Drugs for treating infections caused by non-tubercular mycobacteria: a narrative review from the study group on mycobacteria of the Italian Society of Infectious Diseases and Tropical Medicine.

BACKGROUND: Non-tuberculous mycobacteria (NTM) are generally free-living organism, widely distributed in the environment, with sporadic potential to infect. In recent years, there has been a significant increase in the global incidence of NTM-related disease, spanning across all continents and an increased mortality after the diagnosis has been reported. The decisions on whether to treat or not and which drugs to use are complex and require a multidisciplinary approach as well as patients' involvement in the decision process. METHODS AND RESULTS: This review aims at describing the drugs used for treating NTM-associated diseases emphasizing the efficacy, tolerability, optimization strategies as well as possible drugs that might be used in case of intolerance or resistance. We also reviewed data on newer compounds highlighting the lack of randomised clinical trials for many drugs but also encouraging preliminary data for others. We also focused on non-pharmacological interventions that need to be adopted during care of individuals with NTM-associated diseases CONCLUSIONS: Despite insufficient efficacy and poor tolerability this review emphasizes the improvement in patients' care and the needs for future studies in the field of anti-NTM treatments.

Evidence for increase in finger blood flow, evaluated by laser Doppler flowmetry, following iloprost infusion in patients with systemic sclerosis: a week-long observational longitudinal study.

OBJECTIVES: Iloprost plays an important role in the treatment of Raynaud's phenomenon (RP), but has transient vasodilatory effects owing to its very short half-time. We aimed to evaluate short- and medium-term haemodynamic effects of iloprost by measuring dorsal finger microvessel blood flow using laser Doppler flowmetry (LDF), in patients with RP associated with systemic sclerosis (SSc). METHOD: In 24 consecutive SSc patients with RP (disease duration 10.5 ± 1.3 years), LDF with heating probes was used to measure blood flow in four fingers by occlusive and heating tests, at baseline, after 3 consecutive days of iloprost infusion, and at 24 h and 7 days after last iloprost infusion. Nailfold videocapillaroscopy (NVC) patterns of microvascular damage were investigated. Sixteen healthy controls were studied to compare baseline flows. RESULTS: Compared to controls, SSc patients showed significantly impaired axon reflex vasoregulation and nitric oxide responses at baseline (p = 0.001 and p = 0.03, respectively). After iloprost, a prompt but transient significant improvement in endothelial-dependent vasodilation (occlusive test) was seen only in SSc patients with an 'active' NVC pattern (p ≤ 0.05). The iloprost effects vanished within 7 days after the last infusion. No significant differences were found, in the whole study, between patients with and without digital ulcers. CONCLUSIONS: Microcirculatory blood flow increases following 3 days of iloprost infusion but fades shortly after treatment. Although iloprost is effective in reducing the severity of RP in SSc, the most suitable regimen and timing to obtain longer lasting vasodilatory benefits remain to be established.

Evidence-based algorithm for diagnosis and assessment in psoriatic arthritis: results by Italian DElphi in psoriatic Arthritis (IDEA).

Psoriatic arthritis (PsA) is a chronic inflammatory disease involving skin, peripheral joints, entheses, and axial skeleton. The disease is frequently associated with extrarticular manifestations (EAMs) and comorbidities. In order to create a protocol for PsA diagnosis and global assessment of patients with an algorithm based on anamnestic, clinical, laboratory and imaging procedures, we established a DElphi study on a national scale, named Italian DElphi in psoriatic Arthritis (IDEA). After a literature search, a Delphi poll, involving 52 rheumatologists, was performed. On the basis of the literature search, 202 potential items were identified. The steering committee planned at least two Delphi rounds. In the first Delphi round, the experts judged each of the 202 items using a score ranging from 1 to 9 based on its increasing clinical relevance. The questions posed to experts were How relevant is this procedure/observation/sign/symptom for assessment of a psoriatic arthritis patient? Proposals of additional items, not included in the questionnaire, were also encouraged. The results of the poll were discussed by the Steering Committee, which evaluated the necessity for removing selected procedures or adding additional ones, according to criteria of clinical appropriateness and sustainability. A total of 43 recommended diagnosis and assessment procedures, recognized as items, were derived by combination of the Delphi survey and two National Expert Meetings, and grouped in different areas. Favourable opinion was reached in 100% of cases for several aspects covering the following areas: medical (familial and personal) history, physical evaluation, imaging tool, second level laboratory tests, disease activity measurement and extrarticular manifestations. After performing PsA diagnosis, identification of specific disease activity scores and clinimetric approaches were suggested for assessing the different clinical subsets. Further, results showed the need for investigation on the presence of several EAMs and risk factors. In the context of any area, a rank was assigned for each item by Expert Committee members, in order to create the logical sequence of the algorithm. The final list of recommended diagnosis and assessment procedures, by the Delphi survey and the two National Expert Meetings, was also reported as an algorithm. This study shows results obtained by the combination of a DElphi survey of a group of Italian rheumatologists and two National Expert Meetings, created with the aim of establishing a clinical procedure and algorithm for the diagnosis and the assessment of PsA patients. In order to find accurate and practical diagnostic and assessment items in clinical practice, we have focused our attention on evaluating the different PsA domains. Hence, we conceived the IDEA algorithm in order to address PsA diagnosis and assessment in the context of daily clinical practice. The IDEA algorithm might eventually lead to a multidimensional approach and could represent a useful and practical tool for addressing diagnosis and for assessing the disease appropriately. However, the elaborated algorithm needs to be further investigated in daily practice, for evidencing and proving its eventual efficacy in detecting and staging PsA and its heterogeneous spectrum appropriately.

Correlation between serum levels of IL-15 and IL-17 in patients with idiopathic inflammatory myopathies.

OBJECTIVES: To assess the serum levels of interleukin (IL)-15 and IL-17 in patients with idiopathic inflammatory myopathies (IIM) and correlate them with levels of IL-1 receptor antagonist (IL-1ra), IL-6, IL-10, interferon (IFN)-γ, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1α, and MIP-1ß. Possible correlations with disease activity parameters were also evaluated. METHOD: Sera from 14 patients with new-onset polymyositis (PM), 10 with dermatomyositis (DM), seven with anti-synthetase syndrome (ASS) and 19 healthy controls (HC) were analysed by multiplex immunoassay. Sera from 19 patients were analysed after a median follow-up of 5 months. All patients underwent physical examination, manual muscle testing (MMT) using the five-point MMT scales, the Health Assessment Questionnaire (HAQ), and serum creatine kinase (CK) measurement. All patients received glucocorticoids, and 13 were taking immunosuppressive therapy. RESULTS: At baseline, serum levels of IL-15, IL-17, MCP-1, and MIP-1ß were significantly higher in IIM patients than in HC. IL-17 serum levels were directly correlated (r = 0.39, p = 0.02) with disease duration while a significant inverse correlation was detected between IL-17 levels and MMT scores (r = -0.4, p = 0.02). The highest IL-15 levels were present in DM patients (p = 0.02 vs. PM). The most striking finding was the strong correlation between IL-15 and IL-17 levels (r = 0.60, p = 0.0001), and this correlation was even stronger in DM patients (r = 0.82, p = 0.006). CONCLUSIONS: The strong correlation between IL-15 and IL-17 in IIM patients, and especially in DM, suggests that there may be an interplay between the two cytokines in the pathogenesis of myositis. Further studies of larger patient cohorts and of muscle biopsies are needed to confirm these preliminary data.

Two-year survival rates of anti-TNF-α therapy in psoriatic arthritis (PsA) patients with either polyarticular or oligoarticular PsA.

OBJECTIVES: To evaluate the 2-year drug survival rates of the tumour necrosis factor (TNF)-α blockers adalimumab, etanercept, and infliximab in psoriatic arthritis (PsA) patients with either oligoarticular (oligo-PsA) or polyarticular PsA (poly-PsA). METHOD: We studied a prospective cohort of 328 PsA patients with peripheral arthritis (213 with poly-PsA and 115 with oligo-PsA), beginning their first ever anti-TNF-α treatment with adalimumab, etanercept, or infliximab. The aim of the study was to evaluate the drug survival rates and possible baseline predictors at 2 years. RESULTS: After 24 months, persistence in therapy with the first anti-TNF-α blocker was not statistically different in the oligo-PsA (70.4%) and poly-PsA (65.7%) subsets. Predictors of drug discontinuation were female sex [hazard ratio (HR) 1.63, 95% confidence interval (CI) 1.00-2.68, p = 0.04] and starting the therapy in years 2003-8 (HR 0.51, 95% CI 0.33-0.80, p = 0.003). In poly-PsA, the persistence of etanercept (68.3%) was significantly higher than that of adalimumab (51.9%, p = 0.01), whereas in oligo-PsA no significant difference was detected. In poly-PsA, the period 2003-8 was a negative predictor (HR 0.36, 95% CI 0.21-0.62, p = 0.0001) whereas in oligo-PsA female gender was a positive predictor of drug discontinuation (HR 2.08, 95% CI 1.02-4.24, p = 0.04). With regard to clinical outcomes, the best responses in terms of European League Against Rheumatism (EULAR) 'good' response or Disease Activity Score (DAS28) remission, crude or adjusted according to the LUND Efficacy indeX (LUNDEX), were seen in patients on etanercept or infliximab. CONCLUSIONS: Our study provides some evidence that anti-TNF-α drugs may perform differently in PsA, and that the analysis of clinical disease subsets may improve our knowledge and promote better management of PsA.

Suboptimal methotrexate use in rheumatoid arthritis patients in Italy: the MARI study.

OBJECTIVES: Methotrexate (MTX) is the first choice in the treatment of rheumatoid arthritis (RA), but the doses and regimens vary significantly. For this purpose, we conducted an observational study on the use of MTX for RA in Italy (MARI study). METHODS: The MARI study included 1,327 RA patients on MTX treatment for at least 12 months, at 60 Italian rheumatology units. Concomitant medications with corticosteroids, other DMARDs or biological therapies were recorded. The clinical assessment included the Disease Activity Score 28 (DAS28) and the serological positivity for the rheumatoid factor or for the anti-citrullinated protein antibodies. RESULTS: The included patients were treated with either oral (n=288) or parenteral (n=1039) MTX. Only 15.5% of the total number of the patients was on adequate MTX dose (i.e. ≥ 15 mg for the oral route of administration and >12 mg for the parenteral one). The initially established MTX dose was modified in 37.1% of the patients, for intolerance or clinical criteria. A DAS28 remission (DAS28 <2.6) was observed only in 58.5% of the cases, while 52.9% of the patients still presenting an active form of the disease were on suboptimal doses of MTX. CONCLUSIONS: The weekly dose of MTX prescribed for the treatment of RA is often suboptimal, even in conditions of inadequate control of the disease activity. The recommendations for the use of MTX in RA patients should take into account the efficacy and tolerability data derived from its use in real clinical practice.

Erasmus syndrome in a marble worker.

Erasmus syndrome is defined as the association of silica exposure and subsequent development of systemic sclerosis. The limited number of cases reported in the literature mainly involves miners and only sporadically other professionals. We describe a case of Erasmus syndrome in a marble worker. A 68 year old man came to our observation complaining pelvic and scapular girdle pain, evening fever, intense weakness and emaciation for about 1 month. He also reported to have had Raynaud's phenomenon in his hands for the last 13 years. Also, his occupational history revealed a chronic exposure to silica dust. The patient presented pain in his shoulders and hips, moderate skin thickening and sclerosis in his hands and fingers extending proximally to his wrists. The diagnosis of systemic sclerosis was determined according to his clinical and medical history, the positivity of anti-Scl 70 antibodies, the nailfold capillaroscopy suggestive of an active scleroderma pattern and the detection of a mild restrictive pulmonary syndrome. The evaluation of the organbased complications excluded a gastroenterological and cardiovascular involvement, while the chest computed tomography (CT) detected multiple small nodules with a mantle distribution and enlarged lymph nodes with no signs of interstitial lung disease and fibrosis. Additional tests (positron emission tomography-CT, flexible bronchoscopy and broncho-alveolar lavage) excluded infectious diseases and cancer. However, given the pulmonary involvement, we performed a histological examination of the parenchyma and lymph nodes, which revealed a picture of pneumoconiosis. In the end, the occupational history and the findings from the diagnostic procedures led to the diagnosis of pulmonary silicosis. The precise definition of the pulmonary involvement was essential to the therapeutic approach to this patient.

Influence of TNF-α inhibition on oxidative stress of rheumatoid arthritis patients.

The aim of this study was to assess circulating levels of reactive oxygen metabolites (ROMs) as a marker of oxidative stress in rheumatoid arthritis (RA) patients during an anti-tumor necrosis factor alpha (TNF-α) treatment. We enrolled 40 patients with RA (36 females; age 53 ± 13 yrs) treated with different subcutaneously administered TNF-α inhibitors. The oxidative status was determined on the basis of plasma samples taken before, at 24 and 52 weeks of the anti-TNF-α treatment. Hydroperoxide levels were measured using the d-ROMs test, a useful clinically proven oxidative stress marker. During the anti-TNF-α therapy, we observed a significant reduction in serum ROMs levels in RA patients from 33.2 ± 10 mg H2O2/L at baseline to 29.5 ± 7 and 29.3 ± 9 mg H2O2/L, at 24 and 52 weeks, respectively (p<0.05). We also identified a significant correlation between the oxidative stress status and the disease activity score on 28 joints/C-reactive protein and health assessment questionnaire disability index. The results of our study demonstrate that a good control of the disease with anti-TNF-α agents can reduce oxidative stress in RA patients. However, further studies of larger patient cohorts are needed to confirm these preliminary data.

Coexistence of axial spondyloarthritis and thromboangiitis obliterans in a young woman.

A peculiar coexistence of axial spondyloarthritis and ischemia of the feet and the fourth finger of the left hand in a young woman, who was a heavy smoker, is discussed in this report. This picture was considered within the context of thromboangiitis obliterans. Positivity of anti-nuclear antibodies and mild elevation of inflammatory parameters were noted. Computed tomography angiograms of upper and lower limbs showed luminal narrowing and occlusion of the left humeral, left anterior/posterior tibial and right anterior tibial arteries. Daily iloprost perfusions were started, and smoking cessation was strongly recommended. Coldness and rest pain in the distal extremities improved within a few weeks. The possibility that spondyloarthritis might precede the clinical picture of thromboangiitis obliterans should be considered in heavy smokers.

The role of tumour necrosis factor in the pathogenesis of immune-mediated diseases.

Immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis, psoriatic arthritis, psoriasis, axial spondyloarthropathies, Crohn's disease, ulcerative colitis and juvenile idiopathic arthritis, comprise a group of chronic disorders characterized by an immune-mediated pathogenesis. Although at clinical presentation these diseases appear unrelated, they have been recognized to share similar pathogenic mechanisms. Data from epidemiological and genetic studies further support the concept that IMIDs are interrelated, as they can co-occur in the same patient and share a similar genetic susceptibility. The specific aetiologies of IMIDs remain unknown, but all are known to involve dysregulation of the immune system, including an over-expression of the pro-inflammatory cytokine tumour necrosis factor (TNF). The pivotal role played by TNF in the pathogenesis and pathophysiology of IMIDs has been documented by extensive preclinical and clinical investigations, and confirmed by the efficacy of anti-TNF biotechnological drugs, such as etanercept, infliximab and adalimumab, in the therapeutic management of these disorders. In this narrative review, we discuss the available data on the TNF-dependent pathogenesis of IMIDs and associations among the different disorders. Although much remains to be discovered about the pathogenesis and aetiology of IMIDs, their common inflammatory pathological features may explain why they can be successfully targeted by anti-TNF drugs. Among these, adalimumab, a fully human monoclonal antibody, has been approved for treatment of nine distinct IMID indications and it is likely to become a valuable therapeutic tool for this complex cluster of chronic inflammatory disorders.

anti-TNF agents as therapeutic choice in immune-mediated inflammatory diseases: focus on adalimumab.

The complex pathogenesis of immune-mediated inflammatory diseases (IMIDs) has been extensively investigated and dysregulation of cytokines, such as tumour necrosis factor (TNF) has been shown to play a dominant role in the pathogenesis of various IMIDs, such as rheumatoid arthritis, ankylosing spondylitis, Crohn's disease, ulcerative colitis, psoriasis and psoriatic arthritis. The subsequent development of biological agents capable of blocking TNF has led to important advances in the pharmacotherapy of such diseases and confirmed the concept of a common pathophysiology among IMIDs with TNF having a predominant role. Five TNF inhibitors have currently been approved for treatment of one or more IMIDs; these include infliximab, etanercept, adalimumab, golimumab and certolizumab pegol. Given the similarities in the pathogenic background of IMIDs, one could expect that anti-TNF agents be similarly effective and with comparable tolerability profiles; however, this may not be the case. Structural and pharmacological differences among the anti-TNF drugs are likely to result in differences in efficacy and tolerability among the agents in the different IMIDs, together with differences in potency, therapeutic dose ranges, dosing regimens, administration routes, and propensity for immunogenicity. Among the five TNF inhibitors approved for treatment of IMIDs, adalimumab has the widest range of indications. Data from controlled clinical trials of adalimumab, showing its excellent efficacy and tolerability in a wide range of indications, are supported by real-world long-term data from observational studies, which confirm the value of adalimumab as a suitable choice in the management of IMIDs.

Adalimumab in the treatment of immune-mediated diseases.

Tumour necrosis factor (TNF) plays an important role in the pathogenesis of immune-mediated inflammatory diseases (IMIDs). TNF inhibition results in down-regulation of abnormal and progressive inflammatory processes, resulting in rapid and sustained clinical remission, improved quality of life and prevention of target organ damage. Adalimumab is the first fully human monoclonal antibody directed against TNF. In this article, we review the role and cost effectiveness of adalimumab in the treatment of IMIDs in adults and children. The efficacy and tolerability of adalimumab has been demonstrated in patients with a wide range of inflammatory conditions, leading to regulatory approval in rheumatoid arthritis (RA), psoriatic arthritis (PsA), plaque psoriasis, inflammatory bowel diseases (Crohn's disease, ulcerative colitis, paediatric Crohn's disease, and intestinal Behçet's disease), ankylosing spondylitis (AS), axial spondyloarthritis (SpA) and juvenile idiopathic arthritis. The major tolerability issues with adalimumab are class effects, such as injection site reactions and increased risk of infection and lymphoma. As with all anti-TNF agents, adalimumab is immunogenic, although less than infliximab, and some patients receiving long-term adalimumab will develop anti-drug antibodies, causing a loss of response. Comparisons of its clinical utility and cost effectiveness have shown it to be a valid treatment choice in a wide range of patients. Recent data from Italian economic studies show the cost effectiveness of adalimumab to be below the threshold value for health care interventions for most indications. In addition, analysis of indirect costs shows that adalimumab significantly reduces social costs associated with RA, PsA, AS, Crohn's disease and psoriasis. The fact that adalimumab has the widest range of approved indications, many often presenting together in the same patient due to the common pathogenesis, may further improve the utility of adalimumab. Current clinical evidence shows adalimumab to be a valuable resource in the management of IMIDs. Further research, designed to identify patients who may benefit most from this drug, will better highlight the role and cost-effectiveness of this versatile TNF inhibitor.

Possible interplay between interleukin-15 and interleukin-17 into the pathogenesis of idiopathic inflammatory myopathies.

The aim of this study was to assess the serum levels of interleukin (IL)-15 and IL-17 in patients with idiopathic inflammatory myopathies (IIM) and correlate them with IL-6, IL-10, monocyte chemoattractant protein-1 (MCP-1), macrophage inflammatory protein-1α (MIP-1α), MIP-1ß levels. Possible correlations with disease activity parameters were also evaluated. Sera from 14 polymyositis (PM), 10 dermatomyositis (DM), 7 anti-synthetase syndrome new onset patients and 19 healthy controls (HCs) were analyzed by multiplex immunoassay. Sera from 19 patients were analyzed after 5 months median follow-up. All patients underwent physical examination, the 5-points manual muscle test (MMT), the health assessment questionnaire and serum creatine kinase measurement. All patients received glucocorticoids, and 13 were taking also immunosuppressive therapy. At baseline, serum levels of IL-15, IL-17, MCP-1 and MIP-1ß were significantly higher in IIM patients than in HCs. IL-17 serum levels were directly correlated with disease duration (r=0.39, P=0.02), while a significant inverse correlation was detected between IL-17 levels and MMT scores (r=-0.4, P=0.02). The highest IL-15 levels were present in DM patients (P=0.02 vs PM). The most striking finding was the strong correlation between IL-15 and IL-17 levels (r=0.60, P=0.0001), and this correlation was even stronger in DM patients (r=0.82, P=0.006). The strong correlation between IL-15 and IL-17 in IIM patients, and especially in DM, suggests that there may be a interplay between the two cytokines in the pathogenesis of myositis. Further studies of larger patient cohorts and muscle biopsies are needed to confirm these preliminary data.

Intra-articular therapy with tumor necrosis factor-α antagonists: an update.

The aim of the study was to review from the present literature the intra-articular (IA) use of the TNF-blocking drugs. A total of 28 papers about this topic were found through a search in PubMed; the first publication's date was July 2003. These studies include a total of 214 patients affected by 12 different joint diseases that reported a total of 1046 intra-articular therapies carried out in 10 different joint sites. Infliximab and etanercept were the most widely used medications. The safety of this treatment clearly emerges from our analysis, while more difficult was the evaluation of its efficacy. Nevertheless we deduced an ideal patient profile that may better respond to the IA anti-TNF treatment.

A false occult hepatitis B virus infection developed in a patient with psoriatic arthritis under infliximab and methotrexate therapy.

Despite lacking of international guidelines about the management of patients with occult hepatitis B virus infection (OBI) starting TNF-α blockers, there is some evidence from real life settings that these drugs are safe in OBI patients with rheumatic diseases. On the contrary, the management of the so-called false OBI patients appears still undefined. We describe a case of acute hepatitis B virus (HBV) infection occurred in an anti-HBs and anti- HBc positive patient affected by psoriatic arthritis, who had been treated for five years with infliximab. Baseline HBV-DNA analysis had not been performed. Although HBs Ag was still negative and the transaminases in the normal range, HBV-DNA serum analysis surprisingly showed high replication rate. Entecavir was added, and three months later HBV-DNA was no longer detectable. Even if HBs Ag is persistently negative, the assessment of HBV-DNA should be recommended at least at baseline in order to rule out hidden active necro-inflammatory liver disease.

Body mass does not affect the remission of psoriatic arthritis patients on anti-TNF-α therapy.

OBJECTIVES: There is evidence that fat tissue may influence the response to therapy in patients with arthritis. The aim of this study was to assess whether the body mass index (BMI) affects rates of clinical remission in patients with psoriatic arthritis (PsA) treated with anti-tumour necrosis factor (TNF)-α biological drugs. METHOD: We retrospectively studied 135 patients with active peripheral PsA (45 obese, 47 overweight, and 43 normal-weight). Baseline BMI was correlated with the clinical response to adalimumab, etanercept, or infliximab. After 36 months (median, range 6-79) of treatment, disease remission rates were assessed using the Disease Activity Score in 28 joints (DAS28) or the Simplified Disease Activity Index (SDAI). Possible predictors of clinical outcomes were assessed by multivariate analysis. RESULTS: At baseline, BMI was significantly correlated only with the Health Assessment Questionnaire (HAQ) score (r = 0.21, p = 0.02) and not with disease activity. BMI did not predict disease remission or changes in HAQ score following anti-TNF-α therapy. Obese patients showed a significantly higher HAQ score and took significantly lower doses of prednisone than normal-weight or overweight patients, but their disease remission rates on the DAS28 (37%) or the SDAI (21%) were not significantly different from those of the other two groups (44% and 21%, respectively), regardless of the TNF-α inhibitor prescribed. CONCLUSIONS: In our retrospective analysis, disease activity and clinical response to anti-TNF-α therapy in PsA do not seem to be affected by BMI. Further prospective studies are needed to confirm these preliminary results.

Papular-purpuric gloves and socks syndrome due to parvovirus B19: a report of two simultaneous cases in cohabitant families.

The so-called papular-purpuric gloves and socks syndrome (PPGSS) is a condition characterized by acute onset of intense erythema, edema and petechiae with a typical localization on the hands and feet, besides mucosal lesions of the oral cavity. The syndrome has a favorable and self-limited course, requiring only a symptomatic therapy. In the 50% of the cases described in literature (ninety cases in 22 years), is documented an acute infection caused by parvovirus B19 and in only two cases the onset of PPGSS is reported among different members of the same family. The aim of the work is to describe two cases of PPGSS arisen during a short time period in two family members affected by an acute parvovirus B19 infection found by serum sampling. The peculiarity of the study was the infrequence of the syndrome and the rareness of the description of PPGSS in rheumatology. This syndrome is usually described in dermatology, but it is also interesting for the rheumatologist because it comes in differential diagnosis with various autoimmune diseases.

Rituximab treatment for Sjogren syndrome-associated non-Hodgkin's lymphoma: case series.

Five per cent of patients with primary Sjogren's syndrome (pSS) develop malignant non-Hodgkin's lymphoma (NHL), usually of the mucosa-associated lymphoid tissue (MALT) and most frequently located in the major salivary glands. Rituximab (RTX), a chimeric monoclonal antibody against the CD20 molecule expressed on the surface of mature B cells that has been approved for the treatment of NHL, has been used to treat pSS-associated lymphoma. We have described two cases: one with MALT lymphoma in the parotid glands and the other with a rare thymus lymphoma accompanied by the rare complication of a bullous pneumopathy. Both were treated with RTX at haematological doses, which was unsuccessful in the patient with a salivary lymphoma; in the case of the patient with a thymus lymphoma, the mediastinum mass disappeared and did not relapse. Both patients experienced an improvement in the subjective symptoms of dryness, and their Schirmer's test and scialoscintigraphy results stabilised. The pulmonary bullae remained unchanged.

GISEA: an Italian biological agents registry in rheumatology.

The GISEA registry is an independent database that was established by the Italian Group for the Study of Early Arthritis (GISEA) in 2008, funded by the Italian Association of Rheumatic Patients (ANMAR - ONLUS). In line with the network's epidemiological strategy, the initial protocol was designed to collect long-term follow-up data concerning patients with rheumatic diseases treated with biological agents in order to investigate the realworld characteristics in terms of disease activity, comorbidities and survival on treatment. We here describe the design and methodology used to collect patient data. Information concerning demographics, disease activity, treatment changes (including the reasons for changing and the duration of each therapy), concomitant therapies and adverse events is available to all the members of the study groups by means of a web-based interface that allows queries and the presentation of numerical data, as well as graphics to illustrate trends. Fourteen Italian rheumatology centres have contributed patients to the database which, at the time writing, includes 5145 patients (72% women) with a mean age of 53 years (range 16-88). The initial diagnoses were rheumatoid arthritis (3494 patients, 67.9%), psoriatic arthritis (833, 16.2%), ankylosing spondylitis (493, 9.6%), undifferentiated spondylo-arthritides (307, 5.9%), enteropathic arthritis (14, 0.3%) and spondylitis following reactive arthritis (4, 0.1%). These patients have been followed for up to 10 years, and 1927 (35.8%) have been treated for at least three years. The biological treatments received include etanercept, infliximab, anakinra, adalimumab, abatacept, rituximab and tocilizumab. A total of 2926 adverse events have been observed, with 1171 patients (22%) reporting at least one. Analysis of the accumulated data will provide insights into the critical early phase of the studied arthritides, and enable us to identify the clinical and laboratory profiles that may predict responsiveness to a specific therapy.

Heterogeneity and penetration of HIV-1 non-subtype B viruses in an Italian province: public health implications.

This study assessed changes in prevalence and distribution of HIV-1 non-subtype B viruses in Italian and immigrant patients over two decades in a province in Italy. All HIV-positive patients who underwent genotypic resistance testing were selected. Prevalence of non-subtype B viruses in 3-year periods was calculated. All sequences of non-subtype B and those provided by REGA as unassigned were analysed for phylogenetic relationships. In total, 250/1563 (16%) individuals were infected with a non-subtype B virus. Prevalence increased over time, reaching a peak (31.5%) in 2004-2006. In Italian patients, the most frequent subtypes were B (92.5%) and F1 (4%). F1 subtype was also prevalent in patients from South America (13.6%); in patients of African origin, CRF02_AG (54.9%) and G (12.3%) were the most frequent. HIV-1 non-subtype B infections in Italians were mostly found in patients who acquired HIV sexually. A phylogenetic relationship between F subtypes in Italian and representative HIV-1 sequences from Brazil was found. C subtypes in Italians were phylogenetically related to subtypes circulating in Brazil. Inter-subtype recombinants were also found in the latest years. The HIV-1 epidemic in Brescia province evolved to the point where about 1/3 patients recently diagnosed harboured non-B HIV subtypes. The distribution of HIV-1 non-B subtypes in Italian patients resembled that in South American patients and phylogenetic relatedness between some Italian and South American HIV-1 strains was found. The possible epidemiological link between these two populations would have been missed by looking only at risk factors for HIV acquisition declared by patients. The evidence of inter-subtype recombinants points to significant genetic assortment. Overall our results support phylogenetic analysis as a tool for epidemiological investigation in order to guide targeted prevention strategies.