李忱 李菁 董振华 刘晋河

[摘要]目的:SAPHO综合征属罕见病,尚缺乏统一的治疗方案,本文旨在探讨抗肿瘤坏死因子-α拮抗剂在本病治疗中的作用。方法:对8例难治性SAPHO综合征患者的临床资料、治疗及转归进行分析并复习相关文献。结果:8例患者均为女性。7例表现为掌跖脓疱病,1例无皮肤损害。骨关节受累中上胸壁处受累8例,外周关节受累6例,骶髂关节受累6例,脊柱关节受累2例。8例患者均给予非甾体抗炎药(NSAID),糖皮质激素或(和)改变病情抗风湿药(DMARD)或(和)双磷酸盐,症状均无改善,后加用抗肿瘤坏死因子-α拮抗剂,症状均改善。但在治疗过程中,1例出现皮疹加重,1例出现颌下腺炎;4例停药后复发;3例配合中药治疗,症状均不同程度改善。结论:抗肿瘤坏死因子-α可显著改善SAPHO综合征的症状,但个别患者出现皮疹加重,有潜在的感染风险,且停药后易复发;中医药治疗本病有一定作用,有望成为治疗本病的新方法。

[Abstract]

Objective Synovitis, acne, pustulosis, hyperostosis, osteitis (SAPHO) syndrome is a very rare disease and still lack standardized therapy. We analyzed the clinical efficacy of anti-tumor necrosis factor-α (TNF-α) inhibitor therapy in treatment of SAPHO syndrome.

Methods We analyzed 8 patients with refractory SAPHO syndrome treating with anti-TNF-α inhibitors, and reviewed cases treating with anti-TNF-α inhibitors reported in the literature.

Results 8 patients were all female: 7 of them had palmoplantar pustulosis, the other one was free of skin lesions.Their osteoarticular manifestations included anterior chest wall involving in 8 patients,peripheral joints involving in 6 patients, sacroiliac joints involving in 6 patients, and vertebral joints involving in 2 patients. All patients were treated with non-steroidal anti-inflammatory drugs (NSAIDs) as the first-line therapy, and corticosteroid and/or disease modifying anti-rheumatic drugs (DMARDs) as the second-line drug, but the symptoms cannot be ameliorated. Patients received anti-TNF-α inhibitors as the third-line therapy, and each of them had their symptoms improved. During the treatment of anti-TNF-α inhibitors, skin rash of 1 patient aggravated, and 1 patient developed submandibular sialadenitis. 4 patients had disease relapse after cessation of anti-TNF-α inhibitor therapy. 3 patients received Chinese traditional medicine as additional therapy, and had symptoms improved further.

Conclusion Anti-TNF-α inhibitors can ameliorate symptoms of SAPHO syndrome patients significantly, but skin rash in some patients aggravate during the treatment. The risk of infection is the most potential side-effect of anti-TNF-α therapy. Relapse of disease is not unusual after the cessation of treatment. Chinese traditional medicine is proved to be valid in SAPHO syndrome, and would be developed into the potential new therapy of this rare disease.

 

[关键词] SAPHO综合征 治疗 抗肿瘤坏死因子-α拮抗剂

[Key words] synovitis,acne,pustulosis,hyperostosis,osteitis (SAPHO) syndrome;treatment; anti-TNF-α inhibitor

 

1987 年Chamot[1]首次提出以SAPHO 综合征来命名一组特殊的症候群:滑膜炎、痤疮、脓疱病、骨肥厚、骨炎(synovitis acne pustulosis hyperostosis osteitis,SAPHO)。2009年[2]全球文献报道约450余例,我国多为个例报道。临床上主要以皮肤和骨关节损害为主。皮肤损害可表现为掌跖脓疱病(Palmoplantar pustulosis,PPP)、聚合性痤疮(conglobata)、暴发性痤疮(acne fulminans)、化脓性汗腺炎hidradenitis suppurativa)、毛囊闭锁三联征(Follicular occlusion triad syndrome)等。骨关节损害包括:(1)上胸壁处的胸锁关节骨肥厚症(sternocostoclavicular hyperostosis,SCCH),表现为上胸壁处疼痛;(2)骶髂关节炎(sacroiliitis,SI),以下腰部、臀部疼痛为主;(3)僵硬的脊柱骨肥厚(ankylosing spinal hyperostosis,ASH),以脊柱关节僵硬、疼痛为主;(4)外周关节炎(peripheral arthritis,PA ),以外周关节如指(趾)、腕、肘、肩、膝、踝、下颌关节等疼痛为主。因为其血清类风湿因子阴性、相对高发的中轴关节和骶髂关节受累,有学者认为本病可以归纳在血清阴性脊柱关节病中[3]。治疗策略也受血清阴性脊柱关节病启示:非甾体抗炎药(NSAID)通常作为首选对症治疗药物控制关节症状,局部外用药治疗皮肤病变作为一线治疗;若症状控制不满意,糖皮质激素和改变病情抗风湿药(DMARD),如环磷酰胺、甲氨蝶呤、柳氮磺吡啶、环孢素A、沙利度胺等作为二线治疗,同时可以辅助抗生素类物及双磷酸盐;若经上述治疗,病情仍未控制的称难治性SAPHO综合征,抗肿瘤坏死因子-α(TNF-α)拮抗剂作为三线治疗。

资料与方法

1、一般资料:2010年4月至2012年4月北京协和医院住院及门诊就诊的资料完整的难治性SAPHO患者共8例(见表1),均为女性,年龄31岁~57岁,平均40.3±8.5岁。骨关节损害:SCCH发生率为100%(8/8),SI发生率为75%(6/8),PA发生率为83.3% (6/8) ,ASH发生率为25%(2/8)。皮肤损害:7例为PPP,1例无皮疹,PPP发生率为87.5%(7/8)。

2、方法:8例患者均给予NSAID及局部皮肤外用药作为一线治疗。因症状无好转加用二线治疗:7例给予糖皮质激素,7例给予甲氨蝶呤,4例给予柳氮磺胺吡啶,2例给予来氟米特,2例给予雷公藤多甙,4例辅助双磷酸盐。经上述症状仍不缓解,给予抗肿瘤坏死因子-α拮抗剂作为三线治疗,包括英夫利西单抗(商品名类克)、依那西普(商品名益赛普)、阿达木单抗(商品名修美乐)。用法:英夫利西单抗200mg,分别在0、2、6周各1次,后每8周1次;依那西普25mg,每周2次;阿达木单抗40mg,每2周1次。

结果

初始治疗方面:8例中7例给予益赛普作为初始治疗,6例症状改善(5例在治疗2次好转,1例在治疗3次好转),1例治疗4次无效改为类克治疗、治疗1次后症状改善;1例给予类克作为初始治疗,1次后症状改善。维持治疗方面:应用益赛普治疗6例中,1例持续应用12个月病情稳定;1例应用2月、皮疹加重停药;其余4例维持治疗2-3月后停药,1例病情平稳,3例复发(1例改为类克治疗,1例改为口服中药治疗,1例调整二线治疗方案)。应用类克治疗2例中,1例因颌下腺炎停药,后症状未复发;1例治疗3次后停药复发,改为中药治疗。不良反应方面:1例出现皮疹加重,1例出现颌下腺炎。目前8例随访8月~24月,平均15.6±6.3月,均未见严重骨骼关节并发症或残疾的患者。

讨论:

1961年Windom等首次发现了骨骼肌肉疾病与聚合性痤疮之间存在着联系。1978年Bjorksten等认为慢性复发性多灶性骨髓炎(chronic recurrent multifocal osteomyelitis,CRMO)与掌跖脓疱病之间存在着联系。1987 年Chamot等分析了85 例患者临床资料后,首次提出SAPHO综合征。目前尚缺乏大规模的流行病学研究,文献报道多来自欧洲和日本,欧洲报道高加索人不超过1/10000[4];而日本报道的发病率在0.00 144/100 000 [5]。

对于本病的发病机制尚不明确。有两种假说:一种认为SAPHO 综合征属于血清阴性脊椎关节病,因其血清类风湿因子阴性、相对高发的中轴关节和骶髂关节受累,可伴随银屑病或炎性肠病[3]。一种认为本病可能是在遗传背景下,痤疮丙酸杆菌感染诱导体液免疫和细胞前炎症反应激发SAPHO综合征。已有报道[6、7]从SAPHO综合征患者分离出痤疮丙酸杆菌(Propionibacterium acnes),认为痤疮丙酸杆菌感染,能够触发机体自身非特异性的T细胞免疫反应异常激活,来消除致病微生物,引起持续的炎症状态,造成炎性细胞因子IL-1、 IL-8、TNF-α高表达,从而造成非特异性的炎性损伤。不管是前者还是后者,都为TNF-α拮抗剂治疗,提供了有力依据。TNF-α拮抗剂治疗也越来越多的应用到临床,复习相关文献,总结如表2。

文献中25例均表现为难治性SAPHO综合征,既往曾应用一、二线治疗,症状无缓解。临床上给予TNF-α拮抗剂作为三线治疗。初始治疗方面:22例用英夫利西单抗 (infliximab, INF)、2例用依那西普 (etanercept,ETN)、1例用阿达木单抗 (adalimumab,ADA);治疗1次缓解率为64%(16/25),治疗2次缓解率为28%(7/25),治疗3次缓解率为8%(2/25);治疗缓解率100%,与我们观察的8例病人均缓解一致(除1例应用4次益赛普治疗无效后改为类克1次治疗缓解)。不良反应方面:出现支气管哮喘1例、肺炎1例、过敏性荨麻疹1例、银屑病样皮疹1例。维持治疗方面:多数患者均给予长期维持治疗,少数患者症状改善后停药,76%(19/25)持续缓解;24%(6/25)在治疗中或停药中复发,复发后换用TNF-α拮抗剂的种类,2例部分缓解。

值得注意的是,结合我们和国外的资料均发现,TNF-α拮抗剂治疗后出现新发皮疹和存在皮疹加重的现象。文献也报道英夫利西单抗治疗后的皮疹多在治疗后几个月出现,可表现为多形红斑、皮肤血管炎、青苔样皮疹、环形肉芽肿、湿疹样皮疹。意大利学者也发现英夫利西单抗治疗SAPHO综合征,对掌跖脓疱病不如对骨关节改善好,甚至可加重皮疹[12]。在最近文献复习中,应用TNF-α拮抗剂针对性治疗有皮肤表现的120例患者时,37例皮疹复发[19]。推测一个可能的原因是在应用TNF-α拮抗剂后痤疮丙酸杆菌被激活,使皮肤脓疱病加重。因此联合应用抗生素治疗,可能是合理的解决方案[20]。同时,我们还观察到1例出现颌下腺炎,文献中1例出现肺炎,对于潜在的感染也不能忽视。

TNF-α拮抗剂短期疗效目前已被普遍认可,但长期疗效、合理的疗程时长以及潜在的风险,目前尚不能确定。而且TNF-α拮抗剂价格昂贵,长期治疗的费用也不可忽视。我们观察的8例中4例因停药复发,3例给予口服中药治疗,症状缓解。目前已有中药治疗SAPHO的成功个例报道[21],有望作为本病治疗的新方法。

综上所述,我们认为对于难治性SAPHO综合征,TNF-α拮抗剂有效,并且见效快,但因为本病相对少见,随机对照双盲的实验难以进行,需要大样本的病人来证实本结论。同时治疗过程中皮疹加重和潜在的感染风险也不能忽视,联合应用抗生素可能是合理的解决方案。TNF-α拮抗剂长期应用价格昂贵,针对我国国情,尚不能普及应用,急需替代疗法,中医药在个例报道中已取得一定疗效,有望成为本病的新疗法。

 

参考文献:

[1]Chamot AM, Benhamou CL, Kahm MF, et al. Acne-pustulosis-hyperostosis-osteitis syndrome. Results of a national survey. 85 cases[J]. Rev Rheum,1987,54(3):187-196.

[2]Huber CE, Judex AG, Freyschmidt J, et al. Sequential combination therapy leading to sustained remission in a patient with SAPHO syndrome[J]. Open Rheumatol J,2009,3:18-21.

[3]Rohekar G, Inman RD. Conundrums in nosology: synovitis, acne, pustulosis, hyperostosis and osteitis syndrome and spondylarthritis[J]. Arthritis Care and Res,2006,55(4):665-669.

[4]Kahn MF, Khan MA. The SAPHO syndrome[J]. Baillieres Clin Rheumatol,1994,8(2):333-362.

[5]Hukuda S, Minami M, Saito T, et al. Spondyloarthropathies in Japan: nationwide questionnaire survey performed by the Japan Ankylosing Spondylitis Society[J]. J Rheumatol,2001,28(3):549-554.

[6]Govoni M, Colina M.“SAPH0 syndrome and infections” [J].Autoimmunity Reviews,2009,81(8):256-259.

[7]Magrey M, Khan MA. New insights into synovitis, acne, pustulosis, hyperostosis, and osteitis (SAPHO) syndrome[J]. Curr Rheumatol Rep,2009,11(5):329-333.

[8]Wagner AD, Andresen J, Jendro MC, et al. Sustained response to tumor necrosis factor alpha-blocking agents in two patients with SAPHO syndrome[J]. Arthritis Rheum,2002,46(7):1965-8.

[9]Olivieri I, Padula A, Ciancio G, et al. Successful treatment of SAPHO syndrome with infliximab: report of two cases[J]. Ann Rheum Dis,2002,61(4):375-6.

[10]Iqbal M, Kolodney MS. Acne fulminans with synovitis- acne- pustulosis- hyperostosis- osteitis (SAPHO) syndrome treated with infliximab[J]. J Am Acad Dermatol,2005,52 (5 Suppl 1):S118-20.

[11]Deutschmann A, Mache CJ, Bodo K, et al. Successful treatment of chronic recurrent multifocal osteomyelitis with tumor necrosis factor-blockage[J]. Pediatrics,2005,116(5):1231-3.

[12]Massara A, Cavazzini PL, Trotta F. In SAPHO syndrome anti-TNF-a therapy may induce persistent amelioration of osteoarticular complaints, but may exacerbate cutaneous manifestations[J]. Rheumatology (Oxford),2006,45(6):730-3.

[13]Widmer M, Weishaupt D, Brühlmann P, et al. Infliximab in the treatment of SAPHO syndrome: clinical experience and MRI response[J]. Ann Rheum Dis,2003,62(4):250-1A.

[14]Asmussen KH. Successful treatment of SAPHO syndrome with infliximab-a case report[J]. Arthritis Rheum,2003,48(Suppl):S621A.

[15]Kyriazis NC, Tachoula AV, Sfontouris CI. Successful treatment of refractory SAPHO syndrome with infliximab[J]. Ann Rheum Dis,2004,63(4):388-91.

[16]Moll C, Hernandez MV, Canete JD, et al. Ilium osteitis as the main manifestation of the SAPHO syndrome: Response to infliximab therapy and review of the literature[J]. Semin Arthritis Rheum,2008,37(5):299-306.

[17]Sabugo F, Liberman C, Niedmann JP, et al. Infliximab can induce a prolonged clinical remission and a decrease in thyroid hormonal requirements in a patient with SAPHO syndrome and hypothyroidism[J]. Clin Rheumatol,2008,27(4):533-5.

[18]Ben Abdelghani KDran DGGottenberg JE, et al. Tumor necrosis factor-alpha blockers in SAPHO syndrome[J]. J Rheumatol,2010,37(8):1699-704.

[19]Wollina U, Hansel G, Koch A, et al. Tumor necrosis factor-alpha inhibitor-induced psoriasis or psoriasiform exanthemata: first 120 cases from the literature including a series of six new patients[J]. Am J Clin Dermatol,2008,9(1):1-14.

[20]Rozin AP. SAPHO syndrome: Is a range of pathogen-associated rheumatic diseases extended? [J].Arthritis Res Ther,2009,11(6):131.

[21]刘颖,董振华.柴胡桂枝汤加减治疗SAPHO综合征2例[J].环球中医药,2012,5(1):60-62

.表1:8例患者的临床资料、治疗、转归及随访

治疗:非甾体抗炎药(nonsteroidal antiinflammatory drug,NSAID)、皮质类固醇激素(corticosteroids,CS)、甲氨蝶呤(methotrexate,MTX)、柳氮磺胺吡啶(Sulfasalazine,SASP)、沙利度胺(Thalidomide,THD)、雷公藤多甙(Tripterygium wilfordii,TII)、来氟米特(Leflunomide,LEF)、双磷酸盐(Bisphosphonates,BP)、英夫利西单抗(商品名类克)(infliximab, INF)、依那西普(商品名益赛普)(etanercept,ETN)、阿达木单抗(商品名修美乐)(adalimumab,ADA)→

 

表2:文献中25例难治性SAPHO综合征的临床资料、治疗、转归及随访

治疗:非甾体抗炎药(nonsteroidal antiinflammatory drug,NSAID)、抗生素(antibiotics,ATB) 、双磷酸盐(Bisphosphonates,BP)、皮质类固醇激素(corticosteroids,CS)、环孢素A(cyclosporine, CSA)、甲氨蝶呤(methotrexate,MTX)、柳氮磺胺吡啶(Sulfasalazine,SASP)、英夫利西单抗 (infliximab, INF)、依那西普 (etanercept,ETN)、阿达木单抗 (adalimumab,ADA)