Skip Navigation



Rheumatology Advance Access published online on September 16, 2008
Rheumatology, doi:10.1093/rheumatology/ken357
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/12/1738    most recent
ken357v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Braun, J.
Right arrow Articles by Sieper, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Braun, J.
Right arrow Articles by Sieper, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2008. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Editorial

What is the most important outcome parameter in ankylosing spondylitis?

J. Braun1 and J. Sieper2

1Rheumazentrum Ruhrgebiet, Herne, Ruhr University, Bochum and 2Department of Gastroenterology and Rheumatology, Universitätsmedizin Charité, Universität Berlin, Berlin, Germany

Correspondence to: J. Braun, Rheumazentrum Ruhrgebiet, Landgrafenstr. 15 44652 Herne, Germany. E-mail: j.braun{at}rheumazentrum-ruhrgebiet.de

AS is the most frequent inflammatory rheumatic disease that not only affects the spine, peripheral joints and entheses, but also other organs such as the anterior uvea [1]. The disease starts relatively early in life at a mean age of 26 yrs and is only somewhat more frequent in male than in female patients, with inflammatory back pain being a characteristic symptom [2]. The disease usually takes a chronic course that is characterized by new bone formation with syndesmophytes and ankylosis [1]. More than 30% of the patients carry a heavy burden of disease and have a decreased quality of life [3].

The cornerstones of treatment are physical therapy and drug therapy with NSAIDs [4]. The pros and cons of these agents in the therapy of AS have recently been discussed [5]. Patients in whom the disease activity cannot be adequately controlled by conventional means require [6] and may be treated with biologic agents targeting TNF-{alpha} [7]. This therapy has now gained much importance in the management of AS. As many as 40% of the Assessment in Spondyloarthritis International Society (ASAS) patients in Belgian rheumatological offices were reported [7] to be in need of anti-TNF therapy if recent international recommendations were followed [8, 9]. Anti-TNF therapy with currently three approved agents–infliximab, etanercept and adalimumab–has clearly been shown to improve signs and symptoms, function and spinal mobility on both a short-term [10–13] and a long-term basis of until now up to 5 yrs, as recently reported [14–17]. In general, about half of the patients gain ~ 50% improvement of disease activity as assessed by the Bath Ankylosing Spondylitis Activity Index (BASDAI) [18], ~30–40% show an increase in function as assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI) [19]. Applying the ASAS outcome criteria usually >60% reach ASAS 20 [20] and >40% the ASAS 40 and ASAS 5/6 criteria [21], while 20–30% even achieve ASAS partial remission [20]. Furthermore, AS patients treated with TNF blockers report an improved quality of life and reach higher productivity scores [22–24].

Attempts have been made to grade the degree of response [17] and prediction rules have been proposed, which have identified high CRP levels [25] and marked spinal inflammation as shown by MRI [26] as positive predictors, and older age, structural damage and bad function as negative predictors. There is clear evidence that most of the spinal inflammation that is detected by MRI resolves upon anti-TNF therapy [27–32].

In contrast to the rather dramatic improvement of clinical and imaging parameters reflecting inflammation, structural damage, which manifests in AS mostly as growing syndesmophytes and ankylosis [33, 34], seems not to be inhibited by anti-TNF therapy [35–38]. However, regarding these studies there are some unresolved methodological issues such as the inability to assess the thoracic spine by standard radiography [39], the study design (comparison only with historical cohorts) and the low sensitivity of the currently used modified Stokes AS spinal score scoring method [40], the best currently available tool to quantify radiographic changes in AS [41]. Furthermore, the degree of damage that has been reported to occur in AS is not impressive over 2 yrs with less than one (mean) new syndesmophyte developing in the whole spine.

Reasons for the possible lack of an influence of anti-TNF therapy on syndesmophyte formation have been discussed in detail recently [38] including that (i) inflammation and new bone formation are, at least in part, uncoupled in AS, and/or (ii) anti-TNF therapy by inhibiting osteoclast and promoting osteoblast activity even triggers ankylosing processes by interfering with the Wnt and/or the RANKL pathway [38, 42]. This may be different for NSAIDs which, by inhibition of COX-2, may affect bone healing [43], prevent heterotopic ossification [44] and even decelerate pathological bone growth in AS [45]. Clearly, this situation is different in RA and PsA where structural damage has been regarded as the most important outcome parameter and where all anti-TNF agents were shown to inhibit radiographic progression that is characterized by erosions [46, 47]. The situation in AS is likely to be different since new bone formation (in contrast to bone destruction) is the main factor to influence the structure of affected patients [1]. We have recently argued that new bone formation might be prevented in AS when inflammation is suppressed before erosive structural damage have occurred. However, any ongoing new bone formation as part of the partly possible physiological repair mechanism may just not be stopped by blocking TNF.

Thus, on this basis, the important question arises as to what should be considered as the most important outcome parameter for patients with AS. As well as structural damage, the outcome parameters of interest are: (i) disease activity as best reflected by inflammatory spinal pain, morning stiffness and active inflammation in the SI joints and/or spine as shown by MRI; (ii) function as assessed by questions related to activity (walking, standing, reaching) and participation (toileting, performing jobs around the house); (iii) spinal mobility; and (iv) quality of life. Of course, these are interrelated, and for example, function is determined by both disease activity and structural damage [48], with disease activity being more important early, and structural damage later in the course of the disease. The typical posture of AS patients with long-standing disease can partly also be caused by spinal fractures [49].

What is the patient position here? Patients will usually be most affected by pain and decreased function. There is some information from the International Classification of Function in AS project [50], which shows that there are many ways in which the disease may have an influence on the quality of life of AS patients. The new tool for assessing the patient-acceptable symptom state (PASS) in AS [51], which has been defined as the 75th percentile of the score for patients who considered their state satisfactory has set cut-off values for pain, disease activity and function, which are all close to 3 (on a scale between 0 and 10), and AS patients included in studies usually have pain scores and BASDAI values >6.

When we compare the efficacy of anti-TNF therapy related to pain, disease activity and function in relation to what we know about structural damage, the situation clearly shows that everything but damage improves (Table 1). The effect size of anti-TNF therapy in AS is usually close to or even exceeding 1 for the clinical parameters. How does this relate to radiographic progression? To answer this question we have to look at progression rates in AS. Although the mean rate is rather linear, we have recently shown that ~25% of the patients are rapid progressors [52]. For those, radiographic damage is likely to be a rather relevant outcome parameter, at least in the mid-term. For the remainder, it does not matter much, since it can be demonstrated that in the same period of time when less than one (mean) syndesmophyte has developed [38], function and spinal mobility have even improved [53]. Theoretically, there may be a point in future times when new bone formation will affect function and mobility [54], but it remains to be shown whether and when this will be the case. Bearing this in mind, the discussion that anti-TNF agents are not having disease-modifying capacity in AS seems to be rather odd. It just has to be taken into account that structural damage can mean both osteodestruction and osteoproliferation, and those two just cannot be simply interchanged as outcome parameters.


View this table:
[in this window]
[in a new window]

  		TABLE 1. Outcome parameters and their assessment related to the response to anti-TNF therapy in AS

 
For the treating physician and the patient, there can be no doubt that the clinical performance of anti-TNF agents in terms of improvement in pain, inflammation, function and quality of life is of much greater relevance than the growth of one syndesmophyte within 4 yrs. Based on this background, we would like to propose that the term ‘disease modification’ should not be solely reserved for the prevention of structural damage, because a disease such as AS can obviously be impressively modified by TNF blockers over years even if new bone formation, which is until now over an observation period of 2 yrs, is not clearly inhibited. The observation that AS patients show even better clinical responses to anti-TNF therapy than RA patients [54] clearly adds to this picture. Out of long clinical experience with these agents we would like to finish by stressing that physiotherapy is still very important—also in the age of TNF blockers because muscle strength is critical to keep the back straight and mobile [55, 56].

Disclosure statement: J.B. has received honoraria for talks, consultancies and grants from Centocor, Schering-Plough, Amgen, Wyeth, Abbott, Roche, Bristol-Myers Squibb and Pfizer. J.S. has received honoraria, grants/research support, is a member of a speakers’ bureau and consultant for Abbott, Schering-Plough, Wyeth and Pfizer.

References

  1. Braun J, Sieper J. Ankylosing spondylitis. The Lancet (2007) 369:1379–90.
  2. Rudwaleit M, Metter A, Listing J, Sieper J, Braun J. Inflammatory back pain in ankylosing spondylitis - a reassessment of the clinical history for classification and diagnosis. Arthritis Rheum (2006) 54:569–78.[CrossRef][Web of Science][Medline]
  3. Zink A, Braun J, Listing J, Wollenhaupt J. Disability and handicap in rheumatoid arthritis and ankylosing spondylitis – results from the German rheumatological database. German Collaborative Arthritis Centers. J Rheumatol (2000) 27:613–22.[Web of Science][Medline]
  4. Zochling J, Bohl-Buhler MH, Baraliakos X, Feldtkeller E, Braun J. Nonsteroidal anti-inflammatory drug use in ankylosing spondylitis-a population-based survey. Clin Rheumatol (2006) 6:794–800.
  5. Song IH, Poddubnyy DA, Rudwaleit M, Sieper J. Benefits and risks of ankylosing spondylitis treatment with nonsteroidal antiinflammatory drugs. Arthritis Rheum (2008) 58:929–38.[CrossRef][Web of Science][Medline]
  6. Barkham N, Kong KO, Tennant A, et al. The unmet need for anti-tumour necrosis factor (anti-TNF) therapy in ankylosing spondylitis. Rheumatology (2005) 44:1277–81.[Abstract/Free Full Text]
  7. Vander Cruyssen B, Ribbens C, Boonen A. The epidemiology of ankylosing spondylitis and the commencement of anti-TNF therapy in daily rheumatology practice. Ann Rheum Dis (2007) 66:1072–7.[Abstract/Free Full Text]
  8. Zochling J, van der Heijde D, Burgos-Vargas R. ‘ASsessment in AS’ international working group; European League Against Rheumatism. ASAS/EULAR recommendations for the management of ankylosing spondylitis. Ann Rheum Dis (2006) 65:442–52.[Abstract/Free Full Text]
  9. Braun J, Davis J, Dougados M, Sieper J, van der Linden S, van der Heijde D. ASAS Working Group. First update of the international ASAS consensus statement for the use of anti-TNF agents in patients with ankylosing spondylitis. Ann Rheum Dis (2006) 65:316–20.[Abstract/Free Full Text]
  10. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab - a double-blind placebo controlled multicenter trial. Lancet (2002) 359:1187–93.[CrossRef][Web of Science][Medline]
  11. Brandt J, Kariouzov A, Listing J, et al. Six months results of a German double-blind placebo controlled clinical trial of etanercept in active ankylosing spondylitis. Arthritis Rheum (2003) 48:1667–75.[CrossRef][Web of Science][Medline]
  12. van der Heijde D, Dijkmans B, Geusens P, et al. ATLAS Study Group. Efficacy and safety of infliximab in patients with ankylosing spondylitis - results of a randomized, placebo-controlled trial (ASSERT). Arthritis Rheum. (2005) 52:582–91.[CrossRef][Web of Science][Medline]
  13. van der Heijde D, Kivitz A, Schiff MH, et al. Efficacy and safety of adalimumab in patients with ankylosing spondylitis: results of a multicenter, randomized, double-blind, placebo-controlled trial. Arthritis Rheum (2006) 54:2136–46.[CrossRef][Web of Science][Medline]
  14. Haibel H, Rudwaleit M, Brandt HC, et al. Adalimumab reduces spinal symptoms in active ankylosing spondylitis: clinical and magnetic resonance imaging results of a fifty-two-week open-label trial. Arthritis Rheum (2006) 54:678–81.[CrossRef][Web of Science][Medline]
  15. Braun J, Baraliakos X, Brandt J, et al. Persistent clinical response to the anti-TNF-{alpha} antibody infliximab inpatients with ankylosing spondylitis over 3 years. Rheumatology (2005) 44:670–6.[Abstract/Free Full Text]
  16. Davis JC, van der Heijde DM, Braun J, et al. Efficacy and safety of up to 192 weeks of etanercept therapy in patients with ankylosing spondylitis. Ann Rheum Dis. Advance Access published October 29, 2007.
  17. Braun J, Baraliakos X, Listing J, et al. Persistent clinical efficacy and safety of anti-tumour necrosis factor alpha therapy with infliximab in patients with ankylosing spondylitis over 5 years: evidence for different types of response. Ann Rheum Dis (2008) 67:340–5.[Abstract/Free Full Text]
  18. Brandt J, Listing J, Sieper J, Rudwaleit M, van der Heijde D, Braun J. Development and preselection of criteria for short term improvement after anti-TNF alpha treatment in ankylosing spondylitis. Ann Rheum Dis (2004) 63:1438–44.[Abstract/Free Full Text]
  19. Garrett S, Jenkinson T, Kennedy LG, Whitelock H, Gaisford P, Calin A. A new approach to defining disease status in ankylosing spondylitis: the Bath Ankylosing Spondylitis Disease Activity Index. J Rheumatol (1994) 21:2286–91.[Web of Science][Medline]
  20. Calin A, Garrett S, Whitelock H, et al. A new approach to defining functional ability in ankylosing spondylitis: the development of the Bath Ankylosing Spondylitis Functional Index. J Rheumatol (1994) 21:2281–5.[Web of Science][Medline]
  21. Anderson JJ, Baron G, van der Heijde D, Felson DT, Dougados M. Ankylosing spondylitis assessment group preliminary definition of short-term improvement in ankylosing spondylitis. Arthritis Rheum (2001) 44:1876–86.[CrossRef][Web of Science][Medline]
  22. Braun J, McHugh N, Singh A, Wajdula JS, Sato R. Improvement in patient-reported outcomes for patients with ankylosing spondylitis treated with etanercept 50 mg once-weekly and 25 mg twice-weekly. Rheumatology (2007) 46:999–1004.[Abstract/Free Full Text]
  23. Davis JC Jr, Revicki D, van der Heijde DM, et al. Health-related quality of life outcomes in patients with active ankylosing spondylitis treated with adalimumab: results from a randomized controlled study. Arthritis Rheum (2007) 57:1050–7.[CrossRef][Web of Science][Medline]
  24. van der Heijde D, Han C, DeVlam K, et al. Infliximab improves productivity and reduces workday loss in patients with ankylosing spondylitis: results from a randomized, placebo-controlled trial. Arthritis Rheum (2006) 55:569–74.[CrossRef][Web of Science][Medline]
  25. Rudwaleit M, Listing J, Brandt J, Braun J, Sieper J. Prediction of a major clinical response (BASDAI 50) to tumour necrosis factor alpha blockers in ankylosing spondylitis. Ann Rheum Dis (2004) 63:665–70.[Abstract/Free Full Text]
  26. Rudwaleit M, Schwarzlose S, Hilgert ES, Listing J, Braun J, Sieper J. MRI in predicting a major clinical response to anti-TNF-treatment in ankylosing spondylitis. Ann Rheum Dis (2008) 67:1276–81.[Abstract/Free Full Text]
  27. Braun J, Baraliakos X, Golder W, et al. MRI examinations of the spine in patients with ankylosing spondylitis (AS) before and after infliximab therapy after evaluation of a new scoring system. Arthritis Rheum (2003) 48:1126–36.[CrossRef][Web of Science][Medline]
  28. Rudwaleit M, Baraliakos X, Listing J, Brandt J, Sieper J, Braun J. Magnetic resonance imaging of the spine and the sacroiliac joints in ankylosing spondylitis before and during therapy with etanercept. Ann Rheum Dis (2005) 64:1305–10.[Abstract/Free Full Text]
  29. Lambert RG, Salonen D, Rahman P, et al. Adalimumab significantly reduces both spinal and sacroiliac joint inflammation in patients with ankylosing spondylitis: a multicenter, randomized, double-blind, placebo-controlled study. Arthritis Rheum (2007) 56:4005–14.[CrossRef][Web of Science][Medline]
  30. Braun J, Landewe R, Hermann KG, et al. Major reduction in spinal inflammation in patients with ankylosing spondylitis after treatment with infliximab: results of a multicenter, randomized, double-blind, placebo-controlled magnetic resonance imaging study. Arthritis Rheum (2006) 54:1646–52.[CrossRef][Web of Science][Medline]
  31. Baraliakos X, Brandt J, Listing J, et al. Outcome of patients with active ankylosing spondylitis after two years of therapy with etanercept: clinical and magnetic resonance imaging data. Arthritis Rheum (2005) 53:856–63.[CrossRef][Web of Science][Medline]
  32. Sieper J, Baraliakos X, Listing J, et al. Persistent reduction of spinal inflammation as assessed by magnetic resonance imaging in patients with ankylosing spondylitis after 2 yrs of treatment with the anti-tumour necrosis factor agent infliximab. Rheumatology (2005) 44:1525–30.[Abstract/Free Full Text]
  33. Braun J, Bollow M, Sieper J. Radiologic diagnosis and pathology of the spondyloarthropathies. Rheum Dis Clin North Am (1998) 24:697–735.[CrossRef][Web of Science][Medline]
  34. Baraliakos X, Listing J, Rudwaleit M, et al. Progression of radiographic damage in patients with ankylosing spondylitis: defining the central role of syndesmophytes. Ann Rheum Dis (2007) 66:910–5.[Abstract/Free Full Text]
  35. Baraliakos X, Listing J, Brandt J, et al. Radiographic progression in patients with ankylosing spondylitis after 4 yrs of treatment with the anti-TNF-alpha antibody infliximab. Rheumatology (2007) 46:1450–3.[Abstract/Free Full Text]
  36. van der Heijde D, Landewé R, Einstein S, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with etanercept. Arthritis Rheum (2008) 58:1324–31.[CrossRef][Web of Science][Medline]
  37. van der Heijde D, Landewé R, Braun J, et al. Radiographic progression of ankylosing spondylitis after up to two years of treatment with infliximab. Arthritis Rheum (2008) in press.
  38. Sieper J, Appel H, Braun J, Rudwaleit M. Critical appraisal of assessment of structural damage in ankylosing spondylitis: implications for treatment outcomes. Arthritis Rheum (2008) 58:649–56.[CrossRef][Web of Science][Medline]
  39. Baraliakos X, Landewé R, Hermann KG, et al. Inflammation in ankylosing spondylitis: a systematic description of the extent and frequency of acute spinal changes using magnetic resonance imaging. Ann Rheum Dis (2005) 64:730–4.[Abstract/Free Full Text]
  40. Creemers MC, Franssen MJ, van't Hof MA, Gribnau FW, van de Putte LB, van Riel PL. Assessment of outcome in ankylosing spondylitis: an extended radiographic scoring system. Ann Rheum Dis (2005) 64:127–9.[Abstract/Free Full Text]
  41. Wanders AJ, Landewé RB, Spoorenberg A, et al. What is the most appropriate radiologic scoring method for ankylosing spondylitis? A comparison of the available methods based on the outcome measures in rheumatology clinical trials filter. Arthritis Rheum (2004) 50:2622–32.[CrossRef][Web of Science][Medline]
  42. Diarra D, Stolina M, Polzer K, et al. Dickkopf-1 is a master regulator of joint remodeling. Nat Med (2007) 13:156–63.[CrossRef][Web of Science][Medline]
  43. Wanders A, Heijde D, Landewé R, et al. Nonsteroidal antiinflammatory drugs reduce radiographic progression in patients with ankylosing spondylitis: a randomized clinical trial. Arthritis Rheum (2005) 52:1756–65.[CrossRef][Web of Science][Medline]
  44. Simon AM, Manigrasso MB, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. J Bone Miner Res (2002) 17:963–76.[CrossRef][Web of Science][Medline]
  45. Fransen M, Neal B. Non-steroidal anti-inflammatory drugs for preventing heterotopic bone formation after hip arthroplasty. Cochrane Database Syst Rev (2004) (3). CD001160.
  46. Smolen JS, Han C, Bala M, et al. ATTRACT Study Group. Evidence of radiographic benefit of treatment with infliximab plus methotrexate in rheumatoid arthritis patients who had no clinical improvement: a detailed subanalysis of data from the anti-tumor necrosis factor trial in rheumatoid arthritis with concomitant therapy study. Arthritis Rheum (2005) 52:1020–30.[CrossRef][Web of Science][Medline]
  47. Landewé R, van der Heijde D, Klareskog L, van Vollenhoven R, Fatenejad S. Disconnect between inflammation and joint destruction after treatment with etanercept plus methotrexate: results from the trial of etanercept and methotrexate with radiographic and patient outcomes. Arthritis Rheum (2006) 54:3119–25.[CrossRef][Web of Science][Medline]
  48. Wanders A, Landewé R, Dougados M, Mielants H, van der Linden S, van der Heijde D. Association between radiographic damage of the spine and spinal mobility for individual patients with ankylosing spondylitis: can assessment of spinal mobility be a proxy for radiographic evaluation? Ann Rheum Dis (2005) 64:988–94.[Abstract/Free Full Text]
  49. Vosse D, van der Heijde D, Landewé R, et al. Determinants of hyperkyphosis in patients with ankylosing spondylitis. Ann Rheum Dis (2006) 65:770–4.[Abstract/Free Full Text]
  50. van Echteld I, Cieza A, Boonen A, et al. Identification of the most common problems by patients with ankylosing spondylitis using the International Classification of Functioning, Disability and Health. J Rheumatol (2006) 33:2475–83.[Abstract/Free Full Text]
  51. Tubach F, Pham T, Skomsvoll JF, et al. Stability of the patient acceptable symptomatic state over time in outcome criteria in ankylosing spondylitis. Arthritis Rheum (2006) 55:960–3.[CrossRef][Web of Science][Medline]
  52. Braun J, Deodhar A, Dijkmans B, et al. Efficacy and safety of infliximab in patients with ankylosing spondylitis through 2 years. Arthritis Rheum (2008) in press.
  53. Baraliakos X, Listing J, Von der Recke A, Braun J. The natural course of radiographic progression in ankylosing spondylitis – evidence for non-linear progression in a large proportion of patients. Ann Rheum Dis (2008).
  54. Heiberg MS, Koldingsnes W, Mikkelsen K, et al. The comparative one-year performance of anti-tumor necrosis factor alpha drugs in patients with rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis: results from a longitudinal, observational, multicenter study. Arthritis Rheum (2008) 59:234–40.[CrossRef][Web of Science][Medline]
  55. Dagfinrud H, Kvien TK, Hagen KB. Physiotherapy interventions for ankylosing spondylitis. Cochrane Database Syst Rev (2008) (1). CD002822.
  56. Lubrano E, D’Angelo S, Parsons WJ, et al. Effects of a combination treatment of an intensive rehabilitation program and etanercept in patients with ankylosing spondylitis: a pilot study. J Rheumatol (2006) 33:2029–34.[Abstract/Free Full Text]
Accepted 30 July 2008


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?



This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
47/12/1738    most recent
ken357v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Right arrow Disclaimer
Google Scholar
Right arrow Articles by Braun, J.
Right arrow Articles by Sieper, J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Braun, J.
Right arrow Articles by Sieper, J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?