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ID PMID Title PublicationDate abstract
12083985 Advances in the treatment of rheumatoid arthritis: old versus new therapies. 2002 Jul Rheumatoid arthritis (RA) is a common cause of disability in the western population, with an annual incidence of 0.05% and a prevalence of 1%. Although a small percentage of patients go into natural remission, the untreated disease progresses to cause disability, morbidity and early mortality. Unravelling of the cytokine network in the pathogenesis of RA has led to the development of drugs that target these cytokines and prevent joint damage. Three biological anticytokine agents, etanercept, infliximab and anakinra, are now available for use in RA. More experience will quantify their safety and benefits. The potency of the older disease-modifying antirheumatic drugs (DMARDs), such as methotrexate and sulfasalazine, is also being realised, especially when used early in the disease process and in combination. Leflunomide is a new DMARD with efficacy similar to methotrexate and sulfasalazine. Symptomatic treatment of RA with nonsteroidal anti-inflammatory drugs has also undergone a revolution with the availability of a new class of COX-2-specific inhibitors. These drugs control inflammation and provide pain relief with less GI toxicity. Management of comorbid conditions associated with RA and its treatment (i.e., osteoporosis, cardiovascular and lung disease) has also become a priority for the rheumatologist. It is hoped that more aggressive use of conventional DMARDs and biological agents will result in less disability and a higher proportion of patients achieving remission.
11784123 Clonotypic analysis of T cells accumulating at arthritic lesions in HTLV-I env-pX transgen 2002 Feb Human T cell leukemia virus type I (HTLV-I) env-pX transgenic rats (env-pX rats) develop chronic destructive arthritis resembling rheumatoid arthritis in humans. Immunological characteristics were compared with those of collagen-induced arthritis (CIA). Rheumatoid factor was present in some env-pX rats regardless of the development of arthritis, but not in nontransgenic rats with CIA. All rats with CIA produced anti-type II collagen (IIC) antibody, but never so in env-pX rats with naturally occurring arthritis. Although expansions of oligoclonal T cells were evident in the affected joints, no particular clone was shown to infiltrate into the arthritic lesions in env-pX rats. In contrast to CIA, in which clonal expansions of IIC-specific T cells are implicated, locally expanded T cell clones against various antigens of the joints may play pathogenetic roles in the arthritis seen in env-pX rats. However, complementarity-determining region 3 of the TCR Vbeta gene of T cells accumulating at the affected joints in env-pX rats contained the GGA amino acid sequence, which was reported to be a conserved motif in HTLV-I env-pX transgenic mice with arthritis. These findings suggest that common antigen(s) might be recognized by T cells accumulating at sites of arthritis in both transgenic rats and mice.
12695157 Active leflunomide metabolite inhibits interleukin 1beta, tumour necrosis factor alpha, ni 2003 May BACKGROUND: Leflunomide is now an approved agent for the management of adult rheumatoid arthritis (RA). Its active metabolite A771726 inhibits de novo pyrimidine biosynthesis. Although considered to be an immunosuppressive agent, its mechanism of action remains obscure. OBJECTIVES: Evaluation of the leflunomide active metabolite A771726 (LEF) effect on interleukin 1beta (IL1beta), tumour necrosis factor (TNFalpha), nitric oxide (NO), and stromelysin (metalloproteinase-3 (MMP-3)) production by activated human synovial tissue in culture. METHODS: Synovial tissue was obtained during surgery from patients undergoing total knee replacement owing to RA or osteoarthritis (OA), cut into small pieces, and cultured in Petri dishes with test materials as previously described. IL1beta, TNFalpha, NO, and MMP-3 were measured in the culture media after 48 hours incubation with different doses of LEF by methods previously described. RESULTS: LEF (0.3, 3, and 9 micro g/ml) inhibited IL1beta production in the presence of lipopolysaccharide (LPS; 3 micro g/ml) in a dose dependent manner (p<0.01) at LEF 0.3 micro g/ml. TNFalpha production in the presence of IL1beta (1 ng/ml) was also inhibited in a dose dependent manner (p<0.05 at LEF 0.3 micro g/ml). NO and MMP-3 production in the presence of LPS (3 micro g/ml) was inhibited as well (p<0.01 at LEF 1 micro g/ml and at LEF 0.3 micro g/ml, respectively). Synovial cell viability evaluated by the tetrazolium salt XTT was unaffected by the LEF concentration used. There was no qualitative difference in the response of OA and RA synovial tissue. CONCLUSION: Leflunomide may modulate the rheumatoid articular process by inhibition of local production of IL1beta, TNFalpha, NO, and MMP-3.
12458821 Gastrointestinal outcomes: evidence for risk reduction in patients using coxibs. 2002 Nov This paper examines the importance of clinically relevant gastrointestinal (GI) outcomes in patients using nonsteroidal anti-inflammatory drugs (NSAIDs) and the risk reduction for adverse GI events associated with cyclooxygenase (COX)-2-selective inhibitors. Four large outcomes trials are reviewed, 2 each with celecoxib and rofecoxib. The results of outcomes studies are consistent with randomized controlled trials and demonstrate that coxibs are associated with significant reductions in clinically relevant GI outcomes. The reductions are observed in patients without GI risk factors as well as in those at risk, suggesting that these drugs have the potential to improve outcomes for all patients requiring NSAIDs.
11848453 Gene targeting of components of the fibrinolytic system. 2002 Jan A number of in vitro and in vivo observations have implicated components of the fibrinolytic system in events associated with diverse physiological and pathophysiological processes, ranging from embryo implantation to cancer. Advances in gene targeting technology have led to the generation of mice deficient for components of the fibrinolytic system. Remarkably, these animals survive to adulthood with few spontaneous life threatening events. Thus, these mice are valuable resources for in vivo studies, not only for hemostasis-related research, but also for the relationships of these genes to other disease states associated with cellular growth and mobility, along with angiogenesis, vascular remodeling, inflammation, wound healing, and tumor growth and dissemination.
12209516 Identification of synovium-specific homing peptides by in vivo phage display selection. 2002 Aug OBJECTIVE: To identify homing peptides specific for human synovium that could be used as targeting devices for delivering therapeutic/diagnostic agents to human joints. METHODS: Human synovium and skin were transplanted into SCID mice. A disulfide-constrained 7-amino acid peptide phage display library was injected intravenously into the animals and synovial homing phage recovered from synovial grafts. Following 3-4 cycles of enrichment, DNA sequencing of homing phage clones allowed the identification of specific peptides that were synthesized by a-fluorenylmethyloxycarbonyl chemistry and used in competitive in vivo assays and immunohistochemistry analyses. RESULTS: We isolated synovial homing phages displaying specific peptides that distinctively bound to synovial but not skin or mouse microvascular endothelium (MVE). They retained their tissue homing specificity in vivo, independently from the phage component, the original pathology of the transplanted tissue, and the degree of human/murine graft vascularization. One such peptide (CKSTHDRLC) maintained synovial homing specificity both when presented by the phage and as a free synthetic peptide. The synthetic peptide also competed with and inhibited in vivo the binding of the parent phage to the cognate synovial MVE ligand. CONCLUSION: This is the first report describing peptides with homing properties specific for human synovial MVE. This was demonstrated using a novel approach targeting human tissues, transplanted into SCID mice, directly by in vivo phage display selection. The identification of such peptides opens the possibility of using these sequences to construct joint-specific drug delivery systems that may have considerable impact in the treatment of arthritic conditions.
12854282 [COX-2 inhibitors: a new treatment in rheumatic diseases]. 2003 Jan Progressive increase of the average lifespan pushed up the number of the elderlies in the population. The subsequent spread of degenerative conditions such as osteoarthritis has inflated the request of NSAID despite their frequent toxicity. Side effects of NSAID are sometimes severe and mainly target gastrointestinal tract, renal and platelets function. It has been estimated that around 70% of the patients treated with NSAID develop some degree of gastric damage, ranging from aspecific dyspeptic syndromes to ulcerative diseases. Drugs are now available that selectively inhibit the cyclooxygenase-2: this enzyme is involved in the synthesis of prostaglandins during the inflammatory response. These new drugs have opened new perspectives in the treatment of arthritis; they allow COX-1 to work regularly, so that those prostaglandins that are involved in the maintenance of a regular function of the gastrointestinal tract mucosa and of the platelets. Celecoxib was the firstborn of these new drugs. Differently from FANS, COXIB has got less side effects on gastrointestinal tract and platelets function. Based on the evidence of the more recent clinical experience COXIB has to be recommended; in particular celecoxib, at a schedule of 200-400 mg/die, was shown to be highly effective in the symptomatic treatment of osteoarthritis and rheumatoid arthritis.
12109923 Cardiovascular risk profile of antirheumatic agents in patients with osteoarthritis and rh 2002 Several new drugs have become available for the treatment of patients with osteoarthritis and rheumatoid arthritis (RA). These agents include selective cyclooxygenase (COX)-2 inhibitors, leflunomide and anti-tumour necrosis factor (TNF)-alpha antagonists. COX-2 inhibitors have a more favourable gastrointestinal adverse effect profile than conventional non-steroidal anti-inflammatory drugs (NSAIDs). However, the COX-2 inhibitors are also associated with hypertension, oedema and congestive heart failure, the well-known adverse effects of conventional NSAIDs. Patients with treated hypertension should be monitored regularly when conventional NSAIDs or COX-2 inhibitors are administered. At present, there is a considerable debate regarding the risk of cardiovascular events with the COX-2 inhibitors. The available literature gives no unequivocal answers. This matter can only be solved by an appropriate trial assessing the cardiovascular risk of these agents. Patients with RA appear to have an enhanced cardiovascular risk which might be related to an unfavourable lipid profile. Corticosteroids induce hypercholesterolaemia in patients other than those with RA. It was recently shown that total and high-density lipoprotein (HDL) cholesterol were low in patients with RA who had a high disease activity. Contrary to the expectation, combination therapy with prednisolone rapidly improved the atherogenic index (total/HDL cholesterol). Ongoing studies investigating this topic are underway. It is not known to what extent corticosteroids induce hypertension in patients with RA. Hence, we advocate blood pressure control for these patients. A small percentage of patients with RA develop hypertension when taking leflunomide, and no other serious cardiovascular adverse effects have been reported in the literature. Blood pressure monitoring is recommended especially in the first months of treatment. TNFalpha antagonists are contraindicated in patients with RA who have congestive heart failure. No specific cardiovascular adverse effects have been reported with the use of these agents in the non-cardiovascular compromised patient. TNFalpha antagonists are the most powerful anti-inflammatory drugs presently available. As inflammation plays an important role in RA as well as in cardiovascular disease and, in view of the increased cardiovascular risk in RA, it is tempting to expect that suppression of inflammation ultimately will lower the cardiovascular morbidity and mortality in patients with RA.
12563703 Salazosulfapyridine-induced remission of Felty's syndrome along with significant reduction 2003 Feb Felty's syndrome is characterized by neutropenia, splenomegaly, and leg ulcers in patients with rheumatoid arthritis. The pathogenesis of the neutropenia is an immune-mediated process that involves immune complexes, antineutrophil antibodies, and abnormal white cell kinetics. We prescribed salazosulfapyridine to a 65-year-old woman with this syndrome. The neutropenia improved along with a reduction in neutrophil-bound IgG, demonstrated by flow cytometric analysis. Salazosulfapyridine may be of benefit for the treatment of Felty's syndrome, and flow cytometry can be used to monitor disease activity and therapeutic efficacy.
12605386 High serum transferrin receptor level in anemia of chronic disorders indicates coexistent 2003 Mar Blood transferrin receptor (TR) level is largely determined by the quantum of erythropoiesis and by intracellular iron content of the cells of the erythroid lineage. Hence, a high serum TR level has been found to be useful in distinguishing iron deficiency anemia (IDA) from anemia of chronic disorders (ACD). In order to examine its potential role in the diagnosis of concomitant iron deficiency in ACD, we determined serum TR levels in 130 cases of ACD, in 25 cases of IDA, and in 40 normal adults. As expected, all patients of IDA had significantly higher serum TR levels compared to the normal subjects (4.2-19.2 microg/dL vs. 1.3-3.0 microg/dL) (P < 0.002). In 11/25 cases of IDA, the total iron-binding capacity (TIBC) was in the normal range although bone marrow iron store was absent and serum TR levels were high, thereby highlighting the superiority of TR level in the diagnosis of iron deficiency compared to TIBC. Although 54% (70/130) patients of ACD had normal or low serum TR levels (0.9-3.0 microg/dL) as expected, in 46% (60/130) of ACD patients, serum TR levels were high (3.2-11.0 microg/dL). Mean corpuscular volume, red cell distribution width, and transferrin saturation were significantly lower (P < 0.001) in the latter group of patients compared to the former, and these parameters resembled those in IDA patients. Also, serum iron was lower and TIBC was higher in this group of ACD patients compared to those with normal or low serum TR. All these features point to an "IDA-like" profile of ACD patients with high TR and support the possibility of co-existent iron deficiency in this subgroup of ACD patients. In light of these observations it would be prudent to treat ACD patients with high serum TR levels with iron replacement therapy.
15048718 Enforced Bcl-2 expression in B lymphocytes induces rheumatoid factor and anti-DNA producti 2004 Apr The presence of rheumatoid factors (RF) is a characteristic feature of patients with rheumatoid arthritis, but not systemic lupus erythematosus. In this study, we have explored the role of the anti-apoptotic Bcl-2 protein and the Y-linked autoimmune acceleration (Yaa) mutation in the production of IgG RF in comparison with IgG anti-DNA autoimmune responses. Analysis in C57BL/6 mice, in their F1 hybrids with lupus-prone NZW mice, and in bone marrow chimeras containing mixtures of C57BL/6 bcl-2-transgenic and BXSB non-transgenic cells demonstrated that an enforced Bcl-2 expression in B cells promoted the induction of IgG anti-DNA production in these mice, while significant IgG RF responses were observed only in mice developing high levels of gp70-anti-gp70 immune complexes and lethal glomerulonephritis. Moreover, in contrast to a synergistic interaction between the Yaa mutation and Bcl-2 overexpression on IgG anti-DNA production, the Yaa mutation failed to enhance the production of IgG RF induced in bcl-2-transgenic mice. Our results reveal that defects in the regulation of B cell apoptosis play a critical role in the production of IgG RF, and that the Yaa mutation differentially modulates RF and anti-DNA autoimmune responses, likely related to the nature of autoantigens involved in each autoimmune response.
14550312 Meals and snacks among elderly self-managing and disabled women. 2003 Oct AIM: The aim of this study was to describe the frequency and distribution of self-managing and disabled elderly women's eating events, as well as to investigate which definition/names the women had given their different eating events and to categorise these into meals and snacks. An additional aim was to study the composition of meals and snacks, and analyse the nutritional significance of these eating events in terms of energy and macronutrients. SUBJECTS: Elderly women, both self-managing (n=139) and disabled (n=63; with Parkinson's disease, rheumatoid arthritis or stroke), aged 64-88 years, and living at home participated. METHODS: A repeated 24 h recall and an estimated food diary for three consecutive days were used. RESULTS: The eating events defined by the women that were categorised as meals contributed 74% of the total daily energy intake, while snacks contributed 22-23%. The meals that the women had defined as dinner, was the most energy dense meal. The frequency of eating events not defined by the women, was 30-34%, but contributed only 3-4% of the total daily energy intake. The disabled women had a significantly lower energy content in meals and most snacks, compared to the self-managing women. CONCLUSION: The main conclusion was that elderly women still living at home had their meals distributed during the day and that these meals were characterised by individuality and flexibility.
14722732 Manometric assessment of esophageal motility in patients with primary Sjögren's syndrome. 2005 May OBJECTIVE: The aim of this study was to assess the esophageal motility by manometry in patients with primary Sjögren's syndrome. METHODS: Esophageal manometry was carried out in 40 patients with primary Sjögren's syndrome (SS), 15 with rheumatoid arthritis (RA), 15 with RA and secondary SS, and 21 healthy volunteers. RESULTS: We found that the mean lower esophageal sphincter (LES) pressures measured by station pull-through and rapid pull-through techniques were significantly higher in primary SS patients than with healthy controls and RA patients with or without SS (P<0.05). Our study did not show any major differences when comparing the three patient groups (P>0.05). However, peristaltic contraction velocity was lower and peristaltic contraction duration significantly higher at the middle and lower thirds of the esophagus in primary SS patients than in healthy controls (P<0.05). CONCLUSION: The results of our study support the view that various esophageal motility disorders can be found in patients with primary SS which could be related to an increase in LES pressure. We also found no correlation of the esophageal abnormalities with other factors studied, suggesting that the cause of dysphagia is multifactorial in nature.
11953991 Suppression of collagen-induced arthritis by single administration of poly(lactic-co-glyco 2002 Apr OBJECTIVE: Poly(lactic-co-glycolic acid) (PLGA), a biodegradable polymer, is a carrier for drug delivery systems. This study was undertaken to investigate the tolerogenic effect of single administration of PLGA entrapping type II collagen (CII) on the development of collagen-induced arthritis (CIA). METHODS: The biophysical properties of PLGA nanoparticles entrapping CII (PLGA-CII) were investigated by in vitro release testing of CII, immunohistochemistry analysis, and electron microscopy. PLGA-CII was fed singly to animals 14 days before immunization, and the effect on joint inflammation was assessed. Circulating IgG anti-CII antibodies and T cell responses to CII in draining lymph nodes were assayed by enzyme-linked immunosorbent assay and (3)H-thymidine incorporation assay, respectively. The expression of messenger RNA (mRNA) for transforming growth factor beta (TGFbeta) and tumor necrosis factor alpha (TNFalpha) was determined by reverse transcriptase-polymerase chain reaction. RESULTS: The in vitro release test showed that CII was slowly discharged from PLGA-CII over a period of a month. After single administration of PLGA-CII, numerous particles approximately 300 nm in size were detectable in Peyer's patches, by electron microscopy and immunohistochemical staining for CII, 14 days after the original feeding. Mice fed a single dose of PLGA containing 40 microg of CII had significantly reduced values for incidence and severity of arthritis, serum IgG anti-CII antibodies, and CII-specific T cell proliferation as compared with mice fed solvent alone, those fed 6 doses of 20 microg CII alone, and those fed a single dose of PLGA alone. PLGA-CII was also able to suppress CIA after disease onset. Moreover, PLGA-CII-fed mice showed a higher level of TGFbeta mRNA expression in Peyer's patches, but a lower level of TNFalpha mRNA expression in draining lymph nodes, compared with the other groups of mice. CONCLUSION: Our data show that PLGA may serve as a powerful vehicle to promote the tolerance effect of oral CII and that single administration of PLGA-CII may hold promise as a new treatment strategy in rheumatoid arthritis.
12649695 Psoriatic arthritis as a mountain. 2003 The concept of psoriatic arthritis (PsA) is not yet universally accepted. Indeed, few of the features said to be characteristic for PsA are pathognomonic, and a same patient can be classified as RA, SpA or PsA depending on the physician seen. The heterogeneity of PsA, the lack of significant differences in early-arthritis with and without psoriasis, and a pathogenesis somewhat different in PsA and psoriasis, also argue against the originality of PsA. Nevertheless, although PsA is possibly "just" a syndrome depending on the combination of numerous co-factors (perhaps shared with SpA and/or RA), its more achieved forms deserve to be segregated from other SpA and RA. Indeed, PsA best bridges the gap with SAPHO syndromes. Moreover, the profile of synovial cytokines seems somewhat different in PsA as compared to RA and SpA, and a special pattern of vascularisation has been confirmed by several teams which could account for the demonstrated link between trauma and some PsA onsets. Both the greater familial risk for PsA than for RA or psoriasis alone and the excessive paternal transmission of PsA strongly suggest a genetic background, although so far only MICA-A9 (expressed on gut epithelial cells) seems to be associated with susceptibility to PsA independently from psoriasis. To make further genetics studies informative, a careful selection of unequivocal cases of PsA is needed, which requires criteria selecting patients at the "top of the mountain" of PsA. One can expect that the sets of criteria proposed by McGonagle or Fournié could satisfy this wish.
15584974 Reduction of soluble complement receptor 2/CD21 in systemic lupus erythomatosus and Sjogre 2004 Dec A soluble form of the complement receptor CD21 (sCD21) is shed from the lymphocyte surface. The amount of sCD21 in serum may modulate immunity as sCD21 levels are correlated with several clinical conditions. We report here the serum levels of sCD21 in juvenile arthritis (JA), systemic lupus erythematosus (SLE) and Sjogren's syndrome (SS). Using enzyme-linked immunosorbent assay, we determined sCD21 levels in SLE, SS and JA patients. Mann-Whitney test for nonparametric two-tail P value was performed to obtain statistical significance. Cytometrical analysis of synovial fluid leucocytes of JA patients was done on a FACSsort. While sCD21 levels in SLE and SS are reduced to levels previously found in rheumatoid arthritis (RA), JA sCD21 levels were normal. sCD21 levels did not correlate with clinical parameters and immunophenotype of synovial cells. CD4 T cells in the synovium were almost all of the CD45RO memory type and 13 of 40 patients displayed synovial expansion of gammadeltaT cells. CD21 shedding in JA differs from RA/SS/SLE. JA sCD21 levels in synovial fluid are always lower compared to blood levels of the same patients. Analysis of JA synovial T cells indicates a T-cell driven response.
12457433 Therapies directed at vascular endothelial growth factor. 2002 Dec The inhibition of angiogenesis through vascular endothelial growth factor (VEGF) receptor targeting is a strategy that is relatively tumour selective. The high selectivity achieved with neutralising antibodies, soluble receptors and ribozymes reduces the risk of adverse reactions not related to VEGF inhibition itself. Small-molecule, orally-active protein kinase inhibitors provide an attractive alternative for chronic therapy, although specifically targeting a small subset of protein kinases from the approximately 550 expressed in mammalian cells is a challenge. Current efforts have resulted in promising clinical data for several synthetic VEGF receptor kinase inhibitors, of which PTK787/ZK222584 and ZD6474 are proceeding into large size clinical trials. It seems likely that blockers of the VEGF signalling pathway will be unsuitable for monotherapy, and that their role will be as an adjunct to additional antiangiogenic agents together with directly-acting antitumour agents or radiation therapy. Caution is needed with combinations of anti-VEGF therapies and cytotoxic agents, as coadministration of cytotoxic agents with either the kinase inhibitor SU5416 or the VEGF antibody avastin appears to be associated with bleeding and thrombotic adverse events.
15529241 [Autoimmune cholangitis with vasculitic ulcers, rheumatoid arthritis and IgA glomeruloneph 2004 Nov 5 HISTORY AND ADMISSION FINDINGS: A 51-year-old woman was admitted because of relapsing episodes of fever and leg ulcers for 14 years. In addition, she had polyserositis, polyarthralgias and polyarthritides, renal failure with proteinuria and elevation of gamma-GT and alkaline phosphatase. The patient was in a reduced general condition and cachectic nutritional state. She had slight scleral icterus, the liver being palpable 5 cm under the costal margin, edema of the lower limbs and two ulcers at the right foot. INVESTIGATIONS: Laboratory examinations revealed leukocytosis, anemia, elevation of cholestasis and inflammation parameters as well as renal failure. During a 24 hour collection period, a significant proteinuria was demonstrated. Immunoserologically, an ANA titer of 1:100 and a positive rheumatoid factor were found, ANCAs and AMAs were negative. On ultrasound, both kidneys exhibited a blurred pelvic parenchymal border. Thyroid ultrasound demonstrated parenchymal changes consistent with Hashimoto's disease. Ultrasound of the wrist revealed extensive arthritis with tendovaginitis. A renal biopsy revealed mesangioproliferative glomerulonephritis. DIAGNOSIS, THERAPY AND CLINICAL COURSE: Due to serologically persistent cholestasis, a liver biopsy was performed which, together with negative AMAs, revealed the diagnosis of an autoimmune cholangitis (AIC; AMA-negative primary-biliary cirrhosis (PBC)). In addition, the patient presented with rheumatoid arthritis, polyserositis, IgA glomerulonephritis, vasculitic leg ulcers and Hashimoto's thyreoiditis which were interpreted as extra-hepatic manifestations of the AIC. After initiation of high dosage corticosteroid therapy, rapid healing of the leg ulcers occurred. Therapy of the AIC consisted in ursodeoxycholic acid. CONCLUSION: The multitude of associated immunological phenomena in this patient resulted in a delay of the diagnosis. A AIC/PBC, however, should, always be considered in case of cholestasis.
15539410 Pregnancy in patients with rheumatic disease: anti-inflammatory cytokines increase in preg 2005 Jun OBJECTIVE: To investigate changes in the levels of circulating cytokines with a focus on the Th1/Th2 balance during and after pregnancy in patients with rheumatoid arthritis (RA), juvenile idiopathic arthritis (JIA), and ankylosing spondylitis (AS). METHODS: Plasma and serum samples of 34 pregnant patients, 19 with RA, 6 with JIA, and 9 with AS, and of 30 healthy pregnant women, 20 non-pregnant patients, and 10 non-pregnant healthy women were analysed for levels of interferon gamma (IFNgamma), interleukin (IL) 1beta, IL10, IL1 receptor antagonist (IL1Ra), soluble tumour necrosis factor receptor (sTNFR), and soluble CD30 (sCD30) by ELISA. Clinical assessment and blood sampling in pregnant women was done once in each trimester and 6, 12, and 24 weeks post partum. Disease activity in the patients was evaluated by validated clinical instruments and correlated with circulating levels of cytokines. RESULTS: Low levels of IL10 were found sporadically, whereas IFNgamma and IL1beta were below detection level in the samples tested. Significantly higher concentrations of sTNFR and IL1Ra were measured in pregnant than in non-pregnant subjects. An increase of IL1Ra from the second to the third trimester correlated with improvement of disease activity in patients with RA and AS. Compared with non-pregnant patients and the other pregnant women, patients with RA showed markedly raised levels of sCD30 during pregnancy. CONCLUSIONS: IFNgamma and IL10, markers of a Th1 and Th2 response, respectively, were either low or undetectable in the cohorts analysed. The increase of cytokine inhibitors IL1Ra and sTNFR was related to pregnancy and was independent of an underlying disease. These anti-inflammatory mediators seem to affect disease activity.
15018649 Complex genetic predisposition in adult and juvenile rheumatoid arthritis. 2004 Feb 4 BACKGROUND: Rheumatoid arthritis (RA) and juvenile rheumatoid arthritis (JRA) are complex multifactorial diseases caused by environmental influences and an unknown number of predisposing genes. The present study was undertaken in order to investigate association of polymorphisms in candidate genes with RA and JRA in German subjects. RESULTS: Up to 200 unrelated German RA and JRA patients each and 300-400 healthy controls have been genotyped for HLA-DRB1, TNFa, TNFA -238a/g, TNFA -308a/g, TNFA -857c/t, TNFR1 -609g/t, TNFR1 P12P, TNFR2 del 15bp, IKBL -332a/g, IKBL -132t/a, IKBL C224R, CTLA4 -318c/t, CTLA4 T17A, PTPRC P57P, MIF -173g/c, the MIF and IFNG microsatellites as well as for D17S795, D17S807, D17S1821 by polyacrylamide gel electrophoresis, single-strand conformation polymorphism analysis, restriction fragment length polymorphism analysis or allele specific hybridization. None of the investigated genetic markers is associated with both, RA and JRA, but there are some statistically significant differences between patients and controls that have to be discussed sensibly. CONCLUSIONS: The difficulty in investigating the genetics of complex disorders like RA and JRA may arise from genetic heterogeneity in the clinically defined disease cohorts (and generally limited power of such studies). In addition, several to many genes appear to be involved in the genetic predisposition, each of which exerting only small effects. The number of investigated patients has to be increased to establish the possibility of subdivison of the patients according their clinical symptoms, severity of disease, HLA status and other genetic characteristics.