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The approach to the use of antiviral agents abstract form only order sildalist 120 mg free shipping, and showed that 14% of patients were taken off is shown in Table 1 purchase sildalist 120mgmg with visa. The efficacy of this complex purchase generic sildalist canada, intensive regimen remains unproven. The National Cancer Institute series of 29 patients with blood without ART; before autologous HCT and with high-dose BL treated with R-EPOCH included 10 who were HIV-1-positive melphalan therapy, there was viral rebound at day 6 with a peak of and the compete response rate and OS rate were an impressive 28 000 c/mL and a return to 50 c/mL by day 41 corresponding to 100% at 57 months of follow-up. Regain of viral control was associated with a potent CD8 response. Before ART, the need for alternate approaches transplantation period to control virus for those without such immunity. Approach to the use of antivirals* Raltegravir-based regimen NNRTI-based regimen Boosted PI regimen Continue through conditioning Continue through conditioning Discontinue 96 h prior to conditioning and resume after conditioning NNRTIindicatesNonnucleosidereversetranscriptaseinhibitor;andPI,proteaseinhibitor. However, cure of HIV-1 study enrollment and 2 at the time of stem cell mobilization. The remains the Holy Grail and HCT may provide us the route to this viral loads at study entry therefore ranged from 204 to 750 000 goal. Infusion of resistant allogeneic hematopoietic cells or manipu- copies/mL. Thirteen patients withdrew before stem cell collection, lation of autologous hematopoietic cells to render them resistant to the majority due to progressive disease. Ultimately, 27 of the initial the HIV-1, followed by reinfusion after ablative chemotherapy that 50 patients underwent HCT. The 3-year PFS for the patients who depletes the endogenous reservoir and allows engraftment, are proceeded to HCT was similar to the City of Hope group at 76. To date, the most successful method was the use Multivariate analysis for prognostic factors for survival showed that of allogeneic hematopoietic cells from a donor genetically resistant to HIV-1 into an AIDS patient with acute myelogenous leukemia. Individuals who are homozygous at this locus do not express CCR5 on their cell surface The Bone and Marrow Transplantation Clinical Trials Network 33 and therefore cannot be infected with CCR5 (R5) tropic HIV-1. The HCT, and the patient remains with undetectable HIV-1 RNA in primary end point of the trial is OS at 1 year; analysis is pending. Alternately, genetic modification of autologous hematopoi- level of clinical detection, suggested that a sanctuary site exists from 29 etic cells circumvents the issues of identifying donors and, given the which infection could always be recovered. The tissue repository far lower morbidity of autologous HCT, allows a more viable of HIV-1-infected cells from which this active replicating HIV-1 is 30 approach to hematopoietic cell therapy for HIV-1. The theoretical space that is considered the HIV-1 reservoir consists of CD4 T- A large phase 2 trial of gene-modified autologous hematopoietic lymphocytes and dendritic cells (DCs). DCs, predominantly in- cells infused without conditioning therapy showed only minimal fected by R5 strains of virus or by dual-tropic infection with R5 and detection of gene-marked cells in peripheral blood and a lack of CXCR4 strains, undergo stimulation by cytokines, leading to the significant effect on HIV-1 levels. Therefore, factors that stimulate cytokine release, effects of the genetically modified cells on the HIV infection. There including mucosal damage from high-dose chemotherapy, coinfec- were no long-term deleterious effects of the ATI, so this trial set the tion with microbes, and microbial translocation from the GI tract, platform for this approach in future trials. At the The favorable results of high-dose therapy and autologous in same time, the challenge was also to find a suitable patient HIV-1-associated lymphoma raised the question of whether the population for whom myeloablation could be justified. The lym- apheresis or the high-dose chemotherapy provided any beneficial phoma population was perfectly suited, especially given the poor effects on HIV-1 infection. For example, could the apheresis have long-term survival of patients with relapsed HIV lymphoma. The depleted the reservoir or could myeloablative chemotherapy ablate pilot trial treated 4 relapsed HIV-1-positive NHL patients with the infected lymphocyte pool? To address this, Cillo et al32 reported hematopoietic cells transduced with a lentivirus encoding 3 anti- HIV-1 RNAs, namely TAR, siRNA to tat/rev, and a ribozyme a retrospective analysis of frozen PBMC specimens from AIDS 37 targeting CCR5. The cells were infused in combination with lymphoma HCT recipients who remained on ART during much of unmodified cells after high-dose CBV therapy. Patients had no detectable HIV-1 RNA in the plasma at serious adverse events associated with the genetically modified variable time points after HCT. Specimens from blood, studied 36 cells, but, similar to the aforementioned Mitsuyasu study, levels of before HCT and at one other post-HCT time, used assays for HIV gene marking, although present in all patients in the peripheral RNA and DNA having single-copy sensitivity, a surrogate measure blood, were low at 0. No HIV-1 RNA was detected in plasma by due in part to competition with the much higher levels of unmodi- routine assays, but with the more sensitive assay, 9 of 10 patients fied hematopoietic cells that were infused concomitantly with the were viremic after HCT while on ART, with a range of 0. HIV-1 gene copies/mL, and 9/10 were found to have detectable HIV-1 DNA. This finding may have been due to 2 factors: (1) the The evolving paradigm is that success is contingent upon high levels autologous graft likely had infectious virus in contaminating T-cells of only genetically modified hematopoietic cells being infused or and (2) the endogenous reservoir was still present despite the selection of the protected cells after engraftment. Ultimately, the test cytoreductive conditioning regimen. Patients in cohort 1 (n 6) underwent a 12-week ATI of ART beginning 4 weeks after the T-cell infusion. HIV-1 viral load was undetectable at the start of ATI and became detectable in 4 of the 6 patients at 2-4 weeks after cessation of c-ART. There was a decline of CD4 counts during ATI, but this decline in CCR5-modified cells (1. Only one serious adverse event was associated with the cell infusion and was attributed to a transfusion reaction. Level of gene marking expressed as number of copies of trial has thus successfully set the platform for ZFN editing of cells as vector (WPRE) per 100 blood cells analyzed over time. Unique a viable and well-tolerated approach that may lead to in vivo patient identifiers are listed in the upper right corner of the graph. Limits resistance of these CCR5-edited cells to HIV-1. The future trial of of quantification (stippled) and limits of detection (diagonal lines) values ZFN-1-modified hematopoietic cells in conjunction with nonmyelo- were determined for each amplification reaction and typically were in the ablative busulfan conditioning in selected HIV-1-positive patients range of 0. We have adopted a stepwise approach, with Conflict-of-interest disclosures: A. In addition, infusion of only genetically modified hematopoi- etic Cell Transplantation, Beckman Research Institute, City of Hope etic cells could be justified in the nonmyeloablative setting because Medical Center, 1500 E Duarte Road, Duarte, CA 91010. Phone: early or late graft failure in this setting would not have the same 626-359-8111; Fax: 626-301-8973; e-mail: AKrishnan@coh. A pilot trial using busulfan at nonmyeloablative doses in first-remission HIV-1- References positive NHL patients is open at City of Hope (www. Changing incidence and prognostic factors of survival in AIDS-related non-Hodgkin’s lym- gov identifier #NCT01961063). Busulfan is not considered an antilymphoma therapy, so its use in 2. Primary effusion lym- the current trial is solely to facilitate engraftment. Clinical trials in phoma: a distinct clinicopathologic entity associated with the Kaposi’s human genetic diseases, especially in pediatric populations, using sarcoma-associated herpes virus. Sullivan RJ, Pantanowitz L, Casper C, Stebbing J, Dezube BJ. Candotti et al39 correlated busulfan HIV/AIDS: epidemiology, pathophysiology, and treatment of Kaposi dosing with area under the curve (AUC) measurements demonstrat- sarcoma-associated herpesvirus disease: Kaposi sarcoma, primary effu- 2 sion lymphoma, and multicentric Castleman disease.

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CD4 CD25 T regulatory cells suppress NK ing growth factor-beta-dependent manner buy sildalist 120mg without prescription. Transforming tween natural killer cells and regulatory T cells: perspectives for growth factor beta 1 inhibits expression of NKp30 and NKG2D immunotherapy buy discount sildalist 120 mg on-line. Regulatory T cells: customizing for the dritic cells purchase discount sildalist on line. Bergmann C, Wild CA, Narwan M, Lotfi R, Lang S, Brandau S. Human T regulatory cell Human tumor-induced and naturally occurring Treg cells therapy: take a billion or so and call me in the morning. Activation of tion: main characters or walk-on actors? Crit Rev Oncol human NK cells by plasmacytoid dendritic cells and its Hematol. Regulatory T cells in stem cell transplan- regulatory cells. Gasteiger G, Hemmers S, Bos PD, Sun JC, Rudensky AY. IL-2-dependent adaptive control of NK cell homeostasis. Pabst C, Schirutschke H, Ehninger G, Bornhauser M, Platz- 56. The graft content of donor T cells expressing gamma tuning of NK cell sensitivity for target cells is controlled by delta TCR and CD4 foxp3 predicts the risk of acute graft regulatory T cells. Roy S, Barnes PF, Garg A, Wu S, Cosman D, Vankayalapati R. Postallograft lenalido- prevent CD28-mediated Foxp3 transcription in CD4 CD25- T mide induces strong NK cell-mediated antimyeloma activity and lymphocytes. Transplantation in HIV-infected subjects: is cure possible? Forman2 1Division of Virology, Beckman Research Institute of City of Hope, Duarte, CA; and 2Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA With the advent of effective antiretroviral therapy, the treatment of patients with HIV-related malignancies, especially lymphoma, has greatly improved, yielding results comparable to those seen in patients with lymphoma unrelated to HIV. The platform of transplantation of hematopoietic stem cells has facilitated studies of genetically modified stem cells engineered to express antiretroviral genes to resist infection by the HIV virus, testing the concept that engraftment of these cells will lead to HIV resistance and elimination of the reservoir of virus in the body. Results in patients with HIV and lymphoma have now led to studies that will test these principles in HIV patients without concomitant malignancy. In addition, in a patient with HIV and acute myeloid leukemia, the success of an allogeneic transplantation from an unrelated donor carrying a mutation in the CCR5 genes has demonstrated that, in principle, such an approach could also lead to cure of patients with HIV. Case studies in HIV patients with leukemia undergoing allogeneic transplantation also suggest that there may be a therapeutic effect on the HIV reservoir that could alter the natural history of HIV in the allogeneic setting. Introduction mobilization and successful engraftment in the BM milieu of active It has been more than 20 years since the concept was first proposed viral replication. The first real step forward using ASCT in the of using a preparative transplantation regimen to destroy the setting of HIV infection came in the post-cART era in patients with lymphohematopoietic reservoir of HIV. Currently, the predominant role of HSCT treatment for relapse. It has been in this setting had viral loads 10 000 gc/mL by RT-PCR. With the exception of that parallel questions of control of malignancy and HIV have been one patient who had delayed engraftment until day 23, engraftment posed, seeking to accomplish the dual purpose of cure of the malig- of HSCs was similar to that seen in HIV-negative patients. At the nancy and control, if not cure, of the HIV infection. Although an Autologous transplantation for AIDS-related attempt was made to continue cART therapy throughout the lymphoma transplantation period, only half of the patients were able to tolerate Hematopoietic cell therapy in HIV/AIDS has been most applicable the medications due to nausea and mucositis; however, control of in the setting of AIDS-related lymphoma. Since the advent of virus after transplantation was readily achieved. This experience combination antiretroviral therapy (cART), the survival of patients was evaluated as a case-control analysis of patients with HIV- with HIV infection has improved dramatically, but as life- threatening opportunistic infections have become less common, related lymphoma compared with HIV-negative patients with the same lymphoma histologies. These results confirmed melanoma, which have increased as the HIV-infected population has another retrospective case control study comparing 53 HIV-infected aged. AIDS-defining cancers such as B-cell lymphoma are of signifi- lymphoma patients with negative controls adjusted for histology, cant concern3 and are predominantly of the B-cell subtypes having International Prognostic Index score, and disease status, demonstrat- ing overall survivals of 61% versus 70%, respectively. In addition, there has been a rise in HIV-related Hodgkin retrospective multicenter experience with 68 high risk patients with lymphoma, presumably reflecting immune stimulation driven by the HIV and lymphoma in first complete remission at 20 institutions higher CD4 counts. To address whether the Hematology 2013 389 Genetic modification of HSPC for HIV/AIDS The goal of an HSCT-based strategy for HIV/AIDS is to generate a new immune system to control HIV infection while at the same time destroying the endogenous reservoir, thereby curing the infection. Success would be largely predicated upon the creation of a durable (HIV-resistant) immune system through transplantation of innately resistant or genetically altered hematopoietic stem/progenitor cells (HSPCs); xenogeneic, allogeneic, and autologous stem cell sources have all been tested. The feasibility of transferring HIV resistance via HSPCs was demonstrated when an AIDS patient in Berlin with acute myeloid leukemia received a transplantation with HLA- matched, unrelated donor HSPCs containing a homozygous 32-bp deletion in the chemokine receptor 5 gene (CCR5 32/ 32). The recipient attained complete hematopoietic reconstitution with the donor graft, suspended cART early after transplantation, and has remained with undetectable HIV RNA in the blood and HIV DNA in the tissues using single-copy– sensitive PCR methods for at least 4 years after transplantation. Based on this case, genetic modification and engraftment of HSCs to confer HIV resistance might be a promising alternative to homozygous natural deletions in potential donors, addressing the larger question of cure of HIV in nonmalignancy HIV patients. Retroviral or lentiviral transfer of HIV resistance genes into HSCs would presumably generate progeny that are resistant to reinfection by any endogenous virus and, in the absence of a suitable reservoir, the original virus would be eliminated. Probability of disease-free survival (A) and overall 7 A phase 2 trial of gene-modified autologous cell therapy with a trial survival (B) by HIV-1 status. Recent studies show that Specimens before and after ASCT were studied with single-copy– patients undergoing high-dose chemotherapy and ASCT infused sensitive assays for HIV RNA and DNA as a surrogate measure of with a combination of gene-modified and unmodified stem cells the HIV reservoir. Despite the absence of detectable HIV RNA in could be successfully engrafted without affecting normal hematopoi- the plasma using conventional methods, 9 of the 10 patients were esis. The transplantation recipients volves autologous transplantation of CD34 cells transduced with a were likely “reinfected” with endogenous virus under cover of short hairpin RNA against CCR5; this strategy has shown success- cART, and the conclusion was that the myeloablative chemotherapy ful low-toxicity long-term downregulation of CCR5 in macaques. This finding has mC46 membrane-bound viral fusion inhibitor and a chemotherapy- prompted efforts to modify the infused T cells so that they are resistance marker has demonstrated stable protection from viral resistant to HIV. Outcome of ASCT in high-risk AIDS lymphoma for recurrent lymphoma were treated with HSPCs that had been Conditioning Time to modified by a lentivirus containing 3 different RNA-based antiretro- Study N regimens PFS follow-up viral genes without serious adverse events attributable to the 11 research HSPC product (Figure 2). This study Spitzer et al13 20 BU/CY 50% 23 wk demonstrated the safety and feasibility of the approach after Re et al9 27 BEAM 76% 24 mo myeloablative conditioning, but also showed the limitation in the Balsalobre et al10 68 Not reported 56% 32 mo ability of the autologous approach to engraft adequate numbers of Diez-Martin et al8 53 BEAM 61% 30 mo gene-modified cells. Given that clinical trials on the correction of BEAM indicates carmustine (bis-chloroethylnitrosourea-BCNU), etoposide, cytara- human genetic diseases using gene-modified HSPCs have shown bine (arabinofuranosyl cytidine), melphalan; CY, cyclophosphamide; TBI, total body success using busulfan-based regimens, these approaches are now irradiation;VP16,etoposide;BU,busulfan;andPFS,progression-freesurvival. Kaplan-Meier estimation of the survival of HIV-1–infected Figure 2. Gene marking in the peripheral blood after ASCT for patients after allogeneic HSCT during the period 1983-2010. Adding to this suggestive but finger–based strategies have the advantage of a transient cell anecdotal data is a series of patients demonstrating that all treatment ex vivo that produces a permanent genetic mutation; HIV-infected recipients of reduced intensity transplantations on preclinical development of this approach suggests that it should be cART survived, in remission and off immunosuppression at 1 year feasible in human clinical trials. Although rejection and demonstrated the feasibility of maintaining HIV- HIV DNA was readily detected in peripheral blood mononuclear infected patients on chronic immunosuppression without worsening cells before and 2 to 3 months after transplantation, HIV DNA and the underlying HIV infections as long as cART therapy is contin- RNA were undetectable in the peripheral blood mononuclear cells, ued. The “Berlin patient” index case, showing that transplantation of CD4, and plasma at 21 and 42 months after transplantation. This hematopoietic cells from a donor with homozygous constitutional loss of detectable HIV correlated with full donor chimerism, deletion mutations of the CCR5 receptor could be cured of his development of GVHD, and decreases in HIV-specific antibody underlying AIDS infection, combined with the observation of the levels.

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It also considers other optional domains that may be relevant for some scenarios order sildalist master card, such as a dose-response association buy on line sildalist, plausible confounding that would decrease the observed effect buy sildalist 120mgmg with mastercard, strength of association (magnitude of effect), and publication bias. Table 3 describes the grades of evidence that can be assigned. Grades reflect the strength of the body of evidence to answer key questions on the comparative effectiveness, efficacy, and harms of NSAIDs. Grades do not refer to the general efficacy or effectiveness of pharmaceuticals. Nonsteroidal antiinflammatory drugs (NSAIDs) 15 of 72 Final Report Update 4 Drug Effectiveness Review Project 15 Table 3. Definitions of the grades of overall strength of evidence Grade Definition High confidence that the evidence reflects the true effect. Further research is very unlikely to High change our confidence in the estimate of effect. Moderate confidence that the evidence reflects the true effect. Further research may change our Moderate confidence in the estimate of the effect and may change the estimate. Low confidence that the evidence reflects the true effect. Further research is likely to change our Low confidence in the estimate of the effect and is likely to change the estimate. Insufficient Evidence either is unavailable or does not permit estimation of an effect. Data Synthesis We constructed evidence tables showing the study characteristics, quality ratings, and results for all included studies. We reviewed studies using a hierarchy of evidence approach, where the best evidence is the focus of our synthesis for each question, population, intervention, and outcome addressed. Studies that evaluated one NSAID against another provided direct evidence of comparative effectiveness and adverse event rates. Direct comparisons were preferred over indirect comparisons; similarly, effectiveness and long-term safety outcomes were preferred to efficacy and short-term tolerability outcomes. In theory, trials that compare NSAIDs with other drug classes or with placebos can also provide evidence about effectiveness. This is known as an indirect comparison and can be difficult to interpret for a number of reasons, primarily heterogeneity of trial populations, interventions, and outcomes assessment. Data from indirect comparisons are used to support direct comparisons, where they exist, and are used as the primary comparison where no direct comparisons exist. Indirect comparisons should be interpreted with caution. Quantitative analyses were conducted using meta-analyses of outcomes reported by a sufficient number of studies that were homogeneous enough that combining their results could be justified. These analyses were created using Stats Direct (Cam Code, Altrincham UK) software. In order to determine whether meta-analysis could be meaningfully performed, we considered the quality of the studies and the heterogeneity among studies in design, patient population, interventions, and outcomes. When meta-analysis could not be performed, the data were summarized qualitatively. If necessary, indirect meta-analyses were done to compare interventions for which there were no head-to-head 17 comparisons and where there was a common comparator intervention across studies. Forest 18 plots graphically summarize results of individual studies and of the pooled analysis. Potential sources of heterogeneity were examined by analysis of subgroups of study design, study quality, patient population, and variation in interventions. Meta-regression models were used to formally 16, 21 test for differences between subgroups with respect to outcomes. Public Comment This report was posted to the Drug Effectiveness Review Project website for public comment. We received comments from two pharmaceutical companies. Nonsteroidal antiinflammatory drugs (NSAIDs) 16 of 72 Final Report Update 4 Drug Effectiveness Review Project RESULTS Overview A total of 2941 (1139 from update 4) records were identified from searching electronic databases, reviews of reference lists, pharmaceutical manufacturer dossier submissions, and public comments. By applying the eligibility and exclusion criteria, we ultimately included 159 publications (33 for Update 4). Of these, 68 were trials (23 for Update 4), 47 were observational studies (4 for Update 4), 32 were systematic reviews (4 for Update 4), and 12 were pooled analyses and post-hoc analyses (2 for Update 4). See Appendix E for a list of excluded studies and reasons for exclusion at full text. Figure 1 shows the flow of study selection for Update 4. Results of literature search b 1124 records identified from 15 additional records identified database searches after through other sources removal of duplicates 1139 records screened 990 records excluded at abstract level 149 full-text articles assessed 116 full-text articles for eligibility excluded • 6 non-English language • 5 ineligible outcome • 15 ineligible intervention • 14 ineligible population 31 studies (+2 companion • 15 ineligible publication type publications) included in qualitative synthesis • 45 ineligible study design • 21 trials (+2 companion • 16 outdated or ineligible publications) systematic reviews • 4 observational studies • 4 systematic reviews • 2 others (includes pooled analysis, post hoc analysis of trials, etc. Nonsteroidal antiinflammatory drugs (NSAIDs) 17 of 72 Final Report Update 4 Drug Effectiveness Review Project Key Question 1. Are there differences in effectiveness between NSAIDs, with or without antiulcer medication, when used in adults with chronic pain from osteoarthritis, rheumatoid arthritis, soft-tissue pain, back pain, or ankylosing spondylitis? Summary of Evidence Comparisons between oral drugs • Celecoxib 200 mg/day to 800 mg/day compared with nonselective NSAIDs o Associated with similar pain reduction effects in primarily short-term randomized controlled trials of patients with osteoarthritis, rheumatoid arthritis, soft tissue pain, and ankylosing spondylitis in 11 of 12 trials • Partially selective NSAIDs compared with nonselective NSAIDs o Partially selective NSAIDs (meloxicam, nabumetone, and etodolac) were associated with similar pain reduction effects relative to nonselective NSAIDs in short-term randomized controlled trials • Comparisons among nonselective NSAIDs o Good-quality Cochrane reviews and more recent trials found no clear differences among nonselective NSAIDs in efficacy for treating osteoarthritis of the knee or hip or for low-back pain o Evidence on the comparative efficacy of salsalate was limited to 2 randomized controlled trials that found no significant difference as compared with indomethacin. Comparisons between topical drugs • We found no trials that directly compared the effectiveness or efficacy between different topical drugs • Both diclofenac 1. Comparisons between oral and topical drugs • No significant differences were found between diclofenac 1. Nonsteroidal antiinflammatory drugs (NSAIDs) 18 of 72 Final Report Update 4 Drug Effectiveness Review Project Detailed Assessment Effectiveness Some trials evaluated longer-term (>6-12 months) and real-life (symptoms, clinical ulcers, functional status, myocardial infarctions, pain relief) outcomes, but none were conducted in primary care or office-based settings or used broad enrollment criteria. Efficacy: Comparisons between oral drugs Celecoxib compared with nonselective NSAIDs 22-30 Eleven of 12 randomized controlled trials of arthritis patients found no significant difference in efficacy between celecoxib and an NSAID. The single study finding a difference was a randomized controlled trial of 249 randomized patients with severe osteoarthritis of the hip requiring joint replacement surgery. A significantly greater reduction in pain on walking was found for diclofenac 50 mg 3 times daily compared with celecoxib 200 mg once daily, as measured using an 100 mm visual analog scale, both in the primary 6-week assessment (difference, 12. However, insufficient information was provided to determine if an adequate method was used to conceal the allocation sequence or whether the approach produced treatment groups that were comparable at baseline in terms of important prognostic factors. Baseline characteristics were only provided for the evaluable population (N=141), which only accounted for 60% of the modified intention-to-treat population (N=235). Consequently, this randomized controlled trial was rated poor quality and its results should be interpreted with caution. The Agency for Healthcare Research and Quality Effective Health Care Program 31 Comparative Effectiveness Review found no clear differences in efficacy between celecoxib 22, 24, 26, 29 32, 33 and nonselective NSAIDs based on results from published trials and meta-analyses of published and unpublished trials. Celecoxib and nonselective NSAIDs were associated with similar pain reduction effects (Western Ontario and McMaster Universities Osteoarthritis Index, visual analogue scale, Patient Global Assessment) in published trials of patients with 22, 24, 26, 29 34, 35 36-38 29, osteoarthritis, soft tissue pain, ankylosing spondylitis, or rheumatoid arthritis. Celecoxib 200-400 mg was associated with slightly higher rate of withdrawals than other NSAIDs due to lack of efficacy (relative risk, 1. This estimate of comparative efficacy may be the most precise available, but the validity of the findings cannot be verified as the data used in this analysis is not fully available to the 33 public.