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ObjectivesTo assess the efficacy and safety of olokizumab (OKZ), a monoclonal antibody against the interleukin-6 (IL-6) cytokine, versus placebo (PBO) in patients with prior inadequate response to tumour necrosis factor inhibitors (TNFi-IRs).MethodsIn this 24-week multicentre, placebo-controlled, double-blind study, the patients were randomised in a 2:2:1 ratio to receive subcutaneously administered OKZ 64 mg once every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or PBO plus methotrexate. At week 16, the patients on PBO were randomised to receive either OKZ regime. The primary endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. Disease Activity Score 28-joint count C-reactive protein (DAS28 (CRP))ResultsIn 368 patients randomised, ACR20 response rates were 60.9% in OKZ q2w, 59.6% in OKZ q4w and 40.6% in PBO (pDose-related treatment-emergent serious adverse events were 7% in OKZ q2w, 3.2% in OKZ q4w and none in the PBO group.ConclusionsDirect inhibition of IL-6 with OKZ resulted in significant improvements in the signs and symptoms of rheumatoid arthritis compared with PBO in TNF-IR patients with a similar safety profile as observed for monoclonal antibodies to the IL-6 receptor.Trial registration numberNCT02760433.

Progesterone hormone (P4) is a promising agent against strokes because post-ischemic administration of P4 exerts neuroprotective effects in several young and aged animal models of stroke. However, in contrast to a majority of the studies using male animals, female animals remain underrepresented. In addition, we do not know whether the same administration way of P4 is effective in both male and female animals because there are gender different responses to steroid hormones and stroke. In this study, we thus evaluated long-term histological and functional outcomes in the same treatment with P4 in both 18-month old male and age-matched female rats subjected to transient middle cerebral artery occlusion (MCAO). MCAO aged male and female rats were given a subcutaneous injection of P4 (4 mg/kg) 6 h after MCAO followed by once daily for successive 7 days. The post-ischemic administration of P4 significantly improved the impairments of spatial working memory and motor coordination 28–29 days after MCAO in both aged male and age-matched female rats. However, the P4 administration slightly but not significantly reduced infarct sizes 30 days after MCAO in aged female rats, in contrast to significant better histological outcome in P4-treated aged males. On the other hand, these histological and behavioral analyses showed no adverse effects of P4 in aged rats of both sexes. Collectively, our study provides preclinical evidence to prompt further preclinical studies for post-stroke treatment with P4 and the translation of its clinical trials in old stroke patients of both sexes.

Background/Aims Olokizumab (OKZ) is a new humanised monoclonal antibody targeting IL-6. Here we present the results of the phase III study of OKZ in anti-TNF-IR patients. Methods Patients with moderately to severely active RA who had previously failed TNF inhibitors (ClinicalTrials.gov Identifier NCT02760433/CREDO3) were randomized in a 2:2:1 ratio to receive subcutaneous (SC) injections of OKZ 64 mg every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w) or placebo (PBO), plus MTX. At week 16, all subjects in the PBO group were randomized in a 1:1 ratio to receive either of OKZ regimes. The primary endpoint was ACR20 response at week 12. Results 368 subjects were randomised according to the protocol and 320 patients (87%) completed the 24-week treatment period. Baseline characteristics were comparable across arms. Both regimens of OKZ were significantly better in primary endpoint: ACR20 were 60.9% (p = 0.0029 in comparison vs. PBO) in OKZ q2w, 59.6% in OKZ q2w (p = 0.0040 in comparison vs. PBO) and 40.6% in PBO. The key efficacy outcomes were maintained throughout the 24-week period of the study. Overall incidences of treatment-emergent adverse events (TEAE) were 65.5% in OKZ q2w, 65.0% in OKZ q4w and 50.7% in PBO. Subsequent randomization of PBO arm at week 16 did not change TEAEs incidence rate per treatment group significantly: 64.3% in any OKZ q2w and 59.7% in any OKZ q4w. The majority of TEAEs in all groups were not serious and were of mild or moderate severity. Incidence of treatment-emergent serious adverse events (TESAE) were: 12 (7.0%) subjects in any OKZ q2w; 6 subjects (3.2%) in any OKZ q4w group, all in the first 16 weeks. The most frequently reported TESAEs across all treatment groups were infections and infestations: 2 (1.2%) in OKZ q2w group, 2 (1.1%) in OKZ q4w group. No opportunistic infections including active tuberculosis, major adverse cardiovascular events, gastrointestinal perforations or deaths were reported. Conclusion In this global Phase III trial in patients with moderately to severely active RA inadequately controlled by TNF-α inhibitor therapy, treatment with OKZ plus MTX in both regimes (OKZ 64 mg q2w and OKZ 64 mg q4w) was associated with significant improvements in the signs and symptoms of RA compared to PBO plus MTX over a 24-week period. Treatment with OKZ q2w and q4w in this difficult to treat population was well tolerated and consistent with the established safety profile of anti-IL-6 agents. Disclosure E. Feist: Consultancies; R-Pharm, Abbvie, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi. Honoraria; R-Pharm, Abbvie, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Member of speakers’ bureau; R-Pharm, Abbvie, AB2Bio, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Grants/research support; Lilly, Novartis, Pfizer, Roche/Chugai. S. Fatenejad: Consultancies; RPharm International. Shareholder/stock ownership; Pfizer. S. Grishin: Corporate appointments; Employed by R-Pharm. E. Korneva: Corporate appointments; Employed by R-Pharm. M. Luggen: Consultancies; Amgen, Sun Pharmaceuticals, R-Pharm International. Grants/research support; I havAbbvie, R-Pharm, Sun Pharmaceuticals, Pfizer, Novartis, Lilly, and GSK. E. Nasonov: Honoraria; Lilly, Abbnie, Prizer, Biocad, R-Pharm. Member of speakers’ bureau; Lilly, Abbnie, Prizer, Biocad, R-Pharm. M. Samsonov: Corporate appointments; Employed by R-Pharm.

Background/Aims Olokizumab (OKZ) is a new humanised monoclonal antibody targeting IL-6 directly. Here we present the results of a global randomised clinical trial (RCT) in patients (pts) with RA. Methods This double-blind, placebo (PBO) and active controlled, RCT in pts with moderately to severely active RA despite MTX (ClinicalTrials.gov Identifier NCT02760407, CREDO2) was carried out in 18 counties. Pts were randomized 2:2:2:1 to receive subcutaneous injections of OKZ 64 mg every 2 weeks (q2w), OKZ 64 mg once every 4 weeks (q4w), adalimumab (ADA) 40mg q2w or PBO for 24 weeks, plus MTX. After week 24, subjects either rolled over into an open-label study or entered the Safety Follow-Up Period for another 20 weeks. The primary endpoint was ACR 20% (ACR20) response rate at week 12. Secondary endpoints included: percentage of subjects with DAS28-CRP Results 1,648 subjects were randomised to OKZ 64mg q2w (n = 464), OKZ 64mg q4w (n = 479), ADA 40mg (n = 462) or PBO (n = 243). Baseline characteristics were comparable across treatment arms. The vast majority of the pts completed 24 weeks treatment period 421 (90.7%) in q2w, 437 (91.2%) in q4w, 413 (89.4%) in ADA and 208 (85.6%) in PBO arms and enrolled to open-label extension study: 410 (88.4%), 422 (88.1%), 397 (85.9%) and 199 (81.9%) pts, respectively. Both regimens of OKZ were significantly better than PBO in all primary and secondary endpoints. Furthermore, non-inferiority to ADA was demonstrated for the pre-defined endpoints of ACR20 and DAS28-CRP Conclusion In this global Phase III trial, treatment with OKZ plus MTX in both regimes (OKZ 64 mg q2w and OKZ 64 mg q4w) was associated with significant improvements in the signs, symptoms and physical function of RA compared to PBO plus MTX and non-inferior to ADA plus MTX over a 24-week period. OKZ was well tolerated and no new safety signals were observed. Disclosure E. Feist: Consultancies; R-Pharm, Abbvie, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi. Honoraria; R-Pharm, Abbvie, AB2Bio, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Member of speakers’ bureau; R-Pharm, Abbvie, AB2Bio, BMS, Celgene, Janssen, Lilly, Medac, MSD, Novartis, Pfizer, Roche/Chugai, Sanofi, Sobi, UCB. Grants/research support; Lilly, Novartis, Pfizer, Roche/Chugai. S. Chohan: None. S. Fatenejad: Consultancies; RPharm International. Shareholder/stock ownership; Pfizer. S. Grishin: Corporate appointments; Employed by R-Pharm. E. Korneva: Corporate appointments; Employed by R-Pharm. E.L. Nasonov: Honoraria; Lilly, Abbnie, Prizer, Biocad, R-Pharm. Member of speakers’ bureau; Lilly, Abbnie, Prizer, Biocad, R-Pharm. A. Rowińska-Osuch: Consultancies; R-Pharm. M. Samsonov: Corporate appointments; Employed by R-Pharm.

ObjectiveTo evaluate the efficacy and safety of olokizumab (OKZ) in patients with active rheumatoid arthritis despite treatment with methotrexate (MTX).MethodsIn this 24-week multicentre, placebo-controlled, double-blind study, patients were randomised 1:1:1 to receive subcutaneously administered OKZ 64 mg once every 2 weeks, OKZ 64 mg once every 4 weeks, or placebo plus MTX. The primary efficacy endpoint was the proportion of patients achieving an American College of Rheumatology 20% (ACR20) response at week 12. The secondary efficacy endpoints included percentage of subjects achieving Disease Activity Score 28-joint count based on C reactive protein ResultsA total of 428 patients were randomised. ACR20 responses were more frequent with OKZ every 2 weeks (63.6%) and OKZ every 4 weeks (70.4%) than placebo (25.9%) (pConclusionsTreatment with OKZ was associated with significant improvement in signs, symptoms and physical function of rheumatoid arthritis without discernible differences between the two regimens. Safety was as expected for this class of agents. Low immunogenicity was observed.Trial registration numberNCT02760368.

Progesterone (P4) exerts potent neuroprotection both in young and aged animal models of stroke. The neuroprotection is likely to be mediated by allopregnanolone (ALLO) metabolized from P4 by 5α-reductase, since the neuroprotection is attenuated by the 5α-reductase inhibitor finasteride, which was done only with young animals though. Thus, we do not know the contribution of ALLO to the P4-induced neuroprotection in aged animals. We examined effects of finasteride on the P4-induced neuroprotection in aged (16-18-month-old) male rats subjected to transient focal cerebral ischemia. Transient focal cerebral ischemia was induced by left middle cerebral artery occlusion (MCAO) and occlusion of the bilateral common carotid arteries. MCAO rats were given an 8 mg/kg P4 6 h after MCAO followed by the same treatment once a day for successive 3 days. Finasteride, a 5α-reductase inhibitor, at 20 mg/kg was intraperitoneally injected 30 min prior to the P4-injections. P4 markedly reduced neuronal damage 72 h after MCAO, and the P4-induced neuroprotection was apparently suppressed by finasteride in the aged animals. However, post-ischemic administration of finasteride alone (20 mg/kg) significantly prevented neuronal damage and the impairment of Rotarod performance after MCAO in aged male rats, but not in young ones. The androgen receptor antagonist flutamide markedly suppressed the neuroprotection of finasteride in the cerebral cortex, but not in the striatum, suggesting the androgen receptor-dependent mechanism of the finasteride-induced neuroprotection in the cerebral cortex. Our findings suggested, for the first time, the potential of finasteride as a therapeutic agent in post-ischemic treatment of strokes in aged population.

Background:We previously reported positive efficacy and safety results of olokizumab (OKZ), an interleukin-6-inhibitor, in patients with Rheumatoid Arthritis (RA) inadequately controlled by methotrexate (MTX) (NCT02760368; CREDO-1)1. Here we present the patient reported outcomes (PRO) of CREDO-1 study.Objectives:To assess the effect of OKZ treatment comparing to placebo (PBO) on quality of life, work productivity, and fatigue in patients with moderate to severe RA who have previously failed MTX therapy.Methods:We compared PRO between three groups 1) subcutaneous injections of OKZ 64 mg every 2 weeks (q2w), 2) OKZ 64 mg every 4 weeks (q4w) and 3) PBO every q2w.PRO included change from baseline in: Health Assessment Questionnaire-Disability Index (HAQ-DI); Patient’s Global Assessment of Disease Activity (PtGA), Patient’s Assessment of Arthritis Pain (Pain), Short Form-36 (SF-36) Physical (PCS) and Mental (MCS) components; European Quality of Life- Five-Dimension Questionnaire (EQ-5D), Functional Assessment of Chronic Illness Therapy-Fatigue Scale (FACIT-F) and Work Productivity Survey-Rheumatoid Arthritis (WPS-RA).Results:428 patients were enrolled and 396 completed the study. All PRO baseline characteristics were comparable across treatment arms: mean (SD) PtGA was 69.5 (15.5); Pain was 68.6 (17.5); HAQ-DI was 1.7 (0.5); SF-36 PCS was 32.1 (6.5); SF-36 MCS was 42.3 (10.0); EQ-5D was 40.3 (20.0) and FACIT-F was 26.8 (8.7).Treatment with OKZ 64 mg q2w and 64 mg q4w resulted in significant improvement in PRO measures (Table 1). Improvements in all PRO measures observed at week 12 were persistent up to week 24.Table 1.Changes from baseline at 12 week and 24 week for PRO measuresScore, LSM change from baseline (SE)LSM difference vs PBO97.5% CI for LSM differenceWeek 12Week 24OKZ q2w(n=143)OKZ q4w(n=142)OKZ q2w(n=143)OKZ q4w(n=142)PtGA-30.6(1.72)-17.5-23.0, -12.0-31.0(1.73)-17.9-23.4, -12.4-32.1(1.92)-12.7-18.8, -6.6-36.3(1.96)-16.8-23.0, -10.6Pain-31.6(1.82)-18.7-24.6, -12.9-31.8(1.83)-19.0-24.8, -13.1-34.5(2.05)-13.0-19.5, -6.5-37.1(2.08)-15.7-22.3, -9.1HAQ-DI†-0.54(0.04)-0.34***-0.47, -0.21-0.56(0.04)-0.36***-0.49, -0.23-0.55(0.05)-0.27-0.43, -0.12-0.65(0.05)-0.37-0.53, -0.22SF-36 PCS6.72(0.57)4.532.72, 6.336.03(0.57)3.842.01, 5.677.84(0.67)4.302.19, 6.418.73(0.68)5.203.04, 7.35SF-36 MCS6.48(0.73)3.010.69, 5.337.04(0.73)3.571.23, 5.926.21(0.79)3.721.23, 6.228.86(0.80)6.373.82, 8.92EQ-5D Health Today Score19.7(1.69)12.26.8, 17.618.7(1.72)11.25.8, 16.720.9(1.95)12.66.5, 18.723.6(2.01)15.38.9, 21.7FACIT-F8.2(0.67)4.62.4, 6.88.7(0.68)5.12.9, 7.38.5(0.80)4.82.3, 7.310.6(0.81)6.94.3, 9.5†, secondary endpoint; *** P‹0.0001.PRO changes were analyzed using ANCOVA model adjusted for the baseline value of the corresponding parameter. Missing data resulted from study withdrawal imputed based on the return to baseline assumption.Mean improvements in both OKZ groups over PBO for PtGA, Pain, HAQ-DI, SF-36 PCS and MCS, and FACIT-F surpassed defined MCIDs for these measures. No notable differences in PRO measures were observed between the two dose regimens of OKZ.Conclusion:1. Treatment with OKZ over a 24-week period was associated with significant improvements in PRO in patients with moderate to severe RA.2. There were no discernible differences between the two regimens of OKZ from patient’s perspective.References:[1]Nasonov E.et al. Arthritis Rheumatol. 2019; 71 (suppl 10).Acknowledgments:All patients and investigators of CREDO-1 study.Disclosure of Interests:Evgeny Nasonov Speakers bureau: Lilly, AbbVie, Pfizer, Biocad, R-Pharm, Mariana Ivanova Grant/research support from: R-Pharm, Mikhail Samsonov Employee of: R-Pharm, Tamara Tyabut: None declared, Mark C. Genovese Grant/research support from: Abbvie, Eli Lilly and Company, EMD Merck Serono, Galapagos, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, Pfizer Inc., RPharm, Sanofi Genzyme, Consultant of: Abbvie, Eli Lilly and Company, EMD Merck Serono, Genentech/Roche, Gilead Sciences, Inc., GSK, Novartis, RPharm, Sanofi Genzyme

Progesterone (P4) exerts long-term neuroprotective effects in animal models of stroke, and P4 receptors play a crucial role in this neuroprotection. However, it currently remains unclear whether the activation of P4 receptors alone is sufficient to exert long-term neuroprotection because P4 exhibits other steroidogenic and GABAergic activities via several of its metabolites. Nestorone is a potent selective P4 receptor agonist without other steroidogenic and GABAergic activities. Therefore, we examined the effects of nestorone in adult male rats subjected to transient middle cerebral artery occlusion (MCAO). The dose-response relationship of nestorone showed that the 6-h post-ischemic administration of 10 μg/kg nestorone resulted in greater reductions in infarct sizes 48 h after MCAO than the other two doses tested (5 and 80 μg/kg), and this dose of nestorone significantly decreased astrocyte activation in the peri-infarct cortical region. Moreover, 10 μg/kg nestorone significantly prevented functional impairments on the 28th and 29th days and slightly reduced infarct size on the 30th day after MCAO. The present results suggest that the activation of P4 receptors alone is sufficient to exert neuroprotection against transient cerebral ischemia in adult male rats; therefore, nestorone is a promising agent in post-stroke treatment due to its potent progestational effects without other steroid-related activities.

Confluence-dependent inhibition of epithelial cell proliferation, termed contact inhibition, is crucial for epithelial homeostasis and organ size control. Here we report that among epithelial cells, keratinocytes, which compose the stratified epithelium in the skin, possess a unique, actomyosin-dependent mechanism for contact inhibition. We have observed that under actomyosin-inhibited conditions, cell-cell contact itself through E-cadherin promotes proliferation of keratinocytes. Actomyosin activity in confluent keratinocytes, however, inhibits nuclear localization of β-catenin and YAP, and causes attenuation of β-catenin- and YAP-driven cell proliferation. Confluent keratinocytes develop E-cadherin-mediated punctate adhesion complexes, to which radial actin cables are connected. Eliminating the actin-to-E-cadherin linkage by depleting α-catenin increases proliferation of confluent keratinocytes. By contrast, enforced activation of RhoA-regulated actomyosin or external application of pulling force to ligated E-cadherin attenuates their proliferation, suggesting that tensile stress at E-cadherin-mediated adhesion complexes inhibits proliferation of confluent keratinocytes. Our results highlight actomyosin contractility as a crucial factor that provokes confluence-dependent inhibition of keratinocyte proliferation.

Clay-rich mine tailings from phosphate mine operations in Florida are a major environmental and economic problem. Options for reclamation and restoration for these tailings are very limited and are fundamentally restricted by poor physical properties such as low mechanical strength, low hydraulic conductivity, and heavy metal content. The major control on these bulk physical properties is the mineralogy of the materials. Eight continuous push borings were obtained to investigate stratigraphy, mineralogy, aspects of geochemistry, and bulk properties of a deposit of clay-rich mine tailings from a phosphate mine near Bartow, Florida that ceased operations in the early 1970s. Stratigraphy is dominated by laminated clay-rich sediment with minor units of silt and sand. An intact kaolinite liner occurs near the impoundment walls and the impoundment floor has approximately 4 m of relief. Moisture content varies from 4.35 to 57.40 wt% and organic content varies from 0.41 to 9.53 wt%. Bulk XRF investigation indicates that the P2O5 concentrations vary from approximately 4 to 21 wt%. A very strong correlation (r 2 = 0.92) between CaO and P2O5 indicates that apatite is a major control on the phosphate. The strong correlation (r 2 = 0.77) of Al2O3 and TiO2 suggests that the source materials for this deposit are comparatively uniform. A number of heavy metal elements and trace elements occur. Cr, V, Ni, Cu are interpreted to be in phosphate minerals, largely apatite. Sr and Pb are interpreted to be in both phyllosilicates and phosphate minerals. Two populations of apatite were observed in the clay-sized fraction, one that was Fe and Si- bearing and another that was only Si-bearing. Fe-bearing apatite had Fe2O3 contents that varied from 0.38 to 5.32 wt% and SiO2 contents that varied from 0.90 to 3.32 wt%. The other apatite population had a wider range of SiO2 contents that varied from 0.77 to 8.80 wt%. TEM imaging shows that apatite grains are dominantly single crystals with lesser amounts of aggregates. Wavellite commonly occurs as individual or clusters of lath-like crystals and the chemical composition differs from the pure aluminium phosphate end member with average concentrations of components being that of CaO (1.57 wt%), Fe2O3 (1.98 wt%), SiO2 (5.94 wt%). In the clay-sized phosphate minerals investigated no fluorine was found above detection limit (approximately 0.15 wt%), nor was any uranium, radium, heavy metal, or REE element detected. The phyllosilicate mineralogy of the deposit is dominated by smectite (montmorillonite with lesser amounts of nontronite), palygorskite, illite and kaolinite. No systematic variation in the relative proportions of phyllosilicates was observed in the clay deposit. Energy dispersive spectroscopy EDS analysis indicates that chemical compositions of phyllosilicates are somewhat typical but overall are enriched with respect to Fe compared to theoretical end members. The relative enrichment of Fe is interpreted to be a primary sedimentary feature. Ca content in smectite minerals is high and may inhibit stabilization using lime or similar methods. The high percentages of montmorillonite and palygorskite explain the high bulk water contents observed. This investigation provides fundamentally new details regarding clay tailing deposits from closed phosphate mines in central Florida which can be used in restoration and reclamation efforts.

The study was undertaken to examine the clinical value of serum levels of soluble receptors of tumor necrosis factor-alpha with a molecular mass of 55 kDa (rTNF-alpha-55R) in patients with systemic lupus erythematosus (SLE). The serum level of rTNF-alpha-55R was measured by enzyme immunoassay (a "Quantikine" set, RD System, USA) in 73 patients with SLE and 22 donors. In the patients, the mean level of rTNF-alpha-55R was significantly higher than that in donors. Higher serum levels of rTNF-alpha-55R were noted in 43.8% of the patients with SLE. There was a correlation between the level of rTNF-alpha-55R and the progression of SLE (p0.05), the exacerbation (p0.05), and the clinical manifestations of the disease (cardiac valvular apparatus damage, active lupus nephritis). rTNF-alpha-55R are a marker of the progression and exacerbation of SLE and reflects that there is a prognostically poor factor, i.e. the involvement of the kidneys in a pathological process.

Clinical significance of a soluble vascular adhesion-1 molecule (pVCAM-1) in Sneddon's syndrome (SS) was studied in 48 SS patients by examination of serum pVCAM-1 level using enzyme immunoassay (RD, USA). High serum concentration of pVCAM-1 registered in 62.6% of SS patients was associated with extracerebral thromboses, not with severity of cerebral vessel damage. Lethal outcomes for 2 years of follow-up occurred more frequently in patients with a high basal level of pVCAM-1 than in patients with normal level. Thus, development of the pathological process in SS is associated with elevated concentration of serum pVCAM-1 and may serve an additional laboratory indicator of developing extrabrain thrombotic disorders and marker of unfavourable prognosis.

Serum neopterin (SN), concentration of soluble (s) TNF-receptors (R) with molecular mass 55 kD and sIL-2R, C-reactive protein (CRP), Willebrand factor antigen (WF Ag) were measured in enzyme immunoassay (EIA) or radioimmunoassay (BRAHMS, Berlin, Germany) in 189 patients with autoimmune rheumatic diseases: 52 patients with systemic lupus erythematosus (SLE), 67 patients with rheumatoid arthritis (RA), 44 patients with polymyositis/dermatomyositis and 26 patients with Wegener granulomatosis. SN appeared elevated in autoimmune rheumatic diseases correlating with the disease activity and concentrations of sTNF R and sIL 2R. Assay for neopterin is clinically essential for examination of the immunopathological process activity, prediction of the outcomes, better knowledge about cytokine synthesis profile in autoimmune rheumatic diseases.

To investigate the possible relationship between serum levels of neopterin, soluble tumor necrosis factor-55 receptor (sTNF-55R), and soluble interleukin 2 receptor (sIL-2R) with disease activity in patients with Wegener's granulomatosis (WG).Serum neopterin was measured by radioimmunoassay, sTNF-55R and sIL-2R were measured by ELISA in 26 patients with WG.Serum neopterin, sTNF-55R, and sIL-2R were significantly elevated in patients with generalized WG compared with healthy controls. Concentrations of the analytes correlated with disease activity indices in patients without infectious complications. The highest elevations of all 3 variables were observed in patients with intercurrent infections.The increased serum levels of neopterin, sTNF-55R, and sIL-2R suggest activation of cellular immunity in WG.

Out of 12 patients with hemorrhagic vasculitis (HV) having the disease for 3-3.2 years (5 males and 7 females aged 18-55 years, mean age 34 +/- 13.8 years) renal affection was found in 3 (25%) patients. Renal function was normal in all the patients. One patient had nephrotic and two had mixed nephritis. One patient had gastrointestinal lesions. Serum neopterin was measured by radioimmunoassay. Mean concentration of serum neopterin was significantly higher than in donors (9.15 +/- 6.82 nmol/l and 5.2 +/- 2.1 nmol/l, respectively). A high neopterin level was found in 2 (67%) of 3 patients with nephritis and in 1(11%) of 9 patients free of nephritis. Mean neopterin was significantly higher in 3 patients with renal disorders than in the comparison group. A positive correlation existed between neopterin level and the clinical activity index, ESR, IgA, IgG CIC concentrations.

Quantitation of neopterin and morphological examination of bacteria circulating in the blood of 28 patients with dilated cardiomyopathy gave evidence for elevated neopterin concentrations in 22 of the examinees (10 nM/l). The highest neopterin levels occurred in patients with L-form bacteria. Concentrations of neopterin and antibodies to cytomegalovirus, herpes simplex were related. The above antibodies were associated with high neopterin levels in the serum. It is suggested that high amounts of serum neopterin may result from combination of viral and bacterial infection in dilated cardiomyopathy sufferers.

RIA was used to measure the level of neopterine and beta 2-microglobulin in the sera of 43 patients with a verified diagnosis of dilated cardiomyopathy (DCMP). In DCMP patients, the mean level of neopterine was 11.25 +/- 1.05 nM/l and was significantly higher than in donors (5.6 +/- 0.5 nM/l). The concentration of neopterine exceeding 9 nM/l was discovered in 55% of DCMP patients. The rise of neopterine concentration was particularly marked in patients with inflammatory reaction in the myocardium according to endomyocardial biopsy. In that patients' group, the mean level of neopterine was 12.9 +/- 2.02 nM/l while the rise of its concentration over 9 nM/l was recorded in 9 (81%) of 11 patients examined. The correlation was established between the rise of the concentration of neopterine and beta 2-microglobulin. In patients with the concentration of neopterine over 9 nM/l, the mean level of beta 2-microglobulin constituted 3.33 +/- 0.32 mg/l and in patients with the normal concentration of neopterine, it amounted to 1.91 +/- 0.18 mg/l. The growth of the concentration of beta 2-microglobulin in the groups of patients under comparison was seen in 79 and 14% of cases, respectively. It is concluded that neopterine measurements are advisable in the laboratory diagnosis of myocarditis in DCMP patients. Potential mechanisms of the rise of neopterine formation are discussed from the standpoint of hyperinterferonemia.

IgG and IgM antibodies to the myelin major protein (MMP) have been measured by solid-phase enzyme immunoassay (EIA) in the blood sera of 31 patients with dilatation cardiomyopathy (DCMP), 4 ones with coronary disease (CD), and 20 normal subjects. Nonspecific binding of the native and aggregated human gamma-globulin with the MMP has been examined, as well as the correlation between the blood serum concentrations of circulating immune complexes, IgG and IgM, and the rheumatoid factor, and the titers of IgG and IgM antibodies to MMP; no correlation has been detected (p greater than 0.05). The activities of bovine and porcine MMP in EIA have been under study and found identical (p less than 0.001). No anti-MMP antibody has been detected in CD patients, whereas in DCMP IgG antibodies have been present in 55% and IgM ones in 49% of the cases, and 52% of the patients had both types of antibodies. Dynamic titration of anti-MMP antibody carried out in 9 DCMP patients has revealed a 4-fold and higher elevation of the titers in 4 patients and a reduction of these titers in other 4 patients. Comparison of the titers of IgG and IgM antibodies to MMP and the peripheral blood lymphocyte ability to spontaneous synthesis of immunoglobulins and Phytolacca mitogen-stimulated Ig synthesis by the MMP has revealed a correlation between these parameters. The findings permit a hypothesis on the involvement of the nerve fiber myelin-containing cells, possibly of the afferent system of the heart, in half the examinees with DCMP.

The levels of anaphylatoxins (C3a, C5a) in blood, components of complements C3 and C4, antibodies to cardiolipin, IgG, IgA, IgM, IgE and circulating immune complexes were measured in 21 patients with dilated and hypertrophic cardiomyopathy (DCMP and HCMP) and in 11 donors. The mean level of C3a in DCMP patients (572 +/- 55 ng/ml) was significantly higher than in HCMP patients (344 +/- 30 ng/ml) and in donors (294 +/- 43 ng/ml) (p less than 0.001). On comparison of C5a concentrations in DCMP patients (2.2 +/- 0.52 ng/ml), HCMP patients (3.3 +/- 1.2 ng/ml) and in donors (1.6 +/- 0.82 ng/ml) no significant differences were found (p greater than 0.05). It has been established that in the group of DCMP patients with thromboembolic complications, the concentrations of C3a (736 +/- 95 ng/ml) were significantly higher than in those without such complications (334 +/- 14 ng/ml) (p less than 0.001). The data obtained permit discussing the role of anaphylatoxins in the development of thromboembolic complications in DCMP patients.

To evaluate clinical implications of the serum level of soluable receptors of tumor necrosis factor alpha (TNFa) with molecular mass 55 kDa (rTNF-55R) in rheumatoid arthritis, serum levels of rTNF-55R and rTNF-75R were measured with the use of radioimmunoassay in 76 RA patients, 38 donors and in 25 RA patients, 10 donors, respectively.Elevated serum level of rTNF-55R was recorded in 55.3% RA patients. This level correlated with basic clinical and laboratory parameters of RA, the disease activity, values of DAS indices. It is concluded that a serum level of rTNF-55R adequately reflects clinico-laboratory activity of RA and its measurement can be used for assessment of RA activity and treatment efficiency.

Neopterin radioimmunoassay measurements (Henning, Berlin) were conducted in 26 male and 12 female patients (mean age 32 +/- 8.01) with Behcet's disease (BD) and healthy controls. In BD patients mean serum neopterin concentrations were significantly higher than in the controls (8.7 +/- 4.1 nmol/l against 5.0 +/- 1.9 nmol/l, respectively). Neopterin levels were higher in patients with positive pathergy test than in negative subjects (p0.05). There was a significant correlation between neopterin and CRP (rs=0.42. p0.02). The findings indicate that cellular immunity in BD patients is activated.

Raised serum neopterin concentrations were found in 13 of 27 patients (47%) with Wegener's granulomatosis. The neopterin concentrations significantly correlated with the Birmingham Vasculitis Activity Score as well as with the erythrocyte sedimentation rate and C-reactive protein. High serum neopterin levels were also associated with infectious complications. The finding of increased neopterin concentrations in patients with Wegener's granulomatosis supports the role of cell-mediated immunity and particularly of activated macrophages in the pathogenesis of the disease.

To study content and clinical correlations of sTNF-RI in patients with systemic sclerosis (SS).Thirty nine SS patients were examined with enzyme immunoassay for serum levels of sTNF-RI and soluble adhesion molecules (sSAM) sVSAM-1, sISAM-1 and sR-selectine using RD System kits (USA). The control group consisted of 14 healthy subjects (donors). Content of sTNF-RI and sSAM was considered as elevated if it exceeded relevant mean values by 1SD.sTNF-RI content was significantly higher in the patients than in the controls (p = 0.0001) and was similar in patients with diffuse and limited forms of the disease. A rise in sTNF-RI correlated with a rise in pulmonary artery pressure. In patients with pulmonary hypertension or restrictive pulmonary affection sTNF-RI was higher than in patients free of pulmonary hypertension or impaired external respiration function. A marked correlation was found between sTNF-RI and sVSAM-1. Patients with high CRP had significantly higher sTNF-RI level than patients with normal CRP.SS is characterized by elevated content of sTNF-RI. This content may serve a diagnostic marker of the disease progression.

Measurement of neopterin in the serum of patients with rheumatoid arthritis (RA).59 patients with verified RA diagnosis (22 cases of joint lesion stage I-IIa, 27 of stage IIb-IIIa, 10 of stage IIIb-IV established roentgenologically, 48 patients were seropositive by IgM-rheumatoid factor) were examined for concentrations of serum neopterin and C-reactive protein (CRP). The activity and prognostic factors were characterized by modified Wilke method, the severity index was calculated. 100 healthy donors served controls.Immune inflammation in RA develops with growing neopterin concentration in the serum. This concentration well correlates with inflammation activity and intensification of systemic symptoms.Neopterin measurements may be important for determination of inflammation activity in RA. Further efforts should be made to ascertain relationships between neopterin hyperproduction and disturbances of cellular immunity in RA, clinical value of neopterin assays compared to the other laboratory evidence, feasibility of using neopterin levels to define prognosis and efficacy of on-going therapy.