Identification of highly active systemic lupus erythematosus by combined type I interferon and neutrophil gene scores vs classical serologic markers.

OBJECTIVES: In SLE, heterogeneous clinical expression and activity may reflect diverse pathogenic and/or effector mechanisms. We investigated SLE heterogeneity by assessing the expression of three gene sets representative of type I IFN (IFN-I), polymorphonuclear neutrophil (PMN) and plasmablast (PB) signatures in a well-characterized, multidisciplinary cohort of SLE patients. We further assessed whether individual gene products could be representative of these three signatures. METHODS: Whole blood, serum and clinical data were obtained from 140 SLE individuals. Gene expression was assessed by NanoString technology, using a panel of 37 probes to compute six IFN-I, one PMN and one PB scores. Protein levels were measured by ELISA. RESULTS: Depending on the score, 45-50% of SLE individuals showed high IFN-I gene expression. All six IFN-I scores were significantly associated with active skin involvement, and two of six were associated with arthritis. IFN-induced Mx1 protein (MX1) level was correlated with IFN-I score (P < 0.0001) and associated with a similar clinical phenotype. In all, 25% of SLE individuals showed high PMN gene expression, associated with SLE fever, serositis, leukopoenia and glucocorticoid use. PB gene expression was highly affected by immunosuppressant agents, with no association with SLE features. Combined IFN-I and PMN gene scores were significantly associated with high disease activity and outperformed anti-dsDNA and anti-C1q autoantibody and complement levels for predicting SLE activity. CONCLUSION: IFN-I and PMN gene scores segregate with distinct SLE clinical features, and their combination may identify high disease activity. MX1 protein level performed similar to IFN-I gene expression.

A rare combination: chylous polyserositis and autoimmune myelofibrosis as a presentation of systemic lupus erythematosus.

Chylous polyserositis and autoimmune myelofibrosis occurring concomitantly inn a case of SLE are a rare phenomenon. We here report a case of a 38-year-old woman who was admitted with a history of cough and shortness of breath for 1½ months along with fever and abdominal distension for 1 month. She also had arthralgias, weight loss and pancytopenia. She was diagnosed as a case of SLE with Chylous polyserositis and autoimmune myelofibrosis. She was started on steroids and immunosuppressive therapy, to which she responded. To summarize, this is the first case report where chylous polyserositis and pancytopenia due to autoimmune myelofibrosis occurred which was responsive to steroids and immunosuppressive therapy.

Anti-SmD1 antibodies are associated with renal disorder, seizures, and pulmonary arterial hypertension in Chinese patients with active SLE.

Detection of autoantibodies in systemic lupus erythematosus (SLE) plays an important role in timely diagnosis and earlier treatment of SLE. In this study, we used a SmD1 polypeptide-based ELISA to determine anti-SmD1 antibody in 269 SLE, including100 naïve (had not been treated with steroids or immunosuppressants at study inception) SLE patients and 169 non-naive SLE patients; 233 controls with other rheumatic diseases (RDC) (70 RA, 40 AS, 73SSc, and 50 SS), and 110 healthy controls (HC) group. The positive rate of anti-SmD1 among all SLE patients was 60.97%, higher than that in the RDC group (13.30%, P = 0.000) or the HC group (9.09%, P = 0.000). The positive rate of anti-SmD1 in non-naive SLE patients was higher than that for anti-dsDNA antibodies (44.97%, P = 0.03). Positivity for anti-SmD1 only was found in 14.00% of naive SLE patients and 16.00% of non-naive SLE patients. In naive SLE patients, the serum concentration of anti-SmD1 was lower after treatment than before treatment (P = 0.039). Active SLE patients positive for anti-SmD1 were more likely to have malar rash, rash, nonscarring alopecia, PAH and hypocomplementemia. High positivity for anti-SmD1 only in patients with SLE indicated the importance and necessity of detection of anti-SmD1 in patients with SLE.

Serosal inflammation (pleural and pericardial effusions) related to tyrosine kinase inhibitors.

Tyrosine kinase inhibitors (TKIs) have dramatically changed the treatment of chronic myeloid leukemia (CML) and are increasingly used in other malignancies. Despite the apparent selectivity of these agents significant side effects can occur mainly due to off target kinase inhibition. Clinical consequences of serosal inflammation, including pleural and pericardial effusions, have emerged as a frequent adverse event associated with dasatinib while occurring much less frequently during imatinib and nilotinib therapy. The pathogenesis is uncertain but may involve inhibition of platelet derived growth factor or expansion of cytotoxic T and natural killer cells. The development of serosal inflammation with dasatinib poses a significant challenge to physicians, as it cannot be predicted, the time of onset is variable, and management frequently requires repeat invasive procedures.

[Rituximab for treatment of patients with systemic autoimmune diseases]. / Utilidad del rituximab en el tratamiento de pacientes con enfermedades sistémicas autoinmunitarias.

BACKGROUND AND OBJECTIVE: To assess the value of rituximab in systemic autoimmune diseases which are refractory to others treatments. PATIENTS AND METHOD: Prospective study on 12 patients -7 with systemic lupus erythematosus (SLE), 4 with Wegener's granulomatosis (WG), and 1 with overlapping connective disease and autoimmune thrombocytopenia-, controlled in a specialized unit of a tertiary hospital. Four weekly doses of rituximab, 2 biweekly doses of cyclophosphamide, and glucocorticoids were administered to all patients, and other immunosuppressants were also administered as considered necessary in each case. RESULTS: Mean follow up after treatment with rituximab was 12.8 moths for SLE patients and 12.3 for WG patients. In SLE patients, proteinuria was reduced below 1 g daily in 5 cases (83%), with a clear parallel improvement in the urinary sediment. Serositis was resolved in both cases. One patient required 3 treatment cycles to obtain an adequate response and another required a second cycle for relapse. Only one patient with WG had a favorable response. The patient treated for autoimmune thrombocytopenia had a favorable response, with no relapses, and creatine-kinase levels also tended to return to normal. There were 2 serious adverse events (terminal renal failure and serious colitis in a patient with SLE, and death of one patient with WG), that were not adjudicated directly to rituximab. Immunoglobulin levels did not change substantially. There were no infusion reactions or associated infections. CONCLUSIONS: Rituximab was useful in patients with SLE refractory to other immunosuppressants. On the contrary, its efficacy in WG was limited. The response of thrombocytopenia was complete and maintained.

Diagnosis of active tuberculous serositis by antigen-specific interferon-gamma response of cavity fluid cells.

BACKGROUND: To develop a more accurate methodology for diagnosing active tuberculous pleurisy, as well as peritonitis and pericardits of tuberculous origin, we established an antigen-specific interferon gamma (IFN-gamma)-based assay that uses cavity fluid specimens. METHODS: Over a 19-month period, 155 consecutive, nonselected patients with any cavity effusion were evaluated. Study subjects were 28 patients with bacteriologically confirmed active tuberculous serositis and 47 patients with definitive nontuberculous etiology. Culture was performed for 18 h with fluid mononuclear cells in the supernatant of the effusion together with saline or Mycobacterium tuberculosis-specific antigenic peptides, early secretory antigenic target 6 and culture filtrate protein 10. IFN-gamma concentrations in the culture supernatants were measured. RESULTS: In patients with active tuberculous serositis, antigen-specific IFN-gamma responses of cavity fluid samples were significantly higher than those of nontuberculous effusion samples. Area under the receiver operating characteristic (AUROC) curve was significantly greater for cavity fluid IFN-gamma response (AUROC curve, 0.996) than for cavity fluid adenosine deaminase and whole-blood IFN-gamma responses (AUROC curve, 0.882 and 0.719, respectively; P = .037 and P < .001, respectively). Although the AUROC curve was greater for cavity fluid IFN-gamma response than for background cavity fluid IFN-gamma level (AUROC curve, 0.975), the AUROC curves were not statistically significantly different (P = .74). However, multivariate logistic regression analysis revealed that cavity fluid IFN-gamma responses were significantly associated with the diagnosis, even after adjustment for background IFN-gamma level (adjusted odds ratio, 1.21; 95% confidence interval, 1.03-1.42; P < .001). CONCLUSIONS: The cavity fluid IFN-gamma assay could be a method for accurately and promptly diagnosing active tuberculous serositis.

Serial antinuclear antibodies titre in pleural and pericardial fluid.

The antinuclear antibodies (ANA) test has been a cornerstone of the evaluation of connective tissue disease. The aim of this study was to investigate the diagnostic value of the ANA test in pleural or pericardial effusions of unknown causes. Over a 3-yr period, a total of 126 pleural fluid and 30 pericardial fluid samples were analysed. ANA tests were performed using a commercially available kit. The ANA kit used an indirect immunofluorescent antibody method with a human epithelial (HEP-2) cell line as substrate. Patients with high fluid ANA titre (>1:160) received a second aspiration 2 weeks after the initial aspiration if diagnosis was not confirmed. ANA results were positive in 39 pleural and 10 pericardial fluid samples. All but one of the effusions with positive ANA testing were exudative. Eleven pleural or pericardial effusions due to active systematic lupus erythematosus were identified and all had high ANA titres (1:160) with various staining patterns. Thirty-eight of 145 patients (26%) with effusions of nonlupus aetiologies had positive ANA testing in pleural or pericardial fluid. Thirteen of these 38 patients had high ANA titre. Malignant or paramalignant effusions constituted 11 of the 13 samples. In conclusion, although a negative antinuclear antibodies test makes a diagnosis of lupus serositis unlikely, high antinuclear antibodies titres in pleural or pericardial fluid are not diagnostic of lupus serositis even when as high as 1:5,120. An unexplained high antinuclear antibodies titre in pleural or pericardial effusion warrants search for malignancy.

Serositis: comparative analysis of histological findings and pathogenetic mechanisms in nonbacterial serosal inflammation.

Peritonitis is the established term for infective inflammation of the peritoneum, while serositis generally refers to nonorganismal inflammation in any serous cavity, including the peritoneum. In continuous ambulatory peritoneal dialysis (CAPD) literature, however, culture-negative peritoneal inflammation is referred to as "sterile" or "chemical" peritonitis. These terms not only imply unwarranted etiologic assumptions, but may also deflect attention from the existence of medical conditions to which the peritoneum is subject. This is evident in CAPD literature where there is little recognition that the peritoneum, as a member of the serosa and a secretor of lamellar bodies, is prey to a wide range of disorders. Thus before, during, and after CAPD, the membrane is liable to fall victim to disease states unconnected with the process of dialysis. Significant peritoneal pathology occurs as part of a pan-serositis, which may be metabolic (uremia, cholesterolosis), autoimmune (systemic lupus erythematosus, rheumatoid disease, acute rheumatism, endocrinopathies), genetic (recurrent hereditary polyserositis), allergic (eosinophilic serositis), and granulomatous in nature. This paper presents a comparative analysis of histopathological presentation and pathogenetic mechanisms involved in all forms of peritoneal serositis. It incorporates recent advances in molecular biology of the membrane into a holistic reappraisal of peritoneal pathology, revealing hitherto unrecognized homologies in peritoneal reaction to diverse disorders.

[Polyserositic syndromes and/or sectorial dysventilation with platelet activation induced by immunoallergic etiopathogenesis]. / Sindromi polisierositiche e/o disventilatorie settoriali con attivazione piastrinica da etiopatogenesi immunoallergica.

The author from a study of 5 dysventilatorial syndromes (bronchiolitis-PNX, pneumomediastinal aerial cystis of lung) and 5 polysierositic syndromes pleuritis and peritonitis) evices that all these syndromes show in the anamnesis or in present a viral infection from influenzal virus or rubeola. In addition to that, the Authors shows the presence of a food allergy asserted by RAST and/or Skin Prick Tests or FBST (Food Bronchostimulation test) and the introduction of a food allergen during the viral infection, and a great platelet's activation. The Author, besides, shows the association normal VES and normal neutrophil cells in the dysventilatorial syndrome and high VES, and high neutrophil cells in the polysierositic syndromes; in all cases the negativity of culture exams. Starting from these points she worked out a new etiopathogenetic theory: the viral localization on the Peyer's plates cause the expression on the epithelial surface of the gut's cells of SELF HLA II type recognition. The food allergens' introduction causes a great reaction of II, III, IV, VI type which involves the bronchus, alveolus, and the serous epithelium by PAF activation, in all cases and in the polisierositic syndrome a neutrophil activation as well. The author advices to prize the importance of cortisone therapy and of exclusion of food allergen by diet, besides advices the antibiotic therapy for covering only.

Syndrome and pancreatic disease, subcutaneous fat necrosis and polyserositis. Case report and review of literature.

Immunologic evaluation of a patient with pancreatitis, subcutaneous fat necrosis, pleuritis, pericarditis and synovitis is presented. The previously recognized syndrome of pancreatic disease, subcutaneous fat necrosis and arthritis is reviewed. Based on analysis of all the cases described in the English language literature it is suggested that this syndrome be expanded to include polyserositis rather than arthritis alone. Although experimental and clinical evidence tends to implicate physiocochemical tissue injury by pancreatic lipase as the primary pathogenic mechanism in this syndrome, studies in our patient suggest the possible contribution of immune-mediated injury. Supporting data include eosinophilia, biopsy demonstration of vasculitis antedating the subcutaneous fat necrosis, immunofluorescent identification of immunoglobulin G (IgG) and C3 in the pleura, and reduced levels of total hemolytic complement in the serum, and pleural and pericardial effusions.