Catelas Isabelle, Lehoux Eric A, Hurda Ian, Baskey Stephen J, Gala Luca, Foster Ryan, Kim Paul R, Beaulé Paul E
Department of Mechanical Engineering, University of Ottawa, Ottawa, ON, Canada.
Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada.
Clin Orthop Relat Res. 2015 Dec;473(12):3903-14. doi: 10.1007/s11999-015-4466-8. Epub 2015 Sep 1.
Early adverse tissue reactions around metal-on-metal (MoM) hip replacements, especially pseudotumors, are a major concern. Because the causes and pathomechanisms of these pseudotumors remain largely unknown, clinical monitoring of patients with MoM bearings is challenging.
QUESTIONS/PURPOSES: The purpose of this study was to compare the lymphocyte subpopulations in peripheral blood from patients with a failed MoM hip implant with and without a pseudotumor and patients with a well-functioning MoM hip implant without a pseudotumor. Potential differences in the systemic immune response are expected to reflect local differences in the periprosthetic tissues.
Consenting patients who underwent a revision of a failed MoM hip implant at The Ottawa Hospital (TOH) from 2011 to 2014, or presented with a well-functioning MoM hip implant for a postoperative clinical followup at TOH from 2012 to 2013, were recruited for this study, unless they met any of the exclusion criteria (including diagnosed conditions that can affect peripheral blood lymphocyte subpopulations). Patients with a failed implant were divided into two groups: those with a pseudotumor (two hip resurfacings and five total hip arthroplasties [THAs]) and those without a pseudotumor (10 hip resurfacings and two THAs). Patients with a well-functioning MoM hip implant (nine resurfacings and three THAs) at 5 or more years postimplantation and who did not have a pseudotumor as demonstrated sonographically served as the control group. Peripheral blood subpopulations of T cells (specifically T helper [Th] and cytotoxic T [Tc]), B cells, natural killer (NK) cells, memory T and B cells as well as type 1 (expressing interferon-γ) and type 2 (expressing interleukin-4) Th and Tc cells were analyzed by flow cytometry after immunostaining. Serum concentrations of cobalt and chromium were measured by inductively coupled plasma-mass spectrometry.
The mean percentages of total memory T cells and, specifically, memory Th and memory Tc cells were lower in patients with a failed MoM hip implant with a pseudotumor than in both patients with a failed implant without a pseudotumor and patients with a well-functioning implant without a pseudotumor (memory Th cells: 29% ± 5% [means ± SD] versus 55% ± 17%, d = 1.8, 95% confidence interval [CI] [1.2, 2.5] and versus 48% ± 14%, d = 1.6, 95% CI [1.0, 2.2], respectively; memory Tc cells: 18% ± 5% versus 45% ± 14%, d = 2.3, 95% CI [1.5, 3.1] and versus 41% ± 12%, d = 2.3, 95% CI [1.5, 3.1], respectively; p < 0.001 in all cases). The mean percentage of memory B cells was also lower in patients with a failed MoM hip implant with a pseudotumor than in patients with a well-functioning implant without a pseudotumor (12% ± 8% versus 29% ± 16%, d = 1.3, 95% CI [0.7, 1.8], p = 0.025). In addition, patients with a failed MoM hip implant with a pseudotumor had overall lower percentages of type 1 Th cells than both patients with a failed implant without a pseudotumor and patients with a well-functioning implant without a pseudotumor (5.5% [4.9%-5.8%] [median with interquartile range] versus 8.7% [6.5%-10.2%], d = 1.4, 95% CI [0.8, 2.0] and versus 9.6% [6.4%-11.1%], d = 1.6, 95% CI [1.0, 2.2], respectively; p ≤ 0.010 in both cases). Finally, serum cobalt concentrations in patients with a failed MoM hip implant with a pseudotumor were overall higher than those in patients with a well-functioning implant without a pseudotumor (5.8 µg/L [2.9-17.0 µg/L] versus 0.9 µg/L [0.6-1.3 µg/L], d = 2.2, 95% CI [1.4, 2.9], p < 0.001).
Overall, results suggest the presence of a type IV hypersensitivity reaction, with a predominance of type 1 Th cells, in patients with a failed MoM hip implant with a pseudotumor.
The lower percentages of memory T cells (specifically Th and Tc) as well as type 1 Th cells in peripheral blood of patients with a failed MoM hip implant with a pseudotumor could potentially become diagnostic biomarkers for the detection of pseudotumors. Although implant design (hip resurfacing or THA) did not seem to affect the results, as suggested by the scatter of the data with respect to this parameter, future studies with additional patients could include the analysis of implant design in addition to correlations with histological analyses of specific Th subsets in periprosthetic tissues.
金属对金属（MoM）髋关节置换术后早期的不良组织反应，尤其是假肿瘤，是一个主要问题。由于这些假肿瘤的病因和发病机制在很大程度上仍不清楚，对MoM关节置换患者的临床监测具有挑战性。
问题/目的：本研究的目的是比较MoM髋关节置换失败且有或无假肿瘤患者以及MoM髋关节置换功能良好且无假肿瘤患者外周血中的淋巴细胞亚群。全身免疫反应的潜在差异有望反映假体周围组织的局部差异。
本研究招募了2011年至2014年在渥太华医院（TOH）接受失败的MoM髋关节置换翻修术的患者，或2012年至2013年在TOH接受功能良好的MoM髋关节置换术后临床随访的患者，除非他们符合任何排除标准（包括可影响外周血淋巴细胞亚群的诊断疾病）。植入失败的患者分为两组：有假肿瘤的患者（两例髋关节表面置换和五例全髋关节置换术[THA]）和无假肿瘤的患者（十例髋关节表面置换和两例THA）。植入后5年或更长时间且超声检查未发现假肿瘤的功能良好的MoM髋关节置换患者（九例表面置换和三例THA）作为对照组。免疫染色后，通过流式细胞术分析T细胞（特别是辅助性T细胞[Th]和细胞毒性T细胞[Tc]）、B细胞、自然杀伤（NK）细胞、记忆T细胞和B细胞以及1型（表达干扰素-γ）和2型（表达白细胞介素-4）Th和Tc细胞的外周血亚群。通过电感耦合等离子体质谱法测量血清钴和铬的浓度。
与植入失败但无假肿瘤的患者和功能良好且无假肿瘤的植入患者相比，植入失败且有假肿瘤的MoM髋关节置换患者中总记忆T细胞，特别是记忆Th和记忆Tc细胞的平均百分比更低（记忆Th细胞：29%±5%[平均值±标准差]对55%±17%，d = 1.8，95%置信区间[CI][1.2, 2.5]；对48%±14%，d = 1.6，95% CI[1.0, 2.2]；记忆Tc细胞：18%±5%对45%±14%，d = 2.3，95% CI[1.5, 3.1]；对41%±12%，d = 2.3，95% CI[1.5, 3.1]；所有情况下p < 0.001）。与功能良好且无假肿瘤的植入患者相比，植入失败且有假肿瘤的MoM髋关节置换患者中记忆B细胞的平均百分比也更低（12%±8%对29%±16%，d = 1.3，95% CI[0.7, 1.8]，p = 0.025）。此外，与植入失败但无假肿瘤的患者和功能良好且无假肿瘤的植入患者相比，植入失败且有假肿瘤的MoM髋关节置换患者中1型Th细胞的总体百分比更低（5.5%[4.9%-5.8%][中位数及四分位间距]对8.7%[6.5%-10.2%]，d = 1.4，95% CI[0.8, 2.0]；对9.6%[6.4%-11.1%]，d = 1.6，95% CI[1.0, 2.2]；两种情况下p≤0.010）。最后，植入失败且有假肿瘤的MoM髋关节置换患者的血清钴浓度总体高于功能良好且无假肿瘤的植入患者（5.8μg/L[2.9 - 17.0μg/L]对0.9μg/L[0.6 - 1.3μg/L]，d = 2.2，95% CI[1.4, 2.9]，p < 0.001）。
总体而言，结果表明植入失败且有假肿瘤的MoM髋关节置换患者存在IV型超敏反应，其中1型Th细胞占优势。
植入失败且有假肿瘤的MoM髋关节置换患者外周血中记忆T细胞（特别是Th和Tc）以及1型Th细胞的百分比降低，可能成为检测假肿瘤的诊断生物标志物。尽管植入物设计（髋关节表面置换或THA）似乎未影响结果，正如数据关于该参数的离散情况所表明的那样，但未来纳入更多患者的研究除了分析与假体周围组织中特定Th亚群的组织学分析的相关性外，还可包括植入物设计的分析。
