INTRODUCTION

Ankylosing spondylitis (AS) is a chronic, immune-mediated arthritis that primarily affects the spine and sacroiliac joints. Inflammation of the sacroiliac joints is a hallmark feature of the disease, and grade ≥ 2 radiological sacroiliitis on both sides or unilateral grade ≥ 3 radiological sacroiliitis are the criteria (per the modified New York criteria)for the diagnosis of AS[1] and comprise some of the criteria required for a diagnosis of spondyloarthropathy (SpA)[2]. A strong association between the human leukocyte antigen (HLA) B27 allele and AS was discovered in the early 1970s[3]. AS is also known to run strongly within families, and HLA B27 positivity was observed to be higher in familial AS patients than in their sporadic AS counterparts[4]. According to Jung[5], the proportion of HLA B27 positivity among Korean AS patients was 80%, and in a Korean population study, the HLA B27 positivity rate in Korean AS patients was 83.3% compared to a rate of 4.0% in healthy controls[6].

The HLA B51 antigen is a well-known genetic factor associated with Beh?et’s disease (BD)[7]. In countries such as Korea and Japan where conventional polymerase chain reaction (PCR) for HLA genotyping is available for antigens such as HLA B27 or HLA B51, it is common to perform the HLA B27 test for the evaluation of AS and HLA B51 testing for BD. Interestingly, two cases of Reiter’s syndrome associated with HLA B51 have been reported[8,9] and the possibility of HLA B51-related arthropathy in individuals with HLA B27-negative reactive arthritis or seronegative SpA has also been proposed[10,11]. To date, there have been no reports of familial AS occurrence related to HLA B51. Here, we report the first cases of HLA B51-related AS in a family and the impact of HLA B51 positivity on sacroiliitis.

CASE PRESENTATION

Chief complaints

Case 1: In 2018, an 82-year-old man visited our clinic with the chief complaint of inflammatory low back pain.

Case 2: In 2020, the eldest daughter of the patient described in case 1 visited the clinic.She was 56 years old and complained of back pain, which had started 3 years previously and worsened as she woke up in the morning.

History of present illness

Case 1: He had previously been diagnosed with AS at another hospital. He did not complain of any additional pain in the Achilles tendon or the peripheral joints. He did not have abdominal pain or diarrhea suggestive of inflammatory bowel disease. He also did not have any symptoms of BD, such as oral or genital ulcers.

昨天下午，我正在教室里給學(xué)生上作文課，忽然就感覺講臺上光線一暗，李老黑堵在了教室門口。他像半截黑塔一樣，把秋天明媚的陽光一下子攔截在了門外。李老黑先是表情威嚴(yán)地掃視了一遍學(xué)生，接著掃視了一眼黑板。幾十雙眼睛齊刷刷地望著李老黑，好一陣教室里只剩下了喘氣的聲音。李老黑巡視完以后，用食指對著我勾了勾，我就碎著小步跟在他的大屁股后面走了出去。

3）教學(xué)系統(tǒng)中的相關(guān)產(chǎn)品和實驗設(shè)備是由專業(yè)軟件根據(jù)產(chǎn)品和設(shè)備的相關(guān)參數(shù)通過計算機三維建模形成的，這種虛擬產(chǎn)品或設(shè)備可以在很大程度上提高學(xué)生在工程技術(shù)實踐環(huán)節(jié)的認(rèn)知程度，減少實際實驗設(shè)備的通入與管理空間，節(jié)約資金，改善了實驗條件。

History of past illness

Case 1: There is no personal and family history.

Case 2: She had no previous medical history.

Personal and family history

Case 1: He was suffering from interstitial lung disease.

Case 2: The patient was the first of five daughters of the patient in case 1.

Physical examination

Case 1: The patient’s blood pressure was 126/27 mmHg, pulse rate was 79 beats/min,and respiratory rate was 24 breaths/min at the time of presentation. The body temperature was within the normal range. No abnormal skin lesions were observed on the body. The Schober’s test showed a positive test result of 1 cm, and the distance between the occiput and wall was 10 cm. Chest wall expansion test could not be performed because of dyspnea related to interstitial lung disease. Ophthalmologic examination revealed no evidence of iridocyclitis.

Case 2: Her blood pressure was 98/52 mmHg, pulse rate was 70 beats/minute, and respiratory rate was 20 breaths/min at the time of presentation. Her body temperature was within the normal range. No abnormal skin lesions were found, and no heart murmur was heard. Schober’s test showed a positive result of 2.5 cm. The distance between the occiput and wall and the chest wall expansion test were within normal limits.

Laboratory examinations

Case 1: Laboratory tests showed a white blood cell count of 10190/μL, C-reactive protein (CRP) of 14.3 mg/L (0-5), erythrocyte sedimentation rate (ESR) of 52 mm/h (1-15) and positive antinuclear antibodies with a titer of 1:640. The tests for extractable nuclear antigen antibodies were negative. Rheumatoid factors were not observed. The patient tested negative for HLA B27 and positive for HLA B51, using conventional PCR. With help from the laboratory department, simple HLA genotyping was performed, which further confirmed the presence of HLA B51.

Case 2: Laboratory tests showed a white blood cell count of 5950/μL, CRP of 0.4 mg/L(0-5), and ESR of 14 mm/h (1-15). Neither rheumatoid factor nor anti-nuclear antibodies were present. She tested negative for HLA B27 and was positive for HLA B51, using conventional PCR.

Imaging examinations

Case 1: Radiographic imaging of the sacroiliac joints revealed complete ankyloses, and his spine exhibited a “bamboo” appearance (Figures 1A and 1B). Transthoracic echocardiography revealed a sclerotic mitral and aortic valve.

4.內(nèi)部運作管理體系建立、落實。建筑施工企業(yè)需針對自身實際情況，制定EPC業(yè)務(wù)流程，加強內(nèi)部管控，保障企業(yè)歸口協(xié)調(diào)管理部門或分、子公司與其他業(yè)務(wù)板塊相互支撐、緊密協(xié)作；建立績效管理機制，細(xì)化指標(biāo)，進行有效的指引和約束、激勵。

Case 2: Radiographic imaging of the sacroiliac joints revealed multiple definite erosions with sclerotic changes compatible with grade III bilateral sacroiliitis(Figure 1C). Magnetic resonance imaging of her spine revealed fat deposition at the corners of the vertebral bodies, suggesting changes caused by AS (Figure 1D).

FINAL DIAGNOSIS

Case 1

The final diagnosis in this case was AS. Laboratory findings of leukocytosis and high levels of inflammatory markers were thought to be caused by interstitial lung disease,as the patient did not complain much about back pain and no other symptoms of AS were reported.

Case 2

The final diagnosis of the presented case was AS.

TREATMENT

Case 1

Three daughters, including the patient in case 2 and the youngest daughter, tested positive for HLA B51, and two other daughters were negative for HLA B51. None of the patients tested positive for HLA B27.

Case 2: She did not complain of any other pain in the Achilles tendon or peripheral joints. She did not have abdominal pain or diarrhea suggestive of inflammatory bowel disease. She did not have any symptoms of BD, such as oral or genital ulcers. She did not have any symptoms related to the eyes.

Case 2

The patient was prescribed NSAIDs.

中國典籍不僅是我國傳文學(xué)的主要組成部分，更是中國傳統(tǒng)文化精髓的主要構(gòu)成因素。因此，在對《孟子》一書的翻譯中，必須要注重其英譯本中的創(chuàng)造性叛逆因素，充分利用異化譯法，在翻譯中著重表達出語言及文化背景方面的差異。因此，由于譯者處于不同的語言環(huán)境中，有意或無意的會造成詞匯信息的遺漏或增減或是過度修飾，導(dǎo)致譯本失真，而這也是出現(xiàn)越來越多風(fēng)格迥異的翻譯流派的主要原因。而節(jié)譯與誤譯同屬于創(chuàng)造性叛逆，這里所說的誤譯并非胡亂翻譯所造成的錯誤，而是指有意地誤譯；節(jié)譯時在考慮了原作語言的復(fù)雜性與難譯程度，以及不同語言習(xí)慣、不同的宗教目的等因素，而被迫選擇的一種翻譯技巧。

OUTCOME AND FOLLOW-UP

Case 1

The patient reported that his back pain was under control at the 2 mo follow up. In addition, he complained of dyspnea, and 2 years after the diagnosis of AS in our hospital, the patient passed away due to worsening of interstitial lung disease.

Case 2

She reported that her back pain was under control at 2 mo follow up.

Family of cases 1 and 2

The father (case 1) had five daughters, including the first daughter (case 2) who was previously diagnosed with AS. The family was concerned about the possibility of familial inheritance of AS, and all five daughters agreed to undergo full HLA-B genotyping and computed tomography (CT) of the sacroiliac joint(s) to assess the possibility of AS. HLA-B genotyping was performed using a commercially available polymerase chain reaction sequencing-based kit (AlleleSEQR HLA-B Sequencing Kit,Genome Diagnostics B. V., Utrecht, The Netherlands) for experimental purposes. This study was approved by the Institutional Review Board of Inha University Hospital(Incheon, Korea; IRB 2020-03-003), and written informed consent was obtained from all participants.

但是與往年同期相比，復(fù)合肥原材料價格均有10%-20%的增長。對此，劉真表示，這主要是因為受到環(huán)保壓力及行業(yè)去產(chǎn)能等因素的影響，制約了上游企業(yè)的開工率及產(chǎn)量，從而抬升了相關(guān)產(chǎn)品的價格。

Symptoms

None of the daughters reported signs or symptoms of oral ulcers or genital ulcers, and only the youngest daughter complained of inflammatory back pain. No abnormal skin lesions were observed.

Laboratory examinations

The patient was prescribed non-steroidal anti-inflammatory drugs (NSAIDs).

Imaging examinations

A radiologist who was blinded to patient information interpreted the images. Three daughters had the HLA B51:01 allele, among whom only the eldest daughter (case 2)was diagnosed with AS. However, the other two daughters, including the youngest daughter, were found to exhibit grade 1 sacroiliitis, upon performing pelvic bone CT[(Figures 2A and 2B for 4daughter) and (Figures 2C and 2D for the youngest daughter)]. Two daughters without the HLA B51:01 allele did not exhibit sacroiliitis.The family pedigree is shown in Figure 3.

DISCUSSION

To the best of our knowledge, this is the first report to describe the occurrence of HLA B51-related AS in a family. Three of the five daughters had the HLA B51:01 allele and developed either AS or clinical sacroiliitis; however, the daughters without the HLA B51:01 allele did not exhibit any clinical signs or symptoms of SpA. Low-grade sacroiliitis is indicative of early AS in patients with undifferentiated SpA[12]. Thus, the high prevalence of HLA B51:01 in the daughters with sacroiliitis suggests a strong association of HLA B51 with AS/SpA in the family. It was also interesting to observe that no one in the family manifested clinical symptoms of BD, although the association between HLA B51 and BD is known to be strong.

The clinical significance of HLA B51 related familial AS familial is that this family is from Korea, where HLA B51 is highly prevalent. A previous case control study performed in Korea showed that the preva-lence of HLA B51 positivity in patients with BD was reported to be 55.7%, compared to 15.7% in healthy controls[13]. The prevalence of HLA B51 in BD has been reported to be higher in countries adjacent to the ancient Silk Road, which include Turkey, Iraq, China, Japan, and Korea. In accordance with Korean data, the positivity of HLA B51 in Han Chinese was 55.83% in BD patients and 12% in controls[14], and in Japan it was 59.4% in BD patients and 13.6% in controls[15]. The HLA B51 in the family seemed to be inherited from the father (case 1), and three out of five daughters were positive for HLA B51. The wife of the patient in case 1 passed away years before this study, and HLA genotyping could not be performed. We assumed that she would be positive for HLA B40 and HLA B58 because of occurrence of homogenous HLA B40 and HLA B58 among daughters. All HLA B51 positive daughters had sacroiliitis. Thus, in regions where HLA B51 is prevalent, it could play a role in the development of HLA B27-negative reactive arthritis or seronegative SpA[9,10].

Second, unlike in previous studies, sacroiliitis was observed in most of the daughters (three of five) in this family. There are conflicting reports regarding the prevalence of sacroiliitis in patients with BD. Chang[7] reported that sacroiliitis was diagnosed in 58.9% of SpA patients, 10.3% of those with BD , and 3.6% of healthy controls. Olivieri[16] conducted a similar study using CT scans and reported sacroiliitis in 30% of BD patients and 5% of controls. The difference in the prevalence of sacroiliitis between patients with BD and controls was clinically significant in both the aforementioned studies[7,16]. However, another study showed contrasting results with the prevalence of sacroiliitis seen in 7.4% of individuals with BD and 8% of the control group[17]. Kotevoglu[18] conducted a study using CT and found sacroiliitis in 5% of patients with BD and in 7% of healthy controls. In this family,sacroiliitis was found in 60% of all daughters who exhibited no clinical features of BD.Thus, the high prevalence of sacroiliitis in this family should be interpreted in the context of SpA and not a clinical feature of BD.

Lastly, all family members with sacroiliitis, tested positive for HLA B51 and negative for HLA B27. There are studies about HLA B51 and HLA B27 in SpA, and HLA B27 remains the major factor in AS. In two studies, Chang[7] reported that the majority of SpA patients (67.9%) were HLA B27 positive, whereas the prevalence of HLA B51 positivity was only 21.4% in those with SpA. Similarly, a study by Jung[5] reported that 106 of 153 patients with AS were HLA B27 positive/HLA B51 negative, whereas eight were HLA B51 positive/HLA B2-negative, and 16 patients were both HLA B27 and HLA B51 positive. In clinical practice, HLA typing is usually carried out for determining the presence of HLA B27 for the evaluation of AS, and HLA B51 for the evaluation of BD. If a patient suspected of having SpA, is negative for HLA B27, additional testing of HLA B51 could help facilitate the diagnosis of SpA even if the patient does not have the clinical features of BD.

(2)電解過程中,由于電場作用和離子交換膜限制,陽極室的H+穿過陽膜擴散至產(chǎn)品室,原料室的穿過陰膜擴散至產(chǎn)品室,H+和H2PO-2在產(chǎn)品室反應(yīng)生成H3PO2

圖4顯示的是工況三時滿載地鐵車廂截面半個周期的風(fēng)速分布云圖，該云圖與圖3無太大區(qū)別，最大風(fēng)速位置出現(xiàn)在幅流風(fēng)機出風(fēng)口，約為2.8 m/s，截面平均風(fēng)速為0.51 m/s，符合人體舒適性要求。

A genome-wide association study of AS, which used “immunochip” technology,reported that the presence of the HLA B51:01 allele was associated with an increased risk of AS[3]. In addition, AS is strongly associated with the presence of specific amino acids at position 97 in HLA-B, and position 97 is associated with the cell surface expression of HLA B51[19]. Therefore, in accordance with the present case report,HLA B51 could also potentially contribute to the development of AS.

CONCLUSION

This is the first report of familial inheritance of HLA B27-negative AS and HLA B51 positivity associated with either mild or definite radiological sacroiliitis. No patient in the family exhibited any signs or symptoms of BD. Therefore, it is advisable to check for HLA B51 positivity in patients with HLA B27-negative AS or SpA, even in the absence of clinical signs of BD.

All authors are grateful to the family described in this case series for their participation.