An unusual case of pleural effusion.

CASE PRESENTATION: A 63-year-old man presented with fever, thoracalgia, weight loss, diffuse lymphadenopathy, and a massive pleural effusion. Extensive laboratory and radiologic investigations for possible autoimmune, infectious, hematologic, and neoplastic conditions all resulted negative. A lymph node biopsy showed a granulomatous necrotizing lymphadenitis, suspicious for tuberculosis. Although mycobacterium tuberculosis (MT) was never isolated and tuberculin skin test resulted negative, diagnosis of extrapulmonary tuberculosis was made and anti-tubercular therapy was started. Despite the strict adherence to 5 months of treatment, he returned to the emergency ward complaining of fever, chest pain and pleural effusion; total-body CT and PET scans demonstrated a progression of new disseminated nodular consolidations. DIAGNOSTIC WORK-UP: Microscopic and cultural search for MT and other micro-organisms resulted again negative on urine, stool, blood, pleural fluid, and spinal lesion biopsy. We therefore started considering alternative diagnosis for necrotizing granulomatosis, including multidrug-resistant tuberculosis, Wegener granulomatosis, Churg Strauss syndrome, necrobiotic nodules of rheumatoid arthritis, lymphomatoid granulomatosis and Necrotizing Sarcoid Granulomatosis (NSG). Having already rejected other autoimmune, hematological, and neoplastic disorders, NSG resulted the most consistent hypothesis. With an expert we thus re-examined histological specimens that were suggestive for an atypical presentation of sarcoidosis. Steroid therapy was initiated, achieving symptoms improvement. DISCUSSION: Sarcoidosis is a rare condition that can be challenging to diagnose, due to its variability in clinical presentation, often mimicking alternative conditions like disseminated tuberculosis. A high degree of suspicion and an experienced lab in anatomical pathology are essential for final diagnosis.

Integrative Analysis Reveals a Molecular Stratification of Systemic Autoimmune Diseases.

OBJECTIVE: Clinical heterogeneity, a hallmark of systemic autoimmune diseases, impedes early diagnosis and effective treatment, issues that may be addressed if patients could be classified into groups defined by molecular pattern. This study was undertaken to identify molecular clusters for reclassifying systemic autoimmune diseases independently of clinical diagnosis. METHODS: Unsupervised clustering of integrated whole blood transcriptome and methylome cross-sectional data on 955 patients with 7 systemic autoimmune diseases and 267 healthy controls was undertaken. In addition, an inception cohort was prospectively followed up for 6 or 14 months to validate the results and analyze whether or not cluster assignment changed over time. RESULTS: Four clusters were identified and validated. Three were pathologic, representing "inflammatory," "lymphoid," and "interferon" patterns. Each included all diagnoses and was defined by genetic, clinical, serologic, and cellular features. A fourth cluster with no specific molecular pattern was associated with low disease activity and included healthy controls. A longitudinal and independent inception cohort showed a relapse-remission pattern, where patients remained in their pathologic cluster, moving only to the healthy one, thus showing that the molecular clusters remained stable over time and that single pathogenic molecular signatures characterized each individual patient. CONCLUSION: Patients with systemic autoimmune diseases can be jointly stratified into 3 stable disease clusters with specific molecular patterns differentiating different molecular disease mechanisms. These results have important implications for future clinical trials and the study of nonresponse to therapy, marking a paradigm shift in our view of systemic autoimmune diseases.

Cardiopulmonary exercise testing in a combined screening approach to individuate pulmonary arterial hypertension in systemic sclerosis.

OBJECTIVES: The DETECT algorithm has been developed to identify SSc patients at risk for pulmonary arterial hypertension (PAH) yielding high sensitivity but low specificity, and positive predictive value. We tested whether cardiopulmonary exercise testing (CPET) could improve the performance of the DETECT screening strategy. METHODS: Consecutive SSc patients over a 30-month period were screened with the DETECT algorithm and positive subjects were referred for CPET before the execution of right-heart catheterization. The predictive performance of CPET on top of DETECT was evaluated and internally validated via bootstrap replicates. RESULTS: Out of 314 patients, 96 satisfied the DETECT application criteria and 54 were positive. PAH was ascertained in 17 (31.5%) and pre-capillary pulmonary hypertension in 23 (42.6%) patients. Within CPET variables, the slope of the minute ventilation to carbon dioxide production relationship (VE/VCO2 slope) had the best performance to predict PAH at right-heart catheterization [median (interquartile range) of specificity 0.778 (0.714-0.846), positive predictive value 0.636 (0.556-0.750)]; exploratory analysis on pre-capillary yielded a specificity of 0.714 (0.636-0.8) and positive predictive value of 0.714 (0.636-0.8). CONCLUSION: In association with the DETECT algorithm, CPET may be considered as a useful tool in the workup of SSc-related pulmonary hypertension. The sequential determination of the VE/VCO2 slope in DETECT-positive subjects may reduce the number of unnecessary invasive procedures without any loss in the capability to capture PAH. This strategy had also a remarkable performance in highlighting the presence of pre-capillary pulmonary hypertension.

Identification of a Shared Microbiomic and Metabolomic Profile in Systemic Autoimmune Diseases.

Dysbiosis has been described in systemic autoimmune diseases (SADs), including systemic lupus erythematosus (SLE), Sjögren's syndrome (SjS), and primary anti-phosholipid syndrome (PAPS), however the biological implications of these associations are often elusive. Stool and plasma samples from 114 subjects, including in SLE (n = 27), SjS (n = 23), PAPs (n = 11) and undifferentiated connective tissue (UCTD, n = 26) patients, and geographically-matched healthy controls (HCs, n = 27), were collected for microbiome (16s rRNA gene sequencing) and metabolome (high-performance liquid chromatography coupled to mass spectrometry) analysis to identify shared characteristics across diseases. Out of 130 identified microbial genera, a subset of 29 bacteria was able to differentiate study groups (area under receiver operating characteristics (AUROC) = 0.730 ± 0.025). A fair classification was obtained with a subset of 41 metabolic peaks out of 254 (AUROC = 0.748 ± 0.021). In both models, HCs were well separated from SADs, while UCTD largely overlapped with the other diseases. In all of the SADs pro-tolerogenic bacteria were reduced, while pathobiont genera were increased. Metabolic alterations included two clusters comprised of: (a) members of the acylcarnitine family, positively correlating with a Prevotella-enriched cluster and negatively correlating with a butyrate-producing bacteria-enriched cluster; and (b) phospholipids, negatively correlating with butyrate-producing bacteria. These findings demonstrate a strong interaction between intestinal microbiota and metabolic function in patients with SADs.

Microbial and metabolic multi-omic correlations in systemic sclerosis patients.

Intestinal microbiota has been associated with systemic autoimmune diseases, yet the functional consequences of these associations are elusive. We characterized the fecal microbiota (16S rRNA gene amplification and sequencing) and the plasma metabolome (high-performance liquid chromatography coupled to mass spectrometry) in 59 patients with systemic sclerosis (SSc) and 28 healthy controls (HCs). Microbial and metabolic data were cross-correlated to find meaningful associations after extensive data mining analysis and internal validation. Our data show that a reduced model of nine bacteria is capable of differentiating HCs from SSc patients. SSc gut microbiota is characterized by a reduction in protective butyrate-producing bacteria and by an increase in proinflammatory noxious genera, especially Desulfovibrio. From the metabolic point of view, a multivariate model with 17 metabolite intermediates well distinguished cases from controls. The most interesting peaks we found were identified as glycerophospholipid metabolites and benzene derivatives. The microbial and metabolic data showed significant interactions between Desulfovibrio and alpha-N-phenylacetyl-l-glutamine and 2,4-dinitrobenzenesulfonic acid. Our data suggest that in SSc, intestinal microbiota is characterized by proinflammatory alterations subtly entwined with the metabolic state. Desulfovibrio is a relevant actor in gut dysbiosis that may promote intestinal damage and influence amino acid metabolism.

Preliminary safety and efficacy profile of prucalopride in the treatment of systemic sclerosis (SSc)-related intestinal involvement: results from the open label cross-over PROGASS study.

BACKGROUND: Prokinetics are used to treat enteric dismotility symptoms in systemic sclerosis (SSc) patients, but they often lack adequate efficacy. The most effective prokinetics belonging to the serotonin (5-HT4) receptor agonists class were withdrawn due to cardiac toxicity in relation to modest 5-HT4 receptor affinity. Prucalopride is a high-affinity 5-HT4 receptor agonist with no major cardiac issues, for which the efficacy in SSc has not yet been assessed. METHODS: Forty patients with self-reported mild to moderately severe enteric symptoms were enrolled in a cross-over 2 × 2 study. Subjects were randomized 1:1 to prucalopride 2 mg/day or no treatment for one month and vice versa after a 2-week washout period. Before and after each sequence the patients compiled the University of California Los Angeles gastrointestinal tract (UCLA GIT) 2.0 questionnaire and the numbers of complete intestinal movements were recorded. Oro-cecal transit time (OCTT) was evaluated by lactulose breath test in a subgroup of patients. Data were evaluated by mixed linear models corrected for the number of laxatives used during the study periods. RESULTS: There were 29 subjects who completed the study; 7 subjects withdrew due to side-effects and 4 subjects were not compliant with the study procedures. As compared to dummy treatment, prucalopride was associated with more intestinal evacuations (p < 0.001), improvement of UCLA GIT constipation (-0.672 ± 0.112 vs 0.086 ± 0.115; p < 0.001), reflux (-0.409 ± 0.094 vs 0.01 ± 0.096; p < 0.005) and bloating (-0.418 ± 0.088 vs -0.084 ± 0.09; p = 0.01) scores. Treatment was ranked moderately to more than moderately effective by 22 patients (72.4%). OCTT was significantly reduced during prucalopruide consumption (prucalopride: -20.1 ± 20.1 vs no treatment: 45.8 ± 21.3 minutes; treatment effect = -65.9 minutes; p = 0.035). CONCLUSIONS: The safety profile of prucalopride in SSc is similar to what is known from the literature. In patients with mild to severe gastrointestinal problems, prucalopride may be effective in treating dismotility symptoms, increasing the number of complete bowel movements and improving bowel transit, reducing reflux disease and bloating. TRIAL REGISTRATION: EU Clinical Trial Registry, EudraCT2012-005348-92 . Registered on 19 February 2013.

Role of class II human leucocyte antigens in the progression from early to definite systemic sclerosis.

OBJECTIVE: HLAs have been extensively associated with SSc susceptibility but their role in the progression of the disease is poorly understood. In 2013 the ACR and European League Against Rheumatism (EULAR) jointly defined criteria for the classification of SSc that allow the early identification of definite SSc patients. In this study we investigated the role of HLA class II antigens in the progression from early to definite SSc. METHODS: One hundred and fifty-eight subjects with early SSc according to LeRoy and Medsger criteria and no other manifestation indicative of definite SSc at referral were considered. All the patients underwent high-resolution HLA class II typing and the appraisal of definite SSc was retrospectively conducted in a prospective manner. Lifetime analysis was conducted to gauge the effect of genetic and clinical characteristics on progression of the disease. RESULTS: The median estimated time to progression was 45 months from referral; the 5 and 10 year estimates of progression were 59.8% and 80%, respectively. ACAs were associated with a reduced risk of progression [median survival 55 vs 23 months for ACA-positive vs ACA-negative patients, P = 0.035; hazard ratio (HR) 0.67 (95% CI 0.458, 0.979)]. HLA alleles within the HLA DQ5-DR1 haplotype [HLA-DRB1*0101-HLA-DQA1*0101(4)-HLA-DQB1*0501] reduced the risk of progression of the disease [median survival 108 vs 44 months for DQ5-DR1 carriers vs DQ5-DR1 non-carriers; HR 0.388 (CI 0.211, 0.712), P = 0.001, corrected P = 0.014]. In multivariate models, the effect of genetics was found to be independent of ACA positivity or other baseline factors; additive risks were observed when the DQ5-DR1 haplotype and ACA were jointly considered. CONCLUSION: HLA class II alleles within the HLA DQ5-DR1 haplotype are associated with lower rates of progression from early to definite SSc.

Effect of dihydropyridine calcium channel blockers and glucocorticoids on the prevention and development of scleroderma renal crisis in an Italian case series.

OBJECTIVES: Scleroderma renal crisis (SRC) is a relative rare yet dramatic event in the history of systemic sclerosis (SSc). Several factors that may precipitate or protect from the development of SRC have been described in previous case-control studies. To date, no attempt has been made to evaluate these factors in an observational fashion. METHODS: Retrospective data from 410 SSc patients with disease duration <5 years at referral were evaluated in an observational fashion for the development of hypertensive or normotensive SRC within 5 years from the first visit at our centre. Baseline characteristics as well as the use of steroids or dhiydropyridine calcium-channel blockers (CCB) were analysed via the Cox regression method with time-dependent covariates. RESULTS: In the multivariate model the diffuse subset the disease (HR=5.728 CI(95)=2.199-14.918, p<0.001) and the use of prednisone (HR=1.015, CI(95)=1.004-1.026, p=0.006) resulted to be predictors for the development of SRC, with a risk to develop SRC increased by 1.5% for every mg of prednisone/day consumed the trimester prior SRC. Contrariwise, the risk to develop SRC was highly reduced in those who were prescribed CCBs (HR=0.094, CI(95)=0.038-0.236, p<0.001). CONCLUSIONS: Steroids exhibits a weak effect on the risk to progress toward SRC in our case series, whilst dhyidrophyridines CCB appeared to be protective against that. Further larger prospective studies are warranted to better define the role of CCB in this setting or as a background therapy for SSc.