Sustained Clinical Remission In Patients Research Articles

P698 Role of an exclusion diet (reduced disaccharides, saturated fats, emulsifiers, red and ultraprocessed meats) in maintaining the remission of chronic inflammatory bowel diseases in adults

Abstract Background Inflammatory bowel diseases (IBD) are a main focus in current research with diet being an emerging therapeutic line due to its links both in onset and progression. A Western-style diet high in processed foods, food additives, red meat, and animal fat has been linked to a higher risk of developing IBD. The aim of this study was to establish an association between an anti-inflammatory exclusion diet and maintenance of remission in IBD. Also, we assessed the efficacy and safety of this diet compared to a non-dietary group and the possible therapeutic effect of this diet in the maintenance of IBD remission. Methods One hundred seventeen adult IBD patients in remission (64 patients with Crohn’s disease- CD and 53 patients with ulcerative colitis- UC) were randomized at their own will to a 6-months exclusion diet (n=32) or a habitual diet (n=85). Dietary patterns, clinical activity of the disease and inflammatory markers were assessed at baseline and at the end of dietary intervention. Results The acceptance rate of the exclusion diet in our cohort was 27.35% (30% in UC and 20% in CD). The exclusion diet and control populations were similar, except for immunosuppressive treatment (only 30% of patients in the exclusion diet group had an immunomodullator compared to 70% in the control group (p-value <0.001)). The clinical remission after six months was maintained in the exclusion diet arm (100%). In the control arm, 3 patients had clinically active disease (1 patient with UC and 2 patients with CD) and 80 patients maintained the clinical remission state (96.4%) (p-value = 0.278). Figure 1 is depicting the remission rates in different patient groups. Regarding biochemical markers, erythrocyte sedimentation rate (ESR) at baseline was higher in the exclusion diet arm: 31 (5-62) than in the control arm 14.5 (4-48) (p-value=0.011), but six months after, the groups were similar (p-value = 0.440). Fecal calprotectin at baseline was higher than 300 micrograms/gram in 30% of cases in the exclusion diet arm and in 25.8% of cases in the control arm (p-value = 0.774). Six months after, 50% of cases had a higher fecal calprotectin (>300 micrograms/gram) in the intervention arm and only 20.5% in the control arm (p-value = 0.033). Figure 1. Maintenance of clinical remission 6 months after intervention Conclusion We found a better trend of sustained clinical remission in patients who follow an exclusion diet. However, the threshold for statistical significance was not achieved. The clinical study continues, these are preliminary data. There is also a trend of improvement in ESR in the intervention group, but the levels of fecal calprotectin did not improved.

Predictive value of infliximab trough levels in maintenance therapy for 5-year sustained clinical remission in patients with inflammatory bowel disease.

Despite long-term use of infliximab (IFX) in IBD treatment, its optimized use is unclear due to its complicated pharmacokinetics/dynamics. Hence, the predictive value of IFX trough levels (TL) is important in treatment management. We performed a prospective, cross-sectional, observational study with 74 IBD patients treated with IFX (mean 9.1 years, SD ± 3). TL was measured during maintenance therapy, in which maintenance of remission was followed for 5 years. TL > 3 µg/ml during maintenance therapy was a significant predictor of clinical remission in 5 years in UC patients (82 % vs 62 %, p 3 µg/ml during maintenance therapy in a cohort of IBD patients (p = 0.05). Deviations in percentage of remission and fraction of relapses in TL categories were insignificant in a cohort of CD patients (85 % vs 74 %, p > 0.05). TL > 3 µg/ml during maintenance therapy is a strong predictor of sustained clinical remission for 5 years in UC patients. The use of combination therapy with AZA, due to its significant association with high TL, may have a practical benefit in achieving better clinical outcomes in UC patients (Tab. 2, Fig. 10, Ref. 20).

Bone Marrow GZMK +IL7R + Progenitor-Exhausted CD8 + T Cells Correlate with Sustained Clinical Remission in Patients with Acute Myeloid Leukemia (AML) Undergoing Chemotherapy

IntroductionThe role of T cells in chemotherapy response and maintenance of remission in acute myeloid leukemia (AML) patients is not fully understood. In solid tumors and chronic infections, exhaustion is a multistep process ranging from less differentiated progenitor exhausted (Tpex) to intermediate and terminally exhausted T cells (Beltra et al. 2020). High frequencies of Tpex correlate with response to immune-checkpoint blockade in solid tumors (Miller et al. 2019). In AML, where the backbone of treatment is chemotherapy, the role of dysfunctional T-cell subsets has yet to be elucidated.MethodsSerial bone marrow (BM) samples from 16 AML patients (10 complete responders (Res) and 6 non-responders (NonRes)) at diagnosis and at response assessment after induction chemotherapy and 12 healthy donors (HD) were analyzed by flow cytometry using a 13-color panel. Moreover, we performed single-cell RNA sequencing (scRNAseq) (10X Genomics) on BM samples from 2 HD and 5 AML patients (3 Res, 2 NonRes) at baseline and after chemotherapy. Subsequently, we used a scRNAseq-guided 26-color spectral flow cytometry panel and explored T-cell phenotypes on BM of 22 AML patients (12 Res and 10 NonRes). Custom-made R scripts were employed for high-dimensional flow cytometry and scRNAseq analysis.ResultsInitial flow-cytometry analysis showed a significant increase in BM PD1 +CD28 + CD8 + T cell subset (p<0.01) in Res vs NonRes at baseline and post-chemotherapy (data not shown). To further investigate these results, we performed 5‘ VDJ scRNAseq and used gene signatures mapped in two dimensions via UMAP to annotate the T-cell clusters as naive, Tpex, T effector CX3CR1 + (Teff CX3CR1pos), Terminally exhausted 1 (Term_exh1) and Terminally exhausted 2 (Term_exh2) (Fig 1A). Of note, the two most upregulated genes in Tpex were GZMK and IL-7R. We then performed differential abundance analysis to investigate differences in terms of clusters’ frequencies across the three conditions (Res, NonRes, HD). At both timepoints Res had an increased frequency of Tpex and Teff CX3CR1pos compared to NonRes. Conversely, Term_exh2 cells were more abundant in NonRes (Fig. 1B). Next, we measured the magnitude of clonal expansion in antigen-experienced CD8 + T cells in Res and NonRes generating an overlay of the position of clonally expanded cells projected onto the UMAP. The most clonally expanded subsets were Tpex and Teff CX3CR1pos in Res (Fig. 1C) and Term_exh2 in NonRes (Fig. 1D) revealing a strong relationship between abundance and clonal expansion of the CD8 + T-cell subsets. Our scRNAseq results were then confirmed at the protein level with spectral flow-cytometry. The FlowSOM algorithm identified a CD8 + GZMK +CD127 + subset to be increased at baseline in Res vs NonRes (Fig. 1E). Remarkably, this cluster was also characterized by the expression of TIGIT, PD1 and TCF-1. These results were subsequently reproduced by manual gating of the GZMK +CD127 + subset which was significantly enriched (p<0.01) in Res vs NonRes (Fig. 1F). Of note, patients with a higher-than-median frequency of GZMK +CD127 +CD8 + T cells experienced significantly (p<0.02) prolonged overall survival after therapy (Fig. 1G).ConclusionImproving our understanding of the immune microenvironment in AML is critical for the rational integration of novel treatment strategies that seek to increase the response rate and/or maintain remission. We identified GZMK +IL7R + CD8 + cells as a distinct entity in the early differentiated CD8 + memory T cell pool that is clonally expanded and more abundant in Res compared to NonRes. This subset has a stem-like signature and may be associated with longer in vivo CD8 + T cell persistence and long-term AML control. An in-depth functional characterization with in vitro experiments and in vivo mouse models is currently ongoing. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Short and long-term effectiveness and safety of vedolizumab in treatment-refractory patients with ulcerative colitis and Crohn’s disease – a real-world two-center cohort study

Real-world data about sustained clinical remission (SCR) and treatment optimization with vedolizumab for ulcerative colitis (UC) and Crohn's disease (CD) are scarce. We aimed to investigate the short and long-term effectiveness and safety of vedolizumab in a real-world cohort in Denmark. A retrospective two-center cohort study was conducted between November 2014 and November 2019 with the primary outcomes of clinical remission (CR) at weeks 14, 30, 52 and 104 and SCR defined as CR at week 14 through week 52. The study included 182 patients (UC: 97, CD: 85), all previously exposed to at least one biological therapy. Rates of CR at weeks 14, 30, 52 and 104 were 36.6, 35.1, 34.0 and 27.8%, respectively, in UC, and 31.7, 30.1, 26.5 and 22.4% in CD. SCR was achieved in 19.6 and 20.0%, respectively. In UC and CD, optional dosing of vedolizumab at week 10 (odds ratio [OR] = 0.23 (95% confidence interval [CI], 0.03-1.17), and OR = 0.68 (95% CI, 0.22-2.04)), as well as increase of frequency (OR = .26 (95% CI, 0.01-2.86), and OR = 0.19 (95% CI, 0.01-1.45)), were not associated with CR at week 52. Furthermore, combination treatment with azathioprine was not associated with long-term outcomes. However, dose intensification of vedolizumab successfully restored CR in 65.2 and 57.1% of patients with UC and CD experiencing loss of response. Vedolizumab is effective in achieving and restoring short and long-term CR and SCR in patients with treatment-refractory UC and CD. This study emphasizes that supplementary dosing at week 10, and simultaneous treatment with azathioprine, did not improve long-term outcomes.

P421 Treatment optimization with vedolizumab in treatment-refractory patients with ulcerative colitis and Crohn’s disease – a real-world two-center cohort study

Abstract Background Real-world data about treatment optimization of vedolizumab in ulcerative colitis (UC) and Crohn’s disease (CD) are scarce. Therefore, we aimed to investigate the influence of administration of a supplementary dose of vedolizumab at week ten on short and long-term outcomes. Methods A retrospective two-center cohort study was conducted between November 2014 and November 2019. The primary outcomes were clinical remission (CR) at weeks 14, 30, 52, and 104 and Sustained CR (SCR) defined as CR at week 14 through week 52. Results The study included 182 patients (UC: 97, CD: 85), all previously exposed to at least one biological therapy. As shown in Table 1, patients with CD receiving or not receiving the additional dosing at week ten were comparable in terms of disease activity at weeks 0 and 6, while patients with UC receiving the dosing at week 10 experienced higher disease activity at week 0 but not week 6. The overall efficacy of vedolizumab in UC and CD stratified according to treatment with the optional dosing at week ten is summarized in Figures 1 and 2, demonstrating no statistically significant difference among patients receiving or not receiving vedolizumab at week 10. Furthermore, the optional dosing of vedolizumab at week 10 (odds ratio (OR)=0.23 (95%CI 0.03-1.17), and OR=0.68 (95%CI 0.22-2.04)), was not associated with CR at week 52 among patients with UC and CD, respectively. Conclusion Vedolizumab is effective in achieving short and long-term CR and SCR in patients with treatment-refractory UC and CD. This study emphasizes that supplementary dosing at week 10 did not improve long-term outcomes.

Induction of Sustained Clinical Remission in Early Axial Spondyloarthritis Following Certolizumab Pegol Treatment: 48-Week Outcomes from C-OPTIMISE.

IntroductionAchievement of remission is a key treatment goal for patients with axial spondyloarthritis (axSpA). C-OPTIMISE assessed achievement of sustained clinical remission in patients with axSpA, including radiographic (r) and non-radiographic (nr) axSpA, during certolizumab pegol (CZP) treatment, and subsequent maintenance of remission following CZP dose continuation, dose reduction or withdrawal. Here, we report outcomes from the first 48 weeks (induction period) of C-OPTIMISE, during which patients received open-label CZP.MethodsC-OPTIMISE (NCT02505542) was a two-part, multicenter, phase 3b study in adult patients with early axSpA (r-/nr-axSpA), including a 48-week open-label induction period followed by a 48-week maintenance period. Patients with active adult-onset axSpA, < 5 years’ symptom duration, and fulfilling Assessment of SpondyloArthritis international Society classification criteria, were included. During the induction period, patients received a loading dose of CZP 400 mg at weeks 0, 2, and 4, followed by CZP 200 mg every 2 weeks (Q2W) up to week 48. The main outcome of the 48-week induction period was the achievement of sustained clinical remission (defined as an Ankylosing Spondylitis Disease Activity Score [ASDAS] < 1.3 at week 32 and < 2.1 at week 36 [or vice versa], and < 1.3 at week 48).ResultsIn total, 736 patients (407 with r-axSpA, 329 with nr-axSpA) were enrolled into the study. At week 48, 43.9% (323/736) of patients achieved sustained remission, including 42.8% (174/407) of patients with r-axSpA and 45.3% (149/329) with nr-axSpA. Patients also demonstrated substantial improvements in axSpA symptoms, MRI outcomes and quality of life measures. Adverse events occurred in 67.9% (500/736) of patients, of which 6.0% (44/736) were serious.ConclusionsOver 40% of patients with early axSpA achieved sustained remission during 48 weeks of open-label CZP treatment. Additionally, patients across the axSpA spectrum demonstrated substantial improvements in imaging outcomes and quality of life following treatment. No new safety signals were identified.Trial RegistrationNCT02505542.Electronic Supplementary MaterialThe online version of this article (10.1007/s40744-020-00214-7) contains supplementary material, which is available to authorized users.

ACPA and RF as predictors of sustained clinical remission in patients with rheumatoid arthritis: data from the Ontario Best practices Research Initiative (OBRI)

Objective(s)This study evaluated the interaction of anticitrullinated protein antibody (ACPA) and rheumatoid factor (RF) in predicting sustained clinical response in an observational registry of patients with rheumatoid arthritis (RA) followed...

P504 The variation of faecal calprotectin after 3 months of anti-TNF therapy is a predictor of sustained clinical remission in patients with Crohn's disease

P504 The variation of faecal calprotectin after 3 months of anti-TNF therapy is a predictor of sustained clinical remission in patients with Crohn's disease

Letter: mucosal healing is associated with improved long‐term outcomes in Crohn's disease

We read with interest the article by Shah et al. comparing long-term outcomes in patients with active Crohn's disease who achieve mucosal healing compared with those who do not.1 The authors found that achieving mucosal healing at first endoscopic assessment is associated with increased rates of long-term clinical remission and maintenance of mucosal healing in active Crohn's disease, and may therefore be a reasonable therapeutic target. Shah et al.'s meta-analysis gives rise to the question as to whether either mucosal healing or clinical remission should be the main treatment goal in Crohn's disease. Precise definitions of mucosal healing in Crohn's disease need to be resolved and proper comparative effectiveness trials need to be performed to confirm that this endpoint is clinically meaningful. In some studies, mucosal healing was defined as a Mayo Score of 0 or 1.2, 3 A score of ‘1’ (erythema, diminished vascular markings) might plausibly describe patients with a broad spectrum of symptoms. Therefore, despite meeting the study's definition of mucosal healing, there remains a significant proportion of patients with some degree of persistent endoscopic inflammation. To add to the confusion, the authors could not conclude this result, because it used an entirely different definition of mucosal healing. At the same time, mucosal healing has been refined to a microscopic level, with some studies showing a significant association between the degree of histological inflammation and an increased risk of flaring over the course of Crohn's disease. We agree that mucosal healing is an important endpoint that should be studied in clinical trials. However, some issues still limit the use of mucosal healing as a therapeutic target of Crohn's disease in clinical practice. Firstly, a validated standard system for grading histologic activity does not exist. Validation is a prerequisite to standardize reporting and grading. Secondly, the exact definition of histologic healing, as well as their impact on clinical outcome of Crohn's disease, has yet to be clarified. Thirdly, the optimal staining method for grading the severity of inflammation is still unclear. Haematoxylin–eosin is the most frequently used staining, but more expensive methods, such as immunohistochemistry, may provide information. Fourth, the timing and site of the biopsy to show normalized histology have to be clarified. Fifth, mucosal healing is not a reliable target in clinical practice – it is not an easy goal to reach, and inflammation may persist despite clinical–endoscopic remission. Our study reported that mucosal healing did not predict sustained clinical remission in patients with inflammatory bowel disease when infliximab therapies had been stopped.4 In summary, before considering mucosal healing as a reliable target for the treatment of Crohn's disease, large prospective studies will have to address the key issues we have discussed. Declaration of personal and funding interests: None.

Infliximab Concentration Thresholds During Induction Therapy Are Associated With Short-term Mucosal Healing in Patients With Ulcerative Colitis.

Mucosal healing is an independent predictor of sustained clinical remission in patients with ulcerative colitis (UC) treated with infliximab. We investigated whether infliximab concentrations during induction therapy are associated with short-term mucosal healing (STMH) in patients with UC. We performed a retrospective, single-center analysis of data collected from a tertiary referral center from 101 patients with UC who received scheduled induction therapy with infliximab at weeks 0, 2, and 6 and had an endoscopic evaluation at baseline and after induction therapy. STMH was defined as Mayo endoscopic sub-score ≤1, assessed at weeks 10-14, with baseline sub-score ≥2. Infliximab concentrations were evaluated in serum samples collected at weeks 0, 2, 6, and 14 of infliximab therapy by using an enzyme-linked immunosorbent assay we developed. Fifty-four patients (53.4%) achieved STMH. Patients with STMH had a higher median infliximab concentration at weeks 2, 6, and 14 than patients without STMH. A receiver operating characteristic (ROC) analysis identified infliximab concentration thresholds of 28.3 (area under the ROC curve [AUROC], 0.638), 15 (AUROC, 0.688), and 2.1 μg/mL (AUROC, 0.781) that associated with STMH at weeks 2, 6, and 14, respectively. Multiple logistic regression analysis identified infliximab concentration ≥15 at week 6 (P= .025; odds ratio, 4.6; 95% confidence interval, 1.2-17.1) and ≥2.1 μg/mL at week 14 (P= .004; odds ratio, 5.6; 95% confidence interval, 1.7-18) as independent factors associated with STMH. In an analysis of data from real-life clinical practice, we associated infliximab concentrations during the induction therapy with STMH in patients with UC.

215. Sustained Clinical Remission in Patients with Non-Radiographic Axial Spondyloarthritis after Two Years of Adalimumab Treatment

215. Sustained Clinical Remission in Patients with Non-Radiographic Axial Spondyloarthritis after Two Years of Adalimumab Treatment

Frequency and prognostic role of mucosal healing in patients with Crohn’s disease and ulcerative colitis after one-year of biological therapy

To assess the endoscopic activity before and after a one-year period of biological therapy and to evaluate the frequency of relapses and need for retreatment after stopping the biologicals in patients with Crohn's disease (CD) and ulcerative colitis (UC). The data from 41 patients with CD and 22 patients with UC were assessed. Twenty-four CD patients received infliximab, and 17 received adalimumab. The endoscopic severity of CD was quantified with the simplified endoscopic activity score for Crohn's disease in CD and with the Mayo endoscopic subscore in UC. Mucosal healing was achieved in 23 CD and 7 UC patients. Biological therapy had to be restarted in 78% of patients achieving complete mucosal healing with CD and in 100% of patients with UC. Neither clinical remission nor mucosal healing was associated with the time to restarting the biological therapy in either CD or UC. Mucosal healing did not predict sustained clinical remission in patients in whom the biological therapies had been stopped.

OP0109 Sustained Clinical Remission in Patients with Non-Radiographic Axial Spondyloarthritis after Two Years of Adalimumab Treatment

BackgroundAdalimumab (ADA) is currently approved in the EU for the treatment of severe non-radiographic axial spondyloarthritis (nr-axSpA), in patients (pts) with an elevated CRP and/or positive MRI who have had...

Treatment of epidermolysis bullosa acquisita with intravenous immunoglobulin in patients non‐responsive to conventional therapy: clinical outcome and post‐treatment long‐term follow‐up

Epidermolysis bullosa acquisita (EBA) is a chronic subepidermal blistering disease that is caused by antibodies binding to type VII collagen within anchoring fibrils. It is rare disease with an incidence of 0.25 cases per 1,000,000 population. The objective of this study is to report the treatment outcomes with intravenous immunoglobulin (IVIg) therapy in 10 patients with severe and widespread EBA non-responsive to conventional therapy. Patients were treated according to a protocol published in a Consensus Statement to treat autoimmune mucocutaneous blistering diseases, including EBA with IVIg. A dose of 2 g/kg/cycle was used. Ten patients: four males and six females, all were North American Caucasian. The age at onset varied from 37 to 75 years (mean 57.4). A satisfactory clinical response was observed in all 10 patients. The patients received 16-31 cycles (mean 23.1) of IVIg over a period of 30-52 months (mean 38.8). Once IVIg was initiated, earlier drugs (prednisone, dapsone and others) were gradually withdrawn over a 5-9 month period (mean 7.2). Thereafter, IVIg was used as monotherapy. No serious side-effects were observed. The follow-up period since discontinuation of IVIg varied from 29 to 123 months (mean 53.9). During this follow-up period, recurrence of disease was not observed. The data suggest that IVIg can produce a long-term sustained clinical remission in patients with EBA. In the patients, of this study concomitant therapy could be discontinued and IVIg was used as monotherapy.

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

Mucosal Healing Predicts Sustained Clinical Remission in Patients With Early-Stage Crohn's Disease

Few prospective data are available to support the clinical relevance of mucosal healing in patients with Crohn's disease. This study examined whether complete healing, determined by endoscopy, predicts a better outcome in Crohn's disease. One-hundred thirty-three newly diagnosed and treatment-naïve Crohn's disease patients were given either a combination of immunosuppressive therapy (azathioprine) and 3 infusions of infliximab or treatment with conventional corticosteroids. Patients given azathioprine were given repeated doses of infliximab for relapses, patients given corticosteroids were given azathioprine in cases of corticosteroid dependency and infliximab only if azathioprine failed. A representative subset of 49 patients from the initially randomized cohort underwent ileocolonoscopy after 2 years of therapy. Correlation analysis was performed between different clinical parameters including endoscopic activity (Simple Endoscopic Score) and clinical outcome 2 years after this endoscopic examination. Data were available from 46 patients 3 and 4 years after therapy began. Complete mucosal healing, defined as a simple endoscopic score of 0 after 2 years of therapy, was the only factor that predicted sustained, steroid-free remission 3 and 4 years after therapy was initiated; it was observed in 17 of 24 patients (70.8%) vs 6 of 22 patients with lesions detected by endoscopy (27.3%, Simple Endoscopic Score >0) (P = .036; odds ratio = 4.352; 95% confidence interval, 1.10-17.220). Fifteen of 17 patients with mucosal healing at year 2 maintained in remission without further infliximab infusions during years 3 and 4 (P = .032; odds ratio = 4.883; 95% confidence interval, 1.144-20.844). Complete mucosal healing in patients with early-stage Crohn's disease is associated with significantly higher steroid-free remission rates 4 years after therapy began.

Sustained Clinical Remission in Patients with Moderate to Severe Crohnʼs Disease with Adalimumab, Regardless of Anti-TNF History or Concomitant Immunosuppressant Therapy

Purpose: To evaluate the efficacy of adalimumab (ADA) in sustaining clinical remission in patients with CD with concomitant immunosuppressant (IMM) therapy or history of anti-TNF treatment. Methods: In CHARM, a Phase III, double-blind, placebo-controlled study of the maintenance of clinical remission (CDAI<150) and safety of ADA, pts with active CD (CDAI 220–450) received open-label induction ADA 80 mg at Wk 0 (BL) and 40 mg at Wk 2. At Wk 4, all pts were randomized to placebo (PBO) or 40 mg ADA, every other week (EOW) or weekly (W), through Wk 56. Patients with clinical response, a decrease in CDAI ≥70 from BL (CR70), when randomized at Wk 4 were classified as randomized responders (RR). The% of pts with CDAI<150, stratified by concomitant IMM use and anti-TNF history, were calculated at Wks 26 and 56. Results: Of 854 pts receiving induction therapy, 778 were randomized. Of these, 499 (58%) were RR. BL characteristics were similar across the 3 arms: mean CDAI = 313; concomitant IMM use (such as AZA, 6-MP, or MTX), 47%; history of anti-TNF therapy, 50%. The proportions of RR with CDAI<150 at Wks 26 and 56 by prior anti-TNF or concomitant IMM therapy are in the table.Table: Randomized Responders in Remission by Concomitant/Prior Therapy.Conclusions: Adalimumab was significantly superior to PBO for the long-term treatment of CD irrespective of concomitant IMM therapies. Prior anti-TNF therapy resulted in slightly lower remission rates, but ADA significance vs. PBO was maintained.