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Abstract

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Objective

To investigate the safety, tolerability, pharmacokinetics, and efficacy of apilimod mesylate, an oral interleukin-12 (IL-12)/IL-23 inhibitor, in patients with rheumatoid arthritis (RA).

Methods

We performed a phase IIa, randomized, double-blind, placebo-controlled proof-of-concept study of apilimod, in combination with methotrexate, in 29 patients with active RA (3:1 ratio of apilimod-treated to placebo-treated patients) in 3 stages. Patients received apilimod 100 mg/day or placebo for 4 weeks (stage 1) or 8 weeks (stage 2). In stage 3, patients received apilimod 100 mg twice a day or placebo for 8 weeks, with an optional extension of 4 weeks. Clinical response (Disease Activity Score in 28 joints [DAS28] and American College of Rheumatology [ACR] criteria) was assessed throughout; synovial tissue samples collected at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) were stained for cellular markers and cytokines for immunohistochemistry analysis.

Results

While only mild adverse events were observed in stages 1 and 2, in stage 3, all patients experienced headache and/or nausea. Among apilimod-treated patients (100 mg/day), there was a small, but significant, reduction in the DAS28 on day 29 and day 57 compared with baseline. ACR20 response was reached in only 6% of patients on day 29 and 25% of patients on day 57, similar to the percentage of responders in the placebo group. Increasing the dosage (100 mg twice a day) did not improve clinical efficacy. Consistent with clinical results, apilimod did not have an effect on expression of synovial biomarkers. Of importance, we also did not observe an effect of apilimod on synovial IL-12 and IL-23 expression.

Conclusion

Our results do not support the notion that IL-12/IL-23 inhibition by apilimod is able to induce robust clinical improvement in RA.

Rheumatoid arthritis (RA) is a chronic inflammatory disease affecting synovial tissue. Activated immune cells are important in orchestrating synovial inflammation by producing several cytokines, including interleukin-12 (IL-12) and IL-23 (1). IL-12 is a heterodimeric cytokine (p70) formed by 2 subunits, p40 and p35 (2). The structure of the more recently discovered heterodimeric IL-23 is closely related to that of IL-12 and shares the p40 subunit, but IL-23 contains p19, a unique subunit (3). IL-12 acts in the initial inflammation phase by promoting differentiation of naive CD4+ T cells to interferon-γ–producing Th1 cells. IL-23 induces proliferation of effector memory T cells and plays a critical role in the pathogenesis of RA by inducing IL-17–producing T cells (4). Animal studies confirm this finding, as IL-23–deficient (p19−/−) mice and mice lacking IL-12 and IL-23 (p40−/−) are resistant to collagen-induced arthritis (4).

Apilimod mesylate (STA-5326), an orally administered small molecule, inhibits the production of IL-12 and IL-23. It selectively prevents nuclear translocation of c-Rel, a member of the Rel/NF-κB family of transcription factors, thereby reducing both p35 and p40 promoter activities. However, the exact mechanism of action is unknown. Apilimod significantly reduces the production of IL-12, IL-23, and the IL-12/IL-23 p40 protein by stimulated human peripheral blood mononuclear cells (5). Therefore, we tested apilimod in a phase IIa proof-of-concept study in patients with active RA.

PATIENTS AND METHODS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Patient selection.

This study was conducted at the Academic Medical Center/University of Amsterdam (AMC/UvA). Patients with RA according to the American College of Rheumatology (ACR) classification criteria (6), who had a disease duration of ≥6 months, were included. All patients had active disease, classified as the presence of ≥4 tender and swollen joints and arthritis of 1 knee or ankle joint. Furthermore, study patients fulfilled one of the following criteria: C-reactive protein (CRP) level ≥12 mg/liter, erythrocyte sedimentation rate ≥28 mm/hour, or morning stiffness ≥45 minutes' duration. Patients were receiving stable doses of methotrexate (MTX) (at least 7.5 mg/week) and discontinued other disease-modifying antirheumatic drugs or biologic agents, 1 month or 3 months, respectively, prior to the start of study treatment. Oral glucocorticoids (≤10 mg/day) and stable doses of nonsteroidal antiinflammatory drugs were allowed. The study was approved by the Medical Ethics Committee of the AMC/UvA and performed according to the Declaration of Helsinki. All participants provided written informed consent.

Study design.

For all stages, patients were randomized (3:1 ratio of apilimod-treated to placebo-treated patients) on day 1. In stage 1 (4 weeks' duration), 9 patients were treated with apilimod 100 mg/day and 3 patients were treated with placebo. In stage 2 (8 weeks' duration), 8 patients received apilimod 100 mg/day and 2 patients received placebo. The dosage of apilimod was increased to 100 mg twice a day in stage 3 (8 weeks' duration with an optional extension of 4 weeks), and 5 patients were treated with apilimod and 2 patients with placebo. Two-week supplies of apilimod were dispensed on clinic days for at-home oral administration.

Clinical assessment, safety, and pharmacokinetics.

Routine safety and clinical assessments were performed on days 1, 15, and 29 for all stages. For stages 2 and 3, assessments were also performed on day 43 and day 57, and for the stage 3 extension, additional assessments were performed on day 71 and day 85. A followup visit was performed 1 week after discontinuation of the study drug. Patients were evaluated according to the Disease Activity Score in 28 joints (DAS28) (7) and the ACR response criteria (8). On days 1, 15, and 29 of stage 1, blood was drawn before the dose was administered and at 1, 2, 4, 6, and 8 hours postdose, for extensive pharmacokinetic determination of apilimod, apilimod metabolites, MTX, and 7-hydroxy-MTX.

Synovial tissue collection and immunohistochemical analysis.

Arthroscopy was performed with the patient under local anesthesia at baseline and on day 29 (stages 1 and 2) or day 57 (stage 3) to obtain synovial tissue from an actively inflamed knee or ankle, as previously described (9). Synovial tissue sections were stained with anti-CD68 antibody (Dako) to detect macrophages, anti–IL-12p70 (R&D Systems), and anti–IL-23 (BioLegend). At a minimum, 6 tissue specimens were embedded en bloc in OCT compound (Tissue-Tek; Sakura) and stored in liquid nitrogen. Serial cryostat sections (5 μm) were cut and mounted on Star Frost adhesive glass slides (Knittelgläser).

In addition to antibodies to CD68, IL-12p70, and IL-23, synovial tissue sections were stained using the following monoclonal antibodies: anti-CD3 (Becton Dickinson) for T cells, anti-CD22 (Bioconnect) for B cells, anti-CD55 (Bioconnect) to detect fibroblast-like synoviocytes, and anti–IL-1β (Acris Antibodies). Primary antibodies were incubated for 1 hour (or overnight for IL-1β staining). After fixation of the sections with acetone for 10 minutes at room temperature, endogenous peroxidase activity was inhibited for 20 minutes using 0.1% sodium azide and 0.3% hydrogen peroxide in phosphate buffered saline. Primary antibodies were incubated for 60 minutes. Bound antibody was detected with a polymer-HRP anti-mouse IgG EnVision Plus System (Dako) for CD3, CD68, CD22, and CD55, and with PowerVision poly-HRP Ready-to-Use (Immunologic; ImmunoVision Technologies) for IL-12p70 and IL-23. The IL-1β staining was performed using a 3-step immunoperoxidase method. Antibody was finally detected using aminoethylcarbazole (Dako) as dye. Sections were counterstained with Gill's hematoxylin. Stained sections were analyzed under blinded conditions with regard to study treatment and time point.

Expression of the various markers was quantified using digital image analysis, as previously described (9, 10). CD3, CD22, CD55, and CD68 were expressed as counts per square millimeter; IL-1β, IL-12p70, and IL-23 were expressed as integrated optical density per square millimeter (an arbitrary unit representing the intensity of staining per square millimeter).

Statistical analysis.

Continuous data were described as mean and SD values if normally distributed, and as the median and interquartile range if not normally distributed. Student's unpaired t-test or Mann-Whitney U test was used for assessing the significance of differences in patient characteristics. Nominal data were represented as percentages and analyzed by Fisher's exact test. Effects of treatment were evaluated by Student's paired t-test or Wilcoxon's signed rank test for non-normal distributions. All statistical analyses were performed with SPSS, version 17.0. P values less than or equal to 0.05 were considered significant.

RESULTS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Patient characteristics and safety and tolerability of apilimod.

Twenty-nine eligible patients were included in this trial. The disease characteristics of the study patients were not significantly different between the apilimod- and placebo-treated groups (see Supplementary Table 1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131), with the groups receiving MTX at an average weekly dosage of 21.1 mg and 22.5 mg, respectively. Since we observed favorable safety and pharmacokinetic (MTX and apilimod) profiles in stage 1 (data not shown), the study was continued to stage 2 and subsequently stage 3. In stage 1, 8 of 9 apilimod-treated patients completed the study, while 1 patient who developed side effects (severe headache), withdrew from the study on day 29. The patient refused to undergo the second arthroscopy, although safety and clinical evaluations were completed. All patients treated in stage 2 completed the study. In stage 3 (100 mg twice a day), 3 of 5 apilimod-treated patients continued until day 57, and 1 of these 3 decided to extend the treatment until day 85. Two patients withdrew prior to day 57 due to side effects. In stages 1 and 2, only mild adverse events (mainly gastrointestinal) were observed, in 15 of the 17 patients treated with apilimod (88%). In stage 3, side effects were experienced in all apilimod-treated patients and in patients receiving placebo (Table 1). A detailed listing of the adverse events is provided in Supplementary Table 2, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131.

Table 1. Clinical response in patients treated with apilimod or placebo*
Study group (n at baseline)BaselineDay 29Day 57Day 85
  • *

    DAS28 = Disease Activity Score in 28 joints; ACR20 = American College of Rheumatology 20% improvement; IQR = interquartile range; NA = not applicable (patient number too small).

  • P = 0.02 by Student's paired t-test.

  • P = 0.004 by Student's paired t-test.

  • §

    P = 0.03 by Student's paired t-test.

  • In stage 1, 1 patient receiving apilimod withdrew on day 29 due to side effects (severe headache); safety and clinical evaluations were completed, but the second arthroscopy was not performed. In stage 3, 1 apilimod-treated patient withdrew on day 15 and 1 patient withdrew on day 29 due to side effects, and therefore, had no second arthroscopy on day 57. For the day 85 extension, only 1 of 5 patients in the apilimod-treated group and 1 patient in the placebo-treated group decided to continue treatment. Thus, the n values for the apilimod-treated group in stage 3 on day 29, day 57, and day 85 were 4, 3, and 1, respectively.

  • #

    Of the placebo-treated patients, all continued until day 29, and 4 participated until day 57. Thus the n values for the placebo group on day 57 and day 85 were 4 and 1, respectively. Placebo samples were pooled from all stages.

Stage 1 (apilimod 100 mg/day) (n = 9)    
 DAS28, mean ± SD5.4 ± 0.75.2 ± 0.8  
 Mean change in DAS28 vs. baseline−0.2  
 ACR20, no. (%)1 (11.1)  
 ACR50, no. (%)0 (0)  
 ACR70, no. (%)0 (0)  
Stage 2 (apilimod 100 mg/day) (n = 8)    
 DAS28, mean ± SD5.5 ± 1.24.8 ± 1.34.9 ± 1.2 
 Mean change in DAS28 vs. baseline−0.7−0.6 
 ACR20, no. (%)0 (0)2 (25) 
 ACR50, no. (%)0 (0)0 (0) 
 ACR70, no. (%)0 (0)0 (0) 
Stages 1/2, pooled (apilimod 100 mg/day) (n = 17)    
 DAS28, mean ± SD5.4 ± 0.95.0 ± 1.0  
 Mean change in DAS28 vs. baseline−0.4§  
 ACR20, no. (%)1 (6)  
 ACR50, no. (%)0 (0)  
 ACR70, no. (%)0 (0)  
Stage 3 (apilimod 100 mg twice daily) (n = 5)    
 DAS28, median (IQR)5.4 (4.8–6.9)5.2 (5.1–5.9)5.1 (5.0–7.0)4.9 (NA)
 Mean change in DAS28 vs. baseline−0.2NANA
 ACR20, no. (%)0 (0)1 (33)1 (33)
 ACR50, no. (%)1 (25)0 (0)0 (0)
 ACR70, no. (%)0 (0)0 (0)0 (0)
Placebo, pooled (n = 7)#    
 DAS28, median (IQR)5.3 (4.8–5.7)4.8 (4.5–5.6)4.6 (2.7–5.3)3.3 (NA)
 Mean change in DAS28 vs. baseline−0.5−0.7NA
 ACR20, no. (%)0 (0)1 (25)0 (0)
 ACR50, no. (%)0 (0)0 (0)0 (0)
 ACR70, no. (%)0 (0)0 (0)0 (0)

Lack of marked clinical improvement in RA patients treated with apilimod.

As seen in Table 1, apilimod-treated patients in stages 1 and 2 (100 mg/day) had a small but statistically significant reduction in the DAS28 on day 29 compared with baseline (P = 0.03) (n = 17) and day 57 (stage 2 only) (P = 0.004) (n = 8), while we did not observe a significant reduction in the DAS28 in the placebo-treated patients. However, neither change could be classified as a response according to the European League Against Rheumatism (EULAR) response criteria (11). An ACR20 response was seen in 1 of 17 patients (6%) after 4 weeks and in 2 of 8 patients (25%) after 8 weeks of treatment. In stage 3, we did not observe a significant reduction in the DAS28 during the study, although the number of patients was small. An ACR20 response was observed in only 1 of 3 patients after 8 weeks (day 57) and 12 weeks (day 85) of apilimod treatment. One patient exhibited an ACR50 response after 4 weeks, but this clinical response disappeared after 8 weeks. Patients in the placebo group showed no significant change in the DAS28 on day 29; patient numbers during later visits were too small to enable us to draw any meaningful conclusions. Taken together, these results indicate that apilimod treatment did not induce robust clinical improvement.

Lack of effect of apilimod treatment on synovial biomarkers.

In apilimod-treated and placebo-treated patients, there was no significant difference in the number of CD68+ synovial macrophages on day 29 compared with baseline (Figure 1). Additionally, no significant changes in the expression of other synovial markers were observed (see Supplementary Figure 1, available on the Arthritis & Rheumatism web site at http://onlinelibrary.wiley.com/journal/10.1002/(ISSN)1529-0131). In stage 3, the number of patients who underwent arthroscopy on day 57 was too small to allow us draw any conclusions. Of importance, apilimod treatment did not result in a decrease in IL-12 and IL-23 expression in the synovial tissue after 4 weeks (Figure 2).

thumbnail image

Figure 1. Effect of apilimod or placebo treatment on CD68+ cells in synovial tissue. Expression of CD68+ macrophages in the sublining layer (A and B) and lining layer (C and D) of synovial tissue from rheumatoid arthritis patients treated with apilimod 100 mg/day (A and C) or placebo (B and D) was determined. To obtain synovial tissue samples, arthroscopy was performed at baseline and on day 29 (stages 1 and 2). Samples from placebo-treated patients were pooled from all stages. There were no significant changes in CD68+ cell expression between baseline and day 29, by nonparametric Mann-Whitney test.

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thumbnail image

Figure 2. Interleukin-12 (IL-12) and IL-23 expression in synovial tissue. A and B, Representative photomicrographs of IL-12p70 and IL-23 staining in biopsy samples obtained before (A) and after (B) treatment with apilimod. Original magnification × 20. CF, Changes in IL-12p70 and IL-23 staining. Expression (integrated optical density [IOD]) of IL-12p70 (C and D) and IL-23 (E and F) in the synovial tissue of patients treated with apilimod 100 mg/day (C and E) or placebo (D and F) was determined. There were no significant changes in IL-12 and IL-23 expression between baseline and day 29, by nonparametric Mann-Whitney test.

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DISCUSSION

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

In the present trial, we evaluated the effects of treatment of RA with apilimod mesylate. Overall, apilimod 100 mg/day was well tolerated and did not interfere with the effects of MTX. However, nearly all patients treated with the double dose of apilimod (100 mg twice a day) experienced side effects. We observed a small, but statistically significant, reduction in the DAS28 after 4 and 8 weeks of treatment with apilimod 100 mg/day, but patients did not fulfill the EULAR response criteria. Moreover, the change in the number of CD68+ synovial sublining macrophages, which has previously been proven to be a sensitive biomarker for clinical response (12), had not reached statistical significance after 4 weeks. In addition, apilimod treatment did not result in its presumed biologic effect: no decrease in IL-12 and IL-23 expression in the synovial tissue was observed after 4 weeks of treatment.

There are several possible reasons why treatment with apilimod did not lead to clinical improvement in RA patients. First, there is the possibility that this was a false-negative result due to the relatively small number of patients in this phase IIa study. However, previous studies with a similar design (12–14) have indicated that the number of patients included in our study should have been sufficient to allow detection of relevant, robust changes in the synovium after effective treatment. A second explanation for the lack of efficacy in our study could be the short treatment duration, although all effective antirheumatic treatments that we have previously tested and found to be effective did induce early changes in the synovium preceding clinical improvement. Moreover, there was no (trend toward) clearcut clinical improvement after 8 weeks of treatment in patients participating in stage 3. Third, we need to take into account the possibility that IL-12/IL-23 is perhaps not a good target for the treatment of RA.

The data from our trial are consistent with the results of a recently published clinical trial in 220 patients with Crohn's disease: treatment with apilimod (50 mg or 100 mg 4 times a day) was not more effective than placebo (15), although this disease responded well to treatment with monoclonal antibodies against the p40 subunit of IL-12/IL-23 (16). Our analyses suggest that the failure of apilimod to influence RA and Crohn's disease may be due to the possibility that insufficient levels of the compound reached the site of inflammation to mediate a potential biologic effect. Consistent with our clinical findings, there was no reduction in the expression levels of IL-12 and IL-23 in the inflamed synovium, in contrast to the effects of apilimod in vitro. Thus, the results of our study do not support further drug development in larger clinical trials for RA. It is too early, however, to conclude that IL-12/IL-23 or its receptor could not be a good target for the treatment of RA.

AUTHOR CONTRIBUTIONS

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

All authors were involved in drafting the article or revising it critically for important intellectual content, and all authors approved the final version to be published. Dr. Tak had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study conception and design. Krausz, Lufkin, van Kuijk, Reedquist, Jacobson, O'Meara, Tak.

Acquisition of data. Krausz, Boumans, Gerlag, Bakker, de Boer.

Analysis and interpretation of data. Krausz, Boumans, Lufkin, Lodde, Jacobson, O'Meara, Tak.

ROLE OF THE STUDY SPONSOR

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

The study protocol was designed by both academic investigators and scientists from Synta Pharmaceuticals. Synta Pharmaceuticals provided writing assistance for the manuscript and reviewed and approved the manuscript prior to submission. The authors independently collected the data, interpreted the results, and had the final decision to submit the manuscript for publication. All authors reviewed the data before publication. Publication of this article was not contingent upon approval by Synta Pharmaceuticals.

REFERENCES

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information
  • 1
    Cooper AM, Khader SA. IL-12p40: an inherently agonistic cytokine. Trends Immunol 2007; 28: 338.
  • 2
    Trinchieri G. Interleukin-12: a cytokine at the interface of inflammation and immunity. Adv Immunol 1998; 70: 83243.
  • 3
    Oppmann B, Lesley R, Blom B, Timans JC, Xu Y, Hunte B, et al. Novel p19 protein engages IL-12p40 to form a cytokine, IL-23, with biological activities similar as well as distinct from IL-12. Immunity 2000; 13: 71525.
  • 4
    Murphy CA, Langrish CL, Chen Y, Blumenschein W, McClanahan T, Kastelein RA, et al. Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003; 198: 19517.
  • 5
    Wada Y, Lu R, Zhou D, Chu J, Przewloka T, Zhang S, et al. Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor. Blood 2007; 109: 115664.
  • 6
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988; 31: 31524.
  • 7
    Prevoo ML, van 't Hof MA, Kuper HH, van Leeuwen MA, van de Putte LB, van Riel PL. Modified disease activity scores that include twenty-eight–joint counts: development and validation in a prospective longitudinal study of patients with rheumatoid arthritis. Arthritis Rheum 1995; 38: 448.
  • 8
    Felson DT, Anderson JJ, Boers M, Bombardier C, Furst D, Goldsmith C, et al. American College of Rheumatology preliminary definition of improvement in rheumatoid arthritis. Arthritis Rheum 1995; 38: 72735.
  • 9
    Kraan MC, Reece RJ, Smeets TJ, Veale DJ, Emery P, Tak PP. Comparison of synovial tissues from the knee joints and the small joints of rheumatoid arthritis patients: implications for pathogenesis and evaluation of treatment. Arthritis Rheum 2002; 46: 20348.
  • 10
    Haringman JJ, Vinkenoog M, Gerlag DM, Smeets TJ, Zwinderman AH, Tak PP. Reliability of computerized image analysis for the evaluation of serial synovial biopsies in randomized controlled trials in rheumatoid arthritis. Arthritis Res Ther 2005; 7: R8627.
  • 11
    Van Gestel AM, Prevoo ML, van 't Hof MA, van Rijswijk MH, van de Putte LB, van Riel PL. Development and validation of the European League Against Rheumatism response criteria for rheumatoid arthritis: comparison with the preliminary American College of Rheumatology and the World Health Organization/ International League Against Rheumatism criteria. Arthritis Rheum 1996; 39: 3440.
  • 12
    Haringman JJ, Gerlag DM, Zwinderman AH, Smeets TJ, Kraan MC, Baeten D, et al. Synovial tissue macrophages: a sensitive biomarker for response to treatment in patients with rheumatoid arthritis. Ann Rheum Dis 2005; 64: 8348.
  • 13
    Thurlings RM, Vos K, Wijbrandts CA, Zwinderman AH, Gerlag DM, Tak PP. Synovial tissue response to rituximab: mechanism of action and identification of biomarkers of response. Ann Rheum Dis 2008; 67: 91725.
  • 14
    Van Kuijk AW, Vergunst CE, Gerlag DM, Bresnihan B, Gomez-Reino JJ, Rouzier R, et al. CCR5 blockade in rheumatoid arthritis: a randomised, double-blind, placebo-controlled clinical trial. Ann Rheum Dis 2010; 69: 20136.
  • 15
    Sands BE, Jacobson EW, Sylwestrowicz T, Younes Z, Dryden G, Fedorak R, et al. Randomized, double-blind, placebo-controlled trial of the oral interleukin-12/23 inhibitor apilimod mesylate for treatment of active Crohn's disease. Inflamm Bowel Dis 2010; 16: 120918.
  • 16
    Mannon PJ, Fuss IJ, Mayer L, Elson CO, Sandborn WJ, Present D, et al. Anti–interleukin-12 antibody for active Crohn's disease. N Engl J Med 2004; 351: 206979.

Supporting Information

  1. Top of page
  2. Abstract
  3. PATIENTS AND METHODS
  4. RESULTS
  5. DISCUSSION
  6. AUTHOR CONTRIBUTIONS
  7. ROLE OF THE STUDY SPONSOR
  8. Acknowledgements
  9. REFERENCES
  10. Supporting Information

Additional Supporting Information may be found in the online version of this article.

FilenameFormatSizeDescription
ART_34339_sm_SupplFig1.TIF118KSupplementary Figure 1
ART_34339_sm_SupplTables.doc84KSupplementary Tables

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