Comparison of the clinical diagnostic criteria and the results of the next-generation sequence gene panel in patients with monogenic systemic autoinflammatory diseases

Clinical Rheumatology - The clinicians initially prefer to define patients with the systemic autoinflammatory disease (SAID)’s based on recommended clinical classification criteria; then,...     

Genetic analysis utility in rare and uncharacterized autoinflammatory diseases

Clinical Rheumatology -     

The laboratory approach in the diagnosis of systemic autoinflammatory diseases

Systemic autoinflammatory diseases are a group of inherited disorders of the innate immunity characterized by the recurrence of febrile attacks lasting from few hours to few weeks and multi-district inflammation of different severity involving skin, serosal membranes, joints, gastrointestinal tube and central nervous system. The vast majority of these conditions is caused by mutations in genes involved in the control of inflammation and apoptosis mechanisms. The group includes familial Mediterranean fever, mevalonate kinase deficiency syndrome, tumor necrosis factor receptor-associated periodic syndrome, cryopyrin-associated periodic syndromes, hereditary pyogenic and granulomatous disorders. Their diagnostic identification derives from the combination of clinical and biohumoral data, though can be sometimes confirmed by genotype analysis.     

Lymphocytotoxic antibodies in systemic lupus erythematosus and clinically related diseases

Sera from patients with systemic lupus erythematosus (SLE) and clinically related diseases were examined for cold-reactive lymphocytotoxic antibodies (LCA). The incidence of LCA was significantly increased in SLE (93%), discoid lupus (50%), and “lupuslike” syndromes associated with congenital complement deficiencies (63%) as compared to normal controls (3%) and patients with drug-induced lupus (11%), mixed connective tissue disease (MCTD) (17%), and necrotizing vasculitis (19%). The diagnostic and pathogenetic implications of these differences are discussed.     

Cancer screening in patients with systemic lupus erythematosus

OBJECTIVE: To examine whether patients with systemic lupus erythematosus (SLE) undergo cancer screening according to established guidelines, to compare their reported screening practices with information from the general population, and to examine potential predictors of screening within our SLE sample. METHODS: We conducted a patient survey of cancer screening practices within the Montreal General Hospital lupus cohort. We compared self-reported frequency of cancer screening to guidelines suggested for the general population, and to figures for cancer screening reported in the general population. We also developed logistic regression models to establish potential predictors of screening for patients with SLE, with cervical cancer screening being the outcome of interest in our primary analyses. RESULTS: Of 48 women aged 50-69, 53% (95% confidence interval, CI: 38-68) had had a mammogram in the past 12 months, compared to 74% (95% CI: 73-75) for similarly aged Quebec women. Of 51 subjects aged 50 and older, only 18% (95% CI: 8-34) reported screening (fecal occult blood check with or without endoscopy) within the recommended time frame, compared to 48% (95% CI: 45-51) for colorectal screening for persons > 50 in the general population. Only 9 of 27 patients with SLE aged less than 30 had Pap tests in the past 12 months (33%, 95% CI: 19-52), compared with a general population rate of 56% (95% CI: 53-59) for similarly aged Quebec women. Our logistic regression model suggested that, among the SLE patients, non-whites, those with lower education, and those with higher disease damage scores were less likely to undergo cervical Pap testing. CONCLUSION: These data suggest that appropriate cancer screening may be overlooked in patients with SLE.     

Lymphocytotoxic antibodies in systemic lupus erythematosus and clinically related diseases.

Sera from patients with systemic lupus erythematosus (SLE) and clinically related diseases were examined for cold-reactive lymphocytotoxic antibodies (LCA). The incidence of LCA was significantly increased in SLE (93%), discoid lupus (50%), and "lupus-like" syndromes associated with congenital complement deficiencies (63%) as compared to normal controls (3%) and patients with drug-induced lupus (11%), mixed connective tissue disease (MCTD) (17%), and necrotizing vasculitis (19%). The diagnostic and pathogenetic implications of these differences are discussed.     

Involvement of a tissue-specific autoantibody in skin disorders of murine systemic lupus erythematosus and autoinflammatory diseases

Human systemic lupus erythematosus (SLE) and its murine model, MRL lpr/lpr mice, are well known to develop a wide range of symptoms, such as glomerulonephritis, dermatitis, and arthritis, as an immune-complex disease. However, the deposition of circulating immune complex does not fully explain the tissue specificity of disease. Tissue-specific autoantigens may also be involved in tissue inflammation. In this study, desmoglein 3 (Dsg3), a major component of epidermal desmosomes, was identified as a skin-specific autoantigen. Several murine models of skin inflammation were found to develop autoantibodies to Dsg3 tightly correlated with disease aggravation, especially in MRL lpr/lpr mice. Furthermore, SLE-prone skin disease-free FcgammaRIIb-deficient mice developed skin inflammation upon immunization with Dsg3. Taken together with histological studies, we concluded that skin-specific Dsg3 serves as an autoantigen in chronic skin inflammatory diseases accompanied by mast cell degranulation, including both murine SLE and other autoinflammatory diseases.     

Involvement of midkine in autoimmune and autoinflammatory diseases

Abstract

Midkine (MK) is a heparin-binding growth factor that markedly expressed during embryogenesis but downregulated to inconsiderable levels in healthy adults. However, MK is upregulated during tissue repair and in many pathologic conditions, mostly malignancies and inflammatory diseases. MK promotes a number of functions in target cells such as migration, proliferation, survival, growth, reproduction and repair, angiogenesis, and gene expression. It acts as a pro-inflammatory cytokine and contributes to chronic inflammation via promoting chemotaxis and tissue infiltration of neutrophils and macrophages. Furthermore, MK upregulated the production of various inflammatory mediators (i.e. interleukin (IL) 6 and IL8). Recent studies have demonstrated strong evidence that MK is involved in the onset and progression of autoimmune rheumatic diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren’s syndrome (SS) and other autoimmune conditions such as multiple sclerosis (MS). Additionally, it has been shown that MK is overexpressed in two major clinically defined forms of inflammatory bowel diseases (IBD), Crohn’s disease (CD) and ulcerative colitis (UC), which are classified as autoinflammatory diseases. Taken together, MK is involved in the pathogenesis of autoimmune and autoinflammatory diseases and may serve as an indicator and biomarker in these conditions. Furthermore, MK inhibitors are expected to contribute in the management of these diseases.     

Suspected systemic rheumatic diseases in patients presenting with cytopenias

Cytopenias may herald or concur with the onset of various systemic rheumatic diseases. Accordingly, patients with reduced blood cell counts are often referred for possible underlying autoimmune disease. Initial evaluation aims to exclude nonrheumatic causes such as drug toxicity, infections, or hematological/myelopoiesis disorders. Patient interview and physical examination are critical to unravel features related to or suggestive of rheumatic disease. Based on the clinical scenario, targeted immunological testing may provide additional diagnostic insights. Yet, not all patients may present with full-fledged, criteria-classified disease at early stages. Accordingly, physicians should have a high index of suspicion for individuals who present with a combination of immune/inflammatory cytopenia(s) and relevant clinical (e.g., synovitis) and/or serological manifestations, even if these are few in number or nonspecific (e.g., ANA). Ongoing studies in preclinical or early autoimmunity cohorts could lead to the discovery of diagnostic biomarkers applicable also to patients with cytopenias and suspected rheumatic disease.     

Hepatitis C virus infection in patients with clinically diagnosed alcoholic liver diseases

Summary To determine the incidence of hepatitis C virus (HCV) infection in patients with alcoholic liver disease (AID), serum samples from 252 patients with AID were tested for anti-HCV and HCV RNA. Serial sera of these patients were collected and stored under optimal conditions to allow exact quantification of HCV RNA. Fifteen patients who visited our hospital during the same period of time with chronic HCV infections served as controls. In those with AID, anti-HCV and HCV RNA were positive in 55.5% and 41.2%, respectively. Patients with histologically diagnosed chronic hepatitis and hepatocellular carcinoma had much higher prevalence rates of HCV RNA (84% and 100%, respectively) compared to those with fatty liver (4.3%), hepatic fibrosis (10.1%) and alcoholic hepatitis (22.2%) ( P < 0.01). Although no difference in serum HCV RNA levels was observed between the patients with both AID and chronic HCV infection and those with chronic HCV infection alone, HCV RNA levels significantly (10-fold) dropped after abstinence in nearly half of the patients ( P < 0.01). These data indicate that HCV infection in patients with AID promotes progression of liver disease, and abstinence from alcohol is associated with a reduction in serum HCV RNA levels.     

Vasculitic syndromes associated with other rheumatic conditions and unclassified systemic vasculitis

Markers for systemic vasculitis may be useful in both assessment of disease activity and ascribing pathogenesis. Endothelial cell damage may be assessed by Factor VIII-related antigen and perhaps fibrinolysis (plasmin inhibitor/plasmin complex). Antibodies to endothelial cells potentially combine both assessment and pathogenesis. Complement fixing antibodies to endothelial cells, previously reported in systemic lupus erythematosus and Kawasaki syndrome, are also elevated in rheumatoid vasculitis. Their relationship to vascular endothelial cell antibodies, reported in a wide spectrum of systemic vasculitis, is not clear. A direct role for neutrophils in some forms of vasculitis is supported by the overlap of rheumatoid vasculitis with Sweet's syndrome, previously associated with both Beh?et's and Crohn's syndrome. An indirect role of persistent neutrophil inflammation at mucosal surfaces is suggested by the vasculitis with antineutrophil cytoplasmic antibodies seen in cystic fibrosis. In other cases, vasculitis may be triggered by direct viral infection such as cytomegalovirus. Experimental models may clarify the confusion. In the MRL mouse, vasculitis appears independent of the B-cell hyperactivity. Experimental models of uveitis also support a role for T cells in the induction of vasculitis.     

Characterization of anticytoplasmic antibodies in patients with systemic autoimmune diseases

We characterized the cytoplasmic staining patterns identified by indirect immunofluorescence (IF) using human epithelial (HEp-2) cells as substrates, and identified autoantigens using enzyme-linked immunosorbent assay (ELISA) and cognate RNA immunoprecipitation techniques in cytoplasmic antibody-positive sera (CA(+)) in patients with systemic autoimmune diseases. Twenty-three sera (3.7%) of 630 patients were found to have a cytoplasmic staining pattern by IF on HEp-2 cells. The fine-pattern IF specificities were as follows: 12 diffuse fine speckled; 7 coarse granular filamentous speckled; 2 diffuse coarse speckled; 1 condensed large speckled; 1 cytoskeletal. No relationship was found between the staining patterns and the diseases. Anti-SS-A antibodies and antimitochondrial (M2) antibodies were detected by ELISA in 6 and 4 sera, respectively, and antismooth muscle antibody was detected by IF in 1 serum. In RNA immunoprecipitation assays, 6, 11, 3, and 1 patients had antibodies that recognized aminoacyltransfer RNA (tRNA) synthetases (including 2 EJ, 2 PL-7, 1 PL-12, and 1 unidentified tRNA-related), SS-A, ribosomes, and SRP, respectively. Moreover, several other autoantigens were detected by Western blotting using human epithelial (HEp-2) cell lysates. This study suggests that autoantibodies against tRNA synthetases, SS-A, ribosomes, mitochondria, and other autoantigens are present in CA(+) sera from patients with a variety of systemic autoimmune diseases.     

Presence of systemic autoimmune disorders in patients with autoimmune thyroid diseases

Methods: 168 consecutive patients with ATD with positive antithyroid antibodies and 75 healthy subjects were tested for the presence of ANA. ANA positive patients were further evaluated by complete history, physical examination, blood and urine tests, and immunological studies. Patients with subjective xerophthalmia and xerostomia were examined by objective tests. Results: 58/168 (35%) patients with ATD were ANA positive compared with 7/75 (9%) healthy controls (p = 0.001). Of 58 ANA positive patients, 6 (10%) had anti-Ro antibodies, 1 had anti-Ro and anti-La antibodies, 7 (12%) had anti-dsDNA antibodies, and 7 (12%) had medium levels of IgG and/or IgM anticardiolipin antibodies (aCL). No healthy subjects had positive anti-dsDNA, antibodies against the extractable nuclear antigens, or aCL. 5/58 (9%) patients fulfilled the criteria for Sjögren''s syndrome (SS). Two patients had features related to systemic lupus erythematosus. No healthy subjects had clinical or laboratory characteristics of systemic autoimmune disorders. Conclusion: ANA are detected in 1/3 of patients with ATD. Anti-dsDNA, anti-Ro, and aCL can also be found in ANA positive patients with ATD. SS occurs in about 1/10 of ANA positive patients with ATD.     

Minimal clinically important difference for 7 measures of fatigue in patients with systemic lupus erythematosus

OBJECTIVE: To determine the minimal clinically important difference (MCID) for 7 measures of fatigue in patients with systemic lupus erythematosus (SLE). METHODS: Study subjects completed 7 fatigue instruments [Fatigue Severity Scale (FSS), Multidimensional Assessment of Fatigue (MAF), Multidimensional Fatigue Inventory (MFI), Vitality scale of the MOS-SF-36, Chalder Fatigue Scale (CFS), Functional Assessment of Chronic Illness Therapy-Fatigue, and a global Rating Scale (RS)] and then participated in a series of interviews with other study participants comparing their fatigue with one another. Each interview participant rated the difference in their fatigue levels on a 7-point transition scale. The MCID was estimated from the mean difference in fatigue scores between each pair of interview participants based on their subjective rating of fatigue contrast. The MCID was also estimated using linear regression modeling. RESULTS: Eighty patients with SLE participated. Patients reported significant levels of fatigue [mean normalized (0 = none, 100 = maximum) fatigue scores for the 7 instruments ranged from 49.8 (CFS) to 71.1 (FSS)]. The MCID of "a little more" fatigue tended to be greater than the MCID for a "little less fatigue" and differed significantly for FSS and MAF. The MCID of normalized scores estimated by linear regression ranged from 7.0 (CFS) to 14.3 (MFI). CONCLUSION: Fatigue is a common and debilitating component of SLE. Estimates of MCID will help to interpret changes observed in a fatigue score and will be critical in estimating sample size requirements for clinical trials including fatigue as an outcome.     

Anti-ribonucleoproteins autoantibodies in patients with systemic autoimmune diseases. Relation with cutaneous photosensitivity

A common feature between patients with a certain group of systemic autoimmune pathologies (SAPs) with rheumatic component, such as lupus erythematosus (LE) in all its forms, is the presence of cutaneous photosensitivity (CP) as well as the existence of autoantibodies (Aabs). These Aabs have also high incidence in other SAPs that do not present CP, like primary Sjögren's syndrome and rheumatoid arthritis. Cutaneous photosensitivity is a condition that consists of an exacerbated skin reaction to solar radiations; its incidence can reach 90% in systemic LE. The mechanisms involved in the development of CP have been extensively studied focusing on different approaches; however, the exact mechanism has not been fully elucidated yet. There are many theories that relate specifically the presence of circulating anti-Ro/SS-A Aabs with the CP phenomenon, though there are several studies which are in disagreement. In this study, we evaluated the Aabs profile (anti-Ro/SS-A 52 kDa, anti-Ro/SS-A 60 kDa, anti-La/SS-B, anti-Sm and ANAs) as well as their titer or reactivity, in a local cohort of 169 patients with SAPs. We related those Aabs profiles and titers with the presence or absence of CP, and we found that there was no significant association between the presence of anti-Ro/SS-A Aabs and the occurrence of CP. On the other hand, a statistically significant positive association was found between CP and high reactivity anti-Sm Aabs, though this fact could be biased by the incidence of both events in SLE patients. To sum up, in the particular population studied, there is no direct relationship between anti-Ro/SS-A Aabs and CP, which is in agreement with some authors and in disagreement with many others, contributing to the endless discussion of this issue.     

Association of antinucleosome antibodies with disease flare in serologically active clinically quiescent patients with systemic lupus erythematosus

OBJECTIVE: To identify the prevalence of serologically active clinically quiescent (SACQ) patients in a cohort of 290 patients with systemic lupus erythematosus (SLE). We investigated if the presence of anti-double-stranded DNA (anti-dsDNA) or antinucleosome (anti-NCS) antibodies during the SACQ period was associated with future flares. METHODS: SACQ patients defined as clinically inactive for 6 months (global British Isles Lupus Activity Group index [BILAG] scores <6) and serologically active (anti-dsDNA antibodies >50 units/ml on at least 2 occasions by enzyme-linked immunosorbent assay [ELISA]) were identified. Patient sera collected during the defined SACQ period were also tested for anti-NCS antibodies (ELISA). We retrospectively reviewed patient clinical details and episodes of flare using the BILAG activity index. RESULTS: Twenty-seven (9%) patients were SACQ. Seventeen (81%) patients experienced a flare (total of 91 flares, up to 12 flares per person) in the next 5 years. Median duration to first flare was 15 months (range 2-46). Time to first flare after SACQ period was significantly correlated with the presence of anti-NCS (P = 0.0012), high anti-NCS antibody titers (P = 0.0006), and anti-dsDNA titers 5 times above the normal limit (P = 0.02). Patients with higher absolute anti-NCS antibody titers showed a significant correlation with the number of flares (r = 0.57, P = 0.007). CONCLUSION: A minority of patients with SLE are SACQ. The majority of these patients experience a flare in the next 5 years and close followup is recommended. Anti-NCS antibodies may be a better predictor than anti-dsDNA antibodies for future flares.