Anti-nuclear antibody and enthesitis were frequently detected in female patients with undifferentiated peripheral spondyloarthritis in Japan

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Peripheral lesions of SpA are more common in women than in men. Compared with reports on psoriatic arthritis (PsA), while reports on patients meeting the criteria for peripheral SpA or patients with undifferentiated peripheral SpA (upSpA) are scarce. This study aimed to elucidate the detailed manifestations of upSpA and the sex differences in situations of low human leukocyte antigen B27 positivity. Methods This multi-center observational study was conducted between April 2020 and June 2024. Among 38 patients with SpA, participants with concomitant inflammatory bowel diseases or meeting with either axial SpA, PsA or reactive arthritis (ReA) criteria were excluded. We collected physical findings and laboratory data on 29 cases of upSpA (19 women and 10 men; mean age [standard deviation]: 41.6 years [16.3] vs. 60.2 years [11.2]). We primarily analyzed the data to examine the relationship between sex and clinical findings. Results The rate of tenderness of the epicondyles of humerus were 79.0% in women and 40.0% in men (p = 0.047). The prevalence rate of tenderness of the Achilles tendon was 52.6% in women and 10.0% in men (p = 0.029). These areas in the women had a higher prevalence rate of enthesitis than those in men. Serum C-reactive protein (CRP) positivity in women (21.1%) were lower than in men (80.0%) (p = 0.004). The positive rate of anti-nuclear antibody, which was defined at a dilution of ≥ 1:160, was higher in women (47.4%) than in men (0%) (p = 0.009). Conclusion Women with upSpA frequently experience enthesitis of the epicondyles of humerus and the Achilles tendon, as well as a lower serum CRP positivity and a higher incidence of positive anti-nuclear antibody, compared to men, in Japan. Undifferentiated peripheral spondyloarthritis Female Male Enthesitis Anti-nuclear antibody Figures Figure 1 Figure 2 Figure 3 Figure 4 Background Spondyloarthritis (SpA) is an inflammatory disease of the axial skeleton characterized by severe pain and functional impairments causing disruptions daily activities. SpA includes ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and inflammatory bowel disease-associated arthritis [1, 2]. Patients with SpA often exhibit peripheral arthritis, which can be self-limiting and is predominant in the lower extremities [3], enthesitis [4], dactylitis [5], inflammatory eye disease, typically associated with anterior uveitis and human leukocyte antigen B27 (HLA-B27) [4], bowel mucosal inflammation [6, 7], and psoriasis. Enthesitis is one of the representative hallmarks of SpA. Peripheral enthesitis spreads to most body parts, with a prevalence of 20–45% in each affected site [8]. In 2009 and 2011, the Assessment of SpondyloArthritis international Society (ASAS) established two classification criteria for SpA, including axial SpA (axSpA) and peripheral SpA (pSpA), so physicians can distinguish between axSpA and pSpA [9, 10]. Moreover, patients fullfiled with ASAS pSpA criteria who do not meet with ClASsification for Psoriatic ARthritis (CASPAR) criteria for PsA [11], reactive arthritis criteria [12] or do not concomitant with inflammatory bowel diseases are often defined as undifferentiated peripheral SpA (upSpA). The clinical features of patients with SpA differs between women and men [13]. In axial lesions of SpA, female cases tend to have lesser radiographic damage in the sacroiliac joint and the spine compared to males [13]. Peripheral lesions of SpA, such as the tender joint and enthesitis scores, also differ between women and men. These peripheral manifestations are more frequent in female cases than in males, in contrast with axial lesions [14]. The mean interval of delay in SpA diagnosis reportedly showed sex-related differences (8.8 years for women and 6.5 years for men) [15]. Therefore, female patients with SpA are often classified as having pSpA, and the diagnosis could be challenging for physicians. To our knowledge, reports on non-psoriatic pSpA and upSpA are scarce. Sex differences also influence treatment responses to SpA. Female sex is associated with a lower response rate to treatment using anti-tumor necrosis factor-α (TNF-α) drugs against axSpA [16, 17]. Post-hoc analyses of SPIRIT-P1 and SPIRIT-P2 trials, which investigated the activity of interleukin-17 (IL-17) antagonist ixekizumab against PsA, revealed that changes in the pain visual analog scale, patient global assessment, serum C-reactive protein (CRP) levels, and psoriasis area and severity index in female patients had smaller numeric improvements from baseline compared with those in male patients [18]. These data imply that biological manifestations of axSpA and pSpA differ between women and men. The survey of SpA needs to be focused on the region or country. In a study that established the ASAS pSpA classification criteria, almost only HLA-B27-positive cases had significant changes in radiographic and magnet resonance imaging (MRI) findings [10]. In the general Japanese population, the HLA-B27 positivity rate is as low as 0.25% [19]. Therefore, classifying pSpA is often challenging in Japan. Physicians must have more knowledge of the clinical manifestations of pSpA in situations of low HLA-B27 positivity to resolve this challenge. In this study, we collected and analyzed accumulated cases of pSpA in our hospitals, focusing on the relationship between sex and physical findings. To our knowledge, the positional distribution of enthesitis and its sex-related differences have seldom been reported. We also collected clinical laboratory data and compared the findings. Methods Study design This multi-center, observational study was conducted at Hiroshima University Hospital, JR Hiroshima Hospital, and Ichiyokai Harada Hospital in Japan between 2020 and 2024. This research was approved by the Ethical Committee for Epidemiology of Hiroshima University (approval numbers: E2020-2046-03, approval date: June 4, 2020 & June 13, 2024), and the requirement for written consent was waived according to their regulations. Inclusion/exclusion criteria and data collection We collected the patients’ background data, such as age, sex, medical histories, physical findings, and laboratory data, from medical records. Patients with histories of inflammatory back pain or multiple enthesitis were included. Exclusion criteria were: 1) patients who had already been treated with biologics or Janus kinase (JAK) inhibitors, 2) patients who met the ASAS axSpA criteria, 3) patients who meet the CASPAR criteria, 4) patients who meet the reactive arthritis criteria, 5) patients with concomitant inflammatory bowel diseases and 6) patients who did not meet the ASAS pSpA criteria [9, 10]. Subsequently, patients who met the ASAS pSpA criteria were defined as upSpA and analyzed in this study. Regarding medication history, cases treated with standard medications, except biologics and JAK inhibitors, such as non-steroidal anti-inflammatory drugs, were included. Laboratory data collected include: serum CRP, erythrocyte sedimentation rate (ESR), serum rheumatoid factor (RF) latex agglutination test, serum anti-cyclic citrullinated peptide (CCP) antibody, serum anti-nuclear antibody (ANA) detected with fluorescent antibody method, and presence of HLA-B27. Definition of cut-off values The cut-off value of serum CRP was set at 5 mg/L, according to previous report [20]. The cut-off value of ESR was 25 mm per hour. Serum RF values ≥ 15 IU/mL were considered positive, according to the rheumatoid arthritis (RA) classification criteria [21]. Serum anti-CCP antibody > 4.5 U/mL was considered positive. Serum ANA level was considered positive at a dilution of ≥ 1:160. Recording of physical findings Physical findings confirmed through physician interview and examination were analyzed. Regarding enthesitis, based on the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC EI) [22] and published reports about MRI on enthesitis [23, 24], data on the presence of tenderness as a presenting symptom were collected in the following seven areas: 1) acromioclavicular joints, including the acromions, 2) sternocostoclavicular joints, including the sternum, 3) clavicles, 4) medial and lateral epicondyles of the humerus, 5) patellar ligament insertion into the inferior pole of the patella or tibial tubercle, 6) Achilles tendon insertion into the calcaneum, and 7) soles or heels (plantar fascia or heel enthesitis). Cases with tenderness on either or both sides were considered positive. The acromioclavicular joint, acromion, and supraspinatus insertion are relatively close in the area around the acromion. The SPARCC EI includes the supraspinatus insertion as an evaluation item; however, in this study, it was described as the acromioclavicular joints because it is easy to detect from the body surface. Pain in the greater trochanter of the femur was not described because none of the patients complained of it. Regarding joint swelling confirmed by the physician's examination, the shoulder, elbow, wrist, metacarpophalangeal, proximal interphalangeal, distal interphalangeal, knee, ankle, and metatarsophalangeal joints were evaluated. The wrist joint included the radiocarpal, midcarpal, and distal radioulnar joints. The ankle joint included the taloclular, subtalar, and distal tibiofibular joints. Moreover, passive pain of the hip joint during motion, the presence of dactylitis, and current spinal pains in the cervical, thoracic, and sacroiliac joints were confirmed upon physicians’ examinations. Statistical analysis The significance of the differences between the two groups was determined using the Student's t-test or Mann–Whitney U test, with p < 0.05 defined as the level of significance. For the t-test, normality was assessed using the chi-square test for goodness-of-fit, while the homogeneity of variance was evaluated using Bartlett's test. Contingency table analyses were performed using Fisher's exact probability test. The data processing and analyzing were conducted using the GraphPad Prism 10 (GraphPad Software Inc., La Jolla, CA, USA). Results Baseline characteristics This study included 50 cases with histories of low back pain or multiple enthesitis. Twenty-one cases were excluded due to any of the following conditions: 1) prior treatment with biologics or JAK inhibitors, 2) meeting either the ASAS axSpA criteria, the CASPAR criteria or the reactive arthritis criteria, or 3) did not meet the ASAS pSpA criteria. Eventually, 19 women and 10 men met the upSpA criteria ( Figure 1 ). The average age of women and men with upSpA was 41.6 years (standard deviation (SD) 16.3) and 60.2 years (SD 11.2), respectively ( Table 1 ). Women had a lower age than men (p=0.003). The median disease duration was 2.0 years (interquartile range (IQR) 0.6–10.5) in women and 1.0 years (IQR 1.0–27.0) in men. HLA-B27 was tested only in patients who requested it. HLA-B27 was positive in only 1 of 20 patients. Distribution of peripheral enthesitis in patients with upSpA We investigated the seven tenderness areas described above to elucidate the distribution of peripheral enthesitis in patients with upSpA ( Table 1 ). The prevalence rate of epicondyles of the humerus was 79.0% in women and 40.0% in men (p=0.047). Achilles tendon was 52.6% in women and 10.0% in men (p=0.029). These two areas had a higher prevalence rate of enthesitis in women than in men. The prevalence rate of acromioclavicular joint tenderness was 68.4% in women and 30.0% in men (p=0.056). Sternocostoclavicular joint involvement was 31.6% in women and 0% in men (p=0.057). For clavicle, 26.3% was in women and 0% in men (p=0.098). Prevalences of enthesitis in these three areas had a higher tendency in women than in men. Differences in the patellar ligaments, soles, or heels were not detected. Overall, tenderness in multiple enthesitis areas was detected frequently in female patients with upSpA ( Figure 2 ). Distribution of swelling joint and other manifestations in patients with upSpA To investigate the distribution of peripheral joint swelling in upSpA patients, we also investigated the nine kinds of joints described above ( Table 1, Figure 3 ). Among these joints, knee joint swelling was the most frequently detected (42.1% of women and 40.0% of men). The prevalence rate of all parts of the joint swellings had no statistical difference between women and men. Moreover, the following five findings did not differ between the two groups: passive motion pain of hip joints, dactylitis, cervical vertebra pain, thoracic vertebra pain, and sacroiliac joint pain. Laboratory findings in patients with upSpA The CRP positivity rate was 21.1% in women and 80.0% in men. Serum CRP positivity and titers were lower in women than in men (p=0.004 and p=0.007, respectively) ( Table 1, Figure 4A ). The ESR positivity rate was 31.6% in women and 80.0% in men. ESR positivity and titers were lower in women than in men (p=0.017 and p=0.016, respectively) ( Table 1, Figure 4B ). The RF and anti-CCP antibody positivity rates were 42.1% and 21.1% in women and 50.0% and 10.0% in men, with no significant differences between the groups ( Table 1, Figure 4C&4D ). ANA was examined by indirect immunofluorescence. The positive rate, defined at a dilution of ≥1:160, was 47.4% in women and 0% in men. Therefore, the frequency of serum ANA was significantly higher in women than in men (p=0.009) ( Table 1 ). Discussion The differences in the clinical features of SpA in women and men are also indicated by the cytokine profile [13]. Serum IL-17A and TNF-α in male patients with ankylosing spondylitis were reportedly higher than those in female patients [13, 25]. This sex difference in the cytokine gap may influence the varying treatment response to SpA [16, 18]. Nevertheless, the clinical characteristics of joint and entheses lesions on upSpA, particularly with sex differences, have rarely been reported. In this study, we specifically analyzed the physical findings by dividing them into detailed affecting sites. Our study revealed a higher prevalence of tenderness in women at multiple sites in the pectoral girdle and more well-known sites, such as the Achilles tendon. We believe diagnosing upSpA in women is extremely difficult because axial lesions are milder compared to men, and HLA-B27 is negative in most cases in Japan. Our report showed that approximately 80% and 40% of female upSpA cases were negative for CRP and positive for RF, respectively. Therefore, physicians will find it difficult to differentiate pSpA from other diseases, such as fibromyalgia or RA. There are no reports comparing ANA in women and men with upSpA. Our data showed that only female upSpA cases had high ANA titers at ≥ 1:160. ANA is also frequently positive in collagen vascular diseases. For instance, some authors reported the prevalence of SpA-like symptoms and positivity of ANA in patients with primary Sjӧgren syndrome (pSS). Approximately 20% of pSS cases had inflammatory spine pain, and approximately 15% fulfilled the ASAS axSpA criteria. Furthermore, in patients with combined axSpA and pSS, approximately 85% were ANA-positive (at 1:160 or more), and approximately 95% were women [26]. In another group, approximately 25% of pSS cases had inflammatory back pain, and approximately 10% had radiographic sacroiliitis proven by X-ray or computed tomography [27]. In addition, one study reported that approximately 40% of female patients with SpA manifestation were ANA-positive, and approximately 30% met the European criteria for SS [28]. In the present study, we determined the prevalence of ANA in patients diagnosed with upSpA. As a result, approximately 50% of female upSpA cases were ANA-positive, whereas ANA was not detected in any male case. ANA positivity in female upSpA cases may be associated with poor treatment response. Anti-TNF-α therapy is often used as a treatment for both RA and SpA. A high ANA titer, at ≥ 1:160, before starting anti-TNF-α drugs in patients with RA, reportedly could predict a relatively poor clinical response [29]. Considering the possibility that female upSpA has immunological abnormalities similar to those of RA, measuring the ANA titer before starting treatment for female patients with upSpA may be beneficial for the prediction of therapeutic response. This study has some limitations. The men included were older than the women. Typical male cases with SpA were excluded because most male patients, whose age at onset was < 45 years old, had radiographic sacroiliitis changes and met the ASAS axSpA criteria. Furthermore, this study was conducted in Japan; therefore, the pre-test probability of HLA-B27 was extremely low. If this study is conducted outside Asia, the results may differ. In the future, more regions and sample sizes will be required to validate the results. Conclusions In conclusion, compared to men, women with upSpA are more likely to test positive for ANA (about 50%) and frequently experience multiple enthesitis including the epicondyles of humerus and the Achilles tendon. The positive rates of RF and CRP in women with upSpA were about 40% and 20%, respectively. Therefore, multiple enthesitis should be considered in suspected cases of SpA in women, even if blood tests are positive for ANA and RF or negative for CRP. Abbreviations ANA anti-nuclear antibody ASAS Assessment of SpondyloArthritis international Society axSpA axial spondyloarthritis CASPAR ClASsification for Psoriatic Arthritis CCP anti-cyclic citrullinated peptide CRP C-reactive protein ESR erythrocyte sedimentation rate HLA human leukocyte antigen IL interleukin IQR interquartile range JAK Janus kinase MRI magnet resonance imaging PsA psoriatic arthritis RA rheumatoid arthritis ReA reactive arthritis RF rheumatoid factor SD standard deviation SpA spondyloarthritis SPARCC EI Spondyloarthritis Research Consortium of Canada Enthesitis Index TNF tumor necrosis factor upSpA undifferentiated peripheral spondyloarthritis Declarations Ethics approval and consent to participate : This research was approved by the Ethical Committee for Epidemiology of Hiroshima University (approval numbers: E2020-2046-03, approval date: June 4, 2020 & June 13, 2024), and the requirement for written consent was waived according to their regulations. Consent for publication : All authors have read and approved the submission of this manuscript. Availability of data and materials : The data that support the findings of this study are available on request from the corresponding author SM. The data are not publicly available due to their containing information that could compromise the privacy of research participants. Competing interests : The authors declare no conflicts of interest. Funding : This study was supported by funding from JSPS KAKENHI (grant number 22K08599 to S Mokuda), Takeda Science Foundation to S Mokuda, Nakatomi Foundation to S Mokuda, Tsuchiya Memorial Medical Foundation to S Mokuda, and Rotary Club of Hiroshima to S Mokuda. Authors' contributions : SM, HK, KA collected the data; SM, HK, KA, MI, HW analyzed the data; SM, HW, TS, YY, SH planned and wrote the manuscript. All authors have read and agreed to the published version of the manuscript. Acknowledgements : None. References ．Zochling J, Brandt J, Braun J. 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A study of 13 cases. Joint Bone Spine. 2002;69:383-7. Yukawa N, Fujii T, Kondo-Ishikawa S, Yoshifuji H, Kawabata D, Nojima T, et al. Correlation of antinuclear antibody and anti-double-stranded DNA antibody with clinical response to infliximab in patients with rheumatoid arthritis: a retrospective clinical study. Arthritis Res Ther. 2011;13: R213. Table Table 1 is available in the Supplementary Files section Additional Declarations The authors declare no competing interests. Supplementary Files Table1.docx Cite Share Download PDF Status: Published Journal Publication published 03 Feb, 2025 Read the published version in Modern Rheumatology → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Watanabe","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Hirofumi","middleName":"","lastName":"Watanabe","suffix":""},{"id":340868356,"identity":"029f6cef-476d-4ba3-8afe-b307ef7d0443","order_by":5,"name":"Tomohiro Sugimoto","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Tomohiro","middleName":"","lastName":"Sugimoto","suffix":""},{"id":340868357,"identity":"75c4eaee-1e40-469e-bafc-259fd1a97be0","order_by":6,"name":"Yusuke Yoshida","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Yusuke","middleName":"","lastName":"Yoshida","suffix":""},{"id":340868358,"identity":"2f7dcb03-cf3f-4533-b8eb-cc3aca2236ee","order_by":7,"name":"Shintaro Hirata","email":"","orcid":"","institution":"","correspondingAuthor":false,"prefix":"","firstName":"Shintaro","middleName":"","lastName":"Hirata","suffix":""}],"badges":[],"createdAt":"2024-08-16 00:17:59","currentVersionCode":1,"declarations":{"humanSubjects":true,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":true,"humanSubjectConsent":true,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-4921637/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4921637/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1093/mr/roaf010","type":"published","date":"2025-02-04T00:00:00+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":62796978,"identity":"c7feea72-acb2-42ff-82a3-dfcea93afb8e","added_by":"auto","created_at":"2024-08-19 15:25:30","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":61987,"visible":true,"origin":"","legend":"\u003cp\u003eFlow diagram for inclusion and exclusion\u003c/p\u003e\n\u003cp\u003e* 7 cases had already been treated with either Infliximab, Adalimumab, Secukinumab or Upadacitinib.\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-4921637/v1/66cc0fda7d0ec5f3eef502eb.png"},{"id":62796438,"identity":"c993e723-ba39-4ab7-bab1-46af6eade9cf","added_by":"auto","created_at":"2024-08-19 15:17:30","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":57202,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of peripheral enthesitis with tenderness\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-4921637/v1/ab0ec9b989b53176900a90c1.png"},{"id":62796977,"identity":"ec91ffa6-6aae-4de8-85a5-d64f60a6d939","added_by":"auto","created_at":"2024-08-19 15:25:30","extension":"png","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":54336,"visible":true,"origin":"","legend":"\u003cp\u003eDistribution of swelling joints\u003c/p\u003e","description":"","filename":"3.png","url":"https://assets-eu.researchsquare.com/files/rs-4921637/v1/c87c90f0ba65a0214b957893.png"},{"id":62796439,"identity":"1e284ebf-fb81-44b1-aba9-79c55224fe78","added_by":"auto","created_at":"2024-08-19 15:17:31","extension":"png","order_by":4,"title":"Figure 4","display":"","copyAsset":false,"role":"figure","size":78705,"visible":true,"origin":"","legend":"\u003cp\u003eLaboratory data comparing female and male patients\u003c/p\u003e\n\u003cp\u003e(A) C-reactive protein (CRP), (B) Erythrocyte sedimentation rate (ESR), (C) Rheumatoid factor (RF), (D) Anti-cyclic citrullinated peptide (CCP) antibody. The significance of the differences between two groups were determined using Mann–Whitney U test. The black line for each group represents the median.\u003c/p\u003e","description":"","filename":"4.png","url":"https://assets-eu.researchsquare.com/files/rs-4921637/v1/0864bf10541cbb9fe52f6b33.png"},{"id":75536077,"identity":"57ab132c-5b7d-4ab7-832e-50c82db4065c","added_by":"auto","created_at":"2025-02-05 14:55:32","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":908779,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4921637/v1/42121720-49fd-4613-b52d-6dc77fb0b733.pdf"},{"id":62796440,"identity":"e103ac58-f5aa-41b5-abe4-945896009214","added_by":"auto","created_at":"2024-08-19 15:17:31","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":41749,"visible":true,"origin":"","legend":"","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-4921637/v1/a3e9427edb3252458523ea6c.docx"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eAnti-nuclear antibody and enthesitis were frequently detected in female patients with undifferentiated peripheral spondyloarthritis in Japan\u003c/p\u003e","fulltext":[{"header":"Background","content":"\u003cp\u003eSpondyloarthritis (SpA) is an inflammatory disease of the axial skeleton characterized by severe pain and functional impairments causing disruptions daily activities. SpA includes ankylosing spondylitis, psoriatic arthritis, reactive arthritis, and inflammatory bowel disease-associated arthritis [1, 2]. Patients with SpA often exhibit peripheral arthritis, which can be self-limiting and is predominant in the lower extremities [3], enthesitis [4], dactylitis [5], inflammatory eye disease, typically associated with anterior uveitis and human leukocyte antigen B27 (HLA-B27) [4], bowel mucosal inflammation [6, 7], and psoriasis. Enthesitis is one of the representative hallmarks of SpA. Peripheral enthesitis spreads to most body parts, with a prevalence of 20\u0026ndash;45% in each affected site [8]. In 2009 and 2011, the Assessment of SpondyloArthritis international Society (ASAS) established two classification criteria for SpA, including axial SpA (axSpA) and peripheral SpA (pSpA), so physicians can distinguish between axSpA and pSpA [9, 10]. Moreover, patients fullfiled with ASAS pSpA criteria who do not meet with ClASsification for Psoriatic ARthritis (CASPAR) criteria for PsA [11], reactive arthritis criteria [12] or do not concomitant with inflammatory bowel diseases are often defined as undifferentiated peripheral SpA (upSpA).\u003c/p\u003e \u003cp\u003eThe clinical features of patients with SpA differs between women and men [13]. In axial lesions of SpA, female cases tend to have lesser radiographic damage in the sacroiliac joint and the spine compared to males [13]. Peripheral lesions of SpA, such as the tender joint and enthesitis scores, also differ between women and men. These peripheral manifestations are more frequent in female cases than in males, in contrast with axial lesions [14]. The mean interval of delay in SpA diagnosis reportedly showed sex-related differences (8.8 years for women and 6.5 years for men) [15]. Therefore, female patients with SpA are often classified as having pSpA, and the diagnosis could be challenging for physicians. To our knowledge, reports on non-psoriatic pSpA and upSpA are scarce.\u003c/p\u003e \u003cp\u003eSex differences also influence treatment responses to SpA. Female sex is associated with a lower response rate to treatment using anti-tumor necrosis factor-α (TNF-α) drugs against axSpA [16, 17]. Post-hoc analyses of SPIRIT-P1 and SPIRIT-P2 trials, which investigated the activity of interleukin-17 (IL-17) antagonist ixekizumab against PsA, revealed that changes in the pain visual analog scale, patient global assessment, serum C-reactive protein (CRP) levels, and psoriasis area and severity index in female patients had smaller numeric improvements from baseline compared with those in male patients [18]. These data imply that biological manifestations of axSpA and pSpA differ between women and men.\u003c/p\u003e \u003cp\u003eThe survey of SpA needs to be focused on the region or country. In a study that established the ASAS pSpA classification criteria, almost only HLA-B27-positive cases had significant changes in radiographic and magnet resonance imaging (MRI) findings [10]. In the general Japanese population, the HLA-B27 positivity rate is as low as 0.25% [19]. Therefore, classifying pSpA is often challenging in Japan. Physicians must have more knowledge of the clinical manifestations of pSpA in situations of low HLA-B27 positivity to resolve this challenge.\u003c/p\u003e \u003cp\u003eIn this study, we collected and analyzed accumulated cases of pSpA in our hospitals, focusing on the relationship between sex and physical findings. To our knowledge, the positional distribution of enthesitis and its sex-related differences have seldom been reported. We also collected clinical laboratory data and compared the findings.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStudy design\u003c/h2\u003e \u003cp\u003eThis multi-center, observational study was conducted at Hiroshima University Hospital, JR Hiroshima Hospital, and Ichiyokai Harada Hospital in Japan between 2020 and 2024. This research was approved by the Ethical Committee for Epidemiology of Hiroshima University (approval numbers: E2020-2046-03, approval date: June 4, 2020 \u0026amp; June 13, 2024), and the requirement for written consent was waived according to their regulations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eInclusion/exclusion criteria and data collection\u003c/h2\u003e \u003cp\u003eWe collected the patients\u0026rsquo; background data, such as age, sex, medical histories, physical findings, and laboratory data, from medical records. Patients with histories of inflammatory back pain or multiple enthesitis were included. Exclusion criteria were: 1) patients who had already been treated with biologics or Janus kinase (JAK) inhibitors, 2) patients who met the ASAS axSpA criteria, 3) patients who meet the CASPAR criteria, 4) patients who meet the reactive arthritis criteria, 5) patients with concomitant inflammatory bowel diseases and 6) patients who did not meet the ASAS pSpA criteria [9, 10]. Subsequently, patients who met the ASAS pSpA criteria were defined as upSpA and analyzed in this study. Regarding medication history, cases treated with standard medications, except biologics and JAK inhibitors, such as non-steroidal anti-inflammatory drugs, were included. Laboratory data collected include: serum CRP, erythrocyte sedimentation rate (ESR), serum rheumatoid factor (RF) latex agglutination test, serum anti-cyclic citrullinated peptide (CCP) antibody, serum anti-nuclear antibody (ANA) detected with fluorescent antibody method, and presence of HLA-B27.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003eDefinition of cut-off values\u003c/h2\u003e \u003cp\u003eThe cut-off value of serum CRP was set at 5 mg/L, according to previous report [20]. The cut-off value of ESR was 25 mm per hour. Serum RF values\u0026thinsp;\u0026ge;\u0026thinsp;15 IU/mL were considered positive, according to the rheumatoid arthritis (RA) classification criteria [21]. Serum anti-CCP antibody\u0026thinsp;\u0026gt;\u0026thinsp;4.5 U/mL was considered positive. Serum ANA level was considered positive at a dilution of \u0026ge;\u0026thinsp;1:160.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003eRecording of physical findings\u003c/h2\u003e \u003cp\u003ePhysical findings confirmed through physician interview and examination were analyzed. Regarding enthesitis, based on the Spondyloarthritis Research Consortium of Canada Enthesitis Index (SPARCC EI) [22] and published reports about MRI on enthesitis [23, 24], data on the presence of tenderness as a presenting symptom were collected in the following seven areas: 1) acromioclavicular joints, including the acromions, 2) sternocostoclavicular joints, including the sternum, 3) clavicles, 4) medial and lateral epicondyles of the humerus, 5) patellar ligament insertion into the inferior pole of the patella or tibial tubercle, 6) Achilles tendon insertion into the calcaneum, and 7) soles or heels (plantar fascia or heel enthesitis). Cases with tenderness on either or both sides were considered positive. The acromioclavicular joint, acromion, and supraspinatus insertion are relatively close in the area around the acromion. The SPARCC EI includes the supraspinatus insertion as an evaluation item; however, in this study, it was described as the acromioclavicular joints because it is easy to detect from the body surface. Pain in the greater trochanter of the femur was not described because none of the patients complained of it. Regarding joint swelling confirmed by the physician's examination, the shoulder, elbow, wrist, metacarpophalangeal, proximal interphalangeal, distal interphalangeal, knee, ankle, and metatarsophalangeal joints were evaluated. The wrist joint included the radiocarpal, midcarpal, and distal radioulnar joints. The ankle joint included the taloclular, subtalar, and distal tibiofibular joints. Moreover, passive pain of the hip joint during motion, the presence of dactylitis, and current spinal pains in the cervical, thoracic, and sacroiliac joints were confirmed upon physicians\u0026rsquo; examinations.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis\u003c/h2\u003e \u003cp\u003eThe significance of the differences between the two groups was determined using the Student's t-test or Mann\u0026ndash;Whitney U test, with p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 defined as the level of significance. For the t-test, normality was assessed using the chi-square test for goodness-of-fit, while the homogeneity of variance was evaluated using Bartlett's test. Contingency table analyses were performed using Fisher's exact probability test. The data processing and analyzing were conducted using the GraphPad Prism 10 (GraphPad Software Inc., La Jolla, CA, USA).\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003eBaseline characteristics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis study included 50 cases with histories of low back pain or multiple enthesitis. Twenty-one cases were excluded due to any of the following conditions: 1) prior treatment with biologics or JAK inhibitors, 2) meeting either the ASAS axSpA criteria, the CASPAR criteria or the reactive arthritis criteria, or 3)\u0026nbsp;did not meet the ASAS pSpA criteria. Eventually, 19 women and 10 men met the upSpA criteria (\u003cstrong\u003eFigure 1\u003c/strong\u003e). The average age of women and men with upSpA was 41.6 years (standard deviation (SD) 16.3) and 60.2 years (SD 11.2), respectively (\u003cstrong\u003eTable 1\u003c/strong\u003e). Women had a lower age than men (p=0.003). The median disease duration was 2.0 years (interquartile range (IQR) 0.6–10.5) in women and 1.0 years (IQR 1.0–27.0) in men. HLA-B27 was tested only in patients who requested it. HLA-B27 was positive in only 1 of 20 patients.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDistribution of peripheral enthesitis in patients with upSpA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe investigated the seven tenderness areas described above to elucidate the distribution of peripheral enthesitis in patients with upSpA (\u003cstrong\u003eTable 1\u003c/strong\u003e). The prevalence rate of epicondyles of the humerus was 79.0% in women and 40.0% in men (p=0.047). Achilles tendon was 52.6% in women and 10.0% in men (p=0.029). These two areas had a higher prevalence rate of enthesitis in women than in men. The prevalence rate of acromioclavicular joint tenderness was 68.4% in women and 30.0% in men (p=0.056). Sternocostoclavicular joint involvement was 31.6% in women and 0% in men (p=0.057). For clavicle, 26.3% was in women and 0% in men (p=0.098).\u0026nbsp;Prevalences of enthesitis\u0026nbsp;in these three areas had a higher tendency in women than in men. Differences in\u0026nbsp;the patellar ligaments, soles, or heels were not detected. Overall, tenderness in multiple enthesitis areas was detected frequently in female patients with upSpA (\u003cstrong\u003eFigure 2\u003c/strong\u003e).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDistribution of swelling joint and other manifestations in patients with upSpA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTo investigate the distribution of peripheral joint swelling in upSpA patients, we also investigated the nine kinds of joints described above (\u003cstrong\u003eTable 1, Figure 3\u003c/strong\u003e). Among these joints, knee joint swelling was the most frequently detected (42.1% of women and 40.0% of men). The prevalence rate of all parts of the joint swellings had no statistical difference between women and men. Moreover, the following five findings did not differ between the two groups: passive motion pain of hip joints, dactylitis, cervical vertebra pain, thoracic vertebra pain, and sacroiliac joint pain.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eLaboratory findings in patients with upSpA\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe CRP positivity rate was 21.1% in women and 80.0% in men. Serum CRP positivity and titers were lower in women than in men (p=0.004 and p=0.007, respectively) (\u003cstrong\u003eTable 1, Figure 4A\u003c/strong\u003e). The ESR positivity rate was 31.6% in women and 80.0% in men. ESR positivity and titers were lower in women than in men (p=0.017 and p=0.016, respectively) (\u003cstrong\u003eTable 1, Figure 4B\u003c/strong\u003e). The RF and anti-CCP antibody positivity rates were 42.1% and 21.1% in women and 50.0% and 10.0% in men, with no significant differences between the groups (\u003cstrong\u003eTable 1, Figure 4C\u0026amp;4D\u003c/strong\u003e). ANA was examined by indirect immunofluorescence. The positive rate, defined at a dilution of ≥1:160, was 47.4% in women and 0% in men. Therefore, the frequency of serum ANA was significantly higher in women than in men (p=0.009) (\u003cstrong\u003eTable 1\u003c/strong\u003e).\u0026nbsp;\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThe differences in the clinical features of SpA in women and men are also indicated by the cytokine profile [13]. Serum IL-17A and TNF-α in male patients with ankylosing spondylitis were reportedly higher than those in female patients [13, 25]. This sex difference in the cytokine gap may influence the varying treatment response to SpA [16, 18]. Nevertheless, the clinical characteristics of joint and entheses lesions on upSpA, particularly with sex differences, have rarely been reported. In this study, we specifically analyzed the physical findings by dividing them into detailed affecting sites. Our study revealed a higher prevalence of tenderness in women at multiple sites in the pectoral girdle and more well-known sites, such as the Achilles tendon. We believe diagnosing upSpA in women is extremely difficult because axial lesions are milder compared to men, and HLA-B27 is negative in most cases in Japan. Our report showed that approximately 80% and 40% of female upSpA cases were negative for CRP and positive for RF, respectively. Therefore, physicians will find it difficult to differentiate pSpA from other diseases, such as fibromyalgia or RA.\u003c/p\u003e \u003cp\u003eThere are no reports comparing ANA in women and men with upSpA. Our data showed that only female upSpA cases had high ANA titers at \u0026ge;\u0026thinsp;1:160. ANA is also frequently positive in collagen vascular diseases. For instance, some authors reported the prevalence of SpA-like symptoms and positivity of ANA in patients with primary Sjӧgren syndrome (pSS). Approximately 20% of pSS cases had inflammatory spine pain, and approximately 15% fulfilled the ASAS axSpA criteria. Furthermore, in patients with combined axSpA and pSS, approximately 85% were ANA-positive (at 1:160 or more), and approximately 95% were women [26]. In another group, approximately 25% of pSS cases had inflammatory back pain, and approximately 10% had radiographic sacroiliitis proven by X-ray or computed tomography [27]. In addition, one study reported that approximately 40% of female patients with SpA manifestation were ANA-positive, and approximately 30% met the European criteria for SS [28]. In the present study, we determined the prevalence of ANA in patients diagnosed with upSpA. As a result, approximately 50% of female upSpA cases were ANA-positive, whereas ANA was not detected in any male case.\u003c/p\u003e \u003cp\u003eANA positivity in female upSpA cases may be associated with poor treatment response. Anti-TNF-α therapy is often used as a treatment for both RA and SpA. A high ANA titer, at \u0026ge;\u0026thinsp;1:160, before starting anti-TNF-α drugs in patients with RA, reportedly could predict a relatively poor clinical response [29]. Considering the possibility that female upSpA has immunological abnormalities similar to those of RA, measuring the ANA titer before starting treatment for female patients with upSpA may be beneficial for the prediction of therapeutic response.\u003c/p\u003e \u003cp\u003eThis study has some limitations. The men included were older than the women. Typical male cases with SpA were excluded because most male patients, whose age at onset was \u0026lt;\u0026thinsp;45 years old, had radiographic sacroiliitis changes and met the ASAS axSpA criteria. Furthermore, this study was conducted in Japan; therefore, the pre-test probability of HLA-B27 was extremely low. If this study is conducted outside Asia, the results may differ. In the future, more regions and sample sizes will be required to validate the results.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eIn conclusion, compared to men, women with upSpA are more likely to test positive for ANA (about 50%) and frequently experience multiple enthesitis including the epicondyles of humerus and the Achilles tendon. The positive rates of RF and CRP in women with upSpA were about 40% and 20%, respectively. Therefore, multiple enthesitis should be considered in suspected cases of SpA in women, even if blood tests are positive for ANA and RF or negative for CRP.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cdiv class=\"DefinitionList\"\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eANA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eanti-nuclear antibody\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eASAS\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eAssessment of SpondyloArthritis international Society\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eaxSpA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eaxial spondyloarthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCASPAR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eClASsification for Psoriatic Arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCCP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eanti-cyclic citrullinated peptide\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eCRP\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eC-reactive protein\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eESR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eerythrocyte sedimentation rate\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eHLA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ehuman leukocyte antigen\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIL\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterleukin\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eIQR\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003einterquartile range\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eJAK\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eJanus kinase\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eMRI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003emagnet resonance imaging\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003ePsA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003epsoriatic arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erheumatoid arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eReA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003ereactive arthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eRF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003erheumatoid factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSD\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003estandard deviation\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSpA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003espondyloarthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eSPARCC EI\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eSpondyloarthritis Research Consortium of Canada Enthesitis Index\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eTNF\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003etumor necrosis factor\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003cdiv class=\"DefinitionListEntry\"\u003e \u003cdiv class=\"Term\"\u003eupSpA\u003c/div\u003e \u003cdiv class=\"Description\"\u003e \u003cp\u003eundifferentiated peripheral spondyloarthritis\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e: This research was approved by the Ethical Committee for Epidemiology of Hiroshima University (approval numbers: E2020-2046-03, approval date: June 4, 2020 \u0026amp; June 13, 2024), and the requirement for written consent was waived according to their regulations.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e: All authors have read and approved the submission of this manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e: The data that support the findings of this study are available on request from the corresponding author SM. The data are not publicly available due to their containing information that could compromise the privacy of research participants.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e: The authors declare no conflicts of interest.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e: This study was supported by funding from JSPS KAKENHI (grant number 22K08599 to S Mokuda), Takeda Science Foundation to S Mokuda, Nakatomi Foundation to S Mokuda, Tsuchiya Memorial Medical Foundation to S Mokuda, and Rotary Club of Hiroshima to S Mokuda.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors' contributions\u003c/strong\u003e: SM, HK, KA collected the data; SM, HK, KA, MI, HW analyzed the data; SM, HW, TS, YY, SH planned and wrote the manuscript. All authors have read and agreed to the published version of the manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e: None.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003e．Zochling J, Brandt J, Braun J. The current concept of spondyloarthritis with special emphasis on undifferentiated spondyloarthritis. Rheumatology (Oxford) 2005;44:1483.\u003c/li\u003e\n\u003cli\u003eRaychaudhuri SP, Deodhar A. The classification and diagnostic criteria of ankylosing spondylitis. J Autoimmun. 2014;48-49:128-33. Review.\u003c/li\u003e\n\u003cli\u003eCarron P, De Craemer AS, Van den Bosch F. Peripheral spondyloarthritis: a neglected entity-state of the art. RMD Open. 2020;6:e001136.\u003c/li\u003e\n\u003cli\u003eL\u0026oacute;pez-Medina C, Molt\u0026oacute; A, Dougados M. Peripheral Manifestations in Spondyloarthritis and their Effect: An Ancillary Analysis of the ASAS-COMOSPA Study. J Rheumatol. 2020;47:211.\u003c/li\u003e\n\u003cli\u003eHamard A, Burns R, Miquel A, Sverzut JM, Chicheportiche V, Wybier M, et al. Dactylitis: A pictorial review of key symptoms. Diagn Interv Imaging. 2020;101:193-207. Review.\u003c/li\u003e\n\u003cli\u003eKarreman MC, Luime JJ, Hazes JMW, Weel AEAM. The Prevalence and Incidence of Axial and Peripheral Spondyloarthritis in Inflammatory Bowel Disease: A Systematic Review and Meta-analysis. J Crohns Colitis. 2017;11:631-642. Review.\u003c/li\u003e\n\u003cli\u003eVan Praet L, Jacques P, Van den Bosch F, Elewaut D. The transition of acute to chronic bowel inflammation in spondyloarthritis. Nat Rev Rheumatol. 2012;8:288-95. Review.\u003c/li\u003e\n\u003cli\u003eMease PJ, Liu M, Rebello S, Hua W, McLean RR, Yi E, et al. Characterization of Patients With Axial Spondyloarthritis by Enthesitis Presence: Data from the Corrona Psoriatic Arthritis/Spondyloarthritis Registry. ACR Open Rheumatol. 2020;2:449-456.\u003c/li\u003e\n\u003cli\u003eRudwaleit M, van der Heijde D, Landew\u0026eacute; R, Listing J, Akkoc N, Brandt J, et al. The development of Assessment of SpondyloArthritis international Society classification criteria for axial spondyloarthritis (part II): validation and final selection. Ann Rheum Dis. 2009;68:777-83.\u003c/li\u003e\n\u003cli\u003eRudwaleit M, van der Heijde D, Landew\u0026eacute; R, Akkoc N, Brandt J, Chou CT, et al. The Assessment of SpondyloArthritis International Society classification criteria for peripheral spondyloarthritis and for spondyloarthritis in general. Ann Rheum Dis. 2011;70:25-31.\u003c/li\u003e\n\u003cli\u003eTaylor W, Gladman D, Helliwell P, Marchesoni A, Mease P, Mielants H; CASPAR Study Group. Classification criteria for psoriatic arthritis: development of new criteria from a large international study. Arthritis Rheum. 2006;54:2665-73.\u003c/li\u003e\n\u003cli\u003eInman RD. Classification criteria for reactive arthritis. J Rheumatol. 1999;26:1219-21.\u003c/li\u003e\n\u003cli\u003eWright GC, Kaine J, Deodhar A. Understanding differences between men and women with axial spondyloarthritis. Semin Arthritis Rheum. 2020;50:687-694.\u003c/li\u003e\n\u003cli\u003eTournadre A, Pereira B, Lhoste A, Dubost JJ, Ristori JM, Claudepierre P, et al. Differences between women and men with recent-onset axial spondyloarthritis: results from a prospective multicenter French cohort. Arthritis Care Res (Hoboken). 2013;65:1482-9.\u003c/li\u003e\n\u003cli\u003eJovan\u0026iacute; V, Blasco-Blasco M, Ruiz-Cantero MT, Pascual E. Understanding How the Diagnostic Delay of Spondyloarthritis Differs Between Women and Men: A Systematic Review and Metaanalysis. J Rheumatol. 2017;44:174-183. Review.\u003c/li\u003e\n\u003cli\u003eLubrano E, Perrotta FM, Manara M, D\u0026apos;Angelo S, Addimanda O, Ramonda R, et al. The Sex Influence on Response to Tumor Necrosis Factor-\u0026alpha; Inhibitors and Remission in Axial Spondyloarthritis. J Rheumatol. 2018;45:195-201.\u003c/li\u003e\n\u003cli\u003eHellamand P, van de Sande MGH, Nurmohamed MT, van Vollenhoven RF, Hollick RJ, Rotariu O, et al. Sex differences in patient-reported outcomes and the association with clinical factors in axial spondyloarthritis patients treated with tumour necrosis factor inhibitors. Rheumatology (Oxford). 2024;keae370. Online ahead of print.\u003c/li\u003e\n\u003cli\u003eEder L, Tony HP, Odhav S, Agirregoikoa EG, Korkosz M, Schwartzman S, et al. Responses to Ixekizumab in Male and Female Patients with Psoriatic Arthritis: Results from Two Randomized, Phase 3 Clinical Trials. Rheumatol Ther. 2022;9:919-933.\u003c/li\u003e\n\u003cli\u003eTada K, Dobashi H, Taniguchi Y, Shuto T, Hagimori K, Hayashi E, et al. A multicentre study of clinical features and HLA typing in Japanese patients with ankylosing spondylitis. Mod Rheumatol. 2023;33:392-397.\u003c/li\u003e\n\u003cli\u003eBraun J, Blanco R, Marzo-Ortega H, Gensler LS, van den Bosch F, Hall S, et al. Secukinumab in non-radiographic axial spondyloarthritis: subgroup analysis based on key baseline characteristics from a randomized phase III study, PREVENT. Arthritis Res Ther. 2021;23:231.\u003c/li\u003e\n\u003cli\u003eAletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, et al. 2010 Rheumatoid arthritis classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Arthritis Rheum. 2010;62:2569-81.\u003c/li\u003e\n\u003cli\u003eMaksymowych WP, Mallon C, Morrow S, Shojania K, Olszynski WP, Wong RL, et al. Development and validation of the Spondyloarthritis Research Consortium of Canada (SPARCC) Enthesitis Index. Ann Rheum Dis. 2009;68:948\u0026ndash;953. \u003c/li\u003e\n\u003cli\u003ePoggenborg RP, Eshed I, \u0026Oslash;stergaard M, S\u0026oslash;rensen IJ, M\u0026oslash;ller JM, Madsen OR, et al. Enthesitis in patients with psoriatic arthritis, axial spondyloarthritis and healthy subjects assessed by \u0026apos;head-to-toe\u0026apos; whole-body MRI and clinical examination. Ann Rheum Dis. 2015;74:823-9.\u003c/li\u003e\n\u003cli\u003eGuo Z, Li B, Zhang Y, Kong C, Liu Y, Qu J, et al. Peripheral enthesitis assessed by whole-body MRI in axial spondyloarthritis: Distribution and diagnostic value. Front Immunol. 2022;13:976800.\u003c/li\u003e\n\u003cli\u003eHuang WN, Tso TK, Kuo YC, Tsay GJ. Distinct impacts of syndesmophyte formation on male and female patients with ankylosing spondylitis. Int J Rheum Dis. 2012;15:163-8.\u003c/li\u003e\n\u003cli\u003eJarrot PA, Arcani R, Darmon O, Roudier J, Cauchois R, Mazodier K, et al. Axial Articular Manifestations in Primary Sj\u0026ouml;gren Syndrome: Association With Spondyloarthritis. J Rheumatol. 2021;48:1037-1046.\u003c/li\u003e\n\u003cli\u003eEren R, Can M, Alibaz-\u0026Ouml;ner F, Yilmaz-Oner S, Yilmazer B, Cefle A, et al. Prevalence of inflammatory back pain and radiologic sacroiliitis is increased in patients with primary Sj\u0026ouml;gren\u0026apos;s syndrome. Pan Afr Med J. 2018;30:98.\u003c/li\u003e\n\u003cli\u003eScotto di Fazano C, Grilo RM, Vergne P, Coyral D, Inaoui R, Bonnet C, et al. Is the relationship between spondyloarthropathy and Sj\u0026ouml;gren\u0026apos;s syndrome in women coincidental? A study of 13 cases. Joint Bone Spine. 2002;69:383-7.\u003c/li\u003e\n\u003cli\u003eYukawa N, Fujii T, Kondo-Ishikawa S, Yoshifuji H, Kawabata D, Nojima T, et al. Correlation of antinuclear antibody and anti-double-stranded DNA antibody with clinical response to infliximab in patients with rheumatoid arthritis: a retrospective clinical study. Arthritis Res Ther. 2011;13: R213.\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table","content":"\u003cp\u003eTable 1 is available in the Supplementary Files section\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"Hiroshima University Hospital","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Undifferentiated peripheral spondyloarthritis, Female, Male, Enthesitis, Anti-nuclear antibody","lastPublishedDoi":"10.21203/rs.3.rs-4921637/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4921637/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003eBackground\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe clinical features of patients with spondyloarthritis (SpA) differ between women and men. Peripheral lesions of SpA are more common in women than in men. Compared with reports on psoriatic arthritis (PsA), while reports on patients meeting the criteria for peripheral SpA or patients with undifferentiated peripheral SpA (upSpA) are scarce. This study aimed to elucidate the detailed manifestations of upSpA and the sex differences in situations of low human leukocyte antigen B27 positivity.\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThis multi-center observational study was conducted between April 2020 and June 2024. Among 38 patients with SpA, participants with concomitant inflammatory bowel diseases or meeting with either axial SpA, PsA or reactive arthritis (ReA) criteria were excluded. We collected physical findings and laboratory data on 29 cases of upSpA (19 women and 10 men; mean age [standard deviation]: 41.6 years [16.3] vs. 60.2 years [11.2]). We primarily analyzed the data to examine the relationship between sex and clinical findings.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults\u003c/b\u003e\u003c/p\u003e \u003cp\u003eThe rate of tenderness of the epicondyles of humerus were 79.0% in women and 40.0% in men (p\u0026thinsp;=\u0026thinsp;0.047). The prevalence rate of tenderness of the Achilles tendon was 52.6% in women and 10.0% in men (p\u0026thinsp;=\u0026thinsp;0.029). These areas in the women had a higher prevalence rate of enthesitis than those in men. Serum C-reactive protein (CRP) positivity in women (21.1%) were lower than in men (80.0%) (p\u0026thinsp;=\u0026thinsp;0.004). The positive rate of anti-nuclear antibody, which was defined at a dilution of \u0026ge;\u0026thinsp;1:160, was higher in women (47.4%) than in men (0%) (p\u0026thinsp;=\u0026thinsp;0.009).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion\u003c/b\u003e\u003c/p\u003e \u003cp\u003eWomen with upSpA frequently experience enthesitis of the epicondyles of humerus and the Achilles tendon, as well as a lower serum CRP positivity and a higher incidence of positive anti-nuclear antibody, compared to men, in Japan.\u003c/p\u003e","manuscriptTitle":"Anti-nuclear antibody and enthesitis were frequently detected in female patients with undifferentiated peripheral spondyloarthritis in Japan","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-08-19 15:17:26","doi":"10.21203/rs.3.rs-4921637/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"63646fbc-e3bc-4340-a9bc-88caee2eaaf1","owner":[],"postedDate":"August 19th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-02-05T14:55:28+00:00","versionOfRecord":{"articleIdentity":"rs-4921637","link":"https://doi.org/10.1093/mr/roaf010","journal":{"identity":"modern-rheumatology","isVorOnly":true,"title":"Modern Rheumatology"},"publishedOn":"2025-02-04 00:00:00","publishedOnDateReadable":"February 4th, 2025"},"versionCreatedAt":"2024-08-19 15:17:26","video":"","vorDoi":"10.1093/mr/roaf010","vorDoiUrl":"https://doi.org/10.1093/mr/roaf010","workflowStages":[]},"version":"v1","identity":"rs-4921637","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4921637","identity":"rs-4921637","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}