ABSTRACT
OBJECTIVE: To compare etanercept and adalimumab biosimilars (SB4 and ABP501) and respective bioriginators in terms of safety and efficacy in a real-life contest. METHODS: We consequently enrolled patients affected by rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, treated with SB4, and ABP501, or with corresponding originators, belonging to the main biological prescribing centers in the Lazio region (Italy), from 2017 to 2020. Data were collected at recruitment and after 4, 8, 12, and 24 months of therapy. RESULTS: The multicenter cohort was composed by 455 patients treated with biosimilars [SB4/ABP501 276/179; female/male 307/146; biologic disease-modifying anti-rheumatic drug (b-DMARD) naïve 56%, median age/ interquartile range 55/46-65 years] and 436 treated with originators (etanercept/adalimumab 186/259, female/ male 279/157, b-DMARD naïve 67,2%, median age/interquartile range 53/43-62 years). No differences were found about safety, but the biosimilar group presented more discontinuations due to inefficacy (p<0.001). Female gender, being a smoker, and being b-DMARD naïve were predictive factors of reduced drug survival (p=0.05, p=0.046, p=0.001 respectively). The retention rate at 24 months was 81.1% for bioriginators and 76.5% for biosimilars (median retention time of 20.7 and 18.9 months, respectively) (p=0.002). Patients with remission/low disease activity achievement at 4 months showed a cumulative survival of 90% to biosimilar therapy until 24 months (p=0.001); early adverse reactions instead represented a cause of subsequent drug discontinuation (p=0.001). CONCLUSIONS: Real-life data demonstrated a similar safety profile between biosimilars and originators, but a reduced biosimilar retention rate at 24 months. Biosimilars could be considered a valid, safe, and less expensive alternative to originators, allowing access to treatments for a wider patient population.
Subject(s)
Antirheumatic Agents , Arthritis, Rheumatoid , Biosimilar Pharmaceuticals , Aged , Female , Humans , Male , Middle Aged , Adalimumab/therapeutic use , Arthritis, Rheumatoid/drug therapy , Biosimilar Pharmaceuticals/therapeutic use , Biosimilar Pharmaceuticals/adverse effects , Etanercept/therapeutic use , Etanercept/adverse effects , Necrosis/chemically induced , Necrosis/drug therapy , Treatment Outcome , AdultABSTRACT
Autoimmune diseases (AIDs) are complex diseases characterized by persistent or recurrent inflammation, alteration of immune response, and production of specific autoantibodies. It is known that different AIDs share several susceptibility genetic loci. Tumor necrosis factor alpha inducible protein 3 (TNFAIP3) encodes the ubiquitin-modifying enzyme A20, which downregulates inflammation by restricting NF-κB, a transcription factor that regulates expression of various proinflammatory genes. Variants in TNFAIP3 gene have been described as associated with susceptibility to several AIDs. Here, we analyzed two TNFAIP3 polymorphisms in Italian patients with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjogren's syndrome (pSS), to verify if the genetic variability of TNFAIP3 gene is involved in genetic predisposition to AIDs also in the Italian population. We recruited 313 SLE patients, 256 RA patients, 195 pSS patients, and 236 healthy controls. Genotyping of rs2230926 and rs6920220 in TNFAIP3 gene was performed by an allelic discrimination assay. We carried out a case/control association study and a genotype/phenotype correlation analysis. A higher risk to develop SLE was observed for rs2230926 (P = 0.02, OR = 1.92). No association was observed between this SNP and the susceptibility to pSS or RA. However, the rs2230926 variant allele seems to confer a higher risk to develop lymphoma in pSS patients, while in RA patients, the presence of RF resulted significantly associated with the variant allele. Regarding the rs6920220 SNP, we observed a significant association of the variant allele with SLE (P = 0.03, OR = 1.53), pSS (P = 0.016, OR = 1.69), and RA (P = 0.0001, OR = 2.35) susceptibility. Furthermore, SLE patients carrying the variant allele showed a higher risk to develop pericarditis, pleurisy, and kidney complications. Our results support the importance of the TNFAIP3 gene variant role in the development of different autoimmune diseases in the Italian population and furtherly confirm a sharing of genetic predisposing factors among these three pathologies.
Subject(s)
Autoimmune Diseases/diagnosis , Autoimmune Diseases/genetics , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Tumor Necrosis Factor alpha-Induced Protein 3/genetics , Alleles , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/genetics , Case-Control Studies , Gene Frequency , Genotype , Humans , Italy , Lupus Erythematosus, Systemic/diagnosis , Lupus Erythematosus, Systemic/genetics , Phenotype , Sjogren's Syndrome/diagnosis , Sjogren's Syndrome/geneticsABSTRACT
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.
Subject(s)
Genetic Markers , Hyaluronan Receptors/genetics , Lupus Erythematosus, Systemic/genetics , Lupus Erythematosus, Systemic/immunology , T-Lymphocytes/immunology , Adult , Case-Control Studies , Disease Progression , Female , Flow Cytometry , Gene Expression , Genetic Variation , Humans , Lupus Erythematosus, Systemic/physiopathology , Male , Middle Aged , Phenotype , Severity of Illness IndexABSTRACT
Rheumatological systemic autoimmune diseases, such as connective tissue diseases, rheumatoid arthritis or spondyloarthritis, are characterized by the presence of joint involvement associated with extra-articular manifestations. Among them, cutaneous diseases are often the most relevant and representative clinical manifestation, as in psoriatic arthritis, scleroderma or systemic lupus erythematosus. In this context, it is useful for rheumatologists to understand better skin diseases and their histopathological features. Evaluation of skin biopsy specimens can be helpful not only to confirm the diagnosis in both classic and clinically atypical variants, but also to improve further our knowledge of the pathogenetic mechanisms and the close link between skin and articular diseases. In this review, we discuss the clinical features, diagnostic evaluation and the histopathological features of skin manifestation of the most relevant rheumatological autoimmune diseases.
Subject(s)
Autoimmune Diseases/pathology , Connective Tissue Diseases/pathology , Skin/pathology , Behcet Syndrome/pathology , Cryoglobulinemia/pathology , Humans , Psoriasis/pathology , Rheumatic Diseases/pathology , Systemic Vasculitis/pathologyABSTRACT
Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to Aspergillus that mainly affects patients with asthma. For diagnosis, elevated serum IgE level are needed according to Greenberger and Patterson criteria. We report a case of 43 years-old woman who developed ABPA with productive cough, fever and radiological findings of multiple confluent areas of consolidation in both upper lobes. Laboratory tests showed elevated peripheral eosinophil counts (9.3 x 10(3)/ml). In bronchial washing A. galactomannans and A. Fumigatus were isolated, although we found normal levels of serum IgE, and the absence of serum IgG and IgE antibodies to Aspergillus and A. galactomannans. In conclusion, clinical and radiological signs of ABPA can be associated with Aspergillus infection also in the absence of a specific serum antibody reaction.
Subject(s)
Antibodies, Fungal/blood , Aspergillosis, Allergic Bronchopulmonary/diagnosis , Aspergillus fumigatus/immunology , Immunoglobulin E/blood , Lung/diagnostic imaging , Tomography, X-Ray Computed , Adult , Aspergillosis, Allergic Bronchopulmonary/blood , Aspergillosis, Allergic Bronchopulmonary/immunology , Aspergillosis, Allergic Bronchopulmonary/microbiology , Aspergillus fumigatus/isolation & purification , Biomarkers/blood , Female , Humans , Lung/immunology , Lung/microbiology , Predictive Value of Tests , Respiratory Function Tests , Serologic TestsABSTRACT
Rheumatoid arthritis (RA) is a systemic autoimmune disease resulting in chronic inflammation of the synovium and consequent cartilage and bone erosion. RA is associated strongly with the presence of rheumatoid factor (RF), and consists of clinical subsets of anti-citrullinated protein antibody (ACPA)-positive and -negative patients. This study was designed to evaluate whether relevant single nucleotide polymorphisms (SNPs) associated with RA and other autoimmune disorders are related to RF, ACPA and clinical phenotype in a cohort of biologic drugs naive Italian RA patients; 192 RA patients and 278 age-matched healthy controls were included. Clinical and laboratory data were registered. We analysed a total of 12 single nucleotide polymorphisms (SNPs) in signal transducer and activator of transcription-4 (STAT-4), interleukin (IL)-10, psoriasis susceptibility 1 candidate 1 (PSORS1C1), protein tyrosine phosphatase, non-receptor type 2 (PTPN2), endoplasmic reticulum aminopeptidase 1 (ERAP1), tumour necrosis factor receptor-associated 3 interacting protein 2 (TRAF3IP2) and microRNA 146a (MIR146A) genes by allelic discrimination assays. Case-control association studies and genotype/phenotype correlation analyses were performed. A higher risk to develop RA was observed for rs7574865 in the STAT-4 gene, while the rs1800872 in the IL-10 gene showed a protective effect. The presence of RF was associated significantly with rs1800872 variant in IL-10, while rs2910164 in MIR146A was protective. ACPA were associated significantly with rs7574865 in STAT-4. The SNP rs2233945 in the PSORS1C1 gene was protective regarding the presence of bone erosions, while rs2542151 in PTPN2 gene was associated with joint damage. Our results confirm that polymorphisms in STAT-4 and IL-10 genes confer susceptibility to RA. For the first time, we described that SNPs in PSORS1C1, PTPN2 and MIR146A genes were associated differently with a severe disease phenotype in terms of autoantibody status and radiographic damage in an Italian RA population.
Subject(s)
Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/genetics , Interleukin-10/genetics , MicroRNAs/genetics , Protein Tyrosine Phosphatase, Non-Receptor Type 2/genetics , Proteins/genetics , STAT4 Transcription Factor/genetics , Adult , Aged , Alleles , Case-Control Studies , Female , Genetic Association Studies , Genotype , Humans , Italy , Male , Middle Aged , Odds Ratio , Phenotype , Polymorphism, Single Nucleotide , Prognosis , Risk Factors , Severity of Illness IndexABSTRACT
Thymosin alpha 1 (Tα1) is a powerful modulator of immunity and inflammation. Despite years of studies, there are a few reports evaluating serum Tα1 in health and disease. We studied a cohort of healthy individuals in comparison with patients affected by chronic inflammatory autoimmune diseases. Sera from 120 blood donors (healthy controls, HC), 120 patients with psoriatic arthritis (PsA), 40 with rheumatoid arthritis (RA) and 40 with systemic lupus erythematosus (SLE), attending the Transfusion Medicine or the Rheumatology Clinic at the Policlinico Tor Vergata, Rome, Italy, were tested for Tα1 content by means of a commercial enzyme-linked immunosorbent assay (ELISA) kit. Data were analysed in relation to demographic and clinical characteristics of patients and controls. A gender difference was found in the HC group, where females had lower serum Tα1 levels than males (P < 0·0001). Patients had lower serum Tα1 levels than HC (P < 0·0001), the lowest were observed in PsA group (P < 0·0001 versus all the other groups). Among all patients, those who at the time of blood collection were taking disease-modifying anti-rheumatic drugs (DMARD) plus steroids had significantly higher Tα1 levels than those taking DMARD alone (P = 0·044) or no treatment (P < 0·0001), but not of those taking steroids alone (P = 0·280). However, whichever type of treatment was taken by the patients, serum Tα1 was still significantly lower than in HC and there was no treatment-related difference in PsA group. Further prospective studies are necessary to confirm and deepen these observations. They might improve our understanding on the regulatory role of Tα1 in health and disease and increase our knowledge of the pathogenesis of chronic inflammatory autoimmune diseases.
Subject(s)
Autoimmune Diseases/blood , Inflammation/blood , Thymosin/analogs & derivatives , Adult , Aged , Autoimmune Diseases/diagnosis , Autoimmune Diseases/drug therapy , Biomarkers , Case-Control Studies , Chronic Disease , Female , Humans , Inflammation/diagnosis , Inflammation/drug therapy , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Thymalfasin , Thymosin/blood , Treatment Outcome , Young AdultABSTRACT
Rheumatoid arthritis (RA) is a systemic chronic inflammatory disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone with joint destruction. The lack of immunological tolerance in RA represents the first step toward the development of autoimmunity. Susceptible individuals, under the influence of environmental factors, such as tobacco smoke, and silica exposure, develop autoimmune phenomena that result in the presence of autoantibodies. HLA and non-HLA haplotypes play a major role in determining the development of specific autoantibodies differentiating anti-citrullinated antibodies (ACPA)-positive and negative RA patients. Rheumatoid factor (RF) and ACPA are the serological markers for RA, and during the preclinical immunological phase, autoantibody titers increase with a progressive spread of ACPA antigens repertoire. The presence of ACPA represents an independent risk factor for developing RA in patients with undifferentiated arthritis or arthralgia. Moreover, anti-CarP antibodies have been identified in patients with RA as well as in individuals before the onset of clinical symptoms of RA. Several autoantibodies mainly targeting post-translational modified proteins have been investigated as possible biomarkers to improve the early diagnosis, prognosis and response to therapy in RA patients. Psoriatic arthritis (PsA) is distinguished from RA by infrequent positivity for RF and ACPA, together with other distinctive clinical features. Actually, specific autoantibodies have not been described. Recently, anti-CarP antibodies have been reported in sera from PsA patients with active disease. Further investigations on autoantibodies showing high specificity and sensibility as well as relevant correlation with disease severity, progression, and response to therapy are awaited in inflammatory arthritides.
Subject(s)
Arthritis, Rheumatoid/blood , Autoantibodies/blood , Animals , Arthritis, Psoriatic/blood , Arthritis, Psoriatic/diagnosis , Arthritis, Psoriatic/immunology , Arthritis, Rheumatoid/diagnosis , Arthritis, Rheumatoid/immunology , Autoimmunity , Biomarkers/blood , Disease Progression , Early Diagnosis , Humans , PrognosisABSTRACT
Abnormalities in peripheral blood natural killer (NK) cells have been reported in women with primary infertility and recurrent spontaneous abortion (RSA) and several studies have been presented to define cutoff values for abnormal peripheral blood NK cell levels in this context. Elevated levels of NK cells were observed in infertile/RSA women in the presence of thyroid autoimmunity (TAI), while no studies have been carried out, to date, on NK cells in infertile/RSA women with non-autoimmune thyroid diseases. The contribution of this study is two-fold: (1) the evaluation of peripheral blood NK cell levels in a cohort of infertile/RSA women, in order to confirm related data from the literature; and (2) the assessment of NK cell levels in the presence of both TAI and subclinical hypothyroidism (SCH) in order to explore the possibility that the association between NK cells and thyroid function is not only restricted to TAI but also to SCH. In a retrospective study, 259 age-matched women (primary infertility [n = 49], primary RSA [n = 145], and secondary RSA [n = 65]) were evaluated for CD56+CD16+NK cells by flow cytometry. Women were stratified according to thyroid status: TAI, SCH, and without thyroid diseases (ET). Fertile women (n = 45) were used as controls. Infertile/RSA women showed higher mean NK cell levels than controls. The cutoff value determining the abnormal NK cell levels resulted ⩾15% in all the groups of women. Among the infertile/RSA women, SCH resulted the most frequently associated thyroid disorder while no difference resulted in the prevalence of TAI and ET women between patients and controls. A higher prevalence of women with NK cell levels ⩾15% was observed in infertile/RSA women with SCH when compared to TAI/ET women. According to our data, NK cell assessment could be used as a diagnostic tool in women with reproductive failure and we suggest that the possible association between NK cell levels and thyroid function can be described not only in the presence of TAI but also in the presence of non-autoimmune thyroid disorders.
Subject(s)
Abortion, Habitual/immunology , Infertility, Female/immunology , Killer Cells, Natural/immunology , Thyroid Diseases/immunology , Adult , Autoimmunity , Female , Humans , Thyroid Gland/immunologyABSTRACT
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by extensive synovitis resulting in erosions of articular cartilage and marginal bone that lead to joint destruction. The autoimmune process in RA depends on the activation of immune cells, which use intracellular kinases to respond to external stimuli such as cytokines, immune complexes, and antigens. An intricate cytokine network participates in inflammation and in perpetuation of disease by positive feedback loops promoting systemic disorder. The widespread systemic effects mediated by pro-inflammatory cytokines in RA impact on metabolism and in particular in lymphocyte metabolism. Moreover, RA pathobiology seems to share some common pathways with atherosclerosis, including endothelial dysfunction that is related to underlying chronic inflammation. The extent of the metabolic changes and the types of metabolites seen may be good markers of cytokine-mediated inflammatory processes in RA. Altered metabolic fingerprints may be useful in predicting the development of RA in patients with early arthritis as well as in the evaluation of the treatment response. Evidence supports the role of metabolomic analysis as a novel and nontargeted approach for identifying potential biomarkers and for improving the clinical and therapeutical management of patients with chronic inflammatory diseases. Here, we review the metabolic changes occurring in the pathogenesis of RA as well as the implication of the metabolic features in the treatment response.
Subject(s)
Arthritis, Rheumatoid/metabolism , Inflammation/complications , Arthritis, Rheumatoid/pathology , Chronic Disease , Humans , Inflammation/pathologyABSTRACT
BACKGROUND: The systemic nature of psoriasis and its association with arthropathy, metabolic syndrome and cardiovascular disease is well established. In contrast, the association between psoriatic disease and other autoimmune disorders is still a matter of debate and data available in the literature are scarce. OBJECTIVE: The aim of this study was to examine the association of common autoimmune diseases (ADs), specified a priori, in an Italian cohort of patients affected by psoriasis and/or psoriatic arthritis (PsA), referred to two integrated Dermatology/Rheumatology outpatient clinics, over a 3-year period. METHODS: Five hundred and two patients, affected by plaque psoriasis, PsA 'sine psoriasis' or a combination of psoriasis and PsA and with a diagnosis of at least one AD, were retrospectively evaluated. Univariate and multivariate binary logistic regression was employed to identify possible association between psoriasis, PsA, psoriasis-PsA and ADs, by calculating corresponding odds ratios and 95% confidence intervals. RESULTS: Patients with psoriasis or PsA may develop one or more autoimmune diseases during their lifetime, with a higher prevalence of most ADs in psoriasis subgroup. We demonstrated for the first time that the combination of psoriasis-PsA appears to be protective towards some autoimmune diseases. However, a gender effect should always be considered due to the different distribution of autoimmune disorders between males and females. CONCLUSION: The new concept of psoriatic disease, focusing on genetic and molecular aspects which are at the basis of the pathogenesis of psoriasis and its related manifestations, extended the traditional idea of a disease confined to skin and joints. In this context, the multidisciplinary assessment of patients in the combined Dermatology/Rheumatology outpatient clinics would allow to identify early clinical and laboratory abnormalities not limited to skin and joint.
Subject(s)
Autoimmune Diseases/epidemiology , Psoriasis/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Ambulatory Care , Arthritis, Psoriatic/complications , Arthritis, Psoriatic/epidemiology , Child , Child, Preschool , Comorbidity , Dermatology , Female , Humans , Italy/epidemiology , Male , Middle Aged , Prevalence , Protective Factors , Psoriasis/complications , Retrospective Studies , Rheumatology , Risk Factors , Young AdultABSTRACT
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.
Subject(s)
Arthritis, Rheumatoid/metabolism , Interleukins/metabolism , Synovial Fluid/metabolism , Adult , Aged , Arthritis, Psoriatic/immunology , Arthritis, Psoriatic/metabolism , Arthritis, Psoriatic/pathology , Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/pathology , Female , Humans , Inflammation/immunology , Inflammation/metabolism , Inflammation/pathology , Interleukins/immunology , Joints/immunology , Joints/metabolism , Joints/pathology , Male , Middle Aged , Synovial Fluid/immunologyABSTRACT
Immune thrombocytopaenic purpura (ITP) is an autoimmune systemic disease detectable by the presence of low blood platelets count (<10(5)/µl) and the production of autoantibodies against glycoproteins expressed on the platelet surface. The clinical course is often acute, and life-threatening events may occur especially in children, with 52% of paediatric patients recovering either spontaneously or after treatment. A chronic ITP evolution is observed in 64% of adults, of whom 12% will develop an overlapping autoimmune disease. Several microbial agents such as CagA-positive Helicobacter pylori or Candida albicans and a number of viruses including CMV, EBV or HIV can potentially trigger ITP through molecular mimicry. Moreover, ITP improves after treatment of the underlying infection. Similarly, vaccines such as MMR may prompt ITP (IRR 5.48, 1.61-18.64, p < 0.006). Early recognition of the underlying microbial trigger and the removal of modifiable aetiopathogenetic factors should be integrated as a complementary treatment strategy in all patients who do not readily improve with standard ITP care.
Subject(s)
Autoantibodies/blood , Autoimmunity , Bacteria/immunology , Blood Platelets/immunology , Molecular Mimicry , Purpura, Thrombocytopenic, Idiopathic/immunology , Vaccines/adverse effects , Viruses/immunology , Animals , Biomarkers/blood , Host-Pathogen Interactions , Humans , Prognosis , Purpura, Thrombocytopenic, Idiopathic/blood , Purpura, Thrombocytopenic, Idiopathic/diagnosis , Purpura, Thrombocytopenic, Idiopathic/therapy , Risk Assessment , Risk FactorsABSTRACT
Etanercept (ETN) is an anti-tumour necrosis factor (TNF)-α agent used in rheumatoid arthritis (RA) and psoriatic arthritis (PsA). Few studies focused on the effects of anti-TNF-α on peripheral blood cells. We aimed to evaluate peripheral blood cells in RA and PsA patients during ETN treatment and to explore their relationships with disease activity. RA (n = 82) and PsA (n = 32) patients who started ETN were included into the study and evaluated prospectively before the beginning of ETN therapy and after 14, 22, 54 and 102 weeks. Patients were studied in terms of disease activity score on 28 joints (DAS28), clinical response and laboratory findings. Natural killer (NK) cells, B cells and T cells were characterized by immunophenotyping. Both the RA and the PsA patients showed reduced NK and B cell count before ETN treatment compared with controls. A negative correlation was demonstrated between DAS28 and B cell count in RA patients at baseline. Sustained significant increase of NK and B cells up to normal levels was observed in RA and PsA patients along ETN treatment. Increase of NK cell count was associated with a good-moderate clinical response to ETN in both RA and PsA patients. During ETN treatment peripheral blood NK and B cells levels were restored in RA and PsA patients. Correlations between NK and B cells with disease activity were observed, suggesting that those effects could be mediated by ETN treatment.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/therapeutic use , Arthritis, Psoriatic/drug therapy , Arthritis, Rheumatoid/drug therapy , B-Lymphocytes/drug effects , Immunoglobulin G/therapeutic use , Killer Cells, Natural/drug effects , Receptors, Tumor Necrosis Factor/therapeutic use , Adult , Aged , Arthritis, Psoriatic/immunology , Arthritis, Rheumatoid/immunology , B-Lymphocytes/immunology , Blood Circulation/drug effects , Blood Circulation/immunology , Cell Count , Disease Progression , Etanercept , Female , Follow-Up Studies , Humans , Immunophenotyping , Killer Cells, Natural/immunology , Male , Middle Aged , Prospective StudiesABSTRACT
OBJECTIVES: The aim of this study was to evaluate clinical and US-PD parameters in PsA during adalimumab treatment. METHODS: A retrospective study has been conducted in forty patients affected by moderate-to-severe peripheral PsA. Clinical, laboratory, and US-PD evaluations were performed at baseline, after 4, 12, and 24 weeks of treatment. They included erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), visual analogue scale (VAS), Health Assessment Questionnaire (HAQ) modified for Spondyloarthritis, Psoriasis Area Severity Index (PASI) score, the 28-joint Disease Activity Score (DAS 28), and US-PD assessment. US-PD findings were scored according to a semiquantitative scale (ranging 0-3) for synovial proliferation (SP), joint effusion (SE), bone erosions (BE), and PD. RESULTS: Data obtained for clinical, laboratory findings and US-PD evaluation showed statistical significant improvement in all the measures performed except for BE. A significant parallel decrease in SE, SP, and PD values were demonstrated. CONCLUSION: This study demonstrated that US-PD is a valid technique in monitoring the response to adalimumab in moderate-to-severe PsA.
Subject(s)
Anti-Inflammatory Agents, Non-Steroidal/administration & dosage , Antibodies, Monoclonal, Humanized/administration & dosage , Arthritis, Psoriatic/drug therapy , Adalimumab , Adult , Aged , Anti-Inflammatory Agents, Non-Steroidal/adverse effects , Antibodies, Monoclonal, Humanized/adverse effects , Arthritis, Psoriatic/diagnostic imaging , Arthritis, Psoriatic/physiopathology , Blood Sedimentation , Bone Resorption/diagnostic imaging , Bone Resorption/pathology , C-Reactive Protein/metabolism , Female , Follow-Up Studies , Humans , Male , Middle Aged , Retrospective Studies , Severity of Illness Index , Synovial Membrane/diagnostic imaging , Synovial Membrane/pathology , UltrasonographyABSTRACT
Patients with hereditary angioedema (HAE) tend to produce autoantibodies and have a propensity to develop immunoregulatory disorders. We characterize the profile of autoantibodies in a group of HAE patients and investigate their memory B cells' phenotype and activation status. We studied the activity status phenotype, Toll-like receptor (TLR)-9 expression and total phosphotyrosine in B cells isolated from HAE patients. Additionally, the following autoantibodies were assessed in the serum of 61 HAE patients: anti-nuclear, rheumatoid factor, anti-cardiolipin, anti-tissue transglutaminase, anti-endomysial, anti-Saccharomyces cerevisiae, anti-thyroid and anti-neutrophil cytoplasmic antibodies. In 47·5% of HAE patients we detected at least one of the tested autoantibodies. Expression of CD69, CD5 and CD21 was found to be significantly higher on memory B cells from HAE patients compared to healthy controls (4·59 ± 4·41 versus 2·06 ± 1·81, P = 0·04, 8·22 ± 7·17 versus 3·65 ± 3·78, P = 0·05, 2·43 ± 0·54 versus 1·92 ± 0·41, P = 0·01, respectively). Total phosphotyrosine in B cells from HAE patients was significantly higher compared to healthy controls (4·8 ± 1·1 versus 2·7 ± 1·3, P = 0·0003). Memory B cells isolated from the HAE group contained higher amounts of TLR-9 compared to healthy controls (8·17 ± 4·1 versus 4·56 ± 1·6, P = 0·0027). Furthermore, the expression of TLR-9 in memory B cells from HAE patients with autoantibodies was significantly higher than the control group (10 ± 4·7 versus 4·56 ± 1·6, P = 0·0002) and from that in HAE patients without autoantibodies (10 ± 4·7 versus 5·8 ± 0·9, P = 0·036). HAE patients have enhanced production of autoantibodies due most probably to the increased activation of B cells, which was found to be in association with a high expression of TLR-9.
Subject(s)
Autoimmunity , B-Lymphocytes/immunology , Complement C1 Inactivator Proteins/deficiency , Hereditary Angioedema Types I and II/immunology , Adult , Aged , Autoantibodies/blood , B-Lymphocytes/classification , Case-Control Studies , Complement C1 Inhibitor Protein , Female , Hereditary Angioedema Types I and II/etiology , Humans , Immunologic Memory , Lymphocyte Activation , Male , Middle Aged , Signal Transduction/immunology , Toll-Like Receptor 9/metabolism , Young AdultABSTRACT
OBJECTIVES: Treatment with anti-TNF agents is well established in psoriatic arthritis (PsA). Anti-TNF agents are capable of modulating complement activity in vitro but there are no data on the in vivo effect. Anti-TNF have high costs and potential risks, thus, there is an urgent need for accurate predictors of response. We aimed at studying the usefulness of erythrocyte-sedimentation-rate (ESR), C-reactive protein (CRP), and complement for response prediction and monitoring of anti-TNF treatment in PsA patients. METHODS: Fifty-five patients were included consecutively before starting etanercept or adalimumab. ESR, CRP, plasma complement C3, C4, and C3 and B cleavage fragments were evaluated at baseline and after 22 weeks of anti-TNF treatment. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. Complement was evaluated at baseline in 30 healthy subjects as well. RESULTS: At baseline, C3 and C4 levels were significantly higher than in controls (C3 126.9±22 vs. 110±25 mg/dl, p=0.000002; C4 31.2±9.2 vs. 22.7±8.3 mg/dl, p=0.0003). After anti-TNF therapy, C3 and C4 levels were significantly reduced to normalization (p=0.0009 and 0.0005, respectively) and ESR, CRP and DAS28 showed a significant reduction (p=0.002, 0.004 and 0.0001, respectively). Split products of C3 and B were not observed at baseline and after 22 weeks. Higher baseline C3 levels were associated with EULAR non-response (p=0.011). CONCLUSIONS: PsA patients with moderate to severe disease show elevated C3 and C4 levels, reverted by anti-TNF treatment. High C3 may be considered a hallmark of inflammation and C3 revealed the highest predictive value for response to anti-TNF.
Subject(s)
Arthritis, Psoriatic/immunology , Complement System Proteins/metabolism , Adult , Aged , Antirheumatic Agents/therapeutic use , Arthritis, Psoriatic/drug therapy , C-Reactive Protein , Female , Humans , Male , Middle Aged , Predictive Value of Tests , Severity of Illness Index , Treatment Outcome , Tumor Necrosis Factor-alpha/antagonists & inhibitorsABSTRACT
Autoantibodies (rheumatoid factor, RF; anti-citrullinated-protein antibodies, ACPA) and complement system are involved in rheumatoid arthritis (RA). ACPA and anti-TNF agents are capable of in vitro modulating complement activity. We investigated the relationships between complement, autoantibodies, and anti-TNF treatment in vivo. One-hundred fourteen RA patients (89F/25M), diagnosed according to 1987 ACR criteria, and 30 healthy controls were enrolled. Serological analysis included ESR, CRP, complement C3, C4 and CH50, RF and ACPA (ELISA, cut-off>20 U/ml). Split-products (SP) of C3 and B were studied by immunoelectrophoresis/counterimmunoelectrophoresis. Seventy-six patients started anti-TNF treatment and were studied at baseline and after 22 weeks. Disease activity was measured with DAS28 and response to therapy with EULAR criteria. At baseline, RA patients showed significantly higher levels of C3 and C4 than controls (C3 127.9±26.5 vs 110±25 mg/dl, P=0.0012; C4 29.7±10.2 vs 22.7±8.3mg/dl, P=0.0003). No differences in C3, C4 and CH50 levels were observed between ACPA+ (n=76) and ACPA- (n=38) patients. After 22 weeks of anti-TNF, C3, C4 and RF were significantly reduced (P<0.003, <0.005 and <0.04, respectively) and RF changes showed negative correlation with CH50. SP of C3 and B were observed neither at baseline nor after 22 weeks. DAS28 significantly improved after 22 weeks. Patients showing higher baseline C3 or lower reduction of C3 levels after 22 weeks had a worse EULAR outcome (X2=22.793, P<0.001). RF levels seem to correlate with complement CH50. The presence of high levels of C3 in RA patients may reflect a pro-inflammatory status and represent a negative prognostic factor for anti-TNF therapy.
Subject(s)
Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/drug therapy , Arthritis, Rheumatoid/immunology , Autoantibodies/blood , Complement C3/metabolism , Tumor Necrosis Factor-alpha/antagonists & inhibitors , Adult , Aged , Analysis of Variance , Arthritis, Rheumatoid/diagnosis , Biomarkers/blood , Chi-Square Distribution , Complement C4/metabolism , Complement Hemolytic Activity Assay , Enzyme-Linked Immunosorbent Assay , Female , Humans , Immunoelectrophoresis , Italy , Male , Middle Aged , Peptides, Cyclic/immunology , Prospective Studies , Rheumatoid Factor/blood , Severity of Illness Index , Time Factors , Treatment OutcomeABSTRACT
Glutathione (GSH), a component of the antioxidant defence system, plays a role in autoimmunity and the complement system is often responsible for tissue damage in autoimmune diseases. The aim of this study is to evaluate the effects of GSH on the complement system. The complement system was examined in the normal human sera (NHS) of 30 healthy subjects. Increasing quantities of GSH (1, 2, 10, 20 mg) were incubated in 1 ml of each NHS. The mixtures were evaluated for complement activities (THC, CPA and APA) and for the presence of cleavage fragments of activation of C3 and B. GSH was also incubated with human complement in the presence of classical and alternative pathway activators. The results showed an inhibitory effect of GSH on the complement system starting from a dosage of GSH≥1 mg/ml. Indeed, when NHS was incubated with GSH at such dosage, a significant reduction of the complement activities THC, CPA, and APA was observed (P<0.0001, P<0.005, P=NS, respectively), and no cleavage fragments of C3 or B were found. Further analysis demonstrated that the inhibition was exerted on C3-9 and to a lower extent on classical and alternative pathway C3-convertases. Our results indicate that GSH is capable of inhibiting the complement system. These findings are relevant for the design of interventions aimed at modulation of GSH metabolism to inhibit complement-mediated damage in autoimmune diseases.
Subject(s)
Complement Inactivating Agents/pharmacology , Glutathione/pharmacology , Complement Pathway, Alternative/drug effects , Complement Pathway, Classical/drug effects , Glutathione/metabolism , Glutathione/therapeutic use , HumansABSTRACT
BACKGROUND: Hereditary angioedema (HAE) is an autosomal-dominant disorder resulting from C1-inhibitor (C1INH) deficiency. Smell impairments were found in patients affected with systemic lupus erythematosus, that, similarly to HAE, is characterized by the activation of the classical complement pathway with C4 consumption. In this study, we aimed at evaluating the sense of smell in patients with HAE. METHODS: Thirty patients with HAE and 30 healthy age- and sex-matched controls were evaluated for olfactory functions using the 3-stages Sniffin'-Sticks kit (threshold, discrimination, and identification [TDI]). TDI scores were analyzed according to complement levels (C1INH, C3, C4 and CH50), Beck depression inventory (BDI-II) and danazol treatment. RESULTS: A significant decrease in olfactory function was observed in patients affected with HAE compared with controls in total TDI score (P < 0.001), and in the discrimination (P < 0.001) and identification scores (P = 0.012). Anosmia was present only in patients with HAE (3.3%) who also exhibited more frequently hyposmia (53.3%vs 3.3%, P < 0.0001). Complement levels were reduced in patients with HAE. C4 serum levels showed positive correlation with total TDI score (P < 0.001), and with discrimination (P = 0.002) and identification (P = 0.011) scores. CH50 complement levels showed positive correlation with total TDI score (P < 0.001), and with threshold (P = 0.002) and discrimination (P = 0.011) scores. Sex, age, danazol treatment, BDI-II scores were not different between the patients and controls and did not influence TDI scores significantly. CONCLUSION: Evidence for an impaired sense of smell was found in patients with HAE. The reduction in olfactory function in these cases seems to correlate with complement C4 and CH50 levels. Immune and genetic mechanisms might play a role in this defect.