Role of Inflammasome Activation in Systemic Lupus Erythematosus: Are Innate Immune Cells Activated? / Rol de la activación del inflammasome en lupus eritematoso sistémico: están las células del sistema inmune innato activados?

Background: Systemic lupus erythematosus (SLE) is characterized by a wide spectrum of clinical and immunological abnormalities. New data have emerged about the role of inflammasomes in autoimmune diseases. We aimed to investigate whether basal inflammasome activation occurs in SLE patients, and whether a relationship between inflammasome-related-cytokines and disease activity exists. Methods: Fourteen (14) consecutive SLE patients and 13 healthy individuals, matched by sex, age and ethnicity, were included. Demographics, laboratory and clinical data were recorded. Peripheral blood mononuclear cells (PBMCs) from patients and controls were obtained and monocytes were isolated by negative selection. Purified monocytes were stimulated with LPS in the presence or absence of Caspase-1 inhibitor. CD14 and Caspase-1 expression were analyzed by flow cytometry. Cytokine levels were determined in plasma and culture supernatants by ELISA. Student's t test and Mann–Whitney tests were used for statistical analysis. Results: The percentage of CD14+/Caspase-1+ was significantly higher in monocytes from SLE patients compared to normal controls (p<0.01). These findings paralleled with higher plasma levels of IL-1β (p<0.05) and IL-18 (p<0.01) in those patients. Purified monocytes from SLE patients displayed a robust inflammatory response after LPS stimulation where Caspase-1, IL-1β and IL-18 were highly expressed. Plasma levels of IL-18 were also significantly higher in SLE patients with active disease (p<0.05). In addition, the production of IL-18 was reduced by 3 fold when Caspase-1 inhibitor was added to the cultures. Conclusions: Monocytes from SLE patients exhibited increased inflammasome activation, characterized by high expression of Caspase-1, IL-1β and IL-18. Caspase-1 specific inhibitor decreased inflammasome activation (in vitro) by suppressing the production of IL-18.(AU)

Introducción: El lupus eritematoso sistémico (LES) se caracteriza por presentar diversas anormalidades clínicas e inmunológicas. El ensamblaje de los componentes del inflamasoma da lugar a la activación de caspasa-1, generando la liberación de citoquinas pro-inflamatorias IL-1β e IL-18. Objetivos: Evaluar si existe una activación basal del inflamasoma en pacientes con LES y determinar la asociación de las citoquinas IL-1β e IL-18 con la actividad de la enfermedad. Materiales y métodos: Se incluyeron 14 (n=14) pacientes consecutivos con LES y 13 (n=13) controles, pareados por edad, sexo y raza. Se recogieron datos clínicos, demográficos y de laboratorio. Los monocitos fueron aislados a partir de células mononucleares de sangre periférica obtenidas de pacientes y controles. Los monocitos purificados fueron estimulados con LPS, en presencia y ausencia de inhibidor de caspasa-1. La expresión de CD14 y caspasa-1 fueron determinados por citometría de flujo. Niveles de citoquinas fueron determinadas en plasma y en sobrenadantes de cultivos mediante técnica de ELISA. Test de Student y Mann-Whitney fueron usados para el análisis estadístico. Resultados: El porcentaje de CD14+/caspasa-1+ fue significativamente superior en monocitos de pacientes con LES vs. controles (p<0,01). En forma paralela, se encontraron niveles plasmáticos significativamente superiores de IL-1β (p<0,05) y de IL-18 (p<0,01) en pacientes con LES. Monocitos purificados de pacientes lúpicos presentaron una robusta respuesta inflamatoria luego de ser estimulados con LPS, donde caspasa-1, IL-1β e IL-18 fueron altamente expresados. Niveles plasmáticos de IL-18 fueron significativamente mayores en pacientes con LES y enfermedad activa (p<0,05). Por otro lado, la producción de IL-18 se redujo casi 3 veces cuando se agregó inhibidor de caspasa-1 en cultivos.(AU)

Role of Inflammasome Activation in Systemic Lupus Erythematosus: Are Innate Immune Cells Activated?

BACKGROUND: Systemic lupus erythematosus (SLE) is characterized by a wide spectrum of clinical and immunological abnormalities. New data have emerged about the role of inflammasomes in autoimmune diseases. We aimed to investigate whether basal inflammasome activation occurs in SLE patients, and whether a relationship between inflammasome-related-cytokines and disease activity exists. METHODS: Fourteen (14) consecutive SLE patients and 13 healthy individuals, matched by sex, age and ethnicity, were included. Demographics, laboratory and clinical data were recorded. Peripheral blood mononuclear cells (PBMCs) from patients and controls were obtained and monocytes were isolated by negative selection. Purified monocytes were stimulated with LPS in the presence or absence of Caspase-1 inhibitor. CD14 and Caspase-1 expression were analyzed by flow cytometry. Cytokine levels were determined in plasma and culture supernatants by ELISA. Student's t test and Mann-Whitney tests were used for statistical analysis. RESULTS: The percentage of CD14+/Caspase-1+ was significantly higher in monocytes from SLE patients compared to normal controls (p<0.01). These findings paralleled with higher plasma levels of IL-1ß (p<0.05) and IL-18 (p<0.01) in those patients. Purified monocytes from SLE patients displayed a robust inflammatory response after LPS stimulation where Caspase-1, IL-1ß and IL-18 were highly expressed. Plasma levels of IL-18 were also significantly higher in SLE patients with active disease (p<0.05). In addition, the production of IL-18 was reduced by 3 fold when Caspase-1 inhibitor was added to the cultures. CONCLUSIONS: Monocytes from SLE patients exhibited increased inflammasome activation, characterized by high expression of Caspase-1, IL-1ß and IL-18. Caspase-1 specific inhibitor decreased inflammasome activation (in vitro) by suppressing the production of IL-18.

Ixekizumab, an interleukin-17A specific monoclonal antibody, for the treatment of biologic-naive patients with active psoriatic arthritis: results from the 24-week randomised, double-blind, placebo-controlled and active (adalimumab)-controlled period of the phase III trial SPIRIT-P1.

OBJECTIVE: To assess the safety and efficacy of ixekizumab, a monoclonal antibody that inhibits interleukin-17A, in a double-blind phase III trial enrolling patients with active psoriatic arthritis (PsA). METHODS: Patients naive to biologic therapy with active PsA were randomised to subcutaneous injections of placebo (N=106), adalimumab 40 mg once every 2 weeks (active reference; N=101), ixekizumab 80 mg once every 2 weeks (IXEQ2W) (N=103), or ixekizumab 80 mg once every 4 weeks (IXEQ4W) (N=107). Both ixekizumab regimens included a 160-mg starting dose. The primary objective was to assess the superiority of IXEQ2W or IXEQ4W versus placebo as measured by the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response at week 24. RESULTS: Significantly more patients treated with ixekizumab achieved an ACR20 response with IXEQ2W (62.1%) or IXEQ4W (57.9%) than placebo (30.2%) (p≤0.001; non-responder imputation method). Disease activity and functional disability were significantly improved with both ixekizumab doses versus placebo at weeks 12 and 24, and there was significantly less progression of structural damage at week 24 (p≤0.01). Clearance of plaque psoriasis was greater with ixekizumab than placebo (p≤0.001). Efficacy results with adalimumab, the active reference arm, showed significant improvements versus placebo. Treatment-emergent adverse events were more frequent with ixekizumab (65.7-66.4%) and adalimumab (64.4%) than placebo (47.2%) (p<0.05). CONCLUSIONS: In biologic-naive patients with active PsA, ixekizumab treatment resulted in improvements in disease activity and physical function, as well as in the inhibition of structural damage progression. Overall, adverse events were more frequent in all active groups compared with placebo. TRIAL REGISTRATION NUMBER: NCT01695239; EudraCT2011-002326-49; Results.

Distinct genetic profile in peripheral blood mononuclear cells of psoriatic arthritis patients treated with methotrexate and TNF-inhibitors.

Psoriatic arthritis (PsA) is a systemic inflammatory condition associated with psoriasis. Despite considerable heterogeneity in clinical presentation, genetic studies and animal models support the notion that PsA is a distinct disease. We aimed to characterize the PsA genotype by gene expression profile and to research the effect in gene modulation of methotrexate (MTX) and TNF-inhibitors (TNF-I) in PsA-treated patients. Nine PsA patients, according to CASPAR criteria, and three healthy controls were recruited from an outpatient rheumatology clinic. Three out of nine PsA patients were naïve to treatment, three received TNF-I, and the remaining three were on MTX-monotherapy. Blood samples were collected and analyzed by human genome U95 Array-Affymetrix (GeneChip® instrument system). Identification of statistically significant differences between differentially expressed genes was determined by Mann-Whitney and t test (p < 0.05). The microarray profile identified a predominance of differentially expressed genes with an increased expression in baseline PsA patients: 115/12,000 genes were up-regulated and 13/12,000 down-regulated, as compared to healthy controls. The great majority were involved in inflammatory cells and pathways. In the biologic-treated patients, a higher number of down-regulated genes were expressed vs. the MTX patients, 161 vs. 33, respectively. This study shows that in PsA patients, TNF-I and MTX are able to modulate the gene expression in a synergistic and additive manner.

Are anti-CCP antibodies in psoriatic arthritis patients a biomarker of erosive disease?

To determine the frequency of anticyclic citrullinated peptide (CCP) antibodies in a cohort of psoriatic arthritis (PsA) patients and to compare clinical, serological and radiological characteristics between PsA patients with and without anti-CCP antibodies. Patients with PsA, according to classification criteria for PsA, were consecutively recruited from an outpatient rheumatology clinic. Demographic and clinical data were collected in all cases. Serum samples from all patients were analyzed for rheumatoid factor and anti-CCP antibodies. Radiographs of hands and feet were obtained and the presence of erosions was recorded. The study included 81 patients; 43 (53 %) were men, with a median age of 45.7 years (interquartile range (IQR) 39-72) and median disease duration of 9.4 years (IQR 2-14). Anti-CCP antibodies were found in 11 patients (13.5 %), median titer 174.9 U/ml. Polyarticular involvement (72.7 vs. 17.1 %), frequency of erosive disease (72.7 vs. 37.1 %) and use of tumor necrosis factor-α inhibitors (54.5 vs. 28.5 %) were significantly higher in PsA patients with anti-CCP positivity. Anti-CCP negative PsA patients had predominantly more oligoarticular (62.8 vs. 27.2 %) and nail (81.4 vs. 36.3 %) involvement. Presence of enthesitis, dactylitis and Psoriasis Area Severity Index scores were similar in both groups. Anti-CCP antibodies were found in a subset of PsA patients, and their presence was associated with more severe disease phenotype. Further studies in a larger population are needed to define the role of anti-CCP as a biomarker of erosive disease in PsA.

Steps in the management of psoriatic arthritis: a guide for clinicians.

Psoriatic arthritis is a common systemic inflammatory disorder, which in addition to skin and nail involvement may be associated with peripheral and axial joint involvement, enthesitis, dactylitis, and important comorbidities - especially cardiovascular morbidity. Better insights into the involved pathogenic mechanisms have resulted in an improved therapeutic armamentarium, which targets key pathways in its pathogenesis. This has resulted in significant clinical responses to newer therapeutic agents, especially those directed at inhibition of tumor necrosis factor α. Biological therapy leads to significant levels of remission, improved quality of life, and retards or improves structural radiological damage.

Vasculopathy, hematological, and immune abnormalities associated with levamisole-contaminated cocaine use.

OBJECTIVES: To report 4 cases of cocaine-related purpura and to review previously reported cases of levamisole, levamisole-contaminated cocaine, and cocaine-induced vasculopathy. METHODS: We describe 4 patients suspected of vasculopathy associated with levamisole-tainted cocaine use. A retrospective review of the literature was performed using the PubMed, PubJet, MD consult, and Cochrane review databases. RESULTS: Four cases (2 females and 2 males), 46 to 55 years of age, presented with cocaine-related purpura, mainly affecting the ears, neutropenia, and autoantibodies. Skin biopsies revealed a mixed pattern of leukocytoclastic vasculitis and microvascular thrombosis in 2 cases, and pure thrombosis in the third case. The mixed vasculopathic pattern in association with neutropenia, both known adverse effects of levamisole, and levamisole positivity in 2 cases point to this compound as the true etiologic agent in our patients. Eleven cases of levamisole-contaminated cocaine-induced vasculopathy have been described in the English literature. Among these, 10 were females. Age range was 22 to 57 years. Urine levamisole positivity was tested and confirmed in 3 of the 11 cases. The clinical characteristics, laboratory features, histology, treatment, and recovery rates were compared for the published cases of levamisole, levamisole-contaminated cocaine, and cocaine-induced vasculopathy. CONCLUSIONS: Adulterated cocaine abuse is an increasingly recognized phenomenon in North America. Levamisole is among the many contaminants that have been detected in seized cocaine throughout North America and Europe. Recent reports described an association between levamisole-tainted cocaine and purpuric skin rash, neutropenia, and the presence of autoantibodies.

Comparative assessment of biologics in treatment of psoriasis: drug design and clinical effectiveness of ustekinumab.

The development of psoriasis and psoriatic arthritis is a multistep process that leads to chronic or recurrent inflammation. Recent studies have suggested the importance of T helper (TH)1 and TH17 cells, accessory cells, and proinflammatory cytokines in the pathogenesis of the enthesis, synovium, and skin involvement in psoriasis in the presence of susceptibility genes that remain quiescent until triggered. Biologics, such as soluble CTLA-4 immunoglobulin, tumor necrosis factor (TNF) inhibitors, and ustekinumab, inhibit T cell activation which eventually leads to further stimulation of the interleukin 12, 17, and 23 axis, TNF-α, and lymphotoxin-α. Treatment with TNF-α blockers has been effective in refractory psoriasis and psoriatic arthritis, but there is still a subgroup of patients who do not respond to TNF inhibitors and, paradoxically, when treated, may develop TNF-induced psoriasis. Ustekinumab, because of its different mechanism of action at the level of the interleukin 12, 17, and 23 pathways, is an alternative treatment for this group of patients.

Tumor necrosis factor-alpha (TNF-α)-blockade-induced hepatic sarcoidosis in psoriatic arthritis (PsA): case report and review of the literature.

To study the cytokine profile in a 52 year old woman with psoriasis, PsA, and HCV who developed hepatic sarcoidosis following Etanercept therapy for 7 months. 11 PsA patients on TNF blockers mean disease duration 158.4 (SD 114.5), mean treatment duration 72.1 (SD 42.14) months, 8/11 PsA were on Etanercept and 5 healthy controls were studied. TNF-α, sTNF RI/RII, IFN-α/ß/γ, IL-1 α, IL-15, IL-6, VEGF, s IL-1 R, sIL-6 R, IL-12, IL-23, IL-17, Adiponectin, Leptin and EGF were assessed. All PsA and controls tested negative for Quantiferon TB Gold, hepatitis B/C, HIV, ACE level, chest x-ray, liver function test (LFTs). Serologic biomarkers of the subject in comparison to the controls indicate that sTNF RI value was significantly higher; and IL-1 alpha level has a high outlier compared to the 11 PsA patients on TNF blockers. The clinical course, histologic findings, increased levels of s TNF R I and IL-1 α in the subject as compared to the other PsA on TNF blockade and controls, suggest that most likely Etanercept induced inflammatory cytokine imbalance was responsible for inducing hepatic sarcoidosis.

Undifferentiated spondyloarthritis: recent clinical and therapeutic advances.

The spondyloarthropathies comprise a large clinical spectrum of disorders that include well-defined clinical disorders such as ankylosing spondylitis and less well-defined disorders such as undifferentiated spondyloarthritis, which refers to patients with inflammatory back pain not fulfilling classification criteria for ankylosing spondylitis and without radiologic evidence of sacroillitis. These disorders share clinical and genetic features and are linked by their association with HLA-B27 and by the presence of enthesitis as the basic pathologic lesion. The prevalence of the entire group ranges between 0.6% and 1.9%. This article reviews the recent advances in our understanding of the clinical spectrum, pathogenesis, genetics, and management of undifferentiated spondyloarthritis.

Undifferentiated spondyloarthritis following allogeneic stem cell transplantation.

BACKGROUND: Stem cell transplant has been utilized in the treatment of malignancies and rheumatic disease. Rheumatic disease may be transferred from the donor with active disease or may be developed in a recipient de novo as a late complication of SCT. CASE PRESENTATION: We here report the rare case of a 26-year old male patient, who has been diagnosed with undifferentiated spondyloarthropathy after unique circumstance. The patient suffered from intermittent inflammatory back pain and peripheral joint swelling for several years and did not find relief through multiple emergency room visits at different medical facilities. After a thorough history and physical exam, it was noted that our patient had developed signs of axial disease along with dactylitis and overall that he had been insidiously developing an undifferentiated spondyloarthopathy after allogeneic stem cell transplantation. CONCLUSION: Our observation supports the hypothesis that de novo rheumatic disease can develop after stem cell transplant for a variety of reasons. Thus, larger studies and awareness of this association are needed to delineate the exact underlying mechanism(s).

Systemic vasculitis in childhood.

Systemic vasculitis is a group of disorders with multiorgan involvement. These disorders have diverse clinical manifestations associated with significant morbidity and mortality. The most common vasculitides in children--Henoch-Schönlein purpura and Kawasaki disease--are self-limiting conditions. The lifelong and chronic vasculitides (eg, giant cell arteritis, Wegener's granulomatosis, microscopic polyangiitis, Churg-Strauss syndrome, polyarteritis nodosa, and Takayasu arteritis) are rarely seen in children. Therefore, the outcome in general is more favorable in children. This article offers an overview of the epidemiologic, etiologic, pathophysiologic, and clinical features of vasculitis in children, with emphasis on common conditions.

Pathophysiology and clinical spectrum of infections in systemic lupus erythematosus.

Systemic lupus erythematosus (SLE) is an inflammatory and multisystemic autoimmune disorder characterized by an uncontrolled autoreactivity of B and T lymphocytes leading to the production of autoantibodies against self-directed antigens and tissue destruction. Environmental factors, such as infections, which are an important cause of morbidity and mortality, are potential triggers of the disease. This article discusses bacterial, viral, and opportunistic microorganism infections in SLE, and the role of immunosuppressive therapy and immunodeficiencies in the disease.

Does TNF-alpha blockade play any role in cardiovascular risk among rheumatoid arthritis (RA) patients?

UNLABELLED: The aims of this study were to determine the association and potential mechanisms between TNF-antagonists and increased cardiovascular risk in rheumatoid arthritis (RA) patients. Three groups of RA patients were studied; ten treated with TNF-antagonists, 13 with methotrexate, and 14 were naïve to treatment. Mean age: 47.2 (SD 11.3), 52.3 (SD 16.6), and 51.2 (SD 13.3) years; mean disease duration 102 (SD 90.4), 72.9 (SD 67.3), and 71.3 (SD 87.1) months, and treatment duration 24.2 (SD 18.5), 34.7 (SD 32.2), and 0 months for each group. CLINICAL DATA: systolic and diastolic blood pressure and body mass index were assessed. Disease activity was determined by DAS-28 index. An ELISA assay for IL-6, sIL-6 R, IFN-gamma, TNF-alpha, sTNFRI, sTNFRII, IGF I, and adiponectin were performed. Fasting glucose, insulin, lipid profile, CRP, and ESR were also done. HOMA-IR and QUICKI indexes were calculated. Statistically significant differences observed between the TNF group and the other two groups were: TNF-alpha levels (p, 0.0014), soluble TNF RII (p, 0.0432), IFN-gamma (p, 0.008), and DAS-28 <2.6 (p, 0.033). Finding of elevated levels of sTNFRII and IFN-gamma in patients with RA on anti-TNF suggests that this therapy does not completely suppress the inflammatory process and may promote atherogenesis.

Biologic therapy (TNF-alpha antagonists)-induced psoriasis: a cytokine imbalance between TNF-alpha and IFN-alpha?

We report 3 patients with psoriatic arthritis and 2 with rheumatoid arthritis who developed worsening, and/or de novo psoriasis, and/or psoriasiform rash, while on tumor necrosis factor antagonist therapy. All 5 patients initially presented with active skin, and/or joint inflammatory involvement, and exhibited significant clinical response to tumor necrosis factor antagonist therapy. Within approximately 6 months, however, psoriatic and/or psoriasiform rash developed de novo in 2 rheumatoid arthritis patient and exacerbated in the other 3 patients. Biopsy findings revealed histologic and immunohistochemical changes indistinguishable from psoriasis.Psoriatic rash improved after discontinuation of biologic therapy and/or initiation of a short course of oral prednisone. One patient with psoriatic arthritis was rechallenged with infliximab due to exacerbation of both psoriasis and psoriatic arthritis, and this was followed by prompt improvement of both conditions. At 6 months follow-up, this patient remains under excellent control. To date, there have been over 50 cases of this type of dermatologic complication described. Interferon alpha seems to play an important role in the pathogenesis of this complication. This type of complication has been described with all 3 available tumor necrosis factor inhibitors, and most patients improve after discontinuation of biologic therapy.

Acute Charcot arthropathy successfully treated with pamidronate: long-term follow-up.

Charcot arthropathy is a relatively rare complication of diabetic neuropathy that may lead to significant discomfort, deformity, and disability, including severe function loss and limb amputation. Initial diagnosis of Charcot arthropathy is often delayed for several weeks, and it is compounded by the lack of specific clinical and laboratory diagnostic parameters. Increasing understanding of the underlying pathogenic events provide strong support for an important role for osteoclastic activity and pro-inflammatory cytokines. This has led to the successful use of bisphosphonates in patients with acute presentation. Herein we report 3 patients with active (acute) Charcot arthropathy secondary to diabetic neuropathy that exhibited an excellent long-term clinical response to intravenous pamidronate therapy.