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Editorial
 
Tumor Necrosis Factor Inhibitors "SPARCC" an Interest in Consensus
ALLEN SAWITZKE, MD; Address reprint requests to Dr. Daniel O. Clegg, Division of Rheumatology, University of Utah Medical Center, 50 North Medical Drive, Room 4B181, Salt Lake City, UT 84132. The seronegative spondyloarthropathies (SpA) are prevalent rheumatologic conditions that are practically unknown to the general public and, unfortunately, are not well known to many care providers. Together, the SpA have a prevalence exceeding the 1% typically attributed to rheumatoid arthritis (RA) in North America1. They are as fascinating for their genetic associations and their extraarticular features as they are devastating to patients. Data from the German rheumatological database show that ankylosing spondylitis patients are more likely to be unemployed than are patients with RA2. A 1998 study shows loss of productivity costs of having AS in the USA as $4945/year2. In addition, there are quality of life issues where the economic impact becomes even more difficult to measure. There is little wonder that these diseases, which have severe consequences for patients, frustrate clinicians in part because of the striking lack of proven effective therapies. In this issue of The Journal Maksymowych and co-members of the "SpA Research Consortium of Canada" (SPARCC) state their purpose "to evaluate the clinical evidence in support of the use of biologic response modifiers in spondyloarthritis in Canada"3. The authors address 3 main points: a review of the usual "treatment of the spondyloarthritis," a brief discussion of therapeutic endpoints, and finally a plea to the third party payers for flexibility in allowing providers and their patients to individualize therapeutic decision-making. This group took a novel tack in producing this consensus document using an evidence-based literature and opinion review without a priori evidence that a specific mandate was being addressed by the document. Their review of the current approach to SpA is solid. Following a brief discussion of recent attempts to better classify the SpA, they highlight the devastating effects of these diseases, including disability, decreased productivity, and economic burden to patients and their families. Most importantly, they provide a review of currently used therapies for the treatment of SpA. This review will be of particular value to medical education as the role of physical therapy, nonsteroidal antiinflammatory drugs (NSAID), steroids, methotrexate, and sulfasalazine are concisely summarized. A more complete treatment of the generally less well-known "anti-tumor necrosis factor (TNF) directed therapies" is also provided. The manuscript presents a concise means to acquaint oneself with the developing body of information on the role of TNF inhibition in the treatment of SpA. The authors, however, have not properly addressed examining the potential for longterm problems to biologic-based therapies in this population. No discussion of adverse drug reactions (ADR) is present and no cost analysis is referenced, estimated, or discussed. Some details on these issues can be found in the American College of Rheumatology Guidelines4 and others are highlighted in a manuscript summarizing the international experience by Braun, et al5. Further, other treatments that may act by lowering TNF-a were not discussed despite limited data (category C) supporting them. For example, thalidomide has been shown to suppress TNF-a production6 and in a 1-year open label trial demonstrated greater than 20% improvement in 80% of the completers7,8. Discussion of sulfasalazine congeners such as mesalamine also was not included. The data on TNF inhibition are developed enough that the results from randomized controlled trials (RCT) best highlight the expectations. Two European trials have tested infiximab versus placebo in SpA patients. The trial by Braun and colleagues examined infliximab at 5 mg/kg at times 0, 2, and 6 weeks versus placebo. They found 53% of patients (vs 9% placebo) had greater than a 50% response measured as Bath Ankylosing Spondylitis Disease Activity Index (BASDAI)5,9. The other trial by Van den Bosh and colleagues in SpA also used 5 mg/kg infliximab at times 0, 2, and 6 weeks. They report a change in average BASDAI from 58.9 at baseline to 26.6 at week 1210. A single center RCT of etanercept in patients with AS has been reported. Patients received 25 mg twice weekly for 4 months. Again an improved response was seen with the etanercept group compared to the placebo at all time points and was statistically significantly different at 3 of 4 time points11. What then are the questions that need be answered in order to guide our use of TNF inhibitors for the treatment of SpA? Among the major answers needed are: who, when, with how much medication, and for how long. Further, how can treatment be adjusted over time? If one inhibitor fails, should we try another? Are they effective in both new-onset and long-standing disease? Some trials have shown improvement even in patients with advanced disease with ankylosis5. Since answers to these questions are not yet available, the approach has been to use consensus. In addition to this effort by the Canadian SPARCC, an international meeting was held in January 2003 in Berlin, Germany, to produce a similar guidance document. For now, we are left to use therapeutic trials of limited duration, using dosages based principally on data from RA studies. This empiric approach to the use of TNF inhibitors leads to the question of what endpoints should be used for assessing the degree of response and therefore whether continued use is appropriate. The Bath AS Functional Index and the BASDAI are often not familiar to the rheumatologist in the office setting, which could lead to the development of unique schema by practitioners and by 3rd party payers alike. To date, consensus groups have not adequately addressed issues related to disease activity and assessment of treatment response for the office. While Assessment in Ankylosing Spondylitis Working Group (ASAS) outcome measures are important for use in a RCT, does any single measure that could be done in the office acceptably differentiate responders from non-responders? Can a 20% or other agreed upon difference in response to treatment can be demonstrated? The ASAS has published that the critical domains of response are spinal pain and patient global scores12. Perhaps a visual analog scale (VAS) patient rating of spinal pain as performed in the ASAS core set13 or a patient VAS global score could substitute for the more complete BASDAI in the clinic or 3rd party payers' offices. The more complete index should be used in clinical trials. Many different combinations of measures were tested by the ASAS, but unfortunately single measure of response effectiveness has not been published. Review of the response to patient global assessment by 100 mm VAS in the Belgium based trial of infliximab versus placebo suggests that this may be useful in this regard10. After review of the data, SPARCC makes the following conclusions: 1. TNF inhibition has an important role in the treatment of SpA 2. All therapeutic options should be equally available for use when indicated 3. It would be "below current standard of optimal practice to deny these therapies" based on economic considerations. The authors provided 2 postscript points aimed at practitioner responsibility. The manuscript is a SPARCC developed consensus with the hope of improving access to anti-TNF therapies for SpA patients in Canada. The fiscal problems caused by the revolution in biologics-based therapy are not limited to patients from Canada but will impact patients throughout the world. Because cost effectiveness analyses remain to be performed, a longterm view on behalf of payers will be required in order to achieve economic advantages such as less future disability and fewer surgeries, while less suffering for patients with SpA may be more readily shown. That is to say, lower productivity costs, improved quality of life, and enhanced psychological well being for patients with SpA. Perhaps "metaguidance document" is the single best description of this work, as it provides a mix of information that addresses provider, 3rd-party payers, and to a lesser extent patient education, as well as an endorsement of the use of etanercept and infliximab for the signs and symptoms of moderate to severe active SpA derived via an approach reminiscent of evidence-based metaanalyses. Much less information on safety of these agents in treating SpA was presented. Along with the authors, we hope that agents with proven disease modifying activity (disease modifying antirheumatic drugs) will soon become available for treatment of patients affected by the SpA throughout the world. In the interim TNF inhibitors do appear to be disease controlling antirheumatic treatments for SpA13. Recent treatment successes will need to be balanced by the similarly important needs of fiscal responsibility and patient safety. It is likely that many groups will develop their own guidelines to determine who can and cannot have access to these medications. We agree with the authors, that it is critical that those guidelines not substitute for reasonable and responsible patient-directed therapeutic decisions between patients and their rheumatologic care providers. 1. Khan MA. Update on spondyloarthropathies. Ann Intern Med 2002:136:896-907. [MEDLINE] 2. Sieper J, Braun J, Rudwaleit M, Boonen A, Zink, A. Ankylosing spondylitis: an overview. Ann Rheum Dis 2002:61 Suppl 3:iii8-18. 3. Maksymowych WP, Inman RD, Gladman DD, et al. Canadian Rheumatology Association consensus on the use of anti-tumor necrosis factor-alpha directed therapies in the treatment of spondyloarthritis. J Rheumatol 2003;30:1356-63. 4. Furst DE, Breedveld FC, Kalden JR, et al. Updated consensus statement on biological agents for the treatment of rheumatoid arthritis and other rheumatic diseases. Ann Rheum Dis 2002:61 Suppl 2:ii2-7. 5. Braun J, Sieper J, Breban M, et al. Anti-tumour necrosis factor alpha therapy for ankylosing spondylitis: international experience. Ann Rheum Dis 2002:61 Suppl 3:iii51-60. 6. Ossandon A, Cassara EA, Priori R, Valesini G. Thalidomide: focus on its employment in rheumatologic diseases. Clin Exp Rheumatol 2002;20:709-18. [MEDLINE] 7. Huang F, Gu J, Zhao W, Zhu J, Zhang J, Yu DT. One-year open-label trial of thalidomide in ankylosing spondylitis. Arthritis Rheum 2002:47:249-54. [MEDLINE] 8. Huang F,. Wei JC, Breban M. Thalidomide in ankylosing spondylitis. Clin Exp Rheumatol 2002:20 Suppl 28:S158-61. 9. Braun J, Brandt J, Listing J, et al. Treatment of active ankylosing spondylitis with infliximab: a randomised controlled multicentre trial. Lancet 2002:359:1187-93. [MEDLINE] 10. Van den Bosch F, Kruithof E, Baeten D, et al. Randomized double-blind comparison of chimeric monoclonal antibody to tumor necrosis factor alpha (infliximab) versus placebo in active spondyloarthropthy. Arthritis Rheum 2002: 46:755-65. [MEDLINE] 11. Gorman JD, Sack KE, Davis JC Jr. Treatment of ankylosing spondylitis by inhibition of tumor necrosis factor alpha. N Engl J Med 2002:346:1349-56. [MEDLINE] 12. van Tubergen A, van der Heijde D, Anderson J, et al. Comparison of statistically derived ASAS improvement criteria for ankylosing spondylitis with clinically relevant improvement according to an expert panel. Ann Rheum Dis 2003;62:215-21. [MEDLINE] 13. van der Heijde D, Braun J, McGonagle D, Siegel J. Treatment trials in ankylosing spondylitis: current and future considerations. Ann Rheum Dis 2002:61 Suppl 3:iii24-32. [MEDLINE] |
