Browse

Search for: rheumatoid arthritis    methotrexate    autoimmune disease    biomarker    gene expression    GWAS    HLA genes    non-HLA genes   

ID PMID Title PublicationDate abstract
16440498 [Association of systemic lupus erythematosus and Sjögren's syndrome]. 2005 Dec 11 INTRODUCTION: Systemic lupus erythematosus and Sjögren's syndrome are multisystemic autoimmune diseases which can be associated to each other. OBJECTIVE: To investigate if there are any distinct clinical, laboratory or serologic features due to the association of the two diseases that can influence the follow up of these patients. PATIENTS AND METHODS: The authors proved the association of these two autoimmune diseases in 56 patients, and these patients' clinical, laboratory and immunoserologic alterations. 50 patients with Sjögren's syndrome and 50 patients with systemic lupus erythematosus were used as control groups. RESULTS: Compared with Sjögren's syndrome alone, in the cases of the association of the diseases, rheumatoid factor was present less frequently, Ro/SS-A, La/SS-B and DNA antibodies were present more frequently, such as antiphospholipid autoantibodies and antiphospholipid syndrome. Anaemia, leukopenia and lymphopenia were detected more often and the patients were younger than in Sjögren's syndrome. Also, affection of the lung, kidney, skin, central nervous system and serous membranes are more common. The group with systemic lupus erythematosus differs in being older, having thyroiditis, Ro/SS-A, La/SS-B and DNA more frequently. CONCLUSION: Definitive clinical, laboratory and serological features make the difference between the association of the two diseases and the diseases observed alone.
16881124 Inhibited apoptosis of synovial fluid lymphocytes in children with juvenile idiopathic art 2006 Aug OBJECTIVE: Inhibited apoptosis of lymphocytes present in synovial fluid (SFL) and persistently infiltrating synovial tissue may be crucial in the pathogenesis of rheumatoid arthritis (RA). Similarly, this may be the case in juvenile idiopathic arthritis (JIA). Little is known about lymphocyte apoptosis in this disease. Recently, we reported significantly enhanced apoptosis of peripheral blood lymphocytes (JIA-PBL) compared to synovial fluid (JIA-SFL) or healthy lymphocytes, with downregulation of p53 in JIA-SFL. In this study we assessed other possible molecular mechanisms of this phenomenon. METHODS: PBL from 31 children with JIA and 26 healthy children were examined. SFL obtained from 18 patients was also studied. Apoptosis was assessed by TdT-mediated dUTP-biotin nick-end labeling (TUNEL) method. Expression of several apoptosis-regulating proteins was analyzed, including myeloid cell leukemia 1 (Mcl-1), cross-linked inhibitor of apoptosis (XIAP), FLICE-inhibitory protein (FLIP), or Bcl-xL inhibitors and proapoptotic p53, Bcl-w, Bak, and Bid. RESULTS: We found significant overexpression of Mcl-1 and XIAP in JIA-SFL (p < 0.001 and p < 0.02, respectively). Expression of Mcl-1 and XIAP in SFL correlated inversely with the apoptotic index (p < 0.002 and p < 0.01, respectively). FLIP expression was also distinctly higher in SFL than in JIA-PBL; however, the difference was not statistically significant (p = 0.061). No statistically significant differences were found in the expression of other proteins between SFL and PBL. CONCLUSIONS: This is the first study showing that upregulation of anti-apoptotic Mcl-1 and XIAP proteins, along with downregulation of p53 protein, is correlated with inhibition of JIA-SFL apoptosis.
16051692 Role of glucocorticoid-induced TNF receptor family gene (GITR) in collagen-induced arthrit 2005 Aug In rheumatoid arthritis (RA), a widespread autoimmune/inflammatory joint disease, early activation of effector CD4+ T lymphocytes, and cytokine production is followed by recruitment of other inflammatory cells, production of a range of inflammation mediators, tissue damage, and disease. GITR (glucocorticoid-induced TNFR family-related gene), a costimulatory molecule for T lymphocytes, increases CD4+CD25- effector T cell activation while inhibiting suppressor activity of CD4+CD25+ T regulatory (Treg) cells. We analyzed the role of GITR in type II collagen (CII) -induced arthritis (CIA) using GITR-/- and GITR+/+ mice. Results indicate significantly less CIA induction in GITR-/- mice than in GITR+/+ mice, with marked differences in erythema, edema, neutrophil infiltration, joint injury, and bone erosion. Production of IFNgamma, IL-6, TNFalpha, MIP-1alpha, and MIP-2, inducible NOS (iNOS), COX-2, and nitrotyrosine poly-ADP-ribose (PAR) were also less in CII-treated GITR-/- mice. Although CD4+CD25+ Treg cells from GITR+/+ and GITR-/- CII-challenged mice exerted similar suppressor activity in vitro, GITR triggering abrogated GITR+/+ Treg suppressor activity and costimulated CD4+CD25- GITR+/+ effector cells. Furthermore, Treg cells from GITR-/- protected more than Treg cells from GITR+/+ mice against CIA when cotransferred with Treg-depleted splenocytes from arthritic GITR+/+ animals into severe combined immunodeficient (SCID) mice. In conclusion, GITR plays a critical role in the immunological response against CII and in the development of CIA.
17029078 Reactive arthritis after influenza vaccination: report of a case. 2005 We describe a patient with reactive arthritis (ReA) induced by influenza vaccination. A healthy 79-year-old Japanese man began suffering from migrating polyarthritis 2 days after receiving influenza vaccine. He proved negative for rheumatoid factor, showing no evidence for microbial infections such as Streptoccocci, Chlamydia, or Parbovirus B19. Human leukocyte antigen (HLA) typing analysis revealed positive results for HLA-B54 (22), which is one of the cross-reactive antigens to HLA-B27. His arthritis improved with administration of nonsteroidal anti-inflammatory drugs, and recovery was attained within 6 weeks. Reactive arthritis is a rare adverse effect induced by influenza vaccination; however, it is important that it is recognized by all physicians.
16846800 Modulating TNF-alpha signaling with natural products. 2006 Aug Natural products have been, and continue to be, a major source of pharmacologically active substances from which drugs can be developed. Currently, tumor necrosis factor-alpha (TNF-alpha) inhibitors from natural origins are being advanced for the treatment of inflammatory disorders. Elevated TNF-alpha synthesis has been associated with the development of diabetes, septic shock, tumorigenesis, rheumatoid arthritis, psoriatic arthritis and inflammatory bowel disease. Currently, only protein-based drugs are available for the clinical inhibition of TNF-alpha activity. Small-molecule drugs that can regulate TNF-alpha levels or activity might provide a cost-effective alternative to protein-based therapeutics. This review briefly highlights the physiological and pathological roles of TNF-alpha, and covers those natural compounds capable of interfering with TNF-alpha activity.
16445417 Etanercept for psoriasis in the pediatric population: experience in nine patients. 2006 Jan Psoriasis commonly affects children and adolescents, and the need for safe, effective therapy is a special consideration in the pediatric population. In recent years, the use of targeted immunomodulatory biologic agents has been increasingly studied for the treatment of psoriasis. Of these, etanercept, a tumor necrosis factor-alpha antagonist, has been approved for the treatment of psoriasis and psoriatic arthritis in adults, and while it is approved for use in juvenile rheumatoid arthritis, formal studies are needed to demonstrate its safety and efficacy for childhood psoriasis. We present our preliminary experience of treating nine pediatric patients with generalized, recalcitrant psoriasis with etanercept therapy.
16320829 Expression and regulation of antimicrobial peptides in articular joints. 2005 Nov Articular joint infection is a surprisingly rare event considering the frequency of joint arthrocentesis and other invasive procedures applied to limb joints. This observation led us to the hypothesis that a local "chemical shield" in the form of antimicrobial proteins provides synovial membrane and articular cartilage with resistance to infection. We subsequently began a systematic analysis of in vitro and in vivo antimicrobially active proteins in healthy articular joints and in disease states such as pyogenic arthritis, rheumatoid arthritis, and osteoarthritis. An anatomical approach with systematic characterization combined with antimicrobial testing revealed expression and production of human antibiotic peptides and proteins. In this review, we focus on the most prominent antimicrobial proteins in articular joints, which we have identified as lysozyme, lactoferrin, secretory phospholipase A2, RNase 7, CAP37, the cathelicidin LL37, and especially the human beta-defensin-2 and -3 (HBD-2/-3). Activation pathways and possible antimicrobial functions are discussed and the involvement in non-antimicrobial processes such as tissue remodelling is also considered.
16841771 [Traumatic pseudo-boutonniere of the metacarpophalangeal joint of the little finger. Case 2006 Jun Dislocation of the extensor tendon over the metacarpophalangeal joint is common among patients with rheumatoid arthritis. Patients without arthritis are exceptionally involved. The authors describe a new case of traumatic boutonniere-like of the metacarpophalangeal joint of the little finger. This lesion is a rarely, only eleven cases are described in literature. Patients are usually young adults and dislocation is related to a direct axial trauma on their fifth metacarpophalangeal joint. Diagnosis is clinical and relies on an incomplete active extension of the metacarpophalangeal joint, secondary to the dislocation of the extensor apparatus. Diagnosis is often delayed the lesion remaining unnoticed with the occurrence of others hand lesions. Proper treatment is surgery, based on suturing side to side both extensor digiti minimi and common extensor tendon over the fifth metacarpophalangeal joint. Results are excellent, with a complete range of motion and the absence of recurrence.
15837335 Design and synthesis of potent pyridazine inhibitors of p38 MAP kinase. 2005 May 2 Novel potent trisubstituted pyridazine inhibitors of p38 MAP (mitogen activated protein) kinase are described that have activity in both cell-based assays of cytokine release and animal models of rheumatoid arthritis. They demonstrated potent inhibition of LPS-induced TNF-alpha production in mice and exhibited good efficacy in the rat collagen induced arthritis model.
16052597 Baseline levels of C-reactive protein and prediction of death from cardiovascular disease 2005 Aug OBJECTIVE: To test the hypothesis that the C-reactive protein (CRP) concentration at baseline is an independent predictor of death from cardiovascular disease (CVD) in newly diagnosed patients with inflammatory polyarthritis (IP). METHODS: Patients with IP (n = 506) who were recruited from the Norfolk Arthritis Register between 1990 and 1992 were followed up to the end of 2001, and complete data on mortality were obtained. At baseline, subjects underwent a structured interview and joint examination and completed a Health Assessment Questionnaire (HAQ). Blood was obtained and analyzed for rheumatoid factor (RF) and CRP concentration. Cox regression was used to calculate hazards ratios (HRs) for risk of death from CVD. RESULTS: The median followup was 10.1 years (interquartile range 9.3-10.8). There were 104 deaths, 40 of which were the result of CVD. Elevated CRP levels (> or=5 mg/liter) predicted death from CVD in univariate analyses: HR 3.9 (95% confidence interval [95% CI] 1.2-13.4) for men, and HR 4.22 (95% CI 1.4-12.6) for women. After adjusting for age and sex, the CVD mortality association was strongest in the subgroup of patients who were RF positive at baseline (adjusted HR 7.4 [95% CI 1.7-32.2]). Multivariate analysis revealed that elevated CRP levels remained a significant independent predictor of death from CVD, even after adjusting for age, sex, smoking status, HAQ score, RF positivity, and swollen joint counts (HR 3.3 [95% CI 1.4-7.6]). CONCLUSION: The CRP concentration at baseline is an important predictor of subsequent death from CVD in patients with new-onset IP and is independent of other indicators of disease severity. This supports the theory that CRP may play a direct role in the pathogenesis of CVD.
15974846 Experimental arthritis in rats induces biomarkers of periodontitis which are ameliorated b 2005 Feb BACKGROUND: Periodontal disease (PD) and rheumatoid arthritis (RA) share many common pathophysiologic features, but a clinical relationship between the two conditions remains controversial, in part because of the confounding effects of anti-inflammatory drug therapy universally used in the latter disease. To further explore this issue, inflammatory arthritis was induced in rats to determine the effect on gingival biomarkers of inflammation and tissue destruction and to investigate the effect of a therapeutic intervention devoid of conventional anti-inflammatory properties. METHODS: Adjuvant arthritis (AA) was induced in Lewis male rats by injecting mycobacterium cell wall in complete Freund's adjuvant using standard techniques. One group of animals was treated by induction of systemic tissue inhibitor of matrix metalloproteinases (TIMP-4). At 3 weeks, arthritis severity was recorded and both paw and gingival tissues were collected for matrix metalloproteinase activity (MMP) and cytokine analysis. In addition, the maxillary jaws were removed for assessment of periodontal bone loss. RESULTS: The development of arthritis was associated with elevated joint tissue MMPs, tumor necrosis factor (TNF)-alpha, and interleukin (IL)-1beta levels compared to control rats. In the gingival tissue of the untreated arthritic rats, gelatinase, collagenase, TNF-alpha, and IL-1beta were also elevated compared to control rats. Periodontal bone loss and tooth mobility were also increased significantly (P <0.05) in untreated arthritic rats. All parameters improved after TIMP-4 gene therapy. CONCLUSIONS: To our knowledge, this is the first study to report an association between experimental systemic arthritis in rats and elevated gingival tissue MMPs, cytokine levels, and periodontal disease. Reversal of these changes with TIMP-4 gene therapy strengthens the pathophysiologic correlation between systemic and local disease.
15924698 [The clinical feature, diagnosis and treatment of uveitis associated with juvenile chronic 2005 Apr OBJECTIVE: To investigate the clinical features, diagnosis and treatment of uveitis associated with juvenile chronic arthritis (JCA). METHODS: A retrospective study was performed on the clinical data of 26 patients with uveitis associated with JCA, referred to Zhongshan Ophthalmic Center from 1996 to 2002. Taking of history, examination with slit-lamp microscope and ophthalmoscope were carefully performed in all of these patients. Laboratory tests including antinuclear antibodies, erythrocyte sedimentation rate, rheumatoid factor, C reactive protein and antistreptolysin O were used to disclose possible causes. Human leukocyte antigen B 27 and X-ray examination of sacroiliac joints and spine were carried out if necessary. Data about the treatment, visual outcome and complications were analyzed. RESULTS: Twenty-six patients, 11 males and 15 females, were included in the present studies. Age of onset of JCA and uveitis averaged 8 years and 9 years, respectively. Twenty-one patients had chronic anterior uveitis. Acute anterior uveitis and chronic panuveitis were noted in 3 and 2 patients, respectively. Twenty-two patients had bilateral uveitis, the other 4 had unilateral involvement. The ophthalmologic examination revealed that 33 of the 48 affected eyes showed mild aqueous humor flare, 24 had few cells in the anterior chamber. Complicated cataract, band keratopathy and secondary glaucoma were noted in 30, 20 and 12 eyes, respectively. The laboratory examination revealed positive antinuclear antibodies in 18 cases and rheumatoid factor positive in one case. In acute episode, patients were treated with extensive topical cycloplegic agents and corticosteroids eyedrops. In the 6 cases with severe uveitis, 3 patients were treated with cyclosporine A (5 mg.kg(-1).d(-1)) and the other 3 were treated with chlorambucil (0.1 mg.kg(-1).d(-1)). The intraocular inflammation in all of these patients was satisfactorily controlled with these treatments. Visual acuity improvement was noted in 32 affected eyes but not in the other 16 eyes which had already serious complications before the treatment. CONCLUSIONS: Uveitis associated with JCA is characterized by a chronic and recurred iridocyclitis, which usually developed within 5 year after JCA onset. Although the intraocular inflammation associated with JCA is usually white uveitis, complications such as cataract, secondary glaucoma and keratopathy occur frequently in these patients. The diagnosis is mainly based on typical clinical manifestations, the history of arthritis and positive antinuclear antibodies. Adequate application of cycloplegic agents, corticosteroids eyedrops, immunosupressives and the regular follow-up should be kept in mind in the treatment of these patients.
16335880 Psoriasis arthropathy and HLA-B51: report of 5 cases. 2005 Jul Psoriasis arthropathy (PsA) is a chronic inflammatory arthropathy characterized by the association of arthritis with psoriasis. Although the precise mechanisms of PsA still remain obscure, several genetic and environmental factors have been suggested to play important roles. HLA-B51 has been strongly associated with Behçet's disease; however, its association with PsA has not been documented. We describe herein five Japanese patients (4 males and 1 female) with PsA and positive for HLA-B51. The clinical forms defined by Moll and Wright revealed that the polyarticular pattern was noted in two cases, and oligoarticular, distal, and spondyloarthropathy patterns were noted in one case each. Positive rheumatoid factor was detected in one patient, and antinuclear antibody in two patients. The other HLA subclasses were A2 and A31 in 3 cases, respectively. HLA-B51 was detected in 5 out of 17 patients with PsA examined in our department; in contrast, HLA-B51 was not detected in 17 patients with psoriasis vulgaris. Our observations suggest that HLA-B51 may play a role in the pathogenesis of PsA in the Japanese population.
15860512 Tumour necrosis factor receptor gene therapy affects cellular immune responses in collagen 2005 Nov BACKGROUND: Collagen induced arthritis (CIA) is an animal model of rheumatoid arthritis (RA) amenable to immunotherapy directed against tumour necrosis factor alpha (TNFalpha). OBJECTIVE: To evaluate whether local TNF receptor (TNF-R) gene therapy in DBA/1 mice exerts an influence beyond anti-inflammatory effects. Two measures of CIA pathogenesis were investigated-namely, immunity to collagen II (CII) 245-270 peptide (the major immunodominant epitope within bovine CII) and the preferential activation of T cell Vbeta8.2 variable region receptors in arthritic DBA/1 mice. METHODS: DBA/1 mice received single periarticular injections of media or retroviral vectors containing LacZ or human TNF-R into affected arthritic paws at disease onset. Disease severity was monitored, immune responses towards the immunodominant bovine CII 245-270 and subdominant CII 334-360 peptide epitopes were assessed by ELISA, and T cell Vbeta usage was analysed by real time polymerase chain reaction for the LacZ transduced, TNF-R, and viral-free media treated control animals. The therapeutic influence of TNF-R gene transduction was compared with other groups at different times after treatment. RESULTS: Reduced disease severity was seen 15-35 days after treatment, with a concomitant increase in immunity towards the subdominant CII 334-360 peptide epitope rather than the immunodominant CII 245-270 peptide in TNF-R treated animals. Early in the disease, TNF-R treated animals demonstrated a reduction of bias towards the otherwise predominant Vbeta8.2 T cell subset. CONCLUSIONS: TNF-R gene therapy influences cellular immunity in CIA, leading to overall disease amelioration, thus suggesting that TNF inhibition may have therapeutic potential beyond the control of inflammation in RA.
16888023 TWEAK is a novel arthritogenic mediator. 2006 Aug 15 TNF-like weak inducer of apoptosis (TWEAK) is a TNF family member with pleiotropic effects on a variety of cell types, one of which is the induction of proinflammatory cytokines by synovial fibroblasts derived from rheumatoid arthritis (RA) patients. In this study, we report that the serum TWEAK level was dramatically elevated during mouse collagen-induced arthritis (CIA) and blocking TWEAK by a neutralizing mAb significantly reduced the clinical severity of CIA. Histological analyses also revealed that TWEAK inhibition diminished joint inflammation, synovial angiogenesis, as well as cartilage and bone erosion. Anti-TWEAK treatment proved efficacious when administered just before the disease onset but not during the priming phase of CIA. Consistent with this, TWEAK inhibition did not affect either cellular or humoral responses to collagen. In contrast, TWEAK inhibition significantly reduced serum levels of a panel of arthritogenic mediators, including chemokines such as MIP-1beta (CCL-4), lymphotactin (XCL-1), IFN-gamma-inducible protein 10 (IP-10) (CXCL-10), MCP-1 (CCL-2), and RANTES (CCL-5), as well as the matrix metalloprotease-9. Exploring the possible role of the TWEAK/Fn14 pathway in human RA pathogenesis, we showed that TWEAK can target human primary chondrocytes and osteoblast-like cells, in addition to synovial fibroblasts. We further demonstrated that TWEAK induced the production of matrix metalloproteases in human chondrocytes and potently inhibited chondrogenesis and osteogenesis using in vitro models. These results provide evidence for a novel cytokine pathway that contributes to joint tissue inflammation, angiogenesis, and damage, as well as may inhibit endogenous repair, suggesting that TWEAK may be a new therapeutic target for human RA.
17059713 Trends in elective hand surgery referrals from primary care. 2006 Oct INTRODUCTION: Two prospective audits of activity in a hand unit were performed, in 1989-1990 and during 2000-2001, to identify trends in elective hand surgery referrals from primary care. PATIENTS AND METHODS: Two 6-month prospective audits of activity in a hand unit were performed, including elective referrals from primary care. Data were collected on all in-district referrals with elective hand disorders. Cross boundary flow was identified to permit assessment of changes in referrals by diagnosis over a decade. RESULTS: There was a 36% increase in health authority referrals for elective hand surgery over the decade (from 289 to 392 per 100,000 of population per year). The number of elective hand surgery operations rose 34% over the decade (from 149 to 199 operations per 100,000 of population per year). Carpal tunnel syndrome (the commonest reason for elective referral) almost doubled (from 59.7 to 112 per 100,000 of population per year). Referrals for ganglion, the second most common elective referral, rose modestly. Referrals for osteoarthritis (commonly basal thumb arthritis) almost trebled over the decade to become the fourth commonest condition referred to the hand unit (from 12.7 to 34 per 100,000 of population per year). Referrals for Dupuytrens disease, trigger finger and rheumatoid arthritis were relatively unchanged over the decade. Congenital hand referrals are uncommon but doubled during the decade. CONCLUSIONS: Hand surgery referrals rose by 36% over the decade. Analysis of the commoner conditions referred reveal a high prevalence within the community with the possibility of increased referrals in years to come.
16819616 [Low-grade-/high-grade-synovitis: synovitis-score as a gold standard?]. 2006 Aug BACKGROUND: Synovectomy specimens represent important material submitted from the orthopedist to the pathologist. However, no consistent histopathological grading system for chronic synovitis has been established so far. PATIENTS AND METHODS: The three compartments of chronic synovitis (enlargement of lining cell layer, density of synovial stroma cells, leukocytic infiltrate) are graded semiquantitatively (from 0=absent to 3=strong), and the points for each compartment add up to the synovitis score: 0-1 = no synovitis, 2-4 = low-grade synovitis, 5-9 = high-grade synovitis. A total of 618 synovial specimens (resections n=559, biopsies n=59) from degenerative and inflammatory joint diseases were graded by two independent observers. RESULTS: Median synovitis scores when correlated to clinical diagnoses were: 1, control; 2, osteoarthritis and post-traumatic arthritis; 3, psoriatic arthritis; 5, reactive and rheumatoid arthritis. The differences between rheumatic and non-rheumatic diseases were significant (p<0.001). The correlation between the two observers was high (p<0.001). CONCLUSIONS: The proposed synovitis score enables stratification of chronic synovitis into low-grade (score 2-4) and high-grade (score >4), which is correlated to the nature of the disease (low-grade to non-rheumatic, high-grade to rheumatic), and it therefore contributes to the diagnosis of rheumatic and non-rheumatic joint diseases.
16134733 An uncommon cause of scleroderma. 2005 May The human immunodeficiency virus (HIV) pandemic is nearly 20 years old. HIV infection is characterized by profound immunodeficiency resulting in an increased incidence of opportunistic infections and neoplasms. However, the greatest paradox is the occurrence of certain autoimmune disorders in the setting of HIV. These include diffuse interstitial lymphocytosis syndrome (DILS), reactive arthritis, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). It has also been seen that even in the absence of these well-defined diseases, various rheumatological manifestations such as arthralgias, arthritis, myopathy, vasculitis, and sicca syndrome are commonly associated with HIV. To the best of our knowledge, the association of HIV with scleroderma has not previously been reported.
17078892 Interactions between IL-32 and tumor necrosis factor alpha contribute to the exacerbation 2006 IL-32 is a newly described cytokine in the human found to be an in vitro inducer of tumor necrosis factor alpha (TNFalpha). We examined the in vivo relationship between IL-32 and TNFalpha, and the pathologic role of IL-32 in the TNFalpha-related diseases - arthritis and colitis. We demonstrated by quantitative PCR assay that IL-32 mRNA was expressed in the lymphoid tissues, and in stimulated peripheral T cells, monocytes, and B cells. Activated T cells were important for IL-32 mRNA expression in monocytes and B cells. Interestingly, TNFalpha reciprocally induced IL-32 mRNA expression in T cells, monocyte-derived dendritic cells, and synovial fibroblasts. Moreover, IL-32 mRNA expression was prominent in the synovial tissues of rheumatoid arthritis patients, especially in synovial-infiltrated lymphocytes by in situ hybridization. To examine the in vivo relationship of IL-32 and TNFalpha, we prepared an overexpression model mouse of human IL-32beta (BM-hIL-32) by bone marrow transplantation. Splenocytes of BM-hIL-32 mice showed increased expression and secretion of TNFalpha, IL-1beta, and IL-6 especially in response to lipopolysaccharide stimulation. Moreover, serum TNFalpha concentration showed a clear increase in BM-hIL-32 mice. Cell-sorting analysis of splenocytes showed that the expression of TNFalpha was increased in resting F4/80+ macrophages, and the expression of TNFalpha, IL-1beta and IL-6 was increased in lipopolysaccharide-stimulated F4/80+ macrophages and CD11c+ dendritic cells. In fact, BM-hIL-32 mice showed exacerbation of collagen-antibody-induced arthritis and trinitrobenzen sulfonic acid-induced colitis. In addition, the transfer of hIL-32beta-producing CD4+ T cells significantly exacerbated collagen-induced arthritis, and a TNFalpha blockade cancelled the exacerbating effects of hIL-32beta. We therefore conclude that IL-32 is closely associated with TNFalpha, and contributes to the exacerbation of TNFalpha-related inflammatory arthritis and colitis.
16134732 Pancytopenia induced by low-dose methotrexate. A study of the cases reported to the Finnis 2005 May OBJECTIVE: To study cases of low-dose methotrexate-induced pancytopenia with special reference to clinical outcome and factors predisposing to bone marrow suppression. METHODS: Patient files of 14 cases of methotrexate-induced pancytopenia reported to the National Agency for Medicines in Finland from 1991 to 1999 were reviewed. A review of four additional cases was included. RESULTS: Of the 18 patients (median age 72 years), 12 had rheumatoid arthritis, one psoriatic arthritis, five psoriasis without arthritis, and one pemphigus erythematosus. Major co-morbidity was recorded in 12 patients, and 16 patients used significant concomitant drugs. Eight patients had a mildly or moderately elevated serum creatinine concentration. In every patient the occurrence of cytopenia was abrupt. Eight patients (44%) died, and the most frequent cause of death was infection. CONCLUSIONS: Our data show that methotrexate-induced pancytopenia is associated with high mortality especially in cases with significant co-morbidity and concomitant medications.