By Laurie Barclay, MD
Medscape Medical News

The tumor necrosis factor (TNF)–α inhibitor adalimumab may be helpful as adjunct treatment of sciatica, according to the results of a multicenter, randomized, double-blind, placebo-controlled trial reported online April 6 inArthritis & Rheumatism.

"The use of TNF-α blocking agents to treat radiculopathy associated with disc herniation is a topic of current interest, because of the debated pathophysiological role of proinflammatory cytokines in the development of radiculopathy induced by disc herniation," Ambrogio Capria, MD, from the Department of Internal Medicine at Tor Vergata University of Rome in Rome, Italy, told Medscape Rheumatologywhen asked for independent comment. "The rationale for use of anti-TNFα inhibitors in patients with sciatica is supported by the data of several experimental studies, but the clinical trials based on the administration of TNF-α inhibitors, such as infliximab and etanercept, in sciatica, have produced controversial results."

Actual Trial

Between May 2005 and December 2007, Stephane Genevay, MD, from University Hospitals of Geneva, and colleagues performed this trial in Switzerland. Inclusion criteria were lumbar disk herniation confirmed on imaging and radicular leg pain that was acute (< 12 weeks) and severe (Oswestry Disability Index [ODI] > 50).

"Patients were enrolled in the presence of sciatica for less than 12 weeks, with either a positive nerve root tension sign or a corresponding neurological deficit; disc herniation had to be confirmed by magnetic resonance imaging or computed tomography and had to correspond to clinical symptoms, as level and side," Dr. Capria said.

Exclusion criteria included a history of intolerance to adalimumab, concurrent infections, a history of cancer or tuberculosis, or sequelae of tuberculosis on chest radiographs. The study authors predefined clinically meaningful categories to reflect individual improvement, in addition to group improvement. Patients were defined as "responders" (improved by > 30% from the baseline) or with "low residual disease impact" (reaching a state of minimal and acceptable level, with a visual analog scale [VAS] score between 0 and 20 without requiring surgery).

Participants were randomly assigned to receive adjuvant therapy with 2 subcutaneous injections of 40-mg adalimumab, 7 days apart, or matching placebo. Leg pain measured by VAS (0 - 100) was the main study endpoint, which was recorded every day for 10 days and then at 6 weeks and at 6 months.

Of 265 patients screened, 61 were enrolled; 31 were randomly assigned to adalimumab, and 4 were lost to follow-up. Compared with the placebo group, the adalimumab group had more favorable evolution of leg pain with time (P < .001). However, the effect size was relatively small, with a difference of only 13.8 (95% confidence interval [CI], –11.5 to 39.0) at last follow-up.

"The overall evolution of leg pain was significantly different between the two groups, in favor of adalimumab, essentially due to a difference in evolution during the first days after therapy; the largest difference between the two treatment groups was observed at week 24, but it was not statistically significant," Dr. Capria said. "Also, the evolution of back pain was significantly different between 2 groups in favor of adalimumab (P < .0001), with the largest difference at weeks 6; in terms of back pain, at 6 months, 65% of the patients in the adalimumab group met the criteria for responders vs 27% in the placebo group (P < .01)."

Twice as many patients in the adalimumab group as in the placebo group fulfilled the criteria for "responders" concerning leg pain (71% vs 43 %; P = .03) and for "low residual disease impact" (leg pain VAS < 20 without surgery, 58% vs 30%; P< .05). This group also fared better regarding fewer surgical diskectomies performed (6 vs 13; P = .04).

"The addition of a short course of adalimumab to the treatment regimen of patients suffering from acute and severe sciatica resulted in a small decrease in leg pain and in significantly fewer surgical procedures," the study authors write.

Limitations of this study include inability to determine the sufficient dose and best route of administration for TNF-α inhibitors in radiculopathy because of disk herniation, or to identify subgroups of patients most likely to respond to this treatment.

Future Studies Necessary

"Previous studies have demonstrated that tissue TNF-α levels are increased, in an early phase of the disease, in discal and peridiscal tissue involved in sciatica induced by disc herniation; these and other findings support evidence that TNF-α, IL-1α, IL-1β, IL-6 [interleukin] and prostaglandin E2 are pathophysiologically relevant in the induction of radiculopathy with sciatalgia," Dr. Capria concluded.

"The severity of the nerve damage, with myelin involvement, due both to mechanical and inflammatory mechanisms, should be assessed, demonstrating the occurrence and grade of electrophysiologic changes, as an impaired nerve conduction velocity, demonstrated to be induced by the effects of TNF-α, and the amelioration after administration of TNF-α inhibitors.

Further clinical studies are necessary in patients with a radiculopathy due to disc herniation, to state the adequate dose and the best route of administration of TNF-α inhibitors, elucidating the effective therapeutic role of TNF-α inhibitors in this disease and determining the dosage, times and route of administration, as well as evaluating the possible occurrence of harmful events, as serious infections or adverse cardiovascular events, as seen in patients with rheumatoid arthritis treated with biological drugs."

This study was supported by an unrestricted scientific grant from Abbott. The study authors and Dr. Capria have disclosed no relevant financial relationships.

Arthr Rheum. Published online April 6, 2010

根據線上發表於4月6日關節炎與風濕病(Arthritis & Rheumatism)期刊的多中心、隨機雙盲、安慰劑控制試驗結果,腫瘤壞死因子(TNF)–α抑制劑adalimumab可能作為坐骨神經痛的輔助治療。
  義大利羅馬Tor Vergata大學內科的Ambrogio Capria醫師受Medscape Rheumatology之邀發表獨立評論時表示,使用TNF-α阻斷劑治療椎間盤突出相關的神經根病變是目前的一個熱門議題,爭論點在於,促發炎細胞激素在發生椎間盤突出引起之神經根病變中的病理生理角色。有許多實驗型研究支持坐骨神經痛病患使用抗-TNFα抑制劑,但是,根據使用infliximab和etanercept等TNFα抑制劑於坐骨神經痛之臨床試驗,產生的結果有所爭議。
  在2005年5月至2007年12月,日內瓦大學醫院的Stephane Genevay醫師等人在瑞士進行了這個試驗。納入規範是經影像檢查確認的腰椎椎間盤突出,以及急性(< 12週)和嚴重型(Oswestry失能指數[ODI]> 50)腳部神經疼痛。
  排除規範包括,曾發生無法耐受adalimumab、當下有感染、有癌症或結核病史、胸部X光檢查發現有結核病後遺症。研究作者事先定義有臨床意義的分類,以反應出個別的改善,以及整體的改善。病患定義為「有反應者」(比開始時改善> 30%)或「少有殘留疾病影響」(達到最小且可接受的程度狀態,視覺類比量表[VAS]分數介於0-20且不需要手術)。
  研究對象被隨機指派接受安慰劑或者輔助治療:2次皮下注射40-mg的adalimumab、每次間隔7天,主要研究終點是以VAS (0 - 100)測量腳部疼痛,記錄方式是,每天記錄10天之後在第6週和第6個月時再記錄。
  篩檢的265名病患中,納入了61人;31人被隨機指派接受adalimumab,有4人失去追蹤。相較於安慰劑組,adalimumab組隨著時間有較多可接受的腳痛緩解(P < .001),不過,影響程度相對較小,最後追蹤時的差異只有13.8 (95%信心區間[CI]為 –11.5至39.0)。
  Capria醫師表示,兩組之間的整體腳痛緩解有顯著差異,adalimumab較優,特別是治療開始後的前幾天;兩組的最大差異出現在第24週時,但是未達統計上的顯著意義,此外,兩組之間背痛改善的顯著差異出現在使用adalimumab者(P < .0001),最大差異出現在第6週時;就背痛而言,第6個月時,adalimumab組有65%的病患符合「有反應者」的規範,安慰劑組只有27%(P < .01)。
  就腳痛方面,符合「有反應者」規範的病患,adalimumab組是安慰劑組的近兩倍(71% vs 43 %; P = .03),「少有殘留疾病影響」也是(腳痛之VAS < 20且無手術,58% vs 30%;P < .05),adalimumab組也較不需要進行椎間盤切除術(6 vs 13;P = .04)。
  Capria醫師結論表示,之前的研究顯示,在疾病早期時、在椎間盤突出引起的坐骨神經痛之椎間盤與其周邊組織處,組織TNF-α值增加;這些與其他發現提供證據支持TNF-α、IL-1α、IL-1β、IL-6 [介白素]和前列腺素E2與減少坐骨神經痛的神經根病變有病理生理相關。


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