RESUMEN
14-3-3η protein is a proinflammatory mediator that may represent a novel diagnostic and prognostic biomarker for rheumatoid arthritis (RA). We assessed the correlation between changes in serum 14-3-3η levels and changes in clinical disease activity measures in RA patients treated with Tofacitinib (TOF). Paired serum samples from 35 patients with RA were obtained at baseline and 5 months after the initiation of treatment with TOF. The levels of 14-3-3η were measured by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). The cut-off was defined as 0.19 ng/ml. 14-3-3η positivity was found in 57% of the patients at baseline and in 37% of the patients after 5 months of treatment. Mean ± SD baseline 14-3-3η levels [4.92 ± 8.86 ng/ml] were significantly higher (p < 0.005) than 14-3-3η levels following treatment [1.97 ± 4.59 ng/ml]. A statistically significant improvement (p < 0.001) of CDAI, SDAI, DAS4ESR and DAS4CRP was achieved after 5 month of treatment. Decrease in 14-3-3η protein levels was highly correlated with improvement in DAS4ESR (r = 0.50, p < 0.01), DAS4CRP (r = 0.46, p < 0.01) and ESR (r = 0.36, p = 0.03) and moderately correlated with improvement in CDAI (r = 0.32, p = 0.065) and SDAI (r = 0.33, p = 0.051). The correlation between decrease in 14-3-3η levels and improvement in DAS4ESR remained significant in a partial correlation analysis controlling for ESR (r = 0.39, p = 0.02). This study demonstrates that in RA patients who were treated with TOF, decrease in 14-3-3η levels is correlated with improvement in clinical disease activity parameters. The 14-3-3η protein may serve as an objective biomarker for monitoring of TOF therapy response.
Asunto(s)
Proteínas 14-3-3/sangre , Artritis Reumatoide/sangre , Artritis Reumatoide/tratamiento farmacológico , Piperidinas/uso terapéutico , Inhibidores de Proteínas Quinasas/uso terapéutico , Pirimidinas/uso terapéutico , Pirroles/uso terapéutico , Adulto , Artritis Reumatoide/diagnóstico , Biomarcadores/sangre , Estudios de Cohortes , Femenino , Humanos , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
14-3-3η may represent a useful diagnostic biomarker for rheumatoid arthritis (RA). We assessed the prevalence and serum levels of 14-3-3η in patients with RA and in patients with other rheumatic diseases. Serum levels of 14-3-3η were measured in 96 patients with RA, in 101 patients with other rheumatic diseases, and in 66 healthy subjects. All of the sera samples were evaluated by JOINT stat 14-3-3η ELISA test kits (Augurex Life Sciences Corp.). Median (IQR) 14-3-3η levels were significantly higher in the early RA group [0.25 ng/ml (0.075-3.11)] and in patients with established RA [0.15 ng/ml (0.08-1.26)] than in healthy subjects [0 ng/ml (0-0)] and disease controls: SLE [0.01 ng/ml (0-0.055)], AS [0.05 ng/ml (0-0.255)], and PsA [0.01 ng/ml (0-0.065)]. The prevalence of 14-3-3η positivity in patients with early RA was 58%, significantly higher than that in disease controls and healthy subjects (p < 0.001). In patients with established RA, this prevalence was 43%, and it was significantly higher than that in patients with other rheumatic diseases and healthy subjects (p < 0.05), excluding the AS group (p = 0.054). In the early RA cohort, the positivity for 14-3-3η, RF, and anti-CCP was 58%, 67%, and 71%, respectively. Eighty-two percent of the patients in this cohort were positive for at least one of these biomarkers. The concentration of 14-3-3η protein may be used to distinguish between patients with early RA and patients with other rheumatic diseases.
Asunto(s)
Proteínas 14-3-3/sangre , Artritis Reumatoide/diagnóstico , Biomarcadores/sangre , Artritis Reumatoide/patología , Femenino , Humanos , Masculino , Persona de Mediana EdadRESUMEN
Hydroxychloroquine (HCQ) is widely used to treat autoimmune/rheumatic diseases such as systemic lupus erythematosus (SLE). The immune modulation effects of HCQ have been highlighted as beneficial for maintaining remission of SLE as well as ameliorating skin, joint and other manifestations. Moreover, HCQ exposure for prolonged periods as well as during pregnancy is considered safe, therefore it is recommended for the vast majority of SLE patients. Although HCQ therapy requires follow-up by a specialist, its most common side effects are mild gastrointestinal disturbances, sensitivity to light and skin rashes. Of these side effects, hypersensitivity skin reactions have been suggested to play a role in reduced compliance to HCQ therapy. In the current study we present a two-stage HCQ desensitization protocol that was successfully implemented among 12 out of 13 patients. We exhibit that prolonged HCQ oral desensitization is an effective method for overcoming mild to moderate late hypersensitivity reactions and thoroughly address possible mechanisms of action.
Asunto(s)
Antirreumáticos/administración & dosificación , Antirreumáticos/efectos adversos , Desensibilización Inmunológica/métodos , Erupciones por Medicamentos/prevención & control , Hidroxicloroquina/administración & dosificación , Hidroxicloroquina/efectos adversos , Lupus Eritematoso Sistémico/tratamiento farmacológico , Administración Oral , Adulto , Anciano , Esquema de Medicación , Erupciones por Medicamentos/diagnóstico , Erupciones por Medicamentos/inmunología , Femenino , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Factores de Riesgo , Índice de Severidad de la Enfermedad , Factores de Tiempo , Resultado del TratamientoRESUMEN
One of the adverse events of tocilizumab (TCZ) is a transient, dose-dependent neutropenia. The recommendations of the Summary of Product Characteristics state that this neutropenia should be managed according to the absolute neutrophil count (ANC). However, the approach to a patient who had a history of neutropenia induced by previous DMARDs and developed TCZ-induced neutropenia remains unclear. We would like to report a series of four patients with rheumatoid arthritis who developed Grade 2 neutropenia (ANC 1-1.5 × 10(9)/L) following intravenous TCZ treatment at a dose of 8 mg/kg. All of them had a previous history of neutropenia (Grade 2 or Grade 3) due to Etanercept (three patients) and Sulfasalazine (one patient). Therefore, we decided to decrease the TCZ dosage by 10-20% approximately. Reducing of the dosage did not have any influence on the efficacy of TCZ, and all of our patients remained in clinical remission. The mechanisms underlying neutropenia induced by Tocilizumab, Etanercept and Sulfasalazine are also discussed in this article.
Asunto(s)
Anticuerpos Monoclonales Humanizados/efectos adversos , Antirreumáticos/efectos adversos , Artritis Reumatoide/complicaciones , Neutropenia/inducido químicamente , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Etanercept , Femenino , Humanos , Inmunoglobulina G/efectos adversos , Persona de Mediana Edad , Neutropenia/diagnóstico , Receptores del Factor de Necrosis Tumoral , Sulfasalazina/efectos adversos , Resultado del TratamientoRESUMEN
Granulomatosis and angiitis (GPA) is a multisystemic disease characterized by a granulomatous inflammation, tissue necrosis, and vasculitis of small and medium-sized blood vessels. Although the disease has a predilection for the upper respiratory tract, lungs, and kidneys, any organ system may be affected. Here, we present a case of generalized GPA manifested initially by necrotizing isolated parotitis and later by pulmonary-renal syndrome. Simultaneously with pulmonary hemorrhage, our patient developed an antiphospholipid syndrome (APS) presenting with deep vein thrombosis and strongly positive lupus anticoagulant. To the best of our knowledge the coincidence of parotitis and pulmonary-renal syndrome due to GPA and APS has never been reported previously. Concomitant venous thromboembolism may be life-threatening in a patient with GPA. Early diagnosis and institution of the proper therapy are critical in order to prevent organ damage.
Asunto(s)
Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/diagnóstico , Síndrome Antifosfolípido/etiología , Glomerulonefritis/etiología , Granuloma/diagnóstico , Hemorragia/etiología , Enfermedades Pulmonares/etiología , Parotiditis/complicaciones , Vasculitis Asociada a Anticuerpos Citoplasmáticos Antineutrófilos/complicaciones , Síndrome Antifosfolípido/terapia , Glomerulonefritis/terapia , Granuloma/complicaciones , Hemorragia/terapia , Humanos , Enfermedades Pulmonares/terapia , Inhibidor de Coagulación del Lupus , Masculino , Persona de Mediana Edad , Trombosis de la Vena/etiologíaRESUMEN
AIM: To evaluate the effect of physical activity on the structural, morphological, and metabolic characteristics of the gastrocnemius muscle in familial Mediterranean fever (FMF) patients, utilizing quantitative (31)P magnetic resonance spectroscopy (MRS), in order to elucidate the mechanism of their exertional leg pain. MATERIALS AND METHODS: Eleven FMF patients suffering from exertional leg pain (eight male, three female; mean age 33 years) and six healthy individuals (three male, three female; mean age 39 years) constituted the control group. All of the participants underwent magnetic resonance imaging (MRI) and non-selective (31)P MRS (3 T) of the leg muscles before and after graded exercise on a treadmill. Phosphocreatine (PCr):inorganic phosphate (Pi), PCr:adenosine triphosphate (ATP) ratios and the intracellular pH of the leg muscles were measured using (31)P MRS. RESULTS: For both groups, normal muscle mass with no signal alterations was observed on the MRI images after exercise. The normal range of pre- and post- exercise MRS muscle parameters was observed in both groups. However, the intracellular pH post-exercise, was significantly higher (less acidic) in the FMF group compared to the control group [pH (FMF) = 7.03 ± 0.02; pH (control) 7.00 ± 0.02; p < 0.0006]. CONCLUSIONS: The finding of a less prominent, post-exercise acidification of the gastrocnemius muscle in this FMF patient group suggests a forme fruste of glycogenosis. This preliminary observation should be further investigated in a future, larger-scale study.
Asunto(s)
Fiebre Mediterránea Familiar/complicaciones , Imagen por Resonancia Magnética/métodos , Espectroscopía de Resonancia Magnética/métodos , Músculo Esquelético/fisiopatología , Dolor/etiología , Dolor/fisiopatología , Esfuerzo Físico , Adulto , Metabolismo Energético , Prueba de Esfuerzo/métodos , Femenino , Humanos , Pierna , Masculino , Músculo Esquelético/metabolismoRESUMEN
BACKGROUND: 'Erysipelas-like' erythema (ELE) is a well recognized, although uncommon, manifestation of familial Mediterranean fever (FMF), which is frequently mistaken for infectious erysipelas, especially when forming the initial disease presentation. AIM: To clinically and genetically characterize ELE as the first manifestation of FMF. METHODS: FMF patients with ELE as the first disease presentation (study group), were compared with FMF patients with ELE, appearing during the disease course (control group I), and to those FMF patients who never had ELE (control group II). RESULTS: Patients of the study group were comparable to patients without ELE with respect to all demographic, clinical and genetic features studied, and yet differed from patients with ELE appearing later in the disease course in disease severity score (1.7 ± 0.4 vs. 2.4 ± 0.6, P = 0.01), length of diagnosis delay (7.2 ± 6.4 vs. 2.3 ± 3.3 years, P=0.037), age of FMF onset (24.8 ± 19.9 vs. 5.6 ± 5.7 years of age, P=0.014) and rate of homozygosity to the M694V mutation (14.3% vs. 68.7% respectively). ELE traits in the study and control groups were alike. CONCLUSIONS: FMF with ELE as the first disease manifestation form an uncommon subgroup, clinically and genetically diverging from the rest of the FMF-ELE patients.
Asunto(s)
Eritema/etiología , Fiebre Mediterránea Familiar/complicaciones , Fiebre Mediterránea Familiar/diagnóstico , Adolescente , Niño , Erisipela , Eritema/genética , Fiebre Mediterránea Familiar/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
OBJECTIVES: Familial Mediterranean fever (FMF) is characterized by recurrent episodes of fever, peritonitis, arthritis, and pleuritis, caused by neutrophil-induced sterile serositis. Another clinical manifestation in patients with FMF is exertional leg and ankle pain that appears after minor exercise, for which the underlying mechanism is obscure. The purpose of the current study was to feature distal leg changes in FMF patients complaining of exertional leg pain, using magnetic resonance imaging (MRI). METHODS: Eleven patients with FMF who suffer from exertional leg pain (eight males, three females; mean age 33 years) and six unaffected controls (three males, three females; mean age 39 years) underwent MRI (3 T) of the ankle, including conventional T1 and T2 with fat saturation sequences, before and after graded exercise on a treadmill. Clinical and genetic data and sacroiliac radiographs were obtained. RESULTS: Ten patients (91%) with FMF but none of the control group had signs compatible with enthesitis of the Achilles tendon, long plantar ligament, or the plantar fascia (including enthesophytes, erosions, and bone marrow oedema). Nine patients (80%) had radiographic signs of sacroiliitis on the pelvic radiograph. CONCLUSIONS: Exertional leg pain in FMF patients, shown to be associated with signs of enthesopathy on imaging, may be included within the spectrum of spondyloarthropathy.
Asunto(s)
Tendón Calcáneo/patología , Fiebre Mediterránea Familiar/complicaciones , Pierna/patología , Dolor/etiología , Espondiloartropatías/complicaciones , Adulto , Ejercicio Físico , Fiebre Mediterránea Familiar/patología , Femenino , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Dolor/patología , Enfermedades Reumáticas , Espondiloartropatías/patologíaRESUMEN
The objective of this study was to assess the prevalence of the Mediterranean FeVer (MEFV) gene mutations in systemic lupus erythematosus (SLE) patients and their effect on organ involvement, as well as disease activity and severity. The frequencies of three familial Mediterranean fever-related MEFV gene mutations (M694V, V726A and E148Q) were investigated in 70 SLE patients. Organ involvement, Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) damage index and Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) scores were correlated with mutation carriage. Eleven of 70 patients (15.7%) were found to carry an MEFV mutation. A single patient harbored two mutations, E148Q and V726A, without overt familial Mediterranean fever while the rest were heterozygous carriers. Four of the 11 carried an M694V mutation, four carried V726A and two carried E148Q. The majority of MEFV mutation carriers were Sephardic while non-carriers were mainly of Ashkenazi origin (72.7% vs. 45.7% and 47.4% vs. 9.1%, respectively, p = 0.02). SLE onset was significantly earlier in MEFV carriers (27.6 ± 9.7 vs. 38.2 ± 15.5 years, in carriers vs. non-carriers, p = 0.02). Hematologic and serologic parameters were comparable among mutation carriers and non-carriers. Febrile episodes were more common among MEFV mutation carriers (45.4% vs. 15.2%, p = 0.035) and there was a trend for excess episodes of pleuritis as well (54.5% vs. 23.7%, p = 0.06 in carriers vs. non-carriers, respectively). The frequency of secondary anti-phospholipid antibody syndrome was equivalent among the groups. Conversely, compound urinary abnormalities and renal failure was not observed among MEFV carriers yet was present in 33.4% and 18.6% of non-carriers (p = 0.027 and 0.19, respectively). SLICC damage index and SLEDAI activity index did not differ significantly between the groups. MEFV mutation carriage appears to modify the SLE disease phenotype in that it contributes to an excess of inflammatory manifestations such as fever and pleuritis on the one hand, while thwarting more severe renal involvement on the other.
Asunto(s)
Proteínas del Citoesqueleto/genética , Lupus Eritematoso Sistémico/genética , Mutación , Adulto , Fiebre Mediterránea Familiar/genética , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , PirinaRESUMEN
Silicone, a synthetic polymer considered to be a biologically inert substance, is used in a multitude of medical products, the most publicly recognized of which are breast implants. Silicone breast implants have been in use since the early 1960s for cosmetic and reconstructive purposes, and reports of autoimmune disease-like syndromes began appearing in the medical literature soon thereafter. Over the previous year, silicone implants have been suggested as playing a role in a new syndrome that encompasses a wide array of immune-related manifestations, termed ASIA ('Autoimmune Syndrome Induced by Adjuvant'). Scleroderma, a relatively rare connective tissue disease with skin manifestations and systemic effects, has also been described in association with silicone implantation and rupture. However, epidemiological studies and meta-analyses have failed to corroborate the clinical impression of silicone-induced scleroderma. The following review describes the mechanisms by which silicone may mediate autoimmunity in general, as well as the evidence for causal associations with more specific autoimmune syndromes in general, and scleroderma in particular.
Asunto(s)
Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Implantes de Mama/efectos adversos , Esclerodermia Sistémica/inducido químicamente , Esclerodermia Sistémica/inmunología , Siliconas/efectos adversos , Autoinmunidad/inmunología , Ensayos Clínicos como Asunto , Ambiente , Humanos , Factores de RiesgoRESUMEN
Morphea and other scleroderma-like skin conditions are occasionally linked with exposure to chemical compounds such as silicone. We treated a 56-year-old woman with generalized severe skin induration accompanied with systemic symptoms and peripheral eosinophilia, which appeared 2.5 years after breast silicone implantation and abdominal liposuction. Blood test results and histopathological examination of her skin suggested the diagnosis of morphea overlapping with eosinophilic fasciitis. Her skin disease was presumed to be an autoimmune reaction to silicone implantation. While the removal of the implants did not improve her illness, treatment with 1 mg/kg prednisone and PUVA bath was initiated, with some improvement. This patient illustrates an example of ASIA (Autoimmune Syndrome Induced by Adjuvants), as her disease appeared following exposure to an adjuvant stimulus, with 'typical', although not well-defined, autoimmune manifestations.
Asunto(s)
Adyuvantes Inmunológicos/efectos adversos , Enfermedades Autoinmunes/inducido químicamente , Implantes de Mama/efectos adversos , Esclerodermia Localizada/etiología , Esclerodermia Localizada/inmunología , Siliconas/efectos adversos , Enfermedades Autoinmunes/inmunología , Eosinofilia/etiología , Eosinofilia/inmunología , Eosinofilia/patología , Fascitis/etiología , Fascitis/inmunología , Fascitis/patología , Femenino , Humanos , Persona de Mediana Edad , Medio Oriente , Esclerodermia Localizada/patologíaRESUMEN
The presence of two mutations in the familial Mediterranean fever gene, without overt familial Mediterranean fever (FMF), designated as phenotype III, predisposes to developing 'silent' AA amyloidosis, recognized as phenotype II, due to the absence of medical supervision and colchicine prophylaxis. We sought to determine the prevalence of phenotype III in large families with only one subject affected with FMF, in order to assess the population at risk for transformation to phenotype II. A total of seven large families were recruited for the study. Siblings were screened for MEFV mutations and underwent a clinical interview to assess for unrecognized FMF manifestations. Phenotype III, most commonly associated with a V726A/E148Q genotype, was detected in 10% of siblings of index cases from informative families, corresponding to a 10-fold increase in comparison to the expected rate in the general population (p < 0.01). Unnoticed 'FMF-like' manifestations were detected among two siblings in the five families in which the index case was heterozygous, but in none of the siblings of the homozygous index cases. The enrichment for phenotype III and detection of occult FMF in large families, in which only a single member is afflicted with FMF, mandates routine clinical evaluation and genetic screening of siblings.
Asunto(s)
Fiebre Mediterránea Familiar/genética , Mutación , Genotipo , Humanos , FenotipoRESUMEN
The immune balance in patients with rheumatoid arthritis (RA), a disease characterized by TH1 dominance, treated by the preferred combined anti-tumor necrosis factor (anti-TNF) and methotrexate (MTX) therapy was evaluated by assessing the chemokine and cytokine receptors as well as apoptosis induction. A meta-analysis of combined therapy by TNF blockers and MTX in 15 RA patients, MTX monotherapy in 20 RA patients, and 11 diagnosed but untreated RA patients was performed by assessing several immune markers in the whole lymphocyte population, as well as in specific CD4 cells, by both flow cytometry and image analysis. A significant downregulation of CXCR3 and IL-12 receptors (both TH1 markers) and a significant increase in the chemokine receptor CCR4 and, to a lesser extent, IL-4R (both TH2 markers) were found; a particularly marked increase was found in patients treated by combined therapy. This phenomenon was pronounced in CD4 cells and was accompanied by a high proportion of apoptotic cells. The therapeutic effect of MTX and TNF blockers may be due to apoptosis induction in lymphocytes infiltrating from the inflammation site and restoring the TH1/TH2 balance.
Asunto(s)
Artritis Reumatoide/tratamiento farmacológico , Homeostasis/efectos de los fármacos , Células TH1 , Células Th2 , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Antirreumáticos/farmacología , Apoptosis , Biomarcadores/análisis , Linfocitos T CD4-Positivos , Quimioterapia Combinada , Humanos , Metotrexato/uso terapéutico , Células TH1/citología , Células Th2/citologíaRESUMEN
BACKGROUND: Abdominal attacks of familial Mediterranean fever (FMF) may simulate acute appendicitis and bring about considerable uncertainty. The similar presentation of the two clinical entities often leads to an unnecessary appendectomy. METHODS: 182 consecutive FMF patients were retrospectively reviewed for this study. Clinical and genetic data was compared between those who had undergone an appendectomy (n=71) and those who had not (n=111). RESULTS: The frequency of appendectomy found in FMF was far above the reported rate in the general population (40% vs. 12-25%). The rate of non-inflamed appendectomies was extremely high (80% vs. 20%) and remained constant over time. Tertiary hospitals and improved therapeutic and diagnostic measures that have evolved over the years did not reduce misdiagnosis of acute appendicitis in FMF. Severe phenotype and homozygosity for M694V were identified as risk factors for appendectomy in FMF. A change from the regular diffuse involvement to right lower quadrant abdominal pain was found to be the best predictor of inflamed appendix in FMF patients undergoing appendectomy for suspected acute appendicitis. CONCLUSION: Reliance on clinical parameters should improve diagnostic accuracy of acute appendicitis in the FMF patient population.
Asunto(s)
Apendicectomía , Apendicitis/diagnóstico , Apendicitis/cirugía , Errores Diagnósticos , Fiebre Mediterránea Familiar/complicaciones , Procedimientos Innecesarios , Dolor Abdominal/etiología , Dolor Abdominal/cirugía , Adulto , Apendicectomía/efectos adversos , Apendicitis/patología , Estudios de Casos y Controles , Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/genética , Fiebre Mediterránea Familiar/patología , Femenino , Humanos , Masculino , Persona de Mediana Edad , Mutación , Pirina , Estudios Retrospectivos , Adulto JovenRESUMEN
Serositis is a common clinical manifestation of systemic lupus erythematosus (SLE), as well as being the hallmark of familial Mediterranean fever (FMF), the most prevalent monogenic disease in the Jewish population. We have treated four patients who suffered from both SLE and FMF since 2001 in our clinic, which also serves as the national center for FMF. Our cases illustrate both similarities and dissimilarities between the clinical manifestations of these two diseases, an aspect which should be borne in mind, especially in the young female patients. In general, it seems that co-occurrence of FMF moderates the presentation of lupus.
Asunto(s)
Fiebre Mediterránea Familiar/fisiopatología , Lupus Eritematoso Sistémico/fisiopatología , Adolescente , Adulto , Niño , Fiebre Mediterránea Familiar/genética , Fiebre Mediterránea Familiar/patología , Femenino , Humanos , Judíos/genética , Lupus Eritematoso Sistémico/genética , Lupus Eritematoso Sistémico/patología , Persona de Mediana Edad , Embarazo , Literatura de Revisión como Asunto , Serositis/fisiopatologíaRESUMEN
OBJECTIVE: The mechanism by which low dose methotrexate (MTX, the gold standard treatment for rheumatoid arthritis) exerts its anti-inflammatory effect in rheumatoid arthritis (RA) patients is still debated. Lately, the MTX immunosuppressive effect has been related to apoptosis, especially in active RA patients, with ROS involvement. METHODS: In the present research we investigated MTX oxidative effect and its ability to modulate immune balance in active versus non-active RA patients. RESULTS: Our results show that MTX induces IL-10 secretion (a TH2 cytokine) and significantly reduces TH1 profile in Peripheral Mononuclear Cells (PMNC) derived from active RA patients (n=28). Additionally, we found that MTX modulates the immune status towards TH2 dominance by decreasing the IL-12R and the CXCR3 receptors typical for the TH1 population. Moreover, MTX was found to inhibit the production of nitric oxide (NO) in these patients, a phenomenon that might contribute to MTX action toward cytokine homeostasis. A significant correlation was found between MTX IL-10 induction and NO inhibition in active RA patients. CONCLUSION: Our data suggest that, in active RA patients, apoptosis induction by MTX may be primarily due to IL-10 production via modulation of oxidative stress, which may restore the critically important immune balance. These findings may contribute to determining which group of RA patients may better respond to MTX therapy.
Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Reumatoide/tratamiento farmacológico , Metotrexato/administración & dosificación , Células TH1/efectos de los fármacos , Células Th2/efectos de los fármacos , Enfermedad Aguda , Apoptosis/efectos de los fármacos , Apoptosis/inmunología , Artritis Reumatoide/inmunología , Artritis Reumatoide/metabolismo , Humanos , Interleucina-10/metabolismo , Óxido Nítrico/metabolismo , Especies Reactivas de Oxígeno/metabolismo , Receptores CXCR3/metabolismo , Receptores de Interleucina-12/metabolismo , Células TH1/inmunología , Células TH1/metabolismo , Células Th2/inmunología , Células Th2/metabolismoRESUMEN
Glomerulonephritis, particularly IgA nephropathy (IgAN), seems to be more common in familial Mediterranean fever (FMF), an inherited disease caused by mutations in the MEditerranean FeVer gene (MEFV). The present study is aimed to determine, in populations not suffering from FMF, whether carriage of MEFV mutations may modify or precipitate IgAN and other forms of primary glomerulonephritis (PGN). Forty patients with biopsy proven IgAN and 40 with PGN were surveyed for the presence of the three most common MEFV mutations (M694V, V726A and E148Q), using polymerase chain reaction amplification and restriction enzyme analysis. The rate of MEFV mutations in the patients was related to the expected carrier rate in the general population of the same ethnic extraction. The effect of mutation carriage on the disease course was determined in the IgAN patient group. The frequency of MEFV mutations in IgAN or PGN was comparable to that found in ethnically adjusted general population (p = 0.1 and 0.5, respectively). Carriage of mutated MEFV was not associated with the course and severity of the disease or findings in kidney biopsy and urine analysis. In a population, mostly of Jewish extraction, MEFV mutations do not seem to predispose to the development of IgAN and other forms of PGN or affect the phenotype.
Asunto(s)
Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/genética , Glomerulonefritis por IGA/genética , Adulto , Análisis Mutacional de ADN , Femenino , Humanos , Masculino , Persona de Mediana Edad , PirinaRESUMEN
Antiphospholipid syndrome (APS) is a clinical autoimmune disorder characterized by arterial and/or venous thrombosis and/or pregnancy morbidity, associated with the persistence of lupus anticoagulant or anticardiolipin (aCL) antibodies. Accumulating evidence indicates that phospholipid binding protein, beta2-glycoprotein I (beta2GPI) represents the major target antigen for antiphospholipid (aPL) antibodies and plays a role in the pathogenesis of APS. It is widely accepted that aPL antibodies detected by conventional solid phase assays in patients with APS are mainly directed against a complex of aCL and anti-beta2GPI, although antibodies against beta2GPI protein can now also be detected by specific ELISA using purified proteins in solid phase. Despite the fact that these antibodies are not listed in the new diagnostic criteria, a high specificity of anti-beta2GPI assay for the clinical features of APS was established. During the last decade, numerous studies have investigated the clinical link between aCL and/or anti-beta2GPI antibodies and diverse features of APS. This manuscript reviews the current studies published recently in this field and discusses the relationship between the existence of aCL and anti-beta2GPI antibodies and the main and unusual manifestations of APS.
Asunto(s)
Anticuerpos Anticardiolipina/inmunología , Síndrome Antifosfolípido/inmunología , Síndrome Antifosfolípido/fisiopatología , beta 2 Glicoproteína I/inmunología , Aborto Habitual/inmunología , Aborto Habitual/fisiopatología , Anticuerpos Antifosfolípidos/inmunología , Progresión de la Enfermedad , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Enfermedades Renales/inmunología , Enfermedades Renales/fisiopatología , Enfermedades del Sistema Nervioso/inmunología , Enfermedades del Sistema Nervioso/fisiopatología , Embarazo , Trombocitopenia/inmunología , Trombocitopenia/fisiopatología , Trombosis/inmunología , Trombosis/fisiopatologíaRESUMEN
OBJECTIVES: To determine the spectrum of mutations in the Mediterranean fever gene (MEFV) of Iranian Jews with familial Mediterranean fever (FMF) and to analyse their clinical manifestations. METHODS: FMF patients with both parents of Iranian-Jewish (IJ) extraction or with one IJ parent (IJ-other, 10 of each) were characterized for clinical manifestations, and the B30.2 (PRYSPRY) domain of their MEFV was sequenced for mutations. RESULTS: Only one rare mutation, R653H, and one new mutation, G632S were present in the IJ group (in 2/10 patients), whereas the new, and common mutations were present in the IJ-other patients (8/10 patients). The new mutation was traced thrice to an IJ ancestor, and although carried asymptomatically by family members, it was over-represented in the patients (3/28 unrelated IJ alleles) compared non-affected IJ subjects (1/126 alleles, P = 0.03) or with non-Jewish Iranians (0/108 alleles, P = 0.001). The mutation was associated with a distinct phenotype regarding sites involved in the attack (P = 0.001), mild severity, sole expression of febrile episodes (P = 0.01) and a male bias (P = 0.01). In two 3D PRYSPRY models the G632S mutation was localized to a surface loop and close to a putative binding site. CONCLUSIONS: Iranian Jews with FMF have a unique spectrum of mutations including a newly described mutation with a non-typical phenotype.
Asunto(s)
Proteínas del Citoesqueleto/genética , Fiebre Mediterránea Familiar/genética , Judíos/genética , Mutación , Adolescente , Adulto , Secuencia de Bases , Niño , Proteínas del Citoesqueleto/química , Femenino , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Linaje , Estructura Terciaria de Proteína , Pirina , Índice de Severidad de la EnfermedadRESUMEN
BACKGROUND: Behcet's disease (BD) is an inflammatory disorder of unknown cause, associated with vasculitis. Arterial or venous thrombosis occurs in about 25% of BD patients. Familial Mediterranean fever (FMF) is another inflammatory disorder, which stems from mutations in the FMF gene (MEFV) and shares a number of features with BD. OBJECTIVE: MEFV analysis in patients with BD suggests that mutated MEFV may act as a susceptibility gene in BD. We studied the rate and the clinical correlates of MEFV mutations in Israeli BD patients. METHODS: Included were 54 BD patients who satisfied the International Study Group criteria for BD. All BD patients were genotyped using polymerase chain reaction (PCR) and restriction enzyme analysis for the three most common MEFV mutations (M694V, V726A, and E148Q). The association between BD manifestations and MEFV alleles was analysed. RESULTS: Twenty-one BD patients were found to carry a single MEFV mutation and three additional patients were compound heterozygotes, a frequency significantly higher than that expected for ethnically matched healthy individuals. There were no statistically significant differences between carriers and non-carriers with respect to gender, frequency of HLA B5 antigen, cutaneous lesions, joint disease, and severity score. However, carriers did experience thrombosis more often [54% vs. 17%, p<0.005, odds ratio (OR) = 6.9, 95% confidence interval (CI) 1.75-26.9] and uveitis less often (20% vs. 40%, p<0.05, OR = 0.2, 95% CI 0.04-0.92). CONCLUSIONS: MEFV appears to be a susceptibility and modifier gene in BD.