Vasculitis associated with adenosine deaminase 2 deficiency: at the crossroads between Behçet's disease and autoinflammation. A viewpoint.

Adenosine deaminase 2 deficiency (DADA2) is a rare monogenic vasculopathy caused by loss-of-function homozygous or compound heterozygous mutations in ADA2, formerly CECR1 (cat eye syndrome chromosome region 1) gene. The DADA2 phenotype is widely heterogeneous, and patients may present with fever, weight loss, livedo reticularis/racemosa, digital ischemia, cutaneous ulceration, peripheral neuropathy, abdominal pain, bowel perforation, and portal or nephrogenic hypertension. More specific manifestations include early-onset ischemic or hemorrhagic stroke, mild immunodeficiency and hypogammaglobinemia, cytopenia, and vision disturbances. Herein, we present the case of a young male with vasculitis associated with DADA2. The presence of HLA-B51 and the clinical features of this patient raised the question of similarities between ADA2 deficiency, Behçet's disease, and NOD2-associated diseases. Treatment of this rare monogenic disease is challenging and based on small case series. The long-term experience of this patient proved the difficulties of prednisone tapering and the lack of satisfactory therapeutic strategies.

The Institute for the History of Rheumatology, an offspring of the Italian Society of Rheumatology, is born in Venice.

Not available.

Reply to the Letter to the Editor: The Italian Society of Rheumatology clinical practice guidelines for the management of polymyalgia rheumatica.

Not available.

The Italian Society of Rheumatology clinical practice guidelines for the management of polymyalgia rheumatica.

OBJECTIVE: to provide evidence-based up-to-date recommendations for the management of patients with a definite diagnosis of polymyalgia rheumatica (PMR). METHODS: A systematic literature review was performed to find the existing clinical practice guidelines (CPGs) on PMR and the framework of the Guidelines International Network Adaptation Working Group was used to appraise (AGREE II), synthesize, and customize the recommendations according to the needs of the Italian healthcare context. Rheumatologists on behalf of the Italian Society of Rheumatology (SIR) and from the SIR Epidemiology Unit joined the working group and identified the key health questions on PMR to guide the systematic literature review. Physicians, including general practitioners and specialists, and health professionals who manage PMR in the clinical practice were the target audience. The final recommendations were rated externally by a multi-disciplinary and multi-professional group of stakeholders. RESULTS: From the systematic search in databases (Medline, Embase) and grey literature, 3 CPGs were identified and appraised by two independent raters. Combining the statements and the evidence from these CPGs, 9 recommendations were developed by endorsement or adaptation in response to the initial key health questions. The quality of evidence was graded and the working group discussed the final recommendations in view of their implementation in the Italian healthcare context. CONCLUSIONS: In absence of national guidelines so far, these recommendations are the first to provide guidance for the management of patients with a diagnosis of PMR in Italy and they are expected to ensure the best evidence-based clinical practice for this disease.

The Italian Society of Rheumatology clinical practice guidelines for the management of polymyalgia rheumatica

To provide evidence-based up-to-date recommendations for the management of patients with a defi-nite diagnosis of polymyalgia rheumatica (PMR).Methods: A systematic literature review was performed to find the existing clinical practice guidelines (CPGs) on PMR and the framework of the Guidelines International Network Adaptation Working Group was used to appraise (AGREE II), synthesize, and customize the recommendations according to the needs of the Italian healthcare context. Rheumatologists on behalf of the Italian Society of Rheumatology (SIR) and from the SIR Epidemiology Unit joined the working group and identified the key health questions on PMR to guide the systematic literature review. Physicians, including general practitioners and specialists, and health profession-als who manage PMR in the clinical practice were the target audience. The final recommendations were rated externally by a multi-disciplinary and multi-professional group of stakeholders.Results: From the systematic search in databases (Medline, Embase) and grey literature, 3 CPGs were identi-fied and appraised by two independent raters. Combining the statements and the evidence from these CPGs, 9 recommendations were developed by endorsement or adaptation in response to the initial key health questions. The quality of evidence was graded and the working group discussed the final recommendations in view of their implementation in the Italian healthcare context. Conclusions: In absence of national guidelines so far, these recommendations are the first to provide guid-ance for the management of patients with a diagnosis of PMR in Italy and they are expected to ensure the best evidence-based clinical practice for this diseas

A rare regulatory variant in the MEF2D gene affects gene regulation and splicing and is associated with a SLE sub-phenotype in Swedish cohorts.

Systemic lupus erythematosus (SLE) is an autoimmune disorder with heterogeneous clinical presentation and complex etiology involving the interplay between genetic, epigenetic, environmental and hormonal factors. Many common SNPs identified by genome wide-association studies (GWAS) explain only a small part of the disease heritability suggesting the contribution from rare genetic variants, undetectable in GWAS, and complex epistatic interactions. Using targeted re-sequencing of coding and conserved regulatory regions within and around 215 candidate genes selected on the basis of their known role in autoimmunity and genes associated with canine immune-mediated diseases, we identified a rare regulatory variant rs200395694:G > T located in intron 4 of the MEF2D gene encoding the myocyte-specific enhancer factor 2D transcription factor and associated with SLE in Swedish cohorts (504 SLE patients and 839 healthy controls, p = 0.014, CI = 1.1-10). Fisher's exact test revealed an association between the genetic variant and a triad of disease manifestations including Raynaud, anti-U1-ribonucleoprotein (anti-RNP), and anti-Smith (anti-Sm) antibodies (p = 0.00037) among the patients. The DNA-binding activity of the allele was further studied by EMSA, reporter assays, and minigenes. The region has properties of an active cell-specific enhancer, differentially affected by the alleles of rs200395694:G > T. In addition, the risk allele exerts an inhibitory effect on the splicing of the alternative tissue-specific isoform, and thus may modify the target gene set regulated by this isoform. These findings emphasize the potential of dissecting traits of complex diseases and correlating them with rare risk alleles with strong biological effects.

Extra-articular rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic inflammatory disease that mainly affects the joints, though a consistent proportion of patients may also display extra articular manifestations (EAMs). From rheumatoid nodules to interstitial lung disease, from cardiovascular events to vasculitis, the spectrum of EAMs encompasses various conditions with different prognoses. EAMs may also occur as first RA manifestation, therefore the coordination with other health professionals, including general practitioners, is needed. The aim of this article is to provide an overview on EAMs in RA with particular focus on the recognised risk factors and the available recommendations for managing them, as well as comorbidities in RA patients.

Histopathology of salivary glands.

Salivary gland (SG) biopsy is a technique broadly applied for the diagnosis of primary Sjögren's syndrome (pSS), lymphoma accompanying SS, sarcoidosis, amyloidosis, and IgG4-related disease The most peculiar feature of pSS on biopsy is focal lymphocytic sialadenitis. In the past, several histological scores have been reported in the literature to describe glandular involvement during pSS. However, the variability among centres in reporting glandular scores is one of the rationales behind the development of standardised consensus guidance. SGs as well as lacrimal glands are involved in up to 50% of patients with IgG4-related disease with 3 histopathological hallmarks such as dense lymphoplasmacytic infiltration, storiform fibrosis and obliterative phlebitis. SGs can be also affected by amyloidosis with MSG biopsy being more sensitive than that of rectal mucosa or subcutaneous fat. SG involvement is a rare manifestation during sarcoidosis, and the presence of non-caseating granulomas needs to be differentiated from granulomas of other etiology. This review article provides an overview of normal and pathological SGs in the context of rheumatic diseases, identifying key elements in the tissue as diagnostic and prognostic biomarkers, useful in the current clinical practice.

Association between anti-citrullinated alpha enolase antibodies and clinical features in a cohort of patients with rheumatoid arthritis: a pilot study.

In recent years several antibodies against citrullinated peptides (ACPAs) have been identified in patients with rheumatoid arthritis (RA) and their pathogenic, diagnostic and prognostic significance is under intense investigation. Among ACPAs, those targeting citrullinated alpha enolase (anti-CEP1) have been identified in RA but data about their ability to predict the development of erosive disease are conflicting. Furthermore, no data are currently available concerning their possible association with extra-articular manifestations (EAMs) in RA. The aim of this study was to investigate the prevalence and significance of anti-CEP1 from a prognostic point of view. In this pilot study we confirmed that anti-CEP1 Abs are associated with higher prevalence of bone erosions, but we also provided the first evidence of an association between anti-CEP1 Abs and RA interstitial lung disease (ILD). These results provide the basis to investigate the association between anti-CEP1 Abs and EAMs in larger cohorts of RA patients to possibly confirm its role as biomarker for RA-ILD.

The clinical spectrum of primary Sjögren's syndrome: beyond exocrine glands.

Although primary Sjögren's syndrome (pSS) is a mild indolent chronic disease mainly characterized by mucosal dryness in the majority of cases, a consistent subgroup of patients display extra-glandular manifestations. Virtually any organs and systems can be affected, leading to a more serious disease prognosis. Therefore, the prompt identification of patients at higher risk of extra-glandular manifestations is necessary to start a thorough follow up and an aggressive treatment. The aim of this review article is to provide an overview of epidemiological, clinical and serological features of extra-glandular manifestations in pSS as well as current knowledge about putative biomarkers useful in clinical practice.

Interleukin (IL)-17-producing pathogenic T lymphocytes co-express CD20 and are depleted by rituximab in primary Sjögren's syndrome: a pilot study.

Compelling evidence suggests that interleukin (IL)-17 and IL-17-producing cells play a pivotal role in the pathogenesis of primary Sjögren's syndrome (pSS). We investigated phenotypical and functional effects of the anti-CD20 antibody rituximab (RTX) on circulating and glandular IL-17-producing T cells in pSS. RTX is able to deplete glandular IL-17(+) CD3(+) CD4(-) CD8(-) double-negative (DN) and CD4(+) Th17 cells as well as circulating IL-17(+) DN T cells. A fraction of glandular and circulating IL-17(+) DN cells and CD4(+) T helper type 17 (Th17) cells co-expresses CD20 on the cell surface explaining, at least in part, such depletive capacity of RTX. The exposure to RTX does not rescue the in-vitro corticosteroid resistance of IL-17(+) DN T cells. Our results support further the therapeutic role in pSS of RTX that, despite its B cell specificity, appears able to also hamper IL-17-producing T cells in this disease.

The onset site of rheumatoid arthritis: the joints or the lung?

The etiopathogenesis of rheumatoid arthritis (RA) is not yet fully elucidated and the site of inflammation onset is still a matter of debate. The presence of autoantibodies as well as clinical manifestations, such as interstitial lung disease, before the onset of arthritis seems to be in favour of the hypothesis that initial pathogenic events take place in tissues other than the joint. In this review article we summarize the most recent literature on extra-synovial autoimmunity triggers eventually leading to RA, with particular focus on the role of the lung. To date, anti-cyclic citrullinated peptide antibodies (ACPAs) are considered central players in RA pathogenesis and represent the gold-standard for disease diagnosis. Lungs and mucosae are exposed to environmental stimuli such as dusts and smoke which have been shown to foster citrullination of peptides in lungs thereby triggering the production of ACPA. In addition, other mechanisms of disease pathogenesis independent of citrullination play an important role. Deeper knowledge of these processes could represent a huge step forward in the management of RA, with dramatic impact on diagnosis, prevention, prognostic stratification and treatment of the disease.

Multiple Changes of Gene Expression and Function Reveal Genomic and Phenotypic Complexity in SLE-like Disease.

The complexity of clinical manifestations commonly observed in autoimmune disorders poses a major challenge to genetic studies of such diseases. Systemic lupus erythematosus (SLE) affects humans as well as other mammals, and is characterized by the presence of antinuclear antibodies (ANA) in patients' sera and multiple disparate clinical features. Here we present evidence that particular sub-phenotypes of canine SLE-related disease, based on homogenous (ANA(H)) and speckled ANA (ANA(S)) staining pattern, and also steroid-responsive meningitis-arteritis (SRMA) are associated with different but overlapping sets of genes. In addition to association to certain MHC alleles and haplotypes, we identified 11 genes (WFDC3, HOMER2, VRK1, PTPN3, WHAMM, BANK1, AP3B2, DAPP1, LAMTOR3, DDIT4L and PPP3CA) located on five chromosomes that contain multiple risk haplotypes correlated with gene expression and disease sub-phenotypes in an intricate manner. Intriguingly, the association of BANK1 with both human and canine SLE appears to lead to similar changes in gene expression levels in both species. Our results suggest that molecular definition may help unravel the mechanisms of different clinical features common between and specific to various autoimmune disease phenotypes in dogs and humans.

Cardiovascular disease risk burden in primary Sjögren's syndrome: results of a population-based multicentre cohort study.

OBJECTIVE: Systemic autoimmune diseases, in particular systemic lupus erythematosus and rheumatoid arthritis, are characterized by a high risk of premature cardiovascular (CV) events. Disease-related characteristics and traditional CV disease risk factors may contribute to atherosclerotic damage. However, there are limited data on the risk of overt CV events in primary Sjögren's syndrome (pSS). METHODS: We retrospectively analysed a cohort of patients with 1343 pSS. Disease-related clinical and laboratory data, traditional CV disease risk factors and overt CV events were recorded. Prevalence of traditional CV disease risk factors and of major CV events was compared between a subgroup of 788 female patients with pSS aged from 35 to 74 years and 4774 age-matched healthy women. RESULTS: Hypertension and hypercholesterolaemia were more prevalent, whereas smoking, obesity and diabetes mellitus were less prevalent, in women with pSS than in control subjects. Cerebrovascular events (2.5% vs. 1.4%, P = 0.005) and myocardial infarction (MI) (1.0% vs. 0.4%, P = 0.002) were more common in patients with pSS. In the whole population, central nervous system involvement (odds ratio (OR) 5.6, 95% confidence interval (CI) 1.35-23.7, P = 0.02) and use of immunosuppressive therapy (OR 1.9, 95% CI 1.04-3.70, P = 0.04) were associated with a higher risk of CV events. Patients with leucopenia had a higher risk of angina (P = 0.01). CONCLUSIONS: pSS is associated with an increased risk of cerebrovascular events and MI. Disease-related clinical and immunological markers may have a role in promoting CV events.

Clinical and biological differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome: results of a large multicentre study.

OBJECTIVES: To determine the clinical and laboratory differences between cryoglobulinaemic and hypergammaglobulinaemic purpura in primary Sjögren's syndrome (pSS), in a large Italian multicentre cohort. METHOD: Patients were selected according to the following criteria: fulfilling the American-European classification criteria for pSS, serum cryoglobulin and gammaglobulin levels evaluated, and lack of hepatitis C virus (HCV) infection. Multinomial analyses were performed by distinguishing three groups of pSS: (i) purpura associated with cryoglobulinaemic vasculitis (CV), (ii) purpura associated with hypergammaglobulinaemic vasculitis (HGV), and (iii) pSS patients without purpura (pSS controls). Patients with purpura but without cryoglobulins or hypergammaglobulinaemia were excluded. RESULTS: A total of 652 patients were enrolled in this study. Group 1/CV comprised 23/652 patients (3.53%), group 2/HGV 40/652 patients (6.13%), and group 3/pSS controls 589/652 (90.34%). The three groups were found to be significantly different from each other (post-estimation test: group 1/CV vs. group 3/pSS controls: p < 0.0001; group 1/CV vs. group 2/HGV: p = 0.0001; group 2/HGV vs. group 3/pSS controls: p = 0.0003), thus confirming the different phenotypes of purpura in pSS.Multivariate analyses revealed that peripheral neuropathy (p < 0.001), low C4 (p < 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.02), and the presence of anti-SSB/La antibodies (p = 0.02) characterized CV whereas rheumatoid factor (p = 0.001), leucopaenia (p = 0.01), serum monoclonal component (p = 0.01), and anti-SSA/Ro antibodies (p = 0.049) were significantly associated with HGV. Lymphoma was associated only with CV. CONCLUSIONS: HGV is a cutaneous vasculitis, related to a benign B-cell proliferation, whereas CV is a systemic immune complex-mediated vasculitis with complement activation and a higher risk of lymphoma, thus confirming CV but not HGV as a prelymphomatous condition in pSS.

A retrospective, multicenter study evaluating the prognostic value of minor salivary gland histology in a large cohort of patients with primary Sjögren's syndrome.

OBJECTIVE: The objective of this report is to investigate the prognostic value of minor salivary glands (MSG) assessment, routinely performed with hematoxilin-eosin (H&E) staining, for the diagnosis of primary Sjögren's syndrome (pSS). METHODS: We retrospectively evaluated clinical, serological and histological features of 794 pSS patients. H&E-stained sections were assessed using the Chisholm and Mason grading system and/or the focus score (FS). RESULTS: FS allowed the identification of a number of differences in the disease spectrum, and its prognostic role was further confirmed by quantifying the association between FS value and clinical/serological variables with binary logistic regression. Moreover, hypocomplementemia and FS resulted the only variables associated with lymphoma at univariate analysis, and FS appeared to be associated with lymphoma independently on complement fraction concentrations. Conversely, when patients were divided according to the Chisholm and Mason grading system, we failed to observe any significant difference between subgroups. CONCLUSION: In addition to its diagnostic role, our data seem to support that the routine assessment of MSG-FS with H&E staining is useful to predict at the time of diagnosis the adverse outcomes, such as lymphoma and extraglandular manifestations, that complicate the pSS course. On this basis, it should be recommended that an MSG biopsy be performed even in those patients displaying clinical and serological criteria, allowing the diagnosis of pSS independent of histological status.

Interferon gamma-inducible protein 16 (IFI16) and anti-IFI16 antibodies in primary Sjögren's syndrome: findings in serum and minor salivary glands.

The interferon (IFN) signature, namely the overexpression of IFN-inducible genes is a crucial aspect in the pathogenesis of primary Sjögren's syndrome (pSS). The IFN-inducible IFI16 protein, normally expressed in cell nuclei, may be overexpressed, mislocalized in the cytoplasm and secreted in the extracellular milieu in several autoimmune disorders including pSS. This leads to tolerance breaking to this self-protein and development of anti-IFI16 antibodies. The aim of this study was to identify pathogenic and clinical significance of IFI16 and anti-IFI16 autoantibodies in pSS. IFI16 and anti-IFI16 were assessed in the serum of 30 pSS patients and one-hundred healthy donors (HD) by ELISA. IFI16 was also evaluated in 5 minor salivary glands (MSGs) of pSS patients and 5 MSGs of non-pSS patients with sicca symptoms by immunohistochemistry. Normal MSGs do not constitutively express IFI16. Conversely, in pSS-MSGs a marked expression and cytoplasmic mislocalization of IFI16 by epithelial cells was observed with infiltrations in lymphocytes and peri/ intra-lesional endothelium. pSS patients display higher serum levels of both IFI16 and anti-IFI16 autoantibodies compared to HD. Our data suggest that IFI16 protein may be involved in the initiation and perpetuation of glandular inflammation occurring in pSS.

Rituximab in primary Sjögren's syndrome: a ten-year journey.

Primary Sjögren's syndrome (pSS) is an autoimmune disorder affecting exocrine glands and characterized in most cases by a rather mild clinical picture. However, a subgroup of pSS patients experience systemic extraglandular involvement leading to a worsening of disease prognosis. Current therapeutic options for the treatment of pSS are mainly empirical, often translated by other autoimmune diseases, and recent systematic reviews have highlighted the lack of evidence-based recommendations for most of the drugs commonly employed in the spectrum of extraglandular involvement. Because of the well-established role of B-lymphocytes in the pathogenesis of pSS, a B-cell targeting therapy may represent a new and intriguing therapeutic approach; in this context, growing evidence suggests that B-cell depletion by rituximab (RTX) is also effective in pSS. Of interest, besides clinical efficacy, RTX also showed biologic effects, consistently affecting the inflammation and the lymphoid organization that occur in target tissue. Moreover, the good results observed in the published trials after RTX treatment in pSS should represent the starting point to develop evidence-based guidelines for the use of biologic therapy in this disease.

IL-17-producing double-negative T cells are expanded in the peripheral blood, infiltrate the salivary gland and are partially resistant to corticosteroid therapy in patients with Sjögren's syndrome.

A small CD3+ T-cell population, that lacks both CD4 and CD8 molecules, defined as double negative (DN), is expanded in the peripheral blood of patients with systemic lupus erythematosus, produces IL-17 and accumulates in the kidney during lupus nephritis. Since IL-17 production is enhanced in salivary gland infiltrates of patients with primary Sjögren's syndrome (pSS), we aimed to investigate whether DN T cells may be involved in the pathogenesis of salivary gland damage. Fifteen patients with SS and 15 normal controls (NC) were enrolled. Peripheral blood mononuclear cells were stimulated with anti-CD3 antibody and cultured in presence or absence of dexamethasone (Dex). Phenotypic characterization was performed by flow cytometry in freshly isolated cells and after culture. Minor salivary glands (MSG) from pSS were processed for immunofluorescence staining. Total circulating DN T cells were increased in pSS compared to NC (4.7±0.4% vs 2.6±0.4%). NC and pSS freshly isolated DN T cells produce consistent amounts of IL-17 (67.7±5.6 in NC vs 69.2±3.3 in pSS). Notably, DN T cells were found in the pSS-MSG infiltrate. Dex was able to down-regulate IL-17 in vitro production in NC (29±2.6% vs 15.2±1.9% vs 13±1.6%) and pSS (49±4.8% vs 16±3.8% vs 10.2±0.8%) conventional Th17 cells and in DN T cells of NC (80±2.8% vs 3.8±2.1% vs 4.2±1.8%), but not of pSS (81±1.5% vs 85.4±0.8% vs 86.2±1.7%). DN T cells are expanded in pSS PB, produce IL-17 and infiltrate pSS MSG. In pSS, conventional Th17 cells are inhibited by Dex, but DN T cells appear to be resistant to this effect. Taken together, these data suggest a key role of this T-cell subset in the perpetuation of chronic sialoadenitis and eventually in pSS prognosis.