New JAK inhibitors for the treatment of psoriasis and psoriatic arthritis.

Psoriasis is a common inflammatory skin disease that can be associated with various pathological conditions among which arthritis is a frequent comorbidity. Based on the current pathogenetic model, development of psoriasis is mainly driven by the IL-23/IL-17A axis. Though the therapeutic armamentarium is expanding in the latest years, new therapies are needed because of the lack or loss of response or intolerance/contraindication to the currently approved drugs. The most recently developed drugs for the treatment of psoriasis and psoriatic arthritis specifically target cytokines, cytokine receptors, and intracellular signaling transducers that are involved in the pathogenesis of psoriasis. Janus kinase (JAK) pathway transduces signals of multiple cytokines, such as TNF-α, IL-23, IL-12, IFN, IL-6, IL-17, that have resulted crucial in the induction and maintenance of psoriasis inflammation. Thereby, JAK-1, JAK-3, TYK-2 belonging to the JAK family, have been identified as valid therapeutic targets in the treatment of psoriasis. Nowadays, different JAK inhibitors have been investigated in clinical trials showing promising results in terms of efficacy and safety. In this review, we systematically collected publications and data related to JAK inhibitors used in psoriasis and psoriatic arthritis providing the state-of-the-art on this new class of molecules in the treatment of these diseases.

An Integrated Analysis of the Safety of Tofacitinib in Psoriatic Arthritis across Phase III and Long-Term Extension Studies with Comparison to Real-World Observational Data.

INTRODUCTION: Tofacitinib is an oral Janus kinase inhibitor for the treatment of psoriatic arthritis (PsA). OBJECTIVE: Our objective was to compare the incidence rates (IRs) of adverse events in tofacitinib clinical trials and real-world observational data for alternative treatments. METHODS: The tofacitinib "dose-comparison cohort" included months 0-12 of two phase III studies (tofacitinib 5 [n = 238] and 10 [n = 236] mg twice daily [BID]); the "all-tofacitinib comparison cohort" (n = 783) included two phase III and one ongoing long-term extension study (data cutoff May 2016). An "observational comparison cohort" (n = 5799) comprised patients initiating a conventional synthetic disease-modifying antirheumatic drug (DMARD), biologic DMARD, or apremilast in the US Truven MarketScan database from 2010 to 2015. IRs for serious infections (SIEs; requiring hospitalization), herpes zoster (HZ), malignancies (excluding non-melanoma skin cancer [NMSC]), NMSC, and major adverse cardiovascular events (MACE) across cohorts were qualitatively compared. RESULTS: IRs (patients with events/100 patient-years) for SIEs were similar between the tofacitinib dose-comparison cohort (5 mg BID: 1.3; 10 mg BID: 2.0) and the observational comparison cohort (1.1-7.9; treatment dependent). The tofacitinib dose-comparison cohort had a higher rate of HZ (5 mg BID: 2.0; 10 mg BID: 2.7) than did the observational comparison cohort (0.8-2.0). IRs for NMSC were generally lower in the all-tofacitinib comparison cohort (0.5) than in the observational comparison cohort (0.4-6.0). IRs for MACE, malignancies excluding NMSC, and NMSC were similar between cohorts. CONCLUSION: In patients with PsA, tofacitinib had a safety profile similar to that of other systemic therapies in real-world settings, except for the risk of HZ, a known risk of tofacitinib. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01877668; NCT01882439; NCT01976364.

Targeted synthetic pharmacotherapy for psoriatic arthritis: state of the art.

INTRODUCTION: In recent years, different studies regarding psoriatic arthritis (PsA) have shown the pathogenetic role of dysfunction of signaling pathways involving the phosphodiesterase-4 enzyme and transcription factors or enzymes belonging to the kinase (JAK)-signal family pathway. These also represent the target of several drugs known as targeted synthetic disease-modifying antirheumatic drugs (tsDMARDs). AREAS COVERED: The authors performed a systematic literature search using the PubMed database, as well as through retrieving data from randomized controlled trials, their post-hoc analysis, and pooled data analysis on the efficacy and safety profile of the PDE4 inhibitor (PDE4i), apremilast, and the inhibitors of JAK (JAKis), tofacitinib, filgotinib, baricitinib, and upadacitinib, in PsA. EXPERT OPINION: In PsA, the PDE4i, apremilast, and the JAKi, tofacitinib, are effective across multiple clinical domains and have an acceptable tolerability profile, thus expanding the treatment options available for PsA patients. Apremilast and tofacitinib show several advantages mainly represented by their oral administration, a fast onset of action, and a short half-life. Data on tsDMARDs in PsA are still limited, and randomized trials and real-life studies are advocated.

Correlation of High-Density Lipoprotein-Associated Paraoxonase 1 Activity With Systemic Inflammation, Disease Activity, and Cardiovascular Risk Factors in Psoriatic Disease.

OBJECTIVE: To compare the activity of high-density lipoprotein (HDL)-associated paraoxonase 1 (PON1) in patients with psoriasis (PsO) and patients with psoriatic arthritis (PsA), and to evaluate the association of PON1 activity with the extent of disease activity and severity of the cardiovascular disease (CVD) burden in these patients. METHODS: Serum levels of paraoxonase and arylesterase activity (both measures of PON1 function in humans) were measured in patients with PsA (n = 198, 51.0% male) and patients with PsO (n = 145, 50.3% male) who were enrolled in a longitudinal psoriatic disease biorepository. Data on PsA disease activity (using the Disease Activity Score in 28 joints [DAS28], Clinical Disease Activity Index, and painful/swollen joint counts), preexistent CVD and CVD risk factors (including diabetes, dyslipidemia, hypertension, and smoking), Framingham Risk Scores for CVD, quality of life measures, and laboratory test findings (erythrocyte sedimentation rate, C-reactive protein level, and lipid profiles) were recorded. RESULTS: Serum arylesterase activities were significantly lower in patients with PsO and patients with PsA (mean ± SD 111.1 ± 25.5 µmoles/minute/ml and 124.4 ± 33.4 µmoles/minute/ml, respectively) compared to healthy controls (144.3 ± 33.4 µmoles/minute/ml) (each P < 0.001 versus healthy controls). Serum arylesterase activity decreased in parallel with increasing levels of disease activity (DAS28 scores, P = 0.012), older age (P = 0.013), higher body mass index (P = 0.042), greater incidence of metabolic syndrome (P = 0.004) and hypertension (P = 0.014), and worsening Framingham Risk Scores (P = 0.001). However, no correlation was seen between serum arylesterase activity and the extent of disease activity or CVD burden in patients with PsO. Serum paraoxonase activity trended lower both in patients with PsO and in patients with PsA (each P = 0.073 versus healthy controls). However, no association was seen between serum paraoxonase activity and the extent of disease activity or CVD burden in either of the patient cohorts. CONCLUSION: PON1 activity is decreased in psoriatic diseases. In the PsA cohort, decreases in arylesterase activity correlated with increasing severity of joint disease and CVD burden. Arylesterase activity, as compared to paraoxonase activity, appeared to serve as a more sensitive predictor of preexisting CV risk factors in the PsA cohort. However, this correlation was not observed in the PsO population.

Ex Vivo Signaling Protein Mapping in T Lymphocytes in the Psoriatic Arthritis Joints.

We assessed signaling protein mapping in total T cells, to analyze the proportions of T regulatory (Treg) and TCD4+ effector (Teff) cell phenotypes, and the respective interleukin 6Rα (IL-6Rα) expression in the inflammatory microenvironment of synovial fluid (SF) of patients with sustained psoriatic arthritis (PsA). Our approach was to measure the IL-6 level in SF using a multiplex bead immunoassay. Reverse-phase protein array was used to assess Janus kinase (JAK) 1 and JAK2, extra-cellular regulated kinase (ERK) 1 and 2, protein kinase Cδ (PKCδ), signal transducer and activator and transcription (STAT) 1, STAT3, and STAT5 phosphoproteins in total T cell lysates from SF of patients with PsA. Frequencies of CD4+IL-17A-F+IL-23+ CD4+ Th cells producing IL-17A and IL-17F (Th17) and CD4+CD25high intracellular forkhead box transcription factor+ (FOXP3+) phenotypes, and the percentage of Treg- and Teff- cells were quantified in SF and matched peripheral blood (PB) of patients with PsA and PB of healthy controls (HC) by flow cytometry. Our results were the following: In PsA SF samples, a coordinate increase of JAK1, ERK1/2, STAT1, STAT3, and STAT5 phosphoproteins was found in total T cells in SF of PsA; where IL-6 levels were higher than in PB from HC. Expanded CD4+IL-17A-F+IL-23+ Th17, CD4+ CD25- Teff- and CD4+CD25(high) FoxP3+Treg subsets, showing similar levels of enhanced IL-6Rδ expression, were confined to PsA joints. In our studies, the transcriptional network profile identified by ex vivo signaling protein mapping in T lymphocytes in PsA joints revealed the complex interplay between IL-1, IL-6, and IL-23 signaling and differentiation of Th17 cells and CD4+Tregs in sustained joint inflammation in PsA.

JAK/STAT/PKCδ molecular pathways in synovial fluid T lymphocytes reflect the in vivo T helper-17 expansion in psoriatic arthritis.

Looking to the sustained psoriatic arthritis (PsA) joint as a model of local human inflammation, this study was designed to assess the T lymphocyte signal transduction pathways potentially involved in this chronic immune-mediated inflammatory process, as characterized by direct ex vivo analysis of T helper (Th)-17 T effector (Teff) cell phenotypes in synovial fluid (SF) and peripheral blood (PB) of clinically active PsA patients. The reverse-phase protein arrays (RPPA) technique was employed to identify STAT3, STAT1, JAK1, JAK2, PKCδ and ERK1/2 phosphoprotein levels on total T cell lysates in SF samples of PsA patients. Frequencies of T CD4(+)IL-17A-F(+) and T CD4(+)IL-23R(+) Th17 cells were quantified in SF and matched PB of PsA patients by flow cytometry and compared with PB of healthy controls (HC). Increased levels of JAK1, STAT3, STAT1 and PKCδ phosphoproteins were found in SF T cells of PsA patients, compared with PB of HC. The expansion of T CD4(+)IL-17A-F(+) cells, as well as of T CD4(+) cells expressing IL-23Rp19 (T CD4(+) IL-23R(+)), considered as the pathogenic phenotype of effector Th17 cells, was found to be confined to the joints of PsA patients, as the frequencies of both populations were significantly higher in SF than in matched PB, or in PB of HC. In conclusion, T lymphocyte signal transduction pathway mapping revealed an enhanced activation of JAK1/STAT3/STAT1 and PKCδ phosphoproteins that may drive the local inflammatory process, characterized by the in vivo expansion of T CD4(+)IL-17A-F(+) and T CD4(+)IL-23R(+) Th17 Teff cells in SF of clinically active joints of PsA patients.

Dermal distribution of hyaluronan in psoriatic arthritis; coexistence of CD44, MMP3 and MMP9.

Psoriatic arthritis is a chronic systemic disease in which patients develop persistent inflammation of the skin and joints, leading to disability and joint damage. The extracellular component hyaluronan (HA) plays an important role in regulatory processes such as inflammation, wound healing and tumour progression. At any site of inflammation HA can be depolymerized to low-molecular weight fragments, which, in turn, induce an array of inflammatory mediators that can lead to chronic inflammation. This study describes the serum concentration and dermal distribution of HA, its receptor CD44 and the metalloproteinases 3 and 9 in skin biopsies from patients with different types of psoriatic arthritis. Fifty-one patients with psoriatic arthritis were included in the study and classified as oligo- or poly-arthritic PsA with and without treatment. Biopsies were obtained from both involved and non-involved skin and compared with biopsies from healthy individuals. Serum HA was analysed for estimation of the total turnover of HA. The main findings were an overall redistribution of HA in both involved and non-involved psoriatic skin and an epidermal imbalance between HA and CD44. The structurally and functionally important basement membrane zone was found to be disintegrated and devoid of HA irrespective of the type of articular involvement, treatment or skin affection.

Proteolytic activity and expression of the 20S proteasome are increased in psoriasis lesional skin.

BACKGROUND: Deregulation of the proteasome pathway has been shown to be involved in the pathogenesis of several inflammatory disorders. To date limited information exists on proteasome and immunoproteasome expression and activity in psoriasis skin. OBJECTIVES: To investigate the potential role of proteasomes in the pathogenesis of psoriasis. METHODS: Thirty-six patients with psoriasis and 40 healthy subjects were included. The protein and mRNA expression levels and proteolytic activity of proteasome and immunoproteasome subunits were determined using immunohistochemistry, quantitative polymerase chain reaction and fluorogenic peptide substrate in lesional and nonlesional psoriasis skin. We additionally measured the plasmatic proteasome (p-proteasome) levels using enzyme-linked immunosorbent assay. RESULTS: We reveal an increased expression of proteasome and immunoproteasome subunits but stable mRNA levels in lesional psoriasis skin as compared with nonlesional psoriasis skin (n = 19), suggesting that proteasome and immunoproteasome expression is regulated post-transcriptionally. This proteasome overexpression was associated with a significant increase of the proteasomal chymotrypsin-like activity that was threefold higher in lesional skin than in nonlesional skin (n = 3). p-Proteasome levels were enhanced in patients with psoriasis (mean ± SEM 3960 ± 299 ng mL(-1) , range 1484-8987) when compared with controls (2535±187 ng mL(-1) , range 654-6446, P<0·001) and were significantly higher in psoriatic arthritis (4937±572 ng mL(-1) , range 2600-8987). In addition, they were correlated to the body surface area involved and appeared thus as a new biomarker of psoriasis severity. CONCLUSIONS: Altogether these results strongly suggest the involvement of the proteasome system in the pathogenesis of psoriasis and support the relevance of proteasome inhibitors in local or systemic treatment of psoriasis.

Folate pathway enzyme gene polymorphisms and the efficacy and toxicity of methotrexate in psoriatic arthritis.

OBJECTIVE: To determine the association between folate pathway gene polymorphisms and the effectiveness, toxicity, and drug survival of methotrexate (MTX) in psoriatic arthritis (PsA). METHODS: Data were obtained from a longitudinal cohort of PsA patients evaluated according to a standard protocol. Data on duration of drug therapy, dose, side effects, and reasons for discontinuation are systematically recorded. Patients treated with MTX after clinic admission who had > or = 3 swollen joints prior to initiating MTX therapy were selected for evaluation of effectiveness. Response to MTX treatment was assessed at 6 months. Data from all patients treated in the clinic with MTX were used in evaluation of toxicity and drug survival. The following single-nucleotide polymorphisms (SNP) were measured using the Sequenom platform: MTHFR 677C>T (rs1801133), MTHFR 1298A>C (rs1801131), DHFR -473T>C (rs1650697), DHFR 35289A>G (rs1232027), and RFC 80G>A (rs1051266). Fisher's exact test, logistic regression, and Cox proportional hazard analyses were used to determine association. RESULTS: Two hundred eighty-one patients were identified from the database. All patients were included in the analysis for side effects and drug survival, and 119 patients were included in the effectiveness analysis. The minor A allele of DHFR gene at +35289 was the only SNP demonstrating association with response to MTX therapy (OR 2.99, p = 0.02). Patients homozygous for the minor allele of MTHFR 677C/T (677TT) had more liver toxicity (Fisher exact test, p = 0.04). CONCLUSION: Polymorphisms of the DHFR gene may be associated with MTX efficacy. MTHFR 677TT may have a relationship with MTX-induced liver toxicity in PsA.

The protein tyrosine phosphatase, non-receptor type 22 R620W polymorphism does not confer susceptibility to psoriasis in the genetic homogeneous population of Crete.

Recent whole-genome and candidate-gene association studies in patients with psoriasis (PS) have identified a number of single-nucleotide polymorphisms (SNPs) that predispose to disease with moderate risk. Predisposition to PS is known to be affected by genetic variation in human leukocyte antigen-C as well as other non-human leukocyte antigen genes. We recently reported for the first time as a PS-associated SNP the signal transducer and activator of transcription-4 (STAT4) rs7574865 polymorphism, which is also associated with several autoimmune diseases. The aim of this study was to assess whether the functional R620W polymorphism of protein tyrosine phosphatase, non-receptor type 22 (PTPN22) gene encoding the lymphoid-specific tyrosine phosphatase, which is known to be associated with various autoimmune diseases, also confers increased risk for PS in the genetic homogeneous population of Crete. A case-control study was performed with 173 PS patients consecutively recruited and 348 healthy controls, all of them from the island of Crete. We found that the mutated T allele of the PTPN22 1858T SNP was more common in control individuals than in patients with PS (odds ratio = 0.39, 95% confidence interval = 0.11-1.04, p = 0.09). No considerable difference was observed in terms of sex, age of onset, or clinical presentation of psoriatic arthritis. Our results provide evidence that the PTPN22 1858T allele is not a susceptibility factor for PS in the Cretan population.

Elevated liver enzyme tests among patients with rheumatoid arthritis or psoriatic arthritis treated with methotrexate and/or leflunomide.

INTRODUCTION: Potential hepatotoxicity associated with disease-modifying antirheumatic drugs (DMARDs) requires laboratory monitoring. In patients with rheumatoid arthritis (RA) or psoriatic arthritis (PsA), the incidence of elevated alanine aminotransferase/aspartate aminotransferase (ALT/AST) enzymes associated with methotrexate (MTX), leflunomide (LEF) and MTX+LEF versus other DMARDs was examined. METHODS: Patients with RA and PsA enrolled in the Consortium of Rheumatology Researchers of North America (CORRONA) initiating DMARDs were identified. Abnormalities were identified when either was 1- or 2-fold times above the upper limits of normal (ULN). Odds ratios (OR) between MTX/LEF dose and elevated ALT/AST enzymes were estimated using generalised estimating equations. Interaction terms for use of MTX+LEF quantified the incremental risk of the combination compared with each individually. RESULTS: Elevated ALT/AST levels (>1x ULN) occurred in 22%, 17%, 31% and 14% of patients with RA receiving MTX, LEF, MTX+LEF or neither, respectively; elevations were 2.76-fold (95% CI 1.84 to 4.15) more likely in patients with PsA. Elevations >2x ULN occurred in 1-2% of patients on MTX or LEF monotherapy compared with 5% with the combination. After multivariable adjustment and compared with either monotherapy, the combination of MTX and LEF was associated with a greater risk according to MTX dose used as part of the combination: MTX 10-17.5 mg/week, OR 2.91 (95% CI 1.23 to 6.90); MTX > or =20 mg/week, OR 3.98 (95% CI 1.72 to 9.24). CONCLUSIONS: Abnormal ALT/AST levels developed in 14-35% of patients with RA or PsA initiating DMARD therapy. The risks were incrementally greater in those with PsA and in those receiving MTX (> or =10 mg/day) + LEF. These findings should help inform monitoring for potential hepatotoxicity in these patient populations.

Lack of association between angiotensin I-converting enzyme insertion/deletion polymorphism and psoriasis or psoriatic arthritis in Spain.

Data on the potential influence of the angiotensin-converting enzyme (ACE) insertion/ deletion (I/D) genotype on psoriasis are contradictory. Our aim was to investigate the relationship between the ACE gene I/D polymorphism and psoriasis/psoriatic arthritis. To investigate this, a genetic association study was conducted among 268 unrelated patients with psoriasis and 272 controls. The distribution of DD, ID, and II genotypes did not significantly differ between psoriatic patients and controls (DD: 39.6% vs. 34.2%; ID: 46.3% vs. 53.3%; II: 14.1% vs. 12.5%). In conclusion, the ACE polymorphism is not likely to be associated with either psoriasis or psoriatic arthritis in this study.

Association of angiotensin-converting enzyme (ACE) gene insertion-deletion polymorphism with spondylarthropathies.

Low back pain (LBP) is a common medical problem. Interaction between genetic and environmental factors predisposes individuals to LBP even at an early age. Inflammatory back pain or spondylarthropathies include ankylosing spondylitis (AS), psoriatic arthritis (PSA), reactive arthritis enteropathic and undifferentiated arthropathies. Angiotensin-converting enzyme (ACE) plays an important role in circulatory homeostasis, physiology of vasculature and inflammation. The insertion-deletion (I/D) polymorphism of the ACE gene has been shown to determine the plasma and tissue levels of ACE especially in the synovial fluid. The aim of this study was to investigate an association between ACE gene I/D polymorphism and inflammatory back pain (spondylarthropathies) secondary to ankylosing spondylitis (AS), psoriatic arthritis, inflammatory bowel disease and undifferentiated spondylarthropathies. The prevalence of ACE gene I/D polymorphism genotypes was determined in 63 patients with inflammatory back pain by polymerase chain reaction (PCR) and compared with that in 111 healthy controls. Of the 63 patients studied, 45 (71.4%) were with AS, 13 (20.6%) were with PSA, 4 (6.3%) were with reactive arthropathy and 1 (1.6%) manifested undifferentiated arthropathy. There were 43 males and 20 females. Mean age of patients was 39.0+/-11.36 years, age at onset of spondylarthropathy was 27.7+/-7.49 years and disease duration was 10.3+/-7.74 months. The controls were selected to match with the patients group in terms of gender ratio, age and ethnicity. The ACE gene polymorphism showed an overall significant difference between patients and controls (p=0.050). When the ID and II genotype frequency was combined and compared with that for DD genotype amongst patient and control groups, a considerably higher incidence was detected for ID and II genotypes than the DD genotype in spondylarthropathy patients compared to that in the controls (p=0.036). This study showed a significant association of the I-allele of ACE gene I/D polymorphism with spondylarthropathy in Kuwaiti Arabs.

[Bone turnover markers evaluation in psoriatic arthritis]. / Evaluarea anumitor mediatori ai turnover-ului osos din artrita psoriazica.

UNLABELLED: The aim of this study was to investigate the blood level of bone turnover markers: osteoprotegerin (OPG), bone alkaline phosphatase (Bone-ALP), and receptor activator of NF-kappa B ligand (RANKL) of patients with psoriatic arthritis. METHODS: Twenty-four patients with psoriatic arthritis (CASPAR classification criteria) and twenty healthy controls were included. The OPG, Bone-ALP and RANKL levels were quantified by using ELISA method. RESULTS: Peripheral blood levels of bone turnover markers were higher in psoriatic arthritis than martors and there was a strong negative correlation between OPG-RANKL and Bone-ALP- RANKL. CONCLUSION: The OPG and Bone-ALP serum level is strongly negative related to the increase in RANKL serum level in patients with psoriatic arthritis. The increase in OPG and Bone-ALP serum level induces the production of bone matrix parallel to the bone destruction mediated by RANKL. Follow up of patients with psoriatic arthritis, by use of early determination of RANKL, OPG and Bone-ALP serum levels, and also of bone metabolism markers (they have specific role in bone remodeling), allows a precise evaluation of disease activity and, in future, could be a criteria for the initiation of specific, targeting treatment.

Tumour necrosis factor alpha (TNF-alpha)-converting enzyme (TACE) and soluble TNF-alpha receptor type 1 in psoriasis patients treated with narrowband ultraviolet B.

PURPOSE: The aim of the study was to examine the tumour necrosis factor alpha (TNF-alpha)-converting enzyme (TACE) concentration in peripheral blood mononuclear cells (PBMC) and its relationship with plasma concentration of soluble TNF-alpha receptor type 1 (sTNF-R1) and with the disease severity in psoriasis patients treated with narrowband ultraviolet B (NB-UVB). METHODS: The study has been conducted among 40 patients with plaque-type psoriasis vulgaris: 23 had only skin lesions (PV) and 17 had co-existing, inactive, psoriatic arthritis (PsA). Control blood samples were obtained from 20 healthy subjects. The assessment of the severity of skin lesions (using Psoriasis Area and Severity Index - PASI), TACE and sTNF-R1 concentrations (using quantitative sandwich enzyme immunoassays) have been performed at baseline (T 0) and after 20 NB-UVB irradiations (T 20). RESULTS: The baseline sTNF-R1 and TACE concentrations in all patients was higher than that in controls (2.55 +/- 1.67 vs. 1.70 +/- 0.15 ng/ml, P<0.001, respectively, and 2.62 +/- 0.32 vs. 1.31 +/- 0.30 ng/ml, P<0.001, respectively). The sTNF-R1 and TACE concentrations were lower in PV than in PsA patients (2.47 +/- 0.16 vs. 2.65 +/- 0.13 ng/ml, and 2.52 +/- 0.22 vs. 2.76 +/- 0.39 ng/ml, P<0.05, respectively). The baseline PASI correlated with sTNF-R1 and to TACE concentrations (R=0.48 and 0.39, P<0.05, respectively). The sTNF-R1 correlated to TACE concentration (R=0.52, P<0.05). The significant decline in sTNF-R1 and TACE concentrations at T 20 was noticed, TACE reached control values (1.20 +/- 0.44 ng/ml in PV patients and 1.16 +/- 0.48 ng/ml in PsA patients, respectively). CONCLUSION: TACE from PBMC can contribute to up-regulation of sTNF-R1 in patients with active psoriasis vulgaris and with psoriatic arthritis. It also can serve as a sensitive marker of the disease severity.

Angiotensin-converting enzyme gene polymorphism in patients with psoriatic arthritis.

To investigate the frequency of angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism genotypes in adults with psoriatic arthritis (PsA), a heterogeneous chronic disease with autoimmune pathology. ACE gene I/D polymorphism influences the plasma and tissue levels of ACE and has an involvement in inflammatory mechanism. The frequency of ACE gene I/D polymorphism genotypes was determined in 51 adults with PsA from Kuwait, and compared to that in 100 ethnically matched healthy controls using polymerase chain reaction. The distribution of ACE I/D polymorphism and allele frequencies in PsA patients were not significantly different from controls (P > 0.05). Further analyses of PsA patients showed that ACE I/D gene polymorphism was not associated with family history, clinical manifestations, and disease severity. However, the frequency of II genotype was significantly higher in patients with late disease onset than in those with early onset (25 vs. 3%; P = 0.04). No difference was found between the distribution of the ACE genotype in PsA patients and the general population in Kuwait. However, the presence of II genotype may confer susceptibility to the development of late onset PsA.

Differential regulation of Cu, Zn- and Mn-superoxide dismutases by retinoic acid in normal and psoriatic human fibroblasts.

Superoxide dismutases' (SODs) expression is altered in several diseases including Alzheimer, atherosclerosis, cancer and psoriasis. Previously, we reported a marked increase in Mn-SOD and Cu,Zn-SOD functional activity in human dermal psoriatic fibroblasts. As retinoic acid (RA) has been used in the treatment of psoriasis and a mechanism for its beneficial effects is not understood, we investigated the effects of RA on SOD mRNA and protein expression levels in human normal and psoriatic fibroblasts. Prior to RA exposure, Cu,Zn-SOD protein and mRNA levels were similar in normal compared to psoriatic fibroblasts while Mn-SOD protein and mRNA levels were increased in psoriatic cells. However, in contrast to normal fibroblasts, exposure of psoriatic fibroblasts to 1 microM RA down-regulated Mn-SOD mRNA, and also decreased Mn-SOD activity by approximately 80% with no change in Mn-SOD protein levels. In contrast, Cu,Zn-SOD protein and enzymatic activity were modestly reduced by RA treatment in both normal and psoriatic fibroblasts. Furthermore, RA treatment of psoriatic fibroblasts also caused a decrease in Cu,Zn-SOD steady-state mRNA levels. These results indicate that RA can serve as a regulatory agent to down-regulate the steady-state levels of both Mn-SOD and Cu,Zn-SOD in psoriatic cells. These findings offer a new model for the antiinflammatory activity of RA when used in the treatment of psoriasis.

Antibodies to tissue transglutaminase and Saccharomyces cerevisiae in ankylosing spondylitis and psoriatic arthritis.

OBJECTIVE: Subclinical gut inflammation has been described in patients with ankylosing spondylitis (AS) or psoriatic arthritis (PsA). Joint involvement has also been reported related to celiac disease. We investigated IgA antibodies to bovine tissue tranglutaminase (tTg) and IgA and IgG antibodies to human tTg and to Saccharomyces cerevisiae (ASCA) in patients with AS and PsA. METHODS: We evaluated the frequency of IgA antibodies to bovine tTg, and of IgA and IgG antibodies to human tTg and to ASCA in 43 patients with AS and 75 with PsA. As control groups we considered 79 patients with rheumatoid arthritis (RA) and 78 healthy blood donors. RESULTS: We detected antibodies as follows: IgA antibodies to bovine tTg in 1/43 patients with AS, 3/75 with PsA, 1/79 with RA, and in 9/78 healthy controls; IgA antibodies to human tTg in 1/43 patients with AS, 1/75 with PsA, 1/79 with RA, and in 3/78 healthy controls; IgG antibodies to human tTg in 1/43 patients with AS, 4/75 with PsA, 5/79 with RA, and in 7/78 healthy controls. IgA ASCA were confirmed in 10/43 patients with AS, 7/75 with PsA, 14/79 with RA, and in 7/78 healthy controls; IgG ASCA were present in 5/43 patients with AS, 4/75 with PsA, 8/79 with RA, and in 8/78 healthy controls. No statistically significant difference was observed in the prevalence of IgA or IgG antibodies to bovine and human tTg and in the frequency and in mean level of IgA or IgG ASCA between the studied groups or between each group and healthy controls. CONCLUSION: Our data fail to show an increased prevalence of autoantibodies associated with celiac and Crohn's disease in patients with AS and PsA.

MMP-2, MMP-9, TIMP-1 and TIMP-2 levels in patients with rheumatoid arthritis and psoriatic arthritis.

OBJECTIVE: Rheumatoid arthritis (RA) and psoriatic arthritis (PA) are both chronic rheumatic inflammatory diseases characterized by disruption of the extra-cellular matrix (ECM) protein of the cartilage, likely induced by proteolytic enzymes such as matrix metalloproteases (MMPs). The goal of this study was to quantify the expression of MMPs such as MMP-2 and MMP-9, and their physiological tissue inhibitors TIMP-2 and TIMP-1, respectively, in serum and synovial fluid. METHODS: Serum and synovial fluid from 24 RA patients and 17 PA patients were studied to determine the levels of MMP-2 and MMP-9 proteolytic activity using a modified gelatin zymography procedure. TIMP-1 and TIMP-2 were measured by a commercially available ELISA kit. RESULTS: Our results show that MMP-2 was detected in the latent form only, while MMP-9 was present in latent and active form. Both gelatinases were more concentrated in synovial fluid than in serum, and TIMP-1 and TIMP-2 concentrations were also more elevated in synovial fluid than in serum. CONCLUSIONS: To investigate the remodelling of cartilage ECM proteins, the evaluation of synovial fluid concentrations of MMP-2, MMP-9, TIMP-1 and TIMP-2 is more reliable than that determined in serum. In view of these data, MMPs inhibitors might represent a possible target for new therapies delivered directly in the joint space.