Assessment of Serum sRANKL, sRANKL/OPG Ratio, and Other Bone Turnover Markers with the Estimated 10-Year Risk of Major and Hip Osteoporotic Fractures in Rheumatoid Arthritis: A Cross-Sectional Study.

BACKGROUND: Fracture risk assessment tool (FRAX) index was developed for estimating of the 10-year risk of major or hip osteoporotic fracture. To date, there is insufficient information regarding the correlation between FRAX and serum bone turnover markers (BTMs), such as soluble ligand of receptor activator of nuclear factor-κB (sRANKL), osteoprotegerin (OPG), and other molecules related with secondary osteoporosis in rheumatoid arthritis (RA). Therefore, this study is aimed at assessing the correlation between the FRAX and serum levels of sRANKL, OPG, sRANKL/OPG ratio, Dickkopf-1 (DKK-1), and sclerostin (SOST) in RA. METHODS: Cross-sectional study included 156 postmenopausal women with RA. Bone mineral density (BMD) was measured at lumbar spine (L1-L4) and total hip using dual-energy X-ray absorptiometry (DXA). RA patients were divided into (A) RA + osteoporosis and (B) RA without osteoporosis. FRAX scores were calculated including the total hip BMD. Serum sRANKL, OPG, DKK-1, and SOST levels were measured by ELISA. Pearson tests were used for assessing the correlation between serum levels of these molecules and FRAX scores in RA. RESULTS: The RA + osteoporosis group had elevated sRANKL levels (p = 0.005), higher sRANKL/OPG ratio (p = 0.017), decreased DKK-1 (p = 0.028), and lower SOST levels (p < 0.001). Low total hip BMD correlated with high sRANKL (p = 0.001) and sRANKL/OPG ratio (p = 0.005). Total hip and lumbar spine BMD correlated with DKK-1 (p = 0.009 and p = 0.05, respectively) and SOST levels (p < 0.001 and p < 0.001, respectively). Higher sRANKL levels and sRANKL/OPG ratio correlated with estimated 10-year risk of a major osteoporotic fractures (p = 0.003 and p = 0.003, respectively) and hip fracture (p = 0.002 and p = 0.006, respectively). High serum SOST levels were associated with a low estimated 10-year risk of a major osteoporotic fracture (p = 0.003) and hip fracture (p = 0.009). CONCLUSION: High sRANKL levels and sRANKL/OPG ratio can be useful to detect a subgroup of RA patients who has an increased 10-year risk of major and hip osteoporotic fractures.

Polymorphism rs2073618 of the TNFRSF11B (OPG) Gene and Bone Mineral Density in Mexican Women with Rheumatoid Arthritis.

Osteoporosis (OP) is highly prevalent in rheumatoid arthritis (RA) and is influenced by genetic factors. Single-nucleotide polymorphism (SNP) rs2073618 in the TNFRSF11B osteoprotegerin (OPG) gene has been related to postmenopausal OP although, to date, no information has been described concerning whether this polymorphism is implied in abnormalities of bone mineral density (BMD) in RA. We evaluated, in a case-control study performed in Mexican-Mestizo women with RA, whether SNP rs2073618 in the TNFRSF11B gene is associated with a decrease in BMD. RA patients were classified as follows: (1) low BMD and (2) normal BMD. All patients were genotyped for the rs2073618 polymorphism by PCR-RFLP. The frequency of low BMD was 74.4%. Higher age was observed in RA with low BMD versus normal BMD (62 and 54 years, resp.; p < 0.001). Worse functioning and lower BMI were observed in RA with low BMD (p = 0.003 and p = 0.002, resp.). We found similar genotype frequencies in RA with low BMD versus RA with normal BMD (GG genotype 71% versus 64.4%, GC 26% versus 33%, and CC 3% versus 2.2%, resp.; p = 0.6). We concluded that in Mexican-Mestizo female patients with RA, the rs2073618 polymorphism of the TNRFS11B gene is not associated with low BMD.

Association of 86 bp variable number of tandem repeat (VNTR) polymorphism of interleukin-1 receptor antagonist (IL1RN) with susceptibility and clinical activity in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic, systemic disease of unknown etiology. Several studies have reported a variable number of tandem repeat (VNTR) 86 bp (rs2234663) in the intron 2 of IL1RN gene with RA risk. The present study was designed to determine the frequencies of this polymorphism in patients with RA and control subjects (CS) and its association with RA in a western Mexican population. An analytical cross-sectional study was performed, in which 350 patients with RA and 307 CS were included. The identification of IL1RN VNTR polymorphism was carried out by polymerase chain reaction (PCR), and genotypes were associated with clinical variables (DAS28 and CRP). The presence of A1/A2 genotype was associated with RA risk (p = 0.03, OR = 1.45, 95% CI = 1.02-2.05). Also, results indicate that the presence of heterozygote genotypes which include A2 was associated with RA risk (p = 0.01, OR = 1.5, 95% CI = 1.07-2.11). Patients carrier of A2/A2 genotype have a higher score of DAS28 (5.64 [4.49-6.70]). A-/A- has higher level of CRP (2.30 [0.62-9.10]) in comparison with A2/A- (1.06 [0.37-2.82]). A1/A2 genotype was associated with susceptibility to RA in a western Mexican population. The presence of the A2/A2 genotype in RA is associated with increased disease activity.

Association between bone turnover markers, clinical variables, spinal syndesmophytes and bone mineral density in Mexican patients with ankylosing spondylitis.

OBJECTIVES: To compare bone turnover marker (BTM) levels and bone mineral density (BMD) between patients with ankylosing spondylitis (AS) and healthy controls (HC) and to evaluate, in AS, the association between BTM levels and clinical variables, spinal syndesmophytes, and BMD using multivariate analysis. METHOD: Seventy-eight AS patients were compared with 58 HC matched by gender. Spinal syndesmophytes in AS and other characteristics were assessed. C-terminal telopeptide fragments of type I collagen (CTX), bone-specific alkaline phosphatase (BAP), osteocalcin (OC) serum levels, and BMD of the lumbar spine, femoral neck, and forearm were evaluated. RESULTS: AS males and females had lower BAP levels than their respective HC (p < 0.001 and p = 0.001). AS patients with bridging syndesmophytes had higher OC levels than AS patients either with non-bridging syndesmophytes (p = 0.001) or without spinal syndesmophytes (p < 0.001). OC and CTX levels correlated significantly with the modified Stoke Ankylosing Spondylitis Spinal Score (mSASSS). In the multivariate linear regression adjusted by age, gender, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), BMD in the lumbar spine, and C-reactive protein (CRP), we observed an association between BAP levels and anti-tumour necrosis factor (anti-TNF) use (p = 0.05) whereas OC levels were associated with mSASSS (p < 0.001) and anti-TNF use (p = 0.05), and CTX levels were exclusively associated with mSASSS (p = 0.03). In the logistic regression analysis, only OC levels were associated with the presence of syndesmophytes in AS [odds ratio (OR) 2.42, 95% confidence interval (CI) 1.19-5.75]. CONCLUSIONS: We observed an increase in OC levels in AS patients with syndesmophytes. BTM levels were associated with the severity of spinal damage. Future longitudinal studies should evaluate whether these BTMs should be included as tools to determine the prognosis and progression of spinal damage.

Association analysis of vitamin D receptor gene polymorphisms and bone mineral density in postmenopausal Mexican-Mestizo women.

We investigated associations between vitamin D receptor (VDR) gene polymorphisms, FokI T>C (rs2228570), BsmI G>A (rs1544410), ApaI G>T (rs7975232), and TaqI T>C (rs731236), with bone mineral density (BMD) in postmenopausal Mexican-Mestizo women. Three hundred and twenty postmenopausal women participated, who were classified according to World Health Organization criteria as non-osteoporotic (Non-OP; N = 88), osteopenic (Opn; N = 144), and osteoporotic (OP; N = 88). BMD measurements at the lumbar (L1-L4) spine and at the left and right femoral neck were obtained by dual-energy X-ray absorptiometry. Single nucleotide polymorphisms (SNPs) were genotyped using real-time polymerase chain reaction and TaqMan probes. Genotype and allelic frequencies of the 4 VDR SNPs were similar among the 3 groups. Polymorphic allele frequencies were as follows: FokI (C) 0.53, 0.49, 0.56; BsmI (A) 0.26, 0.22, 0.23; ApaI (T) 0.43, 0.39, 0.44; TaqI (C) 0.27, 0.22, 0.23 for the Non-OP, Opn, and OP groups, respectively. Although no associations were found between the SNPs and BMD, based on the putative function of the FokI SNP, we constructed, for the first time, the haplotype with the 4 VDR SNPs, and found that the CGGT haplotype differed between the Non- OP and OP groups (21.8 vs 31.8%, P < 0.05). The risk analysis for this haplotype was nearly significant under the dominant model (OR = 1.783, 95%CI = 0.98-3.25, P = 0.058). This result suggests a possible susceptibility effect of the C allele of the FokI SNP for the development of osteoporosis in postmenopausal Mexican-Mestizo women.

Pulmonary function in ankylosing spondylitis: association with clinical variables.

To evaluate the association between pulmonary function and clinical variables in ankylosing spondylitis (AS) and to compare the pulmonary function of patients with AS with that of healthy controls, 61 AS patients and 74 healthy controls were included. In AS, we assessed clinical disease indices (BASDAI, BASFI, BASG), morning stiffness, number of hypersensitive entheses, metrology measures, 6-min walking test, acute phase reactants, radiological presence of "bamboo spine," and severity of radiological involvement in sacroiliac and vertebral joints. AS and healthy controls had similar age and gender. All the parameters of pulmonary function were significantly diminished in AS than in healthy controls (p < 0.001), with a higher proportion of restrictive pattern (57.4 vs. 5.4 %). In AS, pulmonary function correlated negatively with BASDAI, BASFI, BASG, morning stiffness, number of hypersensitive entheses, occiput-wall distance, and ESR, and positively with 6-min walking test. There was no association between pulmonary function with radiological stage of vertebral joints and sacroiliac joints, "bamboo spine," disease duration, or chest expansion. A higher frequency of AS patients had a decreased pulmonary function and results of the 6-min walking test. These abnormalities in AS were more related with disease activity than with mobility limitation.

The ACTN3 R577X polymorphism is associated with inflammatory myopathies in a Mexican population.

BACKGROUND: The ACTN3 gene encodes the fast muscle protein α-actinin-3. The ACTN3 R577X polymorphism is a premature stop codon and results in absence of α-actinin-3 in 577XX homozygotes. The aim of this study was to determine the ACTN3 genotype in idiopathic inflammatory myopathies (IIMs). METHODS: We performed ACTN3 genotyping on 27 patients with dermatomyositis (DM), 10 with polymyositis (PM), and 85 healthy subjects. Muscle enzyme levels of creatine phosphokinase (CPK), lactic dehydrogenase (LDH), aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were recorded at the time of diagnosis and recruitment. Genotyping was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and the allele frequency was analysed. RESULTS: A total of 36% of healthy subjects had the ACTN3 577XX polymorphism (α-actinin-3 deficiency), 18% had the 577RR (homozygous wild type) genotype, and 46% 577RX (heterozygous). In DM/PM, 70% had the ACTN3 577XX polymorphism, 6% RR, and 24% RX [odds ratio (OR) 4.12, 95% confidence interval (CI) 1.67-10.33, p < 0.001]. In healthy subjects, the R allele was present in 41% and the X allele in 59% compared to 18% and 82%, respectively, in the IIM group (OR 3.21, 95% CI 1.57-6.66, p < 0.001). Thus, the ACTN3 577X allele seemed to increase the risk of developing IIM, and DM in particular, although this was not related to severity of expression of the phenotype. CONCLUSIONS: The ACTN3 577X allele appeared to increase the risk of developing IIM; 70% of IIM patients were deficient in α-actinin-3. By contrast, ACTN3 577XX patients seemed to have less severe disease as reflected in lower muscle enzyme levels.

Polymorphisms C677T and A1298C in the MTHFR gene in Mexican patients with rheumatoid arthritis treated with methotrexate: implication with elevation of transaminases.

Rheumatoid arthritis (RA) is the prototype of the rheumatic diseases worldwide. Methotrexate (MTX) is the drug of first choice in the treatment of this disease due to its immunosuppressant effect. However, side events are present in 30% of the patients. The C677T and A1298C polymorphisms of the methylenetetrahydrofolate reductase (MTHFR) gene are involved in the metabolism of MTX. Earlier studies reported an association between these polymorphisms and elevation of hepatic enzymes. We analyzed the frequencies of both polymorphisms and the presence of transaminasemia in 70 Mexican patients with rheumatic arthritis treated with MTX. The 19% (13/70) of patients had an increase in the serum level of transaminases. The A1298C polymorphism was associated with elevation of transaminases (P=0.024). The identification of MTHFR genotypes for C677T and A1298C polymorphisms could lead clinicians to identify patients in risk of elevation of transaminases, and give them an individualized treatment, as is a goal of pharmacogenetics.

Autoantibodies to a miRNA-binding protein Argonaute2 (Su antigen) in patients with hepatitis C virus infection.

OBJECTIVES: Chronic liver diseases caused by hepatitis B (HBV) or C virus (HCV) are common worldwide. Despite reports on autoimmunity in viral hepatitis, studies on autoantibodies associated with systemic rheumatic diseases are inconsistent. Testing of a small number of selected autoantibody specificities using ELISA appears to be one reason for inconsistency. Sera from patients with viral hepatitis were tested by immunoprecipitation that will allow unbiased screening of autoantibodies found in systemic rheumatic diseases. METHODS: Ninety Mexican patients (37 male, 53 female, 26 HBV, 6 HBV+HCV, 58 HCV) with chronic viral hepatitis, confirmed by nested or RT-nested-PCR, HBsAg and anti-HCV antibodies, were studied. Autoantibodies were tested by immunofluorescence, immunoprecipitation and ELISA. Specificities were verified using reference sera. RESULTS: Antinuclear antibodies were found in 38% HBV, 17% HBV+HCV, and 28% in HCV. Autoantibodies to Argonaute (Ago2, Su antigen), a microRNA binding protein that plays a key role in RNA-induced silencing complex (RISC), was found in 5% (4/64) of HCV or HBV+HCV coinfected patients but not in HBV (0/26). Anti-Ago2/Su was found in 1/2 of I-IFN-treated case vs. 3/62 in cases without I-IFN. HCV did not have other lupus autoantibodies whereas 19% (5/26) of HBV had anti-U1RNP+Ku, Ro+La, RNA polymerase II, or possible U5snRNPs. CONCLUSIONS: Lupus autoantibodies were uncommon in HCV except anti-Ago2/Su. HCV and I-IFN have many ways to affect TLR signaling, miRNA and miRNA binding protein Ago2/Su. To understand the mechanism of specific targeting of Ago2 in HCV may provide a clue to understand the mechanism of specific autoantibody production.

Serum IgG activity against cyclic citrullinated peptide in patients evaluated for rheumatoid factor correlates with the IgM isotype.

The purpose of this study was to evaluate the frequency of seric antibodies against cyclic citrullinated peptide (a-CCP) in patients tested for rheumatoid factor (RF) reactivity, and to analyze the correlation between their titers. We obtained serum from 112 consecutive patients (85 female), aged 47.2 +/- 13.4 years and from 46 clinically healthy subjects (CHS). Patients where stratified into four subgroups: rheumatoid arthritis (RA), probable RA (PRA), spondylarthropathies and other diagnosis. The a-CCP antibodies were determined by enzyme linked immunoassay (ELISA), RF by nephelometric test (IgM) and ELISA (IgG and IgM). Analysis of variance (ANOVA) showed statistically that a-CCP antibodies differs among RA versus CHS and other diagnosis; PRA versus CHS and other diagnosis. A significant Rho value of 0.84 (P < 0.05, Spearman's correlation) was identified between a-CCP antibodies and RF in PRA subgroup. When a correlation of a-CCP antibodies with RF (both isotypes) was done, the higher correlation was observed against IgM RF. The data suggests different pathways and times for each antibody generation.

Factors associated with hyperhomocysteinaemia in Mexican patients with rheumatoid arthritis.

BACKGROUND: Hyperhomocysteinaemia is a factor related to the development of atherosclerosis in rheumatoid arthritis (RA). However, Hispanics with RA develop high rates of coronary disease; there are no studies about the frequency and factors related to high levels of homocysteine in Mexican patients. OBJECTIVE: To evaluate the prevalence and characteristics associated with hyperhomocysteinaemia in Mexican patients with RA. METHODS: One hundred and fifty-two patients with RA were compared with 153 controls. The assessment in RA included clinical characteristics, disease activity (RADAR), functioning (HAQ-Di and global functional status), comorbidity, and radiological damage. Laboratory determinations included total serum homocysteine (tHcy), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), rheumatoid factor (RF), and lipid profile. RESULTS: Median levels of homocysteine were higher in RA compared with controls (11.3 vs. 9.3, p<0.001). Twenty per cent of the patients with RA had hyperhomocysteinaemia (>15 micromol/L) compared with 6% in controls (p<0.001). There was statistical association between hyperhomocysteinaemia in RA with male gender (p<0.001), impairment in the global functional status (p = 0.004), higher radiological damage (p = 0.001), and CRP (p = 0.04). There was no association with RADAR, HAQ-Di, or RF, methotrexate dose or duration of use. In the adjusted multivariate model, the two variables associated with higher risk for hyperhomocysteinaemia were male gender (OR = 4.2, 95% CI 2 to 12, p = 0.006) and higher radiological damage (III-IV) (OR = 3.4, 95% CI 1.3 to 9, p = 0.01). CONCLUSIONS: Our data show a high prevalence of hyperhomocysteinaemia in Mexican patients with RA. More effort is required to evaluate and treat earlier this coronary risk factor.

Oxidized low-density lipoprotein and beta2-glycoprotein I in patients with systemic lupus erythematosus and increased carotid intima-media thickness: implications in autoimmune-mediated atherosclerosis.

Oxidative stress and LDL modification (oxLDL) are early pro-atherogenic events. OxLDL binds beta2GPI producing immunogenic oxLDL/beta2GPI complexes. Antibodies to these complexes have been associated with arterial thrombosis in patients with systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). Circulating oxLDL/beta2GPI complexes, IgG and IgM antibodies to these complexes were measured by ELISA in 30 SLE patients asymptomatic for cardiovascular disease (mean age 31 years) and 27 age/sex matched healthy controls. Carotid intima-media thickness (IMT) was measured by ultrasound in all patients and controls. Forty-seven percent of SLE presented plaques (median IMT of 0.65 +/- 0.12 mm) while only 7% of the controls had plaques (median IMT of 0.50 +/- 0.04 mm, P < 0.001). Median optical density (OD450nm) for oxLDL/beta2GPI complexes in SLE was 0.244 +/- 0.07, higher than controls (0.174 +/- 0.09, P < 0.001). Median OD for IgG anti-oxLDL/beta2GPI antibodies was also higher in SLE (0.297 +/- 0.26) compared to controls (0.194 +/- 0.07, P < 0.001) while the median OD for IgM antibodies in SLE (0.444 +/- 0.46) was not different than controls (0.326 +/- 0.22, P = 0.267). There was no correlation between IMT and oxLDL/beta2GPI complexes, IgG or IgM antibodies, possibly reflecting the complex interrelationship between these serologic elements and tissue factors in the arterial wall. These results support the hypothesis that oxLDL/beta2GPI complexes and IgG (not IgM) anti-oxLDL/beta2GPI antibodies contribute to the development of autoimmune-mediated atherosclerosis.

Serum concentrations of aminoterminal propeptide of type III procollagen and propeptide of human type I procollagen in systemic lupus erythematosus.

The purpose of this study was to assess the association between the serum levels of aminoterminal propeptide of type III procollagen (PIIINP) and carboxyterminal propeptide of type I procollagen (PICP) with disease activity and damage in systemic lupus erythematosus (SLE). Thirty-three patients with SLE were compared with 31 controls. The assessment in SLE included disease activity indices (SLEDAI, MEX-SLEDAI) and damage index (SLICC/ACR). PIIINP and PICP were measured by radioimmunoassay. Compared with controls, mean levels of PIIINP were higher in SLE (2.9+/-1.8 vs. 1.8+/-1.2, P=0.006). PICP was also increased in SLE versus controls (163+/-94 vs. 102+/-62, P=0.007). PIIINP was correlated with SLICC/ACR (r=0.33, P=0.048). No correlation was observed between PICP and PIIINP with other clinical or therapeutic variables. These preliminary data suggests a role of PIIINP as a marker for chronic damage. Follow-up studies are required to evaluate its utility in predicting future damage.

Pimecrolimus 1% cream for the treatment of discoid lupus erythematosus.

OBJECTIVES: To determine the safety and efficacy of pimecrolimus cream on lesions of discoid lupus erythematosus. METHODS: In an open-label phase II trial, patients with discoid lupus were treated with pimecrolimus 1% cream twice daily for 8 weeks. We assessed skin involvement with a clinical severity score, quality of life, patient improvement and toxicity. The changes were documented by skin biopsy at baseline and at the end of treatment. RESULTS: Ten patients with a mean age of 34 +/- 17 yr and disease duration of 3 yr (range 1-8) were studied; 90% were female and 40% had received prior topical or systemic therapy without response. In all patients, improvement of skin damage was observed after therapy. A significant decrease of 52% was observed in the mean +/- s.d. clinical severity score, from 6.1 +/- 1.4 before treatment to 2.9 +/- 1.5 after treatment (P = 0.005). Quality of life score (0 = no effect, 100 = maximum effect on quality of life) showed a mean improvement of 46%, from 42.8 +/- 23.1 before to 23 +/- 16.5 after treatment (P = 0.008). According to the patients' assessment of the response to treatment, 50% qualified as marked improvement, 40% moderate and 10% slight improvement. The treatment was well tolerated; adverse reactions consisted of minimal erythema and pruritus, which resolved without any further action. CONCLUSIONS: Our data suggest that pimecrolimus cream for discoid lupus erythematosus seems to be a safe and clinically effective option. However, this was an open and uncontrolled study, and double-blind, placebo-controlled studies are needed.

Methylenetetrahydrofolate reductase C677T polymorphism and Factor V Leiden variant in Mexican women with preeclampsia/eclampsia.

The etiology of preeclampsia is still a matter of controversy. An association between hyperhomocysteinemia and preeclamptic patients has been described. A common missense mutation in the methylenetetrahydrofolate reductase (MTHFR) gene is associated with increased plasma homocysteine concentrations. In addition, the polymorphism of gene encoding for Factor V Leiden G1691A is associated with a prothrombotic state in heterozygous subjects. Both mutations in these thrombophilic proteins appear to have different prevalence in the general population and in patients with preeclampsia/eclampsia (PE/E). We studied single nucleotide polymorphisms for MTHFR C677T and coagulation Factor V Leiden in 33 Mexican patients with PE/E as a genetic risk factor for these diseases, comparing with a normotensive pregnant control group. The genotype and allele frequencies of MTHFR C677T and Factor V Leiden mutations between Mexican women with PE/E and healthy controls were not different. We conclude that these polymorphisms do not contribute in the etiology of PE/E as it has been reported in other populations.

Acquired ichthyosis associated with systemic lupus erythematosus.

Acquired ichthyosis is an uncommon disease, it is characterized by symmetric scaling of the skin, which ranges from minor roughness and dryness to the desquamation of large plaques. It has been associated with various systemic diseases, although malignant conditions, especially Hodgkin's lymphoma are the most commonly cited. Drugs, HIV infection and autoimmune diseases such as dermatomyositis and mixed connective tissue disease have also been associated, and it has only rarely been found among patients with systemic lupus erythematosus (SLE). Herein, we report a patient with active SLE who developed a generalized acquired ichthyosis corroborated with skin biopsy, which completely disappeared after treatment. The association of autoimmune conditions with acquired ichthyosis could indicate that an abnormal host immune response, probably against components of the granular cell layer in particular the keratohyalin granules, may have a role in the pathogenesis. Thus, this finding may be a relevant cutaneous marker for an autoimmune origin.

Leflunomide in the treatment of psoriasis: results of a phase II open trial.

BACKGROUND: Psoriasis is recognized as the most prevalent T-cell-mediated inflammatory disease in humans, with predominantly activated T-helper (Th) 1 cell effectors. Leflunomide exerts its anti-inflammatory activities by preventing the generation of proinflammatory Th1 effectors and promoting Th2 cell differentiation. OBJECTIVES: To determine the safety and efficacy of leflunomide in patients with moderate to severe plaque-type psoriasis. METHODS: In an open-label phase II trial, eight patients with psoriasis received oral leflunomide 20 mg daily for 12 weeks. Patients were evaluated for improvement in psoriasis, quality of life, histological changes and toxicity. RESULTS: Antipsoriatic effects were obtained in all but two patients. A significant decrease was observed in the mean +/- SD Psoriasis Area and Severity Index score, from 20.08 +/- 6.85 before treatment to 12.51 +/- 11.83 after (P = 0.03). The antipsoriatic efficiency was confirmed histologically, with a significant mean +/- SD decrease in epidermal thickness, from 0.73 +/- 0.19 micro m before to 0.31 +/- 0.16 microm after (P = 0.01). The quality of life score showed an improvement, from 8.58 +/- 2.38 (mean +/- SD) before to 5.33 +/- 1.95 after (P = 0.02). The treatment was well tolerated; adverse reactions primarily consisted of transitory gastrointestinal events. CONCLUSIONS: Our data suggest that leflunomide for plaque-type psoriasis is a safe and clinically effective option as monotherapy. However, double-blind, placebo-controlled studies are needed.

Therapy with intermittent pulse cyclophosphamide for pulmonary hypertension associated with systemic lupus erythematosus.

The aim of this study was to compare the efficacy of intravenous cyclophosphamide (IVCYC) versus oral enalapril in mild or moderate pulmonary hypertension (PH) in systemic lupus erythematosus (SLE). Thirty-four patients with SLE who had systolic pulmonary artery pressure (SPAP) > 30 mmHg by Doppler echocardiography were randomized to receive IVCYC (0.5 g/mt2 body surface area, monthly), or oral enalapril (10 mg/day) for six months. The primary outcome was the significant decrease in SPAP. An additional outcome measure included the improvement in the heart functional class (NYHA). Sixteen patients received cyclophosphamide and 18 enalapril. IVCYC decreased the median values of SPAP from 41 to 28 mmHg (P < 0.001), and enalapril from 35 to 27 mmHg (P = 0.02). IVCYC reduced more than twice as much SPAP than enalapril (P = 0.04). In those patients with SPAP > or = 35 mmHg, cyclophosphamide decreased from 43 to 27 mmHg (P = 0.003), but enalapril was not effective (P = 0.14). The NYHA functional class improved only in those with cyclophosphamide (P = 0.021). Also IVCYC had a higher frequency of side effects including infections (RR = 1.6; 95% CI, 1.001-2.47), and gastrointestinal side effects (RR = 14.6; 95% CI, 2.15-99.68). We concluded that IVCYC was effective in mild and moderate PH associated with SLE. Further research is needed to evaluate its long-term efficacy.

Autoantibodies to receptor induced neoepitopes of fibrinolytic proteins in rheumatic and vascular diseases.

OBJECTIVE: Abnormal plasminogen activation has been implicated in vascular and rheumatic diseases. The development of an autoimmune response to neoepitopes of plasminogen and its activator (tissue-type plasminogen activator, t-PA) was explored in sera from patients with rheumatoid arthritis (RA, n = 30), Behcet's disease (n = 20), primary antiphospholipid syndrome (APS, n = 23), and idiopathic arterial (n = 33) or venous thrombosis (n = 16). METHODS: Sera diluted 1/50 were incubated with either plasminogen or t-PA bound to their natural receptors (immobilized fibrin or monocytic cells), and bound immunoglobulins were detected using a sheep peroxidase labeled anti-human Fab IgG. Controls included plates coated with fibrin or cells alone or plasminogen passively adsorbed to the plastic. Sera were considered positive when the absorbance at 405/490 nm was above the mean + 2 SD of normal sera. RESULTS: Reactivity of sera against plasminogen bound to cells (28%) or to fibrin (22%) was a predominant feature in patients with RA compared with other patient groups and controls. However, some patients with primary APS had reactivity against cell and fibrin bound plasminogen (9 and 13%, respectively). Autoantibodies against fibrin bound t-PA were detected in only 8% of patients with arterial or venous thrombosis. CONCLUSION: Conformational changes induced by molecular assembly of plasminogen on cell or fibrin surfaces result in the expression of neoepitopes recognized by autoantibodies. These autoantibodies could be markers of the proteolytic events associated with plasminogen activation in autoimmune diseases.