Appeal type: Experimental/Investigational
Decision: Upheld Decision of Health Plan

Physician 1The patient is a 69-year-old woman who has followed a typical course for Takayasus arteritis and has stenosis of the left subclavian artery, carotid arteries, right vertebral artery, left ulnar artery, and branches of the aorta supplying the kidneys. She has had numerous bypass surgeries to maintain blood flow to her upper extremities and stenting of her renal arteries. In September 2003, studies revealed 70% stenosis of her celiac axis and superior mesenteric artery. The patients disease continues to be very aggressive despite prednisone treatment and Plaquenil. The patients provider has recommended Enbrel. The Health Plan has denied authorization for Enbrel on the basis that it is considered investigational for treatment of Takayasus arteritis.The pathogenesis of Takayasus arteritis and temporal arteritis are very similar. The Sneller article cited above concludes that the vascular lesions in Wegeners granulomatosis, giant cell arteritis and Takayasus arteritis contain granulomatous inflammation with multinucleated giant cells. Tumor necrosis factor is required for normal granuloma formation and maintenance of the granuloma. In animal models, it has been found that TNF exerts a pro-granulomatous effect during the initial phase of an inflammatory response, and there is indirect evidence that there is excessive production of TNF that could perpetuate the granulomatous inflammatory vascular lesion and subsequent tissue injury. Because of the implications from research that TNF is important in the development of the inflammatory response in patients with giant cell arteritis and Takayasus arteritis, a study by Hoffman and his colleagues looked at the utility of anti-TNF therapy in Takayasus arteritis. Fifteen patients with active, relapsing Takayasus arteritis were treated with the addition of anti-TNF therapy to their corticosteroid treatment. The conclusion of the study was that the addition of Enbrel or infliximab resulted in sustained disease improvement, and often full remission, and allowed for a decrease or discontinuance of steroid treatment. This successful pilot study suggests that there should be further research with randomized, controlled trials. The problem with studying the treatment of Takayasus arteritis is that it is such a rare disease that randomized controlled treatment trials are either lacking or are based on small patient numbers, making it difficult to have good evidence based treatment models. Thus, we have to rely on our understanding of the pathogenesis of Takayasus arteritis, and what existing drugs might be useful in interrupting the disease process. Another article (Ann Rheum Dis, 2003) reports on a patient who had a dramatic response within one month of treatment with Enbrel. The patient in this report suffered from steroid-induced side effects, which is always an issue when used in high doses for prolonged periods. Because of the steroid-induced side effects, it was elected to use Enbrel as a steroid-sparing agent. After six months of treatment with Enbrel, the dose of prednisone was decreased to an average of 6.25mg per day. This patient may benefit from a steroid sparing agent in light of her recent GI bleed while taking 60mg/day prednisone.  However, there is no evidence the patient has failed conventional therapy with methotrexate or azathioprine. Therefore, I have determined that the requested therapy is not likely to be more beneficial for treatment of the patients medical condition than any available standard therapy at this time. The Health Plans denial should be upheld at this time. If evidence is presented that the patient has already failed a trial of methotrexate or azathioprine then the requested therapy should be authorized. If the patient has not yet undergone a trial of methotrexate or azathioprine, a trial should be authorized. Physician 2The patient is a 69-year-old female with Takayasus arteritis diagnosed in 1999. Her treatment has apparently consisted of prednisone, Plaquenil, aspirin, and Coumadin.  There is no mention of any immunosuppressive or steroid-sparing therapy being utilized. The patients illness has been complicated by vascular damage requiring surgical repair, bypass grafting, and revisions. Treatment has been complicated by an implied upper GI lesion causing acute bleeding in spring 2004 while receiving the agents noted above. The current level of inflammatory disease activity is not apparent based on the information provided.The patient and her rheumatologist have requested authorization for Enbrel. The Health Plan has denied the request on the basis that Enbrel is considered experimental for this indication.The standard of care for Takayasus arteritis (as for giant cell arteritis in its more common form) involves the use of standard steroid-sparing agents such as methotrexate or azathioprine for patients failing, or intolerant of, standard steroid regimens. It is beneficial to begin such agents within the first two months of steroid treatment for these illnesses since undesirable and unnecessary side effects are inevitable with prolonged intensive steroid therapy. There is no evidence that the patient has received such treatment.Given that giant cell arteritis in its various forms has granuloma formation as a central element, and that TNF is an important mediator in granuloma formation and maintenance, the use of TNF inhibitors holds the promise of more effective treatment. Scattered case reports suggest benefit with use of etanercept (Enbrel) or infliximab in treating these conditions. The Hoffman article cited above presents the strongest evidence to date describing the use of Enbrel or Remicade in 15 patients with Takayasus arteritis resistant to previous therapy. The results of the study indicate 13 of 15 patients had failed at least one immunosuppressive agent in addition to steroids, while 8 of 15 had failed two such agents. Results of this multicenter open-label trial cannot be taken as conclusive, but the study describes prolonged steroid-free remissions in 10 of 15 patients, significant improvement in 4 of 15 patients, and failure in only 1 patient. If future trials of TNF inhibition produce results similar to these, the use of TNFs is likely to become standard therapy. However, the use of TNF is not yet the standard of rheumatologic care in the absence of immunosuppressive failure. Given the subacute nature of the patients illness, which began five years ago, she should undergo a trial with at least one course of methotrexate or azathioprine as a steroid-sparing agent prior to authorization of Enbrel. Therefore, I have determined that the requested therapy is not likely to be more beneficial for treatment of the patients medical condition than any available standard therapy at this time. The Health Plans denial should be upheld at this time. However, if evidence is presented that a trial of methotrexate or azathioprine has