MMP-9(편측) [일반면역검사] - 간이검사

Abstract

평가 배경 MMP-9(편측)[일반면역검사]-간이검사는 눈물 내 MMP-9 농도를 측정하여 건성안의 임상적 진단 보조 및 경과관찰을 목적으로 하는 검사방법으로, 국내에서는 신의료기술평가 후 2017년에 선별급여 80%로 등재되어 현재까지 사용되고 있다. 해당 의료기술은 내부 모니터링을 통해 발굴된 주제로, 대상선별 임상자문회의 및 우선순위 심의에서 재평가 적합성과 필요성을 인정받아 2021년 제10차 의료기술재평가위원회(2021.10.15.)에서 의료기술재평가 대상으로 선정되었다.

평가방법 본 평가는 MMP-9(편측)[일반면역검사]-간이검사의 안전성 및 효과성 평가를 위해 체계적 문헌고찰을 수행하였다. 모든 평가방법은 평가목적을 고려하여 “MMP-9(편측)[일반면역검사]-간이검사 소위원회(이하 ‘소위원회’)”의 심의를 거쳐 확정하였다. 평가의 핵심질문은 “건성안 의심 환자 및 건성안 환자에서 MMP-9(편측)[일반면역검사]-간이검사는 임상적 진단 보조 및 경과관찰을 목적으로 시행하기에 안전하고 효과적인가?”이다. 문헌검색은 국외 3개, 국내 5개 데이터베이스에서 수행하였으며, 문헌선정 및 배제기준에 따라 두 명의 검토자가 독립적으로 선별하고 선택하였다. 진단법 평가연구는 QUADAS-2를 이용하여 문헌의 비뚤림 위험 평가를 수행하였다. 자료추출은 미리 정해놓은 자료추출 양식을 활용하여 두 명의 검토자가 독립적으로 수행하였으며, 의견 불일치가 있을 경우 제3자와 함께 논의하여 합의하였다. 자료 분석은 정량적 분석이 가능할 경우 메타분석을 수행하고 불가능한 경우 질적 검토를 수행하였다. 본 평가는 소위원회의 검토의견을 고려하여 의료기술재평가위원회에서 최종심의 후 권고등급을 제시하였다.

평가 결과 체계적 문헌고찰을 수행한 결과, 핵심질문을 충족하는 14편의 문헌이 선정되었다. 5편에서 진단정확도 결과를, 7편에서 비교검사와의 상관성을, 4편에서 경과관찰 관련 연구결과를 보고하고 있었다.

안전성 MMP-9 간이검사의 안전성 결과를 보고하고 있는 문헌은 없었으나 체외진단법으로 안전한 의료기술로 보았다.

효과성 건성안 진단을 위한 MMP-9 간이검사의 진단정확도는 5편의 문헌에서 확인되었으며, 메타분석 결과 통합민감도 0.71 (95% CI 0.55, 0.84), 통합특이도 0.96 (95% CI 0.92, 0.98), 통합AUC (area under the curve) 0.96 (95% CI 0.94, 0.97)으로 나타났다. MMP-9 간이검사의 상관관계를 보고하고 있는 7편의 문헌이 확인되었다. 건성안 의심 및 환자에서 MMP-9 간이검사와 다른 검사와의 상관계수(r)는 안구표면질환지수(OSDI)와 0.012~0.284, 삼투압 농도(Osmolarity)와 0.121~0.4, 눈물막파괴시간(TBUT)과 –0.125~0.085, 각막 염색점수(Corneal staining score)와 0.113~0.37, 결막 염색점수(Conjunctival staining score)와 0.06~0.225, 쉬르머(Schirmer) 검사와 –0.019~0.145, 눈물띠(Tear meniscus)관련 지표와 0.216~0.243 범위 내에서 확인되었으며, MMP-9 ELISA와는 0.79로 나타났다. MMP-9 간이검사를 이용하여 질병(건성안)의 경과를 관찰하고 있는 연구는 확인되지 않았으나, 해당 검사결과를 바탕으로 (약물의) 치료반응을 평가하고 있는 4편의 문헌이 확인되었다. 건성안 환자의 치료 후 MMP-9는 유의하게 감소하였고, 특히 치료 전 MMP-9 양성군에서 음성군보다 유의미하게 더 개선되는 것으로 나타나 해당 검사가 치료반응을 예측할 수 있는 것으로 보았다.

결론 및 제언 해당 소위원회는 현재 평가결과에 근거하여 다음과 같이 제언하였다. MMP-9(편측)[일반면역검사]-간이검사는 체외진단법으로 안전한 의료기술이며, 건성안의 진단 보조 검사로 사용하기에 진단정확도는 유효한 수준이었다. 다른 검사와 일대일로 비교한 상관계수는 다소 낮게 나타났으나 이는 건성안이 단독 검사로 진단될 수 없는 것에 기인한 제한적인 결과이며, ELISA와의 상관관계는 높은 수준으로 나타나 분석적 성능에도 문제가 없는 것으로 확인되었다. 해당 검사를 이용하여 질병(건성안)의 경과를 확인한 근거는 확인되지 않았으나, 일부 연구에서 해당 검사결과가 (약물의) 치료반응을 예측하는 역할을 하는 것으로 나타났다. 2022년 제5차 의료기술재평가위원회(2022.5.13.)에서는 소위원회 검토 결과에 근거하여 MMP-9(편측) [일반면역검사]-간이검사에 대해 다음과 같이 심의하였다. 의료기술재평가위원회는 MMP-9(편측)[일반면역검사]-간이검사를 건성안의 임상적 진단 보조 및 경과관찰을 목적으로 ‘조건부 권고함’으로 심의하였다.

주요어 건성안, 안구건조증, MMP-간이검사, 진단정확도

Background MMP-9(unilateral)[Routine Immunoassay Test]-Point-of-Care Test is a test method for the purpose of providing assistance to clinical diagnosis and monitoring/observation of a dry eye (DE) by measuring MMP-9 levels in tears. In the case of South Korea, following New Health Technology Assessment, the technology was listed as a selective benefit item with out-of-pocket coverage at 80%, and it has been used in clinical practice to date. This health technology was identified through internal monitoring and its adequacy and necessity for reassessment was acknowledged through the process of clinical advisory meeting and priority review, and it was finally selected as a technology subject to health technology reassessment (HRT) at the 10th Health Technology Reassessment Committee (October 15, 2021) in 2021.

Methods In this assessment, a systematic review of the related literature was conducted for assessment of the safety and effectiveness of MMP-9(unilateral)[Routine Immunoassay Test]-Point-of-Care Test. All assessment methods were finalized after review by the MMP-9 (unilateral)[Routine Immunoassay Test]-Point-of-Care Test Sub-committee (Hereinafter Sub-committee) in consideration of the purpose of the assessment. The key question of the assessment was “Is MMP-9(unilateral)[Routine Immunoassay Test]-Point-of-Care Test safe and effective for use for the purpose of providing assistance to clinical diagnosis and monitoring/observation for adults with suspected dry eye syndrome (DES) and patients with DES?” In the process of systematic review, three international and five domestic databases were used for literature search and the articles were selected based on independent screening by two reviewers according to the inclusion/exclusion criteria for the related literature. For studies evaluating diagnostic testing methods, a tool of Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) was used to perform assessment of risk of bias. For data extraction, a predefined format was used and this was also performed independently by two reviewers. In case of disagreement, the two reviewers held discussions with a third party to draw consensus on the matter. For data analysis, meta-analysis was performed if quantitative analysis was possible, and qualitative review was conducted otherwise. In this assessment, considering the results of the review by the Sub-committee, Health Technology Reassessment Committee carried out the final review to present the Grade of Recommendation for the technology.

Results As a result of systematic review, fourteen articles satisfying the key question were selected. Five articles reported the results of diagnostic accuracy, seven articles reported correlations with comparative tests, and four articles reported results of studies related to follow-up monitoring/observations.

Safety There was no literature reporting the safety outcomes of the MMP-9 Point-of-Care Test, but the method was considered as a safe health technology since it is in vitro diagnostics.

Effectiveness The diagnostic accuracy of MMP-9 Point-of-Care Test for diagnosis of dry eye syndrome (DES) was reported in five articles. As a result of meta-analysis, pooled sensitivity was 0.71 (95% CI 0.55, 0.84), pooled specificity was 0.96 (95% CI 0.92, 0.98), and pooled AUC (area under the curve) was 0.96 (95% CI 0.94, 0.97). Seven articles reporting the correlation between the MMP-9 Point-of-Care Test with other test methods were identified from the literature review. The correlation coefficient (r) between the MMP-9 Point-of-Care Test and other tests in individuals with suspected DES/patients with DES was as follows: 0.012-0.284 with Ocular Surface Disease Index (OSDI), 0.121-0.4 for osmolarity, –0.125 to 0.085 with Tear Breakup Time (TBUT), 0.113-0.37 with corneal staining score and 0.06-0.225 with conjunctival staining score, -0.019 to 0.145 with Schirmer's test, 0.216-0.243 with tear meniscus related index and 0.79 with MMP-9 ELISA. There were no studies on follow-up monitoring/observation of the course of the disease (DES) using the MMP-9 Point-of-Care Test, but four articles were identified that evaluated the treatment response (pharmacological) based on the test results. After treatment of DES patients, MMP-9 showed a significant decrease, and in particular, the decrease was more significant in the MMP-9 positive group before treatment than in the MMP-9 negative group, indicating that the test is capable of predicting the treatment response.

Conclusion and Suggestions The Sub-committee made the following suggestions based on the results of the present assessment. MMP-9(unilateral)[Routine Immunoassay Test]-Point-of-Care Test is a safe health technology as in vitro diagnostics, and its diagnostic accuracy was effective for use to provide assistance in clinical diagnosis of DES. A one-to-one correlation with other tests was found to be rather low, but it is considered that this low correlation was caused by the fact that DES cannot be used as a single test method for diagnosis. Since the correlation with ELISA was high, it was confirmed that there was no problem in analytical performance of the test method. Although the evidence that reported the course of the disease (DES) using the test has not been confirmed, some studies have shown that the results of the test can be used for prediction of the treatment response (pharmacological). Based on the results of the review by the Sub-committee, at the 5th Health Technology Reassessment Committee (May 13, 2022) in 2022, the following was determined for MMP-9 (unilateral) [Routine Immunoassay Test]-Point-of-Care Test through the final review. The Health Technology Reassessment Committee determined the Grade of Recommendation of MMP-9(unilateral)[Routine Immunoassay Test]-Point-of-Care Test as “Conditional Recommendation” for the purpose of providing assistance to clinical diagnosis and monitoring/observation of DES.

Keywords: Dry Eye Syndromes, MMP-9, InflammaDry, Diagnostic Accuracy