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ID PMID Title PublicationDate abstract
16342085 Longitudinal study of negative workplace events among employed rheumatoid arthritis patien 2005 Dec 15 OBJECTIVE: Most studies of employment in patients with rheumatoid arthritis (RA) have focused on job loss. Less is known about workplace events in patients who continued to work. The goal of this longitudinal study was to compare the incidence of negative workplace events between employed patients with RA and healthy controls. METHODS: Participants completed the work domains of the Psychiatric Epidemiology Research Interview Life Events Scale and the Inventory of Small Life Events Scale measuring major and minor workplace events. Events were compared between groups according to psychosocial, clinical, and job characteristics. RESULTS: A total of 122 patients with RA and 122 healthy controls were enrolled with similar demographic and occupational characteristics. There were no differences in percentages of patients and controls who had at least 1 major (35% versus 31%) or 1 minor (48% versus 55%) negative event. For patients with RA, negative events were associated with having more pain, more fatigue, more social stress, and less job autonomy (P < or = 0.05). For controls, in addition to social stress, negative events were associated with job characteristics, functional status, and social support (P < or = 0.05). CONCLUSION: A comparable number of patients with RA and controls had negative workplace events. In addition to the well-known contributions of job autonomy and pain, social stress and fatigue also were found to be important variables related to negative events in patients with RA. These potentially modifiable variables have not been fully evaluated with respect to long-term employment in these patients.
16652441 B cell targeted therapies: safety considerations. 2006 May Reported data from recent clinical trials have contributed substantially to our growing understanding of the potential effectiveness and safety of B cell targeted therapy in the treatment of rheumatic diseases. Trials with rituximab, an anti-CD20 monoclonal antibody that depletes mature B cells, have amassed the most data of any B cell targeted therapy to date. A number of other B cell directed therapies are under investigation. Interestingly, although they may share a common target, the different agents have quite distinct mechanisms of action, and therefore their efficacy and safety profiles may differ. A common concern with all B cell directed therapies is the potential effect these agents may have on humoral immunity. The safety profile of rituximab in the oncology setting is well known, based on a database of well over 370,000 patients. Phase II trials of rituximab in rheumatoid arthritis (RA) have begun to examine safety issues specifically in the RA population, including issues surrounding longterm and repeated treatment safety profiles. Questions about the longterm safety of B cell therapy remain to be clarified: What will be the safety profile for repeated treatment courses? What will be the safety profile when B cell targeted therapies are used in sequence or in conjunction with other agents? Answers to these important questions are likely to come from careful observations by treating clinicians, data from registries, and longterm followup of patients enrolled in clinical trials.
15660459 What else can I do but take drugs? The future of research in nonpharmacological treatment 2005 Jan Nonpharmacological treatments, including physiotherapy and occupational therapy, have assumed a complementary role to drug therapy in managing inflammatory arthritis. Clinicians and researchers are facing 3 major challenges concerning the use of these treatments. First, strong evidence is only present in a few nonpharmacological interventions, such as exercise, patient education, and low level laser in the treatment of rheumatoid arthritis. The evidence on the majority of interventions is, however, weak or inconclusive. Second, knowledge is lacking on the elements associated with models of nonpharmacological care. The multidisciplinary team approach has been viewed as the standard for arthritis treatment; however, the team structure and the communication style among team members vary around the world. The influence of these elements on treatment success remains unclear. Finally, disparities in knowledge management and translation in nonpharmacological research have hindered the clinical use of these treatments and the growth of research in the field. To address the challenges, the author is recommending 4 research priorities for nonpharmacological treatments: 1. Evaluation of less well-studied interventions; 2. Understanding the relationships among rehabilitation-related variables and disability; 3. Development and evaluation of innovative care models; and 4. Design and evaluation of knowledge transfer innovations.
17068631 [Quantification of expression of leukotriene B4 inducing tumor necrosis factor-alpha and i 2006 Oct 18 OBJECTIVE: To investigate quantification of expression of LTB4 inducing IL-1beta and TNF-alpha at mRNA level in synovial membrane cells of rheumatoid arthritis. METHODS: Primary cultured synovial cells from RA patients were treated with exogenous LTB4, MK-886 (inhibitor of 5-lipoxygenase activating protein) and Bestatin(inhibitor of leukotriene A4 hydrolase) in the presence of LIT respectively, expressions of TNF-alpha and IL-1beta were detected at mRNA level by Real-time Quantitative PCR. RESULTS: Expressions of basic TNF-alpha (TNF-alpha/GAPDH) and IL-beta (IL-beta/GAPDH) at mRNA level in primary cultured synovial cells were 0.02 +/- 0.00 and 0.16 +/- 0.01 respectively. LTB4 (10(-9) mol/L-10(-8) mol/L) was shown to induce dose-dependent increase of mRNA expression of TNF-alpha. (7-15 times) and IL-1beta (1 time) , endogenous product of LTB4 by LIT significantly increased mRNA expressions of TNF-alpha (145 times) and IL-1beta (12 times) respectively. LIT-treated synoviocytes with addition of MK-886 (5-LOX exciting protein FLAP inhibitor) (1-10 micromol/L) were inhibited to secrete LTB4 dose-dependently, following the markedly down-regulated expressions of TNF-alpha (15%-66%) and IL-1beta (41%-71%) at mRNA level . Bestatin(100 mg/L) could also remarkably diminish LTB4-induced mRNA expressions of TNF-alpha(86%) and IL-1beta (79%). CONCLUSION: LTB4 of synovial membrance cells in rheumatoid arthritis could induce expressions of TNF-alpha and IL-1beta at mRNA level, and their expression at mRNA level had been quantified successfully. It is a beneficial help to quantify all kinds of cytokines in methodology.
16421641 [Risk of infection during treatment with tumor necrosis factor-alpha inhibitors]. 2006 Feb Tumor necrosis factor-alpha (TNF) is essential for immune defense. TNF plays a major role in the recruitment of inflammatory cells to the site of infection and in the formation and maintenance of granulomas. In addition, it plays a primary and detrimental role in chronic autoimmune diseases. Drugs that inhibit TNF are effective in the treatment of inflammatory rheumatic and autoimmune diseases. However, the three currently available TNF antagonists (etanercept, infliximab and adalimumab) decrease host resistance to granulomatous diseases such as tuberculosis. The incidence of tuberculosis in patients treated with TNF antagonists is higher than in the general population. There are a number of case reports describing the association of TNF-antagonists and the presentation of other infectious diseases such as histoplasmosis, listeriosis, coccidioidomycosis, candidiasis and aspergillosis. These case reports, however, are anecdotal. Nonetheless, patients treated with TNF antagonists are immunocompromised and infectious diseases are most likely more frequent and may present differently than expected. In this review, we describe the role of TNF in constraining infectious diseases, the difference between the three available TNF antagonists, and we discuss the relevant clinical data published in the literature as related to the risk of anti-TNF therapy for infectious diseases.
15656781 Development of a protein microarray library and a system for rheumatoid-arthritis disease 2005 Oct Early detection and intervention can delay the onset of symptoms of RA (rheumatoid arthritis), but current diagnostic tests suffer from low sensitivity and specificity, making such early disease detection difficult. Analysis of body fluids for the identification of multiple molecular markers and the subsequent determination of modifications in their associated protein structures emerges as a possibility for early detection. The structural modifications of these markers are thought to play a pivotal role in defining the pathological state of diseased joints. Therefore a proteome library and system for RA disease screening has been developed and investigated in the present study. The large (39 S) mammalian ribosomal subunit has been identified as a potential RA marker. This protein is known as L 35, and antibodies to this protein have been found to be expressed in patients suffering from RA.
16287762 The risk of lymphoma development in autoimmune diseases: a meta-analysis. 2005 Nov 14 BACKGROUND: The risk of development of non-Hodgkin lymphoma (NHL) in autoimmune patients has been investigated in several cohort studies. These studies revealed inconclusive results. To shed some light on this controversy, we conducted a meta-analysis of all available cohort studies linking systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and primary Sjögren syndrome (pSS) to the risk of NHL development. METHODS: We searched the PubMed database (1974 to April 2005) for English-language cohort studies using the key words systemic lupus erythematosus, SLE, rheumatoid arthritis, RA, Sjögren syndrome, or SS; non-Hodgkin lymphoma; and relative risk, RR, standardized incidence rate, or SIR. All cohort studies that used established diagnostic criteria for SLE, RA, and pSS; had histologic confirmation of NHL; and provided standardized incidence rates (SIRs) were included in the meta-analysis. RESULTS: The 20 studies chosen for the analysis included 6 for SLE, 9 for RA, and 5 for pSS. Overall, the meta-analysis suggested extreme heterogeneity among the studies (P < .01; I2 > 70%), high risk of NHL development for pSS (random effects SIR, 18.8; 95% confidence interval [CI], 9.5-37.3); moderate risk for SLE (random effects SIR, 7.4; 95% CI, 3.3-17.0); and lower risk for RA (random effects SIR, 3.9; 95% CI, 2.5-5.9). In RA, the random effects SIRs of NHL with conventional antirheumatic treatment, cytotoxic treatment, and treatment with a biological agent were 2.5 (95% CI, 0.7-9.0), 5.1 (95% CI, 0.9-28.6), and 11.5 (95% CI, 3.7-26.9), respectively. CONCLUSIONS: Rheumatic disease may present a potential risk factor for development of NHL. In this regard, we focused on the underlying pathophysiologic mechanisms related to lymphomagenesis in pSS, SLE, and RA, to justify the varying potential for and background of NHL development.
16258581 TNF inhibitors for inflammatory arthritis in New Zealand. 2005 Oct 28 For the vast majority of the estimated 100,000 New Zealanders who suffer from rheumatoid arthritis (RA), relatively inexpensive disease-modifying antirheumatic drugs (DMARD) regimens are sufficient to control inflammatory disease and maintain long-term function. Some DMARDs have been shown to slow, but not arrest, the progression of erosions. All but a few of those who suffer from ankylosing spondylitis (AS) can manage full social participation with non-steroidal anti-inflammatory drugs (NSAIDs) and an exercise regimen. For the small subset of arthritis sufferers who have disabling pain and progressive damage from uncontrolled inflammatory disease, the advent of the biological era offered great promise. In most of the developed world, this promise is being delivered to patients with an expanding range of diseases including RA, AS, and psoriatic arthritis, but central government (PHARMAC) funding for TNF inhibitors in New Zealand has until recently been limited to etanercept for approximately 40 patients with juvenile inflammatory arthritis.
16142859 Anemia in rheumatoid arthritis: association with polymorphism in the tumor necrosis factor 2005 Sep OBJECTIVE: To investigate whether polymorphisms in the tumor necrosis factor receptor I (TNFRSF1A) and receptor II (TNFRSF1B) genes are associated with the anemia observed in rheumatoid arthritis (RA). METHODS: We studied a group of Caucasian patients (n = 160) with established RA on whom longitudinal data of hemoglobin (Hb) levels over 5 years were recorded. A second group of patients (n = 102) with early RA was used for a confirmation study. Polymerase chain reaction restriction fragment length polymorphism analysis was used to genotype patients for the A36G polymorphism in the TNFRSF1A gene, and the T676G polymorphism in TNFRSF1B. Serum levels of ferritin were determined by ELISA and used to differentiate between iron deficiency anemia (IDA) and anemia of chronic disease (ACD). Data were analyzed by Kruskal-Wallis analysis of variance and logistic regression analysis. RESULTS: The TNFRSF1A GG genotype was associated with lower 5-year mean area under the curve Hb levels compared with other genotypes (p = 0.01). Analysis of anemic status showed an increased frequency of anemia in patients carrying a G allele, with the highest frequency in GG homozygotes. The TNFRSF1A GG genotype was significantly associated with IDA in established RA (OR 4.3, p = 0.01), and this was confirmed in a group of patients with early RA (OR 4.8, p = 0.04). Analysis of the combined groups also showed a weak association of the G allele with ACD (OR 2.2, p = 0.04). No association was found between TNFRSF1B variants and anemia when the cohorts were analyzed separately, but an association between carriage of the T allele and ACD was found when the 2 groups were combined (OR 11.5, p = 0.01). CONCLUSION: Our data suggest that polymorphisms within the TNFRSF1A and TNFRSF1B genes are associated with IDA and/or ACD in patients with RA.
16190360 [New immunoserological tests and pathogenesis for rheumatoid arthritis]. 2005 Aug In 1987, the ACR (American College of rheumatology) guidelines for classification of RA were published and the JCR (Japan College of rheumatology) classification of early diagnosis for RA was established in 1994. The determination of rheumatoid factor (RF) was included in both the above classification standards. However, Ig-M type of RF has problems in specificity and sensitivity. Recent progress in various RA studies has revealed the molecular mechanism of RA and new therapy and laboratory tests (ie. CA-RF, MMP-3) have been developed. Thus, determination changes in various diagnostic markers such as MMP-3, and inflammatory cytokines (ie. IL-1beta, IL-2, IL-6, IL-8, IL-18) are important for treatment of RA patients.
16485108 Serum levels of cartilage oligomeric matrix protein (COMP): a rapid decrease in patients w 2006 Sep To examine the influence of intravenous steroid-treatment (IST) on serum levels of Cartilage oligomeric matrix protein (COMP) in patients with active rheumatoid arthritis (RA). Serum levels of COMP and C-reactive protein (CRP) were measured in 12 patients with highly active RA (Steinbrocker stages II-IV) and in 5 patients with highly active reactive arthritis (ReA) (positive testing for HLA-B27) before starting daily IST. Patients received a total steroid dosage between 100 and 500 mg of prednisolone. COMP was measured by a commercially available sandwich-type ELISA-kit developed by AnaMar Medical AB, Sweden. Statistical evaluation was calculated by paired t test. In the RA group, COMP levels ranged from 6.3 to 19.4 U/l (mean 12.9 U/l), CRP from 5 to 195 mg/l (mean 77.8 mg/l), the COMP levels of the ReA group ranged from 5.1 to 7.4 U/l (mean 7.9 U/l), the CRP levels from 13 to 126 mg/l (mean 49 mg/l). We found a significant difference between the initial COMP levels in RA+ and ReA patients (P<0.005). In contrast to the ReA group, serum-COMP levels of RA+ patients (P<0.004) and the VAS (P<0.0001) decreased significantly within 2-10 days after the first treatment with steroids. The CRP levels remained unchanged in both groups. Our results indicate that the intravenous treatment with steroids in patients with highly active RA leads to a significant decrease of cartilage degradation. COMP seems to be a valuable parameter not even as a prognostic factor, but as a marker for monitoring the therapy response in patients with RA.
16496598 Posterior cervical lateral mass fixation for the management of insufficient anterior stabi 2005 PURPOSE: There are clinical situations when anterior fixation alone is not sufficient to adequately stabilize the cervical spine at the level of operation. In vitro biomechanical studies revealed the substantial role of posterior stabilization in such situations. However, no clinical studies of this problem have been published. The usefulness of posterior cervical lateral mass fixation when anterior stabilization failed to offer sufficient spine stability was assessed in the present study. MATERIAL AND METHODS: We enrolled 15 patients who underwent additional posterior fixation due to destabilization of the anterior one. There were five patients with rheumatoid arthritis, six with cervical discopathy, three with cervical trauma, and one with spine tumor. Improvement after posterior fixation was noted in all but one patient. RESULTS: Posterior cervical lateral mass fixation significantly improved cervical spine stability in cases with insufficiency of anterior stabilization. Further investigations on criteria helpful to predict insufficiency of anterior stabilization in cases of multisegmental cervical spine disease are needed.
15967923 Recurrence of alopecia areata in a patient receiving etanercept injections. 2005 Jun BACKGROUND: Alopecia areata is a common condition of patchy hair loss that has been postulated to have an autoimmune pathogenesis involving inflammatory cytokines, including tumor necrosis factor (TNF) alpha. Etanercept is a novel medication that blocks TNF-alpha-mediated processes. We report a case involving the recurrence of alopecia areata in a patient receiving etanercept. OBSERVATIONS: We describe a 49-year-old man with a history of rheumatoid arthritis and alopecia areata who developed a recurrence of his alopecia areata while being treated with etanercept for more than 2 years. CONCLUSIONS: The anti-TNF-alpha effect of etanercept therapy may not be sufficient to prevent the recurrence of alopecia areata. The possible role of TNF-alpha in the pathogenesis of alopecia areata may be called into question if our observation is repeated.
15647419 The EULAR-OMERACT rheumatoid arthritis MRI reference image atlas: the wrist joint. 2005 Feb This paper presents the wrist joint MR images of the EULAR-OMERACT rheumatoid arthritis MRI reference image atlas. Reference images for scoring synovitis, bone oedema, and bone erosions according to the OMERACT RA MRI scoring (RAMRIS) system are provided. All grades (0-3) of synovitis are illustrated in each of the three wrist joint areas defined in the scoring system--that is, the distal radioulnar joint, the radiocarpal joint, and the intercarpal-carpometacarpal joints. For reasons of feasibility, examples of bone abnormalities are limited to five selected bones: the radius, scaphoid, lunate, capitate, and a metacarpal base. In these bones, grades 0-3 of bone oedema are illustrated, and for bone erosion, grades 0-3 and examples of higher grades are presented. The presented reference images can be used to guide scoring of wrist joints according to the OMERACT RA MRI scoring system.
16947774 Tumor necrosis factor alpha antagonist use and cancer in patients with rheumatoid arthriti 2006 Sep OBJECTIVE: Concerns persist about a possible association between tumor necrosis factor alpha (TNFalpha) antagonist treatment and development of cancers in patients with rheumatoid arthritis (RA). This study was undertaken to estimate the association between treatment with biologic disease-modifying antirheumatic drugs (DMARDs) and development of cancer in patients with RA. METHODS: We conducted a cohort study pooling administrative databases from 2 US states and 1 Canadian province. A cohort of patients who had received a diagnosis of RA on > or =1 occasion and had been prescribed DMARDs was identified. We categorized patients with a prescription for a biologic DMARD as biologic DMARD users, and those with a prescription for methotrexate (MTX) but no biologic DMARD as MTX users. We used time-varying propensity scores to adjust for the large number of possible confounders and stratified proportional hazards regression to estimate the effects of biologic DMARDs on cancer. The primary end points were hematologic malignancies (lymphoma, multiple myeloma, and leukemia) and common solid tumors (colorectal, lung, stomach, breast, prostate, uterine, ovarian, urinary tract/bladder, and melanoma). RESULTS: The pooled cohort included 1,152 biologic DMARD users and 7,306 MTX users. We identified 11 hematologic malignancies and 46 solid tumors during 2,940 person-years of biologic DMARD use, and 88 hematologic malignancies and 558 solid tumors during 30,300 person-years of MTX use. Comparing biologic DMARD users with MTX users, the propensity score-adjusted pooled hazard ratio was 1.37 (95% confidence interval 0.71-2.65) for hematologic malignancies and 0.91 (95% confidence interval 0.65-1.26) for solid tumors. CONCLUSION: Our results indicate that users of biologic agents are unlikely to have a substantial increase in the risk of hematologic malignancies and solid tumors as compared with MTX users. Despite the use of large combined data sets, studying the effect of an infrequent exposure (biologic DMARDs) on rare diseases (hematologic malignancies) remains a challenge.
15677700 Pharmacogenetic and metabolite measurements are associated with clinical status in patient 2005 Aug OBJECTIVE: To investigate the contribution of red blood cell (RBC) methotrexate polyglutamates (MTX PGs), RBC folate polyglutamates (folate PGs), and a pharmacogenetic index to the clinical status of patients with rheumatoid arthritis treated with MTX. METHODS: 226 adult patients treated with weekly MTX for more than 3 months were enrolled at three sites in a multicentred cross sectional observational study. Clinical status was assessed by the number of joint counts, physician's global assessment of disease activity, and a modified Health Assessment Questionnaire (mHAQ). RBC MTX PG and folate PG metabolite levels were measured by high performance liquid chromatography fluorometry and radioassay, respectively. A composite pharmacogenetic index comprising low penetrance genetic polymorphisms in reduced folate carrier (RFC-1 G80A), AICAR transformylase (ATIC C347G), and thymidylate synthase (TSER*2/*3) was calculated. Statistical analyses were by multivariate linear regression with clinical measures as dependent variables and metabolite levels and the pharmacogenetic index as independent variables after adjustment for other covariates. RESULTS: Multivariate analysis showed that lower RBC MTX PG levels (median 40 nmol/l) and a lower pharmacogenetic index (median 2) were associated with a higher number of joint counts, higher disease activity, and higher mHAQ (p<0.09). Multivariate analysis also established that higher RBC folate PG levels (median 1062 nmol/l) were associated with a higher number of tender and swollen joints after adjustment for RBC MTX PG levels and the pharmacogenetic index (p<0.05). CONCLUSION: Pharmacogenetic and metabolite measurements may be useful in optimising MTX treatment. Prospective studies are warranted to investigate the predictive value of these markers for MTX efficacy.
15720905 Early failure of total hip replacements implanted at distant hospitals to reduce waiting l 2005 Jan AIM: In the years 1990-1993, in an effort to reduce waiting-list time, a small number of patients were sent from Exeter to hospitals in London to undergo elective total hip replacement. No medium- or long-term follow-up was arranged. Our aim was to audit the outcome of these hip replacements. PATIENTS AND METHODS: Review of the records of the referring medical practices, Regional Health Authority, local orthopaedic hospital and the distant centres at which the surgery was performed identified 31 cases. A total of 27 hip replacements in 24 patients were available for clinical and radiological review. RESULTS: 12 (44%) hips have so far required revision surgery, at a mean of 6.5 years. Of these, three (11%) have been for deep infection. A further three hips (11%) are radiologically loose and are being closely monitored. Two patients (7%) suffered permanent sciatic nerve palsy. CONCLUSIONS: Patients whose surgery was performed locally over a similar time period have a published failure rate of only 4.9%. This difference is highly statistically significant (P < 0.001). The causes for such a difference in outcome were analysed and include surgical technique, implant selection and absence of follow-up. In the light of this evidence, we would like to urge the government to address waiting list problems by investing in the local infrastructure. Expanding those facilities where properly audited and fully accountable surgeons operate must be the way forward.
17136313 Absence of antibody to cyclic citrullinated peptide in sera of non-arthritic patients with 2007 Jul The objective of this study was to investigate if antibody to cyclic citrullinated peptide (anti-CCP) is detected in sera of patients with chronic hepatitis B virus (HBV) infection. Serum anti-CCP and IgA, IgG, and IgM rheumatoid factor (RF) isotypes were measured by enzyme-linked immunosorbent assay on 176 non-arthritic patients with HBV infection. IgA RF, IgG RF, and IgM RF were detectable in 29.5, 21, and 18.8% of the tested sera, respectively, with a total seropositivity rate of 42.7%. Marginally elevated anti-CCP was detected in one patient (0.6%). By regression analysis, there was no statistically significant association between the serum levels of anti-CCP and serum IgA, IgG, or IgM RF (R (2) = 0.033, with respective p values of 0.224, 0.297, and 0.334). In conclusion, anti-CCP was rarely detected in non-arthritic patients with HBV infection in contrast to RF. Thus, testing for anti-CCP may be a useful tool for the diagnosis of rheumatoid arthritis in this population.
17045630 Incidence and prevalence of rheumatoid arthritis, based on the 1987 American College of Rh 2006 Dec OBJECTIVES: To conduct a systematic review of incidence and prevalence studies of rheumatoid arthritis (RA), based on the 1987 revised American College of Rheumatology (ACR) criteria, to compare their methodologies and summarize their results, and to investigate the possible geographic variations and changes over time in the frequency of the disease. METHODS: We conducted a Medline search between January 1988 and December 2005. Studies reporting the incidence and prevalence of RA in adult populations (16 to 20 years and over), based on 1987 ACR criteria, were eligible for inclusion. From each study included, we extracted the country, year of publication, type of study (retrospective, prospective, or cross-sectional), and incidence or prevalence rates. The study areas were grouped into (a) North American countries; (b) north European countries; (c) south European countries; and (d) developing countries. We examined the geographical differences of prevalence and incidence rates using the Mann-Whitney and the Kruskall-Wallis tests. RESULTS: A total of 28 studies were identified meeting the inclusion criteria. Nine were incidence studies, 17 were prevalence studies, and 2 estimated both prevalence and incidence rates. Incidence studies were not available from developing countries. There is a significant difference of prevalence estimates between northern European and American countries and developing countries. South European countries have lower median incidence rates than North American and north European countries. As concerning the time trends of RA occurrence, only 3 incidence studies provided secular data from the same study area, based on ACR criteria, using the same methods of case ascertainment. Two of these studies indicate a decreasing incidence of RA in Finland and United States of America. CONCLUSIONS: The occurrence of RA varies among countries and areas of the world. A decreasing trend has been observed in countries characterized by high rates of RA incidence and prevalence. However, the relatively small number of studies for most areas of the world and the lack of incidence studies for the developing countries limits the understanding of worldwide RA epidemiology.
16447235 PUMA regulation and proapoptotic effects in fibroblast-like synoviocytes. 2006 Feb OBJECTIVE: Although p53 is overexpressed in rheumatoid arthritis (RA) synovial tissue (ST), few synoviocytes undergo apoptosis. This could be partly due to low expression of proapoptotic genes. Deficient p53 up-regulated modulator of apoptosis (PUMA), which is a major effector of p53-mediated cell death, could contribute to this phenomenon. To evaluate a method to induce apoptosis, the expression and function of PUMA was investigated in ST and cultured fibroblast-like synoviocytes (FLS). METHODS: PUMA expression in ST was measured by immunohistochemistry, Western blot analysis, and quantitative polymerase chain reaction analysis. Ad-p53 and plasmids encoding hemagglutinin-tagged, full-length PUMA expression vector (HA-PUMA), PUMA lacking the Bcl-2 homology 3 domain, or pCEP4 were used to transfect FLS. Apoptosis was quantified by trypan blue exclusion, DNA fragmentation, and caspase 3 activation. RESULTS: PUMA protein was detected in RA ST, although most of the immunoreactive protein was localized to sublining cells rather than the intimal lining synoviocytes. Western blot analysis showed no difference between RA ST and osteoarthritis (OA) ST. PUMA messenger RNA was detected in RA and OA ST, although the amounts were markedly lower than in the spleen and FLS. To determine if PUMA was inducible, FLS were transduced with Ad-p53. Even though p53 protein was produced and p21 expression was increased, PUMA expression was not enhanced. Consistent with this observation, Ad-p53 did not induce apoptosis in FLS. However, HA-PUMA transfection into FLS resulted in rapid apoptosis with the activation of caspase 3. CONCLUSION: PUMA can induce apoptosis by FLS and represents a potential target in RA.