure of the intestinal epithelium to a variety of different metabolites, many of which have an unknown function. In this perspective, and in complex disorders like autoimmune diseases, not only the genetic makeup, sex and immunologic context of the individual but also the structure of his microbial community should be taken into account.ConclusionsHere we provide a review of the role of the microbiota in the onset, severity and progression of chronic inflammatory arthritis as well as its impact on the therapeutic management of these patients. Furthermore we point-out the complex interwoven link between gut-joint-brain and immune system by reviewing the most recent data on the literature on the importance of environmental factors such as diet, smoke and stress.

Reversion of resistance to immunosuppressive agents in three patients with psoriatic arthritis by cyclosporine A: modulation of P-glycoprotein function.

Secondary resistance may be a major problem in the management of autoimmune diseases. P-glycoprotein (P-gp) over-function has been described as a mechanism of drug resistance in autoimmune patients. P-gp function can in vitro be inhibited by cyclosporine A (CSA) and verapamil; moreover, P-gp reduction by CSA in systemic lupus erythematosus and rheumatoid arthritis has been demonstrated. Here, P-gp function before and after CSA administration in three psoriatic arthritis (PsA) patients, who developed a resistance to MTX/SSA, has been evaluated. P-gp function on patient cells was analyzed by measuring the changes in rhodamine-123 (Rh-123) fluorescence after verapamil incubation. CSA treatment resulted in good clinical outcome that was related with a significant P-gp function reduction at CD3+ and CD8+ levels. In addition to its immunosuppressive activity, CSA results may also be related to MTX/SSA effect restoration through P-gp inhibition. This is the first time that CSA has been demonstrated as being able to revert MTX/SSA resistance in PsA.

B cell modulation strategies in autoimmunity: the SLE example.

The paradigm that T cells are the prime effectors of autoimmune diseases has been recently challenged by growing evidence that B-lymphocytes play a role in the development, re-activation and persistence of autoimmune disorders. B-cells of different subsets may play different roles in autoimmune pathologies due to their ability to secrete antibodies, produce cytokines, present antigen and form ectopic germinal centers. Thus, a given therapeutic approach or drug may have distinct outcomes depending on which specific B cell subset is targeted. Immunosuppressive therapies such as azathioprine (AZA), cyclophosphamide (CyC) or methotrexate (MTX) are conventionally used in autoimmune diseases with the aim of reducing disease activity and improving the patients general health conditions. These treatments do not target a specific cellular type or subset and have substantial side effects, such as impairment of liver function and fertility. Moreover, autoimmune patients may be refractory to immunosuppressive therapy. In these cases finding an effective treatment becomes a challenge. The fast evolution in antibody technology is leading to the production of a wide array of humanized monoclonal antibodies, targeting specific cell types or pathways, initiating a new era in the treatment of autoimmune disorders. In addition, the recent discovery that toll like receptors (TLRs) activation can fire up autoimmunity in humans and maintain disease gives the grounds for the development of new drugs targeting the TLR/MyD88 pathway. In contrast to conventional immune-suppression, the availability of drugs interfering with B-cell specific pathogenetic pathways gives the possibility to choose therapies tailored to each disease and, possibly, to each patient.

Therapeutic management of patients with rheumatoid arthritis and associated interstitial lung disease: case report and literature review:

Rheumatoid arthritis (RA) is an inflammatory autoimmune disease that can present different extrarticular manifestations involving heart, lungs and kidneys. In recent years there has been a growing awareness of the central role played by the lungs in the onset and progression of RA. In particular interstitial lung disease (ILD) is a common pulmonary manifestation that may be related to the inflammatory process itself, infectious complications and to the treatments used. Management of patients with ILD/RA is still a challenge for clinicians, both synthetic [mainly methotrexate (MTX), leflunomide] and biologic immunosuppressors [mainly anti-tumor necrosis factor (TNF)α] have in fact been related to the onset or worsening of lung diseases with conflicting data. Here we report the case of a 61-year-old male patient with severely active early RA, previously treated with MTX, who developed subacute ILD, along with a review of ILD/RA topic. Tocilizumab (humanized monoclonal antibody against the interleukin-6 receptor) was introduced on the basis of its effectiveness in RA without concomitant MTX and the ability to overcome the profibrotic effects of interleukin (IL)-6. After 3 months of treatment the clinical condition of the patient strongly improved until it reached low disease activity. He no longer complained of cough and dyspnea and bilateral basal crackles were no more present. Considering its distinctive features, tocilizumab, in such a challenging clinical condition, appears to be a safe and effective therapy, thus it enables RA remission without deteriorating ILD, at 1-year follow up, as confirmed by ultrasonography of the affected joints and chest high-resolution computed tomography (HRCT).

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.

Lack of evidence for post-vaccine onset of autoimmune/lymphoproliferative disorders, during a nine-month follow-up in multiply vaccinated Italian military personnel

Anecdotal case reports, amplified by mass media and internet-based opinion groups, have recently indicated vaccinations as possibly responsible for autoimmunity/lymphoproliferation development. Multiply vaccinated Italian military personnel (group 1, operating in Italy, group 2, operating in Lebanon) were followed-up for nine months to monitor possible post-vaccine autoimmunity/lymphoproliferation onset. No serious adverse event was noticed in both groups. Multivariate analysis of intergroup differences only showed a significant association between lymphocyte increase and tetanus/diphtheria vaccine administration. A significant post-vaccine decrease in autoantibody positivity was observed. Autoantibodies were also studied by microarray analysis of self-proteins in subjects exposed to ≥4 concurrent vaccinations, without observing significant difference among baseline and one and nine months post-vaccine. Moreover, HLA-A2 subjects have been analyzed for the possible CD8T-cell response to apoptotic self-epitopes, without observing significant difference between baseline and one month post-vaccine. Multiple vaccinations in young adults are safe and not associated to autoimmunity/lymphoproliferation onset during a nine-month-long follow-up.

Increased serum IgM, immunodeficiency, and autoimmunity: A clinical series.

Background: Primary immunodeficiencies (PIDs) are generally characterized by recurrent infections; however they may be complicated by other clinical disorders such as allergy, autoimmunity, and lymphoproliferation. In particular, autoimmunity may be the first manifestation of the disease in patients with low serum immunoglobulins (Ig) levels. Here we describe a group of patients that share features of immunodeficiency and autoimmunity. Materials and Methods: All patients went through a complete T and B cell subset characterization and a B cell function analysis in the peripheral blood by flow-cytometry. B cell proliferation and plasma cell differentiation was measured, in vitro, after CpG stimulation for 7 days as previously described. Semi-quantitative PCR analysis for AID and UNG expression as well as serum levels of BAFF were carried out in order to better define the diagnosis. Results: Immunological and molecular analysis did not lead to the identification of known molecular defect typical of Hyper IgM syndrome. A comparative study of the peripheral blood B cell subsets between patients and healthy donors showed that in patients with autoimmune manifestations all circulating B cells expressed high amounts of surface IgM. Conclusions: These results suggest that the increased IgM expression on circulating B cells, reflecting B cell activation, might identify a clinical condition characterized by hyper IgM serum levels of unknown molecular defects, associated with susceptibility to infections and autoimmunity.