RESUMEN
LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.
Asunto(s)
Péptidos Catiónicos Antimicrobianos/inmunología , Autoanticuerpos/inmunología , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Anticuerpos Antiproteína Citrulinada/inmunología , Anticuerpos Antinucleares/inmunología , Formación de Anticuerpos/inmunología , ADN/inmunología , Células Dendríticas/inmunología , Femenino , Humanos , Lupus Eritematoso Sistémico/etiología , Masculino , Psoriasis/etiología , Psoriasis/inmunología , Células Th17/inmunología , CatelicidinasRESUMEN
BACKGROUND: Thrombocytopenia is a manifestation associated with primary antiphospholipid syndrome (PAPS), and many studies have stressed the leading role played by platelets in the pathogenesis of antiphospholipid syndrome (APS). Platelets are highly specialized cells, and their activation involves a series of rapid rearrangements of the actin cytoskeleton. Recently, we described the presence of autoantibodies against D4GDI (Rho GDP dissociation inhibitor beta, ARHGDIB) in the serum of a large subset of SLE patients, and we observed that anti-D4GDI antibodies activated the cytoskeleton remodeling of lymphocytes by inhibiting D4GDI and allowing the upregulation of Rho GTPases, such as Rac1. Proteomic and transcriptomic studies indicate that D4GDI is very abundant in platelets, and small GTPases of the RHO family are critical regulators of actin dynamics in platelets. METHODS: We enrolled 38 PAPS patients, 15 patients carrying only antiphospholipid antibodies without clinical criteria of APS (aPL carriers) and 20 normal healthy subjects. Sera were stored at - 20 °C to perform an ELISA test to evaluate the presence of anti-D4GDI antibodies. Then, we purified autoantibodies anti-D4GDI from patient sera. These antibodies were used to conduct in vitro studies on platelet activation. RESULTS: We identified anti-D4GDI antibodies in sera from 18/38 (47%) patients with PAPS, in sera from 2/15(13%) aPL carriers, but in no sera from normal healthy subjects. Our in vitro results showed a significant 30% increase in the activation of integrin αIIbß3 upon stimulation of platelets from healthy donors preincubated with the antibody anti-D4GDI purified from the serum of APS patients. CONCLUSIONS: In conclusion, we show here that antibodies anti-D4GDI are present in the sera of PAPS patients and can prime platelet activation, explaining, at least in part, the pro-thrombotic state and the thrombocytopenia of PAPS patients. These findings may lead to improved diagnosis and treatment of APS.
Asunto(s)
Anticuerpos Antifosfolípidos/inmunología , Síndrome Antifosfolípido/inmunología , Autoanticuerpos/sangre , Plaquetas/inmunología , Activación Plaquetaria/inmunología , Trombocitopenia/etiología , Anticuerpos Antifosfolípidos/sangre , Síndrome Antifosfolípido/sangre , Síndrome Antifosfolípido/complicaciones , Autoanticuerpos/inmunología , Biomarcadores/sangre , Ensayo de Inmunoadsorción Enzimática , Estudios de Seguimiento , Humanos , Proteómica , Estudios Retrospectivos , Trombocitopenia/sangre , Trombocitopenia/inmunologíaRESUMEN
BACKGROUND: Adhesion molecule CD44 contributes to T cell migration into target organs. A higher expression of CD44v3 and v6 isoforms has been identified on T cells from systemic lupus erythematosus (SLE) patients. The aim of this study was to investigate the expression of CD44v3/v6 on T cells of SLE patients in order to evaluate their correlation with clinical features. METHODS: Sixteen healthy subjects (HSs) and 33 SLE female patients were enrolled. Fifteen patients were in remission (Systemic Lupus Erythematosus Disease Activity Index-2000 (SLEDAI-2K) = 0) and 18 patients had an active disease (SLEDAI-2K ≥ 4). Experiments were conducted by flow cytometry. RESULTS: Expression of CD44v3 on CD4+ and CD8+ T cells was higher in active patients compared to HSs ( p = 0.0097 and p = 0.0096). CD44v3 on CD8+ T cells was also higher in active patients compared to patients in remission ( p = 0.038). CD44v6 was higher on CD4+ and CD8+ T cells from active patients compared to HSs ( p = 0.003 and p = 0.0036) and to patients in remission ( p = 0.01 and p = 0.02). In active patients the ratio CD44v3/v6 was unbalanced towards isoform v6 on both T cell populations. In a receiver operating characteristic curve analysis, CD44v6 on CD4+ T cells was the most sensitive and specific one (specificity of 81.8%, sensitivity of 75%). Expression of CD44v6 on CD4+ and CD8+ T cells correlated with the SLEDAI-2K ( p = 0.03, r = 0.38 and p = 0.02, r = 0.39). CD44v6 and CD44v3 on CD8+ T cells associated with nephritis and arthritis ( p = 0.047 and p = 0.023). CONCLUSIONS: CD44v3/v6 can be used as biomarkers of disease activity and phenotypes; isoform v6 on CD4+ T cells can be useful as a diagnostic biomarker.
Asunto(s)
Marcadores Genéticos , Receptores de Hialuranos/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/inmunología , Linfocitos T/inmunología , Adulto , Estudios de Casos y Controles , Progresión de la Enfermedad , Femenino , Citometría de Flujo , Expresión Génica , Variación Genética , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Índice de Severidad de la EnfermedadRESUMEN
Specific indices are not available to evaluate systemic lupus erythematosus (SLE) joint involvement; indeed, the application of indices validated for rheumatoid arthritis has been suggested. We evaluated the usefulness of organ specific composite indices, i.e. the Disease Activity Score on 28 joints (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), and the ratio of swollen to tender joints (STR), to assess SLE joint activity by analyzing the correlation between these indices and ultrasonography (US) inflammatory status. We evaluated SLE patients with arthralgia and/or arthritis: the above-mentioned indices were calculated and the SLE Disease Activity Index 2000 (SLEDAI-2k) was applied to assess global disease activity. US of I-V metacarpophalangeal, I-V proximal interphalangeal, wrist, and knee bilateral was performed. Synovial effusion/hypertrophy and power Doppler findings were scored according to a semi-quantitative scale (0-3) to obtain an inflammatory total score (0-216). One hundred and six patients (M/F 7/99, median age 49.5 years (IQR 17.0), median disease duration 8.5 years (IQR 17.0)) were enrolled. We identified a positive correlation between US score and DAS28-CRP ( r = 0.3, p = 0.007), STR ( r = 0.42, p = 0.0005), SDAI ( r = 0.33, p = 0.02), CDAI ( r = 0.29, p = 0.03); US score reflected different levels of clinimetric joint activity. In conclusion, we suggest the ability of composite indices in detecting SLE joint inflammation and their possible real-life use.
Asunto(s)
Artralgia/etiología , Artritis/etiología , Articulaciones/fisiopatología , Lupus Eritematoso Sistémico/complicaciones , Sinovitis/etiología , Adulto , Femenino , Humanos , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Persona de Mediana Edad , Valores de Referencia , Índice de Severidad de la Enfermedad , Ultrasonografía DopplerRESUMEN
BACKGROUND: Autophagy has emerged as a key mechanism in the survival and function of T and B lymphocytes, and its activation was involved in apoptosis resistance in rheumatoid arthritis (RA). To investigate whether the relationship between autophagy and apoptosis may impact the response to the therapy, we analyzed ex vivo spontaneous autophagy and apoptosis in patients with RA subjected to treatment with anti-tumor necrosis factor (TNF) drugs and in vitro the effects of TNFα and anti-TNF drugs on cell fate. METHODS: Peripheral blood mononuclear cells (PBMCs) from 25 RA patients treated with anti-TNF drugs were analyzed for levels of autophagy marker LC3-II by western blot and for the percentage of annexin V-positive apoptotic cells by flow cytometry. The same techniques were used to assess autophagy and apoptosis after in vitro treatment with TNFα and etanercept in both PBMCs and fibroblast-like synoviocytes (FLS) from patients with RA. RESULTS: PBMCs from patients with RA responsive to treatment showed a significant reduction in LC3-II levels, associated with an increased apoptotic activation after 4 months of therapy with anti-TNF drugs. Additionally, the expression of LC3-II correlated with DAS28. TNFα was able to induce autophagy in a dose-dependent manner after 24 h of culture in RA PBMCs and FLS. Moreover, etanercept caused a significant reduction of autophagy and of levels of citrullinated proteins. CONCLUSIONS: Our results show how the crosstalk between autophagy and apoptosis can sustain the survival of immune cells, thus influencing RA progression. This suggests that inhibition of autophagy represents a possible therapeutic target in RA.
Asunto(s)
Apoptosis/efectos de los fármacos , Artritis Reumatoide/tratamiento farmacológico , Autofagia/efectos de los fármacos , Etanercept/uso terapéutico , Metotrexato/uso terapéutico , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Anciano , Antirreumáticos/uso terapéutico , Artritis Reumatoide/metabolismo , Artritis Reumatoide/patología , Células Cultivadas , Etanercept/metabolismo , Femenino , Humanos , Leucocitos Mononucleares/efectos de los fármacos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Evaluación de Resultado en la Atención de Salud , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Anti-phospholipid syndrome (APS) is characterized by arterial and/or venous thrombosis and pregnancy morbidity. It is well known that in these patients thrombosis may be the result of a hypercoagulable state related to anti-ß2-glycoprotein I (ß2-GPI) antibodies. Moreover, platelets may play a role in thrombotic manifestations by binding of anti-ß2-GPI antibodies. Platelets express tissue factor (TF), the major initiator of the clotting cascade, after activation. We primarily analyzed whether anti-ß2-GPI antibodies may trigger a signal transduction pathway leading to TF expression in human platelets. Platelets from healthy donors were incubated with affinity purified anti-ß2-GPI antibodies for different times. Platelet lysates were analyzed for phospho-interleukin-1 receptor-associated kinase 1 (IRAK), phospho-p65 nuclear factor kappaB (NF-κB) and TF by Western blot. IRAK phosphorylation was observed as early as 10 min of anti-ß2-GPI treatment, with consequent NF-κB activation, whereas TF expression, detectable at 45 min, was significantly increased after 4 h of anti-ß2-GPI treatment. Virtually no activation was observed following treatment with control immunoglobulin IgG. We then analyzed TF expression in platelets from 20 APS patients and 20 healthy donors. We observed a significant increase of TF in APS patients versus control subjects (P < 0·0001). This work demonstrates that anti-ß2-GPI antibodies may trigger in vitro a signal transduction pathway in human platelets, which involves IRAK phosphorylation and NF-κB activation, followed by TF expression. Furthermore, ex vivo, platelets of APS patients showed a significantly increased expression of TF. These findings support the view that platelets may play a role in the pathogenesis of APS, with consequent release of different procoagulant mediators, including TF.
Asunto(s)
Síndrome Antifosfolípido/inmunología , Plaquetas/fisiología , Quinasas Asociadas a Receptores de Interleucina-1/metabolismo , Tromboplastina/metabolismo , beta 2 Glicoproteína I/inmunología , Adulto , Formación de Anticuerpos , Autoanticuerpos/metabolismo , Coagulación Sanguínea , Células Cultivadas , Femenino , Humanos , Masculino , Persona de Mediana Edad , FN-kappa B/metabolismo , Fosforilación , Transducción de Señal , Tromboplastina/genética , Transgenes/genéticaRESUMEN
Microparticles (MPs) are small membrane vesicles released by many cell types under physiological and pathological conditions. In the last years, these particles were considered as inert cell debris, but recently many studies have demonstrated they could have a role in intercellular communication. Increased levels of MPs have been reported in various pathological conditions including infections, malignancies, and autoimmune diseases, such as rheumatoid arthritis (RA). RA is an autoimmune systemic inflammatory disease characterized by chronic synovial inflammation, resulting in cartilage and bone damage with accelerated atherosclerosis increasing mortality. According to the literature data, also MPs could have a role in endothelial dysfunction, contributing to atherosclerosis in RA patients. Moreover many researchers have shown that a dysregulated autophagy seems to be involved in endothelial dysfunction. Autophagy is a reparative process by which cytoplasmic components are sequestered in double-membrane vesicles and degraded on fusion with lysosomal compartments. It has been shown in many works that basal autophagy is essential to proper vascular function. Taking into account these considerations, we hypothesized that in RA patients MPs could contribute to atherosclerosis process by dysregulation of endothelial autophagy process.
Asunto(s)
Artritis Reumatoide/inmunología , Aterosclerosis/inmunología , Autofagia/inmunología , Micropartículas Derivadas de Células/inmunología , Animales , Enfermedades Autoinmunes/inmunología , Autoinmunidad/inmunología , Humanos , Inflamación/inmunologíaRESUMEN
Infectious sacroiliitis is an infection of the sacroiliac joint, not easy to diagnose because of its non-specific signs, symptoms and laboratory abnormalities. We describe a case of a 16 year-old male with 5 days' history of fever, abdominal pain, constipation, low-back and left hip pain extended to the left knee associated with sudden inability to walk. In the first place, magnetic resonance imaging (MRI) examination of his sacroiliac joint revealed an enlarged corpuscolated fluid collection near the left iliopsoas muscle, extended to homolateral paravertebral muscles and a little fluid at the left sacroiliac joint. Drainage by aspiration of the iliopsoas abscess was applied; Staphylococcus aureus was found in the aspirated fluid and isolated from the blood too. Therefore intravenous antibiotic therapy was begun. Follow-up MRI exams confirmed the muscle abscess and revealed also a spongy bone edema of the left sacroiliac joint, persisting despite the disappearance of symptoms and the normalization of inflammatory values. It is important to make an early diagnosis of infectious sacroiliitis in order to begin antibiotic therapy as soon as possible, because of the increasing morbidity of infection of sacroiliac joint. In our case MR findings have provided significant orientation towards the final diagnosis of infectious sacroiliitis.
Asunto(s)
Imagen por Resonancia Magnética , Absceso del Psoas/diagnóstico por imagen , Absceso del Psoas/microbiología , Sacroileítis/diagnóstico por imagen , Sacroileítis/microbiología , Infecciones Estafilocócicas , Adolescente , Humanos , Masculino , Absceso del Psoas/complicaciones , Sacroileítis/complicaciones , Infecciones Estafilocócicas/complicacionesRESUMEN
Several studies have suggested a link between human microbiome and rheumatoid arthritis (RA) development. Porphyromonas gingivalis seems involved in RA initiation and progression, as supported by the high occurrence of periodontitis. In this case-control study, we analysed tongue P. gingivalis presence and quantification in a large healthy and RA cohort. We enrolled 143 RA patients [male/female (M/F) 32/111, mean ± standard deviation (s.d.), age 57·5 ± 19·8 years, mean ± s.d. disease duration 155·9 ± 114·7 months); 36 periodontitis patients (M/F 11/25, mean ± s.d., age 56 ± 9·9 years, mean ± s.d. disease duration 25·5 ± 20·9 months); and 57 patients (M/F 12/45, mean ± s.d., age 61·4 ± 10·9 years, mean ± s.d. disease duration 62·3 ± 66·9 months) with knee osteoarthritis or fibromyalgia. All subjects underwent a standard cytological swab to identify the rate of P. gingivalis/total bacteria by using quantitative real-time polymerase chain reaction. The prevalence of P. gingivalis resulted similarly in RA and periodontitis patients (48·9 versus 52·7%, P = not significant). Moreover, the prevalence of this pathogen was significantly higher in RA and periodontitis patients in comparison with control subjects (P = 0·01 and P = 0·003, respectively). We found a significant correlation between P. gingivalis rate in total bacteria genomes and disease activity score in 28 joints (DAS28) (erythrocyte sedimentation rate) (r = 0·4, P = 0·01). RA patients in remission showed a significantly lower prevalence of P. gingivalis in comparison with non-remission (P = 0·02). We demonstrated a significant association between the percentage of P. gingivalis on the total tongue biofilm and RA disease activity (DAS28), suggesting that the oral cavity microbiological status could play a role in the pathogenic mechanisms of inflammation, leading to more active disease.
Asunto(s)
Artritis Reumatoide/inmunología , Infecciones por Bacteroidaceae/inmunología , Microbiota/inmunología , Periodontitis/inmunología , Porphyromonas gingivalis/fisiología , Lengua/patología , Adulto , Anciano , Artritis Reumatoide/epidemiología , Infecciones por Bacteroidaceae/epidemiología , Biopelículas , Estudios de Casos y Controles , Estudios de Cohortes , Progresión de la Enfermedad , Femenino , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Lengua/microbiologíaRESUMEN
This longitudinal retrospective study aims at describing the safety profile and the reasons for discontinuation of antimalarials in patients with systemic lupus erythematosus (SLE) and discoid lupus erythematosus (DLE), focusing on ocular toxicity. We analyzed the clinical data of 845 SLE and DLE patients; 59% of them were taking antimalarials: 1.4% chloroquine (CQ), 88.5% hydroxychloroquine (HCQ) and 10.1% both. The mean therapy duration was 82.5 ± 77.4 months. At least one side effect was reported by 19.4% of patients, leading to temporary or permanent withdrawal in 9.1% and 10.3% of cases, respectively; 19.3% of patients experienced side effects with HCQ and 8.6% with CQ. In 55.1% of cases, the adverse event was mild or moderate. Ophthalmological alterations were reported by 8.5% but were confirmed by the ophthalmological examination in 5.5% of cases. Retinal alterations were associated with age, disease duration and duration of the antimalarial therapy, but not to drug dose and comorbidities or lupus nephritis. This is the largest monocentric longitudinal study confirming the good safety profile of antimalarials in DLE and SLE patients. The main adverse events during the therapy were mild or moderate, but maculopathy-reported in a low percentage of patients-remains the main cause of treatment withdrawal.
Asunto(s)
Antimaláricos/uso terapéutico , Cloroquina/uso terapéutico , Lupus Eritematoso Discoide/tratamiento farmacológico , Lupus Eritematoso Sistémico/tratamiento farmacológico , Adulto , Antimaláricos/efectos adversos , Cloroquina/efectos adversos , Femenino , Humanos , Hidroxicloroquina/uso terapéutico , Estudios Longitudinales , Lupus Eritematoso Discoide/diagnóstico , Lupus Eritematoso Sistémico/diagnóstico , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Ciudad de Roma , Factores de Tiempo , Resultado del TratamientoRESUMEN
Objective Several studies have evaluated the prevalence of rheumatoid factor (RF) and anti-citrullinated proteins antibodies (ACPA) in systemic lupus erythematosus (SLE) patients but no data are available on the anti-carbamylated proteins (anti-CarP), a new biomarker for rheumatoid arthritis (RA). We evaluated the anti-CarP prevalence in SLE patients with joint involvement and the associations with different phenotypes. Methods Seventy-eight SLE patients with joint involvement were enrolled (F/M 73/5; mean ± SD age 47.6 ± 11.2 years; mean ± SD disease duration 214.3 ± 115.6 months). As control groups, we evaluated SLE patients without joint manifestations ( N = 15), RA ( N = 78) and healthy individuals (HS, N = 98). Anti-CarP were assessed by home-made ELISA in all patients and controls, RF and ACPA in SLE patients with joint involvement (commercial ELISA kit). Results The prevalence of anti-CarP in SLE patients with joint involvement was similar to RA ( p = NS) and significantly higher compared with SLE without joint involvement and HS ( p < 0.0001, p < 0.0001, respectively). Four patients were positive for all three antibodies: seventy-five percent of these showed Jaccoud arthropathy. Fourty-five percent of ACPA-ve/RF-ve patients were anti-CarP + ve. Conclusions The evaluation of anti-CarP in SLE joint involvement demonstrated a prevalence of almost 50%, similar to RA and significantly higher than SLE without joint involvement and HS.
Asunto(s)
Autoanticuerpos/sangre , Artropatías/inmunología , Lupus Eritematoso Sistémico/inmunología , Adulto , Estudios de Casos y Controles , Cianatos/inmunología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Recently, a study has shown that a polymorphism in the region of MIR1279 modulates the expression of the TRAF3IP2 gene. Since polymorphisms in the TRAF3IP2 gene have been described in association with systemic lupus erithematosus (SLE) susceptibility and with the development of pericarditis, our aim is to verify if the MIR1279 gene variability could also be involved. The rs1463335 SNP, located upstream MIR1279 gene, was analyzed by allelic discrimination assay in 315 Italian SLE patients and 201 healthy controls. Moreover, the MIR1279 gene was full sequenced in 50 patients. A case/control association study and a genotype/phenotype correlation analysis were performed. We also constructed a pericarditis genetic risk profile for patients with SLE. The full sequencing of the MIR1279 gene in patients with SLE did not reveal any novel or known variation. The variant allele of the rs1463335 SNP was significantly associated with susceptibility to pericarditis ( P = 0.017 and OR = 1.67). A risk profile model for pericarditis considering the risk alleles of MIR1279 and three other genes (STAT4, PTPN2 and TRAF3IP2) showed that patients with 4 or 5 risk alleles have a higher risk of developing pericarditis ( OR = 4.09 with P = 0.001 and OR = 6.04 with P = 0.04 respectively). In conclusion, we describe for the first time the contribution of a MIR1279 SNP in pericarditis development in patients with SLE and a genetic risk profile model that could be useful to identify patients more susceptible to developing pericarditis in SLE. This approach could help to improve the prediction and the management of this complication.
Asunto(s)
Lupus Eritematoso Sistémico/complicaciones , MicroARNs/genética , Pericarditis/etiología , Proteínas Adaptadoras Transductoras de Señales , Adulto , Alelos , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad , Humanos , Italia , Lupus Eritematoso Sistémico/genética , Masculino , Persona de Mediana Edad , Pericarditis/genética , Polimorfismo de Nucleótido Simple , Proteína Tirosina Fosfatasa no Receptora Tipo 2/genética , Factor de Transcripción STAT4/genética , Péptidos y Proteínas Asociados a Receptores de Factores de Necrosis Tumoral/genéticaRESUMEN
OBJECTIVES: Literature data suggest a significantly higher mortality in patients affected by systemic lupus erythematosus (SLE) developing chronic damage. Therefore, damage prevention is a major goal in the management of SLE patients. In the present study, we assessed damage by means of the Systemic Lupus International Collaborative Clinics/American College of Rheumatology (SLICC/ACR) damage index (SDI), in a large cohort of SLE patients. Additionally, we aimed at evaluating its association with demographic and clinical features as well as with disease activity and laboratory findings. PATIENTS AND METHODS: We enrolled consecutive patients affected by SLE diagnosed according to the American College of Rheumatology (ACR) 1997 revised criteria. Chronic damage was determined by SDI calculated at the last examination in all patients with at least six months of follow-up. Disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index 2000 (SLEDAI-2K); flare was defined as an increase of SLEDAI-2K ≥ 4 compared with the previous visit. RESULTS: We evaluated 349 SLE patients (M/F 25/324, mean age ± SD 42.7 ± 12.4 years, mean disease duration ± SD 164.9 ± 105.2 months). Among the enrolled patients, 125 (35.8%) showed a SDI ≥ 1 (mean SDI ± SD 1.7 ± 0.9, range 0-5). The musculo-skeletal was the most frequently involved organ/system in SDI score (41/349 patients, 11.7%), with deforming/erosive arthritis in 21/349 (6.0%). The presence of chronic damage was associated with age (P < 0.001), disease duration (P < 0.001), number of flares (P = 0.02) and with the use of glucocorticoids (P = 0.02). The logistic regression analysis revealed the association between neuropsychiatric damage and antiphospholipid syndrome (P = 0.01, OR = 3.9) and between the presence of cardiovascular damage and anti-ß2GPI antibodies (P = 0.01, OR 6.2). CONCLUSIONS: In the present study chronic damage was identified in about one third of SLE patients. The association between SDI and the number of flares claim for a thigh-control of the disease activity in order to prevent the chronic damage. The possible role of antiphospholipid antibodies (aPL) in the development of neuropsychiatric and cardiovascular damage may suggest a more careful assessment of such aPL positive patients.
Asunto(s)
Anticuerpos Antifosfolípidos/sangre , Progresión de la Enfermedad , Glucocorticoides/efectos adversos , Lupus Eritematoso Sistémico/complicaciones , Adolescente , Adulto , Factores de Edad , Anciano , Estudios Transversales , Femenino , Glucocorticoides/uso terapéutico , Humanos , Modelos Logísticos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Análisis Multivariante , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
Anti-phospholipid antibody syndrome (APS) is a systemic autoimmune disease characterized clinically by arterial and/or venous thromboses, recurrent abortions or fetal loss and serologically by the presence of 'anti-phospholipid antibodies' (aPL). The main target antigen of the antibodies is ß2 glycoprotein I (ß2 GPI). Post-translational oxidative modifications of the protein have been widely described. In this study we aimed to analyse sera reactivity to glucose-modified ß2 GPI (G-ß2 GPI). Sera collected from 43 patients with APS [15 primary APS (PAPS) and 28 APS associated with systemic lupus erythematosus (SLE) (SAPS)], 30 with SLE, 30 with rheumatoid arthritis (RA) and 40 healthy subjects were analysed by an enzyme-linked immunosorbent assay (ELISA) using a G-ß2 GPI. Nine of 15 consecutive PAPS out-patients (60%) and 16 of 28 SAPS (57.1%) showed serum antibodies [immunoglobulin (Ig)G class] against G-ß2 GPI (anti-G-ß2 GPI) by ELISA. The occurrence of anti-G-ß2 GPI was significantly higher in APS patients compared to patients suffering from SLE. No RA patients or control healthy subjects resulted positive for anti-G-ß2 GPI. Of note, aG-ß2 GPI prompted to identify some APS patients (four PAPS and seven SAPS), who were negative in the classical anti-ß2 GPI test. Moreover, in APS patients, anti-G-ß2 GPI titre was associated significantly with venous thrombosis and seizure in APS patients. This study demonstrates that G-ß2 GPI is a target antigen of humoral immune response in patients with APS, suggesting that ß2 GPI glycation products may contain additional epitopes for anti-ß2 GPI reactivity. Searching for these antibodies may be useful for evaluating the risk of clinical manifestations.
Asunto(s)
Síndrome Antifosfolípido/inmunología , Artritis Reumatoide/inmunología , Autoanticuerpos/inmunología , Lupus Eritematoso Sistémico/inmunología , beta 2 Glicoproteína I/inmunología , Adolescente , Adulto , Anciano , Anticuerpos/sangre , Anticuerpos/inmunología , Anticuerpos Anticardiolipina/sangre , Anticuerpos Anticardiolipina/inmunología , Anticuerpos Antifosfolípidos/sangre , Anticuerpos Antifosfolípidos/inmunología , Autoanticuerpos/sangre , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Masculino , Persona de Mediana Edad , Convulsiones/sangre , Convulsiones/inmunología , Trombosis de la Vena/sangre , Trombosis de la Vena/inmunología , Adulto JovenRESUMEN
Joint involvement is a common manifestation in systemic lupus erythematosus (SLE). According to the SLE disease activity index 2000 (SLEDAI-2K), joint involvement is present in case of ≥2 joints with pain and signs of inflammation. However this definition could fail to catch all the various features of joint involvement. Alternatively the Swollen to Tender joint Ratio (STR) could be used. This new index, which was originally proposed for rheumatoid arthritis (RA) patients, is based on the count of 28 swollen and tender joints. Our study is, therefore, aimed to assess joint involvement in a SLE cohort using the STR. SLE patients with joint symptoms (≥1 tender joint) were enrolled over a period of one month. Disease activity was assessed by SLEDAI-2K. We performed the swollen and tender joint count (0-28) and calculated the STR. Depending on the STR, SLE patients were grouped into three categories of disease activity: low (STR1.0). We also calculated the disease activity score based on a 28-joint count and the erythrocyte sedimentation rate (DAS28-ESR). We enrolled 100 SLE patients [F/M 95/5, mean±standard deviation (SD) age 46.3±10.6 years, mean±SD disease duration 147.1±103.8 months]. The median of tender and swollen joints was 4 (IQR 7) and 1 (IQR 2.5), respectively. The median STR value was 0.03 (IQR 0.6). According to the STR, disease activity was low in 70 patients, moderate in 23 and high in 7. A significant correlation was identified between STR values and DAS28 (r=0.33, p=0.001). The present study suggests a correlation between STR and DAS28, allowing an easier and faster assessment of joint involvement with the former index.
Asunto(s)
Artralgia/etiología , Articulaciones/fisiopatología , Lupus Eritematoso Sistémico/complicaciones , Índice de Severidad de la Enfermedad , Adulto , Antirreumáticos/uso terapéutico , Autoanticuerpos/sangre , Sedimentación Sanguínea , Femenino , Humanos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/fisiopatología , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Evaluación de SíntomasRESUMEN
OBJECTIVES: To investigate the prevalence of anti-carbamylated protein antibodies (anti-CarP) in the healthy first-degree relatives (HFDRs) of patients with rheumatoid arthritis (RA). METHODS: We enrolled 141 HFDRs of 63 patients with RA diagnosed accordingly to the 2010 ACR/EULAR criteria. Fifty-six normal healthy subjects (NHS), sex- and age-matched, served as controls. Anti-CarP IgG, anti-cyclic citrullinated peptide antibody (anti-CCP) IgG and rheumatoid factors (RF) isotypes (IgG, IgA, IgM) were assessed by solid-phase ELISA. RESULTS: Anti-CarP were detectable in 13 HFDRs (9.2%), anti-CCP in 9 (6.3%), IgG-RF in 10 (7%), IgA-RF in 17 (12%), and IgM-RF in 13 (9.2%) HFDRs. Twenty-nine (46%) RA patients were positive for anti-CarP, 31 (49.2%) for anti-CCP, and 34 (53.9%) for RF. One NHS (1.7%) resulted positive for anti-CarP, none for anti-CCP and RF. Anti-CarP showed significantly higher serum levels in RA and HFDRs than in NHS (p<0.0001 and p=0.0012, respectively). A significant correlation between anti-CCP and RF were found among RA patients (p=0.0002), whereas no correlations were reported between autoantibodies tested in the HFDRs. CONCLUSIONS: Anti-CarP can be found in the sera of HFDRs of RA patients and their prevalence is significantly higher than in NHS. No correlation of anti-CarP with anti-CCP and RF antibodies in RA HFDRs was found.
Asunto(s)
Artritis Reumatoide , Autoanticuerpos/sangre , Carbamatos/inmunología , Familia , Péptidos Cíclicos/inmunología , Factor Reumatoide/sangre , Adulto , Artritis Reumatoide/diagnóstico , Artritis Reumatoide/inmunología , Autoantígenos/inmunología , Salud de la Familia , Femenino , Humanos , Pruebas Inmunológicas/métodos , Masculino , Estadística como AsuntoRESUMEN
Pulmonary arterial hypertension (PAH) can be idiopathic or secondary to autoimmune diseases, and it represents one of the most threatening complications of systemic sclerosis (SSc). Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine with proinflammatory functions that appears to be involved in the pathogenesis of hypoxia-induced PH. In SSc patients, high serum levels of MIF have been associated with the development of ulcers and PAH. Stem cell growth factor ß (SCGF ß) is a human growth factor that, together with MIF, is involved in the pathogenesis of chronic spinal cord injury. The aim of our study was to measure serum levels of MIF in patients with idiopathic and SSc-associated PAH. We enrolled 13 patients with idiopathic PAH and 15 with SSc-associated PAH. We also selected 14 SSc patients without PAH and 12 normal healthy controls, matched for sex and age. PAH was confirmed by right hearth catheterism (mPAP>25 mmHg). MIF and SCGF ß levels were measured by ELISA. We found significantly higher circulating levels of MIF and of SCGF ß in patients with idiopathic PAH (P=0.03 and P=0.004) and with PAH secondary to SSc (P=0.018 and P=0.023) compared to SSc patients without PAH. Higher levels of MIF were found in those patients with an higher New York Heart Association (NYHA) class (P=0.03). We can hypothesize that MIF and SCGF ß are able to play a role in PAH, both idiopathic or secondary, and in the future they may be evaluated as useful biomarkers and prognostic factors for this serious vascular disease.
Asunto(s)
Hipertensión Pulmonar/sangre , Factores Inhibidores de la Migración de Macrófagos/sangre , Esclerodermia Sistémica/sangre , Factor de Crecimiento Transformador beta/sangre , Anciano , Biomarcadores/sangre , Estudios de Casos y Controles , Femenino , Humanos , Hipertensión Pulmonar/diagnóstico , Hipertensión Pulmonar/inmunología , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Esclerodermia Difusa/sangre , Esclerodermia Limitada/sangre , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/inmunología , Sensibilidad y EspecificidadRESUMEN
The aim of this study was to investigate the expression of the interleukin (IL)-36 axis in patients with primary Sjögren's syndrome (pSS). Blood and minor labial salivary glands (MSG) biopsies were obtained from 35 pSS and 20 non-Sjögren's syndrome patients (nSS) patients. Serum IL-36α was assayed by enzyme-linked immunosorbent assay (ELISA). IL-36α, IL-36R, IL-36RA, IL-38, IL-22, IL-17, IL-23p19 and expression in MSGs was assessed by reverse transcription-polymerase chain reaction (RT-PCR), and tissue IL-36α and IL-38 expression was also investigated by immunohistochemistry (IHC). αß and γδ T cells and CD68(+) cells isolated from MSGs were also studied by flow cytometry and confocal microscopy analysis. IL-36α was over-expressed significantly in the serum and in the salivary glands of pSS. Salivary gland IL-36α expression was correlated with the expression levels of IL-17, IL-22 and IL-23p19. IL-38, that acts as inhibitor of IL-36α, was also up-regulated in pSS. αß(+) CD3(+) T cells and CD68(+) cells were the major source of IL-36α in minor salivary glands of pSS. γδ T cells were not significantly expanded in the salivary glands of pSS but produced more IL-17, as their percentage correlated with the focus score. Higher expression of IL-36α and IL-36R was also demonstrated in γδ T cells isolated from pSS compared to controls. In this study we demonstrate that a significant increase in circulating and tissue levels of IL-36α occurs in pSS patients.
Asunto(s)
Interleucina-1/inmunología , Receptores de Interleucina/inmunología , Glándulas Salivales/inmunología , Síndrome de Sjögren/inmunología , Linfocitos T/inmunología , Adulto , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación Mielomonocítica/genética , Antígenos de Diferenciación Mielomonocítica/inmunología , Estudios de Casos y Controles , Femenino , Regulación de la Expresión Génica , Humanos , Interleucina-1/genética , Interleucina-17/genética , Interleucina-17/inmunología , Subunidad p19 de la Interleucina-23/genética , Subunidad p19 de la Interleucina-23/inmunología , Interleucinas/genética , Interleucinas/inmunología , Masculino , Persona de Mediana Edad , Cultivo Primario de Células , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Interleucina/genética , Glándulas Salivales/patología , Transducción de Señal , Síndrome de Sjögren/genética , Síndrome de Sjögren/patología , Linfocitos T/patología , Interleucina-22RESUMEN
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.
Asunto(s)
Enfermedades Cardiovasculares/epidemiología , Medición de Riesgo/métodos , Síndrome de Sjögren/complicaciones , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Enfermedades Cardiovasculares/etiología , Femenino , Estudios de Seguimiento , Humanos , Italia/epidemiología , Masculino , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Síndrome de Sjögren/epidemiología , Adulto JovenRESUMEN
Evidence exists that interleukin (IL)-10 family cytokines may be involved in the pathogenesis of rheumatoid arthritis (RA). We sought to determine whether or not these cytokines are involved in psoriatic arthritis (PsA). We conducted a prospective study on patients with PsA, RA and osteoarthritis (OA); healthy controls (HC) were also included. We analysed IL-20, IL-24 and IL-19 serum and synovial fluid (SF) levels and change of serum levels following treatment with biological agents. IL-20 serum levels were increased in PsA and RA compared with OA patients and HC and with matched SF levels. IL-24 serum levels in PsA, RA and OA patients were higher than those in HC and also with respect to matched SF in PsA. IL-19 serum levels were higher in HC and OA compared with PsA and RA patients; IL-19 SF levels were higher in PsA and RA compared with OA patients, and in PsA compared with RA patients. PsA and RA patients showed a reduction of IL-19 serum levels after biological treatment. Therefore, IL-19 seems to be involved mainly in the joint inflammation, whereas IL-20 and IL-24 appear to participate mainly in the systemic responses. These findings may further the comprehension of the contribution of these cytokines to the inflammatory response involved in chronic arthritis, as well as to the development of novel therapeutic strategies.